The ZRT Laboratory Blog

The Interplay of Metabolic Health, Hormones, and NAFLD

Mon, 06 Jan 2025 10:00:35 -0800

Non-Alcoholic Fatty Liver Disease (NAFLD) has emerged as a leading cause of chronic liver disease, affecting a significant portion of the global population. Defined as the accumulation of excess fat in the liver not related to alcohol consumption, NAFLD is closely linked to metabolic syndrome - a cluster of conditions that increase the risk of heart disease, stroke, and diabetes. Any condition that contributes to metabolic syndrome can potentially contribute to the development of NAFLD but underlying endocrine disorders may also promote the development and progression of this common liver disorder. Additionally, exposure to environmental and chemical toxins may also promote the development of NAFLD. In the following article, we will take a closer look at some of the contributing factors and specifically examine endocrine-related and secondary causes of NAFLD.

Prevalence and Disease Progression

In the United States, one-third of the population has NAFLD and 2-5% have progressed to non-alcoholic steatohepatitis (NASH). NASH involves inflammatory processes in the presence of fatty infiltration (NAFLD) and can ultimately progress to liver fibrosis, cirrhosis, and liver cancer. In 20-25% of NAFLD cases, steatosis (fatty infiltration) will evolve to NASH and 20% of these patients will develop cirrhosis. The progression to NASH often occurs in the presence of diabetes, insulin resistance, and other preexisting conditions associated with metabolic issues (1).

Diagnosis of NAFLD

The definitive diagnosis of NAFLD is via liver biopsy showing lipid content in at least 5% of hepatocytes (liver cells). Only biopsy can assess inflammation and fibrosis, but diagnosis can be inaccurate due to sampling variability (1).

Less invasive diagnostic methods do exist using various types of imaging techniques that can measure liver fat content. Proton magnetic resonance spectroscopy is the most accurate, but ultrasound is the most common diagnostic method. The drawback is that ultrasound can only detect liver fat content when it exceeds 35% (1).

Elevation in liver enzymes can be a clue to liver fat accumulation, but these measurements are neither specific nor sensitive. Up to 70% of those with NAFLD will have normal liver enzymes. Regardless, a diagnosis of NAFLD should be considered if there are elevated liver enzymes and one metabolic risk factor such as insulin resistance, high cholesterol, hypertension, atherosclerosis, and obesity (1).

Development and Progression of NAFLD

The progression of liver injury in NAFLD is thought to result from the “two hit” hypothesis involving insulin resistance and adipokine production. The “first hit” involves the accumulation of triglycerides (TG) and free fatty acids (FFA) in hepatocytes secondary to insulin resistance. Once fatty infiltration is established, progression to steatohepatitis involves the “second hit” which consists of inflammation, mitochondrial dysfunction, and enhanced oxidative stress resulting from reactive oxygen species (ROS), lipid oxidation, and ongoing production of adipokines (1).

Adipokines are cytokines (cell-signaling molecules) released by adipose tissue that mediate inflammation and contribute to metabolic issues. The combination of insulin resistance and adipokine production can result in oxidative stress and cell death (apoptosis). Ultimately, this can lead to hepatocyte damage and fibrosis. Other factors that can impact liver injury involve gut bacteria that further promote inflammation (1).

Fig 1. Schematic summary of NAFLD pathophysiology according to the "two-hit hypothesis".

Image credit: Marino, Laura, and François R. Jornayvaz. “Endocrine Causes of Nonalcoholic Fatty Liver Disease.” World Journal of Gastroenterology : WJG, vol. 21, no. 39, Oct. 2015, pp. 11053–76. PubMed Central, https://doi.org/10.3748/wjg.v21.i39.11053.

Main Causes of NAFLD

The main physiological mechanism associated with the development of NAFLD is insulin resistance which often leads to obesity, metabolic syndrome, type II diabetes, and dyslipidemia. An unhealthy lifestyle is considered a modifiable risk factor for NAFLD. The key factors that contribute to metabolic dysfunction that may promote the development of NAFLD are common to many diseases.

High-carbohydrate/high-sugar diet - Excessive consumption of simple carbohydrates and high-sugar foods often lead to insulin resistance and the accumulation of visceral adipose tissue (VAT) that becomes dysfunctional and produces an excess of pro-inflammatory cytokines leading to excessive systemic inflammation thus worsening insulin resistance (2). According to research out of UC, San Diego, fructose in particular, can drive fat accumulation in the liver and increase gut permeability leading to an increase in circulating endotoxins. The inflammatory process induced by endotoxins enhances fatty deposition in the liver and progressive inflammation (3).

Sedentary lifestyle – Reduced physical activity contributes to weight gain and metabolic risk whereas, regular exercise increases insulin sensitivity, helps to manage weight, and reduces the risk for conditions associated with metabolic syndrome. Physical activity and regular exercise are key regulators of metabolism and have a measurable impact on several drivers of metabolic disease. Ultimately, along with dietary changes, exercise can help manage weight and moderate stress (4).

Insufficient sleep – Reduced quality and quantity of sleep can disrupt hormonal balance, leading to increased appetite and weight gain, further exacerbating metabolic issues. Researchers out of China analyzed self-reported sleep behaviors from 5,011 Chinese adults with fatty liver disease and found late bedtime, snoring, and daytime napping for over 30 minutes were significantly associated with an increased risk of fatty liver disease. Most participants qualified as having measurable markers associated with metabolic issues. The study revealed that even a moderate improvement in sleep quality led to a 29% reduction in fatty liver disease risk (5).

Ongoing stress – Though stress is a part of life, ongoing stress with no end in sight, can lead to chronically elevated cortisol and catecholamines that may promote weight gain and the accumulation of VAT. The association of perceived stress with cardiovascular and metabolic abnormalities has been well-documented. Stress can be a component of nearly every disease process because of fundamental endocrine, metabolic, and cardiovascular dysregulation that occurs in the presence of ongoing stress (6).

Endocrine-Related Disorders and NAFLD

NAFLD and metabolic syndrome are the most common causes of NASH, but NAFLD itself may be linked with other endocrine disorders. (1). These common endocrine disorders can significantly impact metabolic health, often contributing to the development of metabolic syndrome. Hormonal imbalances can alter insulin sensitivity, fat metabolism, and have effects on appetite regulation.

Hypothyroidism – Thyroid hormones are integral to hepatic lipid metabolism. Thyroid hormones promote lipolysis within the liver thus modifying hepatic fat accumulation. Hypothyroidism has been associated with disorders of glucose and insulin metabolism and high cholesterol, which are both associated with metabolic syndrome. Though there is no cause/effect relationship between hypothyroidism and NAFLD, hypothyroidism may be an independent risk factor for NAFLD as some studies report a prevalence of hypothyroidism of 15.2–36.3% among patients with NAFLD/NASH (1).

Subclinical and overt hypothyroidism may cause secondary NAFLD but may also worsen primary NAFLD. Interestingly, thyroid hormone receptor agonists are currently being evaluated for the treatment of NASH and have proven effective in reducing hepatic fat accumulation after 12 and 36 weeks of treatment in a phase II trial (7).

PCOS – Insulin resistance occurs in approximately 50% of women with PCOS. The prevalence of NAFLD in PCOS women occurs somewhere between 15% and 55%. In a study that compared the prevalence of NAFLD amongst lean and obese women with PCOS, 39% of the lean women had NAFLD. In addition to the known effects of insulin resistance, hyperandrogenism likely plays a key role in the development of NAFLD as it is associated with down-regulation of the LDL-receptor. This prolongs the half-life of VLDL and LDL, inducing the accumulation of fat in the liver (8).

In premenopausal women, hyperandrogenism is associated with increased visceral fat and insulin resistance, and an increase in free testosterone shows a greater association with NAFLD. Elevated sex hormone binding globulin (SHBG) can also be associated with an increased risk of developing NAFLD and might be considered a good surrogate marker for the severity of NAFLD if metabolic issues are not present (8). Additionally, women with hyperandrogenism tend to have higher levels of liver enzymes, particularly ALT (1).

Growth Hormone Deficiency – Growth hormone (GH) has several important functions in adults, including maintenance of lean body and bone mass, promoting lipolysis thus limiting visceral adiposity, and regulating carbohydrate metabolism, cardiovascular function, aerobic exercise capacity, and cognitive function. GH deficiency can be the result of hypopituitarism that may be caused by tumors, brain injuries, infections, genetics, or medications. GH deficiency is also associated with normal aging where production peaks in puberty and declines by 15% every decade starting in the third decade of life. GH deficiency may be an underlying factor in secondary NAFLD. In a Japanese study of patients with GH deficiency, 77% had NAFLD as compared to age-, sex-, and BMI-matched controls (10).

Age-Related Hormone Loss – Aging and sex hormone loss are also risk factors for the development of NAFLD as there is a bidirectional relationship between metabolic issues and loss of sex hormones as both men and women age. In both males and females, insulin resistance and metabolic syndrome are associated with an increase in visceral adipose tissue (VAT) that becomes dysfunctional and produces an excess of adipokines and pro-inflammatory cytokines leading to excessive systemic inflammation. Adipokines are cytokines produced by adipose tissue and are involved in adipose homeostasis and lipid metabolism. Leptin, ghrelin, and adiponectin are adipokines that decrease insulin resistance, but their output becomes dysfunctional in the presence of excess adipose tissue and metabolic disorders (2).

Men tend to have a higher rate of NAFLD than women, but this gender association becomes less pronounced as women enter menopause. Declining androgens in males and declining estrogen in women are associated with features of metabolic syndrome in both sexes as they age. Sex hormones have effects on energy homeostasis with testosterone directing adipose tissue physiology via androgen receptors by preventing adipose accumulation and maintaining lean body mass in men. Studies have shown an association between low testosterone and increased sonographic evidence of hepatic fat accumulation in men (2).

Hypercortisolism – As mentioned above when discussing stress as a contributing factor to the development of NAFLD, high levels of cortisol can impair insulin sensitivity leading to insulin resistance. The extreme effects of hypercortisolism can be demonstrated in Cushing’s syndrome which is a disease of high cortisol caused by over-exposure to corticosteroids or pituitary or adrenal tumors that ultimately increase output of cortisol from the adrenal glands. Cushing syndrome is associated with the development of insulin resistance, type II diabetes, dyslipidemia, hypertension, visceral obesity, and NAFLD (1). Hypercortisolism in response to ongoing stress combined with other contributing factors that promote metabolic issues may result in a similar presentation.

Fig. 2: Pathophysiological mechanisms linking polycystic ovary syndrome and NAFLD.

HRT and NAFLD

Some studies suggest that estrogen may play a regulatory role in the development of NAFLD. Estrogen exerts anti-steatotic effects thus preventing fat accumulation in hepatocytes. Estrogen also has an anti-inflammatory effect in the Kupffer cells which function as macrophages and are key to healthy liver function (11).

Hormone replacement therapy (HRT) can reduce the development of NAFLD, but route of delivery is determinate of its benefits. In 2024, Kim et al conducted a 12-month retrospective cohort study evaluating the benefits of transdermal vs. oral estrogen in reducing the development or progression of NAFLD. The study included 368 menopausal women of similar health status. Seventy-five women received transdermal estradiol and 293 received oral estrogen as either estradiol or conjugated equine estrogens. Women with a uterus received either oral micronized progesterone or a synthetic progestin. All were evaluated for NAFLD via ultrasonography, liver function tests, fasting glucose and insulin, HgA1c, and a lipid panel. Insulin resistance was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR) calculation (11).

Prior to treatment, 24% of the women in the transdermal group were positive for NAFLD. After 12 months on transdermal estradiol, only 17.3% were positive for NAFLD. In the group of women on oral estrogen, 25.3% were positive for NAFLD prior to hormone treatment, but this increased to 29.4% after 12 months of oral estrogen (11).

Secondary Causes/Contributors to NAFLD and NASH

Not all subjects with NAFLD experience obesity, insulin resistance, diabetes, and endocrine disorders, so there are other factors that can contribute to this pathologic spectrum of liver diseases. As part of the “two-hit” hypothesis of the development of NAFLD and NASH, there is the potential contribution of occupational and environmental chemicals (12).

Toxicant associated steatohepatitis (TASH) describes a liver condition in which fatty infiltration occurs associated with excessive exposure to various chemicals including volatile organic chemicals (VOCs), persistent organic pollutants (POPs), metals, particulate matter, and pesticides. Many of these chemicals can be classified as endocrine disruption chemicals (EDCs), metabolism disrupting chemicals (MDCs), and signaling disrupting chemicals (SDCs). EDCs interfere with aspects of hormone function and MDCs promote metabolic changes that can result in obesity and type II diabetes. Many of these chemicals are known to be hepatotoxic and are cleared from the body through liver detoxification pathways (12).

Gut microbiota and NAFLD

Gut microbiota plays an important role in human metabolism and the metabolites of gut flora have effects on organ systems and tissues throughout the body. The liver is exposed to a high concentration of bacterial metabolites as it is closely linked to the intestines through the gut-liver axis and is the first organ to receive blood from the intestines via the portal system. Pathogenic bacteria along with a leaky gut can trigger a pathological reaction in the liver as well as contributing to metabolic disorders (8).

Enhanced intestinal permeability coupled with an abundance of LPS-producing gram-negative bacteria can lead to liver inflammation by triggering toll-like receptor (TLR) signaling pathways. TLRs play a central role initiating an immune response in the presence of microbial antigens. Increased levels of LPS and the resulting cytokines can promote the proliferation and deposition of intrahepatic fibrous connective tissue that results in cirrhosis. The presence of LPS in the liver also results in intrahepatic resistance to blood flow which can lead to portal hypertension that can further damage the liver (9).

Treatment of NAFLD

NAFLD is one of the top reasons for liver transplants. It’s hard to believe that poor diet and lifestyle can potentially lead to the need to replace a major organ. Even though the liver is a workhorse with the capacity to regenerate itself, it can’t hold up to the ongoing effects of metabolic disease, fatty infiltration, and inflammation. On a positive note, diet and lifestyle modifications have great potential in the primary prevention of NAFLD. Adopting a healthy lifestyle that includes maintaining a normal body mass index (BMI), eating in line with a Mediterranean diet, cutting back on sedentary behavior, and engaging in daily physical activity can lower the risk of NAFLD. In the larger picture, reducing exposure to toxins and keeping the endocrine system balanced can also have positive and lasting effects.

Randomized controlled trials demonstrate that dietary and exercise interventions for NAFLD reduce BMI, steatosis, and inflammation as determined by MRI and biopsy. The Mediterranean diet seems to be the most effective long-term approach to dietary changes with a focus on healthy fats, lots of veggies, and reduced simple carbohydrates and sugars. Consuming a variety of high-fiber veggies rich in antioxidants can not only support health in general but is also good for a healthy microbiome, which in turn, also supports a healthy liver. Most dietary and lifestyle effects far-surpass the efficacy of drugs currently being evaluated in phase III clinical trials (4).

Foods rich in choline such as fatty fish rich in omega-3s, eggs, and cruciferous vegetables can be supportive of liver function and bile production. Choline deficiency promotes the rapid progression of NAFLD to NASH. Diets deficient in choline reduce the production of phosphatidylcholine which is essential for the creation of very low-density lipoproteins (VLDLs) and results in liver fat accumulation (8). Choline is also necessary for the formation of bile and movement of fats and toxins out of the liver. Several genetic polymorphisms associated with choline metabolism have been linked to liver damage. Aside from dietary sources, choline can be supplemented directly by way of phosphatidylcholine or citicoline.

Additional nutritional supplements that are supportive of liver health include vitamin E, vitamin D, CoQ10, EGCG from green tea, prebiotics and probiotics, milk thistle, and curcumin (4, 13). Though nutritional supplements may have benefits, they are best when combined with a healthy diet and regular exercise.

The cure is in the cause

A predisposition to developing NAFLD may occur in the presence of genetic mutations that affect liver function, but the main driver of its development is diet and lifestyle in which underlying endocrine disorders, toxic exposures, and secondary causes may be contributing factors. Long-term changes in dietary and lifestyle habits can be challenging because they require education, determination, and discipline, but these changes are possible and beneficial to good health on many levels.

Definition of terms

Steatosis: fat accumulation in the liver.

Steatohepatitis: fat accumulation + inflammation.

Fibrosis: development of scar tissue in the liver to any degree.

Cirrhosis: extreme degree of scar tissue in the liver that is severe and permanent and significantly affects liver function.

VAT: Visceral Adipose Tissue

References:

1. Marino, Laura, and François R. Jornayvaz. “Endocrine Causes of Nonalcoholic Fatty Liver Disease.” World Journal of Gastroenterology : WJG, vol. 21, no. 39, Oct. 2015, pp. 11053–76. PubMed Central, https://doi.org/10.3748/wjg.v21.i39.11053.

2. Vincenzo, Angelo Di, et al. “Sex Hormones Abnormalities in Non-Alcoholic Fatty Liver Disease: Pathophysiological and Clinical Implications.” Exploration of Medicine, vol. 2, no. 4, Aug. 2021, pp. 311–23. www.explorationpub.com, https://doi.org/10.37349/emed.2021.00049.

3. Todoric J, Di Caro G, Reibe S, Henstridge DC, Green CR, Vrbanac A, Ceteci F, Conche C, McNulty R, Shalapour S, Taniguchi K, Meikle PJ, Watrous JD, Moranchel R, Najhawan M, Jain M, Liu X, Kisseleva T, Diaz-Meco MT, Moscat J, Knight R, Greten FR, Lau LF, Metallo CM, Febbraio MA, Karin M.Todoric J, et al. Nat Metab. 2020 Aug 24. doi: 10.1038/s42255-020-0261-2, https://www.nih.gov/news-events/nih-research-matters/how-high-fructose-intake-may-trigger-fatty-liver-disease

4. Hallsworth, Kate, and Leon A. Adams. “Lifestyle Modification in NAFLD/NASH: Facts and Figures.” JHEP Reports, vol. 1, no. 6, Dec. 2019, pp. 468–79. ScienceDirect, https://doi.org/10.1016/j.jhepr.2019.10.008.

5. Jialu Yang, Shiyun Luo, Rui Li, Jingmeng Ju, Zhuoyu Zhang, Jichuan Shen, Minying Sun, Jiahua Fan, Min Xia, Wei Zhu, Yan Liu, Sleep Factors in Relation to Metabolic Dysfunction-Associated Fatty Liver Disease in Middle-Aged and Elderly Chinese, The Journal of Clinical Endocrinology & Metabolism, Volume 107, Issue 10, October 2022, Pages 2874–2882, https://doi.org/10.1210/clinem/dgac428.

6. Kang, Danbee, et al. “Perceived Stress and Non-Alcoholic Fatty Liver Disease in Apparently Healthy Men and Women.” Scientific Reports, vol. 10, no. 1, Jan. 2020, p. 38. www.nature.com, https://doi.org/10.1038/s41598-019-57036-z.

7. Liebe, Roman, et al. “Diagnosis and Management of Secondary Causes of Steatohepatitis.” Journal of Hepatology, vol. 74, no. 6, June 2021, pp. 1455–71. ScienceDirect, https://doi.org/10.1016/j.jhep.2021.01.045.

8. Carrieri, Livianna, et al. “Premenopausal Syndrome and NAFLD: A New Approach Based on Gender Medicine.” Biomedicines, vol. 10, no. 5, May 2022, p. 1184. PubMed Central, https://doi.org/10.3390/biomedicines10051184.

9. Wang, Li, et al. “The Role of Gut Microbiota in Some Liver Diseases: From an Immunological Perspective.” Frontiers in Immunology, vol. 13, July 2022, p. 923599. PubMed Central, https://doi.org/10.3389/fimmu.2022.923599.

10. Garcia, Jose M., et al. “Growth Hormone in Aging.” Endotext, edited by Kenneth R. Feingold et al., MDText.com, Inc., 2000. PubMed, http://www.ncbi.nlm.nih.gov/books/NBK279163/.

11. Kim, Sung Eun, et al. “Different Effects of Menopausal Hormone Therapy on Non-Alcoholic Fatty Liver Disease Based on the Route of Estrogen Administration.” Scientific Reports, vol. 13, no. 1, Sept. 2023, p. 15461. www.nature.com, https://doi.org/10.1038/s41598-023-42788-6.

12. Wahlang, Banrida, et al. “Mechanisms of Environmental Contributions to Fatty Liver Disease.” Current Environmental Health Reports, vol. 6, no. 3, Sept. 2019, p. 80. pmc.ncbi.nlm.nih.gov, https://doi.org/10.1007/s40572-019-00232-w.

13. Baradeiya, Ahmed M., et al. “Can Nutritional Supplements Benefit Patients With Nonalcoholic Steatohepatitis and Nonalcoholic Fatty Liver Disease?” Cureus, vol. 15, no. 6, June 2023, p. e40849. pmc.ncbi.nlm.nih.gov, https://doi.org/10.7759/cureus.40849.

Hormone Therapy for Women Beyond the Age of 65

Thu, 17 Oct 2024 15:52:46 -0700

I recently had a conversation with a patient who was entering menopause and fearful of starting hormone replacement therapy (HRT) because she witnessed the decline in her mother’s health after she stopped HRT at age 65. She assumed that the decline in her mother’s health was due to the use of HRT rather than the discontinuation of it. There has been much confusion and contradiction around the use of hormone therapy for menopause since 2002 when the Women’s Health Initiative (WHI) released the results of their prematurely halted hormone therapy clinical trial revealing an increase in disease parameters for women on HRT. The far-reaching effects of this trial still exist today even though a deeper look into the revelations and shortcomings of the WHI study has been published numerous times and in various publications.

After delivering a near-fatal blow to the use of HRT for menopausal women, a reshuffling of the WHI data began to tell a different story. Distinct differences in outcomes were revealed when the participants of the study were stratified by age and time since menopause. There were also differences in outcomes when comparing the use of conjugated equine estrogens (CEE) + medroxyprogesterone acetate (MPA) against CEE alone (1).

Now, 22 years later, a recent study published by The Journal of the Menopause Society, gathered data from 10 million senior Medicare women from 2007-2020 on the use of various forms of hormone replacement therapy (HRT) beyond the age of 65. This data was evaluated for the type, route, and dosage of HRT and its effects on all-cause mortality, breast, lung, endometrial, colorectal, and ovarian cancers, ischemic heart disease, heart failure, venous thromboembolism, stroke, atrial fibrillation, acute myocardial infarction, and dementia. In general, the data revealed that the use of HRT beyond the age of 65 was associated with a reduction in the above-listed diseases, but dosage, route of delivery, and the hormone formulation were key to better outcomes (2).

The science around hormone replacement therapy is still evolving and over two decades after the WHI, we have seen a major shift in the recommendations for HRT. We have gone from the fear of stroke, heart disease, and breast cancer to considering the use of HRT beyond the age of 65. So, what have we learned in the past 22 years? Before answering this question, let’s take a closer look at some of the details of the WHI hormone trial and how a reassessment of the data revealed specific details that were overlooked back in 2002.

The Women’s Health Initiative Revisited

The Women’s Health Initiative (WHI) is funded by the National Heart, Lung, and Blood Institute, a bureau within the National Institute of Health. The original study began in 1992 and consisted of three clinical trials, an observational study, and a community prevention study. Data collection for the original study was completed in 2005. Extension studies consisting of annual collection of health updates and outcomes related to heart disease and aging will be ongoing until 2026 (2).

The WHI hormone therapy trial was one of the randomized clinical trials and consisted of 27,347 postmenopausal women aged 50-79. The primary outcome of interest was coronary heart disease (CHD) because prior to the WHI, physicians prescribing HRT had believed that the use of hormone therapy could prevent CHD and other chronic diseases in post-menopausal women of all ages. Other safety and efficacy outcomes of interest were osteoporosis and breast cancer. Other measurable endpoints included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death (1).

In the WHI hormone therapy clinical trial, 16,608 women with an intact uterus were randomized to a daily combination of oral conjugated equine estrogen (CEE, Premarin) at a dosage of 0.625 mg and oral medroxyprogesterone acetate (MPA, Provera) at a dosage of 2.5 mg or placebo. The trial of estrogen-only therapy was randomized to the 10,739 women without a uterus who received 0.625 mg of oral CEE daily or placebo. The average age of the participants was 63 years with 32.3% of the participants in the 50-59-year age range, 45.2% in the 60-69-year age range, and 22.5% in the 70-79- year age range (1).

The trial was planned for 9 years but was halted early due to an increase in disease parameters amongst the participants receiving HRT. The CEE+MPA branch of the trial was halted at 5.6 years due to an increased risk of invasive breast cancer. The CEE only branch of the trial was halted at 7.2 years due to an increased risk of stroke (1).

From that point onward, the study participants were followed observationally to evaluate the persistence of treatment effects. Most of the risks and benefits of hormone therapy dissipated within 5-7 years after discontinuation of treatment. In the CEE+MPA group, there was still a very slight increase for breast cancer but most of the cardiovascular risks waned. Positive effects included an overall reduction in risk for hip fracture and endometrial cancer. In the CEE only group, breast cancer risk continued to decline as did dementia and mortality (1).

The WHI has been a monumental undertaking that includes a large population base of postmenopausal women aged 50-79 spanning over 35 years. That’s a lot of data to work with and it will continue to provide the raw material for further analysis for years to come. However, despite the amount of data that was provided by the WHI hormone trial, it can only measure the effects of oral Premarin (CEE) and Provera (MPA) because that was the only hormone therapy given to the women in the trial. We cannot assume that these results will translate to other routes of delivery (e.g. topical, transdermal patch, vaginal, etc.), different dosages, and bioidentical hormones (e.g. estradiol and progesterone). What has been most clear upon re-evaluation of the WHI data is the timing hypothesis in which the initiation of HRT has greater benefits when started within the first ten years of menopause.

Age Stratification

In a 2020 article in The Journal of the North American Menopause Society titled “The Women’s Health Initiative Trials of Menopause Hormone Therapy: Lessons Learned,” Manson et al accessed data from a 2013 overview of 13 years of follow up with the participants, which included an age-stratified analysis. It was determined that age and time since menopause was an important differentiating factor that contributed to coronary outcomes. The women with better outcomes had started HRT closer to the onset of menopause. Starting HRT early may slow the development of atherosclerosis whereas later initiation (10 years beyond menopause) may promote inflammation and advance existing atherosclerotic plaques (1). We should also consider that age alone can be a risk factor for cardiovascular disease. In the WHI study, there was a 29-year spread between the youngest and the oldest participants which is nearly three decades of potential disease progression with or without HRT.

The Early versus Late Intervention Trial with Estradiol (ELITE Trial) was a 6-year randomized trial of 643 healthy postmenopausal women and reported that oral estradiol (1mg/day) with or without vaginal micronized progesterone gel (45 mg/day) significantly slowed the progression of carotid atherosclerosis in women within six years of menopause but not in women more than 10 years past menopause onset. However, the increased risk of stroke, transient ischemic attack, and systemic embolism still existed in the younger group and the risk gradually increased with age (3). As noted by Goldstajn et al when comparing the effects of oral versus transdermal estrogen, there is clear evidence that oral administration of estrogens increases the risk of venous thromboembolism (4).

Premarin (CEE) vs. Estradiol

CEE is estrogen from the urine of pregnant mares and, though it is natural, eight of the ten estrogens in Premarin are not bioidentical to human estrogen. Estradiol is bioidentical estrogen and is used in both pharmaceutical and compounded formulas. Estradiol is the form of estrogen that is produced in the greatest amount by the ovaries during the reproductive years. The composition of CEE differs significantly from the estrogens found in premenopausal women and the activity of these different estrogens will vary in terms of their downstream effects on thrombosis, inflammation, and cancer progression (5, 6, 7).

Provera (MPA) vs. Progesterone

Let’s start with a definition of terms because they are often used interchangeably in the literature when discussing any form of progestogen. Progestogen is the name for the broad category that includes both synthetic and bioidentical progesterone. Progestins are synthetic forms of progesterone. Progesterone is a reproductive hormone produced naturally in the body or it can be formulated as a bioidentical hormone for HRT.

MPA is a synthetic progestin that binds with high affinity to cellular progesterone receptors, but its structure and physiologic effects are somewhat different than bioidentical progesterone and even other synthetic progestins. MPA can have effects that are quite different than the effects of bioidentical progesterone in the brain, nervous system, cardiovascular system, and breast tissue (8).

Route of Hormone Delivery – Oral or Transdermal

Premarin is an oral form of estrogen with a first pass through the liver from the digestive tract before it is delivered to target tissues. This first pass through the liver increases clotting factors that may promote thromboembolic events. In the WHI hormone trial, the CEE only group did not show an increase in breast cancer but did show an increase in ischemic stroke due to blood clots. The older a woman was at the beginning of the trial, and the longer the age since menopause, the higher the risk for stroke (1).

A 2022 systemic literature review that included 51 studies, compared the health effects of oral versus transdermal administration routes of estrogen in postmenopausal women. This study did not make the distinction between “transdermal” and “percutaneous” administration of estrogen. Transdermal estrogen application is specific to patches that deliver a higher concentration of estrogen to the blood whereas percutaneous administration is specific to the gel or spray that was included in the review. The study included estrogen therapy alone, combined-cyclic, and combined continuous dosing (combined = estrogen + progestogen) (4).

The results of the review showed that oral administration compared to transdermal and percutaneous were similar regarding bone mineral density, glucose metabolism, improvement of lipid profile, breast cancer, endometrial disease, and cardiovascular risk. However, there was clear evidence that the risk of venous thromboembolism (VTE) was higher with the oral administration route. The higher the dosage of oral estrogen, the greater the risk for VTE and amongst the different combinations with progestins, oral estrogen with MPA seemed to correlate with the highest risk (4).

Transdermal and percutaneous estradiol is metabolized partly in the skin and requires lower dosing than oral estrogen. This results in lower levels of serum estrone similar to premenopausal levels. Transdermal and percutaneous administration have different pharmacodynamics as compared to oral administration providing differing safety profiles related to risk of VTE especially in those who have a prothrombotic mutation like Factor V Leiden (4).

Hormone Dosage

In the WHI, all women received the same dosage of hormones regardless of their age and time since menopause. We have learned over the years that a one-size-fits-all approach doesn’t work for every woman. The dose of Premarin (0.625 mg/day) that was used in the WHI study is considered a moderate dosage. For women who are ten or more years past menopause and have not used HRT in the past, a moderate dose of estrogen may be too much. Symptom evaluation and accurate testing can provide the feedback needed for both practitioner and patient. Methods of testing hormone levels when supplementing are also specific to the route of delivery to ensure against over or under supplementation.

Fig.1 A Guide to Steroid Hormone Testing in Different Body Fluids Following Different Routes of Hormone Administration.

As evidenced by the results of the 10 million Medicare women in the study referenced above, those who used HRT beyond the age of 65 years had the best outcomes with a low dosage. The benefits of HRT for bone density, cardiovascular health, and brain health are greatest within the first years of menopause and the benefits appear to extend beyond the age of 65 years. However, if HRT is not started within the first 10 years of menopause, higher dosages of hormones later in life cannot recapture what has already been lost (2).

So, what have we learned?

The age of the patient and time since menopause matters, the dosage of hormones matters, the route of delivery matters, and the type of hormone (CEE, synthetic, bioidentical) matters. All these parameters need to be taken into consideration when evaluating any literature on hormone replacement therapy. The study objective that reviewed the records of 10 million senior Medicare women assessed the use of menopausal hormone therapy beyond the age of 65 years and its health implications by types of estrogen/progestogens (both progestin and progesterone were evaluated), routes of delivery, and dosage. Overall, risk reduction appears to be greater with lower estrogen dosage, vaginal, transdermal or percutaneous rather oral preparations, and estradiol rather than conjugated equine estrogen (CEE) (2).

The results revealed that compared with women who never used HRT or discontinued use after age 65, the use of estrogen alone beyond age 65 was associated with significant risk reduction in mortality, breast cancer, lung cancer, colorectal cancer, congestive heart failure, venous thromboembolism, atrial fibrillation, acute myocardial infarction, and dementia. With the use of estrogen + progestin (norethindrone) there was a marginal risk reduction in endometrial and ovarian cancers, ischemic heart disease, congestive heart failure and venous thromboembolism. Estrogen+ (oral*) progesterone only exhibited a risk reduction in congestive heart failure (2).

A Personal Decision

In the end, a woman’s decision to use HRT is a personal health choice made between doctor and patient. Those who feel that the benefits outweigh the risks and need relief from hot flashes, night sweats, heart palpitations, insomnia, and mood issues may choose HRT. Now, with recent data showing benefits to long-term health, women may also choose to stay on HRT well into their senior years. We’ve come a long way since the 2002 results of the WHI hormone trial and the latest study by Baik et al has confirmed what many women and their doctors already knew – HRT, when appropriately prescribed, can add life to your years and years to your life.

*The route of delivery for the progesterone was not stated. This study was based on Medicare records, so it is likely that the progesterone prescribed is in the form of oral micronized progesterone (OMP) either as Prometrium or its generic equivalent.

References:

1.Manson, JoAnn E., et al. “The Women’s Health Initiative Hormone Therapy Trials: Update and Overview of Health Outcomes During the Intervention and Post-Stopping Phases.” JAMA : The Journal of the American Medical Association, vol. 310, no. 13, Oct. 2013, pp. 1353–68. PubMed Central, https://doi.org/10.1001/jama.2013.278040.

2.Baik, Seo H., et al. “Use of Menopausal Hormone Therapy beyond Age 65 Years and Its Effects on Women’s Health Outcomes by Types, Routes, and Doses.” Menopause (New York, N.Y.), vol. 31, no. 5, May 2024, pp. 363–71. PubMed, https://doi.org/10.1097/GME.0000000000002335. https://www.nhlbi.nih.gov/science/womens-health-initiative-whi.

3.Hodis, Howard N., et al. “Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol.” New England Journal of Medicine, vol. 374, no. 13, Mar. 2016, pp. 1221–31. DOI.org (Crossref), https://doi.org/10.1056/NEJMoa1505241.

4.Goldštajn, Marina Šprem, et al. “Effects of Transdermal versus Oral Hormone Replacement Therapy in Postmenopause: A Systematic Review.” Archives of Gynecology and Obstetrics, vol. 307, no. 6, 2023, pp. 1727–45. PubMed Central, https://pubmed.ncbi.nlm.nih.gov/35713694.

5.Bhavnani, Bhagu R., and Frank Z. Stanczyk. “Pharmacology of Conjugated Equine Estrogens: Efficacy, Safety and Mechanism of Action.” The Journal of Steroid Biochemistry and Molecular Biology, vol. 142, July 2014, pp. 16–29. PubMed, https://doi.org/10.1016/j.jsbmb.2013.10.011.

6.Diaz-Ruano, Ana Belén, et al. “Estradiol and Estrone Have Different Biological Functions to Induce NF-κB-Driven Inflammation, EMT and Stemness in ER+ Cancer Cells.” International Journal of Molecular Sciences, vol. 24, no. 2, Jan. 2023, p. 1221. PubMed Central, https://doi.org/10.3390/ijms24021221.

7.Knowlton, A. A., and A. R. Lee. “Estrogen and the Cardiovascular System.” Pharmacology & Therapeutics, vol. 135, no. 1, July 2012, pp. 54–70. PubMed Central. Accessed 5 Aug. 2024. https://doi.org/10.1016/j.pharmthera.2012.03.007.

8.Bethea, Cynthia L. “MPA: Medroxy-Progesterone Acetate Contributes to Much Poor Advice for Women.” Endocrinology, vol. 152, no. 2, Feb. 2011, pp. 343–45. PubMed Central, https://doi.org/10.1210/en.2010-1376.

Functional Hypothalamic Amenorrhea: A Tale of Stress, Starvation, and Excessive Exercise

Mon, 10 Jun 2024 12:59:02 -0700

A healthy and regular menstrual cycle is considered a vital sign of good health for premenopausal women. A normal menstrual cycle should occur every 25-35 days, (give or take a few days on either end), with the average cycle length falling at about 28 days. The length of the period can range from 3-7 days and the flow can be light, moderate, or heavy within a single menstrual cycle. A woman’s experience of her menstrual cycle may be unique to her, and what constitutes normal can have a broad range. Most importantly, each woman should be familiar enough with her own cycle to know if something has changed and when it is appropriate to seek help. One such situation would be the complete loss of a menstrual cycle for 3 months or more.

Amenorrhea is defined as a complete absence of menses in a woman of reproductive age. Primary amenorrhea is the failure to reach menarche (the first menstrual cycle) during normal development and is diagnosed when there is no history of menstruation by the age of 15 or 3 years after thelarche (breast bud development, which usually occurs around age 10). Secondary amenorrhea is defined as the absence of menses for ≥3 months in a woman with previously regular menstrual cycles or ≥6 months in any woman with at least one previous spontaneous menstruation (1). 

Primary amenorrhea can be classified into general groups: sexual development abnormalities, obstruction to menstrual flow, ovarian insufficiency, hypothalamic or pituitary disorders, and other endocrine gland disorders. Secondary amenorrhea may be caused by hormonal disturbances, physical damage to the endometrium preventing its growth, or a physical obstruction that prevents menstrual outflow (2).

Functional hypothalamic amenorrhea

Functional hypothalamic amenorrhea (FHA) is the most common cause of secondary amenorrhea in women of childbearing age and is related to low energy availability due to psychological stress, excessive exercise, disordered eating, or a combination of all three. FHA is responsible for approximately 30% of secondary amenorrhea and 3% of primary amenorrhea. The diagnosis of FHA is usually determined by exclusion after ruling out other etiologies of amenorrhea and is characterized by low serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (3,4).

FHA results in hypogonadotropic hypogonadism and is presumed to be a consequence of functional disruption of the pulsatile hypothalamic gonadotropin-releasing hormone (GnRH) secretion, leading to reduced levels of FSH and LH that regulate the ovarian cycle. Reduced levels of FSH and LH result in the absence of normal follicular development, anovulation, and low serum estradiol. Variable neuroendocrine patterns of LH secretion are also reported, including reduced frequency and/or amplitude of LH pulses (5,6).

Genetic factors that contribute to FHA

Most young women experience stress in one form or another, and given societal pressures, some will undereat and overexercise to maintain a certain body weight and fitness level. Many young women who are involved in athletics are required to maintain a level of fitness that can lead to the “female athlete triad”, in which low energy intake, high energy output, and stress result in loss of the menstrual cycle and reduced bone density. However, not all women who are under stress, have a restricted diet, and exercise to the point of weight loss will develop FHA. There is considerable variability in the degree of weight loss and/or physical exertion necessary to induce FHA (4).

The predisposition of some women for developing FHA may be due to genetic variants associated with GnRH deficiency, where individual mutations may contribute to a greater or lesser susceptibility to the various stressors associated with FHA. Kisspeptin is a neuropeptide that participates in the release of gonadotropin-releasing hormone (GnRH), which regulates the HPO axis. Kisspeptin is released by hypothalamic nuclei, but its release can be disrupted when a woman’s energetic balance is decreased – not enough calories consumed and too many calories burned. Kisspeptins are a group of proteins encoded by the KISS1 gene discovered in Hershey, PA, in 1996 (hence the name KISS after Hershey’s Kiss). Mutations that inactivate the KISS1 gene are linked to FHA, while activating mutations may lead to premature puberty (7,4).

The effects of stress on the HPO axis

Stress can come in various forms, whether it is psychological or physiological. The stress response can be viewed as a survival mechanism that keeps us alive until we can escape whatever might be causing the stress. Reproductive function is not essential for survival and requires a large amount of energy, so it is understandably suppressed during times of great stress (7).

Various forms of stress can reduce the formation of kisspeptin by inhibiting the expression of the KISS1 gene. Corticotrophin-releasing hormone (CRH) from the hypothalamus, corticotropin (ACTH) from the pituitary, and cortisol from the adrenal glands produced in response to stress, directly inhibit the production of kisspeptin as well as GnRH. CRH inhibits the pulsatile frequency of GnRH, while cortisol inhibits reproductive function at the hypothalamus, pituitary, and uterine levels (4).

Gonadotropin inhibiting hormone (GnIH), produced in the hypothalamus, suppresses the synthesis and release of GnRH, FSH, and LH. GnIH increases in response to acute and chronic stressors further leading to dysregulation of the HPO axis and suppression of reproduction. Experimental trials revealed an increase in GnIH and a decrease in GnRH when corticosterone was administered. Kisspeptin and GnIH are two neuropeptides that provide a chemical link between the effects of stress and inhibited reproduction (7,4).

Meczekalski et al. conclude that stress-induced changes are the main driver of reproductive inhibition in women with FHA. Compared to healthy controls, FHA patients were characterized by lower serum kisspeptin levels and higher serum CRH. Stress-related FHA highlights the complex interplay between the HPA and HPO axes. Receptors for CRH and cortisol are expressed on kisspeptin neurons in the hypothalamus indicating that kisspeptin functions as a signaling bridge between the HPA and HPO axes (7).

Other factors that influence kisspeptin levels include body mass index, in which low body mass correlates with lower levels of kisspeptin. Leptin, a peptide hormone that signals satiety, is positively correlated with kisspeptin and GnRH in that leptin stimulates the expression of the KISS1 gene. Ghrelin, another peptide hormone that opposes the effects of leptin by stimulating hunger, tends to increase in states of energy deficiency, or lack of satiety, and tends to suppress the hypothalamic expression of the KISS1 gene and impairs GnRH secretion (7,4).

Additionally, energy-deficient states can lead to dysfunction within the hypothalamic-pituitary-thyroid (HPT) axis, resulting in hypothyroidism as a means to slow metabolic rate for self-preservation. While thyroid-stimulating hormone (TSH) may remain stable, triiodothyronine (T3) decreases, and thyroxine (T4) will be normal or low. A state of hypothyroidism can ultimately impair bone formation and remodeling at a time when bone mineral density should be reaching its peak (4,6).

Diagnosis of FHA

In addition to measuring serum levels of gonadotropins (FSH, LH), estradiol, and ruling out pregnancy, an assessment for FHA should include a gynecological exam and a thorough history that includes evaluation of diet and exercise habits, recent weight loss, and perception of stress level. Additional bloodwork to rule in or out any possible contributors or causes of amenorrhea might include a complete thyroid panel, prolactin level, androgen level, and anti-Mullerian hormone as a measure of ovarian reserve. Imaging studies may also be warranted to rule out ovarian cysts, structural anomalies, and pituitary or hypothalamic conditions (4,6).

In a clinical setting, a GnRH stimulation test would result in a positive response of FSH and LH. In younger women, this test might be appropriate to differentiate delayed puberty from FHA. The administration of a progestin challenge is not useful in the diagnosis of FHA because the withdrawal bleed is scant or nonexistent due to low estrogen (8).

Salivary testing to measure the daily rhythm of cortisol can provide objective data revealing the physiological response to stress. ZRT offers several salivary tests to measure cortisol rhythm, sex hormones, and DHEA. Dried blood spot samples can be used to measure sex hormones, gonadotropins (FSH, LH), and thyroid function, providing additional data to support an accurate evaluation of the causes and contributors to the development of FHA. Further evaluation for mood disorders related to depression and anxiety should also be considered, as these conditions often coexist as a contributing factor to the development of FHA and as a result of hypoestrogenism. Dried urine testing for neurotransmitters can further reveal imbalances that may be contributing to stress patterns and mood disorders.

Short- and long-term consequences of FHA

The loss of a regular menstrual cycle in a previously menstruating woman is not without consequences. Adequate levels of estrogen are needed to support fertility, bone health, cardiovascular health, and brain health.

Fertility

The dysfunction of the HPO axis results in anovulation and infertility. If a woman with FHA experiences spontaneous ovulation and conceives, there is a tendency toward increased risk of miscarriage or preterm labor. Low estrogen in women with FHA can lead to changes in vaginal mucosa and pH, predisposing to genitourinary tract infections. The reproductive and hormonal issues associated with FHA are reversible and can resolve over time after the return of hormone levels and normalization of the menstrual cycle (4).

Cardiovascular System

A low estrogen state can contribute to cardiovascular disease in women. This relationship has been well-established in studies on menopausal women who develop hypertension and cardiovascular disease in menopause. Low estrogen leads to endothelial dysfunction, dysregulated activity of nitric oxide (which is associated with vasodilation), and excessive activation of the renin-angiotensin system – all three states contribute to the development of hypertension. Additionally, low estrogen contributes to changes in the lipid profile, resulting in higher total cholesterol, triglycerides, and LDL cholesterol (4,6).

Bone Health

Hypoestrogenism causes changes in bone turnover with decreased bone formation, and increased bone resorption. Women who experience FHA may end up with lower bone mineral density due to reduced nutritional and energy status, low estrogen, high cortisol, and excessive exercise. Stress fractures are more common in women who experience amenorrhea, especially if it is associated with intense exercise. Women with FHA who exercise intensely in adolescence and young adulthood have a lower bone mineral density Z-score in the lumbar spine when compared to menstruating women. Bone mineral density can be restored once hormone levels normalize or through supplementation with estrogen (4,6).

Brain health and state of mind

Going through menopause is not something that a woman can opt out of, and they know all too well the effects of low estrogen on brain function and mood. Women with FHA experience psychological symptoms similar to women in menopause because of hypoestrogenism. Estrogen modulates the activity of many neurotransmitters and neuromodulators in the brain such as serotonin, norepinephrine, acetylcholine, and dopamine. Poorly managed stress is a contributor to FHA but may also result from the loss of estrogen and its effects on brain health and mood. Additionally, women with FHA tend to have a higher rate of perfectionism when compared to eumenorrheic peers, which adds a degree of stress (6).

Treatment of FHA

Lifestyle

Addressing lifestyle and stress management should be the first approach to treating FHA. Increasing nutrition in the form of high-quality food and sufficient calories, reducing and managing stress effectively, and moderating exercise are key to normalizing menstrual cycles and ovarian activity. If a woman is underweight, a moderate weight gain of as little as five pounds may make the difference between amenorrhea and normal cycles. Attaining a normal BMI (body mass index) of at least 18.5 aids in recovery from FHA and increases fertility (4,6,8).

Psychological counseling

Anxiety and other mood disorders often coexist with FHA and may be a contributing factor. Evaluating young women for eating disorders is also warranted if body weight is very low and there are signs of disordered eating, unhealthy and rigid dietary habits, and body dysmorphia. Guidance on managing stress through cognitive behavioral therapy (CBT), family counseling, and relaxation techniques can be useful tools that have a positive effect across a woman’s lifetime (4,6,8).

Hormones

If menstrual cycles have been absent for 6-12 months and underlying lifestyle factors have been addressed with other potential causes of amenorrhea ruled out, replacement of hormones may be necessary to prevent further issues associated with hypoestrogenism. The use of cyclic transdermal estradiol and oral progestogen therapy is commonly used to address FHA and has been demonstrated to improve lumbar and hip bone density. Transdermal estrogen has a greater effect on bone density because it does not decrease the IGF-1 level, which is needed to build bone whereas, oral contraceptives decrease IGF-1. The use of oral contraceptives is discouraged for the hormonal treatment of FHA as it has a continued suppressive effect on ovulation (4,8,6).

The use of hormones can also have a positive effect on cognitive function, mood, and weight gain. Low-dose estrogen may positively modulate the spontaneous restart of gonadotropin release. The use of low-dose estrogen provides positive feedback to the hypothalamus and pituitary and may restore the HPO axis by initiating the maturation of ovarian follicles and promoting the thickening of the endometrium (8, 4).

Botanicals and supplements

First and foremost, a healthy energy status needs to be maintained with adequate nutrition to support the return of a menstrual cycle, as energy deficiency is a key underlying cause. Botanicals and supplements are secondary to a healthy diet with sufficient calories, reduced exercise, and management of stress. Introducing a high-quality multivitamin, minerals, essential fats, and vitamin D can help to build and restore nutritional reserves. Botanicals that support ovulation and the HPO axis in general, might only be effective if estrogen is restored by addressing the underlying cause or through initial cyclical supplementation of estrogen.

Figure 1. Treatment of women with FHA includes a reduction of excessive exercise, dietary evaluation and psychological support to reduce stress, an enhancement of behavioral change and an increase of energy availability. Estrogen replacement therapy may be considered after 6 to 12 months of nutritional, psychological, and exercise-related interventions in those with low bone density and/or evidence of skeletal fragility. Assisted reproductive technologies may be considered in patients wishing to conceive. Low-dose estrogen use in patients with FHA is still under study. (8)

Image credit: Battipaglia, Christian, et al. “Low-Dose Estrogens as Neuroendocrine Modulators in Functional Hypothalamic Amenorrhea (FHA): The Putative Triggering of the Positive Feedback Mechanism(s).” Biomedicines, vol. 11, no. 6, June 2023, p. 1763. PubMed Central.

In summary

FHA is a functional disorder leading to amenorrhea in previously menstruating women. The dysfunction that leads to FHA can appear simple on the surface, but it can reflect a deeper psychological pathology that should be addressed with care. Body image issues are perpetuated in young women through images viewed on various media platforms. Popular influencers on social media may promote extreme diets and exercise programs that feed this dysfunction. Eating disorders and body dysmorphia are nothing new, but the platforms that influence young women have grown excessively through access to social media.

Young women who might follow advice acquired on these platforms may be well-intentioned and trying to improve their health and fitness level. While this is a noble goal that can have lifelong benefits, the complete loss of menstruation is a signal – a vital sign – that something is off. Consulting with an educated professional on caloric needs relative to energy output, along with strategies to effectively manage stress, can be a wise investment in a young woman’s health and well-being that will serve her well throughout the phases of her reproductive life.

References

The Complex Web of Premenstrual Dysphoric Disorder: Part II

Tue, 09 Apr 2024 12:08:43 -0700

Premenstrual Dysphoric Disorder (PMDD) is a premenstrual disorder characterized by physical and psychological symptoms that occur in the luteal phase of the menstrual cycle and are often more extreme than the more common symptoms associated with Premenstrual Syndrome (PMS). PMS affects 20-40% of menstruating women and common symptoms include fatigue, irritability, mood swings, depression, abdominal bloating, breast tenderness, acne, changes in appetite and food cravings. PMDD occurs in 5-8% of menstruating women and is characterized by extreme mood and physical symptoms that interfere with quality of life to a significant degree (1).

Relationships, school, and work can often suffer in the last one or two weeks leading up to the menstrual cycle. Potentially half of a woman’s reproductive years may be spent in a state of serious depression, anxiety, and irritability. Beyond reproduction, hormones are powerful signaling molecules with receptors throughout the body, brain, and nervous system. Estrogen and progesterone have a profound influence on mood, cognitive function, stress tolerance, sleep, and an overall sense of well-being.

In Part II of this examination of PMDD, we will take a closer look at the effects of estrogen, thyroid function, and the hypothalamic-pituitary-adrenal (HPA) axis. The difficulty in regulating emotion is characteristic of PMDD and is related to sex hormone fluctuations and their influence on key areas of the brain that control emotion, memory, and cognition. I will also provide a brief overview of common conventional and complementary treatment considerations along with testing options to identify potential contributors to PMDD.

Depression and anxiety disorders in women

Though this is an article on PMDD, which is classified as a major depressive disorder (MDD) with a temporal relationship to the luteal phase of the menstrual cycle, it is important to acknowledge that there is an increased tendency for women to experience issues with general depression and anxiety two to three times as often as their male counterparts. Several studies point to the relationship of estrogen and its impact on cognitive function, mood, emotional regulation, and stress management (2).

Estrogen and progesterone receptors are highly expressed in areas of the brain involved in emotion and cognition such as the amygdala and the hippocampus (3). Increased vulnerability to depression in women often begins in puberty with a decline in new onset mood disorders after menopause. Perimenopause is a particularly vulnerable time for mood disorders as menstrual cycles become dysregulated (2). Progesterone tends to drop off sharply due to anovulatory cycles and estrogen levels can become erratic with higher highs and lower lows, making menopause a welcome end to the unpredictable hormonal fluctuations.

PMDD has often been described as a heightened sensitivity of the central nervous system to normal variations in ovarian hormones across the menstrual cycle. While ovarian hormones are key to reproductive function, they also regulate neurotransmitter systems within the brain and nervous system. It follows that if hormones regulate neurotransmitter production and receptor sensitivity, the fluctuation of hormones will also affect neurotransmitter systems.

Estrogen and PMDD

The effects of estrogen on mood are well-established. However, both estrogen and progesterone are present in the luteal phase of the menstrual cycle, so it is important to understand the effects of estrogen in relation to progesterone.

The presence of estrogen is necessary to create progesterone receptors and the presence of progesterone downregulates estrogen receptors (4). Both hormones need to be present to optimize and regulate the function of the other. In a 1988 study by Holt et al examining the mechanisms of steroidogenesis in the corpus luteum of rabbits, it was determined that the presence of estrogen was necessary to increase progesterone levels. The mechanism by which this occurred was through estrogen’s effect on the storage of cholesterol and the further processing of cholesterol to pregnenolone (steroidal hormone precursor) in the mitochondria. In estrogen-deprived rabbits, the serum progesterone levels fell precipitously in vivo within 24-hours. In the rabbits with ongoing estrogen stimulation, serum progesterone levels remained high (5).

In a more recent study, Yen et al concluded that single point analysis of hormones in the luteal phase of the cycle does not reveal the hormonal dynamics that may occur throughout the luteal phase of the menstrual cycle. In a more nuanced comparative analysis of hormonal fluctuations in women with PMDD, subtle differences in hormone levels in the early and late luteal phases of the menstrual cycle are revealed. Yen et al evaluated estrogen and progesterone levels in the early luteal (EL) and late luteal (LL) phases of the menstrual cycle amongst 63 women with PMDD and 53 controls (6).

The results revealed that women with PMDD have lower EL-phase and LL-phase estrogen along with a higher level of EL-phase progesterone as compared to controls. The low estrogen and higher progesterone levels in the EL-phase also show an association with LL-phase PMDD severity. It was concluded that EL-phase low estrogen may promote a vulnerability to the effect of progesterone (and its metabolite allopregnanolone) in women with PMDD (6).

Ko et al also revealed that women with higher estrogen in the mid luteal phase experienced less severe PMDD symptoms. These findings were consistent with other studies indicating the potential for estrogen to mitigate stress and depressive symptoms by enhancing cognitive function and protecting hippocampal activity while under stress (7). These effects may also be attributed to the enhanced effect of serotonin in the presence of higher estrogen levels.

In a 2007 study conducted by Huo et al, variants in the estrogen receptor alpha gene (ESR1) are demonstrated in women with PMDD. ESR1 plays a major role in brain stimulation, and dysfunction of this receptor may lead to the cognitive, somatic, and mood changes seen in PMDD. ESR1 also regulates signaling of neurotransmitter systems implicated in both the pathogenesis and treatment of PMDD (8).

Estrogen affects multiple neurotransmitter systems which regulate mood, cognition, sleep, and appetite. Women with PMDD can have low estrogen levels in the luteal phase of their cycle, which decreases the effects of serotonin, leaving PMDD sufferers more sensitive to estrogen and progesterone fluctuations. This again highlights the complex interaction of ovarian hormones, neurotransmitters, and mood (3).

Figure 3. Role of neurosteroids in the modulation of the four main neurotransmitters. Estrogen (green) and progesterone (yellow) interact with GABAergic, glutamatergic, serotonergic, and dopaminergic synapses at different levels: neurotransmitter synthesis, release, degradation, and neurotransmitter receptor synthesis, activation or inhibition 5HT, serotonin; MAO, monoamino oxidase; POA, preoptic area; PFC, prefrontal cortex.

Image Credit: Del Rio, Alliende, et al."Steroid Hormones and Their Action in Women's Brains: The Importance of Hormonal Balance" Frontiers Public Health, Vol. 6, 2018.

Thyroid function and PMDD

Subclinical thyroid disorders are abundant amongst women with menstrual, depressive, and fertility disorders. Hypothyroidism is commonly associated with depression, dysphoria, and cognitive decline while hyperthyroidism can be associated with agitation, acute psychosis, and apathy. Thyroid hormone and its receptors are abundant within the central nervous system modulating neurotransmission and exerting some influence over serotonin and norepinephrine which both have extensive effects on mood and cognitive function (9).

A 2021 pilot study out of India evaluated the correlation between thyroid dysfunction and PMDD. Of the 60 women in the study with PMDD, 63% were diagnosed with subclinical hypothyroidism. The study concluded that women with PMDD should be evaluated for thyroid dysfunction as it relates to ovarian hormone output and imbalances. Addressing thyroid dysfunction is a modifiable endocrine factor that can be easily addressed and may contribute to improvement in PMDD symptoms (9).

HPA axis, cortisol, stress, and PMDD

Along with the core mood symptoms of PMDD, women also experience increased sensitivity to stress during the luteal phase. This includes not only greater subjective perceived stress but also an altered physiologic stress response from the hypothalamic-pituitary-adrenal (HPA) axis (11). Given that cyclical ovarian hormones and their metabolites interact with the HPA axis, a history of chronic stress and adversity may contribute to the development of PMDD and increase premenstrual symptom severity (12).

Ko et al measured multiple markers in their study of 58 women with PMDD against 50 controls. Ultimately their findings revealed that women with PMDD have higher luteal phase progesterone and cortisol, and lower BDNF and VEGF which are noted to be protective against stress and promote neurogenesis and neuroplasticity (7). Progesterone can be a precursor hormone to cortisol so it may follow that higher progesterone during the luteal phase of the menstrual cycle might lead to a higher level of cortisol in response to stress.

In a 2019 article in The Annual Review of Clinical Psychology, Albert and Newhouse review the interactions of estrogen and stress in relation to depression. Major depressive disorder (MDD) can be characterized by HPA axis dysregulation. It has been demonstrated that during phases of low estrogen, women with MDD show greater negative mood and less hippocampal activity during acute stress than they do during phases of high estrogen. They conclude that estrogen may support an efficient and dynamic stress response through supporting neuroplasticity, cognitive function, serotonin, and norepinephrine (2).

Chronically elevated cortisol levels are associated with depression and structural changes within the brain. How the brain perceives stress is regulated by ventral and dorsal systems within the brain. The ventral system allows for quick appraisal of emotionally charged stimuli and includes the amygdala which participates in the regulation of autonomic and endocrine functions, including activation of the fight-or-flight response. The dorsal system includes the hippocampus that is involved in memory, learning, and emotion. The dorsal system allows for secondary appraisal of stressful stimuli modulating the emotional, physiological, and cognitive response of the more rapidly responsive ventral system (2).

Albert et al propose that mood dysregulation is the result of an imbalance in the functional activity of the ventral and dorsal systems and is mediated by hormonal fluctuations experienced across the menstrual cycle. In women, the cortisol response to stress is decreased during the phases of the menstrual cycle when estrogen is high. Estrogen enhances the response of the dorsal system that allows for a more integrated assessment of stressful stimuli (2).

PMDD treatment options

Selective Serotonin Reuptake Inhibitors (SSRIs) – Considered the gold standard for PMDD, SSRIs can be dosed continuously or exclusively in the luteal phase. Unlike other depressive and anxiety disorders, the effect on symptoms of PMDD is rapid and requires relatively low doses (13).
Inhibition of Ovulation - Therapies that inhibit ovulation and luteal phase hormone fluctuation include:
- Combined Oral Contraceptives (COC) - COCs have proven effective for somatic symptoms of PMDD but show inconsistent results on affective symptoms and must be dosed continuously without the use of placebo pills during menstruation (13).
- Gonadotrophin Releasing Hormone (GnRH) Receptor Agonists - GnRH receptor agonists act to suppress ovulation through down-regulation of GnRH receptors but inhibit the production of estrogen and progesterone altogether and induce menopausal symptoms (13).
- Estradiol Patch and Progestogen – Continuous use of a low-dose estradiol patch and cyclical progestogen or the use of a Mirena IUD has been presented as an option for the treatment of PMDD (14, 15).
High Dose Progesterone - PMDD symptoms are often experienced when progesterone and ALLO are declining. PMDD symptom severity is related to ALLO serum concentration in an inverted U-shaped curve indicating that low or high concentrations of ALLO can have a positive effect on mood (3).
Botanicals
- Vitex Agnus-Castus (Chasteberry) reduces prolactin secretion which increases the chance of ovulation and formation of the corpus luteum allowing adequate production of progesterone. Vitex also increases dopamine transmission and activates estrogen and opioid receptors (13, 16).
- Hypericum perforatum (St. John’s wort) is an antidepressant and anxiolytic that acts as a reuptake inhibitor of serotonin, dopamine, and norepinephrine (13, 17).
Nutrients – Vitamin B6 is included among the first-line therapies for PMDD due to its function as a cofactor in the synthesis of monoamines (serotonin, dopamine, epinephrine, norepinephrine) and GABA. The additional use of thiamine, calcium, zinc, magnesium, nutritional lithium, vitamin D, fish oil, and evening primrose oil have all been cited in the literature as having some degree of positive effect (13, 18).
Therapies – Cognitive Behavioral Therapy (CBT) as a psychotherapeutic modality has proven effective in the treatment of PMDD. Acupuncture, acupressure, massage, yoga, Epsom salt baths, and regular meditation all serve to calm the nervous system and reduce symptoms associated with PMDD (13).
Lifestyle – High-quality, whole food diet along with regular exercise and 7-9 hours of quality sleep supports a healthy lifestyle and provides a solid foundation of good health that can only be supportive of reducing PMDD symptoms.

Putting it all together

In addition to the reproductive role that sex hormones play, they also have profound effects throughout the brain and body. While hormonal fluctuations are necessary to create the menstrual cycle, those same fluctuations are experienced within the brain and the various tissues throughout the body that also respond to these hormones. The contributing factors that lead to PMDD create a complex web of interactions that may need to be addressed at multiple levels with an individualized approach. I am inclined to believe that the presence of adequate estrogen in the luteal phase has a stabilizing influence on the effects of progesterone and ALLO on brain function and mood. This goes back to the notion that a balanced level of both hormones is necessary to create a healthy cycle.

It is always interesting to get feedback from women who have found a way to successfully manage their PMDD symptoms. In reviewing various online articles on PMDD that allowed for public comment, it is clear that some women do well with progesterone, some do well with estrogen, some do well with both, some benefit by using cyclical SSRIs, some benefit by treating thyroid dysfunction, and some do well with a combination of all or some of these modalities. Perhaps as we learn more about the causative factors contributing to PMDD, we may discover that there are two or more subtypes that require unique and specific interventions.

ZRT Testing – revealing the potential contributors to PMDD

The personal and unique history of every woman who experiences this disorder can offer clues to the cause. Treatment of PMDD is clearly not a one-size-fits-all proposition and may involve a journey of trial and error before improvement. To increase the chances of improving symptoms, testing sex hormones, thyroid function, adrenal hormones, and neurotransmitter levels may point us in the right direction.

ZRT offers menstrual cycle mapping through dried urine testing which allows us to see the rise and fall of estrogen, progesterone, and luteinizing hormone from the mid-follicular phase through the late luteal phase of the menstrual cycle. This allows us to see not only the direct measurement of estrogen and progesterone but also the relationship between them. Thyroid hormones and antibodies can be conveniently measured in dried blood spot and cortisol levels are measured in a multi-point salivary test to capture the cortisol rhythm during the waking hours. Neurotransmitter testing is also available through dried urine testing which can be combined with single day dried urine hormone measurements that include estradiol and the progesterone metabolites of pregnanediol and allopregnanolone.

References

The Complex Web of Premenstrual Dysphoric Disorder: Part I

Mon, 25 Mar 2024 14:59:37 -0700

The fluctuation of hormones throughout the menstrual cycle is a normal process that supports ovulation and menstruation. Unfortunately, for some women, the inherent fluctuation of their hormones creates a rollercoaster of physical and emotional symptoms that can be extreme to the point of intolerable. While all women experience hormonal fluctuations throughout their cycle, some women experience only mild discomfort while other women feel as if their world is crashing around them.

Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Disorder (PMDD) are premenstrual disorders characterized by physical and psychological symptoms that occur in the luteal phase (after ovulation) of the menstrual cycle. PMS affects 20-40% of menstruating women and common symptoms include fatigue, irritability, mood swings, depression, abdominal bloating, breast tenderness, acne, changes in appetite and food cravings. PMDD occurs in 5-8% of menstruating women and is characterized by extreme mood and physical symptoms to such a degree that it is difficult to function in daily life (1).

Currently, PMDD is listed as a depressive disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) but it was not until 1987 that formal criteria for this diagnosis were proposed. While the pathophysiology of PMDD remains unclear, it has been hypothesized that sensitivity to hormonal fluctuations during the luteal phase of the menstrual cycle, abnormal serotonergic activity, genetic variations, and aberrations in progesterone, estrogen and GABA may all play a role (1).

In the first part of this two-part series, we will explore the symptoms, risk factors, diagnosis, and the relationship of progesterone and its main metabolite, allopregnanolone (ALLO), to the function of GABA-A receptors. GABA is our main inhibitory neurotransmitter and is associated with reducing anxiety and inducing a sense of calm. Reduced sensitivity between GABA-A receptors and the presence of ALLO is considered the main pathogenic factor in the development of PMDD (2).

Common symptoms of PMDD

While women with PMDD experience the typical physical symptoms associated with PMS, they also experience depression, anxiety, panic attacks, extreme irritability, rage, insomnia, a sense of overwhelm, poor stress management, difficulty concentrating, fatigue, and binge eating (3). Symptoms can be extreme to the point of suicidality. The distinguishing feature of PMDD as compared to other major depressive disorders is the temporal relationship between the onset of symptoms and the luteal phase of the cycle followed by resolution of symptoms with the onset of menses.

Risk factors associated with PMDD

Like other conditions, PMDD has associated risk factors that may predispose to its development. Epidemiological studies show an association with major depressive disorder, anxiety, PMS, family history of PMS/PMDD and a history of trauma. The association of trauma and PMDD may be linked to a heightened perception of stress and alteration in the stress response system. Other risk factors include cigarette smoking, obesity, and specific genetic variants (1).

Diagnosis of PMDD

PMDD may be superimposed on other mental health disorders which can make diagnosis difficult. The coexistence of PMDD with a diagnosed depressive disorder may interfere with accurate diagnosis as it is assumed that cyclical behavioral and mood changes are associated with a previously diagnosed disorder. Hormonal changes around pregnancy, childbirth, and perimenopause can worsen symptoms of PMDD due to the extreme level of hormonal fluctuations that occur during these events (1).

To differentiate between depressive disorders and PMDD, it is important to understand the timing of the onset of symptoms by asking the patient to keep a journal relating mood to the phase of the menstrual cycle over 2-3 months. To receive a diagnosis of PMDD, a patient must have at least 5 out of 11 specific symptoms that occur during the week before menstruation and improve within a few days after the onset of menses. The PMDD symptoms must occur for at least 2 menstrual cycles (1). These symptoms include:

Mood swings
Irritability or anger
Anxiety, tension, feeling on edge
Depression, feelings of hopelessness, self-deprecating thoughts
Lack of interest in daily activities and relationships
Fatigue, lethargy
Feeling out of control
Lack of concentration or trouble thinking
Food cravings/binge eating
Insomnia or hypersomnia
Physical symptoms such as breast tenderness, aching muscles and joints, bloating, headaches

Menstrual magnification

Several psychiatric and physical disorders are exacerbated prior to menses such as IBS, migraines, depression, and anxiety. This is known as menstrual magnification or premenstrual exacerbation. The temporal relationship between the exacerbation of existing conditions may result in a provisional diagnosis of PMDD. However, just as it is important to make the distinction between PMDD and other disorders, it is also important to avoid misdiagnosing PMDD when other issues may exist that need appropriate assessment and treatment (4).

Causes of PMDD

Determining the cause of PMDD has proven to be complex with much contradiction throughout the literature. The interaction of neurotransmitters, genetic variations, enzyme activity, receptor activation, and thyroid and HPA axis function, set against the background of fluctuating ovarian hormones creates a multitude of variables that are difficult to capture in a single study.

Most studies suggest that reproductive hormone release patterns are no different in women with PMDD than in women without symptoms. It has therefore been presumed that women with PMDD may experience heightened sensitivity to cyclical variations in levels of reproductive hormones predisposing them to mood, behavioral, and somatic symptoms at an extreme level (1).

Neurosteroids (inclusive of pregnenolone, estradiol, and progesterone) are steroid hormones that are produced in endocrine tissue or the central nervous system that interact with neuronal receptors and have an impact on the level and activity of neurotransmitters such as GABA and serotonin. Estrogen and progesterone receptors are highly expressed in areas of the brain involved in emotion and cognition. Ovarian hormones can also act on multiple receptor types throughout the brain and exert immediate effects on synaptic activity. Ovarian hormones have neuroregulatory, neurotrophic, and neuroprotective effects in brain physiology so it is not surprising that fluctuations throughout the menstrual cycle would have effects on mood and cognition (5).

Progesterone and allopregnanolone

Allopregnanolone (ALLO) is a neurosteroid and a metabolite of progesterone. It can be synthesized in the central nervous system de novo from cholesterol, progesterone, or pregnenolone. ALLO exerts anxiolytic, anti-stress, and antidepressant effects by acting as a positive allosteric modulator of the GABA-A receptor potentiating the effects of GABA in the brain. ALLO is synthesized from progesterone through the sequential action of 5-alpha-reductase type I and 3-alpha-hydroxysteroid dehydrogenase. These enzymes can account for the rate-limiting steps in the production of ALLO from progesterone (6).

The sensitivity to hormonal fluctuations within the luteal phase of the cycle are mediated through the various subunits of the GABA-A receptor and ALLO. The majority of PMDD symptoms occur within the last week of the luteal phase when progesterone and its metabolite ALLO are declining. When the decrease in ALLO is rapid, there is an increase in the expression of certain GABA-A subunits that decrease their sensitivity to ALLO leading to an inhibition of GABA release. It is the reduction in GABA that contributes to the development of PMDD symptoms (2).

Instability and reduced plasticity within the GABA-A receptor subunits reduces the ability of the GABA-A receptor to adapt to fluctuating levels of ALLO. Under normal circumstances, ALLO will bind to the GABA-A receptor and enhance the GABA-gated chloride channel resulting in the release of GABA. When ALLO decreases too rapidly, the ability of ALLO to bind to the GABA-A receptor decreases resulting in a decrease of chloride influx and a decrease in GABA production. As stated by Gao et al, issues related to rapidly decreasing ALLO and its effect on GABA-A receptors is the main pathogenic factor in the development of PMDD and has become an area of exploration for treatment options focusing on the stabilization of the GABA-A receptor and its various subunits (2).

Figure 2. ALLO-mediated GABA_A receptor subunit sensitivity participates in the pathogenesis of PMDD. When the decrease in ALLO is too rapid, there is an increase in the expression of GABA_A receptor α4 β subunits (10) and decreases in the sensitivity (decreased affinity, reduced plasticity), and leading to a decrease in chloride influx, which, in turn, inhibits the release of GABA from GABAergic interneurons, reduces the inhibition of pyramidal neurons, and then increases the excitability of pyramidal neurons, leading to the development of PMDD. The ALLO-mediated GABA_A receptor remains the main pathogenic factor of PMDD. (2)

Image credit: Gao, Qian, et al. “Role of Allopregnanolone-Mediated γ-Aminobutyric Acid A Receptor Sensitivity in the Pathogenesis of Premenstrual Dysphoric Disorder: Toward Precise Targets for Translational Medicine and Drug Development.” Frontiers in Psychiatry, vol. 14, 2023, p. 1140796. PubMed.

SSRIs and ALLO

Serotonin reuptake inhibitors (SSRIs) are considered the gold standard for the treatment of PMDD. Studies have shown that SSRIs increase brain levels of ALLO without altering the brain levels of other neurosteroids. The concentration of ALLO in the cerebral spinal fluid (CSF) of 15 subjects before and after SSRI use over an 8-10-week period showed that the subjects with major depression had a 60% lower concentration of ALLO prior to SSRI use than non-depressed controls. In the depressed subjects, SSRIs normalized ALLO levels in the CSF. There was also a statistically significant improvement in depressive symptoms amongst the participants who received the SSRI (6).

When SSRIs are used to treat other depressive and anxiety disorders, the medication may take several weeks to have the desired effect. However, when used to treat PMDD, the effect is rapid and achieved at relatively low doses. As highlighted above, this is likely due to increased synthesis of ALLO. The rapid effect of SSRIs through this mechanism allows for dosing exclusively in the luteal phase of the cycle when PMDD symptoms occur (7).

Inhibition of progesterone and ALLO

Somewhat contradictory to the conclusions above, an article by Kaltsouni et al implicates progesterone and ALLO as the causative factors in PMDD. Their conclusion is supported by the fact that PMDD symptoms improve with anovulation resulting in low progesterone in the luteal phase with a return of symptoms when hormones are added back. In their study, they treated women with the selective progesterone receptor modulator (SPRM) ulipristal acetate and found a 41% reduction in PMDD symptoms. It was stated that the SPRM eventually leads to anovulation, but estradiol levels remained steady at mid-follicular levels. They conclude, as many studies do, that altered GABA-A receptor sensitivity to ALLO across the menstrual cycle is likely the cause of PMDD symptoms (8).

As reported by Carlini et al, dutasteride (Avodart) a 5-alpha-reductase inhibitor commonly used in the treatment of benign prostatic hyperplasia, inhibits one of the key steps in the production of ALLO. In a small double-blind placebo-controlled study, a 2.5 mg dose of dutasteride demonstrated significant efficacy in ameliorating anxiety, irritability, melancholy, bloating, and food cravings. Long-term use, however, is not recommended in women of child-bearing age but the study did seem to prove a point (7).

In a 2024 study by Ko et al evaluating the effect of estrogen, progesterone, cortisol, brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), results revealed that women with PMDD who had higher levels of progesterone in the mid and late luteal phase experienced greater PMDD symptom severity. Additionally, women with PMDD who had a greater rise in progesterone from ovulation to mid luteal phase experienced more severe PMDD symptoms. Ko et al surmise that the cumulative sum of luteal phase progesterone correlates with increased severity of PMDD symptoms. They also cite studies in which the addition of progesterone can trigger PMDD is vulnerable women (9).

In these three studies, it is clear that PMDD symptoms are associated with the presence of progesterone and its metabolite, ALLO. Kaltsouni and Carlini prove that by completely inhibiting the production of progesterone and/or ALLO, either through inducing anovulation or by blocking the conversion of progesterone to ALLO, there can be a relief of symptoms. While this creates a clear link between PMDD and the presence of progesterone and ALLO, these studies do not reveal how these hormones contribute to PMDD. By eliminating progesterone, they have effectively eliminated the production of ALLO and the potential for any fluctuation of either hormone.

The Goldilocks principle and hormones – not too much, not too little, just right

The activity of any hormone can often be determined by the receptors available to receive it. We understand the principle of tachyphylaxis in which too much hormone will cause a down-regulation of its receptor, resulting in symptoms of deficiency for that hormone. Likewise, the positive effects of ALLO occur according to an inverse U-shaped curve showing that suboptimal levels (too low or too high) can be anxiogenic and optimal levels (just right) can be anxiolytic (5,2).

Most studies involve one or two serum measurements of the hormones of interest without actually seeing the dynamic fluctuation of these hormones from one day to the next within the luteal phase of the cycle. From a practical standpoint, study participants are not likely to submit to daily phlebotomy to measure hormones, but it is often the rapid decline in hormones that contributes to the onset of symptoms, and this cannot be captured with only one to two serum measurements within the luteal phase.

A broader perspective

Conditions other than PMDD that are associated with a rapid decline in hormones are post-partum depression, cyclical migraines, hot flashes, night sweats, brain fog, and emotional lability. Hormones rise and fall within the luteal phase of the cycle so everything that is under the influence of these hormones experiences that rise and fall and must adapt to these changes. The typical progesterone curve in the luteal phase actually looks like a roller coaster ride where you might experience one set of symptoms going up and an entirely different set of symptoms going down. At the bottom of the downslope is when everything levels out and there is a chance to equilibrate.

A woman’s unique history, physiology, genetics, diet, lifestyle, and foundational health can influence her experience of fluctuating hormones. Rather than completely eliminating the menstrual cycle, the goal should be to create a background of stability that can buffer the effects of cyclical changes. We may not be able to completely eliminate mood and physical symptoms associated with fluctuating hormones, but with knowledge of the potential contributors, we can provide much needed support.

In part II of The Complex Web of PMDD, we will explore the effects of estrogen, thyroid, and stress and the hypothalamic-pituitary-adrenal (HPA) axis on the symptoms of PMDD. Testing for underlying causes related to thyroid and adrenal function, as well as assessing hormonal fluctuations within the cycle, can provide actionable data that may create more stability within the endocrine system as a whole. We will also review some common conventional treatments and integrative and alternative approaches to addressing this disorder.

References

Common Risk Factors - Alzheimer’s, Cardiovascular Disease, and Inflammation

Fri, 12 Jan 2024 13:30:50 -0800

Alzheimer’s disease (AD) can develop over the course of many years without obvious symptoms until it has become quite advanced and is potentially beyond the point of reversal. The research states that the root cause of Alzheimer’s has yet to be discovered; however, if we continue to look for that ‘one thing,’ we may never find it. The development of Alzheimer’s disease is likely due to several factors that contribute to neuronal degeneration over several years.

The characteristic markers of AD are the build-up of beta amyloid plaques and the formation of neurofibrillary tangles (NFTs) within the brain. While we know these markers are associated with neuronal degeneration and brain deterioration, what allows for them to develop? Are they a cause, effect, or both? The prevention of chronic degenerative diseases such as cardiovascular disease (CVD), hypertension, diabetes, cerebrovascular disease, and drivers of chronic inflammation have proven beneficial when applied to the prevention of AD.

In this article, we will explore some of the risk factors associated with the development of AD and their association with cardiovascular disease and chronic inflammation. Though the literature states there is no common causal link between CVD and AD, there is strong evidence that CVD can contribute to the progression of AD as they share many common risk factors. There are also many drivers of chronic inflammation that increase the risk of developing AD. If we can address the common and familiar risk factors associated with CVD and inflammation, we have the potential to reduce the risk of developing AD.

Risk factors for Alzheimer’s

Age, family history, genetics, cardiovascular disease (CVD), and related disorders such as diabetes, hypertension, high cholesterol, and obesity can contribute to the development of Alzheimer’s disease. Other risk factors include traumatic brain injury, periodontal disease, gut dysbiosis, chronic infections, smoking, excessive alcohol consumption, depression, social isolation, and a sedentary lifestyle (1,2). Suboptimal levels of nutrients, chronic inflammation, reduced hormones, loss of neurotransmitters, mitochondrial dysfunction, reduced brain glucose metabolism, and toxic exposures can also contribute to the development of AD and other chronic degenerative disorders (3).

Cardiovascular disease and inflammation strongly associated with Alzheimer’s disease

As mentioned above, there are numerous potential contributors to the development of Alzheimer’s disease. Some of these contributors are underlying disease processes and some are due to environmental exposures, deficiency states, infections, and cellular and metabolic dysfunction. Because this is a blog and not a book, examining the development of Alzheimer’s from a few key risk factors may offer a simplified perspective.

Cardiovascular disease and inflammation contribute to and are a consequence of many of the underlying processes associated with the development of AD. Despite numerous research studies over the past several decades, no singular cause of AD has been established. From a simplistic perspective, AD may be the brain’s response to inflammation and the effects of vascular disease. Perhaps by analyzing and addressing the risk factors associated with CVD and inflammation, we can reduce the occurrence of AD.

Fig. 1. Common pathways of aging-associated disorders: The risk of Alzheimer's disease (AD) in elderly individuals is increased by other aging-associated comorbidities including obesity, diabetes and cardiovascular impairment. Oxidative stress, mitochondrial dysfunction and chronic inflammation observed in these conditions are also some of the important causes of AD.

Image Credit: Common Neurodegenerative Pathways in Obesity, Diabetes, and Alzheimer’s Disease - Scientific Figure on ResearchGate.

Cardiovascular disease and AD

According to the Alzheimer’s Association, there is an 80% correlation between the development of AD and the presence of cardiovascular disease. Anything that has the potential to damage the heart and blood vessels can also damage the brain. Also noted by the Alzheimer’s Association, the development of beta-amyloid plaques and NFTs may not always lead to AD. Autopsy studies suggest that plaques and NFTs may be present in the brain without causing symptoms of cognitive decline unless the brain also shows evidence of vascular disease (4).

Cardiovascular diseases are a diverse set of disorders that include atherosclerosis, arteriosclerosis, and cerebrovascular disease. Although various therapies have been developed to treat several contributors to CVD, pathological alterations are often irreversible and cannot be completely cured (5). Conditions associated with the development of CVD tend to emerge in midlife, so it is imperative that measures be taken early to prevent advancement of this common risk factor for AD.

The risks of developing AD and cardiovascular disease are both increased by a common range of conditions that include hypertension, dyslipidemia, high cholesterol, diabetes, obesity, gut dysbiosis and periodontal disease. Lifestyle factors that contribute to these conditions include smoking, physical inactivity, excess alcohol consumption, and nutritional deficiencies.

Many of these conditions occur together and contribute to the overall disease process that leads to CVD and AD. Let’s take a closer look at a few of these conditions.

Hypertension

Hypertension adversely affects the structural integrity of cerebral blood vessels, promotes the formation of atherosclerotic plaques in cerebral arteries, and induces hyperlipidemia (5). In a double-blind placebo-controlled study, the use of antihypertensive medication reduced the risk of dementia by 50% as compared to the control group. It is postulated that blood pressure regulation in midlife may postpone the onset of AD. However, the use of antihypertensives in those with existing AD showed no improvement in cognitive performance (5). Perhaps this was a ‘too little, too late’ scenario. If one has the diagnosis of AD, the process of disease development has been occurring for several years and addressing a potential risk factor ten or more years later cannot undo the damage.

Cerebrovascular disease

Cerebrovascular disease is a common feature of AD and other forms of dementia. The presence of beta amyloid can be a cause and consequence of cerebrovascular disorders. Reduced blood flow to the brain and disruption of the blood-brain barrier can be induced by the presence of beta amyloid and vascular pathology. These conditions can lead to lower oxygen supply resulting in acidosis, mitochondrial dysfunction, and oxidative stress. Consequently, this process further leads to the production of reactive oxygen species and perpetuates the formation of beta amyloid and NFTs. Disruption of the blood-brain barrier (BBB) impairs the clearance of beta amyloid from the brain and cerebrospinal fluid. Decreased blood flow and disruption of the BBB both lead to an accumulation of beta amyloid and the formation of NFTs resulting in neuronal loss and cognitive decline (5).

Type II diabetes

According to several epidemiological studies, type 2 diabetes (T2DM) doubles the risk for AD as well as vascular dementia. Patients with T2DM were more likely to have cerebral infarcts and more extensive vascular pathology leading to a higher risk of dementia. Interestingly, the brains of AD patients showed reduced insulin production and reduced insulin receptors. Impaired glucose metabolism in the brain is one of the most recognized abnormalities in AD (5).

Insulin affects the electrochemical and biochemical action on neurons that form neurotransmitters associated with memory and learning. Insulin also influences the enzymes that breakdown beta amyloid. A reduced ability to respond to insulin signaling is directly related to the development of neuroinflammation, amyloidogenesis, oxidative stress, and mitochondrial dysfunction. Disruption of the insulin-signaling pathway is commonly referred to as brain insulin resistance or “type 3 diabetes” and ultimately results in impairments in synaptic, metabolic, and immune response functions in the brain (5).

Gut microbiota

An imbalanced gut microbiota may play a secondary role in the pathophysiology of various diseases due to its influence on immune function and inflammatory processes. The gut microbiome of those with CVD produces more proinflammatory mediators enhancing chronic inflammation and impeding gut barrier function. Impaired gut barrier function allows for the translocation of microbial metabolites such as lipopolysaccharide (LPS) which has been associated with advancement of CVD and poor glycemic control (5).

The interaction between the central nervous system and the gut is well established and commonly referred to as the gut-brain axis indicating bi-directional communication between the gut and the brain. Both the BBB and the intestinal mucosa are more permeable during an inflammatory state. Increased permeability allows for the passage of LPS, a known neurotoxin, from the gut into general circulation inciting an inflammatory cascade which may potentiate neuroinflammation and neuronal impairment. LPS can stimulate the misfolding of beta-amyloid proteins and activate the inflammasome pathways perpetuating neuronal damage, chronic inflammation, and oxidative stress (5).

Periodontal disease

Periodontal disease is a known contributor to CVD. The bacteria associated with periodontal disease, (P. gingivalis, T. denticola, T. forsythia) have also been identified in the brains of those with AD. As mentioned above, the BBB becomes more permeable during an inflammatory state. The proximity of the oral cavity to the brain may allow for easy translocation of oral bacteria to the brain under a state of inflammation. Beta-amyloid is an antimicrobial peptide that increases in the presence of infections. It has been postulated that one of the drivers of accumulated beta-amyloid plaques is the colocalization of these plaques at the site of infections and inflammation in the brain (5).

Inflammation

Commonly associated with an immune response to infection or injury, inflammation is a normal process that attacks an infection and promotes a healing response. Many of the risk factors associated with the development of AD can promote chronic inflammation within the brain. Sustained inflammation has emerged as a core driver of the formation of beta-amyloid plaques and neurofibrillary tangles (NFTs). The presence of the beta-amyloid and NFTs results in persistent activation of microglia, the brain’s resident macrophages, which has further been implicated in the pathogenesis of AD. This sustained inflammatory response has been observed in the postmortem brain tissue of AD patients (6).

Acute inflammation in the brain occurs in defense against infections, toxins, and injury; however, an imbalance between pro-inflammatory and anti-inflammatory signaling results in chronic inflammation that sustains activation of microglial cells and the release of various cytokines that mediate inflammation. Markers of chronic brain inflammation are a common feature of neurodegenerative disorders and also occur in Parkinson’s disease, traumatic brain injury with chronic encephalopathy, amyotrophic lateral sclerosis, and multiple sclerosis (6).

Inflammation also occurs in response to the pathological changes in the brain related to beta-amyloid and NFTs but also perpetuates and exacerbates the development of these two core pathologies. Brain inflammation begins as a neuroprotective response in the acute phase but is detrimental when it becomes chronic. Chronically activated microglia release proinflammatory and toxic products including reactive oxygen species, nitric oxide, and various cytokines (6).

It is suspected that the microglia are primarily activated by the presence of beta-amyloid and are initially effective at clearing beta-amyloid plaque; however, microglial capacity for removing amyloid plaque diminishes while its capacity for producing inflammatory cytokines is sustained. Proinflammatory cytokines also trigger a signaling response that results in the hyperphosphorylation of tau contributing to the development of neurofibrillary tangles (NFTs) adding to the inflammatory and neurodegenerative process. This results in a feed forward loop that leads to reactive microgliosis and sustained brain inflammation (6).

Beta-amyloid protein: cause or effect?

Though vilified as the causative agent of AD, beta-amyloid protects the brain from a broad spectrum of infectious agents, supports the integrity of the BBB, enhances recovery from traumatic brain injury, reduces oxidative stress, and boosts synaptic plasticity, learning and memory. In order for beta-amyloid to exert its positive effects, it must exist in a state of hormesis whereby low-dose amounts have a beneficial effect and high-dose amounts are either inhibitory to optimal function or toxic. The presence of beta-amyloid plaques in the brain of AD patients is indicative of the brain’s attempt to heal itself in the presence of underlying dysfunction often driven by the many risk factors listed above. Getting rid of the beta-amyloid plaques does not remove what drives the overproduction (7).

Early intervention

While we cannot alter our genetics or family history, we can proactively take measures to optimize health by addressing the risk factors for cardiovascular disease and reducing triggers for chronic inflammation. We can protect the brain with a nutrient-dense diet rich in anti-oxidants, and engage in regular physical activity, mental stimulation, and social interaction. Avoiding toxic exposures through food and our environment, supporting the gut and oral microbiome, and enhancing a healthy immune response, reduces oxidative stress and inflammation that drive the overproduction of beta-amyloid and NFTs.

Mid-life is when the pathological changes that lead to AD begin to develop, so it is critical to implement dietary and lifestyle changes early enough to potentially alter the trajectory of AD and other chronic degenerative diseases that may contribute to its development. All of the actions we can take to reduce our chances of developing AD also contribute to good health on multiple levels and most of these recommendations are familiar to all of us.

Regular screening for risk factors associated with the development of AD can direct efforts to make positive changes that may have lasting effects for the prevention of many chronic degenerative diseases. ZRT Laboratory offers a variety of metabolic tests that measure risk factors associated with CVD, diabetes, and inflammation. Additionally, ZRT offers comprehensive evaluation of urinary neurotransmitters, sex hormones, heavy metals, cortisol and thyroid hormones – all of which influence brain health and cognitive function at any age.

Early and consistent interventions can change the trajectory of disease processes while monitoring progress through objective data can further guide our efforts along the way. When we consider that Alzheimer’s disease, as of this writing, has no effective cure, prevention of common risk factors is our best bet.

References:

Women and Alzheimer’s Disease

Mon, 06 Nov 2023 11:46:41 -0800

The numbers are grim. It is estimated that by 2050, 13.8 million Americans will be living with Alzheimer’s disease of which over 9 million will be women (1). Alzheimer’s is the most common form of dementia and is the only disease of the nation’s 10 most common causes of death that has no highly effective pharmaceutical treatment. Alzheimer’s progresses slowly over years, robbing its victims of everything that makes them who they are – their memories, their independence, a feeling of love and connection to family and friends, even basic language for communication. In their moments of awareness, they can feel themselves and all that they are, slipping from their grasp. It is a very slow death and extremely difficult to endure as the victim and for those who love them.

Though both men and women develop Alzheimer’s, it is diagnosed in women twice as much as it is in men. In this brief article, we take a closer look at what Alzheimer’s is and the unique factors that tend to predispose women to the disease with greater frequency than men. Some of these factors include brain structure and function, effect of stress and cortisol on the female brain, and the influence of sex hormones over a woman’s lifetime.

What is Alzheimer’s disease?

Alzheimer’s is a progressive neurodegenerative disease marked clinically by dementia and pathologically by the development of neurofibrillary tangles (NFTs), beta-amyloid plaque deposition, excessive neural pruning, synapse loss, and eventual neuronal death (2, 3). Neural pruning is a normal process in which the brain removes unnecessary connections between neurons to make the brain more efficient. However, in Alzheimer’s, this process has gotten out of control and is often perpetuated by inflammation, suboptimal levels of nutrients and antioxidants, vascular conditions, reduced hormones, and neurotransmitters that support synaptic communication, and toxic exposures (4).

Characteristic of Alzheimer’s is the presence of beta-amyloid plaques and NFTs. Beta-amyloid plaques arise from the improper cleavage of amyloid precursor protein, resulting in the formation of three distinct proteins, one of which is beta-amyloid that forms plaques and fibrils. Beta-amyloid provides an anti-trophic (anti-growth) signal that promotes neuronal death. Beta-amyloid plaques may accumulate for up to 10 years prior to any discernable signs of Alzheimer’s (1, 4).

NFTs arise from the hyperphosphorylation of tau protein. Tau is found predominantly in neurons and stabilizes the internal microtubules that are part of the cytoskeleton of each neuronal cell. Microtubules are involved in mitosis (cell division) and function as tracks for intracellular transport of nutrients. When tau is hyperphosphorylated, it is removed from the microtubule, causing the microtubule to collapse. This results in disruption of several cellular processes including protein transport and cellular morphology. As tau is removed from the microtubules, it forms aggregates that lead to the development of NFTs, loss of neuronal function, and ultimately neuronal death. The overall NFT load is associated with the degree of cognitive decline (1).

The causes of hyperphosphorylation of tau protein have not been fully elucidated. It is suspected that key enzymes, that either mediate or inhibit the process of phosphorylation are upregulated and downregulated, respectively. Some of these mechanisms may be mediated by impaired glucose uptake and metabolism, which is a well-established cause of neurodegeneration (5). Additional core pathologies in Alzheimer’s include gliosis, brain atrophy with accompanying inflammation, synaptic alterations, and neurovascular breakdown (3).

Clinically, cognitive changes can begin in one’s 40s as subjective cognitive impairment (SCI). SCI is typically noticed by the individual, but standard neuropsychological testing is normal. Mild cognitive impairment typically follows SCI with standard neuropsychological testing showing the beginning of cognitive impairment. Alzheimer’s does not always follow these memory changes, but it is usually preceded by it (1).

Women and Alzheimer’s

The majority of those who suffer from Alzheimer’s are women, but this is only partially due to the fact that women tend to live longer than men. Although older age is the greatest risk factor for developing Alzheimer’s, there are distinct biological mechanisms that increase the risk and progression of Alzheimer’s in women. These risk factors include differences in brain structure and function, differences in the immune system, greater tendency to depression and sleep disorders, psychosocial stress responses, and hormonal changes over a woman’s lifetime (3). Also included in those risk factors are genetics, inflammation, and vascular issues, which can also be found in males with Alzheimer’s but develop in women through mechanisms that are unique to being female.

Female vs. Male: Brain structure and Function

Across the literature, it is agreed that men typically have larger brains than women, which may be due in part to the fact that many men are physically larger than women. Men start with larger brain volume than women and tend to have less or slower structural loss in Alzheimer’s. This has been confirmed by numerous brain imaging studies showing that annual atrophy rates were slower in male Alzheimer’s patients when compared to females (3).

Women tend to have greater cortical thickness (width of gray matter), which provides a measure of protection as it is associated with general intelligence (6). However, women also tend to have a higher rate of pathophysiological changes associated with mitochondrial function and increased oxidative stress that can lead to more rapid neurodegeneration once Alzheimer’s begins. Women also experience greater changes in the white matter of the brain that is responsible for connecting the different areas of the brain and organizing communication and information. In contrast to males with Alzheimer’s, women show a significant association between loss of white matter and lower cognition (3).

When assessing brain structure and function over a lifetime, socioeconomic status related to education, work outside of the home, income level, and engagement in activities that stimulate the brain to learn, adapt, and develop resilience are also important factors to consider. As noted by Calvo and Einstein, resilience mechanisms that prevent neuron loss include verbal processing in which the ability to produce complex, linguistically dense communication early in life seems to reduce the chance of late-life Alzheimer’s (7).

Women and the Stress Response

Adverse life events that potentiate the release of cortisol can lead to brain changes in structure and function that may increase the risk of developing post-traumatic stress disorder, depression and other neuropsychiatric disorders that might predispose women to higher rates of Alzheimer’s (3). Increased stress hormones, specifically cortisol, have been associated with cognitive impairment and Alzheimer’s. The level of corticotrophin-releasing factor 1 (CRF1) was found to be elevated in the hippocampal brain region in people with Alzheimer’s. The hippocampus is the area of the brain that allows us to form new memories. Levels of cortisol in women with Alzheimer’s were found to be much higher than in men. Increased CRF1 signaling is linked to an increase in the Alzheimer’s core pathologies of amyloidosis and tauopathy and women tend have a greater output of CRF1 in response to stress (2, 3). Differing biochemical responses to stress between men and women may reveal one of the intrinsic, sex-dependent risk factors women have for Alzheimer’s.

Stress elicits a very quick response in the brain where activation of the amygdala, hypothalamus, and the brain stem increase dopaminergic and adrenergic activity that alters the function of the prefrontal cortex. Activation of the sympathetic nervous system promotes the release of epinephrine (adrenaline) and norepinephrine (noradrenaline) from the adrenal medulla. Subsequent stimulation of the hypothalamic-pituitary-adrenal axis results in the release of cortisol. Cortisol crosses the blood-brain-barrier where it binds to receptors in the hippocampus, amygdala, and prefrontal cortex (8).

In an acute stress response, this process is normal and returns to a homeostatic state once the stressor has resolved; however, chronic activation of this process can result in the production of pro-inflammatory cytokines that influence neural activity in the brain, resulting in a reduction in synaptic plasticity and impaired memory and learning (2, 8). In human models, both men and women tend to have similar levels of peak cortisol during a stressful event, but the duration of elevated cortisol is longer in women. The effects of cortisol in response to a stressor may be relative to a woman’s level of estrogen. It is suspected that estrogen can act as a buffer against high cortisol, which might explain why symptoms of Alzheimer’s worsen or appear in menopause (2).

Through the process of aging, glucocorticoid (GC) receptors become less responsive, and the production of cortisol-binding globulin may decrease as sex hormones decrease, allowing for a higher degree of circulating free cortisol. This free cortisol can alter the normal circadian rhythm, resulting in disrupted sleep and perpetuation of the stress response with higher cortisol output (8). In both mouse and human models, beta amyloid increased in response to behavioral stressors. Stress also tends to increase the affinity of GC receptors for cortisol in the hippocampus, resulting in a reduction of hippocampal volume (2).

Estrogen Loss and Alzheimer’s disease

Sex differences in Alzheimer’s are significantly linked to the effects of estrogen. As women enter perimenopause and menopause, they can start to experience issues with short-term memory, executive function, and verbal decline. While these symptoms are often transient during the menopause transition, there is also strong correlation between Alzheimer’s development and the loss of steroid hormones as women age (7).

Neurons and glial cells are influenced by estrogen, progesterone, and androgens. More specifically, 17-beta-estradiol is protective against the development of Alzheimer’s due to its effects on neuronal and glial plasticity in women. Glial cells maintain a healthy environment to support neuronal function (7).

The figure shows areas of the brain regulated by steroid hormones (Top), and some of the effects found when a normal or abnormal balance between estrogen and progesterone is present (Bottom) PFC, prefrontal cortex.

Image Credit: Del Río JP, Alliende MI, Molina N, et al. Steroid hormones and their action in women’s brains: the importance of hormonal balance. Front Public Health. 2018;23:6:141. Open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).

In rodent studies where males were deprived of testosterone and females were deprived of estradiol, the female rodents showed a greater loss of neuronal density (7). It appears that the effects of estradiol have a uniquely important role in the female brain as compared to testosterone in the male brain. It is also important to note that the decline in estrogen during menopause occurs more dramatically and over a shorter period of time when compared to the decline of testosterone in men.

Both men and women benefit from the neuroprotective effects of estrogen, but men may maintain higher brain levels of estrogen later in life from aromatase conversion of androgens to estrogen. In both sexes, a major site of extra-gonadal estrogen synthesis is in the brain through aromatase activity. In men, in whom circulating estrogen levels are low, aromatase-dependent production of estrogens from androgens is the main source of estrogens in the brain. This is not true in premenopausal women, in whom brain levels of estrogen derive from local production as well as peripheral estrogens produced in the ovary, which diffuse freely into the brain (9). Menopausal women have low peripheral production of estrogen and lower circulating testosterone levels than men, which limits their ability to make a significant amount of estrogen in the brain through aromatase activity.

Steroid hormones play an essential role in neuronal excitability that contributes to neuroplasticity. In women, estradiol shapes memory circuits by promoting hippocampal activity. Estradiol may enhance dopamine activity, neurogenesis, and cell proliferation, while decreasing cell death and inflammation throughout the brain and nervous system. Reduced tendency towards inflammation adds to the resiliency against the development of Alzheimer’s (7).

Estradiol loss during menopause also leads to reduced mitochondrial function and neurovascular dysfunction both of which may lead to cognitive impairment. Reduced energy production in the brain and decreased blood flow can ultimately lead to cognitive decline. Neurovascular function is influenced by gonadal hormones with estradiol having the greatest influence on blood flow to the brain (7).

Estrogen Replacement Therapy

Calvo and Einstein from the University of Toronto conducted a literature review to explore the steroidal hormone mechanisms that may underlie risk and resilience in women as they age. Their goal was to determine if steroid hormones had a positive or negative influence on the development of Alzheimer’s and the impact steroid hormones would have on glial cells, neuroplasticity, brain reserve, verbal cognitive reserve, and linguistic expression (7).

Calvo and Einstein confirmed the benefits of the postmenopausal use of estradiol and concluded that it significantly reduced the risk of Alzheimer’s. They also make the distinction between the use of conjugated equine estrogens and estrogen (estradiol) replacement therapy and note that there are still questions comparing the benefits of one over the other.

Calvo and Einstein also acknowledge the potential benefits of progesterone and testosterone in the regulation of brain-derived neurotrophic factor, which influences the survival, growth, and maintenance of neurons. It was also noted that timing is key when starting hormone replacement therapy (HRT). The sooner HRT is started, the greater the benefits for preventing Alzheimer’s markers (7).

There is an optimal window of time in which the use of HRT can have its most beneficial effects. This is due to the “healthy cell bias” hypothesis that suggests that neuronal cells need to be healthy to respond positively to HRT. Once the neuronal cells have degraded, the response to HRT can be neutral or even negative (3).

Gathering Information and Starting Early

As women, we will never be without stress, and we cannot avoid the inevitable march towards menopause. We can, however, address some of the modifiable risk factors that specifically predispose women to the development of Alzheimer’s. Monitoring sex hormone levels and measuring salivary cortisol is a good start. Getting baseline values at key points in a woman’s life can guide her in making decisions as she moves through the process of hormonally transitioning from pre-menopause to menopause.

Understanding the source of our stressors and understanding the physiological influence of stress hormones on brain health is something we can all do early in life. Seeing the effects of stress on measured cortisol levels can motivate us to make the necessary changes before these habits become too deeply ingrained and have lasting effects on the health of the brain and body.

ZRT offers several testing options to measure sex hormones and salivary cortisol through all phases of a woman’s hormonal life. Cortisol can be easily measured in multi-point salivary testing taken at timed intervals throughout the day. Sex hormones can be measured in saliva, dried bloodspot, or dried urine. As a woman ages, assessing metabolic markers of HbA1c, fasting insulin, hsCRP and a complete lipid profile can provide additional information that guides dietary and lifestyle choices that aid in the prevention of glucose management issues and cardiovascular disease.

References

ADHD in Women: From the Dreamy-Eyed Girl in the Back of the Classroom to the Menopausal Woman Who Can’t Find Her Keys (Again)

Mon, 14 Aug 2023 08:24:20 -0700

Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in children; however, boys are diagnosed two to nine times more often than girls are (1). Girls do have ADHD, but it often goes unnoticed because it can present much differently than it does in boys. Girls tend to be quiet and inattentive whereas boys tend to be active and disruptive. Children with ADHD can present with symptoms of inattention, hyperactivity/impulsivity, or all of the above, although symptoms may also shift over time (https://www.cdc.gov/ncbddd/adhd/diagnosis.html).

The presentation of ADHD in girls is typically not disruptive to classroom activity, so it may go unnoticed until later in life when coexisting conditions arise either as a consequence of undiagnosed ADHD, or as independent diagnoses. ADHD can present as depression, anxiety, bipolar disorder, issues with self-esteem, underachievement, isolation, and difficulty forming friendships (2). The presence of coexisting disorders tends to reduce the likelihood that girls and young women will be diagnosed with ADHD as many providers are quick to attribute their symptoms of inattentiveness or impulsivity to depression or bipolar disorder (1).

When to suspect ADHD in girls and women

Before diagnosing other disorders in girls who are having issues with self-esteem, difficulty in school or at work, or problems with friendships and other relationships, it is important to determine if there are other family members with ADHD. There is no simple etiology because both genetic and environmental factors can increase the likelihood for ADHD; however, having a first-degree relative with ADHD is associated with a two- to eight-fold increased likelihood regardless of gender (2). Studies in twins indicate that 75%–90% of ADHD is caused by genetic factors. If one person in a family is diagnosed with ADHD there is a 25%–35% probability that another family member also has ADHD. Approximately 50% of parents who have ADHD will have a child with the disorder (3).

Symptoms of ADHD in girls may present as daydreaming, inattentiveness, anxiety, and shyness. They may also have a more impulsive-type presentation expressed as excessive talking, nervousness, risk-taking behavior, and a tendency to be domineering. During adolescence and up to 25 years of age, frontal lobe development related to skills in executive function are emerging and developing. In those with ADHD, this development is delayed, and the lack of skills promotes additional anxiety and dysfunctional behavior furthering issues with self-esteem (2).

For most people, ADHD is not something that you outgrow so diagnosis in adulthood is not uncommon. The mean age of diagnosis in women who have not been diagnosed in childhood is 36 to 38 years of age. The diagnosis often occurs because of a diagnosis in their own children. Prior to a diagnosis of ADHD, these women may have been diagnosed with a mood or anxiety disorder (2). Though these conditions can coexist with ADHD, they may also be a misdiagnosis because ADHD was never considered as the primary cause of their symptoms.

Coping with ADHD

Women who are not aware that they have ADHD may exist with the constant feeling that they can’t seem to measure up to their peers. To make up for a feeling of lack, some women with ADHD can go to the extreme of perfectionism and diligence in certain areas of their lives to attain a sense of control over the internal overwhelm that seems to define their existence. Many women do not present with the physical hyperactivity of ADHD, but that hyperactivity is turned inward and manifests as a racing mind and a sense of overwhelm (1).

Through maturity and necessity, women learn various coping mechanisms and strategies that help them to manage what may feel like a level of internal chaos. Life often becomes overwhelming for young and middle-aged women as they attempt to manage life, work, children, and social expectations (1). Most of these women are very intelligent and develop strategies to cope with their own personal idiosyncrasies; however, the need to implement these coping mechanisms can be exhausting as it adds an extra layer of complexity to an already complex life.

Hormones and ADHD

Specific for women with ADHD are the hormonal fluctuations that accompany puberty, monthly menstrual cycles, pregnancy, perimenopause, and menopause. Hormonal fluctuations can be more extreme in women with ADHD as there is already a tendency towards emotional dysregulation. Depression, premenstrual syndrome and premenstrual dysphoric disorder tend to be more common in women who have ADHD. Symptoms of ADHD can be better during the late follicular and ovulatory phases when estrogen is rising and worse during the luteal phase when progesterone is rising and potentially decreasing the beneficial effects of estrogen on the brain (4). Overall, hormonal fluctuations and transitional periods of life can influence the symptoms and presentation of ADHD in women (2).

Estradiol has complex and widespread effects on the nervous system. The aging process that occurs in the nervous system is closely related to the aging process in the endocrine system. The perimenopausal phase of a woman’s life is often characterized by symptoms such as headaches, sleep disturbance, mood fluctuations, anxiety, depression, and impaired cognitive function. When the hormonal balance is disrupted, women are at greater risk of developing neurocognitive dysfunction (5).

A diagnosis of ADHD may occur at the time of menopause because the severity of hormonal decline unmasks the underlying diagnosis. Correspondingly, the decline in executive function may simply appear similar to the symptoms of ADHD because of the effects of declining hormones on neurotransmitter levels and cognitive function.

Executive function and menopause

Executive function is a set of mental skills that includes working memory, cognitive flexibility, and self-control. We use these skills to learn, focus, and manage everyday life. Issues with executive function make it difficult to focus, plan, organize, prioritize, finish tasks and projects, and manage emotions (6). The definition of executive function deficit describes the symptoms of ADHD very closely because it is a main contributor to the disorder. Executive function issues also arise with menopause because of the loss of estrogen and its effects on dopamine.

A study by Epperson et al on the effects of lisdexamfetamine (LDX) in 32 perimenopausal and early postmenopausal women experiencing mid-life onset executive function difficulties revealed a significantly positive effect of LDX over placebo. LDX, also known as Vyvanse®, is a stimulant medication often used in the treatment of ADHD in adults and children. Stimulant medication enhances the dopaminergic system and improves executive function. It is important to note that none of the women in this study were diagnosed with ADHD prior to the onset of perimenopause and menopause (7).

Neurosteroids, neurotransmitters and brain function

Fluctuations in sex hormones affect the central nervous system and influence various brain areas that regulate mood, behavior, and cognitive abilities. Sex hormones are part of the larger category of steroid hormones. Steroid hormones with activity in the nervous system are called neurosteroids. Steroid hormones are mostly synthesized peripherally in the ovaries, adrenals, and adipose tissue and enter the nervous system by crossing the blood-brain-barrier. Neurosteroids can also be produced in the central and peripheral nervous systems by neurons and glial cells (5).

Neurosteroids participate in the regulation of neurotransmitters and neuronal excitability at the synaptic level. Neurotransmitters are signaling molecules that carry messages from one neuron to another. Dopamine is one of the main neurotransmitters responsible for focus and attention. Alterations in the dopamine signaling system are prevalent in ADHD and in menopause-related cognitive decline (8).

Fig 1. Role of neurosteroids in the modulation of the four main neurotransmitters. Estrogen (green) and progesterone (yellow) interact with GABAergic, glutamatergic, serotonergic, and dopaminergic synapses at different levels: neurotransmitter synthesis, release, degradation, and neurotransmitter receptor synthesis, activation or inhibition 5HT, serotonin; MAO, monoamino oxidase; preoptic area; PFC, prefrontal cortex. Del Rio JP, Alliende MI, Molina N, et al. Steroid hormones and their action in women’s brains: the importance of hormonal balance. Front Public Health. 2018;6:141. Creative Commons licensing.

Dopamine and ADHD

ADHD is viewed as a heritable neuropsychiatric condition linked to pathogenesis of brain dopamine. Molecular genetic studies have identified several genes that may mediate susceptibility to ADHD. The consensus in the literature on ADHD points to a dysfunction in the dopamine system that mediates the brain reward cascade. Blum et al see ADHD as part of a larger umbrella condition referred to as reward deficiency syndrome in which there is a disruption of the normal cascade of neurotransmitters that stimulate the reward centers of the brain (3). This may be why the decline in executive function in menopause is aptly described by the symptoms of ADHD.

The genetic trait that predisposes to ADHD is due in part to the D2 dopamine receptor (DRD₂) A1 allele that prevents the expression of the normal production of dopamine receptors in brain reward sites. The brain lacks sufficient numbers of dopamine receptor sites to receive a normal amount of dopamine. This ultimately results in a reduction in dopamine production in the reward centers of the brain (3).

While the DRD₂ gene may play a significant role in ADHD predisposition, it must be tied to a certain subset of additional genes for the clinical expression of ADHD (3). Additional genetic traits associated with ADHD include variants of the dopamine receptor D4 gene that influences the post-synaptic action of dopamine and DAT1, which is a dopamine transporter gene that mediates the reuptake of dopamine from the neural synapse (9). Stimulant medications commonly used to treat ADHD enhance dopamine signaling and improve the ability to focus.

Estrogen and dopamine

Through various signaling mechanisms, estrogen interacts with neurotransmitters that are highly involved in cognition and mood. Of the neurotransmitters that estrogen is involved with, the dopaminergic system is the most pronounced (10). Estradiol has been shown to impact working memory by enhancing dopamine activity and slowing reuptake (8).

Estradiol has a dopamine agonist-like effect on behavioral and neural processes that promote dopamine production and signaling. Certain estrogen metabolites (catechol estrogens) can also inhibit enzymes (catechol-o-methyltransferase) that inactivate dopamine. This is particularly true for dopamine in the pre-frontal cortex (PFC), which allows for the increased availability and stimulation of this powerful neurotransmitter (8). In short – increased estrogen and estrogen metabolites promote dopamine activity. If estrogen and its metabolites are low, the availability and action of dopamine in the PFC is also reduced.

Another mechanism by which estrogen influences dopamine levels and activity is through the DAT1 responsible for the reuptake of dopamine that ultimately terminates dopaminergic transmission. Estrogen inhibits DAT1 activity, which decreases uptake and increases the time for dopamine to exert its effect within the synaptic space (11).

Estrogen levels and cognitive abilities through the lifespan

Symptoms of ADHD appear differently in females than in males and cognitive abilities are affected by fluctuations in estrogen throughout the lifespan. As a woman enters perimenopause and menopause, cognitive complaints are common as hormones, particularly estradiol, are declining. The impact of declining estrogen on the dopaminergic system is a key component in the symptoms related to cognitive dysfunction and can present very similarly to ADHD. Estrogen clearly has neuroprotective effects over a woman’s lifetime as evidenced by studies reporting that prolonged exposure to estrogen results in better cognitive outcomes later in life (12).

In the brain, estradiol has neuroprotective effects that include modulation of neuropeptides and neurotransmitters, reduced cell apoptosis, modulation of neuronal growth and synaptic plasticity, support of mitochondrial activity, antioxidant properties, increased vasodilation and cerebral blood flow, regulation of brain glucose metabolism, reduced inflammation, and decreased formation of beta-amyloid, which is associated with the development of Alzheimer’s disease (12).

As women enter menopause, the timing of hormone replacement therapy is crucial for preserving cognitive function. The neuroprotective effects of estrogen are optimized early before deterioration within the brain and nervous system has occurred. This is referred to as the “healthy cell bias” (13). The sooner hormones are started, the better the outcome.

Between 1995 and 2006, the Cache County population-based study analyzed the records of 1,768 women who had provided a detailed history on the age at menopause and the use of hormone therapy. The study revealed that the women who used any type of hormone therapy within five years of menopause had a 30% reduced risk of Alzheimer’s disease. In contrast, women who started hormone therapy five years beyond the age of menopause showed increased rates of Alzheimer’s disease (14). As a woman’s neurological status progresses from healthy to unhealthy, the benefits of estrogen therapy decrease. If neurons are healthy at the time of estrogen exposure, their response to estrogen is beneficial for both neurological function and survival. In contrast, if neurological health is compromised, estrogen exposure over time exacerbates neurological demise (13).

Testing sex hormones, cortisol, and neurotransmitters

ZRT Laboratory offers a number of tests to measure sex hormones, cortisol, and neurotransmitters. As a young woman or a woman enters the middle phase of life, testing can provide valuable information regarding hormonal status, the stress response, and the balance between several neurotransmitters and metabolites.

Managing symptoms of ADHD or cognitive dysfunction related to menopause can create additional stress that may be revealed in a salivary adrenal stress profile. In the premenopausal years, assessing sex hormones within the menstrual cycle can reveal imbalances between estrogen and progesterone that may be contributing to symptoms related to cognitive dysfunction. If hormone replacement therapy is a consideration, testing hormones while in perimenopause or menopause can confirm the need for hormone replacement.

Neurotransmitter testing through ZRT provides a measurement of 14 neurotransmitters and metabolites that provides insight regarding the source of deficiency or excess. The information provided by hormone, adrenal, and neurotransmitter testing can be used to determine where to begin in the process of addressing executive function issues and cognitive dysfunction throughout a woman’s lifespan.

References

The Estrobolome: The Bidirectional Relationship Between Gut Microbes and Hormones

Mon, 17 Jul 2023 11:44:49 -0700

The human microbiome maintains a close relationship with the endocrine system, indicating that these systems engage in meaningful communication and have a deep influence on each other. This is especially true in the case of estrogens and the gut microbiome. The estrobolome is the portion of the microbiome that influences estrogen metabolism. First defined in 2011, the estrobolome is the collection of all enteric bacteria capable of metabolizing estrogens (1). The estrobolome can impact endogenous estrogen metabolism by modulating the enterohepatic circulation of estrogens thus influencing plasma estrogen levels (2). Dysbiosis, diet, and gut infections can alter the microbial environment that influences how estrogens are metabolized and cleared from the body.

Function of the estrobolome

The gut microbiome encodes a vast number of enzymes that function in a variety of metabolic pathways, including the biosynthesis of essential nutrients, the breakdown of complex carbohydrates and the biotransformation of metabolic products such as conjugated estrogens. The estrobolome contributes to estrogen homeostasis where both elimination and recycling help to maintain a healthy balance of estrogens. Estrogens also regulate the gut microbiome in a positive manner by increasing the diversity of the gut microbiota and augmenting the enzymes that metabolize estrogens (3).

Interactions between the human host and microbes have the potential to influence carcinogenesis through mechanisms such as chronic inflammation, induction of genotoxic responses, and alteration of the microenvironment where this interface occurs (4). Estrogens can impact the gut microbiota to support immune function, regulate inflammation, and influence hormone-dependent cancers especially after menopause. While the reactivation of estrogen metabolites may serve specific functions, it has also been hypothesized that a woman’s estrobolome plays an influential role in the development of several hormonal disorders, including breast, endometrial, and ovarian cancers (2).

Liver metabolism and estrogens

Estrogens are primarily produced by the ovaries in premenopausal women and by the adrenal glands and adipose tissue in postmenopausal women. They circulate in the bloodstream in free or protein-bound forms and undergo metabolism primarily in the liver where they are converted to inactive metabolites through Phase I and Phase II liver detoxification pathways (4). Phase I liver detoxification involves cytochrome P450 enzyme pathways, converting estrogens into more water-soluble compounds.

Phase II liver detoxification conjugates (sulfation and glucuronidation), oxidizes, reduces, and/or methylates estrogen metabolites from Phase I liver detoxification. The conjugation of estrogens to glucuronic acid specifically marks the estrogen-glucuronide for elimination where it eventually passes through the kidneys for elimination through the urine or is moved out of the liver through the bile where it is ultimately released into the bowel for elimination through the stool. Conjugated estrogens excreted in the bile can be deconjugated by β-glucuronidase enzymes produced by resident bacteria in the intestines. This subsequently leads to estrogen reabsorption through enterohepatic circulation and ultimately enables estrogens to enter target tissues, where they bind to and activate estrogen receptors (4).

Gut enzymes and estrogen metabolism

The gut microbiome is a principal regulator of circulating estrogens (5). There are 279 β-glucuronidases that have been identified in the Human Microbiome Project and they are produced by a variety of normal gut microbial species and have varying degrees of activity. Additionally, sulfatase enzymes, though less characterized than β-glucuronidases, also play a role in estrogen metabolism. Gut microbial sulfatases process sulfated forms of estrogens and DHEA (6).

A bidirectional regulatory system between β-glucuronidases and estrogens exists to maintain estrogen homeostasis in the body (7). Beyond simple reactivation of estrogens, the estrobolome acts as an estrogen reservoir in the gut and is capable of creating estrogenic metabolites for local and nonlocal functions (2). Estrogens regulate the gut microbiome in a positive manner by increasing microbial diversity. Increased microbial diversity is associated with decreased production of β-glucuronidases, allowing for greater excretion of conjugated estrogens.

When systemic estrogens are low, as in perimenopause or menopause, microbial diversity decreases and production of β-glucuronidases increases, potentially allowing for enhanced estrogen recycling (3). Though β-glucuronidases aid in the regulation of local and systemic levels of estrogens, an overabundance of these enzymes in the gut and other tissues may contribute to a state of estrogen dominance, where estrogen levels are high relative to progesterone and cause excessive stimulation of growth of estrogen sensitive tissues such as the breasts and uterus.

Signs of estrogen dominance include:

Fibrocystic breasts
Uterine fibroids
PMS/PMDD
Mood swings/anxiety/depression
Hormone-related headaches
Heavy menses/irregular cycles
PCOS
Infertility
Endometrial hyperplasia
Breast cancer
Weight gain and water retention

β-glucuronidase enzymes reactivate estrogens. Gut microbial β-glucuronidase enzymes within the GI deconjugate estrone-3-and estradiol-17-glucuronides to the aglycones estrone and estradiol, respectively. This reactivation allows unbound estrogens to be recirculated through the bloodstream, possibly contributing to a variety of hormonal disorders including breast cancer and endometriosis. Ervin SM, Li H, Lim L, et al. Gut microbiome–derived β-glucuronidases are components of the estrobolome that reactivate estrogens. J Biol Chem. 2019;294(49): jbc.RA119.010950. Creative Commons licensing.

Balanced gut bacteria and the estrobolome

Bacteroidetes and Firmicutes, the main phyla dominant within the GI tract, are the primary source of β-glucuronidases. A higher ratio of Firmicutes to Bacteroidetes may be indicative of a high-fat diet in which saturated fat from meats has the greatest effect on promoting bacteria that produce β-glucuronidases. As noted by Sui et al, a considerable number of studies have linked a high-fat diet with increased β-glucuronidase activity. Additionally, a higher ratio of Firmicutes to Bacteroidetes is linked to obesity, which predisposes one to several chronic diseases, including cancer. The β-glucuronidases produced from the Firmicutes phyla of bacteria have the highest level of estrogen reactivation as compared to those from the Bacteroidetes phyla (7).

What about androgens and progesterone?

You’re probably asking– what about an androbolome or a progestobolome? There are some studies showing that androgens and progesterone interact with the gut microbiome in a bidirectional manner, but it is less well characterized than the estrobolome. Changes in the gut microbiome when testosterone and progesterone are increased have been demonstrated, and we can see the systemic effects of that relationship (8, 9).

In the liver, testosterone is metabolized similarly to estrogens that are hydroxylated by Phase I enzymes in the liver and then glucuronidated or sulfated in Phase II. The testosterone conjugates are then absorbed and excreted through the urine or expelled through the bile into the intestines. The β-glucuronidase enzymes can act on testosterone-glucuronides just as these enzymes can act on estrogen-glucuronide, resulting in the freeing of testosterone to be reabsorbed systemically (10). This familiar mechanism can result in increased systemic testosterone with increased β-glucuronidase levels in the gut, and would potentially free testosterone for reabsorption.

Progesterone metabolism is more complex, resulting in multiple metabolites formed through sequential enzymatic reduction pathways that ultimately form pregnanediols. In Phase I reactions, progesterone is converted primarily to pregnanediol that is converted to pregnanediol-glucuronide. Progesterone is also metabolized to allo-pregnanolone, a neuroactive molecule that freely enters the brain and has a calming effect through its interaction with GABA-A receptors (11). Removal of the glucuronide in the gut transforms pregnanediol-glucuronide back to pregnanediol, which is inert and does not have the anti-estrogenic activity of progesterone. This would mean that gut metabolism of glucuronides of estradiol and pregnanediol would lead to an overabundance of estradiol without the protective actions of progesterone.

Qi et al have noted changes in the gut microbiota of pregnant women which were linked to differences in metabolic, immunological, and hormonal variations. High progesterone levels are essential for a healthy pregnancy and fetal development. In turn, dramatic shifts in hormone levels also impact gut function and bacterial composition, accompanied by unique inflammatory and immune changes that are supportive of pregnancy (11).

Seeing the unseen

Stool testing can help us to ‘see the unseen’ by examining the various species of bacteria in the gut. We can also review functional markers of digestion, inflammation, mucosal immunity, and deconjugating enzymes such as β-glucuronidase. Poor digestion of proteins, carbohydrates and fats can contribute to bacterial imbalances throughout the GI tract and may indicate the need for digestive support and functional evaluation of the liver, biliary tract, and pancreas.

Elevated inflammatory markers may be indicative of infections, food sensitivities and intolerances, inflammatory bowel disease, and cancer. Elevated markers of mucosal immunity may indicate infection and inflammatory processes that can eventually lead to gut permeability (leaky gut) and systemic disease and inflammation. Low levels of mucosal immune markers indicate poor resistance to infection, microbial imbalances, and chronic stress. A high level of β-glucuronidase enzymes on a stool test is associated with dysbiosis and may increase circulating levels of estrogens, mostly estrone and estradiol.

Testing of saliva and blood for estrogens, progestogens, and androgens and urine for steroid hormone metabolites should help determine the source of estrogen dominance that may be precipitated by gut dysbiosis.

What exactly is dysbiosis?

Dysbiosis is a broad term used to describe an imbalance in bacterial composition, changes in bacterial metabolic activities, or changes in bacterial distribution within the gut (12). Dysbiosis disrupts homeostasis by reducing microbial diversity and is associated with increased oxidative stress, inflammation, and damage to DNA repair mechanisms (3). Dysbiosis may also increase the Firmicutes to Bacteroidetes ratio which can lead to an inflammatory state that is detrimental to the health of gut epithelial cells and can compromise gut barrier integrity, leading to intestinal permeability and bacterial translocation (5). Lipopolysaccharides (LPS) are components of gram-negative bacteria that, when systemically absorbed through a permeable gut membrane, can trigger inflammation and induce systemic diseases such as insulin resistance, PCOS, and metabolic syndrome (11).

The three main types of dysbiosis and support options include:

Loss of beneficial bacteria or deficiency dysbiosis as is often seen with antibiotic use and reduced consumption of a wide variety of plant-based foods. Support with prebiotics, probiotics, increased consumption of plant-based foods and sources of fiber.
Overgrowth of potentially pathogenic bacteria as seen with co-infections (microbial, parasitic, fungal) and high-carb, high-fat diets. Support with botanical antimicrobials, probiotics, binders, digestive enzymes, fiber and treatment of underlying infections.
Loss of overall bacterial diversity as seen with poor diet, disease, antibiotics, and chronic gut inflammation. Support with prebiotics, probiotics, increased consumption of plant-based foods and sources of fiber along with regular exercise.

Supporting a healthy estrobolome

Diet, lifestyle, and robust elimination support a healthy estrobolome and keep β-glucuronidase and sulfatase enzymes within a healthy range to maintain a homeostatic state between estrogen elimination and estrogen reactivation. Excessive alcohol, sugar, processed foods, antibiotics, a lack of physical activity, and exposure to chemical toxins are contributors to microbial imbalance. A diet rich in fiber and resistant starches that feed the good bacteria in the GI tract are key to supporting a healthy balance of good bacteria and short-chain fatty acids, as well as keeping the bowels regular.

Daily elimination of estrogens through the gut and urine is necessary for the clearance of end-products of detoxification. The longer the estrogen conjugates from Phase II liver detoxification reside in the bowel, the greater the opportunity for deconjugating enzymes to act on these products and release excessive estrogens back into the systemic circulation. In addition to supporting the clearance of hormones, glucuronidation also participates in the elimination of neurotransmitters, thyroid hormones, bilirubin, chemical toxins including Bisphenol-A, drugs, mycotoxins, and other carcinogens (13).

Addressing underlying infections and dysbiosis by employing the use of botanicals, prebiotics, probiotics, and a diet weighted towards a variety of plant-based foods is supportive of gut health and a balanced estrobolome. Additionally, spending time in nature, with pets, and gardening are activities that are supportive of developing a healthy and diverse microbiome that gives back to us on multiple levels. As we learn more about the bacterial composition and function of our various microbiomes, we can understand the importance of supporting and optimizing their various roles in keeping us healthy.

Monitoring hormones

Correlating symptoms of estrogen excess with measured hormone levels provides objective data that can be monitored over time as efforts are made to improve estrogen metabolism through liver and microbiome support. Symptoms of estrogen excess or deficiency may be related to how efficiently hormones are cleared from the body. Estrogen clearance and recycling that occurs via the enzymes produced by the estrobolome can impact the systemic effects of estrogen. ZRT Laboratory offers a variety of tests to evaluate hormone levels either through dried urine, salivary, or dried blood spot sampling and can also be utilized to monitor efforts to create balance between estrogen elimination and recycling.

References

Catecholamines, Cortisol and Long COVID

Fri, 21 Apr 2023 09:13:09 -0700

In a previous four-part series, I examined some of the main issues associated with long COVID, focusing on the central nervous system, ongoing inflammation and autoimmunity, mitochondrial dysregulation and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. While the science regarding these topics is still evolving, taking a closer look at the effects of long COVID on epinephrine, norepinephrine, and cortisol will provide some insight regarding the toll that COVID can take on the autonomic nervous system (ANS) and the HPA axis.

The symptoms of long COVID can be so severe that the sufferer cannot return to their previously productive life. Some of the most debilitating symptoms are fatigue, brain fog and blood pressure issues associated with ANS dysfunction. This unfortunate combination of symptoms renders the sufferer physically and mentally incapacitated and unable to work or perform basic activities of daily living. In this article, we will take a closer look at the mechanisms of dysfunction in these conditions and how the SARS-CoV-2 virus and the COVID vaccine contribute to these conditions.

Definition of Long COVID

According to the CDC, the long-term effects of COVID can be referred to as long COVID, long-haul COVID, post-COVID condition, post-acute COVID-19, post-acute sequelae of SARS-CoV-2 infection (PASC), long-term effects of COVID, and chronic COVID. Regardless of the name, the condition is defined by a wide range of symptoms that can last weeks, months, or even years after the initial infection. The symptoms may have a waxing and waning nature and the development of the condition is not dependent upon the severity of the illness (1).

There is currently no single test to diagnose long COVID and standard blood tests, scans and x-rays may all appear normal. Long COVID presents similarly to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is also considered a post-viral syndrome presenting with unrelenting fatigue, brain fog, body pain, sleep issues, dizziness, and orthostatic intolerance. Similar to ME/CFS, long COVID tends to relapse after exercise (post-exertional malaise), and with physical or mental activity and stress (2). Long COVID has a significant impact on the endocrine system where many of the generalized symptoms overlap with symptoms of adrenal insufficiency.

Long COVID as a Disability – Where Have All the Workers Gone?

It is suspected that symptoms of long COVID affect approximately 30-50% of those who have been infected (3). Long COVID is considered a disability under the Americans with Disabilities Act because it can substantially limit one or more major life activities and presents with physical or mental impairment associated with past COVID infection (4). A recent article in the Journal of the American Medical Association suggests that unemployment rates are higher among those with self-reported symptoms of long COVID (5). Fortune magazine estimates two to four million members of the American workforce are unemployed due to long COVID. These numbers are based on U.S. Census Bureau data released in June 2022 (6).

Long COVID symptoms are also prevalent in those who received the COVID vaccine but have not had the virus (7). The common feature between infection with the virus and the vaccine is the spike protein. If the spike protein from the infection is a major player in the development of long COVID, we must acknowledge the potential for similar symptoms to occur in the vaccinated population who have high levels of spike protein and antibodies to the spike protein.

Function of the Autonomic Nervous System

One of the most debilitating symptoms of long COVID is orthostatic intolerance, which is associated with ANS dysfunction. The ANS is part of the peripheral nervous system that regulates involuntary physiological functions such as blood pressure, heart rate, respiratory rate, and digestion (8).

The hypothalamus is one of the main autonomic centers in the brain and may serve as the route by which SARS-CoV-2 can reach the autonomic network. The hypothalamus houses a structure called the paraventricular nucleus (PVN) that not only controls neuroendocrine and autonomic function, but also regulates the HPA axis through the release of corticotrophin-releasing hormone (CRH) that stimulates the pituitary to produce adrenocorticotropic hormone (ACTH) (8). ACTH stimulates the adrenal cortex to produce cortisol as part of the stress response.

The PVN also exerts negative feedback control over the HPA axis through the presence of cortisol receptors. There must be an adequate production of cortisol as part of the stress response to provide negative feedback to the PVN in the hypothalamus. If cortisol is low, the stress response cannot self-regulate and may result in excess production of catecholamines (epinephrine, norepinephrine) (8).

Fig 1. Signaling pathways between the central nervous system and the peripheral nervous system that maintain chronic illness with relapse and partial recovery phases. Tate W, Walker M, Sweetman E, et al. Molecular mechanisms of neuroinflammation in ME/CFS and long COVID to sustain disease and promote relapses. Front Neurol. 2022;13:87772. Open access under the Creative Commons CC-BY license.

Mechanisms of Autonomic Dysfunction Post-COVID 19

Autonomic dysfunction can present as fatigue, dizziness, fainting, shortness of breath, orthostatic intolerance, nausea, vomiting, and heart palpitations. Direct infection of the hypothalamus by the SARS-CoV-2 virus via neuronal or hematogenous routes can lead to autoantibodies against brain tissue, cause persistent inflammation, and contribute to hypoxia (8).

The hypothalamic response to infection can lead to sympathetic overactivation and increased release of epinephrine and norepinephrine. The dysfunctional ANS presentation seen in long COVID may be due to the excessive release of catecholamines in response to orthostatic intolerance and brain hypoxia. Autonomic dysfunction can occur as a presyncope or syncope episode, both of which are caused by decreased blood flow to the brain. Syncope is the medical term for fainting and usually occurs from a vasovagal, situational, or carotid sinus event. Presyncope and syncope can occur with orthostatic hypotension and postural orthostatic tachycardia syndrome (POTS). Autonomic dysfunction can also present as hypertension and cardiac arrythmias through sympathetic nervous system (SNS) hyperactivation and the resulting elevated catecholamine levels. The SNS activation occurs as a corrective response to orthostatic hypotension (8).

Low blood pressure and low blood volume activate the SNS to create high levels of catecholamines. The overactivation of the SNS may trigger an accentuated counter-regulatory response through activation of the vagus nerve resulting in paradoxical vasodilation and sympathetic withdrawal, which clinically presents as dizziness, hypotension, and ultimately presyncope or syncope (9).

Fig 2. Potential underlying mechanisms by which long COVID leads to dysautonomia and postural orthostatic tachycardia syndrome (POTS). Chadd KR, Blakey EE, Huang C, et al. Long COVID -19 and postural orthostatic tachycardia syndrome – is dysautonomia to be blamed?
Front Cardiovasc Med. 2022;9:860198. Open access under the Creative Commons CC-BY license.

Symptoms of Autonomic Dysfunction

Orthostatic hypotension is defined as a drop in systolic blood pressure by 20 mmHg and a drop in diastolic blood pressure by 10 mmHg within three minutes of standing from a supine position. The same symptoms occur with POTS, but it is accompanied by tachycardia with a heart rate reaching at least 100 bpm within three minutes of standing. People with POTS can also experience impaired attention, processing speed and executive function, which presents as the common descriptor of brain fog. Though not proven, it is suspected that these symptoms occur due to decreased blood flow to the brain and elevated levels of norepinephrine (8).

In a study referenced by Jammoul et al, nine patients with long COVID experienced reduced cerebral blood flow upon standing, which was comparable to a group of patients with a diagnosis of POTS. The study participants also presented with symptoms of high epinephrine. Additional symptoms included diarrhea, face flushing, restlessness, and tremors. As previously mentioned, the activation of the SNS can be accentuated and ongoing if low cortisol cannot provide the negative feedback to reset the stress response and turn off the production of catecholamines (8).

HPA Axis Dysfunction and Low Cortisol Post-COVID

Hypocortisolism is the main hormonal disorder diagnosed in patients with long COVID. Central adrenal insufficiency is also described in patients with active SARS-CoV-2 infection. ACTH shares similar amino acid sequences with the SARS-CoV-2 virus, which may result in antibody production against ACTH in response to the presence of the virus (10).

Molecular mimicry is one of the leading mechanisms by which infectious or chemical agents may induce autoimmunity. It occurs when similarities between foreign and self-peptides favor an activation of autoreactive immune cells in a susceptible individual. As a result of molecular mimicry, the antibodies targeted for the virus may inactivate endogenous ACTH and destroy ACTH-secreting cells in the pituitary (2). ACTH is necessary to stimulate the adrenal cortex to produce cortisol.

The adrenal cortex also produces angiotensin-converting enzyme 2 (ACE2) receptors in the zona fasciculata and the zona reticularis. Binding of the virus to the adrenal ACE2 receptors may lead to direct damage to cells within the adrenal cortex, resulting in reduced cortisol production. Autopsy studies in patients with COVID-19 revealed necrosis of the adrenal cortical cells and identified the virus in the adrenal glands (2).

Susceptible cells in the adrenals also need to express co-receptors required for SARS-CoV-2 internalization such as transmembrane serine protease 2 and furin protease. Several reports have confirmed the expression of these receptors in the adrenal glands, indicating that the virus may actively replicate in adrenocortical cells (11). Active infection of adrenocortical cells with SARS-CoV-2 is also associated with inflammation and activation of apoptosis. Treatment of COVID with high-dose, very potent synthetic steroids may also suppress endogenous cortisol production (12).

Some studies have addressed the concern of adrenal insufficiency with long COVID. Sara Bedrose, MD, MSc, an adrenal endocrine specialist at Baylor College of Medicine, has noted that a large percentage of COVID survivors experience suboptimal cortisol secretion during ACTH stimulation testing, which is diagnostic of central adrenal insufficiency. It is suspected that the adrenal insufficiency may in part be due to pituitary gland inflammation or direct hypothalamic damage from infection (13).

Small Fiber Neuropathy and Mast Cell Activation Syndrome

Other conditions that contribute to autonomic dysfunction and have been linked to the development of long COVID are small fiber neuropathy (SFN) and mast cell activation syndrome (MCAS). Both conditions can stimulate the stress response via the SNS and the HPA axis as described above. General symptoms of SFN include fatigue, cognitive disturbances, headache, and widespread musculoskeletal pain (14). SFN has been associated with ME/CFS and has been diagnosed as a contributing disorder in the symptom profile of ME/CFS, fibromyalgia, long COVID and as a side effect of the SARS-CoV-2 mRNA vaccine.

In a July 2022 article in the Journal of Family Medicine and Primary Care, Josef Finsterer cites three cases of post-vaccine SFN. The collection of symptoms in all three women included fatigue, dizziness, flushing, palpitations, diarrhea, muscle weakness, gait disturbance, balance problems, brain fog, dysphagia, sleep problems, presyncopal sensations, hair loss, chest pain, dyspnea, paresthesias, irregular menstrual cycles, and hives. All three patients underwent a skin biopsy confirming SFN, which revealed reduced intraepidermal nerve fiber density (7). None of the patients had been diagnosed with COVID prior to their vaccinations and had uneventful medical histories. It was presumed that the SFN was immune mediated as it responded well to intravenous immunoglobulin therapy.

MCAS occurs when excessive amounts of inflammatory mediators (cytokines, histamine, heparin, growth factors) are released in response to triggers such as foods, fragrances, stress, exercise, medications, or temperature changes. Excessive release of mast cell mediators can also occur during acute and chronic infections as mast cells participate in innate and adaptive immunity. Increased activation of aberrant mast cells induced by SARS-CoV-2 infection by various mechanisms may underlie part of the pathophysiology of long COVID (15). Symptoms of MCAS include episodes of abdominal pain, cramping, diarrhea, flushing, itching, wheezing, coughing, fatigue, body pain, fainting, rapid pulse, and low blood pressure.

SFN and MCAS both have effects on vascular function, which can present as orthostatic intolerance and autonomic dysfunction. These conditions can trigger the SNS and HPA axis to release catecholamines and cortisol to regulate blood pressure and vascular dynamics. If cortisol output is low due to adrenal insufficiency, the initial response of the SNS via catecholamines may not receive adequate feedback from cortisol to decrease the output of catecholamines. Continuous activation of the HPA axis can also result in excessive release of CRH, which further stimulates mast cells (3).

The New Frontier

We are over three years into the pandemic-response-sequelae of COVID-19, and it’s not done with us yet. While the severity of the acute infection with the virus has waned, coronaviruses tend to mutate quickly so keeping up with emerging variants via vaccine protection seems to fall into the realm of “chasing our tails.” We are also faced with the somewhat daunting task of learning how to address long COVID and spike protein illness that can arise from either the virus or the vaccine. Focusing on the effects of the spike protein on different systems within the body will guide our way through this process.

The effects of the spike protein on the adrenals and the broader HPA axis has been the focus of this discussion. SARS-CoV-2 can have direct impact on the adrenals themselves and, through dysfunction in other systems, affect the overall functional response of the stress mechanisms that stimulate the HPA axis. The suspicion of adrenal insufficiency can easily be validated through timed measurements of salivary cortisol and DHEA-S. In addition, diurnal measurements of urinary cortisol, cortisone, epinephrine and norepinephrine provide insight regarding the stimulation of the SNS. Measuring cortisol and catecholamines can encompass the major players in the stress response loop. While we always must consider the underlying drivers of an imbalanced stress response, we can appropriately support the HPA axis while we attempt to address larger issues.

Recommended Testing for Long COVID

ZRT Laboratory has developed tests to evaluate response of the HPA axis and peripheral SNS in patients with long COVID syndrome. Research studies have shown that long COVID symptoms are closely associated with disrupted circadian rhythms and abnormal levels of stress hormones. Cortisol, cortisone, melatonin, norepinephrine, and epinephrine are biomarkers of the stress response to inflammation from viruses like SARS-CoV-2 and the aftermath of the disease that cause long COVID. The five stress markers are tested by LC-MS/MS in urine collected four times throughout the day (first morning, second late morning, late afternoon, and night), allowing for diurnal assessment of their levels as it relates to disease status or recovery from viral infections like COVID.

The five stress markers are stabilized by collecting and drying the urine on filter strips, which prevents degradation of norepinephrine and epinephrine, which occurs rapidly in liquid urine. Dried urine strips allow for convenient shipment to the testing lab at ambient temperature, avoiding costly and inconvenient cold chain shipment as required for liquid urine samples. Test results for each of the five stress hormones, analyzed at the four time points, are presented on real time 24-hour contiguous graphs compared with expected reference ranges in healthy individuals. This test is an excellent tool to evaluate the stress impact of long COVID, as well as other inflammatory diseases such as cardiovascular disease, cancer, diabetes, and senile dementia on adrenal and SNS function. For more information about ZRT’s Diurnal Urinary Stress Hormone Test (DUSHT), give our Customer Service Team a call at 866.600.1636.

Acronym key

Adrenocorticotropic Hormone (ACTH)
Angiotensin-Converting Enzyme 2 (ACE2)
Autonomic Nervous System (ANS)
Corticotrophin-Releasing Hormone (CRH)
Diurnal Urinary Stress Hormone Test (DUSHT)
Hypothalamic-Pituitary-Adrenal (HPA)
Liquid Chromatography-Mass Spectrometry (LC-MS/MS)
Mast Cell Activation Syndrome (MCAS)
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Paraventricular Nucleus (PVN)
Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)
Postural Orthostatic Tachycardia Syndrome (POTS)
Small Fiber Neuropathy (SFN)
Sympathetic Nervous System (SNS)

References

Curious About Iodine, Part 3: Antioxidant, Immune Support, Anti-Cancer

Mon, 13 Feb 2023 08:02:07 -0800

At the most fundamental level, the beneficial actions of iodine derive from its ability to function as both an antioxidant and an oxidant. These basic qualities also support its effects as an antimicrobial, anti-proliferative and anti-cancer agent. How iodine functions within the human body is determined by its form, the tissue in which it resides and the overall physiological context. Iodine’s role as an antioxidant is determined by its ability to donate electrons and quench free radicals thereby reducing tissue damage and oxidative stress that may lead to chronic disease. As an oxidant, iodine can support the immune system by effectively supporting antimicrobial activity. In the presence of cancer, iodine can trigger mechanisms that are antiproliferative, promote cellular differentiation and induce apoptosis.

Iodine as an antioxidant

Free radicals are generated from both endogenous and exogenous sources. Immune cell activation, inflammation, ischemia, infection, cancer, excessive exercise, mental stress, and aging are all responsible for endogenous free radical production. Free radical production from exogenous sources results from exposure to environmental pollutants, heavy metals, certain medications, chemical solvents, certain cooking methods, cigarette smoke, alcohol, and radiation (1).

Fig 1. Iodine as a cofactor in peroxidase reactions (according to Thomas and Aune).
P-S-S = protein disulphide, PSI = iodinated protein, PSH = protein with SH-group.

Credit: Winkler R. Iodine—a potential antioxidant and the role of iodine/iodide
in health and disease. Natural Science. 2015;7: 548-557.

Antioxidants inhibit cellular damage caused by oxidative stress. Iodide functions as an antioxidant through its action as an electron donor when it interacts with peroxidase enzymes (2). In its role as an electron donor, iodide can neutralize reactive oxygen species (ROS) and prevent lipid peroxidation of cell membranes. The formation of iodolipids through the interaction of iodide with the double bonds of unsaturated fatty acids found in cell membranes, makes them less reactive to ROS. In an experiment comparing the antioxidant capacity of iodine with ascorbic acid (vitamin C) and potassium iodide, molecular iodine (I₂) was 10 times more potent than ascorbic acid and 50 times more potent than potassium iodide (KI) (3).

While the body has several endogenous systems to address oxidative stress, mineral antioxidants play an important role in electron transfer and in redox chemical reactions in the tissues where they concentrate. Overall, iodine has been shown to have a favorable impact on total serum antioxidant status (3).

Iodine as a pro-oxidant

The oxidative properties of iodine are also well documented and active within immune cells. Myeloperoxidase enzymes in leukocytes use iodine to produce iodine-free radicals that act as potent oxidants with strong bactericidal activity (4). Following application of povidone iodine (PVP-1), elemental iodine can take several forms in aqueous solution, with molecular iodine (I₂) and hypoiodous acid (HOI) having the highest antimicrobial activity. Iodine molecules oxidize vital pathogen structures including amino acids, nucleic acids and membrane components. The action of iodine disrupts microbial cell walls by inducing pore formation, leading to cytosol leakage with eventual destruction of the pathogen (5).

Iodine can support the innate immune system to fight bacterial and viral infection and has immunomodulatory effects on immune cells.

Iodine and the immune system

Iodine is taken up and metabolized by immune cells where its function as either an anti-inflammatory or proinflammatory agent is determined by the physiological context. Iodine can support the innate immune system to fight bacterial and viral infection and has immunomodulatory effects on immune cells. This immune enhancing effect increases expression of cytokines and chemokines that control cell trafficking and regulate the nature of the immune response. Overall, this has the effect of enhancing the immune system’s ability to fight infection while keeping the immune response balanced (6).

Phagocytes, granulocytes and monocytes, types of leukocytes cells within the immune system, harbor the highest concentration of iodide transporters. In vitro studies show that iodine induces transcriptional modification in human leukocytes, resulting in the upregulation of genes that promote activation of cytokines and chemokines. The observed transcriptional changes in the leukocytes produced a mix of cytokines that were both pro- and anti-inflammatory, indicating a balanced immune response that can both promote and resolve inflammation (7).

Respiratory infections

It is well established that iodine has a broad spectrum of antimicrobial activity against bacterial, viral, fungal, and protozoal pathogens and has been used as an antiseptic for the prevention of wound infections for several decades. A 2021 article in Ear, Nose & Throat Journal, published an in vitro study by Pelletier et al establishing that nasal and oral povidone iodine (PVP-1) solutions are effective at inactivating SARS-CoV-2 at a variety of concentrations after 60-second exposure times. They concluded that the formulations tested may help to reduce the transmission of SARS-CoV-2 if used for nasal decontamination, oral decontamination, or surface decontamination in known or suspected cases of COVID-19 (8).

Pelletier’s study was duplicated using a different iodine formula known as Essential Iodine Drops (EID), which is a derivative of fulvic acid complexed with molecular iodine (I₂) at a concentration of 200 mcg/mL. The SARS-CoV-2 virus was exposed to EID in vitro for 60 and 90 seconds and in both cases, the viral load decreased by 99% (9).

Nasal goblet and ciliated cells within the respiratory epithelium have the highest expression of angiotensin-converting enzyme 2 (ACE2), the main receptor for COVID-19. The mechanism of action of PVP-I and EID as a mouth rinse and nasal spray targets the ACE2 receptor for inhibition. It diminishes the ACE2 receptors in the lymphocytes of the mucosal tissue, reducing the concentration of SARS-CoV-2 shed into saliva and nasal fluid (9).

Although 10% PVP-I solutions had been previously tested against human coronaviruses SARS-1 and MERS, these solutions are unsuitable for use in the nasal and oral cavities at commercially available concentrations. Diluting this 10% solution to a 1% solution allows for use of PVP-I in the nasal and oral cavities. Solutions as low as 0.5% PVP-I have been found to be effective at appreciably reducing SARS-CoV-2 in vitro (9).

The use of oral potassium iodide (KI) in the treatment of respiratory syncytial virus (RSV) was studied in lambs, as they respond similarly to this virus as infants. As mentioned above, iodine supports oxidative pathways as part of an effective immune response. Iodide can be concentrated in the nasal mucosa after oral iodide administration and integrates into the oxidative system that generates hypoiodous acid (HOI), which has potent microbicidal activity against bacteria and viruses, including RSV. Overall findings indicate that the use of high-dose potassium iodide (1.7 mg/kg body weight) in vivo lessens the severity of RSV infections through augmentation of the mucosal oxidative defenses (10).

Anti-cancer effects of iodine

Iodine concentrates in many extrathyroidal tissues and has particular anti-tumorigenesis effect in mammary, prostate, pancreas, lung, and nervous system tissue.

In addition to functioning as an antioxidant, anti-inflammatory, and antiproliferative agent, iodine also has the ability to induce apoptosis and differentiation in cancer cells. The reactive oxygen species of singlet oxygen, superoxide anions, hydrogen peroxide and hydroxyl radials have a wide range of cellular and molecular effects, resulting in mutagenicity, cytotoxicity, and alterations in gene expression. Molecular iodine (I₂) can function as a scavenger and antioxidant that neutralizes various ROS that are known to be cytotoxic and implicated in the development of cancer (3).

Molecular iodine (I₂) inhibits cell proliferation and induces apoptosis in cancer cells through a direct mitochondrial effect and an indirect effect through iodolipid generation. Through its oxidant/antioxidant properties, molecular iodine (I₂) can directly dissipate the mitochondrial membrane potential, triggering mitochondrion-mediated apoptosis in cancer cells without affecting the mitochondria of normal tissue (3).

Fig 2. Anti-cancer effects of iodine associated with mitochondria and PPAR gamma.

Credit: Aceves C, Mendieta I, Anguiano B, et al. Molecular iodine has extrathyroidal effects as an
antioxidant, differentiator, and immunomodulator. Int J Mol Sci. 2021; 22(3):1228.

In the presence of high levels of arachidonic acid (AA), molecular iodine (I₂) induces the formation of 6-iodolactone (6-IL), which is an iodinated derivative of AA. AA is a polyunsaturated free fatty acid present in the membrane phospholipid layer of all mammalian cells. Tumors contain a significantly higher concentration of AA, and when treated with molecular iodine (I₂), 6-IL greatly increases. It is proposed that the increase in 6-IL indirectly contributes to the antiproliferative and apoptotic effect of molecular iodine (I₂) (3, 11).

Additionally, 6-IL has a high affinity for peroxisome proliferator-activated receptor gamma (PPARγ). PPARs are nuclear transcription factors that regulate cancer cell proliferation in addition to their classical role in maintaining lipid and glucose homeostasis (11). PPARs exist as three substrates, with PPARγ having the highest affinity for IL-6. AA is a natural ligand of PPARs, meaning that it binds readily to this receptor. When molecular iodine (I₂) promotes the formation of 6-IL in the presence of AA, 6-IL will bind to PPARγ with an affinity six times higher than AA. The binding of 6-IL to PPARγ results in a regulating effect on cancer cell proliferation (11). In a preliminary clinical study of 22 women with breast cancer, those who received 5 mg/day of molecular iodine (I₂) rather than placebo showed an increase in PPARγ expression, increased apoptosis, and decreased proliferation of cancer cells (12).

Iodine and breast health

Iodine concentrates in many extrathyroidal tissues and has particular anti-tumorigenesis effect in mammary, prostate, pancreas, lung, and nervous system tissue. These tissues exhibit the specific ability to take up molecular iodine (I₂) and promote apoptosis through the induction of PPARγ. Molecular iodine (I₂) and 6-IL have been studied in the treatment of several types of tumor cell lines, showing a suppressive effect on the development and size of both benign and cancerous neoplasias (3, 13).

Molecular iodine's (I₂’s) role in maintaining breast health is evident in its ability to effectively address cyclic mastalgia from fibrocystic breast disease. Both in vitro and in vivo studies of mammary cancer have shown that molecular iodine (I₂) treatment induces apoptosis and increases expression of sodium-iodide symporter (NIS) and pendrin (iodine receptors), to increase the uptake of iodine. Molecular iodine (I₂) also promoted a reduction in metastatic inducers such as vascular endothelial growth factor that, in this context, increases blood flow to cancerous tissues. It is suspected that the trigger for these events is through the activation of PPARγ which, as mentioned above, is apoptotic, antiproliferative, and promotes differentiation (3).

In a study presented by Aceves et al, 0.05% molecular iodine (I₂) solution prevented the induction of DNA adduct formation in premalignant cancer tissues in the presence of dimethylbenz(α)anthracene, a potent carcinogen. DNA adducts can initiate and promote cancer and tend to be present in high amounts in the urine of breast cancer patients and women at high risk for breast cancer. Breast cancer tissue also contains a higher concentration of AA. After treatment with 0.05% molecular iodine (I₂), 6-IL levels increased 15-fold higher than in normal mammary tissue, promoting apoptosis and reducing proliferation by increasing the activity of PPARγ (3).

The fact that 30% of the global population is iodine deficient is concerning especially when we consider that iodine has so many functions and concentrates in a variety of tissues.

Iodine and prostate health

In prostate tissue, iodine has proven useful in both benign and cancerous conditions. Japanese men have much lower rates of prostate cancer than men in the United States. The Japanese diet is notably high in iodine as compared to an American diet with an estimated consumption over 20 times that of people in the United States. As reported by Tina Kaczor, ND, in Natural Medicine Journal, animal studies using 0.05% molecular iodine (I₂) supplementation reduced symptoms of benign prostatic hyperplasia (BPH). It was also noted that 5 mg per day of Lugol’s solution improved urine flow and reduced prostate-specific antigen values over an eight-month period (14).

Iodine’s effects in prostate cancer are noted by Navarra in a 2010 issue of Urology where the NIS was found in 52% of prostate adenocarcinomas and was associated with an increased aggressiveness of the tumor (15). The presence of NIS in the tumors can be an indication of iodine deficiency in the prostate tissue, reducing its ability to prevent cellular changes associated with the tumorigenesis.

The dose response effect of iodine in benign and cancerous conditions

Molecular iodine (I₂) is the form of iodine heralded for its antineoplastic effects. Although seaweed contains iodine in several chemical forms, molecular iodine (I₂) is commonly found in seaweed consumed in traditional Asian cultures and used for treatment of breast cancer due to its ability to soften tumors and reduce nodulation (3).

Dose response studies in humans demonstrated that iodine supplemented at 1.5 mg/day or less had no effect on benign pathologies whereas, dosages of 3.5 mg/day up to 6 mg/day, mainly in the form of molecular iodine (I₂), exhibited significant beneficial actions on mastalgia and BPH. Dosages at 9 mg/day and 12 mg/day showed the same benefits but had a greater impact on thyroid function and produced a variety of minor side effects (3, 13).

In summary

I hope this three-part series has satisfied your curiosity about iodine as much as it has mine. The fact that 30% of the global population is iodine deficient is concerning especially when we consider that iodine has so many functions and concentrates in a variety of tissues. Our need for iodine may be dependent on a number of factors including where we live, what we consume and how much iodine our own body needs to stay sufficient while supporting all of the processes that depend on an adequate amount of iodine.

Testing for iodine sufficiency

ZRT Laboratory measures iodine through a dried urine sample taken upon waking and before bed. This test does not require a high-loading dose of iodine prior to collecting the urine sample and is more representative of daily consumption. The options for testing include a singular Iodine Panel, or a measurement of iodine in the Urine Toxic & Essential Elements add-on profile and the Comprehensive Thyroid Panel, which is a combination of the Elite Thyroid Panel and the add-on Urine Toxic & Essential Elements.

References

Curious About Iodine, Part 2: Beyond the Thyroid

Fri, 09 Dec 2022 14:15:54 -0800

The role that iodine plays in the thyroid is well established. We need iodine to make thyroid hormones, and the numeric designation in T3 and T4 represents the number of iodine molecules attached to the amino acid tyrosine. In part one of this series on iodine, I examined the versatility of this unique element and its uses throughout history and explored the sources and forms of iodine found in foods and supplements. In part two of this series, I take a closer look at the role that iodine plays in the thyroid and in various extrathyroidal tissues where it supports breast health, ovarian function, fertility and the normal development of the brain and nervous system in the fetus and newborn.

Tissues that concentrate iodine

Iodine is present in every organ and tissue of the human body in differing concentrations (1). The total body concentration of iodine is estimated to be 15-20 mg. The amount of iodine stored in the thyroid depends on total body iodine sufficiency. The lower our body concentration of iodine, the greater the percentage of dietary iodine sequestered by the thyroid. Higher total body content would result in a lower overall percentage of dietary iodine being sequestered by the thyroid, which allows for wider distribution of iodine to extrathyroidal tissues. In a state of iodine sufficiency, approximately 50-70% of total iodine goes to extrathyroidal tissues (1).

In addition to the thyroid, other tissues that store iodine are the breasts, ovaries, prostate, uterus, placenta, thymus, salivary glands, lacrimal glands, eyes, skin, gastric mucosa, choroid plexus, renal cortex, pancreas, liver, small and large intestinal mucosa, nasopharynx, and the adrenal cortex (2). While the thyroid tends to concentrate a higher percentage of iodide (I¯), extrathyroidal tissues tend to utilize a greater percentage of molecular iodine (I₂), which exerts multiple and complex actions related to its role as an antioxidant, an anti-inflammatory, a pro-inflammatory, an inducer of apoptosis, an immune modulator, and a promotor of cell differentiation (3).

Figure 1. Organs and tissues that take up iodine. (Aceves C, Mendieta I, Anguiano B, et al. Molecular iodine has extrathyroidal effects as an antioxidant, differentiator, and immunomodulator. Int J Mol Sci. 2021;22(3):1228.)

A closer look at iodine and the thyroid

Iodine is necessary for the normal development of breast tissue and suppresses breast cancer cell and tumor growth.

The process of thyroid hormone production begins in the follicular cells of the thyroid gland. The thyroid traps iodide via active transport through the sodium-iodide symporter (NIS) protein in the follicular cells of the thyroid gland. The thyroid gland synthesizes and releases thyroglobulin, which houses approximately 140 tyrosine residues that are released into the lumen of the thyroid follicular cells. Iodide enters the follicular lumen via the pendrin transporter where it is oxidized to iodine by thyroid peroxidase enzyme (TPO). TPO also links the available tyrosine residues with iodine to form T1 and T2. T4 is formed through the binding of two T2 molecules and T3 is formed by the binding of T1 and T2. This process is also catalyzed by TPO. The thyroid hormones of T4 and T3 are released into general circulation at a relative ratio of 4:1 (4).

T4 can be converted to triiodothyronine (T3) in the peripheral tissues of the liver, kidneys, and muscles. The conversion of T4 to T3 via deiodinase enzymes, releases one molecule of iodine that can be salvaged and redistributed to an intracellular iodine pool (4). If peripheral conversion of T4 to T3 is weak, this may result in lower levels of iodine available to extrathyroidal tissues. The overall effect of reduced iodine from T4 to T3 conversion can be compounded by deficient iodine consumption.

The thyroid gland and extrathyroidal tissues use iodide transporters as a gatekeeper for iodide tissue concentrations. If the tissue level of iodide is low, there is an increased expression of iodide transporters. Thyroid hormone levels may be well within the normal range because the thyroid receives a greater percentage of dietary iodine even when extrathyroidal tissues are deficient. Therefore, we cannot rely on thyroid markers for a complete assessment of iodine status especially under the current Recommended Dietary Allowance of 150 mcg/day, which was established with the singular goal of preventing goiter. Under these recommendations, it is possible that extrathyroidal tissues may bear the consequences of suboptimal iodine levels (5).

Iodine and breast tissue

Breast tissue stores iodine especially during lactation in which the mammary glands concentrate iodine and secrete it into breast milk to provide this essential nutrient to the newborn (6). Iodine deficiency has been associated with fibrocystic breast disease and, more recently, with the development of distant metastatic breast cancer in young women aged 25-39. This trend toward the development of breast cancer in younger women has been associated with the reemergence of iodine deficiency in the U.S. since the 1970s (7).

Iodine is necessary for the normal development of breast tissue and suppresses breast cancer cell and tumor growth. In an article dating back to March of 2000, the Journal of Clinical Endocrinology and Metabolism referenced a research study proving that molecular iodine (I₂) rather than iodide (I⁻) when administered together with the carcinogen dimethylbenzanthracene resulted in a significant reduction in the incidence and size of multiple mammary tumors after the cancer developed. It was also reported that a higher tumor iodine content together with a significantly reduced tumor size were evident in rats treated with medroxyprogesterone acetate and iodine than in those treated with medroxyprogesterone acetate alone, suggesting that the active uptake of iodine had a suppressive effect on tumor growth (8).

The hormonal environment that supports the development of fibrocystic breast disease may also be associated with an increased risk of developing breast cancer in some women. Studies in rats have shown that iodine deficiency can result in hyperresponsiveness to estradiol, which increases alveolar cell proliferation in breast tissue (7). Both fibrocystic breast disease and breast cancer have been associated with iodine deficiency, and both have the potential to respond well to iodine therapy by improving estrogen metabolism via the cytochrome P450 enzyme pathways that direct estradiol down the 2-hydroxyestradiol pathway, which has antiproliferative effects (9).

Iodine and the ovaries

Of the tissues that utilize iodine, the ovaries have one of the highest concentrations in the body.

Of the tissues that utilize iodine, the ovaries have one of the highest concentrations in the body. Iodine is an essential micronutrient for normal reproductive function and deficiency is associated with reduced fertility. In an observational study conducted between 2005 and 2009 by the National Institute of Child and Human Development, 467 women trying to conceive were examined for iodine status. It was discovered that 44.3% were considered iodine deficient as determined by a urinary iodide concentration less than 50 mcg/g. Compared with women of normal urinary iodide concentration (>100 mcg/g), those with low iodine were 46% less likely to achieve pregnancy during each menstrual cycle (10, 11).

The exact role of iodine and fertility has not been fully elucidated but it is suspected that iodine is necessary for the process of ovulation as small and growing follicles take up iodine to support secretory activities. When iodine deficiency was artificially created in cows, the cows experienced anovulatory cycles (12). If iodine is used to support fertility, the effects of supplementation may also have a positive effect on thyroid function, which has a regulating effect on ovulation as well.

PCOS and iodine deficiency

Polycystic ovary syndrome (PCOS) is one of the most common hormonal disorders in women of childbearing age who experience anovulatory cycles and the formation of ovarian cysts. Iodine deficiency negatively impacts folliculogenesis and the maturation of the ovarian follicle. If a follicle does not mature, ovulation cannot occur. The immature follicle can evolve into a fluid-filled cyst within the ovary that causes pain and discomfort (13). An increase in androgen production may also occur, resulting from the continuous stimulation of the follicles by luteinizing hormone. If iodine deficiency can lead to anovulatory cycles, the use of iodine for PCOS may be an essential nutrient in the treatment of this common disorder to support normal ovarian function.

Iodine and the endometrium

Other ways in which iodine may affect reproductive health relates to levels of iodide transporters and pregnancy outcomes. In a 2020 study, Bilal et al evaluated the levels of iodide transporters in the endometrial tissue of women with recurrent reproductive failures. Compared to controls, women with two or more reproductive failures had a greater than fivefold increase in NIS and pendrin iodide transporters, which suggests possible abnormal iodine metabolism and a deficiency of iodine in the endometrial tissue (5).

It was also noted that there is an increased demand for T4 production during pregnancy as it is needed by the fetus in the first trimester and beyond to make fetal thyroid hormones. Reduced thyroid hormones during pregnancy can result in fetal neurological damage, congenital hypothyroidism, miscarriages, and reproductive failures. Bilal et al propose that although iodine in the form of thyroid hormones is essential, iodides (I¯) and molecular iodine (I₂) also play a role in optimizing reproductive organs and pregnancy outcomes by preventing localized iodine deficiency (5).

Brain development in the growing fetus and newborns

Adequate iodine intake during the first few weeks of gestation is essential for neurocognitive development in the growing fetus.

Iodine is necessary for normal brain and nervous system myelination both in utero and during the early postpartum period (6). Iodine deficiency continues to be the most common cause of preventable intellectual underdevelopment worldwide. The most vulnerable groups are pregnant and lactating women and their developing fetuses and newborns. Adequate iodine intake during the first few weeks of gestation is essential for neurocognitive development in the growing fetus (14). Iodine supplementation should begin during preconception and no later than 4-6 weeks gestation. NHANES data from 2007–2014 indicate that iodine status among pregnant women is insufficient. Another analysis showed that although approximately 75% of pregnant women took a prenatal supplement in 2011–2014, only 18% of the supplements contained iodine (15).

In two prospective studies of iodine supplementation, infants born to mothers who received iodine during pregnancy had improved psychological and neurocognitive measures compared to those born to mothers who did not supplement with iodine (14). A meta-analysis of 37 studies that included a total of 12,291 children demonstrated that children of mothers living in severely iodine-deficient areas had an average of 12.45 lower intelligence quotient (IQ) points, whereas children born to mothers who supplemented with iodine before and during pregnancy experienced an increase of 8.7 IQ points (14).

Iodide and molecular iodine

Making the distinction between iodide (I¯) and molecular iodine (I₂) is important as they have differing functions dependent upon the tissues in which they concentrate. Iodide is primarily used by the thyroid gland to make thyroid hormone and while extrathyroidal tissues also use iodide, molecular iodine tends to have a greater role as an antioxidant, cell differentiator and immunomodulator. The capture of I₂ in the thyroid is 40% lower than in extrathyroidal tissues and under conditions of iodine deficiency, I¯ is more efficient than I₂ at restoring the goitrous thyroid to normal function. Dose-response studies in humans have demonstrated that I₂ at concentrations of 1 to 6 mg per day had significant beneficial effects on fibrocystic breast disease, prostatic hyperplasia and polycystic ovaries (3). While the uptake of iodide is dependent on transporter systems that seem to function as a gatekeeper in the thyroid and extrathyroidal tissues, the uptake of I₂ appears to occur through a facilitated diffusion system, which may be a conserved evolutionary system similar to what occurs in marine algae where much of the earth’s iodine is concentrated (9).

Controversies in iodine dosing

Recommendations for daily iodine dosing can be very controversial, ranging from 150 mcg/day up to 100 mg/day. Though much of the high dose iodine may flush out through the kidneys, the effects can uncover latent thyroid disease. Based on an assessment of iodine consumption through food sources in Japan by Zava and Zava, more reasonable dosing may fall into the range of 1-3 mg/day to support both thyroid function and the needs of extrathyroidal tissues (16). Using a supplement that contains both iodide and molecular iodine may have the benefit of supporting the thyroid with iodide while also supporting extrathyroidal tissues with molecular iodine. Assuring a good complement of other nutrients needed for iodine utilization and thyroid hormone function (selenium, iron, zinc, copper, magnesium and vitamin A) would also help to reduce potential negative effects of extra iodine and potentially optimize the supportive effects that iodine can provide.

Coming up…

In part three of the iodine series, we will look at the benefits of iodine for immune function, its role as an antioxidant and the potential of iodine as an anti-cancer agent.

References

Curious About Iodine, Part 1: Just the Basics

Fri, 04 Nov 2022 11:25:11 -0700

The use of iodine dates back to 4th century China where seaweed and burnt sea sponge were effectively used to treat goiter. It was not until 1811 that iodine was isolated as a specific element that exhibited properties similar to the other halogens of bromine, chlorine, and fluorine. In 1829, Jean Guillaume Auguste Lugol, MD, introduced potassium iodide as an effective treatment for the effects of tuberculosis, and John Murray, MD, used iodine to treat croup, asthma, consumption, and other respiratory diseases [1].

Tincture of iodine has been a staple in every first aid kit for the treatment of wounds to prevent infection and support healing. Surgeons scrub up with a betadine solution and paint it on the body of those undergoing surgery to assure the skin is free of microbes. Over its long history, iodine has been used as an effective treatment for goiter, upper respiratory infections, asthma, and croup. It has also been used as an antiseptic, disinfectant, an expectorant, an amoebicide, and an anti-syphilitic remedy. Iodine has also been used topically for the treatment of various skin disorders [1].

Iodine Deficiency Disorder is the most common endocrinopathy in the world and is also the most preventable.

Iodine is a very versatile element in that its mechanism of action is somewhat determined by where it is stored in the body. The thyroid gland needs iodine to make thyroid hormones, which support growth, metabolism, and cognitive development, but iodine is also concentrated in numerous extrathyroidal tissues where it acts intracellularly as an antioxidant, supports cellular differentiation, has anti-inflammatory effects, and supports apoptosis [2].

Approximately 30% of the global population is iodine deficient due to reduced consumption and exposure to foods and environmental factors that inhibit iodine absorption. Let’s explore some of the basics about iodine – where we get it, common forms, symptoms of deficiency, and how much we actually need, not only to prevent deficiency, but to optimize tissue levels beyond what is needed to support thyroid function.

Sources of iodine

The oceans are the world’s main repository of iodine with some deposition in coastal soil due to volatilization of ocean water from ultraviolet radiation. Very little of the earth’s iodine is actually found in soil and the further we are from the coast, the lower the iodine content [3]. Food sources of iodine are seaweed (kombu, nori, kelp, wakame), seafood, iodized salt, dairy, eggs, baked goods made with iodate dough conditioner, breast milk, infant formula, beef liver and chicken [4].

Iodine versus iodide

Although iodide and iodine are used interchangeably, they are structurally and functionally different. Iodine and iodide are closely related terms because iodide is derived from iodine; however, iodine is a chemical element whereas iodide is an anion [5].

Iodine (I²) – Iodine rarely occurs as the single element seen on the periodic table. Iodine as I² is molecular iodine in which two atoms of iodine are bound together.
Iodide (I¯) – Iodide is the anion of iodine and typically binds to other elements to form a salt such as potassium iodide or sodium iodide. Iodide is formed from iodine with the addition of an extra electron.

Iodine deficiency

Iodine Deficiency Disorder (IDD) is the most common endocrinopathy in the world and is also the most preventable. The most recent data suggests that at least one-third of the world’s population is iodine deficient [6]. According to data from the National Health and Nutrition Examination Survey [7], the median urinary iodine concentration of adults in the U.S. decreased by over 50% from the early 1970s to the late 1990s [8]. Decreased consumption of dietary iodine in the U.S. is potentially due to variations in the iodine content of dairy products or avoidance of dairy, the removal of iodate dough conditioners in commercially produced bread, new recommendations for reduced salt intake for blood pressure control, and use of non-iodized salt [8].

Iodine deficiency defined

Iodine levels are measured in the urine as much of what we consume is eliminated through the kidneys. To determine regional iodine deficiency, the measurement of urinary iodide is done across large populations and does not involve the use of a high loading dose of iodine. The American Thyroid Association defines iodine deficiency as a median urinary iodide concentration less than 100 mcg/L in a nonpregnant population, or <150 mcg/L in pregnant women [9].

Symptoms of iodine deficiency

Much of the systemic effects of iodine deficiency are the result of deficiency of thyroid hormones [3]. Though many tissues concentrate iodine and all cells of the body utilize iodine, it is the thyroid that gets the lion’s share from dietary sources. Deficiencies are most pronounced within the thyroid gland with extenuating effects on other iodine-concentrating glandular tissues. Common symptoms of iodine deficiency include weight gain, brain fog, psychiatric disorders, reduced intellectual capacity, cancer (breast, stomach, prostate), prostate enlargement, depression, fatigue, goiter, menstrual issues, polycystic ovary syndrome (PCOS), saliva deficiency, thyroid nodules, migraines, miscarriages, and stillbirths [3].

Absorption of Iodine

The various forms of iodine that we consume in food or through supplementation is reduced to iodide in the stomach and upper small intestine before absorption. Iodide is actively transported into cells primarily through the sodium-iodide symporter (NIS). In the thyroid, the function of the NIS is regulated by thyroid-stimulating hormone, thyroglobulin, and iodide concentrations. The NIS is also expressed in other tissues that concentrate iodide. These tissues include the tear ducts, salivary glands, choroid plexus, stomach, intestines, lactating breasts, kidneys, placenta, the ovaries, and cells of the immune system [10].

The sodium iodide symporter (NIS) is a plasma membrane protein that facilitates the active transport of iodide into the thyroid gland and various extrathyroidal tissues.

In addition to iodide transport, the NIS can also transport other chemicals that may inhibit iodide absorption and NIS function. Perchlorate is a common environmental chemical that inhibits NIS function and impairs iodide absorption. Perchlorate is pervasive in the environment and our food chain as it is commonly found in fertilizers, rocket fuel, missiles, fireworks, and other explosives, leaving remnants to settle into the soil and groundwater [11].

Nitrates can also inhibit the NIS and though they are commonly found in vegetables, meat, and dairy, higher concentrations are found in fertilizers that saturate the soil and seep into groundwater. The active component of goitrogenic foods is thiocyanate. It is found in high concentrations in uncooked cruciferous vegetables, millet, soy, and sweet potatoes, and is another common inhibitor of the NIS and iodine absorption [11].

Bromine, chlorine, fluorine, and iodine are part of the family of halogens on the periodic table, so they have similar properties. Like iodine, the halogens can exist in their ionic form as bromide, chloride, and fluoride. These halides exist in food, water, medications, and our environment and competitively inhibit the absorption of iodine.

How much iodine do we need?

The Recommended Dietary Allowance (RDA) for iodine is 150 mcg for an adult, 220 mcg during pregnancy and 290 mcg for lactating women with the upper daily limit set at 1100 mcg per day [12]. Iodine deficiency is primarily from lack of iodine consumption, but we are also exposed to components in food and the environment that inhibit the assimilation of iodine into the tissues that need it the most.

Iodine levels are measured in the urine as much of what we consume is eliminated through the kidneys.

The RDA of 150 mcg was proposed decades ago as the amount of iodine needed to prevent goiter. Given the presence of naturally occurring and man-made chemicals in our environment that have the potential to inhibit iodine absorption, our need for iodine may be greater than the RDA. In a 2011 assessment of iodine consumption in Japan, Zava and Zava determined that the average iodine intake, largely from seaweed, averaged 1000-3000 mcg/day [13].

In comparison to the RDA, residents of Japan who consume a traditional diet, ingest between 7-20 times our RDA and the Japanese Ministry of Health has set the upper limit of iodine at 3000 mcg/day [14]. The increased consumption of iodine may have a significant effect on the lower rates of breast, gastric and prostate cancer in Japan as compared to the U.S.

Additional nutrients to support iodine

Food sources with a higher iodine content may be better tolerated than higher levels from supplements as iodine is combined with additional nutrients that support absorption and utilization. Selenium, iron, zinc, copper, magnesium, and vitamin A are all supportive of thyroid function and hormone production. Combining iodine supplementation with these nutrients supports the enzymes needed to make thyroid hormone, reduces oxidative stress, and supports conversion of T4 to T3 [15].

The paradoxical effect of too much iodine

Read any literature on the use of iodine and you will encounter the cautionary tale of the Wolff-Chaikoff effect. This is a real phenomenon, and it occurs when too much iodine enters thyroid tissue and has an inhibitory effect on thyroid hormone production and release. As mentioned above, the NIS is partly regulated by iodine concentration within thyroid cells. Too much iodine decreases the activity of the NIS, leaving the thyroid in a state of reduced activity for anywhere between 2-15 days. Eventually, the thyroid may return to normal function but in those with an underlying thyroid disorder such as subclinical hypothyroidism or Hashimoto’s, the thyroid may not return to normal function and ongoing treatment with thyroid medication may be necessary [13].

Though many tissues concentrate iodine and all cells of the body utilize iodine, it is the thyroid that gets the lion’s share from dietary sources.

High dosages of iodine can also cause hyperthyroidism especially in populations that have been living in a state of iodine deficiency where nodules can form an excessive amount of thyroid hormone from supplemented iodine [14]. It is always important to remember that in high doses, nutrients can have a drug-like effect. Just because a little is good does not mean more is better.

Measuring iodine status

ZRT Laboratory measures iodine through a dried urine sample taken upon waking and before bed. This test does not require a high loading dose of iodine prior to collecting the urine sample and is more representative of daily consumption. The options for testing urine iodine include a standalone Iodine Panel; as part of a Comprehensive Thyroid Profile; or in conjunction with other essential minerals and heavy metals, in either the Urine Toxic & Essential Elements or the Comprehensive Toxic & Essential Elements.

Up next

To further our understanding of the many benefits of adequate iodine, I will be looking into the role that iodine plays in extrathyroidal tissues as well as a closer look at thyroid function and iodine status. If IDD is the most common endocrinopathy, what are the effects of iodine deficiency on fertility, PCOS, skin disorders, immune function, fibrocystic breasts, and breast, prostate, and other cancers? Stay tuned…

References

Skipping a Beat: Hormones and Heart Palpitations

Fri, 24 Jun 2022 12:56:39 -0700

There it is again! That distinct flutter in your chest that kicks up your heart rate and leaves you feeling a bit breathless. It might feel as though your heart just skipped a beat or flip-flopped in your chest and you’re left wondering, “Did my body just take me on a little roller coaster ride or was that a heart palpitation?” For most women without underlying cardiovascular issues, the experience of a heart palpitation can range from a mild sensation to moderate discomfort, not because they are typically painful, but because they can make you acutely aware of your heartbeat.

Heart palpitations can be associated with menopause, anxiety, hormonal fluctuations, hyperthyroidism, nutrient deficiencies, excessive caffeine, medications, mitral valve prolapse and heart arrhythmias. Heart palpitations are common and usually inconsequential. Although they can occur in the absence of heart disease, they may also be associated with a serious heart condition. If they are of new onset, occur frequently, and are associated with symptoms of dizziness, syncope, and pain, seeing your doctor for a complete evaluation is warranted.

Heart Palpitations and Hormones

Heart palpitations related to hormonal fluctuations can occur in women of all ages. Premenopausal women may experience heart palpitations during specific phases of their menstrual cycle when hormones are fluctuating. Pregnant women may also experience palpitations from rising hormones, increased blood volume and anemia. Heart palpitations in menopausal women occur from fluctuating and declining hormone levels.

Much of the medical literature on heart palpitations and hormones confirms that women in midlife and those entering menopause do experience palpitations.

Sex hormones can influence the rhythm of the heart by modifying ion channels that regulate electrical activity as well as regulating input from the autonomic nervous system (ANS). Menopause can be associated with a decrease in heart rate variability (HRV) due to either reduced parasympathetic or increased sympathetic outflow to the heart. Changes in electrical activity of the heart along with an increase in sympathetic tone, catecholamines (epinephrine or adrenaline, norepinephrine or noradrenaline) and cortisol can contribute to the development of heart palpitations.

What Is a Heart Palpitation?

A palpitation is a discernable change in cardiac rate or rhythm. There are four main physiological causes of palpitations:

Extra-cardiac stimulation of the sympathetic nervous system (SNS), resulting in excess production of catecholamines and cortisol.
Sympathetic overdrive, which may occur from stress, anxiety, panic disorder, hypoglycemia, and hypoxia.
Increased circulatory volume, which may result in vasodilation and decreased blood pressure.
Abnormal heart rhythms such as supraventricular tachycardia and atrial fibrillation, to name a few. Abnormal heart rhythms can range from mild to life-threatening and should always be treated appropriately.

Stressors and Midlife

Much of the medical literature on heart palpitations and hormones confirms that women in midlife and those entering menopause do experience palpitations. This seems to fall into the, “thanks for telling me what I already know” category. We know they’re happening, but why?

A deeper dive into the literature reveals some correlations that are not too surprising. More frequent and severe heart palpitations are associated with insomnia, a higher level of perceived stress, depression, and poor quality of life. Less physical activity, past or current smoking, and surgical versus natural menopause also contribute to increased frequency and severity of heart palpitations. Most of these correlates can be linked to a heightened stress response, and as mentioned above, heart palpitations can occur under increased SNS activity or activation of the stress response.

From the (medical) gallery of Mikael Häggström, MD. Last updated: 2022-04-07. Licensing: Creative Commons CC0 1.0 Universal Public Domain Dedication.

What makes our experience of stress during perimenopause and menopause different than our earlier years? What influences do estrogen and progesterone have on the stress response and the cardiovascular system that, without them, our hearts are a flutter – and not in a good way? Perhaps understanding the measurable effects of each hormone on heart rhythm is a good place to start.

Heart Rhythm and Hormones

A palpitation is experienced as a change in the rate and rhythm of the heart. Sex hormones can influence the rhythm of the heart in very distinct ways. As represented on an ECG, estrogen prolongs the QT interval while progesterone and testosterone shorten the QT interval. The QT interval represents the time it takes for the ventricles of the heart to contract and relax. On an ECG, the QT interval represents the electrical activity that occurs in the heart to generate a normal heartbeat. One QT interval is one heartbeat.

Rege S. QTc prolongation and psychotropics – management of prolonged QTc interval in psychiatry. Psychscenehub. 2022. Accessed May 31, 2022.

Relative ratios of estrogen and progesterone influence how the heart maintains a regular rate and rhythm. The individual effects of sex hormones tend to counterbalance each other via the expression and function of cardiac ion channels that regulate action potentials to coordinate a normal heartbeat. Cardiac myocytes have receptors for sex hormones whose activation can alter the electrical activity of the heart through modulation of ion channels that control the flow of sodium, potassium, and calcium.

Fluctuating hormone levels can lead to changes in the behavior and expression of myocardial ion channels and therefore interfere with a normal heartbeat. When hormones are balanced, the heart is less likely to experience an irregular rhythm in the presence of SNS stimulation or stress.

Sex Hormones and Cardiovascular Health

The effects of hormone replacement therapy (HRT) on cardiovascular outcomes in menopausal women can vary depending on the type of hormone used (synthetic versus bioidentical) and the route of delivery (oral, transdermal). Hormones are chemical messengers that regulate biological processes. The message that hormones deliver is based on their chemical structure. Synthetic hormones have a different structure than bioidentical hormones and may produce divergent effects within the cardiovascular system as compared to bioidentical hormones. For example, the use of oral forms of estrogen can be prothrombotic whereas the use of transdermal hormones does not seem to present with the same complication.

When hormones are balanced, the heart is less likely to experience an irregular rhythm in the presence of SNS stimulation or stress.

Estrogen tends to moderate stimulation of the heart and provides cardioprotective benefits in general. This is evidenced by the fact that premenopausal women have a decreased incidence of hypertension and cardiovascular disease as compared to men of the same age and women who are menopausal. Estrogen moderates blood pressure through three key mechanisms: dilation of blood vessels, inhibition of the renin-angiotensin system in the kidneys and moderation of SNS stimulation. Additionally, estrogen promotes cardiovascular health by reducing low-density lipoprotein, increasing high-density lipoprotein, improving glucose metabolism, decreasing insulin, protecting against atherosclerosis, and improving blood vessel response to injury.

The benefits of progesterone on cardiovascular health have not been as well studied as the benefits of estrogen. This may be due to the differing effects of synthetic progestins on cardiovascular health as compared to bioidentical or natural progesterone. Bioidentical progesterone has very different effects on the cardiovascular system as compared to synthetic progestins and tends to be associated with positive effects in both cardiovascular markers and overall function of the heart. Some of the cardiovascular benefits of bioidentical progesterone include decreased blood pressure, inhibition of coronary hyperactivity, and vasodilation. Bioidentical progesterone also has a natriuretic effect that reduces blood sodium levels, which in turn, can reduce blood pressure.

Sex Hormones, the SNS and the Stress Response

Both estrogen and progesterone are neurosteroids that act within the brain and nervous system, influencing biological functions and behavior. The main stress mechanism, the hypothalamic-pituitary-adrenal (HPA) axis and the SNS, interact with sex hormones in mediating the effects of stress. If sex hormones are fluctuating or have decreased altogether, their ability to moderate the stress response as well as regulate electrical signals within the heart is impaired. An increase in sympathetic tone and output coupled with less stable electrical activity within the heart can contribute to heart palpitations.

Much of the medical literature focuses on the drop in estrogen as a causative factor. In reference to the first two bullet points listed above regarding sympathetic tone, estrogen has the benefit of calming input into the SNS, which initiates the stress response. Estradiol and its metabolites, the catechol estrogens, appear to inhibit tyrosinase activity, which is an enzyme needed for the synthesis of norepinephrine.

Végh A, Duim S, Smits A, et al. Part and parcel of the cardiac autonomic nerve system: unravelling its cellular building blocks during development. J Cardiovasc Dev Dis. 2016; 3:28.

The presence of circulating estrogen creates a balance between the SNS responsible for the “fight or flight” response and the parasympathetic nervous system responsible for the “rest and digest” response.

Oophorectomized women demonstrated a decrease in HRV as compared to women of the same age who still had their ovaries. Decreased HRV indicates a decrease in parasympathetic tone or, in simple terms, less engagement of the branch of our ANS that promotes a sense of calm.

In postmenopausal women, estrogen therapy reportedly attenuates responses to mental stress rendering typically stressful events less stimulating to the SNS. In other words, we become more tolerant and better at managing stressful input. This is likely because estrogen moderates the release of norepinephrine, reducing activation of the HPA axis during a stressful event.

Studies on the effects of progesterone in the mid- and late luteal phase of the menstrual cycle show an increase in sympathetic nerve activity as measured by skin blood flow changes. Perhaps the higher levels of progesterone may be supportive of cortisol production as a means of providing negative feedback to inhibit continued production of norepinephrine from the SNS.

Both estrogen and progesterone are necessary to regulate input to the sympathetic nervous system and are necessary to coordinate a normal heart rhythm.

We need adequate cortisol to complete the loop of the stress response. Cortisol is a secondary responder whereas norepinephrine and epinephrine are the primary responders that initiate the physiological changes, which kick the body into action when under stress. Cortisol mobilizes energy to support that action but also tells the nervous system, “I’ll take it from here.”

Studies on the effects of progesterone on norepinephrine can be more telling. In animal models, injecting progesterone and corticosterone decreased norepinephrine and epinephrine. Metabolites of progesterone, particularly allopregnanolone, can have a calming effect on the brain and nervous system by potentiating the effects of gamma aminobutyric acid (GABA). GABA moderates the release of norepinephrine and epinephrine from the adrenal medulla thus lessening the initiation of the stress response within the adrenal glands.

In Summary

Heart palpitations in the perimenopausal woman can be related to changes in both estrogen and progesterone. This momentary irregular rhythm can occur in response to stimulation from the SNS in the presence of fluctuating and declining estrogen levels. Though progesterone plays a role in regulating mediators of the stress response, its distinct role in heart palpitations is less clear as it is not as well studied in its effects on the heart as estrogen. However, both estrogen and progesterone are necessary to regulate input to the SNS and are necessary to coordinate a normal heart rhythm.

Employing strategies that reduce stress, improve sleep, and balance fluctuating hormones can greatly improve heart palpitations. As a woman progresses into menopause, HRT may be her best option to address heart palpitations especially if they are frequent and bothersome. Sleep issues can be common during perimenopause and can add to the burden of stress that potentiates heart palpitations. If sleep is disrupted by hot flashes and heart palpitations are worse due to lack of sleep, hormone replacement might be the answer. Additionally, supplementing with a complete mineral complex, B vitamins and essential fats can provide the heart muscle with essential nutrients needed to maintain normal electrical activity.

Measuring Thyroid, Adrenal and Sex Hormones

ZRT offers a broad range of testing to assess sex hormones during all phases of a woman’s menstrual life. Estrogen, progesterone, and testosterone can be easily measured in saliva and dried blood spot (DBS). ZRT also offers dried urine testing that measures estrogen, progesterone metabolites, testosterone, cortisol, norepinephrine, and epinephrine, which provides a complete evaluation of sex hormones and stress response mediators. Ruling out thyroid dysfunction is often warranted with an irregular heart rhythm and ZRT offers a complete thyroid panel easily done at home through dried blood sampling. Saliva profiles can also provide a four-point measurement of cortisol to further assess the stress response. Additional cardiovascular markers, including blood lipids, fasting insulin and hsCRP, can be also conveniently measured in DBS.

Resources

Why does my heart feeling like it is doing hurdles? The Centre for Menstrual Cycle and Ovulation Research. 2013. Accessed May 30, 2022.

Wyss JM, Carlson SH. Effects of hormone replacement therapy on the sympathetic nervous system and blood pressure. Curr Hypertens Reps. 2002;5(3)3:241-246.

Hart EC, Charkoudian N, Miller VM. Sex, hormones and neuroeffector mechanisms. Acta Physiol (Oxf). 2011;203(1):155-165.

Sudhir K, Elser MD, Jennings EL, et al. Estrogen supplementation decreases norepinephrine-induced vasoconstriction and total body norepinephrine spillover in perimenopausal women. Hypertension. 1997;30(6):1538-1543.

Sedla T, Shufelt C, Iribarren C, et al. Sex hormones and the QT interval: a review. J Women’s Health (Larchmt). 2012;21(9):933-941.

Odening KE., Koren G. How do sex hormones modify arrhythmogenesis in long-QT syndrome? Sex hormone effects on arrhythmogenic substrate and triggered activity. Heart Rhythm. 2014;11(11):2107-2115.

Cersosimo MG, Benarroch EE. Estrogen actions in the nervous system: complexity and clinical implications. Neurology. 2015;85(3):263-273.

Costa S, Saguner AM, Gasperetti A, et al. The link between sex hormones and susceptibility to cardiac arrhythmias: from molecular basis to clinical implications. Front Cardiovasc Med. 2021;8:644279.

Placzek K. Feel awful at that time of the month? It’s more than just your hormones. TheZRT Laboratory Blog. Accessed May 30, 2022.

Smith A. The connection between GABA & sleep disturbances. TheZRT Laboratory Blog, Accessed May 30, 2022.

Moderating and Resolving Inflammation with Specialized Pro-Resolving Mediators

Fri, 27 May 2022 09:47:26 -0700

Acute inflammation has a purpose and occurs when we are injured or sick and need to mobilize an efficient immune response to heal an injury or attack an infection. When all goes well, the response of the immune system is swift and complete. The job is done, the immune cells recede, and the clean-up crew disposes of the debris. Chronic inflammation, on the other hand, tends to linger without purpose or resolution. It may be the leftover remnant of an acute inflammatory process that never fully resolved, or it may exist as its own process triggered by low-level infections, food sensitivities, toxin exposure, metabolic dysregulation, and autoimmune processes.

Addressing the cause is the first and most important step and can often be the most challenging as there may be several promoters of ongoing inflammation. While we sleuth our way through what can be a tedious process of discovery, it is important to dampen the inflammation, reduce damage and oxidative stress from the inflammatory process, and support a healthy resolution.

What’s New in the World of Essential Fats

Essential fats have been studied for several decades and entire books have been written on the subject, yet we are still learning about the role these fats play in regulating inflammation. Within the study of essential fats, some new players have emerged—the specialized pro-resolving mediators or SPMs. These are important metabolites of omega-3 fats and arachidonic acid that, as the name implies, specifically help to resolve inflammation. So how do they do that, where do they come from, and how can we get some?

Omega-3 & Omega-6 Fatty Acid Sources

Our main sources of essential fats are the omega-3 and omega-6 fatty acids. These are polyunsaturated fatty acids and are considered essential because we must get them through our diet. The parent fatty acid of omega-6 fats is linoleic acid, and the parent fatty acid of omega-3 fats is alpha-linolenic acid. Through enzymatic activity, each of the parent fatty acids can be converted to other omega-6 or omega-3 fatty acids or we can get them from specific foods or supplements. The process of converting one fatty acid to another requires the presence of specific enzymes. Both omega-6 and omega-3 fats use the same enzymes to convert one fat to another so the presence of adequate omega-3 fats can competitively inhibit the production of the omega-6 fatty acids, which can be a good thing as the omega-3 fats tend to be anti-inflammatory. Genetics and aging can have an inhibitory effect on enzyme production rendering those conversion pathways less effective so getting a variety of essential fats from foods and supplements is often recommended.

The three main omega-3 fatty acids and their sources are:

There are four types of omega-6 fats that are abundantly available in many of the foods that we eat, making it much easier to get our fill of omega-6 fats over omega-3.

The four omega-6 fatty acids and their sources are:

Omega-3 and omega-6 fats are structurally different, so they behave differently. As these fatty acids are metabolized through enzymatic pathways, they produce specific products that may promote or inhibit inflammation.

Wikipedia contributors. (2022, March 9). Eicosanoid. In Wikipedia,

The Free Encyclopedia. Retrieved May 24, 2022.

Eicosanoids

Prostaglandins, leukotrienes, and thromboxanes are eicosanoids produced from the enzymatic breakdown of arachidonic acid (omega-6), EPA (omega-3) and DGLA (omega-6). Eicosanoids are derived from fatty acids that are 20 carbon units in length and function as signaling molecules that promote or inhibit inflammation. Arachidonic acid produces more inflammatory eicosanoids while EPA and DGLA produce eicosanoids that are less inflammatory. The designation of pro-inflammatory and anti-inflammatory may be an over-simplification as each eicosanoid exerts a specialized effect dependent upon the tissues in which they are produced and where they exert their activity. Inflammation is a necessary part of the immune response and is not always a negative. We need both inflammation and resolution as part of the immune response just as we need the gas and the brake in a vehicle—both serve a purpose.

Specialized Pro-Resolving Mediators

Another component of fatty acid breakdown are the specialized pro-resolving mediators (SPMs). These are lipid mediators that help to resolve inflammation and restore normal cellular function following an inflammatory episode. SPMs are produced from arachidonic acid, EPA, and DHA. Resolvin, maresin and protectin are produced from EPA and DHA, and lipoxin is produced from arachidonic acid. SPMs are further designated as E-series if they are derived from EPA, and D-series if they are derived from DHA. Lipoxin is the only SPM produced from an omega-6 fatty acid and functions as the lead family of pro-resolving mediators to reduce inflammation and restore tissue integrity.

Chiang N, Serhan CN. Essays in Biochemistry. 2020;64(3).

How Do SPMs Resolve Inflammation?

SPMs stimulate macrophage-mediated clearance of the debris that is produced as part of an immune response. Neutrophils that have engulfed a pathogen will undergo apoptosis. This signals macrophages to engulf the spent neutrophils and carry them into the lymph system for clearance. Efferocytosis is the process of removing post-inflammatory cellular debris by macrophages and is key to supporting the resolution of inflammation. If macrophages are not recruited to the scene, the dying neutrophils release their cell contents, which signals that tissue damage has occurred. If damage is occurring in the tissues, more immune cells are recruited to the site and inflammation continues rather than resolves.

The acute inflammatory process initiated towards a pathogen should be self-limiting with the return of the tissue to a pre-inflammatory state. SPMs participate in the process of resolution of the inflammatory state, which allows tissues to begin the process of repair and regeneration rather than slipping into a state of chronic inflammation.

Sources of SPMs – What You Make and What You Take

Supplementing with omega-3 fats has been a recommendation of both alternative and conventional medical practitioners for decades. The pathways that the omega-3 and omega-6 fats take, and the enzymes involved in their conversions are well-mapped out. We have a clear understanding of which eicosanoids promote inflammation and which reduce inflammation, and it seems clear that if we get enough omega-3 fats in our diet, we should produce enough SPMs. But that might not always be the case.

Enzymatic production of SPMs from fish oil has been identified as one of the bioactive processes that contributes to the anti-inflammatory effects. Conversion of EPA and DHA to SPMs can be a slow and complex process in which success is dependent upon several factors. If the enzymes necessary for the conversion of fish oil are insufficient, we cannot produce the SPMs and benefit from their effects. The enzymes necessary to support the conversion process have roles in other pathways and may be diverted to other uses, leaving the production of SPMs deficient. Aging, toxic overload, poor diet, stress, genetics, and lack of sleep can also complicate this process via reduction of biosynthetic potential.

Ultimately, the formation of SPMs is determined by the presence of omega-3 fats in the diet, the ability to absorb fats, and availability of the necessary enzymes to create SPMs. If any one of those components is missing, the benefits of supplementing with fish oil are greatly reduced. Several supplement companies have developed fish oil products using a patented fractionation process that creates immediate precursors to SPMs, which helps get around all the factors that may limit their availability.

Benefits of SPMs

Glucocorticoids, aspirin, other non-steroidal anti-inflammatory drugs, and more recently, biologics that inhibit specific mechanisms of inflammation all function through the inhibition of inflammatory pathways. Supplementing directly with SPMs can support the resolution of acute inflammation, as well as addressing chronic inflammatory processes without compromising a healthy immune response. Acute inflammation is necessary; however, inflammation that does not resolve can perpetuate tissue damage and advance an ongoing disease process.

SPMs have proven useful in supporting recovery from lung infections, surgery, head trauma, and stroke. Additionally, SPMs show efficacy in helping to resolve cardiovascular inflammation, asthma, inflammatory bowel disease, sepsis, periodontal disease, and injury to muscles and bone. Combining supplementation of SPMs with specific antioxidants and phytonutrients that provide protection from oxidation is ideal in addressing ongoing inflammation. Quercetin, resveratrol, turmeric, epigallocatechin gallate from green tea, vitamins C and E along with a diet rich in vegetables can reduce oxidative stress and reduce tissue damage from an ongoing inflammatory process.

While we want the immune system to do its job in supporting the clearance of pathogens and allowing us to heal from injury, the resolution of inflammation is also an important component of a healthy immune response. Inflammation can be a contributing factor in the development of countless chronic diseases and can interfere with recovery from an acute illness. SPMs can support the body’s efforts to bring a complete resolution to the inflammatory process, allowing tissues to heal and return to normal function.

ZRT Testing: The Link to Inflammation

Inflammation can be an underlying process in any chronic disease. Hormone imbalances, hypothalamic-pituitary-adrenal axis dysfunction, metabolic syndrome, insulin resistance, cardiovascular disease, and autoimmune conditions can contribute to or result from chronic inflammation. Screening for functional imbalances in sex, thyroid and adrenal hormones can provide some insight regarding underlying contributors to general inflammation. Measuring cholesterol, triglycerides, HgA1C and fasting insulin in a dried blood spot is a convenient way to screen for elevated blood lipids, poor blood sugar control, and insulin resistance. These markers can be indicative of developing cardiovascular disease and metabolic disorders, which all contribute to and are worsened from unresolving inflammation. Lastly, ZRT measures high-sensitivity C-reactive protein, which increases in the blood with inflammation and infection, and is often used as a predictive tool for the development of cardiovascular disease.

Resources

1. Basil MC, Levy BD. Specialized pro-resolving mediators: endogenous regulators of infection and inflammation. Nat Rev Immunol. 2016;16(1):51-67.

2. Rosenthal MD, Patel J, Staton K, et al. Can specialized pro-resolving mediators deliver benefit originally expected from fish oil? Curr Gastroenterol Rep. 2018;20(9):40.

3. The spectrum of pro-resolving mediators (PRMs). Big Bold Health Professional. 2021. Accessed May 20, 2022.

4. Silverman R. Specialized pro-resolving mediators: a new tool for resolving inflammation. 2017. Accessed May 20, 2022.

Comorbidities and COVID-19: Addressing Type II Diabetes and Metabolic Syndrome

Fri, 04 Feb 2022 08:18:31 -0800

We are nearly two years into the COVID-19 pandemic. Lives have been lost around the world and the virus continues to mutate with several strains of concern circulating globally. At the time of this writing the Delta variant is responsible for most of the infections in the US and elsewhere, while the Omicron variant is rapidly emerging. Ask anyone who has survived COVID-19 what it was like, and the answers may range from symptoms of a moderate cold to extreme body pain, fatigue, and respiratory distress, landing them in the hospital. This can be a serious illness even in those with good health and no comorbidities. For those with comorbidities, such as type II diabetes mellitus (T2DM), metabolic syndrome, cardiovascular disease (CVD) and hypertension, the risk of morbidity and mortality with COVID-19 increases greatly. This was the case for a close relative who became ill with COVID-19 in March 2021. But instead of COVID-19 taking his life, it saved him. Let me explain.

Brian was over 350 pounds and his health was deteriorating as a result. We knew that he had hypertension and we could only assume that he harbored metabolic disorders and CVD as well, due to his weight. When he got sick with COVID-19, he was treated with early therapies to reduce the viral load and lessen the inflammation. While his symptoms were manageable, he could not maintain normal oxygen saturation on room air alone and needed to use an oxygen concentrator. His fatigue was unrelenting, his lungs hurt with every breath, and his chest felt heavy. For him, past respiratory infections led to bronchitis or pneumonia and we were concerned that he was headed in that direction. Like many people confronting a COVID-19 infection, he did not want to go to the hospital for fear of being put on a ventilator. However, when all therapies that could be done at home were finally exhausted, his wife convinced him to go to urgent care for an exam and a chest x-ray, where he was diagnosed with COVID-19 pneumonia.

At the time of his exam, his oxygen saturation was below 80, which was very dire. He was admitted to the hospital and quickly placed on a five-day recovery protocol that included remdesivir, high-dose steroids, and convalescent serum that he responded to very well. After the five days, he was released from the hospital and referred to his family physician for follow-up care.

Here is where the “COVID-19 saved his life” story comes in. Being in the hospital for five days made him captive to doctor’s orders and extensive lab work. It was discovered during his stay that he had severe T2DM with a blood glucose level over 300 and hemoglobin A1C at 10.1. He was given insulin injections six times a day to bring his blood sugar down. He knew that he needed to make some serious changes—stay on the same path and get worse or commit to dietary and lifestyle changes to get better. He chose the latter and as of this writing he has successfully shed over 120 pounds by following a modified ketogenic diet and getting regular exercise. I am so proud of him for embarking on this journey to better health. He credits his wife with his success as he knows that he couldn’t have done this without her support and participation.

For Brian, a conscious decision was made to improve his health and this decision reduced his total risk of disease morbidity and mortality from all causes. Whatever health issues he confronts in his life he is now better positioned for a positive outcome. Metabolic disorders, CVD, and hypertension can influence how the immune system responds to an acute illness. It is likely that COVID-19 will become an endemic disease despite vaccination so it is important that we address our health issues now to improve the outcome should we get infected with this persistent and ubiquitous virus.

Coronavirus and Metabolic Disorders

Metabolic disorders, CVD, and hypertension can influence how the immune system responds to an acute illness. It is likely that COVID-19 will become an endemic disease despite vaccination so it is important that we address our health issues now to improve the outcome should we get infected with this persistent and ubiquitous virus.

The metabolic dysregulation common to T2DM, metabolic syndrome, and CVD creates an imbalanced immune response that can potentiate inflammatory mediators while inhibiting the immune system’s ability to effectively mobilize against an infection (1). The coronavirus SARS-CoV-2 that causes COVID-19, enters human cells via the envelope spike glycoprotein, which is found on the surface of the virus. This glycoprotein binds to the ectoenzyme angiotensin-converting enzyme 2 (ACE-2) located on human cell surfaces to gain entry into the cell for replication. T2DM induces expression of ACE-2 in the lungs, liver and heart, which would allow for enhanced viral replication and contribute to the severity of the infection (2). At its most extreme, this enhanced reaction can result in a cytokine storm that, if not brought under control, can cause multi-organ failure and death. Identifying populations where severe viral disease can advance rapidly, encourages early intervention when a virus occurs. Early identification of those at risk can also allow time for interventional strategies to prevent a serious reaction to a viral infection and halt the progression of chronic disease associated with metabolic disorders.

Metabolic Dysregulation and Inflammation

The mechanisms by which these pre-existing conditions can make a serious viral infection potentially fatal are not fully understood; however, it is known that hyperglycemia activates metabolic pathways that compromise innate immunity, increase oxidative stress, and potentiate tissue damage through uncontrolled inflammation. The innate immune system is the more primitive of the two main systems of immune defense. The other is the adaptive immune system that creates antibodies and immune memory. The innate immune system mobilizes immune cells to the site of infection via the production of cytokines that initiate an inflammatory reaction. Inflammation generates reactive oxygen species that aid in the defense against pathogens; however, if the process goes on too long, tissue damage can occur (2). During a cytokine storm, what starts out as a normal innate immune response accelerates into a flood of inflammation, resulting in tissue damage, capillary leakage, fluid accumulation, sepsis, hypotension, and clot formation. This can be a very dire situation and is associated with serious lung infections like SARS CoV-1 and SARS CoV-2, especially in those who have comorbid conditions predisposing to chronic inflammation (3).

Looking for the Red Flags

Chronic hyperglycemia and insulin resistance are associated with T2DM, metabolic syndrome, CVD, and hypertension. These disorders could easily exist along a continuum ranging from metabolic syndrome to severe CVD as one disorder can lead to the other if the dysfunction is not addressed early. A diagnosis of insulin resistance or metabolic syndrome serves as a warning that trouble is ahead. Evaluating serum or blood spot markers for fasting glucose and insulin, high-sensitivity C-reactive protein (hsCRP), hemoglobin A1c, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) can provide an overview of key markers that reveal metabolic status. According to a report published by the Centers for Disease Control and Prevention in 2017, over 30 million adults aged 18 years or older, or over 12% of the US population, have T2DM. About 25% of that population was unaware that they had diabetes. The link between T2DM and the development of CVD is well established, and it is estimated that 50% of those with diabetes will go on to develop CVD. The prevalence of metabolic syndrome is even higher at 30% of the US population. When we expand these numbers to a global scale, the prevalence of metabolic syndrome is estimated to be about 25% of the world’s population (4).

Metabolic Syndrome and Risk Factors

Metabolic syndrome is a cluster of conditions consisting of increased visceral fat, dyslipidemia, elevated glucose, insulin resistance, and hypertension. This syndrome can be the precursor to T2DM and CVD, and is primarily related to diet, lifestyle and, to a lesser degree, genetics. Overconsumption of simple carbohydrates and processed foods along with a sedentary lifestyle are major contributors. Additional factors that contribute to metabolic syndrome include stress, insomnia, exposure to viruses, overuse of antibiotics, microbiome imbalances, vitamin D and other nutrient deficiencies, and hormone imbalances. Exposure to metal and non-metal environmental toxins, particularly endocrine-disrupting chemicals during key developmental stages, can have far-reaching effects later in life and across generations (5).

Hormone Imbalances

Outside of diet and lifestyle factors that can reduce the risks associated with metabolic syndrome, addressing sex hormone imbalances, thyroid dysfunction, managing stress, and supporting adrenal function and sleep can help to rebalance metabolic disorders. Relative estrogen dominance can be associated with an overactive immune response in both men and women. Men who have excessive belly fat will tend to aromatize testosterone to estrogen so they may have higher estrogen levels than their lean counterparts. A 2018 article in Frontiers in Immunology states, “Besides gender, sex hormones contribute to the development and activity of the immune system, accounting for differences in gender-related immune responses. Both innate and adaptive immune systems bear receptors for sex hormones and respond to hormonal cues.” Sex hormones not only regulate the reproductive system, but also direct the development and function of the immune system (6). Balancing sex hormones supports a more balanced immune response.

Stress and Cortisol

Addressing stress and the resulting output of cortisol can also help keep the immune system balanced. While each of us may have our own strategies for dealing with mental-emotional stress, decreasing physiological stressors is also important. Maintaining stable blood sugar, getting restful sleep, avoiding allergenic and inflammatory foods, and addressing gut inflammation can reduce the physiological triggers of excess cortisol. As a glucocorticoid hormone, cortisol’s primary job is to mobilize glucose for energy when we confront a stressor. Increasing blood glucose triggers the release of insulin to usher glucose into our cells for energy. This response was designed to save our lives and provide us with the energy we might need to fight or flee. However, today’s stressors usually do not require a burst of physical energy so that rush of glucose and insulin results in energy storage rather than energy expenditure. If this process is occurring frequently throughout the day, the resulting dysregulation can set the stage for the development of metabolic syndrome. Elevated cortisol also suppresses the immune system leaving us more vulnerable to infections.

Sleep

While we can take personal inventory of our food choices, body weight, and activity level, unless we test for specific blood, salivary, and urine markers, we will not know the extent of metabolic imbalance we may be experiencing.

Sleep can help to reset the immune system and support a healthy response in the presence of an infection. Sleep and the circadian rhythm are strong regulators of immune cells, and their functions seem to display a synchronous rhythm. Differentiated immune cells peak during the day as they can be efficiently mobilized against a pathogen. Undifferentiated immune cells peak during sleep when the slower adaptive immune response is initiated, allowing for the creation of immune memory. Lack of sleep results in a heightened stress response with increased cortisol and catecholamines. This invokes a non-specific production of pro-inflammatory cytokines, leading to low-grade inflammation (7).

Sleep disorders may contribute to the development of insulin resistance and metabolic syndrome. The converse may also be true in that metabolic abnormalities associated with metabolic syndrome and insulin resistance may exacerbate sleep disorders. There is an inverse linear relationship between weight and sleep time. Lack of sleep and metabolic syndrome both result in a pro-inflammatory state (8).

Thyroid

Thyroid dysfunction occurs in 30% of those with metabolic syndrome and in those without overt or subclinical hypothyroidism, thyroid-stimulating hormone tends to be in the upper end of the range as compared to those without metabolic syndrome. The thyroid sets the metabolic rate, makes proteins, regulates growth, and drives sensitivity to other hormones. Hypothyroidism is associated with increased blood pressure, fasting glucose, total cholesterol, thyroglobulin, LDL and hsCRP, and decreased HDL (9). Though both hypothyroid and metabolic syndrome are independent risk factors for the development of CVD, these metabolic markers are very similar in each disorder. Factors that interfere with optimal thyroid function are elevated cortisol levels, iodine and selenium deficiency, high carbohydrate and low-protein diets, heavy metal and chemical toxicity, and high estrogen.

Gut Inflammation

Microbiome imbalances often result from poor diet and the overuse of antibiotics, which reduce key strains of necessary bacteria. A healthy and diverse microbiome keeps inflammation in check and maintains a healthy mucosal barrier, preventing the excess absorption of lipopolysaccharide or endotoxin, which potentiates systemic inflammation and is a known contributor to the development of metabolic syndrome. As stated in a 2013 article in the Journal of Molecular Endocrinology, metabolic endotoxemia may trigger toll-like receptor-4-mediated inflammatory activation, eliciting a chronic low-grade pro-inflammatory and pro-oxidative stress status associated with obesity, which may result in cardiovascular damage. Toll-like receptors are proteins that play a key role in the innate immune system and are crucial in the defense against pathogenic microbes through the induction of inflammatory cytokines (10). The main cytokines induced are tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL1-beta), and interleukin 6 (IL-6). These cytokines also happen to be increased in insulin resistance and metabolic syndrome (1).

COVID-19 and Beyond

Metabolic syndrome is a complex state that originates from an imbalance between caloric intake and energy expenditure. The body must find a way to store excess energy, which often results in inflammation and metabolic derangement that has multi-system effects. In the face of COVID-19, we are confronted with the immune dysregulation of underlying metabolic imbalances that reduce the body’s ability to mount a healthy and balanced immune response. This results in an over-expression of the pro-inflammatory cytokines TNF-alpha, IL-1 beta, IL-6—the severity of which is often determined by one’s genetic predisposition and current health status.

Beyond the COVID-19 pandemic, the pathophysiology that leads to the development of metabolic syndrome, T2DM, and CVD increases our risk of morbidity and mortality from all causes. This metabolically dysfunctional state alters our physiological and biochemical processes at a very fundamental level with far-reaching systemic effects. How we respond to any physiological challenge will be determined by several inherent factors; however, we do have some control over how we set the stage for a balanced or dysregulated response to a serious viral infection. The cluster of conditions that are part of metabolic syndrome are largely preventable through improved dietary and lifestyle measures coupled with the knowledge of particular risk factors. While we can take personal inventory of our food choices, body weight, and activity level, unless we test for specific blood, salivary, and urine markers, we will not know the extent of metabolic imbalance we may be experiencing.

The risk factors for COVID-19 shed light on the fact that how we take care of ourselves matters, especially in the face of a serious viral infection. There are many factors including age and genetics that can determine our response to a particular virus, and the variables can be many. However, being aware of where we stand metabolically and taking steps to improve our health during these uncertain times is one thing that we can control. Working with a qualified health professional and using appropriate testing to guide this process can be the beginning of better health, now and in the future.

ZRT Tests to Consider:

CardioMetabolic Profile

Weight Management Profile

Sleep Balance Profile

Female/Male Saliva Profile III

Comprehensive Thyroid Profile/Essential Thyroid Profile/Elite Thyroid Profile

Heavy Metal & Essential Elements Profiles

References

Creating Balance: Norepinephrine, Epinephrine, Cortisol, and the Stress Response

Mon, 03 Jan 2022 13:49:57 -0800

If you have ever experienced a near-miss collision or other accident, you have likely felt the rush of adrenaline coursing through your veins almost instantly. In that moment, your heart rate, blood pressure, and respiratory rate increased, your pupils dilated, and your brain felt immediately more alert. These are the effects of adrenaline, otherwise known as epinephrine, which is produced in the adrenal medulla when we encounter a significant stressor.

In a “life or death” situation, the stress response can literally save our lives by readying us to act and facilitating a physiological response to support that action. But an extreme stressor isn’t always required to stimulate a stress response. The body is in a constant state of flux and adaptation to our changing internal and external environment, making subtle physiological adjustments to maintain a relatively stable equilibrium known as homeostasis. The maintenance of homeostasis involves the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis through their respective chemical mediators, which include norepinephrine (noradrenaline), epinephrine (adrenaline), and cortisol.

The degree to which these chemical mediators are engaged often depends on the type of stressor and the magnitude of the response. Not all stressors are equal and not all stress is negative. We adapt to the dynamic and challenging situations that we encounter because we are equipped with complex networks that integrate the body and the brain to enhance performance, promote adaptation, and help us to survive (1). If the stress response cannot self-regulate and return to a homeostatic state, disease processes may develop. Testing the levels of these stress mediators can provide useful data that allows for quantifying the effects of stress and implementing strategies to improve both physical and mental health.

A Brief Overview of the Nervous System and the Stress Response

The nervous system is composed of the central nervous system (CNS), housed within the brain and spinal cord, and the peripheral nervous system (PNS), which is further divided into the autonomic and somatic nervous systems. The ANS includes the sympathetic, parasympathetic, and enteric nervous systems (2).

In simple terms, the sympathetic nervous system (SNS) controls the “fight or flight” response, while the parasympathetic nervous system (PSNS) controls the “rest and digest” response. The functions of the sympathetic and parasympathetic branches oppose and complement one another to create balance and maintain homeostasis.

The body’s stress response is mediated by the interplay between the central and sympathetic nervous systems and the HPA axis (3). Upon perceiving a stressor, the CNS relays a signal to the SNS, triggering the release of norepinephrine, which initiates the stress response and primes the body for action. In addition, the SNS signals the adrenal medulla to release epinephrine and additional norepinephrine into general circulation. When epinephrine and norepinephrine bind to adrenergic receptors on target tissues, we experience an increase in heart rate, blood pressure, and cardiac output. The bronchi of the lungs dilate so that we can receive more oxygen to meet the increased demand from the cardiovascular system. Our pupils also dilate reflecting intense concentration and focus. Bodily functions that do not serve immediate survival, such as salivation, lacrimation, urination, and digestion, are decreased (3).

Finally, activation of the stress response stimulates the HPA axis to produce and release cortisol into the bloodstream. Cortisol mobilizes stored glucose, fats, and amino acids to support the energy needed to cope with the stressor. The release of norepinephrine and epinephrine provides an immediate jumpstart to the stress response, while stimulation of the HPA axis and the release of cortisol provides fuel to sustain the response until the stressor is resolved (3).

Norepinephrine, Epinephrine, and Cortisol

Intense activation of norepinephrine without an adequate rise in cortisol, results in a failure to contain the biological stress response and leads to a persistent stress reaction.

Norepinephrine and epinephrine are catecholamines that act as both neurotransmitters and hormones and are vital to the maintenance of homeostasis (4). Catecholamines are synthesized in the brain, in the adrenal medulla, and by sympathetic nerve fibers. About 80% of norepinephrine is produced through the sympathetic nerve fibers with the remaining 20% coming from the adrenal medulla. All the epinephrine produced as part of the stress response comes from the adrenal medulla and is 10 times more potent in its physiological effects than norepinephrine (5).

Norepinephrine functions more as a neurotransmitter as it is primarily a product of the sympathetic nerve fibers and is released directly to receptors on innervated target tissue. Epinephrine functions more like a hormone in that it is released from the adrenal medulla into general circulation where it is transported via the blood to various target tissues (5). Norepinephrine has a stronger influence on blood pressure while epinephrine has a stronger influence on heart rate, contractility, and bronchodilation.

High levels of catecholamines with low cortisol results in a dysregulated stress response. Cortisol secretion, in addition to the activation of catecholamine receptors in target tissues, provides the signal to downregulate the acute stress response. Intense activation of norepinephrine without an adequate rise in cortisol, results in a failure to contain the biological stress response and leads to a persistent stress reaction (6). In the adrenal medulla the enzyme that catalyzes the transformation of norepinephrine to epinephrine is formed only in the presence of high local concentrations of cortisol from the adrenal cortex (7). Low or dysregulated cortisol output can contribute to a recurrent stress loop that cannot resolve appropriately, potentially resulting in elevated norepinephrine. All chemical mediators of the stress response are needed to maintain healthy feedback mechanisms and resolution of the stress response.

Homeostasis and Allostasis

Homeostasis is the ability or tendency of the body to seek and maintain a condition of relative stability as it deals with internal and external changes. The body uses feedback controls and other regulatory mechanisms to maintain a constant internal environment (8). Any physical or psychological event that disrupts homeostasis triggers a stress response. Allostasis is the process by which the body achieves stability or homeostasis through change and reflects the body’s ability to adapt the internal physiological environment to match the external demand (9, 10). A stressful event will stimulate the release of chemical mediators that help us to cope with the situation, while the process of allostasis allows us to return to that homeostatic state.

Allostatic Load

We are always experiencing some form of stress that requires the body to recalibrate to maintain homeostasis. This occurs all day, every day without our awareness. The physiological impact of stress is commonly referred to as the allostatic load. While the chemicals that mediate the stress response have both protective and adaptive effects in the short term, they can result in pathophysiological changes in multiple systems over the long term if produced in deficient or excessive amounts (9).

Allostatic overload occurs when stress is too frequent or longstanding and can result in physiological breakdown (10). The physiological effects of stress brought about by an unmanageable allostatic load can be cumulative over a lifetime and are often the result of modest dysregulation in multiple systems over many years. These cumulative effects are often reflected in basic parameters such as decreased heart rate variability, increased blood pressure, increased fasting glucose, reduced insulin sensitivity, and changes in growth hormone output. Chronically elevated levels of norepinephrine and epinephrine reflect increased sympathoadrenal activation. Under these circumstances, the allostatic load has exceeded the body’s ability to manage the stressor and a return to homeostasis cannot occur (9).

Allostatic Overload, the Stress Response, and Disease

Although the SNS is necessary for basic physiological functions, chronic overactivation can contribute to many disease states. In an article reviewing the maladies and mechanisms of sympathetic overactivity, Fisher et al explore the relationship between sympathetic nerve activation and blood pressure, cardiovascular disease, and metabolic disorders. An overactive SNS has become characteristic of several cardiovascular diseases including ischemic heart disease, chronic heart failure, and hypertension. Outside of the cardiovascular system, excessive activity of the sympathoadrenal system is associated with type II diabetes, obesity, metabolic syndrome, osteoporosis, depression, and an overall acceleration of aging (11).

Stress, Eustress, and Distress

From a psychological perspective, stress can be categorized as good stress or bad stress. Both types of stressors result in the same physiological response. We experience an increased heart rate, breathing rate, and focus, but one sensation is positive and the other is negative. Eustress, or good stress, is a term coined by Hans Selye, MD, PhD, and is often associated with motivation, focus, excitement, enhanced performance, productive energy, and the expectation of a positive outcome. Distress, on the other hand, is associated with procrastination, avoidance, decreased focus, fear, restless energy, impaired performance, and fear of a negative outcome. Some of the main elements that differentiate eustress from distress are the feelings of control within the situation, a predictable timeline, and the ability to handle a situation or task (12). Carter et al further describes distress as emotional stress that involves consciousness, aversiveness, and adrenal stimulation (7).

Particular events and experiences are universally stressful, so to expect that we should never experience distress is unrealistic. Events that trigger the feeling of distress or eustress are often related to our perception, memories, thought processes, past experiences, and genetics. We can modulate physiological stressors through a healthy diet and lifestyle that involves exercise, maintaining a healthy body weight, meditation, reducing factors that contribute to inflammation, and getting adequate sleep. The management of psychological stressors can seem more elusive because multiple factors contribute to how we respond to stressors (see “Anxiety, Depression, and the Cortisol Awakening Response,” July 2021). Whether through a physiological imbalance or a perceived stressful event, the brain and CNS are the starting point of the stress response.

Countering the Effects of Stress by Activating the Parasympathetic Nervous System

To elicit the stress response, we must first have an awareness of the stressor. That awareness occurs in the brain and CNS where we integrate sensorial, physiological, and emotional information and ultimately transmit that information to the ANS (1). Through training and awareness, we can employ methods to activate the PSNS and modify an overactive stress response. If the brain and CNS are where the stress response begins, this is also where we can initiate efforts to subdue or balance the response.

Activation of the PSNS facilitates lowered heart rate, decreased cardiac output, bronchoconstriction, increased sexual arousal, salivation, lacrimation, digestion, defecation, and urination. These are all physiological processes that require a level of relaxation. One method of engaging the PSNS and achieving this balance is through activation of the vagus nerve. The vagus nerve is the 10th cranial nerve and plays an integral role in the activity of the PSNS. It is the longest nerve in the body, originating in the brainstem and extending to the neck, thorax, and abdomen (13).

The vagus nerve contains 80% afferent and 20% efferent nerve fibers, which indicates that most of the communication through the vagus nerve is from the body to the brain. The brainstem is the area of the brain that senses, processes, and regulates most of the autonomic function. The afferent branch of the vagus nerve constantly provides homeostatic parameters from various organ systems to the brainstem, allowing it to respond in a regulatory manner (14).

Other activities that are known to activate the vagus nerve include humming, singing, chanting, cold bathing, sunlight exposure, yoga, pilates, tai chi, social interaction, listening to music, massage therapy, and acupuncture.

Vagus nerve activity is modulated by respiration where it is suppressed during inhalation and facilitated during exhalation and slow respiration cycles. Calming activities that involve breath control activate the vagus nerve and promote a sense of relaxation. Various forms of meditation, movement and mindfulness exercises enhance parasympathetic activity primarily through breathing techniques that slow and deepen respiration (14). Other activities that are known to activate the vagus nerve include humming, singing, chanting, cold bathing, sunlight exposure, yoga, pilates, tai chi, social interaction, listening to music, massage therapy, and acupuncture (13).

Positive social interaction and laughter engage and promote the activity of the PSNS. Laughter exercises the diaphragm and forces us to breathe deeply. Being among friends and loved ones can also increase the release of oxytocin, the bonding hormone, which moderates the stress response (15). Daily exposure to sunlight through our eyes and skin reinforces our connection to the cycles of light and dark in which cortisol plays a significant role as a chemical mediator of the circadian rhythm. Regular exposure to sunlight during the day can also promote a better night’s sleep, which is restorative on many different levels (13).

Enhancing vagal tone and engaging the PSNS can improve physical and mental health as well as cognitive function. The physical benefits of increased vagal tone include a decrease in cardiometabolic risk factors and an increase in cardiopulmonary health and fitness, decreased inflammatory markers, and improved general physical function. The mental health benefits include a decrease in perceived stress and an increase in well-being. Cognitive function is enhanced in the area of executive function, working memory, focus, and creativity (14).

Credit: medicalstocks

Assessment of the Stress Response and Related Markers

We can easily rate our perceived stress level through basic questionnaires and lifestyle assessment but to understand the physiological toll of those stressors, we need to measure some basic functional markers. We can assess the physiological effects of our allostatic load by measuring cortisol, epinephrine, norepinephrine, dehydroepiandrosterone sulfate, blood lipid markers and cholesterol ratios, hemoglobin A1c, high-sensitivity C-reactive protein, and fasting insulin, and relate those values to our perceived level of stress. Stress can be difficult to quantify as the experience of stress is unique to the individual; however, we can measure specific markers that reveal the degree to which homeostasis is compromised and this provides us with the opportunity to employ strategies to improve markers that indicate an imbalance.

The “NeuroAdvanced Stress Profile” tests urinary levels of five stress markers: cortisol, cortisone, melatonin, norepinephrine, and epinephrine. These markers are tested in dried urine samples by LC-MS/MS from urine collected at four time points (morning, late morning, early evening, and night before bed). Measuring the diurnal patterns of these stress markers provides a much more complete picture of the stress response as opposed to testing only cortisol and cortisone.

In healthy individuals the four data points would be expected to follow close to the center (median) line of each graph within the 20-80% reference range outlined in green. Typical abnormal diurnal patterns of each stress marker are shown for a highly stressed overweight individual with metabolic syndrome. The circadian patterns of cortisol and cortisone are flat, reflecting a poor cortisol awakening response (CAR) and inability of the adrenal glands to keep pace (hypocortisolism) with daily stressors by mid-morning. Diurnal melatonin is flat, which is common with pineal calcification caused by diseases of aging such as metabolic syndrome. The peripheral nervous system neurotransmitters, norepinephrine, and epinephrine are elevated throughout most of the day as a means to compensate for low cortisol to help meet the excessive demands of the stressors caused by metabolic syndrome.

ZRT Test to Consider

NeuroAdvanced Stress Profile: includes 4x diurnal profiles of urinary Cortisol, Cortisone, Norepinephrine, Epinephrine, and Melatonin measured by LC-MS/MS

References

Anxiety, Depression, and the Cortisol Awakening Response

Fri, 23 Jul 2021 13:16:49 -0700

The Cortisol Awakening Response (CAR) is the predictable rise in cortisol within the first hour of awakening. There are two events that contribute to this dynamic rise in morning cortisol. The first is in response to adrenocorticotropic hormone output from the pituitary as a part of the normal circadian activities of the hypothalamic–pituitary–adrenal (HPA) axis with involvement from the sympathetic nervous system. The second occurs in response to exposure to daylight with the activation of the suprachiasmatic nucleus in the hypothalamus, which happens within 30-45 minutes after awakening and can increase cortisol by 50-60% from the waking value. These events take place in a timed and metered fashion, allowing for a rise and fall of cortisol over a one-hour period [1].

The CAR is under the influence of the circadian clock and helps to synchronize the daily circadian rhythms, while the remainder of daily cortisol production is more influenced by daily stressors [2]. The purpose of the CAR is to mobilize glucose for energy needs, augment cardiovascular function, engage the motor system, and initiate and enhance cognitive processes that allow us to restore consciousness and engage in activity that requires us to be alert and ready for action [3]. Depression, anxiety, and early life trauma can influence the stress response. The CAR is often used to predict the onset of depression or anxiety in certain populations and may be used to monitor the efficacy of treatment for these conditions.

What Does the CAR Tell Us?

Since waking seems to function as a mini stress test, we can use the CAR to determine how robust the HPA axis is in response to the stress of waking up and relate those results to an individual’s history. The CAR is most often measured with additional cortisol levels taken throughout the day up until bedtime. This comprehensive analysis of cortisol dynamics allows us to visualize the morning rise (MR) in cortisol and the diurnal cortisol slope (DCS) throughout the day. A robust MR and steep decline in the DCS are associated with a healthy HPA axis [4, 5].

Personality and Life Experience: Factors that Influence the CAR

In a one-hour time period, the CAR can encapsulate the baseline response to stress and the status of the HPA axis. It is difficult to know if the association between cortisol levels and mood disorders, such as anxiety and depression, reflects a causal relationship and if so, in which direction. Which is the cause, and which is the effect? The studies mentioned below have used the CAR to predict events of major depressive disorder or anxiety, but it is unclear if cortisol patterns within the CAR are contributing to anxiety and depression or are a result of existing anxiety or depression [3].

We often refer to a perceived level of stress when addressing HPA axis dysfunction. My perception of stress may be quite different than yours under the exact same circumstances and that perception is built on past experiences, memories, and personality traits. Perhaps who we are can often be reflected in the chemicals that mediate our emotional responses to the events of life. Patterns of cortisol output, within the CAR and throughout the day, can provide necessary insight regarding personal characteristics, personality traits, and life experiences that can have far-reaching effects on health and wellness over a lifetime.

Trait vs State

Patterns of cortisol output, within the CAR and throughout the day, can provide necessary insight regarding personal characteristics, personality traits, and life experiences that can have far-reaching effects on health and wellness over a lifetime.

The mental-emotional factors that influence the CAR and daily cortisol output can be either trait- or state-specific. A trait is a relatively stable characteristic that causes people to behave in certain ways; more specifically described as a personality trait. According to the American Psychological Association Dictionary of Psychology, a personality trait is stable, consistent, and enduring, and is inferred from behaviors, attitudes, feelings, and habits [6]. An article in Psychology Today outlines the “Big Five” personality traits, which are broad dimensions used to describe a person’s general temperament [7]. The Big Five include:

Openness to Experience – interest in new ideas and experiences vs cautious and rigid
Conscientiousness – completing what is started vs carelessness, loss of interest
Extraversion – high degree of sociability and positive emotion vs solitary and reserved
Agreeableness – friendly and compassionate vs critical and overly rational
Neuroticism – anxiety, depression, low-self-esteem, nervous vs resilient, confident

These personality traits can exist along a spectrum, and we are usually a combination of all of them to varying degrees with perhaps a few that dominate [6]. Personality traits can change over time through both life experience and maturity, and a focused intention to change if the trait, or lack thereof, tends to result in psychological, social, or relational issues.

On the other hand, a state is a temporary way of being (i.e., thinking, feeling, behaving, and relating) and is usually situational and transient. The importance of the trait vs state distinction helps to differentiate between what might be a normal response to situational stress (state) and a predisposition to have an exaggerated stress response regardless of the situation (trait). Trait-specific influences may be more reflected in the CAR as these values tend to be remarkably consistent over time regardless of the stress a person may be experiencing [8]. Variations in diurnal cortisol output, outside of the CAR, may be more reflective of the stress response in relation to physiological and situational stressors.

Resilience

Resilience can be defined as the ability to withstand stress and recover without extending consequences, and it tends to be associated with more positive personality traits and better physical health. In a recent study on Chinese undergraduate students in which the CAR and the diurnal rhythm of cortisol were measured over three days, Lai et al determined that higher resilience was associated with an enhanced CAR and a steeper DCS from waking to bedtime. They conclude that an accentuated CAR indicates effective coping with life stressors and a steeper DCS indicates effective cortisol regulation [5]. The rise and fall of cortisol in this manner characterizes the effective activation and deactivation of the HPA axis and provides a neuroendocrine representation of the positive association between resilience and good health [5].

Resilience in life can be fostered through early life influences such as supportive and attentive parenting, a loving and supportive environment, positive relationships with adults and peers, experience in overcoming manageable life challenges, and avoidance of repeated exposure to uncontrollable stress and trauma. Other factors that support resilient behavior in adulthood include adaptive stress responses, rapid stress recovery, high coping skills, ability to cognitively evaluate situations, emotional regulation, and self-confidence [9]. The ability to implement coping strategies and foster resilience is often associated with positive personality traits and can be learned if early life influences were lacking.

Depression and Anxiety

The toxic stress response is believed to play a role in the development of depressive disorders, behavioral problems, PTSD and psychosis, and is likely more common than we realize.

Certain psychological traits such as neuroticism, hopelessness, negative affect, subclinical depression, or a family history of depression have been associated with increased vulnerability to developing a depressive disorder [3]. An elevated CAR at baseline measurement, seemed to be predictive of a major depressive episode (MDE) within two and a half years. Dedovic suggests that the CAR could be used as a predictor of an upcoming MDE independent of future stressful life events. An extremely stressful event often precedes the onset of a major depressive episode with subsequent episodes of depression occurring over minor events due to stress sensitization and perhaps maladaptation of the HPA axis, resulting in desensitization of normal feedback loops that regulate cortisol output [3].

Anxiety often coexists with depression and can result in an elevated CAR and a DCS that is flat but elevated throughout the day, indicating a prolonged activation of the HPA axis. In a 2014 six-year prospective study analyzing the association between the CAR and anxiety disorders (AD), a higher CAR was a strong and significant predictor of a first onset anxiety disorder. The study included 232 older adolescents who shared personality traits, and cognitive, life event, and biological factors that predisposed the participants for an increased risk of developing anxiety. Over 1,900 students were screened for neuroticism, which is a known risk factor for mood and anxiety disorders. The students who were chosen to participate in the study scored in the top third for neuroticism as they were most likely to go on to develop an anxiety disorder.

Salivary cortisol samples were taken six times a day for three consecutive days at the beginning of the study. Samples were collected upon waking, 30-40 minutes after waking and at bedtime with three additional collections of saliva at unanticipated times during the day. Each participant was evaluated annually for significant mood or anxiety disorders using a Structured Clinical Interview for DSM-IV (non-patient edition). Of the 232 participants, 25 developed an anxiety disorder, the majority of which (11/25) fell into the category of social anxiety disorder (SAD), while the remaining participants fell into five different categories of AD. As stated by Adams et al, HPA-axis activity is particularly sensitive to perceived social stress and is the most powerful activator of the HPA axis in studies of experimentally-induced stress. Social anxiety often results in loneliness and isolation, which is also associated with a higher CAR. Of those who developed an AD, the CAR turned out to be a significant predictor of onset [10].

Genetics and Environment

Both genetics and environment can play a crucial role in the development of personality traits that are either supportive of resilience, which fosters a healthy response to stressful events, or neuroticism, which can predispose to anxiety and depression. Through a search of the current literature on genetics and heritability of resilience, Maul et al determined that certain genes combined with epigenetic factors can predispose to less resilience. Polymorphisms in the genes of the neuroendocrine stress response system can lead to increased stress sensitivity and a tendency to develop depression under stress exposure especially in those who have experienced early childhood trauma. Variations in the genes that code for the production, metabolism and breakdown of serotonin, dopamine, and norepinephrine have been associated with less resilience and the development of post-traumatic stress disorder (PTSD) and major depressive disorder.

Specific genetic variations also occur within the HPA axis that can either promote resilience or increase the chance of dysregulation. Certain polymorphisms in the genes that code for corticotrophin releasing hormone (CRH) are associated with a reduced risk of depression after being exposed to early life stress and provides a strong indication of the genetic impact on resilience [9]. Polymorphisms in the glucocorticoid receptor (GR) genes are associated with PTSD and depression. Additional genes that interact with the GR can decrease negative feedback regulation of the HPA axis and lead to GR resistance [9]. We often see a blunted and elevated DCS in people with a maladaptive stress response indicating a loss of feedback regulation of cortisol output.

Epigenetic factors, which would include environment, play a large role in the development of any health issue and the same is true here. Maul et al referred to early childhood trauma as an epigenetic factor that contributes to the expression of genetic traits that reduce resilience and increase sensitivity to stressful events. Trauma in early childhood has often been associated with a maladaptive stress response linked to a deeply ingrained fear response in the amygdala of the brain. From a developmental perspective, young children lack the cognitive ability and life experience to make sense of terrible circumstances, which ultimately leaves them with an enhanced stress response that extends into adulthood.

Adverse Childhood Experiences (ACEs) and a Maladaptive Stress Response

When we understand how we respond to stressors and why we respond as we do, we can find ways to better manage our stress to avoid the long-term outcomes and improve overall health and well-being.

Research into ACEs shows a strong correlation between early childhood adversity and poor physical and mental health later in life. The National Scientific Council on the Developing Child coined the term “toxic stress” to describe the effects of excessive activation of the stress response on a developing child’s brain, immune system, metabolic regulatory systems, and the cardiovascular system. When a child experiences multiple ACEs over time without the supportive relationships to buffer the effects of these stressors, these experiences will trigger an excessive stress response [11].

Toxic stress results in the derangement of the neuro-endocrine-immune response, leading to excessive and prolonged activation of cortisol along with a persistent inflammatory state. The child cannot deactivate the stress response after the stressor is removed. Children who experience early life toxic stress are at risk of long-term adverse health effects that may not manifest until adulthood. ACEs often include one or more of the following: emotional, physical and/or sexual abuse, neglect, mental illness of a caregiver, household violence, and substance abuse. The adverse effects that may result from ACEs include maladaptive coping skills, poor stress management, unhealthy lifestyles, mental illness, and physical disease [12].

A child experiencing toxic stress is at risk of permanent changes to brain architecture, epigenetic alteration, and modified gene function. As mentioned above, polymorphisms associated with genes that regulate neuroendocrine function and the stress response are more pronounced in people who experienced adversity in childhood. Under these extremely stressful situations, children are at risk for long-term health and developmental effects including increased risk for stress-related diseases [12]. The toxic stress response is believed to play a role in the development of depressive disorders, behavioral problems, PTSD and psychosis, and is likely more common than we realize.

Physical Effects of Stress and a Maladaptive Stress Response

Having an intact stress response can literally save your life; however, eliciting a stress response that far exceeds the stressor without the ability to effectively deactivate that stress response can affect both mental and physical health. Sustained and persistent stressful conditions can precipitate the excessive production of free radicals, increasing oxidative burden and promoting inflammation that further contributes to chronic disease. Oxidative stress contributes to neuronal degeneration that can result in cognitive dysfunction, memory loss, dementia, and other neurodegenerative diseases that result from the loss of synaptic connectivity and neuronal networks throughout the brain. Excessive stress can also interfere with the normal production of neurotransmitters, the chemical messengers throughout our brain and nervous system that contribute to mood and cognitive function [13].

The long-term physiological effects of chronic stress can also lead to hormonal shifts that suppress reproduction, growth, and thyroid function via suppression of gonadotropin-releasing hormones, growth hormone, and thyrotropin-releasing hormone. Excessive levels of cortisol may precipitate high glucose levels that can ultimately lead to insulin resistance, increased visceral adiposity, and decreased lean body mass. High levels of cortisol can also suppress osteoblastic activity leading to bone loss that may advance to osteoporosis. Stress can be a contributing factor to just about every disease. When we understand how we respond to stressors and why we respond as we do, we can find ways to better manage our stress to avoid the long-term outcomes and improve overall health and well-being.

A Simple Salivary Test and a Good History Can Go a Long Way

Evaluating HPA-axis function by measuring salivary cortisol provides a link between an objective and quantifiable marker, and the subjective experience of stress. Cortisol is an end-point hormone that can tell the story of our past as well as our present. Using the CAR provides us with specific insight as to how a person operates and can be predictive of anxiety and depression if it is overly accentuated, or representative of chronic fatigue and burnout if it is blunted. Laboratory data in combination with a good patient history can reveal a lot about our patients and help guide us as practitioners to address the core issues.

We cannot undo our patients’ past, but we can help them navigate the present and future with more resilience by teaching skills to cope with stress in a more productive way that allows for the reframing of experiences to moderate an overly accentuated stress response. For individuals at risk for depression or anxiety, an elevated CAR may be the first clue as to where they are headed. If we can use this information to intervene early, we may have the opportunity to change the trajectory of their health on many levels.

ZRT Tests to Consider

ZRT Laboratory provides a comprehensive list of testing that is valuable in assessing the causes and contributors to anxiety and depression. The CAR can be assessed through ZRT’s Cortisol Awakening Response Profile, which measures six salivary samples of cortisol with the first three samples taken within the first hour of waking. The additional three salivary samples are taken at designated times up until bedtime. To measure sex hormone levels in combination with the CAR, the salivary Hormone Trio measures estradiol, progesterone, and testosterone.

When addressing the potential contributors to depression or anxiety, the NeuroAdvanced Profile provides a comprehensive measurement of urinary neurotransmitters. This test is performed on dried urine samples for ease of collection and handling. ZRT also provides several dried urine tests that can be added on to the NeuroAdvanced Profile. These tests include: 1) Diurnal Cortisol & Melatonin, 2) Diurnal Cortisol, Norepinephrine & Epinephrine, 3) Diurnal Cortisol, Melatonin, Norepinephrine & Epinephrine and 4) Urine Toxic & Essential Elements. Urinary cortisol measurements in combination with timed measurements of neurotransmitters can provide useful data regarding the stress response and its relationship to melatonin, norepinephrine, and epinephrine. The presence of toxic elements can predispose an individual to chronic illness and the deficiency or excess of essential elements can influence the production of neurotransmitters and hormones.

Related Resources

References

Part IV: Long COVID and HPA Axis Dysregulation

Thu, 24 Jun 2021 13:08:27 -0700

Anyone who has dealt with issues related to chronic fatigue has likely evaluated their hypothalamic–pituitary–adrenal (HPA) axis performance through a multi-point salivary test. Cortisol is readily measured in saliva when samples collected at predetermined intervals throughout a single day reveal one’s physiological resilience and metabolic reserve in response to daily stressors. HPA axis testing is a mainstay in the world of integrative, naturopathic, and functional medicine.

For the past 18 months, the world has existed under the constant shadow of COVID-19. To say that we have been “stressed” is an understatement. Mental-emotional stressors certainly trigger the activation of the stress response pathways, but physiological and lifestyle factors contribute to these physiological processes as well. Furthermore, inflammation due to infection provoke the adrenal glands to release cortisol to regulate the inflammatory response and support the immune system. In the case of COVID-19, the research cited below has shown that cortisol does not rise in response to the SARS-CoV-2 infection as expected. In fact, surprisingly, the opposite is true - cortisol levels drop in the presence of SARS-CoV-2, leaving the body vulnerable to escalating and unchecked inflammation, and predisposing the individual to the life-threatening adrenal crisis.

HPA axis dysfunction can occur under many types of chronic stressors; however, viral infections can trigger specific dysfunction within the HPA axis, leaving its host with chronic fatigue and weakness long after the initial infection has been resolved. Some of the latest research also takes a closer look at other endocrine organs such as the thyroid, hypothalamus, pituitary, pancreatic and gonadal tissue, and how each may be affected by the SARS-CoV-2 virus. In the last installment of this four-part series on long COVID, we will look at the mechanisms involved with the SARS-CoV-2 virus and the HPA axis, and what this means for COVID long-haulers.

SARS-CoV-2 and Adrenal Insufficiency

SARS-CoV-2 can influence cortisol output through three different pathways.

In a letter to the editor of the American Journal of Physiology-Endocrinology and Metabolism, Siejka postulates that adrenal insufficiency (AI) related to COVID-19 may occur for the following reasons: 1) hypophysitis and adrenalitis resulting from direct infection with the SARS-CoV-2 virus, leading to secondary or primary AI; 2) production of adrenocorticotropic hormone (ACTH) antibodies; and 3) critical illness-related corticosteroid insufficiency (CIRCI) [1]. It has been determined that the hypothalamus, pituitary, and the adrenal glands all have angiotensin-converting enzyme (ACE)2 receptors so direct infection of these organs is plausible. In fact, histological findings report focal necrosis and vasculitis of the small veins of the adrenal glands, and structural and functional damage within the hypothalamus and the pituitary in those who were infected with the SARS-CoV-2 virus [1].

According to the recent article published in Medical Hypotheses, the uncanny ability of SARS-CoV-2 to inhibit the host’s corticosteroid stress response is a means to evade the immune system [2]. SARS viruses have a unique mechanism to inhibit the activation of the stress response and prevent cortisol release by expressing a series of amino acids that mimic parts of the ACTH amino acid structure, a process that can be best described as molecular mimicry. What happens next is the immune system forms antibodies against both the coronavirus and ACTH, and the antibody-bound ACTH becomes completely ineffective at stimulating the release of cortisol, resulting in hypocortisolism [3]. It is postulated that the virulence of SARS-CoV-2 may be related to the degree of antigenic similarity between ACTH and its molecular mimic within the virus [2].

A condition referred to as critical illness-related corticosteroid insufficiency (CIRCI) occurs in patients with an acute stress response, leading to reduced cortisol levels that do not match the severity of the disease. CIRCI is presumed to occur in several critical conditions, including sepsis and septic shock, severe community-acquired pneumonia, acute respiratory distress syndrome, cardiac arrest, head injury, trauma, burns, and following major surgery [4]. Because of the mechanisms involved in suppressing the release of cortisol, Siejka recommends early use of steroids not only to replace what is deficient, but also because hydrocortisone protects against endothelial barrier dysfunction, which is strongly associated with COVID-19 [1].

Early Treatment of COVID-19 with Steroids to Inhibit Disease Progression

Early in the COVID-19 crisis, it was the general consensus that steroids given too early in the disease process might suppress the immune system’s ability to fight the infection and reduce viral replication. As noted above, antibodies are produced against ACTH during SARS-CoV-2 infection. These antibodies interfere with ACTH’s normal signaling to trigger cortisol production as part of the stress response. Lower cortisol levels then provide feedback to the hypothalamus and pituitary to increase the production of ACTH to release more cortisol. Instead, increased ACTH production increases ACTH antibodies that do nothing to fight the viral infection. It is proposed by both Siejka and Wheatland that if corticosteroids are administered early, shortly after the start of the infection, ACTH production and therefore antibody production toward ACTH would decrease, freeing up the immune system’s antibody response to fight against the virus rather than ACTH [1, 2]. The increase in exogenously-administered corticosteroids may also help fine-tune the inflammatory response early, which would keep tissue damage under control. Early intervention with lower potency steroids like hydrocortisone, may act as a replacement for what is missing due to the interference of cortisol production by the virus. Perhaps this proves the adage that, “an ounce of prevention is worth a pound of cure.”

Studies Related to SARS and Adrenal Insufficiency

One small study on 28 hospital patients demonstrated that adrenal response to infection with SARS-CoV-2 was unexpectedly decreased – patients had low plasma cortisol and ACTH levels consistent with central adrenal insufficiency. Lower plasma cortisol and ACTH levels were consistent with higher disease severity, suggesting a direct link between COVID-19 and impaired glucocorticoid response [3]. Interestingly, ACE2 receptors, the gateway for SARS-CoV-2 entry into cells, are expressed in the hypothalamus, pituitary and adrenal glands, allowing the virus to enter these tissues. Autopsy studies on patients who died from the SARS-CoV-1 infection showed evidence of the viral genome in hypothalamic tissue.

In a recent case study, a 51-year-old male presented to the emergency department complaining of two episodes of vomiting. He had received a positive COVID-19 test via polymerase chain reaction testing 10 days prior but was asymptomatic with stable vital signs and a normal chest X-ray at the time of diagnosis. No laboratory studies were done, and he was instructed to quarantine at home. When he presented to the ER, he was hypotensive with multiple electrolyte derangements that could not be substantiated by only two episodes of vomiting. Adrenal insufficiency was confirmed by low morning cortisol levels and an ACTH stimulation test. The patient was started on 20 mg of prednisolone daily with subsequent improvement in blood pressure and sodium levels [5].

In another case study, a 47-year-old male with a recent diagnosis of COVID-19, developed new onset central hypocortisolism in the convalescent phase of a mild case of COVID-19. He was sent to an isolation facility but returned to the hospital one week later due to a new onset seizure. The patient’s vital signs were normal, and he was well-oxygenated on room air. His bloodwork revealed elevated eosinophils and he complained of new onset persistent dyspepsia. Hypocortisolism was suspected and confirmed with a serum cortisol of 19 (normal range = 133-537 nmol/L) and an ACTH of 7.1 (normal range = 10.0-60.0 ng/L). He also presented with elevated thyroxine and thyroid stimulating hormone (TSH). This led his physicians to believe that the hypocortisolism was due to effects within the hypothalamic-pituitary pathways, affecting both adrenal and thyroid function [6].

SARS-Induced Endocrinopathy

The deleterious impact of SARS-CoV-2 on the various organs within the endocrine system are becoming clearer as further research reveals the far-reaching health consequences of the virus.

The deleterious impact of SARS-CoV-2 on the various organs within the endocrine system are becoming clearer as further research reveals the far-reaching health consequences of the virus. As we develop an understanding of the extent of these effects, we can better intervene with appropriate therapy. We understand from current research that SARS-CoV-2 can induce new onset or worsen existing conditions, such as diabetes mellitus, trigger hypocortisolism, and contribute to thyroid and reproductive aberrations [7]. The available data suggest that effects on endocrine tissues can occur either from direct viral damage or from immune-mediated mechanisms on endocrine tissues precipitated by the SARS-CoV-2 virus [7].

Diabetes mellitus increases the risk for the development of COVID-19 complications and adverse outcomes. In reviewing the effects of SARS-CoV-1, it was suggested that the virus could directly damage pancreatic cells that express ACE2 receptors, leading to a state of hyperglycemia, which reduces immune response and increases organ damage and systemic complications [8]. In a recent article in Endocrine, Mongioi et al hypothesized that patients with COVID-19 may be subject to virus-mediated pancreatic damage, resulting in the development of diabetes. It is uncertain at this point if the onset of diabetes is permanent or a transient effect of the virus that will eventually resolve with recovery from the infection [8].

Little is known about the effects of SARS-CoV-2 on thyroid function; however, some research has revealed a relationship between SARS-CoV-1 and central hypothyroidism secondary to hypothalamic-pituitary dysfunction resulting in low TSH. In secondary hypothyroidism, if the thyroid is not receiving the message from TSH to stimulate the production of thyroid hormones, T3 and T4 will also be low. SARS-CoV-1 did not directly invade the thyroid; however, tissue studies revealed injury to the follicular epithelium with an increase in cell apoptosis, suggesting that the damage was likely mediated by an immune response against the thyroid [8]. Direct damage to thyroid tissue could result in impaired function and a decrease in thyroid hormones and calcitonin levels as compared to controls. It appears that both primary and secondary hypothyroidism may be caused by the virus. The effects of COVID-19 on thyroid function appear to be transient and resolve shortly after recovery from the viral infection [7].

Though no evidence exists that SARS-CoV-2 infects the ovaries, increases in serum prolactin, follicle-stimulating hormone, and luteinizing hormone with a reduction in estradiol and progesterone levels was noted in SARS patients as compared to controls. We do know that ACE2 is highly expressed in testicular tissue and past studies have found tissue damage indicative of orchitis on autopsy of six patients who died with SARS-CoV-1. Tissue effects may also be representative of immune-mediated damage triggered by the presence of the virus [8]. Some researchers suspect that testicular tissue provides an additional site of infection and may increase viral load in males as compared to females.

The hypothalamic and pituitary tissue also have ACE2 receptors and can be sites of SARS-CoV-2 infection if the virus enters the brain. As previously mentioned, it is suspected that SARS-CoV-2 can enter the brain via the olfactory pathway where it gains access to the brain across the porous cribriform plate. The virus can then enter the hypothalamus fairly easily as the blood-brain barrier is permeable near this structure. Infection of the hypothalamus may result in hypophysitis (inflammation of the hypothalamus) and would have broad effects across the entire endocrine system.

Long COVID and Adrenal Insufficiency

Adrenal insufficiency tends to develop in COVID-19 patients during the late stage of the disease and appears to be secondary to hypophysitis or direct damage to the hypothalamus from the SARS-CoV-2 virus. In 2005, Leow et al explored the function of the HPA axis in 61 SARS-CoV-1 survivors by evaluating serum electrolytes, cortisol, ACTH levels, and 24-hour urinary-free cortisol three months after the acute infection. Adrenal insufficiency was defined as cortisol values <550 nmol/L 30 minutes after an ACTH stimulation test. Nearly 40% of patients tested had hypocortisolism and among them 83% had central adrenal insufficiency, which is secondary to ACTH deficiency [9]. Of those with hypocortisolism, 62.5% recovered within one year paralleled by the resolution of orthostatic hypotension and an overall improved sense of well-being. The majority of the patients in the study exhibited cortisol dynamics analogous to patterns seen in chronic fatigue syndrome, post-traumatic stress disorder, and fibromyalgia [9].

It is important to note that patients may also experience hypocortisolism due to treatment with dexamethasone to reduce inflammation during active infection. Treatment of COVID-19 with potent steroids to address the immunoinflammatory response to the infection may result in short-term adrenal insufficiency that may require evaluation and supportive care. In the 2005 study by Leow et al referenced above, the majority of the patients studied had not been treated with steroids during the course of their illness. Four of the six who had received high-dose parenteral glucocorticoids did not develop post-SARS hypocortisolism as demonstrated by the lack of prolonged suppression of the HPA axis as revealed in serial ACTH stimulation tests [9].

Addressing Long COVID through HPA Axis Support

Many of the symptoms of post-viral syndromes interfere with our ability to thrive, which indicates involvement of the autonomic nervous system (ANS), leaving us with orthostatic intolerance, cognitive dysfunction, muscle weakness, fatigue, dizziness, and heart rate abnormalities. Although isolating where some of these symptoms may be coming from is a starting point to treatment, it is necessary to consider the contribution of other organ systems to each dysfunction. Many of the symptoms associated with autonomic dysfunction may be related to the ability of the mitochondria to make energy and support metabolic processes. Involvement of the HPA axis with the sympathetic branch of the ANS contributes to maintaining adequate blood sugar and blood pressure, as well as inhibiting inflammation and supporting a balanced immune system response. An appropriate response of the HPA axis during an acute stressor is necessary for survival, but frequent and prolonged activation can alter the functional tone of the stress response reducing the ability of the HPA axis to respond efficiently and effectively [10].

Post-viral illness is difficult to address in that it cannot be cured by treating only one symptom or one system. Genetic susceptibility, nutritional status, and state of health prior to infection will likely play a role in the development of long COVID, and the supportive care to pull through the long-term sequelae of this virus will require a multi-pronged approach. Our ability to respond to stressors involves the sympathoadrenal system and the HPA axis, and interactions between these two systems play a central role in adaptation. Healthy function of the HPA axis is dependent on healthy mitochondria for steroid hormone conversion and an intact ANS to support a normal stress response. Long-term changes to the HPA axis may occur in response to the stress of an acute illness that has altered the metabolism of cortisol, leading to a reduced capacity to respond to stress [4]. To address the oncoming tidal wave of COVID-19 survivors who have ongoing symptoms, supporting the HPA axis through nutrition, supplementation, adaptogenic herbs, glandulars, and hydrocortisone if needed, will likely offer some relief. Options for support of the nervous system, immune system, and mitochondria have been outlined in parts one through three of this series.

Testing the HPA Axis

Genetic susceptibility, nutritional status, and state of health prior to infection will likely play a role in the development of long COVID, and the supportive care to pull through the long-term sequelae of this virus will require a multi-pronged approach.

Aside from infection with the SARS-CoV-2 virus, the stress of the pandemic itself has been extensive. Fear of infection, lockdowns, social isolation, financial instability, and emotional distress have taken a toll on our collective psyche. The extraordinary amount of stress that we have been under can certainly have lasting consequences in chronic activation of the stress response systems, leading to ongoing dysfunction of the HPA axis. For those who have been infected with the virus, early testing of the HPA axis offers another opportunity for intervention and recovery from COVID-19 and can be easily done at home through a multi-point salivary test measuring cortisol output throughout the day. As the above-referenced studies indicate, developing hypocortisolism is a real possibility after the infection with SARS-CoV-2 and may likely be a major contributor to the symptoms of long COVID. Testing for and addressing this issue is key to a full recovery.

In addition to multi-point cortisol measurements, ZRT Laboratory can also provide testing to assess melatonin levels, dehydroepiandrosterone sulfate (DHEA-S), high-sensitivity C-reactive protein (hsCRP), vitamin D, sex hormones, thyroid hormones, and neurotransmitters. Melatonin increases in response to darkness but may be compromised due to dysregulation within the circadian rhythm. In addition to regulating sleep, melatonin is a potent antioxidant that can help to neutralize reactive oxygen species produced during inflammation. DHEA-S functions in the brain and nervous system as a neurosteroid, is a potent immune-modulating hormone and functions as a counter-regulatory hormone to cortisol. The main neurobiological effects of DHEA-S in the brain include neuroprotection, neurogenesis, apoptosis, catecholamine synthesis and secretion, and antioxidant and anti-inflammatory effects. Measuring sex hormones and thyroid markers can provide much needed data that may help to address the symptoms associated with post-viral illness.

While an initial infection can resolve, it can leave behind an inflammatory footprint that propagates further damage. Measuring hsCRP can provide us with information regarding general inflammation and infection. hsCRP can be readily measured in a dried blood spot (DBS) sample alongside other cardiovascular and metabolic markers. Healthy vitamin D levels are associated with a robust and balanced immune response and can also be measured in DBS. ZRT Laboratory can also provide testing to assess neurotransmitters that impact mood, cognitive ability, and sleep. Neurotransmitters are responsible for functionally integrating the immune and endocrine systems, indicating that neurotransmitter imbalances often reach beyond the brain.

As we face the burgeoning issue of long COVID, the approach to treatment will involve addressing inflammation and dysregulation within the central nervous system, autoimmune issues, mitochondrial function, and hormone and HPA axis dysregulation. We have a long road ahead of us and there will likely be many who suffer from the long-term consequences of this pandemic – those who acquired the infection and those who simply lived through it. Our personal timelines may be forever referred to by pre-COVID and post-COVID events. My hope is that through the efforts of the many brilliant minds in medical research and through the practice of preventive and interventional therapies, we have learned how to better prepare for and respond to a novel virus. Early treatment for viral infections and immune system support are still important as coming up with new vaccines for each novel virus may not be practical, timely or safe. We may not be able to prevent infection, but by investing in our health every day, we may effectively support our recovery.

ZRT Tests to Consider

NeuroAdvanced Profile with Add-on Diurnal Cortisol, Melatonin, Norepinephrine & Epinephrine
Adrenal Profile
Female/Male Saliva Profile III
Female/Male Blood Spot Profile II
Comprehensive Female/Male Profile II
CardioMetabolic Profile
Essential Thyroid Profile
Elite Thyroid Profile
hsCRP as a single test in blood spot
Vitamin D as a single test in blood spot

References

Part III: Long COVID and Mitochondrial Dysregulation

Mon, 17 May 2021 09:35:42 -0700

In parts one and two of this series, we looked at the issues related to long COVID and its impact on the nervous and the immune systems. The effects of COVID-19 on the nervous system can present as localized effects such as loss of smell and taste to chronic fatigue, headaches, postural orthostatic tachycardia syndrome, and cognitive issues. The potential to trigger an autoimmune reaction is a very real possibility with any infection and is stimulated by molecular mimicry, bystander activation, and viral persistence. The presence of a healthy and diverse gut and lung microbiome helps to regulate the immune system and supports a robust and balanced innate immune response.

The most common reported symptom of long COVID is fatigue and the overall symptom picture resembles that of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is often triggered by a viral infection. Fatigue can be described as lack of energy; and when we think of energy production, we think of the mitochondria. In addition to being the powerhouses of the cell, mitochondria are also involved in maintaining cell immunity, homeostasis, cell survival, and cell death. Mitochondria also play a role in cell apoptosis (programmed cell death), calcium signaling, regulation of cellular membrane potential, and steroid synthesis [1]. SARS-CoV-2 hijacks the mitochondria and uses it for protection and viral replication, diverting resources from supporting normal cellular function to now serving as a viral factory.

Decreased mitochondrial function means less cellular energy, resulting in generalized fatigue, muscle weakness, and brain fog on a broader scale. In part three of this series, we will explore the effect of viral infection on mitochondrial function, how SARS-CoV-2 specifically affects mitochondria, resulting in symptoms of long COVID and what we can do to support mitochondrial function to prevent the long-term effects of COVID-19.

Basic Overview of Mitochondrial Function

Mitochondria are responsible for the majority of energy production in the form of adenosine triphosphate (ATP), which is readily used by cells as a source of chemical energy. Cellular respiration is the process by which mitochondria produce chemical energy from glucose. Through the process of glycolysis, one molecule of glucose is converted to two molecules of pyruvate, two molecules of nicotinamide adenine dinucleotide (NADH) and two molecules of ATP. The pyruvate enters the mitochondria where it is converted into acetyl-coenzyme-A, which enters the tricarboxylic acid (TCA or Krebs) cycle and produces two additional molecules of ATP. The energy-rich products of the TCA cycle, NADH and flavin adenine dinucleotide, undergo oxidative phosphorylation (OXPHOS) via the electron transport chain (ETC), producing water and 32 additional molecules of ATP. The entire process of cellular respiration results in approximately 36 molecules of ATP to support cellular energy needs [2].

The process of glycolysis, which is the first step in cellular respiration, occurs in the cytosol of the cell. If there is enough oxygen available for cellular respiration, the process of energy production will advance to the TCA cycle and OXPHOS along the ETC. However, if oxygen is low, glycolysis results in the production of two molecules of ATP and lactic acid. Anaerobic glycolysis can occur for quick energy production during extreme exercise or illness where oxygen delivery to cells is deficient. The reliance on anaerobic glycolysis as a means of energy production can result in fatigue and muscle pain due to the buildup of lactic acid [2].

Another form of energy production is through aerobic glycolysis also known as the Warburg effect. Once thought to occur solely in cancer cells, aerobic glycolysis may occur in specific immune cells in response to signaling events and the physiological environment. In the field of immunometabolism, it has been observed that metabolic shifts in immune cells may occur to facilitate specific immune responses, and many viruses induce metabolic reprogramming in host cells similar to the Warburg effect observed in cancer cells to produce a quick and readily available source of energy [3, 4].

Viral Influence on Mitochondrial Function

SARS-CoV-2 hijacks the mitochondria and uses it for protection and viral replication, diverting resources from supporting normal cellular function to now serving as a viral factory.

Under the influence of a viral infection, mitochondria experience a loss of integrity in structure and function and can trigger an immune response that activates the production of inflammasomes, which may contribute to autoimmunity and ongoing inflammatory reactions [5]. Inflammasomes are intracellular proteins that trigger the activation of inflammatory cytokines. Mitochondria play a central role in the host response to viral infection and immunity, and function as a platform for immune signaling by engaging the interferon system, which operates as a liaison between the innate and adaptive immune systems [6]. SARS-CoV-2 has the ability to disable the initial immune response by inhibiting the production of interferons. Reduced interferon production delays the release of natural killer cells and stagnates T cell response. Hepatitis C, hepatitis B, adenoviruses, herpes simplex virus-I, Epstein Barr virus, cytomegalovirus, influenza A and coronaviruses have adaptations that allow them to inhibit the interferon pathway to prolong survival and evade the immune system, leaving them with a greater chance to replicate and spread [6]. Viral influence on mitochondrial activities can lead to altered energy levels by changing mitochondrial density and function, resulting in suboptimal energy output [7].

Mitochondria also produce reactive oxygen species (ROS) as a by-product of the process of oxidative phosphorylation. Once thought to have only harmful effects, it is now known that ROS function as signaling molecules, which increase the production of antioxidants, promote apoptosis, and trigger the production of new mitochondria. Mitochondrial ROS also induce mitochondrial anti-viral signaling (MAVS), resulting in induction of type I interferons, heralded as key regulators of antiviral activity [5]. ROS are a normal product of oxidative phosphorylation and can be neutralized through adequate availability of antioxidants; however, this process can become overwhelmed during infection, when ROS production increases beyond the body’s ability to control the oxidative stress. Infection can also interfere with the energy-producing pathway of the mitochondria, leaving cells and tissues with an energy deficit and an excess of ROS.

SARS-CoV-2 Hijacks Mitochondrial Function

Host response against viral infections depends on optimal mitochondrial function but the presence of SARS-CoV-2 can cause structural and metabolic changes within the mitochondria, interfering with an appropriate immune response. Host cell metabolism and activation of signaling pathways is reprogrammed by SARS-CoV-2 viral proteins [4]. SARS-CoV-2 uses its spike glycoprotein, assisted by host transmembrane serine protease 2 (TMPRSS2), to gain access to cells via the angiotensin-converting enzyme-2 (ACE2) receptor on the host cell. Binding of this receptor by the virus decreases the production of ACE2, which has a regulatory effect on mitochondrial function. Less ACE2 results in less ATP production [6].

Once the virus has entered the cell, viral RNA, RNA transcriptase, and viral open-reading frames (ORFs) enter the mitochondria to hijack and manipulate function. ORFs are segments of DNA or RNA from the virus that code for particular proteins. Viral ORFs interact with mitochondrial proteins to directly manipulate mitochondrial function to evade host cell immunity, suppress immune response, and support viral replication [6]. The presence of the virus also creates stress within the mitochondria, leading to the formation of double-walled vesicles, which give the virus a place to hide and replicate. These vesicles function like portable organelles, taking viral information to the endoplasmic reticulum to further aid in viral replication [6].

SARS-CoV-2 also promotes a metabolic shift to aerobic glycolysis to facilitate viral replication and survival. The Warburg effect appears to be involved in several processes during COVID-19 infection [4]. In response to hypoxia, the Warburg effect is induced in lung endothelial cells, which in the presence of atherosclerosis, can lead to vasoconstriction and thrombosis. Initially, aerobic glycolysis supports the activation of pro-inflammatory pathways that are needed to mobilize defenses against infections; however, a subsequent shift to the OXPHOS pathway is also needed to promote anti-inflammatory pathways that are reparative. Aging, cardiovascular disease, metabolic syndrome, type II diabetes, obesity, hypertension, and chronic kidney disease along with mitochondrial senescence contribute to a state of chronic inflammation, which promotes the Warburg effect and prevents the metabolic transition to OXPHOS to decrease inflammation and initiate repair mechanisms [4].

Aging, Comorbidities, and Mitochondrial Function

Factors that favorably contribute to the takeover of mitochondrial function by the SARS-CoV-2 virus are aging, chronic inflammation, and genetic susceptibility. The aging process results in less mitochondria and lower production of ATP with a decrease in autophagy of mitochondria, which contributes to unregulated inflammasome activity leading to chronic inflammation. The process of aging is marked by the progressive decline in cellular function, which increases susceptibility to age-related morbidity and mortality [6]. One of the hallmarks of aging is mitochondrial dysfunction, which induces senescence and contributes to the process of inflammaging. Senescence occurs when cells lose the power to divide and grow, and inflammaging is the increase in systemic inflammation as one ages. The overall effect reduces mitochondrial capacity by about 50%, resulting in fatigue and muscle weakness [6].

Many of the conditions that are considered comorbidities for SARS-CoV-2 contribute to a state of chronic inflammation. Diabetes, heart disease, obesity, and metabolic diseases are commonly present with mitochondrial dysfunction. Mitochondrial genetic mutations may also be a contributing factor in determining the severity of post-viral sequelae related to mitochondrial function. While there are no studies on the long-term effects of SARS-COV-2 on mitochondrial function, past studies on ME/CFS strongly implicate mitochondrial dysfunction as a central cause of ME/CFS symptoms [8, 9]. A renewed interest in the causes of post-viral syndromes will likely be forthcoming as we progress through this pandemic.

Mitochondrial Issues in Post-Viral Syndromes and ME/CFS

Mitochondria play a central role in the host response to viral infection and immunity, and function as a platform for immune signaling by engaging the interferon system, which operates as a liaison between the innate and adaptive immune systems.

Although no single cause has been associated with ME/CFS, viral infections have often been cited to trigger the onset of this disorder. In the case of SARS-CoV-2 and other viruses, there may be a direct impact on mitochondrial function from the virus itself [10]. The oxidative stress that occurs during an infection can leave mitochondria in a state of dysfunction. The mitochondria of our cells are responsible for the production of ATP and produce 90-95% of the body’s total energy [11]. ATP drives all the necessary chemical reactions in the body and if there is a shortage of ATP production, basic biochemical reactions may not be optimized. As a point of comparison, mitochondrial diseases associated with genetic mutations manifest as fatigue, muscle weakness, and cognitive decline along with waxing and waning energy patterns typical of ME/CFS.

While there are no definitive markers to identify ME/CFS specifically, there are a range of different markers that can be used to assess mitochondrial function including mitochondrial proteins, production of ATP, and oxygen consumption of live plated cells. The earliest evidence of the relationship between ME/CFS and mitochondrial issues was seen in structural changes of skeletal muscle cell mitochondria in peripheral blood mononuclear cells. Also noted was the decrease in OXPHOS and an increase in aerobic glycolysis, resulting in less ATP production in ME/CFS patients as compared to controls. As reported by the Journal of Translational Medicine, Sweetman et al concluded that mitochondrial dysfunction can happen via oxidative damage as might occur during an extreme inflammatory reaction to an infection [12].

In a 2019 article in Mitochondrion, Robert Naviaux, MD, PhD, discusses the cell danger response (CDR) and its connection to environmental health, mitochondrial function, and chronic illness. The CDR is a universal response to environmental threat, stress, infection or injury, and it is the mitochondria that sense and respond to changes in the cellular environment and mediate the regulators of the CDR that signal safety or danger within the cell. Once initiated, the CDR cannot be turned off and must cycle through to completion to effectively resolve the danger response. If the CDR persists abnormally, whole body metabolism, the gut microbiome, and multiple organ systems become impaired and chronic disease can emerge. Previous illness, stress, environmental toxins, chronic inflammatory illnesses, hormonal imbalances, autoimmune disorders, and allergies can impede the process of resolution of the CDR [13]. As much of the CDR is mediated by the mitochondria, supporting mitochondrial function, and employing general habits of good health can support a healthy CDR and potentially resolve chronic illness.

Mitochondrial Support

To offset the production of ROS within the mitochondria, enzymes, and coenzymes such as vitamin E and CoQ10 (ubiquinone) help to remove ROS to prevent damage. If essential nutrients, such as vitamin E and CoQ10 are deficient, removal of the ROS is impaired and damage through oxidative stress occurs. CoQ10 is the only lipid-soluble antioxidant that is produced endogenously in humans [11]. Ubiquinol is the reduced form of CoQ10 and acts as an antioxidant by reducing ROS and regenerating other antioxidants. It is also found in the highest concentration in the most metabolically active tissues such as the heart, liver, and muscle.

If the mitochondria are already in a state of dysfunction due to preexisting health issues and oxidative stress from low-level inflammation, their ability to keep up with energy demands becomes severely compromised.

Deficiencies of CoQ10 can occur with less endogenous production as we age and can be depleted with certain medications like statins to reduce cholesterol. CoQ10 deficiency may also be associated with dysfunctional OXPHOS, which can occur in ME/CFS. A study of 58 ME/CFS participants and 22 healthy controls, showed that the ME/CFS participants had lower overall levels of CoQ10, and their degree of fatigue was associated with a lower concentration of CoQ10 in plasma. It was also noted that ATP levels were significantly decreased while lipid peroxidation was increased, indicating mitochondrial dysfunction [11].

In a study out of Spain, Castro-Marrero et al evaluated the effects of CoQ10 and reduced NADH supplementation on the symptoms associated with ME/CFS. Seventy-three female participants were randomized to either the CoQ10+NADH or placebo group. In addition to improvements in fatigue according to the Fatigue Impact Scale, after eight weeks supplementing with 200 mg of CoQ10 and 20 mg of NADH, participants in the supplement group showed a decrease in oxidative damage, improvement in mitochondrial function, and enhanced energy [14]. CoQ10 and NADH can stimulate energy production by replenishing depleted cellular stores of ATP, and together they can act as free radical scavengers that can reduce lipid peroxidation and DNA damage caused by oxidative stress. Mitochondria are very susceptible to environmental toxins, nutrient deficiencies, and oxidative stress [15]. Additional support for mitochondrial function includes acetyl-L-carnitine, pyrroloquinoline quinone, vitamin C, choline, α-lipoic acid, α-ketoglutaric acid, resveratrol, N-acetyl cysteine, magnesium, and a quality multivitamin and mineral complex. Several professional product lines have mitochondrial support products that include most of the above-listed nutrients.

In Summary

Age and health status prior to infection can be a predictor of outcomes and may help us to determine who will develop long COVID. Metabolic issues associated with aging, obesity, and a sedentary lifestyle are not supportive of mitochondrial health. Viruses can manipulate the energy-producing pathway of the mitochondria to favor glycolysis over OXPHOS. If the mitochondria are already in a state of dysfunction due to preexisting health issues and oxidative stress from low-level inflammation, their ability to keep up with energy demands becomes severely compromised [10]. The hijacking of the mitochondria to serve the needs of the virus structurally and functionally changes the mitochondria, resulting in ongoing inflammation and a reduced ability to support the energy needs of cells. Symptoms such as fatigue and weakness, are often the result of these cellular changes.

COVID-19 long-haulers may experience excessive oxidative damage in response to extreme inflammation generated by the infection; however, poor mitochondrial status and deficiencies in nutrients that are needed to quench ROS may also be prevalent among those who experienced only mild to moderate illness. This might explain why the severity of COVID-19 does not seem to predict who experiences post-viral syndrome or long COVID. Having less metabolic reserve due to stress, inadequate sleep, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, poor diet, chronic inflammation, a constant low level of oxidative stress, and the existence of comorbidities may lead to the development of long COVID even if the acute infection is mild to moderate.

Assessing Key Markers with ZRT Testing

ZRT Laboratory can offer a number laboratory tests to assess a variety of markers related to inflammation, metabolic health, nutrient status, sex hormones, adrenal hormones, neurotransmitters, heavy metals, and minerals. The CDC suspects about 30% of COVID-19 survivors may go on to develop persistent symptoms after recovery from the acute illness. While the trigger for the onset of post-viral syndromes may be a singular event, the effects are broad and involve multiple systems. As we face the burgeoning issue of long COVID, the approach to treatment will involve addressing inflammation and dysregulation within the CNS, autoimmune issues, mitochondrial function, and hormone and HPA axis dysregulation. In the fourth and final installment on long COVID, we will explore issues related to HPA axis dysfunction and its relationship to post-viral syndrome.

ZRT Tests to Consider

NeuroAdvanced Profile with Add-on Diurnal Cortisol, Melatonin, Norepinephrine & Epinephrine
Adrenal Profile
Female/Male Saliva Profile III
Female/Male Blood Spot Profile II
Comprehensive Female/Male Profile II
CardioMetabolic Profile
Essential Thyroid Profile
Elite Thyroid Profile
hsCRP as a single test in blood spot
Heavy Metal and Essential Elements Profiles

Related Sources

References

Long COVID: Immune and Systemic Effects of Post-Viral Infection Part II: Ongoing Inflammation and Autoimmunity

Thu, 22 Apr 2021 14:35:40 -0700

In the first part of this series on post-COVID illness, I reviewed some of the issues of post-viral syndromes and their relationship to the current pandemic with a deeper look into the effects of SARS-CoV-2 on the nervous system. Many of the symptoms associated with long COVID present as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with some additional symptoms specifically associated with COVID-19. Post-viral syndromes are not new, but it is not completely clear as to why some patients experience lasting symptoms after a viral infection and some do not. We do know that immune system activation by a virus increases systemic inflammation, oxidative stress, and tissue damage. We also know that our genetics play a role, as evidenced by the tendency to develop autoimmune conditions for those with specific human leukocyte antigen (HLA) phenotypes that can be triggered by certain infections. The tendency to develop ongoing inflammation and lingering symptoms after an infection might be relative to baseline inflammation and immune system balance upon encountering the virus. The potential to unmask underlying chronic infections may also contribute to the symptoms of long COVID. We are all exposed to viruses and other infectious agents throughout our lifetime that can exist in a latent state only to reactivate during a time of stress and immune dysregulation, which adds to the complexity of post-viral syndromes including long COVID.

SARS-CoV-2 and the Immune System

Viruses have evolved to evade the immune system in many ways. SARS-CoV-2 disables the innate immune system during early infection by blocking the ability of Toll-like receptors (TLR) to signal the production of interferon-I (IFN-I), which is crucial for reducing viral replication and spread [1,2,3]. This gives the virus a greater chance to replicate during early infection, leading to higher viral titers and the potential for a heightened inflammatory reaction later. Innate immune response during early infection determines what will happen later in the disease process and possibly beyond recovery from the acute infection. Reducing viral load early may decrease the chance of continued inflammation, autoimmunity, and poor viral clearance.

In a mouse model of SARS-CoV-2 infection, local IFN responses in the lungs were delayed relative to peak viral replication, which greatly reduced viral clearance and was associated with the development of cytokine release syndrome (CRS) [1]. Through various mechanisms, coronaviruses are known to inhibit the early production of IFN but increase the production of nuclear factor kappa light chain enhancer of activated B cells (NF-KB), resulting in production of inflammatory cytokines and chemokines. IFN acts as a central liaison between the innate and adaptive immune systems and signaling can trigger various messages that dictate how and when the innate and adaptive immune systems respond to viral infection.

Use of INF during early infection has shown some promise to reduce viral replication; however, the timing of use is critical. Introducing INF too late in the disease process may result in a heightened inflammatory response that may contribute to the development of a cytokine storm and interfere with effective recovery [1]. Given the safety concerns regarding the use of IFN as a treatment option for COVID-19, considering nutraceuticals that can boost IFN-I might be a better option. McCarty et al identify key mechanisms of action of ferulic or lipoic acid, spirulina, N-acetyl cysteine (NAC), selenium, glucosamine, zinc, beta-glucan, and elderberry, which can interfere with the ability of the virus to inhibit IFN-I through support of TLR activity and boosting of IFN-I production [2]. We are familiar with most of these nutraceuticals as immune system support and specific dosages are highlighted in the article.

Recent studies out of Casanova’s lab at The Rockefeller University have also discovered the relationship between genetic mutations and inborn errors of IFN-I immunity and the severity of COVID-19. They have also noted some patients with severe COVID-19 can develop autoantibodies to IFN-I [4]. With a reduction in IFN-I activity whether through viral inhibition, genetic predisposition or the production of autoantibodies, the net effect is an increase in viral replication in the early phase of disease, which can have the effect of inducing an overly robust inflammatory reaction as the viral load increases. This overreaction may induce autoimmunity and/or chronic inflammation through bystander activation.

Immune System Dysregulation/Autoimmunity

Innate immune response during early infection determines what will happen later in the disease process and possibly beyond recovery from the acute infection.

There are three ways that a virus might induce autoimmunity: molecular mimicry, bystander activation, and viral persistence. Molecular mimicry between a virus or other pathogen and host proteins can lead to immunological cross-reactivity and subsequent attack on self. As stated in the Journal of Translational Autoimmunity, the existence of homology (molecular mimicry) between viral and human proteins is well-established in viral- or vaccine-induced autoimmunity [5]. As the body induces an immune response to the viral proteins, it also attacks similar proteins within body tissues that can extend beyond the initial infection, inciting ongoing inflammatory reactions in various tissues. The infection may have resolved; however, the inflammatory trigger is ongoing because the presence of the virus woke up the immune system in a way that initiated a reaction to proteins that were similar within the virus and within self. Much of this reaction is determined by the genetics, which is why people react differently to viruses and other pathogens. Some may recover without long-term sequelae while others battle ongoing symptoms after the acute infection.

To highlight the potential issue of molecular mimicry and SARS-CoV-2, a recent article in Clinical Immunology by Aristo Vojdani, PhD, MSc, CLS, and Datis Kharrazian, PhD, DHSc, DC, MS, MMSc, FACN, examined cross-reactivity of viral antibodies with various body tissues. They tested five different blood specimens confirmed positive for SARS-CoV-2 immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies for anti-nuclear antibody (ANA), anti-extractable nuclear antigen (anti-ENA), anti-double stranded DNA, actin antibody, mitochondrial antibody, rheumatoid factor, and complement component 1q immune complexes. Three of the five specimens had elevated ANA, anti-ENA, actin, and mitochondrial antibodies. Further studies revealed 21 out of 50 tissue antigens reacted with the SARS-CoV-2 antibodies, indicating a cross-reaction between SARS-CoV-2 proteins and several tissue proteins. These tissues included the lungs, connective tissue, cardiovascular tissue, gastrointestinal (GI) tissue, and the nervous system [6]. This is a very timely representation of the potential for viruses to induce autoimmunity and is likely to have occurred in the past in relation to post-viral syndromes and chronic inflammation.

Bystander activation can occur when virus-activated T cells kill infected cells along with uninfected neighboring cells. Cytokines and other inflammatory mediators that are released in the process increase tissue damage, which furthers the inflammatory reaction. Bystander activation occurs in the midst of an inflammatory milieu interacting with nearby tissues. This process can promote autoimmunity but may also result in a transient inflammatory event that eventually resolves [7,8]. This may explain why inflammation and autoimmunity might occur in tissues where there is no detection of the virus or other infectious agent. How and when the inflammation resolves may be dependent upon baseline inflammation and the ability of the immune system to self-regulate.

The virus may also persist at a low level where it continues to be presented on host cells leading to prolonged immunopathology. Persistent viral infections can lead to immune-mediated tissue damage due to the constant presence of the viral antigen [8]. Viral persistence may also occur when the virus has learned to evade the immune system by decreasing the host cell’s ability to present surface antigen, which alerts the immune system and results in cell destruction. Another theory regarding viral persistence is T cell exhaustion and an increase in immune system regulator cells that increase immune tolerance, resulting in failure of the immune system to purge the virus [9]. Viruses may also develop a strategy to replicate without destroying the cell in which it occupies. Persistent viruses can also occupy differentiated or specialized cells creating specific dysfunction within those cells. Examples include viruses that interfere with the ability of neurons to make neurotransmitters, block endocrine cells from making hormones, and dysregulate the production and release of immune mediators that either suppress or enhance immune function [9]. This might explain the ongoing symptoms experienced by those with ME/CFS and other complex chronic illnesses. Viral persistence seems most concerning for long COVID as it leaves the virus to linger and develop more ways to evade the host’s immune response while interfering with homeostasis and cell function.

The Gut-Lung Axis and Mucosal Immunity

About 70% of our immune system resides in the GI tract. Our mucosal surfaces are where we encounter what is outside of ourselves. The mouth, sinuses, digestive tract, vaginal mucosa, and the lungs all directly interface with the outside world and it is through these surfaces that we encounter certain viruses. The gut microbiome directs immune function within the GI tract and beyond, and there is a bidirectional relationship between the GI tract and the lungs. The lungs also have their own microbiome that supports immune system function within the respiratory tract by modulating inflammation and creating homeostasis. The gut microbiome influences the lungs by way of the gut-lung axis and is linked through the mucosal immune system where gut bacteria-derived metabolites travel to the lungs via the mesenteric lymphatic system and general circulation. Likewise, conditions within the lungs can alter the microbiota in the GI tract [10]. Our greatest impact on mucosal immunity is through support of a healthy gut microbiome that promotes an effective immune response in the lungs via the gut-lung axis. In addition to a balanced immune response, the microbiome of various tissues supports immune tolerance so that we do not become excessively reactive to non-pathogenic antigens and regulates our response to infectious pathogens.

The diversity and volume of bacteria that makes up the microbiome may influence the severity of COVID-19, as well as the magnitude of the immune system response to the infection. Imbalances in the makeup of the microbiome may also be implicated in persisting inflammatory symptoms associated with long COVID as indicated by a recent study comparing the gut flora of patients infected with and recovering from COVID-19. In this 100-patient cohort study, the bacterial composition of serial stool samples was compared to blood markers of inflammation. Of the 100 hospitalized patients, 27 were followed for up to 30 days past the clearance of the virus. Regardless of antimicrobial intervention, there were consistent differences in the microflora of COVID and non-COVID patients [11].

This altered concentration of bacteria was also commensurate with disease severity and researchers concluded that compositional changes play a role in exacerbating disease by contributing to dysregulation of the immune response.

Several of the bacteria that were abundant in COVID-positive patients are associated with dysregulated inflammation in other illnesses. COVID-negative patients had an abundance of bacteria that are associated with reduced inflammation and better immune system regulation. It is important to note that these alterations in microbial flora persisted beyond recovery from COVID-19. The authors went on to state that microbiome analysis may help to determine individuals at risk of severe disease and the potential development of ongoing inflammation as seen in long COVID and may also be useful in guiding intervention with specific probiotics [11]. The authors of this study also state that it has not been determined if the microbial composition of COVID-positive patients occurred prior to or as a result of the infection.

In another recently published article in Gut Pathogens, Chhibber-Goel focuses on the role of angiotensin-converting enzyme 2 (ACE2) and the ACE2 receptor that specifically applies to the infectivity of SARS-CoV-2. Chhibber-Goel states that the number of ACE2 receptors increases in the duodenum with age, which increases viral entry and replication. With increased binding of the ACE2 receptors, the production of ACE2 is reduced. In the gut, ACE2 is responsible for supporting the gut endothelium and the microbial communities within the gut by improving circulation. Impaired ACE2 expression is associated with viral infection, immune imbalance and bacterial dysbiosis in the intestines [12]. Dysbiosis of the gut modulates the immune response of neutrophils, T cell subsets, inflammatory cytokines, and TLRs, which have an influence on lung function and the ability to mount a balanced immune response [12]. As stated by Chhibber-Goel, the gut microbiome is changed during the COVID-19 infection and increases host susceptibility to other infections or potentially unmasks an underlying infection that was kept in check by a healthy microbiome and a balanced immune response. This shift in the microbiome, where there is a change in the type and volume of bacteria beyond the initial infection, has been implicated in the development of long COVID.

Use of probiotics to support a healthy microbiome confers protection from infections through direct competition with disease-causing microbes, enhancement of epithelial barrier functions, and support of a balanced and robust immune response. In addition to the gut-lung axis, the more familiar gut-brain axis is also an important consideration in the development of long COVID. Gut microbiota exerts significant effects on the central nervous system (CNS), brain neurochemistry, and activity through microbial products such as short-chain fatty acids (SCFA) and serotonin. These microbial products influence brain immunity through signaling pathways or by directly crossing the blood-brain barrier [10]. In particular, SCFAs have a role in the development and function of microglia, which are the brain’s macrophages involved in antigen presentation, phagocytosis, and modulating inflammation. The CNS also affects the gut microbiota via secretion of catecholamines that further influences gut physiology and barrier integrity via autonomic nervous system function. Modulation of gut microbiota with probiotics has shown positive effects on neuroinflammatory disorders, anxiety, depression, and symptoms associated with chronic fatigue [10]. Supporting a healthy and balanced immune response by promoting an abundant and diverse microbiome may help reduce the severity of acute COVID, as well as the lasting sequelae of long COVID.

Benefits of Reducing Viral Load Early

There are definite benefits to reducing viral replication early in the disease process. As stated earlier, what occurs in the replication phase of COVID-19 determines what will occur later in the disease—and this may also be true for long COVID. The issue is and has been that there are no broadly accepted outpatient treatments for early COVID-19 that would inhibit viral replication within the first few days of diagnosis. When considering potential pharmaceuticals to treat early COVID, the best and quickest options are repurposed medications with known safety profiles and mechanisms of action that can be effectively applied to the pathophysiology of SARS-CoV-2. Some of the options that are currently being considered fall under the categories of antivirals, immune-modulating treatments, antithrombotics, and other medications with specific actions that can prevent replication of the SARS-CoV-2 virus [13]. As early interventions are implemented, the relationship between reduced viral replication during early infection and the potential reduction in the development of long COVID will become more defined as conclusions are drawn from the data. At present, research is more focused on the immediate outcomes of reducing disease severity, hospitalization, and death.

Supporting a Healthy Immune Response

Until the world of medicine can agree upon some form of early pharmaceutical treatment that is appropriate in the outpatient setting, is scalable to large populations, and is safe, supporting the immune system and general health through nutritional supplements, dietary, and lifestyle measures are the best and most readily available options. Following a plant-rich anti-inflammatory diet that is similar in macronutrient balance to the Mediterranean diet is a good starting point and is supportive of a robust and diverse microbiome. Adding in nutritional supplements that support the immune system with targeted nutrients to slow the spread of viruses is also key. Nutrients that are helpful include vitamin D, C, A, quercetin, fish oil, zinc, selenium, NAC, probiotics, and melatonin to name a few. A good night’s sleep and regular exercise are also key in supporting the immune system and reducing stress.

Assessing Key Markers with ZRT Testing

The symptoms of long COVID include fatigue, post-exertional malaise, insomnia, cognitive difficulties, anxiety, depression, and muscle and joint pain. While an initial infection can resolve, it can leave behind an inflammatory footprint that propagates further damage. Measuring high-sensitivity C-reactive protein (hsCRP) can provide us with information regarding general inflammation. ZRT’s hsCRP can be readily measured in a dried blood spot (DBS) sample and can be combined with other ZRT cardiovascular and metabolic markers. Healthy vitamin D levels are associated with a robust and balanced immune response and can also be measured in DBS.

Some of the symptoms of long COVID are related to mood and sleep, which indicate that inflammation within the CNS can manifest as depression, anxiety, cognitive dysfunction, and sleep issues. ZRT can provide testing that may assess the potential effects of neuroinflammation in relation to neurotransmitters that impact mood, cognitive ability, and sleep. Neurotransmitters are responsible for functionally integrating the immune and endocrine systems indicating that neurotransmitter imbalances can reach beyond the brain.

ZRT can also provide testing to assess melatonin levels, cortisol, and dihydroepiandrosterone sulfate (DHEA-S). Melatonin increases in response to darkness but may be compromised due to dysregulation within the circadian rhythm. A four-point cortisol measurement can provide an evaluation of the hypothalamic-pituitary-adrenal (HPA) axis. Elevated cortisol may indicate an elevated sympathetic tone due to common stressors, infection, pain, inflammation, and lack of sleep. DHEA-S functions in the brain and nervous system as a neurosteroid, is a potent immune-modulating hormone, and functions as a counter-regulatory hormone to cortisol. The main neurobiological effects of DHEA-S in the brain include neuroprotection, neurogenesis, apoptosis, catecholamine synthesis and secretion, antioxidant, and anti-inflammatory effects. Measuring sex hormones and thyroid markers can also provide much needed data that may help to address the symptoms associated with post-viral illness.

When addressing chronic inflammation and autoimmunity, heavy metals can have an inhibitory and excitatory effect on different branches of the immune system. Assessing and effectively removing heavy metals can help to restore a more balanced response within the immune system. ZRT Lab provides heavy metal and essential element profiles in both DBS and dried urine measuring of both toxic and essential elements.

The CDC suspects about 30% of COVID survivors may go on to develop persistent symptoms after recovery from the acute illness. While the trigger for the onset of post-viral syndromes may be a singular event, the effects are broad and involve multiple systems. As we face the burgeoning issue of long COVID, the approach to treatment will involve addressing inflammation and dysregulation within the CNS, autoimmune issues, mitochondrial function, and hormone and HPA axis dysregulation. In the next installment on long COVID, we will explore issues related to mitochondrial dysfunction and its relationship to post-viral syndrome.

ZRT Tests to Consider

NeuroAdvanced Profile with Add-on Diurnal Cortisol, Melatonin, Norepinephrine & Epinephrine
Adrenal Profile
Female/Male Saliva Profile III
Female/Male Blood Spot Profile II
Comprehensive Female/Male Profile II
CardioMetabolic Profile
Essential Thyroid Profile
Elite Thyroid Profile
hsCRP as a single test in blood spot
Heavy Metal and Essential Elements Profiles

References

Long COVID and the Systemic Effects of Post-Viral Syndromes Part I: The Central Nervous System

Thu, 15 Apr 2021 16:08:37 -0700

SARS-CoV-2 has been circulating in the global population for over a year. According to Worldometer, at the time of this writing on March 2, 2021, 115 million people have been infected with the virus, 2.5 million have died, and 90 million have survived the infection to go on to have possible immunity. The immune response to the virus can range from asymptomatic to severe illness and death and has aroused fear and uncertainty around the world. For those who have been infected with SARS-CoV-2 and survived, some experience prolonged symptoms beyond recovery from the acute illness. Long COVID presents with ongoing symptoms of fatigue, post-exertional malaise (PEM), sleep issues, headaches, brain fog, cognitive issues, depression, anxiety, musculoskeletal pain, respiratory distress, and muscle weakness that extends far beyond initial recovery.

Post-viral syndromes are not uncommon and are suspected of contributing to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM), disorders that can have lasting effects far beyond the initial infection. Cases of chronic post-SARS syndrome related to SARS-CoV-1 are noted in the literature and while currently we do not have the longer lens of time to evaluate the lasting effects of SARS-CoV-2, we know that issues exist and are similar to other post-viral syndromes.

The questions that arise related to the long-term effects of COVID-19 are:

(1) Who is likely to experience long COVID?

(2) What can we do to prevent its occurrence?

(3) Is there any way to effectively treat long COVID?

Apparently, the NIH has posed similar questions and just received $1.5 billion in funding from Congress to study issues surrounding long COVID. This new research may improve our understanding of other post-viral syndromes and ME/CFS.

In order to truly understand the long-term consequences of SARS-CoV-2, we have to carefully review what we know about other post-viral syndromes. Although SARS-CoV-2 has reached pandemic proportions, the good news is that this is still a virus that generally behaves like other viruses of similar origin. Reaching into past research will provide a conceptual foundation upon which to build further knowledge. Specific data regarding the long-term effects of SARS-CoV-2 on various systems in response to the infection will likely be forthcoming as we have more individuals who have recovered from the acute infection.

Evaluating issues related to the brain and nervous system, the immune system, mitochondrial function, hormones, and the hypothalamic-pituitary-adrenal (HPA) axis in response to the viral infection can direct us to some basic naturopathic and functional medicine assessment and treatment options to help long-haulers fully recover. In part one of this series, I will explore the long-term effects of viral infection on the central nervous system (CNS) and some current hypotheses that are emerging as scientists and physicians around the world observe, treat, research, and gather data on SARS-CoV-2.

Post-Viral Syndrome Related to SARS-CoV-1

Specific data regarding the long-term effects of SARS-CoV-2 on various systems in response to the infection will likely be forthcoming as we have more individuals who have recovered from the acute infection.

SARS-CoV-2 and SARS-CoV-1 have a 78% genetic similarity so it is fair to assume that post-viral symptoms associated with the first SARS virus might also be associated with SARS-CoV-2. In March 2003, SARS-CoV-1 arrived in Ontario, Canada, where health authorities effectively contained the virus with only 273 confirmed cases and 44 total deaths. By June 2003, there were no new cases; however, a cohort of 50 post-SARS-CoV-1 patients out of Ontario, Canada, experienced ongoing symptoms marked by extreme fatigue, muscle weakness, sleep disruption, and cognitive difficulties resulting in an inability to return to work for several months to three years post-infection. In a 2011 BioMedCentral Neuroscience article, Modolfsky and Patcai conducted sleep studies on the above-mentioned cohort and discovered an association between the seemingly abnormal sleep patterns in the post-SARS group and common sleep patterns seen in ME/CFS and FM. All groups presented with sleep instability and poor-quality sleep as indicated by a delay in sleep onset and lack of deep sleep cycles throughout the night [1]. The authors presumed that symptoms associated with post-SARS may have been related to the virus crossing the blood-brain barrier (BBB), thus invading the CNS [1, 2]. Past research has demonstrated that viral particles could be isolated from neuronal tissues in the hypothalamus and cortex tissue from eight deceased patients who had tested positive for the virus, confirming that certain viruses cross the BBB into the brain [1, 2]. Mouse studies reveal that viruses can enter the brain primarily through the olfactory bulb, resulting in chronic post-inflammatory CNS pathology affecting sleep, pain sensitivity, and energy [1].

In December 2009, the Journal of the American Medical Association published a study, “Mental Morbidities and Chronic Fatigue in Severe Acute Respiratory Syndrome Survivors.” This study focused on the fatigue and mental health symptoms associated with the first SARS virus among 181 survivors at a four-year follow-up. In those who did not have a psychiatric disorder prior to contracting SARS-CoV-1, 42% experienced at least one psychiatric illness post-infection with the most common diagnoses being post-traumatic stress disorder, depression, somatoform pain disorder, panic disorder, and obsessive-compulsive disorder. Chronic fatigue was common among both psychiatric and non-psychiatric groups as determined by the Chalder fatigue scale questionnaire. It was presumed that the relationship between fatigue and psychiatric disorders could be interactive and bidirectional; however, the high rate of fatigue among both groups suggested that psychiatric disorders did not account for the chronic fatigue. Because most SARS-CoV-1 patients were treated with high-dose steroids at the time of infection, there was some concern with ongoing hypocortisolism, developing as a side effect of treatment, which was reported in about 40% of survivors one year after the infection [3].

What We Know About ME/CFS and FM

ME/CFS and FM are very similar to each other with FM having more specific body pain issues. Both syndromes involve fatigue lasting more than six months, brain fog and cognitive dysfunction, orthostatic intolerance, PEM, sleep disturbances, and muscle pain and weakness. PEM is a hallmark symptom of ME/CFS and involves an abnormal response following physical, emotional, mental or orthostatic exertion, resulting in loss of physical and mental stamina and rapid muscular and cognitive fatigability [4].

Although the first definition of ME/CFS was published back in 1988, there has been no isolated singular cause. A 2019 evaluation of ME/CFS concluded that 80% experienced an upper respiratory viral infection prior to the onset of their symptoms [5]. The consensus throughout the literature states that the trigger for ME/CFS can be related to infections, extreme stress or physical trauma but regardless of the cause, there is ample evidence for complex dysregulation of the immune and autonomic nervous systems [4], with broader effects extending to the cardiovascular system, musculoskeletal system, endocrine system, and more specifically the mitochondria within each cell. ME/CFS is a condition that can persist for years and there is no targeted treatment that works under all circumstances.

A subset of ME/CFS patients can also develop antibodies against one or more muscarinic and adrenergic receptors that may contribute to unstable vascular dynamics affecting muscular and cerebral blood flow. This could lead to orthostatic dysfunction and potentially induces a state of hypoxia and ischemia within the brain and musculature, making physical and mental activities exhausting. Viral infections can often be the trigger for ME/CFS, leading to cerebral cytokine dysregulation and neuroinflammation, which can impact lymphatic/glymphatic clearance from the brain and CNS, and influence cerebral spinal fluid dynamics that further impact the function of the central and peripheral nervous system. Ongoing inflammation within the CNS can create an imbalance in the production of key neurotransmitters that produce inhibitory and excitatory signals, which keep the brain and nervous system balanced.

Sleep issues are also common among those suffering from ME/CFS and may be related to elevated sympathetic tone (i.e., high norepinephrine) and decreased vagal response. Lack of sleep can have severe health consequences; it is proposed to contribute to a reduction in prefrontal cortex gray matter volume and potentiates daytime fatigue and cognitive dysfunction. Additionally, evidence of a hypometabolic state and low urinary free cortisol excretion suggests mitochondrial and HPA axis dysfunction as a part of the total ME/CFS picture [4, 6].

Dysregulation of the Autonomic Nervous System

Many of the symptoms associated with post-viral syndromes extend from dysregulation of the autonomic nervous system and can include severe exhaustion, muscular and mental fatigue, exercise intolerance, PEM, impaired cognitive ability, poor sleep quality, muscle and joint pain, headache, orthostatic intolerance, dizziness, spatial disorientation, gut motility issues, sweating, and heart palpitations. In a 2020 study published in Autoimmunity Reviews, researchers isolated antibodies against key receptors that regulate vascular tone [4]. Autoantibodies to β2 adrenergic receptors (β2AdR) and M3 acetylcholine receptors were determined to be elevated in a subset of ME/CFS patients in which the removal of these antibodies led to rapid improvement in most of the patients [4]. Both β2AdR and M3 acetylcholine receptors play an important role in vasoregulation. Antibodies to these receptors result in enhanced vasoconstriction and consequential vascular dynamics that result in low blood pressure, low blood volume, ischemia, and hypoxia. This mechanism may explain why so many who have ME/CFS experience orthostatic dysfunction and postural tachycardia syndrome, along with mental and muscular fatigue. Autoantibodies against β2AdR and M3 acetylcholine receptors are presumed to occur following an infection resulting in immune dysregulation and autoimmunity in a subset of patients. It has also been noted that polymorphisms of β2AdR genes have been associated with adolescent chronic fatigue syndrome [4].

Overstimulation of the Sympathetic Nervous System

As noted by Wirth in Autoimmunity Reviews, studies on ME/CFS reveal a decrease in heart rate variability suggesting a chronic stimulation of the sympathetic nervous system. Under chronically elevated sympathetic tone, β2AdR can become desensitized and, along with autoantibodies and potential genetic mutations, this can lead to severe autonomic dysfunction. Under the conditions described above, low vascular, atrial, and ventricular filling due to hypovolemia leads to low cardiac output, which may further activate the sympathetic nervous system as compensation for low blood volume. The muscle weakness and pain associated with ME/CFS may be due to vasoconstriction that results from activation of the sympathetic nervous system. Vasoconstriction can also lead to decreased vascular flow within the brain, contributing to cognitive dysfunction, brain fog, and dizziness [4].

Lymphatic/Glymphatic Drainage and the CNS

What we know is that the virus is generating an immune response within the brain and nervous system that compromises normal neurological function.

In a letter to the editor of Medical Hypotheses, osteopathic physician Raymond Perrin, DO, PhD, Manchester University, School of Medicine, in the United Kingdom, proposed a possible mechanism by which COVID-19 might contribute to developing symptoms associated with post-viral syndrome. In a post-mortem evaluation of brain tissue samples, it was determined that SARS-CoV-1 crossed the BBB and entered the hypothalamus via the olfactory pathway, which disturbed lymphatic drainage from the microglia in the brain. The main pathway of lymphatic drainage for the brain is via the perivascular spaces along the olfactory nerves through the cribriform plate and into the nasal mucosa. The cribriform plate is a sieve-like structure between the anterior cranial fossa and the nasal cavity. The effect of the virus on this pathway may explain the anosmia (lack of smell) associated with SARS-CoV-2. The disturbance of this drainage pathway results in the buildup of pro-inflammatory cytokines affecting the neurologic control of the glymphatic system, which is commonly seen in ME/CFS [7]. This buildup of cytokines and toxins within the CNS and hypothalamus due to poor drainage, can lead to autonomic dysfunction manifesting as fatigue, interruptions of the sleep/wake cycle and cognitive difficulties associated with ME/CFS. Dr. Perrin proposed the use of lymphatic drainage techniques involving Osteopathic Manipulative Treatment (OMT) and lymphatic massage to aid central and peripheral lymphatic drainage [7].

In a similar article in Medical Hypotheses, Peter Wostyn, MD, proposed that post-COVID fatigue syndrome may result from damage to the olfactory sensory neurons causing an increased resistance to cerebrospinal fluid (CSF) outflow, leading to congestion of the glymphatic system with subsequent accumulation of toxins within the CNS. Inhibition of CSF outflow can lead to glymphatic overload within the CNS, resulting in postural idiopathic CSF hypertension. As mentioned above, the olfactory pathway is the major site for CSF drainage. Olfactory dysfunction was the most commonly reported neurological manifestation of SARS-CoV-2 presenting as anosmia in over 80% of those with symptomatic infection. Dr. Wostyn hypothesized that damage to the olfactory nerve fibers from infection with SARS-CoV-2 may contribute to poor glymphatic drainage within the CNS, leading to a buildup of CSF pressure and toxins. Dr. Wostyn recommended the use of a technique for glymphatic drainage in addition to OMT as mentioned above [8].

Hulens et al also maintains a similar hypothesis in relation to fibromyalgia and other chronic widespread pain disorders. He proposed that cerebrospinal pressure dysregulation could cause increased pressure within the CNS that then extends to the peripheral nervous system and contributes to chronic generalized pain [9]. While his focus was primarily on pain disorders, the mechanism that he suggested is similar to Wostyn and Perrin in that, whatever the cause, there is an increase in pressure due to faulty drainage within the CNS, which potentially leads to dysfunction within the autonomic and peripheral nervous systems.

Does SARS-CoV-2 Directly Infect the Brain and Nervous System?

Some studies on SARS-CoV-1 have isolated the virus in the brain and nervous system [2] while other studies have only found inflammatory markers associated with the infection [10]. Either way, what we know is that the virus is generating an immune response within the brain and nervous system that compromises normal neurological function. In past literature on SARS-CoV-1, the virus was detected in brain tissue specimens and given the similarity between SARS 1 and 2, there is suspicion that SARS-CoV-2 can in fact enter the brain and nervous system through either the olfactory route or by crossing the BBB [11, 12]. The epithelium in the nasal mucosa is rich in angiotensin-converting enzyme 2 (ACE2) receptors and transmembrane serine protease 2 (TMPRSS2), which work together synergistically to facilitate viral entry and replication.

Viral dissemination into systemic circulation along with the production of inflammatory cytokines could also disrupt the integrity of the BBB and facilitate entry of the virus into the brain. SARS-CoV-2 may also enter the brain through the hypothalamus, which is an area of the brain with a more permeable BBB due to small openings in the capillary walls. Some research states that hypothalamic capillaries express ACE2 and TMPRSS2, which could allow for viral entry and replication in the hypothalamus and provide a gateway to the rest of the brain and nervous system [7, 12, 13]. In a preprint study in bioRxiv, Nampoothiri et al summarized their current research article entitled, “The Hypothalamus as a Hub for SARS-CoV-2 Brain Infection and Pathogenesis,” by stating that the brain not only possesses the cellular and molecular machinery necessary to be infected, but that the hypothalamus, which contains neural circuits regulating a number of risk factors for severe COVID-19 and is linked to olfactory and brainstem cardiorespiratory centers, could be a preferred port of entry and target for the virus [13].

In a recent study on cancer patients infected with SARS-CoV-2 who experienced neurologic toxicity from the infection, an analysis of CSF revealed that virus particles were not detected; however, an increase in inflammatory cytokines nearly two months after the initial infection persisted [10]. Researchers proposed that the increase in CSF cytokines was likely due to an increase in BBB permeability and local production by cells within the CNS. These findings support the hypothesis that a secondary immune activation might be the cause of inflammatory cytokines in the CSF [10]. It is important to note that these studies using CSF samples were done two months after the initial infection. If there was a virus present within the CNS, two months may have been a long enough period of time for the initial infection to resolve but still leave behind an inflammatory footprint. Regardless of the trigger, neuroinflammation is widely regarded as a chronic condition that can have lasting effects on brain and nervous system function.

In October 2020, The Lancet called for a global consortium to coordinate studies and data as a means of elucidating the full impact of the virus on the nervous system. To that end, the Global Consortium Study of Neurological Dysfunction in COVID-19 was established to conduct a formal collaboration of research and data [14].

Evaluating the Effects of Neuroinflammation

Some of the symptoms of long COVID are related to mood and sleep, which suggests that inflammation within the CNS can manifest as depression, anxiety, cognitive dysfunction, and sleep issues. ZRT Laboratory can provide testing that may assess the potential effects of neuroinflammation in relation to neurotransmitters that impact mood, cognitive ability, and sleep. After all, neurotransmitter signaling in the periphery and in the brain is responsible for functionally integrating the nervous, immune and endocrine systems, indicating that neurotransmitter imbalances can influence symptoms beyond the brain.

ZRT Laboratory also offers testing to assess melatonin levels, cortisol, DHEA-S, hsCRP and vitamin D. Melatonin levels increase in response to decreased light in order to usher in sleep onset, but may be compromised due to dysregulated circadian rhythms. A four-point cortisol measurement can provide an evaluation of the HPA axis. Elevated cortisol together with high norepinephrine and epinephrine may indicate increased HPA axis activity and sympathetic tone due to common stressors, infection, pain, inflammation, and lack of sleep. Functioning in the brain and nervous system as a neurosteroid, DHEA-S is a potent immune-modulating hormone and works as a counter-regulatory hormone to cortisol. The main neurobiological effects of DHEA-S in the brain include neuroprotection, neurogenesis, apoptosis, catecholamine synthesis and secretion, antioxidant, and anti-inflammatory effects. Measuring sex hormones and thyroid markers can also provide much needed data that may help to address the symptoms associated with post-viral illness.

The CDC suspects about 30% of COVID-19 survivors may go on to develop persistent symptoms after recovery from acute illness and has funded an initiative called the Innovative Support for Patients with SARS-CoV-2 Infection Registry to examine the causes of long COVID. Since the first definition for ME/CFS was developed over 30 years ago, scientists and physicians have struggled to find a singular cause of this potentially debilitating illness. While the trigger for the onset of post-viral syndromes may be a singular event, the effects are broad and involve multiple systems. As we face the burgeoning issue of long COVID, the approach to treatment will involve addressing inflammation and dysregulation within the CNS, autoimmune issues, mitochondrial function, and hormone and HPA axis dysregulation. In the next installment on long COVID, we will explore autoimmune activation and immune system dysregulation in the presence of a serious viral infection.

ZRT Tests to Consider

NeuroAdvanced Profile with Add-on Diurnal Cortisol, Melatonin, Norepinephrine & Epinephrine
Adrenal Profile
Female/Male Saliva Profile III
Female/Male Blood Spot Profile II
Comprehensive Female/Male Profile II
CardioMetabolic Profile
Essential Thyroid Profile
Elite Thyroid Profile
hsCRP as a single test in blood spot
Vitamin D as a single test in blood spot

Related Resources

References

Vitamin D: Its Role in Health and the Importance of Adequacy in Acute and Chronic Illness

Mon, 11 Jan 2021 14:22:37 -0800

The fact that we produce vitamin D in our skin in the presence of sunlight signifies how necessary it is to our health. Even though it seems easy enough to get, according to recent data published in the European Journal of Clinical Nutrition, vitamin D deficiency is prevalent in 24% of Americans, 37% of Canadians and 40% of Europeans [1]. Data from 2012 indicate that 50% of the world’s population are vitamin D insufficient. A deeper look reveals that vitamin D deficiency and insufficiency vary by age, sex, ethnicity and geographic location, with reduced time spent outdoors and insufficient consumption of vitamin D-rich foods having the greatest impact on suboptimal levels [2]. The medical community is certainly testing more than it did in the past, naturally picking up on more deficiencies, and providing us with the opportunity to address this key biomarker of good health. This blog discusses sources of vitamin D, contributors to vitamin D deficiency, and its role in chronic and acute disease, especially its association with comorbidities that predict an increased risk of complications and poor outcomes to COVID-19.

Sources of Vitamin D

There are 2 forms of vitamin D – D3 (cholecalciferol) which is found in animal-based foods, and D2 (ergocalciferol) which is found in plant-based and fortified foods. The richest sources of vitamin D3 are foods such as fatty fish, cod liver oil, egg yolk, pork, lamb, and beef. Vitamin D fortified foods like cereals and dairy products may contain D2 or D3. Mushrooms are the only plant-based food that are a rich source of vitamin D as they contain ergosterol that is converted to vitamin D2 upon exposure to ultraviolet light [2]. Mushrooms, much like humans, need to have exposure to UV light, in particular UVB rays, to enhance their production of vitamin D. A 1-cup serving of mushrooms can provide the recommended daily allowance of vitamin D2 and can be an excellent source for vegans and vegetarians [3].

Aside from food, the best sources of vitamin D are sunlight and supplementation. To produce enough vitamin D through sunlight, we need to safely expose our skin to unfiltered sunlight for 15-20 minutes 3-4 times a week. Sunscreen and air pollution filter out UVB rays which are needed for vitamin D production, and people with darker skin need more time in the sun to produce the same amount of vitamin D as a high concentration of pigment in the skin from melanin slows production. Vitamin D produced through sunlight and from the diet or supplements can be stored in the liver and adipose tissue. These stores of inactive vitamin D can be drawn upon for later use if sun exposure or diet are insufficient during the winter months.

Vitamin D – Nutrient or Hormone?

While vitamin D is not officially a nutrient, we can get it through food in its inactive form. Vitamin D more appropriately qualifies as a pro-hormone in that its structural backbone is that of a steroid hormone. We can produce Vitamin D in our skin through sunlight-activated photoconversion of 7-dehydrocholesterol to D3, which is released into the bloodstream and transported to various cells and tissues. There it binds to the vitamin D receptor (VDR) to influence gene expression. Once inactive vitamin D is formed from sunlight or consumed in foods, it is converted in the liver to 25-hydroxycholecalciferol (25(OH)D) then to its active form of 1,25-dihydroxycholecalciferol (1,25(OH)₂D) in the kidney. Vitamin D is the prohormone, while 25(OH)D is the major circulating and storage form that can be measured in serum or dried blood spot. While 1,25(OH)₂D is the hormonally active form of Vitamin D, it is less stable and not more clinically relevant than 25(OH)D regarding its relationship to health benefits.

Vitamin D and Bone Health

Sunscreen and air pollution filter out UVB rays which are needed for vitamin D production, and people with darker skin need more time in the sun to produce the same amount of vitamin D as a high concentration of pigment in the skin from melanin slows production.

Vitamin D is necessary for the absorption of calcium and phosphorus from the intestines and for bone formation through activation of osteoclasts and osteoblasts. The active form of vitamin D produced in the kidneys increases intestinal absorption of calcium by 30-40% and phosphorus by 80% [2]. Active vitamin D also increases bone resorption of calcium, which together with increased calcium absorption from the intestines results in an increase in blood calcium levels. The increase in blood calcium decreases the production of parathyroid hormone (PTH), which is responsible for mobilizing body stores of calcium when blood levels get too low. Low PTH and adequate blood calcium increases calcitonin which deposits calcium back into the bone [4]. Getting enough dietary calcium and vitamin D, either from food or sunlight, reduces bone resorption and contributes to a healthy balance between breakdown (osteoclastic) and formation (osteoblastic) of bone. Too much vitamin D without adequate calcium may contribute to accelerated bone resorption to increase blood calcium levels, with the net result of bone loss. Elevated blood calcium can lead to calcification of arteries and soft tissues and potentially contribute to kidney stones [5].

A 2019 article reported a double-blind, randomized clinical trial which evaluated the bone density effects of 3 different vitamin D dosages in 311 participants over a 3-year period. The participants ranged in age from 55-70 years and none of the participants had osteoporosis. Baseline serum values of 25(OH)D ranged between 30-125 nmol/L. The vitamin D dosages given to the 3 groups within the study were 400 IU, 4000 IU, and 10,000 IU daily for 3 years. Calcium supplementation was also provided to those who received less than 1200 mg per day from food sources. Bone density scans were done at the end of the 3-year period. The group that received the highest dosage of vitamin D had lower total volumetric radial and tibial bone mineral density than the other 2 groups [6]. These results show that daily vitamin D supplementation at these doses result in an inverted U-shaped distribution where optimal dosing appears to be in the 4000 IU range. Too little vitamin D results in poor calcium and phosphorus absorption which can lead to lower bone density. Likewise, too much vitamin D can result in increased bone resorption which can also lead to lower bone density, especially if dietary or supplemental calcium are inadequate.

Systemic Effects of Vitamin D

Outside of the bone and kidneys, the hydroxylase enzyme that is responsible for the conversion of inactive vitamin D to active vitamin D is expressed in multiple epithelia, the placenta, the intestines, platelets, beta cells of the pancreas, the prostate, and various immune cells [7]. Most tissues throughout the body have VDRs indicating the broad range of biological actions of this pro-hormone. Once bound to tissue-specific VDRs, vitamin D can influence the modulation of cell growth, support neuromuscular functions, influence immune system response, inhibit angiogenesis, stimulate insulin production, inhibit the renin-angiotensin-aldosterone system, and reduce inflammation [2]. Deficiencies in vitamin D have been associated with heart disease, hypertension, type 1 and type 2 diabetes, obesity, depression, fractures and falls, autoimmune disease, influenza, cancer, and cognitive impairment [2].

Vitamin D and the Immune System

Deficiencies in vitamin D have been associated with heart disease, hypertension, type 1 and type 2 diabetes, obesity, depression, fractures and falls, autoimmune disease, influenza, cancer, and cognitive impairment.

Vitamin D can modulate the innate and adaptive immune response, and deficiency has been associated with increased autoimmunity and increased susceptibility to infections. Vitamin D receptors are expressed on B cells, T cells and antigen-presenting cells, which are all capable of producing the active form of vitamin D. Within the immune system, production of the hydroxylase enzyme that converts inactive vitamin D to active vitamin D may be induced by the presence of cytokines such as IFN-gamma, IL-1, and TNF-alpha.

The conversion of inactive Vitamin D to its active form by B and T cells in the presence of inflammatory mediators occurs as a localized reaction to enhance immune activity against infections while controlling excessive inflammation. This localized reaction functions independently of feedback controls related to vitamin D and bone homeostasis. Vitamin D inhibits B and T cell proliferation and differentiation, shifts the immune response from a Th1 to a Th2 phenotype, and facilitates the production of T regulatory cells to moderate inflammation [8]. Vitamin D also decreases the production of inflammatory cytokines (IL-17, IL-21) while increasing the production of anti-inflammatory cytokines such as IL-10 [8]. Several cells involved in immune function express VDR and hydroxylase enzyme; this suggests that the active form of vitamin D influences immune function in both innate and adaptive responses.

Vitamin D and COVID-19 Comorbidities

Supplementation, food sources, and sun exposure to improve vitamin D status are important considerations in those who live with obesity, type 2 diabetes, cardiovascular disease and hypertension, as these comorbidities are associated with a poor COVID-19 prognosis and deficiency of vitamin D tends to be high in these populations. Accumulating data suggest that serum vitamin D is inversely related to metabolic syndrome [9]. In fact, there is a strong relationship between vitamin D deficiency and the degree of obesity, particularly central adiposity. Decreased outdoor activities and sun exposure along with an increase in sedentary lifestyle are the obvious contributors; however, there are certain biochemical dynamics that may also contribute to the relationship between vitamin D deficiency and obesity which can be the precursor to metabolic syndrome, type 2 diabetes, and cardiovascular disease.

In vitro studies on murine, porcine, chicken and human adipocyte cell lines revealed that vitamin D interferes with the adipocyte differentiation process which inhibits adipogenesis [9]. VDR expression in adipose tissue, food intake, and exercise levels also seem to be associated with vitamin D deficiency in obese individuals. The master regulator of adipogenesis is peroxisome proliferator-activated receptor gamma (PPARγ). This regulator of adipogenesis and VDR share a common binding partner, retinoid X receptor (RXR). A higher presence of VDR competitively inhibits the binding of PPARy to RXR, which decreases the chance of adipogenesis-related gene expression [9]. It is also suspected that an increase in adipose tissue will tend to sequester vitamin D, keeping it from entering the circulation and binding to receptors.

Hypertension and cardiovascular disease are also associated with vitamin D deficiency. Vitamin D deficiency and insufficiency have been observed to upregulate the renin-angiotensin-aldosterone system (RAAS) resulting in hypertension, as there is a direct link between vitamin D deficiency and upregulation of this system. A pioneering study at the University of Chicago in 2002 proved vitamin D to be an antihypertensive agent. VDR knockout mice have elevated blood pressure, cardiac hypertrophy and increased activation of the RAAS. Vitamin D acts as a potent suppressor in renin biosynthesis which initiates the activation of the RAAS [10].

The cardiovascular benefits of adequate vitamin D may be related to its ability to decrease vascular calcification, reduce immune-associated inflammation, improve cardiac contractility, and support healthy cardiac tissue [9]. The mechanisms by which vitamin D may protect against cardiovascular disease have yet to be fully elucidated, but the fact that the heart and vascular system have VDRs reveals the potential necessity of vitamin D for healthy cardiovascular function. Most of the available evidence includes large observational studies and smaller randomized trials that are lacking in their ability to evaluate cardiovascular outcomes as primary endpoints. A recent meta-analysis of randomized clinical trials that included more than 83,000 participants found that vitamin D supplementation was not associated with reduced risks of major adverse cardiovascular events, myocardial infarction, stroke, cardiovascular disease mortality, or all-cause mortality, compared with placebo [11].

It is important to note that cardiovascular disease develops in humans as a result of many confounding factors, and to isolate a single pro-hormone as the ‘one thing’ that contributes to or prevents a disease process is impossible. While it is difficult to create an absolute cause and effect relationship between low vitamin D and cardiovascular disease, retrospective analyses have shown an association. The reality is, we cannot expect to prevent or reverse cardiovascular disease with a single supplement even though it may contribute to key biochemical functions that are supportive of good health. A single compound is a small part of a much larger whole and many lifestyle factors that contribute to cardiovascular disease may also contribute to vitamin D deficiency.

Vitamin D and COVID-19 Infection and Recovery

Though there are no current conclusive studies on vitamin D status and outcomes for COVID-19, there is enough data on the basic functions of active vitamin D and its effects on the immune system to come to the reasonable conclusion that in the presence of any bacterial, viral or fungal infection, adequate vitamin D levels can be supportive of recovery and lessen the duration and severity of disease by supporting a healthy and balanced immune response.

In the presence of COVID-19, blood levels of vitamin D can be a potential predictor of outcome as it relates to the balance between proinflammatory and anti-inflammatory mediators, vascular stability, and the ability to fight the infection. During respiratory viral infection, inactive vitamin D can be converted to active vitamin D by the alveolar epithelial cells increasing production of cathelicidin and defensins, which reduce the survival and replication of viruses [12]. Cathelicidin and defensins are anti-microbial peptides found in neutrophils, epithelial cells, and macrophages, and are activated by the presence of bacteria, viruses, fungi and the active form of vitamin D. A recent article in The Lancet states that vitamin D favorably modulates host responses to severe acute respiratory syndrome induced by SARS-CoV-2, both in the early viremic and the later hyperinflammatory phase of COVID-19 [13]. Though there are no current conclusive studies on vitamin D status and outcomes for COVID-19, there is enough data on the basic functions of active vitamin D and its effects on the immune system to come to the reasonable conclusion that in the presence of any bacterial, viral or fungal infection, adequate vitamin D levels can be supportive of recovery and lessen the duration and severity of disease by supporting a healthy and balanced immune response.

As stated above, vitamin D has a regulatory effect on the renin-angiotensin-aldosterone system (RAAS) which is involved in controlling blood pressure. The SARS-CoV-2 virus enters cells through the ACE2 receptor. ACE2 is the enzyme that converts angiotensin II, a vasoconstrictor, to angiotensin I-7, a vasodilator. The binding of the virus to the ACE2 receptor results in a downregulation of ACE2 leading to an increase in angiotensin II causing vasoconstriction and increased blood pressure. An increase in angiotensin II can result in acute respiratory distress syndrome (ARDS), myocarditis and cardiac injury [12]. Renin is a positive regulator of angiotensin II, meaning that increased renin leads to increased angiotensin II. Vitamin D is a potent inhibitor of renin; therefore, low vitamin D status can lead to increased activation of the RAAS and an increase in angiotensin II [12]. The effect of SARS-CoV-2 on the ACE2 receptor and its consequent downregulation are further compounded in the presence of a vitamin D deficiency. Supplementation with vitamin D in those who are deficient can suppress the release of renin, which is the first step in the activation of the RAAS, and thereby decrease the release of angiotensin II and possibly decrease the potential to advance to ARDS.

Causes of Vitamin D Deficiency

Severe Vitamin D deficiency manifests as rickets in children and osteomalacia in adults. Over a decade ago, Vitamin D deficiency was considered an epidemic with over a billion people worldwide at deficient or insufficient levels. Too much time spent indoors, advancing age, having darker skin or never exposing the skin to natural sunlight, and living at latitudes that are far north or south of the equator, are the main contributors to vitamin D deficiency; however, malabsorption from chronic intestinal inflammation as in Crohn’s disease and ulcerative colitis, poor digestive capacity, biochemical and genetic disorders, and certain medications can prevent absorption and activation of vitamin D.

Medications that may interfere with vitamin D status activate the pregnane X receptor which plays a crucial role in the detoxification of xenobiotics and drugs. When activated, the pregnane X receptor increases a specific hydroxylase enzyme that degrades active and inactive vitamin D, converting them into physiologically inactive metabolites that are eventually excreted from the body. Pregnane X receptor is also very similar in structure to the VDR and binds to elements associated with VDRs, interfering with key processes associated with the biochemical actions of vitamin D [14].

Classes of medications that activate the pregnane X receptor include antiepileptic drugs such as phenytoin and carbamazepine, antineoplastic drugs such as tamoxifen, Taxol and cyclophosphamide, antihypertensives such as nifedipine and spironolactone, antiretrovirals such as ritonavir and saquinavir, antibiotics such as clotrimazole and rifampicin, endocrine medications such as cyproterone acetate, and the anti-inflammatory, dexamethasone [14]. Polypharmacy is a common problem especially amongst the elderly population and those with chronic illness. Medications that affect vitamin D status can have far-reaching consequences that extend beyond bone density. It is a good idea to evaluate 25(OH)D status at least twice a year and supplement with vitamin D to help to avoid complications of deficiency associated with medications.

Supplementing with Vitamin D

Daily supplementation with vitamin D should be part of a regular supplement program, especially for those who live at higher latitudes and spend more time indoors, as it can take several months of supplementation and moderate sun exposure to bring vitamin D to optimal levels. Vitamin D3 has a higher affinity for binding proteins and a longer half-life than D2, so it is usually recommended for supplementation. Both D2 and D3 are effective at raising circulating levels of 25(OH)D; however, vitamin D2 tends to be less bioactive so must be given at higher dosages. It has also been noted that vitamin D2 is somewhat less stable than D3 and is not the preferred form of vitamin D by the hydroxylase enzymes in the liver that convert D2 or D3 to 25(OH)D [15].

The RDA recommendation for vitamin D supplementation is 600-800 IU/day [16]; however, for those who have little sun exposure and low levels of 25(OH)D as measured in serum or dried blood spot, supplementing with 2000-4000 IU/day may be warranted to bring up baseline values to an optimal range. Food sources of vitamin D are also high in vitamin A and the 2 nutrients may act synergistically together to support a balanced immune response. Using 1 tablespoon of high-quality cod liver oil daily is a rich source of both nutrients in a whole food form.

Measuring Vitamin D Status

In the past decade, we have developed a deeper appreciation for the role that vitamin D can play in our health from bone support to immune function. Testing vitamin D levels has become a standard in annual blood work and vitamin D supplementation is readily available and affordable. The normal range as defined by the Endocrine Society is 20-80 ng/mL; however, according to the Vitamin D Council, optimal levels would be somewhere between 40-80 ng/mL. ZRT Laboratory offers an easy at home finger-stick dried blood spot test measuring vitamins 25(OH)-D2 and 25(OH)-D3. Both forms of vitamin D are measured because some people supplement with D2, especially when dosing at a higher concentration less frequently, as is often recommended in a primary care setting. By measuring both forms of vitamin D, ZRT provides a comprehensive view of vitamin D status. Vitamin D is offered as a single test as well as being included in our Weight Management, Wellness Metrics, Fitness Metrics , and Elite Athlete Metrics profiles.

As we face the current coronavirus pandemic, knowing our baseline level of vitamin D and supplementing appropriately has never been more important. Assuring that we have a healthy and balanced immune response that can effectively reduce viral load and suppress uncontrolled inflammation is crucial for prevention and recovery. Spending time outdoors and exposing our skin to a little bit of sunshine is also good for the body and mind.

Related Resources

References

Naturopathic Therapy for Prevention and Support of Viral Illness: Part 3 – Vitamin C

Tue, 22 Dec 2020 10:47:48 -0800

In the final part of this 3-part blog series on important nutrients in the fight against viral illness following on from part 1 discussing quercetin and part 2 discussing zinc, we will look at the role of vitamin C, which has been used to prevent and treat viral infections since Linus Pauling, PhD endorsed its benefits decades ago.

Vitamin C – a brief history

Vitamin C (also called ascorbate, or ascorbic acid) was one of the first nutrients to be intensely studied for its role in overall health and immune support. It is an essential water-soluble nutrient that functions as a potent antioxidant due to its ability to readily donate electrons and reduce oxidative stress. Vitamin C also contributes to the production of collagen (skin, tendons, ligaments, bone), carnitine (cardiovascular function, energy production), and neurotransmitters (catecholamines) via support of various enzymes involved in their production. Vitamin C has potent anti-inflammatory properties and influences cellular immunity and vascular integrity. Linus Pauling, PhD proposed that high dose vitamin C could reduce the duration and severity of the common cold and recommended a 2000 mg daily dose for prophylaxis. He was both ridiculed and revered in his day for his views on vitamin C, and controversy still exists around whether high-dose vitamin C plays a role in the prevention and treatment of illness.

Vitamin C has potent anti-inflammatory properties and influences cellular immunity and vascular integrity.

The Linus Pauling Institute at Oregon State University, where Dr. Pauling attended as an undergraduate, confirms the research that vitamin C is supportive of the immune system and is a potent antioxidant [1]. The institute does state, however, that dosages of only 400 mg per day are needed to maintain plasma and cell saturation in healthy non-smokers. This recommendation is based on current scientific evidence, which the Institute notes is incomplete because of ongoing research into the many roles of vitamin C in the human body [1] and the pharmacokinetics in differing populations based on age, lifestyle and health status.

Beyond staving off deficiency, Dr. Pauling was most interested in the therapeutic benefits of vitamin C to both prevent and treat disease. The Linus Pauling Institute acknowledges that people suffering from certain diseases, whether acute or chronic, may require substantially larger dosages to achieve optimum levels and derive therapeutic benefit. Interestingly, relying on white blood cell levels of vitamin C, as opposed to serum or plasma, may give us a better idea of tissue distribution, as vitamin C is concentrated in the leukocytes, the eyes, the adrenals, the pituitary and the brain[1].

Vitamin C in immune support

The use of Vitamin C to support immune system function has become a mainstay in the prevention and treatment of viral illness and has shown benefit in many chronic health conditions such as cardiovascular disease, diabetes and cancer. Even in small amounts, vitamin C can protect proteins, fats, carbohydrates, DNA and RNA from damage by free radicals and reactive oxygen species (ROS) that are generated during normal metabolism, immune system response and from exposure to toxins and pollutants. Vitamin C also participates in redox recycling of other important antioxidants including quercetin, which keeps their antioxidant capacity intact and supports overall function.

Vitamin C has been shown to stimulate both the production and function of white blood cells (leukocytes), especially neutrophils, lymphocytes and phagocytes. These immune cells accumulate vitamin C in high concentrations which protects them from oxidative damage as they respond to infections. In response to invading microorganisms, leukocytes produce superoxide radicals, hypochlorous acid, and peroxynitrite. These reactive oxygen species kill pathogens but can also damage the leukocytes themselves and contribute to an enhanced inflammatory reaction. As an antioxidant, vitamin C protects leukocytes from self-inflicted oxidative damage thereby keeping inflammation under control.

Vitamin C has also been shown to increase interferon production in vitro and can enhance the chemotactic and microbial killing capacities of neutrophils making them more effective overall. In support of adaptive immunity, the role of vitamin C in lymphocytes is less clear, but it has been shown to enhance differentiation and proliferation of B and T cells [2]. Vitamin C is also needed for apoptosis and clearance of neutrophils from sites of infection by macrophages thereby reducing potential tissue damage. Vitamin C also supports epithelial barrier function, externally through the skin and internally through the mucosal barrier, against pathogen penetration reducing the chance of infection.

Vitamin C and COVID’s cytokine storm

Those who are severely ill with COVID-19 are likely to have elevated inflammatory markers indicative of a cytokine storm. Interleukin-6 (IL-6) is a cytokine and a key inflammatory mediator in the progression of COVID-19. High levels of IL-6 can be predicative of respiratory failure and are associated with an increased risk of mortality. It has been noted that as people age, there is an overexpression of IL-6 during an inflammatory episode and this condition tends to be associated with a higher frequency of organ failure [3]. Another inflammatory mediator in the progression of COVID-19 is endothelin-1 (ET-1) which is a potent vasoconstrictor and proinflammatory cytokine. The increased expression of ET-1 has been associated with pneumonia, pulmonary hypertension, interstitial lung fibrosis and acute respiratory distress syndrome (ARDS).

Vitamin C can reduce the hypersecretion of IL-6, ET-1 and C-reactive protein as well as other inflammatory cytokines, thereby reducing the chance of developing an extreme inflammatory reaction when the immune system is activated against a viral pathogen. Vitamin C reduces oxidative stress associated with immune stimulation and aids in the healing process of tissues damaged through the inflammatory process. Vitamin C may also inhibit the formation of neutrophil extracellular traps (NETs) which have been associated with organ damage [3]. NETs are webs formed from chromatin, microbicidal proteins, and oxidant enzymes, which are produced by neutrophils to contain infections [4]. However, if they are not kept under control, NETs can potentiate inflammation and microvascular thrombosis. With COVID-19, this process occurs in the lungs and contributes to acute respiratory distress syndrome (ARDS).

Dietary sources and supplemental vitamin C

The good news is that vitamin C is very abundant in food - it is found in most plant-based foods and accompanies the many phytonutrients that benefit from its antioxidant capacity. Foods rich in vitamin C include bell peppers, strawberries, guavas, oranges, tomatoes, broccoli, kale, and brussels sprouts. Most fruits and vegetables are likely to have some vitamin C, so eating a broad variety should provide a decent amount. In foods, vitamin C exists as a complex with bioflavonoids, minerals and other nutrients where they exist in mutual support of absorption and utilization. The uptake of vitamin C by immune cells increases during an infection to support antioxidant needs and key aspects of immune function. Oral tolerance of vitamin C can limit how much we can take in a 24-hour period; however, during acute illness, oral tolerance to vitamin C can increase greatly as the body effectively utilizes this nutrient to support immune function, increase antioxidant capacity and reduce inflammation. Oral supplementation and IV administration have the ability to increase tissue levels to exert a desired therapeutic effect that cannot be attained from food alone.

According to the NIH, the Recommended Daily Allowance (RDA) of vitamin C, set at 90 mg per day for adult men and 75 mg per day for adult women, is based on the vitamin C needed to maintain near-maximal neutrophil concentration with minimal urinary excretion of ascorbate [5]. The current RDA is generally directed toward preventing deficiency rather than supporting health or treating disease. The Tolerable Upper Intake Level (UL) for adults is set at 2000 mg per day, beyond which the adverse effects are osmotic diarrhea and gastrointestinal disturbances.

Use of high dosages of vitamin C

Higher dosages of vitamin C, beyond that which prevents deficiency, may be a necessity for good health due to the ever-increasing exposure to environmental toxins and the existence of inflammation which adds to the burden of oxidative stress. The dosage that is considered reasonable for prophylaxis is 2000 mg per day – just what Dr. Pauling recommended. For those who are acutely ill, higher oral dosages up to 10 grams per day may be tolerated. Like quercetin, the limits of intestinal absorption can reduce that amount of vitamin C that can be taken as a single dose; however, the use of liposomal vitamin C can increase intestinal absorption and enhance cellular permeability allowing for higher oral dosing without intestinal upset.

The use of intravenous vitamin C (IV Vit-C) has allowed for administration of much higher dosages which greatly increases cellular concentration and utilization of vitamin C by immune cells. In vitro studies show that high dose vitamin C induces virucidal activity [6]. Reports out of Shanghai show promising results not only during infection, but also as a preventive and post-infection therapy [7]. IV Vit-C improves outcomes with COVID-19 by reducing the chance of a cytokine storm that injures endothelial cells in the lungs, increases neutrophil infiltration, damages the alveolar-capillary barrier and results in uncontrolled inflammation and oxidative stress [6]. The anti-inflammatory and antioxidant effects of vitamin C are potentized through high dose IV administration and has proven to be safe, cost-effective and well-tolerated. The Shanghai Expert Panel noted that those who received IV Vit-C decreased their hospital stay by 3-5 days. Dosages used in the Shanghai study were 100 mg/kg/day for hospitalized patients and 200 mg/kg/day to control a cytokine storm [8]. There are currently clinical trials occurring on the use of IV Vit-C for COVID-19 in the United States and Canada.

This 3-part blog series introduced 3 important nutrients: quercetin, zinc, and vitamin C, which can be considered as nutritional support for viral illness. Limiting viral replication early in the disease process may reduce the severity of its inflammatory phase, especially in those with comorbid conditions and nutrient deficiencies. Use of quercetin, zinc, and vitamin C together potentiates their individual effects and they are often combined in single product formulations.

Related Resources

References

Linus Pauling Institute. Vitamin C. Available at: https://lpi.oregonstate.edu/mic/vitamins/vitamin-C.
Carr AC, Maggini S. Vitamin C and Immune Function. Nutrients. 2017;9:1211.
Feyaerts AF, Luyten W. Vitamin C as prophylaxis and adjunctive medical treatment for COVID-19? Nutrition. 2020;79-80:110948.
Zuo Y, et al. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020;5(11):e138999.
National Institutes of Health Office of Dietary Supplements - Vitamin C Fact Sheet for Health Professionals. Available at: https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/ .
Boretti A, Banik BK. Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome. PharmaNutrition. 2020;12:100190.
Cheng RZ, et al. Ascorbate as Prophylaxis and Therapy for COVID-19-Update from Shanghai and U.S. Medical Institutions. Glob Adv Health Med. 2020;9:2164956120934768.
Anderson PS. Intravenous ascorbic acid for supportive treatment in hospitalized COVID-19 patients. J Orthomolecular Med 2020;35(1).

Naturopathic Therapy for Prevention and Support of Viral Illness: Part 2 – Zinc

Fri, 18 Dec 2020 12:31:16 -0800

Following on from part 1 of this 3-part blog series discussing 3 important nutrients that can enhance our immune function against viral infection as well as regulate the inflammatory response to COVID-19, this second part of the series discusses the essential mineral zinc.

The Many Roles of Zinc

The body uses zinc in countless ways. After iron, zinc is the most abundant trace mineral in the body and is present in every cell. Zinc is necessary for the activity of over 50 enzymes that aid in metabolism, digestion, nerve function and many other processes. We need zinc for gene expression, immune function, protein and DNA synthesis, reproductive function, wound healing, and growth and development [1]. Zinc is involved in both innate and adaptive immunity and influences immune cell proliferation and maturation. Phagocytosis, natural killer cell and cytokine production all require adequate zinc. Zinc status affects the growth and function of T and B cells and also the balance between T cell subsets contributing to an effective immune response and inflammation resolution. The ability of zinc to function as an antioxidant and stabilize cell membranes suggests that it has a role in the prevention of free radical-induced injury during inflammatory processes [2]. Zinc also maintains anti-inflammatory activity by decreasing pro-inflammatory mediators and reducing reactive oxygen species (ROS) which regulates the progression of inflammation.

Prevalence and Consequences of Zinc Deficiency in the Context of COVID-19

Published research shows that zinc deficiency is strongly associated with the comorbid conditions predisposing to a poor prognosis of COVID-19 – pulmonary disease, cardiovascular disease, kidney disease, obesity and diabetes.

The essentiality of zinc was only recognized approximately 50 years ago in the Middle East where zinc deficient patients died from severe immune dysfunction. In addition to being zinc deficient, their diets were also high in cereals and grains which contain phytates that prevent zinc absorption. Even today, zinc deficiency is prevalent in developing countries where populations depend on cereal proteins as a major food source. The World Health Organization (WHO) assumes that approximately one-third of the world’s population is zinc deficient. Risk groups include the elderly and those with chronic inflammatory diseases and cancer. Published research shows that zinc deficiency is also strongly associated with the comorbid conditions predisposing to a poor prognosis of COVID-19 – pulmonary disease, cardiovascular disease, kidney disease, obesity and diabetes [3]. Each of these disorders has an inflammatory component, in which zinc is shuttled into cells and used for protein synthesis and neutralization of free radicals propagated by underlying inflammation, leading to reduced plasma levels of zinc.

Moderate zinc deficiency symptoms include growth retardation and male hypogonadism in adolescents, rough skin, poor appetite, cognitive impairment, delayed wound healing, cell-mediated immune dysfunctions, decreased lean body mass and neurosensory changes including impaired taste and smell, as well as night blindness. It is interesting to note that one of the presenting symptoms of COVID-19 is a loss of taste and smell which may be associated with an increased cellular uptake of zinc to inhibit viral replication [4]. Even a mild zinc deficiency can result in oligospermia and decreased testosterone in males along with decreased natural killer cell activity, decreased IL-2 production and decreased thymus gland activity [2]. In consideration of decreased testosterone production in the presence of zinc deficiency, low testosterone in males has been associated with a poor prognosis of COVID-19 [5]. It is important to note that zinc deficiency in males is not the only cause of low testosterone. Age, obesity, type 2 diabetes, chronic illness, injury, genetic disorders and general nutritional status can also have an impact on testosterone production. It is clear, however, that even a mild zinc deficiency can negatively impact biochemical and immunological function [2].

Effects of Zinc Deficiency on Immunity

Zinc deficiency decreases innate and adaptive immunity and allows a permissive environment for increased inflammatory cytokines and oxidative stress.

Zinc deficiency decreases innate and adaptive immunity and allows a permissive environment for increased inflammatory cytokines and oxidative stress. The good news is that in experimental human models, all compromised immune activity that was initiated during a zinc-depletion phase was corrected upon zinc repletion. These studies also suggest that cell-mediated immune dysfunction in the presence of zinc deficiency may be due to an imbalance between Th1 and Th2 cell function. Production of IFN-gamma and IL-2 (products of Th1) were decreased, whereas production of IL-4, IL-6, and IL-10 (products of Th2) were not affected during zinc deficiency [2]. In a study done on children under 5 years of age with pneumonia, supplementation with zinc improved production of IFN-gamma and IL-2 in addition to improving respiratory rate and oxygen saturation [6]. Zinc is also an essential component of the pathogen-eliminating signal transduction pathways leading to neutrophil extracellular traps (NET) formation that trap and kill invading microorganisms, without potentiating excess inflammation and microvascular thrombosis that can be associated with NET activity [7].

Immune system hallmarks of zinc deficiency include thymic atrophy, lymphopenia and compromised cell and antibody-mediated responses resulting in increased infections and compromised immune response. It has been observed that COVID-19 patients with lymphopenia have a poor prognosis. In rodent studies, lymphocyte counts were normalized upon zinc supplementation and there is a large body of research stating that zinc supplementation is necessary to reverse lymphopenia [3]. In chronic zinc deficiency, the immune system adapts to function differently beginning with the activation of the stress response (HPA axis activation) which results in excessive production of glucocorticoids (cortisol) that accelerates apoptosis of pre-B and pre-T cells leaving the thymus in a state of atrophy. Elevated cortisol also mobilizes stored glucose, triggering the release of insulin and exacerbating glucose dysregulation along with the imbalanced inflammatory response often associated with this physiological state, which is a common comorbid condition of COVID-19.

Antioxidant Properties of Zinc

As an antioxidant, zinc induces the production of metallothionein, which is rich in cysteine and is an efficient scavenger of hydroxide ions. Zinc also inhibits the activity of NADPH, a group of oxidase enzymes that catalyze the conversion of oxygen to oxide ion. Both hydroxide and oxide are reactive oxygen species (ROS) that inflict cellular damage through oxidative stress and inflammation [2]. Zinc may also decrease oxidative stress by decreasing inflammatory cytokines which also contribute to the generation of ROS. Additionally, zinc reduces inflammation by modulating Nuclear Factor Kappa-B (NF-kappa B), a transcription factor that is the master regulator of pro-inflammatory responses.

Antiviral Actions of Zinc

Zinc also has direct antiviral functions in that it can inhibit the entry and replication of a virus within the cell. Zinc can prevent fusion of the virus with the host cell membrane, block viral particle release and can destabilize the viral envelope resulting in decreased viral replication. Zinc supplementation can also decrease RNA synthesis of SARS-CoV by directly inhibiting RNA polymerase activity [3]. When combined with EGCG, quercetin, chloroquine or hydroxychloroquine, the ability of zinc to reduce viral replication is enhanced by its increased cellular concentration which is attributed to the action of each of these compounds as an ionophore that efficiently transports zinc across cell membranes.

In addition to cellular protection from viruses, zinc supports mucosal barriers to protect the body from infection. In animal studies, zinc supplementation increased ciliary beat frequency within bronchial cilia, improving removal of viral particles and reducing the risk of secondary infections [3]. Zinc has proven effective in preserving the integrity of respiratory epithelia thus preventing viral penetration through support of tight junction proteins in the lungs. Zinc may also affect the molecular structure of ACE-2 receptors in pneumocytes, thereby reducing the binding affinity of the virus to this receptor [3]. The ACE-2 receptor is the cellular entry site for the SARS-CoV-2 virus.

Dietary Sources and Zinc Supplements

When combined with EGCG, quercetin, chloroquine or hydroxychloroquine, the ability of zinc to reduce viral replication is enhanced by its increased cellular concentration which is attributed to the action of each of these compounds as an ionophore that efficiently transports zinc across cell membranes.

Zinc is found in grains, nuts, legumes and animal-based foods. Shellfish, beef, and other red meats are rich sources of zinc, with oysters having the highest content by far. Bioavailability from animal-based foods is high as they are rich in sulfur-based compounds that improve zinc absorption. Nuts and legumes are good plant sources of zinc with relatively good bioavailability. Zinc in whole grains and plant proteins has less bioavailability due to their high content of phytate which inhibits zinc absorption.

Numerous controlled trials and meta-analyses have proven zinc’s potential as a potent immune support supplement especially in the presence of respiratory infections. The RDA for zinc is 11 mg daily for men and 8 mg daily for women with the tolerable upper limit intake (UL) set at 40 mg per day. Short-term dosing at 60 mg per day for treatment of deficiency or used as immune support is tolerable for two weeks without risk of copper deficiency. However, high dose zinc supplementation for an extended period can inhibit copper bioavailability by inducing the synthesis of metallothionein, a copper-binding protein [8].

Zinc lozenges that slowly dissolve in the mouth and saturate the oropharyngeal tissue, the site at which we would most likely encounter a virus, is the most recommended form of zinc supplementation. Zinc tablets or capsules should not be taken on an empty stomach as they may induce nausea. The zinc in lozenges is absorbed more slowly which decreases the chance of nausea.

In the final part of this 3-part series we will examine the role for Vitamin C, which has been used to prevent and treat viral infections since Linus Pauling, PhD endorsed its benefits decades ago.

Related Sources

References