Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women of reproductive age. It is characterised by excessive ovarian androgen production which, in turn, has been implicated in the aetiology of aberrant follicular development. We have previously reported that prenatal exposure to androgens activates follicle growth1. It has been suggested that androgens may interact with the IGFs to promote the activation and growth of follicles. The aim of this study was to investigate the effects of androgen on the type 1 IGF receptor (IGFR1) and the transcription factor, Forkhead box (Foxo)3a (a downstream target of IGF signalling), using cultured whole ovaries from neonatal mice.
Whole ovaries were collected from neonatal C57BL/6 mice at PND 4 and cultured, in the presence or absence of dihydrostestosterone (DHT a non-aromatisable androgen), for 7 days. At the end of culture ovaries were fixed for immunohistochemical localisation of IGFR1 or Foxo3a. Image analysis was carried out to assess the proportion of primordial, and developing follicles, the abundance of IGFR1 and the subcellular localisation of Foxo3a.
Treatment with DHT (10 nM) decreased the proportion of primordial follicles and increased the proportion of multi-layered follicles compared to control (P<0.001). Foxo3a and IGFR1 were observed in the oocyte and granulosa layer, respectively, of every follicle analysed. Treatment with androgen caused an increase in the proportion of cytoplasmic expression and a decrease in the proportion of nuclear Foxo3a in primordial, transitional and multilayered follicles compared to control (P<0.001 and P<0.05, respectively). Furthermore, the addition of DHT resulted in increased IGFR1 protein expression in transitional and multi-layered follicles (P<0.0001). In conclusion, this study provides strong evidence that androgen dependent dysregulation of growth of preantral follicles is exerted through interactions with Foxo3a and IGFR1, key factors known to stimulate follicle activation and growth. This study is supported by MRC programme grant G0802782.
1. Forsdike RA, et al. J Endocrinol 2007 192 421.