Developmental Programming: Insulin Sensitizer Prevents the GnRH-Stimulated LH Hypersecretion in a Sheep Model of PCOS. Academic Article uri icon


  • 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 LH, androgen receptor, and insulin receptor-, whereas it reduced estrogen receptor (ER) protein levels. Although postnatal F normalized pituitary androgen receptor and insulin receptor-, it failed to prevent an increase in LH expression. Contrarily, postnatal R treatment restored ER and partially normalized LH pituitary levels. Immunohistochemical findings confirmed changes in pituitary ER 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 ER 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.

published proceedings

  • Endocrinology

altmetric score

  • 1.25

author list (cited authors)

  • Cardoso, R. C., Burns, A., Moeller, J., Skinner, D. C., & Padmanabhan, V.

citation count

  • 19

complete list of authors

  • Cardoso, Rodolfo C||Burns, Ashleigh||Moeller, Jacob||Skinner, Donal C||Padmanabhan, Vasantha

publication date

  • December 2016