New study to examine the role of estrogen

What is the role of estrogen in protecting post-menopausal women’s hearts? While recent research indicates that the hormone may not benefit cardiovascular health in older women,1-3 a group of privately funded researchers is re-examining the role of the hormone in women ages 40-55.

The Kronos Early Estrogen Prevention Study (KEEPS) trial will address whether estrogen therapy delays atherosclerosis in recently menopausal women, the group most likely to initiate hormone therapy, explains JoAnn Manson, MD, DrPH, chief of the division of preventive medicine at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston. Manson will serve as principal investigator of the new trial.

"Previous randomized trials have not focused on younger, recently menopausal women; most participants have been 10-15 years past menopause," states Manson. "Additionally, KEEPS will address the role of estrogen formulation and route of delivery by comparing transdermal estrogen to low-dose oral estrogen to placebo."

What prompted the Phoenix-based Kronos Longevity Research Institute (KLRI), a facility that focuses its clinical research on aging and age-related diseases, to undertake the KEEPS project?

"The stimulus was the sense that someone ought to do something’ to clear up the overinterpretation of the Women’s Health Institute data, which left the impression with both professional and lay public that it is now incontrovertibly clear that the risk/benefit ratio for long-term menopausal hormone therapy [MHT] is unfavorable for all women," states Mitchell Harman, MD, PhD, the institute’s director and president.

According to Harman, the WHI data only addressed the issue for women initiating estrogen relatively long after the menopause (average about 12 years); however, women decide to use MHT between ages 40-55, within six months or a year of their last period, he points out.

Results from earlier observational studies suggest that hormone therapy protects against heart disease,4 and the latest analysis from the WHI’s estrogen-only arm indicates that women ages 50 to 59 had a 44% lower risk of heart disease compared with the placebo group.2 With those findings in hand, the institute is moving forward with the KEEPS trial in an effort to settle the question of MHT use.

"The fact is that, over the next 30 years or so, many millions of women may suffer needless heart attacks and bone fractures through eschewing MHT, if, as we hypothesize, hormones initiated early do really retard development of atherosclerosis," says Harman.

Funding for the five-year KEEPS trial, which is expected to cost more than $14 million, is being underwritten by the Phoenix-based Aurora Foundation, headed by billionaire John Sperling.5 KLRI is seeking additional funding sources for additional research as part of KEEPS.

Eight centers join in

Eight centers will participate in the randomized, placebo-controlled double-blinded, prospective trial: Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center and Columbia University College of Physicians and Surgeons, both based in New York City; Harvard Medical School/ Brigham and Women’s Hospital in Boston; Mayo Clinic College of Medicine in Rochester, MN; University of California-San Francisco/ Center for Reproductive Health, San Francisco; University of Utah School of Medicine in Salt Lake City; University of Washington School of Medicine in Seattle; and Yale University College of Medicine in New Haven, CT.

Approximately 720 perimenopausal women will be recruited for the study. They will receive transdermal estrogen, oral estrogen, or placebo. The study drug regimens include:

  • a daily oral tablet containing 0.45 mg conjugated estrogens (Premarin, Wyeth, Philadelphia) and a placebo skin patch;
  • an oral placebo tablet and a skin patch delivering 50 mcg estradiol daily for 3.5 days and applied twice weekly (Vivelle-Dot, Novartis Corp., New York City);
  • a placebo tablet and a placebo skin patch.

Progestin will be administered as a transvaginal progesterone gel (Prochieve, Columbia Laboratories, Livingston, NJ) every day for the last 10 days of the artificial cycle to women receiving active estrogens. Women not receiving active estrogens will apply a placebo gel.

When will you see results?

What can clinicians and women expect to see results from the KEEPS trial? Harman offers the following timeline:

"If we can stay on schedule, women will be randomized beginning in September 2004, and with any luck, the study will fill [to] 720 women before Aug. 31, 2005," he explains. "That means the last subject will complete the study in August 2010."

Researchers will need an additional two to three months to evaluate data and prepare initial reports, so first publication of final KEEPS results may arrive in late 2010, estimates Harman.

"However, we tentatively plan to have a peek at the data after all women have completed three years, [about] August 2008," states Harman. "What, if anything, will be published at that point depends on the decision of the principal investigators." 

References

1. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. JAMA 2004; 291:1,701-1,712.

2. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003; 349:523-534.

3. Rossouw JE, Anderson GL, Prentice RL, et al. 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.

4. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses’ health study. N Engl J Med 1991; 325:756-762.

5. Powledge TM. HRT gets another chance. The Scientist, April 22, 2004. Aaccessed at: www.biomedcentral.com/news/20040422/03.