Delayed puberty - Symptoms, Causes, Images, and Treatment Options

Diseases

Highlights & Basics

Key Highlights

Delayed puberty is defined as the lack of pubertal signs at an age that is 2 to 2.5 standard deviations later than the population mean, typically by the age of 13 years in girls and 14 years in boys. It is more common in boys.
Delayed puberty may be functional (constitutional delay, underlying chronic disease, malnutrition, excessive exercise) or organic, due to either a lack of serum gonadotropin production or action (hypogonadotropic hypogonadism), or gonadal insufficiency with elevated gonadotropins (hypergonadotropic hypogonadism).
Many patients seek medical assistance because of slow growth rather than slow pubertal development.
Careful assessment of height and pubertal stage is crucial for evaluation of the underlying cause.
The distinction between organic gonadotropin deficiency and constitutional (self-limited) delay of puberty is not easy and is often resolved only with the passage of time.

Quick Reference

History & Exam
- Key Factors
- Other Factors
More information...
Diagnostics Tests
More information...
Treatment Options
More information...

Definition

Epidemiology

Etiology

Pathophysiology

Images

Hypothalamo-pituitary-gonadal feedback loop. GnRH, gonadotropin-releasing hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone
Growth in a patient with constitutional delay in growth and puberty; X indicates bone age; arrow indicates age at onset of pubertal development
Prader orchidometer
Method of comparing testicular size using the Prader orchidometer
Tanner staging: A, genital rating standards in boys; B, pubic hair rating standards in boys; C, breast rating standards in girls; D, pubic hair rating standards in girls
Evaluation of a patient with delayed puberty. CDGP, constitutional delay of growth and puberty; DP, delayed puberty; FT4, free T4; GHD, GH deficiency; PRL, prolactin; TFT, thyroid function test

Citations

Key Articles

Palmert MR, Dunkel L. Clinical practice. Delayed puberty. N Engl J Med. 2012 Feb 2;366(5):443-53.[Abstract]
Howard SR, Dunkel L. The genetic basis of delayed puberty. Neuroendocrinology. 2018;106(3):283-91.[Abstract][Full Text]
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969 Jun;44(235):291-303.[Abstract][Full Text]
Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child. 1970 Feb;45(239):13-23.[Abstract][Full Text]

Referenced Articles

1. Palmert MR, Dunkel L. Clinical practice. Delayed puberty. N Engl J Med. 2012 Feb 2;366(5):443-53.[Abstract]
2. Timmreck LS, Reindollar RH. Contemporary issues in primary amenorrhea. Obstet Gynecol Clin North Am. 2003 Jun;30(2):287-302.[Abstract]
3. Nielsen J, Wohlert M. Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet. 1991 May;87(1):81-3.[Abstract]
4. Jacobs PA, Melville M, Ratcliffe S, et al. A cytogenetic survey of 11,680 newborn infants. Ann Hum Genet. 1974 May;37(4):359-76. [Abstract]
5. Laitinen EM, Vaaralahti K, Tommiska J, et al. Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland. Orphanet J Rare Dis. 2011 Jun 17;6:41.[Abstract][Full Text]
6. Delemarre-van de Waal HA. Secular trend of timing of puberty. Endocr Dev. 2005;8:1-14.[Abstract]
7. Tanner JM. Trend towards earlier menarche in London, Oslo, Copenhagen, the Netherlands and Hungary. Nature. 1973 May 11;243(5402):95-6.[Abstract]
8. Biro FM, Khoury P, Morrison JA. Influence of obesity on timing of puberty. Int J Androl. 2006 Feb;29(1):272-7.[Abstract]
9. Aksglaede L, Sørensen K, Petersen JH, et al. Recent decline in age at breast development: the Copenhagen Puberty Study. Pediatrics. 2009 May;123(5):e932-9.[Abstract]
10. de la Puente ML, Canela J, Alvarez J, et al. Cross-sectional growth study of the child and adolescent population of Catalonia (Spain). Ann Hum Biol. 1997 Sep-Oct;24(5):435-52.[Abstract]
11. Mul D, Fredriks AM, van Buuren S, et al. Pubertal development in The Netherlands 1965-1997. Pediatr Res. 2001 Oct;50(4):479-86.[Abstract]
12. Wu T, Mendola P, Buck GM. Ethnic differences in the presence of secondary sex characteristics and menarche among US girls: the Third National Health and Nutrition Examination Survey, 1988-1994. Pediatrics. 2002 Oct;110(4):752-7.[Abstract]
13. Himes JH. Examining the evidence for recent secular changes in the timing of puberty in US children in light of increases in the prevalence of obesity. Mol Cell Endocrinol. 2006 Jul 25;(254-55):13-21.[Abstract]
14. Ogden CL, Carroll MD, Flegal KM. High body mass index for age among US children and adolescents, 2003-2006. JAMA. 2008 May 28;299(20):2401-5.[Abstract][Full Text]
15. Osler DC, Crawford JD. Examination of the hypothesis of a critical weight at menarche in ambulatory and bedridden mentally retarded girls. Pediatrics. 1973 Apr;51(4):675-9.[Abstract]
16. Day FR, Bulik-Sullivan B, Hinds DA, et al. Shared genetic aetiology of puberty timing between sexes and with health-related outcomes. Nat Commun. 2015 Nov 9;6:8842.[Abstract][Full Text]
17. Sedlmeyer IL, Palmert MR. Delayed puberty: analysis of a large case series from an academic center. J Clin Endocrinol Metab. 2002 Apr;87(4):1613-20.[Abstract][Full Text]
18. Varimo T, Miettinen PJ, Känsäkoski J, et al. Congenital hypogonadotropic hypogonadism, functional hypogonadotropism or constitutional delay of growth and puberty? An analysis of a large patient series from a single tertiary center. Hum Reprod. 2017 Jan;32(1):147-53.[Abstract][Full Text]
19. Howard SR, Dunkel L. The genetic basis of delayed puberty. Neuroendocrinology. 2018;106(3):283-91.[Abstract][Full Text]
20. Wehkalampi K, Widén E, Laine T, et al. 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 Mar;93(3):723-8.[Abstract][Full Text]
21. Rugarli EI, Ballabio A. Kallmann syndrome: from genetics to neurobiology. JAMA. 1993 Dec 8;270(22):2713-6.[Abstract]
22. Dattani MT, Robinson IC. The molecular basis for developmental disorders of the pituitary gland in man. Clin Genet. 2000 May;57(5):337-46.[Abstract]
23. Reutens AT, Achermann JC, Ito M, et al. Clinical and functional effects of mutations in the DAX-1 gene in patients with adrenal hypoplasia congenita. J Clin Endocrinol Metab. 1999 Feb;84(2):504-11.[Abstract][Full Text]
24. Mehta A, Dattani M. Congenital disorders of the hypothalamic-pituitary axis. In: Brook CG, Clayton PE, Brown RS, eds. Clinical pediatric endocrinology. 5th ed. Hoboken, NJ: Wiley-Blackwell; 2005:67-89.
25. Scarzello G, Buzzaccarini MS, Perilongo G, et al. Acute and late morbidity after limited resection and focal radiation therapy in craniopharyngiomas. J Pediatr Endocrinol Metab. 2006 Apr;19(suppl 1):399-405.[Abstract]
26. Oerter KE, Kamp GA, Munson PJ, et al. Multiple hormone deficiencies in children with hemochromatosis. J Clin Endocrinol Metab. 1993 Feb;76(2):357-61.[Abstract]
27. Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med. 1998 Jun 22;158(12):1309-14.[Abstract][Full Text]
28. Toniolo D. X-linked premature ovarian failure: a complex disease. Curr Opin Genet Dev. 2006 Jun;16(3):293-300.[Abstract]
29. Hoek A, Schoemaker J, Drexhage HA. Premature ovarian failure and ovarian autoimmunity. Endocr Rev. 1997 Feb;18(1):107-34.[Abstract][Full Text]
30. Bakker B, Massa GG, Oostdijk W, et al. Pubertal development and growth after total-body irradiation and bone marrow transplantation for haematological malignancies. Eur J Pediatr. 2000 Jan-Feb;159(1-2):31-7.[Abstract]
31. Ojeda SR, Lomniczi A, Mastronardi C, et al. Minireview: the neuroendocrine regulation of puberty: is the time ripe for a systems biology approach? Endocrinology. 2006 Mar;147(3):1166-74.[Abstract][Full Text]
32. Jonsdottir-Lewis E, Feld A, Ciarlo R, et al. Timing of pubertal onset in girls and boys with constitutional delay. J Clin Endocrinol Metab. 2021 Aug 18;106(9):e3693-3703.[Abstract][Full Text]
33. Martha PM Jr, Rogol AD, Veldhuis JD, et al. Alterations in the pulsatile properties of circulating growth hormone concentrations during puberty in boys. J Clin Endocrinol Metab. 1989 Sep;69(3):563-70.[Abstract]
34. Veldhuis JD, Metzger DL, Martha PM Jr, et al. Estrogen and testosterone, but not a nonaromatizable androgen, direct network integration of the hypothalamo-somatotrope (growth hormone)-insulin-like growth factor I axis in the human: evidence from pubertal pathophysiology and sex-steroid hormone replacement. J Clin Endocrinol Metab. 1997 Oct;82(10):3414-20.[Abstract][Full Text]
35. Krone N, Arlt W. Genetics of congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab. 2009 Apr;23(2):181-92.[Abstract][Full Text]
36. Kiserud CE, Fosså A, Bjøro T, et al. Gonadal function in male patients after treatment for malignant lymphomas, with emphasis on chemotherapy. Br J Cancer. 2009 Feb 10;100(3):455-63.[Abstract][Full Text]
37. Howard SR, Dunkel L. Delayed puberty-phenotypic diversity, molecular genetic mechanisms, and recent discoveries. Endocr Rev. 2019 Oct 1;40(5):1285-317.[Abstract][Full Text]
38. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969 Jun;44(235):291-303.[Abstract][Full Text]
39. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child. 1970 Feb;45(239):13-23.[Abstract][Full Text]
40. Simpson JL, Rajkovic A. Ovarian differentiation and gonadal failure. Am J Med Genet. 1999 Dec 29;89(4):186-200.[Abstract]
41. Gravholt CH, Andersen NH, Conway GS, et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol. 2017 Sep;177(3):G1-70.[Abstract][Full Text]
42. Bayley N, Pinneau SR. Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standards. J Pediatr. 1952 Apr;40(4):423-41.[Abstract]
43. Howard SR. Interpretation of reproductive hormones before, during and after the pubertal transition-Identifying health and disordered puberty. Clin Endocrinol (Oxf). 2021 Nov;95(5):702-15.[Abstract][Full Text]
44. Nathwani NC, Hindmarsh PC, Massarano AA, et al. Gonadotrophin pulsatility in girls with the Turner syndrome: modulation by exogenous sex steroids. Clin Endocrinol (Oxf). 1998 Jul;49(1):107-13.[Abstract]
45. Segal TY, Mehta A, Anazodo A, et al. 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. 2009 Mar;94(3):780-5.[Abstract][Full Text]
46. Coutant R, Biette-Demeneix E, Bouvattier C, et al. Baseline inhibin B and anti-Mullerian hormone measurements for diagnosis of hypogonadotropic hypogonadism (HH) in boys with delayed puberty. J Clin Endocrinol Metab. 2010 Dec;95(12):5225-32.[Abstract][Full Text]
47. Johannsen TH, Andersson AM, Ahmed SF, et al. Peptide hormone analysis in diagnosis and treatment of Differences of Sex Development: joint position paper of EU COST Action 'DSDnet' and European Reference Network on Rare Endocrine Conditions. Eur J Endocrinol. 2020 Jun;182(6):P1-15.[Abstract]
48. Nordenström A, Ahmed SF, van den Akker E, et al. Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline. Eur J Endocrinol. 2022 Apr 21;186(6):G9-49.[Abstract][Full Text]
49. Al Sayed Y, Howard SR. Panel testing for the molecular genetic diagnosis of congenital hypogonadotropic hypogonadism - a clinical perspective. Eur J Hum Genet. 2022 Dec 15 [epub ahead of print].[Abstract][Full Text]
50. Mehta A, Hindmarsh PC, Mehta H, et al. Congenital hypopituitarism: clinical, molecular and neuroradiological correlates. Clin Endocrinol (Oxf). 2009 Sep;71(3):376-82.[Abstract]
51. Abbara A, Eng PC, Phylactou M, et al. Kisspeptin-54 accurately identifies hypothalamic gonadotropin-releasing hormone neuronal dysfunction in men with congenital hypogonadotropic hypogonadism. Neuroendocrinology. 2021;111(12):1176-86.[Abstract][Full Text]
52. Chan YM, Lippincott MF, Sales Barroso P, et al. Using kisspeptin to predict pubertal outcomes for youth with pubertal delay. J Clin Endocrinol Metab. 2020 Aug 1;105(8):e2717-25.[Abstract][Full Text]
53. American College of Radiology. ACR-ACOG-AIUM-SPR-SRU practice parameter for the performance of ultrasound of the female pelvis. 2019 [internet publication]. [Full Text]
54. Ahmed SF, Achermann J, Alderson J, et al. Society for Endocrinology UK guidance on the initial evaluation of a suspected difference or disorder of sex development (revised 2021). Clin Endocrinol (Oxf). 2021 Dec;95(6):818-40.[Abstract][Full Text]
55. Zitzmann M, Aksglaede L, Corona G, et al. European Academy of Andrology guidelines on Klinefelter syndrome: Endorsing organization: European Society of Endocrinology. Andrology. 2021 Jan;9(1):145-67.[Abstract][Full Text]
56. Raivio T, Falardeau J, Dwyer A, et al. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med. 2007 Aug 30;357(9):863-73.[Abstract][Full Text]
57. Rohayem J, Hauffa BP, Zacharin M, et al. 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 (Oxf). 2017 Jan;86(1):75-87.[Abstract]
58. Dunkel L, Prasad R, Senniappan S, et al. Protocol for induction of puberty with gonadotropins in adolescent males with GnRH or gonadotropin deficiency pubertal induction with gonadotropins. Version 1.6. September 2021 [internet publication].[Full Text]
59. Ankarberg-Lindgren C, Elfving M, Wikland KA, et al. 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 Jul;86(7):3039-44.[Abstract][Full Text]
60. Mohamed S, Alkofide H, Adi YA, et al. Oxandrolone for growth hormone-treated girls aged up to 18 years with Turner syndrome. Cochrane Database Syst Rev. 2019 Oct 30;2019(10):CD010736.[Abstract][Full Text]
61. Hero M, Varimo T, Raivio T. Aromatase inhibitors in puberty. Curr Opin Endocr Metab Res. 2020 Oct;14:37-41.[Full Text]
62. Varimo T, Huopio H, Kariola L, et al. Letrozole versus testosterone for promotion of endogenous puberty in boys with constitutional delay of growth and puberty: a randomised controlled phase 3 trial. Lancet Child Adolesc Health. 2019 Feb;3(2):109-120.[Abstract]
63. Mauras N, Gonzalez de Pijem L, Hsiang HY, et al. Anastrozole increases predicted adult height of short adolescent males treated with growth hormone: a randomized, placebo-controlled, multicenter trial for one to three years. J Clin Endocrinol Metab. 2008 Mar;93(3):823-31.[Abstract][Full Text]
64. Mauras N, Ross JL, Gagliardi P, et al. Randomized trial of aromatase inhibitors, growth hormone, or combination in pubertal boys with idiopathic, short stature. J Clin Endocrinol Metab. 2016 Dec;101(12):4984-93.[Abstract][Full Text]