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  • Print publication year: 2009
  • Online publication date: May 2010

Chapter 2 - Male hypothalamic–pituitary–gonadal axis


The male hypothalamic-pituitary-gonadal (HPG) axis is a finely controlled system whose role is to promote spermatogenesis and androgen biosynthesis. Testosterone is thought to feed back to restrain activity of the gonadotropin-releasing hormone (GnRH)-gonadotrope secretory unit. GnRH is released from the hypothalamus in a pulsatile pattern, and the stimulation of gonadotropin biosynthesis and secretion by GnRH is dependent on the pulsatile nature of GnRH delivery to the anterior pituitary. Gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are glycoproteins consisting of a common a subunit and a hormone-specific β subunit that are associated through noncovalent interactions. GnRH stimulates in vitro the synthesis of gonadotropin subunits and increases a, LH-β, and FSH-β subunit mRNA levels as well as the transcriptional activity of corresponding gene promoters. Testosterone seems to exert a direct feedback control of LH secretion, while its action on FSH secretion is mostly indirect.

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[1] PadmanabhanV, EvansNP, DahlGE, et al. Evidence for short or ultrashort loop negative feedback of gonadotropin-releasing hormone secretion. Neuroendocrinology 1995; 62: 248–58.
[2] DePaoloLV, KingRA, CarrilloAJ. In vivo and in vitro examination of an autoregulatory mechanism for luteinizing hormone-releasing hormone. Endocrinology 1987; 120: 272–9.
[3] WitkinJW, SilvermanAJ. Synaptology of luteinizing hormone-releasing hormone neurons in rat preoptic area. Peptides 1985; 6: 263–71.
[4] PompoloS, RawsonJA, ClarkeIJ. Projections from the arcuate/ventromedial region of the hypothalamus to the preoptic area and bed nucleus of stria terminalis in the brain of the ewe: lack of direct input to gonadotropin-releasing hormone neurons. Brain Res 2001; 904: 1–12.
[5] XuC, XuXZ, NunemakerCS, MoenterSM. Dose-dependent switch in response of gonadotropin-releasing hormone (GnRH) neurons to GnRH mediatedthrough the type I GnRH receptor. Endocrinology 2004; 145: 728–35.
[6] KrsmanovicLZ, StojilkovicSS, MertzLM, TomicM, CattKJ. Expression of gonadotropin-releasing hormone receptors and autocrine regulation of neuropeptide release in immortalized hypothalamic neurons. Proc Natl Acad Sci U S A 1993; 90: 3908–12.
[7] KrsmanovicLZ, Martinez-FuentesAJ, AroraKK, et al. Autocrine regulation of gonadotropin-releasing hormone secretion in cultured hypothalamic neurons. Endocrinology 1999; 140: 1423–31.
[8] KrsmanovicLZ, MoresN, NavarroCE, AroraKK, CattKJ. An agonist-induced switch in G protein coupling of the gonadotropin-releasing hormone receptor regulates pulsatile neuropeptide secretion. Proc Natl Acad Sci U S A 2003; 100: 2969–74.
[9] GammonCM, FreemanGM, XieW, PetersenSL, WetselWC. Regulation of gonadotropin-releasing hormone secretion by cannabinoids. Endocrinology 2005; 146: 4491–9.
[10] EblingFJP, LincolnGA. Endogenous opioids and the control of seasonal LH secretion in Soay rams. J Endocrinol 1985; 107: 341–53.
[11] SchanbacherBD. Effects of intermittent pulsatile infusion of luteinizing hormone-releasing hormone on dihydrotestosterone-suppressed gonadotropin secretion in castrate rams. Biol Reprod 1985; 33: 603–11.
[12] MoldrichG, WengerT. Localization of the CB1 cannabinoid receptor in the rat brain: an immunohistochemical study. Peptides 2000; 21: 1735–42.
[13] WhiteRB, EisenJA, KastenTL, FernaldRD. Second gene for gonadotropin-releasing hormone in humans. Proc Natl Acad Sci U S A 1998; 95: 305–9.
[14] ChengCK, LeungPck. Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II and their receptors in humans. Endocr Rev 2005; 26: 283–306.
[15] MillarRP, LuZL, PawsonAJ, et al. Gonadotropin-releasing hormone receptors. Endocr Rev 2004; 25: 235–75.
[16] KauffmanAS, BojkowskaK, WillsA, RissmanEF. Gonadotropin-releasing hormone-II messenger ribonucleic acid and protein content in the mammalian brain are modulated by food intake. Endocrinology 2006; 147: 5069–77.
[17] DensmoreVS, UrbanskiHF. Relative effect of gonadotropin-releasing hormone (GnRH)-I and GnRH-II on gonadotropin release. J Clin Endocrinol Metab 2003; 88: 2126–34.
[18] ZhenS, ZakariaM, WolfeA, RadovickS. Regulation of gonadotropin-releasing hormone (GnRH) gene expression by insulin-like growth factor I in a cultured GnRH-expressing neuronal cell line. Mol Endocrinol 1997; 11: 1145–55.
[19] MessagerS, ChatzidakiEE, MaD, et al. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci U S A 2005; 102: 1761–6.
[20] TilbrookAJ, ClarkeIJ. Negative feedback regulation of the secretion and actions of gonadotropin-releasing hormone in males. Biol Reprod 2001; 64: 735–42.
[21] CaratyA, LocatelliA. Effect of time after castration on secretion of LHRH and LH in the ram. J Reprod Fertil 1988; 82: 263–9.
[22] JacksonGL, KuehlD, RhimTJ. Testosterone inhibits gonadotropin-releasing hormone pulse frequency in the male sheep. Biol Reprod 1991; 45: 188–94.
[23] TilbrookAJ, de KretserDM, CumminsJT, ClarkeIJ. The negative feedback effects of testicular steroids are predominantly at the hypothalamus in the ram. Endocrinology 1991; 129: 3080–92.
[24] El MajdoubiM, RamaswamyS, SahuA, PlantTM. Effects of orchidectomy on levels of the mRNAs encoding gonadotropin-releasing hormone and other hypothalamic peptides in the adult male rhesus monkey (Macaca mulatta). J Neuroendocrinol 2000; 12: 167–76.
[25] HerbisonAE. Multimodal influence of estrogen upon gonadotropin-releasing hormone neurons. Endocr Rev 1998; 19: 302–30.
[26] NunemakerCS, DefazioRA, MoenterSM. Estradiol-sensitive afferents modulate long-term episodic firing patterns of GnRH neurons. Endocrinology 2002; 143: 2284–92.
[27] BelchetzPE, PlantTM, NakaiY, KeoghEJ, KnobilE. Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin-releasing hormone. Science 1978; 202: 631–3.
[28] WeissJ, JamesonJL, BurrinJM, CrowleyWF. Divergent responses of gonadotropin subunit messenger RNAs to continuous vs. pulsatile gonadotropin-releasing hormone in vitro. Molecular Endocrinology 1990; 4: 557–64.
[29] WiermanME, RivierJE, WangC. Gonadotropin-releasing hormone-dependent regulation of gonadotropin subunit messenger ribonucleic acid levels in the rat. Endocrinology 1989; 124: 272–8.
[30] KaiserUB, JakubowiakA, SteinbergerA, ChinWW. Differential effects of gonadotropin-releasing hormone (GnRH) pulse frequency on gonadotropin subunit and GnRH receptor messenger ribonucleic acid levels in vitro. Endocrinology 1997; 138: 1224–31.
[31] LoumayeE, CattKJ. Homologous regulation of gonadotropin-releasing hormone receptors in cultured pituitary cells. Science 1982; 215: 983–5.
[32] Savoy-MooreRT, SchwartzNB, DuncanJA, MarshallJC. Pituitary gonadotropin-releasing hormone receptors during the rat estrous cycle. Science 1985; 209: 942–4.
[33] Savoy-MooreRT, SwartzKH. Several GnRH stimulation frequencies differentially release FSH and LH from isolated, perfused rat anterior pituitary cells. Adv Exp Med Biol 1987; 219: 641–5.
[34] WildtL, HauslerA, MarshallG, et al. Frequency and amplitude of gonadotropin-releasing hormone stimulation and gonadotropin secretion in the rhesus monkey. Endocrinology 1981; 109: 376–85.
[35] NunemakerCS, StraumeM, DefazioRA, MoenterS. Gonadotropin-releasing hormone neurons generate interacting rhythms in multiple time domains. Endocrinology 2003; 144: 823–31.
[36] SairamMR, FleshnerP. Inhibition of hormone-induced cyclic AMP production and steroidogenesis in interstitial cells by deglycosylated lutropin. Mol Cell Endocrinol 1981; 22: 41–54.
[37] ThemmenAP, HuhtaniemiI. Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. Endocr Rev 2000; 21: 551–83.
[38] LaymanLC, PortoAL, XieJ, et al. FSHβ gene mutations in a female with partial breast development and a male sibling with normal puberty and azoospermia. J Clin Endocrinol Metab 2002; 87: 3702–7.
[39] ClarkAD, LaymanLC. Analysis of the Cys82Arg mutation in follicle-stimulating hormone beta (FSHβ) using a novel FSH expression vector. Fertil Steril 2003; 79: 379–85.
[40] TapanainenJS, AittomäkiK, MinJ, VaskivuoT, HuhtaniemiIT. Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility. Nat Genet 1997; 15: 205–6.
[41] DierichA, SairamMR, MonacoL, et al. Impairing follicle-stimulating hormone (FSH) signaling in vivo: targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance. Proc Natl Acad Sci U S A 1998; 95: 13612–17.
[42] WeissJ, AxelrodL, WhitcombRW, et al. Hypogonadism caused by a single amino acid substitution in the β subunit of luteinizing hormone. N Engl J Med 1992; 326: 179–83.
[43] WangGM, O’ShaughnessyPS, ChubbC, et al. Effects of insulin-like growth factor I on steroidogenic enzyme expression levels in mouse Leydig cells. Endocrinology 2003; 144: 5058–64.
[44] WangGM, HardyMP. Development of Leydig cells in the insulin-like growth factor I (IGF-1) knockout mouse: effects of IGF-1 replacement and gonadotropic stimulation. Biol Reprod 2004; 70: 632–9.
[45] BakerJ, HardyMP, ZhowJ, et al. Effects of an IGF-1 gene null mutation on mouse reproduction. Mol Endocrinol 1996; 10: 903–18.
[46] SriramanV, SairamMR, RaoAJ. Evaluation of relative roles of LH and FSH in regulation of differentiation of Leydig cells using an ethane 1,2-dimethylsulfonate-treated adult rat model. J Endocrinol 2003; 176: 151–61.
[47] PayneAH, HardyMP, RussellLD, eds. The Leydig Cell. Vienna, IL: Cache River Press 1996.
[48] HodgsonYM, de KretserDM. Serum testosterone response to single injection of hCG ovine-LH and LHRH in male rats. Int J Androl 1982; 5: 81–91.
[49] CounisR, LaverrièreJN, GarrelG, et al. Gonadotropin-releasing hormone and the control of gonadotrope function. Reprod Nutr Dev 2005; 45: 243–54.
[50] HayesFJ, DeCruzS, SeminaraSB, BoepplePA, CrowleyWF. 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: 53–8.
[51] HayesFJ, SeminaraSB, DecruzS, BoepplePA, CrowleyWJ. Aromatase inhibition in the human male reveals a hypothalamic site of estrogen feedback. J Clin Endocrinol Metab 2000; 85: 3027–35.
[52] SmithEP, BoydJ, FrankGR, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 1994; 331: 1056–61.
[53] MorishimaA, GrumbachMM, SimpsonER, FisherC, QinK. Aromatase deficiency in male and female sibling caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995; 80: 3689–99.
[54] CaraniC, QinK, SimoniM, et al. Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 1997; 337: 91–5.
[55] SchnorrJA, BrayMJ, VeldhuisJD. Aromatization mediates testosterone’s short-term feedback restraint of 24-hour endogenously driven and acute exogenous gonadotropin-releasing hormone-stimulated luteinizing hormone and follicle-stimulating hormone secretion in young men. J Clin Endocrinol Metab 2001; 86: 2600–6.
[56] HayesFJ, PitteloudN, DeCruzS, CrowleyWF, BoepplePA. Importance of inhibin B in the regulation of FSH secretion in the human male. J Clin Endocrinol Metab 2001; 86: 5541–6.
[57] WallaceEM, GroomeNP, RileySC, ParkerAC, WuFCW. Effects of chemotherapy-induced testicular damage on inhibin, gonadotropin, and testosterone secretion: a prospective longitudinal study. J Clin Endocrinol Metab 1997; 82: 3111–15.
[58] BergendahlM, EvansWS, VeldhuisJD. Current concepts on ultradian rhythms of luteinizing hormone secretion in the human. Hum Reprod Update 1996; 2: 507–18.
[59] KeenanD, VeldhuisJD. A biomathematical model of time-delayed feedback in the human male hypothalamic–pituitary–Leydig cell axis. Am J Physiol 1998; 275: E157–76.
[60] PadmanabhanV, McFaddenC, MaugerDT, KarschFJ, MidgleyAR. Neuroendocrine control of follicle-stimulating hormone (FSH) secretion. I. Direct evidence for separate episodic and basal components of FSH secretion. Endocrinology 1997; 138: 424–32.
[61] HamernikDL, NettTM. Gonadotropin-releasing hormone increases the amount of messenger ribonucleic acid for gonadotropins in ovariectomized ewes after hypothalamic–pituitary disconnection. Endocrinology 1988; 122: 959–66.
[62] SheridanR, LorasB, SurardtL, EctorsF, PasteelsJL. Autonomous secretion of follicle-stimulating hormone by long term organ cultures of rat pituitaries. Endocrinology 1979; 104: 198–204.
[63] ForestaC, BordonP, RossatoM, MioniR, VeldhuisJD. Specific linkages among luteinizing hormone, follicle-stimulating hormone, and testosterone release in the peripheral blood and human spermatic vein: evidence for both positive (feed-forward) and negative (feedback) within-axis regulation. J Clin Endocrinol Metab 1997; 82: 3040–6.
[64] VeldhuisJD, IranmaneshA. Pulsatile intravenous infusion of recombinant human luteinizing hormone under acute gonadotropin-releasing hormone receptor blockade reconstitutes testosterone secretion in young men. J Clin Endocrinol Metab 2004; 89: 4474–9.
[65] AnawaltBD, BebbRA, MatsumotoAM, et al. Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction. J Clin Endocrinol Metab 1996; 81: 3341–5.
[66] MarchettiC, HamdaneM, MitchellV, et al. Immunolocalization of inhibin and activin α and βB subunits and expression of corresponding messenger RNAs in the human adult testis. Biol Reprod 2003; 68: 230–5.
[67] YoungJ, CouzinetB, ChansonP, et al. Effects of human recombinant luteinizing hormone and follicle-stimulating hormone in patients with acquired hypogonadotropic hypogonadism: study of Sertoli and Leydig cell secretions and interactions. J Clin Endocrinol Metab 2000; 85: 3239–44.
[68] KinniburghD, AndersonRA. Differential patterns of inhibin secretion in response to gonadotropin stimulation in normal men. Int J Androl 2001; 24: 95–101.
[69] RobertsonDM, StephensonT, McLachlanRI. Characterization of plasma inhibin forms in fertile and infertile men. Hum Reprod 2003; 18: 1047–54.
[70] ByrdW, BennettMJ, CarrBR, et al. Regulation of biologically active dimeric inhibin A and B from infancy to adulthood in the male. J Clin Endocrinol Metab 1998; 83: 2849–54.
[71] CroftonPM, EvansAE, GroomeNP, et al. Inhibin B in boys from birth to adulthood: relationship with age, pubertal stage, FSH and testosterone. Clin Endocrinol (Oxf) 2002; 56: 215–21.
[72] MatthiessonKL, RobertsonDM, BurgerHG, McLachlanRI. Response of serum inhibin B and pro-αC levels to gonadotrophic stimulation in normal men before and after steroidal contraceptive treatment. Hum Reprod 2003; 18: 734–43.
[73] BakerJ, HardyMP, ZhouJ, et al. Effects of an IGF1 gene null mutation on mouse reproduction. Mol Endocrinol 1996; 10: 903–18.
[74] WangG, HardyMP. Development of Leydig cells in the insulin-like growth factor-I (IGF-1) knockout mouse: effects of IGF-1 replacement and gonadotropic stimulation. Biol Reprod 2004; 70: 632–9.
[75] ChatelainPG, SanchezP, SaezJM. Growth hormone and insulin-like growth factor I treatment increase testicular luteinizing hormone receptors and steroidogenic responsiveness of growth hormone deficient dwarf mice. Endocrinology 1991; 128: 1857–62.
[76] GoddardI, BourasM, KeramidasM, et al. Transforming growth factor-β receptor types I and II in cultured porcine Leydig cells: expression and hormonal regulation. Endocrinology 2000; 141: 2068–74.
[77] BenahmedM. Growth factors and cytokines in the testis. In: ComhaireFH, ed. Male Infertility. London: Chapman and Hall, 1996: 55–97.
[78] GnessiL, FabbriA, SperaG. Gonadal peptides as mediators of development and functional control of the testis: an integrated system with hormones and local environment. Endocr Rev 1997; 18: 541–609.
[79] SordoilletC, ChauvinMA, HendrickJC, et al. Sites of interaction between epidermal growth factor and transforming growth factor-β1 in the control of steroidogenesis in cultured porcine Leydig cells. Endocrinology 1992; 130: 1352–8.
[80] BessetV, ColletteJ, ChauvinMA, FranchimontP, BenahmedM. Effect of transforming growth factor-β1 on the insulin-like growth factor system in cultured porcine Leydig cells. Mol Cell Endocrinol 1994; 99: 251–7.
[81] FabbriA, TinajeroJC, DufauML. Corticotropin releasing factor is produced by rat Leydig cells and has major local antireproductive role. Endocrinology 1990; 127: 1541–3.
[82] ColonE, SvechnikovKV, Carlsson-SkwirutC, BangP, SoderO. Stimulation of steroidogenesis in immature rat leydig cells evoked by interleukin-1α is potentiated by growth hormone and insulin-like growth factors. Endocrinology 2005;f 146: 221–30.