Role of FSH in the Control of Testicular Function

Abstract

Follicle stimulating hormone (FSH) binds to the plasma membranes of Sertoli cells and, apparently, spermatogonia; the hormone may then be taken into the cytoplasm of its target cells and metabolized there. In the immature testis, binding of FSH to Sertoli cells leads to activation of adenylate cyclase, formation of cyclic AMP (cAMP), and activation of a cAMP-dependent protein kinase. There is a subsequent increase in the rates of RNA, protein, and DNA synthesis. Normal adult testis is unresponsive to FSH, one reason being the destruction of cAMP by a phosphodiesterase. After hypophysectomy of adult animals this enzyme disappears and FSH is again able to stimulate RNA and protein synthesis. Other factors contributing to the insen-sitivity of the mature testis are an FSH binding inhibitor, a protein kinase inhibitor, and in-activation of FSH.

FSH increases the formation by Sertoli cells of structural proteins and an androgen-binding protein (ABP) that the Sertoli cells secrete into the extracellular fluid surrounding the cells of the germinal epithelium. It is thought that ABP buffers fluctuations in the concentration of androgen in the extracellular fluid of the germinal epithelium as well as transporting androgen to the lumen of the epididymis.

In immature animals FSH increases the number of Sertoli cells, which accounts for the testicular hypertrophy that follows hemicastration. FSH is responsible for maturational changes in immature Sertoli cells and for morphological changes associated with in vitro aggregation of Sertoli cells to form colonies. FSH-induced changes in the shape of Sertoli cells are mediated by a calcium-dependent regulator protein, calmodulin. FSH also stimulates the Sertoli cells to secrete a plasminogen activator whose role is not known.

FSH has effects on testicular germ cells in immature animals and during the restoration of spermatogenesis in adults, but it is not known whether the Sertoli cells mediate its actions on the germ cells, though this would seem likely. Administration of FSH to immature rats and mice increases the number of spermatogonia by reducing the proportion that degenerate. This may be due to a stimulatory effect of the hormone on DNA synthesis. Androgen and FSH appear to act synergistically to stimulate accumulation of primary spermatocytes and formation of spermatids in immature rats. During the restoration of spermatogenesis in adult rats and mice FSH also acts synergistically with androgen, increasing the proportions of cells passing through meiosis and spermiogenesis. Immunization experiments suggest that FSH is needed for the formation of normal numbers of spermatocytes and spermatids in immature animals, but studies in adults have given conflicting results.

FSH appears to influence development of the interstitial tissue, particularly by inducing luteinizing hormone (LH) receptors on Leydig cells. The presence of some LH may be necessary for FSH to have this effect. FSH can stimulate a number of steroid transformations, such as conversion of testosterone to dihydrotestosterone (DHT), in Sertoli cells from immature rats but there is no conclusive evidence that the gonadotropin is capable of stimulating the critical step in steroidogenesis, production of pregnenolone from cholesterol. FSH also stimulates Sertoli cells from immature rats to convert testosterone to a substance cross-reacting with antibodies to estradiol. It has been suggested that loss of the ability of FSH to stimulate estrogen production in maturing Sertoli cells allows the Leydig cells to secrete increased amounts of androgen at puberty.

Highly purified preparations of human gonadotropins are not available in sufficient quantity for clinical use. Menopausal gonadotropin, which contains LH as well as FSH activity, stimulates proliferation of immature Sertoli cells and spermatogonia and formation of spermatocytes in prepubertal boys. Treatment with human chorionic gonadotropin (hCG) has similar effects but in addition early spermatids are formed when both preparations are given together. Stimulation of spermatogenesis and, rarely, fertility have occurred in a proportion of eunuchoidal men treated with gonadotropin preparations containing both FSH and LH activity, and combined treatment has also stimulated spermatogenesis after hypophysectomy. Unfortunately gonadotropin treatment has benefited only a small proportion of azoospermic or oligozoospermic men not suffering from androgen deficiency. Isolated deficiency of FSH has been reported in four men but these reports throw little light on the role of FSH in the control of testicular function in normal men.

Most studies in immature animals leave little doubt that FSH has an essential role in the stimulation of developmental changes in the testis. At this stage androgen secreted in response to LH may act synergistically with FSH on the germinal tissue. In the normal mature testis it is not clear whether there is a requirement for FSH. If so, its place is subordinate to that of androgen.

Key Words:

• FSH
• Testicular function
• cAMP
• Sertoli cell
• Spermatogenesis