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.

Raloxifene, soy phytoestrogens and endothelial function in postmenopausal women.

OBJECTIVE: To compare the effects of raloxifene and soy phytoestrogens on endothelial function in healthy, postmenopausal women. DESIGN: Randomized, double-blind, placebo-controlled, cross-over trial. Subjects (n = 22; mean age 58.5 years) underwent endothelial function testing at baseline and following 6 weeks of daily raloxifene 60 mg, soy phytoestrogens 55 mg, and placebo in random sequence with intervening 6-week wash-out periods. Endothelial function was assessed as flow-mediated vasodilatation (FMD) of the brachial artery using high-resolution ultrasound; digital flux was measured with laser Doppler velocimetry. RESULTS: Baseline (pretreatment) FMD was almost within normal range at 9.6% (+/-6.4). FMD did not change from baseline within any treatment group, and no between-group differences were detected. FMD values following treatment with raloxifene, soy, and placebo were 10.3% (+/-12.3), 8.3% (+/-7.7), and 9.5% (+/-4.4), respectively. Area under curve ratios showed no treatment differences for digital velocimetry. CONCLUSIONS: In this study, neither raloxifene nor soy enhanced endothelial function in postmenopausal women. However, the cohort had relatively normal endothelial function at baseline. Further study is required to determine if particular subgroups of postmenopausal women derive vascular benefit from the use of selective estrogen receptor modulators or soy phytoestrogens.

A clinical trial of estrogen-replacement therapy after ischemic stroke.

BACKGROUND: Observational studies have suggested that estrogen-replacement therapy may reduce a woman's risk of stroke and death. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of estrogen therapy (1 mg of estradiol-17beta per day) in 664 postmenopausal women (mean age, 71 years) who had recently had an ischemic stroke or transient ischemic attack. Women were recruited from 21 hospitals in the United States and were followed for the occurrence of stroke or death. RESULTS: During a mean follow-up period of 2.8 years, there were 99 strokes or deaths among the women in the estradiol group, and 93 among those in the placebo group (relative risk in the estradiol group, 1.1; 95 percent confidence interval, 0.8 to 1.4). Estrogen therapy did not reduce the risk of death alone (relative risk, 1.2; 95 percent confidence interval, 0.8 to 1.8) or the risk of nonfatal stroke (relative risk, 1.0; 95 percent confidence interval, 0.7 to 1.4). The women who were randomly assigned to receive estrogen therapy had a higher risk of fatal stroke (relative risk, 2.9; 95 percent confidence interval, 0.9 to 9.0), and their nonfatal strokes were associated with slightly worse neurologic and functional deficits. CONCLUSIONS: Estradiol does not reduce mortality orthe recurrence of stroke in postmenopausal women with cerebrovascular disease. This therapy should not be prescribed for the secondary prevention of cerebrovascular disease.

Effects of oat and wheat cereals on endothelial responses.

BACKGROUND: This study was undertaken to determine the effects of month-long whole grain oat and wheat cereal supplementation on endothelial function following a fatty meal as measured by brachial artery reactivity studies. METHODS: Fifty healthy adult subjects underwent brachial artery reactivity studies before and after a high-fat meal along with alpha-tocopherol (vitamin E), oats, or a comparable bowl of wheat cereal and were again tested after the high-fat meal following month-long supplementation with oat or wheat cereal in a random crossover with interim washout. RESULTS: In the acute phase, the fatty meal attenuated the hyperemic brachial artery flow response when administered concurrently with wheat cereal (-13.4%; P = 0.02), whereas hyperemic flow was maintained by concurrent administration of either oatmeal or alpha-tocopherol. Following month-long supplementation, postprandial peak flow (wheat +3.88 +/- 5.62%; oat -10.78 +/- 7.15%), and peak diameter (wheat -1.40 +/- 0.96%; oat -0.86 +/- 0.88%) did not differ from preprandial values. Oat and wheat treatments did not differ when directly compared. CONCLUSIONS: Month-long, daily supplementation with either whole-grain oat or wheat cereal may prevent postprandial impairment of vascular reactivity in response to a high-fat meal.

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.

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.

Effects of hormone replacement therapy on sexual psychophysiology and behavior in postmenopause.

Investigators continue to define the exact relationship between sexual function and changes in hormonal status during menopause. The availability of different preparations that could replace estrogens and androgens has led to many studies of the use of hormone replacement therapy (HRT) for sexual dysfunction. Dyspareunia due to vaginal dryness appears to be most responsive to estrogen replacement therapy (ERT) via restoration of vaginal cells, pH, and blood flow. Progestins, to a certain extent, can oppose these changes and lead to a recurrence of dryness and dyspareunia. ERT has also been reported to enhance sexual desire in a significant percent of women. Although treatment with ERT has been shown to be efficacious for many women, there are others whose sexual difficulties remain unresponsive. There also appears to be a significant subgroup of women whose sexual difficulties respond initially to ERT but who subsequently revert to their initial problems, especially when the problem has been loss of libido. For these women, the addition of androgen has proved helpful.

Blood pressure exceeding national guidelines among women after stroke.

BACKGROUND AND PURPOSE: After a transient ischemic attack or stroke, the risk for recurrence may be reduced by treatment of hypertension. The purpose of this study was to determine how commonly blood pressure exceeds national guidelines among patients who have had one of these events. METHODS: Subjects were 644 women participating in a randomized trial of estrogen for secondary stroke prevention. We measured blood pressure 1 month after the stroke or TIA while patients were under the care of their personal physicians. Among 536 patients, a second measure was made at an average of 2.9 years after the first. RESULTS: The mean age of participants was 71 years, and 73% reported a history of hypertension. At baseline, only 44% (280/644) of the women had blood pressure values within national guidelines (<140/90 mm Hg). With separate guidelines used for diabetics (<130/85 mm Hg) and nondiabetics (<140/90 mm Hg), the proportions of women within the guidelines were 27% and 44%, respectively. Overall, 39% of patients were within the diabetes-adjusted guidelines. Among patients whose blood pressure exceeded 140/90 mm Hg at first examination, 55% were still in excess at follow-up. Features associated with severe hypertension at first examination (>160/100 mm Hg) were history of hypertension, education less than college, and higher cognitive functioning. CONCLUSIONS: Blood pressure values in excess of national guidelines are common after stroke and TIA, especially among diabetic patients. Efforts to lower blood pressure control may enhance secondary prevention.

The stroke prognosis instrument II (SPI-II) : A clinical prediction instrument for patients with transient ischemia and nondisabling ischemic stroke.

BACKGROUND AND PURPOSE: In 1991 we developed the Stroke Prognosis Instrument (SPI-I) to stratify patients with transient ischemic attack or ischemic stroke by prognosis for stroke or death in 2 years. In this article we validate and improve SPI-I (creating SPI-II). METHODS: To validate SPI-I, we applied it to 4 test cohorts and calculated pooled outcome rates. To create SPI-II, we incorporated new predictive variables identified in 1 of the test cohorts and validated it in the other 3 cohorts. RESULTS: For SPI-I, pooled rates (all 4 test cohorts) of stroke or death within 2 years in risk groups I, II, and III were 9%, 17%, and 24%, respectively (P<0.01, log-rank test). SPI-II was created by adding congestive heart failure and prior stroke to SPI-I. Each patient's risk group was determined by the total score for 7 factors: congestive heart failure (3 points); diabetes (3 points); prior stroke (3 points); age >70 years (2 points); stroke for the index event (not transient ischemic attack) (2 points); hypertension (1 point); and coronary artery disease (1 point). Risk groups I, II, and III comprised patients with 0 to 3, 4 to 7, and 8 to 15 points, respectively. For SPI-I, pooled rates (3 cohorts excluding the SPI-II development cohort) of stroke or death within 2 years in risk groups I, II, and III were 9%, 17%, and 23%, respectively. For SPI-II, pooled rates were 10%, 19%, and 31%, respectively. In receiver operator characteristic analysis, the area under the curve was 0.59 (95% CI, 0.57 to 0.60) for SPI-I and 0.63 (95% CI, 0.62 to 0.65) for SPI-II, confirming the better performance of the latter. CONCLUSIONS: Compared with SPI-I, SPI-II achieves greater discrimination in outcome rates among risk groups. SPI-II is ready for use in research design and may have a role in patient counseling.

The differential effects of oestrogens and progestins on vascular tone.

The purpose of this paper is to present reported findings of the effects of ovarian steroids on vascular tone. The medical literature was reviewed for relevant contributions. Oestrogen replacement therapy in postmenopausal women is associated with a reduction in mortality from coronary artery disease. Many different cellular actions have been described which help explain the cardioprotective effects of oestrogens, and among these are effects on vascular tone. Oestrogens induce vasodilation through mechanisms involving the arterial endothelium and through endothelial-independent actions. Progestins have varying effects on arterial tone, including induction of vascular smooth muscle relaxation as well as induction of smooth muscle constriction. The effects of oestrogens and progestins on vascular tone are clinically meaningful. Pathophysiological arterial conditions, including angina pectoris and migraine headaches, have been associated with oestradiol deficiency and improvement has been associated with oestradiol replacement. Women with coronary artery disease show improved arterial vasodilator responses after oestradiol treatment which can be reduced by the addition of progestin treatment. Androgens are also vasoactive. Study of the effects of ovarian hormones on vascular tone has become an important area for basic and clinical research.

Vitamin D and calcium dysregulation in the polycystic ovarian syndrome.

Over the past 30 years, numerous studies in invertebrates and vertebrates have established a role of calcium in oocyte maturation as well as in the resumption and progression of follicular development. Polycystic ovarian syndrome (PCO) is characterized by hyperandrogenic chronic anovulation, theca cell hyperplasia, and arrested follicular development. The aim of this observational study was to determine whether vitamin D and calcium dysregulation contribute to the development of follicular arrest in women with PCO, resulting in reproductive and menstrual dysfunction. Thirteen premenopausal women (mean age 31 +/- 7.9 years) with documented chronic anovulation and hyperandrogenism were evaluated. Four women were amenorrheic and nine had a history oligomenorrhea, two of whom had dysfunctional bleeding. Nine had abnormal pelvic sonograms with multiple ovarian follicular cysts. All were hirsute, two had alopecia, and five had acanthosis nigricans. The mean 25 hydrovitamin D was 11.2 +/- 6.9 ng/ml [normal (nl): 9-52], and the mean 1,25 dihydroxyvitamin D was 45.8 +/- 18 pg/ml. with one woman with a 1,25 dihydroxyvitamin D <5 pg/ml (nl: 15-60). The mean intact parathyroid hormone level was 47 +/- 19 pg/ml (nl: 10-65), with five women with abnormally elevated parathyroid hormone levels. All were normocalcemic (9.3 +/- 0.4 mg/dl). Vitamin D repletion with calcium therapy resulted in normalized menstrual cycles within 2 months for seven women, with two experiencing resolution of their dysfunctional bleeding. Two became pregnant, and the other four patients maintained normal menstrual cycles. These data suggest that abnormalities in calcium homeostasis may be responsible, in part, for the arrested follicular development in women with PCO and may contribute to the pathogenesis of PCO.

Psychosexual effects of menopause: role of androgens.

Ovarian hormones-estrogens, androgens, and progesterone-produce a myriad of effects in the nervous system. The effects of androgens in the brain are mediated through androgen-specific receptors and by the aromatization of testosterone to estradiol. Alterations in the circulating levels of androgens play an important role in psychologic and sexual changes that occur after menopause. The effects of short-term estrogen therapy in improving psychologic symptoms, maintaining vaginal lubrication, decreasing vaginal atrophy, and increasing pelvic blood flow in postmenopausal women are well documented. However, some patients require more than estrogen alone to improve psychologic dysfunction, decreased sexual desire, or other sexual problems associated with menopause. Results from clinical studies show that hormone replacement therapy with estrogen plus androgens provides greater improvement in psychologic (eg, lack of concentration, depression, and fatigue) and sexual (eg, decreased libido and inability to have an orgasm) symptoms than does estrogen alone in naturally and surgically menopausal women.

Improving adherence to hormone replacement therapy with effective patient-physician communication.

Surgically menopausal women are 5 times more likely to begin hormone replacement therapy than are naturally menopausal women, and they continue therapy for longer periods. The primary reasons that women refuse hormone replacement are fear of cancer and perceived side effects. In contrast, withdrawal bleeding is the major reason that women discontinue hormone replacement therapy. Physician-patient communication plays an important role in a woman's decision to use hormone replacement therapy, to fill her prescription, and to adhere to the regimen. The first visit at which hormone replacement therapy is discussed is crucial to establishing an effective patient-physician relationship. At least 15 minutes, and preferably 45 minutes, should be reserved for this visit. Patient follow-up-either by phone or in person-during the first month can help improve adherence because this is when many women may have nuisance side effects and discontinue therapy.

A case of fatal pulmonary thromboembolism associated with the use of intravenous estrogen therapy.

OBJECTIVE: To report a case of fatal pulmonary embolism associated with the use of i.v. estrogen therapy for menometrorrhagia. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 52-year-old woman with fibroid uterus treated with GnRH analogues with add-back therapy who presented with excessive vaginal bleeding. INTERVENTION(S): Intravenous conjugated estrogens were administered for a total of six doses. MAIN OUTCOME MEASURE(S): Fatal thromboembolic event. RESULT(S): The day after i.v. conjugated estrogens were administered, the patient had only scant vaginal bleeding, but she experienced the sudden onset of respiratory distress, became comatose, and subsequently had ventricular fibrillation leading to asystole. All resuscitative efforts failed. Postmortem examination revealed bilateral pulmonary artery thromboembolism (saddle embolus). CONCLUSION(S): Intravenous conjugated estrogen therapy may be complicated by fatal thromboembolic events. This potential adverse effect must be considered in the use of such therapy for severe menometrorrhagia, especially when treating a patient at increased risk.

Risks and benefits of hormone replacement therapy for the prevention of cardiovascular disease.

Study of the circulatory effects of ovarian hormones has become a subject of increasing interest with the promise of new treatment approaches for the prevention of cardiovascular disease. Work with estrogens is the most extensive and does indicate the benefits outweigh the risks albeit we continue to await the findings of several large, prospective randomized trials. The addition of progestins does appear to be compromising but it is possible that an approach will be developed that is cardioprotective without increasing the cancer risk.

Estrogen and estrogen-androgen replacement in postmenopausal women dissatisfied with estrogen-only therapy. Sexual behavior and neuroendocrine responses.

OBJECTIVE: To investigate the efficacy of esterified estrogens alone and combined with oral androgen on sexual function and menopausal symptoms in postmenopausal women. STUDY DESIGN: Twenty postmenopausal women dissatisfied with their estrogen or estrogen-progestin therapy volunteered to enter a double-blind, randomized trial in which they received either oral esterified estrogens or esterified estrogens + androgen for eight weeks after a single-blind, placebo, lead-in period. Sexual function was assessed with a questionnaire used in the Yale midlife survey, and plasma levels of estradiol, estrone, sex hormone binding globulin (SHBG) and beta-endorphin were measured at two- to four-week intervals. RESULTS: Estrogen-androgen therapy significantly improved sexual sensation and desire after four and eight weeks of double-blind treatment in comparison to previous estrogen therapy and postplacebo baseline assessments. Plasma levels of estradiol and estrone increased significantly in all patients as compared to the postplacebo baseline and decreased in comparison to circulating estrogen concentrations on previous therapy. Relative proportions of free and bound steroid hormone exhibited contrasting shifts during estrogen and estrogen-androgen therapy. SHBG increased in the estrogen group and decreased in the estrogen-androgen group, leading to lower amounts of free androgens during estrogen therapy and increased free androgen levels during estrogen-androgen therapy. Since proportions of free (bioavailable) ovarian steroids would correlate inversely with plasma protein binding capacity, the beneficial effects of oral estrogen-androgen therapy on sexual sensation and desire may be due either to the administered androgen or to the increased availability of endogenous and exogenous androgens, particularly in the central nervous system. CONCLUSION: Sexual desire, satisfaction and frequency in postmenopausal women taking hormonal therapy were improved significantly by combined estrogen-androgen therapy but not by estrogen or estrogen-progestin therapy. Sexual function improved with estrogen-androgen therapy even though circulating estrogen levels were lower than those measured during previous estrogen therapy. This leads to the conclusion that androgens play a pivotal role in sexual function but that estrogens are not a significant factor determining levels of sexual drive and enjoyment.

Cardiovascular aspects of androgens in women.

A review of the literature of androgen actions affecting the circulatory system indicates early enthusiasm for use of testosterone in cardiac patients, subsequent disenchantment with androgens due to negative effects on lipid metabolism, and recent renewed interest as new technologies and understandings of the cardio-protective effects of estrogens has led to re-examination of the beneficial and adverse effects of androgens. Ovarian steroids, including androgens, have effects on lipid metabolism in the liver and direct effects in the arterial wall, which influence the development and progress of atherosclerosis. Androgens lower total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides but also decrease high-density lipoprotein (HDL) cholesterol levels. Androgen arterial-wall effects help maintain the mechanisms involved in vasodilation. Androgens alone appear to promote atherosclerosis but when administered with estrogens have the opposite effect in the arterial wall. Recognition of the cellular actions of androgens and the decrease in androgen production as women age after the menopause has led to increased use of androgen replacement therapy for postmenopausal women. Preliminary clinical findings in women using postmenopausal estrogen/androgen treatment indicate a good safety profile. However, in comparison to the many years and experience in evaluating the effects of estrogens, studies of androgen effects must be considered to be at a preliminary stage.

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.