Clinical relevance of animal models for the study of androgen actions

Anabolic Running Review

How To Increase Your Testosterone

Get Instant Access

A comprehensive set of data is available to indicate that the cynomolgus monkey model is highly representative for preclinical studies on the endocrine regulation of spermatogenesis. Unlike the rhesus monkey, bonnet monkey or Japanese macaque, this nonhuman primate species does not show annual variations of testicular activity. A series of experimental studies is available and has been reviewed above. The findings obtained clearly prove that the data collected in the cynomolgus monkey on the LH/testosterone and FSH regulation of spermatogenesis are fully representative for what would be seen in man. This relationship holds even true for quantitative aspects of spermatogenesis. Hence, at present, the cynomolgus monkey is recommended as preclinical model for the study of the relationship between testosterone and other reproductive hormones and human spermatogenesis.

The rat model provides an interesting feature regarding the effects of selective testosterone replacement. In the gonadotropin-suppressed rat testosterone paradoxically stimulates the levels of FSH. Studies showed that testosterone maintains and restores the levels of immunoactive and bioactive FSH by direct action on pituitary FSH expression and also release. This is in sharp contrast to gonadotropin-suppressed nonhuman primates and men, in whom testosterone does not alter FSH secretion at all. Hence the rat model has only limited suitability for studying the relative roles of LH/testosterone and FSH for spermatogenesis.

Targeted disruption of FSH or the FSH receptor was initially thought not to interfere with spermatogenesis in mice (Kumar et al. 1997). Whether this really indicates that FSH is dispensable for mouse spermatogenesis remains to be seen. This view is derived from the fact that FSH receptor is only expressed in Sertoli cells and, hence, such specific expression pattern would imply a physiological role. More recently, it has become clear that FSH action is also important for spermatogenesis in the mouse (Huhtaniemi 2000; Sairam and Krishnamurthy 2001, and discussion above).

Another interesting exception to the endocrine control of primate spermato-genesis is provided by the seasonal control of reproduction in the Djungarian hamster. This species is a short-day breed undergoing testicular involution when the LD light regimen is shifted from 16:8 to 8:16. In this species administration of LH to animals with regressed testes is unable to restore spermatogenesis, whereas FSH reinitiates the entire process including the production of fertile sperm (Lerchl et al. 1993; Niklowitz et al. 1997). It is not entirely clear whether this separation of LH and FSH sensitivity of the involuted testis is confined to this hamster species or applies more generally to seasonally breeding mammals. In the prairie dog (Cynomys ludovicanus) also FSH but not LH/testosterone induced germ cell activation when administered during the seasonal involution phase (Foreman 1998). Interestingly, in the seasonal bonnet monkey, merely blocking the nocturnal peak of testosterone secretion is sufficient to inhibit spermatogenesis, implying a surprising dependence of adult spermatogenesis on diurnal testosterone in a primate. In general, however, usingseasonal experimental species as models for the endocrine control of human spermatogenesis does not seem advisable in view of the fact that a highly relevant non-seasonal primate model (cynomolgus monkey) is available.

An alternative route of stimulating testosterone production from Leydig cells has apparently developed in the common marmoset (Callithrix jacchus). In the intact and normal marmoset, LH receptor exon 10, although genomically present, is not expressed (Zhang etal. 1997). For the human LH receptor, this exon is necessary for the expression of receptor protein (Zhang etal. 1998). Interestingly, a clinical case lacking LH receptor exon 10 has been described (Gromoll etal. 2000). This boy had developed a male phenotype but presented with retarded pubertal development, small testes and delayed bone maturation, all indicative of androgen deficiency. Given the similarity to marmoset LH receptor status, this patient was successfully treated with hCG, indicating that exon 10 is involved in differential LH/hCG recognition. More recently it was found that marmoset pituitary expresses hCG (Gromoll et al. 2003) raising the possibility that marmoset Leydig cells are driven by hCG rather than LH. It would be interesting to know the dependence of marmoset spermatogenesis on intratesticular testosterone. In any case, it is obvious that the control of Leydig cell function and testosterone production by LH is entirely different in humans and marmosets. Equally interesting, lack of LH receptor exon 10 expression was also found in Cebidae and other Callithrichidae, raising the question whether this particular LH receptor type II could be predominant in neotropical primate species.

5.10 Key messages

• Testosterone is able to qualitatively initiate, maintain and re-initiate spermatogenesis and formation of spermatozoa.

• FSH is able to qualitatively initiate, maintain and re-initiate spermatogenesis and formation of spermatozoa.

• Under physiological circumstances, only the combination of testosterone and FSH yields quantitatively normal germ cell numbers.

• Adult primate spermatogenesis is probably more dependant on FSH than on testosterone.

• Testosterone acts indirectly via somatic testicular cells on spermatogenesis. Whether ABP or non-genomic actions mediate direct testosterone effects on germ cells is unclear.

• The testicular effects of testosterone are mediated via DHT and estradiol. Whether estradiol is essential for spermatogenesis is still unclear.

• Testosterone and FSH cooperate during regulation of spermatogenesis but act via different mechanisms.

• Macaques currently represent the most appropriate preclinical model for the study of the role of testosterone in spermatogenesis.


Alastalo TP, Lonnstrom M, Leppa S, Kaarniranta K, Pelto-Huikko M, Sistonen L, Parvinen M

(1998) Stage-specific expression and cellular localization of the heat shock factor 2 isoforms in the rat seminiferous epithelium. Exp Cell Res 240:16-27

Arslan M, Weinbauer GF, Schlatt S, Shahab M, Nieschlag E (1993) FSH and testosterone, alone or in combination, initiate testicular growth and increase the number of spermatogonia and Sertoli cells in a juvenile non-human primate (Macaca mulatta). J Endocrinol 136:235243

Aslam H, Rosiepen G, Krishnamurthy H, Arslan M, Clemen G, Nieschlag E, Weinbauer GF

(1999) The cycle duration of the seminiferous epithelium remains unaltered during GnRH antagonist-induced testicular involution in rats and monkeys. J Endocrinol 161:281-288

Assinder SJ, Rezvani A, Nicholson HD (2002) Oxytocin promotes spermiation and sperm transfer in the mouse. Int J Androl 25:19-27 Awoniyi CA, Zirkin BR, Chandrashekar V, Schlaff WD (1992) Exogenously administered testosterone maintains spermatogenesis quantitatively in adult rats actively immunized against gonadotropin-releasing hormone. Endocrinology 130:3283-3288

Bartlett JM, Charlton HM, Robinson IC, NieschlagE (1990a) Pubertal development and testicular function in the male growth hormone-deficient rat. J Endocrinol 126:193-201 Bartlett JM, Weinbauer GF, Nieschlag E (1990b) Stability of spermatogenic synchronization achieved by depletion and restoration of vitamin A in rats. Biol Reprod 42:603-612 Behre HM, Nieschlag E, Meschede D, Partsch CJ (2000) Diseases of the hypothalamus and the pituitary gland. In: Andrology - Male reproductive health and dysfunction. Nieschlag E, Behre HM (eds) Springer, Berlin, pp 125-143 Bockers TM, Nieschlag E, Kreutz MR, Bergmann M (1994) Localization of follicle-stimulating hormone (FSH) immunoreactivityand hormone receptor mRNA in testiculartissue of infertile men. Cell Tissue Res 278:595-600 Boekelheide K, Schoenfeld HA (2001) Spermatogenesis by Sisyphus: proliferating stem germ cells fail to repopulate the testis after 'irreversible' injury. Adv Exp Med Biol 500:421-428 Boekelheide K, Fleming SL, Allio T, Embree-Ku ME, Hall SJ, Johnson KJ, Kwon EJ, Patel SR, Rasoulpour RJ, Schoenfeld HA, Thompson S (2003) 2,5-hexanedione-induced testicular injury. Annu Rev Pharmacol Toxicol 43:125-147 Bremner WJ, Millar MR, Sharpe RM, Saunders PT (1994) Immunohistochemical localization of androgen receptors in the rat testis: evidence for stage-dependent expression and regulation by androgens. Endocrinology 135:1227-1234 Brown GR, Nevison CM, Fraser HM, Dixson AF (1999) Manipulation of postnatal testosterone levels affects phallic and clitoral development in infant rhesus monkeys. Int J Androl 22: 119-128

Carreau S, Bourguiba S, Lambard S, Galeraud-Denis I, Genissel C, Bilinska B, Benahmed M, Levallet J (2001) Aromatase expression in male germ cells. J Steroid Biochem Mol Biol 79: 203-208

Chandolia RK, Weinbauer GF, Fingscheidt U, Bartlett JM, Nieschlag E (1991) Effects of flutamide on testicular involution induced by an antagonist of gonadotrophin-releasing hormone and on stimulation of spermatogenesis by follicle-stimulating hormone in rats. J Reprod Fertil 93:313-323

Chen H, Chandrashekar V, Zirkin BR (1994) Can spermatogenesis be maintained quantitatively in intact adult rats with exogenously administered dihydrotestosterone? J Androl 15:132-138 Clermont Y (1969) The cycle of the seminiferous epithelium in man. Am J Anat 112:35-46 Clermont Y (1972) Kinetics of spermatogenesis in mammals: seminiferous epithelium cycle and spermatogonia renewal. Physiol Rev 52:198-236 Clermont Y, Leblond CP (1955) Spermatogenesis of man, monkey, ram and other mammals as shown by the "periodic acid-schiff" technique. Am J Anat 96:229-253 Clouthier DE, Avarbock MR, Maika SD, Hammer RE, Brinster RL (1996) Rat spermatogenesis in mouse testis. Nature 381:418-421 Cunningham GR, Huckins C (1979) Persistence of complete spermatogenesis in the presence of low intratesticular concentrations of testosterone. Endocrinology 105:177-186 Dankbar B, Brinkworth MH, Schlatt S, Weinbauer GF, Nieschlag E, Gromoll J (1995) Ubiquitous expression of the androgen receptor and testis-specific expression of the FSH receptor in the cynomolgus monkey (Macacafascicularis) revealed by a ribonuclease protection assay. J Steroid Biochem Mol Biol 55:35-41

de Franca LR, Hess RA, Cooke PS, Russell LD (1995) Neonatal hypothyroidism causes delayed Sertoli cell maturation in rats treated with propylthiouracil: evidence that the Sertoli cell controls testis growth. Anat Rec 242:57-69 de Kretser DM, Phillips DJ (1998) Mechanisms of protein feedback on gonadotropin secretion.

J Reprod Immunol 39:1-12 de Rooij DG, Grootegoed JA (1998) Spermatogonia stem cells. Curr Opin Cell Biol 10:694-701

de Roux N, Young J, Misrahi M, Genet R, Chanson P, Schaison G, Milgrom E (1997) A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasinghormone receptor. N Engl J Med 337:1597-1602 Depenbusch M, von Eckardstein S, Simoni M, Nieschlag E (2002) Maintenance of spermatogenesis in hypogonadotropic hypogonadal men with human chorionic gonadotropin alone. Eur J Endocrinol 147:617-624 Dietrich T, Schulze W, Riemer M (1986) Classification ofthe germinal epithelium in Java monkeys

(Macaca cynomolgus) using digital image processing. Urologe [A] 25:179-186 EblingFJ, Brooks AN, Cronin AS, Ford H, Kerr JB (2000) Estrogenic induction of spermatogenesis in the hypogonadal mouse. Endocrinology 141:2861-2869 El Shennawy A, Gates RJ, Russell LD (1998) Hormonal regulation of spermatogenesis in the hypophysectomized rat: cell viability after hormonal replacement in adults after intermediate periods ofhypophysectomy. J Androl 19:320-334; discussion 341-342 Ergun S, Harneit S, Paust HJ, Mukhopadhyay AK, Holstein AF (1998) Endothelin and endothelin receptors A and B in the human testis. Anat Embryol (Berl) 199:207-214 Fingscheidt U, Weinbauer GF, Fehm HL, Nieschlag E (1998) Regulation of gonadotrophin secretion by inhibin, testosterone and gonadotrophin-releasing hormone in pituitary cell cultures of male monkeys. J Endocrinol 159:103-110 Foreman D (1998) Effects of exogenous hormones on spermatogenesis in the male prairie dog

(Cynomys ludovicianus). Anat Rec 250:45-61 Franca LR, Ogawa T, Avarbock MR, Brinster RL, Russell LD (1998) Germ cell genotype controls cell cycle during spermatogenesis in the rat. Biol Reprod 59:1371-1377 Graf KM, Dias JA, Griswold MD (1997) Decreased spermatogenesis as the result of an induced autoimmune reaction directed against the gonadotropin receptors in male rats. J Androl 18:174-185

Gromoll J, Simoni M, Nieschlag E (1996) An activating mutation of the follicle-stimulating hormone receptor autonomously sustains spermatogenesis in a hypophysectomized man. J Clin Endocrinol Metab 81:1367-1370 Gromoll J, Partsch CJ, Simoni M, Nordhoff V, Sippell WG, Nieschlag E, Saxena BB (1998) A mutation in the first transmembrane domain ofthe lutropin receptor causes male precocious puberty. J Clin Endocrinol Metab 83:476-480 Gromoll J, EiholzerU, Nieschlag E, Simoni M (2000) Male hypogonadism caused by homozygous deletion of exon 10 of the luteinizing hormone (LH) receptor: differential action of human chorionic gonadotropin and LH. J Clin Endocrinol Metab 85:2281-2286 Gromoll J, Wistuba J, Terwort N, Godmann M, Muller T, Simoni M (2003) A new subclass of the luteinizing hormone/chorionic gonadotropin receptor lacking exon 10 messenger RNA in the New World monkey (Platyrrhini) lineage. Biol Reprod 69:75-80

Guo Q, Kumar TR, Woodruff T, Hadsell LA, DeMayo FJ, Matzuk MM (1998) Overexpression of mouse follistatin causes reproductive defects in transgenic mice. Mol Endocrinol 12:96-106 Harris GC, Nicholson HD (1998) Stage-relateddifferences in rat seminiferous tubule contractility in vitro and their response to oxytocin. J Endocrinol 157:251-257 Haywood M, Tymchenko N, Spaliviero J, Koch A, Jimenez M, Gromoll J, Simoni M, Nordhoff V, Handelsman DJ, Allan CM (2002) An activated human follicle-stimulating hormone (FSH) receptor stimulates FSH-like activity in gonadotropin-deficient transgenic mice. Mol Endocrinol 16:2582-2591 Haywood M, Spaliviero J, Jimemez M, King NJ, Handelsman DJ, Allan CM (2003) Sertoli and germ cell development in hypogonadal (hpg) mice expressing transgenic follicle-stimulating hormone alone or in combination with testosterone. Endocrinology 144:509-517 Heckert LL, Griswold MD (2002) The expression of the follicle-stimulating hormone receptor in spermatogenesis. Recent Prog Horm Res 57:129-148 Hess RA, Bunick D, Lee KH, Bahr J, Taylor JA, Korach KS, Lubahn DB (1997) A role for oestrogens in the male reproductive system. Nature 390:509-512 Holstein AF, Maekawa M, Nagano T, Davidoff MS (1996) Myofibroblasts in the lamina propria of human semi-niferous tubules are dynamic structures of heterogeneous phenotype. Arch HistolCytol 59:109-125 Huang HF, Nieschlag E (1986) Suppression of the intratesticular testosterone is associated with quantitative changes in spermatogonial populations in intact adult rats. Endocrinology 118:619-627

Huhtaniemi I (2000) The Parkes lecture. Mutations of gonadotrophin and gonadotrophin receptor genes: what do they teach us about reproductive physiology? J Reprod Fertil 119:173-186 Jarow JP, Chen H, Rosner TW, Trentacoste S, Zirkint BR (2001) Assessment of the androgen environment within the human testis: minimally invasive method to obtain intratesticular fluid. J Androl 22:640-645 Jegou B (1993) The Sertoli-germ cell communication network in mammals. Int Rev Cytol 147: 25-96

Johnsen SG (1978) Maintenance of spermatogenesis induced by HMG treatment by means of continuous HCG treatment in hypogonadotrophic men. Acta Endocrinol (Copenh) 89: 763-769

Johnson L, McKenzie KS, Snell JR (1996) Partial wave in human seminiferous tubules appears to be a random occurrence. Tissue Cell 28:127-136 Joseph DR, O'Brien DA, Sullivan PM, Becchis M, Tsuruta JK, Petrusz P (1997a) Overexpression of androgen-binding protein/sex hormone-binding globulin in male transgenic mice: tissue distribution and phenotypic disorders. Biol Reprod 56:21-32 Joseph DR, Power SG, Petrusz P (1997b) Expression and distribution of androgen-binding protein/sex hormone-binding globulin in the female rodent reproductive system. Biol Reprod 56:14-20

Kinniburgh D, Anderson RA, Baird DT (2001) Suppression of spermatogenesis with desogestrel and testosterone pellets is not enhanced by addition of finasteride. J Androl 22:88-95 Kolho KL, Huhtaniemi I (1989a) Neonatal treatment of male rats with a gonadotropin-releasing hormone antagonist results in altered function of the pituitary-testicular axis in adult age. Biol Reprod 41:1084-1090

Kolho KL, HuhtaniemiI (1989b) Suppression ofpituitary-testis function in rats treated neonatally with a gonadotrophin-releasing hormone agonist and antagonist: acute and long-term effects. J Endocrinol 123:83-91

Kremer H, Kraaij R, Toledo SP, Post M, Fridman JB, Hayashida CY, van Reen M, Milgrom E, Ropers HH, Mariman E (1995) Male pseudohermaphroditism due to a homozygous missense mutation ofthe luteinizing hormone receptor gene. Nat Genet 9:160-164 Krishnamurthy H, Danilovich N, Morales CR, Sairam MR (2000a) Qualitative and quantitative decline in spermatogenesis of the follicle-stimulating hormone receptor knockout (FORKO) mouse. Biol Reprod 62:1146-1159 Krishnamurthy H, Kumar KM, Joshi CV, Krishnamurthy HN, Moudgal RN, Sairam MR (2000b) Alterations in sperm characteristics of follicle-stimulating hormone (FSH)-immunized men are similar to those of FSH-deprived infertile male bonnet monkeys. J Androl 21:316-327 Krishnamurthy H, Kats R, Danilovich N, Javeshghani D, Sairam MR (2001) Intercellular communication between Sertoli cells and Leydig cells in the absence of follicle-stimulating hormone-receptor signaling. Biol Reprod 65:1201-1207 Kula K (1988) Induction of precocious maturation of spermatogenesis in infant rats by human menopausal gonadotropin and inhibition by simultaneous administration of gonadotropins and testosterone. Endocrinology 122:34-39 Kumar TR, Wang Y, Lu N, Matzuk MM (1997) Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility. Nat Genet 15:201-204 Larriba S, Esteban C, Toran N, Gerard A, Audi L, Gerard H, Reventos J (1995) Androgen binding protein is tissue-specifically expressed and biologically active in transgenic mice. J Steroid Biochem Mol Biol 53:573-578 Lerchl A, Sotiriadou S, Behre HM, Pierce J, Weinbauer GF, Kliesch S, Nieschlag E (1993) Restoration of spermatogenesis by follicle-stimulating hormone despite low intratesticular testosterone in photoinhibited hypogonadotropic Djungarian hamsters (Phodopus sungorus). Biol Reprod 49:1108-1116

Lindstedt G, Nystrom E, Matthews C, Ernest I, Janson PO, Chatterjee K (1998) Follitropin (FSH) deficiency in an infertile male due to FSH beta gene mutation. A syndrome of normal puberty and virilization but underdeveloped testicles with azoospermia, low FSH but high lutropin and normal serum testosterone concentrations. Clin Chem Lab Med 36:663-665 Liu PY, Gebski VJ, Turner L, Conway AJ, Wishart SM, Handelsman DJ (2002) Predicting pregnancy and spermatogenesis by survival analysis during gonadotrophin treatment of gonadotrophin-deficient infertile men. Hum Reprod 17:625-633 Lunn SF, Recio R, Morris K, Fraser HM (1994) Blockade of the neonatal rise in testosterone by a gonadotrophin-releasing hormone antagonist: effects on timing of puberty and sexual behaviour in the male marmoset monkey. J Endocrinol 141:439-447 Lunn SF, Cowen GM, Fraser HM (1997) Blockade ofthe neonatal increase in testosterone by a GnRH antagonist: the free androgen index, reproductive capacity and postmortem findings in the male marmoset monkey. J Endocrinol 154:125-131 Maddocks S, Sharpe RM (1989) Dynamics of testosterone secretion by the rat testis: implications for measurement of the intratesticular levels of testosterone. J Endocrinol 122: 323-329

Mann DR and Fraser HM (1996) The neonatal period: a critical interval in male primate development. J Endocrinol 149:191-197 Mann DR, Akinbami MA, Gould KG, Tanner JM, Wallen K (1993) Neonatal treatment of male monkeys with a gonadotropin-releasing hormone agonist alters differentiation of central nervous system centers that regulate sexual and skeletal development. J Clin Endocrinol Metab 76:1319-1324

Mann DR, Akinbami MA, Gould KG, Paul K, Wallen K (1998) Sexual maturation in male rhesus monkeys: importance of neonatal testosterone exposure and social rank. J Endocrinol 156: 493-501

Marshall GR, Wickings EJ, Nieschlag E (1984) Testosterone can initiate spermatogenesis in an immature nonhuman primate, Macaca fascicularis. Endocrinology 114:2228-2233 Marshall GR, Zorub DS, Plant TM (1995) Follicle-stimulating hormone amplifies the population of differentiated spermatogonia in the hypophysectomized testosterone-replaced adult rhesus monkey (Macaca mulatta). Endocrinology 136:3504-3511 Matsumiya K, Meistrich ML, Shetty G, Dohmae K, Tohda A, Okuyama A, Nishimune Y (1999) Stimulation of spermatogonial differentiation in juvenile spermatogonial depletion (jsd) mutant mice by gonadotropin-releasing hormone antagonist treatment. Endocrinology 140:4912-4915

McConnell DS, Wang Q, Sluss PM, Bolf N, Khoury RH, Schneyer AL, Midgley AR, Jr., Reame NE, Crowley WF, Jr., Padmanabhan V (1998) A two-site chemiluminescent assay for activin-free follistatin reveals that most follistatin circulating in men and normal cycling women is in an activin-bound state. J Clin Endocrinol Metab 83:851-858 McKinnell C, Saunders PT, Fraser HM, Kelnar CJ, Kivlin C, Morris KD, Sharpe RM (2001) Comparison of androgen receptor and oestrogen receptor beta immunoexpression in the testes of the common marmoset (Callithrixjacchus) from birth to adulthood:low androgen receptor immunoexpression in Sertoli cells during the neonatal increase in testosterone concentrations. Reproduction 122:419-429 McLachlan RI (2000) The endocrine control of spermatogenesis. Baillieres Best Pract Res Clin

Endocrinol Metab 14:345-362 McLachlan RI, O'Donnell L, Meachem SJ, Stanton PG, de Kretser DM, Pratis K, Robertson DM (2002a) Identification of specific sites of hormonal regulation in spermatogenesis in rats, monkeys, and man. Recent Prog Horm Res 57:149-179 McLachlan RI, O'Donnell L, Stanton PG, Balourdos G, Frydenberg M, de Kretser DM, Robertson DM (2002b) Effects of testosterone plus medroxyprogesterone acetate on semen quality, reproductive hormones, and germ cell populations in normal young men. J Clin Endocrinol Metab 87:546-556

Meistrich ML, Shetty G (2003) Suppression oftestosterone stimulates recovery ofspermatogenesis after cancer treatment. Int J Androl 26:141-146 Meistrich ML, van Beek MEAB (1993) Spermatogonial stem cells. In: Desjardins C, Ewing LL (eds) Cell and molecular biology of the testis. Oxford University Press, New York, pp. 266-295 Meriggiola MC, Costantino A, Bremner WJ, Morselli-Labate AM (2002) Higher testosterone dose impairs sperm suppression induced by a combined androgen-progestin regimen. J Androl 23:684-690

Millar MR, Sharpe RM, Weinbauer GF, Fraser HM, Saunders PT (2000) Marmoset spermatogenesis: organizational similarities to the human. Int J Androl 23:266-277 Moudgal NR, Jeyakumar M, Krishnamurthy HN, Sridhar S, Krishnamurthy H, Martin F (1997a)

Development of male contraceptive vaccine-a perspective. Hum Reprod Update 3:335-346 Moudgal NR, Sairam MR, Krishnamurthy HN, Sridhar S, Krishnamurthy H, Khan H (1997b) Immunization of male bonnet monkeys (M. radiata) with a recombinant FSH receptor preparation affects testicular function and fertility. Endocrinology 138:3065-3068 Moudgal NR, Sairam MR (1998) Is there a true requirement for follicle stimulating hormone in promoting spermatogenesis and fertility in primates? Hum Reprod 13:916-919 Murata Y, Robertson KM, Jones ME, Simpson ER (2002) Effect of estrogen deficiency in the male: the ArKO mouse model. Mol Cell Endocrinol 193:7-12 Narula A, Gu YQ, O'Donnell L, Stanton PG, Robertson DM, McLachlan RI, Bremner WJ (2002) Variability in sperm suppression during testosterone administration to adult monkeys is related to follicle stimulating hormone suppression and not to intratesticular androgens. J Clin Endocrinol Metab 87:3399-3406 Nieschlag E, Simoni M, Gromoll J, Weinbauer GF (1999) Role of FSH in the regulation of spermatogenesis: clinical aspects. Clin Endocrinol (Oxf) 51:139-146 Niklowitz P, Lerchl A, Nieschlag E (1997) In vitro fertilizing capacity of sperm from FSH-treated photoinhibited Djungarian hamsters (Phodopus sungorus). J Endocrinol 154:475-481 O'Donnell L, Narula A, Balourdos G, GuYQ, Wreford NG, Robertson DM, Bremner WJ, McLachlan RI (2001a) Impairment ofspermatogonial development and spermiation after testosterone-induced gonadotropin suppression in adult monkeys (Macaca fascicularis). J Clin Endocrinol Metab 86:1814-1822

O'Donnell L, Robertson KM, Jones ME, Simpson ER (2001b) Estrogen and spermatogenesis. Endocr Rev 22:289-318

Overstreet JW, Fuh VL, Gould J, Howards SS, Lieber MM, Hellstrom W, Shapiro S, Carroll P, Corfman RS, Petrou S, Lewis R, Toth P, Shown T, Roy J, Jarow JP, Bonilla J, Jacobsen CA, Wang DZ, Kaufman KD (1999) Chronic treatment with finasteride daily does not affect spermatogenesis or semen production in young men. J Urol 162:1295-1300 Phillip M, Arbelle JE, Segev Y, Parvari R (1998) Male hypogonadism due to a mutation in the gene for the beta-subunit of follicle-stimulating hormone. N Engl J Med 338:1729-1732 Ramaswamy S, Pohl CR, McNeilly AS, Winters SJ, Plant TM (1998) The time course of follicle-stimulating hormone suppression by recombinant human inhibin A in the adult male rhesus monkey (Macaca mulatta). Endocrinology 139:3409-3415 Rannikko A, Penttila TL, Zhang FP, Toppari J, Parvinen M, Huhtaniemi I (1996) Stage-specific expression ofthe FSH receptor gene in the prepubertal and adult rat seminiferous epithelium. J Endocrinol 151:29-35

Rea MA, Marshall GR, Weinbauer GF, Nieschlag E (1986a) Testosterone maintains pituitary and serum FSH and spermatogenesis in gonadotrophin-releasing hormone antagonist-suppressed rats. J Endocrinol 108:101-107 Rea MA, Weinbauer GF, Marshall GR, Nieschlag E (1986b) Testosterone stimulates pituitary and serum FSH in GnRH antagonist- suppressed rats. Acta Endocrinol (Copenh) 113:487-492

Ren HP, Russell LD (1991) Clonal development of interconnected germ cells in the rat and its relationship to the segmental and subsegmental organization of spermatogenesis. Am J Anat 192:121-128

Rhoden EL, GobbiD,MentiE, Rhoden C,TelokenC (2002) Effects ofthe chronic use of finasteride on testicular weight and spermatogenesis in Wistar rats. BJU Int 89:961-963 Robertson DM, Pruysers E, Stephenson T, Pettersson K, Morton S, McLachlan RI (2001) Sensitive LH and FSH assays for monitoring low serumlevelsinmen undergoing steroidal contraception. Clin Endocrinol (Oxf) 55:331-339 Rommerts FF (1988) How much androgen is required for maintenance of spermatogenesis? J Endocrinol 116:7-9

Rosiepen G, Chapin RE, Weinbauer GF (1995) The duration of the cycle of the seminiferous epithelium is altered by administration of 2,5-hexanedione in the adult Sprague-Dawley rat. J Androl 16:127-135

Russell LD, Brinster RL (1996) Ultrastructural observations of spermatogenesis following transplantation of rat testis cells into mouse seminiferous tubules. J Androl 17:615-627 Sairam MR, Krishnamurthy H (2001) The role of follicle-stimulating hormone in spermatogenesis: lessons from knockout animal models. Arch Med Res 32:601-608 Santiemma V, Rossi F, Guerrini L, Markouizou A, Pasimeni G, Palleschi S, Fabbrini A (2001) Adrenomedullin inhibits the contraction of cultured rat testicular peritubular myoid cells induced by endothelin-1. Biol Reprod 64:619-624 Schlatt S, Weinbauer GF, Arslan M, Nieschlag E (1993) Appearance of alpha-smooth muscle actin in peritubular cells of monkey testes is induced by androgens, modulated by follicle-stimulating hormone, and maintained after hormonal withdrawal. J Androl 14:340-350 Schlatt S, Arslan M, Weinbauer GF, Behre HM, Nieschlag E (1995) Endocrine control of testicular somatic and premeiotic germ cell development in the immature testis of the primate Macaca mulatta. Eur J Endocrinol 133:235-247 Schulze W, Rehder U (1984) Organization and morphogenesis ofthe human seminiferous epithelium. Cell Tissue Res 237:395-407 Sharpe RM (1994) Regulation of spermatogenesis. In: Knobil E and Neill JD (eds) The physiology of reproduction. Raven Press, New York, pp 1363-1394 Sharpe RM, Donachie K, Cooper I (1988a) Re-evaluation ofthe intratesticular level of testosterone required for quantitative maintenance of spermatogenesis in the rat. J Endocrinol 117: 19-26

Sharpe RM, Fraser HM, Ratnasooriya WD (1988b) Assessment ofthe role of Ley dig cell products other than testosterone in spermatogenesis and fertility in adult rats. Int J Androl 11:507-523 Sharpe RM, Walker M, Millar MR, Atanassova N, Morris K, McKinnell C, Saunders PT, Fraser HM (2000) Effect of neonatal gonadotropin-releasing hormone antagonist administration on sertoli cell number and testicular development in the marmoset: comparison with the rat. Biol Reprod 62:1685-1693

Shenker A, Laue L, Kosugi S, Merendino JJ, Jr., Minegishi T, Cutler GB, Jr. (1993) A constitutively activating mutation ofthe luteinizing hormone receptor in familial male precocious puberty. Nature 365:652-654

Shetty G, Krishnamurthy H, Krishnamurthy HN, Bhatnagar S, Moudgal RN (1997) Effect of estrogen deprivation on the reproductive physiology of male and female primates. J Steroid Biochem Mol Biol 61:157-166 Shetty G, Krishnamurthy H, Krishnamurthy HN, Bhatnagar AS, Moudgal NR (1998) Effect of long-term treatment with aromatase inhibitor on testicular function of adult male bonnet monkeys (M. radiata). Steroids 63:414-420 Siiteri JE, Karl AF, Linder CC, Griswold MD (1992) Testicular synchrony: evaluation and analysis of different protocols. Biol Reprod 46:284-289 Simoni M, Nieschlag E, Gromoll J (2002) Isoforms and single nucleotide polymorphisms of the FSH receptor gene: implications for human reproduction. Hum Reprod Update 8:413421

Singh J, O'Neill C, Handelsman DJ (1995) Induction of spermatogenesis by androgens in gonadotropin-deficient (hpg) mice. Endocrinology 136:5311-5321 Sinha Hikim AP, Rajavashisth TB, Sinha Hikim I, Lue Y, Bonavera JJ, Leung A, Wang C, Swerdloff RS (1997) Significance of apoptosis in the temporal and stage-specific loss of germ cells in the adult rat after gonadotropin deprivation. Biol Reprod 57:1193-1201 Sjogren I, Ekvarn S, Zuhlke U, Vogel F, Bee W, Weinbauer GF, Nieschlag E (1999) Lack of effects of recombinant human GH on spermatogenesis in the adult cynomolgus monkey (Macaca fascicularis). Eur J Endocrinol 140:350-357 Smithwick EB, Young LG, Gould KG (1996) Duration of spermatogenesis and relative frequency of each stage in the seminiferous epithelial cycle of the chimpanzee. Tissue Cell 28:357-366 Suarez-Quian CA, Martinez-Garcia F, Nistal M, Regadera J (1999) Androgen receptor distribution in adult human testis. J Clin Endocrinol Metab 84:350-358 Suresh R, Medhamurthy R, Moudgal NR (1995) Comparative studies on the effects of specific immunoneutralization of endogenous FSH or LH on testicular germ cell transformations in the adult bonnet monkey (Macaca radiata). Am J Reprod Immunol 34:35-43 Takamiya K, Yamamoto A, Furukawa K, Zhao J, Fukumoto S, Yamashiro S, Okada M, Haraguchi M, Shin M, Kishikawa M, Shiku H, Aizawa S (1998) Complex gangliosides are essential in spermatogenesis of mice: possible roles in the transport of testosterone. Proc Natl Acad Sci USA 95:12147-12152

Teerds KJ, de Rooij DG, Rommerts FF, van den Hurk R, Wensing CJ (1989) Proliferation and differentiation of possible Leydig cell precursors after destruction of the existing Leydig cells with ethane dimethyl sulphonate: the role of LH/human chorionic gonadotrophin. J Endocrinol 122:689-696 Tripiciano A, Peluso C, Morena AR, Palombi F, Stefanini M, Ziparo E, Yanagisawa M, Filip-pini A (1999) Cyclic expression of endothelin-converting enzyme-1 mediates the functional regulation of seminiferous tubule contraction. J Cell Biol 145:1027-1038 Turner KJ, Morley M, Atanassova N, Swanston ID, Sharpe RM (2000) Effect of chronic administration of an aromatase inhibitor to adult male rats on pituitary and testicular function and fertility. J Endocrinol 164:225-238 Ulloa-Aguirre A, Timossi C, Barrios-de-Tomasi J, Maldonado A, Nayudu P (2003) Impact of carbohydrate heterogeneity in function of follicle-stimulating hormone: studies derived from in vitro and in vivo models. Biol Reprod 69:379-389

van Alphen MM, van de Kant HJ, de Rooij DG (1988) Follicle-stimulating hormone stimulates spermatogenesis in the adult monkey. Endocrinology 123:1449-1455 van Alphen MM, van de Kant HJ, de Rooij DG (1989) Protection from radiation-induced damage of spermatogenesis in the rhesus monkey (Macaca mulatta) by follicle-stimulating hormone. Cancer Res 49:533-536

van Roijen JH, Van Assen S, Van Der Kwast TH, de Rooij DG, Boersma WJ, Vreeburg JT, Weber RF (1995) Androgen receptor immunoexpression in the testes of subfertile men. J Androl 16:510-516

Vannier B, Loosfelt H, Meduri G, Pichon C, Milgrom E (1996) Anti-human FSH receptor monoclonal antibodies: immunochemical and immunocytochemical characterization of the receptor. Biochemistry 35:1358-1366 Veldhuis JD, Iranmanesh A, Samojlik E, Urban RJ (1997) Differential sex steroid negative feedback regulation of pulsatile follicle-stimulating hormone secretion in healthy older men: deconvo-lution analysis and steady-state sex-steroid hormone infusions in frequently sampled healthy older individuals. J Clin Endocrinol Metab 82:1248-1254 Vicari E, Mongioi A, Calogero AE, Moncada ML, Sidoti G, Polosa P, D'Agata R (1992) Therapy with human chorionic gonadotrophin alone induces spermatogenesis in men with isolated hypogonadotrophic hypogonadism-long-term follow-up. Int J Androl 15:320-329 Vornberger W, Prins G, Musto NA, Suarez-Quian CA (1994) Androgen receptor distribution in rat testis: new implications for androgen regulation of spermatogenesis. Endocrinology 134:2307-2316

Weinbauer GF, Nieschlag E (1996) The Leydig cell as a target for male contraception. In: Payne

AH, Hardy MP, Russell LD (eds) The Leydig cell. Cache River Press, Vienna, pp 629-662 Weinbauer GF, Nieschlag E (1998) The role oftestosterone in spermatogenesis. In: Nieschlag E, Behre HM (eds) Testosterone - action, deficiency, substitution. Springer Verlag, Berlin, pp.143-168

Weinbauer GF, Korte R (eds) 1999 Reproduction in nonhuman primates: a model system for human reproductive physiology and toxicology. Waxmann Publisher, Muenster/New York Weinbauer GF, Gockeler E, Nieschlag E (1988) Testosterone prevents complete suppression of spermatogenesis in the gonadotropin-releasing hormone antagonist-treated nonhuman primate (Macaca fascicularis). J Clin Endocrinol Metab 67:284-290 Weinbauer GF, Behre HM, Fingscheidt U, Nieschlag E (1991) Human follicle-stimulating hormone exerts a stimulatory effect on spermatogenesis, testicular size, and serum inhibin levels in the gonadotropin-releasing hormone antagonist-treated nonhuman primate (Macaca fascicularis). Endocrinology 129:1831-1839 Weinbauer GF, Schubert J, Yeung CH, Rosiepen G, Nieschlag E (1998) Gonadotrophin-releasing hormone antagonist arrests premeiotic germ cell proliferation but does not inhibit meiosis in the male monkey: a quantitative analysis using 5-bromodeoxyuridine and dual parameter flow cytometry. J Endocrinol 156:23-34 Weinbauer GF, Aslam H, Krishnamurthy H, Brinkworth MH, Einspanier A, Hodges JK (2001a) Quantitative analysis of spermatogenesis and apoptosis in the common marmoset (Callithrix jacchus) reveals high rates of spermatogonial turnover and high spermatogenic efficiency. Biol Reprod 64:120-126

Weinbauer GF, Schlatt S, Walter V, Nieschlag E (2001b) Testosterone-induced inhibition of spermatogenesis is more closely related to suppression of FSH than to testicular androgen levels in the cynomolgus monkey model (Macaca fascicularis). J Endocrinol 168:25-38 Wistuba J, Schrod A, Greve B, Hodges JK, Aslam H, Weinbauer GF, Luetjens CM (2003) Organization of seminiferous epithelium in primates: relationship to spermatogenic efficiency, phylogeny, and mating system. Biol Reprod 69:582-591 Wreford NG, Rajendra Kumar T, Matzuk MM, de Kretser DM (2001) Analysis of the testicular phenotype of the follicle-stimulating hormone beta-subunit knockout and the activin type II receptor knockout mice by stereological analysis. Endocrinology 142:2916-2920 Zannini C, Turchetti S, Guarch R, Buffa D, Pesce C (1999) Cell counting and three-dimensional reconstruction to identify a cellular wave in human spermatogenesis. Anal Quant Cytol Histol 21:358-362

Zhang FP, Rannikko AS, Manna PR, Fraser HM, Huhtaniemi IT (1997) Cloning and functional expression of the luteinizing hormone receptor complementary deoxyribonucleic acid from the marmoset monkey testis: absence of sequences encoding exon 10 in other species. Endocrinology 138:2481-2490 Zhang FP, Kero J, Huhtaniemi I (1998) The unique exon 10 of the human luteinizing hormone receptor is necessary for expression of the receptor protein at the plasma membrane in the human luteinizing hormone receptor, but deleterious when inserted into the human follicle-stimulating hormone receptor. Mol Cell Endocrinol 142:165-174 Zhengwei Y, Wreford NG, Royce P, de Kretser DM, McLachlan RI (1998a) Stereological evaluation of human spermatogenesis after suppression by testosterone treatment: heterogeneous pattern of spermatogenic impairment. J Clin Endocrinol Metab 83:1284-1291 Zhengwei Y, Wreford NG, Schlatt S, Weinbauer GF, Nieschlag E, McLachlan RI (1998b) Acute and specific impairment of spermatogonial development by GnRH antagonist-induced gonadotrophin withdrawal in the adult macaque (Macaca fascicularis). In J Reprod Fertil 112:139-147

Zirkin BR, Awoniyi C, Griswold MD, Russell LD, Sharpe R (1994) Is FSH required for adult spermatogenesis? J Androl 15:273-276

Was this article helpful?

0 0
10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook

Post a comment