Puberty is a complex maturation process that begins during fetal life and persists until the acquisition of reproduction function. The fundamental event that activates puberty occurs in the hypothalamus. A complex neuron network stimulates GnRH secretion, which stimulates pituitary gonadotropin secretion and then gonadal steroid secretion. Pubertal delay is defined as the presentation of clinical signs of puberty 2-2.5 SD later than in the normal population. Three major groups of etiopathogeneses are described: (1) hypogonadotropic hypogonadism, (2) hypergonadotropic hypogonadism, and (3) constitutional delay of puberty (CDP) - the most common cause of delayed puberty in boys. The differential diagnosis between CDP and isolated hypogonadotropic hypogonadism remains difficult. Mechanisms of pubertal timing are now better understood and genetic or epigenetic causes can explain some pubertal delays. However, there are still unexplained mechanisms. Treatment of delayed puberty is necessary to ensure full pubertal development for the adolescent and in case of hypogonadism, to restore fertility. Finally, precocious diagnosis of hypogonadism is primordial but can be difficult during childhood and in cases of partial hypogonadism. The study of genetic pubertal diseases or of different animal models could help to discover new diagnostic or therapeutic tools.

Keywords:
Hypogonadism, Puberty, Kallmann syndrome, Fertility treatment, Constitutional delay of puberty
1.
Ankarberg-Lindgren C, Elfving M, Wikland KA, Norjavaara E: Nocturnal application of transdermal estradiol patches produces levels of estradiol that mimic those seen at the onset of spontaneous puberty in girls. J Clin Endocrinol Metab 2001;86:3039-3044.
2.
Palmert MR, Boepple PA: Variation in the timing of puberty: clinical spectrum and genetic investigation. J Clin Endocrinol Metab 2001;86:2364-2368.
3.
Ojeda SR, Lomniczi A, Sandau US: Glial-gonadotrophin hormone (GNRH) neurone interactions in the median eminence and the control of GnRH secretion. J Neuroendocrinol 2008;20:732-742.
4.
Rey RA, Grinspon RP, Gottlieb S, Pasqualini T, Knoblovits P, Aszpis S, Pacenza N, Stewart Usher J, Bergada I, Campo SM: Male hypogonadism: an extended classification based on a developmental, endocrine physiology-based approach. Andrology 2013;1:3-16.
5.
Palmert MR, Dunkel L: Clinical practice. Delayed puberty. N Engl J Med 2012;366:443-453.
6.
Bhagavath B, Podolsky RH, Ozata M, Bolu E, Bick DP, Kulharya A, Sherins RJ, Layman LC: Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism. Fertil Steril 2006;85:706-713.
7.
Coutant R, Biette-Demeneix E, Bouvattier C, Bouhours-Nouet N, Gatelais F, Dufresne S, Rouleau S, Lahlou N: Baseline inhibin B and anti-müllerian hormone measurements for diagnosis of hypogonadotropic hypogonadism in boys with delayed puberty. J Clin Endocrinol Metab 2010;95:5225-5232.
8.
Hero M, Tommiska J, Vaaralahti K, Laitinen EM, Sipila I, Puhakka L, Dunkel L, Raivio T: Circulating anti-müllerian hormone levels in boys decline during early puberty and correlate with inhibin B. Fertil Steril 2012;97:1242-1247.
9.
Stanhope R, Adams J, Jacobs HS, Brook CG: Ovarian ultrasound assessment in normal children, idiopathic precocious puberty, and during low-dose pulsatile gonadotrophin-releasing hormone treatment of hypogonadotrophic hypogonadism. Arch Dis Child 1985;60:116-119.
10.
Margolin DH, Kousi M, Chan YM, Lim ET, Schmahmann JD, Hadjivassiliou M, Hall JE, Adam I, Dwyer A, Plummer L, Aldrin SV, O'Rourke J, Kirby A, Lage K, Milunsky A, Milunsky JM, Chan J, Hedley-Whyte ET, Daly MJ, Katsanis N, Seminara SB: Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. N Engl J Med 2013;368:1992-2003.
11.
Wehkalampi K, Widen E, Laine T, Palotie A, Dunkel L: Association of the timing of puberty with a chromosome 2 locus. J Clin Endocrinol Metab 2008;93:4833-4839.
12.
Sisk CL, Foster DL: The neural basis of puberty and adolescence. Nat Neurosci 2004;7:1040-1047.
13.
Karges B, Karges W, de Roux N: Clinical and molecular genetics of the human GnRH receptor. Hum Reprod Update 2003;9:523-530.
14.
Guran T, Tolhurst G, Bereket A, Rocha N, Porter K, Turan S, Gribble FM, Kotan LD, Akcay T, Atay Z, Canan H, Serin A, O'Rahilly S, Reimann F, Semple RK, Topaloglu AK: Hypogonadotropic hypogonadism due to a novel missense mutation in the first extracellular loop of the neurokinin b receptor. J Clin Endocrinol Metab 2009;94:3633-3639.
15.
Goodman RL, Lehman MN, Smith JT, Coolen LM, de Oliveira CV, Jafarzadehshirazi MR, Pereira A, Iqbal J, Caraty A, Ciofi P, Clarke IJ: Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology 2007;148:5752-5760.
16.
Plant TM, Moossy J, Hess DL, Nakai Y, McCormack JT, Knobil E: Further studies on the effects of lesions in the rostral hypothalamus on gonadotropin secretion in the female rhesus monkey (Macaca mulatta). Endocrinology 1979;105:465-473.
17.
Roth CL, Mastronardi C, Lomniczi A, Wright H, Cabrera R, Mungenast AE, Heger S, Jung H, Dubay C, Ojeda SR: Expression of a tumor-related gene network increases in the mammalian hypothalamus at the time of female puberty. Endocrinology 2007;148:5147-5161.
18.
Sangiao-Alvarellos S, Manfredi-Lozano M, Ruiz-Pino F, Navarro VM, Sanchez-Garrido MA, Leon S, Dieguez C, Cordido F, Matagne V, Dissen GA, Ojeda SR, Pinilla L, Tena-Sempere M: Changes in hypothalamic expression of the Lin28/let-7 system and related microRNAs during postnatal maturation and after experimental manipulations of puberty. Endocrinology 2013;154:942-955.
19.
Ojeda SR UH: Puberty in the Rat. New York, Raven Press, 2007.
20.
Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA: Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J Neurosci 2009;29:11859-11866.
21.
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.
22.
Bouligand J, Ghervan C, Tello JA, Brailly-Tabard S, Salenave S, Chanson P, Lombes M, Millar RP, Guiochon-Mantel A, Young J: Isolated familial hypogonadotropic hypogonadism and a GnRH1 mutation. N Engl J Med 2009;360:2742-2748.
23.
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 USA 2009;106:11703-11708.
24.
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;337:1597-1602.
25.
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;18:14-15.
26.
Beranova M, Oliveira LM, Bedecarrats GY, Schipani E, Vallejo M, Ammini AC, Quintos JB, Hall JE, Martin KA, Hayes FJ, Pitteloud N, Kaiser UB, Crowley WF Jr, Seminara SB: Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2001;86:1580-1588.
27.
Trarbach EB, Teles MG, Costa EM, Abreu AP, Garmes HM, Guerra G Jr, Baptista MT, de Castro M, Mendonca BB, Latronico AC: Screening of autosomal gene deletions in patients with hypogonadotropic hypogonadism using multiplex ligation-dependent probe amplification: detection of a hemizygosis for the fibroblast growth factor receptor 1. Clin Endocrinol (Oxf) 2010;72:371-376.
28.
Chevrier L, Guimiot F, de Roux N: GnRH receptor mutations in isolated gonadotropic deficiency. Mol Cell Endocrinol 2011;346:21-28.
29.
De Roux N, Young J, Brailly-Tabard S, Misrahi M, Milgrom E, Schaison G: The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred. J Clin Endocrinol Metab 1999;84:567-572.
30.
Topaloglu AK, Lu ZL, Farooqi IS, Mungan NO, Yuksel B, O'Rahilly S, Millar RP: Molecular genetic analysis of normosmic hypogonadotropic hypogonadism in a Turkish population: identification and detailed functional characterization of a novel mutation in the gonadotropin-releasing hormone receptor gene. Neuroendocrinology 2006;84:301-308.
31.
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;349:1614-1627.
32.
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.
33.
Lanfranco F, Gromoll J, von Eckardstein S, Herding EM, Nieschlag E, Simoni M: Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism. Eur J Endocrinol 2005;153:845-852.
34.
Semple RK, Achermann JC, Ellery J, Farooqi IS, Karet FE, Stanhope RG, O'Rahilly S, Aparicio SA: Two novel missense mutations in G protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2005;90:1849-1855.
35.
Tenenbaum-Rakover Y, Commenges-Ducos M, Iovane A, Aumas C, Admoni O, de Roux N: Neuroendocrine phenotype analysis in five patients with isolated hypogonadotropic hypogonadism due to a L102P inactivating mutation of GPR54. J Clin Endocrinol Metab 2007;92:1137-1144.
36.
Teles MG, Trarbach EB, Noel SD, Guerra-Junior G, Jorge A, Beneduzzi D, Bianco SD, Mukherjee A, Baptista MT, Costa EM, De Castro M, Mendonca BB, Kaiser UB, Latronico AC: A novel homozygous splice acceptor site mutation of KiSS1R in two siblings with normosmic isolated hypogonadotropic hypogonadism. Eur J Endocrinol 2010;163:29-34.
37.
Nimri R, Lebenthal Y, Lazar L, Chevrier L, Phillip M, Bar M, Hernandez-Mora E, de Roux N, Gat-Yablonski G: A novel loss-of-function mutation in GPR54/KiSS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family. J Clin Endocrinol Metab 2011;96:E536-E545.
38.
Topaloglu AK, Tello JA, Kotan LD, Ozbek MN, Yilmaz MB, Erdogan S, Gurbuz F, Temiz F, Millar RP, Yuksel B: Inactivating KiSS1 mutation and hypogonadotropic hypogonadism. N Engl J Med 2012;366:629-635.
39.
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;41:354-358.
40.
Gianetti E, Tusset C, Noel SD, Au MG, Dwyer AA, Hughes VA, Abreu AP, Carroll J, Trarbach E, Silveira LF, Costa EM, de Mendonca BB, de Castro M, Lofrano A, Hall JE, Bolu E, Ozata M, Quinton R, Amory JK, Stewart SE, Arlt W, Cole TR, Crowley WF, Kaiser UB, Latronico AC, Seminara SB: TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. J Clin Endocrinol Metab 2010;95:2857-2867.
41.
Dode C, Hardelin JP: Kallmann syndrome. Eur J Hum Genet 2009;17:139-146.
42.
Legouis R, Hardelin JP, Levilliers J, Claverie JM, Compain S, Wunderle V, Millasseau P, Le Paslier D, Cohen D, Caterina D, et al: The candidate gene for the X-linked kallmann syndrome encodes a protein related to adhesion molecules. Cell 1991;67:423-435.
43.
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 2003;33:463-465.
44.
Miura K, Acierno JS Jr, Seminara SB: Characterization of the human nasal embryonic LHRH factor gene, NELF, and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism. J Hum Genet 2004;49:265-268.
45.
Dode 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.
46.
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;118:2822-2831.
47.
Kim HG, Ahn JW, Kurth I, Ullmann R, Kim HT, Kulharya A, Ha KS, Itokawa Y, Meliciani I, Wenzel W, Lee D, Rosenberger G, Ozata M, Bick DP, Sherins RJ, Nagase T, Tekin M, Kim SH, Kim CH, Ropers HH, Gusella JF, Kalscheuer V, Choi CY, Layman LC: WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet 2010;87:465-479.
48.
Hanchate NK, Giacobini P, Lhuillier P, Parkash J, Espy C, Fouveaut C, Leroy C, Baron S, Campagne C, Vanacker C, Collier F, Cruaud C, Meyer V, Garcia-Pinero A, Dewailly D, Cortet-Rudelli C, Gersak K, Metz C, Chabrier G, Pugeat M, Young J, Hardelin JP, Prevot V, Dode C: SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with kallmann syndrome. PLoS Genet 2012;8:e1002896.
49.
Miraoui H, Dwyer AA, Sykiotis GP, Plummer L, Chung W, Feng B, Beenken A, Clarke J, Pers TH, Dworzynski P, Keefe K, Niedziela M, Raivio T, Crowley WF Jr, Seminara SB, Quinton R, Hughes VA, Kumanov P, Young J, Yialamas MA, Hall JE, Van Vliet G, Chanoine JP, Rubenstein J, Mohammadi M, Tsai PS, Sidis Y, Lage K, Pitteloud N: Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet 2013;92:725-743.
50.
Villanueva C, de Roux N: FGFR1 mutations in Kallmann syndrome. Front Horm Res 2010;39:51-61.
51.
Pitteloud N, Acierno JS Jr, Meysing AU, Dwyer AA, Hayes FJ, Crowley WF Jr: Reversible Kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. J Clin Endocrinol Metab 2005;90:1317-1322.
52.
Raivio T, Avbelj M, McCabe MJ, Romero CJ, Dwyer AA, Tommiska J, Sykiotis GP, Gregory LC, Diaczok D, Tziaferi V, Elting MW, Padidela R, Plummer L, Martin C, Feng B, Zhang C, Zhou QY, Chen H, Mohammadi M, Quinton R, Sidis Y, Radovick S, Dattani MT, Pitteloud N: Genetic overlap in Kallmann syndrome, combined pituitary hormone deficiency, and septo-optic dysplasia. J Clin Endocrinol Metab 2012;97:E694-E699.
53.
Sedlmeyer IL, Hirschhorn JN, Palmert MR: Pedigree analysis of constitutional delay of growth and maturation: determination of familial aggregation and inheritance patterns. J Clin Endocrinol Metab 2002;87:5581-5586.
54.
Wehkalampi K, Widen 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;93:723-728.
55.
Grumbach MM, Styne DM: Williams Textbook of Endocrinology, ed 9. Philadelphia, Saunders, 1998, pp 1550-1551.
56.
Traggiai C, Stanhope R: Disorders of pubertal development. Best Pract Res Clin Obstet Gynaecol 2003;17:41-56.
57.
Hochberg Z, Belsky J: Evo-devo of human adolescence: beyond disease models of early puberty. BMC Med 2013;11:113.
58.
Fraietta R, Zylberstejn DS, Esteves SC: Hypogonadotropic hypogonadism revisited. Clinics 2013;68(suppl 1):81-88.
59.
Raivio T, Wikstrom AM, Dunkel L: Treatment of gonadotropin-deficient boys with recombinant human FSH: long-term observation and outcome. Eur J Endocrinol 2007;156:105-111.
60.
Bouvattier C, Maione L, Bouligand J, Dode C, Guiochon-Mantel A, Young J: Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism. Nat Rev Endocrinol 2012;8:172-182.
61.
Zitzmann M, Nieschlag E: Hormone substitution in male hypogonadism. Mol Cell Endocrinol 2000;161:73-88.
62.
Han TS, Bouloux PM: What is the optimal therapy for young males with hypogonadotropic hypogonadism? Clin Endocrinol (Oxf) 2010;72:731-737.
63.
Fukami M, Maruyama T, Dateki S, Sato N, Yoshimura Y, Ogata T: Hypothalamic dysfunction in a female with isolated hypogonadotropic hypogonadism and compound heterozygous TACR3 mutations and clinical manifestation in her heterozygous mother. Horm Res Paediatr 2010;73:477-481.
© 2014 S. Karger AG, Basel
2014
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.