Redrawn with permission of The Endocrine Society. Convincing evidence supporting the premise that FSH secretion in men is regulated by the negative feedback action of testicular inhibin is at last accumulating. Many years ago, it was demonstrated that selective hypersecretion of FSH could exist in the face of normal T levels in men with azoospermia Initial measurement of circulating inhibin levels by RIA in such men failed to reveal the expected inverse relationship between FSH and the testicular protein The inhibin hypothesis suffered a further set back when specific ELISAs for inhibin A, one of two dimeric forms of the mature hormone, failed to detect this molecule in the circulation of normal men Thus, it is reasonable to reaffirm the proposal that testicular inhibin is the major gonadal signal regulating the secretion of FSH in the human male, a conclusion that is strongly reinforced by our studies of the rhesus monkey.
Inhibin B may antagonize the paracrine action of activin by either binding to and inactivating the ligand binding subunit of the activin receptor , or by binding to a specific inhibin receptor, which in turn antagonizes the action of activin.
Neither betaglycan nor InhBP, however, has an intrinsic kinase domain , , and presumably, if these proteins serve as inhibin receptors they must do so by antagonizing the paracrine action of activin. Recent studies by Woodruff and her colleagues using suppression of activin-stimulated gene expression in a transfected cell line as an index of inhibin activity indicate that inhibin B may be the ligand favored by InhBP.
If this is the case, it may be anticipated the InhBP will be found to be highly expressed in the gonadotroph of the male primate, a species in which inhibin B is the major testicular regulator of FSH secretion in the adult. The physiological significance of the FSH-inhibin B feedback loop in the regulation of spermatogenesis in the adult monkey may be demonstrated by removing one testis and examining the impact of this perturbation on the dynamic relationship between the endocrine changes effected on the one hand and the germinal response of the remaining testis on the other As expected, unilateral orchidectomy results in a rapid and permanent deficit in circulating inhibin B levels, which is followed by a robust and sustained increase in FSH secretion in the face of only a very transient perturbation of LH and T secretion Fig.
The hypersecretion of FSH, in turn, is followed by a progressive enlargement of the remaining testis as it is driven toward its spermatogenic ceiling by the increased FSH drive Fig. It is important to note that, in the monkey, the response of the FSH-secreting gonadotroph to changes in circulating inhibin tone is robust and contrasts with the less sensitive relationship between changes in FSH levels and testicular inhibin B production This differential gain in the feedforward FSH-inhibin B and feedback inhibin B-FSH arms of this feedback loop in the monkey is responsible, after unilateral orchidectomy, for the persistent error signal a decrease in circulating inhibin B at the hypophysial level for the release of FSH; it is therefore the key element underlying the ability of this feedback control system to set the level of circulating FSH, thereby regulating the rate of sperm production in the monkey That the FSH-inhibin B feedback loop in men may operate in a manner similar to that described for the monkey is suggested by the finding that whereas chronic FSH treatment of men with idiopathic fertility was associated with an increase in testicular volume, circulating inhibin B levels in these subjects did not respond to FSH stimulation Moreover, in normal men, administration of a large dose of rhFSH that resulted in an approximately 7-fold increase in circulating concentration of the gonadotropin elicited only a fold increase in plasma inhibin B levels Although unilateral orchidectomy in men see above is usually associated with elevated FSH secretion, in contrast to the monkey, the hypersecretion of gonadotropin was not restricted to FSH , — Changes in circulating inhibin B concentrations top panel , circulating FSH concentrations middle panel , and testicular volume of the remaining testis bottom panel after unilateral orchidectomy on d 0 in a group of adult male rhesus monkeys.
Before closing our discussion on the regulation of FSH secretion, it is important to state that the release of this gonadotropin in male primates is not insensitive to inhibition by testicular steroids.
In fact, supraphysiological plasma levels of either T or E2, achieved by administration of exogenous steroid, dramatically suppress circulating FSH concentrations in normal men and male macaques — , probably by exerting actions at both the pituitary and hypothalamic levels — The relative contribution of such steroid inhibition in the feedback control system governing FSH secretion in a physiological setting, however, appears to be noticeably less important than that produced by the inhibin B signal.
In normal men, abolishing testicular steroidogenesis with ketoconazole, although largely preserving the inhibin B tone in these subjects, resulted in a minor increase doubling in circulating FSH concentrations This is to be compared with the dramatically elevated levels of circulating FSH observed in the absence of all testicular feedback signals in castrate or hypogonadal men The steroid component of the testicular inhibition of FSH secretion in men appears to be mediated by ER activation in response to an E2 signal generated either by secretion of the steroid directly from the testis or by peripheral or central neural aromatization of secreted T.
This view is based on several findings. A simple model that describes the role and operation of the FSH-inhibin B feedback loop in the maintenance of spermatogenesis in the testis of the adult primate is shown in Fig. According to this model, the circulating concentration of FSH is posited to provide the signal that sets the level of sperm production above the basal rate induced by intratesticular T.
The action of FSH on the germ cells is indirect and mediated by a paracrine signal s of Sertoli cell origin that acts as a survival factor for differentiated spermatogonia and therefore amplifies a basal level of spermatogenesis that is maintained by T.
FSH secretion, although absolutely dependent on pulsatile GnRH stimulation, is relatively insensitive to frequency modulation of the hypophysiotropic signal, and the rate of FSH secretion is selectively dictated by the negative feedback action of testicular inhibin B secreted by the Sertoli cell. Although proteins that specifically bind inhibin have been described, the relative importance of these putative receptors or coreceptors in mediating the action of inhibin B at the level of the primate gonadotroph remains to be established.
An essential feature of this feedback control system is that the feedback arm of the loop inhibin B-FSH is more robust than the feedforward arm FSH-inhibin B , and thus, a change in the testicular feedback signal inhibin B results in a sustained perturbation to FSH secretion.
The physiological set point of the feedback loop is such that the circulating concentration of FSH is insufficient to drive the seminiferous tubule to its ceiling of operation.
The latter finding is consistent with the notion that the spermatogenic ceiling of the adult primate testis may be set by the size of the population of renewing stem Ap spermatogonia extant upon completion of puberty rather than by the number of Sertoli cells established at this stage of development.
Although the pubertal proliferation of Sertoli cells appears to be produced by an combined action of FSH and LH, the endocrine drive underlying division of Ap spermatogonia at this stage of development is less clear.
From a physiological perspective, an unresolved question concerns the cell biology that inversely couples production of mature germ cells with inhibin B secretion, but presumably, feedback signals from the germ cells to the Sertoli cell must be involved. A model of the negative feedback control system that regulates sperm production by the primate testis.
According to this model, FSH amplifies a basal level of spermatogenesis that is dependent on intratesticular T. The degree of amplification is directly related to the circulating concentration of FSH, and the FSH drive is relayed to the germinal epithelium via the production of a paracrine factor by the Sertoli cell. This paracrine factor favors the survival of differentiated B spermatogonia B , which leads to an increase in the number of subsequent generations of germ cells. The mechanism that controls the rate of inhibin B secretion by the testis 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.
With regard to the issue of fertility control on the one hand and the treatment of infertility in men on the other, we are of the following opinion. From the extant data, it seems reasonable to conclude that interruption of the feedforward arm of this control system in men and other male primates i.
The question of the quality of the sperm produced in the absence of FSH, however, remains to be answered. The view that FSH is not required for fertility is epitomized by the contemporary finding that men with an inactivating mutation of the FSH-R can be fertile. Because biological systems exhibit redundancy and plasticity, the impact of the loss of a gene from conception may be later compensated for by an alternate pathway.
Indeed, in the monkey, the postpubertal interruption of FSH action using immunoneutralization was found to be associated with infertility. Therefore, in our view, the question of whether a complete and specific abolition of FSH signal transduction imposed after puberty in the human male would be associated with infertility remains to be answered.
The issue of a super inhibin receptor agonist as a male contraceptive must await resolution of the latter question. As for male infertility, the value of FSH treatment, particularly in subsets of subjects with idiopathic infertility, should not be dismissed at the present time. Zeleznik for discussing FSH signaling with us, and Dr. Talal El-Hefnawy for his translation of the reference in Swedish We also thank June M. Marshall for help with the illustrations. Nat Genet 15 : — Google Scholar.
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Normal testicular function is dependent upon hormones acting through endocrine and paracrine pathways both in vivo and in vitro. Sertoli cells provide factors necessary for the successful progression of spermatogonia into spermatozoa. Sertoli cells have receptors for follicle stimulating hormone FSH and testosterone which are the main hormonal regulators of spermatogenesis.
Menstrual periods become less frequent and finally cease; this process is known as menopause. There are still eggs and potential follicles on the ovaries, but without the stimulation of FSH and LH, they will not produce a viable egg to be released.
The outcome of this is the inability to have children. Various symptoms are associated with menopause, including hot flashes, heavy sweating, headaches, some hair loss, muscle pain, vaginal dryness, insomnia, depression, weight gain, and mood swings.
Estrogen is involved in calcium metabolism and, without it, blood levels of calcium decrease. To replenish the blood, calcium is lost from bone, which may decrease the bone density and lead to osteoporosis. Supplementation of estrogen in the form of hormone replacement therapy HRT can prevent bone loss, but the therapy can have negative side effects, such as an increased risk of stroke or heart attack, blood clots, breast cancer, ovarian cancer, endometrial cancer, gall bladder disease, and, possibly, dementia.
Privacy Policy. Skip to main content. Animal Reproduction and Development. Search for:. Hormonal Control of Human Reproduction. Male Hormones The onset of puberty is controlled by two major hormones: FSH initiates spermatogenesis and LH signals the release of testosterone.
Learning Objectives Explain the function of male hormones in reproduction. FSH causes the Sertoli cells of the testes which help nurse developing sperm cells to begin the process of spermatogenesis in the testes. LH triggers the production of testosterone from the Leydig cells of the testis; testosterone causes the development of secondary sex characteristics in the male. As spermatogenesis and testosterone production increase, the Sertoli cells produce inhibin, which, together with rising levels of testosterone, inhibit the release of FSH and LH from the pituitary gland.
Female Hormones The stages of the ovarian cycle in the female are regulated by hormones secreted by the hypothalamus, pituitary, and the ovaries.
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