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.
Original language | English (US) |
---|---|
Pages (from-to) | 133-146 |
Number of pages | 14 |
Journal | Neuroendocrinology |
Volume | 107 |
Issue number | 2 |
DOIs | |
State | Published - Sep 1 2018 |
Funding
We thank Drs. Deborah Barnett, Cristin Bruns, Rao Zhou, and Jason Lang, as well as Jim Turk, for technical assistance, together with Animal, Veterinary and Assays Services of the WNPRC for excellent service support; and Drs. Matthew Flowers and Marissa Kraynak for commenting on earlier drafts of this manuscript. This work was funded in part by NIH grants P50 HD044405 (PI: Dunaif), P50 HD028934 (PI: Marshall), and R01 RR013635 (PI: Abbott).
Keywords
- Androgens
- Developmental origins of health and disease
- Gonadal steroids
- Gonadotropin-releasing hormone
- Gonadotropins
- Hypothalamus
- Primates
- Testosterone
ASJC Scopus subject areas
- Endocrine and Autonomic Systems
- Endocrinology
- Cellular and Molecular Neuroscience
- Endocrinology, Diabetes and Metabolism