title: Prenatal Testosterone Exposure Leads to Gonadal Hormone-Dependent Hyperinsulinemia and Gonadal Hormone-Independent Glucose Intolerance in Adult Male Rat Offspring.
abstract: Elevated testosterone levels during prenatal life lead to hyperandrogenism and insulin resistance in adult females. This study evaluated whether prenatal testosterone exposure leads to the development of insulin resistance in adult male rats in order to assess the influence of gonadal hormones on glucose homeostasis in these animals. Male offspring of pregnant rats treated with testosterone propionate or its vehicle (control) were examined. A subset of male offspring was orchiectomized at 7 wk of age and reared to adulthood. At 24 wk of age, fat weights, plasma testosterone, glucose homeostasis, pancreas morphology, and gastrocnemius insulin receptor (IR) beta levels were examined. The pups born to testosterone-treated mothers were smaller at birth and remained smaller through adult life, with levels of fat deposition relatively similar to those in controls. Testosterone exposure during prenatal life induced hyperinsulinemia paralleled by an increased HOMA-IR index in a fasting state and glucose intolerance and exaggerated insulin responses following a glucose tolerance test. Prenatal androgen-exposed males had more circulating testosterone during adult life. Gonadectomy prevented hyperandrogenism, reversed hyperinsulinemia, and attenuated glucose-induced insulin responses but did not alter glucose intolerance in these rats. Prenatal androgen-exposed males had decreased pancreatic islet numbers, size, and beta-cell area along with decreased expression of IR in gastrocnemius muscles. Gonadectomy restored pancreatic islet numbers, size, and beta-cell area but did not normalize IRbeta expression. This study shows that prenatal testosterone exposure leads to a defective pancreas and skeletal muscle function in male offspring. Hyperinsulinemia during adult life is gonad-dependent, but glucose intolerance appears to be independent of postnatal testosterone levels.
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Amar S
authors.initials: AS
authors.lastname: More
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Mishra
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Kathirvel
authors.initials: K
authors.lastname: Gopalakrishnan
authors.affiliation: Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas.
authors.forename: Chellakkan S
authors.initials: CS
authors.lastname: Blesson
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hankins
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, Texas kusathis@utmb.edu.
authors.forename: Kunju
authors.initials: K
authors.lastname: Sathishkumar
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002096:C-Peptide / Q000378:metabolism; D005260:Female; D018149:Glucose Intolerance / Q000209:etiology* / Q000473:pathology; D017588:Hyperandrogenism / Q000209:etiology; D006946:Hyperinsulinism / Q000209:etiology* / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000187:drug effects; D007515:Islets of Langerhans / Q000473:pathology; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology; D009919:Orchiectomy; D010179:Pancreas / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism; D013739:Testosterone / Q000097:blood; D043343:Testosterone Propionate / Q000633:toxicity*
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D013739:Testosterone; D011972:Receptor, Insulin; D043343:Testosterone Propionate
keywords: developmental programing; glucose intolerance; gonadectomy; hyperinsulinemia; insulin resistance; pancreas