Type 2 diabetes (T2D) is reduced in postmenopausal women randomized to estrogen-based hormone therapy (HT) compared with placebo. Insulin sensitivity is a key determinant of T2D risk and overall cardiometabolic health, and studies indicate that estradiol (E 2) directly impacts insulin action.
We hypothesized that the timing of E 2 administration after menopause is an important determinant of its effect on insulin action.
Study participants were early postmenopausal (EPM; ≤6 years of final menses; n = 22) and late postmenopausal (LPM; ≥10 years since last menses; n = 24) women naive to HT.
The study's main outcome was insulin-mediated glucose disposal (glucose disposal rate [GDR]) via hyperinsulinemic-euglycemic clamp.
Compared to EPM women, LPM women were older (mean ± SD; 63 ± 3 vs 56 ± 4 years, P < .05) and more years past menopause (12 ± 2 vs 3 ± 2 years, P < .05). Body mass index (24 ± 3 vs 25 ± 7 kg/m 2) and fat mass (25 ± 7 vs 23 ± 6 kg) did not differ between groups, but fat-free mass (FFM) was lower in LPM women compared to EPM women (40 ± 4 vs 43 ± 5 kg, P < .05). Baseline GDR did not differ between groups (11.7 ± 2.8 vs 11.5 ± 2.9 mg/kg FFM/min). In support of our hypothesis, 1 week of E 2 decreased GDR in LPM women compared to an increase in EPM women (+0.44 ± 1.7 vs − 0.76 ± 2.1 mg/kg FFM/min, P < .05).
There was not an apparent decline in GDR with age or time since menopause per se. However, E 2 action on GDR was dependent on time since menopause, such that there was an apparent benefit early (≤6 years) compared to harm later (≥10 years) in menopause. E 2-mediated effects on insulin action may be one mechanism by which HT reduces the incidence of T2D in early postmenopausal women.