Ho

estradiol-17ß

FIGURE 5 Biosynthesis of testicular steroids. Catalyzed changes at each step are shown in blue. Testosterone comprises more than 99% of testicular steroid hormone production.

enzyme P450arom (aromatase) and may also convert androgens to estrogens. Estradiol is present in seminal fluid and may be essential for reabsorption of seminal tubular fluid in the rete testis. The presence of estrogen receptors in the epididymis and several testicular cells, including Leydig cells, suggests that estradiol may have other important actions in normal sperm formation and maturation.

Germinal Epithelium

The function of the germinal epithelium is to produce large numbers of sperm that are capable of fertilization.

The Sertoli cells, which are interposed between the developing sperm and the vasculature, harbor and nurture sperm as they mature. Sertoli cells are the only cells known to express FSH receptors in human males and therefore are the only targets of FSH. In the immature testis, FSH increases Sertoli cell proliferation and differentiation and probably maintains their functional state throughout life; in its absence, testicular size is severely reduced and sperm production, which is limited by Sertoli cell availability, is severely restricted. It has been known for many years that FSH, LH, and testosterone all play vital roles in spermatogenesis. It is likely that FSH indirectly regulates development of spermatogonia by stimulating Sertoli cells to produce both growth and survival factors that prevent germ cell apoptosis. Withdrawal of FSH and LH arrests spermato-gonial development, which is the major rate-limiting step in spermatogenesis. Once formed, spermatocytes progress through meiosis normally in the absence of gonadotropic support. Although FSH and testosterone are required for initiation of normal rates of spermato-genesis, sperm formation can be maintained indefinitely with very high doses of testosterone alone or with sufficient LH to stimulate testosterone production.

Sertoli cells lack receptors for LH but are richly endowed with androgen receptors, indicating that the actions of LH on Sertoli cell function are indirect and are mediated by testosterone, which reaches them in high concentration by diffusion from adjacent Leydig cells, and perhaps also by peptide factors produced by Leydig cells. Testosterone readily passes through the blood-testis barrier and is found in high concentrations in seminiferous fluid. However, the absence of androgen receptors in developing human sperm cells indicates that support of sperm cell development by testosterone is also exerted indirectly by way of the Sertoli cells. Although testosterone is critically important for sper-matogenesis, it is ineffective in this regard when administered in amounts sufficient to restore normal blood concentrations. For reasons that are not understood, the intratesticular concentration needed to support spermatogenesis is many times higher than that necessary to saturate androgen receptors. The concentration of testosterone in testicular venous blood is 40 to 50 times that found in peripheral blood, and its concentration in aspirates of human testicular fluid is more than 100 times higher than the concentration found in blood plasma.

The FSH receptor is closely related to the LH receptor, and, when stimulated, activates adenylyl cyclase through the agency of the stimulatory alpha G protein (Gas; see Chapter 2). The resulting activation of protein kinase A catalyzes phosphorylation of proteins that regulate the cytoskeletal elements that maintain the tortuous shape of these cells, production of the membrane glycopro-teins that govern adherence to developing sperm, and expression of specific genes that code for proteins that directly and indirectly regulate germ cell development (Fig. 6). Some of the proteins secreted by Sertoli cells into the seminiferous tubules are thought to facilitate germ cell maturation in the epididymis and perhaps more distal portions of the reproductive tract. Upon stimulation by FSH, Sertoli cells may also secrete paracrine factors that enhance Leydig cell responses to LH.

FSH and testosterone have overlapping actions on Sertoli cells and act synergistically, but the precise actions of each remain unknown. Recently described "experiments of nature'' have shed some light on the relative importance of FSH and testosterone in spermatogenesis. Inactivating mutations of the p subunit of LH in humans

Leydig cell

Sertoli cell

FIGURE 6 Actions of FSH and LH on the testis. FSH acts directly only on Sertoli cells, while LH acts directly solely on Leydig cells. Paracrine cross-talk between mediated by growth factors likely takes place between Sertoli and Leydig cells and between Sertoli cells and germ cells. cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cAMP response element binding protein; StAR, steroid acute regulatory protein; P450c17, 17a hydroxylase/lyase; AR, androgen receptor; AMH, anti-miillerian hormone; ABP, androgen-binding protein.

Leydig cell

Sertoli cell

FIGURE 6 Actions of FSH and LH on the testis. FSH acts directly only on Sertoli cells, while LH acts directly solely on Leydig cells. Paracrine cross-talk between mediated by growth factors likely takes place between Sertoli and Leydig cells and between Sertoli cells and germ cells. cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cAMP response element binding protein; StAR, steroid acute regulatory protein; P450c17, 17a hydroxylase/lyase; AR, androgen receptor; AMH, anti-miillerian hormone; ABP, androgen-binding protein.

or rodents results in total failure of spermatogenesis, despite normal prenatal sexual development (see below), suggesting that testosterone is indispensable. In contrast, inactivating mutations of the gene for the FSH receptor did not prevent affected men or mice from fathering offspring. Thus, FSH apparently is not absolutely required for spermatogenesis, but the patients and rodents with inactive FSH receptors had small testes, low sperm counts, and a preponderance of defective sperm. Stimulation by FSH at some period of life, then, is required for production of a normal quantity and quality of sperm.

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