9
Although we have always known that women are not immune from atherosclerotic cardiovascular disease, they clearly enjoy a distinct advantage over men. Heart attacks and strokes are roughly three times as common in men than women below age 50, and this difference narrows but does not disappear at older ages. The relative protection of women from heart attacks, strokes, and other adverse consequences of atherosclerosis accounts for much of their distinct advantage in life expectancy, which grew from two years (48.3 to 46.3) in 1900 to 7.4 years (74.0 versus 66.6) as the heart disease pandemic crested in 1968, and has fallen to 4.7 years in 2017 as the pandemic subsided.1 This gender difference and the rise of heart attack rates in women after they reach the age of menopause raised the possibility that the female hormone estrogen might be useful in preventing or treating atherosclerotic heart disease as early as the 1960s when two doses of estrogen were tried (unsuccessfully) in men in the Coronary Drug Project.2 Estrogen had no effect, other than to stimulate unwanted breast enlargement.
The relative protection of younger women from atherosclerosis also meant that they were excluded from most clinical cardiovascular trials in the 1960s and 1970s—at least those focused on patients without pre-existing cardiovascular disease. While this was understandable in view of the constraints on clinical trials to choose high-risk participants to keep the sample size and costs down, it meant that heart disease in women received little attention. However, by 1990, atherosclerosis was no longer seen as the natural and inevitable consequence of aging, and seniors—particularly older women—were increasingly viewed as prime targets for health interventions.
In the mid–1970s, analyses of epidemiologic studies began to report a strong association of menopausal hormone therapy and strikingly reduced rates of cardiovascular events and mortality.3 In a meta-analysis of 16 studies, all but one (Framingham) found that post-menopausal estrogen users enjoyed significantly lower rates of cardiovascular events and deaths than non-users; the average estimated risk reduction was a whopping 44%.4 While estrogen used by itself can cause uterine cancer, this risk does not exist in women who have undergone hysterectomy and can be mitigated in women who still have their uterus by co-administering progesterone.5 Estrogen also has favorable effects on other cardiovascular risk factors, specifically HDL cholesterol, which is typically 10 mg/dL higher in White women than in White men below age 45, a difference that becomes less pronounced after age 50.6 Now, I have already shown several examples illustrating the need for extreme caution in uncritically applying observational associations to clinical practice, especially when it comes to comparing persons who voluntarily decide to seek or not to seek a drug prescription for a particular condition. The NIH had appointed a task force to consider options for clinical trials of hormones and women’s health as early as 1983. By 1990, the time was clearly ripe to put the hypothesis that menopausal hormone therapy could reduce cardiovascular risk to the test.
The politics were also ripe for clinical trials in women’s health. In the late 1980s, Congress had grown justifiably critical of the NIH for neglecting women in its cardiovascular research portfolio and urged the development of new initiatives that focused on cardiovascular disease in women. Accordingly, one of my colleagues, Irma Mebane, developed the Postmenopausal Estrogen/Progestin Intervention Trial (PEPI), a short-term (three-year) trial in 875 healthy postmenopausal women, which compared the effects of five different combinations of estrogen and progestin and a placebo on a constellation of cardiovascular risk factors, notably HDL cholesterol.7 In 1995, PEPI concluded that conjugated equine estrogen (Premarin) was optimal for women who had undergone a hysterectomy, and that cyclic micronized progesterone should be added for women who had not. In 1990, the NHLBI launched a two-year pilot study (under my lead) for a statin trial in seniors, the majority of whom would be women.8 The Cholesterol Reduction In Seniors Program (CRISP) eventually led to the incorporation of a 10,000-patient statin trial as a partial factorial component in the ALLHAT BP trial (see Chapter 4).9 Finally, and most importantly, another NHLBI colleague, Jacque Rossouw, developed an initiative for a new large primary clinical endpoint trial of menopausal hormone therapy in healthy postmenopausal women.10 An investigator-initiated secondary prevention trial in women with pre-existing cardiovascular disease was being considered for funding at about the same time but was rejected and later picked up by Wyeth-Ayerst as the Heart and Estrogen/Progestin Replacement Study (HERS), which randomized 2763 women with known cardiovascular disease.11 Then, in 1991, Bernadine Healy, who had just been appointed by President George H.W. Bush as the first female NIH Director, reassigned the primary prevention trial from the NHLBI to the Office of Disease Prevention in the Office of the Director of NIH. There it became the centerpiece of the $625 million Women’s Health Initiative (WHI), which announced plans in 1992 to randomize 64,500 healthy postmenopausal women into a complex partial factorial trial, which incorporated a dietary and a calcium/vitamin D supplementation trial as well as an estrogen trial, and to recruit an additional 100,000 healthy postmenopausal women into a long-term observational epidemiologic study.12
In the late 1990s, the NHLBI developed its own portfolio of small short-term menopausal hormone trials in women with known coronary artery disease, in which progression would be measured by quantitative coronary angiography, a technique in which dye is injected into the coronary circulation and atherosclerotic plaques are visualized and measured with great precision. The Women’s Angiographic Vitamin and Estrogen (WAVE) trial arose from an initiative that I developed, which also incorporated a trial of antioxidant vitamins C and E in a 2×2 factorial design.13 Two similar concurrent trials—David Herrington’s Estrogen Replacement and Atherosclerosis (ERA) trial in 309 women and Howard Hodis’s Women’s Estrogen-Progestin Lipid Lowering Hormone Atherosclerosis Regression Trial (WELL-HART) in 226 women—were conducted with NHLBI grants under my stewardship.14
Although these five trials used slightly differing drug regimens, all except HERS (which excluded women with hysterectomies) administered estrogen alone (usually Premarin) to women who had undergone hysterectomy and administered a combination of estrogen and progestin to women who still retained their uteri. The results of these trials, announced over an eight-year period from 1996 to 2004, were depressingly similar. The HERS trial announced in 1996 that menopausal hormone therapy produced no reduction in heart attacks despite an 11% mean reduction in LDL cholesterol and a 10% increase in HDL cholesterol.15 It was noted that the null effect on cardiovascular events reflected an early adverse trend that appeared to improve and reverse over time; therefore, final judgment was withheld until additional follow-up data were available. Nevertheless, null findings for angiographic progression from the ERA (1998) and WAVE (2002) trials dampened expectations. Still, everyone eagerly awaited the results from the far larger WHI, which (unlike HERS) included women with prior hysterectomy who were treated with estrogen only and would be the first trial to address primary prevention in women who did not already have known cardiovascular disease.
The first shoe dropped in 2002 when the combined estrogen-progestin treatment component of the WHI in 16,608 women with intact uteri was stopped early, after completing 5.2 of its planned 8.5-year duration, due to a net adverse effect on health outcomes in the women who received active menopausal hormone therapy relative to placebo.16 The significant adverse trends included not only a 29% increase in coronary events (mainly heart attacks), but also a 26% increase in breast cancer, a 41% increase in stroke, a 113% increase in pulmonary embolism (a life-threatening complication that occurs when a portion of a blood clot that forms in the deep calf veins breaks off and lodges in the pulmonary circulation), and a 22% combined increase in all adverse cardiovascular events. Partially offsetting significant beneficial trends were reported in the incidence of colorectal cancer (34% decrease), endometrial cancer (17% decrease), and hip fractures (34% decrease). Although menopausal hormone-treated women did not suffer a significant net increase in total cancers or deaths from all causes, they suffered a significant 15% worsening in their “global health index,” a composite of major health outcomes selected for their gravity, which was defined in advance by the WHI investigators in their study protocol. Translating these results into absolute risk per 10,000 persons years of estrogen plus progestin exposure, seven extra coronary events, eight extra strokes, eight extra pulmonary emboli, and eight extra invasive breast cancers, but six fewer colorectal cancers and five fewer hip fractures were attributable to their menopausal hormone treatment. The net tradeoff was an increase of 19 global health index events—a bad deal by any reasonable accounting.
Still, the estrogen-only component of the WHI in in 10,739 postmenopausal women who had undergone hysterectomies continued, and there was still hope that estrogen would be beneficial in this setting. The HERS follow-up results, published in the same month (July 2002) as the first installment of the WHI, reported no continuation of the positive late trend seen in their 1998 report and thereby effectively put the final nail in the coffin of combined estrogen-progestin menopausal hormone therapy.17 Negative results from the WELL-HART angiographic trial in 2003 were not encouraging. Finally, in April 2004, the second and last shoe dropped. The estrogen-only component of the WHI was stopped early after 6.8 of its planned 8.5 years of follow-up due to futility—meaning that the study’s external data and safety monitoring board had determined that there was no discernable overall benefit or harm of estrogen therapy and that there was no realistic possibility that a significant trend would emerge in the remaining 1.7 years of planned follow-up.18 The only statistically significant results (expressed as absolute attributable risk) were eight extra strokes and six fewer hip fractures per 10,000 person-years of exposure to estrogen, with no meaningful change in global risk index. However, estrogen-treated women had a nearly significant 23% decrease in breast cancer, in contrast to the significant 26% increase associated with combined estrogen-progestin treatment in the WHI cohort with intact uteri. This intriguing difference may represent the play of chance. So, from the perspective of cardiovascular and other major health outcomes, estrogen therapy after hysterectomy is a wash.
While these generally negative results sorely disappointed the many proponents of menopausal hormone therapy, their importance to the public health and to the cause of women’s health ought not be underestimated. By the mid–1990s (before the HERS results were announced), as many as 40% of U.S. women were prescribed hormone therapy at menopause, in part because of its hypothetical cardiovascular benefits.19 In addition, hormone therapy was increasingly being prescribed in women well past their menopause. In 2004, Buist et al. reported a 46% decline (14.6% to 7.9%) in the prevalence of women taking estrogen plus progestin and a 28% decline (12.6% to 9.1%) in the prevalence of women taking estrogen only between 1999 and 2002 in a cohort of 169,586 40- to 80-year-old women.20 The decrease was driven mostly by 13.8% of women discontinuing their hormone therapy after the initial WHI results were announced in October 2002. Menopausal hormone use continued to decline rapidly over the next five years. A 2011 survey of office-based physicians reported a 63% decline in menopausal hormone use in the U.S. from 16.3 million women in 2001 to 6.1 million in 2009.21 This decline was more reflective of the discontinuation of menopausal hormone therapy among older longtime users of than of reduced usage by younger newly menopausal women. A 2014 modeling study calculated that 126,000 breast cancers and 76,000 cardiovascular disease events were prevented because of the WHI.22 Despite the 263,000 fractures that might have been prevented by hormone therapy, the WHI results were estimated to have added 145,000 quality-adjusted years of life and saved more $37.1 billion in net costs—a 140-fold return on the investment in the WHI. In short, the WHI and other menopausal hormone trials had a profound effect on clinical practice. While short-term menopausal hormone therapy is still appropriate for women with significant vasomotor menopausal symptoms, especially following hysterectomy, long-term menopausal hormone therapy is no longer justified.23
The Women’s Health Initiative did not end in 2004. The participants in both the randomized trial and observational studies continue to be followed. A 2013 report from the two menopausal hormone treatment trials confirmed the trends seen in the active treatment phase, albeit with some narrowing (as expected in any long-term follow-up) of the in-trial differences.24 The results of the WHI diet trial will be covered in Chapter 14. The WHI has also spawned several spinoffs, like the WHI Memory Study (WHIMS) in the hormone trial cohort and the WHI Strong and Healthy (WHISH) exercise study, which also leverages the WHI observational study cohort.25
Impact of Menopausal Hormone Therapy on the Decline in Heart Attack Mortality
Menopausal hormone therapy offers no apparent cardioprotective effect and therefore has not contributed to the decline in cardiovascular mortality since 1960. One may speculate that the growing popularity of menopausal hormone therapy in 1975–95 may have acted as a slight drag on the early decline of heart attack and stroke mortality and that the subsequent fall-off in menopausal therapy prescriptions in 1995–2009 may have slightly accelerated this decline, but these offsetting effects are probably negligible. The peak popularity of menopausal hormone therapy was mainly in women in their 50s and early 60s (whose contribution to overall mortality is relatively small), and their absolute excess risk in WHI was only seven heart attacks and eight strokes per 10,000 women treated with estrogen plus progestin and zero for women treated with estrogen only. Ford et al. appropriately did not include menopausal hormone therapy in their IMPACT model of the decline in heart attack mortality.26
1. L Medina, S Sabo, J Vespa. Living Longer: Historical and Projected Life Expectancy in the United States, 1960–2060. Population Estimates and Projections. Current Population Reports. February 2020. https://www.census.gov/content/dam/Census/library/publications/2020/demo/p25-1145.pdf.
2. The Coronary Drug Project. Initial findings leading to modifications of its research protocol. JAMA 1970, Nov 16; 214(7):1303–1313.
3. TL Bush. Noncontraceptive estrogen use and risk of cardiovascular disease: an overview and critique of the literature. The Menopause: Biological and Clinical Consequences of Ovarian Failure, Evolution and Management. SG Korenman (ed.) Norwell, MA: Serono Symposia, USA, 1990, 211–2240.
D Grady, SM Rubin, DB Petiti, CS Fox, D Black, B Ettinger, VL Ernster, SR Cummings. Hormone therapy to prevent disease and prolog life in postmenopausal women. Ann Intern Med 1992; 117:1016–1037.
4. MJ Stampfer, GA Colditz. Estrogen replacement and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med 1991; 20:47–63.
5. American Cancer Society. Menopausal hormone therapy and cancer risk. https://www.cancer.org/cancer/cancer-causes/medical-treatments/menopausal-hormone-replacement-therapy-and-cancer-risk.html.
6. HA Tyroler, CJ Glueck, B Christenson, PO Kwiterovich. Plasma high density lipoprotein cholesterol comparisons in black and white populations. The Lipid Research Clinics Prevalence Study. Circulation 1980; 62(suppl IV):99–107.
7. JC LaRosa, W Applegate, JR Crouse, D Hunninghake, R Grimm, R Knopp, J Eckfelt, CE Davis, DJ Gordon. Cholesterol lowering in the elderly: Results of the Cholesterol Reduction in Seniors Program (CRISP) pilot study. Arch Int Med 1994; 154:529–539.
8. The ALLHAT Officers and Coordinators for the ALLHAT Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin versus usual care: The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial. JAMA 2002; 288:2998–3007
9. The Writing Group for the PEPI Trial. Effects of Estrogen or Estrogen/Progestin Regimens on Heart Disease Risk Factors in Postmenopausal Women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995; 273:199–208.
10. JE Rossouw, LP Finnegan, WR Harlan, VW Pinn, C Clifford, JA McGowan. The evolution of the Women’s Health Initiative: perspectives from the NIH. J Am Med Women’s Assoc 1995; 50:50–55.
11. S Hulley, D Grady, T Bush, C Furberg, D Herrington, B Riggs, E Vittinghoff, for the Heart and Estrogen/Progestin Replacement Study (HERS) research group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280:605–613.
12. The Women’s Health Initiative Study Group. Design of the Women’s Health Initiative Clinical Trial and Observational Study. Controlled Clin Trials 1998; 19:61–109.
13. DB Waters, EL Alderman, J Hsia, BV Howard, FR Cobb, WJ Rogers, P Ouyang, P Thompson, JC Tardif, L Higginson, V Bittner, M Steffes, DJ Gordon, M Proschan, N Younnes, J Verter. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women. JAMA 2002; 288:2432–2440.
14. DM Herrington, DM Reboussin, B Brosnihan, PC Sharp, SA Schumaker, TE Snyder, CD Furberg, GJ Kowalchuk, TD Stuckey, WJ Rogers, DH Givens, D Waters. Effects of estrogen replacement on the progression of coronary artery atherosclerosis. N Engl J Med 2000; 343:522–529.
HN Hodis, WJ Mack, SP Azen, RA Lobo, D Shoupe, PR Mahrer, DP Faxon, L Cashin-Hemphill, ME Sanmarco, WJ French, TL Shook, TD Gardner, AO Mehra, R Rabbani, A Sevanian, AB Shil, M Torres, KH Vogelbach, RH Selzer, for the Women’s Estrogen/Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial.
15. DB Petiti. Hormone replacement therapy for prevention. More evidence, more pessimism. JAMA 2002; 288:99–101.
16. Writing Group for the Women’s Health Study. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321–333.
17. D Grady, D Herrington, V Bittner, R Blumenthal, M Davidson, M Hlatky, J Hsia, S Hulley, A Herd, S Khan, IK Newby, D Waters, E Vittinghoff, N Wenger, for the HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/Progestin Replacement Study follow-up (HERS II). JAMA 2002; 288:49–57.
18. The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women’s Health Initiative randomized controlled trial. JAMA 2004; 291:1701–1712.
19. E Nabel. The Women’s Health Initiative—a victory for women and their health. JAMA 2013; 310:1349–1350.
20. DS Buist, KM Newton, DL Miglioretti, K Beverly, MT Connelly, S Andrade, CL Hartsfield, F Wei, A Chan, L Kessler. Hormone therapy prescribing patterns in the United States. Osbtet Gynecol 2004; 104:1042–1050.
21. SA Tsai, ML Stefanik, RS Stafford. Trends in menopausal hormone therapy use of U.S. office-based physicians, 2000–2009. Menopause 2011; 18:285–392.
22. JA Roth, R Etzioni, TM Waters, M Pettinger, JE Rossouw, GL Anderson, RT Chlebowski, JE Manson, M Hlatky, KC Johnson, SD Ramsey. Economic return from the Women’s Health Initiative estrogen plus progestin clinical trial: a modeling study. Ann Intern Med 2014, May 6; 160(9):594–602. doi: 10.7326/M13–2348.
23. U.S. Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute. Facts about Menopausal Hormone Therapy. NIH Publication No. 05–5200 (June 2005 Revision). https://www.nhlbi.nih.gov/files/docs/pht_facts.pdf.
24. JE Manson, RT Chebowski, ML Stefanick, AK Aragaki, JE Rossouw, RL Prentice, G Anderson, BV Howard, CA Thomson, AZ LaCroix, J Wactawski-Wende, RD Jackson, M Limacher, KL Margolis, S Wasserthal-Smoller, SA Beresford, JA Cauley, CB Eaton, M Gass, J Hsia, KC Johnson, C Kooperberg, LH Kuller, CE Lewis, S Liu, LW Martin, JK Ockene, MJ O’Sullivan, LH Powell, MS Simon, L Van Horn, MZ Vitolina, RB Wallace. Menopausal hormone therapy and health outcomes during the intervention and extended post-stopping phases of the Women’s Health Initiative randomized trials. JAMA 2013; 310:1353–1368.
25. ClinicalTrials.gov. The Women’s Health Initiative Memory Study (The WHIMS Study). https://clinicaltrials.gov/ct2/show/NCT00685009?term=women%27s+health+initiative&draw=2&rank=1.
ClinicalTrials.gov. The Women’s Health Strong and Healthy Study (The WHISH Study). https://clinicaltrials.gov/ct2/show/NCT02425345?term=women%27s+health+initiative&draw=1&rank=3.
26. ES Ford, UA Ajani, JB Croft, JA Critchley, DR Labarth, TE Kottke, WH Giles, S Capewell. Explaining the Decrease in U.S. Deaths from Coronary Disease, 1980–2000. N Engl J Med 2007; 356:2388–2398. DOI: 10.1056/NEJMsa053935.