figure 12-8 Schematic diagram of the male hypothalamic-pituitary-testicular axis. Abbreviations: LH, luteinizing hormone; GnRH, gonadatropin-releasing hormone; FSH, follicle-stimulating hormone; T, testosterone; E2, estradiol. Dashed lines indicate a negative influence, and solid lines indicate a positive influence. This figure should be compared with Figure 13-6, which diagrams the female hypothalamic-pituitary-ovary axis.

region of the hypothalamus. Destruction of the arcuate nucleus of the brain leads to decreased secretion of both LH and testosterone. Neurons having their origins in the central nervous system impinge upon hypothalamic cells and locally secrete catecholamines, endorphins, and/or dopamine, which results in the episodic production and release of GnRH into the hypophyseal portal system. The presence of GnRH on specific ade-nohypophyseal cell membrane receptors then results in the release of LH. The LH is transported systemically to the Leydig cells of the testes.

In the human, the Leydig cells differentiate and begin secretion of testosterone during the seventh week of fetal life; during the same time interval there is also activation of the fetal pituitary secretion of LH. Then, following birth, the Leydig cells revert to a relatively undifferentiated state until they are again activated at puberty (see also Figure 12-7).

B. Leydig Cell Control and Function

Figure 12-9 illustrates the complexity of the local anatomical organization of the Leydig cells and seminiferous tubules in the testes. Although it is pedagogi-cally useful to consider the physiological relationships of the testis Leydig cells and Sertoli cells as separate topics, it is quite clear that their activities are intimately related. In this regard, it is helpful to understand the cellular distribution of the male hormone receptors in this system. Although it is known that LH is able to produce biological responses in both Leydig and Sertoli cells, receptors for LH are found only on the Leydig cells. This implies that the LH actions in Sertoli cells are mediated through paracrine processes. Receptors for FSH are present principally on Sertoli cells and to some extent on spermatogonia. In addition, functional androgen nuclear receptors have been demonstrated in Leydig, Sertoli, and peritubular cells.

Leydig cells serve two principal functions: (a) they are the site of production of testosterone, producing approximately 7 mg daily for systemic transport to distal target tissues; and (b) they initiate paracrine interactions with the immediately adjacent seminiferous tubules and Sertoli cells to influence the process of spermatogenesis (see Figures 12-3 and 12-8).

LH-mediated stimulation of testosterone synthesis and secretion is initiated by the binding of LH to hormone-specific receptors on the outer membranes of the Leydig cell, which results in the concomitant production of cAMP inside the cell. During puberty, as a consequence of the increased secretion of LH, an increase in the secretion of testosterone by the Leydig cells results. In some circumstances, prolactin, through binding to its Leydig cell membrane, is also known to potentiate the actions of LH on testosterone production.

The rate of testosterone biosynthesis and secretion is positively correlated with the blood levels of LH. The secretion of the gonadotropin can be diminished by increasing blood concentrations of sex steroids (both testosterone and estradiol), which facilitate their binding to steroid receptors in both the hypothalamus and pituitary; this is termed "suppressive negative feedback." In circumstances of a fall in the blood levels of testosterone and estradiol, LH levels can increase; this is termed the "recovery phase of negative feedback." The precise details of the feedback mechanisms are not yet clear. Since both androgens and estrogens potentially are subject to further metabolism in selected regions of the hypothalamus, it is possible that the initiating signal for the reduction of LH secretion is a metabolite of the sex steroid (T or E2) rather than the parent steroid. It is believed that the feedback effects on LH secretion are mediated both by influencing the amount of GnRH released by the hypothalamus and by changing the sensitivity of the adenohypophyseal LH-secreting cells to GnRH.

C. Seminiferous Tubule Function

During puberty, due to the increased secretion of hypothalamic GnRH and FSH, there is a maturation of the Sertoli cells in terms of both their biochemical capability as well as their cellular anatomical development. Thus, the blood-testis barrier (see Figure 123) forms at puberty, and the Sertoli cells initiate five

seminiferous ' ; ' tubule

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