Skip to main content
SpringerLink
Log in

Central Hypogonadism in the Male: Physiopathology, Diagnosis and Treatment

  • Living reference work entry
  • First Online:
Hypothalamic-Pituitary Diseases

Part of the book series: Endocrinology ((ENDOCR))

Abstract

The hypothalamic-pituitary-gonadal (HPG) axis coordinates two functions essential for male reproductive capacity: synthesis and secretion of sex steroid hormones, primarily testosterone, and production of spermatozoa. Our understanding of the physiologic principles of male reproductive health have substantially increased in recent years, enabling physicians not only to identify genetic causes of hypogonadism among a wide spectrum of possible disorders, but also to establish therapeutic strategies. Men with hypothalamic or pituitary disorders nowadays have an excellent prognosis for fertility restoration and for paternity by natural intercourse or using assisted reproductive techniques.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Similar content being viewed by others

References

  • Abbara A, Jayasena CN, Christopoulos G, Narayanaswamy S, Izzi-Engbeaya C, Nijher GM, Comninos AN, Peters D, Buckley A, Ratnasabapathy R, Prague JK, Salim R, Lavery SA, Bloom SR, Szigeti M, Ashby DA, Trew GH, Dhillo WS. Efficacy of kisspeptin-54 to trigger oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS) during in vitro fertilization (IVF) therapy. J Clin Endocrinol Metab. 2015;100:3322–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Achermann JC, Meeks JJ, Jameson JL. Phenotypic spectrum of mutations in DAX-1 and SF-1. Mol Cell Endocrinol. 2001;185:17–25.

    Article  CAS  PubMed  Google Scholar 

  • Alqwaifly M, Bohlega S. Ataxia and hypogonadotropic hypogonadism with intrafamilial variability caused by RNF216 mutation. Neurol Int. 2016;8:6444.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bang AK, Nordkap L, Almstrup K, Priskorn L, Petersen JH, Rajpert-De Meyts E, Andersson AM, Juul A, Jørgensen N. Dynamic GnRH and hCG testing: establishment of new diagnostic reference levels. Eur J Endocrinol. 2017;176:379–91.

    Article  CAS  PubMed  Google Scholar 

  • Barrio R, De Luis D, Alonso M, Lamas A, Moreno JC. Induction of puberty with human chorionic gonadotropin and follicle-stimulating hormone in adolescent males with hypogonadotropic hypogonadism. Fertil Steril. 1999;71:244–8.

    Article  CAS  PubMed  Google Scholar 

  • Behre HM, Nieschlag E. Testosterone preparations for clinical use in males. In: Nieschlag E, Behre HM, Nieschlag S, editors. Testosterone: action, deficiency, substitution. 4th ed. Cambridge: Cambridge University Press; 2012. p. 309–35.

    Chapter  Google Scholar 

  • Behre HM, Nieschlag E, Partsch CJ, Wieacker P, Simoni M. Diseases of the hypothalamus and the pituitary gland. In: Nieschlag E, Behre HM, editors. Andrology: male reproductive health and dysfunction. 3rd ed. Berlin: Springer; 2010. p. 169–92.

    Chapter  Google Scholar 

  • Behre HM, von Eckardstein S, Kliesch S, Nieschlag E. Long-term substitution therapy of hypogonadal men with transscrotal testosterone over 7–10 years. Clin Endocr. 1999;50:629–35.

    Article  CAS  PubMed  Google Scholar 

  • Behre HM, Tammela TL, Arver S, Tolrá JR, Bonifacio V, Lamche M, Kelly J, Hiemeyer F, European Testogel® Study Team, Giltay EJ, Gooren LJ. A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up. Aging Male. 2012;15:198–207.

    Article  CAS  PubMed  Google Scholar 

  • Behre HM, Zitzmann M. Imaging diagnosis. In: Nieschlag E, Behre HM, editors. Andrology: male reproductive health and dysfunction. 3rd ed. Berlin: Springer; 2010. p. 101–7.

    Chapter  Google Scholar 

  • Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E. Hypophyseal responses to continuous and intermittent delivery of hypothalamic gonadotropin releasing hormone. Science. 1978;202:631–3.

    Article  CAS  PubMed  Google Scholar 

  • Beneduzzi D, Trarbach EB, Min L, Jorge AA, Garmes HM, Renk AC, Fichna M, Fichna P, Arantes KA, Costa EM, Zhang A, Adeola O, Wen J, Carroll RS, Mendonça BB, Kaiser UB, Latronico AC, Silveira LF. Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay. Fertil Steril. 2014;102:838–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM, Task force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;6:2536–59.

    Article  CAS  Google Scholar 

  • Bhasin S, Pencina M, Jasuja GK, Travison TG, Coviello A, Orwoll E, Wang PY, Nielson C, Wu F, Tajar A, Labrie F, Vesper H, Zhang A, Ulloor J, Singh R, D'Agostino R, Vasan RS. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham heart study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab. 2011;96:2430–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A, Maghnie M, Pitteloud N, Prevot V, Raivio T, Tena-Sempere M, Quinton R, Young J. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism–pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2015;11:547–64.

    PubMed  Google Scholar 

  • Bouligand J, Ghervan C, Tello JA, Brailly-Tabard S, Salenave S, Chanson P, Lombès M, Millar RP, Guiochon-Mantel A, Young J. Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. N Engl J Med. 2009;360:2742–8.

    Article  CAS  PubMed  Google Scholar 

  • Bouloux P, Warne DW, Loumaye E. Efficacy and safety of recombinant human follicle-stimulating hormone in men with isolated hypogonadotropic hypogonadism. Fertil Steril. 2002;77:270–3.

    Article  PubMed  Google Scholar 

  • Bouloux PM, Nieschlag E, Burger HG, Skakkebaek NE, FC W, Handelsman DJ, Baker GH, Ochsenkuehn R, Syska A, McLachlan RI, Giwercman A, Conway AJ, Turner L, van Kuijk JH, Voortman G. 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;24:604–11.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Burgués S, Calderón MD. Subcutaneous self-administration of highly purified follicle stimulating hormone and human chorionic gonadotrophin for the treatment of male hypogonadotrophic hypogonadism. Hum Reprod. 1997;12:980–6.

    Article  PubMed  Google Scholar 

  • Burris AS, Rodbard HW, Winters SJ, Sherins RJ. Gonadotropin therapy in men with isolated hypogonadotropic hypogonadism: the response to human chorionic gonadotropin is predicted by initial testicular size. J Endocrinol Metab. 1988;66:1144–51.

    Article  CAS  Google Scholar 

  • Butler MG, Wang K, Marshall JD, Naggert JK, Rethmeyer JA, Gunewardena SS, Manzardo AM. Coding and noncoding expression patterns associated with rare obesity-related disorders: Prader-Willi and Alström syndromes. Adv Genomics Genet. 2015;2015:53–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chan YM, de Guillebon A, Lang-Muritano M, Plummer L, Cerrato F, Tsiaras S, Gaspert A, Lavoie HB, Wu CH, Crowley WF Jr, Amory JK, Pitteloud N, Seminara SB. GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A. 2009;106:11703–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan YM, Lippincott MF, Butler JP, Sidhoum VF, Li CX, Plummer L, Seminara SB. Exogenous kisspeptin administration as a probe of GnRH neuronal function in patients with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2014;99:E2762–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Claahsen-van der Grinten HL, Otten BJ, Takahashi S, Meuleman EJ, Hulsbergen-van de Kaa C, Hermus AR. Testicular adrenal rest tumors in adult males with congenital adrenal hyperplasia: evaluation of pituitary-gonadal function before and after successful testis-sparing surgery in eight patients. J Clin Endocrinol Metab. 2007;92:612–5.

    Article  CAS  PubMed  Google Scholar 

  • Clément K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougnères P, Lebouc Y, Froguel P, Guy-Grand B. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998;392:398–401.

    Article  PubMed  Google Scholar 

  • Coutant R, Biette-Demeneix E, Bouvattier C, Bouhours-Nouet N, Gatelais F, Dufresne S, Rouleau S, Lahlou N. Baseline inhibin B and anti-Mullerian hormone measurements for diagnosis of hypogonadotropic hypogonadism (HH) in boys with delayed puberty. J Clin Endocrinol Metab. 2010;95:5225–32.

    Article  CAS  PubMed  Google Scholar 

  • Costa-Barbosa FA, Balasubramanian R, Keefe KW, Shaw ND, Al-Tassan N, Plummer L, Dwyer AA, Buck CL, Choi JH, Seminara SB, Quinton R, Monies D, Meyer B, Hall JE, Pitteloud N, Crowley WF Jr. Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes. J Clin Endocrinol Metab. 2013;98:E943–53.

    Article  PubMed  PubMed Central  Google Scholar 

  • Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. The J Pain. 2002;3:377–84.

    Article  PubMed  Google Scholar 

  • Debruyne FM, Behre HM, Roehrborn CG, Maggi M, Wu FC, Schröder FH, Jones TH, Porst H, Hackett G, Wheaton OA, Martin-Morales A, Meuleman E, Cunningham GR, Divan HA, Rosen RC, Investigators RHYME. Testosterone treatment is not associated with increased risk of prostate cancer or worsening of lower urinary tract symptoms: prostate health outcomes in the registry of hypogonadism in men. BJU Int. 2017;119:216–24.

    Article  CAS  PubMed  Google Scholar 

  • Delemarre-van de Waal HA. Application of gonadotropin releasing hormone in hypogonadotropic hypogonadism-diagnostic and therapeutic aspects. Eur J Endocrinol. 2004;151(Suppl 3):U89–94.

    Article  CAS  PubMed  Google Scholar 

  • Depenbusch M, von Eckardstein S, Simoni M, Nieschlag E. Maintenance of spermatogenesis in hypogonadotropic hypogonadal men with hCG alone. Eur J Endorinol. 2002;147:617–24.

    Article  CAS  Google Scholar 

  • de Ronde W. Hyperandrogenism after transfer of topical testosterone gel: case report and review of published and unpublished studies. Hum Reprod. 2009;24:425–8.

    Article  PubMed  CAS  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 U S A. 2003;100:10972–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • de Roux N, Young J, Misrahi M, Genet R, Chanson P, Schaison G, Milgrom E. A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med. 1997;337:1597–602.

    Article  PubMed  Google Scholar 

  • De Sousa SM, Chapman IM, Falhammar H, Torpy DJ. Dopa-testotoxicosis: disruptive hypersexuality in hypogonadal men with prolactinomas treated with dopamine agonists. Endocrine. 2017;55:618–24.

    Article  PubMed  CAS  Google Scholar 

  • Dhindsa S, Miller MG, McWhirter CL, Mager DE, Ghanim H, Chaudhuri A, Dandona P. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care. 2010;33:1186–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dinsmore WW, Wyllie MG. The long-term efficacy and safety of a testosterone mucoadhesive buccal tablet in testosterone-deficient men. Br J Urol Int. 2012;110:162–9.

    Article  CAS  Google Scholar 

  • Dodé C, Levilliers J, Dupont JM, De Paepe A, Le Dû N, Soussi-Yanicostas N, Coimbra RS, Delmaghani S, Compain-Nouaille S, Baverel F, Pêcheux C, Le Tessier D, Cruaud C, Delpech M, Speleman F, Vermeulen S, Amalfitano A, Bachelot Y, Bouchard P, Cabrol S, Carel JC, Delemarre-van de Waal H, Goulet-Salmon B, Kottler ML, Richard O, Sanchez-Franco F, Saura R, Young J, Petit C, Hardelin JP. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet. 2003;33:463–5.

    Article  PubMed  CAS  Google Scholar 

  • Dodé C, Teixeira L, Levilliers J, Fouveaut C, Bouchard P, Kottler ML, Lespinasse J, Lienhardt-Roussie A, Mathieu M, Moerman A, Morgan G, Murat A, Toublanc JE, Wolczynski S, Delpech M, Petit C, Young J, Hardelin JP. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet. 2006;2:e175.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dohle GR, Arvers S, Bettocchi C (2012) Guidelines on male hypogonadism. European Association of Urology. www.uroweb.org.

    Google Scholar 

  • Doty RL, Bromley SM, Stern MB. Olfactory testing as an aid in the diagnosis of Parkinson's disease: development of optimal discrimination criteria. Neurodegeneration. 1995;4:93–7.

    Article  CAS  PubMed  Google Scholar 

  • Dunkel L, Quinton R. Transition in endocrinology: induction of puberty. Eur J Endocrinol. 2014;170:229–39.

    Article  CAS  Google Scholar 

  • Dwyer AA, Phan-Hug F, Hauschild M, Elowe-Gruau E, Pitteloud N. TRANSITION IN ENDOCRINOLOGY: Hypogonadism in adolescence. Eur J Endocrinol. 2015;173:R15–24.

    Article  CAS  PubMed  Google Scholar 

  • Dwyer AA, Raivio T, Pitteloud N. MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism. Eur J Endocrinol. 2016;174:R267–74.

    Article  CAS  PubMed  Google Scholar 

  • Eiholzer U, l'Allemand D, Rousson V, Schlumpf M, Gasser T, Girard J, Grüters A, Simoni M. Hypothalamic and gonadal components of hypogonadism in boys with Prader-Labhart-Willi syndrome. J Clin Endocrinol Metab. 2006;91:892–8.

    Article  CAS  PubMed  Google Scholar 

  • European Metrodin HP Study Group EMHSG. Efficacy and safety of highly purified urinary follicle-stimulating hormone with human chorionic gonadotropin for treating men with isolated hypogonadotropic hypogonadism. European Metrodin HP Study Group. Fertil Steril. 1998;70:256–62.

    Article  Google Scholar 

  • Falardeau J, Chung WC, Beenken A, Raivio T, Plummer L, Sidis Y, Jacobson-Dickman EE, Eliseenkova AV, Ma J, Dwyer A, Quinton R, Na S, Hall JE, Huot C, Alois N, Pearce SH, Cole LW, Hughes V, Mohammadi M, Tsai P, Pitteloud N. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J Clin Invest. 2008;118:2822–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fennell C, Sartorius G, Ly LP, Turner L, Liu PY, Conway AJ, Handelsman DJ. Randomized cross-over clinical trial of injectable vs. implantable depot testosterone for maintenance of testosterone replacement therapy in androgen deficient men. Clin Endocrinol. 2010;73:102–9.

    CAS  Google Scholar 

  • Finkel DM, Phillips BA, Snyder PJ. Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism. N Engl J Med. 1985;313:651–5.

    Article  CAS  PubMed  Google Scholar 

  • Fischer-Posovszky P, von Schnurbein J, Moepps B, Lahr G, Strauss G, Barth TF, Kassubek J, Mühleder H, Möller P, Debatin KM, Gierschik P, Wabitsch M. A new missense mutation in the leptin gene causes mild obesity and hypogonadism without affecting T cell responsiveness. J Clin Endocrinol Metab. 2010;95:2836–40.

    Article  CAS  PubMed  Google Scholar 

  • Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R, Samuels MH. Hormonal replacement in hypopituitarism in adults: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101:3888–921.

    Article  CAS  PubMed  Google Scholar 

  • Frapsauce C, Ravel C, Legendre M, Sibony M, Mandelbaum J, Donadille B, Achermann JC, Siffroi JP, Christin-Maitre S. Birth after TESE-ICSI in a man with hypogonadotropic hypogonadism and congenital adrenal hypoplasia linked to a DAX-1 (NR0B1) mutation. Hum Reprod. 2011;26:724–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gelhorn HL, Vernon MK, Stewart KD, Miller MG, Brod M, Althof SE, DeRogatis LR, Dobs A, Seftel AD, Revicki DA. Content validity of the hypogonadism impact of symptoms questionnaire (HIS-Q): a patient-reported outcome measure to evaluate symptoms of hypogonadism. Patient. 2016;9:181–90.

    Article  PubMed  Google Scholar 

  • Gooren L. Hypogonadotropic hypogonadal men respond less well to androgen substitution treatment than hypergonadotropic hypogonadal men. Arch Sex Behav. 1988;17:265–70.

    Article  CAS  PubMed  Google Scholar 

  • Greulich WW, Pyle SI, editors. Radiographic atlas of skeletal development of hand and wrist. 2. ed. California: Stanford University Press; 1959.

    Google Scholar 

  • Grinspon RP, Rey RA. Anti-mullerian hormone and sertoli cell function in paediatric male hypogonadism. Horm Res Paediatr. 2010;73:81–92.

    Article  CAS  PubMed  Google Scholar 

  • Habiby RL, Boepple P, Nachtigall L, Sluss PM, Crowley WF Jr, Jameson JL. Adrenal hypoplasia congenita with hypogonadotropic hypogonadism: evidence that DAX-1 mutations lead to combined hypothalmic and pituitary defects in gonadotropin production. J Clin Invest. 1996;98:1055–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haring R, Baumeister SE, Nauck M, Völzke H, Keevil BG, Brabant G, Wallaschofski H. Testosterone and cardiometabolic risk in the general population – the impact of measurement method on risk associations: a comparative study between immunoassay and mass spectrometry. Eur J Endocrinol. 2013;169:463–70.

    Article  CAS  PubMed  Google Scholar 

  • Harrington J, Palmert MR. Clinical review: Distinguishing constitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism: critical appraisal of available diagnostic tests. J Clin Endocrinol Metab. 2012;97:3056–67.

    Article  CAS  PubMed  Google Scholar 

  • Hayes FJ, Seminara SB, Decruz S, Boepple PA, Crowley WF Jr. Aromatase inhibition in the human male reveals a hypothalamic site of estrogen feedback. J Clin Endocrinol Metab. 2000;85:3027–35.

    CAS  PubMed  Google Scholar 

  • Hier DB, Crowley WF Jr. Spatial ability in androgen-deficient men. N Engl J Med. 1982;306:1202–5.

    Article  CAS  PubMed  Google Scholar 

  • Huhtaniemi IT, Tajar A, Lee DM, O'Neill TW, Finn JD, Bartfai G, Boonen S, Casanueva FF, Giwercman A, Han TS, Kula K, Labrie F, Lean ME, Pendleton N, Punab M, Silman AJ, Vanderschueren D, Forti G, Wu FC, EMAS Group. Comparison of serum testosterone and estradiol measurements in 3174 European men using platform immunoassay and mass spectrometry; relevance for the diagnostics in aging men. Eur J Endocrinol. 2012;166:983–91.

    Article  CAS  PubMed  Google Scholar 

  • Hummel T, Kobal G, Gudziol H, Mackay-Sim A. Normative data for the "Sniffin' Sticks" including tests of odor identification, odor discrimination, and olfactory thresholds: an upgrade based on a group of more than 3,000 subjects. Eur Arch Otorhinolaryngol. 2007;264:237–43.

    Article  CAS  PubMed  Google Scholar 

  • Jadhav U, Harris RM, Jameson JL. Hypogonadotropic hypogonadism in subjects with DAX1 mutations. Mol Cell Endocrinol. 2011;346:65–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Janssen N, Bergman JE, Swertz MA, Tranebjaerg L, Lodahl M, Schoots J, Hofstra RM, van Ravenswaaij-Arts CM, Hoefsloot LH. Mutation update on the CHD7 gene involved in CHARGE syndrome. Hum Mutat. 2012;33:1149–60.

    Article  CAS  PubMed  Google Scholar 

  • Johnsen SG. Maintenance of spermatogenesis induced by hMG treatment by means of continuous hCG treatment in hypogonadotropic men. Acta Endocrinol. 1978;89:763–9.

    CAS  PubMed  Google Scholar 

  • Karaca Z, Tanrıverdi F, Ünlühızarcı K, Kelestimur F. GH and pituitary hormone alterations after traumatic brain injury. Prog Mol Biol Transl Sci. 2016;138:167–91.

    Article  CAS  PubMed  Google Scholar 

  • Kelleher S, Turner L, Howe C, Conway AJ, Handelsman DJ. Extrusion of testosterone pellets: a randomized controlled clinical study. Clin Endocrinol. 1999;51:469–71.

    Article  CAS  Google Scholar 

  • Kelly DF, Chaloner C, Evans D, Mathews A, Cohan P, Wang C, Swerdloff R, Sim MS, Lee J, Wright MJ, Kernan C, Barkhoudarian G, Yuen KC, Guskiewicz K. Prevalence of pituitary hormone dysfunction, metabolic syndrome, and impaired quality of life in retired professional football players: a prospective study. J Neurotrauma. 2014;31:1161–71.

    Article  PubMed  PubMed Central  Google Scholar 

  • Khan SA, Muhammad N, Khan MA, Kamal A, Rehman ZU, Khan S. Genetics of human Bardet-Biedl syndrome, an update. Clin Genet. 2016;90:3–15.

    Article  CAS  PubMed  Google Scholar 

  • Kliesch S, Behre HM, Nieschlag E. Recombinant human follicle-stimulating hormone and human chorionic gonadotropin for induction of spermatogenesis in a hypogonadotropic male. Fertil Steril. 1995;63:1326–8.

    Article  CAS  PubMed  Google Scholar 

  • Kühnert B, Byrne M, Simoni M, Köpcke W, Gerss J, Lemmnitz G, Nieschlag E. Testosterone substitution with a new transdermal, hydroalcoholic gel applied to scrotal or non-scrotal skin: a multicentre trial. Eur J Endocrinol. 2005;153:317–26.

    Article  PubMed  CAS  Google Scholar 

  • Laitinen EM, Tommiska J, Sane T, Vaaralahti K, Toppari J, Raivio T. Reversible congenital hypogonadotropic hypogonadism in patients with CHD7, FGFR1 or GNRHR mutations. PLoS One. 2012;7:e39450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Layman LC, Cohen DP, Jin M, Xie J, Li Z, Reindollar RH, Bolbolan S, Bick DP, Sherins RR, Duck LW, Musgrove LC, Sellers JC, Neill JD. Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism. Nat Genet. 1998;18:14–5.

    Article  CAS  PubMed  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;151:3479–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O'Kirwan F, Whitby R, Liang L, Cohen P, Bhasin S, Krauss RM, Veldhuis JD, Wagner AJ, DePaoli AM, McCann SM, Wong ML. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci U S A. 2004;101:4531–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu L, Banks SM, Barnes KM, Sherins RJ. Two-year comparison of testicular responses to pulsatile gonadotropin-releasing hormone and exogenous gonadotropins from the inception of therapy in men with isolated hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 1988;67:1140–5.

    Article  CAS  PubMed  Google Scholar 

  • Liu PY, Gebski VJ, Turner L, Conway AJ, Wishart SM, Handelsman DJ. Predicting pregnancy and spermatogenesis by survival analysis during gonadotrophin treatment of gonadotrophin-deficient infertile men. Hum Reprod. 2002;17:625–33.

    Google Scholar 

  • Liu PY, Swerdloff RS, Christenson PD, Handelsman DJ, Wang C. Hormonal Male Contraception Summit Group. Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis. Lancet. 2006;367:1412–20.

    Google Scholar 

  • Liu PY, Baker HW, Jayadev V, Zacharin M, Conway AJ, Handelsman DJ. Induction of spermatogenesis and fertility during gonadotropin treatment of gonadotropin-deficient infertile men: predictors of fertility outcome. J Clin Endocrinol Metab. 2009;94:801–8.

    Article  CAS  PubMed  Google Scholar 

  • Lofrano-Porto A, Barra GB, Giacomini LA, Nascimento PP, Latronico AC, Casulari LA, da Rocha Neves Fde A. Luteinizing hormone beta mutation and hypogonadism in men and women. N Engl J Med. 2007;357:897–904.

    Article  CAS  PubMed  Google Scholar 

  • Mackey MA, Conway AJ, Handelsman DJ. Tolerability of intramuscular injections of testosterone ester in oil vehicle. Hum Reprod. 1995;108:862–5.

    Article  Google Scholar 

  • Mantovani G, Ozisik G, Achermann JC, Romoli R, Borretta G, Persani L, Spada A, Jameson JL, Beck-Peccoz P. Hypogonadotropic hypogonadism as a presenting feature of late-onset X-linked adrenal hypoplasia congenita. J Clin Endocrinol Metab. 2002;87:44–8.

    Article  CAS  PubMed  Google Scholar 

  • Mao JF, Liu ZX, Nie M, Wang X, HL X, Huang BK, Zheng JJ, Min L, Kaiser UB, Pulsatile WXY. Gonadotropin-releasing hormone therapy is associated with earlier spermatogenesis compared to combined gonadotropin therapy in patients with congenital hypogonadotropic hypogonadism. Asian J Androl. 2016. https://doi.org/10.4103/1008-682X.193568.

  • Matthews CH, Borgato S, Beck-Peccoz P, Adams M, Tone Y, Gambino G, Casagrande S, Tedeschini G, Benedetti A, Chatterjee VK. Primary amenorrhoea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone. Nat Genet. 1993;5:83–6.

    Google Scholar 

  • 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;62:1184–92.

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto AM, Snyder PJ, Bhasin S, Martin K, Weber T, Winters S, Spratt D, Brentzel J, O’Dea L. Stimulation of spermatogenesis with recombinant human follicle-stimulating hormone (follitropin alfa; GONAL-f): long-term treatment in azoospermic men with hypogonadotropic hypogonadism. Fertil Steril 2009;92:979–990.

    Google Scholar 

  • McNicholas T, Ong T. Review of Testim gel. Expert Opin Pharmacother. 2006;7:477–84.

    Article  CAS  PubMed  Google Scholar 

  • Nelson D, Ho J, Pacaud D, Stephure D. Virilization in two pre-pubertal children exposed to topical androgen. J Pediatr Endocrinol Metab. 2013;24:1–5.

    Google Scholar 

  • Netchine I, Sobrier ML, Krude H, Schnabel D, Maghnie M, Marcos E, Duriez B, Cacheux V, Moers A, Goossens M, Gruters A, Amselem S. Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet. 2000;25:182–6.

    Article  CAS  PubMed  Google Scholar 

  • Nieschlag E. Clinical trials in male hormonal contraception. Contraception. 2010;82:457–70.

    Article  CAS  PubMed  Google Scholar 

  • Nieschlag E, Nieschlag S. Testosterone deficiency: a historical perspective. Asian J Androl. 2014;16:161–8.

    Google Scholar 

  • Nieschlag E, Vorona E. Medical consequences of doping with anabolic androgenic steroids: effects on reproductive functions. Eur J Endocrinol. 2015;173:47–58.

    Article  CAS  Google Scholar 

  • Nieschlag E, Behre HM, Bouchard P, Corrales JJ, Jones TH, Stalla GK, Webb SM, Wu FC. Testosterone replacement therapy: current trends and future directions. Hum Reprod Update. 2004;10:409–19.

    Article  CAS  PubMed  Google Scholar 

  • Nieschlag E, Bouloux P-MG, Stegmann BJ, Shankar RR, Guan Y, Tzontcheva A, McCrary Sisk C, Behre H. Efficacy and safety of the long-acting Corifollitropin Alfa in combination with hCG in adult men with hypogonadotropic hypodonadism. Reprod Endocr Biol. 2017;15:17.

    Article  Google Scholar 

  • 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. 1999a;51:757–63.

    Article  CAS  Google Scholar 

  • Nieschlag E, Simoni M, Gromoll J, Weinbauer GF. Role of FSH in the regulation of spermatogenesis: clinical aspects. Clin Endocrinol. 1999b;51:139–46.

    Article  CAS  Google Scholar 

  • Nieschlag E, Wang C, Handelsman DJ, Swerdloff RS, Wu FCW, Einer-Jensen N, Waites GMH, editors. Guidelines for the use of androgens. Geneva: WHO Special Programme of Research/Development and Research Training in Human Reproduction; 1992.

    Google Scholar 

  • Phillip M, Arbelle JE, Segev Y, Parvari R. Male hypogonadism due to a mutation in the gene for the beta-subunit of follicle-stimulating hormone. N Engl J Med. 1998;338:1729–32.

    Article  CAS  PubMed  Google Scholar 

  • Pitteloud N, Dwyer AA, DeCruz S, Lee H, Boepple PA, Crowley WF Jr, Hayes FJ. 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;93:784–91.

    Article  CAS  PubMed  Google Scholar 

  • Pitteloud N, Hayes FJ, Dwyer A, Boepple PA, Lee H, Crowley WF Jr. Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2002;87:4128–36.

    Article  CAS  PubMed  Google Scholar 

  • Pitteloud N, Quinton R, Pearce S, Raivio T, Acierno J, Dwyer A, Plummer L, Hughes V, Seminara S, Cheng YZ, Li WP, Maccoll G, Eliseenkova AV, Olsen SK, Ibrahimi OA, Hayes FJ, Boepple P, Hall JE, Bouloux P, Mohammadi M, Crowley W. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest. 2007;117:457–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quaynor SD, Kim HG, Cappello EM, Williams T, Chorich LP, Bick DP, Sherins RJ, Layman LC. The prevalence of digenic mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome. Fertil Steril. 2011;96:1424–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quinton R, Cheow HK, Tymms DJ, Bouloux PM, Wu FC, Jacobs HS. Kallmann’s syndrome: is it always for life? Clin Endocrinol. 1999;50:481–5.

    Google Scholar 

  • Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, et al. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med. 2007;357:863–73.

    Article  CAS  PubMed  Google Scholar 

  • Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, Kaur G, Bruera E. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer. 2004;100:851–8.

    Article  CAS  PubMed  Google Scholar 

  • Rochira V, Zirilli L, Genazzani AD, Balestrieri A, Aranda C, Fabre B, Antunez P, Diazzi C, Carani C, Maffei L. 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;155:513–22.

    Article  CAS  PubMed  Google Scholar 

  • Rogol AD. Pubertal androgen therapy in boys. Pediatr Endocrinol Rev. 2005;3:383–90.

    Google Scholar 

  • Rohayem J, Hauffa BP, Zacharin M, Kliesch S, Zitzmann M. The “German Adolescent Hypogonadotropic Hypogonadism Study Group”. Testicular growth and spermatogenesis: new goals for pubertal hormone replacement in boys with hypogonadotropic hypogonadism? -a multicentre prospective study of hCG/rFSH treatment outcomes during adolescence. Clin Endocrinol (Oxford). 2017;86:75–87.

    Google Scholar 

  • Rohayem J, Nieschlag E, Kliesch S, Zitzmann M. Inhibin B, AMH, but not INSL3, IGF1 or DHEAS support differentiation between constitutional delay of growth and puberty and hypogonadotropic hypogonadism. Andrology. 2015;3:882–7.

    Article  CAS  PubMed  Google Scholar 

  • Rohayem J, Sinthofen N, Nieschlag E, Kliesch S, Zitzmann M. Causes of hypogonadotropic hypogonadism predict response to gonadotropin substitution in adults. Andrology. 2016;4:87–94.

    Article  CAS  PubMed  Google Scholar 

  • Rohayem J, Tüttelmann F, Mallidis C, Nieschlag E, Kliesch S, Zitzmann M. Restoration of fertility by gonadotropin replacement in a man with hypogonadotropic azoospermia and testicular adrenal rest tumors due to untreated simple virilizing congenital adrenal hyperplasia. Eur J Endocrinol. 2014;170:K11–7.

    Article  CAS  PubMed  Google Scholar 

  • Sartorius G, Spasevska S, Idan A, Turner L, Forbes E, Zamojska A, Allan CA, Ly LP, Conway AJ, McLachlan RI, Handelsman DJ. Serum testosterone, dihydrotestosterone and estradiol concentrations in older men self-reporting very good health: the healthy man study. Clin Endocrinol. 2012;77:755–63.

    Article  CAS  Google Scholar 

  • Schopohl J. Pulsatile gonadotrophin releasing hormone versus gonadotrophin treatment of hypothalamic hypogonadism in males. Hum Reprod. 1993;8:175–9.

    Article  CAS  PubMed  Google Scholar 

  • Sedlmeyer IL, Palmert MR. Delayed puberty: analysis of a large case series from an academic center. J Clin Endocrinol Metab. 2002;87:1613–20.

    Article  CAS  PubMed  Google Scholar 

  • Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O'Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349:1614–27.

    Article  CAS  PubMed  Google Scholar 

  • Shiraishi K, Oka S, Matsuyama H. Assessment of quality of life during gonadotrophin treatment for male hypogonadotrophic hypogonadism. Clin Endocrinol. 2014;81:259–65.

    Article  CAS  Google Scholar 

  • Sidhoum VF, Chan YM, Lippincott MF, Balasubramanian R, Quinton R, Plummer L, Dwyer A, Pitteloud N, Hayes FJ, Hall JE, Martin KA, Boepple PA, Seminara SB. Reversal and relapse of hypogonadotropic hypogonadism: resilience and fragility of the reproductive neuroendocrine system. J Clin Endocrinol Metab. 2014;99:861–70.

    Article  CAS  PubMed  Google Scholar 

  • Siegel ET, Kim HG, Nishimoto HK, Layman LC. The molecular basis of impaired follicle-stimulating hormone action: evidence from human mutations and mouse models. Reprod Sci. 2013;20:211–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Şimşek E, Montenegro LR, Binay C, Demiral M, Acıkalin MF, Latronico AC. Clinical and hormonal features of a male adolescent with congenital isolated follicle-stimulating hormone deficiency. Horm Res Paediatr. 2016;85:207–12.

    Article  PubMed  CAS  Google Scholar 

  • Sinisi AA, Esposito D, Maione L, Quinto MC, Visconti D, De Bellis A, Bellastella A, Conzo G, Bellastella G. Seminal anti-Mullerian hormone level is a marker of spermatogenic response during long-term gonadotropin therapy in male hypogonadotropic hypogonadism. Hum Reprod. 2008;23:1029–34.

    Article  CAS  PubMed  Google Scholar 

  • Sisk CL, Zehr JL. Pubertal hormones organize the adolescent brain and behavior. Front Neuroendocrinol. 2005;26:163–74.

    Article  CAS  PubMed  Google Scholar 

  • Soliman AT, De Sanctis V. An approach to constitutional delay of growth and puberty. Indian J Endocrinol Metab. 2012;16:698–705.

    Article  PubMed  PubMed Central  Google Scholar 

  • Spratt DI, Carr DB, Merriam GR, Scully RE, Rao PN, Crowley WF. The spectrum of abnormal patterns of gonadotropin-releasing hormone secretion in men with idiopathic hypogonadotropic hypogonadism: clinical and laboratory correlations. J Clin Endocrinol Metab. 1987;64:283–91.

    Article  CAS  PubMed  Google Scholar 

  • Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet. 1998;18:213–5.

    Article  CAS  PubMed  Google Scholar 

  • Swerdloff RS, Wang CL. Review of guidelines on diagnosis and treatment of testosterone deficiency. In: Nieschlag E, Behre HM, Nieschlag S, editors. Testosterone: action, deficiency, substitution. 4th ed. Cambridge: Cambridge University Press; 2012. p. 408–20.

    Chapter  Google Scholar 

  • Swerdloff RS, Pak Y, Wang C, Liu PY, Bhasin S, Gill TM, Matsumoto AM, Pahor M, Surampudi P, Snyder PJ. Serum testosterone (T) level variability in T-gel-treated older hypogonadal men: treatment monitoring implications. J Clin Endocrinol Metab. 2015;100:3280–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takeda T, Takasu N, Yamauchi K, Komiya I, Ohtsuka H, Nagasawa Y, Ohara N, Yamada T. Magnetic resonance imaging of the rhinencephalon in a patient with Kallmann’s syndrome. Intern Med. 1992;31:394–6.

    Article  CAS  PubMed  Google Scholar 

  • Tarnutzer AA, Gerth-Kahlert C, Timmann D, Chang DI, Harmuth F, Bauer P, Straumann D, Synofzik M. Boucher-Neuhäuser syndrome: cerebellar degeneration, chorioretinal dystrophy and hypogonadotropic hypogonadism: two novel cases and a review of 40 cases from the literature. J Neurol. 2015;262:194–202.

    Article  CAS  PubMed  Google Scholar 

  • Tenforde AS, Barrack MT, Nattiv A, Fredericson M. Parallels with the female athlete triad in male athletes. Sports Med. 2016;46:171–82.

    Article  PubMed  Google Scholar 

  • Tommiska J, Jørgensen N, Christiansen P, Juul A, Raivio T. A homozygous R262Q mutation in the gonadotropin-releasing hormone receptor presenting as reversal of hypogonadotropic hypogonadism and late-onset hypogonadism. Clin Endocrinol. 2013;78:316–7.

    Article  CAS  Google Scholar 

  • Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Ozbek MN, Imamoglu S, Akalin NS, Yuksel B, O'Rahilly S, Semple RK. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat Genet. 2009;41:354–8.

    Article  CAS  PubMed  Google Scholar 

  • Valdes-Socin H, Rubio Almanza M, Tomé Fernández-Ladreda M, Debray FG, Bours V, Beckers A. Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes. Front Endocrinol (Lausanne). 2014;5:109.

    Google Scholar 

  • Wabitsch M, Ballauff A, Holl R, Blum WF, Heinze E, Remschmidt H, Hebebrand J. Serum leptin, gonadotropin, and testosterone concentrations in male patients with anorexia nervosa during weight gain. J Clin Endocrinol Metab. 2001;86:2982–8.

    Article  CAS  PubMed  Google Scholar 

  • Waldstreicher J, Seminara SB, Jameson JL, Geyer A, Nachtigall LB, Boepple PA, Holmes LB, Crowley WF Jr. The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human. J Clin Endocrinol Metab. 1996;81:4388–95.

    CAS  PubMed  Google Scholar 

  • Wang C, Harnett M, Dobs AS, Swerdloff RS. Pharmacokinetics and safety of long-acting testosterone undecanoate injections in hypogonadal men: an 84-week phase III clinical trial. J Androl. 2010;31:457–65.

    Article  CAS  PubMed  Google Scholar 

  • Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Berman N, Hull L, Swerdloff RS. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 2004;89:2085–98.

    Article  CAS  PubMed  Google Scholar 

  • Warne DW, Decosterd G, Okada H, Yano Y, Koide N, Howles CM. A combined analysis of data to identify predictive factors for spermatogenesis in men with hypogonadotropic hypogonadism treated with recombinant human follicle-stimulating hormone and human chorionic gonadotropin. Fertil Steril. 2009;92:594–604.

    Article  CAS  PubMed  Google Scholar 

  • Wehkalampi K, Widén E, Laine T, Palotie A, Dunkel L. Patterns of inheritance of constitutional delay of growth and puberty in families of adolescent girls and boys referred to specialist pediatric care. J Clin Endocrinol Metab. 2008;93:723–8.

    Article  CAS  PubMed  Google Scholar 

  • World Health Organization (WHO). WHO Laboratory Manual for the Examination and Processing of Human Semen. 5th ed. Geneva: World Health Organization; 2010.

    Google Scholar 

  • Wilson DA, Hofman PL, Miles HL, Unwin KE, McGrail CE, Cutfield WS. Evaluation of the buserelin stimulation test in diagnosing gonadotropin deficiency in males with delayed puberty. J Pediatr. 2006;148:89–94.

    Article  CAS  PubMed  Google Scholar 

  • Wu W, Cogan JD, Pfaffle RW, Dasen JS, Frisch H, O'Connell SM, Flynn SE, Brown MR, Mullis PE, Parks JS, Phillips JA 3rd, Rosenfeld MG. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet. 1998;18:147–9.

    Article  CAS  PubMed  Google Scholar 

  • Young J, George JT, Tello JA, Francou B, Bouligand J, Guiochon-Mantel A, Brailly-Tabard S, Anderson RA, Millar RP. Kisspeptin restores pulsatile LH secretion in patients with neurokinin B signaling deficiencies: physiological, pathophysiological and therapeutic implications. Neuroendocrinology. 2013;97:193–202.

    Article  CAS  PubMed  Google Scholar 

  • Zacharin M, Sabin MA, Nair VV, Dagabdhao P. Addition of recombinant follicle-stimulating hormone to human chorionic gonadotropin treatment in adolescents and young adults with hypogonadotropic hypogonadism promotes normal testicular growth and may promote early spermatogenesis. Fertil Steril. 2012;98:836–42.

    Article  CAS  PubMed  Google Scholar 

  • Zhu J, Choa REY, Guo MH, Plummer L, Buck C, Palmert MR, Hirschhorn JN, Seminara SB, Chan YM. A shared genetic basis for self-limited delayed puberty and idiopathic hypogonadotropic hypogonadism. The Journal of Clinical Endocrinology & Metabolism 2015;100:E646–E654.

    Google Scholar 

  • Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab. 2006;91:4335–43.

    Article  CAS  PubMed  Google Scholar 

  • Zitzmann M, Nieschlag E. Androgen receptor gene CAG repeat length and body mass index modulate the safety of long-term intramuscular testosterone undecanoate therapy in hypogonadal men. J Clin Endocrinol Metab. 2007;92:3844–53.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center of Reproductive Medicine and Andrology, University of Münster, Münster, Germany

    Julia Rohayem & Eberhard Nieschlag

Authors
  1. Julia Rohayem
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eberhard Nieschlag
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Julia Rohayem .

Editor information

Editors and Affiliations

  1. DepT of Endocrinology and Nutrition, Univ de Santiago de Compostela, Santiago de Compostela, Spain

    Felipe F. Casanueva

  2. Division of Endocrinology, Diabetol, University of Torino, Torino, Torino, Italy

    Ezio Ghigo

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Rohayem, J., Nieschlag, E. (2018). Central Hypogonadism in the Male: Physiopathology, Diagnosis and Treatment. In: Casanueva, F., Ghigo, E. (eds) Hypothalamic-Pituitary Diseases. Endocrinology. Springer, Cham. https://doi.org/10.1007/978-3-319-38681-2_10-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-38681-2_10-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-38681-2

  • Online ISBN: 978-3-319-38681-2

  • eBook Packages: Springer Reference MedicineReference Module Medicine

Publish with us

Policies and ethics

Search

Navigation