The ZRT Laboratory Blog

Melatonin – An Important Piece of the COVID-19 Puzzle?

Fri, 24 Apr 2020 18:48:15 -0700

The Italian magazine Evolutamente recently published a well-researched article exploring the link between melatonin and COVID-19, pneumonia and inflammation. It’s a compelling article so let’s take a look at the key argument and see why melatonin could be so important.

Melatonin and Health

Melatonin is a hormone produced by the pineal gland during the hours of darkness to usher the initiation of sleep, and peaks at around 2 a.m. Its production is reduced when we are exposed to light during the night, such as when watching TV or looking at other electronic screens late at night. Melatonin production is also compromised in jet lag, shift workers, and non-24 sleep-wake disorder.

The role of melatonin in our health is extensive. It is a potent free radical scavenger and antioxidant, protecting DNA and other molecules from injury. It therefore has a significant anti-cancer effect [1,2] and the ability to protect against premature aging and other diseases related to oxidative stress, such as cardiovascular disease and type 2 diabetes [3].

Not only is melatonin a powerful antioxidant, it is also anti-inflammatory through modulation of cytokines. In particular, it has been found to be protective against activation of inflammasomes – specifically, the NLRP3 inflammasome [4]. Inflammasomes are intracellular components that are responsible for inducing the secretion of proinflammatory cytokines, which are part of the body’s inflammatory response against infection and injury.

COVID-19 and Inflammasomes

While the release of proinflammatory cytokines is part of the body’s normal defense mechanism, in the case of viral infections it can also mediate and enhance the spread of the infection throughout the body. As the article in Evolutamente points out, cytokines are “dangerous double-edged swords exploited by coronaviruses”. The reason why COVID-19 is so deadly is because it can induce a very severe acute pneumonia, which is particularly dangerous in people least able to withstand such an infection because of weakened lungs or compromised immunity. And the activation of the NLRP3 inflammasome is a key mediator of the acute respiratory distress that is characteristic of COVID-19 infection. Melatonin’s ability to inhibit activation of this inflammasome could therefore be a key to its potential importance in the war against COVID-19.

Melatonin and Age

It has been widely observed that children are not as susceptible to the most severe aspects of COVID-19 as older people, although they can still become infected and transmit the virus. The risk of dying from COVID-19 seems to increase starting at age 40 and going up significantly over 70 (see https://www.worldometers.info/coronavirus/coronavirus-age-sex-demographics/). This somewhat mirrors, in reverse, the age-related decline in melatonin production. A 1988 study found that during the first 6 months of life serum night-time melatonin production was low (mean 27.3 pg/mL), but it increased to a peak value at 1-3 years old (mean 329.5 pg/mL) and then declined later in childhood, correlating negatively with body size increase (mean 62.5 pg/mL at age 15-20). It then showed a progressive, but moderate decline until age 70-90 (29.2 pg/mL) [5]. While this does not exactly track the rise in COVID-19 severity with age, it could be a big factor in the natural protection that very young children appear to have against the virus.

Assessing Melatonin and Supplementing

Regarding supplementing with melatonin, this can be a controversial issue. Excessive supplementation results in sleepiness during the following day. Clinical studies have shown promising results in lowering oxidative stress markers with doses ranging from 10-20 mg/day [6,7] and the evidence shows that it has few adverse effects [8]. A review of dosages ranging up to 50 mg/day used in older adults (age 55 and over) suggested avoiding excessive dosing that resulted in supraphysiological levels and instead to use the lowest dose possible to mimic normal production in people with disordered circadian rhythms [9]. A prolonged-release formulation giving 2 mg/day has been used successfully to treat primary insomnia and poor sleep quality [10]. A typical dose for an over-the-counter supplement to help with sleep is 1-3 mg/day, but your doctor may be able to help with appropriate dosing for protection against oxidative stress.

For those who want to check the adequacy of their melatonin production, ZRT Laboratory includes dried urinary diurnal testing of the melatonin metabolite MT6s in our Sleep Balance profile, our Advanced Metabolites Profile, and can be added on to our Neurotransmitter testing; and we also offer first morning saliva melatonin in our LCMS Saliva Steroid Profile. But we can all help ourselves to more melatonin naturally by getting adequate sleep, ensuring that we don’t expose ourselves to bright light late in the evening and keep our bedroom as dark as possible during the night, and try to be asleep during the hours of darkness (not good news for those “night owls”!)

References

The Younger, Sexy Me…...nopause!

Fri, 15 Nov 2019 11:52:48 -0800

Sometimes you look back and wonder where all the time went.

Let’s see - in my twenties, the younger, sexier me had been to University and embarked on a career in medical research, and I’d been very active in my leisure time – including hiking and skiing every year in the Alps. I was too invested in my career and hobbies to have children and wanted to put that off until the right time.

In my thirties, I eventually realized it was time to start a family before it was too late. At age 35 I saw a gynecologist who said “at your age, the chances of getting pregnant are very low. You’re probably only producing a viable egg about every 3 months, and you’ll be at higher risk for pregnancy complications as an ‘elderly primagravida’.” Despondent, but undeterred, I set about trying to get pregnant and succeeded within the first month. So much for the gynecologist. At age 36 I gave birth to my son, and at age 38 to my daughter.

But something strange happened when I entered my early forties. After my daughter was born, my periods eventually came back – but very irregularly. I wasn’t too worried at first since I was breastfeeding, but after a year or so it seemed odd that they were still so erratic. I moved to the USA in 2000 and put the still-irregular periods and trouble sleeping down to the stress of an international move with young children. But when I started having more symptoms, including hot flashes and night sweats, and saw my doctor for a checkup, she did an FSH test and said, “guess what – you’re in menopause.” At age 42. When I mentioned this to one of my aunts in the UK she said, “oh yes, that happened to me in my early forties, and your other aunt as well.” Who knew – early menopause runs in families!

What is Early Menopause?

Typically, menopause – characterized by the cessation of periods for a year, and a very high blood FSH level – happens in a woman’s early fifties. “Premature menopause” is a term that refers to premature ovarian failure (POF) affecting around 1% of women under the age of 40, whereas spontaneous early menopause affects 5% of women aged 40-45 [1]. Early menopause can also result from certain medical conditions (e.g., autoimmune diseases, epilepsy, or chromosomal abnormalities), a history of smoking, or certain infections, e.g., mumps, and can be induced as a side effect of chemotherapy or radiation. Removal of both ovaries (bilateral oophorectomy) brings about a “surgical menopause” at whatever age the surgery is done.

Early menopause can also occur when there is a family history of early menopause. Since none of the other medical factors applied to me, that was what happened in my case. A population-based case-control study carried out in 1995 [2] found that 37% of the early menopause (before age 46) cases reported early menopause in a mother, sister, aunt, or grandmother, while only 9% of the controls (who entered menopause after age 46) had such a family history. The cause of spontaneous early menopause when there is a family history is not known.

Health Risks of Early Menopause

Whether spontaneous, induced surgically or by chemotherapy, or as a result of other medical conditions, early menopause comes with health risks of its own [1]. In most cases, these are consequences of the early loss of estrogen production by the ovaries. Estrogen is important for the optimal functioning of the cardiovascular, nervous, and skeletal systems, and of course this is the primary reason why women undergoing menopause seek hormone replacement therapy. We know from all the hoopla surrounding the Women’s Health Initiative, which famously looked mostly at women who started hormone replacement many years after entering menopause, that hormone replacement started a short time after the onset of menopause is recommended to prevent chronic health conditions such as cardiovascular disease and osteoporosis. Results of subsequent trials such as the Kronos Early Estrogen Prevention Study (KEEPS) have demonstrated the efficacy and safety of starting hormone therapy soon after the onset of menopause [3].

Surgical Menopause and Low Testosterone

Not only did I struggle with insomnia, hot flashes, night sweats, mood changes, and all the other joys of a natural menopause, but I then experienced some pelvic pain and was diagnosed with a growth on one of my ovaries, so I ended up having a bilateral oophorectomy resulting in surgical menopause to boot. Fortunately, the growth turned out to be benign; but the surgery had the unforeseen consequence of sending my testosterone down to undetectable levels.

So not only did I have severe estrogen deficiency, I ended up with testosterone deficiency as well. Let me tell you, this is not fun. Forget the younger, sexy me, menopause or not – without testosterone, there is no libido at all. In women undergoing non-surgical menopause the ovaries do continue to produce testosterone, which can to a large extent “take over” from estrogen in terms of bone support, maintaining vitality, and supporting nervous system and cardiovascular health. But when there are no ovaries, testosterone levels plummet. Low testosterone in women has been linked with low libido and lack of sexual desire, but there is still controversy about the use of testosterone in women [4]. I can only say from experience that the consequences of low testosterone were very real for me.

Getting Help

It is no accident that my plunge into early menopause, and then surgical menopause, eventually led me to ZRT Laboratory. The almost complete absence of both estrogens and androgens from my body, and my dissatisfaction with the synthetic hormones prescribed after my oophorectomy, sent me on a quest to find out as much as I could about natural hormone replacement. It’s not always easy to find a health care practitioner who really understands what you are going through in terms of hormone health, and can identify the right testing to home in on the most suitable hormone replacement therapy. I saw several doctors before finding the best fit for me, and I always went in armed with my own research and understanding so that I could feel confident in proper hormone restoration without unnecessary side effects.

Thank goodness I met Dr. Zava and ZRT Laboratory along my journey and was able to find the best testing around and the practitioner who could properly interpret it and prescribe appropriately! If this blog rings all too true for you, find out how ZRT can help you with your menopause symptoms today.

Now in my early sixties, I may not be young any more but with proper hormone replacement the zest for life is definitely back – with my children now in their early twenties and getting on with their own lives, I’m back to hiking regularly and I’m going skiing again this winter for the first time in 20 years!

Related Resources

References

[1] Shuster LT, et al. Premature menopause or early menopause: long-term health consequences. Maturitas. 2010;65:161-6.

[2] Cramer DW, et al. Family history as a predictor of early menopause. Fertil Steril. 1995;64:740-5.

[3] Miller VM, et al. The Kronos Early Estrogen Prevention Study (KEEPS): what have we learned? Menopause. 2019 Apr 1.

[4] Davey DA. Androgens in women before and after the menopause and post bilateral oophorectomy: clinical effects and indications for testosterone therapy. Womens Health (Lond). 2012;8:437-46.

Exploring the Connection Between BDNF and Alzheimer's Disease

Fri, 20 Sep 2019 12:05:08 -0700

The incidence of Alzheimer’s disease is growing, now affecting 10% of people aged 65 and older. Two-thirds of Americans with Alzheimer’s Disease are women, and African Americans and Hispanics are more likely to be affected than Caucasians. Low serum BDNF levels have been observed in patients with Alzheimer’s disease, begging the question: what is the connection between BDNF and Alzheimer’s disease? And what could it mean for early detection of brain cell damage and the possibility of interventions to prevent or mitigate the disease?

What is BDNF?

Brain-derived neurotrophic factor, known as BDNF, is a protein produced by brain cells that regulates normal neuronal development and synaptic plasticity. Insufficient production of BDNF limits the growth and differentiation (maturation) of new nerve cells and lowers the ability of nerve cells to connect with each other and transmit information. Consequences include impairment of memory formation and degeneration of other brain functions.

How Can We Measure BDNF Production in the Brain?

Despite the name, BDNF is not only produced in the brain; other types of cells in the body produce it, and in particular blood platelets contain large amounts. When a blood sample is taken and allowed to clot, BDNF is released from the platelets and remains in the serum layer where it can be assayed [1]. Low serum levels of BDNF have been found in neurological conditions including depression and bipolar disorder as well as neurodegenerative conditions like Alzheimer’s, Huntington’s, and Parkinson’s diseases in multiple studies [2,3], and analyses of brain levels of BDNF post mortem in patients who had these conditions show a correlation of brain BDNF with cognitive decline. This led researchers to suggest that serum BDNF levels are indicative of brain levels.

Why would platelet levels reflect brain levels? The most plausible theory lies in the discovery of neuronal BDNF gene transcripts in megakaryocytes, the platelet-generating cells [4]; therefore, the conditions that alter the expression of this gene (and consequently synthesis of the BDNF protein) affect endogenous BDNF production to a similar extent in both neurons and megakaryocytes. So while BDNF is actually produced in the megakaryocytes, it is retained within the platelets. However, in some acute situations, for example the increase in serum BDNF during strenuous exercise or the decrease during depressive episodes, the level of BDNF in platelets may be more likely reflective of the degree of platelet activation [4].

Studies have suggested that Alzheimer’s is actually the 3rd leading cause of death behind heart disease and cancer in the 75 and older age group.

What is Alzheimer’s Disease?

Alzheimer’s disease represents 60-80% of cases of dementia, a term that encompasses a group of symptoms involving a decline in memory and other thinking skills. The second most common type of dementia after Alzheimer’s is the vascular dementia that develops after a stroke.

Alzheimer’s Disease is a progressive neurodegenerative disease. And it’s not an insignificant problem – studies have suggested that Alzheimer’s has been under-reported as a cause of death, and that it is actually the third leading cause of death behind heart disease and cancer in the 75 and older age group. In Alzheimer’s Disease changes occur in brain cells that damage them and affect connections (synapses) between brain cells. Cells in the hippocampus, the memory/learning center of the brain, are among the first to become damaged, so short term memory loss is an early sign of the disease. Symptoms of dementia gradually worsen over time.

The disease, named after Dr. Alois Alzheimer after his observations in 1906, is characterized by amyloid deposition (plaques) and tangled nerve fibers (tangles) in the brain and a loss of connections between neurons. Age-related changes that can trigger the neurological damage leading to Alzheimer’s disease can include inflammation, vascular damage, increases in free radicals, and mitochondrial dysfunction. But early onset Alzheimer’s Disease that can start anywhere between the 30s and 60s is linked to a genetic defect in the Apolipoprotein E gene.

Is There a Link between BDNF and Hormonal Decline during Aging?

In an earlier blog, I looked at the link between the decline in estrogen levels during menopause and changes to the hippocampus, the part of the brain responsible for formation of new memories and transferring short-term to long-term memory. As previously mentioned, cells in the hippocampus are among the first to show damage in Alzheimer’s Disease. A local supply of estrogens and androgens in hippocampal neurons maintains synaptic plasticity, maintaining connections between neurons that are essential for storing memories [5]. But is there also a link between hormones and BDNF?

In fact, estrogen both stimulates synthesis of BDNF and enhances its actions by regulating expression of tropomyosin-related kinase B (TrkB), a high-affinity BDNF receptor [6]. Activation of TrkB leads to downstream events necessary for neuronal survival and synapse formation. Since the hippocampus is particularly influenced by estrogens (and androgens, via local aromatase activity that converts testosterone to estradiol) its effects on hippocampal BDNF expression are crucial to maintaining the health of this memory/learning center.

Stress hormones are also connected to BDNF expression, possibly explaining the links between mood disorders and changes in BDNF levels [7]. Chronic elevations in cortisol due to HPA axis hyperactivity cause changes in the brain including reduced hippocampal volume. It has been suggested that BDNF and glucocorticoid activities in the brain are calibrated: normal BDNF synthesis is optimal during a normal diurnal fluctuation in cortisol production, but sustained cortisol peaks seen in chronic stress result in reduced BDNF synthesis [8].

Can Early Detection Help?

Genetic and non-genetic markers are being developed that can help identify the onset of disease and provide the opportunity for early drug treatments.

Genetic and non-genetic markers are being developed that can help identify the onset of disease and provide the opportunity for early drug treatments [9]. But since there is a vascular and inflammatory component to the decline in brain health that can lead to dementia, lifestyle changes that are commonly suggested to reduce risk for metabolic syndrome and cardiovascular disease, such as the Mediterranean and DASH (Dietary Approaches to Stop Hypertension) diets, could also help keep brain cells healthy [10]. Trials of diet along with other modifiable lifestyle factors including social and cognitive engagement, brain exercises, and physical exercise in older adults are underway [11].

Stress is another major factor in neurological damage as chronic, excess cortisol production exacerbates inflammation and cell damage, as well as increasing risk factors for cardiovascular disease. Meditation practices, psychological well-being and spiritual fitness have been proposed to mitigate the effects of stress on the brain and reduce risk of Alzheimer’s Disease [12,13].

Low serum BDNF levels can be a useful indicator that neurodegeneration may be occurring and wake people up to the possibility of improving their lifestyle. A healthier diet and an increase in physical exercise are always a good start. ZRT is one of very few labs to offer a serum test for BDNF. In addition, serum testing for hormonal imbalances such as low sex hormones (estradiol, progesterone, testosterone) or persistently high cortisol in combination with BDNF may provide valuable information for treatment strategies to help prevent or slow the progression of Alzheimer’s.

For more information about serum testing for BDNF, sex hormones, and cortisol contact ZRT Laboratory at info@zrtlab.com or 866.600.1636.

Related Resources

References

[1] Naegelin Y, et al. Measuring and Validating the Levels of Brain-Derived Neurotrophic Factor in Human Serum. eNeuro. 2018;5(2).

[2] Teixeira AL, et al. Circulating levels of brain-derived neurotrophic factor: correlation with mood, cognition and motor function. Biomark Med. 2010;4:871-87.

[3] Hashimoto K. Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci. 2010;64:341-57.

[4] Chacón-Fernández P, et al. Brain-derived Neurotrophic Factor in Megakaryocytes. J Biol Chem. 2016;291:9872-81.

[5] Ooishi Y, et al. Modulation of synaptic plasticity in the hippocampus by hippocampus-derived estrogen and androgen. J Steroid Biochem Mol Biol. 2012;131:37-51.

[6] Carbone DL, Handa RJ. Sex and stress hormone influences on the expression and activity of brain-derived neurotrophic factor. Neuroscience. 2013;239:295-303.

[7] Hashimoto K. Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci. 2010;64:341-57.

[8] Jeanneteau F, Chao MV. Are BDNF and glucocorticoid activities calibrated? Neuroscience. 2013;239:173-95.

[9] The Need for Early Detection and Treatment in Alzheimer's Disease. EBioMedicine. 2016;9:1-2.

[10] van den Brink AC, et al. The Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) Diets Are Associated with Less Cognitive Decline and a Lower Risk of Alzheimer's Disease-A Review. Adv Nutr. 2019 Jun 18. [Epub ahead of print]

[11] McMaster M, et al. Body, Brain, Life for Cognitive Decline (BBL-CD): protocol for a multidomain dementia risk reduction randomized controlled trial for subjective cognitive decline and mild cognitive impairment. Clin Interv Aging. 2018;13:2397-2406.

[12] Khalsa DS. Stress, Meditation, and Alzheimer's Disease Prevention: Where The Evidence Stands. J Alzheimers Dis. 2015;48:1-12.

[13] Innes KE, et al. Meditation and Music Improve Memory and Cognitive Function in Adults with Subjective Cognitive Decline: A Pilot Randomized Controlled Trial. J Alzheimers Dis. 2017;56:899-916.

Testosterone Deficiency in Younger Men – Is It Real?

Thu, 16 May 2019 13:55:41 -0700

Low testosterone in older men, often referred to as “male menopause” or even “andropause” is fairly well known — and testosterone replacement therapy in this age group has not been without its share of controversy, particularly with respect to heart health. Proper testing and dosing are all-important, as well as understanding a man’s physiology and all the factors that affect testosterone levels. For example, when giving testosterone transdermally it is critical to use testing methods such as dried blood spot or saliva to properly assess absorption of testosterone into the body, avoiding the problem of overdosing to achieve “normal” serum levels.

But while a decline in testosterone is a struggle that older men are coming to expect, what about the alarming suggestion that low testosterone is now becoming more prevalent in younger men? An article published last year has brought some attention to a link between poor health and low testosterone levels in younger men. Let’s take a closer look at this article to see who might be at risk.

Study of Testosterone Levels in 3 Age Groups

The investigators who wrote the article, published in Scientific Reports [1], analyzed publicly available data from the CDC’s National Health and Nutrition Examination Survey (NHANES). Of the men older than 20 who participated in NHANES, 2161 had the complete information required for this study, including a serum total testosterone measurement, information on chronic diseases including cardiometabolic risk factors, and handgrip strength measurements.

Total testosterone (TT) deficiency, defined as a serum level <300 ng/dL, was seen in:

22.6% of the young men (aged 20-39.9 years)
35.8% of the middle-aged men (aged 40-59.9 years)
34.6% of the older age group (aged 60 or older)

Among the men with low TT there was a significantly higher prevalence of either a single chronic disease or multiple diseases (multimorbidity). This was particularly striking in the younger age group, in which 36.4% of the men with low TT had more than one chronic disease, compared to only 13.5% of the men with normal TT.

Why the Difference with Published Reference Ranges for Young Men?

Harmonized, age-specific reference ranges for TT were recently published to help with diagnosis of hypogonadism and were based on 4 cohort studies in the US and Europe [2]. The 5^th-95^th percentile range for TT in healthy, non-obese men aged 19-39 was 303-852 ng/dL. However, TT values in the same age group in the NHANES cohort were substantially lower; the 5^th percentile of this cohort had a TT of only 182 ng/dL. All testosterone measurements in the cohort studies and the NHANES cohort were by mass spectrometry (LC-MS/MS in the NHANES, the Framingham Heart Study cohort, and the Sibling Study of Osteoporosis epidemiologic study; and GC-MS/MS in the European Male Aging Study and the Osteoporotic Fractures in Men study).

Notably, the average BMI in the younger men (aged 20-39.9 years) in the NHANES study [1] was 27.95 kg/m², and the prevalence of obesity (defined as a BMI > 30 kg/m²) was 29.8% in this group. Therefore, the authors of the NHANES-based study argue, using only healthy, non-obese men for the harmonized reference range is not really representative of the current demographics in the US, where obesity is now prevalent even in younger age groups.

Is it surprising that a group of men with an average BMI of 27.95, already in the “overweight” category (BMI between >25 up to 30), of whom almost 30% are technically obese, shows a high prevalence of TT deficiency — as well as a high prevalence of the same chronic diseases that are linked to obesity? The diseases that were significantly more prevalent in the men in the young age group with TT deficiency were: abdominal obesity, diabetes, cardiovascular disease, hypertension, clinical depression, low HDL cholesterol, and high triglycerides. Shouldn’t we also note that some of the drugs used to treat these conditions are known to lower testosterone levels in men, including statins, some antidepressants, and anti-hypertensives? The study authors state in their paper that the cross-sectional design of NHANES meant that it was not possible to tell whether low T caused the higher incidence of chronic diseases or whether the poor health of the men itself caused the decline in T levels, and that they were also not able to tell if medication use by the men influenced the results.

Low Testosterone and Chronic Diseases

Abdominal obesity, often referred to as “central adiposity,” is known to be a strong cardiometabolic risk factor that is linked with the development of chronic diseases like insulin resistance, metabolic syndrome, and ultimately diabetes.

Studies have found that men with low T and low SHBG who do not yet have metabolic syndrome or diabetes are significantly more likely to go on to develop insulin resistance or diabetes

Where does testosterone come in? Large, population-based longitudinal studies have found that men with low T and low sex hormone binding globulin (SHBG) who do not yet have metabolic syndrome or diabetes are significantly more likely to go on to develop insulin resistance or diabetes [3][4]. SHBG is the main binding protein for testosterone in the circulation and largely controls the availability of free testosterone to tissues, and it also affects the total amount of circulating testosterone – the more SHBG, the greater the amount of total testosterone being carried around in the circulation, and vice versa. Obesity is known to decrease SHBG levels while aging increases them, but the effect of obesity in driving down SHBG is greater than the effect of aging in raising it, with consequent effects on total testosterone measurements [5].

Low SHBG has also been identified as a surrogate marker for insulin resistance because of its strong negative association with fasting insulin levels. Studies have indicated that the suppression of hepatic SHBG production in insulin resistance is mediated through monosaccharide-induced lipogenesis, which in turn reduces levels of a hepatic transcription factor that controls the SHBG promoter [6][7]. So young men who are showing a tendency towards insulin resistance will have low SHBG and consequently low TT.

What Could Influence Total Testosterone in the Younger Men with Multimorbidities?

A number of mechanisms have been proposed to explain low TT levels in men with central adiposity and/or insulin resistance:

1) low SHBG associated with adiposity and insulin resistance drives down TT levels;

2) aromatase present in adipose tissue uses up testosterone as it converts to estradiol, which then further shuts down testosterone production in the Leydig cells through negative feedback on the hypothalamic-pituitary-gonadal system;

3) insulin resistance itself directly inhibits testosterone production in Leydig cells.

What about men who exhibit low TT before developing central adiposity or insulin resistance? If they have a sedentary lifestyle or a habitual high refined carbohydrate intake, this can impact SHBG production directly through hepatic monosaccharide exposure, predisposing them to both low TT and risk of obesity.

Can Lifestyle Modification Be the Key to Increasing Total Testosterone?

In obese or overweight men, lifestyle changes that reduce central adiposity, such as diet and exercise, naturally increase endogenous testosterone production. As adiposity and insulin levels decrease through weight loss, SHBG rises and thereby increases circulating TT levels. Could testosterone replacement help things along? A single blind 52-week study in older (late 50s) hypogonadal men with type 2 diabetes found that a diet and exercise program significantly improved testosterone levels, measures of glycemic control and metabolic syndrome markers, but the improvements were enhanced by the addition of 50 mg/day transdermal testosterone gel treatment [8].

What about the effects of stress on young men today as they pursue their careers and raise young families? Chronic elevations in cortisol levels as a result of persistent stress prolong the metabolic changes that are normally supposed to be a short-term response to a stress stimulus, and these changes can lead to visceral (central) adiposity and insulin resistance, lowering SHBG and TT levels.

Before young men start rushing off to their doctors and demanding testosterone replacement therapy in the hopes that it will reverse their chronic health conditions, they would be wise to take a look at their lifestyles and see if they can modify some of their own risk factors. Losing some weight, getting more exercise, getting a handle on chronic stress, and eating a healthier diet are all great ways to start. But also addressing health conditions like depression and hypertension by non-pharmacological means, with the support of an integrative health physician, would help avoid using the drugs that can lower testosterone. Not only will more natural interventions help improve their overall health, but any resulting increase in their own testosterone production will also improve vitality and energy.

Younger men can take a leaf from the book of older men who are already looking for natural ways to improve their hormone balance – it’s never too early to start!

Related Resources

References

[1] Peterson MD, et al. Testosterone deficiency, weakness, and multimorbidity in men. Scientific Reports 2018;8:5897.

[2] Travison TG, et al. Harmonized Reference Ranges for Circulating Testosterone Levels in Men of Four Cohort Studies in the United States and Europe. J Clin Endocrinol Metab. 2017;102:1161-1173.

[3] Laaksonen DE, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 2004;27:1036-41.

[4] Stellato RK, et al. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care. 2000;23:490-4.

[5] Cooper LA, et al. The association of obesity with sex hormone-binding globulin is stronger than the association with ageing--implications for the interpretation of total testosterone measurements. Clin Endocrinol (Oxf). 2015;83:828-33.

[6] Pugeat M, et al. Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome. Mol Cell Endocrinol. 2010;316:53-9.

[7] Selva DM, et al. Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene. J Clin Invest. 2007;117:3979-87.

[8] Heufelder AE, et al. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl. 2009;30:726-33.

ZRT Cares About the Environment with Eco-Friendly Materials

Thu, 11 Apr 2019 14:07:23 -0700

As a laboratory that tests for hormone imbalances and exposure to environmental hazards such as heavy metals and BPA, we are acutely aware of the need to be responsible caretakers of the environment. We try to do our part in minimizing unnecessary waste products that can ultimately find their way into the food we eat, the water we drink and air we breathe. This blog looks at some of the ways we strive to do our part to use sustainable materials and limit waste.

No Radioactivity in Our Assays

We use several methodologies to test saliva, blood spot, dried urine, and serum samples; these include various types of mass spectrometry, immunoassays, and others. One method we choose not to use is radioimmunoassay (RIA). RIAs are generally accurate, easy to perform, and relatively inexpensive. They also produce radioactive waste. Instead, we choose to use other highly sensitive enzyme-based immunoassays with appropriate extraction steps to maximize assay sensitivity and accuracy.

Sustainable Kit Boxes

Our versatile plastic “clamshell” kit boxes are made of sustainable packaging containing up to 100% post-consumer recycled content. This EcoStar® PET (polyethylene terephthalate) material made by Placon is composed of recycled plastic bottles and mixed bales of thermoform packaging, which meets current domestic RPPC (Rigid Plastic Packaging Container Program) laws and contributes to keeping more than 1 billion plastic bottles from entering landfills each year.

Saliva Tubes Made from Recycled Plastic

All packing peanuts that we use are made from compostable vegetable starch.

Our saliva collection tubes are made of recycled polypropylene.

Biodegradable Packing Materials

We occasionally receive requests from concerned health care providers not to include packing peanuts in their test kit shipments. We are happy to assure you that all packing peanuts we use are made from compostable vegetable starch. These are entirely biodegradable, leaving no residue, and are water-soluble.

Recycling

Wherever possible when following safety and quality protocols, we recycle. Since we ship and receive hundreds of packages of test kits and human specimens every day, that amounts to a lot of recycling. This includes several hundred pounds per week of cardboard shipping boxes, plastic clamshells, as well as paper items such as instructions and inlays from returned sealed kits.

Providers Can Go Paperless

All test results provided by ZRT Laboratory, as well as most account management features, are available digitally through our myZRT portal and can be integrated with several electronic health records (EHR) providers. At present, over 80% of test reports are accessed using one of these paperless options.

Employee Mass Transit Subsidies

ZRT offers subsidized passes to employees who take advantage of mass transit, as an incentive to keep a few extra cars off the road.

Environmental Consciousness at the Lab

All lighting at the ZRT laboratory facility is either energy-efficient T5 or T8 fluorescent lighting with electronic ballasts, compact fluorescent lights, or LED lighting. Staff are conscientious about turning off lights when they leave the building (or a stern reminder is sent by our facilities manager!) Also, no glyphosate herbicides are used around the building for weed control.

At ZRT we try to be mindful of our surroundings and to live the message we preach about optimizing health and protecting ourselves from chronic diseases. Avoiding putting harmful things into our bodies is a good start when seeking to improve wellness, and testing for harmful toxins like heavy metals or assessing disturbances in hormone balance that may be related to exposure to endocrine disruptors can be key to recognizing hidden dangers. Learn more about ZRT's Heavy Metals and Essential Elements testing today.

Related Resources

Reverse T3 – Why It’s Not Useful for Routine Thyroid Testing

Fri, 25 Jan 2019 13:39:20 -0800

When getting to the root of health issues by accurate laboratory testing of hormones and other analytes, it’s important to distinguish theories from facts and make sure that our interpretation of the science is valid and corresponds with what is seen clinically. This month, as the weather and the time of year put us in the middle of winter, let’s take a critical look at a hormone sometimes referred to as the “hibernation hormone,” reverse T3 (rT3), and how it fits into the picture of thyroid function.

What is Reverse T3?

Reverse T3 (3,3’,5’-triiodothyronine, rT3) is a biologically inactive metabolite of thyroxine (T4) formed by selective deiodination; the active thyroid hormone T3 is formed by removal of an iodine atom in the outer ring of T4, while rT3 is formed by removal of an iodine atom in the inner ring of T4. This deiodination is mediated by deiodinase enzymes.

The Deiodinases - Gatekeepers to Intracellular Thyroid Hormone Bioavailability

For a closer look at the deiodinases and how they determine thyroid hormone availability, see our earlier blog on this topic and good reviews [1][2][3][4].

“Hibernation Hormone” is a Misnomer

It turns out that the term “hibernation hormone” is inappropriate when describing reverse T3. Reverse T3 has been described as such because higher levels are associated with some conditions characterized by a reduction in the metabolic rate. These conditions include starvation or extreme carbohydrate restriction [5]; chronic heart failure – particularly when associated with permanent atrial fibrillation [6]; and non-thyroidal illness syndrome (also called “euthyroid sick syndrome” or “low T3 syndrome”) that is seen in critical illness, very elderly patients, chronic stress, myocardial infarction, and chronic inflammatory states [7]. Altered intracellular thyroid hormone metabolism results from metabolic changes caused by the condition itself, and it is these changes in expression of the deiodinases that induce the rise in rT3.

No Effects of rT3 on Nuclear Thyroid Receptors

Since high rT3 is linked with conditions associated with slow metabolism, it has been claimed in internet articles, but not in peer-reviewed papers, that rT3 causes a slowing in metabolism by blocking or obstructing the nuclear thyroid receptors. These receptors are the target sites where the primary active thyroid hormone, T3, binds, triggering its actions to drive cellular metabolism and maintain body temperature. Yet there is no credible scientific evidence that rT3 even enters the nucleus of the cell. While rT3 does not bind to, and has no known transcriptional activity at, the thyroid receptor, it does have potent non-genomic activity, mediated by binding to a specific thyroid receptor in the cytoplasm, as an initiator of actin polymerization in astrocytes in the brain [8][9]. Actin polymerization is important to cell structure and motility, as well as to normal brain development.

There appears to be little clinical justification for routine testing of rT3 for thyroid function assessment.

Diagnostic Value of High Levels of rT3 Relative to T3

How do the metabolic changes associated with severe illnesses, as described earlier, result in high rT3 levels? As explained in our earlier blog, reactivation of the D3 deiodinase and downregulation of the D1 deiodinase result in increased rT3 formation and reduced rT3 clearance, while at the same time reducing T3 synthesis from T4. Metabolic conditions created by macronutrient restriction affect the expression of D1 and D3 in this way and thus have a profound impact on circulating levels of T3 and rT3 and the T3/rT3 ratio. This ratio therefore has been found to have some value in assessing prognosis in severely ill [10] or very elderly patients [11]. However, there is no clinical basis for the use of this ratio in routine thyroid function assessment in non-critically ill people.

In some patients being treated with exogenous thyroxine treatment, elevations in serum rT3 have been seen, but this can be a result of cross-reaction of T4 in immunoassays for rT3, resulting in a false increase in rT3 in the presence of high serum T4. Mass spectrometry testing for rT3 avoids this issue and is more reliable. Also, in a study in euthyroid subjects receiving thyroxine a rise in rT3 was seen and interpreted as a result of increased substrate availability for peripheral inactivation of T4 [12]. Interestingly, elderly patients may potentially have an adaptive response that reduces thyroid hyperactivity at the tissue level or have a type of non-thyroidal illness with consequent reactivation of D3, both causing increased T4 inactivation via conversion to rT3; older hypothyroid patients may therefore require lower thyroxine replacement doses [13].

The Bottom Line – Is the rT3 Test Useful?

There appears to be little clinical justification for routine testing of rT3 for thyroid function assessment [14]. The main applications of an rT3 test are as a prognostic/diagnostic indicator in non-thyroidal illness syndrome or to monitor patients receiving amiodarone, which inhibits liver type 1 deiodinase activity and increases rT3 relative to T3. A healthy balance of rT3 and T3 levels can be maintained and thyroid function kept optimal with proper nutrition – avoid extreme dieting or severe carbohydrate restriction which create a starvation signal; normal iodine and selenium levels (assessed with dried urine testing); and avoidance of excessive stress.

Related Resources

References

1. Gereben B, et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev. 2008;29:898-938.

2. Maia AL, et al. Deiodinases: the balance of thyroid hormone: type 1 iodothyronine deiodinase in human physiology and disease. J Endocrinol. 2011;209:283-97.

3. Williams GR, Bassett JH. Deiodinases: the balance of thyroid hormone: local control of thyroid hormone action: role of type 2 deiodinase. J Endocrinol. 2011;209:261-72.

4. Dentice M, Salvatore D. Deiodinases: the balance of thyroid hormone: local impact of thyroid hormone inactivation. J Endocrinol. 2011;209:273-82.

5. Komaki G, et al. Changes in the hypothalamic-pituitary-thyroid axis during acute starvation in non-obese patients. Endocrinol Jpn. 1986;33:303-8.

6. Jakowczuk M, et al. Permanent atrial fibrillation in heart failure patients as another condition with increased reverse triiodothyronine concentration. Neuro Endocrinol Lett. 2016;37:337-342.

7. Van den Berghe G. Non-thyroidal illness in the ICU: a syndrome with different faces. Thyroid. 2014 Oct;24(10):1456-65.

8. Leonard JL. Non-genomic actions of thyroid hormone in brain development. Steroids. 2008;73:1008-12.

9. Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev. 2010;31:139-70.

10. Peeters RP, et al. Serum 3,3',5'-triiodothyronine (rT3) and 3,5,3'-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. J Clin Endocrinol Metab. 2005;90:4559-65.

11. van den Beld AW, et al. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab. 2005;90:6403-9.

12. LoPresti JS, et al. Alterations in 3,3'5'-triiodothyronine metabolism in response to propylthiouracil, dexamethasone, and thyroxine administration in man. J Clin Invest. 1989;84:1650-6.

13. Mariotti S. Thyroid function and aging: do serum 3,5,3'-triiodothyronine and thyroid-stimulating hormone concentrations give the Janus response? J Clin Endocrinol Metab. 2005;90:6735-7.

14. Gomes-Lima C, Burman KD. Reverse T(3) or perverse T(3)? Still puzzling after 40 years. Cleve Clin J Med. 2018;85:450-455.

A Case Study for Breast Cancer Awareness Month

Thu, 18 Oct 2018 11:51:00 -0700

Did you know that ZRT offers clinical case reviews for neurotransmitter testing?

If you want to learn more, check out Dr. Kate’s Clinical Cases, a library of presentations, created by Dr. Kate Placzek, to assess patient issues with the aid of neurotransmitter testing.

You’ll find case presentations focused on various conditions from anxiety and depression, ADHD, PTSD, insomnia and many others, highlighting real patients and their results, ranging in age from children to postmenopause, as well as a veteran with PTSD.

For Breast Cancer Awareness Month let’s take a closer look at a recent case study of a postmenopausal woman with breast cancer.

Loretta’s Case Study

Loretta is a 62-year-old postmenopausal woman suffering from breast cancer as well as depression, anxiety, and stress. Dr. Kate presents a breakdown of her self-reported symptoms before going into the details of her test results and a thorough explanation of biochemical factors at play that explain both her symptoms and her observed results. Finally, she summarizes the whole picture and presents a suggested way to address the problems and help Loretta get back into balance.

Symptoms

Self-reported symptoms that Loretta rated as severe included breast cancer, rapid aging, bone loss, allergies, sensitivity to chemicals, and obsessive-compulsive disorder (OCD). Moderately severe symptoms included anxiety, depression, stress, nervousness, addictive behaviors, dry/brittle hair, breaking nails, increased urinary urge, and morning fatigue. In addition, she had multiple symptoms that she rated as mild in severity.

Taking a closer look at breast cancer, Dr. Kate talks about factors that influence breast cancer risk; some are not modifiable, such as a family history of breast cancer, age at first pregnancy, age at menopause, etc. But other risk factors are lifestyle-related and could be modified to reduce risk, e.g., alcohol use, smoking, exposure to heavy metals, and stress. She also presents Dr. Zava’s “Estrogen Matrix” from his book “What Your Doctor May Not Tell You About Breast Cancer” showing how hormonal pathways, in particular estrogen metabolism and the factors that influence it, contribute to breast cancer.

Elements Test Results

Loretta’s test results included heavy metals and nutrients testing in dried urine and dried blood spot and this showed high levels of bromine and arsenic in urine and high levels of mercury in both urine and blood spot (urinary mercury is an indicator of cumulative exposure to this toxic element, while blood spot indicates recent exposure). The blood spot elements test also showed that her levels of zinc and selenium were low, which is not healthy for anyone but especially for someone with breast cancer.

Dr. Kate explains how her elements test results relate to increased oxidative stress, which results in mitochondrial injury and DNA damage that can initiate breast cancer. Oxidative stress also speeds up aging. The body produces a natural antioxidant, glutathione, which helps counteract oxidative stress and detoxifies the body – but toxic heavy metals like arsenic and mercury interfere with glutathione production, and inadequate selenium also compromises glutathione synthesis, so Loretta is clearly suffering from a double whammy impact on glutathione availability.

Neurotransmitter Test Results

Dr. Kate then looks at her neurotransmitter results in relation to the neurotransmitter pathways, and shows that Loretta has a “brain on fire” pattern where everything is running either higher than normal or at the high end of the normal range. Paradoxically, her GABA and glycine are high, but her glutamate is normal – why is this? Dr. Kate points out that it is important to remember we are looking at urinary levels of neurotransmitters, and for glutamate to arrive in the urine it needs to be taken up by the kidneys. In Loretta’s case, her high levels of oxidative stress interfere with the glutamate transport in the kidneys, so less glutamate appears in the urine than would be expected.

In postmenopause when estradiol levels are low, this increases serotonin degradation, so levels are often lower than normal and levels of the serotonin metabolite 5-HIAA are high. In Loretta’s case, she also has a low zinc/copper ratio which also has the effect of enhancing serotonin degradation and likely contributes to her feelings of depression.

Loretta’s histamine levels are high, which can be seen in patients with sensitivity to chemicals, and her high PEA is indicative of severe anxiety, a racing mind and sleep problems.

Dr. Kate discusses Loretta’s epinephrine, norepinephrine, and cortisol/cortisone results and how they relate to stress and her adrenal glands. A sustained high cortisol level, in particular high cortisol production during the night as in Loretta’s case, increases the conversion of norepinephrine (NE) to epinephrine (EPI), increasing her levels of both EPI and normetanephrine (NMN) which is the adrenal product of NE metabolism, and this is typical in breast cancer patients where we often see high cortisol production.

Solutions for Loretta

Finally, Dr. Kate summarizes Loretta’s symptom picture and how it is reflected in her test results. What can Loretta’s doctor do to address this picture? Dr. Kate suggests how each aspect of Loretta’s health can be tackled, starting with supporting her overall wellness with stress reduction, sleep support, relaxation techniques such as yoga and meditation, and an anti-inflammatory diet. She covers nutritional support to help reduce her oxidative stress and increase glutathione production, including increasing her selenium and zinc and supplementing with N-acetyl cysteine (NAC). Finally, she suggests herbs for adrenal/HPA axis support, and follow-up neurotransmitter testing to check how Loretta is doing.

See the full case study here.

Related Resources

A Case Study for Menopause Awareness

Fri, 14 Sep 2018 10:33:00 -0700

Looking for case studies on how neurotransmitter testing can help patients? Want to learn more about interpreting these tests?

We invite you to discover Dr. Kate’s Clinical Cases, a library of presentations, created by Dr. Kate Placzek, to assess patient issues with the aid of neurotransmitter testing. You’ll find case reviews on conditions including anxiety and depression, ADHD, PTSD, insomnia and many others – highlighting real patients and their results, ranging in age from children to post-menopause, as well as a veteran with PTSD.

For Menopause Awareness Month, let’s take a closer look at a recent case study of a postmenopausal woman. Guest speaker Dr. Allison Smith joins Dr. Kate Placzek to present a common scenario of mood and vasomotor symptoms in menopause.

Julia’s Menopause Case Study

Julia is a 51-year-old newly postmenopausal woman suffering from intense hot flashes and night sweats, as well as anxiety, insomnia, and stress. Dr. Smith presents a breakdown of the patient’s self-reported symptoms before going into the details of her test results – where she highlights the biochemical factors that explain both her symptoms and her observed results. Finally, she summarizes the whole picture and presents a suggested way to address the problems and help Julia get back into balance.

A Host of Hormone Imbalance Symptoms

Only ZRT reports offer 68 self-reported patient symptoms that are summarized into 8 hormone imbalance categories.

In Julia’s case, symptoms she rated as severe included depression, anxiety, and sleep disturbances. Commonly seen in newly menopausal patients, moderate symptoms included hot flashes, night sweats, foggy thinking, vaginal dryness, and mood swings. In addition, she had multiple symptoms that she rated as mild in severity.

Dr. Smith shows how these self-reported symptoms are translated on the test report into 8 hormone imbalance categories – in this case, the main problem categories were estrogen dominance, estrogen/progesterone deficiency symptoms, both high and low cortisol symptoms, low androgen symptoms, and hypometabolism.

Julia had already tried multiple supplements in an attempt to address her own symptoms – these included elements like magnesium, calcium, selenium, zinc, and copper, as well as L-theanine and Rhodiola, vitamin D, fish oil, and some probiotics. Dr. Smith wanted to see if there was a better way to focus her supplement regimen based on her test results.

Saliva Hormone Test Results

Julia’s test kit included a saliva hormone test as well as the dried urinary neurotransmitter testing. Her saliva hormone results showed low estradiol and progesterone, low DHEA, but higher than normal testosterone, which could relate to blood sugar issues in this case. Low estradiol and progesterone levels explained many of her menopause-related symptoms.

Neurotransmitter Test Results

Julia’s serotonin levels were at the low end of the optimal range whereas levels of the serotonin metabolite 5-HIAA were high. Using the neurotransmitter pathway diagrams that are included in the test report, Dr. Smith shows that this suggests increased serotonin degradation. This is a common picture that we see in postmenopausal women, because estradiol helps maintain adequate serotonin levels by potentiating its synthesis and preventing its degradation. Estradiol acts as a mild monoamine oxidase (MAO) inhibitor, thus maintaining enough serotonin for optimal mood and sleep and mitigates the depressive effects of increased serotonin breakdown. Low serotonin availability also contributes to menopausal symptoms of night sweats, hot flashes, and mood changes. The diagram on the right illustrates estradiol’s role in modulating serotoninergic tone.

Julia’s glycine and glutamate levels were also below optimal – these amino acids are needed for the production of glutathione, a major antioxidant in the body that normally counteracts oxidative stress. PEA was also lower than normal, which can contribute to brain fog and mental fatigue, and her DOPAC was higher than normal, indicating increased dopamine degradation with resulting negative effects on mood. Her low norepinephrine levels could also contribute to depression, low blood pressure, and fatigue.

Solutions for Julia

Dr. Smith looks at each aspect of Julia’s test results and how they relate to her symptoms, going into detail regarding possible solutions to address them.

To address the hormone deficiency problems, if Julia is a good candidate, a hormone replacement therapy-based approach would involve estradiol and progesterone supplementation. A low dose of estradiol can be given as a patch, and dosage could be modified depending on how she does with the low dose. Estradiol would help slow the serotonin and dopamine breakdown and improve Julia’s sleep, while oral progesterone taken at night would promote sleep, due to its metabolism to the neuroactive steroid allopregnanolone, as well as help with estrogen dominance symptoms.

If hormone therapy is not an option, SSRIs (selective serotonin reuptake inhibitors) can improve serotonin availability and help with mood lability, hot flashes and night sweats (although won’t help with bone loss and vaginal dryness). There are also herbs, botanical MAO inhibitors that decrease serotonin breakdown, such as Curcumin and Passion flower.

For Julia’s low glycine and glutamate, Dr. Smith suggests giving N-acetyl cysteine (NAC) and/or glutathione to support her body’s response to oxidative stress.

For low PEA, vitamin B6, phenylalanine, and exercise can all help. Adrenal adaptogens can assist with low norepinephrine and overall HPA axis support, some of which (like Ashwagandha) are also effective for sleep issues.

Dr. Smith emphasizes the importance of support for general wellness, in particular a healthy Mediterranean diet, yoga practice, and biofeedback.

She also suggests additional testing for this patient, to include a thyroid panel to address the hypometabolism issues, and metabolic syndrome markers like HbA1c and insulin to detect any tendency towards prediabetes. She would also do a diurnal epinephrine and norepinephrine test, which would give more insight than the pooled total level in her current report into the adrenal connection to Julia’s sleep issues.

For more case reports like this, go to Dr. Kate’s Case Studies web page.

Related Resources

Research Updates – Trials of HRT Started in Early Menopause

Fri, 15 Sep 2017 09:09:00 -0700

One of the primary objectives of the Women's Health Initiative was to see if postmenopausal hormone replacement therapy (HRT) improved long-term risk of coronary heart disease, among other chronic diseases.

However, the combined estrogen/progestin (Prempro) arm was halted in 2002, citing that the participants’ risk of cardiovascular disease outweighed any potential benefit of HRT in the prevention of colorectal cancer and bone fracture [1]. The conjugated equine estrogen (CEE)-only arm was also halted in 2004 citing no improvement in heart disease risk but an increased incidence of stroke, and no benefit in terms of fractures, although there was a reduced breast cancer risk [2].

Yet the WHI investigators published a report this week [3] after a cumulative follow-up of 18 years finding that there was no overall increase in all-cause, cardiovascular, or cancer mortality as a result of either Prempro or CEE-only treatment during their participation in the trial.

Much debate has ensued since the WHI was halted regarding the type of HRT used, and whether or not the same effects could be extrapolated to all forms of hormone therapy, including bioidentical hormone replacement therapy (BHRT). However, one important criticism of WHI was that it enrolled women aged anywhere from 50 to 79 years old, and the bulk of the study participants were starting HRT well over a decade after entering menopause.

In an attempt to address this problem with the study design, two new trials were started which specifically looked at the long-term vascular effects of hormone therapy started early in the postmenopausal period. These trials were ELITE (Early versus Late Intervention Trial with Estradiol) and KEEPS (Kronos Early Estrogen Prevention Study). In Menopause Month, it would be interesting to see what the current news is on those two trials of menopause research.

Early versus Late Intervention Trial with Estradiol – ELITE

This study compared women who started HRT within 6 years of menopause with women who started more than 10 years after entering menopause. The HRT consisted of 1 mg/day oral 17β-estradiol plus 45 mg/day progesterone vaginal gel for 10 days each month for the women who had a uterus, or placebo plus placebo gel. Vascular health was determined by measuring carotid intima-media thickness (CIMT) every 6 months as an indicator of subclinical atherosclerosis, as well as CT scans to assess any actual coronary atherosclerosis.

Results after a median of 5 years since starting treatment were published in 2016 [4], and these showed that there was a clear difference in the outcome between the early and late menopausal groups. Women treated within 6 years of menopause had less progression of subclinical atherosclerosis, as indicated by a small increase in CIMT compared to the placebo group. In contrast, women who started HRT more than 10 years after menopause were not protected from atherosclerosis, as they showed no improvement in CIMT progression compared to the corresponding placebo group. Neither early nor late menopausal groups had any improvement in atherosclerosis evident on CT scans.

Kronos Early Estrogen Prevention Study (KEEPS)

When interpreting results of the above-mentioned and other studies, it is important to take into consideration the route of administration, the dose of hormone used, and the outcomes measured.

Like ELITE, KEEPS studied women using HRT in the early stages of menopause, but was designed to determine whether a very low, physiological dose of estrogen would be beneficial in preventing atherosclerosis. Women within 3 years of their final menstrual period were randomized to a weekly 50 µg/day estradiol transdermal patch or 0.45 mg/day oral CEE (conjugated equine estrogens), both combined with 200 mg oral micronized progesterone for 12 days/month, or placebo.

Unlike ELITE, the KEEPS results announced in 2012 were disappointing in that they showed no significant effect of either of the estrogen treatments on CIMT progression, suggesting that the lower estrogen dose was insufficient to produce a change at the arterial wall level. However, the active treatment groups receiving HRT did have substantial reductions in hot flashes and night sweats and some improvement in bone density compared to placebo.

Recently, a group of publications have appeared giving further data on additional quality of life benefits to the women in the KEEPs trial. Let's take a look at these recent publications.

Effects of Oral vs Transdermal Estrogen Therapy on Sexual Function in Early Postmenopause: Ancillary Study of the Kronos Early Estrogen Prevention Study (KEEPS) [5]

This ancillary study assessed measures of sexual function including desire, arousal, lubrication, orgasm, sexual satisfaction, and dyspareunia (pain) scored using the Female Sexual Function Inventory (FSFI). FSFI scores were moderately, but with statistical significance, improved in women using the estradiol transdermal patch compared with placebo, while there was no significant difference in score between the women using low-dose oral CEE and those using placebo. The main contributors to the improved FSFI score in the transdermal estradiol group were increased lubrication and decreased pain on intercourse.

Effects of oral versus transdermal menopausal hormone treatments on self-reported sleep domains and their association with vasomotor symptoms in recently menopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS) [6]

Using the Pittsburgh Sleep Quality Index, KEEPS participants recorded various aspects of sleep quality on entry to the trial and at 6, 18, 36, and 48 months during treatment. Sleep quality index scores improved in both treatment groups (oral low-dose CEE and estradiol patch) compared to placebo, and scores correlated with severity of hot flashes and night sweats. While most of the individual aspects of sleep quality recorded were similar in both treatment groups, the score for sleep disturbances improved to a greater extent in the estradiol patch users than the CEE users.

Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study [7]

Menopausal symptoms (hot flashes, night sweats, insomnia, and irritability) were recorded in KEEPS participants at screening and at 6, 12, 24, 36, and 48 months after starting treatment. Substantial reductions in hot flashes and night sweats were reported by women using either low-dose oral CEE or a low-dose transdermal estradiol patch compared to placebo, and these reductions were seen at 6 months and sustained during all 4 years of follow-up. Reported insomnia was reduced intermittently in both treatment groups compared to placebo; CEE was more effective than placebo at 36 and 48 months, while the estradiol patch was more effective than placebo at 48 months. Irritability was not reported to improve with either estrogen treatment compared to placebo.

Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study [8]

This ancillary study looked at measures of mood and cognition, including the Modified Mini-Mental State examination, cognitive factors, verbal learning/memory, auditory attention/working memory, visual attention/executive function, mental flexibility, and the Profile of Mood States (POMS). Neither treatment group showed an improvement in any of the cognitive outcomes. Regarding mood, the low-dose oral CEE group showed improved depression and anxiety symptoms during the 4 years of follow-up compared to placebo, while the estradiol patch had similar mood scores to the placebo group.

When interpreting results of the above-mentioned and other studies, it is important to take into consideration the route of administration, the dose of hormone used, and the outcomes measured. The rule of thumb is that physiologic dosing of hormones, mimicking endogenous production, is recommended when trying to achieve normal, pre-menopausal levels. Balancing estrogen with progesterone is important, both when symptoms of estrogen dominance are present and to protect the uterus from endometrial proliferation. In order to ensure balance in the hormonal milieu, saliva testing is best for assessing the free, bioavailable fraction of hormone and urine is best for assessing total levels and metabolite status.

Related Resources

References

[1] Rossouw JE, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-33.

[2] Anderson GL, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-12.

[3] Manson JE, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. JAMA. 2017;318(10):927-938.

[4] Hodis HN, et al. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med. 2016;374(13):1221-31.

[5] Taylor HS, et al. Effects of Oral vs Transdermal Estrogen Therapy on Sexual Function in Early Postmenopause: Ancillary Study of the Kronos Early Estrogen Prevention Study (KEEPS). JAMA Intern Med. 2017 Aug 28. [Epub ahead of print]

[6] Cintron D, et al. Effects of oral versus transdermal menopausal hormone treatments on self-reported sleep domains and their association with vasomotor symptoms in recently menopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Menopause. 2017 Aug 21. [Epub ahead of print]

[7] Santoro N, et al. Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study. 2017;24(3):238-246.

[8] Gleason CE, et al. Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. PLoS Med. 2015;12(6):e1001833; discussion e1001833.

Your Checklist for Partnering with a Quality Lab

Thu, 20 Apr 2017 12:20:00 -0700

Quality testing is a vital component of a physician's evaluation of a patient with a view to successful treatment. But how can health care providers ensure that the lab they are working with is giving them the quality they need?

We’re often asked "Why should I partner with your lab? What distinguishes you from the others?" While many providers are expecting the obvious answers like fair prices and fast, reliable results – which are definitely important – we like to dig a bit deeper than this.

At ZRT Laboratory, we think there are six important measures to help determine the quality of a lab.

1. Certification

CLIA (Clinical Laboratory Improvement Amendments) certification is one important criterion that ensures a lab conforms to federal regulations regarding testing. ZRT is a CLIA-certified laboratory and is subject to regular inspections of all aspects of the lab's procedures to ensure ongoing compliance. This, in turn, assures health care providers that the lab is adhering to proper scientific procedures.

2. Assay Validation

Federal regulations governing assay validation are specified in the CLIA standards for quality assurance. This validation includes rigorous criteria for assay precision, accuracy, and sensitivity, and an important aspect of assay validation is to establish a reference range of expected values in a population that is as healthy as possible.

Tests developed by ZRT undergo a comprehensive assay validation procedure before they can be used commercially. The regulations require that reference ranges are provided with test reports so that providers can see if their patients' results are within or outside that range and make treatment determinations accordingly.

3. Research Involvement

Labs that are highly respected are often involved in research studies into various aspects of health. Researchers have to rely on accurate and reliable testing, and labs involved in research need to meet stricter criteria in order to be approved by the funding sources for research studies, such as the National Institutes of Health (NIH). ZRT has partnered with NIH-funded research groups and universities around the world as well as the Centers for Disease Control, to provide test results that can ultimately contribute to advances in medical science.

Key Fact: ZRT is the only specialty hormone laboratory to have qualified for the CDC’s Hormone Standardization Program (HoSt) – meaning that ZRT has successfully passed the performance criteria to qualify for the CDC Testosterone Reference Method and the CDC Estradiol Reference Method

4. Conflicts of Interest

Another consideration when assessing the quality of a lab's results is whether the lab sells supplements or other treatments for conditions identified by its own testing. While this may seem obvious, it can be a serious pitfall – as at least one prominent lab has recently been found guilty of doing just that.

Over its nearly 20 year history, ZRT has never sold anything except lab results. This keeps our focus on accurate testing and avoids any conflicts of interest that could arise by publishing reference ranges that are too narrow, resulting in test reports that might identify too many patients as having an abnormal result. Since we have no vested interest in potential treatments for imbalances, such as supplements, we identify results as abnormal only when they fall outside our established reference ranges that are based on a healthy population.

5. Clinical Support

Testing labs usually assist physicians with interpretation of patients' results in some way. A detailed test report, giving not only the reference ranges and a determination of whether results are within or outside those ranges, but also some pertinent information to help with clinical interpretation of abnormal results is something to look for in a lab partner.

ZRT's test reports, along with our comprehensive provider resources, are highly detailed and include citations of relevant clinical studies to support the information presented. To allow fast turnaround times, results are interpreted with the help of an "artificial intelligence" system so that they can be categorized appropriately in the test report, which is then reviewed and approved by our clinical consultant team before being finalized. Clinical consultants are available by telephone to provide additional assistance.

6. Industry Standards

A commitment to excellence is something that patients and health care providers should expect from their lab of choice.

A desire to meet and exceed standards set by the industry is another measure of lab quality. A commitment to excellence is something that patients and health care providers should expect from their lab of choice.

Proficiency testing is a big part of ongoing quality control, and ZRT participates in proficiency testing programs relevant to the analytes we test. These include the College of American Pathologists (CAP), DEQAS (the Vitamin D External Quality Assessment Scheme), EQUIP (Ensuring the Quality of Urinary Iodine Procedures), and LAMP (the CDC’s Lead and Multi-Element Proficiency program). Within the saliva testing industry, since no external organization prepares saliva samples for proficiency testing, ZRT took the step of establishing the Saliva Proficiency Inter-Laboratory Testing (SPIT) program in an effort to maintain quality in saliva hormone testing.

With the prevalence of specialty labs today, health care providers are fortunate to have a choice for quality testing services. Never settle for a lab in which you don’t have absolute confidence, and don’t be afraid to ask about qualifications. Any lab you choose should be glad to have a conversation about these six characteristics of quality.

In fact, if you have any additional questions about ZRT's quality standards, we’ll gladly answer them.

Webinar Review: The Nuts & Bolts of Neurotransmitter Testing

Fri, 03 Mar 2017 16:20:00 -0800

ZRT's senior research scientist Dr. Kate Placzek presented a webinar about the neurotransmitter testing ZRT began offering last year.

Neurotransmitter testing is a natural progression of the wellness testing options that ZRT has developed and offered over the years, and in some ways encompasses many aspects of the testing in other areas such as steroid hormone and metabolite testing, adrenal and thyroid health assessment, cardio-metabolic parameters, and heavy metals.

She addresses these questions that are commonly asked by health care providers who call in to enquire about this testing.

How do I know if neurotransmitter testing is right for my patients?

Dr. Placzek presents these assessment tools: our patient quiz, which helps with assessment of patients' mental wellbeing; and the ZRT requisition form on which patients report symptoms along with their test samples. Some are very pertinent to possible neurotransmitter imbalances, including those that don't immediately appear to relate directly to brain health.

Which panel should I choose?

The NeuroBasic profile has 7 tests – serotonin, GABA, glutamate, phenylethylamine (PEA), dopamine, norepinephrine, and epinephrine, forming a good basic screening test.

The NeuroIntermediate profile has the above 7 tests plus glycine and histamine, useful for assessing patients with problems such as migraine, allergies, and/or low libido.

The NeuroAdvanced profile provides a comprehensive functional assessment that can be used to tailor treatments.

The NeuroAdvanced profile has all of the above plus the major metabolites of the main players in the neurotransmitter rainbow: 5HIAA (serotonin metabolite), DOPAC and HVA (dopamine metabolites), NMN (norepinephrine metabolite), and VMA (norepinephrine and epinephrine metabolite). This therefore provides a comprehensive functional assessment that can be used to tailor treatments. It is particularly useful for patients with suspected methylation issues affecting neurotransmitter metabolism, or those with unusual symptoms.

Optional add-ons to testing are diurnal cortisol, diurnal melatonin, and diurnal norepinephrine and epinephrine. These are possible because patients collect 4 urine samples on filter cards during the day at specified time points that are tested individually, allowing a diurnal pattern to be assessed. Assessment of diurnal cortisol, melatonin, norepinephrine and epinephrine are useful in identifying an individual’s response to stress, particularly when the patient is affected by circumstances or conditions that affect sleep.

Dr. Placzek outlines how patients should prepare for the test for best results; e.g., avoiding some foods that have a large effect on urine NT levels (bananas, nuts, pineapple, and avocado), excessive exercise, and some medications that can affect results (e.g., acetaminophen and vitamin C). She also explains what happens to the sample when it arrives at ZRT, and the importance of the testing method for these small molecules, which require highly accurate and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) analysis by our well-trained lab professionals.

How do I interpret the results and use the report to navigate appropriate treatments?

Dr. Placzek explains some general considerations when interpreting NT test results, and these comprise:

The balance between inhibitory and excitatory NTs.
How different patterns emerge, and how they relate to one another.

She presents a test report and explains the different sections of the report and how to read it effectively to use all the information the patient provided as well as the test results.

She explains how the reference ranges for each analyte were determined at ZRT and why it's important to consider the optimal range when interpreting results.

The report also includes the main neurotransmitter metabolic pathways to help with interpretation of what is happening to the neurotransmitters in the body and what impacts their levels, such as factors that affect their metabolism. Dr. Placzek explains how to use these pathways to see what is happening in a patient in light of their results, and what supplements might help influence the pathway to bring the neurotransmitter picture more into balance.

How do urine neurotransmitter levels relate to brain function?

The webinar outlines neurotransmitter production in the body and explains how the peripheral neurotransmitter production and metabolism relates to that in the central nervous system. Urinary neurotransmitters typically come from peripheral tissues since most do not normally cross the blood-brain barrier. Ninety percent of serotonin, for example, is produced in the gut, and most of the dopamine in the urine is produced in the kidney. However, research in this area is very active and studies show how peripheral levels of neurotransmitters and their metabolites reflect the overall homeostasis of the neurotransmitter production in both the brain and the peripheral tissues.

Case studies

Dr. Placzek presents three case studies highlighting a range of typical patients: a "burned-out male," a premenopausal woman with suspected HPA axis dysfunction, and a child with an ADHD diagnosis. She gives detailed interpretations of their test reports and how these relate to their symptoms, and includes recommended treatment considerations, including a detailed rationale for these, in each case.

Finally, she summarizes some general treatment considerations for both overall low and overall high neurotransmitter levels, emphasizing that each patient is different and must be assessed on a case by case basis. She also explains the importance of considering the potential interaction of the neurotransmitter system with a patient’s overall hormone picture, including steroid and thyroid hormone balance, heavy metal exposure, and diurnal cortisol patterns to assess stress burden.

Endocrine Disruptors: What They Are & How To Avoid Them

Fri, 17 Feb 2017 14:01:00 -0800

As a hormone testing lab, ZRT understands the importance of a well-balanced endocrine system in maintaining overall health.

Hormone balance is achieved through multiple feedback mechanisms, and when any part of the system is thrown out of whack by forces beyond its control, there is a knock-on effect on the rest of the body systems that are under endocrine control.

Such forces can include extreme or chronic stress, or exposure to environmental toxins that enter the body through the air we breathe or in our diets. Substances in the environment that upset the endocrine system are known as endocrine-disrupting chemicals, or EDCs.

How do EDCs cause disruption?

There are 3 main mechanisms by which substances in the environment exert endocrine disrupting effects. First, they can mimic, or act as, a hormone that occurs naturally in the body, activating that hormone’s receptors and often producing inappropriate or excessive hormonal effects. Second, they can block the activity of endogenous hormones by occupying their receptors without activating them. And third, they can interfere with synthesis or metabolism of hormones and/or their receptors, indirectly affecting or modulating the body’s responses to endogenous hormones.

Because of the importance of the endocrine system in early development, some of the greatest risks from EDCs are to pregnant and breastfeeding mothers and to children at important stages of growth and development, in whom endocrine disruption can have very serious long-term consequences including problems with fertility and increased cancer risk when they reach adulthood. But the effects of EDC exposure in adulthood are also implicated in infertility and risks of some cancers.

Those EDCs that interfere with the hypothalamic-pituitary-gonadal axis, notably polychlorinated biphenyls (PCBs), bisphenol A (BPA), and lead, are particularly damaging to the developing reproductive system, and depending on the dose can either delay or hasten puberty, and cause long-term effects on male and female fertility. However, there is little evidence for alterations in endogenous hormone levels as a result of exposure to EDCs.

What are the main culprits?

Estrogenic EDCs are of concern because of their potential to increase risk of hormone-dependent cancers, particularly breast cancer

Many substances in the environment, both naturally occurring and man-made, have been identified as EDCs. These include pharmaceuticals, agricultural chemicals such as pesticides, plasticizers like BPA, and heavy metals. These substances can be found in plastic materials used for food storage, food itself, cosmetics, detergents, household cleaning products, and flame retardants.

Organizations such as the Environmental Working Group (EWG) have provided materials that can help people know where EDCs occur and avoid them – for example, their annually-updated list of produce items that are most likely to be contaminated with pesticides (the "dirty dozen") for which consumers are advised to buy organic instead, and those that are least likely to be contaminated (the "clean fifteen").

A significant group of EDCs consists of those that have estrogen-like activity. These include naturally occurring phytoestrogens (e.g., genistein), xenoestrogens (non-naturally occurring estrogen mimics like BPA), and the metalloestrogens (heavy metals that can activate the estrogen receptor). Estrogenic EDCs are of concern because of their potential to increase risk of hormone-dependent cancers, particularly breast cancer. Let's look in more detail at these estrogen-mimicking EDCs.

Bisphenol A

BPA is found principally in linings of food and beverage cans and in thermal paper used in receipts. We are mainly exposed to it by consuming canned foods and beverages, and we absorb smaller amounts through the skin when handling cash register receipts or paper money, which is contaminated with BPA through incidental contact with receipts. BPA acts like a weak estrogen in the body, but it isn’t a steroid – it is made from two phenol molecules, each of which consist of a 6-carbon ring with a hydroxyl group attached, combined chemically with acetone; hence the name: bis (2) phenol A (acetone), as shown below.

However, its structure is similar enough to estradiol (see the structures below, showing BPA oriented similarly to estradiol) that it can exert endocrine-disrupting effects through its strong binding to estrogen-related receptor γ (ERR-γ) and, more weakly, to estrogen receptors (ER) α and β.

BPA Estradiol

Heavy metals

The metalloestrogens include metal/metalloid anions, e.g., arsenite, and bivalent cations, e.g., cadmium, cobalt, copper, nickel, chromium, lead, mercury, and tin. We are exposed to these metals through the diet, drinking water, and, for cadmium especially, smoking. The bivalent cations can activate the estrogen receptor α (ERα) in the absence of estradiol, putatively by mimicking the binding of calcium to the ligand-binding domain of the receptor [1], while arsenic's interference with ER-mediated gene expression has been less clearly defined and could involve multiple mechanisms [2].

Heavy metals have multiple toxic effects, particularly at high doses, which are not necessarily related to endocrine disruption. For example, exposure to lead is well known to induce male infertility by impacting spermatogenesis, but the mechanisms for this are different depending on the level of exposure. High doses from occupational exposure have direct cellular toxicity in the male reproductive system, while long-term low-level exposure, rather than the more obvious occupational exposure, can be much harder to detect but can result in adverse effects as a result of endocrine disruption. These effects include suppression of hormone synthesis by disrupting signaling in the hypothalamic-pituitary-testosterone axis, adversely affecting testicular function and spermatogenesis [3]. Mercury is a weak estrogen mimic and has been implicated in animal studies in feminization of males and suppression of fertility in females, although as with lead, effects of mercury on reproductive function are different at different levels of exposure [4].

Those metals that can accumulate in the body over many years – notably cadmium, lead, and mercury – are of particular concern. Cadmium’s properties as a metalloestrogen are the best characterized of all the heavy metals [4], and its potential for increasing risk of estrogen-dependent cancers such as breast cancer is compounded by its bio-accumulative properties. Cadmium exposure in non-smokers is mainly from the diet, as foods grown in areas where soil cadmium levels are high can be contaminated, while smokers are at particularly high risk of direct cadmium exposure via inhalation of tobacco smoke.

Be aware of exposure to EDCs

For EDCs like BPA and heavy metals, it’s important to be aware of where these occur, and do what we can to minimize exposure. For example, look for BPA-free cans and plastics for food storage, avoid smoking, and be aware of heavy metals in the environment by paying attention to news of leaks from industrial activity. We can also detect exposure by urine testing; BPA testing is included in ZRT’s hormone metabolite testing, while heavy metals are tested in ZRT’s heavy metal and nutrient profiles.

Related Resources

References

[1] Byrne C, et al. Metals and Breast Cancer. J Mammary Gland Biol Neoplasia. 2013;18(1):63–73.

[2] Watson WH, et al. Arsenic: Extension of its Endocrine Disruption Potential to Interference with Estrogen Receptor-Mediated Signaling. Toxicol Sci 2007; 98(1):1-4.

[3] Vigeh M, Smith DR, Hsu P-C. How does lead induce male infertility? Iranian Journal of Reproductive Medicine. 2011;9(1):1-8.

[4] Dyer CA. Heavy Metals as Endocrine-Disrupting Chemicals. In: Gore AC, editor. Endrocrine-disrupting chemicals: From basic research to clinical practice. Totowa, NJ: Humana Press Inc; 2007.

Do Hormonal Contraceptives Increase Risk of Depression?

Sat, 08 Oct 2016 12:54:00 -0700

Practical Takeaway: A recent study found the risk of depression with contraceptive use decreased with increasing age, and was highest in the youngest age group studied, namely teenagers aged 15-19, than in the women aged 20-34.

These findings are from a new Danish study [1] suggesting that hormonal contraception might increase risk of depression, and that previous studies may not have highlighted this link because they did not include women who stopped taking their birth control as a result of depressive symptoms.

This study got around that problem by including in their survey women who had been using birth control at any time during the previous 6 months. So what is the fuss all about?

Additional findings from the study

The study did find an association between use of hormonal contraception and the subsequent use of antidepressant medications and diagnosis of depression. The risk of depression with contraceptive use decreased with increasing age, and was highest in the youngest age group studied, namely teenagers aged 15-19, than in the women aged 20-34. The authors acknowledged that antidepressants are prescribed for other reasons than depression. They also acknowledged that adolescent girls are “more vulnerable to risk factors for depression” than older women, partly explaining the higher incidence of antidepressant use in this age group.

Progestins versus progesterone

The study showed that progestin-only contraceptive products were the most likely to result in use of antidepressant medication or a diagnosis of depression. But an unfortunate confusion between progesterone and progestins was created by a statement in the introduction of the study [1] saying “The 2 female sex hormones – estrogen and progesterone – have been hypothesized to play a role in the cause of depressive symptoms.” This led to a claim in a popular article about this study that the authors theorized that progesterone, as well as the synthetic progestins used in hormonal contraceptives, plays a role in the development of depression.

A recent blog by ZRT’s senior research scientist and neurotransmitter expert Kate Placzek, PhD, has discussed the neuroendocrine functions of endogenous estrogen and progesterone. Briefly, sex hormones have neuromodulatory roles in brain development and neuronal plasticity, and the regulation of cognition, learning, memory, emotion, mood, and motor control. It’s understandable that mood varies at different times during the menstrual cycle as hormone levels shift dramatically and these neuromodulatory effects come into play. The blog also explains how depression can be a factor in some women, but not others, using hormonal contraception.

It’s important to understand that the study did not report the increased likelihood of using antidepressants as percentage increases, but rather in terms of a calculation of relative risk.

The study authors’ statement regarding estrogen and progesterone’s role in causing depressive symptoms cites 5 studies; however, 2 of these are only about estrogen’s effects, and 2 refer only to synthetic progestins used in oral contraceptives (not progesterone itself). The 5^th was a study of experimental estrogen or progesterone replacement in a very small group of 10 women with premenstrual syndrome and 15 normal women [2]. This study was designed only to study adverse mood symptoms in susceptible women who were prone to PMS. In the experiment, the women were first treated with leuprolide to completely suppress ovarian hormone production, and then the investigators looked at whether or not PMS symptoms returned when estrogen or progesterone was then replaced. Although they found an increase in sadness (not depression) in the women with PMS after this hormone replacement, no such increase was seen in the normal women – thus progesterone adversely affected mood only in those women who were prone to PMS. Also, since the PMS symptoms actually abated during the last week of the experimental hormone replacement, the authors stated that they couldn’t predict whether long-term or low-dose hormone treatment would result in adverse mood symptoms in women.

Adding to the confusion, another statement in the Danish study says “The addition of progesterone to hormone therapy has been shown to induce adverse mood effects in women”; yet this is referenced by 2 citations, both of which concerned a synthetic progestin, not natural progesterone.

The authors do, however, reference a review [3] suggesting that neuroactive metabolites of progesterone, allopregnanolone and pregnanolone, can have adverse mood effects in some women as a result of modulatory effects on the GABA-A receptor, and that this can explain the effects of luteal phase levels of progesterone in women who suffer from PMS, who are particularly sensitive to such effects. This allopregnanolone paradox, known as such because it is found in some women but not the majority, was described in detail in a recent blog on PMS by Dr. Placzek.

How great is the risk of depression in hormonal contraceptive users?

At first glance, the figures seem very stark. An article on this study reported that the highest risk group, which consisted of teenage girls aged 15-19, were “80% more likely to be prescribed an antidepressant when they were on combined birth control pills and 120% more likely when they were on progestin-only pills.” However, it’s important to understand that the study itself did not report the increased likelihood of using antidepressants as percentage increases, but rather in terms of a calculation of relative risk. There is a baseline level of antidepressant use regardless of hormonal contraceptive use, and this is given a relative risk of 1.0. The teenage users of combined oral contraceptives had a calculated relative risk of 1.8, and the progestin-only pill users had a calculated risk of 2.2 compared to non-users. While these figures do represent the percentage increases in relative risk stated in the article, the statistics require more careful interpretation.

The authors also found that relative risk of depression peaked after 6 months of hormonal contraceptive use, and dropped off to a lower risk than non-users after 4 years of use. For people susceptible to such effects with hormonal contraceptives, symptoms would therefore appear relatively soon after starting use, giving the opportunity to switch to a different preparation or method of contraception.

Conclusion

This is an important study to add to others in the literature that have looked at depression associated with use of hormonal contraceptives, and a risk of depression, especially in teenagers, is certainly of concern. However, hormonal methods are overwhelmingly very safe and effective, and practitioners should weigh the pros and cons of each method of contraception when advising patients. Some women may be susceptible to adverse effects on mood, while others may not. The pros and cons of an unwanted pregnancy must also be weighed against any potential drawbacks to using an effective means of contraception.

Related Blogs

References

[1] Skovlund CW, et al. Association of Hormonal Contraception With Depression. JAMA Psychiatry. 2016 Sep 28.

[2] Schmidt PJ, et al. Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med. 1998;338:209-16.

[3] Andréen L, et al. Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators. Psychoneuroendocrinology. 2009;34:1121-32.

Exercise – Good for Neurotransmitters & Your Brain

Wed, 17 Aug 2016 09:32:00 -0700

As the 2016 Olympic games play out in Rio, you might be feeling inspired to get moving yourself. While some sports admittedly look pretty dangerous, and we cringe at the sight of a cyclist skidding into the curb on a wet road and landing on her head, there are others that simply make us marvel at the agility and strength of the human body. For me, when I watch those swimmers cutting through the water at tremendous speed, I just want to get into a pool and see if I could really try to swim faster myself.

We’ve probably all heard by now that “sitting is the new smoking,” and that our health suffers greatly from inactivity. The human body was meant to be in motion at least for an hour or two a day, and this is known to keep the cardiovascular system tuned up as well as preventing excessive weight gain. But did you know that exercise affects levels of neurotransmitters in the body and can actually help you prevent or overcome disorders such as depression?

Depression is a Major Cause of Disability

According to the World Health Organization, an estimated 350 million people are affected by depression. This makes it the leading cause of disability worldwide, and less than half of those affected do not have access to effective treatment. More women than men suffer from depression.

Earlier attributed to a “chemical imbalance,” the causes of depression are now known to encompass multiple factors including oxidative stress, inflammation, changes in neuroactive hormones that affect nerve function and neurotrophins that control nerve growth, and altered brain volume due to changes in brain-derived neurotrophic factor (BDNF)[1].

Exercise can Prevent and Treat Depressive Disorders

Multiple studies have found that regular exercise has an antidepressant effect, but what is the biological basis for this? A recent review [1] describes the evidence showing that physical exercise reduces the oxidative stress and inflammation that can contribute to depression, and that it increases factors that are reduced in depression, including BDNF levels, hippocampal volume, brain capillarization (increasing blood supply to the brain), neuronal plasticity, telomere length, and the activity of the monoamine neurotransmitters serotonin, dopamine, and norepinephrine. Besides, exercise can simply make you feel good – that “runner’s high” feeling comes from the release of endorphins in response to exercise, which have a euphoric effect. Recently, the endocannabinoid anandamide has also been implicated in mediating the benefits of exercise on mood, contributing to a reduction in depression and anxiety [2].

Exercise Increases Neurotransmitters that are Depleted in Depressed Patients

Since physical exercise helps to keep serotonin levels high, this should not only improve mood but also help prevent depression.

Raising brain serotonin levels is the basis of SSRI (selective serotonin reuptake inhibitor) treatment for depressive disorders. Studies have shown that aerobic exercise increases serotonin concentrations, tryptophan availability, and the activity of serotonin receptors. For example, when muscles are working, they take up branched-chain amino acids (BCAAs) as fuel; these BCAAs compete with tryptophan for transport across the blood-brain barrier, and so the reduction in levels of BCAAs as they are used up by the muscles allows more tryptophan to enter the brain tissue where it is available for conversion to serotonin [2]. Since physical exercise helps to keep serotonin levels high, this should not only improve mood but also help prevent depression, and could potentially be used in therapy in place of pharmaceuticals – at least to treat mild depression [3].

Yoga Increases GABA

People with joint issues or those who have been advised by their doctors not to undertake strenuous activity can still experience the positive effects of exercise on brain health with more gentle forms of exercise such as yoga. Yoga is known for its calming effects on stress and anxiety, and brain levels of the inhibitory neurotransmitter GABA (gamma-aminobutyric acid) have been found to increase during yoga practice [4]. A study comparing yoga practice with walking, both for 60 minutes 3 times weekly for 12 weeks, found greater improvements in both mood and anxiety symptoms in the yoga group, and a brain imaging technique showed that increased levels of GABA in the thalamic area of the brain were correlated with these positive mood changes [5]. Some conditions that are exacerbated by stress such as depression, anxiety, PTSD, chronic pain, epilepsy, and mood disorders are all associated with low GABA levels and have been shown to improve using drugs that increase activity of the GABAergic system. It has therefore been suggested that regular yoga practice could benefit people with these disorders [6].

Feel Good about Exercise

You don't have to be an Olympian to feel good about exercising. Yes, it’s great to win a medal, but even some Olympians are happy simply to compete, as Eddie the Eagle exemplified. Hearing the Olympians’ stories of hard work and dedication to achieve their sporting goals is certainly inspiring, but we can all experience a little bit of that sense of achievement by just starting somewhere and setting our own goals.

We can gradually increase activity to a level where we can feel that we are really doing something to take better care of ourselves, and experience that benefit in mood and a feeling of wellbeing as the brain responds. Don’t overdo it, listen to your body (unless it’s telling you to stay on the couch) and award yourself a gold medal for effort.

Learn about Neurotransmitter Testing

Related Resources

References

[1] Pareja-Galeano H, et al. Biological Rationale for Regular Physical Exercise as an Effective Intervention for the Prevention and Treatment of Depressive Disorders. Curr Pharm Des. 2016;22:3764-75.

[2] Heijnen S, et al. Neuromodulation of Aerobic Exercise-A Review. Front Psychol. 2016;6:1890.

[3] Young SN. How to increase serotonin in the human brain without drugs. J Psychiatry Neurosci. 2007;32:394-9.

[4] Streeter CC, et al. Yoga Asana sessions increase brain GABA levels: a pilot study. J Altern Complement Med. 2007;13:419-26.

[5] Streeter CC, et al. Effects of yoga versus walking on mood, anxiety, and brain GABA levels: a randomized controlled MRS study. J Altern Complement Med. 2010;16:1145-52.

[6] Streeter CC, et al. Effects of yoga on the autonomic nervous system, gamma-aminobutyric-acid, and allostasis in epilepsy, depression, and post-traumatic stress disorder. Med Hypotheses. 2012;78:571-9.

Research Puts the "R" in ZRT

Fri, 15 Apr 2016 10:22:00 -0700

I have to admit, I believe that "research" is one of those words that I think is often misused today.

I started my own career in a cancer research lab, continued it in a pharmaceutical company research lab, and then got into medical information research and scientific writing, which meant using a range of medical literature databases and complex searching strategies.

My early research career was back in the days before we had personal computers, so many hours – in between tending to assays and experiments (as well as late in the evening) – were spent thumbing through the pages of massive volumes of Index Medicus, the print version of Medline, in various university libraries to find relevant publications.

Later, such databases became searchable online, usually via a slow modem connection using a telephone and usually for a fee. Eventually PubMed, the free public version of Medline, was made available in 1996 and has been a godsend to medical researchers and writers all over the globe.

So I find it a little irritating when people blithely say they are "researching" something and what they mean is they typed a question into Google and then waded through a list of hits that Google thought were relevant. Not that it doesn't often get you what you're looking for. But in my book, "research" truly means an in-depth analysis of a subject, either in the lab or in the medical literature, using an intelligent experimental strategy, appropriate methods, and a keen eye for results that are meaningful and relevant to the initial question.

So when I refer to research at ZRT, this is very much what I am talking about.

Research at ZRT

Staying at the forefront of the industry has meant continual new development of innovative tests.

ZRT Laboratory was founded on the basis of high level research. In fact, the "R" in ZRT stands for Research. Groundbreaking methodology using a simple-to-collect sample, namely saliva passively collected into a simple tube, was finely honed through years of careful research and validation to achieve the kind of accuracy demanded by the licensing bodies for commercial, high complexity testing.

Our founder, Dr. Zava, wanted to make testing easily available, using simple collection methods, to people with hormonal imbalances to help them get to the root of health issues and allow them to seek therapies such as hormone replacement. Staying at the forefront of the industry has meant continual new development of innovative tests, so our saliva testing was followed by new collection methods such as dried blood spot and dried urine testing, which required extensive validation before being offered commercially.

Quality Assurance

As a commercial testing lab, we are subject to stringent quality assurance procedures and record-keeping as required by CLIA (Clinical Laboratory Improvement Amendments), the US federal regulatory standards applicable to clinical lab testing. But we’re also kept on our toes by our continual involvement with research projects, collaborating with research groups in several academic institutions, including some projects with NIH funding, as well as research organizations or hospitals, and the Centers for Disease Control. Because of this, the methods we use are continually being validated to meet the stringent requirements for accuracy demanded by such organizations, and it keeps us involved at the cutting edge of scientific discovery.

Published Research

When a research study is completed, our testing is either acknowledged or Dr. Zava co-authors the study along with the research group. A list of our published research papers, most of which are in peer-reviewed journals, can be seen in our publications list. We’ve also presented ZRT research, carried out in-house, and taken it to international conferences where we have presented posters and/or had abstracts published in journals reporting on the conference – these can be viewed in our list of abstracts and posters, where the actual poster presented can be downloaded.

State-of-the-Art Test Methodology

Research sample testing as well as our commercial testing is done in the lab at ZRT by state-of-the art methodology, including FDA-approved immunoassays, enzymatic assays, inductively-coupled plasma mass spectrometry (ICP-MS), gas chromatography tandem mass spectrometry (GC-MS/MS), and liquid chromatography tandem mass spectrometry (LC-MS/MS). The research page on our website highlights the advantages of each of our sample collection methods for use in research.

I’m proud to be a part of the ZRT family and to acknowledge our commitment to research and high standards in everything we do.

Book Review: The Role of Stress and the HPA Axis in Chronic Disease Management

Fri, 12 Feb 2016 11:33:00 -0800

It would not be an exaggeration to say that this book covers everything you need to know about the stress response system and how it affects our health.

Dr. Guilliams reminds us that only 80 years ago the concept of stress as a biological process, and how the stress response is regulated by the hypothalamus-pituitary-adrenal (HPA) axis, was yet to be elucidated. He takes us back to the pioneering discoveries of Hans Selye, who in 1936 published a letter in Nature entitled "A syndrome produced by diverse nocuous agents" and went on to describe the body’s response to stressors in terms of what he called a "general adaptation syndrome" in a monograph published in 1950.

While Dr. Selye certainly didn’t have all the answers, he laid the foundations for what became a vast area of research into phenomena that touch every biological system and affect every aspect of our health.

This book offers a clear, well-illustrated review of the HPA axis, explaining how each of its components work and how they interact together, and how dysregulation of the axis impacts multiple aspects of health. He challenges some prevailing ideas, such as the nomenclature of some types of HPA axis dysfunction as "adrenal fatigue," instead suggesting more accurate terminology that better reflects what underlies it. And he reassesses the concept of "pregnenolone steal" by describing the pathways of steroidogenesis starting from cholesterol within the 3 distinct zones of the adrenal cortex, each of which produces a different hormone, and each of which is under the control of different types of receptor signaling the expression of the different enzymes required to synthesize each hormone. This clear description of steroidogenesis within the adrenal gland challenges the notion that overproduction of one hormone in one zone automatically reduces the availability of pregnenolone for hormone production by another, as if all the hormones were being produced from the same pool of pregnenolone within the same cells.

This book goes a long way to explain difficult concepts and bring clinicians up to date with the latest research.

Dr. Guilliams describes in great detail the ways in which various kinds of stress influence the HPA axis and how each of these can be modified. These include perceived stress, involving not only the brain’s reaction to anticipated stress but also disorders of stress perception caused by neurotransmitter imbalances, manifested in conditions such as depression or anxiety. They also include sleep imbalances that affect circadian rhythms, blood sugar dysregulation, and inflammatory signaling as a result of food allergies, gastrointestinal irritation, chronic inflammatory diseases such as rheumatoid arthritis, and obesity.

Aimed at clinicians hoping to better understand and treat HPA axis dysfunction, the book describes laboratory assessments of the HPA axis and explains how to interpret results. It details lifestyle approaches as well as some natural therapeutic protocols that can improve outcomes, including the use of adaptogens and related botanicals. Current research on the effects of physical activity on the HPA axis is summarized, to explain the biological basis for the known benefits of moderate exercise for a wide variety of medical conditions.

For those wishing to have a better understanding of the stress response and the HPA axis, and who have little time to review and synthesize the vast scientific literature on this topic, this book goes a long way to explain difficult concepts and bring clinicians up to date with the latest research. While short enough to be a manageable read, it opens the doors for further investigation of therapeutic approaches that may provide new ideas (and reinforce old ones) for the practicing clinician.

Bio

Thomas G. Guilliams, PhD, earned his doctorate from the Medical College of Wisconsin where he studied molecular immunology in the Microbiology Department. Since 1996, he has spent his time studying the mechanisms and actions of natural-based therapies, and is an expert in the therapeutic uses of nutritional supplements. As the VP of Science and Regulatory Affairs for Ortho Molecular Products, he has developed a wide array of products and programs which allow clinicians to use nutritional supplements and lifestyle interventions as safe, evidence-based and effective tools for a variety of patients. Dr. Guilliams teaches at the University of Wisconsin School of Pharmacy, where he holds an appointment as a Clinical Instructor, and at the University of Minnesota School of Pharmacy, and he is a faculty member of the Fellowship in Anti-aging Regenerative and Functional Medicine (A4M).

Related Resources

How Reference Ranges Determine a "Normal" Lab Test Result

Fri, 13 Nov 2015 10:00:00 -0800

CLIA-certified testing laboratories such as ZRT are required to provide reference ranges as an aid to interpretation of test results.

Ideally, reference ranges provide the expected range of values for a healthy population. When methodology and equipment is identical for testing a particular analyte among different laboratories, reference ranges for that analyte should be the same.

However, when methodologies or equipment for the same test differ somewhat from lab to lab, each lab must provide its own reference range established with its own methods. These ranges are usually very close, but may differ slightly depending on method. An example would be testing testosterone in blood or saliva by extraction and LC-mass spectrometry vs. direct testing by immunoassay.

Do Reference Ranges Define Normality?

Reference ranges do not always reflect a “normal” healthy population free of medications. Most laboratories establish their reference ranges from a large population of people where detailed information on health status, stage of life (premenopausal vs. postmenopausal), and medications and hormones used is unknown, and therefore not taken into account. Couple this with differences in lifestyles, physiology, dietary habits, and genetic heredity, and it’s even more difficult to define, let alone find, a normal population.

Over the past 19 years, we have filed information on over 2 million people who have tested with us.

These variables can have profound effects on test values used to establish a “normal” reference range. For example, in women using topical progesterone, salivary levels of progesterone can rise to levels much higher (500-5000 pg/mL) than what is seen at the peak of luteal phase 100-200 pg/mL. When these subjects are included into range determinations, it results in a very broad reference range that clinically has less meaning to a woman NOT using exogenous progesterone.

To truly establish a “normal” reference range for a given analyte (hormone) it is essential to know that the subject has very few, if any, symptoms of hormonal imbalance, and is not using exogenous hormones or medications to treat a condition. To do that the lab needs to test a large number of healthy people from all walks of life, deem them to be “normal,” and call the range of results obtained a “normal” range.

ZRT collects and stores in our database information on gender, menopausal status, hormones and medications used as well as symptoms associated with specific hormonal imbalances. Over the past 19 years, we have filed information on over 2 million people who have tested with us. With this information, we are able to establish truly “normal” ranges by filtering out subjects using hormones or medications and suffering from hormone-related symptoms. It has also allowed us to establish age- and gender-related reference ranges in healthy subjects who were experiencing few or no symptoms/conditions.

Clinically Useful Ranges – Published Data

For some lab tests, ranges reflect clinical targets based on meta-analyses of large, published studies of disease risk. In these cases, an “optimal” cutoff is recommended, or the range might simply be “less than” or “greater than” a certain number that has been established as a clinical target that people should achieve that reflects a healthy population.

ZRT follows stringent protocols for assay validation and verification using multiple controls and known standards.

For example, ZRT’s reference range for HDL cholesterol is “≥ 40 mg/dL,” which is an optimum range recommended by the National Cholesterol Education Program (NCEP). Similar ranges have been established based on large scale clinical studies for cardiometabolic risk markers (blood lipids, HbA1c, insulin) as well as thyroid hormones such as TSH.

Published reference range values for these analytes are more clinically useful when interpreting test results than a reference range based on a much smaller population tested by the lab. However, even among the academic circles these reference ranges may have limitations and be controversial, such as the reference range cutoff for high TSH, which was once 9, dropped to 4.5, is now recommended at 3 by some, and others argue should be 2 or less [1].

In order to use published ranges, the lab’s results must correlate well with known standards for each test to ensure that results correspond to those from other labs and can therefore be compared to national recommendations. This is certainly the case for reference ranges established at ZRT that conform with national standards.

ZRT follows stringent protocols for assay validation and verification using multiple controls and known standards, and participates in proficiency testing using samples provided by:

College of American Pathologists (CAP)
NY State Department of Health
Vitamin D External Quality Assessment Scheme (DEQAS)
Ensuring the Quality of Urinary Iodine procedures (EQUIP).

For saliva testing, ZRT established the Saliva Proficiency Inter-Laboratory Testing (SPIT) program which cross-compares saliva values among the commercial saliva testing laboratories. All saliva testing laboratories are encouraged to participate as this is the only inter-laboratory proficiency program available in the US.

Because ZRT has developed unique and innovative sample collection methods, our assay validation for blood spot testing involves correlation with standard serum testing for each test, while dried urine tests are validated against equivalent liquid urine samples.

Clinically Useful Ranges – Laboratory Data

For some tests, such as saliva steroid hormone tests, no nationally established, published ranges exist. In these cases, laboratories usually establish their own reference ranges based on their testing populations, i.e., the people whose samples come in for testing.

By definition, the testing population is comprised of people concerned about their health; they are therefore, in the main, more likely to have hormonal issues than not. Without knowing what the conditions (patient age, menopausal status, symptoms, hormones and medications used) it is very difficult to establish an accurate hormone reference range that reflects a “normal and healthy” population.

To eliminate abnormal results at either end of the range spectrum, the values between the 5^th and 95^th percentiles of the range usually comprise the reference range.

To make the reference range as normal as possible, labs make reasonable attempts to exclude values from people who are not healthy. This can be done on the basis of excluding data from subjects with certain disease states such as diabetes, heart disease, or cancer. But these parameters are usually unknown and, in addition, data related to patients’ symptoms of hormonal imbalances, medications, and hormonal therapies that can profoundly affect analyte test values is usually also an unknown and therefore not filtered out of the calculations for ranges. This results in very broad and less clinically meaningful reference ranges.

Usually, to eliminate abnormal results at either end of the range spectrum after initial filtering of the data, the values between the 5^th and 95^th percentiles of the range of results comprise the reference range. In some cases, where a larger proportion of the testing population is likely to be abnormal, the reference range is based on the 20^th to 80^th percentile of the results.

ZRT, therefore, relies on the tens of thousands of test results obtained from the testing population over many years, and filters them to exclude obvious disease states, hormone users, and symptoms commonly associated with high or low test values for the analyte of interest. After this filtering, the spread of values (reference range) between which most testers fall is established, eliminating the outlying values at the top and bottom ends of the range.

The testing population is also sorted according to gender and menopausal status, and ranges are established for each of these subgroups. We also look at test results according to type and dosages of hormone supplementation, and provide supplementation ranges for those where we have established predictable values based on testing of large numbers of hormone users.

For analytes that vary in a predictable way with age, e.g., DHEA-S and testosterone, test results are plotted on the known reference ranges at each age group. For cortisol, which varies with time of day, a graph shows test results plotted on a true 24-hr graph according to the actual time the sample was collected, as opposed to plotting test values on a graph only showing morning, noon, evening, and night collections. In the examples of our test report graphs shown on the right, the reference range is the shaded area, and the test result is the black dot.

We also determine our own reference ranges for dried urine tests for metabolites and elements, based on our testing population and using appropriate cut-offs to eliminate outliers. In the case of elements testing, for example, people with unusually high dietary exposure to certain elements, e.g., iodine, have abnormally high urinary levels and are excluded from the reference range. Ranges are sometimes adjusted, especially for newer tests, as the testing population expands and more values are available in the database on which to base the reference range.

Related Resources

References

[1] Garber JR, et al; American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18:988-1028.

Of Seahorses & Menopause

Tue, 08 Sep 2015 08:08:00 -0700

Many women going through menopause start to see changes in their ability to remember things. Women can find this very worrying; such symptoms are not unlike early signs of dementia, or even Alzheimer’s Disease.

However, age-related memory impairment is quite common and can be explained in part by hormonal changes, in particular loss of estrogen, and it involves a small part of the brain that resembles a seahorse.

The Hippocampus

The name “hippocampus” is actually the Latin word for seahorse.

Image: László Seres

The hippocampus is located in the temporal lobe of the brain and is a component of the limbic system. Although referred to in the singular we actually have two of them, arranged symmetrically one on each side of the brain. It plays an important role in the transfer of short-term memory to long-term memory, and in the formation of new memories.

Anterograde amnesia, the loss of the ability to form new memories, is seen in people with damage to both hippocampi. It’s also important for spatial memory and navigation, like an inner GPS – the 2014 Nobel prize in Physiology or Medicine was awarded for the discovery that the memory of an environment is stored as a specific combination of “place cell” activities in the hippocampus. Interestingly, the hippocampus is also one of the first areas of the brain to show damage in Alzheimer’s disease.

Hormonal Connection to Learning & Memory

As we age, fewer new neurons are formed in the brain, so our ability to learn and form memories results from the strengthening of connections between existing neurons rather than the formation of new ones. The modulation of neural connections is referred to as synaptic plasticity. Enhancement of synaptic plasticity that persists in response to a recent stimulus is called long-term potentiation (LTP). LTP is believed to be the process by which memories are stored, and so it is an important aspect of hippocampal function.

So where do hormones come in? Local steroidogenesis of testosterone, dihydrotestosterone, and estradiol (E2) from cholesterol occurs in hippocampal neurons, resulting in much greater levels of these hormones in the hippocampus than in the circulation. This local supply of androgens and estrogens is essential for influencing synaptic plasticity, through a number of mechanisms mostly involving E2 activity at estrogen receptors [1].

Age-related memory impairment is quite common and can be explained in part by hormonal changes, in particular, loss of estrogen.

Estradiol increases synaptic plasticity both slowly, via classical nuclear estrogen receptors (ERα and ERβ), and rapidly, via ERα and ERβ located in the synapses, the area in between neurons where they communicate. The local synthesis of E2 from androgens requires aromatase activity; patients undergoing treatment with aromatase inhibitors, such as postmenopausal women being treated for breast cancer, therefore have a reduced E2 synthesis and subsequent decrease in hippocampal E2 levels, and could therefore be more likely to experience thinking and memory problems. However, available evidence from clinical trials for such effects is currently not conclusive [2].

Estrogen Receptor Expression Key to Cognitive Function

The ability of E2 to exert beneficial effects on synaptic plasticity and cognitive function declines with advancing age, and this is because estrogen receptor expression decreases with age [3]; it also has to do with the relative expression of ERα and ERβ. Experiments in mice have suggested that supraphysiological E2 preferentially increases synaptic ERβ, which, along with the age-related decline in ERα, decreases the ratio of ERα/ERβ. This imbalanced ratio impairs transcriptional processes that preserve cognitive function, including those involved with neuroprotection and synaptic plasticity. Thus, treatments to enhance ERα expression relative to ERβ could preserve cognitive function even as E2 levels decline with aging [4].

Don’t Close the Barn Door After the (Sea)horse Has Bolted

If estrogen replacement is started too late, this cannot restore hippocampal tissue that was already lost.

The age-related loss of hippocampal brain tissue is significantly greater in females than males, and this is related to low E2, since E2 acts as an antioxidant and protects the hippocampus from ischemic stress damage [5]. Estrogen replacement can protect against this loss early in menopause; however, if estrogen replacement is started too late, this cannot restore hippocampal tissue that was already lost.

In women aged 65 or older, higher endogenous, bioavailable (non-protein-bound) E2 levels have been found to be associated with a reduced likelihood of cognitive impairment assessed with a modified mini mental status examination [6]. However, estrogen replacement therapy was found to have no benefit for cognitive health in older postmenopausal women in the Women’s Health Initiative Memory Study (WHIMS), but transdermal E2 and progesterone given earlier in the postmenopausal period has been found to be beneficial in protecting against cognitive deterioration [7].

Are Women at Greater Risk of Alzheimer’s Disease than Men?

The short answer is no. Although there is a higher prevalence of AD in women compared to men, which some have assumed to be linked with the loss of estrogen after menopause, the explanation is that older age is the single greatest risk factor for AD and women tend to live longer than men. Women are simply more likely than men to reach an age where risk of developing AD is highest; however, they are not more likely than men to develop AD at any given age [8].

Menopause & the Brain – Where are We Now?

It’s clear that hormones play an important role in brain function and neuroprotection. Hormone replacement started early in the menopause, known as the “window of opportunity” hypothesis, can make a difference in preserving functions like memory and preventing the onset and progression of neurodegenerative processes.

However, the neurobiological science underlying these processes is still in its infancy, and studies of how hormone replacement therapy and its timing affect the incidence and progression of neurodegenerative and psychiatric diseases are few. Research in this area is ongoing, and we can hope that proper guidelines emerge for appropriate timing, delivery methods and dosages of hormone replacement to optimize the preservation of brain function in women as they age.

References

1 Hojo Y, Higo S, Kawato S, et al. Hippocampal synthesis of sex steroids and corticosteroids: essential for modulation of synaptic plasticity. Front Endocrinol (Lausanne). 2011;10;2:43.

2 Phillips KA, Ribi K, Fisher R. Do aromatase inhibitors have adverse effects on cognitive function? Breast Cancer Res. 2011;13:203.

3 Bean LA, Ianov L, Foster TC. Estrogen receptors, the hippocampus, and memory. Neuroscientist. 2014;20:534-45.

4 Han X, Aenlle KK, Bean LA, et al. Role of estrogen receptor α and β in preserving hippocampal function during aging. J Neurosci. 2013;33:2671-83.

5 Brann D, Raz L, Wang R, et al. Oestrogen signalling and neuroprotection in cerebral ischaemia. J Neuroendocrinol. 2012;24:34-47.

6 Yaffe K, Lui LY, Grady D, et al. Cognitive decline in women in relation to non-protein-bound oestradiol concentrations. Lancet. 2000;356:708-12.

7 Fischer B, Gleason C, Asthana S. Effects of hormone therapy on cognition and mood. Fertil Steril. 2014;101:898-904.

8 2014 Alzheimer’s Disease Facts and Figures.

Understanding Selenium Supplementation

Tue, 30 Jun 2015 14:20:00 -0700

A balance of nutrients is required by our bodies to maintain good health, and selenium (Se) is an important one that often gets overlooked.

This essential element is a required component of the selenoproteins, which include those that are needed to convert thyroid hormone from the inactive to the active form, and several important anti-oxidants.

While optimal selenium levels are imperative for proper thyroid function, abnormally high selenium intake can be toxic – causing gastrointestinal disturbances, changes in nails and hair, weakness, convulsions and decreased cognitive function. So it’s important to understand the ways in which we take in selenium, both in the diet and as supplements.

When choosing a selenium supplement, the various forms of selenium available can be confusing. The most common forms found in the diet and as supplements are summarized below.

Organic Forms of Selenium

Selenomethionine (as L-selenomethionine; sometimes called selenium monomethionine) is formed in plants when selenium substitutes for sulfur during synthesis of the amino acid methionine, and becomes incorporated into proteins in place of methionine. It is the predominant form of selenium in Brazil nuts, cereals, legumes, and fish.
Selenocysteine, a selenium-containing amino acid. In humans, it is one of the 22 proteinogenic amino acids and is incorporated into 25 known selenoproteins during protein synthesis. These selenoproteins are vital to human health, and include the antioxidants glutathione peroxidase and selenoprotein P, the thioredoxin reductases, and the deiodinases involved in thyroid hormone activation.
Methylselenocysteine (also known as Se-methyl-selenocysteine) and its derivative gamma-glutamyl Se-methylselenocysteine are metabolic products of selenocysteine that are the predominant form of selenium in plants of the allium (onions, garlic) and brassica (cruciferous vegetables, e.g., broccoli, cabbage) families.

Inorganic Selenium

Selenite, used in supplements and the most common form of selenium used in pet foods.
Selenate is the predominant form of selenium in shellfish and vegetables (other than the allium and brassica families) grown in seleniferous soil.

Selenium-Enriched Yeast

The supplement known as selenium-enriched yeast is yeast grown in a medium containing inorganic selenium, usually sodium selenite. The selenium becomes organically bound to the yeast, mostly being incorporated into the yeast proteins. The supplement therefore consists predominantly of selenomethionine (between 60 and 80%), but also has small amounts of selenocysteine, methylselenocysteine and gamma-glutamyl Se-methylselenocysteine. Reputable manufacturers ensure that the majority (at least 90%) of the selenite is organically bound to the yeast; otherwise, the product may simply contain a mixture of inorganic selenite and yeast.

What Form is Best?

Selenium in any form, whether from food or supplements, organic or inorganic, is utilized by the body for selenoprotein synthesis after first being metabolized to hydrogen selenide, the cellular storage form of selenium. Surplus selenium is converted to methylated metabolites and excreted via the urine and in the breath. Excessive buildup of hydrogen selenide can lead to its oxidation, resulting in the production of reactive oxygen species (ROS) leading to oxidative toxic effects in the body. Inorganic selenite also has pro-oxidant properties that can result in toxic effects when present in excess.

All forms of selenium are well absorbed, but absorption of selenomethionine is the best. It uses the same active transport mechanism as for methionine, one of the 9 essential amino acids that can only be obtained from the diet, and this increases the efficiency of absorption of selenomethionine over inorganic forms of selenium. Some supplements include vitamin E and it has been claimed that this facilitates selenium absorption, but there is no evidence that this is the case; vitamin E is included in some supplements because its antioxidant effects are synergistic with selenium.

Selenium Species with Anti-Cancer Effects

The anticancer effects of selenium differ depending on which form is used. An observed association between low selenium status and an increased risk of prostate cancer led to studies of selenium supplementation in an effort to mitigate risk. Supplementation with selenium-enriched yeast in the Nutritional Prevention of Cancer (NPC) trial reduced the incidence of prostate cancer by 52-65%, but the Selenium and Vitamin E Cancer Prevention Trial (SELECT) used selenomethionine supplements with or without vitamin E and was discontinued after 5.5 years when no benefit was seen in terms of prostate cancer risk reduction. Although selenium-enriched yeast predominantly consists of selenomethionine, it also contains small amounts of methylselenocysteine and gamma-glutamyl Se-methylselenocysteine, which are believed to be responsible for the observed anticancer effects in the NPC trial. Also, the pro-oxidant properties of selenium species such as selenite contribute to ROS-mediated apoptosis. Cancer cells usually exist under mildly oxidative conditions and are more susceptible to oxidative stress than normal cells, and so research is ongoing in the development of anticancer drugs based on selenite that utilize this mechanism.

How Much Selenium Do We Need?

When selenium levels are optimized there has been an observed decrease in the risks of prostate, lung, colorectal, and bladder cancer; however, excessive selenium supplementation in selenium-replete populations has been found to increase risk of type 2 diabetes. Additional selenium supplements, whether organic or inorganic, may therefore be detrimental to people with already adequate or high dietary selenium intake. The current recommended dietary allowance (RDA) in adults is 55 micrograms/day. Urine testing while maintaining the patient’s usual diet and supplementation can help determine whether selenium status is adequate, too low or too high.

For detailed recommended intakes and a list of selenium-containing foods, see the NIH Office of Dietary Supplements Dietary Supplement Fact Sheet: Selenium (for Health Professionals).

To learn more about simple dried urine testing for selenium, read ZRT's informational guide on elements and thyroid function .

References

Rayman MP, Infante HG, Sargent M. Food-chain selenium and human health: spotlight on speciation. Br J Nutr. 2008;100(2):238-53.

Rayman MP. Food-chain selenium and human health: emphasis on intake. Br J Nutr. 2008;100(2):254-68.

Rayman MP. Selenium and human health. Lancet. 2012;379(9822):1256-68.

Clearing up the Confusion about Reverse T3: Part 2. The Role of Reverse T3 in Thyroid Assessment

Fri, 08 May 2015 13:00:00 -0700

Part 2

As more health care practitioners have understood the need to assess thyroid function based on what is going on at the cellular level, there has been an increasing demand for testing of reverse T3 (rT3), a hormone sometimes referred to as the “hibernation hormone.” However, there is also much confusion about how it fits into the picture of thyroid function, and controversy regarding whether or not there is a clinical utility for this test in patients suffering from thyroid imbalance symptoms.

The “hibernation hormone” that isn’t

Technically, the term “hibernation hormone” is inappropriate to describe reverse T3. Reverse T3 can be elevated in conditions associated with a reduction in the metabolic rate, notably starvation, extreme carbohydrate restriction, chronic heart failure, and the non-thyroidal illness syndrome (also called “euthyroid sick syndrome” or “low T3 syndrome”) seen in critical illness, very elderly patients, chronic stress, myocardial infarction, and chronic inflammatory states. In these cases, the rise in rT3 is a consequence, not a cause, of the alterations in intracellular thyroid hormone metabolism directed by the deiodinase enzymes, the relative activities of which are affected by the condition itself.

What is Reverse T3? Reverse T3 (3,3’,5’-triiodothyronine, rT3) is a biologically inactive metabolite of thyroxine (T4) formed by selective deiodination; the active thyroid hormone T3 is formed by removal of an iodine atom in the outer ring of T4, while rT3 is formed by removal of an iodine atom in the inner ring of T4.

Relative amounts of each are determined by the activity of the respective deiodinase enzymes, which are regulated by hormonal and nutritional factors and physiological conditions.

Does rT3 really slow metabolism?

It is frequently claimed in articles published on the internet, but not in peer-reviewed papers, that rT3 blocks or “gets in the way of” the nuclear thyroid receptors. The nuclear thyroid receptors are the sites of action where the primary active thyroid hormone, T3, exerts its effects to drive cellular metabolism and maintain body temperature. There is no credible scientific evidence that rT3 enters the nucleus of the cell at all, and the bulk of the scientific literature states clearly that rT3 does not bind to, and has no known transcriptional activity at, the thyroid receptor. It is, however, known to have potent activity in the cytoplasm as an initiator of actin polymerization in astrocytes in the brain [7]. This is mediated in a non-genomic manner by its binding to a very specific thyroid receptor that exists only in the extranuclear compartment. Actin polymerization is important to cell structure and motility, and particularly important to normal brain development.

What do high levels of rT3 relative to T3 indicate?

Any interpretation of the relative levels of T3 and rT3 must take into account all the factors that affect the activity of all three deiodinases. As explained in Part 1, reactivation of the D3 deiodinase and downregulation of the D1 deiodinase contribute to both increased rT3 formation and reduced rT3 clearance, while at the same time reducing T3 synthesis from T4, so conditions affecting the expression of D1 and D3 in this way have a profound impact on circulating levels of T3 and rT3 and the T3/rT3 ratio. The T3/rT3 ratio has therefore been found to have some value in assessing prognosis in severely ill [8] or very elderly patients [9]. There is currently no evidence for a clinical basis for the use of this ratio in routine thyroid function assessment.

Some observed elevations in serum rT3 in the presence of exogenous thyroxine treatment are difficult to interpret, and can depend on the assay used. T4 can cross-react in immunoassays for rT3, resulting in a false increase in rT3 when T4 is high; more reliable tests for rT3 are performed using liquid chromatography/tandem mass spectrometry (LC-MS/MS). A study in euthyroid subjects receiving thyroxine suggested that the observed rise in rT3 was a result of increased substrate availability for the peripheral inactivation of T4 [10]. And elderly patients may either have an adaptive response to reduce thyroid hyperactivity at the tissue level, or have some type of non-thyroidal illness with consequent reactivation of D3, in both cases resulting in increased T4 inactivation via conversion to rT3; it has therefore been suggested that older patients with hypothyroidism may require lower replacement doses of T4 [11].

Want to learn about the Deiodinases & Thyroid Hormone Bioavailability? Read Part I of this blog post.

Related Resources

References

7. Senese R, Cioffi F, de Lange P, Goglia F, Lanni A. Thyroid: biological actions of ‘nonclassical' thyroid hormones. J Endocrinol. 2014;221(2):R1-12.

8. Peeters RP, Wouters PJ, van Toor H, Kaptein E, Visser TJ, Van den Berghe G. Serum 3,3',5'-triiodothyronine (rT3) and 3,5,3'-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. J Clin Endocrinol Metab. 2005;90(8):4559-65.

9. van den Beld AW, Visser TJ, Feelders RA, Grobbee DE, Lamberts SW. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab. 2005;90(12):6403-9.

10. LoPresti JS, Eigen A, Kaptein E, Anderson KP, Spencer CA, Nicoloff JT. Alterations in 3,3'5'-triiodothyronine metabolism in response to propylthiouracil, dexamethasone, and thyroxine administration in man. J Clin Invest. 1989;84(5):1650-6.

11. Mariotti S. Thyroid function and aging: do serum 3,5,3'-triiodothyronine and thyroid-stimulating hormone concentrations give the Janus response? J Clin Endocrinol Metab. 2005;90(12):6735-7.

Clearing up Confusion about Reverse T3: Part 1. The Deiodinases & Thyroid Hormone Bioavailability

Mon, 04 May 2015 13:31:00 -0700

Part One

Thyroid hormones are essential for the normal metabolic functioning of all tissues in the body, and a wide array of symptoms are therefore associated with abnormalities in thyroid hormone production and activation. Even when apparently adequate amounts of thyroxine are produced by the thyroid gland, thyroid function is profoundly affected by anything that disrupts conversion of thyroxine (T4) to the active thyroid hormone, triiodothyronine (T3). This conversion takes place primarily at the cellular level within tissues; only 20% of circulating T3 is generated by conversion of T4 within the thyroid gland itself.

The deiodinases - gatekeepers to intracellular thyroid hormone bioavailability

Both circulating and intracellular thyroid hormone levels are controlled by a complex, highly regulated system involving three iodothyronine deiodinases (known as D1, D2, and D3), which selectively remove iodine atoms to create the different hormones (see diagram). This system not only controls the relative amounts of both active and inactive hormone in the cell, but it also has the effect of conserving iodine, which has multiple intracellular functions (in the thyroid gland, the iodine is recycled for the synthesis of more thyroxine). A full discussion of the deiodinases and how they act as gatekeepers to intracellular thyroid hormone bioavailability and control the metabolic rate is outside the scope of this blog, but it is important to refer to high quality, recent reviews in peer-reviewed journals to understand this system properly [e.g., 1, 2, 3, 4].

What affects circulating levels of rT3 and T3?

Much experimental research into the deiodinase systems in various tissues has necessarily been done in animals other than humans, and when studying the research on reverse T3 (rT3) it is important to remember that humans are not the same as rodents. Bear in mind, for example, that hepatic D1 activity is the major contributor to circulating T3 in the rat, while in humans it is the D2 enzyme present in peripheral tissues that contributes the bulk of circulating T3.

Various disease states, and some drugs, alter the expression of each of the deiodinases, and thereby change the relative concentrations of circulating hormones. In normal adults, rT3 circulates at roughly 40 times the level of free T3 (reference range in normal adults for rT3 is about 9-25 ng/dL, while for free T3 it is 2.5-6.5 pg/mL, i.e., 0.25-0.65 ng/dL). The relative levels of rT3 and T3 are affected by factors that stimulate or inhibit the activities of the deiodinases, as described below.

What is Reverse T3?

Relative amounts of each are determined by the activity of the respective deiodinase enzymes, which are regulated by hormonal and nutritional factors and physiological conditions.

Type 1 deiodinase – D1

In humans, the D1 enzyme has a much higher substrate preference for rT3 than for T4 [2], suggesting that its main function is to deiodinate rT3 to form T2, both conserving iodine and clearing rT3. In conditions in which D1 is downregulated, an increase in circulating rT3 is seen because the conversion of rT3 to T2 is significantly reduced, resulting in an accumulation of rT3. D1 is downregulated by selenium deficiency and in the non-thyroidal illness syndrome, as well as some cancers. It is also inhibited by some drugs, notably amiodarone, propranolol, propylthiouracil, dexamethasone, and ipodate. On the other hand, D1 is upregulated by T3, which restores the clearance of rT3 (via conversion to T2) and reduces the levels of circulating rT3 relative to T3. T3 therapy has therefore been used in some studies of critically ill patients in an attempt to restore intracellular thyroid function by upregulating the D1 deiodinase, but in general such treatment has not affected prognosis and it remains controversial. Most studies find that successful treatment of the underlying illness, as well as maintaining nutritional support and re-introducing mobility as soon as possible, naturally restores the T3/rT3 ratio to normal.

Type 2 deiodinase – D2

Unlike D1 and D3 which are located in the plasma membrane of cells, D2 resides in the endoplasmic reticulum inside the cytosolic compartment, where the T3 generated by its activity can directly enter the nucleus and interact with thyroid receptors. The activity of D2 is therefore a primary determinant of intracellular T3 availability and thyroid receptor occupancy. While T3 generated from the activity of D1 is known to equilibrate rapidly with the plasma, D2-generated T3 remains within the cell and takes several hours to equilibrate with plasma. Unlike D1, D2 activity is increased in non-thyroidal illness.

Type 3 deiodinase – D3

The D3 enzyme is not normally expressed in adult tissues, whereas it is present in the placenta and the neonate where it protects the developing organism from excess thyroid hormone activity. It is, however, reactivated in conditions associated with a reduced metabolic rate, particularly starvation, severe carbohydrate restriction, tissue injury, reduced tissue oxygen supply, and critical illness (or the non-thyroidal illness syndrome), and also in chronic inflammation and some cancers. Its activity is increased in hyperthyroidism and decreased in hypothyroidism in the rat. D3 serves to inactivate T4 by converting it to rT3; this therefore limits the amount of T4 that can be used to form T3, reducing the availability of T3 to the thyroid receptors and thus slowing the metabolic rate. rT3 is rapidly cleared from the circulation, or further deiodinated to T2, which is now thought to exert some important biological effects at the thyroid receptors, albeit at about 100-fold reduced potency compared to T3 [5,6].

Want to learn about the role of reverse T3 in Thyroid Assessment? Read Part II in the follow up blog post.

Related Resources

References

1. Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, Zeöld A,Bianco AC. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev. 2008;29(7):898-938.

2. Maia AL, Goemann IM, Meyer EL, Wajner SM. Deiodinases: the balance of thyroid hormone: type 1 iodothyronine deiodinase in human physiology and disease. J Endocrinol. 2011;209(3):283-97.

3. Williams GR, Bassett JH. Deiodinases: the balance of thyroid hormone: local control of thyroid hormone action: role of type 2 deiodinase. J Endocrinol. 2011;209(3):261-72.

4. Dentice M, Salvatore D. Deiodinases: the balance of thyroid hormone: local impact of thyroid hormone inactivation. J Endocrinol. 2011;209(3):273-82.

5. Orozco A, Navarrete-Ramírez P, Olvera A, García-G C. 3,5-Diiodothyronine (T2) is on a role. A new hormone in search of recognition. Gen Comp Endocrinol. 2014;203:174-80.

6. Leonard JL. Non-genomic actions of thyroid hormone in brain development. Steroids. 2008;73(9-10):1008-12.

New Research on Vitamin D Using Dried Blood Spot Testing

Thu, 23 Apr 2015 17:00:00 -0700

Two vitamin D studies were published recently, both utilizing ZRT's testing in dried blood spot.

Dried blood spot samples are well suited for research applications because they are equivalent to serum but have the advantage of ease of sample collection, shipping, and storage, which doesn’t require any refrigeration or biohazard labeling. Also, samples are easily identified by details that can simply be written on the outside flap of the collection cards, which require minimal freezer space for long-term storage of samples.

Here are brief summaries of each study:

Wakayo T, Belachew T, Vatanparast H, Whiting SJ. Vitamin D Deficiency and Its Predictors in a Country with Thirteen Months of Sunshine: The Case of School Children in Central Ethiopia. PLoS ONE 2015;10(3):e0120963.

In this study, vitamin D levels were tested in schoolchildren living in the sunny climate of Ethiopia. Vitamin D deficiency, defined as 25-hydroxyvitamin D levels <50 nmol/L (equivalent to <20 ng/mL) was significantly more prevalent in children living in an urban environment (61.8%) compared with those in a rural setting (21.2%). Significant predictors of vitamin D deficiency in this study included body fatness, having a TV/computer at home, maternal education, and socioeconomic status. This study highlights lifestyle factors that can predispose people to vitamin D deficiency even in countries with high sun exposure. See full article.

Kerr DCR, Zava DT, Piper WT, Saturn SR, Frei B, Gombart AF. Associations Between Vitamin D Levels and Depressive Symptoms in Healthy Young Adult Women. Psych Res March 2015 [in press].

This study investigated the relationship between vitamin D sufficiency and depression. One hundred eighty healthy young women completed surveys to assess depressive symptoms at baseline and then once a week for 4 weeks, and serum vitamin D levels were determined at baseline and 4 weeks. A high rate of vitamin D insufficiency, defined as levels <30 ng/mL, was seen, occurring in 42% and 46% of the women at baseline and week 4, respectively. Lower vitamin D levels were related to clinically significant depressive symptoms. Purchase full article.

ZRT has a big focus on research, out of which our testing was born and continues to be validated:

- Full list of published studies

- Poster Presentations at scientific meetings

Both pages are updated regularly as new studies are published so be sure to check back often! A link is given for each publication that takes you to either a free download of the full article, if this is available, or to an option to purchase if the article is not free.

Related Resources

Comparing Online Cardiovascular Disease Risk Assessment Tools

Fri, 27 Feb 2015 08:30:00 -0800

We’ve been hearing a lot about heart disease over the past few weeks as awareness of risk factors is actively promoted during American Heart Month in February.

There are several risk factor assessment tools available online. While some basic information is common to all of them, there are differences in the factors included in the assessment, sometimes resulting in a different assessed risk value.

Let’s take a look at the current guidelines, and compare some of the online risk assessment tools.

Development of scoring systems for cardiovascular disease risk

The two most well-known predictors of cardiovascular disease (CVD) risk are the Framingham 10-year general CVD risk score algorithm [1] derived from the results of the Framingham Heart Study and the Reynolds Risk Score algorithms for women [2] and men[3].

Reynolds Score a better predictor in women

An independent validation study published in 2012 directly compared Framingham and Reynolds risk scores for global CVD risk prediction in the Women’s Health Initiative Observational Cohort, which included 1722 cases of major CVD events. The Reynolds score showed improved risk discrimination overall, as well as in white and African American subsets, compared to the Framingham scores [4].

New guideline for atherosclerotic CVD risk
A systematic evidence review published in 2014 by an American College of Cardiology and American Heart Association Task Force announced their guideline on the assessment of atherosclerotic CVD risk [5]. This guideline uses the Framingham general CVD risk prediction equation but includes data from NHLBI-sponsored, racially and geographically diverse cohort studies, and the algorithm takes into account the race and sex of the individual.

Individuals can use several online risk calculators that use the algorithms mentioned above and include various additional known risk factors for CVD.

NHLBI (National Heart, Lung, and Blood Institute) 10-year CVD Risk Calculator

Based on Framingham. Includes age, gender, total cholesterol, HDL, systolic blood pressure, and asks if you smoke or use blood pressure medication.

Reynolds Risk Score

Includes the same factors as the NHLBI calculator with the exception of the question about blood pressure medication, and adds the hs-CRP value.

Mayo Clinic Heart Disease Risk Calculator

Includes the same factors as the American College of Cardiology calculator but adds Hispanic as a choice of race, and asks for your height and weight, history of CVD, family history of early CVD, exercise habits, and your fruit and vegetable and saturated fat consumption.

American Heart Association Heart Attack Risk Assessment Tool

Includes the same factors as the American College of Cardiology calculator but does not include race; asks for your height and weight, waist size, history of CVD, family history of early CVD, fasting blood sugar, diastolic blood pressure, LDL cholesterol, and triglycerides. After completion, shows where you stand regarding the specific modifiable risk factors of cholesterol values, blood pressure, and smoking.

Celebrating Black History Month - An Interview with Naturopathic Dr. Kim Tippens

Thu, 12 Feb 2015 15:26:00 -0800

Dr. Kim Tippens, ND, MS, MPH is an integrative medicine researcher and professor with the National College of Natural Medicine in Portland, Oregon. She is an African American naturopathic doctor, a small minority in a profession dominated by white women.

A survey of licensed naturopathic practitioners in two US states reported that 94% of NDs in Washington and 95% in Connecticut identified themselves as white, while 57% and 58% respectively were women. As the main focus of her work is in addressing access to alternative health care options among medically underserved populations in her community in Portland, Oregon, she is keenly aware of the need for more professional diversity to help increase patient engagement.

I visited Dr. Tippens at her office in the Helfgott Research Institute at NCNM, where she is an Assistant Professor in the School of Research and Graduate Studies. She also serves as the Director of Public Health and Community-Partnered Research, and mentors students doing community-based research.

Following is the interview in which she shared with me some of her current projects and concerns.

Q: Tell me about a clinical research project you are currently doing.

A. Right now we are in the middle of a whole-foods nutrition education study with the Food As Medicine Institute at NCNM. The study will assess the effect of a 12-week nutrition course on eating behaviors, food choices, and cardiometabolic markers in a prediabetic population. We’re very grateful to ZRT laboratory for donating the cardiometabolic testing for this project. For this study, we are partnering with two local churches: one is in North Portland and one in Banks, Oregon, where community members are engaged in the research. We’re providing a 12-week nutrition education course, including hands-on classes on how to cook healthy food. Fasting blood spot tests and food frequency questionnaires are done at the start of the study and at 3 months, 6 months, and 12 months later. Investigators will assess whether helping people to understand and prepare healthier foods will change eating behaviors and lower their risks for diabetes and heart disease.

Q: You are trained in acupuncture – are there some applications for alternative health care approaches such as acupuncture in parts of the community that are underserved?

A: Yes, I’m actually involved in a couple of research proposals that aim to evaluate an established acupuncture program for addiction recovery and assess its impact in an underserved population. Findings from this work would be directly applicable to the severely low income and homeless populations that we work with in the community, since many of them struggle with addictions. Group acupuncture is a complementary approach that seems to play an important role in addiction recovery. I am also interested in models of acupuncture delivery that are accessible to low-income and uninsured populations. The community acupuncture model is one that I have been studying, especially regarding its impact on pain management for medically underserved populations.

Q: What are the main issues that you see regarding access to alternative medicine in the underserved parts of the community?

A: The main problem is access to complementary and alternative medicine services for people without medical insurance or with low incomes. Most of my activities in the community are aimed at increasing awareness of affordable options for holistic health care. Fortunately, there are multiple complementary and integrative medicine teaching institutions in the Portland area that offer low-cost health care.

Q: What kind of things are happening in the community to increase awareness of alternative medicine approaches?

A: We have partnered with a local community acupuncture clinic to design a project focused on treatment of chronic pain, where we will engage with other community organizations and conduct qualitative research on the utility of this treatment. We also have, right here at NCNM in Portland, the Food As Medicine Institute, where we offer to the public healthy cooking classes based on whole grains and a plant-based diet. That helps to increase awareness of lifestyle choices as a key part of improving individual health.

Q: As this is Black History Month, how do you feel about the under-representation of African Americans in the naturopathic community?

A: Most of my work is around access to health care and the quality of care. In order for a health care model to be considered accessible, the care delivered has to be affordable, close by, culturally appropriate, and of high quality. As our profession continues to engage communities and promote awareness of local naturopathic health care options, I believe that more people will embrace natural medicine and its principles of lifestyle adjustment, for example proper nutrition and stress reduction, and centuries-old herbal remedies. Holistic solutions can have huge benefits in health care issues that are known to particularly affect the African American population such as obesity, diabetes, and some cancers. I would love to see more African American representation in my profession.

Reference

Boon HS, Cherkin DC, Erro J, et al. Practice patterns of naturopathic physicians: results from a random survey of licensed practitioners in two US States. BMC Complement Altern Med. 2004;4:14.

Related Resources

Safer Sampling with ZRT Lab Testing Methods

Mon, 01 Dec 2014 23:11:00 -0800

The current concern over the dangerous Ebola virus has heightened awareness about infections that can be transmitted via contact with body fluids.

The last thing we want is to be exposed to body fluids from others infected with dangerous organisms and, ironically, a likely place to encounter such fluids is the phlebotomy station at the doctor’s office.

How can exposure to other people who may be sickened with an infectious agent be minimized?

One way to minimize exposure is to use at-home sample collection methods, a hallmark of ZRT lab testing, which ensure seclusion and don’t require samples to be handled around other patients. That keeps risk of passing on infections such as Ebola to a minimum, since no blood is drawn and transferred to tubes at the doctor’s office, and no wet urine or saliva is handled or collected except at home.

Self-sampling at home is not only simple and convenient, it is in fact essential for capturing the waking saliva sample for a diurnal cortisol assessment, the first-morning urine void for accurate testing of night-time melatonin production, or a fasting sample for insulin assessment. Patients can eat breakfast and get ready to start their day while blood spot and urine samples dry before mailing off to the lab.

Drying blood spot and urine samples for shipment to the lab ensures that most pathogens are inactivated – transmission of infections, particularly viruses, requires contact with a liquid body fluid. Enveloped viruses, which have a protective lipid envelope covering the protein capsid (the infectious part of the virus), are particularly sensitive to drying compared to non-enveloped viruses; Ebola is an enveloped virus. A dry sample therefore carries very minimal (almost zero) risk of infection while it is en route to the lab.

What about exposure of lab personnel once samples arrive for testing?

The laboratory at ZRT is CLIA-certified, requiring documentation of, and adherence to, exacting procedures for testing*. Safety procedures include requirements for safe handling and disposal of chemicals used for testing, and the control of any pathogens (disease-causing organisms) that are transmitted via contact with body fluids.

At ZRT, we closely follow the guidelines for blood-borne pathogen exposure control as outlined by the Occupational Safety and Health Administration’s standard 29 CFR 1910.1030. These require laboratory personnel to wear personal protective equipment (PPE) when handling any biological samples, proper disposal of samples to prevent any infection risk to laboratory and non-laboratory personnel, and cleaning of all work surfaces and equipment that may come into contact with biological samples to prevent any spread of infectious agents.

The best disinfectant that is active against the widest range of infectious agents, including both enveloped and non-enveloped viruses, is a bleach (sodium hypochlorite) solution. However, guidelines issued by OSHA, the CDC, and the WHO all emphasize that bleach solution must be prepared fresh daily otherwise it loses potency as the chlorine slowly evaporates. At ZRT, a 10% bleach solution is prepared fresh every day for routine disinfection of work surfaces and lab equipment.

ZRT – an innovator in testing of samples collected at home

ZRT is committed to improving the health and wellness of people who test with us, not only with reliable, accurate test results but by ensuring that people can collect samples simply and conveniently in their own homes. A pioneer of lab testing using at-home collection methods, ZRT has offered commercial testing in saliva since 1998, in dried blood spot since 2004, and in dried urine since 2013. We are currently the only commercial lab offering testing in all three mediums sampled at home.

*Standard Operating Procedures at ZRT are reviewed, updated, and re-approved at least annually, and these cover the methods used for testing, the quality control of all assays, sample processing procedures including criteria for sample rejection and storage as well as adherence to HIPAA regulations, regular calibration and maintenance of all laboratory equipment, and of course strict guidelines for safety of lab personnel.

Resources:

About Blood Spot Testing
About Dried Urine Testing

The ZRT Laboratory Blog

Melatonin – An Important Piece of the COVID-19 Puzzle?

The Younger, Sexy Me…...nopause!

What is Early Menopause?

Health Risks of Early Menopause

Surgical Menopause and Low Testosterone

Getting Help

Related Resources

References

Exploring the Connection Between BDNF and Alzheimer's Disease

What is BDNF?

How Can We Measure BDNF Production in the Brain?

Studies have suggested that Alzheimer’s is actually the 3rd leading cause of death behind heart disease and cancer in the 75 and older age group.

What is Alzheimer’s Disease?

Is There a Link between BDNF and Hormonal Decline during Aging?

Can Early Detection Help?

Genetic and non-genetic markers are being developed that can help identify the onset of disease and provide the opportunity for early drug treatments.

Related Resources

References

Testosterone Deficiency in Younger Men – Is It Real?

Study of Testosterone Levels in 3 Age Groups

Why the Difference with Published Reference Ranges for Young Men?

Low Testosterone and Chronic Diseases

Studies have found that men with low T and low SHBG who do not yet have metabolic syndrome or diabetes are significantly more likely to go on to develop insulin resistance or diabetes

What Could Influence Total Testosterone in the Younger Men with Multimorbidities?

Can Lifestyle Modification Be the Key to Increasing Total Testosterone?

Related Resources

References

ZRT Cares About the Environment with Eco-Friendly Materials

No Radioactivity in Our Assays

Sustainable Kit Boxes

Saliva Tubes Made from Recycled Plastic

All packing peanuts that we use are made from compostable vegetable starch.

Biodegradable Packing Materials

Recycling

Providers Can Go Paperless

Employee Mass Transit Subsidies

Environmental Consciousness at the Lab

Related Resources

Reverse T3 – Why It’s Not Useful for Routine Thyroid Testing

What is Reverse T3?

The Deiodinases - Gatekeepers to Intracellular Thyroid Hormone Bioavailability

“Hibernation Hormone” is a Misnomer

No Effects of rT3 on Nuclear Thyroid Receptors

There appears to be little clinical justification for routine testing of rT3 for thyroid function assessment.

Diagnostic Value of High Levels of rT3 Relative to T3

The Bottom Line – Is the rT3 Test Useful?

Related Resources

References

A Case Study for Breast Cancer Awareness Month

Loretta’s Case Study

Symptoms

Elements Test Results

Neurotransmitter Test Results

Solutions for Loretta

Related Resources

A Case Study for Menopause Awareness

Julia’s Menopause Case Study

A Host of Hormone Imbalance Symptoms

Saliva Hormone Test Results

Neurotransmitter Test Results

Solutions for Julia

Research Updates – Trials of HRT Started in Early Menopause

Early versus Late Intervention Trial with Estradiol – ELITE

Kronos Early Estrogen Prevention Study (KEEPS)

When interpreting results of the above-mentioned and other studies, it is important to take into consideration the route of administration, the dose of hormone used, and the outcomes measured.

Related Resources

References

Your Checklist for Partnering with a Quality Lab

1. Certification

2. Assay Validation

3. Research Involvement

4. Conflicts of Interest

5. Clinical Support

6. Industry Standards

A commitment to excellence is something that patients and health care providers should expect from their lab of choice.

Further Reading

Webinar Review: The Nuts & Bolts of Neurotransmitter Testing

How do I know if neurotransmitter testing is right for my patients?

Which panel should I choose?

To eliminate abnormal results at either end of the range spectrum, the values between the 5^th and 95^th percentiles of the range usually comprise the reference range.