Gonadotropins

Abstract

The gonadotropins, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and chorionic gonadotropin hormone (CG) play an essential role in reproduction. LH and FSH are synthesized in the gonadotropes of the anterior pituitary gland, while CG is synthesized by the placental syncytiotrophoblasts. Gonadotropins, together with thyroid-stimulating hormone (TSH) synthesized by the thyrotropes of the adenohypophysis, belong to the glycoprotein hormone family. The glycoprotein hormones are complex heterodimers consisting of a common α-subunit non-covalently associated with a β-subunit, which is structurally unique in its peptide sequence to each member of the family and that confers binding specificity at the receptor level. Both subunits are decorated with oligosaccharide chains, whose number vary depending on the particular glycoprotein hormone, and that are involved in many functional aspects, including folding and secretion of the heterodimer, as well as plasma half-life and bioactivity of the hormone at the target cell. The synthesis and secretion of gonadotropins are regulated by the concerted action of several endocrine, paracrine, and autocrine factors of diverse chemical structure, the main player being the hypothalamicdecapeptide gonadotropin-releasing hormone (GnRH). Gonadotropins interact with their cognate receptors (the FSH receptor and the LH/CG receptor) in the ovary and the testes. In the ovary, FSH regulates the growth and maturation of the ovarian follicles as well as estrogen production by the granulosa cells, whereas in the testes FSH stimulates the Sertoli cells lining the seminiferous tubules to influence spermatogenesis. The target cells of LH are the theca cells of the ovarian follicles and the corpus luteum, where it promotes the synthesis of sex steroid hormones and the ovulatory process. In the testes, LH stimulates Leydig cell steroidogenesis, mainly testosterone production, to promote sexual maturation and function, and spermatogenesis. Mutations in the β-subunit genes of LH and FSH leading to gonadotropin deficiency are very rare. When they occur in LHβ, they are clinically manifested by lack of pubertal maturation and infertility in men and infertility in women, whereas mutations in FSHβ may lead to azoospermia in men and absent or partial puberty and infertility in women. Several natural and recombinant preparations of gonadotropins are currently available for therapeutic purposes. Given that glycosylation is well known to vary in a cell- and tissuespecific manner, the main difference between natural and the currently available recombinant preparations massively produced in Chinese hamster ovary cells for commercial purposes lies in the abundance of some of the carbohydrates that comprise the complex glycans attached to the protein core. Because of the functional and pharmacological similarities between natural and recombinant compounds, both may be employed in the clinical arena to treat diseases characterized by gonadotropin deficiency as well as infertility.