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.

Supporting Teens with ADHD: Navigating Hormonal Changes During Puberty

Wed, 04 Dec 2024 15:28:08 -0800

Developing bodies, mood swings, new social dynamics, and increasing schoolwork make puberty a tough time for many young people. For the approximately 5% of children worldwide with the neurodevelopmental condition, Attention Deficit Hyperactivity Disorder (ADHD), these hurdles can feel even more overwhelming.

The significant hormonal changes of puberty can drastically affect the presentation and management of ADHD symptoms. This blog post explores the connection between ADHD and puberty. It offers support for parents and providers as they help teens during these challenging years.

“But Don’t Most Kids Outgrow ADHD?”

Until recently experts believed that about half of children with ADHD would 'outgrow' the disorder. In a 16-year study published in 2021, nearly 10% of young people with ADHD showed stable remission. Most participants experienced fluctuating periods of remission and then saw their symptoms return into young adulthood and beyond. (1)

The Hormonal Changes of Puberty

Puberty is a period of rapid growth and development. It typically occurs between ages 8 and 14 for females and 9 and 16 for males. During this time, the body goes through significant changes driven by increased production of sex hormones. In both males and females, testosterone levels rise, while females also experience changes in estrogen and progesterone levels as they start ovulating and menstruating in a monthly cycle.

Effects of Sex Hormones on the Brain

During puberty, the rise in sex hormones affects more than just secondary sex characteristics such as breasts and facial hair. These hormones also change the brain, both in how it's structured and how it functions. They influence the way brain circuits work and how neurotransmitters are processed. (2)

This process begins long before puberty. Experts believe that higher testosterone levels in boys before and shortly after birth can permanently affect brain development. This is especially true for dopaminergic circuits that control thinking, movement, and the brain's "pleasure and reward" signaling functions.

This early exposure to testosterone can increase the risk of developing inattention and behavioral disorders, making boys more likely to show hyperactive and impulsive behaviors. This leads to a higher rate of ADHD diagnoses and treatments for boys. (2)

As puberty begins, changes in sex hormones activate brain circuits that were affected earlier in development. For example, the effects of estradiol during puberty may change serotonergic pathways. This can put girls at a higher risk for internalizing and mood disorders. (2)

Symptoms of ADHD During Puberty

A recent 8-year study looked at how aging and puberty affect ADHD symptoms. It found the following:

Hyperactivity and impulsivity appeared to decrease as young people got older
Impairment from ADHD and depressive symptoms appeared to increase as puberty progressed
Inattention did not change

These findings may help explain why ADHD in teens has often been overlooked. As they grow, symptoms become less obvious to others. (2)

Additionally, teens may start to assert their independence by refusing ADHD medications or treatments that they previously accepted during elementary school. Some may seek peer acceptance, sometimes with others who struggle socially or academically. They may also experiment with risky behaviors, which some researchers link to pubertal testosterone levels. (3, 4)

ADHD and the Menstrual Cycle

Research shows that hormonal changes during the menstrual cycle can make ADHD symptoms worse for girls. Estrogen tends to increase levels of dopamine and norepinephrine, two important brain chemicals that affect focus and attention. Estrogen does this partly by slowing down enzymes (MAO and COMT) that break down these chemicals.

When estrogen levels are higher, like during the late follicular phase and peak luteal phase of the cycle, girls may find it easier to focus and stay organized. However, when estrogen drops or is low, such as at the end of the luteal phase or during the period, ADHD symptoms often get worse. This can make emotional regulation and attention more difficult.

These hormonal shifts can affect school performance and relationships, which are especially important during adolescence. This highlights the need for strategies and interventions that support girls with ADHD during these challenging times. (5, 6)

Teens, ADHD and Mood Disorders

Puberty is a sensitive development period in general, with teens becoming particularly vulnerable to emotional and behavioral dysregulation and psychiatric conditions. Depressive disorder, which has typical onset during adolescence, impacts about 13% of the US population. (3)

Youth with ADHD may be especially susceptible to depression as hormonal changes affect brain networks that control thinking, decision-making, and feelings of reward. These changes can make it more difficult to stay organized, do well in school, and stay motivated. (3)

Implications for Treatment and Support

Understanding the relationship between ADHD and puberty is essential for developing effective treatment strategies. Healthcare providers should consider the impact of hormonal changes on ADHD symptoms and adjust treatment plans accordingly. For example, small preliminary studies suggest that increasing stimulant medication doses before a woman's period may help improve worsening ADHD and mood symptoms during that time. (7)

Many women with ADHD also report that "cycle synching" is helpful. This means tracking their menstrual cycles and planning demanding tasks for times when their energy, focus, and mood are at their best. (8)

Primary care providers and mental health professionals should work together to provide comprehensive care for children with ADHD, ensuring that both neurodevelopmental and hormonal factors are addressed.

For parents, this may be the time to:

Seek out a therapist or peer support group to incorporate more behavioral therapies alongside medication adjustments.
Enlist educational support such as tutors or an organizational/executive function coach.
Be on the lookout for new, lasting or worsening mood changes.
Use visual cues and reminders at home and on devices. These can help with routines such as self-care, hygiene, homework, activities, and chores.
Discover and focus on your teen’s unique talents, interests and strengths. (9)

Conclusion

The relationship between ADHD and puberty is complex and influenced by normal hormonal changes, gender differences, and comorbid conditions such as depression. In addition to the suggestions above, utilizing convenient at-home hormone and neurotransmitter testing can help provide meaningful insights into the unique challenges faced by adolescents with ADHD during puberty. Armed with this information, healthcare providers can develop more effective, personalized treatment plans to support their teen patients through this critical developmental stage.

References:

1. Sibley, Margaret H., Ph.D., Arnold, L. Eugene, M.D., Swanson, James M., Ph.D., Hechtman, Lily T., Ph.D., Kennedy, Traci M., Ph.D., Owens, Elizabeth, Ph.D., Molina, Brooke S.G., Ph.D. (2021). Variable Patterns of Remission from ADHD in the Multimodal Treatment Study of ADHD. The American Journal of Psychiatry, Vol 179, No. 2. https://psychiatryonline.org/doi/10.1176/appi.ajp.2021.21010032.

2. Eng, Ashley G., Phan, Jenny M., Shitcliff, Elizabeth A., Eisenlohr-Moul, Tory A., Goh, Patrick K., Martel, Michelle M. (2023). Aging and Pubertal Development Differentially Predict Symptoms of ADHD, Depression, and Impairment in Children and Adolescents: An Eight-Year Longitudinal Study. National Library of Medicine. https://pmc.ncbi.nlm.nih.gov/articles/PMC10198896/#R6.

3. Silvery, Larry, M.D. (2020). Boys 2 Men: When ADHD and Puberty Collide: What parents of boys with ADHD should watch for as their sons pass through adolescence. ADDitude Magazine. https://www.additudemag.com/boys-2-men-when-adhd-and-puberty-collide/#:~:text=Fortunately,%20boys%20with%20attention%20deficit%20disorder%20(ADHD%20or%20ADD)%20don%E2%80%99t.

4. Laube, Corinna, Lorenz, Robert, van de Bos, Wouter. (2019). Pubertal testosterone correlates with adolescent impatience and dorsal striatal activity. National Library of Medicine. https://pmc.ncbi.nlm.nih.gov/articles/PMC7242510/.

5. Roberts, Bethan, Esienlohr-Moul, Tory A., Martel, Michelle M. (2018). Reproductive steroids and ADHD symptoms across the menstrual cycle. Science Direct. https://www.sciencedirect.com/science/article/abs/pii/S0306453017312635?via%3Dihub.

6. Eng, Ashley G., Nirjar, Urveesha, Elkins, Anjeli R., Sizemore, Yancey J., Monticello, Krystina N., Peterson, Madeline K., Miller, Sarah A., Barone, Jordan, Eisenlohr-Moal, Tory A., Martel, Michelle M. (2024). Attention-deficit/hyperactivity disorder and the menstrual cycle: Theory and evidence. Science Direct. https://www.sciencedirect.com/science/article/abs/pii/S0018506X23001642#:~:text=Highlights%20%E2%80%A2%20Females%20with%20ADHD%20may%20experience%20both%20organizational%20and.

7. de Jong, M., Wynchank, D. S. M. R., van Andel, E., Beekman, A. T. F., Kooij, J. J. S. (2023). Female-specific pharmacotherapy in ADHD: premenstrual adjustment of psychostimulant dosage. Frontiers in Psychiatry. https://pmc.ncbi.nlm.nih.gov/articles/PMC10751335/#:~:text=Preliminary%20findings%20postulate%20that%20changes%20in%20sex%20hormones%20during%20the.

8. Pesantez, Nathaly. (2024). Menstrual Cycle Phases and ADHD: Why Cycle Syncing is Essential. ADDitude Magazine. https://www.additudemag.com/menstrual-cycle-phases-cycle-syncing-adhd/#:~:text=Here,%20we%E2%80%99ll%20break%20down%20the%20phases%20of%20the%20menstrual%20cycle.

9. (2024). ADHD across the lifespan: What is looks like in children and teens. NIH MedlinePlus Magazine. https://magazine.medlineplus.gov/article/adhd-across-the-lifespan-what-it-looks-like-in-children-and-teens#:~:text=Puberty%20can%20exacerbate%20ADHD%20symptoms%2C%20making%20it%20harder,and%20explore%20different%20activities%20to%20discover%20their%20strengths.

Understanding Estrogen's Vital Role in Perimenopause

Wed, 06 Nov 2024 14:12:04 -0800

Perimenopause is the phase between a woman’s reproductive years and menopause, marking the end of monthly bleeding cycles. During this transition, hormone levels change significantly. There are fluctuations in progesterone, but mainly a decline in estrogen. This drop in estrogen can cause both physical and emotional symptoms.

Understanding how estrogen levels play a key role in perimenopause is crucial for managing symptoms. It can also help improve the quality of life for women experiencing this transition.

What is Perimenopause?

Perimenopause typically begins when women are in their 40s but some may begin to experience symptoms in their mid-30s. This early onset is considered premature menopause. During this time the ovaries gradually produce less estrogen until menstrual periods completely stop, signaling the arrival of menopause.

The common duration of perimenopause is about four years, but can vary for each person (1). However, women who experience premature menopause, or undergo surgical menopause (the removal of the uterus and one or both ovaries), are suddenly menopausal, and may experience symptoms of low estrogen (2). In these cases, some providers prescribe hormone replacement therapy (HRT) containing estrogen to help with menopausal symptoms.

Estrogen’s Role in the Body

Estrogen is a key hormone in the female reproductive system that regulates the menstrual cycle and maintains pregnancy. Beyond its reproductive functions, estrogen also plays a vital role in various body systems, including the cardiovascular, skeletal, and central nervous system (3).

In 2016, the Early Versus Late Intervention Trial (ELITE) was conducted. This study introduced a term called, “the timing hypothesis” (4). This hypothesis suggests that starting menopause hormone therapy (MHT) within 5 to 10 years of menopause is key. It helps estrogen protect the heart and support brain function.

Cardiovascular System: Estrogen helps maintain healthy blood vessels and promotes good cholesterol levels, reducing the risk of heart disease.
Skeletal System: Estrogen helps keep bones strong and protects against osteoporosis.
Central Nervous System: Estrogen influences mood, cognitive function, and overall mental health.

Hormonal Changes During Perimenopause

During perimenopause, the rise and fall of estrogen levels is unpredictable. These fluctuations lead to a range of symptoms, including mood swings, and irregular menstrual cycles (1). The drop in estrogen also affects the hypothalamic thermoregulatory center, which regulates the body temperature (1). This can cause symptoms like hot flashes and night sweats (1).

Symptoms of Estrogen Fluctuations:

Vasomotor Symptoms: Hot flashes and night sweats are among the most common symptoms experienced during perimenopause. These are directly linked to the fluctuating levels of estrogen and their impact on the body’s temperature regulation (1).
Mood Swings and Depression: Changes in estrogen levels can affect neurotransmitter systems in the brain, leading to mood swings, anxiety, and depression (1).
Sleep Disturbances: Many women report difficulties in sleeping, which can be attributed to night sweats and hormonal changes (1).
Cognitive Changes: Some women experience memory lapses and difficulty concentrating, often referred to as "brain fog" (1).
Physical Changes: Weight gain, particularly around the abdomen, and changes in skin firmness and hair texture are also common.

Estrogen Therapy in Perimenopause

Hormone Replacement Therapy (HRT) is a common treatment for reducing perimenopausal symptoms. HRT involves the administration of estrogen or a combination of estrogen and progesterone/progestin to stabilize hormone levels.

Benefits of HRT: HRT can significantly reduce vasomotor symptoms, improve mood sleep quality, and protect against bone loss.
Risks of HRT: While HRT is effective, it is not without risks. Potential side effects include an increased risk of blood clots, stroke, and certain types of cancer. It is essential for women to discuss the benefits and risks with their healthcare provider to make an informed decision.

Non-Hormonal Treatments

For women who cannot or choose not to use HRT, there are non-hormonal options available. These include lifestyle changes, maintaining a healthy diet, regular exercise, and stress management techniques. Additionally, certain medications, like selective serotonin reuptake inhibitors (SSRIs), can help manage mood swings and hot flashes.

Emerging Research

Recent studies have highlighted the complex role of estrogen in perimenopause (4). For example, research suggests that estrogen’s impact on brain pathways involved in inflammation may contribute to mood disorders during this transition. Another study found that the change in estrogen, rather than the actual levels, might be more strongly linked to perimenopausal symptoms.

Views on Menopause Throughout History

Historically, menopause was viewed as a disease. It was seen as needing medical and sometimes psychiatric help, and not as a natural part of a woman's life. In some cultures, or societies, menopause was kept secret, creating a sense of shame and isolation for women. By the mid-20th century attitudes were showing signs of change.

The development and introduction of HRT in the 1960s marked a significant turning point for women. However, it also led to the belief that perimenopause and menopause were due to a deficiency that needed fixing. This further framed a natural female life transition as a medical problem.

Interesting insights come from writer, and oral historian, Dr. Helen Foster (6). She presents the history of menopause, bringing to light the confusion and superstition about menstruation and menopause. Dr. Foster uses audio clips from interviews with modern women to explore the difficult and sometimes violent history of menopause (6). She also dives into the mythology, and taboos around periods and the onset of menopause.

In a podcast episode of The Happy Menopause, Dr. Foster talks about her project, “The Silent Archive Project.” She notes, “I found there was a real gap around women’s stories at midlife, particularly at the mention of menopause… What I couldn’t find was women sharing what their symptoms were and how they felt about them.” “(Menopause), doesn’t really feature in any historical accounts, or very, very few. When there is, they are from the roots of taboo” (6).

Advocating for Change

Right now, there is political legislation that aims to address women’s midlife health issues that are often overlooked (5). The legislation, backed by celebrity support, is set to increase federal funding over a five-year period. This will also provide professional training and resources for healthcare providers on early detection, diagnosis, and treatment of perimenopausal and menopausal symptoms. This initiative is a crucial step toward ensuring that women receive the specific care and attention they deserve.

Perimenopause and menopause are natural biological phases marking the changes toward the conclusion of a woman's reproductive years. Like the onset of menstruation, perimenopause and menopause as an individual feminine experience is culturally acknowledged and celebrated differently throughout the world.

In this article from The Women’s Journal, author Carmen Rodriguez Gonzales discusses how menopause is viewed around the world. She writes, “In many cultures, menopause is seen as a significant milestone in a woman’s life. It is often associated with wisdom, maturity, and the attainment of a new level of spiritual and emotional growth. Understanding the cultural nuances surrounding menopause is crucial to providing appropriate support and empowerment for women during this transformative phase” (7)

How we, as women, see the physical and emotional changes in our bodies is important. It is helpful to explore these feelings with female friends, family, or support groups. Talking about our fears and discussing changes in our bodies with other women can be healing. It benefits both ourselves and all women.

The unique experience of biological changes can be seen in light of a person's religious, cultural, and family background. This context can greatly impact how each of us anticipate the experience and navigate the changes for ourselves.

Were you able to experience your mother going through the perimenopause or menopause transition? If you were fortunate enough to have your mother during this time in her life, how did her experience shape your views? How did it affect how you want to go through your own transition?

Conclusion

Perimenopause is a challenging phase marked by significant hormonal changes, particularly in estrogen levels. Understanding the role of estrogen can help women and healthcare providers better manage the symptoms associated with this transition. While HRT remains a cornerstone of treatment, non-hormonal options and emerging research offer additional avenues for relief. As always, personalized care and informed decision-making are central in navigating perimenopause effectively.

Convenient at-home tests using saliva or dried blood spots can check ovarian hormone levels. These hormones include estrogen and progesterone. This testing can provide meaningful insights for supporting a woman's health as symptoms are being anticipated and experienced. Hormone testing can also help women feel more empowered in their bodies during this transitional stage of life.

References:

1. Dhalwani, N. N., Williams, D., McManus, R. J., & Gokhale, K. M. (2023). Mortality and cardiovascular outcomes with different classes of antihypertensive drugs: A population-based cohort study using electronic health records linked to the UK Biobank. BMJ, 382, e072612. https://doi.org/10.1136/bmj-2022-072612

2. Sohn, E. (2023). Surgical menopause: Estrogen after hysterectomy. WebMD. https://www.webmd.com/menopause/surgical-menopause-estrogen-after-hysterectomy

3. Mehta, M., Jaya, Chester, C., Rebecca, & Kling, M., Juliana. (2019). The Timing Hypothesis: Hormone Therapy Treating Symptomatic Women During Menopause and Its Relationship to Cardiovascular Disease. Journal of the American College of Cardiology, 74(17), 2167–2175. https://doi.org/10.1016/j.jacc.2019.08.1037

4. Russell, K., Jason, Jones, K., Carrie, & Newhouse, A., Paul. (2019). The Role of Estrogen in Brain and Cognitive Aging. National Library of Medicine. https://pmc.ncbi.nlm.nih.gov/articles/PMC6694379/

5. Murkowski, L. (2023, September 21). Senator Murkowski introduces historic new bipartisan legislation to boost menopause research, expand training and awareness around menopause. Senator Lisa Murkowski. https://www.murkowski.senate.gov/press/release/senator-murkowski-introduces-historic-new-bipartisan-legislation-to-boost-menopause-research-expand-training-and-awareness-around-menopause

6. Wellcome Collection. (n.d.). A bloody history of menopause. https://wellcomecollection.org/series/a-bloody-history-of-menopause

7. Rodriguez Gonzalez, C. (n.d.). Menopause in different cultures around the world. The Women’s Journal. https://www.thewomensjournal.co.uk/womens-life/health-wellness/menopause-in-different-cultures-around-the-world/

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.

The History of Saliva Testing: An Interview with Kyle McAvoy, NP and Dr. David Zava

Wed, 11 Sep 2024 13:13:36 -0700

I had the privilege of sitting down with Dr. David Zava, the founder of ZRT Laboratory and someone I’ve had the pleasure of knowing for over 20 years. During our conversation, Dr. Zava shared insights into his fascinating journey from studying environmental chemicals at the University of Tennessee to founding ZRT in Beaverton, Oregon. Over the years, Dr. Zava's pioneering research and unwavering commitment to advancing hormone testing have not only enhanced my practice but also deepened our friendship.

As a practitioner, I’ve always been deeply impacted by Dr. Zava’s work. His relentless pursuit of knowledge and his innovative spirit have influenced not only my clinical practice but also my approach to patient care. One of Dr. Zava's most impactful contributions was his collaboration with Dr. John Lee on the book What Your Doctor May Not Tell You About Breast Cancer, published in 2002. The release coincided with the Women's Health Initiative (WHI) study, which linked hormone replacement therapy to a higher risk of breast cancer, causing widespread concern. Dr. Zava and Dr. Lee's book offered an alternative view, distinguishing between synthetic progestins and natural progesterone and advocating for bio-identical hormones as a safer option. Their work provided clarity during a time of uncertainty and continues to guide informed decisions about hormone therapy.

I encourage you to watch the full interview through the provided link, and for those who prefer to read along, a synopsis of our conversation is included below. This is a unique chance to hear from one of the foremost experts in hormone testing and discover the science and passion fueling ZRT Laboratory’s work. Whether you’re a healthcare professional or simply interested in your own health, Dr. Zava’s insights will leave you with a deeper understanding of hormone health and the cutting-edge approaches being developed to advance it.

Watch Full Video Here:

Read the Synopsis Here:

Kyle: Dr. Zava thank you so much for taking the time to sit down with me today. Having known you for over 20 years, I know how busy you are with all of the work that you do but I do think it is so important that providers and patients learn more about you, your journey and your endless knowledge about biochemistry, hormones, various kinds of testing as well as many diseases. Please tell me about your academic background and how you wound up here in Beaverton, OR founding this laboratory.

DZ: I started out at the University of TN studying environmental chemicals and their impact on the development of cancer. The main chemical I studied was dimethylbenzanthracene which causes cancer in certain animal species. Dimethylbenzanthracene looks very similar in chemical structure to estradiol. When we gave rats this chemical, they developed mammary cancers but didn’t develop cancer anywhere else in their bodies. I studied this effect on the mammary glands of rats during my time at the university.

After this, my postdoctoral fellowship was in San Antonio, TX where I began to study the effects of estrogen. This work was with humans and we began to look at the receptors inside breast cancer cells. This led to evaluating both estrogen and progesterone receptors and their relationship to cancer.

My next move was to Switzerland where I worked as the director of

a lab studying basically the same things. At that time, there was an international breast cancer study and we were looking at the effects of Tamoxifen, an anti-estrogenic drug that can inhibit the growth of breast cancer, as well as those of chemotherapy agents on breast cancer. Our work analyzed women’s breast cancer tumors in terms of their estrogen and progesterone receptors. What we learned is that Tamoxifen does indeed work to inhibit the growth of breast cancer but only for about five years and then its effect diminished. I was very disappointed by this and decided to shift my work towards finding ways to prevent rather than just treat breast cancer.

Kyle: I seem to recall that your work in Switzerland was pivotal in terms of how you viewed the effects of hormones on the development of breast cancer. Can you explain what happened there?

DZ: We were looking at receptors of estrogen and progesterone in breast cancers. What I saw in the tumors, depending on the age of the woman, is that the morphology of the tumors was different, depending on her age. For women in the perimenopause, where you generally tend to have estrogens uncontrolled by progesterone, their tumors were growing faster. So they had a much higher rate of growth, not necessarily more aggressive, but definitely faster growing. Women in the perimenopause were obviously exposed to excessive amounts of estrogen.

Kyle: So from that research, is it fair to say that women in the perimenopause are at higher risk for breast cancer development?

DZ: Yes if they don’t control the excess estrogen. Estrogen causes down regulation of estrogen receptors and up regulation of progesterone receptors , which in the presence of progesterone would then down regulate the estrogen receptors, which is what happens during a menstrual cycle. This is a feedback loop but during the perimenopause, there is inadequate progesterone so this feedback loop is not working.

Kyle: What did you do after you left Switzerland?

DZ: I moved to California around 1995 and worked at a group called Aaron Life Cycles, again doing work on breast cancer. But not only did I look at estrogen receptors but also how these might be affected by women taking estrogen exogenously as well as getting it from various food sources. I wanted to know if these things would increase a woman’s risk of breast cancer. At that time, there was a lot of interest in these issues and the Women’s Health Initiative was also started around this time. I became very interested in developing assays that could monitor the levels of estrogen in women. I was particularly interested in looking at the phytoestrogens in food, such as soy, to see if they could stimulate the growth of a breast cancer because they are estrogenic and can bind to estrogen receptors.

I developed a methodology for this kind of testing. I subsequently applied for and received a grant to study this. In order to do this work, I developed assays in saliva as a non-invasive way to monitor the effects of environmental factors(such as from food) on the levels of estrogen and progesterone.

Kyle: When did you cross paths with Dr. John Lee, the family practice doctor who did a lot of work with progesterone? I know you ended up writing a book with him about breast cancer. Can you tell us about this significant (crucial?) time for you?

DZ: Right around this time, I met Dr. Lee in CA at a lecture that he gave in which he was talking about natural progesterone. By then he had already written three books. The first one was about hormones, the second was “What your doctor may not tell uou about post menopause”, and the third one was about perimenopause. I was probably the only man in the audience amongst a room full of women.

I became very curious about progesterone at this lecture. Sharon McFarland was also there with the ‘Progest people’(those who manufactured progesterone) and had been working with wild yams. I took some of their product back to the lab and measured the level of progesterone on it. At that time, around 1998, it was called ‘progest’, not progesterone. Dr. Lee and I began to do lectures together and at some point, he asked me to co-write a book on breast cancer with him and I agreed. He had extensive experience working as a family practice physician with women and progesterone. I remember hearing that he had a very low incidence of breast cancer in his patients. We went on to write the book

“What your doctor may not tell you about breast cancer”.

Over the years I have heard similar stories from many practitioners who prescribe progesterone for their patients: lower incidence of breast cancer for these patients and in those who do get breast cancer, a less aggressive type. The dose being used is usually between 20-40 mg /day of topical progesterone cream.

When a pathologist looks at a breast cancer tissue specimen under the microscope, on a patient who had been taking progesterone, it was almost not a cancer as it was so well differentiated. I had been the person who often worked with these pathologists and developed methods to look at the proliferation index, which is how fast a tumor is dividing(using immunohistochemistry, which looks at the chromosomes and cell division).

Kyle: Amazing: you really are ‘the man behind the curtain’. You have all of this knowledge and experience that most people who use your laboratory don’t know about. I heard that you had some pretty humble beginnings when your first started your lab in California. Can you tell us about how that all started?

DZ: I actually was the lab director at a lab in CA and we didn’t agree on some things so I left and came to OR and started the lab here. I was on what they call the “J curve”: no money so I sold my house, took the money from that and moved up here and used that money to get started. At the same time, I was writing that book with

Dr. John Lee, which came out in 2002.

Kyle: That was at the same time that the WHI(Women’s Health Initiative)study halted their project and published their findings. What incredible timing. That most have blown things up. Were people shocked by what your book said versus what the WHI was saying?

DZ: Correct. WHI was saying ‘get everyone off of hormones, estrogen is bad for you’. That’s what the initial reaction was: taking estrogen(Premarin) caused breast cancer so that everyone thought that estrogen was bad. But it turned out that the women on Premarin alone actually had a lower incidence of breast cancer but those on Premarin plus progestin had a higher incidence. Progestin, NOT progesterone. And it really didn’t matter what kind of synthetic progestin it was.

The companies that make progestins make many different types because they can be patented and that is how they make their money. Progesterone is the same molecule that Mother Nature made a gazillion years ago and it is a substance that is NOT harmful to the human body. Synthetic progestins can be harmful.

Kyle: As a practitioner at that time, I had quite a few patients on HRT and when the WHI findings came out, there was quite a bit of panic in the U.S. and I didn’t quite know what to do. I did end up learning about bio-identical hormones from a special on public television and then sought out guidance from a local compounding pharmacist. But this was a very unsettling time and I had a hard time finding people to mentor me. Through a series of events, I found your lab which was incredibly fortunate for me. Your lab is known not only for the excellent testing that you do but also for the educational support you offer to providers and patients.

DZ: The early times were hard for me financially : I had a wife and 2 children to support but failure wasn’t an option and I was interested in what I was doing. I was also working with Dr. Lee and Sharon McFarland at Transitions for Health( they make Pro-gest, topical progesterone). We were on the lecture circuit together and there was a lot of demand for testing levels of estrogen and progesterone so everything was moving in the right direction. Women wanted to know: what’s my level? Is it too high, is it too low, is it just right?

Kyle: How did you know to use saliva as the appropriate body fluid?

DZ: When I was in Europe, I knew somebody who was actually just beginning to develop a methodology for saliva testing. I thought that was very interesting so I visited him. It is a body fluid that you can collect non-invasively and it had a good reflection of the bioavailable level of hormones. Many hormones, such as estradiol, progesterone and testosterone are bound up by proteins(about 98% of them are bound)so that only 2% are bioavailable. Saliva represents what is actually bioavailable which is the amount that is going to get into the rest of your body, brain, uterus, breast, skin and every other part of your body.

Part of the problem with early saliva testing is that early on, it wasn’t very accurate so I developed a tool to help standardize testing . We actually then started sending out saliva samples with known amounts of hormones, because by this time, I had developed ‘mass spec technology’, which was extremely accurate. We sent these samples out to other labs so that they could measure their results against this known quantity. Some labs participated, others didn’t of course, but we learned which ones did a better job of measuring hormone levels in saliva. There was no oversight except for cortisol levels. This is why many people cannot get this kind of testing paid for by insurance.

It is easier to measure cortisol than other hormones as the levels are so much higher. Measuring estradiol is a lot more challenging but we have mastered that.

Kyle: I know that you have faced many obstacles along the way, between the challenges of developing testing assays and of course the controversial nature of hormones in general. How do you stay the course sometimes?

DZ: If I had been in a commercial business, I would have had a hard time with it but we do a tremendous amount of research. That has been very satisfying. Along with our testing, we collect data from patients in terms of symptoms and we have developed a huge data base over time. Our lab also developed blood spot testing, which is an alternative to saliva testing and serum testing. Particularly during the COVID pandemic, people didn’t want to go in to a lab and have their blood drawn so this kind of testing allowed people to test from home and send their kits in to our lab for evaluation.

Another test we developed was in dried urine looking at metabolites. We can actually see how estradiol is broken down in the body.

Kyle: Can you talk briefly about the estrogen pathway? I know that you have spoken at length about this , how estrogen tends to be broken down along two main pathways. One leads to a higher risk of breast cancer while the other one does not. Can you address this?

DZ: It’s really a story of the “two and the four’ pathways. If your body is exposed to a lot of pollution, the estrogen that you either make or take will then be metabolized to a ‘bad one’, called fork catechol, the 4 hydroxy pathway. This is going to partially oxidize, bind to DNA and cause mutations. Things that can cause this to happen are trans fats, dry cleaning fluids, heavy metals, pollutants, obesity, etc. This is not something that will happen overnight: it can take years. We talked about this in the book on breast cancer that we wrote.

But if instead, you eat soy, green leafy and cruciferous vegetables, the estradiol will go down the 2 hydroxy pathway. This is the desired route and one that can be influenced by lifestyle. DIM is a supplement that can help drive the estradiol down the 2 OH pathway. In addition, getting more sleep, exercise, dietary changes, taking such supplements as B12, folic acid, B vitamins, vitamin C, D, selenium and iodine can all be quite helpful.

Another main impact on hormone metabolism is stress. When I looked at the cortisol profiles of women with breast cancer, they were flat although the night time cortisol is high at night. This happens after they have been elevated for awhile and then come down. This is another area that we can have an impact on with our interventions.

Kyle: I can testify to the value of using ZRT’s testing over the last 22 years. I almost always order the Hormone Profile III, which tests estradiol, progesterone, testosterone , DHEA-S and four cortisol levels. I always love going over these results with my patients and I am able to identify the patterns of stress by looking at their cortisol curves. Patients just love learning why they are feeling the way that are . I can then advise them to take certain supplements as well as hormones that will help make impactful changes in their lives. Thank you for developing these important tests. They have guided so many providers in helping patients leave healthier lives.

DZ: The reports that we generate come from the levels of hormones plus the answers that patients give on the ‘symptom reporting’ section of the questionnaire. This creates augmented intelligence and spits our individualized results.

Kyle: Not only do you give each patient an individualized report but you provide additional resources for them, such as books and references for them to become more educated. People do so appreciate this information.

Kyle: Can you explain why there is still so much controversy about transdermal progesterone? I have often heard that the levels don’t get high enough to protect the endometrial lining.

DZ: The problem is that most providers use serum testing and that doesn’t show accurate levels of transdermal progesterone. They also don’t see it in urine. We see it in saliva and capillary blood, as measured with the blood spot method. And if anyone would bother to read the literature, studies have been done in Taiwan and France that demonstrate that progesterone applied transdermally actually does get into the breast tissue(Inhibiting the growth of mammary epithelial cells) although it doesn’t show up in the serum. The progestereone applied to the skin gets into the lymphatics. This was also seen in the World Anti-Doping Association . They found high levels of testosterone in saliva and in capillary blood but they didn’t find this in serum. In the last five years, they are now using saliva and blood spot to detect doping.

It is hard to shift people’s paradigms but that is a change.

Kyle: What else are you working on?

DZ: Neurotransmitter testing: we have been doing this for years but now we are looking at ADHD. We are working with OHSU medical school looking at kids with ADHD by measuring levels of neurotransmitters. We are also beginning work on premenstrual dysphoric disorder and autism. We test neurotransmitters in dried urine so this can also be done at home.

Kyle: Recently there was a show on Netflix about the blue zones. They talked about why some people in various regions of the world live to be 100. There are quite a few factors but the main ones were eating a Mediterranean style diet, managing stress, regular exercise, finding joy and most importantly, feeling connected with their community. Obviously this all segues with the work you have done and have done for a very long time.

Thank you Dr. Zava for taking the time to talk with me today. Your background is pretty incredible and you have worked tirelessly for decades. Not only have you developed innovative laboratory tests but you have been passionate about educating providers and their patients. I hope this conversation helps the public have a greater appreciation of who you are and the work of your staff at ZRT.

DZ: Thank you Kyle as well for all that you have done for women, who you have helped and treated. And thank you for being a friend.

Fertility Mapping: Navigating Fertility with PCOS and Insulin Resistance Part II

Fri, 05 Jul 2024 16:02:12 -0700

PCOS is a multifactorial condition impacted by alterations in receptors, metabolism and functionality of hormones, neurotransmitters and nutrients. It is a lifelong condition that contributes to infertility, weight gain, cardiometabolic symptoms and diseases. In this blog, we look at laboratory testing and what can and should be tested in all women where you suspect PCOS.

Lab Testing for PCOS

Polycystic ovarian syndrome (PCOS) diagnosed through the Rotterdam criteria, a comprehensive framework that encompasses a variety of indicators, including clinical symptoms, laboratory findings of elevated testosterone levels, ovulatory dysfunction, and ultrasound evidence of ovarian cysts. Women do not have all the criteria to be diagnosed. In general, PCOS is a clinical diagnosis. For further details on the Rotterdam criteria please refer to the following resource: NCBI Article.

Recommended lab testing:

Women with PCOS are recommended to test the following hormones
17 OH Progesterone – rule out congenital adrenal hyperplasia
Cortisol – rule out Cushing's syndrome
DHEAS
Glucose
Hgb A1c
hsCRP
Insulin
LH/FSH on day 3 or 4 of the cycle (during the period) is usually 1:1 but can be 2:1 or higher.
Lipids/Cholesterol
Prolactin – high prolactin can also stimulate irregular periods and polycystic ovaries
SHBG – if doing total hormone levels.
Testosterone
TSH

In both saliva and bloodspot testing, it is common to observe elevated levels of testosterone and DHEAS, alongside reduced progesterone levels. Although women with PCOS may exhibit symptoms of estrogen dominance, estrogen levels are rarely high. Results from salivary laboratory assessments typically look like this although this patients DHEAS is not elevated.

Due to the tight ranges measuring bio-available testosterone and DHEAS utilized in saliva testing, elevated testosterone levels are often more clearly identified in saliva testing as compared to serum testing.

In this individual you can see that the total testosterone in bloodspot is at the top of the normal range, but the insulin is very high in this fasting sample. The optimal fasting insulin should be less than 10. Although not reported, this individual’s hemoglobin A1c was optimal.

Similarly, in urine analysis, indications of PCOS may include heightened levels of testosterone, androstenedione, DHEA, and DHT. A profile suggestive of PCOS is shown below. Notice the very high DHT as well as the other androgens.

Treatment of PCOS

The first goal for PCOS is to lower insulin levels which then decreases androgen levels and increases progesterone levels via ovulation. Ideally women will have 6 months of health optimization before attempting pregnancy and especially if utilizing assisted reproduction therapies. However, if discontinuing oral contraceptives conception should be attempted the first month after stopping contraceptives.

Insulin Reduction

Interventions encouraging lower simple carbohydrates, increasing complex carbohydrates, and increasing dietary fiber should be a basis for all women with PCOS. Medications like metformin and GLP1s, herbs like Berberine, and nutrients like inositol should be considered in women with higher insulin levels even in with normal body weight.

Inositol, otherwise known as vitamin B8, is a sugar that the body uses in receptor functionality. Inositol also acts as a secondary insulin messaging, therefore reducing insulin resistance. Its action on cellular receptors is not limited to insulin but is involved in the neurotransmitters and all hormones. In women with PCOS, inositol fails to be recycled in the cells and is overall deficient (1). Inositol supplementation has been shown to decrease insulin and glucose, improve menstrual cycles and has improved pregnancy rates. Inositol levels are high in ovum follicular fluid and ovum with higher levels of inositol are associated with higher quality.

Other therapies such as melatonin and vitamin D may be appropriate for many patients. Usage of some of these supplements and medications throughout pregnancy for women with PCOS especially metformin and inositol suggest that optimizing insulin may lead to better pregnancy outcomes (2, 3).

Achieving pregnancy with PCOS may require additional effort. Diligently managing insulin levels and optimizing weight and overall health significantly contribute to success of conception, even when assisted reproductive technologies may be necessary. Incorporating lifestyle optimization into treatment plans for preconception, conception, pregnancy, and postpartum care is essential for nurturing the healthiest eggs, embryos, and babies. ZRT extends heartfelt wishes for success to all.

References:

Fertility Mapping: Navigating Fertility with PCOS and Insulin Resistance: Part I

Wed, 26 Jun 2024 12:52:10 -0700

While it sometimes seems that babies are everywhere, for many people the process of becoming a parent can be a long and heart-wrenching journey. Infertility affects 1 out of 6 people with one-third of the cases due to female issues, one-third due to male issues, and one-third due to the couple together (1).

It is estimated that approximately 10% of all women have polycystic ovarian syndrome (PCOS) and that around 80% of them will struggle with infertility (2). While many women with PCOS will achieve pregnancy on their own, others will need medical assistance to become pregnant.

In the last couple of years, the research world has dramatically expanded our comprehension of PCOS. It has long been known that PCOS involves elevated levels of female androgens particularly testosterone and DHEA. Newer research has provided deeper knowledge into the interplay between environmental, immunological, inflammatory, hormonal, and genetic factors. This rise of knowledge underscores the reality that PCOS is a more systemic imbalance far beyond the ovaries and presenting a more comprehensive challenge to those it affects. As we delve into the conversation about PCOS and its impact on fertility, it's essential to highlight several recent key insights that have emerged:

Hormonal Imbalances: Women with PCOS struggle with higher androgens (testosterone and DHEA/S), but research shows variances in hormone receptors may be to blame. This intricate dance of hormones and their movement in and out of cells play a central role in the condition's development and its myriad of symptoms.
Beyond the Ovaries: While PCOS manifests with ovarian symptoms, it is also a lifelong mental health and cardiometabolic condition. This perspective is crucial, as it emphasizes the importance of a holistic approach to management; recognizing that PCOS affects much more than reproductive health.
Genetic Variances: The field of DNA research is revealing significant genetic variants present in women with PCOS. These include alterations in the cellular functions of adipose tissue, insulin, melatonin, adrenal function, and androgens (notably testosterone and DHEAS). This genetic backdrop contributes to the condition's complexity and individual variability in symptoms and responses to treatment.
A Lifelong Journey: It's important to understand that PCOS is a lifelong condition persisting even if the ovaries are removed. This reality highlights the need for ongoing management and support for those affected.
A Family Affair: PCOS runs in families. Many women with PCOS report having family members who also struggle with the condition reflecting how genetic predispositions play a role in its symptom development.

These insights into PCOS illuminate the condition's multifaceted nature, encouraging a compassionate, informed approach to care and support for those navigating its challenges.

Physiology of PCOS is Complex

Before exploring how PCOS affects fertility, it’s helpful to understand that PCOS embodies a complex physiological condition. In PCOS we find genetic variances in hormone levels, neurochemistry, cell receptor numbers, decreased receptor functionality, and altered hormone metabolism within the cells which all contribute to a variety of patient symptoms. Analogous to cell doorways, receptors serve as entry points for hormones, each requiring a specific key. These "doors" and their mechanisms are inherited and may differ in size, efficiency, and quantity among individuals. In PCOS, receptor dysfunction arises when these keys fail to operate correctly, leading to improper use, recycling, and opening of the receptor "doors."

Many receptors are altered in PCOS including those for norepinephrine, estrogen, vitamin D, adiponectin, cortisol, and testosterone; all which underscores the systemic nature of PCOS. Focusing on the role of insulin, identified as a key factor in approximately 70% of women with PCOS, sheds light on how this condition transcends an isolated ovarian disorder to implicate systemic challenges (3). Insulin levels are generally elevated in women with PCOS independent of weight or carbohydrate intake. Newer research is showing that this is due to anormal insulin receptors and likely abnormal insulin metabolism. Higher insulin then sets off a cascade affecting various hormones including LH, DHEAS, DHEA, androstenedione, and testosterone, contributing to weight gain, abdominal obesity, reduced sex hormone-binding globulin (SHBG), and heightened inflammation. These hormonal imbalances manifest as hallmark symptoms of PCOS, such as:

Weight-gain especially in the abdomen
Acne
Excessive hair growth on the face and body
Scalp hair loss
Irregular or absent menstrual cycles

Furthermore, sustained high insulin levels elevate risks for lifelong conditions including:

Fatty liver disease (NASH/NAFLD)
High blood pressure (hypertension)
Insulin resistance
Diabetes Type 2

High Insulin Impacts Fertility

Elevated insulin levels and higher androgens (testosterone and DHEAS) in PCOS are problematic for fertility. This hormonal landscape often results in a proliferation of immature ovarian cysts, impeding the maturation process of ovum (eggs), and decreasing the progression to ovulation. In scenarios where insulin and testosterone levels are significantly elevated, women may experience challenges in achieving routine ovulation, with some women not experiencing menstrual periods without pharmacological support. On occasions where ovulation is successful, the eggs produced by women with PCOS tend to be of lower maturity, which may affect fertilization, embryo quality, and decrease implantation rates. Despite these challenges, many women with PCOS achieve pregnancy on their own. Others find fertility success through ovulation stimulants or in vitro fertilization (IVF). Treatments such as letrozole or clomiphene are known to elevate gonadotrophin hormones (FSH and LH), fostering the development of more mature ovum. Some women may achieve pregnancy swiftly with these treatments, while others might observe significant benefits from a regimen extending over 3-4 months, which promotes a hormonal environment conducive to healthier egg development.

Semaglutide, GLP1 and Fertility with PCOS

The introduction of GLP1 medications has been notable for individuals with type 2 diabetes, but usage in women with PCOS has shown remarkable weight loss in women who have struggled to lose weight with other medications or regimens. Recently, a flood of reports of “Ozempic babies” has been noted as women have gotten spontaneously pregnant after starting a GLP1 for weight loss including among women who have done IVF unsuccessfully in the past. These occurrences underline the strong negative impact of insulin on fertility even in the face of assisted fertility technologies. Questions remain if the main impact of the GLP1s is to lower overall insulin levels thereby improving egg quality and fertilizations or if the GLP1s have separate action on egg maturity, fertilizations or implantations. What is clear however, is that GLP1s should be considered in women with high insulin levels especially if weight is also an issue, before or as part of a plan to do assisted reproduction.

On "The Pill” for PCOS and Want to Get Pregnant

Many people with PCOS turn to oral contraceptives to regulate menstrual cycles and address symptoms associated with elevated testosterone levels. These medications not only facilitate regular uterine bleeding but also play a significant role in reducing ovarian testosterone production, decreasing adrenal androgens, and fostering an environment rich in estrogen. Additionally, oral contraceptives increase the levels of sex hormone-binding globulin (SHBG) and cortico-binding globulin (CBG), additionally lowering androgens. This control of testosterone effectively alleviates acne, excessive facial and body hair, scalp hair loss, and aids in the maintenance of regular menstrual cycles. Furthermore, for numerous women, the use of oral contraceptives contributes positively to weight management. Although a slight increase in insulin resistance may occur, the overall reduction in androgen levels typically leads to decreased insulin and cortisol levels, and subsequently, weight stability.

However, when the pursuit of fertility becomes a priority, discontinuing oral contraceptives becomes necessary, reintroducing previous challenges. Stopping oral contraceptives prompts the ovaries to resume their natural cycle. While many women are under the belief that they should allow their cycle to happen for several months before attempting pregnancy, the initial 1-2 months post-discontinuation of oral contraceptives may present the highest fertility potential for women with PCOS. This phenomenon contradicts common expectations, as the resumption of natural ovulation commonly and quickly leads to increased testosterone levels which may reduce ovulation frequency and, consequently, reduce the chances of conception. Therefore, for women with PCOS wishing to conceive may wish to attempt pregnancy as soon as possible after discontinuing the contraceptives to optimize fertility opportunities.

Pregnancy and Beyond

Upon achieving pregnancy, it is prudent for women with PCOS to be mindful of the high likelihood of developing gestational diabetes. It is advisable to monitor not only blood sugar levels and hemoglobin A1C but also insulin levels; testing both fasting and those following meals or a glucose challenge. Elevated insulin and glucose levels during pregnancy can lead to various complications, including accelerated growth and increased size of the baby, heightened risk of hypertension in the mother, premature deliveries, neonatal blood sugar complications, and possibly an elevated risk of diabetes in the child later in life. Moreover, increased insulin levels have been implicated in reducing development of breast ducts, potentially complicating lactation post-delivery (4). Embracing a diet rich in protein, low in simple carbohydrates, and abundant in fiber can significantly contribute to maintaining optimal blood sugar and insulin levels throughout pregnancy.

While all of these challenges make pregnancy difficult in women with PCOS, it is important to once again stress that most women with PCOS are able to become pregnant. For providers who are caring for women with PCOS, it is the aim to optimize health for the woman before, during and after pregnancy. With our growing knowledge of this condition, we can appreciate that PCOS is a much more systemic condition than ever before. The next blog on PCOS will look at lab testing and some of the treatments that may wish to be considered.

Figure 1. A summary of the most representative impact of IR and HI in women with PCOS. Abbreviations: SHBG: sex hormone-binding globulin; LH: luteinizing hormone; IGF1: insulin growth factor 1; GnRH: gonadotropin-releasing hormone; ACTH: adrenocorticotropic hormone; HPO: Hypothalamus-pituitary-ovary; HPA: Hypothalamus–pituitary–adrenal (5).

Image credit: Zhao, Han, Zhang, Jiaqi, Cheng, Xiangyi, Nie, & He, Bing, "Insulin resistance in polycystic ovary syndrome across various tissues: an updated review of pathogenesis, evaluation, and treatment." Biomed Central. Journal of Ovarian Research, Jan 11, 2023, Insulin resistance in polycystic ovary syndrome across various tissues: an updated review of pathogenesis, evaluation, and treatment | Journal of Ovarian Research | Full Text (biomedcentral.com).

References:

The Science of Stress: The Time-Dependent Multimodal Effects of Stress Hormones on Memory and Learning

Mon, 24 Jun 2024 10:54:07 -0700

According to the American Institute of Stress, 55% of people in the United States experience daily stress. Stress is, technically defined as the body's nonspecific response to any demand – pleasant or unpleasant – but more commonly perceived as a state of physical, mental, or emotional strain or tension. Chronic stress is especially prevalent in the workplace, with 83% of employees reporting daily work-related stress (1). However, statistics show that stress among students is also significant, common, and increases proportionally to a student’s progress through the educational system.

Recent studies on academic pressure found that three-quarters of American high schoolers and half of middle schoolers described themselves as “often or always feeling stressed" by schoolwork (2). Meanwhile, at American colleges, over a third of students say they’ve considered withdrawing from their program for at least one term, and over half of those cite emotional stress as the primary reason (3).

And yet – not all stress is negative. Some stress is not only unavoidable but may actually be necessary to motivate and enable learning, retention and updating of information. Research has found that stress affects our memory through numerous mechanisms, each with different impacts. While the link between chronic excessive stress and cognitive decline in aging brains has been well established, the variable effects of different stress hormones on memory and learning in younger people have received far less attention to date.

This information may be key to helping learners of all ages understand and manage the impact of the type and timing of stress on their ability to be successful in meeting their educational and career goals. Within the medical community, understanding the hormone connections to learning and memory may help providers to better support patients experiencing elevated stress levels.

The Science of Stress

The two major stress systems have both been shown to be critical for the modulation of learning and memory processes. The autonomic nervous system (ANS) response is rapid and involves the release of catecholamines norepinephrine and epinephrine from the adrenal glands and the brainstem in a matter of seconds. This is how the sympathetic nervous system prepares the body and brain for a ‘fight or flight response,’ dilating the pupils and bronchi while constricting blood vessels and accelerating heart rate. The ANS also rapidly affects neural functioning in multiple brain regions including the amygdala, hippocampus, and pre-frontal cortex, with profound effects on attention, working memory and long-term memory.

The second stress response by the hypothalamic-pituitary-adrenal (HPA) axis is slower, effectively operating on a delay. In response to ANS signaling, the hypothalamus releases corticotropin-releasing hormone (CRH) which stimulates the anterior pituitary to secrete adrenocorticotropic hormone (ACTH), triggering the release of glucocorticoids from the cortex of the adrenal gland – primarily cortisol, a steroid hormone. Levels of cortisol peak about 20 to 30 minutes after the onset of the stressor and bind both glucocorticoid and mineralocorticoid receptors (MR) in the body and brain (4).

Glucocorticoid receptors (GR) are widespread throughout the brain, while MR is primarily expressed in regions associated with memory and emotion - specifically the amygdala, hippocampus and pre-frontal cortex. This allows cortisol to have two separate and opposite modes of action within the brain. Cortisol binding to the MR quickly increases neural excitability in the amygdala and hippocampus, while GR binding has a slower effect, developing over 60-90 minutes after the onset of the stressor, and causes changes to DNA translation and transcription to re-establish homeostasis and calm the neural excitability caused by the acute effects of stress.

This complex symphony of hormones explains why stress can have significant effects on memory that vary by timing of stressor, memory and the type of information being learned.

Fig. 1 The Stress Response System

Stress During and Around the Time of Learning Actually Enhances Memory

Moderate stress just before, during or just after encoding and consolidating new information may strengthen human memory formation.
The release of norepinephrine and cortisol activate the amygdala and hippocampus to enhance emotional processing, memory, and learning.
In particular, stress can lead to better memory for emotionally charged events or for information directly related to the stressor, through norepinephrine's activation of a brain network known as the salience network, which includes the amygdala.
This type of memory enhancement is norepinephrine-dependent and can be disrupted by the beta blocker propranolol, which is currently under study for prevention and treatment of Post-Traumatic Stress Disorder (5).
For example, showing an emotionally arousing, contextually related film before a lesson may enhance encoding and consolidation of pertinent information as a memory.

Stress Long Before Learning or in a Different Context Impairs Memory

In studies, encoding of new information was impaired when a stressor occurred more than 30 minutes before learning, or in a distinctly different context (for example, stress occurring at home versus in the classroom).
This may be attributable to the decrease in hippocampal neural excitability as a late effect (>1 hour) of cortisol exposure, which is theorized to protect the consolidation of the information learned during the stressful encounter, versus allowing new memories to form.
Chronic or excessive secretion of stress hormones can negatively impact long-term memory via structural and functional changes to the hippocampus, a brain region crucial for memory consolidation.

Cortisol Impairs Memory Retrieval

During memory retrieval, such as recall of information during an exam, high cortisol levels can hinder performance.
This effect was observed beginning 20 minutes after a stressor, when cortisol is at peak levels, and was even more prominent during the time when cortisol exerted its longer-acting genomic mode of action.
Cortisol-induced retrieval deficits were found to impact both adults and children aged 8-10, with broad significance for educational assessment of information learned.
Interestingly, context modulated this effect, so that recall was not impaired significantly by stress if the test information was relevant to the stressful situation, or if the learning and the test occurred in the same context.

Stress Hormones Impact Knowledge Updating, Cognitive Flexibility, and Goal-Directed Behavior

Reconsolidation theory suggests that consolidated memories return to a malleable state when they are reactivated. During reconsolidation, which takes place in the hippocampus and prefrontal cortex – key targets of stress hormones - memories may be weakened, strengthened, or altered.
While investigations are still underway, animal studies suggest that stress or cortisol exposure after memory reactivation impairs reconsolidation.
Misinformation studies in humans have also found that highly arousing information learned under stress results in more robust memories that are less susceptible to being updated. This may have negative implications for education, professional learning, and life experiences that require frequent updating of knowledge based on new information.
Under stress, cortisol’s action at the MR appears to shift human behavior toward habit, relying on more rigid striatal stimulus-response learning strategies rather than the cognitive hippocampal memory system. This system allows for the formation and recall of flexible memories and underpins goal-directed (action-outcome) behavior.

Balancing Stress Hormones is Essential for Cognitive Health

Optimal memory function requires a balance in stress hormone levels. Normal physiological responses to moderate acute stress can be beneficial for memory, but chronic stress and elevated cortisol levels are harmful.
Strategies like exercise, mindfulness, strong routines, emotional regulation, and adequate sleep can help regulate stress hormones and support memory and learning (4).

In summary, stress hormones can be a double-edged sword when it comes to memory and learning. In addition to the timing of stressors, individual perceptions of and responses to stress vary, and some people may be more resilient than others.

Fortunately, for anyone concerned about how stress may be impacting memory, attention or learning, saliva cortisol testing - considered the gold standard in cortisol assessment - is readily available from ZRT Laboratory. Alternatively, dried urine diurnal hormone testing may be used to assess cortisol and cortisone, as well as the catecholamines norepinephrine and epinephrine, which are needed in the right amounts at the right time of day to facilitate learning and memory formation. Either test involves collecting four non-invasive samples over the course of a single day to generate a four-point diurnal curve. This information allows health care providers to pinpoint any issues within the sympathetic nervous system and HPA axis that may be contributing to difficulties with attention, focus, memory, learning, and more. Utilizing convenient at-home stress hormone testing can help provide meaningful insights into a patient's health to support a path towards optimal memory, learning, and achievement of goals.

Figure 2. The effects of stress on memory depend on the specific memory process investigated and the temporal proximity between the stressful event and this memory process. While stress (indicated as red flash) long before encoding impairs memory formation, stress shortly before or after the presentation of new information generally enhances subsequent memory performance. In sharp contrast, stress before memory retrieval impairs the recall of information learned previously which may directly affect performance at exams. In education, knowledge needs to be frequently updated by new facts or concepts relating to prior knowledge. In addition to its effects on memory encoding and retrieval, stress appears to impair this integration of new information into existing knowledge structures (6).

Image credit: Vogel, Susan & Schwabe, Lars. "Learning and memory under stress: implications for the classroom." npj Science of Learning, Jun 29, 2016. npj Science of Learning.

References

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

Women's Health Initiative Revisited

Mon, 19 Jun 2023 09:59:13 -0700

Almost certainly, women between the ages of 60 and 90 remember the shocking healthcare news in 2002 with the unexpected, early termination of the Women’s Health Initiative (WHI), a long-term national health study. The release of the initial results of the trials rocked the medical establishment and profoundly changed the lives of many women. Additionally, the news altered the perception of the routine, menopausal hormone replacement prescription for years to come.

The WHI was launched in 1991 as a 15-year trial, one of the largest women’s health studies in the United States, enrolling more than 161,000 women at 40 clinical centers. The WHI included trials designed to examine the effects of the current postmenopausal hormone replacement therapy (HRT), physical activity, diet modification, and calcium with vitamin D supplements on heart disease, bone fractures, breast, and colorectal cancer. These were all major causes of disability, frailty and in some cases death, for women of all races and socioeconomic backgrounds. The WHI hormone clinical trial consisted of two studies, one which looked at the effect of hormone therapy (HT) on the prevention of heart disease and osteoporosis and a separate study that looked at HT and its associated risk of breast cancer. The HT used in the two studies are described below (1):

Estrogen-plus-progestin study of women with a uterus – Premarin® (oral 0.625 mg) plus Provera® (oral 2.5 mg) or placebo (inactive pill)
Estrogen-alone study of women without a uterus - (Premarin (oral 0.625 mg) or placebo (inactive pill)

However, the estrogen plus progestin study was abruptly halted in July 2002 due to perceived evidence of an increased risk of breast cancer, coronary heart disease, stroke and pulmonary embolism. The unopposed estrogen-only trial was halted in February 2004 on the basis that unopposed estrogen did not appear to affect the risk of heart disease, the primary outcome. However, the estrogen-only trial did show a decrease in breast cancer risk (2).

The difference between the two studies is interesting in that the estrogen-plus-progestin study used Provera, (medroxyprogesterone acetate or MPA), a synthetic progestin, instead of bioidentical progesterone. While Provera has an antiproliferative effect on the endometrium as does progesterone, a 2008 review article reported MPA is different from progesterone in its effects on the cardiovascular system. MPA increases vasoconstriction of arteries and results in impaired endothelial function, both of which contribute to cardiovascular disease (3). Progesterone, meanwhile, has been found to have vasodilating effects and has been used for myocardial infarction and post-stroke care (4, 5).

The average age of menopause usually begins around age 51 but may occur earlier or later. Each year thousands of women enter the phase of aging called menopause, including surgical menopause, resulting in the natural decline or abrupt interruption of estrogen being produced by the ovaries. With the subsequent lack of estrogen women commonly experience a myriad of symptoms including hot flashes, night sweats, brain fog, mood swings, sleep disruption, vaginal dryness, and low libido. These symptoms often profoundly alter the quality of a woman’s life, disrupting a previously normal existence and/or work routine. The menopausal transition can last for months to several years. However, hope for relief from women’s symptoms was in sight with the FDA patent approval in 1943 of a Wyeth-Ayerst pharmaceutical product, Premarin.

Premarin was the first conjugated estrogen, formulated from pregnant mares’ urine as a menopausal “estrogen replacement therapy (ERT)” (6). Although a couple of early articles published indicated an increased risk of endometrial cancer with prolonged use of ERT, in 1986 the FDA announced that Premarin was effective for preventing bone loss and granted an osteoporosis indication. Suddenly, the view of estrogen as a “short-term treatment for menopause, was the treatment of choice for bone loss, a long-term, chronic problem” (7). In the 1990s Premarin became the most frequently prescribed drug in the US with more than 30 million prescriptions written (8).

However, due to the conclusions drawn from the WHI study, women, as well as medical professionals, became fearful of using and prescribing estrogen. As a result, Premarin prescriptions dropped dramatically as medical professional declined to refill prescriptions for Premarin or estrogen in general. Many women just ceased taking their Premarin, for fear of breast cancer, with the subsequent return of menopausal symptoms disrupting their lives. Hormone prescriptions for women approaching menopause were also questioned.

With the ensuing reviews of the WHI data, researchers found there were some misleading claims. The age of a woman when starting hormone replacement was found to be more significant than use of the hormone themselves. “A Bayesian meta-analysis of women receiving HT who were under 60 years old, showed a statistically significant reduction in coronary disease” (9). There was also a statistical decrease in mortality, of all causes, in women beginning hormones 10 years or less before menopause. More recent analyses of WHI data regarding HT and breast cancer risk “…is greater in older rather than younger women…” The timing hypothesis that was constructed from the WHI HT trial and other data “suggested that the younger the women were in the trial, the more they showed benefit” (9). Read more information about the timing hypothesis on the ZRT Laboratory website here: Getting to the Heart of Estrogen | ZRT Laboratory.

In the years following the WHI report, medical professionals and women began reconsidering hormone replacement, but with a difference. More attention has been given as to the timing hormones are initiated, the length of time HT is used, as well as the type of hormone delivery, oral or transdermal, delivered in a patch or topical cream. Most of the estrogen now on the manufactured, pharmaceutical market are all bioidentical. Bioidentical progesterone manufactured product Prometrium® also became available as a generic and compounding pharmacies flourished as doctors and pharmacists sought to individualize treatments for women’s menopausal symptoms.

The previously prescribed, pharmaceutically derived Premarin and Provera used in the WHI study have largely been replaced with bioidentical hormones, both in pharmaceutical estrogen preparations and those made up specifically for an individual by a specialized, compounding pharmacy. Bioidentical hormones are defined as hormones with the same molecular structure as the body’s own biologic hormones. Many medical professionals view compounded bioidentical hormones as a safer option for their patients, compared to the pharmaceutical counterparts. While there needs to be more research for the safety of bioidentical hormone use, they continue to be prescribed for menopausal symptom relief with good results.

References

Summary: 10 Key Takeaways for Hormone Replacement Therapy Webinar

Wed, 10 May 2023 16:09:31 -0700

When women enter menopause about 45-50 years of age, their estrogen and progesterone drop precipitously, causing a long list of unpleasant symptoms such as hot flashes, mood swings, and sleep disturbances. The drop in estrogen also leads to greater risk for cardiovascular disease and accelerated bone loss that may lead to osteoporosis and increased fracture risk. Women are faced with making a decision to start taking hormone replacement therapy (HRT) to hopefully alleviate most of the symptoms and risks associated with menopause. First and foremost, the patient must find a healthcare practitioner who is qualified to administer appropriate HRT. For healthcare practitioners, first identifying the hormone problem (usually low estrogen) can be done through observation of symptoms and lab testing. Physicians rely on pharmacists well trained in hormone therapy to help them determine the optimal hormone formula and type, and what method of delivery and dosage to use.

Peter Koshland, PharmD, presented a webinar for ZRT Laboratory on the 10 key takeaways for HRT for women. Dr Koshland is President/CEO of Koshland Pharm, a compounding pharmacy in San Francisco that works closely with patients and their doctors to prescribe medications tailored to individual needs. He is also an Assistant Clinical Professor of Pharmacy at the University of California at San Francisco (UCSF), and a graduate of Georgetown University and the UCSF School of Pharmacy.

Pharmacists see a lot of patients - especially in terms of HRT - so it makes sense to utilize their expertise because of the knowledge they have in this area. They can play a large part in helping patients and their healthcare providers with product selection and symptom management.

Hormone deficiency:

There’s an odd misconception around the idea that it’s natural for women who are going through menopause to live in a hormone-deprived way for about a third of their life (menopause).
It’s an unnatural state and it’s not good physiologically as the abrupt loss of hormones at menopause can accelerate the aging process and lead to disease that otherwise could have been prevented with appropriate hormone therapy.
When hormones are not present or balanced, there are fundamental changes in the way the body works.

The key takeaway: There are great tools that can help reestablish reasonable hormone function in women safely and effectively. We want to protect our patients’ bones, their brains, and muscles. Without estrogen, these protective effects go away.

Hormones are safe:

The key takeaway: At the core of the decision, hormones are safe. Of course, there are exceptions and side effects but there has been such an overfocus on the exceptions, side effects, and perceived risks, some of which haven’t been validated in the literature. The research we have should give healthcare practitioners more confidence in prescribing HRT.

A person’s overall health impacts hormone therapy success:

If we give hormone replacement to an unhealthy person, we may not get the desired outcomes.

The key takeaway: We should encourage our patients to look deeper into their overall health status and address any underlying health issues.

Different routes of administration behave differently. There are lots of options for delivering hormones into the body including:

Transdermal patches
Topical gels and creams
Vaginal
Oral
Sublingual
Troches
Subdermal pellets
Subcutaneous injection

The key takeaway: There are ways to safely switch or move patients from one delivery and dosage form to another. Different patients need different therapeutic deliveries.

Each hormone test type has limitations and advantages:

Serum testing
Saliva testing
Cycle mapping
Blood spot testing
Urine testing

The key takeaway: Match the type of testing with the type of supplementation. It has a great impact on the clinical usefulness of hormone assessments.

General testing considerations:

Does the lab have clinical support to help interpret labs?
What is the most patient-friendly, economical, and clinically relevant test to evaluate hormonal imbalance?

The key takeaway: It’s a good idea to become familiar with the testing labs that have a proven reputation for excellence and provide the best product and service. Be sure to vet the lab.

Develop a relationship with a good compounding pharmacy committed to quality:

Where does the pharmacy source its active pharmaceutical ingredients?
What specific procedures does the pharmacy follow to ensure quality?
How is the pharmacy accountable to the prescriber and to the patient?

The key takeaway: Talk to the pharmacy and ask key questions about their service.

Everyone has their own protocol – find yours

It’s important for practitioners to find their own protocol. You don’t want to reinvent the wheel with every patient. You want to have:

An effective way to evaluate your patients
A good starting regimen
Know there are ways to change the delivery and dosage of hormone to optimize the benefits
Have a good solid foundation to your approach to treating patients with hormones

We hope you’ll tune into Dr. Koshland’s webinar on HRT. He covers so much more including a discussion on baseline testing, key hormones in a comprehensive hormone replacement plan, optimal dosing, and compounded options. If you’re interested in finding a compounding pharmacist in your area, please refer to ZRT’s Find a Provider locator.

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

Q&A with Dr. Jade Teta: Women, Hormones and Weight Loss

Mon, 13 Mar 2023 17:21:07 -0700

Women who are in perimenopause, menopause or post menopause sometimes feel like they’re living in a different body. Many have a hard time losing or controlling their weight—whether it’s due to shifting and declining hormones, and a slowing down of metabolism combined with stress.

We sat down with integrative physician, Jade Teta, to talk about the role of hormones and weight, why he thinks some women are having difficulty losing or controlling their weight, and what they can do about it. As a practitioner of naturopathic medicine, Dr. Teta is an expert in nutrition, exercise, and supplements, with a specialty in integrative endocrinology.

Q: Dr. Teta, can you tell us about hormones and their role in weight loss?
A: There’s no doubt in my mind that hormones dramatically impact weight loss because they either directly or indirectly influence what we eat, what we crave to eat, and how much we eat. They influence appetite, sleep, and have everything to do with stress management, so they play a profound role in all of this.

Q: Which hormones are we talking about?
A: When most people think of hormones that pertain to weight, they’re thinking of estrogen, progesterone, and testosterone. But I would say the most important hormones are thyroid and adrenal, and more importantly, the appetite hormones (for example, leptin, ghrehlin, cholecystokinin, glucagon-like peptide-1, gastric inhibitory polypeptide). Estrogen and progesterone do play a pretty pronounced role—that’s for sure.

Q: How does estrogen influence a woman’s weight?
A: When estrogen is higher than progesterone during the menstrual cycle (a different metabolic reality compared to clinical estrogen dominance), a woman can eat more without storing as much fat. She’s more likely to build muscle. She can eat less and is less likely to have hunger and craving issues and is more likely to burn fat versus muscle. Estrogen makes a woman’s metabolism more flexible, and she will respond better to diet and exercise. She’s more insulin-sensitive and less cortisol reactive. Metabolism usually works in a “Goldilocks” zone—not too much, not too little, but just right. Estrogen helps find that zone.

Q: What about progesterone?
A: Progesterone has some opposite effects. While estrogen makes the body more insulin sensitive, progesterone makes the body more insulin resistant. When estrogen is dominant or higher in the first three weeks of the menstrual cycle, during the follicular or early luteal phase, the female metabolism is more responsive, flexible, able to handle more stress and, more or less, calories.

Q: When do the weight issues for women begin?
A: Once progesterone falls at perimenopause and women stop ovulating as much, stress becomes a bigger issue for a woman. One of the first major changes in perimenopause is that a woman is going to be more stress reactive. What ends up happening in perimenopause is that a woman will say, “My body is shifting. I feel like the same diet and exercise program are not as effective,” and she makes one key mistake here. She is dieting harder and exercising more. At this point in time, the dieting and exercising she was doing when estrogen and progesterone were at sufficient levels was probably not an issue. The body was handling it fine. But once she loses the influence of progesterone, that is more stress on the body.

Q: What can women in perimenopause do about this?
A: When first moving into perimenopause, I recommend that women move away from more exercise and harder dieting to more rest and recovery, easier workouts, more massage time, slow walking, time in nature and with pets, “woosah” activities, sauna therapies, and a more moderated diet—not going to extreme in calorie reduction or exercise. The Goldilocks zone we talked about earlier becomes far more important when progesterone starts to drop. A lot of women have the exact opposite intuition at this time.

Q: How does stress fit into the weight loss/control picture then?
A: Let’s think about when women go on vacation, and they stop dieting and exercising. They lie out in the sun, sleep in, and generally just want to have a great time. When they return, they say, “How could this be possible? I lost weight.” What you’re seeing are the stress-reducing effects showing up. The metabolism is really a stress management system, not a calorie management system. Ultimately, at perimenopause, you want to give your metabolism a vacation and not make it work harder. When progesterone falls at perimenopause, it’s about stress reduction.

Q: What about when women enter menopause and post menopause?
A: Moving into menopause, estrogen falls off, and not only do women need to manage stress even more, but they have to take the rest and relaxation to the extreme. Start resting more and taking it easy. But now women are more insulin resistant, which means in mature women the percentage of calorie reduction coming from carbohydrates may make more sense because carbs are more of an insulin-producing macronutrient. When estrogen falls at menopause, it’s about carb reduction. It’s the time to start moderating sugar and starch intake and begin to elevate vegetable, fiber-based foods, protein-based foods, and maybe even more fat in lieu of carbs to deal with the insulin resistance. Testosterone also becomes a little more dominant during post menopause, so women should do more resistance training versus cardio.

Q: Can a hormone imbalance trigger women to put on weight?
A: When someone uses the term “hormone imbalance,” I say that it’s a stress management issue and stress management issues create hormone imbalances, primarily. By stress, I mean nutrient depletion, too many or too few calories, too much or too little exercise, and inflammatory mechanisms. All of these are stress. Normally when there’s a hormonal imbalance as a result of any stress mechanism, the first thing we’re going to see is a discrepancy between estrogen and progesterone. Progesterone is going to fall and/or estrogen is going to rise. Either way, whether it’s progesterone deficiency or estrogen excess (here I am referring to clinical estrogen dominance) this happens for many reasons. It happens in perimenopause naturally and whenever there’s prolonged or unremitting stress.

Q: What’s the solution?
A: When we think of hormone imbalance, it normally means that estrogen is going to be high, and progesterone is going to be lower. The way to deal with that is by using adaptogens. If a woman is tired but wired, one of the ones I love that’s over the counter and women-specific to combat this would be something like vitex. It tends to help the hypothalamus function a bit better, deal with some of the stress it’s under, help ovulation occur, and help the luteal phase not be defective in any way, meaning you get estrogen and progesterone to kick back up. Certainly, things like ashwagandha and rhodiola would work well too, although I see that more for women who are just tired.

Q: What are other options for women besides the adaptogens?
A: Let’s get the micronutrients on board that have been depleted with stress. That really can make a big difference in the number one place where women get hit—thyroid function. Women have far more thyroid disorders compared to men, and we know that zinc, selenium, and magnesium are helpful for thyroid and adrenal function. The other micronutrient I would add is vitamin D.

Q: If all else fails, what’s next?
A: I recommend then moving to hormone replacement therapy. The best one during perimenopause is oral progesterone therapy if what mentioned above doesn’t work. It can be a godsend for women under stress and is typically for women who are leaner and healthier who don’t have lot of body fat as they start going from perimenopause into post menopause. Slightly overweight women tend to fare better in terms of symptoms. Oral progesterone therapy would come before moving on to using topical estrogens and oral progesterone.

From ZRT: Each woman has a unique body chemistry, so what works for one woman does not necessarily apply to her friend, sister, or next-door neighbor. An effective approach to a woman’s weight gain certainly includes lifestyle and dietary improvements, stress-lowering techniques, key vitamins, minerals, herbs and/or bioidentical hormones as needed, to replenish and restore balance.

If women want to test active bioavailable hormone levels that correlate more closely to any symptoms they may be experiencing during perimenopause, menopause or post menopause, saliva testing is one of the best options because it captures the “free” fraction of hormone that has left the blood stream to become active in the target tissues of the body.

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

What's Getting in Your Way of Saving Your Life?

Mon, 30 Jan 2023 11:12:02 -0800

I was 19 years old when my mom died of metastatic breast cancer. From that point forward, I identified as a “patient-in-waiting.” In my narrative I, of course, would eventually be diagnosed with breast cancer, it was only a matter of when. Each time I went for a screening, I thought, “Is this the time? Will I finally move from patient-in-waiting to just patient?” Every time I felt a change in my body I thought, “Oh this must be cancer.” (Except for the time I had pain in my back and tried to convince my husband I had spinal meningitis.)

Genetic testing was available. I could have had answers, but I put it off for years. I wasn’t feeling symptomatic even though I was psychosomatic. I feared the results, even though I convinced myself that obviously I would test BRCA+. I lived with the fear of cancer as background noise for so long, my narratives became creative writing where I believed I would have a cancer diagnosis and it would destroy me.

Fear is a liar and a bully

We are all overachievers when it comes to imagining worst-case scenarios. Wes Craven couldn’t even come up with some of the scary narratives that most people create around clinical lab testing and their health. The problem is we treat these narratives as truth. In many instances, fear is a liar and a bully.

And even if our worst fears come true, we will manage them, we will navigate the situation, and we will figure things out. I know this because I worked for Sharsheret, a national not-for-profit organization supporting young women diagnosed with breast cancer.

I found out that my narrative wasn’t original. Thousands of women calling into Sharsheret engaged in the same creative writing. The story was mostly the same. “I don’t want to undergo genetic testing.” “I’m not ready to know the truth.” “This isn’t a good time.”

Is there ever a good time to find out you have cancer? Has it ever happened that someone checked their calendar and said to themselves, “Great. I think I have a block of free time in November to receive a cancer diagnosis.”

What didn’t occur to me or to any of these women was maybe health screening tests could be a relief from fears that have been bullying us for years. What if my fears were lying to me? What if I tested BRCA-? What if I tested BRCA+?

Change your narrative and create more choices

Before even one drop of blood was taken from my body, I met with a genetic counselor. She patiently answered all my questions, and for the first time, I understood that genetic testing would save my life, psychologically, emotionally, and/or medically.

If I tested negative, I would change my narrative and realize that I wasn’t necessarily destined to live my mother’s fate. I can put my fears to rest and just continue to be vigilant about my screenings and breast exams.

If I tested positive, I would have choices. Choices that would empower me. Being bullied by fear, I disabled any choices I had available to me. Choosing to look fear in the eye, I now opened my world to choices that would save my life.

In the end, I tested BRCA-. Although I felt relief, I remain vigilant with mammograms and MRIs, because that is the responsible thing to do.

I’ve spoken with thousands of women who ultimately chose to undergo genetic testing. For those who tested BRCA+, it feels like being hit across the head by a 2 x 4 piece of wood. But in almost every instance, the women stood up, found their footing, put together a medical team and support team, and made choices that were right for them.

In reality, thoughts that bully us only have the power we allow them to have. My current narrative is that knowledge can beat fear of the unknown on any playground in the world. Genetic testing and clinical lab testing empower us with choices that can save our lives. I'm a strong advocate of speaking with primary care physicians and genetic counselors to determine if testing is right for each individual. Gather information. Change your narrative.

Resources
https://sharsheret.org
https://www.sheradubitsky.com

Shera Dubitsky is a Therapeutic Coach who has earned three master’s degrees in Clinical, Counseling and Educational Psychology, and completed the course work and clinical training toward a doctoral degree in Clinical Psychology. She is the Senior Advisor on the Medical Advisory Board of Sharsheret, where she previously served as Director of Support Services for 13 years before opening her own practice. Shera has over 30 years’ experience working with children and families living with trauma.

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

Your Guide to Staying Hydrated

Mon, 21 Nov 2022 22:30:24 -0800

Your body is made up of 60% water [1] and drinking enough of it is essential to good health. There are numerous benefits of drinking water: improvements in your skin, organ and brain function; flushing out toxins; aiding in digestion and the gastrointestinal (GI) tract; ability to exercise at your best, and overall feeling more energetic and less sluggish.

Most people do not drink enough water. It’s usually a combination of not feeling thirsty until you are slightly dehydrated, not liking the taste of water or forgetting to drink during the day because you’re too busy.

Signs of dehydration

How fluid is controlled in the body is influenced by the brain, and receptors in the blood vessels including those in the heart, neck, and the kidneys.

One way to see if you’re not getting enough water is to pinch the skin on the back of your hand; if it doesn’t go right back down, you’re dehydrated. Known as the skin pinch dehydration test, it’s used to see if your skin’s elasticity has been reduced due to a loss of fluid. Other signs of dehydration include:

Feeling lightheaded or dizzy
Not urinating enough
Constipation
Dry mouth
Not sweating normally

“Severe dehydration can lead to organ shutdown and death, but fortunately this is rare. Most people are only mildly to moderately dehydrated,” says Lori Vance of Body Fitness Image in Portland, Oregon. Lori is a personal trainer who teaches functional strength and fitness to all age groups.

Causes of dehydration

Hot and humid weather, prolonged exercise, and particularly the two together will require more water intake to allow your body to cool itself through sweating. “Seniors often have a decreased sense of thirst and are at higher risk for dehydration and should be especially careful to drink enough,” Lori notes.

Severe diarrhea and vomiting, diuretics, excessive sweating, and of course not drinking enough water can cause dehydration.

In addition, if you have a headache or feel sluggish, try drinking a big glass of water.

Hydration and hormones

How fluid is controlled in the body is influenced by the brain, and receptors in the blood vessels including those in the heart, neck, and the kidneys. When there is decreased blood flow, the kidneys produce the hormone, renin, which triggers the release of angiotensin constricting blood vessels and triggers the adrenal glands to produce the hormone, aldosterone, and antidiuretic hormone, vasopressin. Aldosterone activates the mineral-corticoid receptors, leading to sodium retention in the kidneys thereby increasing water retention and increasing blood volume. Antidiuretic hormone is produced by the pituitary and causes restriction of blood vessels and causes the kidneys to increase reabsorption of water. As salt levels rise in the blood, the brain is triggered to increase the sense of thirst. Thirst is also triggered by dopamine, habits, taste, and psycho-emotional reasons. [2]

When hormones are well balanced, there is an improvement in water management with improved thirst signaling and water retention.

Estrogen and progesterone both influence the hydration status of the body. During the reproductive years for women, the fluctuations of estrogen and progesterone change water management throughout the month. Higher estrogen states as seen prior to ovulation increase water retention. Higher estrogen lowers the thirst triggers in the brain, requiring a lower amount of sodium in the blood to trigger thirst. Estrogen also increases antidiuretic hormone, which increases retention of fluid. Progesterone on the other hand, competes with the hormone, aldosterone, for mineral-corticoid receptors. This has the mitigating effect of decreasing the sodium retention and decreasing water retention.

Premenstrual syndrome - Many women notice significant water weight gain in the five days prior to their period that is relieved with the onset of the period. This is likely due to fluctuations of estrogens and drop in progesterone as well as other hormonal and chemical balances. Supporting progesterone, limiting salt intake, improving liver detoxification of estrogens, and focusing on proper hydration may all help. [3] Interestingly, a year-long study failed to correlate fluid retention to estrogen and progesterone, suggesting that cytokines and prostaglandins may also play a significant role .

Oral contraceptive pills - High levels of ethinyl estradiol and progestins commonly lead to water retention. If this is an issue for you, the progestin, drosperinone, is related to the medication spironolactone, which opposes aldosterone and leads to increased water excretion.

Menopause - The drop of both estrogen and progesterone leads to changes in water management.

Perimenopause - The drop of progesterone leads women to be relatively estrogen dominant and retain more fluid.

Menopause - The drop in estrogen increases water loss and also decreases the sensitivity of the brain to fluid changes. Essentially, this means that thirst is blunted as women age. All of this combines to have dehydration more common in menopausal women. [4]

Hormone replacement - Imbalances in estrogen and progesterone replacement may cause water retention, which can be seen as weight gain and breast enlargement. But, when hormones are well balanced, there is an improvement in water management with improved thirst signaling and water retention. [4]

How much water should you drink?

Lori recommends a starting point of half your body weight (pounds) in ounces of water daily. “A great idea is to always have a water bottle with you so that you can drink all throughout the day,” she advises, “with more emphasis earlier in the day.” Interestingly, minimal research has been done in how much water is necessary to intake for optimal health, but the Dutch scientists found that 2000-3000 mL (8-10 cups) per day does appear to be adequate (Meinders, 2010). This amount compensates for the amount of water lost through sweat, evaporation, urination, and defecation. This amount is also adequate to decrease aldosterone and increase the circulatory volume signaling adequate intake.

Tips for drinking more water

Experiment to find what you like. Chilled water, sparkling water, and water with fruit or berries are great options. Water-rich fruits such as watermelon, grapes, cherries, and berries are also good choices. “Tea without caffeine and with minimal sweetener is also good,” Lori says. Fruit juices can be used if diluted.

Lori recommends drinking from a metal water bottle, which may give a better taste to the water, and therefore, make water more appealing. Here are a few more suggestions:

Drink a big glass of water when you get up to get your day started on the right track.
Drink room temperature water versus very cold so that you don’t decrease thirst signals before you're hydrated.
Limit caffeine and alcoholic drinks unless you are drinking additional water to offset them.
Sip water throughout the day including during your workout.
Replace juices and sodas with water. Sugar-sweetened beverages are not good as the health effects and calories counterbalance any benefits.
Always have a full water bottle with you.
Avoid drinking large amounts of water close to bedtime as that might disturb your sleep.

Glowing skin is a sign of good health, good nutrition, and good hydration—so, drink up!

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

Not Getting a Good Night’s Sleep? Here are the Best Tips!

Wed, 05 Oct 2022 19:33:07 -0700

Adequate sleep has long been known to be vital to good health but not getting enough sleep can be detrimental on many levels. Sleeplessness at night results in lack of alertness during the day, impairing your judgment and increasing the risk for accidents. Chronic sleeplessness can affect the appearance of your skin, reduce libido and overall vitality, decrease cognitive function, contribute to weight gain, and increase the risk of diabetes and cardiovascular diseases.

Your quality of sleep can be affected by many things including perimenopause (hot flashes, night sweats, sharp drop in melatonin over age 40); obesity (over half of obese people also have sleep apnea); shift work (interrupts sleep/wake cycle) and the use of tablets and phones at bedtime (blue light keeps us awake).

Ideally, the sleep hormone melatonin (produced by the pineal gland) should be in balance with the stress hormone cortisol (produced by the adrenal glands in response to stress), creating a healthy sleep/wake cycle. Disturbances in this balance can affect the quality of your sleep too.

There are some common hormone-related causes of sleep loss that often involve:

High Cortisol

Results in insomnia, anxiety, sugar cravings, feeling tired but wired and increased belly fat.

Low Melatonin

Low melatonin contributes to poor sleep onset or prolonged sleep onset. Poor sleep causes fatigue and depression.

Neurotransmitter Imbalance

Changes in sex steroid hormone levels during menopause can impact neurotransmitter levels, leading to recurring sleep issues.

Healthy solutions to end sleepless nights

The American Academy of Sleep Medicine recommends that adults get at least seven hours of sleep every night. It’s also important to stick to a sleep schedule. “We all have a built-in biological clock called our circadian rhythm and tend to function best if we are ‘in sync’ with our rhythm,” says Fariha Abbasi-Feinberg, MD, FAASM, Medical Director of Sleep Medicine at Millennium Physician Group in Fort Myers, Florida.

“Keeping a regular sleep/wake schedule helps to entrain our circadian rhythm and keeps our bodies healthy and functioning well,” Dr. Abbasi-Feinberg adds. She usually recommends keeping wake-up times within one hour of your normal wake-up time. “If you vary it too much on the weekends, for instance, you can have trouble falling asleep on Sunday night and start the week with sleep deprivation. It can take a few days to retrain your rhythm, so it is healthiest to stick to a schedule.” Dr. Abbasi-Feinberg is board certified in sleep medicine and has been practicing for over 20 years.

Trouble falling asleep quickly and/or lying awake for hours?

Do you ever notice that the harder you try to fall asleep, the more difficult it becomes? If you are struggling to fall asleep, here are a few solutions:

Get out of bed and do something else for a while.
Read or listen to a relaxing podcast.
Consider listening to a favorite show or audiobook over and over each night.
- Choose one that preferably has words and dialogue. This can help you pay attention to the external dialogue versus your own internal dialogue.
- When you listen to a show multiple times, your brain knows what is coming next. This allows the brain to relax, and it becomes easier to fall asleep faster.
- It might sound crazy but sometimes a movie like, “Star Wars,” might be easier to focus on and tune out rather than a meditative show.
Write down your thoughts in a journal, which can often help you work out troubling issues.
Remember to stay away from electronic devices near bedtime as that may delay sleep onset even more.
Skip the nighttime news.

Eating and drinking before bedtime

“It’s always surprising to me, how many people are not aware of the effects of caffeine on sleep,” Dr. Abbasi-Feinberg says. “It can stay in your system for many hours and can interfere with sleep onset and sleep quality.” If you’re having trouble with sleep, she says to stay away from caffeine after 1 - 2 pm, which includes coffee, tea, sodas, energy drinks, chocolate, and some ice creams. Having a very heavy meal and too much sugar can also disrupt sleep, and no alcohol one to two hours before bed.

Studies have shown that the ideal eating time for the best sleep is a few hours before bedtime. There are people who feel very hungry right at bedtime and can’t sleep but do okay with a small light snack. Keep in mind, however, that the human body is designed to have a digestive rest at night so you will probably sleep better if you don’t eat after dinner.

Worry, stress, and naps

Without a doubt, worrying and stress can interfere with sleep. Dr. Abbasi-Feinberg recommends setting up a “worry time” a few hours before bed to write down all your thoughts with possible solutions. She’s also a huge fan of making lists before bed. “So often you are thinking about everything you need to do tomorrow, and you don’t want to forget,” she says. “If you write it down, you know you will not forget, and it relaxes the mind.”

In addition, if you have a ritualistic evening routine, it can slow you down at bedtime and allow sleep to occur. Some people also find meditation and prayer very helpful and there are certain apps and podcasts that can help with relaxation as well.

In terms of napping, there is much individual variability. “For some people, short naps earlier in the day, give them more energy and the ability to enjoy life in the evening hours,” Dr. Abbasi-Feinberg says. But if you have trouble sleeping at night, she usually recommends you avoid naps. “You need to allow the natural drive for sleep to build up during the day and a nap can delay nighttime sleep. If you absolutely have to nap, keep it short (20 to 30 minutes).”

Other tips

What else can be done to set the stage for a good night’s sleep?

Keep your bedroom cool, dark, and quiet (kind of like a cave).
No laptops or TV; white noise or earplugs can help.
Have a comfy bed and the nicest coverings (make it a delight to get into bed).
Participate in regular physical activity and/or exercise early in the day (about four to six hours before bed; too close to bedtime can interfere with sleep). Match your exercise activity to your stress levels.
An evening walk can be beneficial for sleep too.

If you have tried these ideas and are not getting answers, consider testing your neurotransmitter and hormone levels.

Additional Resources