A hormone is a molecular messenger that acts on adjacent cells, the cells that produce it or travel to sites throughout the body that are sensitive to its effects. Hormones regulate your body’s energy production, temperature, growth, immune system, reproductive capabilities and neuroactivity. Your individual hormone balance is influenced by genetics, the environment, your lifestyle, eating habits and the function of your endocrine (hormone producing) system. With aging, hormone levels decline. For most, this heralds a definite decline in quality of life and an increase in problems with health maintenance.
Estrogen, progesterone and testosterone are the three major sex hormones in both men and women, with the ratios and levels varying according to gender. Estrogen and progesterone are the predominant hormones in women. Any discussion of one must include the other, although this article will focus primarily on estrogen.
Estrogen is made in the ovaries, the corpus luteum, adrenal glands, breast and fat cells.
Estrogen is a generic term referring to a group of molecules. In humans, the three main identified estrogen molecules are estriol (E3), estradiol (E2), and estrone (E1). A proper balance of estrogen enhances sensuality, improves the appearance of skin, moisturizes eyes, lubricates the vagina, preserves mental clarity, plumps up the breasts, and protects the bones and cardiovascular system.
When the scientific and lay communities refer to estrogen, they typically refer to its three components as one. At times, this oversimplification leads to errors in separating the individual function of the estrogens, particularly when discussing the differences between estrogen preparations used as hormone-replacement therapy available on the market. Although their actions are perceived and often recorded as one, the component molecules of estrogen have different potencies and effects.
Types of Internal Estrogens
Estradiol is the most powerful, abundant and active form of estrogen. Prior to menopause, it is made mainly by the ovaries. Post menopausal production occurs in individual cells throughout the body, particularly fat cells and stromal cells in the breast. Estradiol directly affects a wide range of cellular functions, as estrogen receptors are ubiquitous.
Estriol is the weakest of the estrogens. Estriol is primarily manufactured during pregnancy by the placenta. It attaches to cell receptors affecting hair, nails, and skin. Recorded data on estriol’s function demonstrate that estriol’s effects are limited mainly to the vaginal walls with little effect on the heart and bones in non-pregnant women. In the non-pregnant, young, and premenopausal woman, estriol is made in the liver in small doses. Studies have shown it to have a protective effect against breast cancer.
Estrone is manufactured in fat cells after menopause primarily from testosterone derivatives (androstenedione). Estrone levels tend to rise after menopause and the increase in estrone has been implicated in an increased incidence of breast tumors but most data have been obtained from animal studies. Overweight older women have high circulating levels of estrone.
Your hormonal health can also be affected by external estrogens and estrogen-like compounds introduced into your body. These include bioidentical estrogens, synthetic estrogens, xenoestrogens, and phytoestrogens. Bioidentical hormones are hormones manufactured with a molecular structure identical to that naturally found in the human body. They are made from a plant source, frequently soy or yams, and are ideal for use in hormone replacement therapy. “Bioidentical hormones” is not a marketing term. The term has been used for more than a decade in the inserts to all FDA-approved commercial hormone preparations that contain hormones molecularly identical to human hormones. Bioidentical estrogen preparations include: 17-Beta estradiol (Alora, Climara, Estrace), 17-Beta estradiol patches (Vivelle-Dot, Vivelle, Estraderm), Estradiol transdermal spray (Evamist) and combinations of estradiol, estriol and estrone in compounded formulations (Biest, Triest). In recent studies, bioidentical estrogens have demonstrated an ability to reduce degradation of telomere length. Telomeres are protective end-caps on chromosomes, the length of which is correlated with biological age.
Synthetic estrogens are chemically manipulated and are molecularly very different from human estrogens. These are the most common formulations used for hormone replacement therapy in the United States. Synthetic estrogens are derived from the urine of pregnant mares, as the name Premarin implies. The most popular preparations are conjugated equine estrogen (Premarin), esterified estrogen (Estaratab), and ethynil estradiol (Estynil).
Xenoestrogens are produced as by-products of the chemical pollution in our society and are very hazardous to your health. They can be absorbed through your skin, inhaled when you breathe and ingested with your food. Examples include dioxins, polychlorinated biphenyls (PCB), and dichlorodiphenal-trichoroethane (DDT), among others. They can be stored in fat cells for long periods of time and although relatively weak, they can act in combination to increase your risk for certain cancers.
Phytoestrogens are abundant in nature and can weakly interact with estrogen receptors. These compounds include lignans found in cereals, vegetables, green tea, legumes and flax; isoflavones in soy, beer, chickpeas, beans and lentils; and coumestrol present in grapes (resveratrol), alfalfa and clover. In moderate doses, phytoestrogens have been shown to exert a protective effect on breast cancer by inhibiting the production of estrogen.
The various metabolites of estrogen must also be considered in evaluating the overall hormonal milieu in your body. These metabolites are 2-hydroxyestrogen (2OH), 4-hydroxyestrogen (4OH) and 16alpha-hydroxyestrogen (16OH). The 2-hydroxyestrogen metabolite is considered a “good” estrogen because it has anti-cancer properties. It does not exert proliferative effects on other cells and antagonizes the effects of other estrogens. This metabolite also reaches very high levels during pregnancy, suggesting a protective effect against high hormone elevations. Synthetic estrogens can reduce the formation of 2-hydroxyestrogens. A competing pathway results in the production of 16alpha-hydroxyestrogen which has a high affinity for the estrogen receptor and strongly stimulates cell proliferation leading to cancerous changes in estrogen sensitive tissues. Studies have shown this 16 alpha metabolite to be important for preservation of bone tissue. It is, therefore, important to maintain an optimal ratio of 2-hydroxy:16alpha-hydroxy metabolites. The ratio can be measured by a urine or blood test. A low ratio may put you at increased risk for breast, uterine and ovarian cancer. A minor pathway leads to the production of the 4-hydroxyestrogen metabolite. This metabolite also promotes cancerous changes but doesn’t bind to an estrogen receptor, rather it works by directly damaging cellar DNA. Synthetic estrogens are metabolized to 4-hydroxy products; another compelling reason to avoid them.
Estrogen and progesterone are antagonists. Their actions are designed to balance each other and keep each other in check. We cannot live in a healthy state without hormonal balance. Hormones do not act independently, under normal circumstances, in healthy bodies.
Progesterone is manufactured primarily by the corpus luteum (the follicle transformed after ovulation) and also to a small degree by the arenals. In the ovary, progesterone production is activated at ovulation (15 days before the next menstruation), stimulated by the release of luteinizing hormone from the pituitary gland and is crucial to the survival of the ovum once fertilized. When pregnancy occurs, progesterone production increases rapidly and its manufacture is taken over by the placenta. If a woman does not get pregnant, the corpus luteum involutes and progesterone production diminishes and eventually disappears in parallel with estrogen production, heralding menstruation.
Progesterone is a precursor to most sex hormones, including estrogen in the ovaries, testosterone, all androgens, and other adrenal hormones, making it an extremely important hormone for reasons far beyond its role as a sex hormone. Progesterone in the breast and uterus counteracts the stimulation of cell growth, which is a direct action of estrogen. It accomplishes this action by activating the progesterone receptor, which in turn, down-regulates the estrogen receptor. Because progesterone suppresses estrogen-driven cell proliferation, progesterone in the natural state helps keep breast cell growth in healthy balance.
Commercially and compounded bioidentical hormone preparations containing progesterone include: Progesterone in peanut oil capsule (Prometrium), progesterone vaginal gel (Crinone), micronized progesterone in various compounded forms (capsules, troches, transdermal creams, vaginal suppositories), combinations of estradiol and progesterone in compounded formulations.
Beyond the commercial bioidentical hormone formulations, individually compounded preparations of bioidentical estrogens, progesterone and testosterone are prepared in compounding pharmacies or laboratories (some are FDA approved; all are regulated by the state they operate in) on an individualized basis as prescribed by a physician. These products contain the same active estrogens, progesterone, and testosterone as those found in the commercial preparations listed above. The difference is that they are individually mixed in tablet, capsule, troches, gels, or creams to the specifications of the prescribing physician for the individual patient.
The synthetic, non-human progestin found in Provera is medroxyprogesterone (MPA). It has very different biologic effects than natural human progesterone. Provera reduces the beneficial effects of estrogen on plasma lipoproteins, can lead to vascular spasms, opposes the beneficial effects of estrogen on the brain and has been shown to enhance the estrogen-induced proliferation of pre-existing breast cancer cells; the opposite effects of bioidentical or natural progesterone.
Among the lay public as well as within the scientific and medical communities, there remains considerable confusion surrounding estrogen and progesterone formulations. The confusion comes from the lack of clear distinction between their molecular formulas, the lack of focus on their different effects in the human body, and the use of nonspecific nomenclature when referring to estrogen and progesterone regardless of their actual differences in chemical structure or activity.
Hormone Replacement Therapy
Scientific studies on the effects of hormone replacement therapy after menopause have had conflicting results and conclusions. As early as 1976, scientific data demonstrating the safety of bioidentical hormones appeared in the conventional medical literature from the American College of Obstetrics and Gynecology. Reports of increased risk of endometrial and breast carcinoma among users of synthetic conjugated estrogens also appeared in the scientific literature around the same time As early as 1980 and continuing into the recent literature, untoward side effects of synthetic progestins, such as thrombotic phenomena; breast tissue cell hyperplastic changes; cardiovascular symptoms, headaches, elevated blood pressure, and changes in cholesterol, carbohydrate, and lipid metabolism prompted more research into bioidentical (micronized) progesterone as a safer option. A double-blind study comparing transdermal estradiol and Premarin reported in the American Journal of Obstetrics and Gynecology as early as 1985 suggested that bioidentical hormones were superior in relieving postmenopausal symptoms without side effects.
Womens Health Initiative
Most recently, the Women’s Health Initiative (WHI) has been the source of confusing and sensationalized reports indicting all hormone replacement for causing breast cancer and heart disease. The goal of the study was to evaluate the long-term effect of hormone-replacement therapy (HRT) versus placebo in the prevention of heart disease, osteoporosis, cancer, and strokes in postmenopausal women. The only form of hormone-replacement therapy used in the study was synthetic conjugated equine estrogens (Premarin) and synthetic progestins (Provera). Unfortunately, the WHI did not include a bioidentical arm even though bioidentical hormone usage and statistically significant studies consistently demonstrated positive results and sustainable safety and efficacy records. The WHI was supposed to definitively answer questions about the efficacy and benefits of HRT but only created confusion and concern. There were three treatment arms in WHI: the first used a combination of synthetic hormones, Premarin plus Provera, called PremPro; a second arm used only a conjugated equine estrogen (CEE), Premarin and a third arm evaluated the effects of calcium and vitamin D on fracture risk. Subjects in the PrePro combined synthetic hormone arm were reported to have an increased risk of breast cancer, stroke and coronary artery disease. The results from the Premarin only group were less publicized but demonstrated a reduced relative risk for both breast cancer and heart disease; the risk of thrombophlebitis was increased. Initial news reports on the calcium and vitamin D arm suggested no benefit from taking those supplements. Subsequent analysis has determined that the study was poorly designed and the initial analysis faulty.
Concerns with the WHI study design include the type of hormone used, dosing pattern, route of administration, timing of hormone usage, mean age of the participants, and prior health status of the participants. The WHI used only synthetic hormones taken orally and at a relatively high, fixed dose. The participants were, on average, 63 years old and more than ten years beyond menopause; the crucial time to mitigate the pro-inflammatory effects of the postmenopause transition. Studies have demonstrated estrogen’s ability to block chronic inflammatory mediators, including interleukin-6, tumor necrosis factor alpha and prostaglandin E2. Estrogen has also been found to have significant antioxidant effects.
Participants in the WHI were not adequately prescreened for breast cancer or subclinical atherosclerotic heart disease, and it was reported in JAMA, the Journal of the American Medical Association in 2002 that a substantial portion of the participants had prior health histories which included obesity, hyperlipidemia, angina, strokes and smoking. The adverse outcomes WHI attributed to hormone therapy, especially cardiovascular, could very well be linked to age and pre-existing risk factors. A reanalysis by Rossouw et al published in JAMA in 2007 separated WHI participants by age and found a reduced risk for coronary heart disease in all women taking hormone therapy 10 or fewer years from menopause. The only statistically significant increase in cardiac events occurred in women 20 plus years postmenopause. Furthermore, the results of the WHI Coronary-Artery Calcium Score Study performed after the conclusion of the WHI, demonstrated a 61% reduction in coronary artery calcification in women taking estrogen. This translates into a reduced incidence of subclinical coronary artery disease in women receiving estrogen. Although breast cancer may be the greater fear for women, 10 times more women die from cardiovascular disease every year than breast cancer.
As mentioned above, the WHI used only synthetic hormones. Synthetic estrogens are metabolized to 4OH estrogen, which has been found to be thirty-times more toxic to cellular DNA than bioidentical estrogens. Synthetic progestins appear to attenuate most beneficial effects of estrogens and enhance estrogen’s proliferative effects. That may explain any increased risk of breast cancer noted after 10 or more years of synthetic hormone replacement therapy.
The synthetic hormones used in WHI, Premarin and PremPro are administered orally. They are subjected to first pass through the liver resulting in increased production of clotting proteins and inflammatory markers, C-reactive protein. Orally administered estrogen preparations have long been associated with an increased risk of venous thromboembolism (VTE), or blood clots. In each of the two hormone therapy arms of the WHI, an increase in VTE was reported. Transdermal estrogen has been shown to eliminate the thromboembolic effects noted by orally administered estrogens. Two studies published in Circulation, the Journal of the American Heart Association, in 2005 and 2007 showed that transdermal estrogens did not increase the risk for blood clots, even when combined with micronized progesterone.
Public perception that all hormone preparations cause breast cancer was fueled by the notoriety gained in the media from the results of the combined estrogen-progestin arm of the WHI that ostensibly revealed an increased risk of invasive breast cancer among hormone users. Those erroneous conclusions of so-called experts have been refuted by subsequent analyses. When corrected for multiple breast cancer risk factors, the results were no longer considered statistically significant. Additionally, the combined WHI arm was discontinued after 5 years, and most cancer researchers agree it takes 7-10 years of dividing for a breast cancer cell to become a detectable lesion. This further suggests that hormone replacement was not the cause of breast cancer. A large review of studies prior to WHI published in the New England Journal of Medicine, 1997 demonstrated a 24% reduction of breast cancer deaths among women during the first ten years of hormone replacement.
Beginning hormone replacement therapy at the onset of menopause and continuing for 10 years significantly reduced the incidence of Alzheimer’s disease in the Cache Cohort Study published in 2002. Women who began HRT ten years or later had an increased incidence of Alzheimer’s. Similar results were reported in the journal, Menopause, in 2005: replacing hormones early in menopause and continuing them for several years protected against cognitive decline and that benefit persisted for up to 15 years later.
Although the controversy surrounding the use of hormone replacement therapy is far from resolved, there is mounting evidence of its benefits for most women. A recent study in Menopause reported that a “significant proportion of obstetrician-gynecologists continue to express skepticism regarding the WHI results”. The medical and scientific community will probably not reach any consensus until a definitive randomized trial directly comparing synthetic hormones with bioidentical hormones, while taking into account age, risk factors, timing and route of administration, and differing biologic activity during the crucial first ten years of menopause.
That being said, there is ample evidence to recommend hormone replacement for most women. Bioidentical hormone therapy should be initiated at menopause or during perimenopause to provide protection for the cardiovascular system, maintain adequate bone mass and body composition, enhance sexual desire and responsiveness, preserve cognitive function, and minimize the unpleasant symptoms associated with the menopausal transition. Women would be best served to seek out a physician specializing in bioidentical hormone therapy. The most effective hormone balancing is achieved within a broader program addressing lifestyle modificatons, proper nutrition and nutritional modulation of hormone metabolites, high quality nutritional supplements, liver-gut detoxification, regular exercise, stress management and adequate sleep. Remember, aging is inevitable, but how you age is up to you.