Menopausal hormone therapy and breast cancer: what is the evidence from randomized trials?

The relationship between menopausal hormone therapy (HT) and breast cancer is complex and further complicated by misinformation, perception, and overgeneralization of data. These issues are addressed in this mini-review through the lens of the Women's Health Initiative (WHI) that has colored the view of HT and breast cancer. In the WHI, unopposed conjugated equine estrogen (CEE) reduced breast cancer risk and mortality. In the WHI CEE plus continuously combined medroxyprogesterone acetate (MPA) trial, although the hazard ratio (HR) was elevated it was statistically non-significant for an association between CEE + MPA and breast cancer. In fact, the increased HR was not due to an increased breast cancer incidence rate in women randomized to CEE + MPA therapy but rather due to a decreased and unexpectedly low breast cancer rate in the subgroup of women with prior HT use randomized to placebo. For women who were HT naïve when randomized to the WHI, the breast cancer incidence rate was not affected by CEE + MPA therapy relative to placebo for up to 11 years of follow-up. The current state of science indicates that HT may or may not cause breast cancer but the totality of data neither establish nor refute this possibility. Further, any association that may exist between HT and breast cancer appears to be rare and no greater than other medications commonly used in clinical medicine.

Menopausal hormone therapy for primary prevention: why the USPSTF is wrong.

The US Preventive Services Task Force (USPSTF) Draft Recommendation statement on Menopausal Hormone Therapy: Primary Prevention for Chronic Diseases, released in May 2017, perpetuates a major disconnect between the primary population affected, women within roughly 10 years of menopause, and the data cited. Furthermore, major elements of the evidence relied upon have been misinterpreted or misstated, particularly in regard to coronary heart disease and breast cancer, for which there is no statistically significant evidence of harm. As currently drafted, the recommendations reiterate the USPSTF statements of 2012, 2005 and 2002, and will perpetuate egregious harm to the public health. In an attempt to avoid that outcome and to facilitate a return to rational discourse regarding menopausal hormone therapy, an ad hoc group of experts in menopausal health submitted this comprehensive response to the USPSTF.

17-beta-Estradiol therapy lessens angina in postmenopausal women with syndrome X.

OBJECTIVES: We sought to investigate the hypothesis that estrogen replacement therapy ameliorates symptoms in postmenopausal women with syndrome X. BACKGROUND: Syndrome X (angina pectoris, positive findings on exercise electrocardiography and normal results on coronary angiography) frequently occurs in menopausal women. This observation, in conjunction with the known vasoactive properties of estrogens, suggests that estrogen depletion may contribute to the pathogenesis of syndrome X in some women. METHODS: Twenty-five postmenopausal patients with syndrome X completed a double-blind, placebo-controlled study of the effect of 17-beta-estradiol cutaneous patches (100 micrograms/24 h) on the frequency of chest pain and on exercise tolerance. Patients were randomly assigned to receive either placebo or 17-beta-estradiol patches for 8 weeks and were then crossed over to the other treatment. RESULTS: During the placebo phase, patients had a mean of 7.3 episodes of chest pain/10 days. A reduction to 3.7 episodes/10 days was observed during the 17-beta-estradiol phase (p < 0.05). No significant differences were observed between the effects of 17-beta-estradiol and placebo on exercise duration or the results of other cardiologic investigations. CONCLUSIONS: Estrogen replacement reduces the frequency of chest pain and may be a useful new therapeutic option for treating postmenopausal women with syndrome X.

Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women.

OBJECTIVES: We sought to compare the effects of estrogen/transvaginal progesterone gel with estrogen/medroxyprogesterone acetate (MPA) on exercise-induced myocardial ischemia in postmenopausal women with coronary artery disease or previous myocardial infarction, or both. BACKGROUND: Estrogen therapy beneficially affects exercise-induced myocardial ischemia in postmenopausal women; however, women with an intact uterus also take progestin to protect against uterine malignancies. The effects of combination estrogen/progestin therapy on myocardial ischemia are unknown. METHODS: Eighteen postmenopausal women (mean +/- SD age 59+/-7 years) were given 17-beta-estradiol in single-blinded manner for four weeks (1 mg/day for three weeks then 2 mg/day for one week). Estradiol (2 mg/day) was then continued, and the patients were randomized (double-blind) for 12 days to either transvaginal progesterone gel (90 mg on alternate days) and oral MPA placebo (10 mg/day), or vice versa. After another two weeks on estradiol alone, the patients crossed over to progestin treatment and repeated the protocol on the opposite treatment. Patients underwent treadmill exercise testing after each estradiol phase and at day 10 of each progestin phase. RESULTS: Exercise time to myocardial ischemia increased after the first estrogen phase as compared with baseline (mean difference with 95% confidence interval [CI]: 72 s [34 to 110], p = 0.001), and was increased by combination estradiol/progesterone therapy as compared with estradiol/MPA therapy (92 s [35 to 149], p = 0.001)). Two patients (11%) were withdrawn while taking estradiol/MPA owing to unstable angina. CONCLUSIONS: Combination estrogen/transvaginal progesterone gel increases exercise time to myocardial ischemia, as compared with estrogen/MPA. These results imply that the choice of progestin in women at higher cardiovascular risk requires careful consideration.

Effect of estrogen replacement therapy on heart rate variability and heart rate in healthy postmenopausal women.

Increased sympathetic drive in symptomatic menopausal women was reduced after estrogen replacement therapy for 4 months, which has a potentially beneficial effect on cardiovascular functions.

Effect of 17 beta-oestradiol on contraction, Ca2+ current and intracellular free Ca2+ in guinea-pig isolated cardiac myocytes.

1. The effect of 17 beta-oestradiol on cardiac cell contraction, inward Ca2+ current and intracellular free Ca2+ ([free Ca2+]i) was investigated in guinea-pig single, isolated ventricular myocytes. The changes of cell length were measured by use of a photodiode array, the voltage-clamp experiments were performed with a switch clamp system and [free Ca2+]i was measured with the Ca2+ indicator, Fura-2. 2. 17 beta-Oestradiol (10, 30 microM) caused a decrease in cell shortening at both 22 and 35 degrees C. This negative inotropic effect was accompanied by a decrease in action potential duration mainly brought about by a shortening of the plateau region of the action potential. 17 beta-Oestradiol (10, 30 microM) induced a similar decrease in cell shortening in voltage-clamped and current-clamped cells. 3. In Fura-2 loaded cells, 17 beta-oestradiol (10 and 30 microM) decreased systolic Fura-2 fluorescence to 72 +/- 7% and 47 +/- 4% (n = 6, P less than 0.001) of control respectively. 17 beta-Oestradiol (10 microM) had no significant effect on diastolic Fura-2 fluorescence, but at higher concentration (30 microM) induced a slight decrease in resting Fura-2 fluorescence. The effect of 17 beta-oestradiol was reversible after 1-2 min of washout of the steroid. 4. 17 beta-Oestradiol (10 and 30 microM) decreased the peak inward Ca2+ current (ICa), which was sensitive to [Ca2+]o, dihydropyridines and isoprenaline, to 59 +/- 3% and 39 +/- 5% (n = 7 approximately 9, P less than 0.01) respectively, without producing any significant change in the shape of the current-voltage relationship.5. The recovery time of ICa from inactivation was delayed by 17beta-oestradiol (10microM). The inhibitory effect of 17beta-oestradiol on ICa was less at a holding potential of -80 mV than at -40 mV.6. We conclude that 17beta-oestradiol has a negative inotropic effect on guinea-pig single ventricular myocytes by inhibiting ICa and so reducing systolic [Ca2+]i. 17beta-Oestradiol may therefore have a Ca2+ channel blocking property in guinea-pig isolated ventricular myocytes.

Endothelium-independent relaxation of rabbit coronary artery by 17 beta-oestradiol in vitro.

1. We assessed the relaxant effect of 17 beta-oestradiol (10(-7), 10(-6) and 10(-5) M) on rabbit isolated coronary arteries precontracted with prostaglandin F2 alpha (3 x 10(-6) M), high extracellular potassium (30 mM) and Bay K 8644 (10(-6) M) plus high extracellular potassium (15 mM) by measuring isometric tension. 17 beta-Oestradiol (10(-6) and 10(-5) M) induced significant relaxation in coronary arteries from male and female rabbits. No differences were seen between arteries with or without endothelium. There were also no differences between coronary arteries isolated from male and female rabbits. 2. Inhibitors of endothelium-derived relaxing factor and vasodilator prostanoids, namely, reduced haemoglobin, N omega-nitro-L-arginine methyl ester and indomethacin, did not affect the relaxation induced by 17 beta-oestradiol in endothelium-intact coronary arteries. 3. Methylene blue, an inhibitor of guanylate cyclase, did not affect the coronary artery relaxation induced by 17 beta-oestradiol. 4. The calcium concentration-dependent contraction curve in potassium-depolarization medium was shifted to the right by 17 beta-oestradiol (10(-6) and 10(-5) M) in the rabbit coronary artery and rat aorta. The -log EC50s of calcium in control and after incubation with 17 beta-oestradiol (10(-6) and 10(-5) M) were 3.7 +/- 0.09, 3.1 +/- 0.10 and 2.8 +/- 0.08 respectively in rabbit coronary arteries and 3.8 +/- 0.11, 3.3 +/- 0.14 and 2.9 +/- 0.15 in rat aorta. 5. The results indicate that 17 beta-oestradiol induces rabbit coronary artery relaxation by an endothelium-independent mechanism in vitro. A calcium antagonistic property may be involved in the mechanism of rabbit coronary arterial relaxation by 17beta-oestradiol.

Estrogen replacement therapy.

More than 40 million American women are menopausal; another 3.5 million women will be reaching the climacteric age each year for the next 12 years. These women will have a life expectancy of more than 30 years after menopause. In America, there are three widely recognized indications for postmenopausal hormone replacement: vasomotor symptoms, dyspareunia, and the progressive development of osteoporosis. Ovarian hormone research indicates a wide variety of nonreproductive effects of ovarian steroids. The recognition of the relationship between ovarian hormone imbalance and signs and symptoms of disturbed function in these systems provides a new frontier for continuing research and preventive health care.

Sexuality and menopause.

A majority of women experience some change in sexual function during the years immediately before and after the menopause. Common sexual complaints include loss of desire, decreased frequency of sexual activity, painful intercourse, diminished sexual responsiveness, and dysfunctions of the male partner. Sexual function is influenced by biologic and nonbiologic factors. Sexual arousal, including sensory perception, central and peripheral nerve discharge, peripheral blood flow, and the capacity to develop muscle tension, as well as sexual desire and frequency of sexual activity, can all be influenced by ovarian hormone levels. Sexual function is also influenced by the interplay of psychological, sociocultural, and interpersonal factors. Health care professionals can play an important role in the evaluation, education, counseling, and treatment of the menopausal woman.

Pain during sex response due to occlusion of the Bartholin gland duct.

The greater vestibular glands produce a secretion during the plateau stage of sexual response. If the duct of the gland is partially or completely occluded, the secretion cannot be released and pain results from the pressure of the entrapped secretion. The pain is specific in its location and is elicited regardless of the mode of sexual stimulation. Four cases are presented in which duct occlusion appears to be the cause of pain during sex response. The gland was removed in 3 cases. In the fourth a marsupialization procedure was performed. The procedures were curative in all 4 cases. Relevant anatomy and sexual physiology are discussed.

Acute effects of oats and vitamin E on endothelial responses to ingested fat.

OBJECTIVE: To assess the effects of oats and vitamin E on endothelial function following a high-fat meal in healthy adults as measured by brachial artery reactivity studies (BARS). METHODS: A total of 25 men and 25 women (N=50) were recruited from a community population to participate in this randomized, crossover study. All subjects were free of known vascular disease, and female subjects were postmenopausal. Subjects underwent BARS before and after a high-fat meal (50 gm fat) on three occasions 1 week apart, one each with vitamin E 800 IU, oatmeal containing 3 gm beta-glucan, or a comparable bowl of wheat cereal serving as a placebo, in random sequence. The ultrasonographer was blinded to treatment status. RESULTS: Endothelial function, as measured by brachial artery peak flow during one minute of post-occlusive hyperemia, declined significantly from baseline when the high-fat meal was consumed with the wheat cereal (-13.4%; p=0.02). There was no difference in brachial artery flow change before and after a high-fat meal with oats (+0.37%; p=0.77) or a high-fat meal with vitamin E (+1.87%; p=0.42). No significant differences in flow-mediated vasodilation before and after the high-fat meal were detected among the three supplements. CONCLUSIONS: Endothelial dysfunction induced by acute fat ingestion in healthy adults is apparently prevented by concomitant ingestion of oats or vitamin E, but not wheat. Nutrient distribution and meal composition may have important implications for cardiovascular health.

Ovarian hormones and vaginal blood flow: using laser Doppler velocimetry to measure effects in a clinical trial of post-menopausal women.

OBJECTIVES: To describe the use of laser Doppler velocimetry for measurement of vaginal blood flow and report the effects of estrogen compared with estrogen-androgen treatment in post-menopausal women. DESIGN: Literature review of pelvic blood flow studies and sexual function. Findings from a prospective, randomized, parallel study. SETTING: Normal human volunteers in an academic research environment. INTERVENTIONS: Laser Doppler measurements of vaginal blood flow were compared before and after the administration of oral esterified estrogens or esterified estrogens plus methyltestosterone for four and eight weeks of daily drug administration. MAIN OUTCOME MEASURES: Vaginal blood flow velocities. RESULTS: Laser Doppler velocimetry proved readily adaptable for measurement of vaginal blood flow. Although esterified estrogens plus methyltestosterone showed greater effects on blood flow than esterified estrogens alone, the results were not statistically significant. CONCLUSIONS: Vaginal blood flow is an objective measure of sexual function which can be determined with laser Doppler velocimetry. The vasodilator effects of esterified estrogens and esterified estrogens with methyltestosterone are similar.

Progesterone induces endothelium-independent relaxation of rabbit coronary artery in vitro.

The effect of progesterone on isolated rabbit coronary arteries and its possible mechanism was investigated by measuring changes of isometric tension. Progesterone (1, 3, 10 and 30 microM) induced significant coronary relaxation in K+ (30 mM)-, prostaglandin F2 alpha (3 microM)- or Bay K 8644 (1 microM plus 15 mM K+)- precontracted arteries. There was no difference between endothelium-intact and -denuded coronary arteries from both male and female rabbits, precontracted with these three agents. Haemoglobin, indomethacin, methylene blue, glibenclamide or barium chloride did not affect the relaxation. In endothelium-denuded rabbit coronary arteries, progesterone shifted calcium concentration-dependent constrictor-response curves to the right, the maximal contraction was also reduced. The -log ED50s were 3.6 in control, and 3.3 and 2.9 after incubation with progesterone (3 and 30 microM), respectively. Similar results were obtained in rat aorta. We conclude that progesterone induces significant endothelium-independent relaxation in rabbit coronary arteries in vitro, possibly by affecting calcium influx.

Vasodilator effects of estrogen are not diminished by androgen in postmenopausal women.

OBJECTIVE: To compare the effects of estrogen with estrogen-androgen treatment on vaginal blood flow velocity and fingertip postocclusive hyperemic blood flow response. DESIGN: Prospective, randomized, parallel, double-blind study. SETTING: Healthy human volunteers in an academic research environment. PATIENT(S): Postmenopausal women receiving estrogen replacement therapy for at least 12 months and treated with placebo before this investigation. INTERVENTION(S): Esterified estrogens or esterified estrogen + methyltestosterone were administered orally; laser Doppler velocimetry was used to determine vaginal and fingertip blood flow responses at baseline and after 4 and 8 weeks of daily drug administration. MAIN OUTCOME MEASURE(S): Fingertip postocclusive area under curve (AUC); vaginal blood flow velocities. RESULT(S): The AUC for postocclusive fingertip blood flow and vaginal blood flow increased to a greater extent in the estrogen-androgen group, but changes were not statistically significant between groups. CONCLUSION(S): Estrogen-androgen treatment does not diminish the vasodilator effects of estrogen treatment in postmenopausal women.

Psychotherapeutic intervention for treatment of couples with secondary infertility.

Twenty couples with a history of secondary infertility and no detectable organic etiology were randomly assigned to one of two groups. One group was seen by a psychotherapist for an interview, the object of which was to detect and discuss previously unrecognized psychosexual problems or psychologic conflicts. The second group was not seen by the psychotherapist. Interviews included the presence of both members of the couple and the infertility specialist. The psychiatric interview did uncover psychologic conflicts, the most prevalent of which was a problem between the woman and her mother in which psychologic boundaries between the two women were confused. Sexual problems, marital discord, and fear of pregnancy were other issues warranting clarification and attention. After 18 months of follow-up, six of the ten women in couples interviewed had become pregnant, and one woman of nine in the control group had become pregnant.

The ST segment--the herald of ischaemia, the siren of misdiagnosis, or syndrome X?

Syndrome X is the term applied to patients with anginal-type chest pain who, despite a positive exercise stress test, have angiographically normal coronary arteries. Such patients probably belong to a heterogeneous group, and in a proportion the exercise test is falsely positive. With the availability of more accurate techniques for the detection of myocardial ischaemia, it is apparent that some patients can be shown to develop transient myocardial ischaemia with stress. The paradox of normal coronary arteries and a positive exercise test may be resolved by improved understanding of the regulatory control of regional myocardial blood flow, particularly at the level of the microvasculature, and of the metabolic expression of myocardial ischaemia.

Ovarian hormones and the circulation.

Ovarian steroids have effects on blood circulation involving the mechanisms which control blood flow and the changes that occur in the pathogenesis of atherosclerosis. Estrogens appear to protect women from cardiovascular disease through their effects on lipid metabolism as well as more direct effects on arterial walls which appear to inhibit atherosclerotic plaque formation. There is increasing evidence that estrogen replacement after menopause can markedly reduce female mortality due to vascular disease. Effects of hormone imbalance and deficiency on vasomotor control are clinically significant and hormone treatment appears to be effective in the management of a variety of conditions due to abnormal blood flow including vasomotor instability, migraine, vaginal dryness and, perhaps, some forms of angina. Most review articles have focused on the effects of ovarian steroids and lipid metabolism as well as the findings of recent epidemiologic studies. This is understandable as those investigations have proved so valuable in understanding the protective effects of estrogens. The present discussion, in contrast, focuses on the effects of ovarian steroids, estrogens in particular, on circulatory mechanisms. At the present time there is increasing interest in these studies. Findings thus far appear to contribute to understanding estrogen cardioprotection and also raise awareness of a variety of clinical conditions in which estrogen treatment could be indicated because of its effects on circulation.

Sex problems after menopause: a study of fifty married couples treated in a sex counseling programme.

This is a study of the sexuality of 50 couples among whom all of the women were post-menopausal. The population was seen in the Sex Counseling Service at Yale for treatment of sexual problems. The impact of biological changes accompanying the menopause appears to influence sexual interest, behaviour and response of both women and their male partners. The possible importance of oestrogen effects on perception and the significance of perceptual changes at menopause to the functioning of the sex response cycle is reported. Findings also include male emotions generated by female biological changes which inhibit male sexuality.

Sex and menopause: defining the issues.

This is a study of 185 women attending a menopause clinic in London, England. Individual interviews carried out by a gynecologist trained in sex therapy found a variety of psychosexual problems affected the lives of a large majority of the women. Sex problems existing prior to menopause were exacerbated. For most of the women, however, problems developed during the years immediately preceding and following menopause. Problems included disorders of sexual desire, sexual response and sexual behavior. Menopause clinic staff should be alert to the presence of sex problems and should play a role in diagnosis, treatment and/or referral.

Skin changes in menopause.

Skin signs and symptoms were examined in 46 menopausal women prior to estrogen replacement therapy. Several symptoms such as pruritus, bruising, dryness and thinning were seen more frequently in sun-exposed skin emphasizing the contribution of photoaging. At the end of a 6-mth treatment period, no significant difference was observed in the prevalence or severity of the cutaneous signs and symptoms when patients receiving transdermal 17 beta-estradiol (Estraderm) were compared with controls (the only exception was cutaneous flushing). Elastic fibers from sun-protected (buttock) skin of menopausal women were studied by light and electron microscopy. In 3 women (ages 30-37) with a history of premature menopause, the elastic fibers had several degenerative changes including coalescence of cystic spaces into lacunae, peripheral fragmentation, granular degeneration and splitting of the fibers into strands. Similar age-related ultrastructural changes are normally found in individuals that are at least 20 yrs older than these patients. These findings are suggestive of a relationship between premature aging of the dermal elastic fibers and estrogen deprivation.