SAT-002 The Ovary Is Not the Primary Site of Reproductive Dysfunction in a Prenatal Androgen-Induced Mouse Model of PCOS

Abstract Disclosure: A.G. Novak: None. N.T. Neifert: None. K.M. Dillon: None. A.M. Moore: None. Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility in individuals of reproductive age. Although the pathophysiology underlying PCOS remains unclear, research suggests that hyperandrogenism is involved in the development of anovulation and abnormal menstrual cycles. It is unclear where androgens act to disrupt the reproductive axis. However, androgen signaling in kisspeptin cells has been implicated in the etiology of reproductive dysfunction in PCOS. Kisspeptin cells are present both in the hypothalamus and the ovaries. Therefore, we aimed to determine which of these is the primary site of disruption in the hypothalamic-pituitary-gonadal axis in PCOS. To achieve this, we performed surgical transplants to swap the ovaries of adult prenatal androgen-treated (PNA) PCOS-like mice with the ovaries of prenatal vehicle-treated (PNV) fertile controls. Pre-transplant assessment of estrous cycles for 14 days showed that PNV mice spend significantly more time in proestrus and estrus and significantly less time in metestrus/diestrus compared to PNA mice (n=6/group, p<0.05), which were acyclic. After transplants, mice underwent an additional 14 days of cyclicity assessment, and ovaries were collected for histological evaluation of corpora lutea (CL). Estrous cycles of PNV and PNA mice did not significantly differ pre- and post-transplant, with PNV mice that received ovaries from PNA mice continuing to cycle, and PNA mice that received ovaries from PNV mice remaining acyclic. Further, the percentage of ovaries containing CL was significantly lower in PNA mice receiving PNV ovaries (n=4) than in PNV mice receiving PNA ovaries (n=5, p<0.05). These data suggest that the ovary is not the primary site of reproductive dysfunction in PCOS and that reproductive symptoms are dependent on upstream brain and/or pituitary changes. Next, we aimed to determine whether kisspeptin-specific androgen receptor knockout (KARKO) in the ovaries could rescue the PCOS-like reproductive phenotype. To test this, we used ovary transplants between PNA wild-type (WT) mice and PNA KARKO mice, examining cyclicity and ovarian morphology in the same manner as the transplants between PNV and PNA mice. Here, we found that the mice receiving PNA KARKO ovaries (n=4) were acyclic both before and after the transplant, having comparable percentages of time spent in metestrus/diestrus to PNA WT mice. However, in examining ovarian morphology, the PNA KARKO ovaries received by the PNA WT mice retained CL, indicating to us that, while the primary cause of reproductive dysfunction in PCOS may be in the brain or pituitary, androgen action in the ovary is additionally required to induce the anovulatory phenotype of PCOS. Presentation: Saturday, July 12, 2025