165 Randel Lecture: Androgen Excess Domestic Livestock Models—What can they Tell us About the Mechanisms Underlying Anovulation?

Abstract

Abstract Ovulatory disorders are a major factor in female infertility. Our laboratory has identified several populations of cows and a population of sheep that have excess androgen (High A4) in dominant follicles and ovarian cortex cultures in the US and in the Middle East with increased steroidogenic enzyme production in somatic cells. Within our research herd, the High A4 females have irregular estrous cycles where behavioral estrus and ovulation are not coupled and are often anovulatory. Follicular waves of growth, during the estrous cycle, are disrupted in High A4 cows with development of persistent follicles, and an absence of normal follicular-wave estrogen patterns in blood plasma compared with Controls. Increased ovarian cortex fibrosis, oxidative stress markers and plasma pro- inflammatory lipids were present in High A4 cows indicating increased inflammation. High A4 granulosa cells have altered gene transcripts indicating cell cycle arrest and expression of genes enriched in other somatic cell types resulting in altered cell identity. Furthermore, High A4 ovarian cortex cultures secrete increased pro-inflammatory cytokines and have reduced follicle progression to later stages supporting follicular arrest. Treatment of High A4 ovarian cortex cultures with Vascular Endothelial Growth Factor 165 suppressed excess steroids, fibrosis, pro-inflammatory cytokines and relieved follicular arrest. Concentrations of Anti-Mullerian Hormone (AMH) were greater in High A4 vs Controls in both follicular fluid and ovarian cortex culture media supporting that AMH could be a factor contributing to follicular arrest. Many of the characteristics of High A4 cows and sheep identified are similar to polycystic ovary syndrome (PCOS) in women. Thus, High A4 cow and sheep are excellent models to unravel androgen excess molecular mechanisms involved in follicular arrest and female infertility contributing to anovulation.