Regulation of antral follicular growth by an interplay between gonadotropins and their receptors

Abstract

Knowledge of the growth and maturation of human antral follicles is based mainly on concepts and deductions from clinical observations and animal models. To date, new experimental approaches and in vitro data contributed to a deep comprehension of gonadotropin receptors' functioning and may provide new insights into the mechanisms regulating still unclear physiological events. Among these, the production of androgen in the absence of proper LH levels, the programming of follicular atresia and dominance are some of the most intriguing. Starting from evolutionary issues at the basis of the gonadotropin receptor signal specificity, we draw a new hypothesis explaining the molecular mechanisms of the antral follicular growth, based on the modulation of endocrine signals by receptor-receptor interactions. The "heteromer hypothesis" explains how opposite death and life signals are delivered by gonadotropin receptors and other membrane partners, mediating steroidogenesis, apoptotic events, and the maturation of the dominant follicle.

Keywords: Antral follicle; Atresia; FSH; GPER; Heteromers; LH.

Fig. 1

Differences between male and female gonadal late gametogenesis. In the testis, FSHR and LHCGR are expressed in Sertoli and Leydig cells, respectively. While Sertoli cells have mainly trophic functions, Leydig cells synthesize androgens fundamental to support spermatogenesis. In the ovary, at the antral stage, theca cells produce androgens under LH stimulation, while FSHR and LHCGR are co-expressed in granulosa cells, which produce estrogens and support oocyte maturation

Fig. 2

Hormone and receptor levels during the antral follicle stage. Follicle growth and atresia are accompanied by variations of gonadotropin levels (orange and light-blue lines) and receptors (dotted lines). Changes in sex steroid hormone levels are represented by green (androstenedione), pink (estradiol), and blue (progesterone) lines. Timeline is to be referred to the first day of the menstrual cycle (day 0) until ovulation (day 15) (adapted and merged from [–44])

Fig. 3

Androgen production during the early antral stage. Poorly expressed LHCGRs heteromerize with FSHRs, cooperating to induce LH-like stimuli through FSH binding to its receptor. Blue arrows indicate LH-like stimuli, while yellow arrows are FSH-dependent steroidogenic signals

Fig. 4

“Receptor heteromer” hypothesis of the antral follicle selection. The very early antral stage, as likely secondary follicles, is characterized by a relatively low number of FSHRs, which are preferentially coupled to intracellular interactors mediating FSH-induced proliferative signals crucial for the proliferation of granulosa cells. The programming of follicular dominance relies on the overexpression of FSHR in follicles becoming atretic, deputed to the synthesis of sex steroids upon FSH stimulation. Estrogens are required to support vital functions of the growing dominant follicle. The latter is rescued from atresia by FSHR/GPER heteromers, shifting FSH-induced stimuli from death to AKT-dependent survival signals. While estrogen synthesis continues during the atretic process, via compartmentalization of steroidogenic signals, LHCGRs replace FSHRs in the dominant follicle