title: Addition of medroxyprogesterone acetate to conjugated equine estrogens results in insulin resistance in adipose tissue.
abstract: The purpose of this study was to determine if the insulin resistance we have previously reported in surgically postmenopausal primates treated with combined hormone therapy (HT) is due in part to effects on adipose tissue. Eighty-seven ovariectomized monkeys were fed a moderately atherogenic diet (0.28 mg cholesterol per kilocalorie [0.07 mg/kJ]) and randomized to receive no hormones (control, n = 29), estrogen therapy (ET, conjugated equine estrogens, 0.625 mg/d human equivalent; n = 29), or HT (ET + medroxyprogesterone acetate, 2.5 mg/d human equivalent; n = 29) in the diet for 2 years. Fasting glycemic measures were made at baseline and at the end of treatment. Circulating adiponectin measures, insulin tolerance tests, glucose tolerance tests, and isolated adipocyte glucose uptake assays were performed at the end of the trial. Hormone therapy-treated animals were insulin resistant, as determined by greater fasting insulin concentrations (P = .008), greater homeostasis model assessment of insulin resistance (HOMA-R) value (P = .005) and slower glucose disposal after insulin administration (K(ITT); P = .02) when compared with controls. Subcutaneous adipocytes from HT-treated monkeys had a greater ED(50) for insulin (P = .04) and lower maximal glucose uptake per cell (P < .001) compared with controls, suggesting impaired adipocyte insulin sensitivity. Adipocytes were smaller (P = .001) and adiponectin concentrations were greatest in the ET group (P = .02), with no difference between controls and HT-treated monkeys. In conclusion, estrogen therapy resulted in smaller adipocyte size and greater adiponectin concentrations than control or HT. Hormone therapy resulted in impaired insulin sensitivity and adipocyte glucose uptake compared with controls, whereas there was no difference between ET and controls. Because no adverse effects were found with ET alone, it is likely that the progestin, medroxyprogesterone acetate, resulted in the negative effects of the combined HT regimen on whole-body insulin sensitivity, which were mediated, in part, by reductions in adipose tissue responses to insulin.
authors.affiliation: Department of Endocrinology, Lexicon Pharmaceuticals, The Woodlands, TX 77381, USA.
authors.forename: Melanie K
authors.initials: MK
authors.lastname: Shadoan
authors.forename: Kylie
authors.initials: K
authors.lastname: Kavanagh
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Mary S
authors.initials: MS
authors.lastname: Anthony
authors.forename: Janice D
authors.initials: JD
authors.lastname: Wagner
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001823:Body Composition; D001835:Body Weight; D015914:Estrogen Replacement Therapy; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology*; D005260:Female; D007333:Insulin Resistance; D008252:Macaca fascicularis; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*
chemical_list: D004966:Estrogens, Conjugated (USP); D017258:Medroxyprogesterone Acetate