Endocrine Reviews 22 (6): 764-786
Copyright © 2001 by The Endocrine Society
The Functional Significance of FSH in Spermatogenesis and the Control of Its Secretion in Male Primates
Tony M. Plant and
Gary R. Marshall
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
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Abstract
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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
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I. Introduction
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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.
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II. Site of FSH Action in the Testis
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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.
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III. Sertoli Cell Ontogeny and the Role of FSH
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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 816 and 1922 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 430 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).

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Figure 1. Schemata of two hypothetical patterns of Sertoli
cell proliferation during postnatal development in higher primates. For
man, the ordinate would span 1215 yr and for the monkey, 35 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.
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Parenthetically, both of the posited patterns of Sertoli cell
proliferation in higher primates might be considered to differ markedly
from that in the rat, in which division of this cell type is generally
accepted to be completed before puberty (20). This is
because puberty in the male rat is usually recognized to be initiated
between 25 and 30 d of age (20, 33), and Sertoli cell
proliferation in this species is completed by 1421 d of age
(34). Differentiated spermatogonia (intermediate
spermatogonia), however, are observed as early as 56 d of age in the
rat (35), and if this developmental marker is used as the
index of the onset of puberty, then the dogma that Sertoli cell
proliferation is completed before puberty in this species would need to
be reevaluated. In any event, whereas the adult complement of Sertoli
cells in the rat is determined during the first few weeks of life, in
higher primates this critical determinant of spermatogenic potential is
not established until several years after birth. In the marmoset
(Callithrix jacchus), a New World monkey, adult numbers of
Sertoli cells are present at 1822 wk of age (36), and in
the Cebus monkey (Cebus apella), another New World primate,
Sertoli cell proliferation is completed between 16 and 52 wk of age
(37). Parenthetically, it may be noted here that because
the adult complement of Sertoli cells in men is not attained until the
second decade of life, the impact of endocrine disrupters on human
fertility may be different from that in rapidly maturing species. Thus,
comparative considerations need to be taken into account when selecting
experimental models with which to examine the action of endocrine
disrupters on the ontogeny of testicular function in men.
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.
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IV. The Role of FSH in Spermatogenesis
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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
).

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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
A1A4 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.
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The production of testicular spermatozoa from undifferentiated
spermatogonia is recognized to unfold according to a fixed kinetic
program, with the cell cycle of each dividing germ cell and the
morphogenic transformations during spermiogenesis considered to be
immutable (52, 67).5 As a
result of this property of spermatogenesis, the germinal epithelium
progresses through a species-dependent set of specific cellular
associations referred to as stages of the seminiferous epithelial
cycle. The duration of this cycle is constant for a particular species
or breed. A schemata of the cycle of the seminiferous epithelium in the
rhesus monkey is shown in Fig. 3
. The
design of this schemata emphasizes that the seminiferous epithelial
cycle is continuous, that its duration is dictated by the 10.5-d cell
cycle time of the undifferentiated type Ap spermatogonia
(56), and that the number and composition of the specific
cellular associations of the cycle are determined by the kinetics of
the linear proliferation and differentiation of the progeny of the Ap
spermatogonia.

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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 IXII. 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 10002000 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. B1B4, Four generations of
type B spermatogonia; PL, preleptotene primary spermatocytes; L,
leptotene spermatocytes; Z, zygotene spermatocytes; P, pachytene
spermatocytes; MII, completion of meiosis; S1S14, 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 ).
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Apoptosis is a normal component of spermatogenesis, and the maximal
theoretical efficiency of producing testicular spermatozoa from
undifferentiated spermatogonia is not reached (20, 70, 71, 72). In the rat, the majority of type A spermatogonia
undergoes apoptosis (70), presumably due to the
constraints imposed by the number of Sertoli cells in the rodent
testis, and only 2530% of the theoretical yield of differentiated
spermatogonia is achieved (70). In the monkey, on the
other hand, the Ap spermatogonia do not appear to undergo apoptosis
because the number of this cell type remains constant across the cycle
of the seminiferous epithelium (53). Moreover, in the
monkey, all Ap spermatogonia divide each cycle of the seminiferous
epithelium (53). Taken together, the latter two
observations raise the possibility that, in nonhuman primates, the
number of type Ap spermatogonia in the adult testis, rather than the
number of Sertoli cells, determines the maximal spermatogenic capacity
or ceiling of the testis.
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 (1114 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 1520 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).

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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 141:1827, 2000
(148 ). Reprinted with permission of The Endocrine
Society.]
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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
141:1827, 2000 (148 ). Reprinted with permission of The
Endocrine Society.].
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Taking the foregoing considerations together, it seems reasonable to
propose that the rate of sperm production by the normal primate testis
is regulated by the circulating concentration of FSH, and that under
physiological situations, blood levels of this gonadotropin are
insufficient to drive spermatogenesis to its ceiling.
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).

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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.
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The identity of the germ cell(s) that responds to the action of FSH to
amplify LH-driven spermatogenesis in the monkey is controversial. In
our laboratory, administration of hFSH to T-treated, hypophysectomized
adult male rhesus monkeys produced a selective amplification of all
four generations of differentiated spermatogonia without a change in
the number of undifferentiated Ap spermatogonia (135).
This finding led us to propose that the action of FSH is exerted on the
first and perhaps subsequent generations of B spermatogonia, a
conclusion supported by the more recent observation that the
hypersecretion of endogenous FSH elicited by unilateral orchidectomy in
this macaque was also associated with an amplification of the four
generations of differentiated spermatogonia, again in the absence of a
change in undifferentiated Ap spermatogonia (148). In an
earlier study of the intact cynomolgus and rhesus monkey, however, FSH
stimulation was reported to lead to an increase in both the number of B
spermatogonia and Ap spermatogonia, and the authors concluded that the
primary effect of FSH was on the undifferentiated spermatogonia
(147, 162). As we have discussed previously
(135), however, the temporal relationship observed
by van Alphen et al. (147) between the increase
in the number of Ap spermatogonia and the increase in B spermatogonia
posited to result from the expansion of the population of Ap
spermatogonia did not conform to what is known of the kinetics of
spermatogenesis in these macaques (53, 56). Specifically,
if amplification of B4 spermatogonia were to
result from a prior increase in Ap spermatogonia, then a sustained
increase in the number of this stem cell (Ap spermatogonia) would have
to be manifest in the preceding cycle of the seminiferous epithelium,
which is at least 16 d before the noted amplification of
B4 spermatogonia. Empirically, however, this was
not the case, as evaluation of the testis 9 d before the observed
amplification of B4 spermatogonia failed to show
an increase in Ap spermatogonia (147).
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 1924 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 13 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
|
|---|
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 Kallmans 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).

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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 (1722 ng/kg
body wt) administered at interpulse intervals of 15120 min. The
corresponding LH levels are shown by the open bars. [From: D. I.
Spratt et al.: J Clin Endocrinol
Metab 64:11791186, 1987 (188 ). Reprinted with
permission of The Endocrine Society.]
|
|
On the other hand, direct testicular negative feedback on FSH secretion
at the level of the gonadotroph is profound in the adult male monkey,
as reflected by the FSH response to bilateral orchidectomy in an
experimental paradigm known as the hypophysiotropic clamp
(193). In this preparation, the endogenous
hypophysiotropic drive to the gonadotroph is interrupted either
experimentally or by activation of a normal physiological control
system. In the former case, the hypothalamus of the adult is lesioned
to abolish pulsatile GnRH release (185). In the latter, a
juvenile monkey in which pulsatile GnRH release is held in check by a
developmental brake, is used (194). In both types of
animals, an adult-like pattern of hormonal activity may be elicited by
an intermittent iv infusion of GnRH. Because the hypophysiotropic drive
to the gonadotroph is clamped in these preparations, any change in
gonadotropin secretion resulting from a perturbation to testicular
feedback signals must be accounted for by a change in feedback directly
at the level of the pituitary. Bilateral orchidectomy in this model
results in a selective and dramatic hypersecretion of FSH (Fig. 8
), which is not prevented by T
replacement at the time of castration (194, 195). In
vitro studies employing primary pituitary cell cultures have also
failed to demonstrate an action of T on FSH secretion directly at the
level of the monkey gonadotroph (196). Moreover, because
passive immunoneutralization against circulating E2 in the
testicular intact hypophysiotropic clamp fails to elicit an increase in
FSH secretion (195), it may be concluded that the specific
testicular FSH-inhibiting factor is nonsteroidal. That this factor is
inhibin was suggested by the finding that passive immunoneutralization
of circulating inhibin in the testicular intact clamp results in an
elevation in FSH secretion similar to that observed after castration
(197). This notion was greatly reinforced by the finding
that, in this experimental paradigm, initiation of a continuous iv
infusion of rh inhibin A at the time of bilateral orchidectomy
prevented the postcastration hypersecretion of FSH and the increase in
levels of mRNA encoding the FSH ß-subunit (198). A
direct effect of inhibin at the monkey gonadotroph to suppress FSH
secretion has also been demonstrated in vitro
(196).

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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 115:21452153, 1984 (185 ).
Reprinted with permission of The Endocrine Society.]
|
|
Thus, the foregoing studies of the hypophysiotropic clamp have led to
the conclusion that, in the monkey, the testicular regulation of FSH
secretion is governed by a control system consistent with that
described by the classic inhibin hypothesis (199). This
view was fully confirmed by studies of the normal intact adult male
monkey. Most notably, passive immunoneutralization of circulating
inhibin in the intact adult male results, as in the clamp, in a
hypersecretion of FSH (200), and a continuous iv infusion
of rh inhibin A results within 54 h in a significant suppression
of circulating FSH concentrations without influencing LH secretion
(Ref. 201 and Fig. 9
). The
findings that inhibin B is the principal form of the dimeric hormone in
the circulation of the adult male monkey, and is of testicular origin,
establishes that inhibin B is indeed the native testicular inhibin in
this species (202).

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Figure 9. Infusion of rh inhibin A (0.8
µg/kg·h, closed data points) to adult male
rhesus monkeys from 096 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 139:34093415,
1998 (201 ). Redrawn with permission of The Endocrine
Society.].
|
|
Convincing evidence supporting the premise that FSH secretion in men is
regulated by the negative feedback action of testicular inhibin is at
last accumulating. Many years ago, it was demonstrated that selective
hypersecretion of FSH could exist in the face of normal T levels in men
with azoospermia (203). Initial measurement of circulating
inhibin levels by RIA in such men failed to reveal the expected inverse
relationship between FSH and the testicular protein (204).
The inhibin hypothesis suffered a further set back when specific ELISAs
for inhibin A, one of two dimeric forms of the mature hormone, failed
to detect this molecule in the circulation of normal men
(205). It is now known, however, that the original RIA
used for infertile men recognizes circulating inhibin
-subunit as
well as dimeric inhibin (206, 207), and that dimeric
inhibin in the circulation of the human male is accounted for entirely
by inhibin B (208, 209, 210). Moreover, inhibin B in men is
present in substantial concentrations (300500 pg/ml), is of
testicular origin, and is inversely related to circulating FSH levels
(209, 210). Thus, it is reasonable to reaffirm the
proposal that testicular inhibin is the major gonadal signal regulating
the secretion of FSH in the human male, a conclusion that is strongly
reinforced by our studies of the rhesus monkey.
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).

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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 141:1827, 2000 (148 ).
Redrawn with permission of The Endocrine Society.].
|
|
Before closing our discussion on the regulation of FSH secretion, it is
important to state that the release of this gonadotropin in male
primates is not insensitive to inhibition by testicular steroids. In
fact, supraphysiological plasma levels of either T or E2, achieved by
administration of exogenous steroid, dramatically suppress circulating
FSH concentrations in normal men and male macaques
(220, 221, 222, 223), probably by exerting actions at both the
pituitary and hypothalamic levels (221, 222, 223, 224, 225). The relative
contribution of such steroid inhibition in the feedback control system
governing FSH secretion in a physiological setting, however, appears to
be noticeably less important than that produced by the inhibin B
signal. In normal men, abolishing testicular steroidogenesis with
ketoconazole, although largely preserving the inhibin B tone in these
subjects, resulted in a minor increase (doubling) in circulating FSH
concentrations (226). This is to be compared with the
dramatically elevated levels of circulating FSH observed in the absence
of all testicular feedback signals in castrate or hypogonadal men
(227). The steroid component of the testicular inhibition
of FSH secretion in men appears to be mediated by ER activation
in response to an E2 signal generated either by secretion of the
steroid directly from the testis or by peripheral or central neural
aromatization of secreted T. This view is based on several findings.
First, circulating FSH concentrations in men with mutations of ER-
or aromatase deficiency are greater than those in control subjects
(228), and treatment of normal men with anastrazole, a
specific inhibitor of aromatase, results in an FSH hypersecretion
comparable to that after ablation of all testicular steroid secretion
with ketoconazole (226).
 |
VI. Summary
|
|---|
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.

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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.
|
|
With regard to the issue of fertility control on the one hand and the
treatment of infertility in men on the other, we are of the following
opinion. From the extant data, it seems reasonable to conclude that
interruption of the feedforward arm of this control system in men and
other male primates (i.e., abolition of FSH secretion or
action) will not prevent either the initiation or maintenance
(qualitative) of spermatogenesis and therefore will not lead to
azoospermia. The question of the quality of the sperm produced in the
absence of FSH, however, remains to be answered. The view that FSH is
not required for fertility is epitomized by the contemporary finding
that men with an inactivating mutation of the FSH-R can be fertile.
Because biological systems exhibit redundancy and plasticity, the
impact of the loss of a gene from conception may be later compensated
for by an alternate pathway. Indeed, in the monkey, the postpubertal
interruption of FSH action using immunoneutralization was found to be
associated with infertility. Therefore, in our view, the question of
whether a complete and specific abolition of FSH signal transduction
imposed after puberty in the human male would be associated with
infertility remains to be answered. The issue of a super inhibin
receptor agonist as a male contraceptive must await resolution of the
latter question. As for male infertility, the value of FSH treatment,
particularly in subsets of subjects with idiopathic infertility, should
not be dismissed at the present time.
 |
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.
 |
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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W. H. Walker
Molecular Mechanisms Controlling Sertoli Cell Proliferation and Differentiation
Endocrinology,
September 1, 2003;
144(9):
3719 - 3721.
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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]
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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]
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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]
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