Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-78c5997874-s2hrs Total loading time: 0 Render date: 2024-11-05T16:47:18.150Z Has data issue: false hasContentIssue false

Chapter 5 - Male Reproductive Endocrinology

from Section 2 - The Biology of Male Reproduction and Infertility

Published online by Cambridge University Press:  06 December 2023

By
Christos Tsametis ,
George Kanakis  and
Dimitrios G. Goulis
Edited by
Douglas T. Carrell ,
Alexander W. Pastuszak  and
James M. Hotaling
Douglas T. Carrell
Affiliation:
Utah Center for Reproductive Medicine
Alexander W. Pastuszak
Affiliation:
University of Utah
James M. Hotaling
Affiliation:
Utah Center for Reproductive Medicine
Get access

Summary

The main functions of the male reproductive system are the synthesis and secretion of male sex steroids (androgens), production of male gametes (spermatozoa), and transport of sperm into the female genital tract. The development, maturation, and normal function of male fertility are mainly under the control of the hypothalamic-pituitary-testicular axis, which constitutes the hormonal component of an interplaying and intercommunicating neuronal and endocrine system, that will be explained in this chapter.

Keywords

male reproductionmale reproductive endocrinologyandrogensspermatozoahypothalamic-pituitary-testicular axistesticular function
Type
Chapter
Information
Men's Reproductive and Sexual Health Throughout the Lifespan
An Integrated Approach to Fertility, Sexual Function, and Vitality
 , pp. 34 - 53
Publisher: Cambridge University Press
Print publication year: 2023

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Fink, G. 60 years of neuroendocrinology: memoir: Harris’ neuroendocrine revolution: of portal vessels and self-priming. J Endocrinol. 2015;226:T13–T24.Google Scholar
Schally, AV, Arimura, A, Kastin, AJ, et al. Gonadotropin-releasing hormone: one polypeptide regulates secretion of luteinizing and follicle-stimulating hormones. Science. 1971;173:1036–1038.CrossRefGoogle ScholarPubMed
Plant, TM. 60 years of neuroendocrinology: the hypothalamo-pituitary-gonadal axis. J Endocrinol. 2015;226:T41–T54.CrossRefGoogle ScholarPubMed
Schally, AV. Use of GnRH in preference to LH-RH terminology in scientific papers. Hum Reprod. 2000;15:2059–2061.CrossRefGoogle ScholarPubMed
Millar, RP. GnRHs and GnRH receptors. Anim Reprod Sci. 2005;88:5–28.Google Scholar
Okubo, K, Nagahama, Y. Structural and functional evolution of gonadotropin-releasing hormone in vertebrates. Acta Physiol (Oxf). 2008;193:3–15.Google Scholar
Kaprara, A, Huhtaniemi, IT. The hypothalamus-pituitary-gonad axis: tales of mice and men. Metabolism. 2018;86:3–17.Google Scholar
White, RB, Eisen, JA, Kasten, TL, Fernald, RD. Second form of gonadotropin-releasing hormone in humans. Proc Natl Acad Sci USA. 1998;95:305–309.Google Scholar
Densmore, VS, Urbanski, HF. Relative effect of gonadotropin releasing hormone (GnRH)-I and GnRH-II on gonadotropin release. J Clin Endocrinol Metab. 2003;88:2126–2134.Google Scholar
Lee, VH, Lee, LT, Chow, BK. Gonadotropin-releasing hormone: regulation of the GnRH gene. FEBS J. 2008;275:5458–5478.Google Scholar
Weinbauer, GF, Luetjens, CM, Simoni, M, Nieschlag, E. Physiology of testicular function. In: Nieschlag, E, Behre, HM, Nieschlag, S, eds. Andrology: Male Reproductive Health and Disfunction. 3rd ed. Springer-Verlag; 2010:11–59.Google Scholar
Herbison, AE. Physiology of the adult gonadotropin-releasing hormone neuronal network. In: Plant, TM, Zeleznik, AJ, eds. Knobil and Neill’s Physiology of Reproduction. 5th ed. Elsevier Inc.; 2015:399–467.Google Scholar
Clifton, DKS. Neuroendocrinology of reproduction. In: Strauss, JF, Barberi, RL, eds. Yen & Jaffe’s Reproductive Endocrinology. Elsevier; 2009: Ch. 1.Google Scholar
Schwanzel-Fukuda, M, Pfaff, DW. Origin of luteinizing hormone-releasing hormone neurons. Nature. 1989;338:161–164.Google Scholar
Wierman, ME, Kiseljak-Vassiliades, K, Tobet, S. Gonadotropin-releasing hormone (GnRH) neuron migration: initiation, maintenance and cessation as critical steps to ensure normal reproductive function. Front Neuroendocrinol. 2011;32:43–52.Google Scholar
Maeda, K, Ohkura, S, Uenoyama, Y, et al. Neurobiological mechanisms underlying GnRH pulse generation by the hypothalamus. Brain Res. 2010;1364:103–115.CrossRefGoogle ScholarPubMed
Moenter, SM, DeFazio, AR, Pitts, GR, Nunemaker, CS. Mechanisms underlying episodic gonadotropin-releasing hormone secretion. Front Neuroendocrinol. 2003;24:79–93.Google Scholar
Carmel, PW, Araki, S, Ferin, M. Pituitary stalk portal blood collection in rhesus monkeys: evidence for pulsatile release of gonadotropin-releasing hormone (GnRH). Endocrinology. 1976;99:243–248.Google Scholar
Antunes, JL, Carmel, PW, Housepian, EM, Ferin, M. Luteinizing hormone-releasing hormone in human pituitary blood. J Neurosurg. 1978;49:382–386.Google Scholar
Belchetz, PE, Plant, TM, Nakai, Y, Keogh, EJ, Knobil, E. Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Science. 1978;202:631–633.CrossRefGoogle ScholarPubMed
Blumenfeld, Z. Investigational and experimental GnRH analogs and associated neurotransmitters. Expert Opin Investig Drugs. 2017;26:661–667.Google Scholar
Moenter, SM, DeFazio, AR, Pitts, GR, Nunemaker, CS. Mechanisms underlying episodic gonadotropin-releasing hormone secretion. Front Neuroendocrinol. 2003;24:79–93.CrossRefGoogle ScholarPubMed
Martinez de la Escalera, G, Choi, AL, Weiner, RI. Generation and synchronization of gonadotropin-releasing hormone (GnRH) pulses: intrinsic properties of the GT1–1 GnRH neuronal cell line. Proc Natl Acad Sci USA. 1992;89:1852–1855.Google Scholar
Wilson, RC, Kesner, JS, Kaufman, JM, Uemura, T, Akema, T, Knobil, E. Central electrophysiologic correlates of pulsatile luteinizing hormone secretion in the rhesus monkey. Neuroendocrinology. 1984;39:256–260.CrossRefGoogle ScholarPubMed
Ezzat, A, Pereira, A, Clarke, IJ. Kisspeptin is a component of the pulse generator for GnRH secretion in female sheep but not the pulse generator. Endocrinology. 2015;156:1828–1837.Google Scholar
Waldhauser, F, Weissenbacher, G, Frisch, H, Pollak, A. Pulsatile secretion of gonadotropins in early infancy. Eur J Pediatr. 1981;137:71–74.CrossRefGoogle ScholarPubMed
Conte, FA, Grumbach, MM, Kaplan, SL, Reiter, EO. Correlation of luteinizing hormone-releasing factor-induced luteinizing hormone and follicle-stimulating hormone release from infancy to 19 years with the changing pattern of gonadotropin secretion in agonadal patients: relation to the restraint of puberty. J Clin Endocrinol Metab. 1980;50:163–168.Google Scholar
Pohl, CR, deRidder, CM, Plant, TM. Gonadal and nongonadal mechanisms contribute to the prepubertal hiatus in gonadotropin secretion in the female rhesus monkey (Macaca mulatta). J Clin Endocrinol Metab. 1995;80:2094–2101.Google Scholar
Boyar, R, Finkelstein, J, Roffwarg, H, Kapen, S, Weitzman, E, Hellman, L. Synchronization of augmented luteinizing hormone secretion with sleep during puberty. N Engl J Med. 1972;287:582–586.Google Scholar
Lee, JH, Miele, ME, Hicks, DJ, et al. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst. 1996;88:1731–1737.Google Scholar
West, A, Vojta, PJ, Welch, DR, Weissman, BE. Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor gene (KISS1). Genomics. 1998;54:145–148.Google Scholar
Pasquier, J, Kamech, N, Lafont, AG, Vaudry, H, Rousseau, K, Dufour, S. Molecular evolution of GPCRs: kisspeptin/kisspeptin receptors. J Mol Endocrinol. 2014;52:T101–T117.Google Scholar
Ohtaki, T, Shintani, Y, Honda, S, et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001;411:613–617.CrossRefGoogle ScholarPubMed
Liu, X, Lee, K, Herbison, AE. Kisspeptin excites gonadotropin-releasing hormone neurons through a phospholipase C/calcium-dependent pathway regulating multiple ion channels. Endocrinology. 2008;149:4605–4614.Google Scholar
Hrabovszky, E, Ciofi, P, Vida, B, et al. The kisspeptin system of the human hypothalamus: sexual dimorphism and relationship with gonadotropin-releasing hormone and neurokinin B neurons. Eur J Neurosci. 2010;31:1984–1998.Google Scholar
Uenoyama, Y, Inoue, N, Pheng, V, et al. Ultrastructural evidence of kisspeptin-gonadotrophin-releasing hormone (GnRH) interaction in the median eminence of female rats: implication of axo-axonal regulation of GnRH release. J Neuroendocrinol. 2011;23:863–870.Google Scholar
Messager, S, Chatzidaki, EE, Ma, D, et al. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci USA. 2005;102:1761–1766.Google Scholar
Lehman, MN, Coolen, LM, Goodman, RL. Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology. 2010;151:3479–3489.Google Scholar
Skorupskaite, K, George, JT, Anderson, RA. The kisspeptin-GnRH pathway in human reproductive health and disease. Hum Reprod Update. 2014;20:485–500.Google Scholar
Topaloglu, AK, Semple, RK. Neurokinin B signalling in the human reproductive axis. Mol Cell Endocrinol. 2011;346:57–64.Google Scholar
Marques, P, Skorupskaite, K, George, JT, et al. Physiology of GNRH and gonadotropin secretion. [Updated 2018 Jun 19]. In: Feingold, KR, Anawalt, B, Boyce, A, et al., eds. Endotext [Internet]. MDText.com, Inc.; 2000–. Available from: www.ncbi.nlm.nih.gov/books/NBK279070/.Google Scholar
Pinilla, L, Aguilar, E, Dieguez, C, Millar, RP, Tena-Sempere, M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev. 2012;92:1235–1316.CrossRefGoogle ScholarPubMed
Ikegami, K, Minabe, S, Ieda, N, et al. Evidence of involvement of neurone-glia/neurone-neurone communications via gap junctions in synchronised activity of KNDy neurones. J Neuroendocrinol. 2017:29.Google Scholar
Dhillo, W, Chaudhuri, O, Patterson, M, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary-gonadal axis in human males. J Clin Endocrinol Metab. 2005;90:6609–6615.Google Scholar
Gutierrez-Pascual, E, Martinez-Fuentes, AJ, Pinilla, L, Tena-Sempere, M, Malagon, MM, Castano, JP. Direct pituitary effects of kisspeptin: activation of gonadotrophs and somatotrophs and stimulation of luteinising hormone and growth hormone secretion. J Neuroendocrinol. 2007;19:521–530.Google Scholar
Navarro, VM, Bosch, MA, Leon, S, et al. The integrated hypothalamic tachykinin-kisspeptin system as a central coordinator for reproduction. Endocrinology. 2015;156:627–637.Google Scholar
Han, SK, Gottsch, ML, Lee, KJ, et al. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci. 2005;25:11349–11356.Google Scholar
de Roux, N, Genin, E, Carel, JC, Matsuda, F, Chaussain, JL, Milgrom, E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA. 2003;100:10972–10976.Google Scholar
Topaloglu, AK, Reimann, F, Guclu, M, et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet. 2009;41:354–358.Google Scholar
Teles, MG, Bianco, SD, Brito, VN, et al. GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med. 2008;358:709–715.Google Scholar
Silveira, LG, Noel, SD, Silveira-Neto, AP, et al. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab. 2010;95:2276–2280.Google Scholar
Clarke, SA, Dhillo, WS. Kisspeptin across the human lifespan: evidence from animal studies and beyond. J Endocrinol. 2016;229:R83–R98.Google Scholar
Comninos, AN, Dhillo, WS. Emerging roles of kisspeptin in sexual and emotional brain processing. Neuroendocrinology. 2018;106:195–202.CrossRefGoogle ScholarPubMed
Dudek, M, Ziarniak, K, Sliwowska, JH. Kisspeptin and metabolism: the brain and beyond. Front Endocrinol (Lausanne). 2018;9:145.Google Scholar
Navarro, VM, Gottsch, ML, Wu, M, et al. Regulation of NKB pathways and their roles in the control of Kiss1 neurons in the arcuate nucleus of the male mouse. Endocrinology. 2011;152:4265–4275.CrossRefGoogle ScholarPubMed
Shibata, M, Friedman, RL, Ramaswamy, S, Plant, TM. Evidence that down regulation of hypothalamic KiSS-1 expression is involved in the negative feedback action of testosterone to regulate luteinising hormone secretion in the adult male rhesus monkey (Macaca mulatta). J Neuroendocrinol. 2007;19:432–438.Google Scholar
Smith, JT, Dungan, HM, Stoll, EA, et al. Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology. 2005;146:2976–2984.Google Scholar
Rochira, V, Zirilli, L, Genazzani, AD, et al. Hypothalamic-pituitary-gonadal axis in two men with aromatase deficiency: evidence that circulating estrogens are required at the hypothalamic level for the integrity of gonadotropin negative feedback. Eur J Endocrinol. 2006;155:513–522.Google Scholar
Raven, G, de Jong, FH, Kaufman, JM, de Ronde, W. In men, peripheral estradiol levels directly reflect the action of estrogens at the hypothalamo-pituitary level to inhibit gonadotropin secretion. J Clin Endocr. 2006;91:3324–3328.CrossRefGoogle ScholarPubMed
Goodman, RL, Coolen, LM, Anderson, GM, et al. Evidence that dynorphin plays a major role in mediating progesterone negative feedback on gonadotropin-releasing hormone neurons in sheep. Endocrinology. 2004;145:2959–2967.Google Scholar
Boutari, C, Pappas, PD, Mintziori, G, et al. The effect of underweight on female and male reproduction. Metabolism. 2020;107:154229.Google Scholar
Mintziori, G, Nigdelis, MP, Mathew, H, Mousiolis, A, Goulis, DG, Mantzoros, CS. The effect of excess body fat on female and male reproduction. Metabolism. 2020;107:154193.CrossRefGoogle ScholarPubMed
Jahan, S, Bibi, R, Ahmed, S, Kafeel, S. Leptin levels in infertile males. J Coll Physicians Surg Pak. 2014;21:393–397.Google Scholar
Quennell, JH, Mulligan, AC, Tups, A, et al. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology. 2009;150:2805–2812.Google Scholar
Smith, JT, Acohido, BV, Clifton, DK, Steiner, RA. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J Neuroendocrinol. 2006;4:298–303.Google Scholar
Yeo, SH, Colledge, WH. The role of Kiss1 neurons as integrators of endocrine, metabolic, and environmental factors in the hypothalamic-pituitary-gonadal axis. Front Endocrinol (Lausanne). 2018;9:188.CrossRefGoogle ScholarPubMed
Farooqi, IS, O’Rahilly, S. Leptin: a pivotal regulator of human energy homeostasis. Am J Clin Nutr. 2009;89:980S–984S.CrossRefGoogle ScholarPubMed
DiVall, SA, Radovick, S, Wolfe, A. Egr-1 binds the GnRH promoter to mediate the increase in gene expression by insulin. Mol Cell Endocrinol. 2007;270:64–72.Google Scholar
Zhen, S, Zakaria, M, Wolfe, A, Radovick, S. Regulation of gonadotropin-releasing hormone (GnRH) gene expression by insulin-like growth factor I in a cultured GnRHexpressing neuronal cell line. Mol Endocrinol. 1997;11:1145–1155.Google Scholar
Farkas, I, Vastagh, C, Sárvári, M, Liposits, Z. Ghrelin decreases firing activity of gonadotropin-releasing hormone (GnRH) neurons in an estrous cycle and endocannabinoid signaling dependent manner. PLoS ONE. 2013;8:e78178.Google Scholar
Oakley, AE, Breen, KM, Clarke, IJ, Karsch, FJ, Wagenmaker, ER, Tilbrook, AJ. Cortisol reduces gonadotropin-releasing hormone pulse frequency in follicular phase ewes: influence of ovarian steroids. Endocrinology. 2009;150:341–349.Google Scholar
Kinsey-Jones, JS, Li, XF, Knox, AM, et al. Down-regulation of hypothalamic kisspeptin and its receptor, Kiss1r, mRNA expression is associated with stress-induced suppression of luteinising hormone secretion in the female rat. J Neuroendocrinol. 2009;21:20–29.Google Scholar
Ducret, E, Anderson, GM, Herbison, AE. RFamide-related peptide-3, a mammalian gonadotropin-inhibitory hormone ortholog, regulates gonadotropin-releasing hormone neuron firing in the mouse. Endocrinology. 2009;150:2799–2804.Google Scholar
Liu, X, Herbison, AE. Kisspeptin regulation of neuronal activity throughout the central nervous system. Endocrinol Metabol. 2016;31:193–205.Google Scholar
Cheng, CK, Leung, PC. Molecular biology of gonadotropin releasing hormone (GnRH)-I, GnRH-II, and their receptors in humans. Endocr Rev. 2005;26:283–306.Google Scholar
Kakar, SS. Molecular structure of the human gonadotropin releasing hormone receptor gene. Eur J Endocrinol. 1997;137:183–192.Google Scholar
Grosse, R, Schmid, A, Schoneberg, T, et al. Gonadotropin-releasing hormone receptor initiates multiple signaling pathways by exclusively coupling to Gq/11 proteins. J Biol Chem. 2000;275:9193–9200.CrossRefGoogle Scholar
Stojilkovic, SS, Reinhart, J, Catt, KJ. Gonadotropin-releasing hormone receptors: structure and signal transduction pathways. Endocr Rev. 1994;15:462–499.Google Scholar
Perrett, RM, McArdle, CA. Molecular mechanisms of gonadotropin-releasing hormone signaling: integrating cyclic nucleotides into the network. Front Endocrinol (Lausanne). 2013;4:180.Google Scholar
Padmanabhan, V, McFadden, K, Mauger, DT, Karsch, FJ, Midgley, AR Jr. Neuroendocrine control of follicle-stimulating hormone (FSH) secretion. I. Direct evidence for separate episodic and basal components of FSH secretion. Endocrinology. 1997;138:424–432.Google Scholar
Kaiser, UB, Jakubowiak, A, Steinberger, A, Chin, WW. Differential effects of gonadotropin-releasing hormone (GnRH) pulse frequency on gonadotropin subunit and GnRH receptor messenger ribonucleic acid levels in vitro. Endocrinology. 1997;138:1224–1231.Google Scholar
Tsutsumi, M, Laws, SC, Rodic, V, Sealfon, SC. Translational regulation of the gonadotropin-releasing hormone receptor in T3–1 cells. Endocrinology. 1995;136:1128–1136.Google Scholar
McArdle, CA, Franklin, J, Green, L, Hislop, JN. Signaling, cycling and desensitization of gonadotropin-releasing hormone receptors. J Endocrinol. 2002;173:1–11.Google Scholar
Harris, D, Chuderland, D, Bonfil, D, Kraus, S, Seger, R, Naor, Z. Extracellular signal-regulated kinase and c-Src, but not Jun N-terminal kinase, are involved in basal and gonadotropin releasing hormone-stimulated activity of the glycoprotein hormone-subunit promoter. Endocrinology. 2003;144:612–622.Google Scholar
Lanciotti, L, Cofini, M, Leonardi, A, Penta, L, Esposito, S. Up-to-date review about minipuberty and overview on hypothalamic-pituitary-gonadal axis activation in fetal and neonatal life. Front Endocrinol. 2018;9:410.Google Scholar
O’Donnell, L, Stanton, P, de Kretser, DM. Endocrinology of the male reproductive system and spermatogenesis. [Updated 2017 Jan 11]. In: Feingold, KR, Anawalt, B, Boyce, A, et al., eds. Endotext [Internet]. MDText.com, Inc.; 2000–. Available from: www.ncbi.nlm.nih.gov/books/NBK279031/.Google Scholar
Pitteloud, N, Dwyer, AA, DeCruz, S, et al. Inhibition of luteinizing hormone secretion by testosterone in men requires aromatization for its pituitary but not its hypothalamic effects: evidence from the tandem study of normal and gonadotropin-releasing hormone-deficient men. J Clin Endocrinol Metab. 2008;93:784–791.Google Scholar
Sheckter, CB, Matsumoto, AM, Bremner, WJ. Testosterone administration inhibits gonadotropin secretion by an effect directly on the human pituitary. J Clin Endocrinol Metab. 1989;68:397–401.Google Scholar
Hayes, FJ, DeCruz, S, Seminara, SB, Boepple, PA, Crowley, WF Jr. Differential regulation of gonadotropin secretion by testosterone in the human male: absence of a negative feedback effect of testosterone on follicle-stimulating hormone secretion. J Clin Endocrinol Metab. 2001;86:53–58.Google Scholar
Rochira, V, Madeo, B, Diazzi, C, Zirilli, L, Daniele, S, Carani, C. Estrogens and male reproduction. [Updated 2016 Nov 24]. In: Feingold, KR et al., eds. Endotext [Internet]. MDText.com, Inc.; 2000–. Available from www.ncbi.nlm.nih.gov/books/NBK278933/.Google Scholar
de Kretser, DM, Robertson, DM. The isolation and physiology of inhibin and related proteins. Biol Reprod. 1989;40:33–47.Google Scholar
Iliadou, PK, Tsametis, C, Kaprara, A, Papadimas, I, Goulis, DG. The Sertoli cell: novel clinical potentiality. Hormones (Athens). 2015;14:504–514.Google Scholar
Namwanje, M, Brown, CW. Activins and inhibins: roles in development, physiology, and disease. Cold Spring Harb Perspect Biol. 2016;8:a021881.Google Scholar
Burger, LL, Dalkin, AC, Aylor, KW, Haisenleder, DJ, Marshall, JC. GnRH pulse frequency modulation of gonadotropin subunit gene transcription in normal gonadotropes-assessment by primary transcript assay provides evidence for roles of GnRH and follistatin. Endocrinology. 2002;143:3243–3249.Google Scholar
Kaiser, UB, Lee, BL, Carroll, RS, Unabia, G, Chin, WW, Childs, GV. Follistatin gene expression in the pituitary: localization in gonadotropes and folliculostellate cells in diestrous rats. Endocrinology. 1992;130:3048–3056.Google Scholar
Tsutsui, K, Saigoh, E, Ukena, K, et al. A novel avian hypothalamic peptide inhibiting gonadotropin release. Biochem Biophys Res Commun. 2000;275:661–667.Google Scholar
Tsutsui, K, Ukena, K. Hypothalamic LPXRF-amide peptides in vertebrates: identification, localization and hypophysiotropic activity. Peptides. 2006;27:1121–1129.Google Scholar
Ubuka, T, Morgan, K, Pawson, AJ, et al. Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis. PLoS ONE. 2009;4:e8400.Google Scholar
Hu, KL, Chang, HM, Li, R, Yu, Y, Qiao, J. Regulation of LH secretion by RFRP-3: from the hypothalamus to the pituitary. Front Neuroendocrinol. 2019;52:12–21.Google Scholar
Hinuma, S, Shintani, Y, Fukusumi, S, et al. New neuropeptides containing carboxy-terminal RFamide and their receptor in mammals. Nat Cell Biol. 2000;2:703–708.Google Scholar
Tsutsui, K, Ubuka, T, Son, YL, Bentley, GE, Kriegsfeld, LJ. Contribution of GnIH research to the progress of reproductive neuroendocrinology. Front Endocrinol (Lausanne). 2015; 6:179.Google Scholar
George, JT, Hendrikse, M, Veldhuis, JD, Clarke, IJ, Anderson, RA, Millar, RP Effect of gonadotropin-inhibitory hormone on luteinizing hormone secretion in humans. Clin. Endocrinol. 2017;86:731–738.Google Scholar
Anderson, RC, Newton, CL, Anderson, RA, Millar, RP. Gonadotropins and their analogs: current and potential clinical applications. Endocr Rev. 2018;39:911–937.Google Scholar
Jiang, X, Liu, H, Chen, X, et al. Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor. Proc Natl Acad Sci USA. 2012;109:12491–12496.Google Scholar
Hsueh, AJ, He, J. Gonadotropins and their receptors: coevolution, genetic variants, receptor imaging, and functional antagonists. Biol Reprod. 2018;99:3–12.Google Scholar
Teerds, KJ, Huhtaniemi, IT. Morphological and functional maturation of Leydig cells: from rodent models to primates. Hum Reprod Update. 2015;21:310–328.Google Scholar
Zirkin, BR, Papadopoulos, V. Leydig cells: formation, function, and regulation. Biol Reprod. 2018;99:101–111.Google Scholar
Wang, Y, Chen, F, Ye, L, Zirkin, B, Chen, H. Steroidogenesis in Leydig cells: effects of aging and environmental factors. Reproduction. 2017;154:R111–R122.CrossRefGoogle ScholarPubMed
Casarini, L, Santi, D, Brigante, G, Simoni, M. Two hormones for one receptor: evolution, biochemistry, actions, and pathophysiology of LH and hCG. Endocr Rev. 2018;39:549–592.Google Scholar
Santi, D, Crépieux, P, Reiter, E, et al. Follicle-stimulating hormone (FSH) action on spermatogenesis: a focus on physiological and therapeutic roles. J Clin Med. 2020;9:1014.Google Scholar
Ruwanpura, SM, McLachlan, RI, Meachem, SJ. Hormonal regulation of male germ cell development. J Endocrinol. 2010;205:117–131.Google Scholar
Xu, HY, Zhang, HX, Xiao, Z, Qiao, J, Li, R. Regulation of anti-Müllerian hormone (AMH) in males and the associations of serum AMH with the disorders of male fertility. Asian J Androl. 2019;21:109–114.Google Scholar
Meachem, SJ, Nieschlag, E, Simoni, M. Inhibin B in male reproduction: pathophysiology and clinical relevance. Eur J Endocrinol. 2001;145:561–571.Google Scholar
Huhtaniemi, I. A short evolutionary history of FSH-stimulated spermatogenesis. Hormones (Athens). 2015;14:468–478.Google Scholar
Griffin, J, Wilson, JD, Snyder, PJ, Matsumoto, AM, Martin, KA. Male reproductive physiology. In: Post, TW, ed. UpToDate. UpToDate; 2013.Google Scholar
Nieschlag, E, Behre, HM, Nieschlag, S. Andrology: Male Reproductive Health and Dysfunction. 3rd ed. Springer-Verlag; 2010.Google Scholar
Matsumoto, A, Bremner, W. Male hypogonadism. In: Melmed, S, Polonsky, K, Larsen, P, Kroneneberg, H, eds. Williams Textbook of Endocrinology. 12th ed. Saunders; 2011:709–755.Google Scholar
Kanakis, GA, Goulis, DG. Classification and epidemiology of hypogonadism. In: Simoni, M, Huhtaniemi, I, eds. Endocrinology of the Testis and Male Reproduction. Springer; 2017:1–23.Google Scholar
Miller, WL, Auchus, RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011;32:81–151.Google Scholar
Miller, WL. StAR search: what we know about how the steroidogenic acute regulatory protein mediates mitochondrial cholesterol import. Mol Endocrinol. 2007;21:589–601.Google Scholar
Tuckey, RC, Cameron, KJ. Catalytic properties of cytochrome P-450scc purified from the human placenta: comparison to bovine cytochrome P-450scc. Biochim Biophys Acta. 1993;1163:185–194.Google Scholar
Kim, CJ, Lin, L, Huang, N, et al. Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc. J Clin Endocrinol Metabol. 2008;93:696–702.Google Scholar
Chung, BC, Picado-Leonard, J, Haniu, M, et al. Cytochrome P450c17 (steroid 17 alpha-hydroxylase/17,20 lyase): cloning of human adrenal and testis cDNAs indicates the same gene is expressed in both tissues. Proc Nat Acad Sci USA. 1987;84:407–411.Google Scholar
Lachance, Y, Luu-The, V, Labrie, C, et al. Characterization of human 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase gene and its expression in mammalian cells. J Biol Chem. 1990;265:20469–20475.Google Scholar
Flück, CE, Miller, WL, Auchus, RJ. The 17, 20-lyase activity of cytochrome p450c17 from human fetal testis favors the delta5 steroidogenic pathway. J Clin Endocrinol Metabol. 2003;88:3762–3766.Google Scholar
Labrie, F, Luu-The, V, Lin, SX, et al. The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid biology. Steroids. 1997;62:148–158.Google Scholar
Manna, PR, Stetson, CL, Slominski, AT, Pruitt, K. Role of the steroidogenic acute regulatory protein in health and disease. Endocrine. 2016;51:7–21.Google Scholar
Winters, SJ, Troen, P. Testosterone and estradiol are co-secreted episodically by the human testis. J Clin Inv. 1986;78:870–873.Google Scholar
Plymate, SR, Tenover, JS, Bremner, WJ. Circadian variation in testosterone, sex hormone-binding globulin, and calculated non-sex hormone-binding globulin bound testosterone in healthy young and elderly men. J Androl. 1989;10:366–371.Google Scholar
Sheckter, CB, Matsumoto, AM, Bremner, WJ. Testosterone administration inhibits gonadotropin secretion by an effect directly on the human pituitary. J Clin Endocrinol Metabol. 1989;68:397–401.Google Scholar
Morishima, A, Grumbach, MM, Simpson, ER, Fisher, C, Qin, K. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metabol. 1995;80:3689–3698.Google Scholar
Sansone, A, Kliesch, S, Isidori, AM, Schlatt, S. AMH and INSL3 in testicular and extragonadal pathophysiology: what do we know? Andrology. 2019;7:131–138.Google Scholar
Bay, K, Hartung, S, Ivell, R, et al. Insulin-like factor 3 serum levels in 135 normal men and 85 men with testicular disorders: relationship to the luteinizing hormone-testosterone axis. J Clin Endocrinol Metabol. 2005;90:3410–3438.Google Scholar
Ferlin, A, Garolla, A, Rigon, F, Rasi Caldogno, L, Lenzi, A, Foresta, C. Changes in serum insulin-like factor 3 during normal male puberty. J Clin Endocrinol Metabol. 2006;91:3426–3431.Google Scholar
de Kretser, DM, Buzzard, JJ, Okuma, Y, et al. The role of activin, follistatin and inhibin in testicular physiology. Mol Cell Endocrinol. 2004;225:57–64.Google Scholar
Boepple, PA, Hayes, FJ, Dwyer, AA, et al. Relative roles of inhibin B and sex steroids in the negative feedback regulation of follicle-stimulating hormone in men across the full spectrum of seminiferous epithelium function. J Clin Endocrinol Metabol. 2008;93:1809–1814.Google Scholar
Anawalt, BD, Bebb, RA, Matsumoto, AM, et al. Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction. J Clin Endocrinol Metabol. 1996;81:3341–3335.Google Scholar
Jamin, SP, Arango, NA, Mishina, Y, Hanks, MC, Behringer, RR. Genetic studies of the AMH/MIS signaling pathway for Müllerian duct regression. Mol Cell Endocrinol. 2003;211:15–19.Google Scholar
Sofikitis, N, Giotitsas, N, Tsounapi, P, Baltogiannis, D, Giannakis, D, Pardalidis, N. Hormonal regulation of spermatogenesis and spermiogenesis. J Steroid Biochem Mol Biol. 2008;109:323–330.Google Scholar
Hammond, GL. Diverse roles for sex hormone-binding globulin in reproduction. Biol Reprod. 2011:85:431–441.Google Scholar
Manni, A, Pardridge, WM, Cefalu, W, et al. Bioavailability of albumin-bound testosterone. J Clin Endocrinol Metabol. 1985;61:705–710.Google Scholar
Giton, F, Fiet, J, Guéchot, J, et al. Serum bioavailable testosterone: assayed or calculated? Clin Chem. 2006;52:474–481.Google Scholar
Goldman, AL, Bhasin, S, Wu, FCW, Krishna, M, Matsumoto, AM, Jasuja, R. A reappraisal of testosterone’s binding in circulation: physiological and clinical implications. Endocr Rev. 2017;38:302–324.Google Scholar
Joseph, DR. Structure, function, and regulation of androgen-binding protein/sex hormone-binding globulin. Vitamins Hormones. 1994;49:197–280.Google Scholar
Stone, J, Folkerd, E, Doody, D, et al. Familial correlations in postmenopausal serum concentrations of sex steroid hormones and other mitogens: a twins and sisters study. J Clin Endocrinol Metabol. 2009:94:4793–4800.Google Scholar
Bhasin, S, Cunningham, GR, Hayes, FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metabol. 2018;103:1–30.Google Scholar
de Ronde, W, van der Schouw, YT, Pols, HAP, et al. Calculation of bioavailable and free testosterone in men: a comparison of 5 published algorithms. Clin Chem. 2006;52:1777–1784.Google Scholar
Schiffer, L, Arlt, W, Storbeck, K-H. Intracrine androgen biosynthesis, metabolism and action revisited. Mol Cell Endocrinol. 2018:465:4–26.Google Scholar
Imperato-McGinley, J, Zhu, Y-S. Androgens and male physiology the syndrome of 5alpha-reductase-2 deficiency. Mol Cell Endocrinol. 2002;198:51–59.Google Scholar
Bertelloni, S, Baldinotti, F, Russo, G, et al. 5α-reductase-2 deficiency: clinical findings, endocrine pitfalls, and genetic features in a large Italian cohort. Sex Develop. 2016;10:28–36.Google Scholar
Swerdloff, RS, Dudley, RE, Page, ST, Wang, C, Salameh, WA. Dihydrotestosterone: biochemistry, physiology, and clinical implications of elevated blood levels. Endocr Rev. 2017:38:220–254.Google Scholar
Wilson, EM, French, FS. Binding properties of androgen receptors. Evidence for identical receptors in rat testis, epididymis, and prostate. J Biol Chem. 1976;251:5620–5629.Google Scholar
Lombardi, G, Zarrilli, S, Colao, A, et al. Estrogens and health in males. Mol Cell Endocrinol. 2001;178:51–55.Google Scholar
Bélanger, A, Pelletier, G, Labrie, F, Barbier, O, Chouinard, S. Inactivation of androgens by UDP-glucuronosyltransferase enzymes in humans. Trends Endocrinol Metabol. 2003;14:473–479.Google Scholar
Rey, RA, Grinspon, RP, Gottlieb, S, et al. Male hypogonadism: an extended classification based on a developmental, endocrine physiology-based approach. Andrology. 2013;1:3–16.Google Scholar
Shukla, GC, Plaga, AR, Shankar, E, Gupta, S. Androgen receptor-related diseases: what do we know? Andrology. 2016;4:366–381.Google Scholar
Lee, DK, Chang, C. Molecular communication between androgen receptor and general transcription machinery. J Steroid Biochem Mol Biol. 2003;84:41–49.Google Scholar
Brinkmann, AO, Faber, PW, van Rooij, HC, et al. The human androgen receptor: domain structure, genomic organization and regulation of expression. J Steroid Biochem. 1989;34:307–310.Google Scholar
Zitzmann, M. Pharmacogenetics of testosterone replacement therapy. Pharmacogenomics. 2009;10:1341–1349.Google Scholar
Foradori, CD, Weiser, MJ, Handa, RJ. Non-genomic actions of androgens. Front Neuroendocrinol. 2008;29:169–181.Google Scholar
Gorczynska, E, Handelsman, DJ. Androgens rapidly increase the cytosolic calcium concentration in Sertoli cells. Endocrinology. 1995;136:2052–2059.Google Scholar
Cheng, J, Watkins, SC, Walker, WH. Testosterone activates mitogen-activated protein kinase via Src kinase and the epidermal growth factor receptor in Sertoli cells. Endocrinology. 2007;148:2066–2074.Google Scholar
Hammes, A, Andreassen, TK, Spoelgen, R, et al. Role of endocytosis in cellular uptake of sex steroids. Cell. 2005;122:751–762.Google Scholar
Tapanainen, J, Kellokumpu-Lehtinen, P, Pelliniemi, L, Huhtaniemi, I. Age-related changes in endogenous steroids of human fetal testis during early and midpregnancy. J Clin Endocrinol Metabol. 1981;52:98–102.Google Scholar
Grumbach, MM. A window of opportunity: the diagnosis of gonadotropin deficiency in the male infant. J Clin Endocrinol Metabol. 2005;90:3122–3127.Google Scholar
Patton, GC, Viner, R. Pubertal transitions in health. Lancet. 2007;369:1130–1139.Google Scholar
Gray, A, Feldman, HA, McKinlay, JB, Longcope, C. Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 1991;73:1016–1025.Google Scholar
Andersson, AM, Toppari, J, Haavisto, AM, et al. Longitudinal reproductive hormone profiles in infants: peak of inhibin B levels in infant boys exceeds levels in adult men. J Clin Endocrinol Metabol. 1998;83:675–681.Google Scholar
Grinspon, RP, Rey, RA. New perspectives in the diagnosis of pediatric male hypogonadism: the importance of AMH as a Sertoli cell marker. Arq Brasil Endocrinol Metabol. 2011;55:512–519.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×