Published online by Cambridge University Press: 01 March 2000
Two-cell, two-gonadotrophin interactions within the ovarian follicle involve stimulating theca cells with luteinizing hormone (LH) to produce androgens which enter granulosa cells where, under the influence of follicle stimulating hormone (FSH), they are aromatized to estradiol. In nonprimate species, autocrine and paracrine functions for estradiol within the follicle have been shown to mediate the trophic effects of FSH on granulosa cells resulting in proliferation, increased expression of FSH receptors, antrum formation, induction of LH receptors, and inhibition of apoptosis. The axiom that estradiol is particularly necessary for follicular growth and maturation has been routinely adopted and perpetuated for decades in discussions on the regulation of follicular function in primates. Focus on the level of estradiol in follicular fluid as an index of follicle, and hence oocyte, quality by many investigators yielded conflicting results. Nonetheless, development of ovarian stimulation protocols that employ exogenous administration of both FSH and LH for the treatment of infertility in women rely on the correlation between the growth of multiple follicles and increasing serum levels of estradiol to predict a successful outcome. Initial reports of rare conditions causing defects in follicular estradiol biosynthesis, such as with P450-17αhydroxylase/17,20 lyase deficiency, associated the disruption of follicular development with estradiol deprivation. However, the elevated levels of gonadotrophins also observed in these patients rather than the absence of intrafollicular estradiol may have led to the dysregulation of folliculogenesis. Evidence to counter the notion that follicles can only grow in an estradiol-replete environment was provided by studies of women with hypogonadal hypogonadism and of medically hypophysectomized macaques, wherein low levels of estradiol were accompanied by induction of multiple preovulatory follicles upon treatment with urinary preparations of FSH alone. Unfortunately, there are no data available from these studies on oocyte performance under conditions of low estradiol resulting from steroidogenic enzyme deficiencies or hypogonadal hypogonadism. Recent studies of steroid-depleted as well as hypogonadal women and macaques reinvestigated the hypothesis that estradiol plays a pivotal role in folliculo- and gametogenesis in primates and are discussed below.