Role of androgens in follicle maturation and atresia

Androgens are products of progestogen metabolism intermediates in oestrogen biosynthesis and local regulators of ovarian function. Current understanding of intraovarian androgen formation, metabolism and action is reviewed, highlighting the contribution of androgens to the paracrine regulation of follicular maturation and atresia. Any factor that alters intracellular cAMP levels is a potential modulator of granulosa cell differentiation, and hence follicular development. Androgen appears to modulate gonadotrophin action on granulosa cells through amplification of cAMP-mediated post-receptor signalling. Here it is argued that during intermediate stages of follicular development, locally produced androgen acts via granulosa cell androgen receptors (AR) to promote follicle-stimulating hormone (FSH)-induced granulosa cell differentiation through amplifying cAMP-mediated post-receptor signalling. During late pre-ovulatory follicular development, higher concentrations of cAMP caused by stimulation with luteinizing hormone (LH) suppress granulosa cell proliferation and downregulate some of the genes induced by FSH at earlier stages of pre-ovulatory development, including aromatase activity. Other granulosa cell functions, including progesterone synthesis, are enhanced by the high concentrations of cAMP induced by LH. There is experimental evidence from studies of rat and non-human primate (common marmoset) ovaries that AR levels in granulosa cells decline during pre-ovulatory follicular maturation. Since androgens augment FSH induced cAMP formation and action, loss of AR could be a means of avoiding inappropriately high cAMP levels and hence avoiding premature activation of 'high-tone' cAMP-response genes that lead to atresia. Negative regulation of the granulosa cell AR could be part of the intra-ovarian mechanism that determines which follicle(s) becomes dominant and secretes oestrogen in the normal menstrual cycle.