Oral Presentation ESA-SRB Conference 2015

Adverse effects of the hyperandrogenic environment on follicle dynamics in culture: a model of Polycystic Ovary Syndrome (PCOS) (#129)

Aimee Caldwell 1 , Dianliang (Harry) Lin 1 2 , Charles Allan 1 , David Handelsman 1 , Kirsty Walters 1
  1. Andrology Laboratory, ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney, NSW 2139, Australia
  2. Human Assisted Reproductive Research Unit, Fujian Provincial Maternity and Children’s Health Hospital, Fuzhou, Fujian Province, People’s Republic of China

Polycystic Ovary Syndrome (PCOS) is a common cause of infertility, affecting 6-10% of women worldwide. Despite advances such as IVF & IVM, PCOS women seeking fertility via ART achieve fewer pregnancies per egg retrieved, reflecting suboptimal oocyte functional viability. Hyperandrogenism is a key feature of PCOS, but its role in PCOS subfertility remains unclear. Using our optimal PCOS mouse model [1], and by combining it with androgen insensitive female (homozygous AR knockout) mice [2], we have provided strong experimental model evidence that AR signalling may be important in the origins of PCOS. The present study investigated the mechanisms of defective follicle selection and ovulation in PCOS using an in vitro follicle culture combined with our optimised DHT-induced PCOS mouse model. Early preantral (EP, 100-150µm), late preantral (LP, 151-200µm), small antral (SA, 201-250 µm), large antral (LA, 251-350µm) and preovulatory (PO, 351-450µm) follicles were isolated from control or PCOS mice and cultured individually. Over 5 days in culture, preantral and antral follicles from PCOS ovaries displayed decreased growth rates, whilst PO follicles exhibited a significant increase in growth rate compared to non-PCOS controls (p<0.01). Preantral follicles from PCOS ovaries maintained health and morphology with normal oocyte:follicle size ratio. By contrast, SA, LA and PO PCOS follicles all exhibited decreased oocyte:follicle ratio (p<0.05), reduced health and survival rates (p<0.01). These findings show that although the earliest stage (preantral) follicles from PCOS mice exhibit slower growth, they retain normal health and survival unlike all later stage follicles. Despite removal from the in vivo hyperandrogenic environment, later stage PCOS follicles display significantly reduced growth rates, indicating that prolonged exposure to androgen excess induces sustained, intrinsic follicular defects. These findings imply important testable hypotheses for the future improvement of ART for PCOS patients, with particular focus on the early culture of preantral follicles.

  1. Caldwell ASL, Middleton LJ, Jimenez M, Desai R, McMahon AC, Allan CM, Handelsman DJ, and Walters KA. Characterization of reproductive, metabolic and endocrine features of polycystic ovary syndrome in female hyperandrogenic mouse models. Endocrinology 2014; 155(8):3146-59 [PMID: 24877633]
  2. Caldwell ASL, Eid S, Kay C, Jimenez M, McMahon AC, Desai R, Allan CM, Smith JT, Handelsman DJ, Walters KA. Haplosufficient genomic androgen receptor signalling is adequate to protect female mice from induction of polycystic ovary syndrome features by prenatal hyperandrogenization. Endocrinology 2015; 156(4):1441-52 [PMID: 25643156]