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Accelerated Episodic Luteinizing Hormone Release Accompanies Blunted Progesterone Regulation in PCOS-like Female Rhesus Monkeys (Macaca Mulatta) Exposed to Testosterone during Early-to-Mid Gestation. Neuroendocrinology 2018;107(2):133-146 PMID: 29949806

Pubmed ID

29949806

DOI

10.1159/000490570

Abstract

BACKGROUND/AIMS: Ovarian theca cell hyperandrogenism in women with polycystic ovary syndrome (PCOS) is compounded by androgen receptor-mediated impairment of estradiol and progesterone negative feedback regulation of episodic luteinizing hormone (LH) release. The resultant LH hypersecretion, likely the product of accelerated episodic release of gonadotropin-releasing hormone (GnRH) from the median eminence of the hypothalamus, hyperstimulates ovarian theca cell steroidogenesis, enabling testosterone (T) and androstenedione excess. Prenatally androgenized (PA) female monkeys exposed to fetal male levels of T during early-to-mid gestation, when adult, demonstrate PCOS-like traits, including high T and LH levels. This study tests the hypothesis that progesterone resistance-associated acceleration in episodic LH release contributes to PA monkey LH excess.

METHODS: A total of 4 PA and 3 regularly cycling, healthy control adult female rhesus monkeys of comparable age and body mass index underwent (1) a 10 h, frequent intravenous sampling assessment for LH episodic release, immediately followed by (2) IV infusion of exogenous GnRH to quantify continuing pituitary LH responsiveness, and subsequently (3) an SC injection of a progesterone receptor antagonist, mifepristone, to examine LH responses to blockade of progesterone-mediated action.

RESULTS: Compared to controls, the relatively hyperandrogenic PA females exhibited ~100% increase (p = 0.037) in LH pulse frequency, positive correlation of LH pulse amplitude (p = 0.017) with androstenedione, ~100% greater increase (p = 0.034) in acute (0-10 min) LH responses to exogenous GnRH, and an absence (p = 0.008) of modest LH elevation following acute progesterone receptor blockade suggestive of diminished progesterone negative feedback.

CONCLUSION: Such dysregulation of LH release in PCOS-like monkeys implicates impaired feedback control of episodic release of hypothalamic GnRH reminiscent of PCOS neuroendocrinopathy.

Author List

Abbott DH, Vepraskas SH, Horton TH, Terasawa E, Levine JE

Author

Sarah Vepraskas MD Assistant Professor in the Pediatrics department at Medical College of Wisconsin




Scopus

2-s2.0-85053342165

MESH terms used to index this publication - Major topics in bold

Androgens
Animals
Disease Models, Animal
Female
Hyperandrogenism
Luteinizing Hormone
Macaca mulatta
Polycystic Ovary Syndrome
Pregnancy
Prenatal Exposure Delayed Effects
Progesterone
Testosterone
jenkins-FCD Prod-310 bff9d975ec7f2d302586822146c2801dd4449aad