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Diagnosi e terapia dell’ipogonadismo nella sindrome di Kallmann

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Riassunto

La sindrome di Kallmann (SK) è una forma congenita di ipogonadismo ipogonadotropo idiopatico in cui l’ipogonadismo si associa a deficit olfattivo (ipo/anosmia) e ad altri difetti non riproduttivi (agenesia renale, sincinesie, palatoschisi, sindattilia). La SK può essere sporadica o familiare, con ereditarietà X-linked, autosomica (dominante o recessiva) o oligogenica. Nel 30% dei casi è stata trovata una mutazione di geni che regolano la migrazione dei neuroni GnRH e/o la morfogenesi dei bulbi olfattori (KAL1, FGFR1, FGF8, PROKR2, PROK2, CHD7). La SK si manifesta come ritardo o assenza della pubertà dopo i 18 anni nel maschio ed i 16 nella donna, insieme con il deficit olfattivo e, incostantemente, con le anomalie somatiche. I bassi livelli di gonadotropine e testosterone (T) o estradiolo (E2) sono diagnostici di ipogonadismo solo dopo l’eta’ di 18 (nei maschi) e 16 anni (nelle donne) e tra la seconda settimana e il terzo mese di vita nei bambini con micropene e/o criptorchidismo. In età adolescenziale i test ormonali basali e dopo stimolo non permettono di differenziare il ritardo costituzionale della pubertà dall’ipogonadismo ipogonadotropo. Lo smell test e la risonanza magnetica sono utili per valutare il deficit sensoriale e la morfologia dei bulbi olfattivi. Il sequenziamento dei geni candidati va effettuato sulla base dei dati clinici e dell’ereditarietà. Per indurre la pubertà si somministrano dosi crescenti di T intramuscolo (i.m.) o transdermico (td) nell’uomo o di E2 (orale, td) nella donna. Nei ragazzi può essere stimolato il T endogeno con l’hCG i.m. L’incremento delle dosi sostitutive va effettuato ogni 3–6 mesi sulla base della risposta clinica e del monitoraggio di laboratorio. Dopo la pubertà la terapia può essere continuata con il T undecaonato i.m. (ogni 10–12 settimane) nel maschio e con combinazioni di estro-progestinici nella donna. Un periodo di sospensione va programmato dopo il completamento della pubertà per poter identificare le forme reversibili. La terapia con gonadotropine (hCG ed FSH nell’uomo, FSH seguito da hCG nella donna) stimola la gametogenesi ed è indicata se si desidera la fertilità. Il counseling genetico permette di determinare il rischio potenziale di trasmissione della sindrome.

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Bibliografia

  1. Seminara SB, Hayes FJ, Crowley WF Jr. Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann’s syndrome): pathophysiological and genetic considerations. Endocr Rev 19: 521, 1998.

    CAS  PubMed  Google Scholar 

  2. Quinton R, Duke VM, Robertson A, Kirk JM, Matfin G, de Zoysa PA, Azcona C, MacColl GS, Jacobs HS, Conway GS, Besser M, Stanhope RG, Bouloux PM. Idiopathic gonadotropin deficiency. Questions addressed through phenotypic characterization. Clin Endocrinol (Oxf) 55: 163, 2001.

    Article  CAS  Google Scholar 

  3. Kallmann FJ, Schoenfeld WA, Barrera SE. The genetic aspects of primary eunuchoidism, Am J Ment Def 48: 203, 1943-1944.

    Google Scholar 

  4. Cariboni A, Maggi R. Kallmann’s syndrome, a neuronal migration defect. Cell Mol Life Sci 63: 2512, 2006.

    Article  CAS  PubMed  Google Scholar 

  5. Pitteloud N, Durrani S, Raivio T, Sykiotis GP. Complex genetics in idiopathic hypogonadotropic hypogonadism. Front Horm Res 39: 142, 2010.

    Article  CAS  PubMed  Google Scholar 

  6. Ballabio A, Bardoni B, Carrozzo R, Andria G, Bick D, Campbell L, Hamel B, Ferguson-Smith MA, Gimelli G, Fraccaro M. et al. Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome, Proc Natl Acad Sci USA, 86: 10001, 1989.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Dode C, Levilliers J, Dupont JM, De Paepe A, Le Du N, Soussi-Yanicostas N, Coimbra RS, Delmaghani S, Compain-Nouaille S, Baverel F, Pecheux 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 33: 463, 2003.

    Article  CAS  PubMed  Google Scholar 

  8. Falardeau J, Chung WCJ, 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 SHS, 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 118: 2832, 2008.

    Article  Google Scholar 

  9. 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 2: e175, 2006.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Cole LW, Sidis Y, Zhang C, Quinton R, Plummer L, Pignatelli D, Hughes VA, Dwyer AA, Raivio T, Hayes FJ, Seminara SB, Huot C, Alos N, Speiser P, Takeshita A, Van Vliet G, Pearce S, Crowley WF Jr, Zhou QY, Pitteloud N. Mutations in prokineticin 2 and prokineti cin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum. J Clin Endocrinol Metab 93: 3551, 2008.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Sinisi AA, Asci R, Bellastella G, Maione L, Esposito D, Elefante A, De Bellis A, Bellastella A, Iolascon A. Homozygous mutation in the prokineticin-receptor2 gene (Val274Asp) presenting as reversible Kallmann syndrome and persistent oligozoospermia: case report. Hum Reprod 23: 2380, 2008.

    Article  CAS  PubMed  Google Scholar 

  12. Abreu AP, Trarbach EB, de Castro M, Costa EM, Versiani B, Baptista MT, Garmes HM, Mendonca BB, Latronico AC. Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome. J Clin Endocrinol Metab 93: 4113, 2008.

    Article  CAS  PubMed  Google Scholar 

  13. Sarfati J, Guiochon-Mantel A, Rondard P, Arnulf I, Garcia-Piñero A, Wolczynski S, Brailly-Tabard S, Bidet M, Ramos-Arroyo M, Mathieu M, Lienhardt-Roussie A, Morgan G, Turki Z, Bremont C, Lespinasse J, Du Boullay H, Chabbert-Buffet N, Jacquemont S, Reach G, De Talence N, Tonella P, Conrad B, Despert F, Delobel B, Brue T, Bouvattier C, Cabrol S, Pugeat M, Murat A, Bouchard P, Hardelin JP, Dodé C, Young J. A comparative phenotypic study of Kallmann Syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 (PROK2) or prokineticin receptor 2 (PROKR2) genes. J Clin Endocrinol Metab 95: 659, 2010.

    Article  CAS  PubMed  Google Scholar 

  14. 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 O. A., 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 117: 457, 2007.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Leroy C, Fouveaut C, Leclercq S, Jacquemont S, Boullay HD, Lespinasse J, Delpech M, Dupont JM, Hardelin JP, Dodé C. Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome. Eur J Hum Genet 16: 865, 2008.

    Article  CAS  PubMed  Google Scholar 

  16. Canto P, Munguía P, Söderlund D, Castro JJ, Méndez JP. Genetic analysis in patients with Kallmann syndrome: coexistence of mutations in prokineticin receptor2 and KAL1. J Androl 30: 41, 2009.

    Article  CAS  PubMed  Google Scholar 

  17. Pinto G, Abadie V, Mesnage R, Blustajn J, Cabrol S, Amiel J, Hertz-Pannier L, Bertrand AM, Lyonnet S, Rappaport R, Netchine I. CHARGE syndrome includes hypogonadotropic hypogonadism and abnormal olfactory bulb development. J Clin Endocrinol Metab 90: 5621, 2005.

    Article  CAS  PubMed  Google Scholar 

  18. Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA, Cole LW, Pearce SH, Lee H, Boepple P, Crowley WF Jr, Pitteloud N. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med 30: 863, 2007.

    Article  Google Scholar 

  19. Doty RL, Shalan P, Kimmelman CP, Dann MS. University of Pennsylvania smell identification test: a rapid quantitative olfactory function test for the clinic. Laryngoscope 94: 176, 1984

    Article  CAS  PubMed  Google Scholar 

  20. Salenave S, Chanson P, Bry H, Pugeat M, Cabrol S, Carel JC, Murat A, Lecomte P, Brailly S, Hardelin JP, Dodé C, Young J. Kallmann’s syndrome: a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations. J Clin Endocrinol Metab 93: 758, 2008.

    Article  CAS  PubMed  Google Scholar 

  21. Courant F, Aksglaede L, Antignac JP, Monteau F, Sorensen K, Andersson AM, Skakkebaek NE, Juul A, Bizec BL. Assessment of circulating sex steroid levels in prepubertal and pubertal boys and girls by a novel ultrasensitive gas chromatography-tandem mass spectrometry method. J Clin Endocrinol Metab 95: 82, 2010.

    Article  CAS  PubMed  Google Scholar 

  22. Andersson AM, Juul A, Petersen JH, Müller J, Groome NP, Skakkebaek NE. Serum inhibin B in healthy pubertal and adolescent boys: relation to age, stage of puberty, and follicle-stimulating hormone, luteinizing hormone, testosterone, and estradiol levels. J Clin Endocrinol Metab 82: 3976, 1997

    CAS  PubMed  Google Scholar 

  23. Sehested A, Juul AA, Andersson AM, Petersen JH, Jensen TK, Müller J, Skakkebaek NE. Serum inhibin A and inhibin B in healthy prepubertal, pubertal, and adolescent girls and adult women: relation to age, stage of puberty, menstrual cycle, follicle-stimulating hormone, luteinizing hormone, and estradiol levels. J Clin Endocrinol Metab 85: 1634, 2000.

    CAS  PubMed  Google Scholar 

  24. Kulin HE. Delayed puberty. J Clin Endocrinol Metab 81: 3460, 1996.

    CAS  PubMed  Google Scholar 

  25. Segal TY, Mehta A, Anazodo A, Hindmarsh PC, Dattani MT. Role of gonadotropin-releasing hormone and human chorionic gonadotropin stimulation tests in differentiating patients with hypogonadotropic hypogonadism from those with constitutional delay of growth and puberty. J Clin Endocrinol Metab 94: 780, 2009.

    Article  CAS  PubMed  Google Scholar 

  26. Grumbach MM. A window of opportunity: the diagnosis of gonadotropin deficiency in the male infant. J Clin Endocrinol Metab 90: 3122, 2005.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  28. Yousem DM, Geckle RJ, Bilker W, McKeown DA, Doty RL. MR evaluation of patients with congenital hyposmia or anosmia. AJR Am J Roentgenol 166: 439, 1996.

    Article  CAS  PubMed  Google Scholar 

  29. Lenzi A, Balercia G, Bellastella A, Colao A, Fabbri A, Foresta C, Galdiero M, Gandini L, Krausz C, Lombardi G, Lombardo F, Maggi M, Radicioni A, Selice R, Sinisi AA, Forti G. Epidemiology, diagnosis, and treatment of male hypogonadotropic hypogonadism. J Endocrinol Invest 32: 934, 2009.

    CAS  PubMed  Google Scholar 

  30. Zitzmann M, Nieschlag E. Hormonal substitution in male hypogonadism. Mol Cell Endocrinol 161: 73, 2000

    Article  CAS  PubMed  Google Scholar 

  31. Gooren LJ. Advances in testosterone replacement therapy. Front Horm Res 37: 32, 2009.

    Article  CAS  PubMed  Google Scholar 

  32. 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 89: 2085, 2004.

    Article  CAS  PubMed  Google Scholar 

  33. Schubert M, Minnemann T, Hübler D, Rouskova D, Christoph A, Oettel M, Ernst M, Mellinger U, Krone W, Jockenhövel F. Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism. J Clin Endocrinol Metab 89: 5429, 2004.

    Article  CAS  PubMed  Google Scholar 

  34. Barrio R, de Luis D, Alonso M, Lamas A, Moreno JC. Induction of puberty with human chronic gonadotropin and follicle-stimulating hormone in adolescent males with hypogonadotropic hypogonadism. Fertil Steril 71: 244, 1999.

    Article  CAS  PubMed  Google Scholar 

  35. Sinisi AA, Esposito D, Bellastella G, Maione L, Palumbo V, Gandini L, Lombardo F, De Bellis A, Lenzi A, Bellastella A. Efficacy of recombinant human follicle stimulating hormone at low doses in inducing spermatogenesis and fertility in hypogonadotropic hypogonadism. J Endocrinol Invest 33: 618, 2010.

    CAS  PubMed  Google Scholar 

  36. 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 94: 801, 2009.

    Article  CAS  PubMed  Google Scholar 

  37. 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 92: 594, 2009.

    Article  CAS  PubMed  Google Scholar 

  38. Bougnères P, François M, Pantalone L, Rodrigue D, Bouvattier C, Demesteere E, Roger D, Lahlou N. Effects of an early postnatal treatment of hypogonadotropic hypogonadism with a continuous subcutaneous infusion of recombinant follicle-stimulating hormone and luteinizing hormone J Clin Endocrinol Metab 93: 2202, 2008.

    Article  PubMed  Google Scholar 

  39. Rosenfield R. Puberty in the female and its disorders. In: Sperling MA (Ed) Pediatric endocrinology. Saunders, Philadelphia-Toronto, 2002, p 455.

    Google Scholar 

  40. Fauser BCJM, Maklon NS. Medical approach to ovarian stimulation for infertility. In: Strauss JF III, Barbieri RL (Eds) Reproductive endocrinology. Elsevier-Saunders, Philadelphia, 2004, p 965.

    Google Scholar 

  41. Krause BT, Ohlinger R, Haase A. Lutropin alpha, recombinant human luteinizing hormone, for the stimulation of follicular development in profoundly LH-deficient hypogonadotropic hypogonadal women: a review. Biologics 3: 337, 2009.

    CAS  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Cattedra di Endocrinologia, Dipartimento di Internistica Clinica e Sperimentale, Sezione di Endocrinologia ed Andrologia Medica, Seconda Università di Napoli, Via Pansini 5, 80131, Napoli, Italia

    Antonio Agostino Sinisi, Luigi Maione, Giuseppe Bellastella, Roberta Asci & Antonio Bellastella

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  1. Antonio Agostino Sinisi
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  2. Luigi Maione
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  3. Giuseppe Bellastella
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Correspondence to Antonio Agostino Sinisi.

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Sinisi, A.A., Maione, L., Bellastella, G. et al. Diagnosi e terapia dell’ipogonadismo nella sindrome di Kallmann. L’Endocrinologo 12, 8–19 (2011). https://doi.org/10.1007/BF03344775

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