Timing of Estradiol Treatment After Menopause May Determine Benefit or Harm to Insulin Action.

CONTEXT: 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 (E2) directly impacts insulin action. OBJECTIVE: We hypothesized that the timing of E2 administration after menopause is an important determinant of its effect on insulin action. DESIGN: We performed a randomized, crossover, placebo-controlled study. PARTICIPANTS: 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. INTERVENTION: Study interventions included short-term (1 week) transdermal E2 and placebo. MAIN OUTCOMES AND MEASURES: The study's main outcome was insulin-mediated glucose disposal (glucose disposal rate [GDR]) via hyperinsulinemic-euglycemic clamp. RESULTS: 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 E2 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). CONCLUSIONS: There was not an apparent decline in GDR with age or time since menopause per se. However, E2 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. E2-mediated effects on insulin action may be one mechanism by which HT reduces the incidence of T2D in early postmenopausal women.

Inter- and intraindividual correlations of background abundances of (2)H, (18)O and (17)O in human urine and implications for DLW measurements.

BACKGROUND/OBJECTIVES: The method of choice for measuring total energy expenditure in free-living individuals is the doubly labeled water (DLW) method. This experiment examined the behavior of natural background isotope abundance fluctuations within and between individuals over time to assess possible methods of accounting for variations in the background isotope abundances to potentially improve the precision of the DLW measurement. SUBJECTS/METHODS: In this work, we measured natural background variations in (2)H, (18)O and (17)O in water from urine samples collected from 40 human subjects who resided in the same geographical area. Each subject provided a urine sample for 30 consecutive days. Isotopic abundances in the samples were measured using Off-Axis Integrated Cavity Output Spectroscopy. RESULTS: Autocorrelation analyses demonstrated that the background isotopes in a given individual were not temporally correlated over the time scales of typical DLW studies. Using samples obtained from different individuals on the same calendar day, cross-correlation analyses demonstrated that the background variations of different individuals were not correlated in time. However, the measured ratios of the three isotopes (2)H, (18)O and (17)O were highly correlated (R(2)=0.89-0.96). CONCLUSIONS: Although neither specific timing of DLW water studies nor intraindividual comparisons were found to be avenues for reducing the impact of background isotope abundance fluctuations on DLW studies, strong inter-isotope correlations within an individual confirm that use of a dosing ratio of 8‰:1‰ (0.6 p.p.m.: p.p.m.) optimizes DLW precision. Theoretical implications for the possible use of (17)O measurements within a DLW study require further study.

Loss of bone strength in response to exercise-induced weight loss in obese postmenopausal women: results from a pilot study.

OBJECTIVE: Exercise-induced weight loss (WL) can lead to decreased areal bone mineral density (aBMD). It is unknown whether this translates into decreased volumetric BMD (vBMD) or bone strength. The purpose of this pilot study was to determine whether exercise-induced WL results in decreased vBMD and bone strength in postmenopausal women. METHODS: Fourteen subjects participated in a 4-month endurance exercise WL intervention. A weight stable (WS) control group (n=10) was followed for 4 months. Proximal femur aBMD was measured by DXA. Femoral neck vBMD and estimates of bone strength (cross-sectional moment of inertia (CSMI) and section modulus (SM)) were measured by quantitative CT. RESULTS: Women were 54.6±2.4 years, BMI 32.1±5.9 kg/m(2) and 54.4±2.9 years, BMI 27.9±3.6 kg/m(2) in the WL and WS groups, respectively. The WL group lost 3.0±2.6 kg which was predominately fat mass. There was a significant decrease in SMmax. Changes in CSMImax and total hip aBMD were not significant. Total hip vBMD did not decrease significantly in response to WL. There were no significant changes in the WS group. CONCLUSIONS: WL may lead to decreased bone strength before changes in BMD are detected. Further studies are needed to determine whether bone-targeted exercise can preserve bone strength during WL.