Declining testosterone levels are commonly seen in men beginning in the fourth decade of life. Suboptimal or low testosterone levels in males are often associated with symptoms of aging and are referred to as andropause or male menopause. This is the equivalent of menopause in women when ovarian production of estrogens and progesterone begins to decline. Testosterone is an important anabolic hormone in men, meaning it plays important roles in maintaining both physical and mental health. It increases energy, prevents fatigue, helps maintain normal sex drive, increases strength of all structural tissues such as skin/bone/muscles including the heart, and prevents depression and mental fatigue. Testosterone deficiency is often associated with symptoms such as night sweats, insulin resistance, erectile dysfunction, low sex drive, decreased mental and physical ability, lower ambition, loss of muscle mass and weight gain in the waist. The primary cause of this increase in girth is visceral fat not excessive subcutaneous fat (fat under the skin). The visceral fat cells are the most insulin resistant cells in the human body. They have excess hormone binding receptors for cortisol and androgens and decreased receptors for insulin (resistance to insulin). As a person ages hormone levels change in favor of insulin resistance. The cortisol and insulin levels rise while progesterone, growth hormone and testosterone decline. The visceral fat cell with its increased receptors, blood supply and innervation, begins to collect more fat in the form of triglycerides. A vicious cycle is initiated, which if not interrupted with natural hormone balancing, will lead to abdominal obesity, diabetes and high cholesterol levels. This phenomenon is known as metabolic syndrome. Stress management, exercise, proper nutrition, dietary supplements (particularly adequate zinc and selenium), and androgen replacement therapy (controversial in prostate cancer) have all been shown to raise androgen levels in men and help counter andropause symptoms. The “trick” is to know how much testosterone is required for each individual male. This is where knowing the salivary testosterone levels come into play. Initial salivary testing and follow up salivary monitoring are crucial for determining the most optimal prescription. Free testosterone can also be calculated in serum using total testosterone, SHBG and PSA levels. With these levels one can calculate the Free Testosterone Index (FTI). The normal FTI range is 0.7-1.0. If one’s FTI is below 0.7, testosterone therapy should be initiated. The final dosage will be the amount required to correct the FTI ratio. Prior to initiation of testosterone therapy the PSA level needs to be within the expected range. There is no evidence that testosterone increases the risk of prostate gland cancer; however, if cancer has already developed testosterone may accelerate its growth. The PSA test is a good guide as to presence or absence of cancer and is a good indicator of inflammation within the prostate gland.
Stress, whether it’s perceived or not perceived, can be physical, mental, emotional and environmental in nature. There are often events and periods of time in life that can be identified as particularly stressful such as a car accident, death of a loved one or job loss. Stress is not only negative but can be associated with positive circumstances as well, such as a wedding or job promotion. In addition to these major life events, there are many factors that add to an individual’s stress load including: infections, allergies, depression, chronic disease, overworking, guilt, sleep deprivation, toxic exposures, blood sugar fluctuations, medications and more. Hormones, including cortisol and DHEA from the adrenal glands, are an integral part of the physiological stress response. While the body’s intricate hormonal system is adept at handling isolated stressful events, today’s busy world equipped with cell phones, fluorescent lights, traffic and more, presents a taxing environment of consistent stressors. This state of consistent stress increases the body’s demand for adrenal hormones and often results in hormonal dysregulation.
Pregnenolone, the primary precursor hormone to all steroid hormones, including cortisol, DHEA, estradiol, progesterone and testosterone, is essential in the body’s quest to maintain adequate cortisol levels during times of chronic and consistent stress. While pregnenolone can be directed toward the production of any of these various hormones, increased demand for cortisol due to constant stress results in the shunting of pregnenolone down the pathway that favors cortisol production thus “stealing” pregnenolone to support adequate cortisol levels and leaving less of this pro-hormone available to produce the other steroid hormones. The hormonal imbalance that ensues further contributes to the overall stress burden of the body, further compounding the existing picture of chronic stress. Estrogen Dominance Estrogen dominance refers to a state where there is a greater influence of estrogen than progesterone on tissues. There are many situations and conditions that can contribute to this imbalance including increases in estrogen production, exposure to exogenous estrogens, and decreased progesterone production. Because the body can convert progesterone to cortisol, increased stress (and a higher demand for cortisol) often results in decreased progesterone production, thereby exacerbating the imbalance between the estrogens and progesterone. No Rest for the Weary Our endocrine system (like many other creatures on this planet) is designed to handle an acute stressful event and allows us to protect ourselves from danger or flee from it. While we rarely find ourselves fighting off a predator in this modern era, the constant barrage of micro-stressful events such as traffic, social stresses, infectious agents, chemical exposures etc. often result in a chronically stimulated adrenal response. While most other animals rest and allow their systems to calm after a stressful encounter, we rarely give our bodies the actual break we need. Over time, with continued stimulation, the stress response becomes less sensitive and the signal to produce cortisol lessens, often to the point of very little cortisol output at all. Individual “Tipping Point” Adrenal exhaustion can happen to some people after a single stressful event, while for others it occurs after an accumulation of smaller stressors. We are all different, and the length of time we can “keep up the pace” is variable. References 1. Adrenal Fatigue: The 21st Century Stress Syndrome. Wilson JL. 2001 Smart Publications.
Labrix has done an extensive literature search to shed light on the confusion over whether the DHEA/ Cortisol ratio provides a clinically relevant gauge. To explore the question from a physiologic view point we need to look at the structure of the adrenal gland. The two main adrenal hormones; Cortisol and DHEA, are secreted from separate compartments in the adrenal cortex. This becomes especially relevant when analyzing adrenal fatigue panel results: (four-timed cortisols and DHEA). Cortisol is produced in the zona fasciculata whereas DHEA is produced in the zona reticularis. Here’s the important point: the two separate compartments, zona fasciculata and zona reticularis do not have a direct feedback loop between them. All communication to these zones is through the brain (HPA axis) via ACTH. This means that the hypothalamic pituitary axis does all the regulation of these hormone levels. In evolving the zones as separate, “non speaking” compartments, the body has evolved a natural “safety net” for production of the two hormones. This is important to remember especially when you discover that both the Cortisol and the DHEA are low or suboptimal (adrenal fatigue). It is imperative to support both zones or supplement with both hormones. Contrary to popular belief, boosting one of these hormones will not support nor boost the other. Conclusion: given that the two hormones are not dependant on each other, the ratio of DHEA to Cortisol is not a signi! cant functional value. Ratios are only meaningful and valuable when the two variables in" uence, alter or depend upon one another. Since these compartments are separate and regulated as such, a ratio of the two has no therapeutic bearing.
The term “estrogen dominance” can be confusing at times because it does not relate solely to the amount of circulating estrogen in the body, but rather to the relationship between estrogen and progesterone. Contrary to popular belief, many of the symptoms experienced during menopause or with PMS are not due to estrogen deficiency, but rather are due to estrogen dominance. Although estrogen levels do decline with age (approximately 40 - 60% at menopause), more relevant is the fact that, at menopause, progesterone levels plummet by close to 90% from premenopausal levels. It is the relative loss of progesterone that causes the majority of symptoms termed “estrogen dominance.” This disproportionate loss of progesterone begins in the latter stages of a woman’s reproductive years, when impairments to the luteal phase of the menstrual cycle begin. The reduction in progesterone production is initiated when the remnant tissue of the follicle post ovulation (called the corpus luteum) begins to lose its functional capacity. Outside of pregnancy, the corpus luteum is the primary source of progesterone in the female body. By the time a woman reaches her mid-thirties, luteal phase defects are common and result in decreased progesterone production by the corpus luteum. Also increasingly common beginning at this time, are anovulatory cycles which result in a lack of corpus luteum formation and thus, a virtual lack of progesterone production. It is during this time that a relative progesterone deficiency, or what has become known as estrogen dominance, develops. Typical symptoms of estrogen dominance are:
• Mood swings • Irritability • Depression • Irregular periods • Increased facial hair • Hot flashes • Vaginal dryness • Water retention • Uterine fibroids • Decreased libido • Headaches • Fatigue • Diffuse aches & pain • Weight gain: hips, thighs & abdomen • Sleep disturbance (insomnia, less REM sleep) • Breast tenderness/Fibrocystic breasts • Bone mineral loss (Osteoporosis) • Short-term memory loss • Lack of concentration • Dry, thin, wrinkly skin • Thinning of scalp hair • Heavy penstrual bleeding
Patients experiencing these symptoms will likely benefit from hormone balancing treatments including natural hormone replacement. The most effective way to assess hormone status is to test saliva for the appropriate hormone levels. Saliva is the best method for testing “functional” or “active” tissue levels of hormones. Estrogen dominance, in both men and women, is evaluated by measuring salivary progesterone and estradiol levels and determining the progesterone to estradiol (Pg/E2) ratio. The optimal Pg/E2 reference ranges were determined by the clinical work and research of John R. Lee, MD. While they are not physiologic ranges, they are optimal values for the protection of the breasts, heart and bones in women, and the prostate in men. Salivary values within these ranges have been shown by Dr. Lee to decrease both breast and prostate cellular proliferation, thereby providing protection to these vital tissues.
What is HPA axis (adrenal) dysfunction? Hypothalamic-pituitary-adrenal axis (HPA axis) dysfunction is commonly referred to as adrenal dysfunction among patients and providers alike. HPA axis dysfunction is an alteration of the stress response resulting in a dysregulation of stress hormones - mainly an alteration in the quantity and/or diurnal pattern of adrenal hormone secretion, including cortisol and DHEA. With over 5,000 current mentions in scientific literature (and growing daily!), the effect of stress on the HPA axis is a common and well-acknowledged health concern that affects people of all ages, genders and backgrounds. Those experiencing HPA axis dysregulation commonly complain of fatigue but may also experience sleep disruptions, weight changes, salt and/or sugar cravings, heightened allergies, anxiousness, nervousness, blood pressure alterations and numerous other symptoms. Who experiences HPA axis (adrenal) dysfunction? Saliva testing reveals that HPA axis dysfunction is widespread with functional medicine clinics having observed over 85% of patients experiencing some level of dysregulation. HPA axis dysfunction does not discriminate – it may be experienced by men as well as women, and it can occur at any age. With today’s hectic schedules and ever-growing expectations, many individuals in their teens and twenties are already experiencing HPA axis dysfunction. What causes adrenal dysfunction? HPA axis dysfunction results from continuous or sudden stress. It may begin abruptly, or as a result of periods of prolonged, repeated stress. Sources of stress may be positive or negative, may or may not be acknowledged by the individual and include (but are not limited to):
• Recurrent disease and illness • Physical stress: injury, diet, surgery, tobacco/ alcohol addiction, etc. • Emotional stress: marriage, divorce, death of a loved one, strenuous work relationships, a new baby, financial insecurity, etc. • Environmental stress: chemical pollution of air, water, food, etc. Identifying HPA axis (adrenal) dysfunction Salivary hormone testing is the gold standard in measuring cortisol levels and is an easy, non-invasive and convenient way to quantify cortisol output and identify dysregulations in diurnal cortisol patterns. HPA axis (adrenal) support Successful support and treatment strategies for those suffering from HPA axis dysfunction include: • Lifestyle modifications to include exercise, healthy sleep patterns, balanced diet high in vegetables and including healthy fats and proteins, and frequent laughter • Stress management plans including deep breathing exercises, breaks for rest and self-time • Avoidance of caffeine, alcohol, refined sugars, and any food allergies/sensitivities Individualized treatment plans may include the following: • Supplementation of dietary cofactors necessary for mitigating the stress response and cortisol production including Vitamins C, B5, B6 and E • Botanical adaptogen therapy including licorice, rhodiola, ashwaganda, etc. • Adrenal glandular supplementation • Physiologic cortisol supplementation • Phosphorylated serine supplementation (elevated cortisol levels only)
Progesterone Is Very Different From Progestin There are many hormone replacement therapy and oral contraception options available for the treatment of estrogen dominance, menopausal symptoms, PMS and birth control available. At some point in their reproductive lives, 80 percent of American women will take oral contraceptives¹ and an estimated 10-15 million postmenopausal women are currently taking hormone replacement therapy. It is becoming clear that some forms of hormone replacement therapy prevent serious diseases such as breast cancer, heart disease, osteoporosis and neurological degeneration while other forms actually increase the risk of these diseases. The most famous study illustrating the risk of HRT actually started out as a study to prove the safety and efficacy of HRT therapy: The Women’s Health Initiative (WHI). The Women’s Health Initiative The WHI studies were the first large, double-blind, placebo-controlled clinical trials of HRT in healthy, postmenopausal women. The estrogen-plus-progestin trial and estrogen-alone trial were both halted early (in July 2002 and February 2004 respectively) because preliminary study results indicated that the health risks of the conjugated equine estrogen and progestin exceeded benefits. It followed over 16,000 women for an average of 5.2 years, half of which were taking a placebo, the other half taking a combination of the progestin medroxyprogesterone acetate and conjugated equine estrogens. The study found statistically significant increases in rates of breast cancer, coronary heart disease, strokes and pulmonary embol for those on synthetic HRT. The study also found statistically significant decreases in rates of hip fracture and colorectal cancer. The conclusion of the study was that the HRT combination presented risks that outweighed its measured benefits. The results were almost universally reported as risks and problems associated with HRT in general, rather than with the specific proprietary combination of conjugated equine estrogen and progestin studied. It is generally accepted that female sex hormones are linked to the genesis of breast cancer. It is well established that estrogens markedly increase the mitotic rate of breast epithelial cells and that estradiol is carcinogenic to breast epithelium. Conversely, the picture is more complex for progesterone. The WHI study showed that synthetic progestins, when added to estrogen in HRT, increased the risk of breast cancer risk much more than estrogen alone. Unfortunately the WHI did not test natural progesterone. Natural progesterone proves protective of the breast in many studies. Understanding the differences between these two forms of HRT (one synthetic and one bioidentical) is vitally important. They are very different molecules and confusing them can have grave consequences for women on HRT. Scan the internet, popular magazines, or even talk to a ‘conventional’ physician and you will find that there is virtually no distinction made between natural and synthetic progesterone when discussing any type of hormone therapy or use. This is unfortunate, because the implications on a woman’s health can be disastrous. So what is the difference between natural and synthetic hormones and why does it matter? Progesterone is the principal hormone of the second half, or luteal phase of the menstrual cycle. Progesterone is essential for reproductive function, breast health, bone strength and memory. Natural progesterone products are made from the phyto-hormones that exist in wild yams and soybeans. The molecular structure of the hormones in these products is identical to those in the body. Synthetic progesterone, known as progestin, is man-made and while its chemical structure resembles the progesterone made in the body, it is not identical. This is a very important distinction. Even a slight difference in the molecular arrangement of a compound can cause dramatically varying responses. Here is a glaring difference between synthetic and natural progesterone: progestin is the active ingredient in many birth control pills and its function is to stop ovulation. To take any kind of progestin during pregnancy creates a large risk of birth defects. Natural progesterone, on the other hand, is produced by pregnant women at levels that are 30-50 times higher than normal. The fetus is bathed in the hormone while in the womb. It is often prescribed by fertility specialists as soon as the patient is aware that she is pregnant. Its name says it all: ‘pro-gest’…pro-gestation. Progesterone in its natural form is used to treat luteal phase deficiency/infertility, to maintain pregnancy in high risk situations, and to alleviate post partum depression. Ironically, taking progestins can actually lower levels of progesterone detectable in saliva. Progestin acts similarly to progesterone within the brain, and a negative feedback begins when the brain thinks that there are sufficient amounts of progesterone circulating and it stops the signal to produce more. The body then becomes low in progesterone and high in the synthetic progestin. The symptoms of PMS or estrogen dominance that women are so desperately trying to alleviate worsen due to low progesterone. Research studies have confirmed that millions of women have successfully used bioidentical (natural) hormones with a great improvement in health and wellbeing. Fewer side effects are noted, and utilization of the hormone is more consistent. ² We stand by the evidence that supports the use of bioidentical hormones, and insist that natural is better. Reference List 1. www.orthoevra.com 2. Pete Hueseman, R.Ph., P.D., 1997
There have been several high profile articles published recently that appear to connect an increased risk of cardiovascular disease with testosterone replacement therapy. Naturally, this is alarming, as it is contrary to what previous studies have determined and contrary to the principles by which most of us prescribe testosterone. Upon close review, there are a number of issues in these studies that are worth mentioning, and serve as good reminders of the importance of reading details rather than simply the headlines. The JAMA article of November 2013 entitled “Association of Testosterone Therapy with Mortality, Myocardial Infarction, and Stroke in Men with Low Testosterone Levels” concluded that testosterone supplementation increased a man’s risk of adverse cardiovascular events; however, there are a number of problems with the way this study was conducted: • It was observational and retrospective in nature, meaning that instead of following randomized groups of subjects who differ only by treatment(s) and comparing to a control group (ie.: randomized placebo controlled study (RCT)), these findings were based on retrospective observation of multiple treatments and variables outside of the control of the investigator. While a study like this may demonstrate associations, causation is better observed in RCT studies. • The cohort consisted of men with prior history of cardiovascular disease (CVD) who had undergone coronary angiography between 2005 and 2011, and who had testosterone levels less than 300 ng/dL at the time of angiography. • The study demonstrates multiple inherent biases and limitations as stated in the discussion section, including: the utilization of ICD9 codes only (no chart review) to determine outcomes, a relatively small group of patients with extended follow up time, and a select group of subjects undergoing angiography in the VA system, limiting generalizability. As such, this study cannot prove causality. • During the duration reviewed, 17.6% of subjects filled their prescription only once, with the remainder refilling their prescriptions more than once. Those subjects who did refill their prescriptions more than once averaged 376 days between refills. This is significant because testosterone refills are only valid for 180 days, suggesting the unlikelihood
Labrix Clinical Services Inc. is dedicated to providing the most accurate and physiologically relevant hormone testing available. In keeping with our dedication to accuracy we have chosen to measure DHEA rather than DHEAS in saliva. We are aware that many laboratories choose to measure DHEAS in spite of the overwhelming evidence that points to DHEA being the only form of DHEA accurately measured in saliva and additionally more clinically relevant. DHEA exists in two forms – free DHEA (DHEA) and sulphated DHEA (DHEAS). DHEAS is the inactive stored reservoir form of DHEA. DHEAS levels do not reflect biologically active DHEA levels. It must be desulfated by the enzyme DHEA sulfotransferase (SULT2A1) in order to be active. Since DHEA is the biologically active form of the hormone, it is the only form which can be converted into androgens and estrogen and only DHEA (not DHEAS) is protective for the brain. The active form of DHEA is produced in the adrenal glands and its free levels in the body can be measured accurately in the saliva. Measuring salivary levels of DHEA is a precise evaluation of the circadian secretions of this hormone by the adrenal cortex. Salivary DHEA reflects the unbound, biologically active fraction of the hormone in the general circulation and shows excellent correlation with free plasma levels of DHEA. DHEA (like other steroid hormones) is a non-polar molecule. Non-polar molecules are transported very easily through the salivary gland and their concentration in saliva matches that of the free circulating levels in the body. DHEAS on the other hand is a polar molecule. Its concentration in saliva is not a reflection of its concentration in the body. Dehydroepiandrosterone (DHEA) is the most abundant hormone in the body. It is primarily produced in the zona reticularis of the adrenal cortex and small amounts of DHEA are produced in the brain. DHEA serves as a metabolic intermediate (prohormone) in the pathway for synthesis of testosterone, androstendione, estrone, and estradiol. All the enzymes required to transform DHEA into androgens and/or estrogens are expressed in a cell-specific manner in a large series of peripheral target tissues (breast, prostate, skin, bone etc.), thus permitting all androgen-sensitive and estrogen-sensitive tissues to make sex steroids locally and control the intracellular levels according to their local needs. DHEA also serves a very important role in the stress response (hence its formation is triggered by ACTH, the same chemical messenger that triggers cortisol f ormation). DHEA has been shown to elevate mood, calm emotions and increase alertness - all essential qualities for responding well to stress. Additionally, DHEA’s affect on mood helps us cope more evenly with the stress and also helps improve memory. (read more on back) DHEA and DHEAS levels do not correlate well in pathological conditions i.e. high DHEA levels do not necessarily lead to high DHEAS levels. It appears that the enzyme that converts DHEA to DHEAS (SULT2A1) is often impaired during ill health. This leads to a reduction in DHEAS levels and a marked increase in DHEA levels. This again underscores the necessity of testing DHEA not DHEAS when evaluating patient and especially for those who are chronically ill. Reference List 1. Clinical correlates of DHEA associated with post-traumatic stress disorder. Yehuda R, Brand SR, Golier JA, Yang RK, Acta Psychiatr Scan. Sep 2006;114(3):187- 93. 2. Helpful diagnostic markers of steroidogenesis for defining hyperandrogenemia in hirsute women. Willenberg HS, Bahlo M, Schott M, Wertenbruch T, Feldkamp J, Scherbaum WA. Steroids. 2008 Jan;73(1):41-6. 3. No evidence for hepatic conversion of dehydroepiandrosterone sulfate fo DHEA – in vivo and in vitro studies. Hammer F, Subtil S, Lux P, et al. J Clin Endocrinol Metab 2005;Mar 8 4. Hormones in Saliva. Vining RF and McGinley RA. Critical Reviews in Clinical Laboratory Sciences. (1986) 23(2):95-146. 5. Is dehydroepiandrosterone a hormone? Labrie F, LuuThe V, Belanger A, Lin SX, Simard J, Pelletier F, Labrie C. J Endocrinol. 2005 Nov;187(2):169-96. 6. Functions and mechanisms of dehydroepiandrosterone in nervous system. Xie L, Sun HY, Gao J. Liao H.. Shen Li Ke XueJin Zhan. 2006 Oct;37(4):335-8. 7. Suppression of DHEA sulfotransferase (Sult2A1) during the acute-phase response. Kim MS, Shigenaga J, Moser A, Grunfeld C, Feingold KR. Am J Physiol Endocrinol Metab. 2004 Oct:287(4):E731-8. 8. Beyond the ovary: steroids and PCOS. Wiebke Arlt. The Endocrinologist. Issue 77. Autumn 2005.
Female sexual dysfunction is defined as a lack of interest in or enjoyment of sexual activity that is distressing to a woman. It can result from a loss of sex drive (libido), an inability to become aroused or to reach an orgasm, or pain during intercourse. A combination of many personal, interpersonal, and medical factors may contribute to sexual dysfunction. Physical causes may include health issues such as: • Diabetes • Heart disease • Nerve disorders • Hormone problems Ask About Sexual History When working with patients it is important to ask these questions regarding sexual history: “How is your libido or interest in sex and has it changed?” And, “How well does your body respond to sexual stimulation?” While some women may loose their libido, they find that when and if sexually active their bodies are still very responsive and able to reach orgasm. Other women will experience a slowing of their physical responsiveness. Hormone Imbalance May Be A Factor All the sex hormones play a role in sexual arousal and libido. Loss of libido is a common complaint with both men and women and becomes more prevalent with age. Though libido is often related to low testosterone, less than half of women will recover their libido through testosterone therapy. For most women with diminished sex drive, deficient testosterone is not the only problem. When testosterone deficiency is not the cause of low libido, other hormone deficiencies or imbalances must be explored. Low sex drive is often a combination of several hormone changes influencing sexual drive and responsiveness. This can include estrogen to progesterone imbalance, low thyroid hormone levels, or hyper or hypo function of the adrenal gland. Understanding the multiple hormones involved can help explain why a woman’s sexual responsiveness is so powerfully influenced by mood, energy, well-being, and other psychological mechanisms. When returning to pre-menopausal levels, estrogen increases vaginal circulation, helping to restore the vaginal lining and increase lubrication and elasticity of the vaginal tissue; progesterone may help with uplifting mood factors and energy. Addressing adrenal fatigue can positively influence a woman’s desire to have sex. Sometimes it takes a little time and tweaking, but once the right balance of hormones is accomplished, most women experience a renewed sexual vitality. A hormonal imbalance may or may not contribute to any one woman’s low sex drive. But if a woman does have a hormonal cause for sexual dysfunction, treatment can include bioidentical hormone therapy.
Why saliva instead of urine for measurement of hormones
When deciding how to assess hormone levels in a patient it is important to establish a methodology that will allow for ongoing testing and monitoring. Urine testing cannot measure progesterone directly…just the metabolites of progesterone so it is not a sufficiently accurate tool for direct measurement for assessing deficiencies and subsequent treatment. In addition, once a patient is started on a prescription of topical hormones the adjusted hormone levels cannot be accurately assessed through urine or blood — only saliva. This is because blood and urine will not show bioavailable hormone levels. Saliva, on the other hand, does reflect changes in hormone levels shown when a patient is on a topical hormone replacement and it is a proven method for adjusting and monitoring therapy. Providers who decide to use urine testing will often find that it takes a long time to get prescription rates correct and existing symptoms continue while new symptoms may appear.
The expanded Comprehensive Plus Panel builds on the Labrix comprehensive panel by including estrone (E1) and estriol (E3) plus an Estrogen Quotient calculation. The Estrogen Quotient is calculated by dividing E3 by E1 + E2 and was developed by Dr. H.M. Lemon in the 1980’s. The EQ is especially pertinent for women who need to focus on minimizing breast cancer risk. When assessing for estrogen dominance you can now use both the Progesterone/Estradiol (Pg/E2) ratio and the Estrogen Quotient (EQ) for riskpreventative assessment in your patients. Estrogen interaction Estrogen exists in the human body in at least three forms. Estrone, estradiol and estriol. Estradiol (E2) is the most potent estrogen in terms of its ability to relieve hot flashes and other menopausal symptoms. Unfortunately, however, estradiol and estrone are also the forms of estrogen that promote cancer growth and play a role in various pathologies including BPH and PCOS. E1 and E2 can be converted back and forth, from one to the other, and various physiologic states determine this cascade. Estriol (E3) is considered the ‘weak’ estrogen, and cannot be converted by the body into estradiol or estrone. It is sometimes referred to as the ‘anti-estrogen’ since, when it is present, it blocks further uptake at the tissue receptor sites by E2 and E1. Both E1 and E2 can be converted into E3, and once the hormone is converted to the E3 form it will not be converted back to E1 or E2. So despite estriol having the weakest activity of the estrogens - it is the only protective estrogen. Measuring these three estrogens through saliva testing is a critical assessment tool for determining when some of your patients have a higher risk for developing certain types of cancer. For women, an optimal EQ is also associated with lower incidence of autoimmune diseases like multiple sclerosis. Estrone Research has shown that elevated estrone is associated with increased risk of cardiovascular disease, endometrial cancer, PCOS, and breast cancer in women. Estrone can also be viewed as a marker for prostate health and cardiovascular disease risk in men. In women: • In post-menopausal women, CRP is higher when estrone and testosterone levels are higher.i • In endometrial cancer cases, circulating levels of E1 and E2 were significantly higher compared with unaffected controls.ii • The combination of elevated estrone and free testosterone appears to discriminate with high sensitivity and specificity between women with and without PCOS.iii • Overweight and obese women with breast cancer have poorer survival compared with thinner women. Obese women had 35% higher concentrations of estrone and 130% higher concentrations of estradiol compared with lighter weight women.iv • In premenopausal women, estrone levels generally parallel those of estradiol. After menopause, estrone levels increase, possibly due to increased conversion of androstenedione to estrone. In men: • Higher estrone is strongly related to an increase in benign prostatic hypertrophy (BPH) and prostate cancer.v • Higher estrone levels may be associated with a poorer prognosis in men with prostate cancer.vi • Men with coronary artery disease had lower testosterone levels and higher levels of estrone.vii Estriol The only time there is a dramatic increase in endogenous estriol is during pregnancy. However, it should also be noted that some women have higher endogenous E3 levels than others, which may protect some from developing breast cancer. Research has shown that supplemental estriol can help to increase bone mineral density, can be an effective treatment for multiple sclerosis and other autoimmune diseases, and decrease the risk of developing breast cancer. • Oral estriol therapy has been shown to increase bone mineral density without increasing triglycerides (commonly seen with CEE) and causes less endometrial proliferation and uterine bleeding.viii • Multiple sclerosis patients who become pregnant experience a significant decrease in relapses. Animal models of MS have shown that the pregnancy hormone estriol can ameliorate disease.ix • Estriol pellets implanted in rats exposed to carcinogenic substances decreased the risk of their developing breast cancer.x Estrogen Quotient EQ=E3/E1+E2 Because of the anticancer effects of estriol in animals, Dr. Lemon investigated whether estriol had any relationship to breast cancer in humans. He developed a mathematical formula, which he called the estrogen quotient (EQ). The EQ is a ratio of the E3 (anti-estrogen) divided by the sum of E1 plus E2 (cancer promoting estrogens) and helps predict breast cancer risk. If a woman’s EQ is low (<1.0), her risk of breast cancer is higher. When the EQ is >1, it is associated with lower cancer risk. The optimal ratio that is considered most protective to the breast is an EQ >1.5.
End Notes i. “Association of endogenous hormones with C-reactive protein, fibrinogen, and white blood cell count in postmenopausal women.” Eur J Epidemiol. 2005;20(12):1015-22. ii. “Circulating Estrogens in Endometrial Cancer Cases and Their Relationship with Tissular Expression of Key Estrogen Biosynthesis and Metabolic Pathways.” J Clin Endocrinol Metab. 2010 Apr 6. iii. “Are there any sensitive and specific sex steroid markers for polycystic ovary syndrome?” J Clin Endocrinol Metab. 2010 Feb; 95(2):810-9. iv. “Adiposity and sex hormones in postmenopausal breast cancer survivors.” J Clin Oncol. 2003 May 15;21(10):1961-6. v. “Sex Hormones and the Risk of Incident Prostate Cancer.” Urology. 2010 May 6. vi. “Estrone sulfate (E1S), a prognosis marker for tumor aggressiveness in prostate cancer (PCa).” J Steroid Biochem Mol Biol. 2008 Mar; 109(1-2):158-67. vii. “Evaluation of sex hormone levels and some metabolic factors in men with coronary atherosclerosis.” Aging Male. 2004 Sept;7(3):197-204. viii. “Beneficial Aspect of Oral Estriol as Hormone Replacement Therapy: Consideration on Bone and Lipid Metabolism.” Tokai J Exp Clin Med., Vol.34, No. 3, pp. 92-98, 2009. ix. “Treatment of Multiple Sclerosis with the Pregnancy Hormone Estriol” Ann Neurol 2002;52:421-428. x. Lemon, Henry M.D. “Estriol Prevention of Mammary Carcinoma Induced by 7,12-Dimethylbenzanthracene and Procarbazine.” Cancer Research 35, 1341-1353, May 1975.
Cortisol levels have a natural diurnal rhythm that varies throughout the day. Cortisol levels should reach their peak approximately 30 minutes after waking and then gradually decline throughout the day. The AM cortisol level is the most important, as it gives us the most information about adrenal function. Note: We request that samples be collected at all four times during the day, regardless of what lab tests have been ordered. We do this for two reasons: 1. When saliva kits are received by our lab, a fifth pooled tube of saliva is created by collecting a measured sample from each of the four submitted tubes. The fifth tube is mixed thoroughly to provide homogenization and becomes the source from which estrogen, progesterone, testosterone and DHEA are measured. These hormone levels fluctuate throughout the day, but do not have a regular schedule like cortisol levels. The pooling of these samples collected throughout the day enables us to provide a much better reflection of each patient’s hormonal status. It is essentially an average of the four submitted samples and more accurately reflects the physiologic hormone levels. 2. Samples are kept for 25 days after arriving at the lab, enabling practitioners to call and add any additional tests that they would like to run.