Article endocrinology

Delayed Puberty
David S. Rosen, MD,
Objectives After completing this article, readers should be able to:
MPH,* and Carol Foster,
MD† 1. Delineate the differential diagnosis of delayed puberty.
2. Compare the prevalence of constitutional delay of puberty with that of other causes of
pubertal delay.
3. Describe the typical presentation and natural history of constitutional delay of puberty.
4. Describe the indications for and initial evaluation of pubertal delay.
5. Recognize the psychosocial sequelae of severe pubertal delay.

Development and maturation of the reproductive system begins in fetal life and is a
surprisingly active process throughout the first postnatal months. The reproductive system
becomes quiescent during childhood until its reactivation triggers pubertal development.
Puberty begins with increased pulsatile secretion of gonadotropin-releasing hormone
(GnRH) from the hypothalamus, increased pituitary responsiveness to GnRH, increased
secretion of gonadotropins, gonadal maturation, and increasing production of sex steroids.
Increased concentrations of sex steroids induce the development of secondary sexual
characteristics, acceleration of growth, and ultimate fertility. Factors that determine the
timing of pubertal onset remain poorly understood and the subject of intense investiga-
tion, but general health, nutrition, and genetic factors all are known to contribute.
The diagnostic criteria for pubertal delay are based roughly on statistical norms (ie,
delay of more than 2 to 3 standard deviations from the mean age of pubertal onset), but in
fact they are somewhat arbitrary. Puberty is considered to be clinically delayed if sexual
maturation has not become apparent by age 14 years in boys or age 13 years in girls. This
clinical diagnosis also is made in the absence of menarche by age 16 years or in the absence
of menarche within 5 years of pubertal onset. Using these criteria, approximately 2.5% of
healthy adolescents will be identified as having pubertal delay. Most are boys. After
evaluation, the majority of these adolescents will be found to have no pathology; rather,
onset of their otherwise normal puberty simply is sufficiently late or slow relative to that of
their peers to have triggered concern and evaluation. When puberty does begin, it is
entirely normal. Some adolescents have a variety of other causes to explain pubertal delay
(Table), and with careful evaluation, most are diagnosed accurately.

Differential Diagnosis
Constitutional Delay
In constitutional delay of puberty, the normal prepubertal growth nadir is protracted.
Presumably, the pubertal increase of pulsatile GnRH secretion is slow to develop, which
delays pubertal levels of sex steroid secretion and their developmental effects on secondary
sexual characteristics and growth hormone production. The prototypic patient who has
constitutional delay of puberty is a 14- or 15-year-old boy who presents after most of his
peers have begun puberty. Boys present far more often than girls because short stature and
sexual immaturity extract a higher psychosocial price in males than in females. In many
cases, delay of puberty is superimposed on constitutional short stature, exaggerating the
effects of the delay.

*Editorial Board.

Professor of Pediatrics and Communicable Diseases; Director, Division of Pediatric Endocrinology, University of Michigan
Medical School, Ann Arbor, MI.

Pediatrics in Review Vol.22 No.9 September 2001 309
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2017 .aappublications.or long-term ● Hypopituitarism consequences for growth or sexual maturation. but it is not a substitute for — by guest on February 5. or limit adequate nutrition. cystic fibrosis). Other explana- ● Noonan syndrome tions for pubertal delay should be investigated when the ● Androgen resistance ● Steroidogenic enzyme defects disease process does not explain maturational insuffi- —Cholesterol desmolase complex deficiency ciency or delay adequately. when more pathologic pubertal de- Other Conditions rangements are detected. Chronic use of —Severe obesity glucocorticoids. although bone age is delayed and consistent with the extent of pubertal maturation.20-desmolase deficiency aggressive management of the underlying condition. The risks and benefits of proposed medica- ● Ataxia-telangectasia syndrome tions and therapies. frequently multifactorial. especially in those conditions where it fre- ● Lawrence-Moon syndrome quently is compromised (eg.22 No. —Infections —Castration Chronic Illness Normal or Low Serum Gonadotropins Chronic illness may affect pubertal onset. about —Isolated gonadotropin deficiency —Kallman syndrome (with anosmia) which they already are acutely self-conscious.9 September 2001 Downloaded from http://pedsinreview. inflammatory bowel dis- ● Bardet-Biedl syndrome ● Bloom syndrome ease. However. only ● Hyperprolactinemia reassurance that puberty ultimately will proceed and —Pituitary adenoma eventual development will be normal is all that is re- —Drug-associated quired.endocrinology delayed puberty History may reveal similarly delayed puberty in the Differential Diagnosis of Table. not well-established. Laboratory evalua- Increased Serum Gonadotropins tion results are normal. tempo. Finally. especially their effects on growth and ● Cerebrohepatorenal syndrome maturation. hormone replace- —3-beta-hydroxysteroid dehydrogenase deficiency ment or augmentation with exogenous sex steroids is —17-alpha-hydroxylase deficiency appropriate in some settings. or radiation therapy may have short. neither sexual maturity nor final adult —Primary testicular failure height is affected by the timing of pubertal onset. Delayed puberty is not a common presentation of pan- hypopituitarism. Findings on physical exam- ination are unremarkable except possibly for early signs Delayed Puberty of puberty unnoticed by the patient. they should be treated early to ● Anatomic abnormalities maximize the potential for catch-up. affected children typically present with 310 Pediatrics in Review Vol. How- —Anorchia (“vanishing testes syndrome”) ever. final height will be —Resistant ovary syndromes —Irradiation short. The pathophysiology of pubertal delay in ● Hypothalamic dysfunction chronic illness is variable. Often. cancer chemotherapy. —17-beta-hydroxysteroid oxidoreductase deficiency Hypopituitarism PANHYPOPITUITARISM (CONGENITAL OR ACQUIRED). and —Malnutrition in some cases. disturb physiologic —Chronic illness —Eating disorders function. with supplementation used where ● LEOPARD syndrome appropriate. —Panhypopituitarism Adolescents who have chronic conditions. Resolving the relative effects of these factors in —Cytotoxic therapy final height has been difficult in the studies performed to —Trauma date. and ● Constitutional delay of puberty potential. deserve —Isolated growth hormone deficiency particularly close monitoring of their pubertal course to ● Hypothyroidism allow early detection of pubertal difficulties. Chronic illness may —Strenuous exercise affect underlying genetic potential. Nutrition should be ● Prader-Willi syndrome a priority. ● Turner syndrome (gonadal dysgenesis) ● Klinefelter syndrome The outcome of isolated constitutional delay of pu- ● Bilateral gonadal failure berty is excellent. patient’s parents or siblings. always should be considered. other medica- —Central nervous system tumors tions. when constitutional delay of puberty is superim- —Premature ovarian failure posed on constitutional short stature.

autoim- Bilateral Gonadal Failure mune.9 September 2001 311 Downloaded from http://pedsinreview. but findings on Turner syndrome require long-term estrogen replace- history and physical examination may be entirely normal ment therapy. but it is an otherwise ties or behavioral difficulties sometimes lead to diagnosis rare cause of delayed puberty. Borderline intellectual abili- primary or secondary amenorrhea. growth spurt seen. and always should be obtained in the presence of galactorrhea. Other congenital tose or its metabolites on the prenatal or neonatal ovary Pediatrics in Review Vol. endocrinopathies. apy. young men who have Klinefelter syndrome to a functioning pituitary adenoma (prolactinoma) or present with small testicles and hypogonadism. postinfectious. and often are difficult to distinguish from constitutional Most girls who have Turner syndrome have primary delay. except for sexual immaturity. primary amenorrhea. In galactosemia. although variable sex- protein that allows fetal GnRH neurons to migrate from ual development still occurs. Measurement of serum prolactin is hormone values are high. Rarely is a pubertal deficiency (IGD) are heterogeneous in clinical presenta. or surgery. The KAL-1 gene encodes a of gonadotropins by adolescence. ACQUIRED CAUSES OF GONADAL FAILURE.aappublications. Klinefelter syndrome is rel- atively common. Deletion of the KAL-1 gene is pubic and axillary hair is typical for most patients. often is gonadotropins. Affected boys tend to be tall in childhood. or metabolic causes. Thyroid replacement therapy older. Acquired gonadal failure also may have traumatic. other unusual central nervous system etiologies (eg. normal puberty. The syndromes of isolated gonadotropin characteristic and begins in utero. kidney malforma. Hyperprolactinemia may cause their pubertal immaturity. the diagnosis will not tion. but Other Endocrinopathies genetic variability and mosaicism occur. common infectious cause of gonadal failure. some spontaneous pubertal development occurs. Delayed bone age is the only consistent laboratory finding. making diagnosis more difficult. In interfere with gonadotropin production and may be due adolescence. For some girls. Langerhans cell TURNER SYNDROME. necomastia. but most girls who have often have a small phallus and testes. KLINEFELTER SYNDROME. Many affected HYPOTHYROIDISM. Testos- related to use of prescribed or illicit drugs (eg. phe. hypothalamic failure. 2017 . Its absence may delay the onset or retard Often. and pes cavus. and some into the hypothalmus. the effects of galac- genesis) and Klinefelter syndrome. Pro. Panhypopituitarism causes of gonadal failure and acquired bilateral gonadal presenting in adolescence is usually due to idiopathic failure are rare. Iatrogenic lactinomas may not be visible on imaging studies of the gonadal failure may occur in the aftermath of chemother- brain. drome have short stature. radiation therapy. terone production is abnormally low. follicle-stimulating nothiazines. The most common causes of gonadal associated with Addison disease and other autoimmune failure are congenital: Turner syndrome (gonadal dys.4 years.XXY. Growth retardation is the most consistent SYNDROME). a rare cause of ovarian failure. by guest on February 5. Girls who have Turner syn- histiocytosis) should be ruled out.22 No. endocrinology delayed puberty short stature earlier in childhood. The genotype is typically 46. and characteristic congenital ISOLATED GONADOTROPIN DEFICIENCIES (KALLMAN anomalies. cocaine). A mi- associated with sensorineural deafness. nority of affected girls experience spontaneous menarche tions. the progress of pubertal maturation by interfering with but testes become fibrotic and smaller as boys become gonadotropin secretion. variable but incomplete pu- berty. Mumps orchitis is the most Bilateral gonadal failure is uncommon and is character. Thyroid hormone is required for boys are not identified until puberty or early adulthood. Males who have Klinefelter syndrome present with usually normalizes gonadotropin secretion and allows small testicles and external genitalia and often have gy- puberty to proceed normally. More than 50% of patients the olfactory placode through the cribiform plate and in one study had some breast development. even in the absence of galactorrhea. They occur more frequently in boys than in girls be made until they present with pubertal insufficiency. and oligospermia or azosper- a useful part of the evaluation for amenorrhea or delayed mia is seen. Autoim- ized by markedly elevated concentrations of serum mune oophritis. Elevated prolactin levels in childhood or may be appreciated in retrospect. and their tall stature sometimes delays diagnosis despite HYPERPROLACTINEMIA. puberty. Boys who have GnRH deficiency at an average age of 13. However. IGD in association with hyposmia or anosmia is ovarian failure that gives rise to markedly elevated levels known as Kallman syndrome.

or symptoms of hypothyroidism and masculine-appearing genitalia are associated with may suggest a specific diagnosis. When these are present.aappublications. with the delays Even when results of these studies are normal. Boys who have into the pelvis (“concealed menarche”). Among patients weight.9 September 2001 Downloaded from http://pedsinreview. findings from the history dehydrogenase) also can lead to pubertal failure. dromes. A positive family history for puber- differentiation of the external genitalia. A careful history can absent testes and failure of puberty. Genetic and physical examination will often point to the specific males who have these disorders are born with ambiguous diagnosis. By adoles- ataxia telangectasia syndrome. The pathophysiology is believed costly evaluation.XX karyo. However. who have complete androgen insensitivity. testicu. gonadal failure consistently renal syndrome. sia. LEOPARD syndrome. may cause hypogonado. failure from other causes of delayed puberty.22 No. tory evaluation may be required to exclude the possibility tropic hypogonadism that results in pubertal delay or of occult chronic illness or endocrinopathy. atrophy. Other girls present in the early teen quently have delayed or absent menarche.” 46.endocrinology delayed puberty may cause delayed or deficient puberty in girls or may be profoundly. requires a systematic and focused approach to evaluation. further labora- tion. Careful measurement of growth and type and typically present with sexual immaturity and determination of sexual maturity are the initial steps in primary amenorrhea. Enzyme defects in steroid synthesis (eg. phenotypic females have the XY genotype and present with primary Congenital Anatomic Abnormalities amenorrhea and sparse or absent pubic and axillary hair Congenital anomalies of the female reproductive tract despite normal thelarche. although women who have eating disorders are at higher risk for menstrual irregularity independent of OTHER CONGENITAL SYNDROMES. Similarly. and measurement of serum Girls who are competitive athletes have significantly later prolactin and serum thyrotropin-stimulating hormone. IGD proportional to the intensity of their training. rocyte sedimentation rate. On the other hand. Many have primary gonadal failure with no The extensive differential diagnosis of delayed puberty spontaneous puberty. Evaluation of Pubertal Delay tently delayed. Determination of serum gondotropin levels will dis- dromes may be associated with pubertal delay or failure. Further evaluation reveals small physical assessment. pubarche and menarche than their peers. delay of puberty. In the “vanishing testes syndrome. usually present with delayed onset of menses despite ciated with hypogonadism.XY karyotype Anosmia. malnutri. Reasonable insufficiency. hypoplasia of the sence of menses include imperforate hymen. and their sexual maturation is consis. Hypogonado. A long list of other congenital disorders and syn. Presumably. Girls are affected more often than boys and screening studies include a complete blood count. or vaginal aplasia. 3-beta-hydroxysteroid pins. produces markedly elevated levels of serum gonadotro- cholesterol desmolase complex. A careful physical examination can help to be due to abnormalities in gonadotropin receptors or to identify stigmata of unsuspected congenital syn- antibodies to these receptors. tinguish disorders of congenital or acquired gonadal These include Bloom syndrome. Weight gain usually corrects these abnor- a cause of menstrual dysfunction. vaginal atre- labia majora and clitoris are seen in girls. who also fre. Congenital anomalies associated with the apparent ab- orchidism are characteristic of boys. Patients who tal delay would support the diagnosis of constitutional have “resistant ovaries syndrome” have a 46. Chromosomal analysis is indicated to confirm genitalia. may eliminate the need for a otropin concentrations. Prader-Willi syndrome is asso. cence (bone age 10 to 12 y). galactorrhea. and infertility is common. clinical suspicion of gonadal dysgenesis or Klinefelter syndrome. 2017 . and the cerebrohepato. and obesity in normal development of secondary sexual characteristics. remains a possible diagnosis because no studies reliably eating disorders can disrupt normal pubertal progress distinguish IGD from constitutional delay (Figs. malities. and excessive exercise. unnoticed by the patient. Micropenis and bilateral crypt. identify excessive exercise or symptoms of chronic illness lar atrophy or destruction occurred some time after fetal or psychiatric disease. eryth- typically present with primary or secondary amenorrhea. Early signs of sexual development. including eating disorders. when serum gonadotro- Hypogonadotropic Hypogonadism pins are normal or by guest on February 5. Noonan syndrome have abnormal testes (cryptorchidism. constitutional delay of puberty is Other conditions. anorchia). 1 and 312 Pediatrics in Review Vol. both males and females. years with cyclic abdominal pain as a result of a normally tropic hypogonadism occurs in both the Laurence-Moon responsive endometrium and spillage of menstrual fluid syndrome and the Bardet-Biedl syndrome. the most frequent diagnosis. ovaries with primordial follicles despite elevated gonad. short stature.

Testosterone currently is in broad general use. Constitutional delay of puberty may be managed by reassurance alone. Growth chart for a patient who presented at age 16 years for pubertal delay. and at final follow-up. but neither study sultation with a pediatric endocrinologist. including hepatic peliosis and premature epiphyseal closure. and demonstrating no psychosocial maladjustment. height was tinued when it is expected that en- 190. 2017 .aappublications. by guest on February 5. or topical gel.3 cm. 1). 6-month intervals to assess re- After evaluation.9 September 2001 313 Downloaded from http://pedsinreview. oral oxandrolone can be used at a starting dose of 1. short-term hor- monal therapy to “jump start” pu- berty may be appropriate when severe delay has led to psychosocial dysfunction.25 mg daily. Expectant management is more ac- ceptable to families when clinicians can point out early signs of puberty that were not obvious to the pa- tient. given our un- derstanding that even striking de- lays will have no effect on final adult height or development (Fig. Pubertal development proceeded. However. dogenous hormone production is dating. external genitalia were fully developed. management of pubertal delay should address increased based on careful follow-up of secondary sexual the underlying cause if one can be identified. transder- Management mal patch. For boys who have not yet begun puberty. For patients characteristics and growth to achieve a relatively normal Pediatrics in Review Vol. supplementation is begun in boys at approximately age 12 years. eating disorder. or chronic illness. and testos. Measurement of first morning urinary testosterone or pin deficiency or hypogonadism require lifelong replace- stimulation testing using a GnRH agonist eventually may ment with sex steroids and should be managed in con- help to differentiate these conditions. Treatment is discon- terone was withheld.22 No.maturation. tes- tosterone enanthate 100 mg intra- muscularly administered monthly for 6 mo) are used for boys whose pubertal development already has begun. the patient was treated with depot testosterone for presumed isolated sponse to treatment and skeletal gonadotropin deficiency. endocrinology delayed puberty whose hypothalamic hypogonad- ism is related to exercise. and the patient was attending college. It may be administered by injection. Doses initially are small and are Ideally. Patients who have gonadotro- 2). every effort should be made to effect changes in overall health and nutri- tion that will allow spontaneous puberty to proceed. Such treatment should be monitored by specialists familiar with the potential side ef- fects. Testosterone injections ( Figure 1. All boys treated with sex steroids should be monitored at 3. Testicular development was seen at age 19 years.

5:129. For girls who have eating disorders. Gonadotropin- ing of secondary sexual characteristics and growth is releasing hormone agonist analog (Nafarelin). using the gonadotropin-releasing hormone agonist nafarelin in the mone therapy is begun to coincide with puberty in peers. 12:1 Rosen DS. and report feelings of unpopularity. Kletter GB. Rosenfield RL. some value their imma- ture body habitus. social with- drawal and isolation.43:105–111 in the top frames.14:207 isks denote significant LH pulses. Some form of hormonal therapy to accelerate puberty may be appropriate in cases of substantial psy- chosocial distress. J Youth Ado- lesc. clock doesn’t ring. Boys who look younger than their chronologic age have fewer opportunities for age- appropriate activities and social interaction. Aster. As with boys. A new test of combined pituitary-testicular function For girls who have hypogonadism. gens or ethinyl estradiol that are increased gradually to Baillieres Clin Endocrinol Metab. age fifteen: psychologic study of twelve boys. The effects of delayed menarche in different contexts: dance and nondance students. date less. 1977. Puberty 18:105 Adolescents who have marked pubertal delay are at risk Rosen D. Satisfaction with body image for the lower frames. Cara JF. J Pediatr Endocrinol. Cuttler L.22 No. 1991. Pediatrician. Simple reassurance may suffice when puberty is expected to proceed and psychosocial effects are few. Significant delay may lead to poor body image. Kletter GB.69:963 Estrogen replacement may be started with a transdermal Houchin LD. Gonadotropin-releasing hormone was ad.12:427– 440 adult replacement levels. J Clin Endocrinol Metab. Zakin DF. constitutional delay of puberty: the case for aggressive therapy. Reprinted with permission Brack CJ. teasing. Lewis VG. differentiation of gonadotropin deficiency from delayed puberty: pilot studies. Once puberty is complete. Goodpasture JC. Ingersoll G.9 September 2001 Downloaded from http://pedsinreview.5:129 314 Pediatrics in Review Vol. lifelong testosterone Ehrmann DA. and school avoidance. J Adolesc Health Care. replacement hor. parental overprotection. Rogol AD. 1992. Pubertal growth and sexual maturation for adoles- Psychosocial Consequences of Delayed cents with chronic illness or disability. 1998. different school environments. and plasma testosterone values are shown in Blyth DA. Clin months (B).9:9 –19 1 to 2 years of estrogen replacement or once break. Levitsky LL. Bobrow NA.5 years (A) and 19 years. Indeed. Brooks-Gunn J. Kletter GB. should be instituted after 1996. bullying. even in cases of constitutional delay in which puberty is expected to progress spontaneously.9:280 when the clock doesn’t ring. Burstein S. 1985. Kelch RP. Warren MP. typically with hypogonadotropic hypogonadism. J Pediatr Endocrinol Metab. early adolescent females: the impact of pubertal timing within ministered at 0800 hours in the second study (arrow). Rolfes-Curl A. et al. low-dose oral contraceptives. for example. 1988. Idiopathic pubertal delay beyond through bleeding has occurred. Pubertal maturation and adolescent from Rosen DS. 2017 .aappublications. Puberty: what to do self-esteem. 1989. Kelch RP. Girls who have pubertal delay present with fewer psychosocial concerns. Stanhope by guest on February 5. Delayed or absent puberty is more troublesome for boys than for girls. Simmins RG.14:285 puberty. declining academic performance. Adolescence. Plasma luteinizing hormone (LH) values are shown Endocrinol. Money J. J Pediatr Endocrinol.endocrinology delayed puberty tively in the initial evaluation. 1995. Orr DP. Figure 2. low self-esteem. 1985. Results of frequent overnight gonadotropin and Suggested Reading testosterone sampling at age 16. 4 Albanese A. J Youth Adolesc. Investigation of delayed puberty. 1992. replacement is continued. early puberty consistently is associated with increasing dissatisfaction with weight or body image. The psychosocial burden imposed on the adolescent by delayed puberty should help to determine the extent of intervention. Puberty: what to do when the for psychosocial difficulties that should be sought ac. A useful diagnos- tic agent for the distinction of constitutional growth delay from required. Cyclic hormonal replacement. careful monitor. Androgen replacement in children with estradiol patch or small daily doses of conjugated estro.

Learning disability. E. B. C. 2017 . The most consistent presenting sign of bilateral gonadal failure in female adolescents is: A. Web neck. E. B. A true statement regarding the psychosocial risks for pubertal delay is that: A.9 September 2001 315 Downloaded from http://pedsinreview. Mumps orchitis. C. 11. Measurement of growth and sexual maturity. E. The best initial step in the etiologic assessment of delayed puberty is to obtain: A. D. Caloric supplements. 10. Karyotype. 8. D. Bone age. D. It is defined by an absence of menarche by age 15 years. C. Serum prolactin measurement. D. endocrinology delayed puberty PIR Quiz Quiz also available online at www. Hormonal therapy may be indicated in constitutional delay when the teen presents with significant psychological problems. C. An etiologic laboratory investigation is usually positive for a treatable pathologic process. Thyroid replacement hormone. Serum gonadotropin measurement. Boys are more likely to have associated eating disorders.22 No. Testosterone injections. Girls are affected more severely than boys. 9. Oral oxandrolone. C. The most appropriate treatment in most adolescents who have constitutional delay is: A. Congenital heart disease. D. Hypothyroidism. E.aappublications. Reassurance. Constitutional delay. Girls present more frequently than boys. A true statement about delayed puberty is that: A. B. Delayed maturation does not prevent males from dating and maintaining social relationships. B. Shield chest. 7. Pediatrics in Review Vol. E. 6. It is defined by a delay of more than 2 standard deviations from the mean age of pubertal onset. Pubertal delay rarely affects body image and self-esteem. E. B. D. Growth by guest on February 5. The most common cause of delayed puberty in boys is: A. Kallman syndrome. Prevalence is 10% in otherwise healthy adolescents. Klinefelter syndrome. B.pedsinreview.

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