The Women's Health Initiative tells us more about what estrogen can and cannot do but does not give us the answer.

T he Women’s Health Initiative (WHI) has told us a lot about postmenopausal women and the effects of conjugated estrogens and medroxyprogesterone on those women. Beginning with the sea change that occurred in July 2002 when the hormone therapy portion of the WHI was suspended early because the outcomes transgressed safety monitoring standards previously set, analysis of the data has drawn conclusion after conclusion about hormone therapy and its consequences. In addition, there have been multiple reports about lifestyle. A review of either the WHI participant Web site (WHI.org) or the WHI scientific resources Web site (www.whiscience.org) is an accessible way to get an overall sense of the extensive body of research that the WHI has produced. The study by Michael et al in this month’s Menopause looks at three performance-based measures of physical function in a generous sample of each of the four arms of the WHI randomized to hormones and no hormones. The women were 65 years or older and followed for 6 years. Their grip strength, chair stand, and 6-meter walking were measured at 1, 3, and 6 years. No surprise, all these measures deteriorated for all participants over time. Why does it matter that estrogen does not attenuate (or accentuate) the inevitable decline in physical function charted in this group of postmenopausal women? Primarily, there is a correlation between physical function and overall disability as women age. As function deteriorates, so does ability to maintain function. (If you cannot complete a daily walk, then the benefits of the exercise a daily walk provides is unattainable). As menopause scientists, we want to know the truth about the relation between estrogen and the physiology and facts of aging. Why might we expect hormone therapy to influence the parameters studied? As in many areas addressing the effects of HT on postmenopausal women, the studies to date are conflicting. Greenspan et al studied HT in older women and showed no difference in physical decline in 3 years compared with placebo. Sipila et al looked at data from the Evergreen Study in Finland and correlated endogenous estrogen levels and greater muscle strength with reduced fracture incidence irrespective of bone density. The women with higher endogenous estrogens seemed to be stronger, and a recent community-based cross-sectional study from Taiwan published in this journal looked at grip strength in women who were postmenopausal compared with those who were premenopausal or perimenopausal. This article reports with statistical assurance that menopause status (and, presumably, estrogen levels) is Ban independent predictor of decreased muscle strength and balance. [ However, the current study does not show that estrogen or estrogen and progestogen make any difference on the three parameters of physical function followed in WHI participants. One baffling finding in the current study that the authors dismissed Bgiven the fact that the effect modification by race was not proposed a priori[ was improved grip strength associated with estrogen plus progestin therapy in nonwhite women. Interestingly enough, a similar result was previously published from the Study of Women Across the Nation, where Ba significant HT-by-race interaction for grip strength was found; African-American HT users had greater grip strength during the study, whereas white HT users did not (P = 0.05). [ Can someone explain this? Almost 49,000 women participated in the WHI, along with academics and researchers too numerous to count. According to one Web-based source, 415 million tax dollars were spent; and another suggested a billion. Others have addressed flaws in its design. In addition, this massive study has continued to uncover misconceptions, raise questions, and most of all, demonstrate the complexity of the relation between estrogen and the human female organism. Apar Kishor Ganti entitles his editorial accompanying the recent Lancet article about estrogen + progestin therapy being associated with more aggressive lung cancer BAnother Nail in the Coffin for Hormone Replacement Therapy. [ I would say that the WHI continues to tell us more about what estrogen can and cannot do but has only scratched the surface in answering questions about this potent hormone’s role in female aging and its therapeutic harms and benefits for our individual patients. The brochure recruiting for the WHI invited women to Bbe a part of the answer,[ but there are many, many more questions.