by Ben Best
After puberty the sex hormones (testosterone, progesterone and estrogens) play a major role in the physical & psychological make-up of most adults. In males testosterone leads to muscle & bone development, deepening voice, facial & pubic hair, thickened skin, genital development and eventually (perhaps) baldness. Testosterone increases basal metabolic rate as much as 15%. Estrogens (oestrogens) are primarily responsible for female sexual characteristics, including development of the ovaries, fallopian tube, uterus, vagina, breasts and external genitalia. Progesterone exerts its main bodily effects on the breast and on the endometrium (the inner membrane of the uterus) — in pregancy and in preparation for pregnancy. In the bloodstream the sex hormones are bound to Sex Hormone Binding Globulin (SHBG ) — testosterone very strongly, estrogen (estradiol) less strongly and progesterone weakly.
Estrogen derives its name from estrus, a word describing the sexually receptive ("in heat") phase of the sexual cycle of most female mammals. Humans and a few other primate species have a menstrual cycle rather than an estrus cycle. The menstrual cycle is characterized by menses (menstruation, a "period") which is bleeding and shedding of the endometrium when pregnancy does not occur — rather than the reabsorption of the endometrium that occurs in the estrus cycle.
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The menstrual cycle is typically represented as a 28-day cycle which begins with the onset of menstrual bleeding, although normal cycles range between 22 and 35 days. Most of the variation occurs in the first portion of the cycle, with the post-ovulation portion being close to 14 days. The menstrual (bleeding) phase can last between 2 and 7 of the first days of the cycle, averaging about 4 days. Average blood flow is about 35 milliLiters, with normal range 10-80 mL.
At the end of menses estrogen (mainly estradiol) levels begin to rise, secreted from egg-containing follicles in the ovary which are developing under the influence of Follicle Stimulating Hormone (FSH) from the anterior pituitary gland. Just before ovulation — at about day 14 — there is a surge of FSH and an even stronger surge of Luteinizing Hormone (LH). It is LH which causes the ovary to ovulate, ie, to release an egg from the follicle and begin its journey down the fallopian tube toward the uterus. (In males LH stimulates testosterone secretion by the testes, whereas FSH stimulates spermatogenesis.)
With ovulation FSH, LH and estrogen levels all drop precipitiously. Soon, however, the ruptured follicle in the ovary develops the corpus luteum, which begins secreting estrogen again, and producing even larger amounts of progesterone. The progesterone promotes endometrial development in preparation for a fertilized egg. Progesterone increases body temperature as much as 1ºF (0.5ºC) and increases bloodstream insulin levels.
Progesterone-like steroids ("progestins ") in contraceptives inhibit LH release from the anterior pituitary, thereby preventing ovulation. Progestins in contraceptives also make the endometrium more resistant to implantation by a fertilized egg, and thicken cervical mucous to create a barrier to sperm. Estrogen in contraceptives inhibit FSH release from the pituitary, reducing ovary follicle development.
If a fertilized egg is detected the endometrium will develop into a placenta, which will begin secreting estrogen & progesterone. Whether fertilization occurs or not, corpus luteum hormone production declines and finally ceases after about 14 days (the end of the 28-day cycle). If a fertilized egg is not detected in the endometrium, menses will occur. Several days before menses many women will begin to experience cramping of the uterus, abdominal pain, fatigue, breast discomfort, headaches, insomnia, irritability and emotional sensitivity characterized as PreMenstrual Syndrome (PMS). Caffeine can worsen the psychic symptoms and salt can worsen the bloating (water retention, breast discomfort). Among women with severe PMS a single daily cup of caffeine beverage increased the chance of PMS by one third, whereas 8-10 daily cups increased the prevalence seven times [AMERICAN JOURNAL OF PUBLIC HEALTH; Rossignol,AM; 80(9):1106-1110 (1990)].
In the third trimester of pregnancy women typically experience an increase in insulin resistance which in some women (usually obese women) can lead to temporary diabetes ("gestational diabetes"). Reduced insulin sensitivity in pregnancy has been incorrectly been attributed to cortisol and/or progesterone, but the actual primary cause is the cytokine Tumor Necrosis Factor-alpha (TNF−α) [DIABETES; Kirwan,JP; 51(7):2207-2213 (2002)]. Although insulin sensitivity rapidly returns to pre-pregnancy levels after childbirth, repeated pregnancies are associated with higher insulin resistance later in life [AMERICAN JOURNAL OF EPIDEMIOLOGY; Kritz-Silverstein,D; 140(4):375-382 (1994)].
Women in their 30s or 40s sometimes experience a decline in progesterone which is not matched by an equivalent decline in estrogen — a condition known as estrogen dominance. Women with estrogen dominance may be reasonably happy (good mood), but suffer from water retention, swollen extremeties, heavy periods and breast tenderness. A study on experimentally estrogen dominant monkeys (ovaries removed, estogen but not progesterone replaced) adds confirmation to the belief that replacing estrogen but not also replacing progesterone ("unopposed estrogen") increases the likelihood of uterine cancer [VETERINARY PATHOLOGY; Baskin,GB; 39(5):572-575 (2002)].
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Estrogen secretion by the ovary peaks not long after puberty, declining gradually until the 40s or 50s beyond which there is a precipitous estrogen decline associated with peri-menopause leading to menopause in the early 50s (on average). When the ovary has run out of follicles (and eggs) at menopause it can no longer produce any estrogen. Within about four years before menopause cycle length typically becomes more variable, including anovulatory periods in which there is little estrogen produced (adding to estrogen dominance). As the number of follicles declines in perimenopause, the production of estrogen declines, which reduces the feedback inhibition of gonadotropin (LH and FSH, primarily FSH) production. Blood FSH typically peaks around age 65 in women and then sharply declines. Melatonin supplementation may delay the onset of menopause [ANNALS OF THE NEW YORK ACADEMY OF SCIENCES; Bellipanni,F; 1057:393-402 (2005)].
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Menopause is often associated with skin flushing ("hot flashes"), irritability, bloating, fatigue and loss of sex drive, as well as severe loss of bone mass and atrophy of tissues in the vagina and other reproductive organs. A 2005 US National Institutes of Health scientific consensus statement states that vasomotor symptoms (hot flashes and night sweats) are the symptoms most strongly linked to menopause (in 30% to 80% of post-menopausal women), followed by vaginal dryness (with painful intercourse) in 17% to 30% of post-menopausal women [ANNALS OF INTERNAL MEDICINE; NIH Panel; 142(12 Part 1):1003-1013 (2005)]. Those symptoms are associated with low estrogen and are relieved by estrogen replacement. Symptoms such as pain & stiffness (skeletomuscular) and tiredness were dismissed as not being menopause-related by the NIH panel, but were the foremost symptoms reported by those on withdrawal from the Women's Health Initiative hormone replacement study [JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Ockene,JK; 294(2):183-193 (2005)].
Hysterectomy (removal of the uterus) often includes removal of the ovaries and, if so, will be hormonally equivalent to menopause. About half of women in the United States will have a hysterectomy during their lifetime and about one fifth will have had a hysterectomy by age 44.
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The sex hormones are all steroids, resembling cholesterol and
ultimately are synthesized from cholesterol. Cholesterol is transformed
into either progesterone or DeHydroEpiAndrosterone (DHEA).
DHEA is a weak androgen produced by the adrenal cortex and is the
most plentiful hormone in the human bloodstream. Progesterone and
DHEA can both be converted into the more potent androgen
androstenedione which can be converted into the most potent
androgen, testosterone.
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Both androstenedione and testosterone can be transformed into estrogens by aromatase cytochrome P450 enzyme, ie, an enzyme that creates an aromatic (benzene-like) ring. There is much more aromatase activity in women than in men, but men have some aromatase activity. Aromatase enzyme activity increases with age. Fat tissue contains the highest levels of aromatase, which is why estrogen production is higher in obese people [JOURNAL OF CLINICAL ONCOLOGY; McTiernan,A; 21(10):1961-1966 (2003)]. After menopause aromatase enzyme in fat tissue is the main source of estrogen for women (fat tissue is the main source of estrogen for men of all ages) [JOURNAL OF BIOLOGICAL CHEMISTRY; Mahendroo,MS; 268(26):19463-19470 (1993)]. All of the estrogens have a benzene-type ring for the steroid ring associated with the lowest-numbered carbon atoms.
Human estrogen is about 90% estriol (E3), 7% estradiol (E2) and 3% estrone (E1). Estradiol (17β−estradiol, to be specific, having a 17β−hydroxyl group on carbon 17) is the most potent estrogen, and is the primary estrogen produced in the ovaries. Estrone is mainly formed in peripheral tissues. Most estriol is made in the liver from estradiol. Estriol is a weak estrogen. The enzyme 17β−HydroxySteroid DeHydrogenase (17-OH-SDH) converts androstenedione to testosterone and also converts estrone to 17β−estradiol.
Replacement of human female sex hormones in modern medicine has
rarely been done with hormones identical to those in the human
female. This raises the question as to whether the problems associated
with the use of these non-human hormone replacements are due to
the replacement process or the nature of the replacement chemicals.
The half-life of progesterone is about five minutes. When administered orally, any progesterone that is absorbed is rapidly metabolized. For these reasons a synthetic progesterone-like drug ("progestin") is used for oral (tablet-form) progesterone replacement — most commonly a medroxyprogesterone-based molecule. Other progestins include levonorgestrel (norgestrel) and norethisterone.
| Progesterone | Medroxyprogesterone |
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![[Progesterone]](Progest.jpg)
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![[Medroxyprogesterone]](Medroxy.jpg)
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The most important medroxyprogesterone prescription drug is the acetate: MedroxyProgesterone Acetate (MPA, Provera, Depo-Provera).
| Progesterone | MPA |
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![[Progesterone]](Progest2.jpg)
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![[MPA]](MPA.jpg)
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Almost all major studies of estrogen replacement have used "conjugated equine estrogen" (Premarin — brand name for Pregnant mare's urine) as the standard estrogen. Early in 2002 Premarin was the most frequently prescribed drug in the United States. No generic version of Premarin has been approved by the Federal Drug Administration (FDA), so in medical & research practice the terms "conjugated equine estrogen", "Premarin" and (unfortunately) "estrogen" have been used as being equivalent. In the interest of being explicit and in not mincing words, for most of this essay I will use the phrase "pregnant horse urine estrogen" in preference to the others.
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Unlike human estrogen in which estradiol is the most active estrogen, the most active estrogens in pregnant horse urine are sodium estrone sulfate and sodium equilin sulfate. Natural human estrogens are only sulfated in the liver prior to excretion and do not include the distinct (for horses) estrogen equilin. Pregnant horse urine estrogen also contains a mixture of other estrogens and constituents which are foreign to the human body — many of which have yet to be identified.
I will attempt to briefly summarize a lengthy, detailed and informative FDA Memorandum about Premarin.
The drug application for Premarin was approved by the FDA in 1942 based on acceptable standards at that time. It was known that Premarin contained estrone and equilin, with estrone used as the reference standard. Premarin concentration is still described as 0.625 mg (milligrams) based on a (now obsolete) rat assay for sodium estrone sulfate. The 1970 United States Pharmacopeia (USP) established a standard for conjugated estrogens as containing sodium estrone sulfate and sodium equilin sulfate. The FDA supported (and continued to support) the contention that the USP standard of sodium estrone sulfate and sodium equilin sulfate are the sole active ingredients of Premarin, although it was later shown that Premarin is as much as 2.5 times more potent than sodium estrone sulfate.
In addition to estrone and equilin, Premarin is
known to contain 17α-dihydroequilin, 17α-estradiol,
17β-dihydroequilin, 17α-dihydroequilenin,
17β-dihydroequilenin, equilenin, 17β-estradiol
and Δ-8,9-DeHydroEstrone Sulfate (DHES) — in that
order of concentration. The complete steroid composition
of Premarin remains undetermined. (Although DHES represents
only 4.4% of the established estrogen concentration of
Premarin, it represents 34% of the blood plasma metabolite
concentration of estrone and equilin. In 1979 the FDA
prohibited the use of DHES in livestock. DHES has been
used as a "morning after pill" to prevent
fertilized egg implantation. The potency of DHES in Premarin
remained undetermined.) The FDA refuses to approve
a generic version of Premarin on the grounds that the
active ingredients of Premarin cannot be identified (an
obvious benefit to the manufacturer, Wyeth).
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Epidemiological studies and clinical trials involve many assumptions that are often mistaken. Experiments with animals, tissues and cell cultures are made under controlled laboratory conditions, but entail different assumptions about applicability to human physiology — which may be mistaken. The search for truth requires effort to reconcile laboratory results with human studies.
There is no conflict between laboratory results and human studies concerning the positive value of estrogen — even pregnant horse urine estrogen — in preventing bone loss (osteoporosis) associated with menopause and other estrogen deficient states. Laboratory studies, however, provide information about the mechanism by which estrogens produce their effects. In particular, cell culture studies indicate that estradiol inhibits cytokines that promote the formation of bone-resorbing cells (osteoclasts), namely InterLeukin−6 (IL−6) [THE JOURNAL OF CLINICAL INVESTIGATION; Pottratz,ST; 93(3):944-950 (1994)] and Tumor Necrosis Factor-alpha (TNF−α) [THE JOURNAL OF CLINICAL INVESTIGATION; Srivastava,S; 104(4):503-513 (1999)]. Estrogen increases production of TGFβ cytokine, which reduces TNF−α production, thereby preventing bone loss [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Gao,Y; 101(47):16618-16623 (2004)].
A study of female monkeys who had their ovaries removed and who were fed a diet intended to produce atherosclerosis showed that giving the monkeys 17β−estradiol reduced coronary artery atherosclerosis by approximately one-half, but that cyclical addition of progesterone had no further effect [ARTERIOSCLEROSIS; Adams,MR; 10(6):1051-1057 (1990)]. Monkeys given MedroxyProgesterone Acetate (MPA) rather than progesterone showed inhibition of the beneficial estrogenic effect on atherosclerotic lesions [ATHEROSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY; Register,TC; 18(7):1164-1171 (1998)]. Monkeys without ovaries given progesterone plus estradiol were protected against coronary artery vasospasm, but MPA plus estradiol failed to protect [NATURE MEDICINE; Miyagawa,K; 3(3):324-327 (1997)]. The protective effect of estrogen against coronary vasoconstriction in female monkeys is inhibited by MPA [AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY; Suparto,IH; 188(5):1132-1140 (2003)].
A study on humans indicated a detrimental effect of MPA on plasma HDL-cholesterol and triglycerides [MATURITAS; de Kraker,AT; 49(3):253-263 (2004)]. MPA has a significantly greater detrimental effect on plasma HDL-cholesterol increase by estrogen than does protgesterone [JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; 273(3):199-208 (1995)]. Progesterone, but not MPA, has been shown to inhibit the adhesion molecules in human vascular endothelial cells that can lead to arteriosclerosis [ATHEROSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY; Otsuki,M; 21(2):243-248 (2001)]. The beneficial effects of estradiol on human endothelial cell nitric oxide expression is significantly potentiated by progesterone, but not by MPA [ENDOCRINOLOGY; Simoncini,T; 145(12):5745-5756 (2004)]. Women given a combination of 17β−estradiol plus progesterone showed a significant increase in their resistance to exercise-induced myocardial ischemia compared to women given 17β−estradiol plus MPA [JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY; Rosano,GMC; 36(7):2154-2159 (2000)]. Pregnant horse urine estrogen supplementation has been shown to increase coronary artery blood flow in post-menopausal women [JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY; Hirata,K; 38(7):1879-1884 (2001)].
Rats given estradiol plus progesterone showed significantly reduced incidence of breast cancer [BREAST CANCER RESEARCH; Rajkumar,L; 6(1):R31-R37 (2004)]. Progesterone has been shown to reduce estradiol-induced proliferation of breast epithelial cells in post-menopausal women [FERTILITY AND STERILITY; Foldart,J; 69(5):963-969 (1998)]. Although estrogen is known as a promoter rather than as an initiator of cancer growth, oxidized estrogen can act as an initiator [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Cavalieri,EL; 94(20):10937-10942 (1997) and CARCINOGENESIS; Li,K; 25(2):289-297 (2004)]. Unlike progesterone, MPA has androgenic effects that may increase breast cancer risk [BREAST CANCER RESEARCH; Ghatge,RP; 7(6):R1036-R1050 (2005)]. MPA plus pregnant horse urine estrogen can increase mammary gland proliferation above that seen with estradiol plus norethindrone acetate [AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY; Suparto,IH; 188(5):1132-1140 (2003)].
In experimental mice vulnerable to breast and ovarian cancer due to BRCA1 gene mutation, progesterone promotes the cancer and progesterone blockers prevent it [SCIENCE; Poole,AJ; 314:1467-1470 (2006)]. Progesterone may increase cancer risk by inhibiting apoptosis in response to DNA damage [ONCOGENE; Vares,G; 23(26):4603-4613 (2004)] whereas MPA can induce apoptosis [CANCER; Abe,M; 88(9):2000-2009 (2000)]. Other studies, however, indicate that progesterone induces apoptosis in cancer cells by up-regulation of p53 tumor-suppressor protein [CANCER; Bu,S; 79(10):1944-1950 (1997). Pregnancy early in life gives women an early experience of high levels of estrogen and progesterone that is believed to cause sustained higher p53 expression and improved lifetime protection against breast cancer [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Sivaraman,L; 98(22):12379-12384 (2001)]. Relative risk of breast cancer decreases by 4.3% for every year that a woman has breastfed [THE LANCET; 360:187-195 (2002)].
After menopause women typically gain weight, particularly visceral fat which can lead to increased cardiovascular mortality and to the metabolic syndrome [THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Carr,MC; 88(6):2404-2411 (2003)]. Hormone replacement with estrogen reduces post-menopausal weight gain [THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Espeland,MA; 82(5):1549-1556 (1997)]. Cytokines produced by visceral fat (IL−6 & TNF−α) and cancerous breast tissue increase aromatase activity and worsen cancer prognosis [BREAST CANCER RESEARCH; Purobit,A; 4(2):65-69 (2002)]. Chemotherapy that opposes aromatase and TNF−α is more effective against breast cancer than anti-estrogens [CANCER RESEARCH; Rubin,GL; 60(6):1604-1608 (2000)].
MPA, but not progesterone, has anti-inflammatory properties [AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY; Elovitz,M; 190(3):693-701 (2004)], but in the presence of natural levels of glucocorticoids the anti-inflammatory effect is antagonized [ENDOCRINOLOGY; Simoncini,T; 145(12):5745-5756 (2004)].
Clinical trials and epidemiological studies on the effects of estrogen are controversial, but laboratory studies strongly support the contention that estrogens are neuroprotective. Estrogens have been shown to reduce lipid peroxidation in brain cell homogenates & cultures, with 17β−estradiol showing significantly greater potency than estrone [JOURNAL OF NEUROCHEMISTRY; Vedder,H; 72(6):2531-2538 (1999)]. Studies with brain cell cultures have demonstrated that 17β−estradiol protects against toxicity from the β−amyloid peptide associated with Alzheimer's Disease [JOURNAL OF NEUROCHEMISTRY; Fitzpatrick,JL; 82(3):674-682 (2002) and [BMC NEUROSCIENCE; Nilsen,J; 7:74 (2006)] and that estradiol protection can be amplified several orders of magnitude by glutathione [MOLECULAR PHARMACOLOGY; Gridley,KE; 54(5):874-880 (1998)]. Once neurons have been damaged by β−amyloid, however, addition of 17β−estradiol exacerbates the β−amyloid-induced cell death [ENDOCRINOLOGY; Chen,S; 147(11):5303-5313 (2006)]. 17β−estradiol has also been shown to protect against ischemia-reperfusion injury in the cerebral cortex [STROKE; Shi,J; 32(4):987-992 (2001) and BIOLOGY OF REPRODUCTION; 63(4):982-985 (2000)] — and to specifically protect cells from excess glutamate [ENDOCRINOLOGY; Mize,AL; 144(1):306-312 (2003)]. Oddly, the 17α form of estradiol (which is not present in the bloodstream, but which is synthesized in the brain) is also neuroprotective and actually becomes elevated in the brain upon removal of the gonads and/or adrenal glands [ENDOCRINOLOGY; 146(9):3843-3850 (2005)]. Protection against brain ischemic damage by 17β−estradiol due to its anti-inflammatory effect is not seen in diabetes or hyperglycemia (high blood glucose) because 17β−estradiol becomes pro-inflammatory and actually exacerbates the ischemia under these conditions [STROKE; Xu,H; 35(8):1974-1978 (2004)].
Progesterone has been shown to significantly reduce neuron destruction due to ischemic damage [ARCHIVES OF MEDICAL RESEARCH; Gonzalez-Vidal,MD; 29(2):117-124 (1998)]. MedroxyProgesterone Acetate (MPA) not only fails to provide this protection, it antagonizes the neuroprotective effects of 17β−estradiol [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Nilsen,J; 100(18):10506-10511 (2003)].
By the late 1990s observational studies of postmenopausal women receiving estrogen and progestin hormone replacement were indicating very positive effects for osteoporosis, cardiovascular disease and prevention of dementia. A meta-analysis of 25 studies published up to 1997 indicated that post-menopausal women who had ever used estrogen replacement were only 70% as likely to have coronary heart disease as never-users. And women who had used estrogen/progestin combinations were only 66% as likely [ANNUAL REVIEW OF PUBLIC HEALTH; Barrett-Conner,E; 19:55-72 (1998)]. A subsequent meta-analysis of 40 observational studies two years later indicated a 35-50% reduction in risk of coronary heart disease for post-menopausal women who take estrogen [ANNALS OF INTERNAL MEDICINE; Grodstein,F; 133(12):933-941 (2000)].
Nonetheless, observational studies in the 1990s were also indicating a 32% increased risk of breast cancer with estrogen replacement and a 41% increased breast cancer risk with estrogen plus progestin replacement — with relative risk in proportion to duration of hormone replacement [ THE NEW ENGLAND JOURNAL OF MEDICINE; Colditz,GA; 332(24):1589-1593 (1995)]. A subsequent meta-analysis concluded that women with high levels of sex hormones in their bloodstream were nearly twice as likely to get breast cancer as women with low levels [JOURNAL OF THE NATIONAL CANCER INSTITUTE; 94(8):606-616 (2002)].
Breast & endometrial cancer risk and gallbladder disease associated with hormone replacement were among the caveats mentioned in the 25-study meta-analysis, but if the coronary heart disease benefit was confirmed it would overwhelm these other risks because so many more women die of heart disease. The ability of estrogen to lower LDL cholesterol and elevate HDL cholesterol was acknowledged, but the analysis noted that observational studies are biased by the fact that women who choose to use hormone replacement tend to be healthier, better educated and of higher socio-economic status than non-users. There is also a user/compliace bias. Studies of both men and women have shown that those who adhere to a placebo are at least twice as likely to survive heart disease as those who do not [JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Gallagher,EJ; 270(6):742-744 (1993)]. The 40-study meta-analysis found a 35% increased risk of stroke in women taking 0.625mg estrogen and a 45% increased stroke risk for women taking estrogen plus progestin. Although it confirmed the reduced coronary heart disease risk, the 40-study meta-analysis concluded that overall cardiovascular disease risk (coronary heart disease plus stroke) reduction was only about 10%. The 40-study meta-analysis also found that 0.3mg estrogen was as effective in reducing coronary heart disease as 0.625mg — with less risk of side effects. The "estrogen" in these studies was pregnant horse urine estrogen.
In contrast to observational studies, large-scale, double-blind placebo-controlled clinical trials are regarded as the "gold standard" of human drug intervention studies. ("Double blind" means that neither the subjects nor the clinicians giving the drugs know whether a particular subject is receiving drug or placebo.) Two such clinical trials for hormone replacement were conducted in the late 1990s and early 2000s: the Heart and Estrogen/progestin Replacement Study (HERS) and the Women's Health Initiative (WHI). Both HERS and WHI used 0.625mg/day of pregnant horse urine estrogen combined with 2.5mg/day MedroxyProgesterone Acetate (MPA). HERS found no significant difference in coronary artery disease between placebo and hormone replacement after the first 4.1 years (blinded) or an additional 2.7 years (unblinded, "HERS II") [JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Grady,D; 288(1):49-57 (2002)].
The WHI trial (intended to last 8.5 years) was halted prematurely after 5.2 years at the end of May 2002 because incidence of breast cancer was exceeding tolerable limits and hormone therapy was increasing rather than decreasing cardiovascular risk. The hormone replacement group had a 26% increase in breast cancer, a 29% increase in coronary heart disease and a 41% increase in stroke [JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; 288(3):321-333 (2002)]. In absolute terms, the incidence of stroke was 1.49% in the hormone replacement group and 1.05% in the placebo group, a difference of less than one-half percent. Similarly, there was less than one-half percent difference for breast cancer and heart disease. Nonetheless, it is reasonable to assume that these percentages would increase as the trials continued and reasonable to believe that lives were saved by halting the study. WHI subsample blood testing showed a 12.7% reduction in LDL cholesterol and a 7.3% elevation of HDL cholesterol after the first year for those receiving hormones (consistent with other studies of the effects of estrogen on cholesterol). The hormones elevated blood triglycerides 6.9%. Those receiving hormones also showed an average increase in systolic blood pressure of 1 mmHg after the first year and about 1.5 mmHg the second year and thereafter. Subsequent analysis indicated that pregnant horse urine estrogen was responsible for stroke increase, whereas MedroxyProgesterone Acetate (MPA) was responsible for the increased incidence of breast cancer [JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Hulley,SB; 291(14):1769-1771 (2004)].
Following the results of WHI sales of Premarin and Prempro (Premarin plus MPA) dropped considerably in the United States. Compared to the first half of 2002 prescriptions in the first half of 2003 declined by 33% for Premarin and 66% for Prempro [JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Hersh,AL; 291(1):47-53 (2004)]. In the first half of 2002 Premarin had been the most frequently prescribed drug in the United States.
Aside from the drugs used for hormone replacement there is good reason to question that HERS or WHI were meaningful studies, much less "gold standard" clinical trials. Of those initially screened only 4.0% (HERS) and 4.5% (WHI) agreed to participate in a randomized trial for post-menopausal hormone replacement. What kind of woman agrees to such participation? 70% of the WHI women were obese and 30% were "morbidly obese". 33% of the HERS women and 36% of the WHI women were taking drugs for high blood pressure. The Danish Nurses Study had found an increase in stroke risk with hormone replacement (particularly for estrogen-progestin) in women with high blood pressure, but no such risk for women with normal blood pressure [ARCHIVES OF NEUROLOGY; Lokkegaard,E; 60(10):1379-1384 (2003)].
An unblinding occurred for over 40% of the WHI women taking hormone replacement because of vaginal bleeding. Nearly 40% of the initial WHI participants had already dropped-out when the study was halted in 2002. Less than one-third of the original participants remained during the final year of HERS (HERS II) [HUMAN REPRODUCTION; Machens,K; 18(10):1992-1999 (2003) and HUMAN REPRODUCTION; Pederson,AT; 18(11):2241-2244 (2003)].
The average age of the participants at the beginning of the trials has also raised concern — 63 for WHI and 67 for HERS, which can be compared to 40-55 (onset of menopause, usually) for the observational studies. The greatest excess coronary heart disease occurred during the first year of therapy for both HERS and WHI (WHI participants were sent warning letters, which may have affected the results). Hormone replacement may be most beneficial if begun at menopause, but result in transient trauma if begin a decade or more later. The arm of the WHI involving mostly younger women who began hormone replacement therapy in association with hysterectomy showed an increased incidence of stroke, but no increase in other cardiovascular disease or breast cancer [JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; 291(14):1701-1712 (2004)]. A new clinical trial (KEEPS) is being initiated to test hormone replacement begun at menopause [JOURNAL OF APPLIED PHYSIOLOGY; Miller,VM; 99(2):381-383 (2005)].
The WHI also found that their women taking hormone replacement had twice the incidence of probable dementia as the women on placebo [JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Shumaker,SA; 289(20):2651-2662 (2003)]. This conflicts with the results of a more long-term (observational) study which showed that women who had used hormone replacement for more than ten years had less than half the incidence of dementia [JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Zandi,PP; 288(17):2123-2129 (2002)].
One could speculate that the observational study suffered from a "healthy user bias" and that the WHI result was due to vascular trauma associated with estrogen resumption. Even more likely is the possibility that non-human horse estrogens caused an inflammatory response leading to cardiovascular disease as well as dementia. In fact, pregnant horse urine estrogen was found to increase inflammation-sensitive C-reactive protein 85% in a 3-year randomized, placebo-controlled clinical trial [CIRCULATION; Cushman,M; 100(7):717-722 (1999)].
The Million Woman study is a UK-based observational study of women in the 50-64 age group participating in the National Health Service Breast Screening Program between 1996-2001 (approximately one quarter of British women in that age group). As with the WHI, an increased incidence of breast cancer was seen for progestin-estrogen replacement, but not for estrogen replacement. The study concluded that the increased incidence of breast cancer with progestin nullified reduced incidence of endometrial cancer on net total cancer cases — resulting in approximately the same increase in total cancers for hormone replacement therapy with or without progestin [THE LANCET; 362:419-427 (2003)]. Critics have noted that the women in the study had a 30% higher incidence of breast cancer than women of that age group in the general population. More frequent examinations may have resulted in more frequent detections insofar as women taking hormone replacement tend to have more breast examinations. The fact that it takes about ten years for a breast tumor to grow to appreciable size suggests that the cancers were already present when hormone replacement began [EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY; van der Mooren,MJ; 113(1):3-5 (2004)]. The study's conclusion that discontinuing hormone replacement therapy eventually restores risk to the level of never-users is biologically implausible because cancer does not regress when a causal agent is removed. In addition to that erroneous conclusion, the study has been criticized for being too poorly designed for the results to be meaningful [ENDOCRINE; Whitehead,M; 24(2):187-193 (2004)].
Concerning the use of 0.625 Premarin and 2.5mg MedroxyProgesterone Acetate (MPA) in the WHI, the July 2002 report on the trial results in the JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION included a "limitations" section containing the statement that "The results do not necessarily apply to lower dosages of these drugs, to other formulations of oral estrogens and progestins, or to estrogen and progestin administration through the transdermal route."
As with the previous observational studies, WHI confirmed the benefit of hormone replacement for reducing fractures and opposing osteoporosis [JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Cauley,JA; 290(13):1729-1738 (2003)]. Although pregnant horse urine estrogen is associated with a significant increase in venous thrombosis for women, no such effect is seem with esterified estrogen [JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Smith,NL; 292(13):1581-1587 (2004)].
A randomized, double-blind, placebo-controlled trial of estriol cream applied topically in the vagina of post-menopausal women showed a normalization of the vaginal mucosa and a significant reduction in the incidence of urinary tract infection [THE NEW ENGLAND JOURNAL OF MEDICINE; Raz,R; 329(11):753-756 (1993)].
For adults under the age of 65 the mortality rate from coronary heart disease is several times greater for men than for women, a difference which is at least partly attributed to a protective effect of estrogen [CIRCULATION; Jousilahti,P; 99(9):1165-1172 (1999)]. Without hormone replacement the incidence of cardiovascular disease increases very dramatically at menopause to levels at least as high as those seen for men. Intuitively, it seems odd that sex hormones that protect against cardiovascular disease before menopause would precipitate cardiovascular disease after menopause. Intuitively it seems reasonable that foreign estrogens from another species (horse) might cause inflammatory reactions leading to cardiovascular disease, but that human sex hormones might be as protective after menopause as they had been before menopause.
Evidence cited in section III indicates
why pregnant horse urine estrogen (Premarin) and MedroxyProgesterone Acetate
(MPA) would cause increases in cardiovascular disease deaths seen in
the Womens' Health Initiative (WHI) while bioidentical hormones
(17β−estradiol and progesterone) would be protective against
cardiovascular disease. The evidence can be summarized in table form:
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The argument that bioidentical hormones could be less likely to
induce breast cancer (and be more protective against breast cancer)
than Premarin/MPA is more debatable. However, the fact that about
ten times as many women die of coronary heart disease as die of
breast cancer (and about twice as many women die of stroke) means
that if bioidenticals can significantly reduce heart disease death,
that can be significantly more important than breast cancer death.
In most instances detected breast cancer does not result in death.
Improved breast cancer detection by women using bioidentical hormone
replacement can further reduce the risk of breast cancer death.
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After menopause many women lose their sex drive, have sleep disturbances, gain weight and suffer from chronic fatigue. Following the initial trauma of menopause onset women without hormone replacement may feel that their symptoms are an inevitable consequence of aging, to which they must resign themselves. If women like Suzanne Somers [author of THE SEXY YEARS (2004) and AGELESS (2006)] can be believed, bioidentical hormone replacement can restore the more youthful pre-menopausal condition.
Bioidentical hormone replacement means using human-identical estrogens (not pregnant horse urine estrogen) and progesterone (not medroxyprogesterone) in a monthly cycle that mimics pre-menopausal hormone cycling (ten days of progesterone per month). This means having periods, something many post-menopausal women are eager to avoid. (Pregnancy is not a risk because post-menopausal women have no eggs.) It would be possible to use a combined bioidentical sex hormone replacement that administered the same amount of estrogen-progestin on a daily basis every month. This would mimic pregnancy and the WHI protocol rather than the pre-menopausal cycle. As in pregnancy the result would be an increase in insulin resistance, leading to weight gain and an increased risk of diabetes & cancer. This was a shortcoming of the WHI protocol. Giving estrogen without progesterone can lead to symptoms of estrogen dominance. Human bioidentical progesterone can only be obtained in the United States by prescription from a compounding pharmacy.
Although bioidentical estrogen replacement carries a risk of increased breast cancer, insulin resistance associated with not replacing estrogen (or with using a combined estrogen-progestin replacement therapy) also carries a risk of cancer, along with weight gain and a risk of diabetes. Osteoporosis and hip fracture associated with low estrogen can be as life-threatening as breast cancer for an elderly woman. If quality of life is significantly improved while cardiovascular risk and dementia risk are reduced by bioidentical hormone replacement, the possibility of a breast cancer risk may be less important.
Unfortunately, there are not likely to be any large clinical trials of bioidentical sex hormone replacement because bioidentical sex hormones cannot be patented and there is little financial incentive. Quality standardization is also a problem, with variable results from one compounding pharmacy to another. Greater uniformity can sometimes be achieved by obtaining compounded prescriptions by mail order (consult the Professional Compounding Centers of America or Women's International Pharmacy for more information on this).
Health concerns over sex hormone replacement therapy (estrogen replacement therapy) to relieve menopausal symptoms have caused many women to turn to soy isoflavones, which have very weak estrogenic effects. Although there is no evidence of harm, evidence of benefit remains debatable [COCHRANE DATABASE OF SYSTEMATIC REVIEWS; Lethaby,A; 4:CD001395 (2007)]. (For more details, see Health Benefits and Possible Hazards of Soy Food: Phytoestrogen effects.)
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Total blood testosterone and free blood testosterone decline gradually in males. By age 80 testosterone is typically about half what it would be in a healthy young man. Although less dramatic than the onset of menopause in women, the effect of sex hormone loss in men is similar to the effect in women: diminished libido, depressed mood, anemia as well as fatigue and fragility associated with loss of bone & muscle mass (osteoporosis & sarcopenia). Because the symptoms have gradual onset they are regarded as an inevitable consequence of aging rather than the product of hypogonadism. There is considerable evidence that testosterone replacement can reverse these symptoms, although there are risks associated.
Oral testosterone (80mg/day as testosterone undecanoate) for one year given to healthy men over 60 has been shown to increase muscle mass and decrease body fat [JOURNAL OF GERONTOLOGY; Wittert,GA; 58A(7):618-625 (2003)]. Testosterone gel has also been shown to have beneficial effects on lean & fat mass and bone mineral density as well as on mood and sexual function in men with low testosterone [THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Wang,C; 89(5):2085-2098 (2004)]. Testosterone has been shown to oppose osteoporosis symptoms in experimental mice by inhibiting InterLeukin−6 (IL−6) gene activity [THE JOURNAL OF CLINICAL INVESTIGATION; Bellido,T; 95(6):2886-2895 (1995)]. Testosterone reduces blood levels of the pro-inflammatory cytokine Tumor Necrosis Factor-alpha (TNF−α) [HEART; Malkin,CJ; 90(8):871-876 (2004)] and TNF−α promotes an increase in IL−6, which is also a pro-inflammatory cytokine that normally increases with age. Estrogen produced by aromatase enzyme conversion of testosterone is an essential part of the bone development resulting from testosterone replacement [THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Maffei,L; 89(1):61-70 (2004) and [THE NEW ENGLAND JOURNAL OF MEDICINE; Carani,C; 337(2):91-95 (1997)].
Intramuscular injections of 100mg testosterone enanthate in older men resulted in significant improvements in spatial memory, spatial ability and verbal memory [NEUROLOGY; Cherrier,MM; 57(1):80-88 (2001)]. Testosterone gel (50-100mg/day) in hypogonadal men improved energy & well-being while reducing sadness & irritability along with increasing lean mass & muscle strength [THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Wang,C; 85(8):2839-2853 (2000)]. The transdermal gel formulation resulted in less skin irritation and greater compliance compared to transdermal testosterone patches.
Moderate doses of testosterone replacement have not been shown to adversely affect blood levels of HDL/LDL cholesterol ratios, lipids or C−reactive protein [AMERICAN JOURNAL OF MEDICINE; Snyder,PJ; 111(4):255-260 (2001) and THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Singh,AB; 87(1):136-143 (2002)]. Aromatase conversion of testosterone to estrogen may prevent elevation of the LDL/HDL ratio, but aromatase evidently does not affect insulin resistance [ANNALS OF INTERNAL MEDICINE; Bagatell,CJ; 116(12 Part 1):967-973 (1992) and THE NEW ENGLAND JOURNAL OF MEDICINE; Carani,C; 337(2):91-95 (1997)].
Men with lower blood levels of testosterone have more atherosclerosis [THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Hak,AE; 87(6):3632-3639 (2002)] and are more likely to have coronary artery disease, although this could be associated with such men being more obese [EUROPEAN HEART JOURNAL; 21(11):890-894 (2000)]. Nonetheless, testosterone replacement significantly reduces atherosclerosis in experimentally castrated male rabbits [CIRCULATION RESEARCH; Alexandersen,P; 84(7):813-819 (1999)]. And despite cardiac arrest in athletes abusing anabolic steroids, testosterone supplementation significantly reduces exercise-induced myocardial ischemia in men with chronic stable angina [CIRCULATION; English,KM; 102(16):1906-1911 (2000)].
The danger of increased prostate cancer due to testosterone supplementation has been a frequent worry. Supplementation with 100mg/day testosterone (gel) has been shown to increase mean serum Prostate-Specific Antigen (PSA) from 0.89ng/mL to 1.19ng/mL [THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Wang,C; 85(8):2839-2853 (2000)]. Another study also indicates that the increased PSA associated with testosterone supplementation is minor and is not associated with an increased risk of prostate cancer [JOURNAL OF ANDROLOGY; Gerstenbluth,RE; 23(6):922-926 (2002)]. Normally, PSA levels below 4.0ng/mL are not considered to indicate risk of prostate cancer, but that is not always the case [THE NEW ENGLAND JOURNAL OF MEDICINE; Thompson,IM; 350(22):2239-2246 (2004)].
Finasteride (a drug that inhibits conversion of testosterone to dihydrotestosterone) reduced detected prostate cancer by nearly 25% in normal males over age 55 while significantly reducing the prostate enlargement (benign prostatic hyperplagia) that causes urinary problems in older men [THE NEW ENGLAND JOURNAL OF MEDICINE; Thompson,IM; 349(3):215-224 (2003)], but there was a 15% greater incidence of high grade cancer in the tumors found in the finasteride group, and the finastride group showed a deleterious effect on libido & sexual function. A study that combined testosterone and finasteride therapy showed improvements in muscle strength & lean body mass could be achieved without dihydrotestosterone [THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Page,ST; 90(3):1502-1510 (2005)]. Another study of testosterone given with finasteride showed spine & hip bone mineral density are markedly increased (reducing osteoporosis) without associated prostate growth or PSA increase [THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Amory,JK; 89(2):503-510 (2004)]. (Saw palmetto at 320mg/day was shown to be no better than placebo for reducing benign prostatic hyperplagia [THE NEW ENGLAND JOURNAL OF MEDICINE; Bent,S; 354(6):557-566 (2006)].). A review of testosterone replacement studies concluded that there is a U−shaped relationship between prostate cancer and androgens in which both very high and very low blood testosterone represents a risk for free prostate cancer [INTERNATIONAL JOURNAL OF IMPOTENCE RESEARCH; Barqawi,A; 18(4):323-328 (2006)].
Studies have shown testosterone replacement helped overcome symptoms of frailty [JOURNAL OF ENDOCRINOLOGY & METABOLISM; Sih,R; 82(6):1661-1667 (1997)], protected against atherosclerosis by an anti-inflammatory effect [JOURNAL OF ENDOCRINOLOGY; Malkin,CJ; 178(3):373-380 (2003)], and increased blood flow in the coronary artery when given to men with coronary artery disease [CIRCULATION; Webb,CM; 100(16):1690-1696 (1999)].
The largest double-blind, placebo controlled trial for testosterone replacement in men aged 60 to 80 for six months showed more lean and less fat mass, but reduced HDL cholesterol and an incidence of 47.8% metabolic syndrome in the replacement group as opposed to 35.5% in the placebo group [JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Emmelot-Vonk,MH;299(1):39-52 (2008)]. This study may not have accounted for the fact that aromatase (the enzyme that converts testosterone to estradiol) increases with age and increased fat [ANNALES D'ENDOCRINIOLIE; Gooren,LJ; 64(2):126-135 (2003) & CURRENT OPINION IN ENDOCRINOLOGY, OBESITY, AND DIABETES; Kalyani,RR; 14(3):226-234 (2007)]. Excess aromatase could both reduce testosterone and increase estradiol in testosterone replacement. Both excess and insufficient estradiol in men is associated with increased mortality [JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Jankowska,EA; 301(18):1892-1901 (2009)]. Testosterone replacement should be accompanied by an aromatase inhibitor to achieve optimal levels of testosterone and estradiol [JOURNAL OF ENDOCRINOLOGY & METABOLISM; Leder,BZ; 89:(1):1174-1180 (2004) & JOURNAL OF STEROID CHEMISTRY AND MOLECULAR BIOLOGY;Ta,N; 107(1-2):127-129 (2007)].
It appears there are considerable benefits associated with testosterone replacement that could outweigh the risks for many older men. Although testosterone does not appear to cause prostate cancer, it could accelerate the growth of existing prostate cancer. Therefore, testosterone supplementation should be accompanied by careful monitoring for possible cancer symptoms as well as for immune system function and red blood cell count.
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