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Endocrine control of spermatogenesis in primates.

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American Journal of Primatology 1:157- 165 (1981)
Endocrine Control of Spermatogenesis in Primates
CHARLES E. GRAHAM
Reproductive Biology Diuzswn, Primate Research Imtitute, New Mexico State University, Holloman
AFB, New Mexico
Control of primate spermatogenesis is reviewed in terms of endogenous regulatory mechanisms and endocrine approaches to contraception and treatment of
infertility. The role of gonadotropins and steroid hormones in maintaining
spermatogenesis in primates is incompletely understood because A) hormonal
interactions are complex, and B) most studies have used rodents rather than
primates. Feedback control, interaction of LH and testosterone, the role of
androgen, androgen in secondary sex organs, regulation of receptor proteins,
roles of prolactin and growth hormone, and the breakdown and modification of
the endocrine controlmechanism are reviewed. The treatment of infertility with
GnRH, gonadotropins, and androgen is discussed. Information is included on
contraception research using the following methods: immunization against
GnRH, use of GnRH analogs, immunization against gonadotropins, induced
suppression of FSH secretion or action, and steroid suppression of spermatogenesis. The importance of studying testicular steroid metabolism in primates is stressed. Significant advances in the understanding of endocrine control of spermatogenesis have been made in recent years, but no primate species
have been thoroughly studied. Variability between species in endocrine control
mechanisms is an important factor in selecting primate models, and it is clear
that such models can be valuable in the development of male contraceptives.
Key words: androgens, contraception, endocrine control, follicle stimulating
hormone (FSH), gonadotropin releasing hormone (GnRH),
infertility, lutenizing hormone (LH),
primates, spermatogenesis,
testosterone
INTRODUCTION
Control of primate spermatogenesis is reviewed in terms of the endogenous regulatory mechanisms and endocrine approaches to treatment of infertility and contraception.
Much of our basic understanding of the subject is drawn from studies of rodents and our
experience of infertility management from the human.
ENDOGENOUS REGULATION OF SPERMATOGENESIS
The role of gonadotropins and steroid hormones in maintaining spermatogenesis is
incompletely understood, in part because of complex hormonal interactions, and also
because there are differencesbetween rodents, in which most studies have been done, and
primates [review by Steinberger & Steinberger, 19721.
Received January 10, 1981; accepted January 23, 1981
Address reprint requests to Charles E. Graham, New Mexico State University, P.O. Box 1027,Holloman AFB, NM
88330.
0275-2565/81/0102-0157$03.00 0 1981 Alan R. Liss, Inc.
158
Graham
Feedback Control of Gonadotropin Secretion
Castration of the adult primate results in a marked elevation of circulating luteinizing
hormone (LH) and follicle stimulating hormone (FSH) levels, and administration of
testosterone results in depressionof LH to precastration levels, indicating the presence of
one or more regulatory feedback loops. Possible sites of action of testosterone or its
metabolites could be the brain, presumably the hypothalamus, so regulating the release
of gonadotropin releasing hormone (GnRH);or the pituitary, regulating the sensitivity
of the gonadotropins to GnRH.
Testosterone administration is incapable of restoring FSH to precastration levels, nor
can large doses of testosterone inhibit circulating levels of FSH in intact men [Swerdloff
& Odell, 19681. Since testosterone negative feedback on the hypothalamus would be
expected to affect both gonadotropins equally, it appears likely that testosterone selectively inhibits the sensitivity of the LH gonadotrophs to GnRH. I t also appears that
another hormone, dubbed “inhibin,”may provide negative feedback inhibition of FSH in
intact males.
Role of Gonadotropins in Control of Spermatogenesis
Although LH or human chorionic gonadotropin (hCG) alone can maintain Leydig cell
function and basic spermatogenesis in hypophysectomized rodents, FSH appears to have
a central role in the control of spermatogenesis in primates. Gonadotropin preparations
rich in FSH, such as human menopausal gonadotropin (hMG), can produce full spermatogenesis in human hypogonadotropic eunuchs [Paulsen, 19681 and hypophysectomized men [MacLeod et al, 1964, 19661. Specific receptors exist for FSH in the testis:
labeled FSH selectively binds to the tubules [Means & Vaitukaitis, 19721and to isolated
Sertoli cells, inducing a dramatic increase in cyclic AMP [Steinberger et al, 19751. The
relative roles of LH and FSH are unclear because there is a shortage of purified LH and
FSH preparations; heterologous gonadotropins can induce neutralizing antibodies
[Maddock, 19491.
Interaction of LH and Testosterone in Control of Spermatogenesis
It is generally accepted that LH stimulation of the Leydig cells maintains a high, local,
peritubular concentration of testosterone essential for spermatogenesis.
The mechanism by which LH controls androgen secretion has been explored by Arslan
et a1 [1978], who showed that testosterone production can be stimulated in vitro by hCG
in adult, but not in prepubertal or juvenile rhesus monkeys. However, priming in vivo
with 300 IU hCG daily for five days, sensitized the immature testis to hCG in vitro.
Arslan et a1 also showed that mature and immature monkeys can be stimulated with
chronic hCG in vivo to increase testosterone levels as much as sevenfold and twofold,
respectively. These data suggest that chronic hCG exposure activates the response
system, probably by enhancing LH/hCG receptor availability.
Role of Androgen in Support of Spermatogenesis
In the hypophysectomized rat, testosterone alone can substantially maintain spermatogenesis; whereas in the rhesus monkey, spermatogenesis is only partly maintained
[Smith, 19381. In hypophysectomized men treated with testosterone, the recovery of the
seminiferous epithelium is much poorer than in the other species; only spermatogonia
and Sertoli cells remain in the seminiferous tubules [Smith, 19381. In view of these
interspecific differences, primate models for study of the endocrine control of spermatogenesis should be chosen with great care.
The mode of action of androgen in supporting spermatogenesis remains unclear, and
whether the active androgen acts on the Sertoli cell or directly on the germ cells is
unknown.
Endocrinology of Primate Spermatogenesis
159
Androgen Action in Secondary Sex Organs
Since the secondary sex structures depend upon androgen for their integrity, androgen
affects sperm maturation at least indirectly. Androgen action in epididymal and testicular epithelia is mediated by a cytoplasmic receptor protein [Hansson et al, 19731. A
separate binding protein is produced by Sertoli cells and is secreted into the rete testis
fluid and caput epididymidis,probably accounting for the high concentration of androgen
in these locations and providing additional input for androgen on sperm maturation.
Regulation of Receptor Proteins
As previously mentioned, LH levels regulate the availability of LH receptor in the
Leydig cells. Prolactin, and perhaps other hormones, also does so. It should be anticipated
that similar endocrine mechanisms regulate the availability of FSH and androgen
receptors since estrogen can induce FSH receptors in the rat ovary ILouvet & Vaitukaitis, 19761.
Role of Prolactin and Growth Hormone in Control of Spermatogenesis
In rodents, prolactin potentiates the action of LH in stimulating spermatogcnesis
[review by Bartke et al, 19781. Prolactin may also play a key role in seasonal testicular
regression. In the Syrian hamster, prolactin, but not exogenous gonadotropins, reverses
the testicular regression and depressed gonadotropin levels induced by a shortened
photoperiod. Prolactin also has antigonadotropic effects, however, and it is noteworthy
that prolactin levels are inversely correlated with seasonal testicular activity in the
rhesusmonkey [Wickings& Nieschlag, 19801.Seasonal primates such asprosimians, the
squirrel monkey (Saimiri sczureus), and the rhesus monkey [Bernstein et al, 1974;
Kinzey, 19711 may be valuable models for the endocrine control of spermatogenesis.
The tropic action of prolactin appears to involve increasing the number of LH receptors
in Leydig cells. Proper prolactin balance is essential; hyperprolactinemia in men can
produce hypogonadism and impotence [review by Bartke et al, 19781. Pharmacological
elevation of prolactin in normal men can result in testosterone elevation [Rubin et al,
19781.
Growth hormone overlaps prolactin in many of its biological properties; it, too, can
partially reverse the effects of shortened photoperiod in the hamster. The role of both of
these hormones in primate spermatogenesis needs to be defined.
Breakdown a n d Modification of the Endocrine Control Mechanism
It is clear that such a complex hormonal regulatory system offers many possibilities for
failure and points of entry for contraception. Thelability of the system is indicated by the
fact that high doses of FSH in the rat [Doener & Deckart, 19621 and of hCG in men
[Maddock & Nelson, 19521 and low doses of androgens, estrogens, and progestins can
damage the seminiferous epithelium or inhibit spermatogenesis. The effect of steroids is
secondary to blockage of gonadotropin secretion 1 Ludwig, 19501.
TREATMENT O F INFERTILITY
The chief problem in the development of strategies for treatment of human fertility has
been lack of adequate controlled studies, variable causes of infertility, and biases introduced by case selection. There is a need for replicable primate models of human endocrine-based infertility in which the endocrine requirements for initiation and maintenance of spermatogenesis can be evaluated. Careful validation of such models must be
undertaken before results can be extrapolated to the human with confidence.
Treatment of Infertility With GnRH
Although the synthesis of GnRH and highly potent agonistic analogs promised an
effective approach to the treatment of infertility associated with an intact pituitary
160
Graham
gland, it was soon found that these agents actually caused damage to the rodent and
human seminiferous epithelium. Perhaps we should have been forewarned by the discovery of Maddock and Nelson in 1952 that hCG administration could block spermatogenesis in rats.
Treatment of Infertility With Gonadotropins
As was mentioned earlier, crude gonadotropin preparations rich in FSH, such as hMG,
are capable of inducing or maintaining spermatogenesis in some hypogonadotropic
patients. The success of such preparations may depend on their partially purified state,
since the exact endocrine requirements of spermatogenesis remain undefined.
Treatment of Infertility With Androgen
Treatment with testosterone seems to have met with little success, probably because it
prevents the attainment of sufficient intratesticular levels of testosterone because of
negative feedback inhibition of LH secretion and, hence, lack of Leydig cell activity.
CONTRACEPTION
Immunization Against GnRH
Hodgen and Hearn 11977I immunized five male marmosets (Callithrixjacchus) with
GnRH-BSA and adjuvants; three of the five males developed high antibody titer, marked
testicular atrophy, and suppression of testosterone secretion. Histological study showed
marked inhibition of seminiferous tubules and of spermatogenesis and a reduction in size
of Leydig cells. In addition, animals with a high anti-GnRH titer showed a reduced LH
response to exogenous GnRH.
Chappel et a1 [1980], in a similar study with male rhesus monkeys, also noted a
reversible inhibition of peripheral serum LH and testosterone levels inversely correlated
with GnRH antibody levels. A dramatic reduction in testis effluent, pituitary content of
LH, venous blood concentration of testosterone, estradiol, dihydrotestosterone, and progesterone also occurred.
The immunological approach will become more promising if the need for adjuvant can
be overcome.
Administration of GnRH Analogs
Competitive antagonistic analogs of GnRH have antifertility action in male rodents. In
female chimpanzees they can block the induction of LH surges induced by exogenous
GnRH, suggesting their potential for ovulation supression [Gosselin et al, 19791; however, the antagonists have not been explored as contraceptive agents in male nonhuman
primates.
Agonistic analogs of GnRH also have potent antifertility action. Such compounds in the
male rat result in involution ofthe seminiferous tubules and accessory organs. Auclair et
a1 [1979] and Defau et a1 119791have shown that potent GnRH agonists, GnRH itself, or
hCG result in great reductions in the number of testicular LH-hCG and prolactin
receptors, and of testosterone production. Direct effects on the gonads have also been
postulated, based on the observation that GnRH inhibits FSH-induced steroidogenesis in
rat granulosa cells in vitro and in hypophsectomized rats [Hsueh & Erickson, 19791.
Another possible mode of action is pituitary desensitization by the high level of stimulation exerted by superagonists. Attempts to inhibit spermatogenesis in nonhuman primates with superagonists have met with mixed results. Wickings and associates in this
symposium, and Vickery and McRae [1980b,and personal communication]have noted no
depression of testosterone levels or of spermatogenesis in rhesus monkeys or M .
fascicularis. By contrast a marked depression of testosterone levels has been noted in
Endocrinology of Primate Spermatogenesis
161
baboons treated with superagonists of GhRH [Vickery & McRae, 198Oal.To what extent
these differences reflect interspecific differences or experimental variables remains to be
defined.
Primates have considerable value as models for the development of contraceptive
strategies using GnRH analogs. However, careful species selection is necessary in view of
interspecific differences in response to GnRH and analogs. In addition to examples
already mentioned, it may be noted that acute GnRH administration does not elicit
consistent responses in rhesus monkeys, whereas it does in chimpanzees and women
[Hobson & Fuller, 1977; Graham et al, 1979; Yen et al, 19731.
The bonnet monkey (Macaca radiatu) is sensitive to GnRH, but it is totally insensitive
to an analog highly potent in rodents [Levitan et al, 19771. Poor activity correlations
have also been noted for some GnRH antagonists between rodents and male and female
chimpanzees [Bowers et al, 1980; Graham & Gosselin, unpublished observation]. The
significance of these differences for humans are not yet clear, but it is possible that some
analogs active in rodents are not active in primates, in which case primates will become
important for preclinical screening of promising contraceptive G&H analogs.
Immunization Against Gonadotropins
Wickings and associates, in this symposium, have reported that both passive and active
immunization against FSH can inhibit spermatogenesis. The latter approach achieved
its objective without affecting testicular steroid secretion, although use of adjuvant was
necessary.
Suppression of FSH Secretion and Action
Identification and synthesis of a specific testicular FSH inhibitor (inhibin) might
provide a means of controlling spermatogenesis without affecting androgen-dependent
secondary sex organs. In male nonprimates, peptides with inhibin-like properties have
been isolated from testicular extracts, testicular lymph, rete testis fluid, semen, and
medium used to culture Sertoli cells [review by Setchell, 19801, and other evidence for
inhibin derives from human subjects with damaged seminiferous epithelium who show
selective elevation of FSH levels [Van Thiel et al, 19711.
Steroid Suppression of Spermatogenesis
Various androgens (eg, Danazol, an ethynyltestosterone derivative) inhibit LH secretion, and so secretion of testosterone by Leydig cells, resulting in insufficient local
concentration of testosterone to support spermatogenesis [Heller et al, 19701. There is
no loss of libido or potentia, but undesirable side effects on lipoprotein metabolism and
blood cell formation occur [Heller et al, 1950; Hotchkiss, 1944; Skoglund & Paulson,
1973; Reddy & Rao, 19721.
Estrogens and progestins can inhibit spermatogenesis, but they also cause painful
gynecomastia, as well as loss of libido and potentia [Heller et al, 19591. Estrogen or
progestin appropriately balanced with androgen could avoid such undesired side effects.
Reversible infertility can be induced with such preparations [Coutinho & Melo, 1973;
Briggs & Briggs, 19741.
Ewing et a1 [19781have described a primate model for the eficient evaluation of efficacy
and safety of steroid combinations, using 20 rhesus monkeys for 50 months to test 30
testosterone-estradiol combinations.The design assumes no carryover of drug effect from
one treatment to the next; end points were number of sperm and volume per ejaculate.
This experimental model seems a powerful analytical tool, although the observation of
seasonal variation in sperm number points to the importance ofhaving a separate control
group rather than using each animal as its own control; alternatively, a less seasonal
162
Graham
species such as the stumptail or pigtail monkey (Mucaca speciosa or M. nemestrina)
could be selected.
Anand Kumar et a1 11980Jhave administered steroids by intranasal spray to rhesus
monkeys. The intranasal route results in a relatively high concentration of administered
steroid in the cerebrospinal fluid and hence in the brain, without raising peripheral
levels significantly. Considerable depression oftestosterone levels and azoospermia after
30 pgiday of estradiol, progesterone, or norethisterone was noted. The testicular regression resembled t h a t which follows oral or systemic administration ofestrogens or progestins in men, except that the intranasal route required M O O or less of the dosage
calculated on a body weight basis. This seems to offer an exciting new approach to male
contraception that might avoid the toxicological problems associated with higher steroid
doses and systemic effects. However, as with other approaches to male contraception that
involve suppression of testosterone levels, a means to maintain the integrity of libido
and accessory organs will have to be worked out before application to the human can be
envisaged.
The competitive testosterone inhibitor cyproterone acetate (CAI can inhibit spermatogenesis in rhesus monkeys and man LPrasad et al, 19771; 697 mgikg CA released
from Silastic capsules did not alter circulating testosterone levels in rhesus monkeys, but
caused reversible oligospermia or azoospermia. CA also appeared to inhibit conversion of
testosterone to dihydrostestosterone (the intracellular active androgen) selectively in
the caput epidymidis, so reducing caput weight and secretory activity.
Steroid Metabolism
The study of testicular steroid metabolism in primates is important for the elucidation
of the mechanism of action of trophic hormones, contraceptive drugs, and toxic compounds that affect spermatogenesis by acting on the testis. In collaboration with E.
Helton and W.C. Hobson, we have commenced to develop an experimental model in the
chimpanzee for this purpose because of general metabolic and endocrine similarity with
man, the large testicular vessels, and the well-developed technology for semen collection
[Martin e t al, 1977; McCormack, 1971; Gould et al, 19781.
Pulse injection of radiolabeled substrate and collection of testiular venous effluent from
one of the relatively large collaterals of the pampiniform plexus of the chimpanzee can
permit repeated i n vivo study of the same subjects. The fairly long time required to clear
the testis of labeled substrate, in this, case pregnenolone, plus the recovery of a variety of
labeled metabolites (identified by high pressure liquid chromatography using suitable
solvent systems to achieve separation) indicates that significant metabolism occurs
under these conditions. Similar metabolic profiles were obtained when the contralateral
unperfused testis was incubated with pregnenolone invitro (Fig. 1);these results suggest
that both systems generate meaningful data and that the in vivo system can be used
repeatedly to study metabolic problems relating to the control of spermatogenesis.
CONCLUSIONS
1. Significant advances have been made in the endocrine control of spermatogenesis in
recent years.
2. Our knowledge is based on relatively few primate species.
3. Variability in endocrine control mechanisms is a significant factor in the selection of
primate models for the study of the endocrinology of spermatogenesis, but the full
extent of variability is unknown.
4. Primates have many applications in the development of male contraceptives.
Endocrinology of Primate Spermatogenesis
163
1
40
IN V l V O
I
30 9
20-
10
-
el
f
X
I
2
-
175
a
n
IN V l T R O
75
50
25
0
20
-
40
TIME frnin)
n
0
Fig. 1. HPLC profiles ofmetabolities of H'-pregnenolone aRer infusion or in uitru incubation of adult, chimpanzee
testis. Identity of peaks: 1,progesteroneiandrostenedione; 2, pregneno1ondDHT 3, DHEA; 4,17uhydroxyprogeskrone; 5, testosterone; 6, 17ohydroxypregnenolone.
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