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Implications for the "Timing Hypothesis"

MaryFran R. Sowers, PhD; John Randolph Jr, MD; Mary Jannausch, MS; Bill Lasley, PhD; Elizabeth Jackson, MD; Daniel McConnell, PhD

Arch Intern Med. 2008;168(19):2146-2153.

Background  The "timing hypothesis," in addressing findings from the Women's Health Initiative trial, suggests that hormone therapy (HT) should be initiated within 6 years of the menopause transition to extend a favorable estrogenic environment after menopause.

Methods  We compared sex steroid and cardiovascular profiles at the 5-year follow-up visit in a community-based, longitudinal study of the menopause transition (Study of Women's Health Across the Nation). Women aged 47 to 57 years were in 1 of 4 groups: premenopausal, women using conjugated equine estrogen with or without progestin, or postmenopausal (<5 years) without HT use. Cardiovascular assays included low-density lipoprotein cholesterol, oxidized low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoproteins A-I and B, F_2a-isoprostanes, C-reactive protein, and lipoprotein (a)-1. Sex steroid assays were performed for estradiol, estrogen receptor ligand load, 2-hydroxyestrone, 16-hydroxyestrone, total testosterone, and sex hormone–binding globulin.

Results  Users of HT had 50% higher levels of sex hormone–binding globulin (P < .001 for both HT groups), which limits binding of sex steroids to their receptors, and higher excreted estrone metabolites (more than 60%; P < .001 for both HT groups) than premenopausal or postmenopausal women. These findings were, in turn, associated with higher levels of F_2a-isoprostanes, an oxidative stress measure, than in premenopausal women. The HT users had a more favorable ratio of high-density to low-density lipoprotein cholesterol than did premenopausal or postmenopausal women (P < .01), but higher triglyceride levels (P < .01).

Conclusion  Although HT users had some more favorable lipid profiles than premenopausal and postmenopausal women, there was evidence of adverse HT effects even in women free of atherosclerosis studied within the approximate 6-year period proposed with the timing hypothesis.

Author Affiliations: Department of Epidemiology, School of Public Health (Drs Sowers and McConnell and Ms Jannausch), and Division of Cardiology, Department of Internal Medicine (Dr Jackson), University of Michigan, and Department of Obstetrics and Gynecology, University of Michigan Health Sciences System (Dr Randolph), Ann Arbor; and Center for Health and the Environment, University of California, Davis (Dr Lasley).

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