Delayed puberty

Delayed puberty
Classification and external resources
Specialty	endocrinology
ICD-10	E30.0
ICD-9-CM	259.0
DiseasesDB	17462
MeSH	D011628

Puberty is described as delayed puberty with exceptions when an organism has passed the usual age of onset of puberty with no physical or hormonal signs that it is beginning. Puberty may be delayed for several years and still occur normally, in which case it is considered constitutional delay, a variation of healthy physical development. Delay of puberty may also occur due to malnutrition, many forms of systemic disease, or to defects of the reproductive system (hypogonadism) or the body's responsiveness to sex hormones.

Normal timing

Approximate mean ages for the onset of various pubertal changes are as follows. Ages in parentheses are the approximate 3rd and 97th percentiles for attainment. For example, less than 3% of girls have not yet achieved thelarche by 13 years of age. Developmental changes during puberty in girls occur over a period of 3 – 5 years, usually between 10 and 15 years of age. They include the occurrence of secondary characteristics beginning with breast development, the adolescent growth spurt, the onset of menarche – which does not correspond to the end of puberty – and the acquisition of fertility, as well as profound psychological modifications.

The normal variation in the age at which adolescent changes occur is so wide that puberty cannot be considered to be pathologically delayed until the menarche has failed to occur by the age of 18 or testicular development by the age of 20.

For North American, Indo-Iranian (India, Iran) and European girls	For North American, Indo-Iranian (India, Iran) and European boys
Thelarche (breast development) 10.0y5m (8y–13y) Pubarche (pubic hair) 11y (8.5–13.5y) Growth spurt 11.25y (10–12.5y) Menarche (first menstrual bleeding) 12.5y (10.5–14.5y) Adult height reached 15.5y (?-?)	Gonadarche (testicular enlargement) 11.5y (9.5–13.5y) Pubarche (pubic hair) 12y (10–14y) Growth spurt 14y (11-17y) Completion of growth 17y (15-20y)

The sources of the data, and a fuller description of normal timing and sequence of pubertal events, as well as the hormonal changes that drive them, are provided in the principal article on puberty. It is worthwhile to consider the world geographical and ethnographic/demographic limits and deficits of this study.

Evaluation

There are three indications that pubertal delay may be due to an abnormal cause.

Lateness

The first is simply degree of lateness: although no recommended age of evaluation cleanly separates pathologic from physiologic delay, a delay of 2–3 years or more warrants evaluation.

• In girls, no breast development by 13 years, or no menarche by 3 years after breast development (or by 16).
• In boys, no testicular enlargement by 14 years, or delay in development for 5 years or more after onset of genitalia enlargement.

A delay of two standard deviations has been proposed as a standard.^[1]

Discordance

The second indicator is discordance of development. In most children, puberty proceeds as a predictable series of changes in specific order. In children with ordinary constitutional delay, all aspects of physical maturation typically remain concordant but a few years later than average. If some aspects of physical development are delayed, and others are not, it is likely that something is wrong.

• For instance, in most girls, the beginning stages of breast development precede pubic hair. If a 12-year-old girl were to reach Tanner stage 3 pubic hair for a year or more without breast development, it would be unusual enough to suggest an abnormality such as defective ovaries.
• Similarly, if a 13-year-old boy had reached stage 3 or 4 pubic hair with testes that still remained prepubertal in size, it would be unusual and suggestive of a testicular abnormality.

Indications of specific disorders

The third indicator is the presence of clues to specific disorders of the reproductive system.

• Malnutrition or anorexia nervosa severe enough to delay puberty will give other clues as well.
• Poor growth would suggest the possibility of coeliac disease,^[2] hypopituitarism or Turner syndrome.
• Reduced sense of smell (hyposmia) or no sense of smell (anosmia) suggests Kallmann syndrome.

Possible causes

• Variation of normal (constitutional delay).^[3]
• In females, prolonged high level of physical exertion, e.g. from being an athlete.^[4]
• Systemic disease, e.g. undiagnosed and untreated coeliac disease (which often occurs without gastrointestinal symptoms),^[5][6] inflammatory bowel disease (principally Crohn's disease),^[7][8] chronic renal failure.^[9]
• Undernutrition e.g. anorexia nervosa, zinc deficiency.
• Hypothalamic defects and diseases e.g. Prader-Willi syndrome, Kallmann syndrome.
• Pituitary defects and diseases e.g. hypopituitarism.
• Gonadal defects and diseases e.g. Turner syndrome, Klinefelter syndrome, Testicular failure due to mumps orchitis, Coxsackievirus B, irradiation, chemotherapy, or trauma. Testicular failure is treated with testosterone replacement,^[10] Ovarian failure.^[10]
• Absence or unresponsiveness of target organs e.g. androgen insensitivity syndrome, Müllerian agenesis.
• Other hormone deficiencies and imbalances, Endocrine disorders.^[11] e.g. hypothyroidism, Cushing's syndrome.
• Cystic fibrosis.^[12]
• Mutations in FSHB.^[13]
• Frasier syndrome.^[14]
• Various forms of congenital adrenal hyperplasia.^[11]
• Gonadotropin deficiency, resulting from a number of congenital and acquired abnormalities of the central nervous system.
• Biedl-Bardet syndrome.
• Brain tumors e.g. craniopharyngioma, prolactinoma, germinoma, glioma; diseases of hypothalamus, irradiation and trauma.

Constitutional delay

Children who are healthy but have a slower rate of physical development than average have constitutional delay in growth and adolescence. These children have a history of stature shorter than their age-matched peers throughout childhood, but their height is appropriate for bone age, and skeletal development is delayed more than 2.5 SD. They usually are thin and often have a family history of delayed puberty. Children with a combination of a family tendency toward short stature and constitutional delay are the most likely to seek evaluation. They quite often seek evaluation when classmates or friends undergo pubertal development and growth, thereby accentuating their delay.

It is often difficult to establish if it is a true constitutional delay or if there is an underlying pathology, because biochemical tests are not always discriminatory.^[15] Short stature, delayed growth in height and weight, and/or delayed puberty may be the only clinical manifestations of coeliac disease, in absence of any other symptoms.^{[2][5][16][17]}

Medical evaluation

Pediatric endocrinologists are the physicians with the most training and experience evaluating delayed puberty. A complete medical history, review of systems, growth pattern, and physical examination will reveal most of the systemic diseases and conditions capable of arresting development or delaying puberty, as well as providing clues to some of the recognizable syndromes affecting the reproductive system.

Since bone maturation is a good indicator of overall physical maturation, an x-ray of the hand to assess bone age usually reveals whether the child has reached a stage of physical maturation at which puberty should be occurring. Visible secondary sexual development usually begins when girls achieve a bone age of 10.5 to 11 years, and boys achieve a bone age of 11.5 to 12 years.

The most valuable blood tests are the gonadotropins, because elevation confirms immediately a defect of the gonads or deficiency of the sex steroids. In many instances, screening tests such as a complete blood count, general chemistry screens, thyroid tests, and urinalysis may be worthwhile.

More expensive and complicated tests, such as a karyotype or magnetic resonance imaging of the head, are usually obtained only when specific evidence suggests they may be useful.

Use of gonadotropin releasing hormone can be of value in the differential diagnosis.^[18]

If delayed puberty is accompanied with a lack of sense of smell (anosmia) or a history of un-descended testicles (cryptorchidism) when born then a diagnosis of Kallmann syndrome could be considered.^[19][20]

Management

If a child is healthy but simply late, reassurance and prediction based on the bone age can be provided. No other intervention is usually necessary. In more extreme cases of delay, or cases where the delay is more extremely distressing to the child, a low dose of testosterone or estrogen for a few months may bring the first reassuring changes of normal puberty.

If the delay is due to systemic disease or undernutrition, the therapeutic intervention is likely to focus mainly on those conditions. In patients with coeliac disease, an early diagnosis and the establishment of a gluten-free diet prevents long-term complications and allows restore normal maturation.^[2][17]

If it becomes clear that there is a permanent defect of the reproductive system, treatment usually involves replacement of the appropriate hormones (testosterone/dihydrotestosterone for boys,^[21] estradiol and progesterone for girls).

Pubertal delay due to gonadotropin deficiency is treated with testosterone replacement or with HCG.^[10]

Growth hormone is another option that has been described.^[22][23]

Subnormal vitamin A intake is one of the aetiological factors in delayed pubertal maturation. Supplementation of both vitamin A and iron to normal constitutionally delayed children with subnormal vitamin A intake is as efficacious as hormonal therapy in the induction of growth and puberty.^[24]

See also

• Developmental milestones
• Endocrinology
• Hypogonadism
• Kallmann syndrome
• Precocious puberty

References

1. Traggiai C, Stanhope R (2003). "Disorders of pubertal development". Best Pract Res Clin Obstet Gynaecol 17 (1): 41–56. doi:10.1053/ybeog.2003.0360. PMID 12758225.
2. "The prevention of coeliac disease". Best Pract Res Clin Gastroenterol (Review) 29 (3): 493–501. Jun 2015. doi:10.1016/j.bpg.2015.04.003. PMID 26060113.
3. Villanueva C, Argente J (2014). "Pathology or normal variant: what constitutes a delay in puberty?". Horm Res Paediatr (Review) 82 (4): 213–21. doi:10.1159/000362600. PMID 25011467.
4. Maïmoun L, Georgopoulos NA, Sultan C (Nov 2014). "Endocrine disorders in adolescent and young female athletes: impact on growth, menstrual cycles, and bone mass acquisition". J Clin Endocrinol Metab (Review) 99 (11): 4037–50. doi:10.1210/jc.2013-3030. PMID 24601725.
5. Leffler DA, Green PH, Fasano A (Oct 2015). "Extraintestinal manifestations of coeliac disease". Nat Rev Gastroenterol Hepatol (Review) 12 (10): 561–71. doi:10.1038/nrgastro.2015.131. PMID 26260366.
6. Tersigni C, Castellani R, de Waure C, Fattorossi A, De Spirito M, Gasbarrini A, Scambia G, Di Simone N (2014). "Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms". Hum Reprod Update (Review) 20 (4): 582–93. doi:10.1093/humupd/dmu007. PMID 24619876.
7. Sanderson IR (Oct 2014). "Growth problems in children with IBD". Nat Rev Gastroenterol Hepatol (Review) 11 (10): 601–10. doi:10.1038/nrgastro.2014.102. PMID 24957008.
8. Wong SC, Catto-Smith AG, Zacharin M (Feb 2014). "Pathological fractures in paediatric patients with inflammatory bowel disease". Eur J Pediatr (Review) 173 (2): 141–51. doi:10.1007/s00431-013-2174-5. PMID 24132387.
9. Thébaut A, Amouyal M, Besançon A, Collet M, Selbonne E, Valentin C, Vonthron M, Zakariya M, Linglart A (Jun 2013). "Puberty, fertility and chronic diseases". Arch Pediatr (Review) 20 (6): 673–84. doi:10.1016/j.arcped.2013.03.015. PMID 23619213.
10. Marianne J. Legato, ed. (2004) "Principles of Gender-Specific Medicine, Volume 1-2", ISBN 0-12-440905-9, p. 22
11. Greenspan, FS; Gardner DG (2004). "Puberty". Basic & Clinical Endocrinology. pp. 617–627. ISBN 0-07-140297-7.
12. Johannesson M, Gottlieb C, Hjelte L (1997). "Delayed puberty in girls with cystic fibrosis despite good clinical status". Pediatrics 99 (1): 29–34. doi:10.1542/peds.99.1.29. PMID 8989333.
13. Layman LC, Lee EJ, Peak DB, et al. (1997). "Delayed puberty and hypogonadism caused by mutations in the follicle-stimulating hormone β-subunit gene". N. Engl. J. Med. 337 (9): 607–11. doi:10.1056/NEJM199708283370905. PMID 9271483.
14. Chan WK, To KF, But WM, Lee KW (June 2006). "Frasier syndrome: a rare cause of delayed puberty". Hong Kong Med J 12 (3): 225–7. PMID 16760553.
15. Wei C, Crowne EC (Sep 9, 2015). "Recent advances in the understanding and management of delayed puberty". Arch Dis Child (Review). archdischild-2014-307963. doi:10.1136/archdischild-2014-307963. PMID 26353794.
16. Guandalini S, Assiri A (Mar 2014). "Celiac disease: a review". JAMA Pediatr 168 (3): :272–8. doi:10.1001/jamapediatrics.2013.3858. PMID 24395055.
17. Levy J, Bernstein L, Silber N (Dec 2014). "Celiac disease: an immune dysregulation syndrome". Curr Probl Pediatr Adolesc Health Care (Review) 44 (11): 324–7. doi:10.1016/j.cppeds.2014.10.002. PMID 25499458.
18. Jungmann E, Trautermann C (1994). "[The status of the gonadotropin releasing hormone test in differential diagnosis of delayed puberty in adolescents over 14 years of age]". Med. Klin. (Munich) (in German) 89 (10): 529–33. PMID 7808353.
19. Oxford Endocrinology Library. Testosterone Deficiency in Men. 2008. ISBN 978-0199545131 Editor: Hugh Jones. Chapter 9. Puberty & Fertility.
20. Male Hypogonadism. Friedrich Jockenhovel. Uni-Med Science. 2004. ISBN 3-89599-748-X. Chapter 3. Diagnostic work up of hypogonadism.
21. Saad RJ, Keenan BS, Danadian K, Lewy VD, Arslanian SA (October 2001). "Dihydrotestosterone treatment in adolescents with delayed puberty: does it explain insulin resistance of puberty?". J. Clin. Endocrinol. Metab. 86 (10): 4881–6. doi:10.1210/jc.86.10.4881. PMID 11600557.
22. Heinrichs C, Bourguignon JP (1991). "Treatment of delayed puberty and hypogonadism in girls". Horm. Res. 36 (3–4): 147–52. doi:10.1159/000182149. PMID 1818011.
23. Massa G, Heinrichs C, Verlinde S, et al. (September 2003). "Late or delayed induced or spontaneous puberty in girls with Turner syndrome treated with growth hormone does not affect final height". J. Clin. Endocrinol. Metab. 88 (9): 4168–74. doi:10.1210/jc.2002-022040. PMID 12970282.
24. Zadik Z, Sinai T, Zung A, Reifen R. (2004). "Vitamin A and iron supplementation is as efficient as hormonal therapy in constitutionally delayed children.". Clin Endocrinol (Oxf). 60 (6): 682–7. doi:10.1111/j.1365-2265.2004.02034.x. PMID 15163330.