Molecular regulation of follicle-stimulating hormone synthesis, secretion and action

Abstract

Follicle-stimulating hormone (FSH) plays fundamental roles in male and female fertility. FSH is a heterodimeric glycoprotein expressed by gonadotrophs in the anterior pituitary. The hormone-specific FSHβ-subunit is non-covalently associated with the common α-subunit that is also present in the luteinizing hormone (LH), another gonadotrophic hormone secreted by gonadotrophs and thyroid-stimulating hormone (TSH) secreted by thyrotrophs. Several decades of research led to the purification, structural characterization and physiological regulation of FSH in a variety of species including humans. With the advent of molecular tools, availability of immortalized gonadotroph cell lines and genetically modified mouse models, our knowledge on molecular mechanisms of FSH regulation has tremendously expanded. Several key players that regulate FSH synthesis, sorting, secretion and action in gonads and extragonadal tissues have been identified in a physiological setting. Novel post-transcriptional and post-translational regulatory mechanisms have also been identified that provide additional layers of regulation mediating FSH homeostasis. Recombinant human FSH analogs hold promise for a variety of clinical applications, whereas blocking antibodies against FSH may prove efficacious for preventing age-dependent bone loss and adiposity. It is anticipated that several exciting new discoveries uncovering all aspects of FSH biology will soon be forthcoming.

Keywords: FSH; LH; extragonadal; miRNA; ovary; pituitary; reproduction; testis; transgenic mice.

Fig. 1. Transcriptional regulation of FSH subunit - encoding genes

The three major players that regulate FSH subunit gene transcription include GnRH, activin-inhibin-follistatin and steroids. GnRH binds to GnRH receptors expressed on gonadotropes. MAPK/ERK phosphorylation is one of the major downstream pathways activated by GnRH. These signals are further transmitted by translocation and recruitment of key transcription factors EGR1, ATF3, SF-1 and MAPK pathway -catenin-dependent activation of c-Jun-c-Fos and AP-1 onto α-GSU and FSHβ -encoding gene promoters. Estrogen, progesterone and testosterone can indirectly regulate FSH subunit encoding gene transcription by suppressing GnRH. Testosterone and glucocorticoids can also directly regulate FSHβ subunit - encoding gene transcription. Estrogen and testosterone can also regulate activin regulation of FSHβ subunit - encoding gene transcription. Activins bind to activin receptor type II and phsophorylate ALK4/7 type 1 receptors. This heterotrimeric complex via a TAK1 pathway, phosphorylates receptor-specific SMAD 2/3 transducers which complex with the phosphorylated common SMAD4 and bind to SMAD binding elements on FSHβ - encoding gene promoter. SMAD7 is an inhibitory SMAD that negatively regulates activin action. SMADS cooperatively bind with other co-factors including a key transcription factor, FOXL2 (not shown in the figure). Follistatin and inhibin bind activin and negatively regulate FSHβ subunit - encoding gene transcription.

Fig. 2. Regulation of FSH secretion

GnRH is secreted in pulses form the hypothalamus. Its secretion is regulated by multiple neuropeptides including PACAP and Kisspeptin. GnRH positively regulates FSH synthesis from pituitary. FSH binds to gonadal cell receptors and produce steroids, which directly or indirectly act at the level of the pituitary or hypothalamus, respectively. Both locally produced factors within gonadotropes such as activins, inhibins and follistatin and other peptides such as PACAP and Kisspeptin whose receptors are expressed by gonadotropes, regulate GnRHR-, and FSHβ subunit - encoding genes. Gonads are also an abundant source of activins and inhibins, which act like typical endocrine factors to regulate FSH secretion from pituitary. FSH is mostly constitutively secreted and its synthesis is tightly linked to it secretion.

Fig. 3. A summary of different signaling mechanisms that mediate FSH actions in target cells

FSH binds to G-protein coupled seven transmembrane - spanning FSHRs expressed on target cells. This leads to activation of a battery of signaling pathways depending on the developmental and physiological context. In the female FSH mainly acts to regulate ovarian folliculogenesis and steroidogenesis. Recently, extra-gonadal actions of FSH mediated via FSHRs, have been identified, particularly in osteoclasts in female rodent bones. These observations have implications for understanding and treating bone loss in post-menopausal women. In the male, FSHRs are expressed on Sertoli cells in the testis. FSH regulates pre-pubertal proliferation and maturation of Sertoli cells. Proper maturation of Sertoli cells is essential for maintaining optimal spermatogenesis. Other extra-gonadal functions of FSH have also been proposed but these are yet to be rigorously tested.