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Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS
Mauro S.B. Silva, … , Melanie Prescott, Rebecca E. Campbell
Mauro S.B. Silva, … , Melanie Prescott, Rebecca E. Campbell
Published April 5, 2018
Citation Information: JCI Insight. 2018;3(7):e99405. https://doi.org/10.1172/jci.insight.99405.
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Research Article Endocrinology Neuroscience

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

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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.

Authors

Mauro S.B. Silva, Melanie Prescott, Rebecca E. Campbell

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Figure 1

Androgen excess in PNA mice develops by PND 50.

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Androgen excess in PNA mice develops by PND 50.
Circulating testosterone...
Circulating testosterone levels from postnatal day (PND) 30 to PND 60 in control (N = 10) and prenatally androgenized (PNA) (N = 9) mice. Data are shown as dot plots for each time point and bars represent mean ± SEM. Dashed blue lines indicate testosterone levels of control mice and red full lines indicate PNA mice. Differences between the groups are reported as *P < 0.05; **P < 0.01 and differences within each groups are reported as #P < 0.05. Data analysis was performed with repeated-measures 2-way ANOVA with Sidak’s post hoc test.

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