The “timing hypothesis”, in addressing findings from the Women’s Health Initiative trial, suggests that hormone therapy (HT) use should be initiated within six years of the menopause transition to extend a favorable estrogenic environment after menopause.
We compared sex steroid and cardiovascular profiles at visit 05 in a community-based, longitudinal study of the menopause transition (Study of Women’s Health Across the Nation). Women, aged 47–57 years, were in one of four groups: premenopausal, using conjugated equine estrogen (CEE) with or without progestin, or postmenopausal (<5 years). Cardiovascular assays included low density lipoprotein cholesterol (LDL-c), oxidized LDL-c, high density lipoprotein cholesterol (HDL-c), triglycerides, apolipoproteins A-1 and B, F2a-isoprostanes, C-reactive protein (CRP), and lipoprotein(a)-1. Sex steroid assays were for estradiol (E2), estrogen receptor ligand load (ERLL), 2-hydroxyestrone (2-OHE1), 16α-hydroxyestrone (16α-OHE1), total testosterone, and sex hormone-binding globulin (SHBG).
HT users had 50% higher SHBG levels (p<0.0001 for both groups), which limits sex steroids binding to their receptors, and higher excreted estrone metabolites (more than 60%, p<0.0001 for both groups) than pre- or postmenopausal women. These were, in turn, associated with higher F2a-isoprostanes, an oxidative stress measure, compared to premenopausal women. HT users had a more favorable HDL-c/LDL-c ratio than pre- or postmenopausal women (p<0.01), but higher triglyceride levels (p<0.01).
Though HT users had some more favorable lipid profiles than pre- and postmenopausal women, there was evidence of adverse HT effects even in women free of atherosclerosis evaluated within the approximate 6-year time period proposed with the “timing hypothesis”.