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Constitutional Delayed Puberty

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Puberty

Abstract

Constitutional delayed puberty (CDP) traditionally has been considered a variant of normal growth with delay of onset of puberty and eventual normal secretion of reproductive system hormones resulting in normal physical development and fertility. In boys, pubertal delay is most commonly associated with CDP, while pubertal delay in girls is much more likely to stem from a pathological cause. Historically CDP has been a diagnosis of exclusion, assumed when there was no evidence of a pathologic cause, but confirmed only after years when reproductive function is within the adult range.

However, gradually over recent years, the perception that CDP is simply a normal variant has been questioned. This change in perception is based on studies of adult CDP with a history of showing lack of attainment of genetically expected adult height, evidence of subfertility, and comparatively low bone mineral density. Further evidence is provided by the finding that some patients previously diagnosed as having permanent hypogonadotropic hypogonadism (HH) have been noted to develop endogenous hormone secretion as late as the third decade of life suggesting an extreme form of CDP in which normal fertility is spontaneously established. In addition, patients with CDP have functional abnormalities and are suggested by the co-occurrence of CDP and HH within the same kindred, and the evidence that gene variants (such as polymorphisms) whose mutations are known to result in permanent HH are also present in those with CDP. While genetic differences between these groups are being investigated, the approach to patients with CDP, including short-term hormonal therapy and long-term follow-up, remains unchanged, but with the understanding that CDP may actually reflect a disordered physiology rather than being merely a benign variant of normal.

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References

  1. Palmert MR, Dunkel L. Clinical practice. Delayed puberty. N Engl J Med. 2012;366:443–53.

    Article  CAS  PubMed  Google Scholar 

  2. Yap F, Hogler W, Broidy J, Moore B, Howman-Giles R, Cowell CT. The skeletal phenotype of men with previous constitutional delay of puberty. J Clin Endocrinol Metab. 2004;89:4306–11.

    Article  CAS  PubMed  Google Scholar 

  3. Sykiotis GP, Pitteloud N, Seminara SB, Kaiser UB, Crowley WF, Jr. Deciphering genetic disease in the genomic era: the model of GnRH deficiency. Sci Transl Med. 2010;2:32rv32.

    Google Scholar 

  4. Arrigo T, Cisternino M, De Luca F, Saggese G, Messina MF, Pasquino AM, et al. Final height outcome in both untreated and testosterone-treated boys with constitutional delay of growth and puberty. J Pediatr Endocrinol Metab. 1996;9:511–7.

    Article  CAS  PubMed  Google Scholar 

  5. 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 

  6. 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. doi:10.3389/fendo.2014.00109. eCollection 2014.

  7. Sidhoum VF, Chan Y-M, Lippincott MF, Balasubramanian R, Quiton R, Plummer L, et al. 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 

  8. Dunkel L, Quinton R. Transition in endocrinology: induction of puberty. Eur J Endocrinol. 2014;170:R229–39.

    Article  CAS  PubMed  Google Scholar 

  9. von Kalckreuth G, Haverkamp F, Kessler M. Constitutional delay of growth and puberty: do they really reach their target height? Horm Res. 1991;35:222–5.

    Article  Google Scholar 

  10. Bertelloni S, Baroncelli GI, Ferdeghini M, Perri G, Saggese G. Normal volumetric bone mineral density and bone turnover in young men with histories of constitutional delay of puberty. J Clin Endocrinol Metab. 1998;83:4280–3.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Zhu J, Choa RE, Guo MH, Plummer L, Buck C, Palmert MR, et al. A shared genetic basis for self-limited delayed puberty and idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2015;100(4):E646–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gianetti E, Tusset C, Noel SD, Au MG, Dwyer AA, Hughes VA, Abreu AP, et al. 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;95:2857–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Beneduzzi D, Trarbach EB, Min L, Jorge AA, Garmes HM, Renk AC, et al. Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay. Fertil Steril. 2014;102(3):838–846.e2.

    Google Scholar 

  15. Kang BH, Kim SY, Park MS, Yoon KL, Shim KS. Estrogen receptor α polymorphism in boys with constitutional delay of growth and puberty. Ann Pediatr Endocrinol Metab. 2013;18:71–5.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Joustra SD, Wehkalampi K, Oostdijk W, Biermasz NR, Howard S, Silander TL, et al. IGSF1 variants in boys with familial delayed puberty. Eur J Pediatr. 2015;174:687–92.

    Article  CAS  PubMed  Google Scholar 

  17. Cousminer DL, Leinonen JT, Sarin AP, Chheda H, Surakka I, Wehkalampi K, et al. Targeted resequencing of the pericentromere of chromosome 2 linked to constitutional delay of growth and puberty. PLoS One. 2015;10(6), e0128524.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 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;93:4833–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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;87:5581–6.

    Article  CAS  PubMed  Google Scholar 

  20. 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;93:723–8.

    Article  CAS  PubMed  Google Scholar 

  21. Nathan BM, Sedlmeyer IL, Palmert MR. Impact of body mass index on growth in boys with delayed puberty. J Pediatr Endocrinol Metab. 2006;19:971–7.

    Article  PubMed  Google Scholar 

  22. Kaplowitz P. Delayed puberty in obese boys: comparison with constitutional delayed puberty and response to testosterone therapy. J Pediatr. 1998;133:745–9.

    Article  CAS  PubMed  Google Scholar 

  23. Wagner IV, Sabin MA, Pfäffle RW, Hiemisch A, Sergeyev E, Körner A, et al. Effects of obesity on human sexual development. Nat Rev Endocrinol. 2012;31:246–54.

    Article  Google Scholar 

  24. Lanes R, Lee PA, Plotnick LP, Kowarski AA, Migeon CJ. Are constitutional delay of growth and familial short stature different conditions? Clin Pediatr. 1980;19:31–3.

    Article  CAS  Google Scholar 

  25. Lindsay R, Feldkamp M, Harris D, Robertson J, Rallison M. Utah growth study: growths standards and the prevalence of growth hormone deficiency. J Pediatr. 1994;125:29–35.

    Article  CAS  PubMed  Google Scholar 

  26. Wehkalampia K, Vangonena K, Laines T, Dunkel L. Progressive reduction of relative height in childhood predicts adult stature below target height in boys with constitutional delay of growth and puberty. Horm Res. 2007;68:99–111.

    Google Scholar 

  27. Degros V, Cortet-Rudelli C, Soudan B, Dewailly D. The human chorionic gonadotropin test is more powerful than the gonadotropin-releasing hormone agonist test to discriminate male isolated hypogonadotropic hypogonadism from constitutional delayed puberty. Eur J Endocrinol. 2003;149:23–9.

    Article  CAS  PubMed  Google Scholar 

  28. Gerner Lawaetz J, Hagen CP, Grunnet Mieritz M, Blomberg Jensen M, Holm Petersen J, Juul A. Evaluation of 451 Danish boys with delayed puberty: diagnostic use of a new puberty nomogram and effects of oral testosterone therapy. J Clin Endocrinol Metab. 2015;100:1376–85.

    Article  Google Scholar 

  29. Coutant R, Biette-Demeneix E, Bouvattier C, Bounours-Nouet N. Baseline inhibin B and anti-mullerian hormone measurements for diagnosis of hypogonadotropic hypogonadism in boys with delayed puberty. J Clin Endocrinol Metab. 2010;95:5225–32.

    Article  CAS  PubMed  Google Scholar 

  30. Hero M, Tommiska J, Varralahti K, Laitnen EM, Sipila I, Puhakka I, et al. Circulating anti-mullerian hormone levels in boys decline during early puberty and correlated with inhibin B. Fertil Steril. 2012;97:1242–7.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  32. Binder G, Schweizer R, Blumenstock G, Braun R. Inhibin B plus LH vs GnRH agonist test for distinguishing constitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism in boys. Clin Endocrinol (Oxf). 2015;82:100–5.

    Article  CAS  Google Scholar 

  33. Kauschansky A, Dickerman Z, Phillip M, Weintrob N, Strich D. Use of GnRH agonist and human chorionic gonadotropin tests for differentiating constitutional delayed puberty from gonadotropin deficiency in boys. Clin Endocrinol (Oxf). 2002;56:603–7.

    Article  CAS  Google Scholar 

  34. Martin MM, Martin AL. Constitutional delayed puberty in males and hypogonadotropic hypogonadism: a reliable and cost-effective approach to differential diagnosis. J Pediatr Endocrinol Metab. 2005;18:909–16.

    Article  PubMed  Google Scholar 

  35. Ghai K, Cara JF, Rosenfield RL. Gonadotropin releasing hormone agonist (nafarelin) test to differentiate gonadotropin deficiency from constitutionally delayed puberty in teen-age boys—a clinical research center study. J Clin Endocrinol Metab. 1995;80:2980–6.

    CAS  PubMed  Google Scholar 

  36. Zevenhuijzen H, Kelnar CH, Crofton PM. Diagnostic utility of a low-dose gonadotropin-releasing hormone test in the context of puberty disorders. Horm Res. 2004;62:168–76.

    CAS  PubMed  Google Scholar 

  37. De Luca F, Argente J, Cavallo L, Crowne E, Delemarre-Van de Wall HA, De Sanctis C, et al. Management of puberty in constitutional delay of growth and puberty. International workshop on management of puberty for optimal auxological results. J Pediatr Endocrinol Metab. 2001;14 Suppl 2:953–7.

    Google Scholar 

  38. Kaplowitz PB. Diagnostic value of testosterone therapy in boys with delayed puberty. Am J Dis Child. 1989;143:1001–2.

    Google Scholar 

  39. Kelly BP, Paterson WF, Donaldson MD. Final height outcome and value of height prediction in boys with constitutional delay in growth and adolescence treated with intramuscular testosterone 125 mg per month for 3 months. Clin Endocrinol (Oxf). 2003;58:267–72.

    Article  CAS  Google Scholar 

  40. Poyrazoglu S, Gumoz H, Darendeliler F, Saka N, Bundak R, Bas F. Constitutional delay of growth and puberty: from presentation to final height. J Pediatr Endocrinol Metab. 2005;18:171–9.

    Article  PubMed  Google Scholar 

  41. Soliman A, Adel A, Sabt A, Elbukhari E, Ahmed H, De Sanctis V. Does priming with ex steroids improve the diagnosis of normal growth hormone secretion in short children? Indian J Endocrinol Metab. 2014;18 Suppl 1:S80–3.

    PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, Hershey Medical Center, Penn State College of Medicine, 500 University Drive, Hershey, PA, 17033-0850, USA

    Peter A. Lee

  2. Department of Pediatrics, Georgia Regents University, 1446 Harper Street, Augusta, GA, 30912, USA

    Christopher P. Houk

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  1. Peter A. Lee
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Correspondence to Peter A. Lee .

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Editors and Affiliations

  1. Medical University Sofia, Sofia, Bulgaria

    Philip Kumanov

  2. American Center for Reproductive Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, USA

    Ashok Agarwal

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Lee, P.A., Houk, C.P. (2016). Constitutional Delayed Puberty. In: Kumanov, P., Agarwal, A. (eds) Puberty. Springer, Cham. https://doi.org/10.1007/978-3-319-32122-6_11

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  • DOI: https://doi.org/10.1007/978-3-319-32122-6_11

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