Menopausal Hormone Therapy for Primary Prevention of Chronic Disease

Cora E. Lewis, MD, MSPH1; Melissa F. Wellons, MD, MHS2

JAMA. 2017;318(22):2187-2189. doi:10.1001/jama.2017.16974



In this issue of JAMA, the US Preventive Services Task Force (USPSTF) presents a Recommendation Statement1 and an accompanying Evidence Report2 that consider the risks and benefits of menopausal hormone therapy for primary prevention of chronic conditions and arrive at a grade D recommendation.1 The recommendations are based only on evidence from randomized trials and do not pertain to women considering hormone therapy for vasomotor symptoms, given the USPSTF mandate to consider specific preventive care services for patients without related signs and symptoms of illness.


It has been a long, winding road to the current USPSTF recommendations regarding menopausal hormone therapy, with numerous key developments along the way. More than 50 years ago, in 1963, Wilson and Wilson3 ascribed to the “estrogen lack” of menopause a litany of adverse health consequences and recommended that a “beneficial estrogen level should be continued throughout life.” Their article recommended oral progestins, such as medroxyprogesterone acetate, to avoid endometrial hyperplasia. Estrogen sales in US dollars, mostly conjugated estrogens, quadrupled between 1962 and 1973. However, in the mid 1970s, several reports suggested an association between conjugated estrogens and increased risk of endometrial cancer.4


In 1989, the first publication of the USPSTF recommended “estrogen prophylaxis” for asymptomatic women at risk for osteoporosis who lacked contraindications and who had received counseling on potential benefits and risks.5 At that time, no randomized trials of estrogen therapy for fracture prevention existed. Recognized benefits were improvements in vasomotor flushes, vaginal atrophy, and lipoprotein profiles; risks were endometrial hyperplasia and cancer with unopposed estrogen. In 1996, based on observational studies and short-term trials, the USPSTF recommended counseling for all perimenopausal and postmenopausal women about possible benefits and risks (grade B), individual decision making based on patient risk factors and symptoms, potential benefits (then including possibly reduced risk of myocardial infarction and fracture), risks (then including increased risk of breast cancer), and individual preferences.6


A 1992 review concluded that hormone therapy should probably be recommended for women who had undergone hysterectomy and for those with or at high risk of coronary heart disease.7 The American College of Physicians recommended that all women should consider “preventive hormone therapy.”8


Despite the lack of defined benefits and risks, a 1995 national survey of 495 women aged 50 to 74 years found that 59% of women who had undergone hysterectomy and 20% of those who had not reported use of hormone therapy.9 At about this time, of nearly 1400 cardiologists, internists, family physicians, and general practitioners surveyed, 82% prescribed hormone therapy; of those, 66% reported prescribing hormone therapy for prevention of coronary heart disease.10 Interest in menopausal hormone therapy for chronic disease prevention had indeed taken off.


However, in 1998, results from the Heart and Estrogen/progestin Replacement Study (HERS)11 raised important concerns about menopausal hormone therapy. In this trial, 2763 women with established coronary heart disease were randomized to receive daily, double-blind, conjugated equine estrogens (0.625 mg) plus medroxyprogesterone acetate (2.5 mg) or placebo. After 4.1 years of follow-up, treatment with the combined hormone regimen did not prevent coronary events relative to placebo, despite significantly improved low-density lipoprotein and high-density lipoprotein cholesterol levels. Significantly more venous thrombotic and gallbladder events occurred in the hormone-treated group.


Further and more convincing concerns became evident with publication of results from the landmark Women’s Health Initiative (WHI) trials of combination estrogen plus progestin therapy in 200212 and of estrogen-alone therapy in 2004,13 both of which were stopped prematurely for excess harm in the hormone-treated groups compared with placebo. The combination therapy trial involving 16 608 postmenopausal women aged 50 to 79 years was stopped early at a mean 5.2 years of follow-up because of excess breast cancer risk in the hormone-treated group (hazard ratio [HR], 1.26 [95% CI, 1.00-1.59]) and a global index supporting more harm than benefit (HR, 1.15 [95% CI, 1.03-1.28]). Other significant harms were coronary heart disease, stroke, and pulmonary emboli. Significant benefits were fewer cases of colorectal cancer and hip fracture in the hormone-treated group.


The estrogen-alone trial that involved 10 739 women was also stopped early with a mean 6.8 years of follow-up,13 with significantly more stroke events and fewer cases of hip fracture in the estrogen-treated group. There were no significant differences for coronary heart disease, breast cancer (HR, 0.77 [95% CI, 0.59-1.01]), pulmonary emboli, colorectal cancer, and the global index. The ancillary Women’s Health Initiative Memory Study (WHIMS) in women aged 65 to 79 years found higher risk for probable dementia in the pooled hormone trials (HR, 1.76 [95% CI, 1.19-2.60]).14 These findings led to grade D recommendations (ie, at least fair evidence that the service is ineffective or that harms outweigh benefits) from the USPSTF in 200515 and in 2012.16


Long-term follow-up data from the WHI, with additional outcomes and 13 years of cumulative follow-up during and following the intervention phase, were published in 2013.17 During the intervention phase, risk in the combination hormone therapy group, relative to placebo, was not significantly higher for coronary heart disease outcomes (HR, 1.18 [95% CI, 0.95-1.45]) but was significantly higher for breast cancer, stroke, pulmonary embolism, deep vein thrombosis, dementia (women aged ≥65 years), gallbladder disease, and urinary incontinence. Hormone therapy had significant benefits for hip fracture, self-reported diabetes, and vasomotor symptoms during intervention. Most risks and benefits dissipated during extended follow-up except for breast cancer (HR, 1.28 [95% CI, 1.11-1.48]), and risks exceeded benefits in all age groups. During the intervention phase, the risks for estrogen-alone therapy were significantly higher for stroke, pulmonary embolism, deep vein thrombosis, gallbladder disease, and incontinence. The risk of invasive breast cancer was not significantly lower with estrogen alone than with placebo (HR, 0.79 [95% CI, 0.61-1.02]), and risks for hip fracture, self-reported diabetes, and vasomotor symptoms were significantly lower. With cumulative follow-up, estrogen alone was associated with lower risk of invasive breast cancer (HR, 0.79 [95% CI, 0.65-0.97]). Women aged 50 to 59 years at baseline had a more favorable risk-benefit ratio when assigned to estrogen alone than did older women.


Most recently, neither hormone regimen was associated with increased risk of all-cause, cardiovascular, or cancer mortality at 18 years of cumulative follow-up, with no significant difference by age group.18 However, both WHI reports17,18 contain unadjusted P values from multiple comparisons in post hoc analyses and should be viewed as hypothesis generating.


In July 2017, the American Association of Clinical Endocrinologists/American College of Endocrinology published updated guidelines on menopause.19 This report used observational study data and relatively small trials that were inadequate to fully assess safety profiles and efficacy on clinical events, to craft recommendations including use of transdermal estrogen rather than oral estrogens, as well as consideration of age and time since menopause.


The current USPSTF report1 updates the 2012 recommendations. Because of the large size of its 2 hormone therapy trials, the WHI continued to strongly influence recommendations. After considering a number of outcomes, the USPSTF again arrived at a grade D recommendation for menopausal hormone use both for women with and without an intact uterus, concluding with moderate certainty that no net benefit exists for chronic disease prevention in either group in most postmenopausal women.


Since the draft report of the USPSTF Recommendation Statement was posted for comment from May 16 to June 12, 2017, the final report1 expands the discussion of the “timing hypothesis” and considers additional cumulative follow-up analyses from the WHI18 relative to it. The timing hypothesis states that starting hormone therapy near the time of menopause may result in a “more beneficial balance of benefits and risks” than experienced by older postmenopausal women. The USPSTF final recommendation1 discusses limitations of these data, concluding that evidence is inadequate to support different benefit-risk balances in subgroups.


Reactions to the USPSTF draft report have already been published. Cano et al20 suggest that the recommendations are misleading because they discuss hormone therapy for conditions not recommended by scientific societies and are irrelevant because postmenopausal women considering hormone therapy for primary prevention of chronic conditions are not found in daily practice. On the other hand, Langer et al21 insist on a role for menopausal hormone therapy in prevention.


Today, fewer postmenopausal women are using hormone therapy. Many physicians and organizations are cautious and only consider hormone therapy appropriate for climacteric symptoms. Some short-term trials and observational studies of other formulations and delivery routes of estrogens and progestins have found better safety profiles than regimens used in the WHI. However, no long-term appropriately powered trials with clinically important outcomes have been conducted to fully document the safety profiles of regimens other than those used in the WHI. While data from observational studies deserve attention when they show potential harms, menopausal hormone therapy represents a “poster child” for potentially misleading benefit signals from observational studies. The timing hypothesis remains alive and well, but trials conducted to address this hypothesis have been relatively short, used surrogate outcomes, and were not adequately powered to address risks and benefits. Testing the timing hypothesis would require extremely large sample sizes, and such a trial is unlikely to be conducted.


However, it does seem appropriate for relatively healthy, younger menopausal women with sufficiently severe vasomotor or other climacteric symptoms to draw some comfort from long-term WHI data. These women can consider hormone therapy for symptom relief. Physicians also have more evidence to impart to their patients during discussions about therapies for menopausal symptoms. Symptom relief is distinct from long-term prevention of chronic disease.





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