The Menstrual Cycle - Hormone Restoration



The Necessity and Safety of Estradiol, Progesterone and Testosterone Restoration in WomenEstradiol, progesterone and testosterone are much more than “sex hormones”; they are required for the function, growth, and maintenance of most tissues and organs in both women and in men. Estradiol is the dominant hormone in women, but is almost completely lost at menopause. The menopausal estradiol deficiency is natural, but is deleterious for a woman’s quality of life and long-term health. Estradiol can be safely restored to optimal levels/effects if done so in the right way and with sufficient progesterone and testosterone. Testosterone has similar benefits for women as for men, but to a lesser extent due to their much lower levels. Unfortunately, women are being denied medically-necessary sex-steroid replacement due to medical ignorance. This failure to replace vital hormones is producing untold suffering and causing thousands of unnecessary deaths every year in the United States alone.The Menstrual CycleIn order to understand the female hormonal system, one must understand the menstrual cycle. Whereas male sex-steroid hormone levels are stable over time, gradually declining with age, female hormone levels vary markedly from week-to-week and with many conditions. The menstrual cycle exists for the purpose of reproduction—to perpetuate the species. Only secondarily does it work to maintain a woman’s well being and health. In fact the menstrual cycle and its disorders create many problems for women’s quality of life and health. The ovaries produce three major sex steroids: estradiol, progesterone, and testosterone; only the levels of estradiol and progesterone vary markedly during the menstrual cycle. The ovaries contain follicles, nests of cells with a central egg surrounded by hormone-producing granulosa and thecal cells. Hormone production is controlled by variations in the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH) by the pituitary gland. (See figure 1.) In the follicular phase, FSH causes follicles in the ovary to ripen and produce estradiol. Estradiol causes the lining of the uterus (endometrium) to thicken. A spike in FSH and LH output causes a single follicle to release and egg. After ovulation, the follicle becomes the corpus luteum which produces large amounts of progesterone. During the luteal phase, progesterone reduces proliferation in the uterine lining and induces changes that are called “decidualization”. This prepares the endometrium to receive a fertilized embryo. If no embryo implants itself into the endometrium, estradiol and progesterone production fall and the uterine lining is sloughed, causing vaginal bleeding. Then the cycle starts all over again. Nature “wants” women to get pregnant; the price for not doing so is the discomfort and inconvenience of menstrual bleeding.Figure 1 From 575310190500Testosterone has little effect on the menstrual cycle and its levels do not vary much, except for a peak at ovulation—well-timed to encourage intercourse.Menopause is both Natural and HarmfulThe ovaries are the only endocrine glands that are pre-programmed to fail at some point in life. This failure occurs because women are born with a fixed number of follicles in their ovaries and they are lost with every menstrual cycle and with aging itself. Even by age 30, estradiol and progesterone production can decline or become irregular due to loss and aging of follicles. The follicles that were most healthy responded to FSH/LH stimulation earlier. Eventually, no more follicles are left and the ovaries cease to function. Whether the postmenopausal ovary produces any hormones is controversial. One study found that it produced small amounts of estradiol and testosterone; another found no evidence of hormone production. After menopause, most of the estradiol and testosterone in a woman’s body is produced from adrenal DHEA and androstenedione in various tissues including fat, breast, bone and brain. Progesterone is always present in low levels in women and men as it is made by the adrenal glands. It is made in large quantities only in women—after ovulation and during pregnancy. If a woman does not ovulate, her progesterone levels stay low, similar to a man’s levels. The clinical effects of premenopausal anovulation vary with how much estradiol is produced. A woman may have no bleeding, irregular bleeding, and possibly very heavy bleeding. Anovulation occurs sporadically in healthy women, and is quite common in the years just prior to menopause. The transition from regular, ovulatory menstrual cycles to irregular bleeding and altered hormone levels prior to menopause is called “perimenopause”. Once the ovaries cease to make estradiol and progesterone, the endometrium is not stimulated and menses cease. The lack of any bleeding for one year in a woman over 45 is considered to be evidence of menopause. The major roles that estradiol and progesterone play in reproduction have blinded physicians to their importance in human physiology. Estradiol, in particular, has hundreds of known actions, in most of the tissues and organs of the body. It maintains the health of the brain, bones and skin,, vagina, urinary tract, heart and blood vessels. Estradiol deficiency causes hot flashes, insomnia, fatigue, depression, vaginal dryness, urinary incontinence, sexual dysfunction, bone fractures, heart disease and dementia (See below.) After 5 years of menopausal estradiol deficiency, both bone density and skin collagen content have fallen by 25-30%. The skin has less collagenTable 1. Estradiol Deficiency Hot flashesIrritability, insomnia, depression, fatigue, aches Poor memory, dementiaAtrophy of skin and connective tissueOsteoporosis, fractures, loss of teethGenital atrophy, vaginal dryness IncontinenceEndothelial dysfunction, hypertensionAtherosclerotic heart diseaseReduced insulin sensitivityIncreased body fat, glycoaminoglycans and water content. Estradiol deficiency increases the expression of a lipogenic gene, causing an increase in body fat after menopause. All these problems can be prevented or reversed with estradiol restoration. The loss of progesterone at menopause increases the risk of breast, uterine and ovarian cancer. (See below.) How is it possible that a natural event like menopause can be harmful? The answer lies in understanding the evolution of the species. The female hormonal system exists to produce, breastfeed and care for children; not to optimize women’s health, strength and stamina does the male hormonal system. Women pay a high endocrine price for bearing the burden of reproduction, both pre- and postmenopausally. They have many menstrual-cycle related symptoms and disorders. They have much lower stamina and muscle strength because of their lower testosterone levels. They suffer from thyroid and cortisol deficiencies much more than men. After menopause, they are left in a state of severe sex-steroid deficiency. Postmenopausal women have the same low progesterone levels as men very low testosterone levels, and much lower estradiol levels than men of the same age! (See figure 2.) This combined sex steroid deficiency has devastating effects upon their quality of life and long-term health. Three of the primary causes of disability and death in women, cardiovascular disease (CVD), osteoporosis and breast cancer, are all rare before menopause. All three are related to estradiol-progesterone-testosterone deficiency and imbalance. Bilateral oophorectomy before age 45 is associated with a higher risk of death from all causes (RR 1.67). The youthful female estradiol-progesterone-testosterone hormonal milieu protects women from these diseases. (See below). Menopause is natural indeed, but it is not good for women. It is not an Figure 2. Menopausal sex steroid deficiencyevolutionary adaptation to prolong a woman’s well-being and survival; it is an evolutionary accident. Our genetic heritage extends far back to the primate and hominid species that preceded us. As mentioned before, the evolutionary adaptation of the species requires the death of individuals. It was much more unlikely for our distant ancestors to survive to age 80 or 90 than it is for us now. There was no evolutionary pressure for hominid and then human females to maintain their health and quality of life for very long after age 50. The survival of our species required only that females were able to produce, breastfeed, and raise to independence several children before they died. The accidental nature of menopause is evidence by the reaction of the brain’s hypothalamic-pituitary system. With either natural or surgical menopause, the pituitary starts to produce extremely high levels of FSH to try to stimulate ovulation and hormone production. FSH and LH levels remain abnormally high for the rest of a woman’s life. The brain continues to try to get the ovaries to function again, just as it does with any other gland that fails. The brain was not programmed to accept menopause as “normal” or good. Seen in this light, the bothersome early symptoms of menopause, like hot flashes and vaginal dryness, are not just symptoms to be suppressed, but early warning signs of an endocrine deficiency that will cause deterioration and death.Testosterone is also essential to the health and well-being of women. Healthy young women have free testosterone levels twice as high as their free estradiol levels. Testosterone has the same benefits in women that is does in men, only to a lesser degree due to their lower levels. Even when high-normal, women’s free testosterone levels are only about 1/10th those of men (ref. ranges: 0-2.2pg/ml for women, 9-25pg/ml for men). Even in these lower amounts testosterone helps to maintain a woman’s bone mass, muscle mass, stamina and sexuality. It improves her mood, mental function, and assertiveness. Testosterone affects how a woman thinks and acts, and even what career she selects. Higher testosterone levels are found in women in professional and managerial positions vs. housewives and clerical workers. Women with higher testosterone levels identify themselves as independent, strong, assertive, impulsive, resourceful, spontaneous, uninhibited, rational, patient and arguing. Whereas, females with lower testosterone concentrations viewed themselves as civilized, socialized, calm, quite, sentimental, shy, nice, sensitive, warmhearted, sympathetic, thoughtful, warm, practical and kind. Lower testosterone and DHEAS levels are associated with low libido in pre- and postmenopausal women., Testosterone levels are only part of a woman’s overall androgen status. As much as 70% of the androgen effect in her body comes from the conversion of DHEA into testosterone with her cells. This is only partly reflected in the serum testosterone level. About 50% of the testosterone in the blood is from the ovaries; the other 50% is adrenal in origin, testosterone that has leaked into the blood from the intracellular conversion of adrenal DHEA into testosterone. Thus adrenal DHEAS production is also very important to a woman’s health and well-being. Women's testosterone levels drop by 50% between the ages of 20 and 40 due to both reduced ovarian and adrenal androgen production., Many women in their 40s and 50s are have extremely low testosterone levels, and their androgen deficiency is made worse by estrogen replacement therapy which lowers DHEAS and testosterone levels by 25% and 45% respectively., Birth control pills or patches lower DHEAS by 30% and free testosterone by 60%., The universal female androgen deficiency of aging is invisible to Reference Range Endocrinology. A national laboratory has a "normal" range for total testosterone of 0-45ng/dL, and for free testosterone 0-2.2pg/ml. Other laboratories report ranges of 0-76ng/dL for total testosterone and 0.2-6.4mg/ml for free testosterone. (A more careful study of healthy menstruating women at age 30 found a 95% free testosterone range of 1.2 to 6.4pg/ml.) As it stands, the lab report tells physicians that no detectable testosterone is perfectly “normal”; so they conclude that women don’t need any testosterone. Progesterone-Estradiol ComplementarityThe female organs, the cyclic hormonal system and the act of reproduction itself all pose many threats to a woman’s quality of life and health. In order to reproduce, the breast, uterine and ovarian tissues must undergo a monthly cycle of proliferation and differentiation, and then breakdown if no pregnancy occurs. Defects in this cycle can lead to many medical disorders and to cancers in the female organs. Consider the historical context again. For a woman to have many years of menstrual cycles in her life is a recent phenomenon. Throughout most of human history, women had unprotected sex from adolescence until menopause. It is estimated that women had menstrual cycles for only 4 years of their lives, on average. They were usually pregnant or breast feeding; both of these states are known to be protective against the development of breast cancer. The exposure of the breasts to pregnancy levels of estradiol and progesterone, even for a short time, causes a differentiation of the mammary ductal epithelium that permanently reduces the risk of breast cancer.,, Pregnancy also reduces breast cancer incidence through its effect on prolactin levels. Prolactin is a pituitary hormone that stimulates breast proliferation in lactation. Higher prolactin levels are associated with breast cancer, and pregnancy reduces prolactin levels for a decade or more. Today, with abstention from sex and with non-hormonal contraceptives, women postpone pregnancy for many years. They can have menstrual cycles for 35 yrs. This puts them at much greater risk of breast, ovarian and uterine cancers, endometriosis, polycystic ovary disease, ovarian cysts, premenstrual syndromes and many other diseases and disorders. During menstrual cycles, women need sufficient progesterone to balance estradiol in their breasts and uterus. Estradiol stimulates the epithelial linings of the breasts uterine uterus, producing cellular proliferation. Progesterone stops this proliferation and promotes maturation and differentiation of the epithelial cells—preparing these organs for pregnancy. In the normal breast, estradiol stimulates growth of the ductal system, while lobular development depends on progesterone. When cells differentiate they become more specialized; they switch off certain genes and reproduce more slowly, making them less likely to undergo malignant transformation. When no pregnancy occurs, the fall in estradiol and progesterone levels leads to necrosis and sloughing of both the uterine lining and breast duct epithelium. This may help to eliminate pre-cancerous cells. Table 2. Progesterone Counteracts EstradiolDecreases the synthesis of estradiol receptors Increases the inactivation of estradiol Reduces production of estradiol from estroneIncreases the sulfation of estradiolInhibits binding of estradiol to receptorsInhibits production of estradiol by aromatizationProgesterone has many known anti-estradiol actions in the uterus and breasts. It decreases the synthesis of estradiol receptors. It increases the conversion of estradiol to inactive estrone by inducing 17β-hydroxysteroid dehydrogenase Type 2. It reduces the conversion of inactive estrone to estradiol by inhibiting 17β-hydroxysteroid dehydrogenase Type 1. It activates estradiol by increasing its sulfation. Progesterone also inhibits the binding of estradiol to its receptors. A metabolite of progesterone found in breast tissue, 20alpha-dihydroprogesterone, inhibits the production of estradiol and estrone from testosterone and androstenedione. A high progesterone/estradiol ratio in the luteal phase of normal menstrual cycles helps to suppress proliferation and to prevent breast and uterine cancer. A low progesterone/estradiol ratio is known as “luteal insufficiency” and produces a state of “estrogen dominance” characterized by excessive breast fullness/tenderness, fluid retention and premature or heavy menstrual bleeding and cramping.Progesterone also has direct beneficial effects in the body. It helps to increase bone mass (see below). It has a calming effect on the nervous system—reducing anxiety and improving sleep. Progesterone has well-studied neuro-protective effects in the brain. It can reduce seizure susceptibility through its conversion to neurosteroids such as allopregnanolone which enhance GABA(A) receptor function and thereby inhibit neuronal excitability. Progesterone also competes with aldosterone at its receptors in the kidneys, producing a diuretic effect, which counteracts estradiol’s fluid-retaining effects. Progesterone and estradiol production begin to decline around age 30. If there is no ovulation, no progesterone is produced at all, putting a woman at greater risk of breast and uterine cancers and other problems. During perimenopause when higher FSH levels are super-stimulating the ovaries, some women can produce pregnancy-like estradiol levels and have very heavy, irregular bleeding. Many hysterectomies are performed at this time, when all that is needed is high-dose progesterone supplementation. Perimenopausal progesterone deficiency increases the initiation of breast and uterine cancers. A poetic way of thinking about estradiol in women is that it is both the “Angel of Life” and “Angel of Death”. Estradiol is essential for both male and female health and to human reproduction, but it also can cause disease and death in women—especially if not properly balanced with sufficient progesterone and testosterone.The Benefits and Safety of Estradiol-Progesterone-Testosterone RestorationEstradiol restoration is the only effective treatment for estradiol deficiency. Estradiol restoration prevents and/or ameliorates all the symptoms and disorders listed table 1. (See Table 2.) Estradiol restoration quickly eliminates hot flashes and improves sleep and mood. It restores vaginal moisture and urogenital health. It improves psychological function. Estradiol protects brain cells from toxic injury, and does progesterone. Estradiol increases serotonin production and urinary serotonin excretion and relieves depression. It reduces body fat mass, intrapelvic fat, and intraperitoneal (belly) fat. It lowers serum leptin and reduces waist-hip ratio. It improves the skin’s collagen content, thickness and moisture., Progesterone supplementation is safe and any dose or level. It reduces proliferation in breast and uterine tissue. Progesterone supplementation can treat any disorder of excess uterine bleeding or cramping. Fibrocystic breast disease is associated with low luteal progesterone levels, and topical progesterone is an effective treatment. We know little about the beneficial effects of progesterone on the rest of the body in women and in men, this requires much more study. Oral micronized Table 2. The Benefits of Estradiol Restoration Eliminates hot flashesImproves sleep, mood and energyReduces achiness Improves memory and mental clarity prevents dementiaSlows and partially reverses atrophy of skin and connective tissueBuilds bone, prevents fractures. Restores vaginal moisture, sexual function, and urogenital health Dilates blood vessels, lowers blood pressuerPrevents atherosclerotic heart diseaseImproves insulin sensitivityReduces visceral (belly) fatprogesterone improves sleep quality. Progesterone acts as a cortisol antagonist at the cortisol receptor. Since excess cortisol promotes intrabdominal fat accumulation, sufficient progesterone can promote a more healthy fat distribution. In the sections below, I will discuss the benefits of estradiol-progesterone replacement for four diseases that cause most of the death and disability in women: cardiovascular disease, breast cancer, osteoporosis and dementia.More specialists are becoming convinced that balanced bioidentical estradiol-progesterone supplementation provides all the expected health benefits without the risks seen with non-bioidentical “HRT”.,,,,,,,,, This should be true by definition since BHRT simply restores a more youthful, therefore healthier hormonal state. However, there is a great deal of confusion about these hormones and their effects, much of it due to the problems caused by doctors using the wrong molecules and/or route of delivery. To understand the implications of the many studies of HRT, one must understand the differences between the various bioidentical and non-bioidentical molecules and the different effects of the different routes of administration (i.e., oral, transdermal, vaginal, etc.). Many, if not most of the studies showing the benefits of menopausal HRT used Premarin?, known generically as conjugated equine estrogens (CEE). CEE contains estradiol and other estrogens that can be converted into estradiol or estradiol-like molecules. CEE raises estradiol levels in women, correcting the deficiency. So one can assume that the quality-of-life and health benefits obtained with CEE in studies are due to estradiol restoration. Conversely, all problems seen with CEE and other non-biodentical hormone treatments are due to their altered chemical structure or route of delivery until proven otherwise. I will use the term “estrogen” below to refer to studies that included CEE. I will use the term “estradiol” if that was the only estrogen studied. In marked contrast to the favorable risk/benefit profile of CEE, the various non-bioidentical progesterone-like molecules (progestins, progestogens) do not produce the same benefits as progesterone and cause many serious problems including increased risk of blood clots, strokes, heart attacks and breast cancer. (See Appendix 3.)Table 2. The Benefits of Testosterone Restoration in WomenImproved energy and moodImproved libido and sexual functionReduction in anxietyGreater physical stamina, enduranceGreater muscle mass and strengthReduced subcutaneous fat Better memory and mental clarity Greater bone mass, less fracture risk Testosterone must be included in menopausal hormone therapy to restore its youthful balance with estradiol and progesterone. Testosterone maintains a woman’s health and improves muscle strength, bone density, mood, energy, libido and sexual function. Testosterone reduces anxiety and general fearfulness—which are much more common in women than in men precisely because women’s testosterone levels are so low. A single dose of testosterone reduces fearfulness in women. Many women tell me that they feel more “centered” on testosterone. It can even allow them to do things that they were afraid to do before. For some women the reduction in fearfulness is ego-dystonic. With higher testosterone levels they are not as afraid to express their dislike or anger as they had been. They misinterpret there new-found boldness as aggressiveness. Other women appreciate this benefit, especially if their work requires bold thought and action. Testosterone supplementation improves mood and spatial cognition in women with anorexia nervosa (who have low testosterone levels). Oophorectomized women receiving both estrogen and testosterone feel more composed, elated, and energetic than those who are given estrogen alone. Testosterone therapy alone in premenopausal women with low libido improves well-being, mood, and sexual function. It is an effective treatment for hypoactive sexual desire disorder. Adding testosterone to EP therapy improves sexual sensation and desire., Since testosterone is aromatized to estradiol, testosterone implants alone in menopause can improve many typical menopausal symptoms: psychological, somatic and urogenital. The benefits of testosterone on sexual function are not due to its aromatization to estradiol. The addition of testosterone to estrogen therapy in oophorectomized women improves energy, well-being, and appetite and reduces somatic, psychological, and menopausal symptoms. Testosterone injections given to women on ERT improve sexual function, lean body mass, and muscle strength. Testosterone and estradiol implants in equal amounts (50mg/3mos) produce marked improvements in bone mass, fat-free (muscle) mass, and sexual function. Transdermal testosterone therapy in hypopituitary women increases muscle size, bone density, mood and sexual function. With testosterone supplementation, women are often very happy to find that they can gain some muscle size and strength when working out at the gym. They have greater physical stamina. They are able to do household tasks with greater ease; even simple things like opening a large door are easier. This greater muscle strength and size combats the frailty that comes with advanced age. Testosterone restoration is safe. Not only does testosterone appear completely safe at female physiological doses, as one would expect, but even giving women male levels of testosterone (in female-to-male transsexuals) for many years is not associated with any increase mortality, breast cancer, vascular disease, or other major health problems., No significant increase in the risk of cardiovascular diseases or breast cancer had been found in women using testosterone (implants, tablets, or injections); the only risks are its androgenic effects (hirsutism, acne, clitoromegaly, etc.). These problems are dose-related and women vary greatly in their susceptibility to them. Some women are genetically predisposed to have more facial hair, or instance, and will not tolerate testosterone supplementation for this reason. Others have very little tendency towards facial hair or acne, even at high testosterone doses. Testosterone’s effects operate on a continuum, and each women must choose her own compromise. They benefit in many ways from higher levels, but at some point the increase in body hair or pimples will become unacceptable and the dose should be lowered. Hormones and Breast CancerBreast cancer, like all cancers, occurs due to a genetic mutation, or number of mutations in the cells of a tissue or organ. Hormones do not cause genetic mutations, they do not cause cancer. However, hormones can play a facultative, enabling role in sex organ cancers. Higher levels of a hormone or hormone-like drug that stimulate a tissue to proliferate increase the likelihood that a mutated cell line will be produced and then will grow faster, avoiding the immune system that could eliminate it. With such stimulation, existing tumors will be detected earlier—leading to a higher incidence of diagnosis during treatment in studies. Even short treatment periods with stimulating hormones/drugs can cause an increase in breast cancer diagnosis. This is the true meaning of studies that reveal an “increased risk of breast cancer” with hormonal treatments. It is an increase in diagnosis of breast cancer. The cancers themselves were most likely present for several years or more before becoming detectable. Mainstream medical organizations hold that both estradiol and progesterone promote breast cancer. It is true that estradiol stimulates cell proliferation in the uterus and the breasts. Unopposed estradiol (with no progesterone) is known to increase uterine cancer risk. This is why conventional (pharmaceutical) HRT guidelines require that progesterone or a progesterone-like drug (“progestin”) be included with any estrogen therapy in a woman with a uterus. Unopposed estradiol has the same effect in the breast, stimulating cellular proliferation and thus facilitating the initiation and growth of breast cancers. In the breast as in the uterus, progesterone reduces cellular proliferation and thus the risk of clinical breast cancer. Fibrocystic breast disease has been associated with higher estradiol and lower progesterone levels,,, and with evidence of progesterone resistance. Longer menstrual cycles, a sign of higher luteal phase progesterone levels, are associated with a lower risk of breast cancer. Higher body mass index in menopause increases the risk of breast cancer, most likely though an increase in bioavailable estradiol in the absence of progesterone. Higher bone density in menopause is associated with higher breast cancer risk—this relationship is explained by higher estradiol levels. In premenopausal women, breast cancer has been repeatedly associated with higher estradiol and lower progesterone levels during the luteal phase.,,, Some studies do not show a correlation with higher estradiol levels, but with higher testosterone levels, particularly when combined with low progesterone.Dr. John Lee was the first person to argue publicly that breast cancer and many other female health problems were due to "estrogen dominance"—an excess of estradiol effect caused by a relative lack of progesterone. Many other researchers now agree with the theory that progesterone insufficiency increases the risk of breast cancer., The effects of progesterone on breast tissue have been studied extensively in vivo and in vitro, and are consistent with progesterone’s known direct effects and its anti-estradiol effects. Progesterone cream applied to female breasts eliminates the proliferative-mitotic effect of estradiol as seen in breast biopsies.,, Applying progesterone to the breasts lowers the risk of breast cancer (RR 0.8). In both normal breast epithelial cells and cancer cells, estradiol increases proliferation while progesterone decreases proliferation and induces apoptosis (cell death).,,,,, Transdermal estradiol given with cyclical (2 weeks per month) oral progesterone did not increase cellular proliferation or increase breast density.Progesterone’s protective effect against breast cancer has been seen in large, multi-year studies. Higher luteal phase progesterone levels were associated with a much lower risk (RR 0.12) of breast cancer diagnosis over the next 5 yrs (see figure 8.). Premenopausal women with low luteal progesterone levels were found to have 5.4x higher risk of early breast cancer. Progesterone’s protective effect has also been seen in several studies of HRT. In most countries, a progestin is prescribed to women with a uterus; only in France is progesterone in common use, generally with transdermal estradiol. The E3N-EPIC study in Europe found that postmenopausal women who took transdermal estradiol alone had a 20% increase in breast cancer diagnosis over women not taking any hormones. This is to be expected given unopposed estradiol’s stimulatory effects in the breasts. Women who took progesterone along with transdermal estradiol (because they had a uterus) had instead a reduction in the incidence of breast cancer (RR-0.9). In a longer follow up with more patients in the same study, the RR increased to 1.0 (no increased risk). Similarly, a large cohort study in France found no increase in breast cancer incidence in women on HRT, most of whom were taking transdermal estradiol and progesterone. A case-control study in France found that women taking estradiol and progesterone were protected against breast cancer relative to never users of HRT (RR=0.8). The MISSION study in France also found a reduction in breast cancer for women taking estradiol and progesterone (RR=0.4). Most women in the taking progesterone in these studies received one 100mg oral capsule daily. This dose and route are relatively ineffective. (See below.) It is likely that a higher effective dose of progesterone would produce a greater decrease in breast cancer diagnosis risk compared to no hormone replacement. Based on such evidence, a European research group concluded that progesterone has anti-proliferative effects in the female breast, and could thereby potentially reduce the risk of breast cancer. Another group stated, “The hypothesis of progesterone and some progesterone-like progestins decreasing the proliferative effect of estradiol in the postmenopausal breast remains highly plausible and (progesterone) should be…the first choice for symptomatic postmenopausal women.” In the next chapter I will explain why the anti-proliferative, anti-cancer effects of progesterone are not known or discussed in the United States. The Key - Intrammamary Estradiol ProductionThe demographics of breast cancer give us more clues to its hormonal influences. The incidence of breast cancer diagnosis begins to rise after age 30, when progesterone production begins to decline, and continues to rise long after menopause (see figure 6.). The fall-off in diagnosis after age 80 is due to reduced screening and/or diagnostic evaluations after that age. It usually takes 5 to 10 yrs. for a breast cancer to grow from one cell to a detectable mass (~1cm). So the initiation of breast cancers continues to increase long after menopause, after both progesterone and estradiol have fallen to low levels in the blood. The same pattern is seen in uterine cancer, which is known to be due to perimenopausal and menopausal progesterone deficiency. (fig 6.). Ovarian cancer also appears to be promoted by estradiol and prevented by progesterone.,, It is well-known that anti-estradiol treatments like tamoxifen and aromatase inhibitors reduce breast cancer diagnosis and recurrence in 5 to 10 yr. follow-ups.An explanation for this continued rise in breast cancer diagnosis throughout menopause and efficacy of anti-estradiol treatment was suggested by two recent studies. The first examined fluid aspirated from the nipples of pre- and postmenopausal women. It found no decrease in the amount of estradiol in the breasts in menopause. Postmenopausal women had as much estradiol in their breasts as premenopausal women. This is possible because breast tissue can produce estrone locally from androstenedione, an androgen produced from adrenal DHEA. Estrone can be converted into estradiol. A probable explanation for the breasts’ ability to produce estradiol is lactation. During breastfeeding a woman’s serum estradiol level remains quite low because the menstrual cycle is suppressed. Estradiol deficiency symptoms like vaginal dryness can occur. During this time, the breasts may require more estradiol than is available from the serum in order to maintain milk production. Intramammary estradiol production may also have been an evolutionary adaptation to allow women to continue to breastfeed children when stress or starvation has caused their menses to stop. It allows even postmenopausal women to lactate. This creates a problem in the breast. While the postmenopausal breast has youthful estradiol levels, it has no progesterone. Progesterone cannot be produced within the breasts, it must come from the circulation. The breasts actually concentrate progesterone to levels 3-4 times higher than in the serum. The post-menopausal breast is in a state of estrogen dominance that can only be corrected by sufficient progesterone supplementation. This lack of intramammary progesterone is a sufficient explanation for why breast cancer incidence continues to rise long after menopause, and for why the majority of breast cancers occur after menopause, in spite of the fact that estradiol levels in the serum are very low. It would be interesting to see the results of long-term trials of progesterone-only supplementation in perimenopause and menopause to prevent breast cancer. However it would be unethical to deprive any woman of necessary estradiol supplementation; and because of its anti-estradiol effects, progesterone supplementation can worsen symptoms of estradiol deficiency. Testosterone, DHEA and Breast CancerThe associations of higher estradiol and lower progesterone with breast cancer are strong. What about the androgens, testosterone and DHEA? Their effect on breast cancer risk is much more complicated and depends upon the estradiol-progesterone status of the woman. Higher testosterone levels in menopause have been related to breast cancer, but this association may be indirect as higher testosterone levels reduce SHBG levels and thereby increase free estradiol levels. Some studies show increased breast cancer risk in premenopausal women with higher testosterone levels, and especially with higher testosterone and lower progesterone levels. The combination of higher testosterone and low progesterone levels in a premenopausal woman may increase breast cancer risk by a factor of 90. Again, the key appears to be progesterone. The usual cause of higher testosterone levels in premenopausal women is polycystic ovary syndrome (PCOS) and its subclinical forms. Women with PCOS have some degree of insulin resistance. Higher insulin levels disturb ovarian function, causing anovulation and increasing testosterone production by the ovaries. Higher insulin levels directly increase the risk of breast cancer. Since women with PCOS do not ovulate, or ovulate rarely, they have low progesterone levels which predispose them to breast cancer. Thus the presence of PCOS of all degrees in the population may be a sufficient explanation for the correlations found between higher premenopausal testosterone levels and breast cancer. In women with low estradiol levels, more testosterone can increase serum estradiol levels through its aromatization into estradiol, and by decreasing SHBG levels and thereby increasing free estradiol levles. However, In the normal premenopausal state of estradiol sufficiency, testosterone opposes estradiol’s proliferative effects in the breast., Regular testosterone injections given to female-to-male transsexuals cause breast atrophy, with a marked reduction in glandular tissue., This occurs even though their estradiol levels are not greatly reduced compared to normal follicular-phase levels. In breast cancer cells, testosterone and its potent metabolite dihydrotestosterone (DHT) oppose estradiol-induced stimulation.,, The addition of testosterone to estrogen/progestin therapy in menopause reduces proliferation in the breast and reduces breast cancer incidence to that of non-users of HRT. Testosterone is also an effective treatment for breast cancer., Thus the majority of the evidence indicates that testosterone supplementation does not increase breast cancer risk in estradiol-replete women. Menopausal BHRT should include testosterone in order to reduce breast cancer risk or recurrence, not to mention to improve a woman’s health and quality-of-life. DHEA can be converted throughout the body, and within the breasts into both estrogens and androgens. This may account for the conficting reports of DHEA levels and breast cancer. Most studies and reviews, but not all, have associated lower levels of DHEAS and its metabolites with increased breast cancer risk in premenopausal women.,,, In postmenopausal women there seems to be either no correlation between DHEAS levels and breast cancer,, or a positive correlation (increased risk with higher DHEAS levels)., What do cell studies show? DHEA administered to androgen-receptor-positive breast cancer cells reduces proliferation and induces apoptosis. DHEA reduces mammary carcinogenesis in rats. Perhaps, overall, with all other hormonal factors being equal, the natural decline in DHEAS with age tends to promote breast cancer. The effect of DHEA on breast cancer also depends upon a woman’s estradiol and progesterone levels. Overall, DHEA supplementation to restore youthful female levels may help prevent breast cancer, when combined with appropriate estradiol, progesterone and testosterone supplementation.BRCA Gene-Variants Associated with Progesterone and Testosterone ResistanceProgesterone resistance has been associated with breast cancer and uterine cancer. The BRCA 1 and 2 gene variants that increase the risk of breast cancer have been found to produce progesterone resistance. They inhibit the activity of the progesterone receptor and of gene expression related to progesterone action. BRCA1 and BRCA2 carriers often do not make progesterone-receptor B (PRB). In breast cancer cells, BRCA1 downregulates the expression of PRA and/or PRB., The normal BRCA1 gene is also a co-activator of the androgen receptor in normal breast cells. Women with BRCA1 mutations (reduced functional BRCA1 protein), have less efficient androgen receptors. There is reduced androgen-mediated growth inhibition of breast epithelial cells and tumors develop more rapidly., Women with both the BRCA1 gene variant and abnormalities of the androgen receptor gene have a higher risk of breast cancer. It is possible that sufficient progesterone and testosterone supplementation would reduce the cancer risk with BRCA mutations to baseline. Cortisol and Thyroid Cortisol opposes estradiol’s stimulatory effects in the uterus I have seen cortisol supplementation reduce uterine bleeding/cramping and the symptoms of endometriosis. I have also seen it reduce breast fullness and tenderness in women. I have also frequently diagnosed cortisol deficiency in women with a history of breast or uterine cancer. This possible connection requires further study. Low thyroid hormone levels and thyroid autoimmunity have also been associated with breast cancer,,, and its recurrence.Vitamin D, Iodine and Breast CancerVitamin D is also a hormone; it should actually be called “Hormone D”. Breast cancer incidence is reduced in women with greater sun exposure., Breast cancer, particularly aggressive breast cancer has been associated with lower levels of Vit. D, especially in postmenopausal women.,,,,,,,, Higher levels of Vit. D have also been associated with improved breast cancer survival.,, Vitamin D and calcium supplementation lowers the incidence of breast cancer. A good target for Vitamin D sufficiency is a 25-OH Vitamin D level of 50 to 60ng/ml. For persons not receiving much sunlight, this generally requires 1500IU/day in infants, 2000IU/day in children ages 1-12, and 4000IU daily for adults. Higher doses can be taken under medical supervision to obtain target serum levels. Some persons require 20,000IU daily to maintain optimal Vitamin D levels.Iodine sufficiency is necessary for normal breast architecture and health, and iodine supplementation may help treat fibrocystic breast disease and prevent breast cancer.,,,,,BHRT after Breast Cancer What about women with who have been diagnosed with breast cancer? The standard “hormonal therapy” for estradiol-receptor-positive breast cancer at this time is complete estradiol deprivation. For women with estradiol-receptor-negative breast cancer, estradiol replacement should not be contraindicated at all, however most physicians discourage it out of fear of being blamed for a recurrence. (See “Corrupting effect of the legal system” in chapter 2.) Due to the breast-cancer-promoting effects of unopposed estradiol and most progestins, they inappropriately believe that hormone replacement of any kind is will promote breast cancer and cause other health problems. (See chapter 6.) Estradiol deprivation is accomplished either with an estrogen blocker, tamoxifen, in women who are premenopausal, or with an aromatase inhibitor in postmenopausal women. The latter prevents them from making estradiol from testosterone and DHEA. As the growth and reproduction of estradiol-receptor-positive cancer cells is partially dependent upon estradiol, estradiol deprivation does slow their proliferation temporarily. Thus the 5 and 10 year recurrence/survival rates are improved slightly with these therapies. However, they do not cure the cancer. It will recur if still present in the body, often in a more aggressive form as a result of hormone deprivation. (For an excellent review of the real effects of breast cancer diagnosis and treatment see this review.). On the other hand, estradiol-deprivation therapies have devastating effects on a woman’s quality of life and overall health. They cause all the symptoms and medical disorders seen with surgical or natural menopause., Many women do not take these drugs for the recommended time due to their symptoms. Breast cancer cells with estradiol and/or progesterone receptors are more normal than receptor-negative cells, and thus are associated with better survival. Progesterone-receptor-positivity is most strongly associated with longer survival,, and given progesterone’s known anti-proliferative, anti-cancer effects in the breast, receptor-positivity provides an opportunity to treat breast cancer with progesterone supplementation.Most people want to feel and function well in the time they have left, not to live a little longer but in misery the entire time. Can postmenopausal women who have been diagnosed with breast cancer improve their quality of life and other aspects of their health by replacing estradiol, progesterone and testosterone? Without seriously reducing the length of their life? Many feel so much better on BHRT that they say they would continue it even if they know they would live a few less years. They certainly have the right to choose to replace their hormones. What does the evidence say about this choice? There have been many observational studies of non-bioidentical estrogen and estrogen/progestin replacement after breast cancer. Most studies and reviews have found either no increase or a reduction in breast cancer recurrence with estrogen-only,, and estrogen-progestin treatment.,,,,, Only one study has shown an increase in breast cancer recurrence events. It involved estradiol+norethisterone, a combination which has been shown to have proliferative effects in the breast and to increase the risk of initial breast cancer diagnosis.So the majority of studies show no increase in recurrence even when women use non-biodentical progestins that are known to increase breast tissue proliferation. Unfortunately, there have been few studies of estradiol and progesterone replacement after breast cancer diagnosis, and none with estradiol, progesterone and testosterone replacement. Two studies were done with rats. Estradiol and progesterone treatment helped prevent and cure breast cancer in rats after exposure to a carcinogen. Progesterone was found to be as effective as tamoxifen in preventing estrogen-induced mammary tumors in rats. In the one human study, estradiol with progesterone had a beneficial effect in advanced breast cancer. I believe that it is probable that progesterone-only and combined estradiol-progesterone-testosterone therapy will reduce breast cancer recurrence rates while restoring health and quality of life. In summary, the evidence regarding hormones and breast cancer shows that:Estradiol-only supplementation promotes breast cancer.Progesterone supplementation prevents breast cancer.Estradiol combined with sufficient progesterone prevents breast cancer.Testosterone supplementation prevents breast cancer in estradiol-replete women.Estradiol-progesterone-testosterone supplementation is not contraindicated in breast cancer, and may be therapeutic. Sex Steroids and Cardiovascular DiseaseWhen it comes to heart disease, estradiol has two effects that must be considered. It prevents atherosclerosis—the formation of plaques in the walls of large arteries. So it lowers the long-term risk of coronary heart disease and stroke. However in the short run, estradiol replacement, especially oral estradiol, increases a woman’s blood-clotting tendency. This can cause thrombotic events (deep vein thrombois, heart attack, and stroke) in susceptible women who have an underlying pro-clotting tendency. (factor V Leiden, prothrombin gene mutation, or deficiencies of antithrombin, protein C, or protein S, etc.) (See Route of Delivery below.)It is well known that the youthful female hormonal milieu is highly protective against cardiovascular disease, particularly against the atherosclerotic process in the coronary arteries that leads to heart attacks. Heart attacks are usually caused by a blood clot forming on an unstable atherosclerotic plaque. Heart attacks are rare in premenopausal women, but after menopause women’s rate of coronary heart disease (CHD) rises faster than men’s. CHD includes heart attacks, angina, and other problems due to atherosclerosis in the coronary arteries. (See Figure 8) Women have a higher risk of CHD than men after age 65, and higher mortality after age 70! This increased risk after menopause is clearly due to the loss of sex steroids, especially estradiol. Premenopausal and perimenopausal women with lower estradiol levels have a higher incidence of CHD. They have a more rapid progression of carotid artery atherosclerosis, which is slowed by estradiol replacement therapy., Premature ovarian failure causes endothelial dysfunction (an early indicator of athersoclerosis) that can be corrected by 6 months of estrogen therapy. Surgical oophorectomy (removal of the ovaries) is associated with 2 to 7 times greater risk of heart attack, and the earlier the ovaries are removed, the greater the risk.,, Estrogen replacement can eliminate this excess risk. Surgical oophorectomy is more deleterious than natural menopause because the postmenopausal ovary continues to make small amounts of estradiol and testosterone. So the removal of the ovaries, even at the usual time of menopause, produces a higher risk of CHD and hip fracture. Needless to say, any woman who has her ovaries removed should immediately start to replace the hormones that she has lost—estradiol, progesterone and testosterone. Estradiol is known to counteract the atherosclerotic process by many mechanisms. Estradiol maintains the health and function of the endothelium—the lining of our blood vessels. It activates endothelial nitric oxide synthase, leading to arterial vasodilation. In the longer-term it modulates the vascular response to injury and atherosclerosis. Long-term oral CEE therapy in menopause was found to reduce risk of heart disease Estradiol vs. Cardiovascular DiseasePrevents the oxidation of LDLImproves lipid profileReduces lipoprotein (a)Reduces blood pressure Improves endothelial functionDilates arteriesLowers blood pressureReduces plaque formationImproves insulin sensitivityin many observational and case-control studies,, Estrogen replacement reduces coronary artery atherosclerotic plaque size and progression with age. Transdermal estradiol replacement has beneficial effects on vascular function and CHD risk markers, and is associated with a 40% reduction in risk of heart attack. Estradiol restoration lowers blood pressure, and LDL cholesterol levels. Transdermal estradiol markedly improves insulin sensitivity, and lower insulin levels help prevent hypertension and atherosclerosis. Progesterone does not counteract estradiol’s beneficial cardiovascular effects, and adds additional benefits. In surgically menopausal monkeys, estradiol-progesterone replacement reduced the accumulation of LDL in the coronary arteries by 70%. Oral estradiol and progesterone improve peripheral blood flow in women. Progesterone decreases proliferation of vascular smooth muscle cells caused by high blood glucose and insulin levels. Progesterone reduces coronary artery hyperreactivity and vasoconstriction in monkeys and enhances coronary blood flow in women with ischemia. Progesterone supplementation alone lowers blood pressure and the blood pressure response to stress.In women with a history of CAD, and thus established atherosclerosis and at higher risk for a myocardial infarction, oral estradiol did not affect subsequent cardiac events, but did lower overall mortality. Only one study found that transdermal estradiol was associated with a small increase in cardiac events, in the first two years, consistent with the slight pro-thrombotic effect of higher estradiol levels, which can be significant in women with an underlying thrombotic tendency. Any small increase in thrombotic events with initiating estradiol replacement in women with CAD must be weighed against all the long-term benefits including slowing the progression of their atherosclerotic disease. Deficiencies of testosterone and other androgens play a role in menopausal heart disease also. Women with CAD have lower free testosterone levels. In postmenopausal diabetic women, lower free testosterone was associated with increased cardiovascular and all-cause mortality. Postmenopausal women with lower testosterone levels have more coronary atherosclerosis at angiography. Postmenopausal women with higher testosterone levels have better flow-mediated arterial dilation. Women who suffer heart attack or stroke have lower androstenedione levels, a weak androgen made from DHEA that can be converted into testosterone, and those on HRT have lower testosterone levels than controls. Lower DHEAS levels are associated with stroke in women. Postmenopausal women with CAD have lower DHEAS levels. Testosterone replacement improves insulin sensitivity. Women with CHD (MI, stroke) who were taking estrogen-progestin therapy had lower testosterone levels than matched controls. Testosterone therapy added to estrogen therapy increased flow-mediated arterial dilation. The favorable changes seen in women’s lipid profiles with estradiol alone are not altered by the addition of testosterone. Women given testosterone injections in various doses producing serum testosterone levels up to 232ng/dl (low in the male reference range) did not have any significant deleterious changes in fasting glucose, fasting insulin, insulin resistance, C-reactive protein, adiponectin, blood pressure, or heart rate. No increase in morbidity or mortality has been seen in female-to-male transsexuals (women given high-normal male levels of testosterone by injections). If male levels cause no health problems, surely lesser levels of testosterone in women will produce no harm.There are many studies done in women that correlate higher testosterone levels with poor CHD outcomes, but these are contaminated by patients with Polycystic Ovary Syndrome (PCOS). This disorder is due in most cases to insulin resistance—a pre-diabetic condition. Insulin resistance rises with overweight and obesity. Most women with PCOS are overweight. The higher insulin levels interfere with ovarian hormone production, causing the ovaries to make more testosterone, less estradiol, and no progesterone. Menstrual cycles become infrequent or stop altogether. The negative health effects of PCOS are caused by the obesity and high insulin levels. The elevated testosterone levels are just another consequence of the pathological processes at work. In summary, the evidence regarding estradiol and progesterone and cardiovascular disease shows that:Youthful female estradiol, progesterone and testosterone levels are protective against atherosclerotic disease.Oral and transdermal estradiol replacement reduce atherosclerosis and heart disease risk in the long term.Oral estrogens, much more than transdermal estradiol, greatly increase the risk of thrombi in susceptible women in the first 2 years of therapy (DVT, stroke, heart attack) Progesterone does not counteract the beneficial effects of estradiol and has additional cardiovascular benefits.Testosterone replacement therapy, even when superphysiological for women, does not increase the risk of CHD or death.OsteoporosisOsteoporosis is very common in menopause, and it is due almost entirely to sex-steroid deficiency, especially estradiol deficiency. Bone is a living tissue; old bone is being constantly reabsorbed by osteoclasts and new bone laid down by osteoblasts. Estradiol inhibits osteoclastic activity, slowing resorption of old bone while testosterone and progesterone stimulate osteoblastic activity, building new bone. Bone loss in women actually begins long before menopause, around age 30, due to declining sex steroid and growth hormone levels. After menopause, women lose 25% of their bone mass in first 5 years. By 20 yrs. after menopause they have a 50% reduction in trabecular bone, 30% reduction in cortical bone. 50% of women age 65 and older have spinal compression fractures. A 50 yr. old woman has a 14% lifetime risk of hip fracture, and after the age of 80 her lifetime risk is 30%. Early menopause (before age 47) is associated with a higher risk of osteoporosis, fractures and death by age 77. Greater bone loss is in premenopausal women with lower testosterone levels and in perimenopausal women with lower estradiol and testosterone levels. Women who do not ovulate due to strenuous physical activity have lower estradiol and progesterone levels and thus lose bone mass. In postmenopausal women, lower bioavailable testosterone, not estradiol levels are associated with hip fracture. Women with the highest bioavailable testosterone had almost no height loss over 16 yrs, compared to 10cm loss for those with the lowest bioavailable testosterone. (See figure 15.) Postmenopausal women with vertebral crush fractures had androstenedione and testosterone production rates that were one-half those of women without such fractures, but no difference in estradiol production rates. Hormone replacement restores bone health—it increases bone density while preserving normal osteoclast-osteoblast bone remodeling. Perimenopausal and postmenopausal bone loss is preventable by EPT therapy begun immediately when estradiol is deficient. Progesterone and testosterone may be started before the onset of estradiol deficiency.-57150-501650Long-term CEE therapy reduces osteoporotic fracture risk in half and maintains much higher bone density. Much better results can be expected with long-term optimal estradiol, progesterone and testosterone replacement. Bone density increases by 4 to 8% in 1 year with estradiol replacement, 4% in 9 months of oral CEE. Collagen cross-linking and strength also increases with estradiol replacement, which improves bone strength but does not show up on DEXA bone density measurements. Estradiol and progesterone supplementation reduce markers of bone turnover and increase bone density, adding testosterone further increases bone density in the hip. Progesterone has a stimulatory effect on bone formation. Progesterone supplementation alone helps build bone. It appears to either act directly on bone by engaging an osteoblast receptor or indirectly through competition at a glucocorticoid osteoblast receptor, reducing cortisol’s effect on bone. Adding testosterone replacement to estradiol produces a greater increase in bone density than estradiol alone.,DHEA supplementation alone in older women increases bone density by 2 -4% in 2 years. Because doctors think that all menopausal hormone replacement is dangerous, (See Appendix) they treat the bone loss caused by sex-steroid deficiencies with bisphosphonate drugs (Fosamax?, Boniva?, Actonel? etc.) These compounds no only do not work as hormone replacement to increase radioagraphic bone density,, they produce abnormal bone that cannot respond properly to injury and eventually becomes weak. These drugs are derived from soap molecules and have the effect of poisoning the osteoclasts. The cessation of bone resorption temporarily increases radiographic bone density and even bone strength, but at the cost of suppressing normal bone turnover. Because old bone is no longer removed, new bone formation is eventually inhibited. The bone cannot adapt to stresses or injury. Bisphosphonates are associated with osteonecrosis of the jaw (“rotting jaw”) in women after tooth extractions and other dental surgery. The jaw cannot make new bone as needed to fill in the void left by the tooth. Orthodontists have also noticed that appliances and braces cannot move the teeth in women on a biphosphonate. Bisphosphonates also delay healing of fractures. Worst of all, after 8 years or so, they produce weak bones that can fracture without any trauma—especially in the femur., Biphosphonates have also been associated with a number of side effects including gastrointestinal problems, muscle and joint pain, and eye inflammation. Evista? (raloxifene) is in a class of non-bioidentical hormone-like drugs known as selective estrogen receptor modifiers, or “designer estrogens”. These drugs do not relieve the other negative effects of menopause, do not have the same health benefits as estradiol, and can have negative health consequences. The only proper prevention and treatment for osteoporosis in women is hormone restoration, accompanied by sufficient Vitamin D and Vitamins K1, and K2. In summary, the evidence shows that;Estradiol, testosterone, and progesterone deficiencies cause bone loss.The proper treatment for osteopenia and osteoporosis is hormone replacement. Bisphosphonates and designer estrogens should be avoided. Sex Steroid Deficiency and DementiaEstradiol receptors are found throughout the brain, and sufficient estradiol is necessray to normal brain function. An almost universal symptom of estradiol deficiency is brain dysfunction. It appears as poor recall of familiar information, lower mood, and insomnia. The memory degradation is also a warning sign of early mental deterioration leading to dementia. Estradiol and progesterone protect against neurotoxicity by various mechanisms., Testosterone and estradiol decrease -amyloid secretion in neuronal cultures. Orchiectomized rats have tendency to hippocampal cell death that is reversed with testosterone replacement. Oophorectomy increases a woman’s risk of dementia and Parkinson’s disease; the early the ovaries are removed, the greater the risk. Bilateral oophorectomy before age 45 increases mortality from neurological and mental disease by 5-fold. After the age of 80, women suffer from much more dementia than men; they have a 4-fold greater risk by age 95. This risk can be reduced by 50%, even elminated, by long-term estrogen therapy.,,, Of course, the earlier estradiol-progesterone-testosterone therapy is started, the greater the immediate and long-term benefits. There will be little short-term benefit in women who have been severely estradiol-deficiency for over 20 years. ................
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