Context.—Observational studies have found lower rates of coronary heart disease
(CHD) in postmenopausal women who take estrogen than in women who do not,
but this potential benefit has not been confirmed in clinical trials.Objective.—To determine if estrogen plus progestin therapy alters the risk for
CHD events in postmenopausal women with established coronary disease.Design.—Randomized, blinded, placebo-controlled secondary prevention trial.Setting.—Outpatient and community settings at 20 US clinical centers.Participants.—A total of 2763 women with coronary disease, younger than 80 years,
and postmenopausal with an intact uterus. Mean age was 66.7 years.Intervention.—Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone
acetate in 1 tablet daily (n=1380) or a placebo of identical appearance (n=1383).
Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were
taking it at the end of 1 year, and 75% at the end of 3 years.Main Outcome Measures.—The primary outcome was the occurrence of nonfatal myocardial infarction
(MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization,
unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke
or transient ischemic attack, and peripheral arterial disease. All-cause mortality
was also considered.Results.—Overall, there were no significant differences between groups in the
primary outcome or in any of the secondary cardiovascular outcomes: 172 women
in the hormone group and 176 women in the placebo group had MI or CHD death
(relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The
lack of an overall effect occurred despite a net 11% lower low-density lipoprotein
cholesterol level and 10% higher high-density lipoprotein cholesterol level
in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically
significant time trend, with more CHD events in the hormone group than in
the placebo group in year 1 and fewer in years 4 and 5. More women in the
hormone group than in the placebo group experienced venous thromboembolic
events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84
vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences
in several other end points for which power was limited, including fracture,
cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38).Conclusions.—During an average follow-up of 4.1 years, treatment with oral conjugated
equine estrogen plus medroxyprogesterone acetate did not reduce the overall
rate of CHD events in postmenopausal women with established coronary disease.
The treatment did increase the rate of thromboembolic events and gallbladder
disease. Based on the finding of no overall cardiovascular benefit and a pattern
of early increase in risk of CHD events, we do not recommend starting this
treatment for the purpose of secondary prevention of CHD. However, given the
favorable pattern of CHD events after several years of therapy, it could be
appropriate for women already receiving this treatment to continue.

https://jamanetwork.com/journals/jama/articlepdf/187879/JOC80678.pdf

Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women

ACOG practice bulletin: Clinical management guidelines for obstetrician-gynecologists

Spontaneous coronary artery dissection (SCAD) has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden death, particularly among young women and individuals with few conventional atherosclerotic risk factors. Patient-initiated research has spurred increased awareness of SCAD, and improved diagnostic capabilities and findings from large case series have led to changes in approaches to initial and long-term management and increasing evidence that SCAD not only is more common than previously believed but also must be evaluated and treated differently from atherosclerotic myocardial infarction. High rates of recurrent SCAD; its association with female sex, pregnancy, and physical and emotional stress triggers; and concurrent systemic arteriopathies, particularly fibromuscular dysplasia, highlight the differences in clinical characteristics of SCAD compared with atherosclerotic disease. Recent insights into the causes of, clinical course of, treatment options for, outcomes of, and associated conditions of SCAD and the many persistent knowledge gaps are presented.

/pdf/spontaneous-coronary-artery-dissection-current-state-of-the-2tmhkoj05i.pdf

Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association.

N A RECENT COLLABORATIVE REanalysis of more than 90% of the world’s epidemiological data on the relationship between menopausal hormone replacement therapy (HRT) and breast cancer risk, it was found that longer durations of recent, but not past, use of HRT increased breast cancer risk, particularly among leaner women and for tumors that were less clinically advanced. 1 Unresolved issues include the extent to which the findings were due to a biological effect of hormones rather than issues of screening and ascertainment. The data were also insufficient to determine whether a combined estrogen-progestin regimen increased risk beyond that associated with estrogen alone. In 1994, we published data on HRT

Menopausal Estrogen and Estrogen-Progestin Replacement Therapy and Breast Cancer Risk

The increased risk of stroke observed in the Women's Health Initiative (WHI) trial in connection with combined estrogen/progestin hormone therapy was one reason for ending the study early. The present authors analyzed theeffects of combined hormone therapy (CHT) on ischemic and hemorrhagic stroke in the 16,608 postmenopausal women, 50 to 79 years of age, who participated in the multicenter, double-blind, placebo-controlled WHI trial and were followed up for 5.6 years on average. All women were followed for at least 3.7 years. The women were randomly assigned to receive either CHT (0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate) or a placebo each day. The rate of stroke was 1.8% in women given CHT and 1.3% in the placebo group. Four of 5 strokes were ischemic. Hemorrhagic stroke accounted for 11.9% of events in the CHT group and 18.6% in the placebo group. There were 23 deaths resulting from stroke, 12 in the CHT group and 11 in placebo recipients. The combined hazard ratio (hour) for all subtypes of stroke combined was 1.31 (nominal 95% confidence interval [CI], 1.02-1.68). Women who had never taken hormones had a 37% excess risk of stroke when given CHT, for a hazard ratio of 1.37 (95% CI, 1.03-1.82). On multivariate analysis, controlling for race/ethnicity and baseline systolic blood pressure did not influence stroke risk for women taking CHT. An excess risk was noted in all age groups; in women with all levels of baseline stroke risk; and in participants with and without hypertension, a history of cardiovascular disease, and statin or aspirin treatment. A number or risk factors for stroke failed to modify the effect of CHT on stroke risk. They included smoking, diabetes, biomarkers of inflammation, and a higher white blood cell count or hematocrit. These findings indicate that, independently of blood pressure, estrogen/progestin therapy augments the risk of stroke in postmenopausal women who are in good general health. Considering the increased risk of invasive breast cancer, myocardial infarction, and venous thrombosis in women participating in the WHI trial, the findings reinforce the view that the overall risk from CHT outweighs its possible benefits.

Effect of estrogen plus progestin on stroke in postmenopausal women: The Women's Health initiative: A randomized trial

The 2017 Hormone Therapy Position Statement of The North American Menopause Society (NAMS) updates the 2012 Hormone Therapy Position Statement of The North American Menopause Society and identifies future research needs. An Advisory Panel of clinicians and researchers expert in the field of women's health and menopause was recruited by NAMS to review the 2012 Position Statement, evaluate new literature, assess the evidence, and reach consensus on recommendations, using the level of evidence to identify the strength of recommendations and the quality of the evidence. The Panel's recommendations were reviewed and approved by the NAMS Board of Trustees. Hormone therapy (HT) remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM) and has been shown to prevent bone loss and fracture. The risks of HT differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. Treatment should be individualized to identify the most appropriate HT type, dose, formulation, route of administration, and duration of use, using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of the benefits and risks of continuing or discontinuing HT. For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is most favorable for treatment of bothersome VMS and for those at elevated risk for bone loss or fracture. For women who initiate HT more than 10 or 20 years from menopause onset or are aged 60 years or older, the benefit-risk ratio appears less favorable because of the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia. Longer durations of therapy should be for documented indications such as persistent VMS or bone loss, with shared decision making and periodic reevaluation. For bothersome GSM symptoms not relieved with over-the-counter therapies and without indications for use of systemic HT, low-dose vaginal estrogen therapy or other therapies are recommended. This NAMS position statement has been endorsed by Academy of Women's Health, American Association of Clinical Endocrinologists, American Association of Nurse Practitioners, American Medical Women's Association, American Society for Reproductive Medicine, Asociacion Mexicana para el Estudio del Climaterio, Association of Reproductive Health Professionals, Australasian Menopause Society, Chinese Menopause Society, Colegio Mexicano de Especialistas en Ginecologia y Obstetricia, Czech Menopause and Andropause Society, Dominican Menopause Society, European Menopause and Andropause Society, German Menopause Society, Groupe d’etudes de la menopause et du vieillissement Hormonal, HealthyWomen, Indian Menopause Society, International Menopause Society, International Osteoporosis Foundation, International Society for the Study of Women's Sexual Health, Israeli Menopause Society, Japan Society of Menopause and Women's Health, Korean Society of Menopause, Menopause Research Society of Singapore, National Association of Nurse Practitioners in Women's Health, SOBRAC and FEBRASGO, SIGMA Canadian Menopause Society, Societa Italiana della Menopausa, Society of Obstetricians and Gynaecologists of Canada, South African Menopause Society, Taiwanese Menopause Society, and the Thai Menopause Society. The American College of Obstetricians and Gynecologists supports the value of this clinical document as an educational tool, June 2017. The British Menopause Society supports this Position Statement.

Phillip M. Sarrel

Papers

The 2017 hormone therapy position statement of The North American Menopause Society.

How Progestins Compromise the Cardioprotective Effects of Estrogens