期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：30
DOI：10.1073/pnas.2203503119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Polycystic ovary syndrome (PCOS) is a major endocrine disorder leading to female infertility worldwide. Patients with PCOS also often experience sexual dysfunction; however, the developmental and central mechanisms mediating this behavioral derangement are unclear. Here, we show that prenatal excess of anti-Müllerian hormone triggers PCOS-like impairment in female sexual behavior in mice. Sexual dysfunction in PCOS-like mice is associated with decreased expression of progesterone-sensitive neuronal nitric oxide synthase (nNOS) neurons in the hypothalamus. Chemogenetic inhibition of nNOS neuronal activity in the ventromedial nucleus of the hypothalamus recapitulates PCOS-like sexual dysfunction. Of clinical relevance, administration of nitric oxide donor rescues normal sexual behavior in PCOS-like mice.
Women with polycystic ovary syndrome (PCOS) frequently experience decreased sexual arousal, desire, and sexual satisfaction. While the hypothalamus is known to regulate sexual behavior, the specific neuronal pathways affected in patients with PCOS are not known. To dissect the underlying neural circuitry, we capitalized on a robust preclinical animal model that reliably recapitulates all cardinal PCOS features. We discovered that female mice prenatally treated with anti-Müllerian hormone (PAMH) display impaired sexual behavior and sexual partner preference over the reproductive age. Blunted female sexual behavior was associated with increased sexual rejection and independent of sex steroid hormone status. Structurally, sexual dysfunction was associated with a substantial loss of neuronal nitric oxide synthase (nNOS)-expressing neurons in the ventromedial nucleus of the hypothalamus (VMH) and other areas of hypothalamic nuclei involved in social behaviors. Using in vivo chemogenetic manipulation, we show that nNOS
VMH neurons are required for the display of normal sexual behavior in female mice and that pharmacological replenishment of nitric oxide restores normal sexual performance in PAMH mice. Our data provide a framework to investigate facets of hypothalamic nNOS neuron biology with implications for sexual disturbances in PCOS.
