Summary
Sriprasert et al. [1] performed a post hoc analysis of a United States multicenter randomized clinical trial (REPLENISH trial) in order to identify the association between the dose of estradiol (E2) and serum E2 levels and metabolic parameters among early (<6 years; n=1,216) as compared to late (≥10 years, n=297) postmenopausal women. To this end, four doses of TX-001HR (a new oral formulation of combined E2 and progesterone [P4]) were tested against placebo. Linear mixed-effects models adjusted for P4 levels were used to verify the associations between E2 (dose and serum levels) and changes in the levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and glucose measured at six visits over 12 months.
They found that higher E2 doses and serum E2 levels were significantly related to lower TC and LDL-C and higher HDL-C levels in early but not in late postmenopausal women. These associations weakened with longer time since menopause onset. Higher E2 serum levels were also associated with lower fasting glucose and higher TG levels in early postmenopausal women. The authors concluded that the dose of E2 differentially affects metabolic measures among early compared with late postmenopausal women, supporting the timing hypothesis of the benefits of E2 therapy on cardiovascular disease risk.
Commentary
During the menopausal transition, due to a decline in ovarian function and estrogen secretion, women are subject to bio-psycho and social changes that can impair their quality of life. More importantly, after menopause, cardiovascular risk increases significantly, partly due to estrogen deprivation. Moreover, an increase in weight and other factors (i.e sedentary lifestyle, dietary habits, etc) negatively impact metabolic parameters, making women more susceptible to cardiovascular events. Various studies suggest that estrogens have positive effects on female lipid profile and vasculature due to their antioxidant effect [2], gene modulation expression [3] and regulation of the inflammatory pathway [4]. Despite this evidence, women and professionals are still reluctant to use menopausal hormone treatment (MHT), especially when cardiovascular risk factors such as obesity, hypertension, diabetes, and smoking, are present. Although cardiovascular disease is the leading cause of death in women after menopause, many require MHT, especially those who are symptomatic and in the early postmenopausal stage.
The present post hoc analysis by Sriprasert et al. [1] clearly demonstrates the beneficial role of estrogen given in early postmenopausal women (<6 years since menopause) on surrogate markers for cardiovascular disease (lipid profile and glucose). The E2 dose effect on lipid levels of the Sriprasert study is consistent with the blood level-dependent E2 effect on changes in lipid levels reported from a meta-analysis that compared the impact of conventional and low dose MHT on coronary heart disease risk factors among 3,360 women [5]. These findings may in part explain why E2 has beneficial effects of in early, but not late, postmenopausal women, as others have reported [6]. According to the MHT timing hypothesis, women benefit more from therapy when initiated closer to menopause, i.e. when the vasculature is still relatively healthy and less affected by atherosclerosis. This study supports the concept that favourable changes in lipid and glucose levels, especially LDL-C and HDL-C, may underlie the beneficial effect of MHT, highlighting the importance that timing is critical for its initiation. Nonetheless, there is a need for further studies to explain the biological mechanisms that may underlie the differential effects of E2 dose and E2 levels on metabolic measures in early compared to late postmenopausal women.
Danny Salazar-Pousada
Instituto de Investigación e Innovación en Salud Integral
Universidad Católica de Santiago de Guayaquil, Guayaquil Ecuador
References
- Sriprasert I, Hodis HN, Bernick B, Mirkin S, Mack WJ. Effects of Estradiol Dose and Serum Estradiol Levels on Metabolic Measures in Early and Late Postmenopausal Women in the REPLENISH Trial. J Womens Health (Larchmt). 2020;29(8):1052-1058.
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https://pubmed.ncbi.nlm.nih.gov/25514104/ - Hodis HN, Mack WJ, Henderson VW, et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N Engl J Med 2016;374(13):1221–1231.
https://pubmed.ncbi.nlm.nih.gov/27028912/
