The Leydig Cell as a Target for Male Contraception

  • Craig Marc Luetjens
  • Joachim Wistuba
  • Gerhard Weinbauer
  • Eberhard Nieschlag
Part of the Contemporary Endocrinology book series (COE)


Control of testicular steroidogenesis and gametogenesis represents the main target of hormonal male contraception. The suppression of testosterone as a Leydig cell product and of follicle-stimulating hormone (FSH) is the main target to prevent spermatogenesis. To this end, both leutinizing hormone (LH) exerting its regulatory action on the Leydig cells and FSH, which acts directly on the seminiferous tubules need to be eliminated. To prevent LH and FSH release, gonadotropin-releasing hormone as the sole releasing factor for both gonadotropins, has to be shut down. The release of gonadotropin-releasing hormone and hence the gonadotropins is under a negative feedback control of testosterone. Downregulation of both LH and FSH leads to spermatogenic arrest, but germ cell maturation is restored as soon as both hormones regain their normal values. Although, intratesticular testosterone is suppressed, peripheral testosterone needs to be replaced in order to maintain normal virility. This is best achieved by testosterone itself, which needs to be combined with a gestagen. At present, hormonal fertility regulation through the Leydig cell provides the most promising method for men who wish to control their fertility.


Sertoli Cell Leydig Cell GnRH Agonist GnRH Antagonist Cyproterone Acetate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Heinemann K, Saad F, Wiesemes M, Heinemann LA. Expectations toward a novel male fertility control method and potential user types: results of a multinational survey. J Androl, 2005;26:155–162.PubMedGoogle Scholar
  2. 2.
    Heinemann K, Saad F, Wiesemes M, White S, Heinemann L. Attitudes toward male fertility control: results of a multinational survey on four continents. Hum Reprod 2005;20: 549–556.PubMedCrossRefGoogle Scholar
  3. 3.
    Barfield JP, Nieschlag E, Cooper TG. Fertility control in wildlife: humans as a model. Contraception, 2006;73:6–22.PubMedCrossRefGoogle Scholar
  4. 4.
    Vadakkadath Meethal S, Atwood CS. The role of hypothalamic-pituitary-gonadal hormones in the normal structure and functioning of the brain. CeU Mol Life Sci2005;62:257–270.CrossRefGoogle Scholar
  5. 5.
    Smith PE. Hypophysectomy and a replacement therapy in the rat. Am J Anat 1930;45:205–256.CrossRefGoogle Scholar
  6. 6.
    Smith PE. Comparative effects of hypophysectomy and therapy on the testes of monkeys and rats. In: Comptes rendues, ed. Brouha Les hormones sexuelles. 1. edn Paris, 1938: pp. 601–605.Google Scholar
  7. 7.
    Greep RO, Fevold HC. The spermatogenic and secretory function of the gonads of hypophysectomized adult rats treated with pituitary FSH and LH. Endocrinol 1937;21:611–618.CrossRefGoogle Scholar
  8. 8.
    Sriraman V, Jagannadha Rao A. Evaluation of the role of FSH in regulation of Leydig cell function during different stages of its differentiation. Mol Cell Endocrinol 2004;224:73–82.PubMedCrossRefGoogle Scholar
  9. 9.
    Matsuo H, Baba Y, Nair RM, Arimura A, Schally AV. Structure of the porcine LH-and FSH-releasing hormone I The proposed amino acid sequence. Biochem Biophys Res Comm 1971;43:1334–1339.PubMedCrossRefGoogle Scholar
  10. 10.
    Somoza GM, Miranda LA, Strobl-Mazzulla P, Guilgur LG. Gonadotropin-releasing hormone (GnRH): from fish to mammalian brains. Cell Mol Neurobiol, 2002;22:589–609.PubMedCrossRefGoogle Scholar
  11. 11.
    Heckel NJ. Production of oligospermia in a man by the use of testosterone propionate. Proc Soc Exp Biol Med 1939; 40:658–659.Google Scholar
  12. 12.
    Heller CG, Nelson WO, Hill IC, Henderson D, Maddock WO, Jungck EC. The effect of testosterone upon the human testis. J Clin Endocrinol Metab 1950;10:816.PubMedGoogle Scholar
  13. 13.
    McCullagh PE, McGurl FJ. The effects of testosterone propionate on epiphyseal closure sodium and chloride balance and on sperm counts. Endocrinol 1940;26:377–384.CrossRefGoogle Scholar
  14. 14.
    Chappell PE. Clocks and the black box: circadian influences on gonadotropin-releasing hormone secretion. J Neuroendocrinol 2005;17:119–130.PubMedCrossRefGoogle Scholar
  15. 15.
    Conn PM, Crowley WF, Jr. Gonadotropin-releasing hormone and its analogues. N Engl J Med 1991;324:93–103.PubMedCrossRefGoogle Scholar
  16. 16.
    Gharib SD, Wiermann ME, Shupnik A, Chin WW. Molecular biology of the pituitary gonadotropins. Endocr Rev 1990;11: 177–199.PubMedCrossRefGoogle Scholar
  17. 17.
    Rosemblit N, Ascoli M, Segaloff DL. Characterization of an antiserum to the rat luteal luteinizing hormone/chorionic gonadotropin receptor. Endocrinology 1988;123:2284–2290.PubMedCrossRefGoogle Scholar
  18. 18.
    Misrahi Thu Vu Hai M, Ghinea N, Loosfelt H, et al. Molecular and cellular biology of gonadotropin receptors. In: The Ovary. 1993; pp. 57–92.Google Scholar
  19. 19.
    Resko JA, Connolly PB, Roselli CE, Abdelgadir SE, Choate JVA. Selective activation of androgen receptors in the subcortical brain of male cynomolgus macaques by physiological hormone levels and its relationship to androgen-dependent aromatase activity. J Clin Endocrinol Metab 1993; 76:1588–1593.PubMedCrossRefGoogle Scholar
  20. 20.
    Canto P, Soderlund D, Ramon G, Nishimura E, Mendez JP. Mutational analysis of the luteinizing hormone receptor gene in two individuals with Leydig cell tumors. Am J Med Genet 2002;108:148–152.PubMedCrossRefGoogle Scholar
  21. 21.
    Kremer H, Mariman E, Often BJ, Moll GW, et al. Cosegregation of missense mutations of the luteinizing hormone receptor gene with familial male-limited precocious puberty. Human Mol Gen 1993;2:1779–1783.CrossRefGoogle Scholar
  22. 22.
    Huhtaniemi I. The Parkes lecture. Mutations of gonadotrophin and gonadotrophin receptor genes: what do they teach us about reproductive physiology? J Reprod Fertil 2000; 119:173–186.PubMedCrossRefGoogle Scholar
  23. 23.
    Kremer H, Kraaij R, Toledo SPA, Psot M, Fridman JB, Hayashida CY, et al. Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene. Nature Genetics 1995;9:160–164.PubMedCrossRefGoogle Scholar
  24. 24.
    Toledo SP. Inactivating mutations of the LH receptor gene: more than two different phenotypes. Eur J Endocrinol 1999;140:186.PubMedCrossRefGoogle Scholar
  25. 25.
    Lei ZM, Mishra S, Ponnuru P, Li X, Yang ZW, Rao ChV. Testicular phenotype in luteinizing hormone receptor knockout animals and the effect of testosterone replacement therapy. Biol Reprod 2004;71:1605–1613.PubMedCrossRefGoogle Scholar
  26. 26.
    Rao CV, Lei ZM. Consequences of targeted inactivation of LH receptors. Mol Cell Endocrinol 2002;187:57–67.PubMedCrossRefGoogle Scholar
  27. 27.
    Zhang FP, Poutanen M, Wilbertz J, Huhtaniemi I. Normal prenatal but arrested postnatal sexual development of luteinizing hormone receptor knockout (LuRKO) mice. Mol Endocrinol 2001;15:172–183.PubMedCrossRefGoogle Scholar
  28. 28.
    Ge RS, Dong Q, Sottas CM, Papadopoulos V, Zirkin BR, Hardy MP. In search of rat stem Leydig cells: Identification, isolation, and lineage-specific development. Proc Natl Acad Sci USA, 2006.Google Scholar
  29. 29.
    Ghinea N, Milgrom E. Transport of protein hormones through the vascular endothelium. J Endocrinol 1995;145:1–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Ghinea N, Milgrom E. A new function for the LH/CG receptor: transcytosis of hormone across the endothelial barrier in target organs. Semin Reprod Med 2001;19:97–101.PubMedCrossRefGoogle Scholar
  31. 31.
    Haider SG. Cell biology of Leydig cells in the testis. Int Rev Cytol 2004;233:181–241.PubMedCrossRefGoogle Scholar
  32. 32.
    Turner TT, Ewing LL, Jones CE, Howards SS, Zegeye B. Androgens in various fluid compartments of the rat testis and epididymis after hypophysectomy and gonadotropin supplementation. J Androl 1985;6:353–358.PubMedGoogle Scholar
  33. 33.
    Setchell BP, Pakarinen P, Huhtaniemi I. How much LH do the Leydig cells see? J Endocrinol 2002;175:375–382.PubMedCrossRefGoogle Scholar
  34. 34.
    Setchell BP. Hormones: what the testis really sees. Reprod Fertil Dev 2004;16:535–545.PubMedCrossRefGoogle Scholar
  35. 35.
    Bergh A, Widmark A, Damber JE, Cajander S. Are leukocytes involved in the human chorionic gonadotropin-induced increase in testicular vascular permeability? Endocrinol 1986;119:586–590.CrossRefGoogle Scholar
  36. 36.
    Kerr JB, Sharpe RM. Focal disruption of spermatogenesis in the testis of adult rats after a single administration of human chorionic gonadotrophin. Cell Tiss Res 1989;257:163–169.CrossRefGoogle Scholar
  37. 37.
    Widmark A, Damber JE, Bergh A. The relationship between human chorionic gonadotropin-induced changes in testicular microcirculation and the formation of testicular interstitial fluid. J Endocrinol 1986;109:419–425.PubMedCrossRefGoogle Scholar
  38. 38.
    van Vliet J, Rommerts FF, de Rooij DG, Buwalda G, Wensing CJG. Reduction of testicular blood flow and focal degeneration of tissue in the rat after administration of human chorionic gonadotrophin. J Endocrinol 1988;117: 51–57.PubMedCrossRefGoogle Scholar
  39. 39.
    Widmark A, Damber JE, Bergh A. High and low doses of luteinizing hormone induce different changes in testicular microcirculation. J Endocrinol 1989;109:419–425.CrossRefGoogle Scholar
  40. 40.
    Damber JE, Maddocks S, Widmark A, Bergh A. Testicular blood flow and vasomotion can be maintained by testosterone in Leydig cell-depleted rats. Int J Androl 1992;15:385–393.PubMedCrossRefGoogle Scholar
  41. 41.
    Bergh A, Damber JE. Vascular controls in testicular physiology. In: Molecular Biology of the Male Reproductive System, 1993; pp. 439–467.Google Scholar
  42. 42.
    Collin O, Bergh A. Leydig cells secrete factors which increase vascular permeability and endothelial cell proliferation. Int J Androl 1996;19:221–228.PubMedCrossRefGoogle Scholar
  43. 43.
    Russell LD, Corbin TJ, Borg KE, Renato de Franca L, Grasso P, Bartke A. Recombinant human follicle-stimulating hormone is capable of exerting a biological effect in the adult hypophysectomized rat by reducing the numbers of degenerating germ cells. Endocrinol 1993;133:2062–2070.CrossRefGoogle Scholar
  44. 44.
    Schlaft S, Weinbauer G, Arslan M, Behre HM, Nieschlag E. Endocrine control of testicular somatic and premeiotic germ cell development in the immature testis of the primate Macaca mulatta. Eur J Endocrinol 1995;133:235–247.CrossRefGoogle Scholar
  45. 45.
    Tao YX, Bao S, Ackermann DM, Lei ZM, Rao CV. Expression of luteinizing hormone/human chorionic gonadotropin receptor gene in benign prostatic hyperplasia and in prostate carcinoma in humans. Biol Reprod 1997;56:67–72.PubMedCrossRefGoogle Scholar
  46. 46.
    Reiter E, Hennuy B, Bruyninx M, et al. Effects of pituitary hormones on the prostate. Prostate 1999;38:159–165.PubMedCrossRefGoogle Scholar
  47. 47.
    Minegishi T, Nakamura K, Takakura Y, Ibuki Y, Igarashi M, Minegish T. Cloning and sequencing of human FSH receptor cDNA. Biochem Biophys Res Commun 1991; 175:1125–1130.PubMedCrossRefGoogle Scholar
  48. 48.
    Simoni M, Gromoll J, Nieschlag E. The follicle-stimulating hormone receptor: biochemistry, molecular biology, physiology, and pathophysiology. Endocr Rev 1997;18:739–773.PubMedCrossRefGoogle Scholar
  49. 49.
    Dym M, Raj HG, Lin YC, Chemes HE, Kotite NJ, Nayfeh SN, French FS. Is FSH required for maintenance of spermatogenesis in adult rats? J Reprod Fertil Suppl 1978;26: 175–181.Google Scholar
  50. 50.
    Berswordt-Wallrabe RVO, Steinbeck H, Neumann F. Effect of FSH on the testicular structure of rats. Endocrinologia 1968;53:35–42.Google Scholar
  51. 51.
    Toppari J, Tsutsumi I, Bishop PC, Parker JW, et al. Flow cytometry quantification of rat spermatogenic cells after hypophysectomy and gonadotropin treatment. Biol Reprod 1989;40:623–634.PubMedCrossRefGoogle Scholar
  52. 52.
    Howell-Skalla L, Bunick D, Bleck G, Nelson RA, Bahr JM. Cloning and sequence analysis of the extracellular region of the polar bear (Ursus maritimus) luteinizing hormone receptor (LHr), follicle stimulating hormone receptor (FSHr), and prolactin receptor (PRLr) genes and their expression in the testis of the black bear (Ursus americanus). Mol Reprod Dev 2000;55:136–145.PubMedCrossRefGoogle Scholar
  53. 53.
    Milette JJ, Sehwartz NB, Turek FW. The importance of follice-stimulating hormone in the initiation of testicular growth in photostimulated Djungarian hamsters. Endocrinol 1988;122:1060–1066.CrossRefGoogle Scholar
  54. 54.
    Nieschlag E, Simoni M, Gromoll J, Weinbauer GF. Role of FSH in the regulation of spermatogenesis: clinical aspects. Clin Endocrinol (Oxf) 1999;51:139–146.CrossRefGoogle Scholar
  55. 55.
    Russell LD, Alger LE, Nequin LG. Hormonal control of pubertal spermatogenesis. Endocrinol 1987;120:1615–1632.CrossRefGoogle Scholar
  56. 56.
    Weinbauer GF, Nieschlag E. Hormonal control of spermatogenesis. In: Molecular Biology of Reproduction De Kretser DM Academic Press NY 1993; pp. 99–143.Google Scholar
  57. 57.
    Asatiani K, Gromoll J, von Eckardstein S, Zitzmann M, Nieschlag E, Simoni M. Distribution and function of FSH receptor genetic variants in normal men. Andrologia 2002;34:172–176.PubMedCrossRefGoogle Scholar
  58. 58.
    Gromoll J, Simoni M, Nordhoff V, Behre HM, De Geyter C, Nieschlag E. Functional and clinical consequences of mutations in the FSH receptor. Mol Cell Endocrinol 1996;125:177–182.PubMedCrossRefGoogle Scholar
  59. 59.
    Lindstedt G, Nystrom E, Matthews C, Ernest I, Janson PO, Chatterjee K. Follitropin (FSH) deficiency in an infertile male due to FSHbeta 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 1998;36:663–665.PubMedCrossRefGoogle Scholar
  60. 60.
    Tapanainen JS, Aittomaki K, Min J, Vaskivuo T, Huhtaniemi IT. Men homozygous for an inactivating mutation of the folliclestimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility. Nat Genet 1997;15:205–206.PubMedCrossRefGoogle Scholar
  61. 61.
    Arslan M, Weinbauer GF, Schlaft S, Shahab M, Nieschlag E. Follicle-stimulating hormone and testosterone alone or in combination activate spermatogonial proliferation and stimulate testicular growth in the immature nonhuman primate (Macaca mulatto). J Endocrinol 1993;136:235–243.PubMedCrossRefGoogle Scholar
  62. 62.
    Bagu ET, Madgwick S, Duggavathi R, et al. Effects of treatment with LH or FSH from 4 to 8 weeks of age on the attainment of puberty in bull calves. Theriogenology 2004; 62:861–873.PubMedCrossRefGoogle Scholar
  63. 63.
    Krishnamurthy H, Danilovich N, Morales CR, Sairam MR. Qualitative and quantitative decline in spermatogenesis of the follicle-stimulating hormone receptor knockout (FORKO) mouse. Biol Reprod 2000;62:1146–1159.PubMedCrossRefGoogle Scholar
  64. 64.
    Kumar TR, Wang Y, Lu N, Matzuk MM. Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility. Nat Genet 1997;15:201–204.PubMedCrossRefGoogle Scholar
  65. 65.
    Sairam MR, Krishnamurthy H. The role of follicle-stimulating hormone in spermatogenesis: lessons from knockout animal models. Arch Med Res 2001;32:601–608.PubMedCrossRefGoogle Scholar
  66. 66.
    Krishnamurthy H, Babu PS, Morales CR, Sairam MR. Delay in sexual maturity of the follicle-stimulating hormone receptor knockout male mouse. Biol Reprod 2001;65:522–531.PubMedCrossRefGoogle Scholar
  67. 67.
    Grover A, Sairam MR, Smith CE, Hermo L. Structural and functional modifications of sertoli cells in the testis of adult follicle-stimulating hormone receptor knockout mice. Biol Reprod 2004;71:117–129.PubMedCrossRefGoogle Scholar
  68. 68.
    Bartlett JM, Weinbauer GF, Nieschlag E. Differential effects of FSH and testosterone on the maintenance of spermatogenesis in the adult hypophysectomized rat. J Endocrinol 1989;121:49–58.PubMedCrossRefGoogle Scholar
  69. 69.
    Chandolia RK, Weinbauer GF, Fingscheidt U, Bartlett JM, Nieschlag E. Effects of flutamide on testicular involution induced by an antagonist of gonadotrophin-releasing hormone and on stimulation of spermatogenesis by follicle-stimulating hormone. J Reprod Fertil 1991;93:313–323.PubMedCrossRefGoogle Scholar
  70. 70.
    Spiteri-Grech J, Weinbauer GF, Bolze P, Chandolia RK, Bartlett JM, Nieschlag E. Effects of FSH and testosterone on intratesticular insulin-like growth factor-I and specific germ cell populations in rats treated with gonadotrophin-releasing hormone antagonist. J Endocrinol 1993;137:81–89.PubMedCrossRefGoogle Scholar
  71. 71.
    Luetjens CM, Weinbauer GF, Wistuba J. Primate spermatogenesis: comparative evidence and new insights into testicular organisation, spermatogenic efficiency and endocrine control. Biol Rev 2005;80:475–488.PubMedCrossRefGoogle Scholar
  72. 72.
    Wickings EJ, Vsadel KH, Dathe G, Nieschlag E. The role of follicle stimulating hormone in testicular function of the mature rhesus monkey. Acta Endocrinol 1990;95:117–128.Google Scholar
  73. 73.
    Weinbauer GF, Behre HM, Fingscheidt U, Nieschlag E. 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). Endocrinol 1991;129:1183–1831.CrossRefGoogle Scholar
  74. 74.
    Weinbauer GF, Fingscheidt U, Khurshid S, Nieschlag E. Endocrine regulation of primate testicular function. In: Perspectives in Primate Reproductive Biology. 1991; pp. 165–172.Google Scholar
  75. 75.
    Van Alphen MM, van de Kant HJ, de Rooij DG. Follicle-stimulating hormone stimulates spermatogenesis in the adult monkey. Endocrinol 1988;123:1449–1455.CrossRefGoogle Scholar
  76. 76.
    Krishnamurthy H, Kumar KM, Joshi CV, Krishnamurthy HN, Moudgal RN, Sairam MR. Alterations in sperm characteristics of follicle-stimulating hormone (FSH)-immunized men are similar to those of FSH-deprived infertile male bonnet monkeys. J Androl 2000;21:316–327.PubMedGoogle Scholar
  77. 77.
    Wistuba J, Schrod A, Greve B, Hodges JK, Aslam H, Weinbauer GF, Luetjens CM. Organization of seminiferous epithelium in primates: relationship to spermatogenic efficiency, phylogeny, and mating system. Biol Reprod 2003;69:582–591.PubMedCrossRefGoogle Scholar
  78. 78.
    Aittomaki K, Lucena JL, Pakarinen P, Sistonen P, et al. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 1995;82:959–968.PubMedCrossRefGoogle Scholar
  79. 79.
    Huhtaniemi IT. Polymorphism of gonadotropin action; molecular mechanisms and clinical implications. Acta Neurobiol Exp (Wars) 1996;56:743–751.Google Scholar
  80. 80.
    Baker PJ, Pakarinen P, Huhtaniemi IT, et al. Failure of normal Leydig cell development in follicle-stimulating hormone (FSH) receptor-deficient mice, but not FSHbeta-deficient mice: role for constitutive FSH receptor activity. Endocrinology 2003; 144:138–145.PubMedCrossRefGoogle Scholar
  81. 81.
    Depenbusch M, Nieschlag E. Stimulation of Spermatogenesis in Hypogonadothropic Men. In: Winters S. 1 edn Male Hypogonadism —Basic, Clinical, and Therapeutic Principles, ed. Humana Press Totowa, NJ, USA 2004:371–396.Google Scholar
  82. 82.
    Depenbusch M, von Eckardstein S, Simoni M, Nieschlag E. Maintenance of spermatogenesis in hypogonadotropic hypogonadal men with human chorionic gonadotropin alone. Eur J Endocrinol 2002;147:617–624.PubMedCrossRefGoogle Scholar
  83. 83.
    Coviello AD, Matsumoto AM, Bremner WJ, et al. Low Dose Human Chorionic Gonadotropin Maintains Intratesticular Testosterone in Normal Men with Testosterone Induced Gonadotropin Suppression. J Clin Endocrinol Metab 2005;90:2595–2602.PubMedCrossRefGoogle Scholar
  84. 84.
    Young J, Rey R, Schaison G, Chanson P. Hypogonadotropic hypogonadism as a model of post-natal testicular anti-Mullerian hormone secretion in humans. Mol Cell Endocrinol 2003;211:51–54.PubMedCrossRefGoogle Scholar
  85. 85.
    Matsumoto AM, Karpas AE, Bremner WJ. Chronic human chorionic gonadotropin administration in normal men: evidence that follicle-stimulating hormone is necessary for the maintenance of quantitatively normal spermatogenesis in man. J Clin Endocrinol Metab 1986;62:1184–1192.PubMedCrossRefGoogle Scholar
  86. 86.
    Bouloux PM, Nieschlag E, Burger HG, et al. Induction of spermatogenesis by recombinant follicle-stimulating hormone (puregon) in hypogonadotropic azoospermic men who failed to respond to human chorionic gonadotropin alone. J Androl 2003;24:604–611.PubMedGoogle Scholar
  87. 87.
    Büchter D, Behre HM, Kliesch S, Nieschlag E. Pulsatile GnRH or human chorionic gonadotropin/human menopausal gonadotropin as effective treatment for men with hypogonadotropic hypogonadism: a review of 42 cases. Eur J Endocrinol 1998;139:298–303.PubMedCrossRefGoogle Scholar
  88. 88.
    Gromoll J, Simoni M, Nieschlag E. An activating mutation of the follicle-stimulating hormone receptor autonomously sustains spermatogenesis in a hypophysectomized man. J Clin Endocrinol Metab 1996;81:1367–1370.PubMedCrossRefGoogle Scholar
  89. 89.
    Liu YX. Control of spermatogenesis in primate and prospect of male contraception. Arch Androl 2005;51:77–92.PubMedCrossRefGoogle Scholar
  90. 90.
    Simoni M, Weinbauer GF, Gromoll J, Nieschlag E. Role of FSH in male gonadal function. Ann Endocrinol (Paris) 1999;60:102–106.Google Scholar
  91. 91.
    McLachlan RI, Wreford NG, Robertson DM, De Kretser DM. Hormonal control of spermatogenesis. Trends Endocrinol Metab 1995;6:95–101.CrossRefPubMedGoogle Scholar
  92. 92.
    Sharpe RM. Testosterone and spermatogenesis. J Endocrinol 1987;113:1–2.PubMedCrossRefGoogle Scholar
  93. 93.
    Sriraman V, Sairam MR, Jagannadha Rao A. Evaluation of relative role of LH and FSH in restoration of spermatogenesis using ethanedimethylsulphonate-treated adult rats. Reprod Biomed Online 2004;8:167–174.PubMedGoogle Scholar
  94. 94.
    Kamischke A, Nieschlag E. Progress towards hormonal male contraception. Trends Pharmacol Sci 2004;25:49–57.PubMedCrossRefGoogle Scholar
  95. 95.
    Gromoll J, Wistuba J, Terwort N, Godmann M, Muller T, Simoni M. A new subclass of the luteinizing hormone/chorionic gonadotropin receptor lacking exon 10 messenger RNA in the New World monkey (Platyrrhini) lineage. Biol Reprod 2003;69:75–80.PubMedCrossRefGoogle Scholar
  96. 96.
    Muller T, Gromoll J, Simoni M. Absence of exon 10 of the human luteinizing hormone (LH) receptor impairs LH, but not human chorionic gonadotropin action. J Clin Endocrinol Metab 2003;88:2242–2249.PubMedCrossRefGoogle Scholar
  97. 97.
    Muller T, Gromoll J, Simula AP, Norman R, Sandhowe-Klaverkamp R, Simoni M. The carboxyterminal peptide of chorionic gonadotropin facilitates activation of the marmoset LH receptor. Exp Clin Endocrinol Diabetes 2004;l12:574–579.CrossRefGoogle Scholar
  98. 98.
    Muller T, Simoni M, Pekel E, et al. Chorionic gonadotrophin beta subunit mRNA but not luteinising hormone beta subunit mRNA is expressed in the pituitary of the common marmoset (Callithrix jacchus). J Mol Endocrinol 2004;32:115–128.PubMedCrossRefGoogle Scholar
  99. 99.
    Maston GA, Ruvolo M. Chorionic gonadotropin has a recent origin within primates and an evolutionary history of selection. Mol Biol Evol 2002;19:320–335.PubMedGoogle Scholar
  100. 100.
    Zhang FP, Rannikko AS, Manna PR, Fraser HM, Huhtaniemi IT. 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 1997;138:2481–2490.PubMedCrossRefGoogle Scholar
  101. 101.
    Cook JC, Klinefelter GR, Hardisty JF, Sharpe RM, Foster PM. Rodent Leydig cell tumorigenesis: a review of the physiology, pathology, mechanisms, and relevance to humans. Crit Rev Toxicol 1999;29:169–261.PubMedCrossRefGoogle Scholar
  102. 102.
    Kawamoto K. Endocrine control of the reproductive activity in hibernating bats. Zool Sci 2003;20:1057–1069.PubMedCrossRefGoogle Scholar
  103. 103.
    Niklowitz P, Khan S, Bergmann M, Hoffman K, Nieschlag E. Differential effects of follicle-stimulating hormone and luteinizing hormone on Leydig cell function and restoration of spermatogenesis in hypophysectomized and photoinhibited Djungarian hamsters (Phodopus sungorus). Biol Reprod 1989;41:871–880.PubMedCrossRefGoogle Scholar
  104. 104.
    Srinath BR, Wickings EJ, Witting C, Nieschlag E. Active immunization with follicle-stimulating hormone for fertility control: a 45 year study in male rhesus monkeys. Fertil Steril 1983;40:110–117.PubMedGoogle Scholar
  105. 105.
    Schaison G, Young J, Pholsena M, Nahoul K, Couzinet B. Failure of combined follicle-stimulating hormone-testosterone administration to initiate and/or maintain spermatogenesis in men with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 1993;77:1545–1549.PubMedCrossRefGoogle Scholar
  106. 106.
    Smals AG, Kloppenborg PW, van Haelst UJ, Lequin R, Benraad TJ. Fertile eunuch syndrome versus classic hypogonadotrophic hypogonadism. Acta Endocrinol (Copenh) 1978;87:389–399.Google Scholar
  107. 107.
    Levalle O, Zylbersztein C, Aszpis S, et al. Recombinant human follicle-stimulating hormone administration increases testosterone production in men, possibly by a Sertoli cellsecreted nonsteroid factor.J Clin Endocrinol Metab 1998;83:3973–3976.PubMedCrossRefGoogle Scholar
  108. 108.
    Nieschlag E, Kamischke A, Behre HM. Hormonal male contraception: the essential role of testosterone. In: Nieschlag and Behre eds. Testosterone—Action Deficiency Substitution. 3rd edn. Cambridge University Press, Cambridge, 2004: pp. 685–714.Google Scholar
  109. 109.
    Mooradian AD, Morley JE, Korenma SG. Biological actions of androgens. Endocr Rev 1987;8:l–27.Google Scholar
  110. 110.
    Nieschlag E, Behre HM. Pharmacology and clinical use of testosterone. In: Testosterone—Action Deficiency Substitution. 1990; pp. 92–114.Google Scholar
  111. 111.
    Quigley HA, De Bellis A, Marschke KB, El-Awady MK, Wilson EM, French FS. Androgen receptor defects: Historical clinical and molecular perspectives. Endocr Rev 1995;16: 271–321.PubMedCrossRefGoogle Scholar
  112. 112.
    Bashin S, Storer TW, Singh AB, et al. Testosterone effects on the skeletal muscle. In: Nieschlag and Behre eds. Testosterone—Action Deficiency Substitution. 3rd edn. Cambridge University Press, Cambridge, 2004; pp. 255–282.Google Scholar
  113. 113.
    Meschede D, Behre HM, Nieschlag E. Disorders of Androgen Target Organs: Andrology—Male Reproductive Health and Dysfunction. 2nd edn. 2000; pp. 371–396.Google Scholar
  114. 114.
    Weinbauer GF, Niehaus M, Nieschlag E, Nieschal E, Behre HM. The role of testosterone in spermatogenesis. In: Nieschlag and Behre eds. Testosterone—Action Deficiency Substitution. 3rd edn. Cambridge University Press, Cambridge, 2004; pp. 173–206.Google Scholar
  115. 115.
    Zitzmann M, Nieschlag E, Nieschal E, Behre HM. Androgens and bone metabolism. In: Nieschlag and Behre eds. Testosterone—Action Deficiency Substitution. 3rd edn. Cambridge University Press, Cambridge, 2004; pp. 233–254.Google Scholar
  116. 116.
    Zitzmann M, Nieschlag E. Androgens and erythropoiesis. In: Nieschlag and Behre eds. Testosterone—Action Deficiency Substitution. 3rd edn. Cambridge University Press, Cambridge, 2004; pp 283–296.Google Scholar
  117. 117.
    Zitzmann M, Nieschlag E. Effects of androgen replacement on metabolism and physical performances in male hypogonadism. J Endocrinol Invest 2003;26:886–892.PubMedGoogle Scholar
  118. 118.
    Hiort O, Zitzmann M. Androgen receptor: pathophysiology. In: Nieschlag and Behre eds. Testosterone—Action Deficiency Substitution. 3rd edn. Cambridge University Press, Cambridge, 2004; pp. 93–124.Google Scholar
  119. 119.
    Burris AS, Banks SM, Carter CS, Davidson JM, Sherins RJ. A long-term, prospective study of the physiologic and behavioral effects of hormone replacement in untreated hypogonadal men. J Androl 1992;13:297–304.PubMedGoogle Scholar
  120. 120.
    Studer LH, Reddon JR, Siminoski KG. Serum testosterone in adult sex offenders: a comparison between Caucasians and North American Indians. J Clin Psychol 1997;53: 375–385.PubMedCrossRefGoogle Scholar
  121. 121.
    Rejeski WJ, Brubaker PH, Herb RA, Kaplan JR, Koritnik D. Anabolic steroids and aggressive behavior in cynomolgus monkeys. J Behav Med 1988;11:95–105.PubMedCrossRefGoogle Scholar
  122. 122.
    McGinnis MY. Anabolic androgenic steroids and aggression: studies using animal models. Ann N Y Acad Sci 2004; 1036: 399–445.PubMedCrossRefGoogle Scholar
  123. 123.
    Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001;86:724–731.PubMedCrossRefGoogle Scholar
  124. 124.
    Moffat SD, Zonderman AB, Metter EJ, Blackman MR, Harman SM, Resnick SM. Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. J Clin Endocrinol Metab 2002;87:5001–5007.PubMedCrossRefGoogle Scholar
  125. 125.
    Hyde JS, Fennema E, Lamon SJ. Gender differences in mathematics performance: a meta-analysis. Psychol Bull 1990;107: 139–155.PubMedCrossRefGoogle Scholar
  126. 126.
    Zitzmann M, Weckesser M, Schober O, Nieschlag E. Changes in cerebral glucose metabolism and visuospatial capability in hypogonadal males under testosterone substitution therapy. Exp Clin Endocrinol Diabetes 2001; 109:302–304.PubMedCrossRefGoogle Scholar
  127. 127.
    Carreau S, Bourguiba S, Marie E. Testicular and blood steroid levels in aged men. Reprod Biol 2004;4:299–304.PubMedGoogle Scholar
  128. 128.
    Coviello AD, Bremner WJ, Matsumoto AM, et al. Intratesticular testosterone concentrations comparable with serum levels are not sufficient to maintain normal sperm production in men receiving a hormonal contraceptive regimen. J Androl 2004; 25:931–938.PubMedGoogle Scholar
  129. 129.
    McLachlan RI, O’Donnell L, Stanton PG, et al. Effects of testosterone plus medroxyprogesterone acetate on semen quality, reproductive hormones, and germ cell populations in normal young men. J Clin Endocrinol Metab 2002;87:546–556.PubMedCrossRefGoogle Scholar
  130. 130.
    Chen H, Chandrashekar V, Zirkin BR. Can spermatogenesis be maintained quantitatively in intact adult rats with exogenously administered dihydrotestosterone? J Androl 1994; 15:132–138.PubMedGoogle Scholar
  131. 131.
    Cunningham GR, Huckins C. Persistence of complete spermatogenesis in the presence of low intratesticular concentrations of testosterone. Endocrinol 1979;105:177–186.CrossRefGoogle Scholar
  132. 132.
    McLachlan RI, Wreford NG, Meachem SJ, De Kretser DM, Robertson DM. Effects of testosterone on spermatogenic cell populations in the adult rat. Biol Reprod 1994; 51:945–955.PubMedCrossRefGoogle Scholar
  133. 133.
    Weinbauer GF, Nieschlag E. The role of testosterone in spermatogenesis. In: Testosterone—Action Deficiency Substitution, 1990; pp. 23–50.Google Scholar
  134. 134.
    Zirkin BR, Santulli R, Awoniyi CA, Ewing BL. Maintenance of advanced spermatogenic cells in the adult rat testis: Quantitative relationship to testosterone concentration within the testis. Endocrinol 1989;124:3034–3049.CrossRefGoogle Scholar
  135. 135.
    Rommerts FFG. How much androgen is required for maintenance of spermatogenesis? Endocrinology 1988;116:1–6.CrossRefGoogle Scholar
  136. 136.
    Awoniyi CA, Zirkin BR, Chandrashekar V, Schlaff WD. Exogenously administered testosterone maintains spermatogenesis quantitatively in adult rats actively immunized against gonadotropin-releasing hormone. Endocrinol 1992;130: 3283–3288.CrossRefGoogle Scholar
  137. 137.
    Awoniyi CA, Santulli R, Sprando RL, Ewing LL, Zirkin BB. Restoration of advanced spermatogenic cells in the experimentally regressed rat testis: quantitative relationship to testosterone concentration within the testis. Endocrinol 1989;124:1217–1223.CrossRefGoogle Scholar
  138. 138.
    Roberts KP, Zirkin BR. Androgen binding protein inhibition of androgen-dependent transcription explains the high minimal testosterone concentration required to maintain spermatogenesis in the rat. Endocrine J 1993;1:41–47.Google Scholar
  139. 139.
    Santulli R, Awoniyi CA, Ewing LL, Zirkin BR. To what extent can spermatogenesis be maintained in hypophysectomized adult rat testis with exogenously administered testosterone? Endocrinol 1990; 126:95–102.CrossRefGoogle Scholar
  140. 140.
    Sharpe RM. Regulation of spermatogenesis. In: The Physiology of Reproduction. 1994; pp. 1363–1434.Google Scholar
  141. 141.
    Sun YT, Irby DC, Robertson DM, DeKretser DM. The effects of exogenously administered testosterone on spermatogenesis in intact and hypophysectomized rats. Endocrinol 1989; 125:1000–1010.CrossRefGoogle Scholar
  142. 142.
    Rea MA, Marshall GR, Weinbauer GF, Nieschlag E. Testosterone maintains pituitary and serum FSH and spermatogenesis in gonadotrophin-releasing hormone antagonist-suppressed rats. J Endocrinol 1986;108:101–107.PubMedCrossRefGoogle Scholar
  143. 143.
    Sharma OP, Khan SA, Weinbauer GF, Arslan M, Nieschlag E. Bioactivity and immunoreactivity of androgen stimulated pituitary FSH in GnRH antagonist-treated male rats. Acta Endocrinol 1990;122:168–174.PubMedGoogle Scholar
  144. 144.
    Kerr JB, Maddocks S, Sharpe RM. Testosterone and FSH have independent synergistic and stage-dependent effects upon spermatogenesis in the rat testis. Cell Tissue Res 1992;268:179–189.PubMedCrossRefGoogle Scholar
  145. 145.
    Mi Y, Zhang C, Xie M, Zeng W. Effects of follicle-stimulating hormone and androgen on proliferation of cultured testicular germ cells of embryonic chickens. Gen Comp Endocrinol 2004;138:237–246.PubMedCrossRefGoogle Scholar
  146. 146.
    Latronico AC. Naturally occurring mutations of the luteinizing hormone receptor gene affecting reproduction. Semin Reprod Med 2000; 18:17–20.PubMedCrossRefGoogle Scholar
  147. 147.
    Liu G, Duranteau L, Carel JC, Monroe J, Doyle DA, Shenker A. Leydig-cell tumors caused by an activating mutation of the gene encoding the luteinizing hormone receptor. N Engl J Med 1999;341:1731–1736.PubMedCrossRefGoogle Scholar
  148. 148.
    Hill CM, Anway MD, Zirkin BR, Brown TR. Intratesticular androgen levels, androgen receptor localization, and androgen receptor expression in adult rat Sertoli cells. Biol Reprod 2004;71:1348–1358.PubMedCrossRefGoogle Scholar
  149. 149.
    O’Donnell L, McLachlan RI, Wreford NG, de Kretser DM, Robertson DM. Testosterone withdrawal promotes stagespecific detachment of round spermatids from the rat seminiferous epithelium. Biol Reprod 1996;55:895–901.PubMedCrossRefGoogle Scholar
  150. 150.
    Payne AH, Kawano A, Jaffe RB. Formation of dihydrotestosterone and other 5-alpha-reduced metabolites by isolated seminiferous tubules and suspension of interstitial cells in a human testis. J Clin Endocrinol Metab 1973;37:448–453.PubMedCrossRefGoogle Scholar
  151. 151.
    Rivarola MA, Podesta EJ, Chemes HE, Aguilar D. In vitro metabolism of testosterone by whole human testis isolate seminiferous tubules and interstitial tissue. J Clin Endocrinol Metab 1973;37:454–463.PubMedCrossRefGoogle Scholar
  152. 152.
    Chang C, Chen YT, Yeh SD, et al. Infertility with defective spermatogenesis and hypotestosteronemia in male mice lacking the androgen receptor in Sertoli cells. Proc Natl Acad Sci USA 2004; 101:6876–6881.PubMedCrossRefGoogle Scholar
  153. 153.
    Weinbauer GF, Göckler E, Nieschlag E. Testosterone prevents complete suppression of spermatogenesis in the gonadotropin-releasing hormone (GnRH) antagonist-treated non-human primate (Macaca fascicularis). J Clin Endocrinol Metab 1988;67:284–290.PubMedCrossRefGoogle Scholar
  154. 154.
    De Gendt K, Swinnen JV, Saunders PT, et al. Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis. Proc Natl Acad Sci USA 2004;101:1327–1332.PubMedCrossRefGoogle Scholar
  155. 155.
    Allan CM, Haywood M, Swaraj S, et al. A novel transgenic model to characterize the specific effects of follicle-stimulating hormone on gonadal physiology in the absence of luteinizing hormone actions. Endocrinology 2001;142: 2213–2220.PubMedCrossRefGoogle Scholar
  156. 156.
    Haywood M, Spaliviero J, Jimemez M, King NJ, Handelsman DJ, Allan CM. Sertoli and germ cell development in hypogonadal (hpg) mice expressing transgenic follicle-stimulating hormone alone or in combination with testosterone. Endocrinology 2003;144:509–517.PubMedCrossRefGoogle Scholar
  157. 157.
    Spaliviero JA, Jimenez M, Allan CM, Handelsman DJ. Luteinizing hormone receptor-mediated effects on initiation of spermatogenesis in gonadotropin-deficient (hpg) mice are replicated by testosterone. Biol Reprod 2004;70:32–38.PubMedCrossRefGoogle Scholar
  158. 158.
    Huang HF, Pogach LM, Nathan E, Giglio W, Seebode JJ. Synergistic effects of follicle-stimulating hormone and testosterone on the maintenance of spermiogenesis in hypophysectomized rats: relationship with the androgen-binding protein status. Endocrinol 1991;128:3152–3161.CrossRefGoogle Scholar
  159. 159.
    Vigier M, Weiss M, Perrard MH, Godet M, Durand P. The effects of FSH and of testosterone on the completion of meiosis and the very early steps of spermiogenesis of the rat: an in vitro study. J Mol Endocrinol 2004;33:729–742.PubMedCrossRefGoogle Scholar
  160. 160.
    Wickings EJ, Neischlag E. The effect of active immunization with testosterone on pituitary-gonadal feedback in the male rhesus monkey (Macaca mulatta). Biol Reprod 1978;18: 602–607.PubMedGoogle Scholar
  161. 161.
    Heller CG, Nelson WO, Roth AA. Functional prepuberal castration in males. J Clin Endocrinol 1943;3:573–588.CrossRefGoogle Scholar
  162. 162.
    Hotchkiss RS. Effects of massive doses of testosterone propionate upon spermatogenesis. J Clin Endocrinol 1944;4:117–120.CrossRefGoogle Scholar
  163. 163.
    Morse HC, Horike N, Rowley MJ, Heller CG. Testosterone concentrations in testes of normal men: effects of testosterone propionate administration. J Clin Endocrinol Metab 1973; 37:882–886.PubMedCrossRefGoogle Scholar
  164. 164.
    Schürmeyer T, Nieschlag E. The Clinical pharmacology and toxicology of androgens. In: Progress in hormone biochemistry and pharmacology. Vol. 2. 1983; pp. 439–462.Google Scholar
  165. 165.
    Nieschlag E, Hoogen H, Bölk M, Schuster H, Wickings EJ. Clinical trial with testosterone undecanoate for male fertility control. Contraception 1978;18:607–614.PubMedCrossRefGoogle Scholar
  166. 166.
    Wistuba J, Luetjens CM, Kamischke A, et al. Pharmacokinetics and pharmacodynamics of injectable testosterone undecanoate in castrated cynomolgus monkeys (Macaca fascicularis) are independent of different oil vehicles. J Med Primatology 2005;34:178–187.CrossRefGoogle Scholar
  167. 167.
    Behre HM, Oberpenning F, Nieschlag E. Comparative pharmacokinetics of androgen preparations: Application of computer analysis and simulation. In: Testosterone—Action Deficiency Substitution. 1990; pp. 115–134.Google Scholar
  168. 168.
    Knuth UA, Yeung CH, Nieschlag E. Combination of 19-nortestosterone-hexyloxyphenylpropionate (Anadur) and depot-medroxyprogesterone-acetate (Clinovir) for male contraception. Fertil Steril 1989;51:1011–1018.PubMedGoogle Scholar
  169. 169.
    Knuth UA, Behre H, L Beikien, H Bents, Nieschlag E. Clinical trial of 19-nortestosterone of male fertility regulation. Fertil Steril 1985;44:814–821.PubMedGoogle Scholar
  170. 170.
    Wu FC, Farley TM, Peregoudov A, Waites GM. Effects of testosterone enanthate in normal men: experience from a multicenter contraceptive efficacy study. World Health Organization Task Force on Methods for the Regulation of Male Fertility. Fertil Steril 1996;65:626–636.PubMedGoogle Scholar
  171. 171.
    Zitzmann M, Nieschlag E. Hormone substitution in male hypogonadism. Mol Cell Endocrinol 2000;161:73–88.PubMedCrossRefGoogle Scholar
  172. 172.
    Rajalakshmi M, Ramakrishnan PR. Pharmakokinetics and pharamkodynamics of a new long-acting androgen ester: maintenance of physiological androgen levels for 4 months after a single injection. Contraception 1989;40:399–412.PubMedCrossRefGoogle Scholar
  173. 173.
    Weinbauer GF, Partsch CJ, Zitzmann M, Schlaft S, Nieschlag E. Pharmacokinetics and degree of aromatization rather than total dose of different preparations determine the effects of testosterone: a nonhuman primate study in Macaca fascicularis. J Androl 2003;24:765–774.PubMedGoogle Scholar
  174. 174.
    Weinbauer GF, Schlaft S, Walter V, Nieschlag E. 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 2001;168:25–38.PubMedCrossRefGoogle Scholar
  175. 175.
    Weinbauer GF, Marshall GR, Nieschlag E. New injectable testosterone ester maintains serum testosterone of castrated monkeys in the normal range for four months. Acta Endocrinol 1986;113:128–132.PubMedGoogle Scholar
  176. 176.
    Behre HM, Nieschlag E. Testosterone buciclate (20 Aet-1) in hypogonadal men: pharmacokinetics and pharmacodynamics of the new long-acting androgen ester. J Clin Endocrinol Metab 1992;75:1204–1210.PubMedCrossRefGoogle Scholar
  177. 177.
    Behre HM, Nieschlag E. Comparative pharmacokinetics of testosterone esters. In: Nieschlag and Behre eds. Testosterone— Action Deficiency Substitution. 2nd edn. Springer Verlag, Berlin, 1998; pp. 329–348.Google Scholar
  178. 178.
    Anderson RA, Wu FC. Comparison between testosterone enanthate-induced azoospermia and oligozoospermia in a male contraceptive study. II. Pharmacokinetics and pharmacodynamics of once weekly administration of testosterone enanthate. J Clin Endocrinol Metab 1996;81: 896–901.PubMedCrossRefGoogle Scholar
  179. 179.
    Behre HM, Baus S, Kliesch C, Keck C, Simoni M, Nieschlag E. Potential of testosterone buciclate for male contraception: Endocrine differences between responders and nonresponders. Endocrinol 1995;80:2394–2403.Google Scholar
  180. 180.
    Behre HM, Abshagen K, Oettel M, Hubler D, Nieschlag E. Intramuscular injection of testosterone undecanoate for the treatment of male hypogonadism: phase I studies. Eur J Endocrinol 1999;140:414–419.PubMedCrossRefGoogle Scholar
  181. 181.
    Gu YQ, Tong JS, Ma DZ, Wang XH, Yuan D, Tang WH, Bremner WJ. Male hormonal contraception: effects of injections of testosterone undecanoate and depot medroxyprogesterone acetate at eight-week intervals in Chinese men. J Clin Endocrinol Metab 2004;89:2254–2262.PubMedCrossRefGoogle Scholar
  182. 182.
    Gu YQ, Wang XH, Xu D, et al. A multicenter contraceptive efficacy study of injectable testosterone undecanoate in healthy Chinese men. J Clin Endocrinol Metab 2003;88: 562–568.PubMedCrossRefGoogle Scholar
  183. 183.
    Kamischke A, Ploger D, Venherm S, von Eckardstein S, von Eckardstein A, Nieschlag E. Intramuscular testosterone undecanoate with or without oral levonorgestrel: a randomized placebo-controlled feasibility study for male contraception. Clin Endocrinol (Oxf) 2000;53:43–52.CrossRefGoogle Scholar
  184. 184.
    Nieschlag E, Büchter D, Von Eckardstein S, Abshagen K, Simoni M, Behre HM. Repeated intramuscular injections of testosterone undecanoate for substitution therapy in hypogonadal men. Clin Endocrinol (Oxf) 1999;51:757–763.CrossRefGoogle Scholar
  185. 185.
    Partsch CJ, Weirbauer GF, Fang R, Nieschlag E. Injectable testosterone undecanoate has more favourable pharmacokinetics and pharmacodynamics than testosterone enanthate. Eur J Endocrinol 1995;132:514–519.PubMedCrossRefGoogle Scholar
  186. 186.
    Zhang GY, Gu YQ, Wang XH, Cui YG, Bremner WJ. A clinical trial of injectable testosterone undecanoate as a potential male contraceptive in normal Chinese men. J Clin Endocrinol Metab 1999;84:3642–3647.PubMedCrossRefGoogle Scholar
  187. 187.
    Gu YQ, Ge ZY, Zhang GY, Bremner WJ. Quantitative and qualitative changes in serum luteinizing hormone after injectable testosterone undecanoate treatment in hypogonadal men. Asian J Androl. 2000;2:65–71.PubMedGoogle Scholar
  188. 188.
    Ersheng G. Inhibiting effects of sino-implant plus testosterone undecanoate on spermatogenesis in Chinese men. Reprod Contraception 1999;10:98–105.Google Scholar
  189. 189.
    Kamischke A, Venherm S, Ploger D, von Eckardstein S, Nieschlag E. Intramuscular testosterone undecanoate and norethisterone enanthate in a clinical trial for male contraception. J Clin Endocrinol Metab 2001;86:303–309.PubMedCrossRefGoogle Scholar
  190. 190.
    Meriggiola MC, Costantino A, Saad F, et al. Norethisterone enanthate plus testosterone undecanoate for male contraception: effects of various injection intervals on spermatogenesis, reproductive hormones, testis, and prostate. J Clin Endocrinol Metab 2005;90:2005–2014.PubMedCrossRefGoogle Scholar
  191. 191.
    Zhang ZH, Zhou XC, Wei P, Hu ZY, Liu YX. Expression of Bcl-2 and Bax in rhesus monkey testis during germ cell apoptosis induced by testosterone undecanoate. Arch Androl 2003;49:439–447.PubMedCrossRefGoogle Scholar
  192. 192.
    Cummings DE, Kumar N, Bardin CW, Sundaram K, Bremner WJ. Pro state-sparing effects in primates of the potent androgen 7alpha-methyl-19-nortestosterone: a potential alternative to testosterone for androgen replacement and male contraception. J Clin Endocrinol Metab 1998;83: 4212–4219.PubMedCrossRefGoogle Scholar
  193. 193.
    Sundaram K, Kumar N, Bardin CW. 7 alpha-methyl-nortestosterone (MENT): the optimal androgen formale contraception. Ann Med 1993;25:199–205.PubMedCrossRefGoogle Scholar
  194. 194.
    Agarwal AK, Monder C. In vitro metabolism of 7 alpha-methyl-19-nortestosterone by rat liver, prostate, and epididymis. Endocrinology 1988;123:2187–2193.PubMedCrossRefGoogle Scholar
  195. 195.
    Ramachandra SG, Ramesh V, Krishnamurthy HN, et al. Effect of chronic administration of 7alpha-methyl-19-nortestosterone on serum testosterone, number of spermatozoa and fertility in adult male bonnet monkeys (Macaca radiata). Reproduction 2002;124:301–309.PubMedCrossRefGoogle Scholar
  196. 196.
    Goncharov NP, Katzia GV, Butnev VU, Richkor EG, Matikainen T, Waites GM. A non-human primate study (baboon; Papio hamadryas) to determine if a long-acting progestogen, levonorgestrel butanoate, combined with a long-acting androgen, testosterone buciclate, can suppress spermatogenesis: I. Dose-finding study. Int J Androl 1995;18:75–82.PubMedCrossRefGoogle Scholar
  197. 197.
    von Eckardstein S, Noe G, Brache V, et al. A clinical trial of 7 alpha-methyl-19-nortestosterone implants for possible use as a long-acting contraceptive for men. J Clin Endocrinol Metab 2003;88:5232–5239.CrossRefGoogle Scholar
  198. 198.
    Kamischke A, Diebäcker J, Nieschlag E. Potential of norethisterone enanthate for male contraception: pharmacokinetics and suppression of pituitary and gonadal function. Clin Endocrinol (Oxf) 2000;53:351–358.CrossRefGoogle Scholar
  199. 199.
    Nieschlag E, Zitzmann M, Kamischke A. Use of progestins in male contraception. Steroids 2003;68:965–972.PubMedCrossRefGoogle Scholar
  200. 200.
    Schearer SB, Alvarez-Sandez F, Anselmo G, Brenner P, et al. Hormonal contraception for men. Int J Androl 1978;(suppl 2):680–712.Google Scholar
  201. 201.
    Pangkahila W Reversible azoospermia induced by an androgenprogestin combination regimen in Indonesian men. Int J Androl 1991;14:248–256.PubMedCrossRefGoogle Scholar
  202. 202.
    Guerin JF, Rollet J. Inhibition of spermatogenesis in men using various combinations of oral progestagens and percutaneous or oral androgens. Int J Androl 1988;11:187–199.PubMedCrossRefGoogle Scholar
  203. 203.
    Anawalt BD, Herbst KL, Matsumoto AM, Mulders TM, Coelingh-Bennink HJ, Bremner WJ. Desogestrel plus testosterone effectively suppresses spermatogenesis but also causes modest weight gain and high-density lipoprotein suppression. Fertil Steril 2000;74:707–714.PubMedCrossRefGoogle Scholar
  204. 204.
    Anderson RA, Zhu H, Cheng L, Baird DT. Investigation of a novel preparation of testosterone decanoate in men: pharmacokinetics and spermatogenic suppression with etonogestrel implants. Contraception 2002;66:357–364.PubMedCrossRefGoogle Scholar
  205. 205.
    Kinniburgh D, Zhu H, Cheng L, Kicman AT, Baird DT, Anderson RA. Oral desogestrel with testosterone pellets induces consistent suppression of spermatogenesis to azoospermia in both Caucasian and Chinese men. Hum Reprod 2002;17:1490–1501.PubMedCrossRefGoogle Scholar
  206. 206.
    Melo JF, Coutinho EM. Inhibition of spermatogenesis in men with monthly injections of medroxyprogesterone acetate and testosterone enanthate. Contraception 1977;15:627–634.PubMedCrossRefGoogle Scholar
  207. 207.
    Meriggiola MC, Bremner WJ, Costantino A, Di Cintio G, Flamigni C. Low dose of cyproterone acetate and testosterone enanthate for contraception in men. Hum Reprod 1998; 13: 1225–1229.PubMedCrossRefGoogle Scholar
  208. 208.
    Meriggiola MC, Bremner WJ, Paulsen CA, et al. A combined regimen of cyproterone acetate and testosterone enanthate as a potentially highly effective male contraceptive. J Clin Endocrinol Metab 1996;81:3018–3023.PubMedCrossRefGoogle Scholar
  209. 209.
    Wu FC, Balasubramanian R, Mulders TM, Coelingh-Bennink HJ. Oral progestogen combined with testosterone as a potential male contraceptive: additive effects between desogestrel and testosterone enanthate in suppression of spermatogenesis, pituitary-testicular axis, and lipid metabolism. J Clin Endocrinol Metab 1999;84:112–122.PubMedCrossRefGoogle Scholar
  210. 210.
    Johnson L, Barnard JJ, Rodriguez L, et al. Ethnic differences in testicular structure and spermatogenic potential may predispose testes of Asian men to a heightened sensitivity to steroidal contraceptives. J Androl 1998;19:348–357.PubMedGoogle Scholar
  211. 211.
    Robaire B, Duron J, Hales BE Effect of estradiol-filled polydimethylsiloxane subdermal implants in adult male rats on the reproductive system fertility and progeny outcome. Biol Reprod 1987;37:327–334.PubMedCrossRefGoogle Scholar
  212. 212.
    Robaire B, Ewing LL, Irby DC, Desjardins C. Interactions of testosterone and estradiol-17beta on the reproductive tract of the male rat. Biol Reprod 1979;21:455–463.PubMedCrossRefGoogle Scholar
  213. 213.
    Sandow J, Engerlbart K, von Rechenberg W. The different mechanisms for suppression of pituitary and testicular function. Med Biol 1985;63:192–200.Google Scholar
  214. 214.
    Hodgson Y, DR, de Kretser DM. The regulation of the testicular function. In: International Review of Physiology. Vol. 27. 1983; pp. 275–327.PubMedGoogle Scholar
  215. 215.
    Kalla NR, Nisula BC, Menard R, Loriaux DL. The effect of estradiol on testicular testosterone biosynthesis. Endocrinol 1980;106:35–39.CrossRefGoogle Scholar
  216. 216.
    Heller CG, Paulsen CA, Moore DJ. Alteration in spermatogenesis of normal men with synthetic and natural progestins. Advance Abstracts of Short Communications, 1960; First International Congress of Endrocrinology, Copenhagen, 465–465.Google Scholar
  217. 217.
    Brache V, Alvarez-Sanchez F, Leon P, Schmidt F, Faundes A. The effect of levonorgestrel and estrone rods on male reproductive function. Contraception 1982;25:591–603.PubMedCrossRefGoogle Scholar
  218. 218.
    Briggs M, Briggs M. Oral contraceptive for men. Nature 1974;252:585–586.PubMedCrossRefGoogle Scholar
  219. 219.
    Lübbert H, Leo-Rosesberg I, Hammerstein J. Effects of ethinyl estradiol on semen quality and various hormonal parameters in a eugonadal male. Fertil Steril 1992;58:603–608.PubMedGoogle Scholar
  220. 220.
    Gopalkrishnan K, Gill-Sharma MK, Balasinor N, et al. Tamoxifen-induced light and electron microscopic changes in the rat testicular morphology and serum hormonal profile of reproductive hormones. Contraception 1998;57:261–269.PubMedCrossRefGoogle Scholar
  221. 221.
    Gill-Sharma MK, Dsouza S, Padwal V, et al. Antifertility effects of estradiol in adult male rats. J Endocrinol Invest 2001;24:598–607.PubMedGoogle Scholar
  222. 222.
    Gill-Sharma MK, Balasinor N, Parte P. Effect of intermittent treatment with tamoxifen on reproduction in male rats. Asian J Androl 2001;3:115–119.PubMedGoogle Scholar
  223. 223.
    Gill-Sharma MK, D’Souza S, Parte P, et al. Effect of oral tamoxifen on semen characteristics and serum hormone profile in male bonnet monkeys. Contraception 2003;67:409–413.PubMedCrossRefGoogle Scholar
  224. 224.
    Adamopoulos DA, Nicopoulou S, Kapolla N, Vassilopoulos P, Karamertzanis M, Kontogeorgos L. Endocrine effects of testosterone undecanoate as a supplementary treatment to menopausal gonadotropins or tamoxifen citrate in idiopathic oligozoospermia. Fertil Steril 1995;64:818–824.PubMedGoogle Scholar
  225. 225.
    Adamopoulos DA, Pappa A, Billa E, Nicopoulou S, Koukkou E, Michopoulos J. Effectiveness of combined tamoxifen citrate and testosterone undecanoate treatment in men with idiopathic oligozoospermia. Fertil Steril 2003;80:914–920.PubMedCrossRefGoogle Scholar
  226. 226.
    Sharpe RM, Skakkebaek NE. Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet 1993;341:1392–1395.PubMedCrossRefGoogle Scholar
  227. 227.
    Atanassova N, McKinnell C, Turner KJ, et al. Comparative effects of neonatal exposure of male rats to potent and weak (environmental) estrogens on spermatogenesis at puberty and the relationship to adult testis size and fertility: evidence for stimulatory effects of low estrogen levels. Endocrinology 2000;141:3898–3907.PubMedCrossRefGoogle Scholar
  228. 228.
    McKinnell C, Atanassova N, Williams K, et al. Suppression of androgen action and the induction of gross abnormalities of the reproductive tract in male rats treated neonatally with diethylstilbestrol. J Androl 2001;22:323–338.PubMedGoogle Scholar
  229. 229.
    O’Donnell L, Robertson KM, Jones ME, Simpson ER. Estrogen and spermatogenesis. Endocr Rev 2001;22:289–318.PubMedCrossRefGoogle Scholar
  230. 230.
    Zitzmann M, Nieschlag E. Hypogonadism in the elderly man. Reliable diagnosis and therapy. Internist (Berl) 2003; 44:1313–1321.CrossRefGoogle Scholar
  231. 231.
    Rolf C, von Eckardstein S, Koken U, Nieschlag E. Testosterone substitution of hypogonadal men prevents the age-dependent increases in body mass index, body fat and leptin seen in healthy ageing men: results of a cross-sectional study. Eur J Endocrinol 2002;146:505–511.PubMedCrossRefGoogle Scholar
  232. 232.
    Neumann FBS, Schenek B, Steinbeck H. Present state of male contraception and future possibilities. International Symposium on Hormonal Contraception. Excerpta Medica International Congress Series. Utrecht, Netherlands. 1978; 441:136–168.Google Scholar
  233. 233.
    Neumann F, Töpert M. Pharmacology of antiandrogens. J Steroid Biochem 1986;25:885–895.PubMedCrossRefGoogle Scholar
  234. 234.
    Ewing LLRC, Töpert M, Adams RJ, Darney KJ, Berry SJ, Bordy MJ, Desjardins C. Testis function in rhesus monkeys treated with a contraceptive steroid formulation. Contraception 1983;27:342–362.Google Scholar
  235. 235.
    Lobl TJ, Kirton KT, Forbes AD, Ewing LL, Kemp PL, Desjardins C, Cochran RC. Contraceptive efficacy of testosterone-estradiol implants in male rhesus monkeys. Contraception 1983;27: 383–389.PubMedCrossRefGoogle Scholar
  236. 236.
    Handelsman DJ, Wishart S, Conway AJ. Oestradiol enhances testosterone-induced suppression of human spermatogenesis. Hum Reprod 2000;15:672–679.PubMedCrossRefGoogle Scholar
  237. 237.
    Chandolia RK, Weinbauer GF, Behre HM, Nieschlag E. Evaluation of a peripherally selective antiandrogen (casodex) as a tool for studying the relationship between testosterone and spermatogenesis in the rat. J Steroid Biochem Mol Biol 1991;38:376–475.CrossRefGoogle Scholar
  238. 238.
    Chandolia RK, Weinbauer GF, Simoni M, Behre HM, Nieschlag E. Comparative effects of chronic administration of the non-steroidal antiandrogens flutamide and Casodex on the reproductive system of the adult male rat. Acta Endocrinol 1991;125:547–555.PubMedGoogle Scholar
  239. 239.
    Knuth UA, Hano R, Nieschlag E. Effect of flutamide or cyproterone acetate on pituitary and testicular hormones in normal men. J Clin Endocrinol 1984;59:963–969.CrossRefGoogle Scholar
  240. 240.
    Viguier-Martinez MC, Hochereau-de-Reviers MT, Barenton B, Perreau C. Endocrinological and histological changes induced by flutamide treatment on the hypothalamo-hypophyseal-testicular axis of the adult male rat and their incidences on fertility. Acta Endocrinol 1983;104:246–252.PubMedGoogle Scholar
  241. 241.
    Schenck B, Neumann F. Influence of antiandrogens on Sertoli cell function and intratesticular androgen transport. Int J Androl 1978;l:459–470.CrossRefGoogle Scholar
  242. 242.
    Bajaj JS, Madan R. New approaches to male fertility regulation: LHRH analogs steroidal contraception and inhibin. In: Endocrine Mechanisms in Fertility Regulation. 1983; pp. 203–231.Google Scholar
  243. 243.
    Furr BJ, Valcaccia B, Woodburn JR, Chesterson G, Tucker H. ICI 1976,334: a novel nonsteroidal peripherally selective antiandrogen. J Endocrinol 1987;113:R7–R9.PubMedCrossRefGoogle Scholar
  244. 244.
    Mowszowicz I, Bieber DE, Chung KW, Bullock LP, Bardin CW. Synandrogenic and antiandrogenic effect of progestins: comparison with non-progestational antiandrogens. Endocrinol 1974;95:1589–1599.CrossRefGoogle Scholar
  245. 245.
    Boccon-Gibod L, Laudat MH, Dugue MA, Steg A. Cyproterone acetate prevents initial rise of serum testosterone-induced by luteinizing hormone-releasing hormone analogs in the treatment of metastatic carcinoma of the prostate. Eur Urol 1986;12:400–402.PubMedGoogle Scholar
  246. 246.
    Fogh M, Corker CS, Hunter WM, et al. The effects of low doses of cyproterone acetate on some functions of the reproductive system in normal men. Acta Endocrinol 1979; 91:545.PubMedGoogle Scholar
  247. 247.
    Moltz L, Römmler A, Post K, Schwartz U, Hammerstein J. Medium dose cyproterone acetate (CPA): effects on hormone secretion and on spermatogenesis in men. Contraception 1980;21:393–413.PubMedCrossRefGoogle Scholar
  248. 248.
    Waites GM, Fairley TM. Contraceptive efficacy of hormonal suppression of spermatogenesis. Proceedings of the 2nd International Andrology Workshop Long Beach. 1995.Google Scholar
  249. 249.
    Meriggiola MC, Bremner WJ, Paulsen CA, Valdiserri A, Incorvaia L, Motta R, Pavani A, Capelli M, Flamigni C. A combined regimen of cyproterone acetate and testosterone enanthate as a potentially highly effective male contraceptive. J Clin Endocrinol Metab 1996;81:3018–3023.PubMedCrossRefGoogle Scholar
  250. 250.
    Meriggiola MC, Bremner WJ, Costantino A, Pavani A, Capelli M, Flamigni C. An oral regimen of cyproterone acetate and testosterone undecanoate for spermatogenic suppression in men. Fertil Steril 1997;68:844–850.PubMedCrossRefGoogle Scholar
  251. 251.
    Meriggiola MC, Costantino A, Bremner WJ, Morselli-Labate AM. Higher testosterone dose impairs sperm suppression induced by a combined androgen-progestin regimen. J Androl 2002;23:684–690.PubMedGoogle Scholar
  252. 252.
    WHO. Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for the regulation of male fertility. Lancet 1990;336:955–959.CrossRefGoogle Scholar
  253. 253.
    Aribarg A, Zhang GY, Cing C, Li Gz, et al. Rates of testosterone-induced suppression to severe oligozoospermia or azoospermia in two multinational clinical studies. World Health Organization Task force on Methods for The Regulations of Male Fertility. Int J Androl 1995;18:157–165.CrossRefGoogle Scholar
  254. 254.
    Aribarg A, Zhang GY, Cao J, Li GZ, et al. Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in normal men. Fertil Steril 1996;65:821–829.Google Scholar
  255. 255.
    van Houten ME, Gooren LJ. Differences in reproductive endocrinology between Asian men and Caucasian men—a literature review. Asian J Androl 2000;2:13–20.PubMedGoogle Scholar
  256. 256.
    Wang C, Chan SY, Leung A, et al. Cross-sectional study of semen parameters in a large group of normal Chinese men. Int J Androl 1985;8:257–274.PubMedCrossRefGoogle Scholar
  257. 257.
    Wang C, Berman NG, Veldhuis JD, et al. Graded testosterone infusions distinguish gonadotropin negative-feedback responsiveness in Asian and white men—a Clinical Research Center study. J Clin Endocrinol Metab 1998;83:870–876.PubMedCrossRefGoogle Scholar
  258. 258.
    Whitten PL, Naftolin F. Reproductive actions of phytoestrogens. Baillieres Clin Endocrinol Metab 1998;12:667–690.PubMedCrossRefGoogle Scholar
  259. 259.
    von Eckardstein S, Schmidt A, Kamischke A, Simoni M, Gromoll J, Nieschlag E. CAG repeat length in the androgen receptor gene and gonadotrophin suppression influence the effectiveness of hormonal male contraception. Clin Endocrinol (Oxf) 2002;57:647–655.CrossRefGoogle Scholar
  260. 260.
    Handelsman DJ, Farley TM, Peregoudov A, Waites GMH. Factors in nonuniform induction of azoospermia by testosterone enanthate in normalmen. Fertil Steril 1995;63: 125–133.PubMedGoogle Scholar
  261. 261.
    Burgus R, Butcher M, Amoss M, Ling N, et al. Primary structure of the ovine hypothalamic luteinizing hormone-releasing hormone factor (LRF). Proc Natl Acad Sci USA 1972; 69:278–285.PubMedCrossRefGoogle Scholar
  262. 262.
    Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR. Gonadotropin-releasing hormone receptors. Endocr Rev 2004;25:235–275.PubMedCrossRefGoogle Scholar
  263. 263.
    Neill JD, Duck LW, Sellers JC, Musgrove LC. A gonadotropin-releasing hormone (GnRH) receptor specific for GnRH II in primates. Biochem Biophys Res Commun 2001;282:1012–1018.PubMedCrossRefGoogle Scholar
  264. 264.
    Millar R, Lowe S, Conklin D, et al. A novel mammalian receptor for the evolutionarily conserved type II GnRH. Proc Natl Acad Sci USA 2001;98:9636–9641.PubMedCrossRefGoogle Scholar
  265. 265.
    Millar RP. GnRH II and type II GnRH receptors. Trends Endocrinol Metab 2003;14:35–43.PubMedCrossRefGoogle Scholar
  266. 266.
    Faurholm B, Millar RP, Katz AA. The genes encoding the type II gonadotropin-releasing hormone receptor and the ribonucleoprotein RBM8A in humans overlap in two genomic loci. Genomics 2001;78:15–18.PubMedCrossRefGoogle Scholar
  267. 267.
    Pavlou SN, Wakefield G, Schlechter NL, Lindner J, et al. Mode of suppression of pituitary and gonadal function after acute or prolonged administration of a luteinizing hormone-releasing hormone antagonist in normal men. J Clin Endocrinol Metab 1989;68:446–454.PubMedCrossRefGoogle Scholar
  268. 268.
    D’Occhio MJ, Fordyce G, Whyte TR, Aspden WJ, Trigg TE. Reproductive responses of cattle to GnRH agonists. Anim Reprod Sci 2000;60–-61:433–442.PubMedCrossRefGoogle Scholar
  269. 269.
    Jennes L, Stumpf WE, Conn PM. Receptor-mediated binding and uptake of GnRH agonist and antagonist by pituitary cells. Peptides 1984;5:215–220.PubMedCrossRefGoogle Scholar
  270. 270.
    Morel G, Dihl F, Aubert ML, Dubois PM. Binding and internalization of native gonadoliberin (GnRH) by anterior pituitary gonadotrophs of the rat. A quantitative autoradiographic study after cryo-ultramicrotomy. Cell Tiss Res 1987; 248:541–550.CrossRefGoogle Scholar
  271. 271.
    Heber D, Dodson R, Swerdloff RS, Channabasavaiah K, Stewart JM. Pituitary receptor site blockade by a gonadotropin-releasing hormone antagonist in vivo: mechanism of action. Science 1982;216:420–421.PubMedCrossRefGoogle Scholar
  272. 272.
    Horvath JE, Bajo AM, Schally AV, Kovacs M, Herbert F, Groot K. Effects of long-term treatment with the luteinizing hormone-releasing hormone (LHRH) agonist Decapeptyl and the LHRH antagonist Cetrorelix on the levels of pituitary LHRH receptors and their mRNA expression in rats. Proc Natl Acad Sci USA 2002;99:15,048–15,053.CrossRefGoogle Scholar
  273. 273.
    Jimenez-Severiano H, D’Occhio MJ, Lunstra DD, et al. Effect of chronic treatment with the gonadotrophin-releasing hormone agonist azagly-nafarelin on basal concentrations of LH in prepubertal bulls. Reproduction 2003;125:225–232.PubMedCrossRefGoogle Scholar
  274. 274.
    Junaidi A, Williamson PE, Cummins JM, Martin GB, Blackberry MA, Trigg TE. Use of a new drug delivery formulation of the gonadotrophin-releasing hormone analogue Deslorelin for reversible long-term contraception in male dogs. Reprod Fertil Dev 2003;15:317–322.PubMedCrossRefGoogle Scholar
  275. 275.
    Penfold LM, Ball R, Burden I, et al. Case studies in antelope aggression control using a GnRH agonist. Zoo Biol 2002;21:435–448.CrossRefGoogle Scholar
  276. 276.
    Rao AJ, Chakraborti R, Kotagi SG, Ravindranath N. Effect of constant infusion of gonadotropin releasing hormone (GnRH) agonist buserelin and antagonist CDB 2085 A using osmotic minipumps on testicular function in adult male bonnet monkey (Macaca radiata). Andrologia 1990; 22:567–573.PubMedCrossRefGoogle Scholar
  277. 277.
    Weinbauer GF, Respondek M, Themann H, Nieschlag E. Reversibility of long-term effects of GnRH agonist administration on testicular histology and sperm production in the non-human primate. J Androl 1987;8:319–329.PubMedGoogle Scholar
  278. 278.
    Weinbauer GF, Nieschlag E. Reversibility of GnRH agonist induced inhibition of testicular function: Differences between rats and primates. In: Therapeutical Progress in Urolgical Cancers. 1988; pp. 75–87.Google Scholar
  279. 279.
    Aslam H, Rosiepen G, Krishnamurthy H, et al. The cycle duration of the seminiferous epithelium remains unaltered during GnRH antagonist-induced testicular involution in rats and monkeys. J Endocrinol 1999;161:281–288.PubMedCrossRefGoogle Scholar
  280. 280.
    Kovacs M, Schally AV, Csernus B, Rekasi Z. Luteinizing hormone-releasing hormone (LH-RH) antagonist Cetrorelix down-regulates the mRNA expression of pituitary receptors for LH-RH by counteracting the stimulatory effect of endogenous LH-RH. Proc Natl Acad Sci USA 2001;98:1829–1834.PubMedCrossRefGoogle Scholar
  281. 281.
    Behre HM, Kliesch S, Pühse G, Reissmann T, Nieschlag E. High loading and low maintenance doses of a gonadotropin-releasing hormone antagonist effectively suppress serum luteinizing hormone, follicle-stimulating hormone, and testosterone in normal men. J Clin Endocrinol Metab 1997;82:1403–1408.PubMedCrossRefGoogle Scholar
  282. 282.
    Boekelheide K, Schoenfeld HA, Hall SJ, et al. Gonadotropin-releasing hormone antagonist (Cetrorelix) therapy fails to protect nonhuman primates (Macaca arctoides) from radiation-induced spermatogenic failure. J Androl 2005;26: 222–234.PubMedGoogle Scholar
  283. 283.
    Kamischke A, Kuhlmann M, Weinbauer GF, et al. Gonadal protection from radiation by GnRH antagonist or recombinant human FSH: a controlled trial in a male nonhuman primate (Macaca fascicularis). J Endocrinol 2003;179:183–194.PubMedCrossRefGoogle Scholar
  284. 284.
    Marshall GR, Bint Akthar F, Weinbauer GF, Nieschlag E. Gonadotrophin-releasing hormone (GnRH) overcomes GnRH antagonist-induced suppression of LH secretion in primates. J Endocrinol 1986;110:145–150.PubMedCrossRefGoogle Scholar
  285. 285.
    Weinbauer GF, Hankel P, Nieschlag E. Exogenous gonadotrophin-releasing hormone (GnRH) stimulates LH secretion in male monkeys (Macaca fascicularis) treated chronically with high doses of a GnRH antagonist. J Endocrinol 1992;133:439–445.PubMedCrossRefGoogle Scholar
  286. 286.
    Zhengwei Y, Wreford NG, Schlatt S, Weinbauer GF, Nieschlag E, McLachlan RI. Acute and specific impairment of spermatogonial development by GnRH antagonist-induced gonadotrophin withdrawal in the adult macaque (Macaca fascicularis). J Reprod Fertil 1998;112:139–147.PubMedCrossRefGoogle Scholar
  287. 287.
    Herbst KL. Gonadotropin-releasing hormone antagonists. Curr Opin Pharmacol 2003;3:660–666.PubMedCrossRefGoogle Scholar
  288. 288.
    Kiesel LA, Rody A, Greb RR, Szilagyi A. Clinical use of GnRH analogues. Clin Endocrinol (Oxf) 2002;56:677–687.CrossRefGoogle Scholar
  289. 289.
    Behre HM, Nashan D, Hubert D, Nieschlag E. Depot gonadotropin-releasing homone agonist blunts the androgen-induced suppression of spermatogenesis in a clinical trial of male contraception. J Clin Endocrinol Metab 1992;74:84–90.PubMedCrossRefGoogle Scholar
  290. 290.
    Bergquist C, Nillius SG, Bergh T, Skering G, Wide GG. Inhibitory effects on gonadotropin secretion and gonadal function in men during chronic treatment with a potent stimulatory luteinizing hormone-releasing hormone analogue. Acta Endocrinol 1979;91:610–618.Google Scholar
  291. 291.
    Bhasin S, Heber D, Steiner BS, Handelsman DJ, Swerdloff RS. Hormonal effects of gonadotropin-releasing hormone (GnRH) agonist in the human male III Effects of long-term combined treatment with GnRH agonist and androgen. J Clin Endocrinol Metab 1985;60:998–1003.PubMedCrossRefGoogle Scholar
  292. 292.
    Bhasin S, Yuan QX, Steiner BS, Swerdloff RS. Hormonal effects of gonadotropin-releasing hormone (GnRH) agonist in men: effects of long term treatment with GnRH agonist infusion and androgen. J Clin Endocrinol Metab 1987;65:568–574.PubMedCrossRefGoogle Scholar
  293. 293.
    Bouchard P, Garcia E. Influence of testosterone substitution on sperm suppression by LHRH agonists. Horm Res 1987;28:175–180.PubMedCrossRefGoogle Scholar
  294. 294.
    Doelle GC, Alexander AN, Evans RM, et al. Combined treatment with an LHRH agonist and testosterone in man. J Androl 1983;4:298–302.PubMedGoogle Scholar
  295. 295.
    Frick J, WA. Effects of a potent LH-RH agonist on the pituitary gonadal axis with and without testosterone substitution. Urol Res 1986;14:261–264.PubMedCrossRefGoogle Scholar
  296. 296.
    Linde R, Doelle GC, Alexander N, et al. Reversible inhibition of testicular steroidogenesis and spermatogenesis by a potent gonadotropin-releasing hormone agonist in normal men. N Engl J Med 1981;305:663–667.PubMedCrossRefGoogle Scholar
  297. 297.
    Michel E, Bents H, Akhtar FB, et al. Failure of high-dose sustained-release luteinizing hormone agonist (buserelin) plus oral testosterone to suppress male fertility. Clin Endocrinol 1985;23:663–675.CrossRefGoogle Scholar
  298. 298.
    Pavlou SN, Interlandi JW, Wakefield G, Rivier J, Vale W, Rabin D. Heterogeneity of sperm density profiles following 16-week therapy with continuous infusion of high-dose LHRH analog plus testosterone. J Androl 1986;7: 228–233.PubMedGoogle Scholar
  299. 299.
    Rabin D, Evans RM, Alexander AN, Doelle GC, Rivier JE, Vale WV, Liddle G. Heterogeneity of sperm density profiles following 20-week therapy with high-dose LHRH analog plus testosterone. J Androl 1984;5:176–180.PubMedGoogle Scholar
  300. 300.
    Schürmeyer Knuth UA, Freischem CW, Sandow J, Akhtar FB, Nieschlag E. Suppression of pituitary and testicular function in normal men by constant gonadotropin-releasing hormone agonist infusion. J Clin Endocrinol Metab 1984;59:1–6.CrossRefGoogle Scholar
  301. 301.
    Akhtar FB, Marshall GR, Nieschlag E. Testosterone supplementation attenuates the antifertility effects of an LH-RH agonist in male monkeys. Int J Androl 1983;6:461–468.PubMedCrossRefGoogle Scholar
  302. 302.
    Akhtar FB, Marshall GR, Wickings EJ, Nieschlag E. Reversible induction of azoospermia in rhesus monkeys by constant infusion of a GnRH agonist using osmotic minipumps. J Clin Endocrinol Metab 1983;56:534–540.PubMedCrossRefGoogle Scholar
  303. 303.
    Bhasin S, Berman N, Swerdloff RS. Follicle-stimulating hormone (FSH) escape during chronic gonadotropin-releasing hormone (GnRH) agonist and testosterone treatment. J Androl 1994;15:386–391.PubMedGoogle Scholar
  304. 304.
    Santen RJ, Demers LM, Max DT, Smith J, Stein BS, Glode LM. Long term effects of administration of a gonadotropin-releasing hormone superagonist analog in men with prostatic carcinoma. J Clin Endocrinol Metab 1984;58:397–400.PubMedCrossRefGoogle Scholar
  305. 305.
    Huhtaniemi IT, Dahl KD, Rannikko S, Hsueh AJ. Serum bioactive and immunoreactive follicle-stimulating hormone in prostatic cancer patients during gonadotropin-releasing hormone agonist treatment and after orchidectomy. J Clin Endocrinol Metab 1988;66:308–313.PubMedCrossRefGoogle Scholar
  306. 306.
    Pavlou SN, Dahl KD, Wakefield G, et al. Maintenance of the ratio of bioactive to immunoreactive follicle-stimulating hormone in normal men during chronic luteinizing-hormone hormone agonist administration. J Clin Endocrinol Metab 1988;66:1005–1009.PubMedCrossRefGoogle Scholar
  307. 307.
    Daneshdoost L, Pavlou SN, Molitch ME, Gennarelli TA, et al. Inhibiton of follicle-stimulating hormone secretion from gonadotroph adenomas by repetitive administration of a gonadotropin-releasing hormone antagonist. J Clin Endocrinol Metab 1990;71:92–97.PubMedCrossRefGoogle Scholar
  308. 308.
    Klibanski A, Jameson JL, Killer BM, Crowley WF, et al. Gonadotropin and alpha-subunit responses to chronic gonadotropin-releasing hormone analog administration in patients with glycoprotein hormone-secreting tumors. J Clin Endocrinol Metab 1989;68:81–86.PubMedCrossRefGoogle Scholar
  309. 309.
    Roman SH, Goldstein M, Kourides IA, Comite F, Bardin CW, Krieger DT. The luteinizing hormone-releasing hormone (LHRH) agonist D-trp6-Pro9-NEt LHRH increased rather than lowered LH and alpha-subunit levels in a patient with an LH-secreting tumor. J Clin Endocrinol Metab 1984;58:313–319.PubMedCrossRefGoogle Scholar
  310. 310.
    Behre HM, Kliesch S, Lemcke B, von Eckardstein S, Nieschlag E. Suppression of spermatogenesis to azoospermia by combined administration of GnRH antagonist and 19-nortestosterone cannot be maintained by this non-aromatizable androgen alone. Hum Reprod 2001;16:2570–2577.PubMedCrossRefGoogle Scholar
  311. 311.
    Behre HM, Böckers A, Schlingheider A, Nieschlag E. Sustained suppression of serum LH FSH and testosterone and increase of high-density lipoprotein cholesterol by daily injections of the GnRH antagonist cetrorelix over 8 days in normal men. Clin Endocrinol 1994;40:241–248.CrossRefGoogle Scholar
  312. 312.
    Behre HM, Klein B, Steinmeyer E, McGregor GP, Voigt K, Nieschlag E. Effective suppression of luteinizing hormone and testosterone by single doses of the new gonadotropin-releasing hormone antagonist cetrorelix (SB-75) in normal men. J Clin Endocrinol Metab 1992;75:393–398.PubMedCrossRefGoogle Scholar
  313. 313.
    Salameh W, Bhasin S, Steiner BS, McAdams LA, et al. Comparative effects of two different delivery systems on gonadotropin-releasing hormone (GnRH) antagonist-induced suppression of gonadotropins and testosterone in man. J Androl 1994;15:22–28.PubMedGoogle Scholar
  314. 314.
    Dahl KD, Bicsak TA, Hsueh AJW. Naturally occurring antihormones: secretion of FSH antagonists by women treated with a GnRH analog. Science 1988;239:72–74.PubMedCrossRefGoogle Scholar
  315. 315.
    Kessel B, Dahl KD, Kazer RR, Liu CH, et al. The dependency of bioactive follicle-stimulating hormone secretion on gonadotropin-releasing hormone in hypogonadal and cycling women. J Clin Endocrinol Metab 1988;66:361–366.PubMedCrossRefGoogle Scholar
  316. 316.
    Pavlou SN, Brewer K, Farley MG, Lindner J, et al. Combined administration of a gonadotropin-releasing hormone antagonist and testosterone in men induces reversible azoospermia without loss of libido. J Clin Endocrinol Metab 1991;73: 1360–1369.PubMedCrossRefGoogle Scholar
  317. 317.
    Pavlou SN, Debold CR, Island DP, et al. Single subcutaneous doses of a luteinizing hormone-releasing hormone antagonist suppress serum gonadotropin and testosterone levels in normal men. J Clin Endocrinol Metab 1986;63:303–308.PubMedCrossRefGoogle Scholar
  318. 318.
    Pavlou SN, Debold CR, Orth DN. LHRH antagonists: clinical studies in man. In: Recent Progress on GnRH and Gonadal Peptides. 1990; pp. 195–208.Google Scholar
  319. 319.
    Tenover JS, Dahl KD, Vale WV, Rivier JE. Hormonal responses to a potent gonadotropin-releasing hormone antagonist in normal elderly men. J Clin Endocrinol Metab 1990;71:881–888.PubMedCrossRefGoogle Scholar
  320. 320.
    Dahl KD, Pavlou SN, Kovacs WJ, Hsueh AJW. The changing ratio of serum bioactive to immunoreactive follicle-stimulating hormone in normal men following treatment with gonadotropin releasing hormone antagonist. J Clin Endocrinol Metab 1986;63:792–794.PubMedCrossRefGoogle Scholar
  321. 321.
    Arslan M, Weinbauer GF, Khan SA, Nieschlag E. Testosterone and dihydrotestosterone but not estradiol selectively maintain pituitary and serum follicle-stimulating hormone in gonadotropin-releasing hormone antagonist treated male rats. Neuroendocrinol 1989;49:395–401.CrossRefGoogle Scholar
  322. 322.
    Bhasin S, Fielder T, Peacock N, SodMoriah UA, Swerdloff RS. Dissociating antifertility effects of GnRH antagonists fromits adverse effects on mating behaviour in male rats. Am J Physiol 1988;32:E84–E91.Google Scholar
  323. 323.
    Sinha-Hikim AP, Swerdloff RS. Temporal and stage-specific changes in spermatogenesis of rat after gonadotropin deprivation by a potent gonadotropin-releasing hormone antagonist treatment. Endocrinol 1993;133:2161–2170.CrossRefGoogle Scholar
  324. 324.
    Sinha Hikim AP, Swerdloff RS. Time course of recovery of spermatogenesis and Leydig cell function after cessation of gonadotropin-releasing hormone antagonist treatment in the adult rat. Endocrinol 1994;134:1627–1634.CrossRefGoogle Scholar
  325. 325.
    Weinbauer GF, Schubert J, Yeung CH, Rosiepen G, Nieschlag E. 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 1998;156:23–34.PubMedCrossRefGoogle Scholar
  326. 326.
    Brinkworth MH, Weinbauer GF, Schlatt S, Nieschlag E. Identification of male germ cell undergoing apoptosis in adult rats. J Reprod Fertil 1995;105:25–33.PubMedCrossRefGoogle Scholar
  327. 327.
    Sinha Hikim AP, Wang C, Leung A, Swerdloff RS. Involvement of apoptosis in the induction of germ cell degeneration in adult rats after gonadotropin-releasing hormone antagonist treatment. Endocrinology 1995;136:2770–2775.CrossRefGoogle Scholar
  328. 328.
    Tapanainen JS, Tilly JL, Vihko KK, Hsueh AJ. Hormonal control of apoptotic cell death in the testis: gonadotropins and androgens as testicular cell survival factors. Mol Endocrinol 1993;7:643–650.PubMedCrossRefGoogle Scholar
  329. 329.
    Khurshid S, Weinbauer GF, Nieschlag E. Effects of testosterone and gonadotropin-releasing hormone (GnRH) antagonist on basal and GnRH-stimulated gonadotrophin secretion in orchidectomized monkeys. J Endocrinol 1991;129:363–370.PubMedCrossRefGoogle Scholar
  330. 330.
    Bagatell CJ, Mclachlan RI, De Kretser DM, Burger HG, Vale WW, Rivier JE, Bremner WJ. A comparison of the suppressive effects of testosterone and a potent new gonadotropin-releasing hormone antagonist on gonadotropin and inhibin levels in normal men. J Clin Endocrinol Metab 1989;69:43–48.PubMedCrossRefGoogle Scholar
  331. 331.
    Bhasin S, Fielder T, Swerdloff RS. Testosterone selectively increases serum follicle-stimulating hormone (FSH) but not luteinizing hormone (LH) in gonadotropin-releasing hormone antagonist-treated male rats: evidence for differential regulation of LH and FSH secretion. Biol Reprod 1988;37:55–59.CrossRefGoogle Scholar
  332. 332.
    Rea MA, Weinbauer GF, Marshall GR, Nieschlag E. Testosterone stimulates pituitary and serum FSH in GnRH antagonist-suppressed rats. Acta Endocrinol 1987;113: 487–492.Google Scholar
  333. 333.
    Dalkin AC, Paul SJ, Haisenleder DJ, Ortolano GA, Yasin M, Marshall JC. Gonadal steroids effect similar regulation of gonadotrophin subunit mRNA expression in both male and female rats. J Endocrinol 1992; 132:39–45.PubMedCrossRefGoogle Scholar
  334. 334.
    Perheentupa A, Huhtaniemi I. Gonadotropin gene expression and secretion in gonadotropin-releasing hormone antagonist-treated male rats: effect of sex steroid replacement. Endocrinol 1990;126:3204–3209.CrossRefGoogle Scholar
  335. 335.
    Wierman ME, Wang C. Androgen selectively stimultes follicle-stimulating hormone—a mRNA levels after gonadotropin-releasing hormone antagonist administration. Biol Reprod 1990;42:563–571.PubMedCrossRefGoogle Scholar
  336. 336.
    Weinbauer GF, Surmann FJ, Akhtar FB, Shah GV, Vickery BH, Nieschlag E. Reversible inhibition of testicular function by a gonadotropin-releasing hormone antagonist in monkeys (Macaca fascicularis). Fertil Steril 1984;42:906–914.PubMedGoogle Scholar
  337. 337.
    Akhtar FB, Weinbauer GF, Nieschlag E. Acute and chronic effects of a gonadotrophin-releasing hormone antagonist on pituitary function in monkeys. J Endocrinol 1985;104:345–354.CrossRefGoogle Scholar
  338. 338.
    Bremner WJ, Bagatell CJ, Steiner RA. Gonadotropin-releasing hormone antagonist plus testosterone: a potential male contraceptive. J Clin Endocrinol Metab 1991;73:465–469.PubMedCrossRefGoogle Scholar
  339. 339.
    Weinbauer GF, Limberger A, Behre HM, Nieschlag E. Can testosterone alone maintain the GnRH antagonist-induced suppression of spermatogenesis in the non-human primate? J Endocrinol 1994;142:485–495.PubMedCrossRefGoogle Scholar
  340. 340.
    Weinbauer GF, Surmann FJ, Nieschlag E. Suppression of spermatogenesis in a nonhuman primate (Macaca fascicularis) by concomitant gonadotropin-releasing hormone antagonist and testosterone treatment. Acta Endocrinol 1987; 114:138–146.PubMedGoogle Scholar
  341. 341.
    Karten MJ, Rivier JE. Gonadotrophin-releasing hormone analog design: Structure-function towards the development of agonists and antagonists: Rationale and perspective. Endocr Rev 1986;7:44–66.PubMedCrossRefGoogle Scholar
  342. 342.
    Weinbauer GF, Nieschlag E. Preclinical studies with GnRH antagonists. In: Horizons in Endocrinology. 1990; pp. 287–296.Google Scholar
  343. 343.
    Karten MJ, Hoeger CA, Hook WA, Lindberg MC, Naqvi RH. The development of safer GnRH antagonists: strategy and status. In: Recent Progess on GnRH and Gonadal Peptides. 1990; pp. 147–158.Google Scholar
  344. 344.
    Weinbauer GF, Nieschlag E. Comparison of the antigonadotropic activity of three GnRH antagonists (Nal-Glu antide and Cetrorelix) in a non-human primate model (Macacafascicularis). Andrologia 1993;25:141–147.PubMedCrossRefGoogle Scholar
  345. 345.
    Trachtenberg J, Gittleman M, Steidle C, et al. A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. J Urol 2002;167:1670–1674.PubMedCrossRefGoogle Scholar
  346. 346.
    Herbst KL, Anawalt BD, Amory JK, Bremner WJ. Acyline: the first study in humans of a potent, new gonadotropin-releasing hormone antagonist. J Clin Endocrinol Metab 2002;87: 3215–3220.PubMedCrossRefGoogle Scholar
  347. 347.
    Matthiesson KL, Amory JK, Berger R, Ugoni A, McLachlan RI, Bremner WJ. Novel male hormonal contraceptive combinations: the hormonal and spermatogenic effects of testosterone and levonorgestrel combined with a 5alpha-reductase inhibitor or gonadotropin-releasing hormone antagonist. J Clin Endocrinol Metab 2005;90:91–97.PubMedCrossRefGoogle Scholar
  348. 348.
    Behre HM, Kliesch S, Pühse G, Nieschlag E. Initial high doses of a GnRH antagonist followed by low maintenance doses suppress serum LH FSH and testosterone effectively in normal men. Exp Clin Endocrinol 1994; 102(suppl 1):27.Google Scholar
  349. 349.
    Behre HM, Kliesch S, Lemcke B, Nieschlag E. Suppression of spermatogenesis to azoospermia by combined administration of GnRH antagonist and 19-nortestosterone cannot be maintained by 19-nortestosterone alone in normal men. Proceedings of the 77th Annual Meeting of the Endocrine Society Progam & Abstract Book OR 29-6. 1995.Google Scholar
  350. 350.
    Swerdloff RS, Bagatell CJ, Wang C, et al. Suppression of spermatogenesis in man induced by Nal-Glu gonadotropin releasing hormone antagonist and testosterone enanthate (TE) is maintained by TE alone. J Clin Endocrinol Metab 1998;83:3527–3533.PubMedCrossRefGoogle Scholar
  351. 351.
    Behre HM, Kliesch S, Bock W, Hermann R, Reissmann T, Engel J, Nieschlag E. Suppression of serum testosterone in normal men by Cetrorelix pamoate a GnRH antagonist depot preparation. Exp Clin Endocrinol 1995;103(suppl 1): 141.Google Scholar
  352. 352.
    Turner L, Conway AJ, Jimenez M, et al. Contraceptive efficacy of a depot progestin and androgen combination in men. J Clin Endocrinol Metab 2003;88:4659–4667.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2007

Authors and Affiliations

  • Craig Marc Luetjens
    • 1
  • Joachim Wistuba
    • 1
  • Gerhard Weinbauer
    • 2
  • Eberhard Nieschlag
    • 1
  1. 1.Institute of Reproductive MedicineUniversity of MünsterMünsterGermany
  2. 2.Covance Laboratories GmbHMünsterGermany

Personalised recommendations