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The Functional Significance of FSH in Spermatogenesis and the Control of Its Secretion in Male Primates

Departments of Cell Biology and Physiology (T.M.P.) and Medicine (G.R.M.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Correspondence: Address all correspondence and requests for reprints to: Tony M. Plant, Ph.D., Department of Cell Biology and Physiology, University of Pittsburgh, S-828A Scaife Hall, 3500 Terrace Street, Pittsburgh, Pennsylvania 15261. E-mail: plant1+{at}pitt.edu

	Abstract

Top Abstract I. Introduction II. Site of FSH... III. Sertoli Cell Ontogeny... IV. The Role of... V. Regulation of FSH... VI. Summary References

 
The aim of this review is to provide an integrative analysis of the role of FSH in the control of testicular function in higher primates, including man. Attention is focused on the action of FSH during neonatal development, puberty, and adulthood. Whether FSH is the major determinant of the adult complement of Sertoli cells and whether FSH is obligatory for the initiation, maintenance, and restoration of spermatogenesis is evaluated. The mechanism whereby the circulating concentration of FSH regulates spermatogonial proliferation to dictate the sperm production rate under physiological conditions in the adult is discussed in detail. Inhibin B is the major component of the testicular negative feedback signal governing FSHß gene expression and FSH secretion, and the evidence for this view is presented. The review concludes with the presentation of a model for the operation of the FSH-inhibin B feedback control system regulating sperm production postpubertally in monkey and man, and with speculation on issues of clinical interest.

I. Introduction

II. Site of FSH Action in the Testis

III. Sertoli Cell Ontogeny and the Role of FSH

IV. The Role of FSH in Spermatogenesis

A. Background

B. Experimental paradigms

C. Initiation of spermatogenesis

D. Maintenance of spermatogenesis

E. Restoration of spermatogenesis

F. Regulation of sperm number

G. Determination of sperm quality

V. Regulation of FSH Secretion

VI. Summary

	I. Introduction

Top Abstract I. Introduction II. Site of FSH... III. Sertoli Cell Ontogeny... IV. The Role of... V. Regulation of FSH... VI. Summary References

 
THIS REVIEW WAS prompted, in part, by the original studies of FSH-deficient transgenic mice (1) and of men with inactivating mutations of the FSH receptor (2), indicating that FSH may not be an absolute requirement for male fertility. The unconditional acceptance of such a notion would have considerable impact on future directions of research taken to elucidate the cell biology underlying testicular function, and on strategies adopted either for treatment of male infertility or for the development of novel approaches for male contraception. Therefore, a critical evaluation of the role of FSH in the initiation and maintenance of testicular function in higher primates¹ is timely. This is particularly pertinent because spermatogenesis and its hormonal control appear to exhibit marked species differences. Most notably, although hypophysectomy of adult primates leads, as it does in rats, to regression of the seminiferous epithelium, in the former species only Sertoli cells and stem spermatogonia remain after removal of the pituitary, whereas in the rat spermatogenesis is arrested during spermiogenesis (4, 5, 6, 7). It is unlikely that this species difference is due to incomplete ablation of the rodent pituitary, as originally suggested by Smith (8), because spermatogenesis is also arrested during spermiogenesis in rats chemically hypophysectomized with a GnRH receptor (GnRH-R) antagonist, which dramatically suppresses gonadotropin secretion (9, 10, 11). Thus, in primates the gonadotropic hormones are obligatory for development of differentiated spermatogonia, spermatocytes, and spermatids, whereas in rats it appears that a limited number of spermatids may be produced in the absence of a gonadotropin drive.

	II. Site of FSH Action in the Testis

Top Abstract I. Introduction II. Site of FSH... III. Sertoli Cell Ontogeny... IV. The Role of... V. Regulation of FSH... VI. Summary References

 
FSH action is exerted on cells expressing the FSH receptor (FSH-R), and the pathways underlying the transduction of a FSH signal have been recently reviewed in detail for this journal by others (12). In brief, the binding of FSH to its receptor results in a dissociation of the -subunit of the receptor-associated Gs protein, which, in turn, leads to the activation of adenylyl cyclase and production of cAMP. cAMP releases the catalytic subunit of PKA, allowing for phosphorylation of numerous intracellular proteins including the transcriptional activator, cAMP response element binding protein. Other pathways for FSH signal transduction have been proposed, but the relative importance of these in mediating FSH action on the testis in vivo is unclear (12).

In the cynomolgus monkey (Macaca fascicularis), expression of the FSH-R has been found only in the testis (13), and with the exception of the observations of Orth and Christensen (14, 15), studies of several nonprimate species have demonstrated that FSH binding in the testis is restricted to the Sertoli cell (see Ref. 12). The foregoing results have led to the widely accepted view that the Sertoli cell is the only target of FSH action in the male (12).

Sertoli cells are of central importance to the spermatogenic function of the testis for many reasons (16). These somatic cells maintain the cytoarchitecture of the germinal epithelium, produce nutrients that provide energy substrates to the germ cells and, in the primate, represent the only cellular component of the blood-testis barrier (17, 18). An important concept deriving from the cytoarchitectural and nutritional functions of the Sertoli cell is that each Sertoli cell can support the development of only a limited number of germ cells (19, 20). Thus, the complement of Sertoli cells in the adult testis dictates, in part, fertility because it is generally recognized that the density of sperm in an ejaculate is a significant parameter of fertility (21, 22). The latter dogma is supported by a recent retrospective study that reported that birth rate in a North American state (Minnesota) over a period of 24 yr fluctuated inversely with sperm density measured during this period in a population of 660 men who were being screened before vasectomy (23). It should be noted that the sperm counts of these men were in the range generally accepted to be fertile (21). In addition, the World Health Organization study of the contraceptive efficacy of T enanthate revealed that in those men rendered oligospermic by administration of the steroid ester, pregnancy rates were directly related to sperm concentration (24). For the foregoing considerations, the determinants of the number of Sertoli cells in the adult testis become important to understand.

	III. Sertoli Cell Ontogeny and the Role of FSH

Top Abstract I. Introduction II. Site of FSH... III. Sertoli Cell Ontogeny... IV. The Role of... V. Regulation of FSH... VI. Summary References

 
Sertoli cells first appear in the fetal human testis at approximately 8 wk of age (25), and at birth the testis of the infant contains approximately 10% of the adult complement of 4000 million cells (26). The findings that anencephaly in man (27) and fetal hypophysectomy in the rhesus monkey, M. mulatta (28), result at term in a marked reduction in testicular size suggests that gonadotropin secretion by the fetal pituitary plays an important role in regulating Sertoli cell proliferation in utero. The relative role of FSH in this regard is unclear, although the primate Sertoli cell expresses FSH-R early in development, as indicated by the finding of specific high affinity binding of radiolabeled FSH in homogenates of fetal testes from man and rhesus monkey at 8–16 and 19–22 wk gestation, respectively (29).

Sertoli cells continue to proliferate postnatally, as reflected by the finding that, in both monkey and man, the number of this cell type increases by a factor of 4–30 between infancy and adulthood (26, 30, 31). Although the temporal aspects of postnatal Sertoli cell proliferation have not been precisely described for any higher primate, two models may be proposed from the extant data (Fig. 1). A central feature of both schemata is a striking pubertal increase in Sertoli cell proliferation in association with the elevation in gonadotropin secretion that occurs at this stage of development. Two temporal patterns of Sertoli cell proliferation before puberty in higher primates may be proposed. The mitosis of Sertoli cells may occur throughout the entire prepubertal period (infantile and juvenile development), or alternatively, the prepubertal proliferation of this cell type may be restricted to infancy, a phase of development in Old World monkeys and man when gonadotropin secretion is elevated, as at the time of puberty (32).

View larger version (44K): [in this window] [in a new window]   Figure 1. Schemata of two hypothetical patterns of Sertoli cell proliferation during postnatal development in higher primates. For man, the ordinate would span 12–15 yr and for the monkey, 3–5 yr. The quantitative changes represented are based on data from the monkey (31 ) and may vary with species. The upper panel shows a biphasic mode of Sertoli cell proliferation with two distinct periods of mitosis: the first occurs during infantile development, and the second is initiated at the onset of puberty. In this model, Sertoli cell mitosis is dependent on the elevations in the secretion of both FSH and LH, which occur at infancy and again at puberty, as shown by the shaded ghost. The lower panel shows a pattern of Sertoli cell proliferation that is initially gonadotropin independent, occurs insidiously before the onset of puberty, and is followed, as in the first schemata, with a gonadotropin-dependent burst in Sertoli cell mitosis at puberty. I, Infant; J, juvenile; P, pubertal; PP, postpubertal.

That Sertoli cell mitosis at the time of primate puberty is driven by the gonadotropic hormones is confirmed by the finding that proliferation of Sertoli cells may be induced precociously in juvenile rhesus monkeys, in which the pituitary-testicular axis is prematurely activated by intermittent stimulation with GnRH (31). FSH plays an important role in this process, as indicated by the findings that in the juvenile rhesus monkey, pulsatile stimulation with recombinant (r) human (h) FSH for 11 d resulted in a near doubling in Sertoli cell number in association with an increase in testicular size (38). This result is consistent with an earlier report of Nieschlag and his colleagues (39), who described an increase in Sertoli cell number per cross section of seminiferous cord after daily injections of purified hFSH to juvenile macaques. Although Sertoli cell number was not determined in the men described in 1997 with an inactivating mutation of the FSH-R gene, these individuals had small testicular volumes (2), also suggesting a role for FSH in the proliferation of this somatic cell type in men.

The pubertal proliferation of Sertoli cells in higher primates is probably not the consequence of an action of FSH alone, because pulsatile iv infusion of single-chain rhLH in juvenile rhesus monkeys for 11 days was as effective as rhFSH in stimulating Sertoli cell proliferation (38). Thus, it seems reasonable to propose that the gonadotropin milieu that provides the physiological stimulus for the initiation of the pubertal proliferation of Sertoli cells will be determined by the temporal relationship between the time courses of circulating FSH and LH concentrations during this developmental event. In the monkey, data describing pubertal changes in gonadotropin secretion are fragmentary, but in man an extensive literature exists on this subject. Although it was originally considered that, in boys, the increase in FSH secretion at the time of puberty preceded that of LH, application of more sensitive assays suggests that the pubertal activation of LH and FSH in the human male occurs concomitantly (32, 40, 41).

The action of LH to stimulate Sertoli cell proliferation is presumably mediated by a direct paracrine action of T secreted by the Leydig cell. This conclusion is supported by the finding that treatment of juvenile monkeys with T alone also stimulated division of this somatic cell type (39), and that primate Sertoli cells, like those of rodents, express the AR (42, 43). In this regard, it should be noted that the action of T to stimulate pituitary FSH secretion in GnRH-R antagonist-treated rodents (9, 10, 44) has not been observed in macaques (45). Additionally, the LH-induced proliferation of Sertoli cells in the juvenile monkey (38) occurs in the absence of an increase in plasma FSH concentrations (S. Ramaswamy, G. R. Marshall, and T. M. Plant, unpublished observations).

In higher primates, Sertoli cell proliferation ceases during puberty, and this stage of development is characterized by the appearance of mature or differentiated Sertoli cells, which typically exhibit a pleomorphic nucleus with a single distinctive nucleolus and specialized junctions that underlie the blood-testis barrier (17, 18). The mechanisms responsible for the differentiation of the primate Sertoli cell at the time of puberty are poorly understood. In juvenile macaques, administration of hCG, but not FSH, resulted in nuclear changes characteristic of adult Sertoli cells, and this was associated with a decline in the number of Sertoli cells expressing proliferating cell nuclear antigen (46). Moreover, because spermatogenesis is initiated in men with inactivating mutations of the FSH-R (2), it seems likely that Sertoli cell differentiation occurred in these subjects.

Before leaving the issue of Sertoli cell differentiation, the significance of the role of thyroid hormone in this regard merits discussion. Hypothyroidism in prepubertal boys may be associated with precocious enlargement of the testis in the absence of virilization (47), and this pathophysiological condition can lead to macroorchidism in adulthood (48). It seems reasonable to expect that the macroorchidism is associated with a greater than normal number of Sertoli cells because transient hypothyroidism induced in rat pups results in an increase in size of the adult testis and amplification of this cell type (49, 50, 51). Although the processes governing differentiation of the Sertoli cell appear to be arrested in the absence of thyroid hormone, those responsible for division are relatively unperturbed and as a result, the number of Sertoli cells is increased (50, 51). Thus, the role of thyroid hormone in Sertoli cell differentiation, albeit obligatory, appears to be permissive, as is the action of this hormone in other tissues. Thus, it seems reasonable to conclude that Sertoli cell differentiation in higher primates is dictated by the pubertal rise in gonadotropin secretion.

	IV. The Role of FSH in Spermatogenesis

Top Abstract I. Introduction II. Site of FSH... III. Sertoli Cell Ontogeny... IV. The Role of... V. Regulation of FSH... VI. Summary References

 
A. Background
Before presenting a discussion of the role of FSH in governing spermatogenesis in higher primates, a brief review of this process, based on the work of others (52, 53, 54, 55, 56, 57), will be presented. Spermatogenesis can be thought of as a process comprising three phases: stem cell renewal, germ cell proliferation, and spermiogenesis. Stem cell renewal is the mechanism that guarantees that a large and undiminishing number of undifferentiated germ cells are continually available for the subsequent steps of spermatogenesis. It is generally considered that there are two types of stem cells in higher primates: dark type A (Ad) and pale type A (Ap) spermatogonia.² The Ad spermatogonia divide rarely and are considered to provide a reserve population of stem cells. Although not extensively studied, Ad spermatogonia have been argued to play a greater role in stem cell renewal in man (59, 60, 61). Whether this putative role of Ad spermatogonia involves division of this cell type has not been established. The Ap spermatogonia, however, are actively dividing stem cells and are therefore to be viewed as the renewing stem cells (62). Ap cells divide and produce two daughter Ap cells. Ten and one-half days later, in the case of the rhesus monkey (56), these daughter cells divide; 50% replicate themselves and the other half produce the first generation of differentiated or type B spermatogonia (type B₁), which marks the beginning of the proliferative phase of spermatogenesis.³ In Old World monkeys, there are three mitotic divisions of the differentiated spermatogonia producing sequential generations of this cell type known as B₂, B₃, and B₄, respectively. This is followed by another mitotic division leading to the primary spermatocytes. Meiosis I and II results in the production of four haploid spermatids from each primary spermatocyte. Although not usually considered proliferation, meiosis also results in an increase in germ cell number and therefore contributes to and terminates the proliferative phase. In man, it has been reported that there is only one generation of B spermatogonia (59). Spermiogenesis, the last phase of spermatogenesis, comprises the morphological changes in the immature spermatids, which culminate in the generation of the highly differentiated testicular spermatozoa.

As shown in Fig. 2, there appear to be fundamental differences between the monkey and rat in the mechanism used for stem cell renewal and germ cell proliferation. According to Dym and Clermont (63), stem cell renewal in the rat involves sequential divisions to produce four generations of undifferentiated spermatogonia (A₁, A₂, A₃, and A₄), and therefore concomitantly contributes in a major fashion to germ cell proliferation.⁴ In the monkey, on the other hand, stem cell renewal follows a far simpler scheme involving only one type of undifferentiated spermatogonia (type Ap),² and therefore contributes to proliferation only indirectly by the production of the first of the four generations of differentiated B spermatogonia (Fig. 2).

View larger version (19K): [in this window] [in a new window]   Figure 2. Schematic patterns of stem cell renewal and spermatogonial proliferation in the monkey (left) and rat (right). In the monkey, Ap spermatogonia are the renewing stem cells, and the major phase of germ cell proliferation results from mitosis of differentiated type B1 to B4 spermatogonia. In rat, type A1–A4 spermatogonia are the renewing stem cells, and mitosis of these cells constitutes the major phase of germ cell proliferation. The last division of the renewing stem cells (A4) in rat leads to the first of two generations of differentiated spermatogonia [intermediate (IN) and B]. It should be noted that the schematic representation of the division of Ap in monkey and of A4 in rat does not necessarily imply asymmetric mitosis. The reserve stem cells, termed Ad spermatogonia in primates and Ao spermatogonia in rats, rarely divide. Arrows indicate mitosis. Derived from Refs. 53 and 63 . See also footnotes 2 and 4.

View larger version (58K): [in this window] [in a new window]   Figure 3. The cycle of the seminiferous epithelium of the rhesus monkey depicted in a highly schematic manner to emphasize its recurring nature. The cellular associations that define the stages of the cycle as described by Clermont (55 ) are indicated with Roman numerals I–XII. The circumference represents time, and the width of each segment is proportional to the duration of each stage, which was derived from the frequency of each stage in 1000–2000 seminiferous tubular cross sections from each of 4 adult male rhesus monkeys (G. R. Marshall, unpublished observations). The increasing intensity of the orange/red color represents maturation of the cell types as the process of spermatogenesis unfolds. Spermatogenesis begins in stage IX when half of the population of Ap spermatogonia divide and produce the first generation of type B spermatogonia (B1). Coincidentally, the remaining Ap spermatogonia also divide to produce Ap spermatogonia, thereby renewing the population of these stem cells. Spermatogenesis terminates in stage VI when S14 spermatids are released into the lumen of the seminiferous tubule. B1–B4, Four generations of type B spermatogonia; PL, preleptotene primary spermatocytes; L, leptotene spermatocytes; Z, zygotene spermatocytes; P, pachytene spermatocytes; MII, completion of meiosis; S1–S14, spermatids at each of the 14 steps of spermiogenesis. The arrows and arrowhead indicate mitosis and the completion of meiosis, respectively. A similar approach to the representation of mammalian spermatogenesis was previously employed by Roosen-Runge (72 ).

If the number of Ap spermatogonia determines spermatogenic ceiling in higher primates, it would become important to understand the mechanisms whereby the adult complement of this cell type is attained. In this regard, the population of Ap spermatogonia in the adult monkey testis is an order of magnitude greater than that in the testis of the juvenile (31), and like the pubertal increase in Sertoli cells (see above), would appear to be gonadotropin dependent because precocious activation of FSH and LH secretion in the juvenile monkey by pulsatile GnRH treatment for 10 wk results in a 3-fold increase in the number of Ap spermatogonia (31). Moreover, because a shorter duration (11 d) of gonadotropic stimulation of the juvenile testis, achieved with recombinant preparations of human gonadotropin, failed to stimulate Ap spermatogonial number (38), it seems reasonable to propose that stem cell proliferation precedes in the wake of an expanding population of Sertoli cells.

B. Experimental paradigms
The issue of experimental models is important from a clinical standpoint because many aspects of the physiology and cell biology of the human testis are not amenable to study directly. When the differences described above in the spermatogenic process of rodents and primates are taken together with the relatively greater role of inhibin B in the testicular regulation of FSH secretion in the latter species (see Section V), it seems reasonable to conclude that a nonhuman primate may frequently represent the model of choice for integrative studies of testicular function and its control in men. It is now immediately necessary to recognize that there are differences in spermatogenesis between men and Old World monkeys, the family of nonhuman primates used most frequently as a paradigm for man. The full extent of these differences is probably not known at the present time, a situation resulting in large part from the difficulty encountered in studying the human testis. Fundamental studies of human spermatogenesis and its kinetics involving the local injection of tritiated thymidine into ligated areas of the testis were conducted in a limited number of men in the 1960s (59). These early studies have not been replicated for ethical reasons, and inevitably, the data at hand are scant. Nevertheless, those differences that have been established merit identification. Perhaps the most notable difference between these primates relates to the number of generations of differentiated B spermatogonia (four in the monkey and one in man). Also, cross sections of the seminiferous tubule in the monkey exhibit only a single stage of the seminiferous epithelial cycle, but in man multiple stages are observed (59). Parenthetically, this cytoarchitectural arrangement of the human seminiferous tubule contributes to the difficulties encountered when estimating durations of the seminiferous epithelial cycle and of spermatogenesis. Other differences include the duration of spermatogenesis, which in the monkey is 48 d (56), whereas that for man has been reported to vary around 74 d (59), as well as the lesser number of stages of the seminiferous epithelial cycle in man (59). The latter presumably reflects species differences in either cell cycle time or in the duration of spermiogenesis and does not imply necessarily distinct endocrine or paracrine control systems governing the germinal epithelium in monkey and man. In any event, these differences, and the uncertainty of the precise nature of key spermatogenic steps in men, such as the function of Ad spermatogonia, must be borne in mind in the extrapolation of results obtained in the monkey to the human situation.

Moreover, as with any experimental model, the use of the monkey for studying human testicular function and its control has limitations, and consideration of some general caveats is relevant here. In many species of monkey, and particularly in the rhesus macaque, the endocrine and spermatogenic activities of the testis, under feral conditions, exhibits marked seasonal fluctuations (74). Although such fluctuations are markedly attenuated or abolished under the rigidly controlled environmental conditions of the laboratory, information on the timing of experiments with respect to the breeding (fall-winter) or nonbreeding (summer) season is nevertheless necessary to fully interpret results.

Although recombinant macaque and baboon FSH and LH have recently been made available to investigators by the National Hormone and Pituitary Program, these remain in such limited supply that in vivo experiments requiring administration of homologous gonadotropins for several weeks are generally not possible. Human preparations must be used for such investigations, and use of heterologous gonadotropins in vivo raises the possibility that circulating antigonadotropin antibodies will be generated in the treated monkeys (75), and therefore, negative results in such studies must always be interpreted with caution.

Limitations common to rodent models apply equally well to primates. Neither surgical nor chemical hypophysectomy is ideal. The former leads to loss of all pituitary hormones, and the possibility exists that systemic administration of GnRH and its analogs may exert direct actions on the primate testis in view of the reports that GnRH-R is expressed in this tissue (76, 77, 78). The ability to establish that gonadotropin secretion has been abolished in hypogonadotropic models rests on the sensitivity and specificity of the assays employed to assess circulating FSH and LH levels. In this regard, it is to be noted that the sensitivities of the RIAs that are available for measuring the macaque pituitary gonadotropins are probably markedly less than those of commercially available immunofluorometric assays for measuring circulating FSH and LH in men.

The number of sperm in an ejaculate is an extremely variable parameter, and therefore caution should be exercised when using sperm number or sperm concentration as a quantitative index of spermatogenesis. Additionally, the use of testicular biopsies for quantitative analysis of spermatogenesis must be interpreted conservatively because the limited amount of tissue harvested may not be representative of the entire organ. Serial biopsies from the same testes present an additional problem because the gonad may be damaged by the surgical procedure. Interpretation of the results obtained by studies employing passive or active immunoneutralization of circulating gonadotropin may not be straightforward. With negative data, the degree to which the circulating gonadotropin was inactivated is difficult to assess, and in experiments in which immunoneutralization interferes with spermatogenesis, nonspecific effects of the immunoneutralization procedure need to be evaluated with the inclusion of appropriate control experiments. These latter caveats apply equally well to studies of both the human and nonhuman primate.

C. Initiation of spermatogenesis
Initiation of spermatogenesis, which occurs at the time of puberty and, in higher primates, is associated with the transition from a relatively hypogonadotropic state of the prepubertal phase of development to the eugonadotropic state of adulthood (32), may be defined as the process that leads to the development of the first generation of testicular spermatozoa. Spermatogenesis may be initiated precociously in higher primates when FSH and LH secretion are prematurely elevated either experimentally (79) or pathophysiologically (80), establishing that the gonadotropic hormones provide the principal drive for this process. In patients with hypogonadotropic hypogonadism, hCG in combination with human menopausal gonadotropin (hMG) or FSH represents the treatment of choice for initiating spermatogenesis (81, 82, 83, 84). Therefore, in the context of the present review, the question becomes, "What is the relative importance of FSH in this process?" A classical approach to examine this issue has been to provide the quiescent prepubertal primate testis with selective FSH stimulation, and to determine whether spermatogenesis is initiated with such a monotropic drive. Up to 12 wk of administration of hFSH alone to the prepubertal monkey resulted in a stimulation of the germinal epithelium, although cells more mature than B spermatogonia were not observed, indicating that a selective increase in FSH stimulation is unable to initiate spermatogenesis (38, 39, 46). This notion is reinforced by the finding that pulsatile stimulation of the testes in two juvenile monkeys with recombinant cynomolgus FSH for 18 wk resulted in germ cells no more mature than differentiated spermatogonia (S. Ramaswamy, G. Marshall, and T. Plant, unpublished observations). Here, it is interesting to note that in men with hypogonadotropic hypogonadism, azoospermia persisted during 2 yr of combined treatment with FSH and T (83). Presumably, the dose of T employed (250 mg T enanthate/week) was insufficient to restore normal intratesticular T content, and therefore, these men provide a clinical paradigm of selective FSH stimulation.

Hypogonadism resulting from inactivating mutations of the LH receptor (LH-R) provides an additional paradigm of selective FSH stimulation, although the abdominal or inguinal location of the testis in such subjects confounds the interpretation of these clinical data. In such patients, spermatogenic arrest has been consistently observed, occurring as early as the first meiotic division or as late as spermatid elongation (85, 86). In cases of complete androgen insensitivity, spermatogenesis is not initiated and the only germ cells observed in the testis are spermatogonia (87). Again, however, the testes are abdominal. A discussion of the fertile eunuch is merited here, because the syndrome was originally considered to reflect a selective loss of LH (88). Subsequent studies, however, have revealed that these men have low to low-normal LH levels in association with circulating T concentrations that are higher than those seen in infertile patients with idiopathic hypogonadotropic hypogonadism (89), and as the latter authors suggest, spermatogenesis in these subjects may be initiated by the combined action of intratesticular T, albeit at a reduced level, and relatively normal circulating FSH concentrations.

The inverse approach to examining the role of FSH in initiating spermatogenesis is to determine whether the process may be imposed prematurely in the juvenile, in the absence of this gonadotropin. In the juvenile macaque, T administration for 3 months stimulated the germinal epithelium, resulting in the premature appearance of primary spermatocytes (39), and exposure to T for 12 months initiated spermatogenesis while the animals were at a prepubertal age (90). The foregoing experimental observations in the monkey are consistent with reports of precocious initiation of spermatogenesis in boys with activating mutations of the LH-R (91) and Leydig cell hyperplasia (92, 93). They are also in keeping with the finding that hCG treatment, alone, initiates spermatogenesis in men with hypogonadotropic hypogonadism (81, 94).

Individuals with isolated FSH deficiency of unknown etiology, and with an apparently otherwise normal phenotype, provided the initial opportunity to examine whether spermatogenesis in the human male is initiated with LH alone at the time of spontaneous puberty (95, 96, 97, 98, 99). The seven men described in the foregoing studies, however, should be viewed as FSH insufficient rather than FSH deficient, and therefore, the significance of the oligospermia observed in the majority of patients is difficult to evaluate.

The recent reports of men with a mutation in the gene encoding either the FSH-R (2) or the FSH ß-subunit (100, 101) have provided additional and potentially cleaner paradigms of FSH deficiency. In all five subjects with the inactivating mutation of the FSH-R, spermatogenesis, as reflected by semen analysis, had been initiated (2). A similar phenotype was subsequently reported for transgenic FSH-R-knockout mice (102). The cell biology of the mutated human receptor, however, merits some discussion. Immortalized mouse Sertoli cells (MSC-1) transfected with the mutant FSH-R gene exhibited a comparable binding affinity but dramatically reduced FSH binding capacity and FSH-induced cAMP production when compared with MSC-1 cells expressing the wild-type FSH-R (103). The compromised signal transduction by the mutated receptor gene in MSC-1 cells may be accounted for, in part, by the apparent 30-fold lower incorporation of the mutant receptor into the membrane (103), perhaps resulting from a defect in the cellular trafficking of the mutant receptor. The absolute levels of expression of the mutated FSH-R within the testes of the affected patients, however, was not established, and because reduced FSH signaling up-regulates its own receptor (104, 105), the possibility that the mutated receptor may be overexpressed in these men should not be excluded. In addition, circulating FSH concentrations in the affected men were substantially higher than those in normal subjects. Hence, with the available information, it is not possible to conclude unequivocally that the FSH drive to the Sertoli cells in these subjects was completely abolished.

The foregoing concern is reinforced by the finding that, in contrast to the men with the FSH-R mutation, azoospermia and infertility were consistent features of the two men described with FSH deficiency due to deletion of the gene encoding the ß-subunit of this gonadotropin (95, 101). Theoretically, the absence of FSH or the inactivation of its receptor should have the same impact upon testicular function, as observed in transgenic mice deficient in either FSHß (1) or FSH-R (102). Thus, the difference in phenotype in these two groups of men is paradoxical and needs to be reconciled. The unsuccessful treatment with rhFSH of one of the men with the FSHß mutation (106) does not necessarily imply an additional deficit in FSH signaling in this individual: the initial attempt to restore ovulation with hMG in a woman with isolated FSH deficiency was also unsuccessful due to the production of anti-FSH antibodies in response to hMG (107). The other FSH-deficient man had low serum T levels, and the relationship between the hypoandrogenism and the FSHß mutation, if there is one, is not known (100). It should be noted that these interesting receptor mutations in men have also been recently discussed by Themmen and Huhtaniemi (108).

In accord with classical studies (see Ref. 109), an interaction between the two gonadotropins to initiate primate spermatogenesis is suggested by the recent finding that although intermittent stimulation of juvenile male monkeys with either LH or FSH alone for 11 d failed to produce germ cells more mature than differentiated type B₁ spermatogonia, the testis of monkeys receiving combined pulsatile gonadotropin treatment for a similar period showed the presence of all four generations of differentiated spermatogonia (B₁, B₂, B₃, and B₄) and preleptotene and leptotene-zygotene spermatocytes (38). The cell biology underlying the synergism between LH and FSH to initiate spermatogenesis is unclear. We propose, however, that because chronic exposure of the prepubertal primate testis to T eventually initiates spermatogenesis (see above), combined gonadotropin stimulation of the undifferentiated Sertoli cell in the juvenile minimizes the time required for maturation of this cell type. Presumably, FSH facilitates the posited LH-dependent differentiation of Sertoli cells (see above). Thus, the time taken for the Sertoli cell to acquire the potential to support spermatogenesis would be reduced under conditions of combined stimulation. In the context of the foregoing hypothesis, it is important to note that the kinetics of spermatogenesis would be identical regardless of whether spermatogenesis is initiated with either LH alone or with LH and FSH in combination.

In summary, the evidence to date supports the view that FSH may not be required for the initiation of spermatogenesis in primates, although this conclusion must be tempered with the caveat raised by the differing phenotypes exhibited by men with mutations of the FSH-R and the FSH ß-subunit. At the same time, however, it should be recognized that the foregoing view does not necessarily imply that LH is obligatory for the initiation of spermatogenesis. This must await the confirmation that this developmental event is not elicited by a selective and sustained pulsatile FSH stimulation of the juvenile testis.

D. Maintenance of spermatogenesis
The maintenance of spermatogenesis, which has been recently reviewed by others (110, 111), may be defined as the process that leads to the sustained production of testicular spermatozoa in the adult testis; the number of these germ cells may be low or high. This notion of the maintenance of spermatogenesis corresponds to what has been previously called "qualitative maintenance" by others (112). It should be noted that the level at which spermatogenesis is maintained in higher primates is not invariant, but rather is subjected to regulation by physiological cues. For example, in certain species of monkey, particularly the rhesus macaque (74), and also in man, sperm count exhibits seasonal fluctuations with a decrease in sperm output during the summer months (113, 114). In primates, however, azoospermia probably does not occur during the nonbreeding season, and therefore, the seasonal paradigm should not be employed as a model for the restoration of spermatogenesis.

If, as argued above, the initiation of spermatogenesis requires only LH stimulation, then it may be inferred that the maintenance of spermatogenesis will also be driven by LH alone. Indeed, a considerable body of evidence exists to suggest that FSH is not obligatory for the maintenance of spermatogenesis in primates. In macaques, surgical or chemical hypophysectomy with immediate T replacement fails to interrupt the maintenance of spermatogenesis (115, 116). Similarly, spermatogenesis is also maintained in normal men rendered FSH deficient during hCG administration (117), and by hCG treatment alone in patients with hypogonadotropic hypogonadism (81, 94).

Moreover, there have been many studies of the impact of immunoneutralizing circulating FSH concentrations in bonnet (M. radiata) and rhesus macaques, and in none of these has the maintenance of spermatogenesis been consistently interrupted (118, 119, 120, 121, 122). Additionally, in a single study of five human subjects actively immunized with ovine FSH over a 10-wk period (123), azoospermia was not observed. Lastly, a reduction in FSH drive to the testis of the adult bonnet monkey, produced by immunoneutralization against the FSH-R (124), did not abolish spermatogenesis, and men with an inactivating mutation of the FSH-R have sperm in semen and can be fertile (2). In view of the substantial body of evidence in support of the notion that LH alone can maintain spermatogenesis in the monkey, the recent observation that severe oligospermia (mean sperm number, <0.2 x 10⁶/ejaculate) or azoospermia was induced in the apparent face of normal intratesticular T concentrations in cynomolgus monkeys rendered hypogonadotropic with im T buciclate injections (125) is surprising. Perhaps an explanation for this finding might be that testicular T content, which was determined 8 wk after the last injection of the steroid, did not reflect androgen status of the testis at wk 5, 6, and 7, the phase of the experiment when the spermatogenic activity of the testis would have been reflected in the ejaculates collected at wk 6, 7, and 8 (126).

The question of whether LH is obligatory for the maintenance of spermatogenesis remains to be unequivocally addressed. In the bonnet macaque, active immunoneutralization of circulating LH with ovine LH for 43 wk resulted in a profound depletion in spermatocytes and spermatids (127), underlining the critical importance of this gonadotropin for spermatogenesis. In the cynomolgus monkey, the number of elongated spermatids was also greatly reduced after 8 wk of LH deficiency, achieved by concomitant GnRH-R antagonist treatment and FSH replacement (128). However, a more protracted study of the LH-deficient condition is ideally needed to determine whether FSH alone is incapable of maintaining spermatogenesis in nonhuman primates. The clinical studies pertaining to this issue are also equivocal. In hypogonadotropic hypogonadal men in which spermatogenesis had been initiated with hMG and hCG, substituting FSH and T for the original treatment failed to maintain spermatogenesis, as reflected by the finding that the patients became azoospermic (83). In a hypophysectomized man expressing a mildly activating mutation/polymorphism of the FSH-R (129), spermatogenesis was found to be maintained after withdrawal of T replacement. The maintenance of spermatogenesis in this individual, however, may not have been maintained by an FSH drive alone because circulating T levels declined to only 5.4 nmol/liter after androgen withdrawal (129).

Although it may be concluded that FSH stimulation is probably not obligatory for the maintenance of spermatogenesis in higher primates, it is premature to infer that LH is sufficient and necessary. Indeed, this will require the development of experimental paradigms in which LH drive may be selectively abolished while chronically preserving a physiological pulsatile FSH drive to the testis.

E. Restoration of spermatogenesis
Although the adult testis, in which regression of the seminiferous tubule has been imposed in response to experimentally induced hypogonadotropism, has been used as a model with which to examine the initiation of spermatogenesis, the processes of initiation and restoration exhibit several salient differences. First, maturation of the germinal epithelium at the time of initiation is intimately associated with Sertoli cell proliferation and differentiation, whereas during restoration, the germinal epithelium matures in the presence of an invariant number of differentiated Sertoli cells. Second, Sertoli cell function is determined in part by the composition of the basement membrane of the seminiferous tubules (130), which exhibits developmental changes (131, 132), and these changes may not be recapitulated during restoration of spermatogenesis of a regressed adult testis. Although the validity of using restoration of spermatogenesis as a paradigm for initiation of spermatogenesis may therefore be challenged, the requirements underlying the restoration of spermatogenesis in the postpubertal testis is of clinical interest and will be considered here.

A classical approach to examining the gonadotropin requirement of restoration has been to attempt to provide the regressed adult testis with selective FSH or LH stimulation, and to determine whether spermatogenesis is restored with such a monotropic drive. The issue of whether FSH alone may restore spermatogenesis, however, remains unclear. Although treatment with hFSH for 8 wk to GnRH-R antagonist-treated adult macaques stimulated the germinal epithelium with the appearance of premeiotic cell types and a few primary spermatocytes, spermatogenesis was not restored (128). However, it should be noted that, in the latter study, a few cells classified as elongated spermatids were found in 20% of the animals using flow cytometry. In contrast, in normal men rendered hypogonadotropic by im injections of a T ester that produced elevated circulating levels of this steroid (11–14 ng/ml), replacement with human pituitary FSH for 3 months resulted in the reappearance of sperm in semen (133). That spermatogenesis was restored by FSH in men, but not in male monkeys, probably reflects differences in the strategies employed to effect suppression of FSH and LH rather than a fundamental species difference. In the hypogonadotropic men, intratesticular T concentrations during FSH stimulation would have been greater than those in the monkey, and may have therefore contributed to the process of restoration.

The evidence that LH stimulation alone can restore spermatogenesis is compelling. More than 50 yr ago, P. E. Smith (6) reported that implantation of T directly into the testis of hypophysectomized monkeys led to restoration in the vicinity of the implant. In pituitary stalk-sectioned monkeys, T replacement that elevated circulating levels of this steroid to concentrations 10-fold greater than those observed in normal adult monkeys partially restored testicular volume and sperm count to pre-stalk section values (134). In a study with hypophysectomized monkeys, in which intratesticular T content was fully restored, testicular volume recovered to 40% of the presurgical value and 15–20 spermatids per cross section were found (135). The latter parameter may be compared with a value of approximately 40 spermatids per cross section from testis of normal adults in our colony (G. R. Marshall, personal observation). Sertoli cell number was similar in the two conditions. In analogous studies in normal men in which the negative feedback action of exogenous T treatment was employed to induce hypogonadotropism, either hCG or hLH treatment restored spermatogenesis, although sperm production remained below normal (136, 137).

F. Regulation of sperm number
Although spermatogenesis in primates may be maintained by intratesticular T produced in response to LH stimulation of the Leydig cell, it is generally recognized that combined stimulation with FSH and LH, as is the case under physiological circumstances, leads to maximal sperm production (109, 111). After hypophysectomy in the monkey and concomitant initiation of T replacement, testicular size declined to 60% or less of presurgical size, and the number of all germ cells more mature than Ap spermatogonia were reduced (115). Similarly, in normal men, a selective FSH deficiency induced indirectly by the chronic administration of hCG was associated with a marked reduction in sperm count, which was largely restored by treatment with FSH (117). The application of immunoneutralization to selectively decrease the FSH drive to the testis has been used extensively in adult male bonnet monkeys by Moudgal and colleagues (118, 121, 122, 127, 138). Active immunization with ovine FSH, or passive immunization with antiovine FSH, resulted in depletion of the germinal epithelium, a consistent and marked decline in sperm count, and occasional azoospermia in the apparent absence of an effect on LH and T secretion. Analogous studies of the rhesus monkey also indicate a reduction in spermatogenesis after immunoneutralization of circulating FSH (119, 120, 139). Similarly, a reduction in FSH drive to the testis of the adult bonnet monkey, produced by immunoneutralization against the FSH-R in a limited number of animals, also led to a reduction in spermatogenesis (123). In a single study of five human subjects actively immunized with ovine FSH over a 10-wk period, a decline in sperm count was reported to occur during and after the period of immunization (124).

Whereas a selective decrease in FSH drive to the seminiferous tubule leads to a decrease in spermatogenesis, an increase in FSH stimulation appears to amplify the process. Although FSH treatment of oligospermic men has not consistently produced robust increases in sperm count (140, 141, 142, 143, 144, 145, 146), certain patients have been reported to respond to FSH stimulation (143, 144, 145, 146). Administration of FSH to normal adult monkeys enhanced testicular germ cell number (147), and an enlargement in testicular volume in response to FSH treatment has been reported in men with idiopathic infertility (140). Moreover, a selective elevation in endogenous FSH secretion elicited in the monkey by unilateral orchidectomy is also associated with amplification of spermatogenesis, as reflected by an approximately 70% increase in volume of the remaining testis (148, 149), an increase in the diameter of the seminiferous tubule, and an increase in the number of all germ cells more mature than type Ap spermatogonia (Fig. 4) in the absence of a change in Sertoli cell number (148). Interestingly, as shown in Fig. 5, although total germ cell number was not correlated to Sertoli cell number in the removed testis, in accord with an earlier finding (150), this relationship became highly significant in the remaining testis. Although unilateral orchidectomy is performed in cases of testicular cancer, torsion, and trauma, it is difficult to generalize on the impact of this surgical procedure on the remaining testis because of the heterogeneity of the subjects and the lack of information on testicular function before unilateral orchidectomy (151, 152, 153, 154, 155). In the context of the present review, however, it is interesting to note that sperm counts comparable to those in normal men have been reported in association with elevated FSH concentrations in as many as 20% of patients after removal of a malignant testis (151, 155), and testicular hypertrophy was noted from 6 months to 30 yr (mean, 5 yr) after unilateral orchidectomy in response to accidental injury (152).

View larger version (18K): [in this window] [in a new window]   Figure 4. The mean number of Ap spermatogonia and differentiated spermatogonia (B1, B2, B3, and B4) per cross section in the testis, which was removed from adult male rhesus monkeys at the time of unilateral orchidectomy (stippled bars, removed testis), and in the remaining testis collected 44 d later (black bars, remaining testis). The horizontal bar indicates the SD, and the asterisk indicates a significant difference from the removed testis. [From: S. Ramaswamy et al.: Endocrinology 141:18–27, 2000 (148 ). Reprinted with permission of The Endocrine Society.]

View larger version (12K): [in this window] [in a new window]   Figure 5. Relationship between Sertoli cell number and total germ cell number in testes removed from adult rhesus monkeys at the time of unilateral orchidectomy (left panel), and when the remaining testes were removed 44 d later (right panel). Note the high correlation between the two cell types in the testis remaining after unilateral orchidectomy, which suggests that, at this time, it was operating closer to the spermatogenic ceiling than it was before unilateral orchidectomy. [From: S. Ramaswamy et al.: Endocrinology 141:18–27, 2000 (148 ). Reprinted with permission of The Endocrine Society.].

Conceptually, the action of FSH to amplify a basal level of spermatogenesis driven by intratesticular T may be viewed to proceed according to one of the two models shown in Fig. 6, which are based on the studies by Zirkin and his colleagues (156, 157, 158) and indicate that, in the rat, intratesticular T content is maintained at a level in excess of the threshold value required to maintain quantitatively normal spermatogenesis in this species. In the first scenario, it is posited that the primate testis, in contrast to that of the rat, cannot be driven to its spermatogenic ceiling with T alone, and maximal sperm production is achieved only with combined FSH and LH (T) stimulation (Fig. 6, top panel). In the second scenario, the relationship between intratesticular T content and sperm output in the primate testis is posited to be similar to that in the model of the rat proposed by Zirkin et al. (156). In contrast to the rat, however, the intratesticular content of the adult primate is less than that required to drive the testis to its spermatogenic ceiling, but the latter may be achieved when the seminiferous tubule is provided with a combined LH (T) and FSH stimulation (Fig. 6, bottom panel). Here, it is relevant to interject that studies to date have failed to demonstrate that FSH amplifies LH-stimulated T production by the primate testis (159, 160). It will be important to determine which of these paradigms correctly describes the role of FSH in regulating primate spermatogenesis, because resolution of this issue should lead to insight into the molecular mechanisms underlying the hormonal drive to the Sertoli cell. For example, if the first scenario is shown to be applicable, it would be difficult to argue for the view that the FSH-R and AR signaling pathways intersect to regulate transcriptional events common to both pathways (161). At the present time, we favor the first scenario because there is no evidence indicating that intratesticular T alone is able to drive the primate testis to its spermatogenic ceiling, or that FSH is able to enhance the sensitivity of the primate Leydig cell to LH stimulation (159, 160).

View larger version (21K): [in this window] [in a new window]   Figure 6. Two hypothetical models to account for the interaction between FSH and LH (T) to maintain spermatogenesis. The relationship between germ cell number (abscissa) and intratesticular content (ordinate) is shown when the seminiferous tubule is stimulated by T alone (broken line) or by FSH and T in combination (continuous line). The shaded vertical bar represents the physiological intratesticular T content. In the first paradigm (top panel), intratesticular T is maintained at a level that, in the absence of FSH, results in maximal androgen-dependent germ cell production. Here, spermatogenic ceiling may only be achieved when FSH stimulation is combined with that of androgen. In the second model (bottom panel), intratesticular T content is maintained at a subthreshold level, and spermatogenic ceiling may be reached by an increase in either the FSH or LH (via intratesticular T) drive to the testis. The conceptual basis for these models was provided by the studies of Zirkin and his colleagues (156 157 158 ) describing the relationship between intratesticular T content and germ cell number in the rat.

This Dutch group (147, 162) rationalized their view of the action of FSH on Ap spermatogonia with our finding that FSH stimulation did not influence the number of Ap spermatogonia in the T-treated hypophysectomized monkey (135) by speculating that, in the absence of FSH, the proportion of Ap spermatogonia dividing is reduced. Such a hypothetical action of FSH, however, is unable to account for the FSH-induced amplification of the population of differentiated spermatogonia in the normal testis. This is because it is recognized that, in the macaque and other monkeys, the entire population of Ap spermatogonia divide in stage IX of the cycle of the seminiferous epithelium (53, 55), and therefore, in these species, an increase in the mitotic activity of this cell type is theoretically impossible because it would violate the concept of an invariant cell cycle time. Moreover, in the monkey, the number of Ap spermatogonia does not diminish as these cells age as spermatogenesis progresses from stage IX to stage VIII of the subsequent cycle (53, 55), indicating that survival of this stem cell is robust. If the foregoing two premises are accepted, then in the normal rhesus monkey, an action of FSH on Ap spermatogonia to increase the population of this stem cell is untenable. A similar argument may be made for the cynomolgus monkey, although in this macaque, there are two schools of thought regarding the precise mechanism used for renewal of Ap spermatogonia. According to the view of Clermont and Antar (53), the rhesus and cynomolgus monkeys are identical in this regard, whereas the results of Fouquet and Dadoune (57) suggest that mitosis of Ap spermatogonia occurs at two stages of the seminiferous cycle (stages VII and X). In stage VII, division leads to the generation of daughter Ap spermatogonia, half of which will divide at stage X to produce differentiated B₁ spermatogonia, whereas the other half survive to divide again in stage VII of the subsequent cycle. Although the latter scheme has been accepted by others (150, 163), it should be noted that the number of B₁ spermatogonia observed in stages XI and XII by Fouquet and Dadoune (57) was twice the number of Ap spermatogonia counted in the preceding stage of the cycle (stage X) and, therefore, in 2-fold excess of the theoretical number. Nevertheless, in the cynomolgus monkey there is general agreement that all Ap spermatogonia divide during each cycle (53, 57), and thus, the same theoretical considerations that were argued for the rhesus monkey may also be applied to the cynomolgus macaque.

As a second possibility to account for the observed increase in the number of Ap spermatogonia in response to FSH treatment, van Alphen et al. (147) also proposed that a transient transformation of Ad spermatogonia to Ap spermatogonia, followed by restoration in the number of Ad spermatogonia, may be activated by the gonadotropin. Although a transient action on Ad spermatogonia may not be excluded, evidence for such an effect of FSH stimulation is not at hand, and a transient restoration of the population of Ad spermatogonia is difficult to conceptualize. Therefore, after re-examining the forgoing considerations, we remain of the opinion that the most parsimonious explanation for the physiological relationship between FSH drive on the one hand and the rate of testicular sperm production by the primate testis on the other is that the gonadotropin exerts an action on the first, and perhaps subsequent, generations of differentiated spermatogonia to amplify the population of these cell types. In consequence, the number of all more mature germ cells is enhanced.

Before discussing the mechanism whereby FSH amplifies the population of B spermatogonia, it is necessary to reiterate that the sequential steps in the production of testicular spermatozoa from undifferentiated spermatogonia is recognized to unfold according to a fixed kinetic program, with the cell cycle of each type of dividing germ cell and the morphogenic transformation during spermiogenesis being immutable (52, 67). It follows from this dogma, therefore, that the action of FSH to amplify the population of B spermatogonia must be attributed to an ability of the gonadotropin to promote survival of at least the first generation of these differentiated germ cell types. The most likely mechanism whereby this may occur is that the FSH directly governs the secretion of a Sertoli cell factor that suppresses apoptosis of this differentiated cell type. The nature of this paracrine control by the Sertoli cell of differentiated spermatogonia in primates has yet to be addressed, but it may be anticipated to use the factors that have been implicated to be operative in cognate systems regulating spermatogonial survival in the testis of nonprimate species (164, 165, 166, 167, 168, 169, 170, 171, 172, 173).

Returning now to the role of gonadotropin in maintaining the population of Ap spermatogonia in the adult testis, the following may be noted. In adult male cynomolgus monkeys rendered hypogonadotropic for several weeks by hypophysectomy or treatment with either a GnRH-R antagonist or T, a marked reduction in the total number of Ap spermatogonia was generally observed in association with a profound depletion in differentiated germ cells (115, 128, 163, 174). Additionally, the gonadotropin dependency of the pubertal proliferation of Ap spermatogonia in the monkey has been noted earlier (31). On the other hand, a decrease in the number of Ap spermatogonia was not observed in five normal men after suppression of gonadotropin secretion during 19–24 wk of treatment with T enanthate, although the hypogonadotropic state produced a marked reduction of all germ cells more mature than undifferentiated spermatogonia (175).

That a loss of FSH action may have contributed to the reduction of Ap spermatogonia observed by Weinbauer et al. (128) in response to chemical hypophysectomy in the cynomolgus monkey was indicated by the finding that initiation of an 8-wk period of FSH treatment at the start of GnRH-R antagonist administration prevented the depletion of Ap spermatogonia. Similarly, it would appear that LH action may also maintain the population of Ap spermatogonia because, in the cynomolgus monkey, the number of this cell type in the testis of T-treated, hypophysectomized animals is similar to that in the intact situation (115). In summary, extant data would suggest that an action of either FSH and/or LH is required to maintain the population of Ap spermatogonia of the normal adult testis. At the time of writing, we view this action of gonadotropin on Ap spermatogonia to be permissive, allowing Ap spermatogonia to divide each cycle and to survive. Such an action of gonadotropin is to be contrasted with the regulatory action of FSH that dictates the number of differentiated spermatogonia that survive. Clearly, further study of the role of the gonadotropins in this regard is needed.

G. Determination of sperm quality
In the final analysis, the quality of sperm is best confirmed by successful fertilization and implantation, events that are not easily amenable to quantitation in primates. Nonetheless, a few studies merit discussion. Most notably, active immunization of bonnet monkeys against ovine FSH resulted in an impairment of sperm motility and in a decrease in the activity of acrosin, an acrosomal enzyme that plays a role in the penetration of the oocyte, and the immunized monkeys failed to impregnate fertile females in a well controlled mating test (138). Moreover, immunoneutralization of circulating FSH in man and monkey is associated with an alteration in the integrity of sperm chromatin and a reduction in the glycoprotein content of the acrosome (176, 177), which in the case of the latter, may underlie the decrease in acrosin activity reported earlier (138). Furthermore, several fertility centers have reported that FSH treatment of infertile, oligospermic, or teratozoospermic men for 1–3 months results in an increase in the number of sperm with normal ultrastructural characteristics (141, 142, 144), and in one report, FSH treatment was associated with an increase in fertilizing efficiency of sperm in vitro (178). Clearly, there is a need for an experimental model in which a selective and absolute FSH deficiency may be induced postpubertally to examine the role of FSH in determining sperm quality.

	V. Regulation of FSH Secretion

Top Abstract I. Introduction II. Site of FSH... III. Sertoli Cell Ontogeny... IV. The Role of... V. Regulation of FSH... VI. Summary References

 
In adult men and male macaques, the central neural drive for FSH secretion, like that for LH synthesis and release, is provided by a network of GnRH-expressing neurons in the hypothalamus (179). This network of GnRH neurons with its attendant afferent neuronal and glial inputs (180) is referred to as the GnRH pulse generator (181, 182). This neuroendocrine system generates an intermittent discharge of GnRH into the hypophysial portal circulation (183), and this episodic stimulation of the pituitary gonadotrophs is obligatory for sustained FSH and LH secretion (184). When this hypophysiotropic drive is congenitally absent, as in the case of Kallman’s syndrome, or is abolished experimentally in the adult male monkey, circulating FSH concentrations are very low and often undetectable (185, 186). Although LH secretion in men and male macaques is sensitive to changes in the frequency of pulsatile GnRH stimulation (185, 187), which under physiological conditions, is dictated by a feedback action of testicular T secretion to retard the hypothalamic GnRH pulse generator (179), the release of FSH, as reflected by mean concentrations of the hormone in blood, appears to be relatively unresponsive to GnRH frequency modulation. In studies by Crowley and his colleagues (188) of men in whom hypothalamic GnRH release was severely compromised, pulsatile stimulation with exogenous GnRH replacement at frequencies ranging from 1 to 8 pulses every 2 h was not associated with changes in plasma FSH concentrations (Fig. 7). Additional slowing of the frequency of GnRH stimulation in similar patients to 1 pulse every 8 h also failed to enhance FSH secretion (189). In one other study of men with idiopathic hypogonadotropic hypogonadism, however, circulating FSH levels during GnRH stimulation at 1 pulse every 90 min was greater than that at the faster frequency (190). The reasons for the different FSH response reported in these two groups of men with idiopathic hypogonadotropic hypogonadism is unclear, although it has been proposed that the extent to which T levels were normalized may be a contributing factor (190). In the hypothalamic-lesioned adult male rhesus monkey, which may be viewed as analogous to the human paradigm, an increase in GnRH pulse frequency 3 wk after castration from 1 pulse every 3 h to 3 pulses every 3 h did not stimulate FSH secretion, but did lead to a robust elevation in LH concentrations (185). Similar results were also obtained in the juvenile cynomolgus monkey when GnRH frequency changes were imposed in the presence of T (191). Taken together, the foregoing studies lead us to propose that FSH secretion in the male primate is relatively emancipated from modulation by the frequency of the hypophysiotropic drive. This may be in contrast to the situation in the male rat, in which FSHß gene expression is markedly modulated by changes in GnRH frequency (192).

View larger version (25K): [in this window] [in a new window]   Figure 7. Circulating FSH concentrations (mean ± SEM, cross-hatched bars) in five GnRH-deficient men failed to respond to successive stepwise increments in frequency of exogenous GnRH stimulation provided by an intermittent iv infusion of an invariant dose of synthetic peptide (17–22 ng/kg body wt) administered at interpulse intervals of 15–120 min. The corresponding LH levels are shown by the open bars. [From: D. I. Spratt et al.: J Clin Endocrinol Metab 64:1179–1186, 1987 (188 ). Reprinted with permission of The Endocrine Society.]

View larger version (20K): [in this window] [in a new window]   Figure 8. The effect of bilateral castration on d 0 on gonadotropin secretion in adult male rhesus monkeys bearing hypothalamic lesions, in which activity in the pituitary-testicular axis was restored with a continuous intermittent iv infusion of GnRH (0.1 µg/min for 3 min every 3 h). Note the dramatic and selective postcastration rise in circulating FSH concentrations (mean ± SE, filled bars) in this experimental paradigm. The corresponding LH levels are shown by the open bars. [From: T. M. Plant and A. K. Dubey : Endocrinology 115:2145–2153, 1984 (185 ). Reprinted with permission of The Endocrine Society.]

View larger version (37K): [in this window] [in a new window]   Figure 9. Infusion of rh inhibin A (0.8 µg/kg·h, closed data points) to adult male rhesus monkeys from 0–96 h (stippled area), which produced a 10-ng/ml increment in circulating inhibin A concentrations (top panel), resulted in a progressive suppression in plasma FSH levels (bottom panel). The open data points show data obtained from the same animals during infusion of vehicle. Mean ± SE values are shown, and asterisks indicate FSH concentrations significantly different from the preinhibin infusion value. [From: S. Ramaswamy et al.: Endocrinology 139:3409–3415, 1998 (201 ). Redrawn with permission of The Endocrine Society.].

The action of inhibin B at the level of the primate gonadotroph has not been studied either in vivo or in vitro, but experiments with rh inhibin A suggest that, in the rhesus monkey, testicular inhibin selectively regulates FSHß gene expression and FSH secretion (198, 201). To date, the most parsimonious mechanism that may be proposed to account for this action of inhibin B is that this testicular peptide antagonizes a constitutively expressed activin drive to the FSH-secreting gonadotroph, a view consistent with the finding that castration of the adult male monkey does not markedly influence the pituitary level of the mRNA encoding either activin/inhibin ßB or follistatin (211, 212). Inhibin B may antagonize the paracrine action of activin by either binding to and inactivating the ligand binding subunit of the activin receptor (213, 214) or by binding to a specific inhibin receptor, which in turn antagonizes the action of activin. With regard to the latter possibility, it may be noted that 1) inhibin binding sites with high affinity and specificity have been described in ovine pituitary cells (215); 2) the type-III TGF-ß receptor, betaglycan, has been demonstrated to mediate inhibin antagonism of activin signaling (216); and 3) a specific inhibin binding protein (InhBP) has been cloned from bovine pituitary cells (217). Neither betaglycan nor InhBP, however, has an intrinsic kinase domain (216, 218), 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 (218) 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 (148). 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. 10). 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. 10). 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 (218). 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 (219). 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 (140). 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 (208). 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 (151, 153, 154, 155).

View larger version (24K): [in this window] [in a new window]   Figure 10. 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. Mean ± SE values are shown. The restoration in circulating inhibin B levels from the immediate postunilateral orchidectomy time point to d 4 was small (24%) but statistically significant (see Ref. 148 ). [From: S. Ramaswamy et al.: Endocrinology 141:18–27, 2000 (148 ). Redrawn with permission of The Endocrine Society.].

	VI. Summary

Top Abstract I. Introduction II. Site of FSH... III. Sertoli Cell Ontogeny... IV. The Role of... V. Regulation of FSH... VI. Summary References

 
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. 11. 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. Inhibin B probably suppresses FSH secretion by antagonizing a constitutively expressed activin drive to FSH ß gene expression. 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.

View larger version (20K): [in this window] [in a new window]   Figure 11. 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 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 FSHß gene expression. 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.

	Acknowledgments

 
We are most grateful to two colleagues in the Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine: Professor Anthony J. Zeleznik for discussing FSH signaling with us, and Dr. Talal El-Hefnawy for his translation of the reference in Swedish (106 ). We also thank June M. Marshall for help with the illustrations.

	Footnotes

 
Abbreviations: Ad, Dark-type A; Ap, pale-type A; FSH-R, FSH receptor; GnRH-R, GnRH receptor; h, human; InhBP, inhibin binding protein; LH-R, LH receptor; MG, menopausal gonadotropin; r, recombinant.

	References

Top Abstract I. Introduction II. Site of FSH... III. Sertoli Cell Ontogeny... IV. The Role of... V. Regulation of FSH... VI. Summary References

 

1. Kumar TR, Wang Y, Lu N, Matzuk MM 1997 Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility. Nat Genet 15:201–104[CrossRef][Medline]
2. Tapanainen JS, Aittomäki K, Min J, Vaskivuo T, Huhtaniemi IT 1997 Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility. Nat Genet 15:205–206[CrossRef][Medline]
3. Romer AS 1959 The vertebrate story. Chicago: University of Chicago Press
4. Clermont Y, Morgentaler H 1955 Quantitative study of spermatogenesis in the hypophysectomized rat. Endocrinology 57:369–382
5. Huang HFS, Marshall GR, Rosenberg R, Nieschlag E 1987 Restoration of spermatogenesis by high levels of testosterone in hypophysectomized rats after long-term regression. Acta Endocrinol (Copenh) 116:433–444[Abstract/Free Full Text]
6. Smith PE 1944 Maintenance and restoration of spermatogenesis in hypophysectomized rhesus monkeys by androgen administration. Yale J Biol Med 17:281–287
7. MacLeod J, Pazianos A, Ray B 1966 The restoration of human spermatogenesis and of reproductive tract with urinary gonadotropins following hypophysectomy. Fertil Steril 17:7–23[Medline]
8. Smith PE 1938 Comparative effects of hypophysectomy and therapy on the testes of monkeys and rats. In: Brouha L, ed. Hormones sexuelles. Paris: Comptes Rendus; 201–209
9. Rea MA, Weinbauer GF, Marshall GR, Neischlag E 1986 Testosterone stimulates pituitary and serum FSH in GnRH antagonist-suppressed rats. Acta Endocrinol (Copenh) 113:487–492[Abstract/Free Full Text]
10. Rea MA, Marshall GR, Weinbauer GF, Nieschlag E 1986 Testosterone maintains pituitary and serum FSH and spermatogenesis in gonadotropin-releasing hormone antagonist-suppressed rats. J Endocrinol 108:101–107[Abstract/Free Full Text]
11. Sinha-Hikim AP, Swerdloff RS 1993 Temporal and stage-specific changes in spermatogenesis of rat after gonadotropin deprivation by a potent gonadotropin-releasing hormone antagonist treatment. Endocrinology 133:2161–2170[Abstract/Free Full Text]
12. Simoni M, Gromoll J, Nieschlag E 1997 The follicle-stimulating hormone receptor: biochemistry, molecular biology, physiology, and pathophysiology. Endocr Rev 18:739–773[Abstract/Free Full Text]
13. Dankbar B, Brinkworth MH, Schlatt S, Weinbauer GF, Nieschlag E, Gromoll J 1995 Ubiquitous expression of the androgen receptor and testis-specific expression of the FSH receptor in the cynomolgus monkey (Macaca fascicularis) revealed by a ribonuclease protection assay. J Steroid Biochem Mol Biol 55:35–41[CrossRef][Medline]
14. Orth J, Christensen AK 1977 Localization of iodine-125 labeled follicle stimulating hormone in the testes of hypophysectomized rats by autoradiography at the light microscope and electron microscope levels. Endocrinology 101:262–278[Abstract/Free Full Text]
15. Orth J, Christensen AK 1978 Autoradiographic localization of specifically bound ¹²⁵I-follicle stimulating hormone on spermatogenesis of the rat testis. Endocrinology 103:1944–1951[Abstract/Free Full Text]
16. Russell LD, Griswold MD, eds. 1993 The Sertoli cell. Clearwater: Cache River Press
17. Dym M 1973 The fine structure of the monkey (Macaca) Sertoli cell and its role in maintaining the blood-testis barrier. Anat Rec 175:639–656[CrossRef][Medline]
18. Dym M, Cavicchia JC 1977 Further observations on the blood-testis barrier in monkeys. Biol Reprod 17:390–403[Abstract]
19. Orth JM, Gunsalus GL, Lamperti AA 1988 Evidence from Sertoli cell-depleted rats indicates that spermatid number in adults depends on numbers of Sertoli cells produced during perinatal development. Endocrinology 122:787–794[Abstract/Free Full Text]
20. Sharpe RM 1994 Regulation of spermatogenesis. In: Knobil E, Neill JD, eds. The physiology of reproduction. New York: Raven Press, Ltd.; 1363–1434
21. Glass RH 1991 Infertility. In: Yen SSC, Jaffe RB, eds. Reproductive endocrinology: physiology, pathophysiology and clinical management. 3rd ed. Philadelphia: W. B. Saunders Co.; 689–709
22. Silber SJ 2000 Evaluation and treatment of male infertility. Clin Obstet Gynecol 43:854–888[CrossRef][Medline]
23. Fisch H, Andrews H, Hendricks J, Goluboff ET, Olson JH, Olsson CA 1997 The relationship of sperm counts to birth rates: a population-based study. J Urol 157:840–884[CrossRef][Medline]
24. World Health Organization Task Force on Methods for the Regulation of Male Fertility 1996 Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril 65:821–829[Medline]
25. Pelliniemi LJ, Fröjdman K, Paranko J 1993 Embryological and prenatal development and function of Sertoli cells. In: Russell LD, Griswold MD, eds. The Sertoli cell. Clearwater: Cache River Press; 88–113
26. Cortes D, Müller J, Skakkebaek NE 1987 Proliferation of Sertoli cells during development of the human testis assessed by stereological methods. Int J Androl 10:589–596[Medline]
27. Baker TG, Scrimgeour JB 1980 Development of the gonad in normal and anencephalic human fetuses. J Reprod Fertil 60:193–199[Abstract/Free Full Text]
28. Gulyas BJ, Tullner WT, Hodgen GD 1977 Fetal or maternal hypophysectomy in rhesus monkeys (Macaca mulatta): effects on the development of testes and other endocrine organs. Biol Reprod 17:650–660[Abstract]
29. Huhtaniemi IT, Yamamoto M, Ranta T, Jalkanen J, Jaffe RB 1987 Follicle-stimulating hormone receptors appear earlier in the primate fetal testis than in the ovary. J Clin Endocrinol Metab 65:1210–1214[Abstract/Free Full Text]
30. Kluin PM, Kramer MF, de Rooij DG 1983 Testicular development in Macaca irus after birth. Intl J Androl 6:25–43[Medline]
31. Marshall GR, Plant TM 1996 Puberty occurring either spontaneously or induced precociously in rhesus monkey (Macaca mulatta) is associated with a marked proliferation of Sertoli cells. Biol Reprod 54:1192–1199[Abstract]
32. Plant TM 1994 Puberty in primates. In: Knobil E, Neill JD, eds. The physiology of reproduction. 2nd ed. New York: Raven Press, Ltd.; vol 2:453–485
33. Ojeda SR, Urbanski HF 1994 Puberty in the rat. In: Knobil E, Neill JD, eds. The physiology of reproduction. New York: Raven Press, Ltd.; vol 2:363–409
34. Orth JM 1982 Proliferation of Sertoli cells in fetal and postnatal rats. Anat Rec 203:485–492[CrossRef][Medline]
35. Clermont Y, Perey B 1957 Quantitative study of the cell population of the seminiferous tubules in immature rats. Am J Anat 100: 241–267
36. Sharpe RM, Walker M, Millar MR, Atanassova N, Morris K, McKinnell C, Saunders PTK, Fraser HM 2000 Effect of neonatal gonadotropin-releasing hormone antagonist administration on Sertoli cell number and testicular development in the marmoset: comparison with the rat. Biol Reprod 62:1685–1693[Abstract/Free Full Text]
37. Rey RA, Campo SM, Bedecarras P, Nagle CA, Chemes HE 1993 Is infancy a quiescent period of testicular development? Histological, morphometric, and functional study of the seminiferous tubules of the cebus monkey from birth to the end of puberty. J Clin Endocrinol Metab 76:1325–1331[Abstract]
38. Ramaswamy S, Plant TM, Marshall GR 2000 Pulsatile stimulation with recombinant single chain human luteinizing hormone elicits precocious Sertoli cell proliferation in the juvenile male rhesus monkey (Macaca mulatta). Biol Reprod 63:82–88[Abstract/Free Full Text]
39. Arslan M, Weinbauer GF, Schlatt S, Shahab M, Nieschlag E 1993 FSH and testosterone, alone or in combination, initiate testicular growth and increase the number of spermatogonia and Sertoli cells in a juvenile non-human primate (Macaca mulatta). J Endocrinol 136:235–243[Abstract/Free Full Text]
40. Albertsson-Wikland K, Rosberg S, Lannerring B, Dunkel L, Selstam G, Norjavaara E 1997 Twenty-four-hour profiles of luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol levels: a semilongitudinal study throughout puberty in healthy boys. J Clin Endocrinol Metab 82:541–549[Abstract/Free Full Text]
41. Mitamura R, Yano K, Suzuki N, Ito Y, Makita Y, Okuno Y 1999 Diurnal rhythms of luteinizing hormone, follicle-stimulating hormone, and testosterone secretion before the onset of male puberty. J Clin Endocrinol Metab 84:29–37[Abstract/Free Full Text]
42. Suárez-Quian CA, Martínez-García F, Nistal M, Regadera J 1999 Androgen receptor distribution in adult human testis. J Clin Endocrinol Metab 84:350–358[Abstract/Free Full Text]
43. Saunders PTK, Millar MR, Majdic G, Bremner WJ, McLaren TT, Grigor KM, Sharpe RM 1996 Testicular androgen receptor protein: distribution and control of expression. In: Desjardins C, ed. Cellular and molecular regulation of testicular cell. New York: Springer-Verlag; 213–229
44. Bhasin S, Fielder TJ, Swerdloff RS 1987 Testosterone selectively increases serum follicle-stimulating hormone (FSH) but not luteinizing hormone (LH) in gonadotropin-releasing hormone antagonist-treated male rats: evidence for differential regulation of FSH and LH secretion. Biol Reprod 37:55–59[Abstract]
45. Khurshid S, Weinbauer GF, Nieschlag E 1991 Effects of administration of testosterone and gonadotrophin-releasing hormone (GnRH) antagonist on basal and GnRH-stimulated gonadotrophin secretion in orchidectomized monkeys. J Endocrinol 129:363–370[Abstract/Free Full Text]
46. Schlatt S, Arslan M, Weinbauer GF, Behre HM, Nieschlag E 1995 Endocrine control of testicular somatic and premeiotic germ cell development in the immature testis of the primate Macaca mulatta. Eur J Endocrinol 133:235–247[Abstract/Free Full Text]
47. Jannini EA, Ulisse S, D’Armiento M 1995 Thyroid hormone and male gonadal function. Endocr Rev 16:443–459[Abstract/Free Full Text]
48. Castro-Magana M, Angulo M, Canas A, Sharp A, Fuentes B 1988 Hypothalamic-pituitary gonadal axis in boys with primary hypothyroidism and macroorchidism. J Pediatr 112:397–402[CrossRef][Medline]
49. Cooke PS, Meisami E 1991 Early hypothyroidism in rats causes increased adult testis and reproductive organ size but does not change testosterone levels. Endocrinology 129:237–243[Abstract/Free Full Text]
50. Cooke PS, Hess RA, Porcelli J, Meisami E 1991 Increased sperm production in adult rats after transient neonatal hypothyroidism. Endocrinology 129:244–248[Abstract/Free Full Text]
51. van Haaster LH, de Jong F, Docter R, de Rooij DG 1992 The effect of hypothyrodism on Sertoli cell proliferation and differentiation and hormone levels during testicular development in the rat. Endocrinology 131:1574–1576[Abstract/Free Full Text]
52. Clermont Y 1972 Kinetics of spermatogenesis in mammals: seminiferous epithelium cycle and spermatogonial renewal. Physiol Rev 52:198–236[Free Full Text]
53. Clermont Y, Antar M 1973 Duration of the cycle of the seminiferous epithelium and the spermatogonial renewal in the monkey Macaca arctoides. Am J Anat 136:153–165[CrossRef][Medline]
54. Clermont Y 1966 Renewal of spermatogonia in man. J Anat 118:509–524
55. Clermont Y 1969 Two classes of spermatogonial stem cells in the monkey (Cercopithecus aethiops). Am J Anat 126:57–72[CrossRef][Medline]
56. de Rooij DG, van Alphen MMA, van de Kant HJG 1986 Duration of the cycle of the seminiferous epithelium and its stages in the rhesus monkey (Macaca mulatta). Biol Reprod 35:587–591[Abstract]
57. Fouquet JP, Dadoune JP 1986 Renewal of spermatogonia in the monkey (Macaca fascicularis). Biol Reprod 35:199–207[Abstract]
58. Cavicchia JC, Dym M 1978 Ultrastructural characteristics of monkey spermatogonia and preleptotene spermatocytes. Biol Reprod 18:219–228[Abstract]
59. Heller CG, Clermont Y 1964 Kinetics of the germinal epithelium in man. Recent Prog Horm Res 20:545–575
60. Paniagua R, Nistal M, Amat P, Rodriguez MC, Alonso JR 1986 Quantitative differences between variants of A spermatogonia in man. J Reprod Fertil 77:669–673[Abstract/Free Full Text]
61. Nistal M, Codesal J, Paniagua R, Santamarie L 1987 Decrease in the number of human Ap and Ad spermatogonia and in the Ap/Ad ratio with advancing age: new data on spermatogonial stem cell. J Androl 8:64–68[Abstract/Free Full Text]
62. Schulze C 1979 Morphological characteristics of the spermatogonial stem cells in man. Cell Tissue Res 198:191–199[Medline]
63. Dym M, Clermont Y 1970 Role of spermatogonia in the repair of the seminiferous epithelium following X-irradiation of the rat testis. Am J Anat 128:265–282[CrossRef][Medline]
64. Huckins C 1971 The spermatogonial stem cell population in adult rats. I. Their morphology, proliferation and maturation. Anat Rec 169:533–557[CrossRef][Medline]
65. Huckins C 1971 The spermatogonial stem cell population in adult rats. II. A radioautographic analysis of their cell cycle properties. Cell Tissue Kinet 4:313–334[Medline]
66. de Rooij DG, Russell LD 2000 All you wanted to know about spermatogonia but were afraid to ask. J Androl 21:776–798[Medline]
67. França LR, Ogawa T, Avarbock MR, Brinster RL, Russell LD 1998 Germ cell genotype controls cell cycle during spermatogenesis in the rat. Biol Reprod 59:1371–1377[Abstract/Free Full Text]
68. Kluin PM, Kramer MF, deRooij DG 1982 Spermatogenesis in the immature mouse proceeds faster than in the adult. Int J Androl 5:282–294[Medline]
69. van Haaster LH, de Rooij DG 1993 Spermatogenesis is accelerated in the immature Djungarian and Chinese hamster and rat. Biol Reprod 49:1229–1235[Abstract]
70. Swerdloff RS, Lue Y-H, Wang C, Rajavashisth T, Sinha Hikim A 1998 Hormonal regulation of germ cell apoptosis. In: Zirkin BR, ed. Germ cell development, division, disruption and death. New York: Springer-Verlag; 150–164
71. Sinha Hikim AP, Wang C, Lue Y-H, Johnson L, Wang X-H, Swerdloff RS 1998 Spontaneous germ cell apoptosis in humans: evidence for ethnic differences in the susceptibility of germ cells to programmed cell death. J Clin Endocrinol Metab 83:152–156[Abstract/Free Full Text]
72. Roosen-Runge ED 1962 The process of spermatogenesis in mammals. Biol Rev 37:343–377
73. Deleted in proof
74. Ewing LL 1982 Seasonal variation in primate fertility with an emphasis on the male. Am J Primatol Suppl 1:145–160
75. Zeleznik AJ, Resko JA 1980 Progesterone does not inhibit gonadotropin-induced follicular maturation in the female rhesus monkey (Macaca mulatta). Endocrinology 106:1820–1826[Abstract/Free Full Text]
76. Bourne GA, Regiani S, Payne AH, Marshall JC 1980 Testicular GnRH receptors – characterization and localization on interstitial tissue. J Clin Endocrinol Metab 51:407–409[Abstract/Free Full Text]
77. Bahk JY, Hyun JS, Chung SH, Lee H, Kim MO, Lee BH, Choi WS 1995 Stage specific identification of the expression of GnRH mRNA and localization of the GnRH receptor in mature rat and adult human testis. J Urol 154:1958–1961[CrossRef][Medline]
78. Kottler M-L, Bergametti F, Carrè M-C, Morice S, Decoret E, Lagarde J-P, Starzec A, Counis R 1999 Tissue-specific pattern of variant transcripts of the human gonadotropin-releasing hormone receptor gene. Eur J Endocrinol 140:561–569[Abstract]
79. Plant TM, Gay VL, Marshall GR, Arslan M 1989 Puberty in monkeys is triggered by chemical stimulation of the hypothalamus. Proc Natl Acad Sci USA 86:2506–2510[Abstract/Free Full Text]
80. Grumbach MM, Styne DM 1992 Puberty: ontogeny, neuroendocrinology, physiology, and disorders. In: Wilson JD, Foster DW, eds. Williams textbook of endocrinology. 8th ed. Philadelphia: W. B. Saunders Co.; 1139–1221
81. Matsumoto AM, Bremner WJ 1987 Endocrinology of the hypothalamic-pituitary-testicular axis with particular reference to the hormonal control of spermatogenesis. Baillieres Clin Endocrinol Metab 1:71–87[CrossRef][Medline]
82. Whitcomb RW, Crowley Jr WF 1990 Diagnosis and treatment of isolated gonadotropin-releasing hormone deficiency in men. J Clin Endocrinol Metab 70:3–7[Abstract/Free Full Text]
83. Schaison G, Young J, Pholsena M, Nahoul K, Couzinet B 1993 Failure of combined follicle-stimulating hormone-testosterone administration to initiate and/or maintain spermatogenesis in men with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 77:1545–1549[Abstract]
84. Zitzmann M, Nieschlag E 2000 Hormone substitution in male hypogonadism. Mol Cell Endocrinol 161:73–88[CrossRef][Medline]
85. Stavrou SS, Zhu Y-S, Cai L-Q, Katz MD, Herrera C, DeFillo-Richart M, Imperato-McGinley J 1998 A novel mutation of the human luteinizing hormone receptor in 46XY and 46XX sisters. J Clin Endocrinol Metab 83:2091–2098[Abstract/Free Full Text]
86. Gromoll J, Eiholzer U, Nieschlag E, Simoni M 2000 Male hypogonadism caused by homozygous deletion of exon 10 of the luteinizing hormone (LH) receptor: differential action of human chorionic gonadotropin and LH. J Clin Endocrinol Metab 85:2281–2286[Abstract/Free Full Text]
87. Ferenczy A, Richart RM 1972 The fine structure of the gonads in the complete form of testicular feminization syndrome. Am J Obstet Gynecol 113:399–409[Medline]
88. McCullagh EP, Beck JC 1952 A syndrome of eunuchoidism with spermatogenesis and normal urinary FSH. J Clin Endocrinol Metab 12:947
89. Smals AGH, Kloppenborg PWC, van Haelst UJG, Lequin R, Benraad TJ 1978 Fertile eunuch syndrome versus classic hypogonadotrophic hypogonadism. Acta Endocrinol (Copenh) 87:389–399[Abstract/Free Full Text]
90. Marshall GR, Wickings EJ, Nieschlag E 1984 Testosterone can initiate spermatogenesis in an immature non-human primate, Macaca fascicularis. Endocrinology 114:2228–2233[Abstract/Free Full Text]
91. Muller J, Gondos B, Kosugi S, Mori T, Shenker A 1998 Severe testotoxicosis phenotype associated with Asp⁵⁷⁸Tyr mutation of the lutrophin/choriogonadotrophin receptor gene. J Med Genet 35:340–341[Abstract/Free Full Text]
92. Kim I, Young RH, Scully RE 1985 Leydig cell tumors of the testis. Am J Surg Pathol 9:177–192[Medline]
93. Steinberger E, Root A, Ficher M, Smith KD 1973 The role of androgens in the initiation of spermatogenesis in man. J Clin Endocrinol Metab 37:746–751[Abstract/Free Full Text]
94. Burris AS, Rodbard HW, Winters SJ, Sherins RJ 1988 Gonadotropin therapy in men with isolated hypogonadotropic hypogonadism: the response to human chorionic gonadotropin is predicted by initial testicular size. J Clin Endocrinol Metab 66:1144–1151[Abstract/Free Full Text]
95. Maroulis GB, Parlow AF, Marshall JR 1977 Isolated folliclestimulating hormone deficiency in man. Fertil Steril 28:818–822[Medline]
96. Hägg E, Tollin C, Bergman B 1978 Isolated FSH deficiency in a male. Scand J Urol Nephrol 12:287–289[Medline]
97. McConnon J, Killinger D, Gracey W, Ghany F 1979 Clomiphene in treatment of male infertility due to isolated follicle-stimulating-hormone deficiency. Lancet 2:525–526[CrossRef][Medline]
98. Al-Ansari AA-K, Khalil TH, Kelani Y, Mortimer CH 1984 Isolated follicle-stimulating hormone deficiency in men: successful long-term gonadotropin therapy. Fertil Steril 42:618–626[Medline]
99. Díez JJ, Iglesias P, Sastre J, Salvador J, Gómez-Pan A, Otero I, Granizo V 1994 Isolated deficiency of follicle-stimulating hormone in man: a case report and literature review. Int J Fertil 39:26–31
100. Phillip M, Arbelle JE, Segev Y, Parvari R 1998 Male hypogonadism due to a mutation in the gene for the ß-subunit of follicle-stimulating hormone. New Engl J Med 338:1729–1732[Free Full Text]
101. Lindstedt G, Nyström E, Matthews C, Ernest I, Janson PO, Chatterjee K 1998 Follitropin (FSH) deficiency in an infertile male due to FSHß gene mutation: a syndrome of normal puberty and virilization but underdeveloped testicles with azoospermia, low FSH but high lutropin and normal serum testosterone concentrations. Clin Chem Lab Med 36:663–665[CrossRef][Medline]
102. Dierich A, Sairam MR, Monaco L, Fimia GM, Gansmuller A, LeMeur M, Sassone-Corsi P 1998 Impairing follicle-stimulating hormone (FSH) signaling in vivo: targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance. Proc Natl Acad Sci USA 95:13612–13617[Abstract/Free Full Text]
103. Aittomäki K, Lucena JLD, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J, Kaskikari R, Sankila E-M, Lehväslaiho H, Engel AR, Nieschlag E, Huhtaniemi I, de la Chapelle A 1995 Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 82:959–968[CrossRef][Medline]
104. Themmen APN, Blok LJ, Post M, Baarends WM, Hoogerbrugge JW, Parmentier M, Vassart G, Grootegoed JA 1991 Follitropin receptor down-regulation involves a cAMP-dependent posttranscriptional decrease of receptor mRNA expression. Mol Cell Endocrinol 78:R7–R13
105. Maguire SM, Tribley WA, Griswold MD 1997 Follicle-stimulating hormone (FSH) regulates the expression of FSH receptor messenger ribonucleic acid in cultured Sertoli cells and in hypophysectomized rat testis. Biol Reprod 56:1106–1111[Abstract]
106. Lindstedt G, Ernest I, Nyström E, Janson PO 1997 Fall av manlig infertilitet. Klinisk Kemi Norden 3:81–87
107. Rabinowitz D, Benveniste R, Lindner J, Lorber D, Daniell J 1979 Isolated follicle-stimulating hormone deficiency revisited. N Engl Med J 300:126–128[Medline]
108. Themmen APN, Huhtaniemi IT 2000 Mutations of gonadotropins and gonadotropin receptors: Elucidating the physiology and pathophysiology of pituitary-gonadal function. Endocr Rev 21:551–583[Abstract/Free Full Text]
109. Steinberger E 1971 Hormonal control of mammalian spermatogenesis. Physiological Rev 51:1–22[Medline]
110. Moudgal NR, Sairam MR 1998 Is there a true requirement for follicle stimulating hormone in promoting spermatogenesis and fertility in primates? Hum Reprod 13:916–919[Abstract/Free Full Text]
111. Nieschlag E, Simoni M, Gromoll J, Weinbauer GF 1999 Role of FSH in the regulation of spermatogenesis: clinical aspects. Clin Endocrinol 51:139–146[CrossRef][Medline]
112. Steinberger E, Steinberger A 1969 The spermatogenic function of the testes. In: McKerns KW, ed. The gonads. New York: Meredith Corp.; 715–737
113. Politoff L, Birkhauser M, Almendral A, Zorn A 1989 New data confirming a circannual rhythm in spermatogenesis. Fertil Steril 52:486–489[Medline]
114. Gyllenborg J, Skakkebæk NE, Nielsen NC, Keiding N, Giwercman A 1999 Secular and seasonal changes in semen quality among young Danish men: a statistical analysis of semen samples from 1927 donor candidates during 1977–1995. Int J Androl 22:28–36[CrossRef][Medline]
115. Marshall GR, Jockenhövel F, Lüdecke D, Nieschlag E 1986 Maintenance of complete but quantitatively reduced spermatogenesis in hypophysectomized monkeys by testosterone alone. Acta Endocrinol (Copenh) 113:424–431[Abstract/Free Full Text]
116. Weinbauer GF, Gockeler E, Nieschlag E 1988 Testosterone prevents complete suppression of spermatogenesis in the gonadotropin-releasing hormone antagonist-treated nonhuman primate (Macaca fascicularis). J Clin Endocrinol Metab 67:284–290[Abstract/Free Full Text]
117. Matsumoto AM, Karpas AE, Bremner WJ 1986 Chronic human chorionic gonadotropin administration in normal men: evidence that follicle-stimulating hormone is necessary for the maintenance of quantitatively normal spermatogenesis in man. J Clin Endocrinol Metab 62:1184–1192[Abstract/Free Full Text]
118. Sheela Rani CS, Murty GSRC, Moudgal NR 1978 Effect of chronic neutralization of endogenous FSH on testicular function in the adult male bonnet monkey—assessment using biochemical parameters. Int J Androl 1:489–500
119. Wickings EJ, Usadel KH, Dathe G, Nieschlag E 1980 The role of follicle stimulating hormone in testicular function of the mature rhesus monkey. Acta Endocrinol (Copenh) 95:117–128[Abstract/Free Full Text]
120. Srinath BR, Wickings EJ, Witting C, Nieschlag E 1983 Active immunization with follicle-stimulating hormone for fertility control: a 41/2-year study in male rhesus monkeys. Fertil Steril 40: 110–117
121. Murty GSRC, Sheela Rani CS, Moudgal NR, Prasad MRN 1979 Effect of passive immunization with specific antiserum to FSH on the spermatogenic process and fertility of adult male bonnet monkeys (Macaca radiata). J Reprod Fert Suppl 26:147–163
122. Aravindan GR, Gopalakrishnan K, Ravindranath N, Moudgal NR 1993 Effect of altering endogenous gonadotrophin concentrations on the kinetics of testicular germ cell turnover in the bonnet monkey (Macaca radiata). J Endocrinol 137:485–495[Abstract/Free Full Text]
123. Moudgal NR, Sairam MR, Krishnamurthy HN, Sridhar S, Krishnamurthy H, Khan H 1997 Immunization of male bonnet monkeys (M. radiata) with a recombinant FSH receptor preparation affects testicular function and fertility. Endocrinology 138:3065–3068[Abstract/Free Full Text]
124. Moudgal NR, Murthy GS, Prasanna Kumar KM, Martin F, Suresh R, Medhamurthy R, Patil S, Sehgal S, Saxena BN 1997 Responsiveness of human male volunteers to immunization with ovine follicle stimulating hormone vaccine: result of a pilot study. Hum Reprod 12:457–463
125. Weinbauer GF, Schlatt S, Walter V, Nieschlag E 2001 Testosterone-induced inhibition of spermatogenesis is more closely related to suppression of FSH than to testicular androgen levels in the cynomolgus monkey model (Macaca fascicularis). J Endocrinol 168:25–38[Abstract]
126. Amann RP, Johnson L, Thompson Jr DL, Pickett BW 1976 Daily spermatozoal production, epididymal spermatozoal reserves and transit time of spermatozoa through the epididymis of the rhesus monkey. Biol Reprod 15:586–592[Abstract]
127. Suresh R, Medhamurthy R, Moudgal NR 1995 Comparative studies on the effects of specific immunoneutralization of endogenous FSH or LH on testicular germ cell transformations in the adult bonnet monkey (Macaca radiata). Am J Reprod Immunol 34:35–43
128. Weinbauer GF, Behre HM, Fingscheidt U, Nieschlag B 1991 Human follicle-stimulating hormone exerts a stimulatory effect on spermatogenesis, testicular size, and serum inhibin levels in the gonadotropin-releasing hormone antagonist-treated nonhuman primate (Macaca fascicularis). Endocrinology 129:1831–1839[Abstract/Free Full Text]
129. Gromoll J, Simoni M, Nieschlag E 1996 An activating mutation of the follicle-stimulating hormone receptor autonomously sustains spermatogenesis in a hypophysectomized man. J Clin Endocrinol Metab 81:1367–1370[Abstract]
130. Dym M 1994 Basement membrane regulation of Sertoli cells. Endocr Rev 15:102–115[Abstract/Free Full Text]
131. Virtanen I, Lohi J, Tani T, Korhonen M, Burgeson RE, Lehto VP, Leivo I 1997 Distinct changes in the laminin composition of basement membranes in human seminiferous tubules during development and degeneration. Am J Pathol 150:1421–1431[Abstract]
132. Loveland K, Schlatt S, Sasaki T, Chu ML, Timpl R, Dziadek M 1998 Developmental changes in the basement membrane of the normal and hypothyroid postnatal rat testis: segmental localization of fibulin-2 and fibronectin. Biol Reprod 58:1123–1130[Abstract/Free Full Text]
133. Matsumoto AM, Karpas AE, Paulsen CA, Bremner WJ 1983 Reinitiation of sperm production in gonadotropin-suppressed normal men by administration of follicle stimulating hormone. J Clin Invest 72:1005–1015
134. Marshall GR, Wickings EJ, Lüdecke DK, Nieschlag E 1983 Stimulation of spermatogenesis in stalk-sectioned rhesus monkeys by testosterone alone. J Clin Endocrinol Metab 57:152–159[Abstract/Free Full Text]
135. Marshall GR, Zorub DS, Plant TM 1995 Follicle-stimulating hormone amplifies the population of differentiated spermatogonia in the hypophysectomized testosterone-replaced adult rhesus monkey (Macaca mulatta). Endocrinology 136:3504–3511[Abstract]
136. Bremner WJ, Matsumoto AM, Sussman AM, Paulsen CA 1981 Follicle-stimulating hormone and human spermatogenesis. J Clin Invest 68:1044–1052
137. Matsumoto AM, Paulsen CA, Bremner WJ 1984 Stimulation of sperm production by human luteinizing hormone in gonadotropin-suppressed normal men. J Clin Endocrinol Metab 55:882–887[Abstract/Free Full Text]
138. Moudgal NR, Ravindranath N, Murthy GS, Dighe RR, Aravindan GR, Martin F 1992 Long-term contraceptive efficacy of vaccine of ovine follicle-stimulating hormone in male bonnet monkeys (Macaca radiata). J Reprod Fertil 96:91–102[Abstract/Free Full Text]
139. Nieschlag E, Srinath BR, Marshall GR, Wickings EJ 1983 Attempts at male fertility control with antibodies directed against FSH: a long-term study in non-human primates. In: Dondero F, Shulman S, eds. Immunological factors in human contraception. Rome: Italia Acta Medica; 183–187
140. Kamischke A, Behre HM, Bergmann M, Simoni M, Schäfer T, Nieschlag E 1998 Recombinant human follicle stimulating hormone for treatment of male idiopathic infertility: a randomized, double-blind, placebo-controlled, clinical trial. Hum Reprod 13:596–603[Abstract/Free Full Text]
141. Acosta AA, Khalifa E, Oehninger S 1992 Pure human follicle stimulating hormone has a role in the treatment of severe male infertility by assisted reproduction: Norfolk’s total experience. Hum Reprod 7:1067–1072[Abstract/Free Full Text]
142. Bartoov B, Eltes F, Lunenfeld E, Har-Even D, Lederman H, Lunenfeld B 1994 Sperm quality of subfertile males before and after treatment with human follicle-stimulating hormone. Fertil Steril 61:727–734[Medline]
143. Iacono F, Barra S, Montano L, Lotti T 1996 Intérêt de la FSH pure à forte dose dans le traitement de l’inferilité masculine idiopathique. J Urol (Paris) 102:81–84[Medline]
144. Glander H-J, Kratzsch J 1997 Effects of pure human folliclestimulating hormone (pFSH) on sperm quality correlate with the hypophyseal response to gonadotrophin-releasing hormone (GnRH). Andrologia 29:23–28[Medline]
145. Foresta C, Bettella A, Ferlin A, Garolla A, Rossato M 1998 Evidence for a stimulatory role of follicle-stimulating hormone on the spermatogonial population in adult males. Fertil Steril 69:636–642[CrossRef][Medline]
146. Foresta C, Bettella A, Merico M, Garolla A, Plebani M, Ferlin A, Rossato M 2000 FSH in the treatment of oligozoospermia. Mol Cell Endocrinol 161:89–97[CrossRef][Medline]
147. van Alphen MMA, van de Kant HJG, de Rooij DG 1988 Follicle-stimulating hormone stimulates spermatogenesis in the adult monkey. Endocrinology 123:1449–1455[Abstract/Free Full Text]
148. Ramaswamy S, Marshall GR, McNeilly AS, Plant TM 2000 Dynamics of the follicle-stimulating hormone (FSH)-inhibin B feedback loop and its role in regulating spermatogenesis in the adult male rhesus monkey (Macaca mulatta) as revealed by unilateral orchidectomy. Endocrinology 141:18–27[Abstract/Free Full Text]
149. Medhamurthy R, Aravindan GR, Moudgal NR 1993 Hemiorchidectomy leads to dramatic and immediate alterations in pituitary follicle-stimulating hormone secretion and the functional activity of the remaining testis in the adult male bonnet monkey (Macaca radiata). Biol Reprod 49:743–749[Abstract]
150. Zhengwei Y, McLachlan RI, Bremner WJ, Wreford NG 1997 Quantitative (stereological) study of normal spermatogenesis in the adult monkey (Macaca fascicularis). J Androl 18:681–687[Abstract/Free Full Text]
151. Berthelsen JG, Skakkebæk NE 1983 Gonadal function in men with testis cancer. Fertil Steril 39:68–75[Medline]
152. Ferreira U, Netto Jr NR, Esteves SC, Rivero MA, Schirren C 1991 Comparative study of the fertility potential of men with only one testis. Scand J Urol Nephrol 25:255–259[Medline]
153. Lin WW, Kim ED, Quesada ET, Lipshultz LI, Coburn M 1998 Unilateral testicular injury from external trauma: evaluation of semen quality and endocrine parameters. J Urol 159:841–843[CrossRef][Medline]
154. Petersen PM, Skakkebæk NE, Rørth M, Giwercman A 1999 Semen quality and reproductive hormones before and after orchiectomy in men with testicular cancer. J Urol 161:822–826[CrossRef][Medline]
155. Jacobsen KD, Theodorsen L, Fossa SD 2000 Spermatogenesis after unilateral orchiectomy for testicular cancer in patients following surveillance policy. J Urol 165:93–96[CrossRef]
156. Zirkin BR, Santulli R, Awoniyi CA, Ewing LL 1989 Maintenance of advanced spermatogenic cells in the adult rat testis: quantitative relationship to testosterone concentration within the testis. Endocrinology 124:3043–3049[Abstract/Free Full Text]
157. Awoniyi CA, Santulli R, Chandrashekar V, Schanbacher BD, Zirkin BR 1989 Quantitative restoration of advanced spermatogenic cells in adult male rats made azoospermic by active immunization against luteinizing hormone or gonadotropin-releasing hormone. Endocrinology 125:1303–1309[Abstract/Free Full Text]
158. Roberts KP, Zirkin BR 1991 Androgen regulation of spermatogenesis in the rat. Ann NY Acad Sci 637:90–106[Medline]
159. Majumdar SS, Winters SJ, Plant TM 1997 A study of the relative roles of follicle-stimulating hormone and luteinizing hormone in the regulation of testicular inhibin secretion in the rhesus monkey (Macaca mulatta). Endocrinology 138:1363–1373[Abstract/Free Full Text]
160. Young J, Couzinet B, Chanson P, Brailly S, Loumaye E, Schaison G 2000 Effects of human recombinant luteinizing hormone and follicle-stimulating hormone in patients with acquired hypogonadotropic hypogonadism: study of Sertoli and Leydig cell secretions and interactions. J Clin Endocrinol Metab 85:3239–3244[Abstract/Free Full Text]
161. Russell LD, Corbin TJ, Borg KE, de França LR, Grasso P, Bartke A 1993 Recombinant human follicle-stimulating hormone is capable of exerting a biological effect in the adult hypophysectomized rat by reducing the numbers of degenerating germ cells. Endocrinology 133:2062–2070[Abstract/Free Full Text]
162. de Rooij DG, van Beek MEAB 1996 Possibilities to improve primate spermatogenesis by way of hormonal treatment. In: Hamamah S, Mieusset R, eds. Male gametes: production and quality. Paris: Institut National de la Santé et la Recherche Médicale; 257–268
163. Zhengwei Y, Wreford NG, Schlatt S, Weinbauer GF, Nieschlag E, McLachlan RI 1998 Acute and specific impairment of spermatogonial development by GnRH antagonist-induced gonadotrophin withdrawal in the adult macaque (Macaca fascicularis). J Reprod Fertil 112:139–147[Abstract/Free Full Text]
164. Khan SA, Söder O, Syed V, Gustafsson K, Lindh M, Ritzen EM 1987 The rat testis produces large amounts of interleukin-1-like factor. Int J Androl 10:495–503[Medline]
165. Pöllänen P, Söder O, Parvinen M 1989 Interleukin-1 stimulation of spermatogonial proliferation in vivo. Reprod Fertil Dev 1:85–87[CrossRef][Medline]
166. Parvinen M, Söder O, Mali P, Fröysa B, Ritzèn EM 1991 In vitro stimulation of stage-specific deoxyribonucleic acid synthesis in rat seminiferous tubule segments by interleukin-1. Endocrinology 129:1614–1620[Abstract/Free Full Text]
167. Söder O, Syed V, Callard GV, Toppari J, Pöllänen P, Parvinen M, Fröysa B, Ritzen EM 1991 Production and secretion of an interleukin-1-like factor is stage-dependent and correlates with spermatogonial DNA synthesis in the rat seminiferous epithelium. Int J Androl 14:223–231[Medline]
168. Hakovirta H, Penttilä TL, Pöllänen P, Fröysa B, Söder O, Parvinen M 1993 Interleukin-1 bioactivity and DNA synthesis in X-irradiated rat testes. Int J Androl 16:159–164[Medline]
169. Rossi P, Dolci S, Albanesi C, Grimaldi P, Ricca R, Geremia R 1993 Follicle-stimulating hormone induction of steel factor (SLF) mRNA in mouse Sertoli cells and stimulation of DNA synthesis in spermatogonia by soluble SLF. Dev Biol 155:68–74[CrossRef][Medline]
170. Dym M, Jia M-C, Dirami G, Price JM, Rabin SJ, Mocchetti I, Ravindranath N 1995 Expression of c-kit receptor and its autophosphorylation in immature rat type A spermatogonia. Biol Reprod 52:8–19[Abstract]
171. Packer AL, Besmer P, Bacharova RF 1995 Kit ligand mediates survival of type A-spermatogonia and dividing spermatocytes in postnatal mouse testes. Mol Reprod Dev 42:303–310[CrossRef][Medline]
172. Hakovirta H, Yan W, Kaleva M, Zhang F, Vänttinen K, Morris PL, Söder M, Parvinen M, Toppari J 1999 Function of stem cell factor as a survival factor of spermatogonia and localization of messenger ribonucleic acid in the rat seminiferous epithelium. Endocrinology 140:1492–1498[Abstract/Free Full Text]
173. Yan W, Linderborg J, Suominen J, Toppari J 1999 Stage-specific regulation of stem cell factor gene expression in the rat seminiferous epithelium. Endocrinology 140:1499–1504[Abstract/Free Full Text]
174. O’Donnell L, Narula A, Balourdos G, Gu Y-Q, Wreford NG, Robertson DM, Bremner WJ, McLachlan RI 2001 Impairment of spermatogonial development and spermiation after testosterone-induced gonadotropin suppression in adult monkeys (Macaca fascicularis). J Clin Endocrinol Metab 86:1814–1822[Abstract/Free Full Text]
175. Zhengwei Y, Wreford NG, Royce P, de Kretser DM, McLachlan RI 1998 Stereological evaluation of human spermatogenesis after suppression by testosterone treatment: heterogeneous pattern of spermatogenic impairment. J Clin Endocrinol Metab 83:1284–1291[Abstract/Free Full Text]
176. Aravindan GR, Krishnamurthy H, Moudgal NR 1997 Enhanced susceptibility of follicle-stimulating-hormone-deprived infertile bonnet monkey (Macaca radiata) spermatozoa to dithiothreitol-induced DNA decondensation in situ. J Androl 18:688–697[Abstract/Free Full Text]
177. Krishnamurthy H, Kumar KM, Joshi CV, Krishnamurthy HN, Moudgal RN, Sairam MR 2000 Alterations in sperm characteristics of follicle-stimulating hormone (FSH)-immunized men are similar to those of FSH-deprived infertile male bonnet monkeys. J Androl 21:316–327[Abstract]
178. Baccetti B, Strehler E, Capitani S, Collodel G, De Santo M, Moretti E, Piomboni P, Wiedeman R, Sterzik K 1997 The effect of follicle stimulating hormone therapy on human sperm structure (Notulae seminologicae 11). Hum Reprod 12:1955–1968[Abstract/Free Full Text]
179. Plant TM 1986 Gonadal regulation of hypothalamic gonadotropin-releasing hormone release in primates. Endocr Rev 7:75–88[Abstract/Free Full Text]
180. Silverman A-J, Livne I, Witkin JW 1994 The gonadotropin-releasing hormone (GnRH), neuronal systems: immunocytochemistry and in situ hybridization. In: Knobil E, Neill JD, eds. The physiology of reproduction, 2nd ed. New York: Raven Press, Ltd.; vol 1:1683–1709
181. Karsch FJ 1980 Twenty-fifth Annual Bowditch Lecture. Seasonal reproduction: a saga of reversible fertility. Physiologist 23:29–38
182. Pohl CR, Knobil E 1982 The role of the central nervous system in the control of ovarian function in higher primates. Annu Rev Physiol 44:583–593[CrossRef][Medline]
183. Clarke IJ, Cummins JT 1982 The temporal relationship between gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH) secretion in ovariectomized ewes. Endocrinology 111:1737–1739[Abstract/Free Full Text]
184. Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E 1978 Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin-releasing hormone. Science 202: 631–633
185. Plant TM, Dubey AK 1984 Evidence from the rhesus monkey (Macaca mulatta) for the view that negative feedback control of luteinizing hormone secretion by the testis is mediated by a deceleration of hypothalamic gonadotropin-releasing hormone pulse frequency. Endocrinology 115:2145–2153[Abstract/Free Full Text]
186. Santoro N, Filicori M, Crowley Jr WF 1986 Hypogonadotropic disorders in men and women: diagnosis and therapy with pulsatile gonadotropin-releasing hormone. Endocr Rev 7:11–23[Abstract/Free Full Text]
187. Crowley Jr WF, Whitcomb RW, Jameson JL, Weiss J, Finkelstein JS, O’Dea LS 1991 Neuroendocrine control of human reproduction in the male. Recent Prog Horm Res 47:27–62
188. Spratt DI, Finkelstein JS, Butler JP, Badger TM, Crowley Jr WF 1987 Effects of increasing the frequency of low doses of gonadotropin-releasing hormone (GnRH) on gonadotropin secretion in GnRH-deficient men. J Clin Endocrinol Metab 64:1179–1186[Abstract/Free Full Text]
189. Finkelstein JS, Badger TM, O’Dea LS, Spratt DI, Crowley Jr WF 1988 Effects of decreasing the frequency of gonadotropin-releasing hormone stimulation on gonadotropin secretion in gonadotropin-releasing hormone-deficient men and perifused rat pituitary cells. J Clin Invest 81:1725–1733
190. Gross KM, Matsumoto AM, Bremner WJ 1987 Differential control of luteinizing hormone and follicle-stimulating hormone secretion by luteinizing-hormone releasing hormone pulse frequency in men. J Clin Endocrinol Metab 64:675–680[Abstract/Free Full Text]
191. Adams LA, Clifton DK, Bremner WJ, Steiner RA 1988 Testosterone modulates the differential release of luteinizing hormone and follicle-stimulating hormone that occurs in response to changing gonadotropin-releasing hormone pulse frequency in the male monkey, Macaca fascicularis. Biol Reprod 38:156–162[Abstract]
192. Haisenleder DJ, Dalkin AC, Marshall JC 1994 Regulation of gonadotropin gene expression. In: Knobil E, Neill JD, eds. The physiology of reproduction. New York: Raven Press; vol 1:1793–1813
193. Plant TM 1994 FSH secretion in the adult male rhesus monkey is controlled in a manner consistent with that proposed by the inhibin hypothesis. In: Burger HG, Findlay J, Robertson D, de Kretser D, Petraglia F, eds. Frontiers in endocrinology: inhibin and inhibin-related proteins. Rome: Ares-Serono; 135–143
194. Abeyawardene SA, Vale WW, Marshall GR, Plant TM 1989 Circulating inhibin concentrations in infant, prepubertal, and adult male rhesus monkeys (Macaca mulatta) and in juvenile males during premature initiation of puberty with pulsatile gonadotropin- releasing hormone treatment. Endocrinology 125:250–256[Abstract/Free Full Text]
195. Dubey AK, Zeleznik AJ, Plant TM 1987 In the rhesus monkey (Macaca mulatta), the negative feedback regulation of follicle-stimulating hormone secretion by an action of testicular hormone directly at the level of the anterior pituitary gland cannot be accounted for by either testosterone or estradiol. Endocrinology 121:2229–2237[Abstract/Free Full Text]
196. Fingscheidt U, Weinbauer GF, Fehm HL, Nieschlag E 1998 Regulation of gonadotrophin secretion by inhibin, testosterone and gonadotrophin-releasing hormone in pituitary cell cultures of male monkeys. J Endocrinol 159:103–110[Abstract]
197. Medhamurthy R, Gay VL, Plant TM 1990 The prepubertal hiatus in gonadotroprin secretion in the male rhesus monkey (Macaca mulatta) does not appear to involve endogenous opioid peptide restraint of hypothalamic gonadotropin-releasing hormone release. Endocrinology 126:1036–1042[Abstract/Free Full Text]
198. Majumdar SS, Mikuma N, Ishwad PC, Winters SJ, Attardi BJ, Perera AD, Plant TM 1995 Replacement with recombinant human inhibin immediately after orchidectomy in the hypophysiotropically clamped male rhesus monkey (Macaca mulatta) maintains follicle-stimulating hormone (FSH) secretion and FSH ß messenger ribonucleic acid levels at precastration values. Endocrinology 136:1969–1977[Abstract]
199. McCullalgh DR 1932 Dual endocrine activity of the testes. Science 76:19–20[Free Full Text]
200. Medhamurthy R, Culler MD, Gay VL, Negro-Vilar A, Plant TM 1991 Evidence that inhibin plays a major role in the regulation of folicle-stimulating hormone secretion in the fully adult male rhesus monkey (Macaca mulatta). Endocrinology 129:389–395[Abstract/Free Full Text]
201. Ramaswamy S, Pohl CR, McNeilly AS, Winters SJ, Plant TM 1998 The time course of follicle-stimulating hormone suppression by recombinant human inhibin A in the adult male rhesus monkey (Macaca mulatta). Endocrinology 139:3409–3415[Abstract/Free Full Text]
202. Plant TM, Padmanabhan V, Ramaswammy S, McConnell DS, Winters SJ, Groome N, Midgley Jr AR, McNeilly AS 1997 Circulating concentrations of dimeric inhibin A and B in the male rhesus monkey (Macaca mulatta). J Clin Endocrinol Metab 82:2617–2621[Abstract/Free Full Text]
203. van Thiel DH, Sherins RJ, Myers Jr GH, De Vita Jr VT 1972 Evidence for a specific seminiferous tubular factor affecting follicle-stimulating hormone secretion in man. J Clin Invest 51:1009–1019
204. de Kretser DM, McLachlan RI, Robertson DM, Burger HG 1989 Serum inhibin levels in normal men and men with testicular disorders. J Endocrinol 120:517–523[Abstract/Free Full Text]
205. Lambert-Messerlian GM, Hall JE, Sluss PM, Taylor AE, Martin KA, Groome NP, Crowley Jr WF, Schneyer AL 1994 Relatively low levels of dimeric inhibin circulate in men and women with polycystic ovarian syndrome using a specific two-site enzyme-linked immunosorbent assay. J Clin Endocrinol Metab 79:45–50[Abstract]
206. Schneyer AL, Mason AJ, Burton LE, Ziegner JR, Crowley Jr WF 1990 Immunoreactive inhibin -subunit in human serum: implications for radioimmunoassay. J Clin Endocrinol Metab 70:1208–1212[Abstract/Free Full Text]
207. Knight PG 1996 Roles of inhibins, activins, and follistatin in the female reproductive system. Front Neuroendocrinol 17:476–509[CrossRef][Medline]
208. Anawalt BD, Bebb RA, Matsumoto AM, Groome NP, Illingworth PJ, McNeilly AS, Bremner WJ 1996 Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction. J Clin Endocrinol Metab 81:3341–3345[Abstract]
209. Illingworth PJ, Groome NP, Byrd W, Raines WE, McNeilly AS, Mather JP, Bremner WJ 1996 Inhibin-B: a likely candidate for the physiologically important form of inhibin in men. J Clin Endocrinol Metab 81:1321–1325[Abstract]
210. Nachtigall LB, Boepple PA, Seminara SB, Khoury RH, Sluss PM, Lecain AE, Crowley Jr WF 1996 Inhibin B secretion in males with gonadotropin-releasing hormone (GnRH) deficiency before and during long-term GnRH replacement: relationship to spontaneous puberty, testicular volume, and prior treatment – a clinical research center study. J Clin Endocrinol Metab 81:3520–3525[Abstract]
211. Attardi B, Marshall GR, Zorub DS, Winters SJ, Miklos J, Plant TM 1992 Effects of orchidectomy on gonadotropin and inhibin subunit messenger ribonucleic acids in the pituitary of the rhesus monkey (Macaca mulatta). Endocrinology 130:1238–1244[Abstract/Free Full Text]
212. Winters SJ, Kawakami S, Sahu A, Plant TM 2001 Pituitary follistatin and activin gene expression, and the testicular regulation of FSH in the adult rhesus monkey (Macaca mulatta). Endocrinology 142:2874–2878[Abstract/Free Full Text]
213. Xu J, McKeehan K, Matsuzaki K, McKeehan WL 1995 Inhibin antagonizes inhibition of liver cell growth by activin by dominant-negative mechanism. J Biol Chem 270:6308–6313[Abstract/Free Full Text]
214. Lebrun JJ, Vale WW 1997 Activin and inhibin have antagonistic effects on ligand-dependent heteromerization of the type I and type II activin receptors and human erythroid differentiation. Mol Cell Biol 17:1682–1691[Abstract]
215. Hertan R, Farnworth PG, Fitzsimmons KL, Robertson DM 1999 Identification of high affinity binding sites for inhibin on ovine pituitary cells in culture. Endocrinology 140:6–12[Abstract/Free Full Text]
216. Lewis KA, Gray PC, Blount AL, MacConell LA, Wiater E, Bilezikjian LM, Vale W 2000 Betaglycan binds inhibin and can mediate functional antagonism of activin signalling. Nature 404:411–414[CrossRef][Medline]
217. Chong H, Pangas SA, Bernard DJ, Wang E, Gitch J, Chen W, Draper LB, Cox ET, Woodruff TK 2000 Structure and expression of a membrane component of the inhibin receptor system. Endocrinology 141:2600–2607[Abstract/Free Full Text]
218. Bernard DJ, Chapman SC, Woodruff TK 2001 Mechanism of inhibin signal transduction. Recent Prog Horm Res 56:417–450[Abstract]
219. Ramaswamy S, Plant TM 2001 Operation of the follicle-stimulating hormone (FSH)-inhibin B feedback loop in the control of primate spermatogenesis. Mol Cell Endocrinol 180:93–101[CrossRef][Medline]
220. Resko JA, Quadri SK, Spies HG 1977 Negative feedback control of gonadotropins in male rhesus monkeys: Effects of tissue after castration and interactions of testosterone and estradiol-17ß. Endocrinology 101:215–224[Abstract/Free Full Text]
221. Abeyawardene SA, Plant TM 1989 Reconciliation of the paradox that testosterone replacement prevents the postcastration hypersecretion of follicle-stimulating hormone in male rhesus monkeys (Macaca mulatta) with an intact central nervous system but not in hypothalamic-lesioned, gonadotropin-releasing hormone-replaced animals. Biol Reprod 40:578–584[Abstract]
222. Finkelstein JS, Whitcomb RW, O’Dea LS, Longcopes C, Schoenfeld DA, Crowley Jr WF 1991 Sex steroid control of gonadotropin secretion in the human male. I. Effects of testosterone administration in normal and gonadotropin-releasing hormone-deficient men. J Clin Endocrinol Metab 73:609–620[Abstract/Free Full Text]
223. Finkelstein JS, O’Dea LS, Whitcomb RW, Crowley Jr WF 1991 Sex steroid control of gonadotropin secretion in the human male. II. Effects of estradiol administration in normal and gonadotropin-releasing hormone-deficient men. J Clin Endocrinol Metab 73: 621–628
224. Sheckter CB, Matsumoto AM, Bremner WJ 1989 Testosterone administration inhibits gonadotropin secretion by an effect directly on the human pituitary. J Clin Endocrinol Metab 68:397–401[Abstract/Free Full Text]
225. Hayes FJ, Seminara SB, Decruz S, Boepple PA, Crowley Jr WF 2000 Aromatase inhibition in the human male reveals a hypothalamic site of estrogen feedback. J Clin Endocrinol Metab 85:3027–3035[Abstract/Free Full Text]
226. Hayes FJ, Decruz S, Seminara SB, Boepple PA, Crowley Jr WF 2001 Differential regulation of gonadotropin secretion by testosterone in the human male: absence of a negative feedback effect of testosterone on follicle-stimulating hormone secretion. J Clin Endocrinol Metab 86:53–58[Abstract/Free Full Text]
227. Winters SJ, Troen P 1983 Reexamination of pulsatile luteinizing hormone secretion in primary testicular failure. J Clin Endocrinol Metab 57:432–435[Abstract/Free Full Text]
228. Grumbach MM, Auchus RJ 1999 Estrogen: consequences and implications of human mutations in synthesis and action. J Clin Endocrinol Metab 84:4677–4694[Abstract/Free Full Text]

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				K. Boukari, G. Meduri, S. Brailly-Tabard, J. Guibourdenche, M. L. Ciampi, N. Massin, L. Martinerie, J.-Y. Picard, R. Rey, M. Lombes, et al. Lack of Androgen Receptor Expression in Sertoli Cells Accounts for the Absence of Anti-Mullerian Hormone Repression during Early Human Testis Development J. Clin. Endocrinol. Metab., May 1, 2009; 94(5): 1818 - 1825. [Abstract] [Full Text] [PDF]

				D. Madhukar and S. Rajender Hormonal Treatment of Male Infertility: Promises and Pitfalls J Androl, March 1, 2009; 30(2): 95 - 112. [Abstract] [Full Text] [PDF]

				H. E. Chemes, R. A. Rey, M. Nistal, J. Regadera, M. Musse, P. Gonzalez-Peramato, and A. Serrano Physiological Androgen Insensitivity of the Fetal, Neonatal, and Early Infantile Testis Is Explained by the Ontogeny of the Androgen Receptor Expression in Sertoli Cells J. Clin. Endocrinol. Metab., November 1, 2008; 93(11): 4408 - 4412. [Abstract] [Full Text] [PDF]

				G. Verhoeven and K. De Gendt Tuberoinfundibular Peptide of 39 Residues: A Neuromodulator Starting a Second Career in the Control of Meiosis Endocrinology, September 1, 2008; 149(9): 4289 - 4291. [Full Text] [PDF]

				M. Grigorova, M. Punab, K. Ausmees, and M. Laan FSHB promoter polymorphism within evolutionary conserved element is associated with serum FSH level in men Hum. Reprod., September 1, 2008; 23(9): 2160 - 2166. [Abstract] [Full Text] [PDF]

				N. Pitteloud, A. A. Dwyer, S. DeCruz, H. Lee, P. A. Boepple, W. F. Crowley Jr., and F. J. Hayes The Relative Role of Gonadal Sex Steroids and Gonadotropin-Releasing Hormone Pulse Frequency in the Regulation of Follicle-Stimulating Hormone Secretion in Men J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2686 - 2692. [Abstract] [Full Text] [PDF]

				S. Schlatt, C. R Pohl, J. Ehmcke, and S. Ramaswamy Age-Related Changes in Diurnal Rhythms and Levels of Gonadotropins, Testosterone, and Inhibin B in Male Rhesus Monkeys (Macaca mulatta) Biol Reprod, July 1, 2008; 79(1): 93 - 99. [Abstract] [Full Text] [PDF]

				J. S. Tash, B. Attardi, S. A. Hild, R. Chakrasali, S. R. Jakkaraj, and G. I. Georg A Novel Potent Indazole Carboxylic Acid Derivative Blocks Spermatogenesis and Is Contraceptive in Rats after a Single Oral Dose Biol Reprod, June 1, 2008; 78(6): 1127 - 1138. [Abstract] [Full Text] [PDF]

				P. A. Boepple, F. J. Hayes, A. A. Dwyer, T. Raivio, H. Lee, W. F. Crowley Jr, and N. Pitteloud Relative Roles of Inhibin B and Sex Steroids in the Negative Feedback Regulation of Follicle-Stimulating Hormone in Men across the Full Spectrum of Seminiferous Epithelium Function J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1809 - 1814. [Abstract] [Full Text] [PDF]

				K. Boukari, M. L. Ciampi, A. Guiochon-Mantel, J. Young, M. Lombes, and G. Meduri Human fetal testis: source of estrogen and target of estrogen action Hum. Reprod., July 1, 2007; 22(7): 1885 - 1892. [Abstract] [Full Text] [PDF]

				W. Dhooge, N. Van Larebeke, F. Comhaire, and J.-M. Kaufman Regional Variations in Semen Quality of Community-Dwelling Young Men From Flanders Are Not Paralleled by Hormonal Indices of Testicular Function J Androl, May 1, 2007; 28(3): 435 - 443. [Abstract] [Full Text] [PDF]

				J. Ehmcke and S. Schlatt A revised model for spermatogonial expansion in man: lessons from non-human primates. Reproduction, November 1, 2006; 132(5): 673 - 680. [Abstract] [Full Text] [PDF]

				N. Rasheed, X. Wang, Q.-T. Niu, J. Yeh, and B. Li Atm-deficient mice: an osteoporosis model with defective osteoblast differentiation and increased osteoclastogenesis Hum. Mol. Genet., June 15, 2006; 15(12): 1938 - 1948. [Abstract] [Full Text] [PDF]

				K. Jahnukainen, J. Ehmcke, and S. Schlatt Testicular xenografts: a novel approach to study cytotoxic damage in juvenile primate testis. Cancer Res., April 1, 2006; 66(7): 3813 - 3818. [Abstract] [Full Text] [PDF]

				Y. S. Devi, K. Sarda, B. Stephen, P. Nagarajan, and S. S. Majumdar Follicle-Stimulating Hormone-Independent Functions of Primate Sertoli Cells: Potential Implications in the Diagnosis and Management of Male Infertility J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 1062 - 1068. [Abstract] [Full Text] [PDF]

				D. R. Simorangkir, G. R. Marshall, J. Ehmcke, S. Schlatt, and T. M. Plant Prepubertal Expansion of Dark and Pale Type A Spermatogonia in the Rhesus Monkey (Macaca mulatta) Results from Proliferation During Infantile and Juvenile Development in a Relatively Gonadotropin Independent Manner Biol Reprod, December 1, 2005; 73(6): 1109 - 1115. [Abstract] [Full Text] [PDF]

				S. Ramaswamy Pubertal Augmentation in Juvenile Rhesus Monkey Testosterone Production Induced by Invariant Gonadotropin Stimulation Is Inhibited by Estrogen J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5866 - 5875. [Abstract] [Full Text] [PDF]

				T R. Kumar What have we learned about gonadotropin function from gonadotropin subunit and receptor knockout mice? Reproduction, September 1, 2005; 130(3): 293 - 302. [Abstract] [Full Text] [PDF]

				G. R. Marshall, S. Ramaswamy, and T. M. Plant Gonadotropin-Independent Proliferation of the Pale Type A Spermatogonia in the Adult Rhesus Monkey (Macaca mulatta) Biol Reprod, August 1, 2005; 73(2): 222 - 229. [Abstract] [Full Text] [PDF]

				J. Ehmcke, C. M. Luetjens, and S. Schlatt Clonal Organization of Proliferating Spermatogonial Stem Cells in Adult Males of Two Species of Non-Human Primates, Macaca mulatta and Callithrix jacchus Biol Reprod, February 1, 2005; 72(2): 293 - 300. [Abstract] [Full Text] [PDF]

				N. N Atanassova, M. Walker, C. McKinnell, J. S Fisher, and R. M Sharpe Evidence that androgens and oestrogens, as well as follicle-stimulating hormone, can alter Sertoli cell number in the neonatal rat J. Endocrinol., January 1, 2005; 184(1): 107 - 117. [Abstract] [Full Text] [PDF]

				J. Wistuba, M. Mundry, C. M. Luetjens, and S. Schlatt CoGrafting of Hamster (Phodopus sungorus) and Marmoset (Callithrix jacchus) Testicular Tissues into Nude Mice Does Not Overcome Blockade of Early Spermatogenic Differentiation in Primate Grafts Biol Reprod, December 1, 2004; 71(6): 2087 - 2091. [Abstract] [Full Text] [PDF]

				P. S. Sarkar, S. Paul, J. Han, and S. Reddy Six5 is required for spermatogenic cell survival and spermiogenesis Hum. Mol. Genet., July 15, 2004; 13(14): 1421 - 1431. [Abstract] [Full Text] [PDF]

				S. A. Hild, B. J. Attardi, and J. R. Reel The Ability of a Gonadotropin-Releasing Hormone Antagonist, Acyline, to Prevent Irreversible Infertility Induced by the Indenopyridine, CDB-4022, in Adult Male Rats: The Role of Testosterone Biol Reprod, July 1, 2004; 71(1): 348 - 358. [Abstract] [Full Text] [PDF]

				E. D. Albrecht, R. B. Billiar, G. W. Aberdeen, J. S. Babischkin, and G. J. Pepe Expression of Estrogen Receptors {alpha} and {beta} in the Fetal Baboon Testisand Epididymis Biol Reprod, April 1, 2004; 70(4): 1106 - 1113. [Abstract] [Full Text] [PDF]

				F.-P. Zhang, T. Pakarainen, M. Poutanen, J. Toppari, and I. Huhtaniemi The low gonadotropin-independent constitutive production of testicular testosterone is sufficient to maintain spermatogenesis PNAS, November 11, 2003; 100(23): 13692 - 13697. [Abstract] [Full Text] [PDF]

				D. R. Simorangkir, G. R. Marshall, and T. M. Plant Sertoli Cell Proliferation during Prepubertal Development in the Rhesus Monkey (Macaca mulatta) Is Maximal during Infancy when Gonadotropin Secretion Is Robust J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4984 - 4989. [Abstract] [Full Text] [PDF]

				W. H. Walker Molecular Mechanisms Controlling Sertoli Cell Proliferation and Differentiation Endocrinology, September 1, 2003; 144(9): 3719 - 3721. [Full Text] [PDF]

				H. Kaneko, J. Noguchi, K. Kikuchi, and Y. Hasegawa Molecular Weight Forms of Inhibin A and Inhibin B in the Bovine Testis Change with Age Biol Reprod, May 1, 2003; 68(5): 1918 - 1925. [Abstract] [Full Text] [PDF]

				S. Ramaswamy, G. R. Marshall, C. R. Pohl, R. L. Friedman, and T. M. Plant Inhibitory and Stimulatory Regulation of Testicular Inhibin B Secretion by Luteinizing Hormone and Follicle-Stimulating Hormone, Respectively, in the Rhesus Monkey (Macaca mulatta) Endocrinology, April 1, 2003; 144(4): 1175 - 1185. [Abstract] [Full Text] [PDF]

				R. A. Anderson and D. T. Baird Male Contraception Endocr. Rev., December 1, 2002; 23(6): 735 - 762. [Abstract] [Full Text] [PDF]

				E. B. Berensztein, M. I. Sciara, M. A. Rivarola, and A. Belgorosky Apoptosis and Proliferation of Human Testicular Somatic and Germ Cells during Prepuberty: High Rate of Testicular Growth in Newborns Mediated by Decreased Apoptosis J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5113 - 5118. [Abstract] [Full Text] [PDF]

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