Timing Estrogen After MenoPaUSe (TEMPUS)

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.

Postmenopausal women more than 10 years since last menses who never used estrogen-based hormone therapy

Estrogen mediated change in glucose disposal rate and time since menopause Baseline GDR (no difference between groups) E2 mediated change (significant difference between groups) randomized order of testing, cross-over design

Estrogen receptors (ERα and ERβ) differences in time since menopause and estrogen treatment randomized order of testing, cross-over design

Estrogen receptors (ERα and ERβ) differences in time since menopause and estrogen treatment randomized order of testing, cross-over design

Adipose tissue estrogen receptor expression associated with age and menopause Abdominal and femoral subcutaneous adipose tissue ERα and ERβ expression

Adipose tissue estrogen receptor expression associated with age and menopause Abdominal and femoral subcutaneous adipose tissue ratio of ERα:ERβ expression

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)

Van Pelt RE, Schwartz RS, Kohrt WM. Insulin secretion and clearance after subacute estradiol administration in postmenopausal women. J Clin Endocrinol Metab. 2008 Feb;93(2):484-90. doi: 10.1210/jc.2007-1657. Epub 2007 Nov 6.

Kanaya AM, Herrington D, Vittinghoff E, Lin F, Grady D, Bittner V, Cauley JA, Barrett-Connor E; Heart and Estrogen/progestin Replacement Study. Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2003 Jan 7;138(1):1-9. doi: 10.7326/0003-4819-138-1-200301070-00005.

Bonds DE, Lasser N, Qi L, Brzyski R, Caan B, Heiss G, Limacher MC, Liu JH, Mason E, Oberman A, O'Sullivan MJ, Phillips LS, Prineas RJ, Tinker L. The effect of conjugated equine oestrogen on diabetes incidence: the Women's Health Initiative randomised trial. Diabetologia. 2006 Mar;49(3):459-68. doi: 10.1007/s00125-005-0096-0. Epub 2006 Jan 27.

Margolis KL, Bonds DE, Rodabough RJ, Tinker L, Phillips LS, Allen C, Bassford T, Burke G, Torrens J, Howard BV; Women's Health Initiative Investigators. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women's Health Initiative Hormone Trial. Diabetologia. 2004 Jul;47(7):1175-1187. doi: 10.1007/s00125-004-1448-x. Epub 2004 Jul 14.

Pentti K, Tuppurainen MT, Honkanen R, Sandini L, Kroger H, Alhava E, Saarikoski S. Hormone therapy protects from diabetes: the Kuopio osteoporosis risk factor and prevention study. Eur J Endocrinol. 2009 Jun;160(6):979-83. doi: 10.1530/EJE-09-0151. Epub 2009 Mar 25.

Park YM, Keller AC, Runchey SS, Miller BF, Kohrt WM, Van Pelt RE, Kang C, Jankowski CM, Moreau KL. Acute estradiol treatment reduces skeletal muscle protein breakdown markers in early- but not late-postmenopausal women. Steroids. 2019 Jun;146:43-49. doi: 10.1016/j.steroids.2019.03.008. Epub 2019 Mar 27.

Park YM, Pereira RI, Erickson CB, Swibas TA, Cox-York KA, Van Pelt RE. Estradiol-mediated improvements in adipose tissue insulin sensitivity are related to the balance of adipose tissue estrogen receptor alpha and beta in postmenopausal women. PLoS One. 2017 May 4;12(5):e0176446. doi: 10.1371/journal.pone.0176446. eCollection 2017.

Pereira RI, Casey BA, Swibas TA, Erickson CB, Wolfe P, Van Pelt RE. Timing of Estradiol Treatment After Menopause May Determine Benefit or Harm to Insulin Action. J Clin Endocrinol Metab. 2015 Dec;100(12):4456-62. doi: 10.1210/jc.2015-3084. Epub 2015 Oct 1.