The aim of the current study is to test whether the effect of estrogen on insulin metabolism depends on the timing of treatment relative to when a woman went through menopause. The investigators hypothesize that estrogen will improve insulin sensitivity in early postmenopausal women, but decrease insulin sensitivity in late postmenopausal women.

Large clinical trials have shown a reduced incidence of type 2 diabetes in postmenopausal women randomized to estrogen-based hormone therapy compared to placebo. Moreover, studies suggest development of diabetes is reduced in postmenopausal women who used hormone therapy for a part of the postmenopausal period compared to women who never used hormone therapy. Consistent with this, our preliminary data suggest that the timing of estrogen treatment relative to the menopause may be an important determinant of whether there are favorable effects on insulin action. Our observations suggest that estrogen improves insulin sensitivity in early postmenopausal women, but may decrease insulin sensitivity in those more than 10 years past menopause. More and more studies suggest estrogens have divergent effects on cardiovascular risk when initiated close to the onset of menopause rather than distant from the menopause; we hypothesize this is also true for diabetes risk. The goal of this study is to determine whether the effects of estrogen on insulin metabolism are different in women who are early postmenopausal compared to late postmenopausal. To meet our goal, we propose to measure insulin sensitivity in women who are within 6 years of the onset of menopause or more than 10 years beyond the menopause and who have not used hormone therapy previously. All women will be studied on two separate occasions, one day with and one day without short-term (1 week) treatment with transdermal estradiol. We expect that estradiol will increase insulin sensitivity in early postmenopausal women and decrease insulin sensitivity in late postmenopausal women. We also expect that estrogen receptors in fat and muscle may change with increasing time after menopause. Thus, we will collect fat and muscle biopsies to compare changes in estrogen receptors between early and late postmenopausal women and in response to 1 week of estradiol treatment. We believe these studies will provide evidence for a benefit of estradiol on insulin sensitivity when administered early, but not late, after menopause; likely contributing to delayed onset of type 2 diabetes in postmenopausal women.

Inclusion Criteria:

• aged 45-70 yr
• postmenopausal (no menses ≥12 mo or bilateral oophorectomy and FSH >30 IU/L)
• ≤6yrs or ≥10yrs of menopause (last menses or oophorectomy)
• BMI <30 kg/m2 and weight stable (±2kg in past 2mo)
• non-smokers
• sedentary to moderately active (<3 days/wk of structured exercise)
• naïve to estrogen-based hormone therapies (previous use ≤6 months)
• CBC, CMP and TSH values within normal ranges specified by lab

Exclusion Criteria:

• underwent a partial hysterectomy (i.e., one or both ovaries left intact)
• underwent menopause (natural, chemical, or surgical) prior to age 45yr
• are between >6yr and <10yr of menopause (last menses or oophorectomy)
• previously used (>6 mo) or are currently using any formulation of estrogen-based HT (e.g., oral Premarin, transdermal 17beta-estradiol, selective estrogen receptor modulators)
• have T2DM or are being treated with glucose-lowering/ insulin sensitizing medications
• have uncontrolled hypertension (SBP>140 and/or DBP>90 mmHg)
• have hypertriglyceridemia (>400 mg/dL)
• have contraindications to estrogen therapy (history of venous thromboembolism, heart disease, myocardial infarction, hormone sensitive cancer)
• have contraindications to biopsies (severe anemia, blood clotting disorders)

4 months participants were randomized in a crossover manner, visits were separated by approximately 2 months. - 1 week of placebo/study testing - 1 week of transdermal E2/study testing.

No deaths or serious adverse events occurred in this study