Disordered follicle development in ovaries of prenatally androgenized ewes

Abstract

Exposure to excess androgens in utero induces irreversible changes in gonadotrophin secretion and results in disrupted reproductive endocrine and ovarian function in adulthood, in a manner reminiscent of the common clinical endocrinopathy of polycystic ovary syndrome (PCOS). We have recently identified an abnormality in early follicle development in PCOS which we suggested might be an androgenic effect. We propose that altered ovarian function in androgenized ewes is due to prenatal androgens not only causing an abnormality of gonadotrophin secretion, but also exerting a direct effect on the early stages of folliculogenesis. Therefore, in this study, we explored the possible differences between small preantral follicles in the ovarian cortex of androgenized female lambs with those of normal lambs. At 8 months of age, small ovarian cortical biopsies (approximately 5 mm3) were obtained at laparotomy from nine female lambs that had been exposed to androgens in utero from embryonic days 30 to 90 of a 147-day pregnancy, and 11 control female lambs. Further, ovarian tissue was obtained at 20 months of age from ten androgenized and nine control animals. Tissue was either fixed immediately for histology or cultured for up to 15 days prior to fixing. The number of follicles in haematoxylin and eosin-stained sections was counted and recorded along with the stage of development. Before culture, the total follicle density (follicles/mm3 tissue) was not statistically significantly different between the two types of ovary at either 8 or 20 months of age. Furthermore, there were no statistically significant differences in the density of follicles at each stage of development. However, there was a lower percentage of primordial follicles, but a higher percentage of primary follicles, in biopsies taken at 8 months from androgenized lambs when compared with controls. At 20 months, the proportions of follicles at the primordial and primary stages were not significantly different between the two groups, but this was mainly attributable to an increase in the proportion of growing follicles in biopsies from control animals. Culture of ovarian cortex from 8-month-old lambs resulted in a progressive increase in the proportion of growing follicles when compared with tissue fixed on the day of surgery. However, there was no difference between androgenized and control tissue in the percentage of growing follicles. The increase in the proportion of growing follicles in the cortex of androgenized animals is reminiscent of similar observations in human polycystic ovaries and suggests that excess exposure to androgen in early life plays a part in the accelerated progression of follicle development from the primordial to the primary stage in polycystic ovaries.