Levels of Sex Steroid and Cardiovascular Disease Measures in Premenopausal and Hormone-Treated Women at Midlife Implications for the “Timing Hypothesis”

Abstract

Data in the Women’s Health Initiative (WHI) and the Heart and Estrogen/Progestin Replacement Study demonstrated that exogenous hormone products were not cardioprotective and led to alternative explanations for underlying cardioprotection in women relative to men at midlife. One such alternative, the “timing hypothesis,” suggests that initiation of hormone therapy (HT) within 6 years of the menopausal transition may help sustain an estrogenic environment after menopause favorable to lipid or cardiovascular profiles. To test this hypothesis, the investigators examined sex steroid and cardiovascular profiles at the 5-year follow-up visit of 2606 women enrolled in the Study of Women’s Health Across the Nation, a longitudinal study of menopausal transition. Women were divided into one of four groups: premenopausal, women using conjugated equine estrogen with or without progestin, and postmenopausal (<5 years) without use of HT. The cardiovascular profile was examined by measurement of high- and low-density lipoprotein cholesterol, oxidized low-density lipoprotein cholesterol, apolipoproteins A-I and B, triglycerides, F2a-isoprostanes, lipoprotein (a)-1, and C-reactive protein. The sex steroid profile was determined by measurement of estradiol, estrogen receptor ligand load, 2-hydroxyestrone, 16α-hydroxyestrone, total testosterone, and sex hormone–binding globulin. Compared to premenopausal or postmenopausal women, levels of sex hormone—binding globulin were 50% higher (P < .01 for both HT groups), which limits sex steroid binding to their receptors. Similarly, estrone metabolite excretion was more than 60% higher among HT users than premenopausal or postmenopausal women (P < .01 for both HT groups). Levels of F2a-isoprostane, a measure of oxidative stress, were higher in women using the conjugated equine estrogen plus progestin preparation than in the other three groups. A more favorable ratio of high-density to low-density lipoprotein cholesterol was found among women in both HT groups than postmenopausal women (P < .01). The HT group using estrogen with progestin had a more favorable ratio than postmenopausal women (P < .01) but not premenopausal women. The triglyceride profile was less favorable in both HT groups than in either premenopausal or postmenopausal women (P < .01 for both HT groups). The investigators conclude from these findings that evidence of adverse HT effects even in women without atherosclerosis in a time frame well within the approximate 6-year period proposed by the timing hypothesis suggests careful consideration of HT use despite benefits for some lipid profiles.