Author(s): Anderson, Garnet L; Limacher, Marian; Assaf, Annlouise R; Bassford, Tamsen; Beresford, Shirley AA; Black, Henry; Bonds, Denise; Brunner, Robert; Brzyski, Robert; Caan, Bette; Chlebowski, Rowan; Curb, David; Gass, Margery; Hays, Jennifer; Heiss, Gerardo; Hendrix, Susan; Howard, Barbara V; Hsia, Judith; Hubbell, Allan; Jackson, Rebecca; Johnson, Karen C; Judd, Howard; Kotchen, Jane Morley; Kuller, Lewis; LaCroix, Andrea Z; Lane, Dorothy; Langer, Robert D; Lasser, Norman; Lewis, Cora E; Manson, JoAnn; Margolis, Karen; Ockene, Judith; O'Sullivan, Mary Jo; Phillips, Lawrence; Prentice, Ross L; Ritenbaugh, Cheryl; Robbins, John; Rossouw, Jacques E; Sarto, Gloria; Stefanick, Marcia L; Van Horn, Linda; Wactawski-Wende, Jean; Wallace, Robert; Wassertheil-Smoller, Sylvia; Women's Health Initiative Steering Committee | Abstract: Despite decades of use and considerable research, the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain.To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States.A randomized, double-blind, placebo-controlled disease prevention trial (the estrogen-alone component of the Women's Health Initiative [WHI]) conducted in 40 US clinical centers beginning in 1993. Enrolled were 10 739 postmenopausal women, aged 50-79 years, with prior hysterectomy, including 23% of minority race/ethnicity.Women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo.The primary outcome was coronary heart disease (CHD) incidence (nonfatal myocardial infarction or CHD death). Invasive breast cancer incidence was the primary safety outcome. A global index of risks and benefits, including these primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer, hip fracture, and deaths from other causes, was used for summarizing overall effects.In February 2004, after reviewing data through November 30, 2003, the National Institutes of Health (NIH) decided to end the intervention phase of the trial early. Estimated hazard ratios (HRs) (95% confidence intervals [CIs]) for CEE vs placebo for the major clinical outcomes available through February 29, 2004 (average follow-up 6.8 years), were: CHD, 0.91 (0.75-1.12) with 376 cases; breast cancer, 0.77 (0.59-1.01) with 218 cases; stroke, 1.39 (1.10-1.77) with 276 cases; PE, 1.34 (0.87-2.06) with 85 cases; colorectal cancer, 1.08 (0.75-1.55) with 119 cases; and hip fracture, 0.61 (0.41-0.91) with 102 cases. Corresponding results for composite outcomes were: total cardiovascular disease, 1.12 (1.01-1.24); total cancer, 0.93 (0.81-1.07); total fractures, 0.70 (0.63-0.79); total mortality, 1.04 (0.88-1.22), and the global index, 1.01 (0.91-1.12). For the outcomes significantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10 000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years. The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10 000 person-years.The use of CEE increases the risk of stroke, decreases the risk of hip fracture, and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years. A possible reduction in breast cancer risk requires further investigation. The burden of incident disease events was equivalent in the CEE and placebo groups, indicating no overall benefit. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women.

/pdf/effects-of-conjugated-equine-estrogen-in-postmenopausal-56019yuhvy.pdf

Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial

Background Recent randomized clinical trials have suggested that estrogen plus progestin does not confer cardiac protection and may increase the risk of coronary heart disease (CHD). In this report, we provide the final results with regard to estrogen plus progestin and CHD from the Women's Health Initiative (WHI). Methods The WHI included a randomized primary-prevention trial of estrogen plus progestin in 16,608 postmenopausal women who were 50 to 79 years of age at base line. Participants were randomly assigned to receive conjugated equine estrogens (0.625 mg per day) plus medroxyprogesterone acetate (2.5 mg per day) or placebo. The primary efficacy outcome of the trial was CHD (nonfatal myocardial infarction or death due to CHD). Results After a mean follow-up of 5.2 years (planned duration, 8.5 years), the data and safety monitoring board recommended terminating the estrogen-plus-progestin trial because the overall risks exceeded the benefits. Combined hormone therapy was associated with a hazard ratio for CHD of 1.24 (nominal 95 percent confidence interval, 1.00 to 1.54; 95 percent confidence interval after adjustment for sequential monitoring, 0.97 to 1.60). The elevation in risk was most apparent at one year (hazard ratio, 1.81 [95 percent confidence interval, 1.09 to 3.01]). Although higher base-line levels of low-density lipoprotein cholesterol were associated with an excess risk of CHD among women who received hormone therapy, higher base-line levels of C-reactive protein, other biomarkers, and other clinical characteristics did not significantly modify the treatment-related risk of CHD. Conclusions Estrogen plus progestin does not confer cardiac protection and may increase the risk of CHD among generally healthy postmenopausal women, especially during the first year after the initiation of hormone use. This treatment should not be prescribed for the prevention of cardiovascular disease.

https://www.nejm.org/doi/pdf/10.1056/NEJMoa030808

Estrogen plus progestin and the risk of coronary heart disease

Estrogen has direct and indirect effects on the cardiovascular system that are mediated by the estrogen receptors ER-a and ER-β. The direct effects of estrogen occur through rapid nongenomic and longer-term genomic pathways. The rapid effects of estrogen are mediated by ERs and result in the activation of endothelial nitric oxide synthase, leading to arterial vasodilation. Longer-term effects involve changes in gene and protein expression, modulating the response to injury and atherosclerosis. Estrogen also indirectly influences serum lipoprotein and triglyceride profiles, and the expression of coagulant and fibrinolytic proteins. Advanced atherosclerosis and certain progestins, however, may attenuate some of the protective effects of estrogen.

Protective effects of estrogen on the cardiovascular system. Discussion

Background
Hormone therapy (HT) is widely provided for control of menopausal symptoms and has been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women. This is an updated version of a Cochrane review first published in 2005.

Objectives
To assess effects of long-term HT (at least 1 year's duration) on mortality, cardiovascular outcomes, cancer, gallbladder disease, fracture and cognition in perimenopausal and postmenopausal women during and after cessation of treatment.

Search methods
We searched the following databases to September 2016: Cochrane Gynaecology and Fertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO. We searched the registers of ongoing trials and reference lists provided in previous studies and systematic reviews.

Selection criteria
We included randomised double-blinded studies of HT versus placebo, taken for at least 1 year by perimenopausal or postmenopausal women. HT included oestrogens, with or without progestogens, via the oral, transdermal, subcutaneous or intranasal route.

Data collection and analysis
Two review authors independently selected studies, assessed risk of bias and extracted data. We calculated risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, along with 95% confidence intervals (CIs). We assessed the quality of the evidence by using GRADE methods.

Main results
We included 22 studies involving 43,637 women. We derived nearly 70% of the data from two well-conducted studies (HERS 1998; WHI 1998). Most participants were postmenopausal American women with at least some degree of comorbidity, and mean participant age in most studies was over 60 years. None of the studies focused on perimenopausal women.

In relatively healthy postmenopausal women (i.e. generally fit, without overt disease), combined continuous HT increased the risk of a coronary event (after 1 year's use: from 2 per 1000 to between 3 and 7 per 1000), venous thromboembolism (after 1 year's use: from 2 per 1000 to between 4 and 11 per 1000), stroke (after 3 years' use: from 6 per 1000 to between 6 and 12 per 1000), breast cancer (after 5.6 years' use: from 19 per 1000 to between 20 and 30 per 1000), gallbladder disease (after 5.6 years' use: from 27 per 1000 to between 38 and 60 per 1000) and death from lung cancer (after 5.6 years' use plus 2.4 years' additional follow-up: from 5 per 1000 to between 6 and 13 per 1000).

Oestrogen-only HT increased the risk of venous thromboembolism (after 1 to 2 years' use: from 2 per 1000 to 2 to 10 per 1000; after 7 years' use: from 16 per 1000 to 16 to 28 per 1000), stroke (after 7 years' use: from 24 per 1000 to between 25 and 40 per 1000) and gallbladder disease (after 7 years' use: from 27 per 1000 to between 38 and 60 per 1000) but reduced the risk of breast cancer (after 7 years' use: from 25 per 1000 to between 15 and 25 per 1000) and clinical fracture (after 7 years' use: from 141 per 1000 to between 92 and 113 per 1000) and did not increase the risk of coronary events at any follow-up time.

Women over 65 years of age who were relatively healthy and taking continuous combined HT showed an increase in the incidence of dementia (after 4 years' use: from 9 per 1000 to 11 to 30 per 1000). Among women with cardiovascular disease, use of combined continuous HT significantly increased the risk of venous thromboembolism (at 1 year's use: from 3 per 1000 to between 3 and 29 per 1000). Women taking HT had a significantly decreased incidence of fracture with long-term use.

Risk of fracture was the only outcome for which strong evidence showed clinical benefit derived from HT (after 5.6 years' use of combined HT: from 111 per 1000 to between 79 and 96 per 1000; after 7.1 years' use of oestrogen-only HT: from 141 per 1000 to between 92 and 113 per 1000). Researchers found no strong evidence that HT has a clinically meaningful impact on the incidence of colorectal cancer.

One trial analysed subgroups of 2839 relatively healthy women 50 to 59 years of age who were taking combined continuous HT and 1637 who were taking oestrogen-only HT versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT: Their absolute risk remained low, at less than 1/500. However, other differences in risk cannot be excluded, as this study was not designed to have the power to detect differences between groups of women within 10 years of menopause.

For most studies, risk of bias was low in most domains. The overall quality of evidence for the main comparisons was moderate. The main limitation in the quality of evidence was that only about 30% of women were 50 to 59 years old at baseline, which is the age at which women are most likely to consider HT for vasomotor symptoms.

Authors' conclusions
Women with intolerable menopausal symptoms may wish to weigh the benefits of symptom relief against the small absolute risk of harm arising from short-term use of low-dose HT, provided they do not have specific contraindications. HT may be unsuitable for some women, including those at increased risk of cardiovascular disease, increased risk of thromboembolic disease (such as those with obesity or a history of venous thrombosis) or increased risk of some types of cancer (such as breast cancer, in women with a uterus). The risk of endometrial cancer among women with a uterus taking oestrogen-only HT is well documented.

HT is not indicated for primary or secondary prevention of cardiovascular disease or dementia, nor for prevention of deterioration of cognitive function in postmenopausal women. Although HT is considered effective for the prevention of postmenopausal osteoporosis, it is generally recommended as an option only for women at significant risk for whom non-oestrogen therapies are unsuitable. Data are insufficient for assessment of the risk of long-term HT use in perimenopausal women and in postmenopausal women younger than 50 years of age.

Long term hormone therapy for perimenopausal and postmenopausal women

Objective: Our objective was to provide a scholarly review of the published literature on menopausal hormonal therapy (MHT), make scientifically valid assessments of the available data, and grade the level of evidence available for each clinically important endpoint. Participants in Development of Scientific Statement: The 12-member Scientific Statement Task Force of The Endocrine Society selected the leader of the statement development group (R.J.S.) and suggested experts with expertise in specific areas. In conjunction with the Task Force, lead authors (n = 25) and peer reviewers (n = 14) for each specific topic were selected. All discussions regarding content and grading of evidence occurred via teleconference or electronic and written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement. Evidence: Each expert conducted extensive literature searches of case control, cohort, and randomized controlled tria...

Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(02)12001-0.pdf

Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial.

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Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial.