Gonadotropins, steroids and their sites of synthesis

Production of gonadotropins
Gonadal regulation begins in the hypothalamus which synthesizes and releases, in a pulsatile manner, the decapeptide gonadotropin-releasing hormone (GnRH)(Fig. 1). GnRH acts directly on the gonadotrophs which are the specific cells in the anterior pituitary that synthesize and secrete the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH are glycoproteins which share structural similarity with thyroid-stimulating hormone and chorionic gonadotropin and which are the primary hormonal mediators of testicular function. These glycoproteins are comprised of two non-covalently linked polypeptides. One protein, the alpha-subunit, is common to both of these hormones while the beta-subunit is unique to each. Formation of the alpha-beta heterodimer within the endoplasmic reticulum of the gonadotrophs is essential for the hormonal activity of the gonadotropins. Synthesis and release of the gonadotropins within the pituitary involves a complex regulatory process. Individual gonadotrophs are capable of secreting either FSH or LH, or both FSH and LH. LH is known to be released in a pulsatile fashion as a result of the pulsatile stimulus of GnRH arriving from the hypothalamus. FSH is released with less frequent and more irregular pulses that have smaller amplitudes. In some species, especially those with seasonal variations in spermatogenesis, another pituitary hormone, prolactin, may play a role in stimulating the re-initiation of spermatogenesis.

Transduction of the LH/FSH signal
Glycoprotein hormones such as FSH and LH elicit responses in target cells by interacting with specific receptor proteins on the plasma membrane. Binding of the hormone to its receptor stimulates an intracellular signal transduction and amplification system that results in a biochemical change within the target cell. Receptors for FSH, LH and thyroid stimulating hormone constitute a closely related subfamily of G-protein coupled receptors that is distinguished by a relatively large external domain. Structurally, G-protein coupled receptors are characterized by a region of hydrophobic helices which span the membrane seven times and anchor the external portion of the protein to the plasma membrane where it can interact with its ligand. In the testis, Sertoli cells have the membrane receptors that make them the target cells for the action of FSH. LH binds to membrane receptors on Leydig cells and stimulates the production of testosterone. The G-proteins are a large family of membrane-associated intracellular proteins that transduce the initial signal (hormone binding to receptor) into a biochemical event such as the production of cAMP and the subsequent stimulation of protein phosphorylation through kinases. Most of the changes in cellular activities that occur because of the actions of the gonadotropins are the result of phosphorylation of specific proteins.
Sites of action of gonadotropins

LH-stimulated Leydig cells convert cholesterol to testosterone which subsequently accumulates in the interstitium and the seminiferous tubules at relatively high concentrations. Extracellular androgens are bound to related carrier proteins such as androgen binding protein (ABP) produced by the Sertoli cells or testosterone binding globulin (TeBG) produced by the liver. The adrenal also produces androgens; however, the contribution of adrenal steroids to testicular function in normal males is negligible. The target cells for testosterone within the testis are the peritubular myoid cells and the Sertoli cells. There is good evidence that the germinal cells do not respond directly to androgens. In some species, a portion of the testosterone may be converted to estrogens by Sertoli or germ cells. The estrogens then feed back to reduce LH stimulation of testosterone biosynthesis by Leydig cells.

FSH stimulates a variety of functions in Sertoli cells including the synthesis of secreted proteins, like transferrin, that are involved in the transfer of nutrients to germ cells. In response to FSH action Sertoli cells also produce inhibin which, along with testosterone, is involved in feedback regulation of pituitary function. Inhibin greatly reduces the release of FSH while testosterone inhibits the secretion of LH.

Suggested Reading

Sinha Hikim AP, Amador A, Klemcke H, Bartke A, Russell LD. Correlative morphology and endocrinology of Sertoli cells in hamster testes in active and inactive states of spermatogenesis. Endocrinology 1989;125:1829-1843.

Griswold MD. Action of FSH on mammalian Sertoli cells. In: Griswold MD, Russell LD, ed. The Sertoli Cell. Clearwater, FL: Cache River Press; 1993:493-508.

Salesse R., Remy JJ, M. LJ, Jallal B, Garnier J. Towards understanding the glycoprotein hormone receptors. Biochemie 1992;73(l):109-120.

Fritz I. Sites of actions of androgens and follicle stimulating hormone on cells of the seminiferous tubule. In: Litwack G, ed. Biochemical Actions of Hormones. New York: Academic Press; 1978:249-278.

Cooke BA, Choi MC, Dirami G, Lopez-Ruiz MP, West AP. Control of steroidogenesis in Leydig cells. J Steroid Biochem Mol Biol 1992;43(5):445-449.