Hormonal Regulation Of Spermatogenesis

The central role of the pituitary to stimulate spermatogenesis5 in adult primates was established nearly 60 yr ago (5). Surgical removal of the pituitary gland in rhesus

5 In the context of this discussion, spermatogenesis is defined as the production of testicular spermatozoa whether one or many.

Fig. 2. A schematic representation of the two mechanisms of stem cell renewal in higher primates. The top two diagrams illustrate the scheme that is common to rhesus monkey (Macaca mulatta), African green monkey (Cercopithecus atheops), and, perhaps, man (Homo sapiens). All type Ap sper-matogonia divide in stage IX; one half of the population produce more Ap spermatogonia and the other half divide and produce type B1 spermatogonia (B1). The B1 spermatogonia divide in stage XII and produce B2 spermatogonia (B2). The number of Ap spermatogonia remains constant throughout the cycle of the seminiferous epithelium of these primate species. The bottom diagram shows the scheme that is common to stump-tailed macaque (M. arctoides) and the crab-eating macaque (M. fas-cicularis). As in the first scheme, all Ap spermatogonia divide, but, in stage VIII and in contrast to the first scheme, only type Ap spermatogonia are produced, resulting in twice as many Ap spermatogonia stage IX. In stage X, half of the population of Ap spermatogonia divide and produce only type B1 spermatogonia. The remaining half of the Ap spermatogonia do not divide until stage VIII of the next cycle. As in the first scheme, the B1 spermatogonia divide in stage XII and produce B2 spermatogonia (B2). This latter scheme of stem cell renewal suggests that the mitoses of Ap spermatogonia are symmetrical. (Drawn after ref. 20.)

monkeys resulted in a precipitous decline in testicular size associated with the complete regression of the seminiferous epithelium to the extent that the tissue comprised only type A spermatogonia and Sertoli cells. More recent experiments using monkeys rendered hypogonadotropic, hypogonadal by either surgical or chemical hypophysec-tomy, have confirmed Smith's earlier observation and have extended it by demonstrating that replacement of testosterone stimulates testicular growth to approx 60% of the pretreatment size (43-45). The gonadal growth primarily resulted from stimulation of spermatogenesis by the androgen, but morphometric analysis of the seminiferous epithelium revealed that the smaller testicular size was accounted for by a deficit in the numbers of all type B spermatogonia. FSH replacement in testosterone-

treated hypophysectomized adults resulted in a greater number of all four generations of type B spermatogonia (46). These results led to the conclusion that testosterone alone stimulates spermatogenesis but FSH is necessary to restore spermatogenesis completely. FSH was posited to accomplish this effect by rescuing type B spermatogonia from programmed cell death.

Unilateral orchidectomy in adult macaques results in the compensatory growth of the remaining testis (46,47). The number of Sertoli cells per testis was identical in the gonad removed at the time of unilateral orchidectomy and in the gonad that remained in the animal for 45 d. By contrast, the number of all germ cells more mature than type Ap spermatogonia was greater in the remaining testis than in the unilateral orchidectomy specimen. Moreover, the removal of one testis was occasioned by a transient decline in testosterone that, in turn, led to a transient increase in LH. By 4 d after surgery, the testosterone and LH concentrations returned to baseline values. The removal of one gonad in these primates was accompanied by a decline in inhibin B levels, which is secreted by Sertoli cells into the circulatory system. FSH concentrations in the circulation increased, confirming the important role of inhibin B in the negative feedback control of FSH secretion.

A model that describes the role and operation of the FSH-inhibin B feedback loop in the stimulation of spermatogenesis in the adult primate is shown in Fig. 3 (48). The circulating FSH concentration is postulated to set the level of sperm production above the basal rate induced by intratesticular testosterone. This FSH action on the germ cells is indirect and mediated by the Sertoli cells. The Sertoli cells stimulated by FSH produce a paracrine factor that rescues or prevents programmed cell death of the type B spermatogonia. The survival of these cells amplifies the basal level of germ cell production that is maintained by testosterone. FSH secretion is dependent on stimulation by pulsatile GnRH. The rate of FSH secretion is selectively dictated by the negative feedback action of testicular inhibin-B. The feedback arm of the loop (inhibin-B-FSH) must be more robust than the feedforward arm (FSH-inhibin-B) for a change in the testicular feedback signal (inhibin-B) to elicit a sustained perturbation to FSH secretion.

In contrast, other investigators have presented results that support the belief that the FSH action to increase the number of germ cells in the primate testis is indirect on type Ap spermatogonia, the renewing stem cells (49-51). For example, FSH administration to adult macaques resulted in an increase in the type Ap spermatogonia in the seminiferous epithelium; however, but an analysis using the kinetics of spermatogen-esis does not support the theory that the increase in germ cell production results from an FSH action to increase the number of Ap spermatogonia (45,48).

In adult crab-eating macaques rendered hypogonadotropic for several weeks either by surgical ablation of the pituitary or by pharmacological suppression of gonadotropin secretion using GnRH-analogs or antagonists, a reduction in the total number of Ap spermatogonia was observed, in association with a profound depletion in all more mature germ cells (43,50-52). However, the population of Ap spermato-gonia was not decreased in five normal men rendered hypogonadotropic during 19-24 wk of treatment with an androgen ester, testosterone enanthate, although a reduction of all germ cells more mature than type A spermatogonia was reported (53). That the loss of FSH action may have contributed to the reduction in the population of Ap spermatogonia during chemical hypophysectomy in the crab-eating macaque

Regulation Spermatogenesis

Spz f

Fig. 3. A model of the negative feedback control system that regulates sperm production by the primate testis. According to this model, follicle-stimulating hormone (FSH) amplifies a basal level of spermatogenesis that is dependent on intratesticular testosterone (T). The degree of amplification is directly related to the circulating concentration of FSH, and the FSH drive is relayed to the seminiferous epithelium via the production of a paracrine factor by the Sertoli cell. This factor favors the survival of differentiated B spermatogonia (B), which leads to an increase in the number of subsequent generations of germ cells. The FSH concentration is regulated by the rate of secretion of inhibin-B (INH-B) by the Sertoli cell. Inhibin-B exerts a brake on FSH secretion by suppressing expression of FSHP gene expression. The mechanism that controls the rate of inhibin-B secretion is controversial, but in the present model, a signal(s) from the differentiated germ cells is proposed to positively regulate inhibin-B production by the Sertoli cell. The intensity of the putative germ cell signal is posited to be related to the number of differentiated germ cells. P, primary spermatocyte; S, round spermatid; Spz, elongating spermatid and testicular spermatozoa; pit, pituitary gland. (From ref. 48. Reprinted with permission of the Endocrine Society.)

was suggested by the finding that initiation of FSH treatment, coincident with the start of GnRH antagonist administration in another group of animals, prevented Ap spermatogonia depletion (50). It should be noted that LH action may also maintain the population of Ap spermatogonia because the number of this cell type in the testis of testosterone-treated, hypophysectomized macaques was similar to that of intact animals (43). This gonadotropin action on Ap spermatogonia may be permissive; that is, allowing these undifferentiated spermatogonia to divide each cycle and survive. In contrast, the regulatory action of FSH that determines the number of differentiated, or type B, spermatogonia that survive. Clearly, further study of the role of the gonadotropins in this regard is necessary.

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Responses

  • travis
    How is spermatogenesis regulated?
    4 years ago
  • niina
    Which factor favors spermatogenesis?
    2 years ago

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