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Timing hypothesis for postmenopausal hormone therapy: its origin, current status, and future

Clarkson, Thomas B. DVM; Meléndez, Giselle C. MD; Appt, Susan E. DVM

doi: 10.1097/gme.0b013e3182843aad
Invited Review

Objective This work aims to review preclinical/clinical cardiovascular studies that led to randomized trials of the risks and benefits of postmenopausal hormone therapy (HT), the pathobiological basis for the timing hypothesis, and subset analyses of randomized trials that tend to support the timing hypothesis; to elaborate experimental data that might inform the results of recent trials; and to summarize evidence regarding how early is early enough for the initiation of HT.

Methods This work used interpretive literature review.

Results Preclinical and large observational studies provided what was considered at the time to be convincing evidence that HT provided protection against progressing coronary artery atherosclerosis. Those findings prompted three randomized, placebo-controlled, prospective trials to determine the risks and benefits of HT. None provided any evidence that HT had any beneficial effects on preexisting coronary artery atherosclerosis. Monkey studies provided clear evidence that HT was effective in slowing the progression of coronary artery atherosclerosis only when administered soon after surgical menopause and that benefit was lost if estrogen therapy was delayed until the plaques had become complicated. The phenomenon was referred to as the “timing hypothesis,” and evidence for its translation into postmenopausal women was sought in subset analyses of data from the Women’s Health Initiative and from newly planned prospective trials.

Conclusions Current data are both supportive and not supportive of the timing hypothesis. However, evidence indicating that estrogens administered in the perimenopausal transition or early in menopause are not harmful to the cardiovascular system and, when given for a few years for the treatment of menopausal symptoms, may slow the progression of atherosclerosis and reduce the postmenopausal cardiovascular disease burden seems convincing.

From the Center for Comparative Medicine and Research, Wake Forest University School of Medicine, Winston-Salem, NC.

Received October 30, 2012; revised and accepted December 20, 2012.

Financial disclosure/conflicts of interest: T.B.C. serves in the advisory committee of Pfizer and has current grants from Pfizer and Merck. S.E.A. participates in the grant from Merck. G.C.M. is a Wake-Merck Cardiovascular Research Fellow supported by a grant from Merck.

Address correspondence to: Thomas B. Clarkson, DVM, Department of Pathology/Comparative Medicine, Center for Comparative Medicine and Research, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1040. E-mail:

© 2013 by The North American Menopause Society.