Issue: December 2012
December 01, 2012
6 min read

Experts discuss HT use 10 years after the Women's Health Initiative

Issue: December 2012
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Ten years have passed since the publication of the first results of the Women’s Health Initiative, which demonstrated that estrogen plus progestin increased the risk for CV complications, deep vein thrombosis and breast cancer, and estrogen alone increased the risk for stroke and deep vein thrombosis, but not CHD or cancer. Both, however, prevented fractures.

The data produced widespread uncertainty for patients and their physicians regarding the safety of hormone therapy (HT) use. Within months of the release of the results, prescribing trends decreased and have continued to decline in the United States. However, some of the dust has settled and experts have reached a consensus on the key points of HT.

Additionally, recent data from the Kronos Early Estrogen Prevention Study (KEEPS) help substantiate the role of low-dose HT in the treatment of menopausal symptoms. Although some experts said it is too early to make any concrete conclusions, there is a feeling of reassurance associated with the early results of KEEPS.

JoAnn Manson

JoAnn Manson

“The pendulum has swung from chronic disease prevention to the more appropriate place of HT reserved for the treatment of menopausal symptoms,” JoAnn Manson, MD, DrPH, NCMP, a principal investigator of the Women’s Health Initiative (WHI) and KEEPS, said of the progress made in the 10 years after the WHI. “There’s an improved understanding of the different balance of benefits and risks when HT is used for short-term symptom management vs. long-term disease prevention.”

Changing an old way of thinking

“The WHI was a landmark study and will never be replicated again in the way that it was,” Martha Gulati, MD, MS, FACC, FAHA, associate professor of medicine, division of cardiology at Ohio State University, said in an interview. “It answered, for me as a cardiologist, an important question about the safety of HT. When the results came out in 2002, they changed practice; they changed the way that we viewed HT; and they changed women’s lives.”

Martha Gulati

Martha Gulati

In the mid- to late-1990s, researchers estimated that more than one-third of postmenopausal women aged 50 to 74 years were taking HT. However, once the estrogen and progestin trial was stopped early in July 2002 and the estrogen alone trial in March 2004, HT prescribing rates began to decrease.

In a study published in Menopause in June, Bruce Ettinger, MD, emeritus clinical professor of medicine at the University of California Medical Center in San Francisco, and colleagues reported that the rate of HT utilization in the United States decreased 30% within the first year after the results of the WHI trial were released. That number continued to progressively decline, reaching a nadir of 70% reduction by 2007 and showing no change over the years 2007-2009.

Early results of KEEPS

Now, long-awaited KEEPS data suggest that HT has several benefits when administered for short-term symptomatic relief, a practice that many experts have been following for the past decade.

At the NAMS 23rd Annual Meeting in October, Manson and colleagues presented early evidence from the 4-year study suggesting that estrogen and progesterone administered shortly after menopause appeared to be safe, relieved various symptoms, and improved mood, sexual function and biomarkers for CV risk.

The double blind, placebo-controlled, randomized study tested low-dose oral or transdermal estrogen and cyclic monthly progesterone in healthy women aged 42 to 58 years who were within 3 years of their final menses at the time of randomization. Participants (n=727) were categorized into three arms, besides cyclical micronized progesterone (Prometrium, Abbott) at 200 mg per day for 12 days per month:

Researchers found that oral conjugated equine estrogens (o-CEE) and transdermal estradiol (t-E2) did not significantly affect systolic or diastolic BP, in contrast to the increased BP observed with the higher dose of CEE in the WHI. Also, o-CEE was linked to increased HDL, decreased LDL and increased triglyceride levels. The t-E2 had neutral effects on HDL, LDL and triglycerides. Additional data indicate that t-E2 improved insulin sensitivity. Additionally, menopausal symptoms such as hot flashes and night sweats were relieved, and the HT had beneficial effects on bone mineral density compared with placebo-treated patients.


During the presentation at NAMS, S. Mitchell Harman, MD, PhD, director and president of the Kronos Longevity Research Institute and chief of the endocrinology division at Phoenix VA Health Care System in Arizona, said the KEEPS results also show no significant risks or benefits of HT regarding the rates of breast cancer, endometrial cancer, MI, stroke or venous thromboembolic events. However, the study was not large enough to provide conclusive evidence on the risk of clinical events. HT also showed no significant effect on atherosclerosis progression assessed by noninvasive imaging.

The publication of the results of KEEPS is expected in late 2012 or early 2013. The investigators hope to receive a renewal of funding to continue follow-up for another 4 or 5 years and examine changes in atherosclerosis progression, cognitive function outcomes, and mammographic density or need for repeat testing with different formulations or doses.

“Overall, [these] findings underscore the importance of individualized care for women and personalized decision making about HT based on a woman’s symptoms, her underlying risk factor status, her personal preferences and her priorities for treatment,” said Manson, who is president of the North American Menopause Society (NAMS); professor of medicine and the Michael and Lee Bell professor of women’s health at Harvard Medical School; and chief of preventive medicine at Brigham and Women’s Hospital.

More data expected, needed

According to Gulati, a decade after the WHI, experts should still have a sense of reserve about HT, but it is important to be open-minded about the future and the need for additional trials. With different formulations of estrogen available, questions surrounding their efficacy and safety need answering.

“I’m open to the idea that there might be some form of estrogen that will at least not increase CV events. We need data, and we need to not be foolish. What we did to women prior to the WHI was experimenting on them; we didn’t have studies and we didn’t follow things appropriately,” she said. “We’re always taught in medicine that we need a randomized controlled trial before we make decisions, and we didn’t listen to that prior to the WHI, when HT was the No. 1 drug without any randomized trials at all.”

More data are emerging, although not from placebo-controlled randomized trials. In an October issue of the British Medical Journal, researchers in Denmark demonstrated that after 10 years of treatment with triphasic estradiol and norethisterone acetate, recently postmenopausal women (or those with perimenopausal symptoms) had a significantly reduced risk for mortality, HF and MI with no increase in risk for cancer, venous thromboembolism or stroke.

Additionally, the United States Preventive Services Task Force (USPSTF) issued a statement on Oct. 22, 2012, addressing the use of HT for the primary prevention of chronic conditions in menopause. It recommends against the use of combined estrogen and progestin for the prevention of chronic conditions in postmenopausal women. “The USPSTF concludes with high certainty that the chronic disease prevention benefits of combined estrogen and progestin do not outweigh the harms in most postmenopausal women,” the task force wrote.

Nanette K. Wenger

Nanette K. Wenger

Cardiology Today Editorial Board member Nanette K. Wenger, MD, MACC, MACP, FAHA, who is professor of medicine (cardiology) at Emory University School of Medicine, said the USPSTF and recent FDA statements agree that, based on current scientific evidence, menopausal HT is not indicated for primary or secondary prevention of CVD.

“The results of the KEEPS study relate to intermediate or surrogate, rather than clinical, outcomes, and clinical outcomes are needed,” she said. “Nonetheless, it is worth emphasizing that neither HERS nor WHI examined transdermal delivery of HIT or the lower dose of conjugated equine estrogen used in KEEPS.”


According to Wenger, “the last chapter on menopausal HT has not been written.

“Although recent data provide reassurance for low-dose, short-term HT use in newly menopausal women for relief of menopausal symptoms, this should not translate into recommendations for use of HT for the prevention of chronic conditions,” she said.

For more information:
Ettinger B. Menopause. 2012;19:610-615.
Majumdar SR. JAMA. 2004;292:1983-1988.
Manson JE. Plenary Symposium #1. Presented at: The North American Menopause Society; October 3-6, 2012; Orlando.
Pal L. Menopause. 2012;19:597-599.
Schierbeck LL. BMJ. 2012;doi:10.1136/bmj.e6409.
Steinkeller AR. Menopause. 2012;19:616-621.
Stuenkel C. Menopause. 2012;19:1-2.
The North American Menopause Society. Menopause. 2012;19:257-271.
The United States Preventive Services Task Force. Manuscript# - M12-2392.
The Women’s Health Initiative Steering Committee. JAMA. 2004;291:1701-1712.
Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.
Martha Gulati, MD, MS, FACC, FAHA, can be reached at The Ohio State University Wexner Medical Center, 473 West 12th Ave., Suite 200, Columbus, OH 43210; email:
JoAnn Manson, MD, DrPH, NCMP, can be reached at Harvard Medical School, 900 Commonwealth Ave., 3rd fl, Boston, Massachusetts 02215; email:
Nanette K. Wenger, MD, MACC, MACP, FAHA, can be reached at Emory University School of Medicine, 49 Jesse Hill Jr. Drive, SE, Atlanta, GA 30303; email:

Disclosure: Ettinger, Gulati, Manson and Wenger report no relevant financial disclosures.