title: Developmental Programming: Insulin Sensitizer Prevents the GnRH-Stimulated LH Hypersecretion in a Sheep Model of PCOS.
abstract: Prenatal testosterone (T) treatment recapitulates the reproductive and metabolic phenotypes of polycystic ovary syndrome in female sheep. At the neuroendocrine level, prenatal T treatment results in disrupted steroid feedback on gonadotropin release, increased pituitary sensitivity to GnRH, and subsequent LH hypersecretion. Because prenatal T-treated sheep manifest functional hyperandrogenism and hyperinsulinemia, gonadal steroids and/or insulin may play a role in programming and/or maintaining these neuroendocrine defects. Here, we investigated the effects of prenatal and postnatal treatments with an androgen antagonist (flutamide [F]) or an insulin sensitizer (rosiglitazone [R]) on GnRH-stimulated LH secretion in prenatal T-treated sheep. As expected, prenatal T treatment increased the pituitary responsiveness to GnRH leading to LH hypersecretion. Neither prenatal interventions nor postnatal F treatment normalized the GnRH-stimulated LH secretion. Conversely, postnatal R treatment completely normalized the GnRH-stimulated LH secretion. At the tissue level, gestational T increased pituitary LHβ, androgen receptor, and insulin receptor-β, whereas it reduced estrogen receptor (ER)α protein levels. Although postnatal F normalized pituitary androgen receptor and insulin receptor-β, it failed to prevent an increase in LHβ expression. Contrarily, postnatal R treatment restored ERα and partially normalized LHβ pituitary levels. Immunohistochemical findings confirmed changes in pituitary ERα expression to be specific to gonadotropes. In conclusion, these findings indicate that increased pituitary responsiveness to GnRH in prenatal T-treated sheep is likely a function of reduced peripheral insulin sensitivity. Moreover, results suggest that restoration of ERα levels in the pituitary may be one mechanism by which R prevents GnRH-stimulated LH hypersecretion in this sheep model of polycystic ovary syndrome-like phenotype.
authors: Department of Pediatrics (R.C.C., A.B., J.M., V.P.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Zoology and Physiology (D.C.S.), University of Wyoming, Laramie, Wyoming 82071.
authors: Rodolfo C
authors: RC
authors: Cardoso
authors: Department of Pediatrics (R.C.C., A.B., J.M., V.P.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Zoology and Physiology (D.C.S.), University of Wyoming, Laramie, Wyoming 82071.
authors: Ashleigh
authors: A
authors: Burns
authors: Department of Pediatrics (R.C.C., A.B., J.M., V.P.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Zoology and Physiology (D.C.S.), University of Wyoming, Laramie, Wyoming 82071.
authors: Jacob
authors: J
authors: Moeller
authors: Department of Pediatrics (R.C.C., A.B., J.M., V.P.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Zoology and Physiology (D.C.S.), University of Wyoming, Laramie, Wyoming 82071.
authors: Donal C
authors: DC
authors: Skinner
authors: Department of Pediatrics (R.C.C., A.B., J.M., V.P.), University of Michigan, Ann Arbor, Michigan 48109; and Department of Zoology and Physiology (D.C.S.), University of Wyoming, Laramie, Wyoming 82071.
authors: Vasantha
authors: V
authors: Padmanabhan
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D005485:Flutamide / Q000494:pharmacology*; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D007986:Luteinizing Hormone / Q000378:metabolism*; D037101:Luteinizing Hormone, beta Subunit / Q000378:metabolism; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D011085:Polycystic Ovary Syndrome / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D000077154:Rosiglitazone; D012756:Sheep; D013739:Testosterone / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D047628:Estrogen Receptor alpha; D037101:Luteinizing Hormone, beta Subunit; D011944:Receptors, Androgen; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D005485:Flutamide; D007986:Luteinizing Hormone; D011972:Receptor, Insulin