FSH inhibits AMH to support ovarian estradiol synthesis in infantile mice

Abstract

Anti-Müllerian hormone (AMH) regulates ovarian function in cyclic females, notably by preventing premature follicle-stimulating hormone (FSH)-mediated follicular growth and steroidogenesis. Its expression in growing follicles is controlled by FSH and by estradiol (E2). In infantile females, there is a transient increase in the activity of the gonadotrope axis, as reflected by elevated levels of both gonadotropins and E2. We previously demonstrated in mice that elevated FSH concentrations are necessary to induce E2 production by preantral/early antral follicles through the stimulation of aromatase expression without supporting their growth. However, whether this action of FSH could involve AMH is unknown. Here, we show that Amh mRNA and protein abundance and serum AMH levels are elevated in infantile mouse females, compared with those in adults. By experimentally manipulating FSH and E2 levels in infantile mice, we demonstrate that high FSH concentrations lower Amh expression specifically in preantral/early antral follicles, whereas E2 has no effect. Importantly, treatment of infantile ovaries in organotypic cultures with AMH decreases FSH-mediated expression of Cyp19a1 aromatase, but it does not alter the expression of cyclin D2-mediating granulosa cell proliferation. Overall, our data indicate that the infantile elevation in FSH levels suppresses Amh expression in preantral/early antral follicles, thereby favoring Cyp19a1 aromatase expression and E2 production. Together with recent discoveries that AMH can act on both the hypothalamus and the pituitary to increase gonadotropin levels, this work suggests that AMH is a critical regulator of the gonadotrope axis during the infantile period, thereby contributing to adult reproductive function programming.

Emerging Roles of Anti-Müllerian Hormone in Hypothalamic-Pituitary Function

“…In rodents, a similar transient FSH peak has been reported at ~12–14 days of postnatal life [95,96]. Remarkably at the same time (PN14), AMH is downregulated in preantral/early antral follicles of the first waves [56]. Using cultures of infantile mice ovaries, these authors have demonstrated the existence of a repressive action of FSH on AMH expression in preantral/early antral follicles of the first follicular waves.…”

“…The authors concluded that although the number of initial primordial follicles available immediately following birth was independent of the presence of AMH, it was an important factor in inhibiting follicular recruitment and thus AMH presence was essential for prolonging fecundity. AMH is already expressed in infantile ovaries in mammals [48,51–56] and the findings from Garrel and colleagues in 2016 raised the intriguing hypothesis that AMH could play a critical role in the female pituitary gonadotropic activity during the infantile period [20]. This issue will be further discussed in section 4.…”

The optimized research of the in vitro culture of preantral follicles in mice

“…31,32 The expression of these enzymes converts androstenedione synthesized from follicular theca cells into E2. Although studies have reported that FSH affects the development of preantral follicles, [33][34][35] there is no report regarding the effect of FSH on the growth pattern of preantral follicles in vitro. The reason may be that the PM follicles and ES follicles were cultured together in previous studies.…”

Production d’œstradiol par l’ovaire lors de la mini-puberté

“…Cette étude révèle que les hauts niveaux de FSH de la mini-puberté répriment l'expression de l'AMH dans les follicules les plus matures, levant ainsi le frein inhibiteur de l'AMH sur la stéroïdogenèse [6]. (Hprt, hypoxanthine phosphoribosyltransferase).…”

“…Nos travaux ont montré que l'AMH était exprimée dans l'ovaire de souris avant la puberté ( Figure 1A), comme chez l'humain et chez d'autres espèces de mammifères [1,5]. Pour étudier l'action de l'AMH lors de cette période, nous avons effectué des cultures organotypiques d'ovaires de souris au stade mini-puberté (12-14 jours postnatals [jpn]) [6]. Les ovaires ont été traités par l'AMH en présence de fortes concentrations de FSH mimant ses niveaux circulants in vivo.…”