Timing of Estradiol Treatment after Menopause Determines Benefit or Harm to Insulin Action

Presentation Number: OR15-5
Date of Presentation: March 6th, 2015

Rocio Ines Pereira*1, Beret Ann Casey2, Tracy Swibas1 and Rachael E Van Pelt1
1University of Colorado Anschutz Medical Campus, Aurora, CO, 2Essentia Health. Wisconsin-Minnesota., Ashland, WI


New incidence of Type 2 diabetes (T2D) is reduced by 30% in postmenopausal women randomized to estrogen-based hormone therapy (HT) compared with placebo. T2D risk reduction is particularly strong when women are treated with HT early after menopause (aged 50-59y, <10yrs past menopause), suggesting that timing of treatment may be important. Insulin action, specifically insulin-mediated glucose disposal rate (GDR), is a key determinant of T2D risk and overall cardiometabolic health, and well-controlled studies indicate that estrogens directly impact insulin action. Consistent with this, our previous studies showed that estradiol (E2) improved insulin action in postmenopausal women, but secondary analyses suggested E2 had the opposite effect (decreased insulin action) in those who were many years beyond menopause. Based on our previous observation we hypothesized that the timing of E2 administration after menopause is an important determinant of its effect on insulin action. To test this hypothesis we studied 42 women (n=21/group) who had never used HT and were either early postmenopausal (EPM; ≤6 yr of final menses) or late postmenopausal (LPM; ≥10 yr since last menses). We measured GDR via hyperinsulinemic-euglycemic clamp after 1 week of transdermal E2 and placebo in a randomized, cross-over design. Compared to EPM, LPM were older (mean±SD; 63±3 vs 56±4 yr, p<0.05) and more years past menopause (12±2 vs 3±2 yr, p<0.05). Body mass index (25±3 vs 24±3 kg/m2) and fat mass (24±6 vs 23±6 kg) did not differ between groups, but fat-free mass (FFM) was lower in LPM compared to EPM (41±4 vs 44±5 kg, p<0.05). Baseline GDR did not differ between groups (11.5±3.0 vs. 11.4±2.8 mg/kg FFM/min). In support of our hypothesis, 1 week of E2 increased GDR in EPM, but decreased GDR in LPM (+0.57±1.7 vs -0.58±1.8 mg/kg FFM/min, p<0.05). Taken together, our data demonstrated that there was not an inevitable decline in insulin action with age or time since menopause per se. However, E2 action on GDR was dependent on time since menopause, such that there was a benefit early (≤6 yr) in menopause but harm later (≥10 yr) in menopause. E2-mediated effects on insulin action may be one mechanism by which HT reduces the incidence of T2D in early postmenopausal women.


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