Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS

JCI Insight. 2018 Apr 5;3(7):e99405. doi: 10.1172/jci.insight.99405.

Abstract

Androgen excess is a hallmark of polycystic ovary syndrome (PCOS), a prevalent yet poorly understood endocrine disorder. Evidence from women and preclinical animal models suggests that elevated perinatal androgens can elicit PCOS onset in adulthood, implying androgen actions in both PCOS ontogeny and adult pathophysiology. Prenatally androgenized (PNA) mice exhibit a robust increase of progesterone-sensitive GABAergic inputs to gonadotropin-releasing hormone (GnRH) neurons implicated in the pathogenesis of PCOS. It is unclear when altered GABAergic wiring develops in the brain, and whether these central abnormalities are dependent upon adult androgen excess. Using GnRH-GFP-transgenic mice, we determined that increased GABA input to GnRH neurons occurs prior to androgen excess and the manifestation of reproductive impairments in PNA mice. These data suggest that brain circuit abnormalities precede the postpubertal development of PCOS traits. Despite the apparent developmental programming of circuit abnormalities, long-term blockade of androgen receptor signaling from early adulthood rescued normal GABAergic wiring onto GnRH neurons, improved ovarian morphology, and restored reproductive cycles in PNA mice. Therefore, androgen excess maintains changes in female brain wiring linked to PCOS features and the blockade of androgen receptor signaling reverses both the central and peripheral PNA-induced PCOS phenotype.

Keywords: Endocrinology; Fertility; Neuroendocrine regulation; Neuroscience; Sex hormones.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Receptor Antagonists / pharmacology
  • Androgens / metabolism*
  • Animals
  • Brain / cytology
  • Brain / metabolism*
  • Dihydrotestosterone / administration & dosage
  • Feedback, Physiological / drug effects
  • Female
  • GABAergic Neurons / drug effects
  • GABAergic Neurons / metabolism*
  • Gonadotropin-Releasing Hormone / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuronal Plasticity / drug effects
  • Ovary / growth & development
  • Ovary / pathology
  • Polycystic Ovary Syndrome / etiology*
  • Polycystic Ovary Syndrome / metabolism
  • Polycystic Ovary Syndrome / pathology
  • Polycystic Ovary Syndrome / prevention & control
  • Pregnancy
  • Prenatal Exposure Delayed Effects / etiology*
  • Prenatal Exposure Delayed Effects / metabolism
  • Prenatal Exposure Delayed Effects / pathology
  • Prenatal Exposure Delayed Effects / prevention & control
  • Receptors, Androgen / metabolism
  • Virilism / chemically induced
  • Virilism / complications

Substances

  • AR protein, mouse
  • Androgen Receptor Antagonists
  • Androgens
  • Receptors, Androgen
  • Dihydrotestosterone
  • Gonadotropin-Releasing Hormone

Grants and funding

14/077