Developmental Programming: Insulin Sensitizer Prevents the GnRH-Stimulated LH Hypersecretion in a Sheep Model of PCOS

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 subs...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 2016-12, Vol.157 (12), p.4641-4653
Main Authors: Cardoso, Rodolfo C, Burns, Ashleigh, Moeller, Jacob, Skinner, Donal C, Padmanabhan, Vasantha
Format: Article
Language:English
Subjects:
Androgen Antagonists - pharmacology
Androgens - pharmacology
Animals
Disease Models, Animal
Estrogen Receptor alpha - metabolism
Female
Flutamide - pharmacology
Gonadotropin-Releasing Hormone - pharmacology
Luteinizing Hormone - secretion
Luteinizing Hormone, beta Subunit - metabolism
Pituitary Gland - drug effects
Pituitary Gland - metabolism
Polycystic Ovary Syndrome - metabolism
Pregnancy
Prenatal Exposure Delayed Effects - metabolism
Receptor, Insulin - metabolism
Receptors, Androgen - metabolism
Sheep
Testosterone - pharmacology
Thiazolidinediones - pharmacology
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Summary: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.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2016-1613