title: Timing of Estradiol Treatment After Menopause May Determine Benefit or Harm to Insulin Action.
abstract: BACKGROUND
  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.
  
  
  METHODS
  We performed a randomized, crossover, placebo-controlled study.
  
  
  METHODS
  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.
  
  
  METHODS
  Study interventions included short-term (1 week) transdermal E2 and placebo.
  
  
  METHODS
  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.
authors.affiliation: Department of Medicine (T.A.S., C.B.E., R.E.V.P.), Division of Geriatric Medicine; Department of Medicine (R.I.P., B.A.C.), Division of Endocrinology, Metabolism and Diabetes; Colorado School of Public Health, Biostatistics and Informatics (P.W.), University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: R I
authors.initials: RI
authors.lastname: Pereira
authors.affiliation: Department of Medicine (T.A.S., C.B.E., R.E.V.P.), Division of Geriatric Medicine; Department of Medicine (R.I.P., B.A.C.), Division of Endocrinology, Metabolism and Diabetes; Colorado School of Public Health, Biostatistics and Informatics (P.W.), University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: B A
authors.initials: BA
authors.lastname: Casey
authors.affiliation: Department of Medicine (T.A.S., C.B.E., R.E.V.P.), Division of Geriatric Medicine; Department of Medicine (R.I.P., B.A.C.), Division of Endocrinology, Metabolism and Diabetes; Colorado School of Public Health, Biostatistics and Informatics (P.W.), University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: T A
authors.initials: TA
authors.lastname: Swibas
authors.affiliation: Department of Medicine (T.A.S., C.B.E., R.E.V.P.), Division of Geriatric Medicine; Department of Medicine (R.I.P., B.A.C.), Division of Endocrinology, Metabolism and Diabetes; Colorado School of Public Health, Biostatistics and Informatics (P.W.), University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: C B
authors.initials: CB
authors.lastname: Erickson
authors.affiliation: Department of Medicine (T.A.S., C.B.E., R.E.V.P.), Division of Geriatric Medicine; Department of Medicine (R.I.P., B.A.C.), Division of Endocrinology, Metabolism and Diabetes; Colorado School of Public Health, Biostatistics and Informatics (P.W.), University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: P
authors.initials: P
authors.lastname: Wolfe
authors.affiliation: Department of Medicine (T.A.S., C.B.E., R.E.V.P.), Division of Geriatric Medicine; Department of Medicine (R.I.P., B.A.C.), Division of Endocrinology, Metabolism and Diabetes; Colorado School of Public Health, Biostatistics and Informatics (P.W.), University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: R E
authors.initials: RE
authors.lastname: Van Pelt
mesh_terms: D050154:Adiposity; D000367:Age Factors; D000368:Aged; D001823:Body Composition; D015992:Body Mass Index; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000517:prevention & control; D004958:Estradiol / Q000627:therapeutic use*; D015914:Estrogen Replacement Therapy / Q000379:methods*; D005260:Female; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance; D008875:Middle Aged; D009043:Motor Activity; D017698:Postmenopause / Q000378:metabolism; D040242:Risk Reduction Behavior; D016896:Treatment Outcome
chemical_list: D004958:Estradiol; D005947:Glucose