Clinical Practice
Delayed Puberty
N Engl J Med 2012; 366:443-453February 2, 2012DOI: 10.1056/NEJMcp1109290
Comments
open through February 8, 2012
- Article
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations.
A 14-year-old boy with an unremarkable medical history presents because of lack of pubertal development. He has always been relatively short, but his growth velocity is slowing as compared with that of his peers. His height is 146 cm (57.5 in., <3rd percentile for age), and his weight is 37 kg (82 lb, 3rd percentile). His father, who is 168 cm (66.1 in.) tall, continued to grow until his second year in college; his mother is 153 cm (60.2 in.) tall and began menstruating at the age of 14.0 years. The patient's target height on the basis of the parental heights is 167 cm (65.8 in.). The physical examination reveals Tanner stage 1 pubic hair and prepubertal-sized testes. How should the boy be evaluated and treated?
The Clinical Problem
Puberty leads to sexual maturation and reproductive capability. It requires an intact hypothalamic–pituitary–gonadal (HPG) axis and is heralded by the reemergence of gonadotropin-releasing hormone (GnRH) secretion from its relative quiescence during childhood. GnRH stimulates the secretion of luteinizing hormone and follicle-stimulating hormone (FSH), which then stimulate gonadal maturation and sex-steroid production. Much is known about components of the HPG axis, but the factors that trigger pubertal onset remain elusive. It is not understood why one boy begins puberty at the age of 10 years and another at the age of 14 years.
Delayed puberty is defined as the absence of testicular enlargement in boys or breast development in girls at an age that is 2 to 2.5 SD later than the population mean (traditionally, the age of 14 years in boys and 13 years in girls). However, because of a downward trend in pubertal timing in the United States1-3 and other countries4,5 and differences in pubertal timing among racial and ethnic groups, some observers have advocated for updated definitions with younger age cutoffs for the general population or perhaps for particular countries or racial or ethnic groups. Development of pubic hair is usually not considered in the definition because pubarche may result from maturation of the adrenal glands (adrenarche), and the onset of pubic hair can be independent of HPG-axis activation.
Late puberty can affect psychosocial well-being, and patients, families, and practitioners are often concerned that it may affect adult stature. Adult height can be affected but on average is only slightly below the genetic target.6 Many adolescents present with delayed puberty combined with relative familial short stature, compounding these concerns and leading to more subspecialty referrals than either condition alone.
Delayed puberty in boys usually represents an extreme of the normal spectrum of pubertal timing, a developmental pattern referred to as constitutional delay of growth and puberty (CDGP). In one large series, approximately 65% of boys and 30% of girls with delayed puberty had CDGP.7 However, because the data were obtained from a tertiary referral center, these percentages may underestimate the frequency of CDGP encountered by primary care providers. The evaluation and treatment of boys with CDGP is the main focus of this review, but consideration is given to other causes of delayed puberty and issues specific to girls.
Although CDGP represents the single most common cause of delayed puberty in both sexes, it can be diagnosed only after underlying conditions have been ruled out. The differential diagnosis of CDGP can be divided into three main categories7: hypergonadotropic hypogonadism (characterized by elevated levels of luteinizing hormone and FSH owing to the lack of negative feedback from the gonads), permanent hypogonadotropic hypogonadism (characterized by low levels of luteinizing hormone and FSH owing to hypothalamic or pituitary disorders), and transient hypogonadotropic hypogonadism (functional hypogonadotropic hypogonadism), in which pubertal delay is caused by delayed maturation of the HPG axis secondary to an underlying condition (Table 1Table 1
Frequency and Common Causes of Delayed Puberty Other Than Constitutional Delay of Growth and Puberty., and Table 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).The cause of CDGP is unknown, but it has a strong genetic basis. It has been estimated that 50 to 80% of variation in the timing of puberty in humans is due to genetic factors,8 and 50 to 75% of patients with CDGP have a family history of delayed puberty.9,10 The inheritance of CDGP is variable but most often is consistent with an autosomal dominant pattern, with or without complete penetrance. CDGP is not sex-specific and is characterized by either relatively delayed development among family members (e.g., the average age at menarche among mothers is 14.3 years, as compared with a mean of 12.7 years among controls9) or evidence of true CDGP. The investigation of patients with the Kallmann syndrome and isolated hypogonadotropic hypogonadism has led to the identification of genes that play critical roles in the development and regulation of the HPG axis, but mutations that have been identified in such genes do not cause CDGP, except in rare instances.11,12 However, the genes causing 60 to 70% of cases of the Kallmann syndrome and isolated hypogonadotropic hypogonadism remain unknown.13 Loci have also been identified that are associated with the age of menarche in the general population,14-18 but these particular loci have likewise not been associated with CDGP.19
Strategies and Evidence
First-Line Evaluation
Ruling Out Underlying Disorders
The aim of initial evaluation is to rule out underlying disorders causing delayed puberty (Table 2Table 2
Investigations for Delayed Puberty., and Table 2 in the Supplementary Appendix).20-28 Pubertal development is assessed clinically and biochemically, providing information that is important for counseling and predicting further pubertal development. Eventual normal progression of puberty verifies the diagnosis of CDGP, whereas absent or slow development or cessation of development after onset is consistent with permanent hypogonadism.Family History
A family history, including childhood growth patterns and age at pubertal onset of the parents, should be obtained. Delayed puberty in a parent or sibling followed by spontaneous onset of puberty suggests CDGP. However, if pubertal development was induced by sex steroids in family members, isolated hypogonadotropic hypogonadism is also possible, since reversal of hypogonadism is noted after the discontinuation of sex steroids in about 10% of patients with isolated hypogonadotropic hypogonadism.29,30
Patients and their parents should be questioned about a history or symptoms of chronic disease, with emphasis on specific disorders (e.g., celiac disease, thyroid disease, and anorexia) that may cause temporary delay of puberty (functional hypogonadotropic hypogonadism), as well as medication use, nutritional status, and psychosocial functioning. Delayed cognitive development associated with obesity or dysmorphic features may suggest an underlying genetic syndrome. Bilateral cryptorchidism or a small penis at birth and hyposmia or anosmia may suggest hypogonadotropic hypogonadism. A history of chemotherapy or radiotherapy may indicate primary gonadal failure (Figure 1Figure 1
Algorithm for the Evaluation of a Patient with Delayed Puberty.).Physical Examination
Previous height and weight measurements should be obtained and plotted so that longitudinal growth can be carefully assessed (Figure 2Figure 2
Linear Growth in Delayed Puberty.). Delayed puberty is often associated with short stature and slow growth for age although the height and growth rate are within the prepubertal normal range. Children who are underweight for height have an increased likelihood of having an underlying condition delaying HPG-axis activation. Conversely, in boys, unlike girls, being overweight can be associated with later pubertal development.20,21 The most widely used pubertal rating system is Tanner staging31,32 (Figure 3Figure 3
Tanner Stages in the Assessment of Delayed Puberty.). In boys, the presence of Tanner stage 2 genitalia marks the onset of pubertal development and is characterized by enlargement of the scrotum and testes and by a change in the texture and color of the scrotal skin. Testicular volume should be measured, with a volume of more than 3 ml indicating the initiation of central puberty. In patients with CDGP, both adrenarche and hormonal activation of the gonads often occur later than average, but in isolated hypogonadotropic hypogonadism, adrenarche usually occurs at a normal age.7,33 Bone-Age Radiography
The bone age should be reviewed by a practitioner who is experienced in interpreting such radiographs. A delay in bone age is characteristic but not diagnostic of CDGP and also may occur in patients with chronic illness, hypogonadotropic hypogonadism, or gonadal failure. Adult height prediction is an important part of counseling if short stature is a component of the presentation, and practitioners should be aware that the Bayley–Pinneau tables overestimate adult height in patients with CDGP if bone age is delayed by more than 2 years (Table 2, and Table 2 in the Supplementary Appendix).
Hormone Measurements and Brain Imaging
Pubertal onset is characterized by the accentuation of diurnal secretion of gonadotropin and testosterone (in boys) and estrogen (in girls) before apparent phenotypic changes. Basal levels of luteinizing hormone and FSH are low in patients with CDGP or hypogonadotropic hypogonadism, whereas such levels are usually elevated in those with gonadal failure. Serum levels of insulin-like growth factor 1 (IGF-1) can be helpful in the evaluation of growth hormone deficiency but must be interpreted carefully because levels are often low for chronologic age but within the normal range for bone age. Thyroid-function tests are routinely obtained. Brain magnetic resonance imaging (MRI) is indicated when there are signs or symptoms to suggest a lesion in the central nervous system. Otherwise, although some clinicians routinely perform brain imaging, a reasonable strategy is to defer such evaluation until the age of 15 years, at which point many patients with CDGP will have spontaneously begun puberty and will require no further evaluation. Full neuroendocrine testing is warranted in patients with hypothalamic–pituitary tumors causing hypogonadotropic hypogonadism, since they may have additional pituitary-hormone deficiencies.
Second-Line Evaluation
Most patients will not have an apparent alternative cause for delayed puberty on initial evaluation, suggesting CDGP as the likely diagnosis. However, no test can reliably distinguish CDGP from isolated hypogonadotropic hypogonadism, so the diagnosis of CDGP cannot be made with certitude. Observation usually resolves this conundrum; isolated hypogonadotropic hypogonadism is diagnosed if endogenous puberty has not begun by the age of 18 years. Several tests have been proposed to distinguish CDGP from isolated hypogonadotropic hypogonadism (Table 2, and Table 2 in the Supplementary Appendix). If basal gonadotropin levels are inconclusive, stimulation by GnRH or a GnRH agonist may be helpful.24,25 Stimulated levels of luteinizing hormone in the pubertal range indicate that the HPG axis has been reactivated and that secondary sexual development is likely to occur within 1 year. However, the GnRH test alone often cannot differentiate CDGP from isolated hypogonadotropic hypogonadism because prepubertal values may be observed in isolated hypogonadotropic hypogonadism or in patients with CDGP in whom the HPG axis has not yet been activated. Recent data suggest that baseline levels of inhibin B may facilitate discrimination between these conditions,28 but replication is needed before this or other tests can be routinely adopted.
Growth hormone secretion in the basal state, as well as after provocative testing, may be decreased in patients with CDGP. If concern about growth is sufficient to warrant stimulation testing of growth hormone, sex-steroid priming with estrogen or testosterone is necessary for reliable results in patients with delayed puberty; estrogen stimulates endogenous growth-hormone secretion, and sex-steroid priming facilitates separation of true growth hormone deficiency from the physiologic low growth hormone secretion that stems from low estrogen levels. If a patient has a normal growth rate, growth hormone provocation testing is not necessary, whereas low IGF-1 levels together with reduced growth velocity warrant testing.
Treatment
Patients with CDGP
The options for management of CDGP include expectant observation or therapy with low-dose testosterone (in boys) or estrogen (in girls) (Table 3Table 3
Medications for the Treatment of Constitutional Delay of Growth and Puberty (CDGP)., and Table 3 in the Supplementary Appendix). If puberty has started, clinically or biochemically, and stature is not a major concern, reassurance with realistic adult height prediction is frequently sufficient. If therapy is initiated, it is usually to assuage psychosocial difficulties that may derive from negative interactions with peers, decreased self-esteem, and anxiety about growth rate or body habitus.Numerous studies of treatment of CDGP in boys have been reported. Although some randomized, controlled trials have been performed with small numbers of subjects, studies have been largely observational and have involved treatment with short courses of low-dose androgens.34-36 The data suggest that treatment leads to increased growth velocity and sexual maturation and positively affects psychosocial well-being, without significant side effects, rapid advancement of bone age, or reduced adult height. Similar data are not available for girls, but similar outcomes are likely as long as therapy is initiated with appropriately low doses of estrogen.
For a subset of patients with CDGP, short stature can be more worrisome than delayed puberty, and indeed CDGP is considered by some observers to be a subgroup of idiopathic short stature. Although the Food and Drug Administration has approved the use of growth hormone for the treatment of idiopathic short stature and height that is 2.25 SD below average for age, this therapy has at best a modest effect on adult height in adolescents with CDGP, and its use in CDGP is not recommended.
In boys with CDGP and short stature, another potential therapeutic approach is aromatase inhibition, but this treatment requires further study before it should be incorporated into routine practice.37,38 Aromatase inhibitors block the conversion of androgens to estrogens; because estrogen is the predominant hormone needed for epiphyseal closure, the use of aromatase inhibitors could prolong linear growth and potentially increase adult height. In controlled trials in boys with short stature or delayed puberty, aromatase inhibitors delayed bone maturation and appeared to increase adult height.37,38 However, the amount of height gained as well as the optimal timing, dose, and duration of therapy with aromatase inhibitors remain uncertain.39 Moreover, potentially adverse effects, especially impaired development of trabecular bone and vertebral-body deformities, which were observed in boys with idiopathic short stature who were treated with letrozole,40 must be considered.
Permanent Hypogonadism
In boys and girls with hypogonadotropic hypogonadism, initial sex-steroid therapy is the same as that for CDGP, but doses are gradually increased to full adult replacement levels during a period of approximately 3 years (Table 3). In hypogonadotropic hypogonadism, exogenous testosterone does not induce testicular growth or spermatogenesis and exogenous estrogen does not induce ovulation, and the induction of fertility in both sexes requires treatment with pulsatile GnRH42-45 or exogenous gonadotropins.44 In girls with hypogonadotropic hypogonadism, treatment with estrogen needs to be combined with progestin for endometrial cycling.
Areas of Uncertainty
Further research is needed to establish appropriate age cutoffs for delayed puberty in different racial and ethnic groups and to better understand the physiological basis of CDGP. Suggested causes of CDGP include increased total energy expenditure46 and increased insulin sensitivity,47 but no definitive cause has been identified. Studies should carefully assess the psychosocial distress among children with delayed puberty, whether this distress has long-term sequelae, and what effect sex-steroid supplementation has on these outcomes. It remains unclear whether adult bone mass is adversely affected by pubertal delay48 and whether this represents a medical reason to initiate sex-steroid replacement. Distinguishing between CDGP and isolated hypogonadotropic hypogonadism remains difficult in many cases, and further assessment of the role of inhibin B or other markers for this purpose is needed. Randomized trials are needed to compare different estrogen formulations, routes of administration (oral vs. transdermal), and drug regimens to determine optimal therapy for girls with delayed puberty. Studies are needed to identify genes that cause CDGP, which would also elucidate factors that regulate the timing of puberty.
Guidelines
To our knowledge, there are no recent guidelines regarding the evaluation and treatment of CDGP.
Conclusions and Recommendations
The patient in the vignette has delayed puberty. Given that he is male and has a family history of late pubertal development, CDGP is the most likely diagnosis. Before making this diagnosis, a careful evaluation is required to rule out other causes; this is especially true among young women, in whom underlying disorders are more common.
In CDGP, in which pubertal delay is transient, the decision regarding whether to treat should be made by the patient; the goal of therapy, when used, is to induce the acceleration of secondary sexual characteristics or growth and to mitigate psychosocial difficulties. For boys who elect to be treated, we initiate monthly intramuscular injections of 50 mg of testosterone ester for 3 to 6 months; this regimen can be repeated for another 3 to 6 months with dose escalation (Table 3). If spontaneous puberty has not occurred after 1 year, other diagnoses, such as permanent hypogonadotropic hypogonadism, should be reconsidered, and MRI of the brain is indicated. We believe that when CDGP is treated, therapy should be with testosterone alone, even if stature is a prominent concern. We do not use growth hormone or anabolic steroids for delayed puberty, nor do we recommend aromatase inhibitors for this indication, pending more data from randomized trials.
Dr. Palmert reports receiving funding as a member of the Hvidøre Study of Childhood Diabetes, which is supported by Novo Nordisk; payment for lectures at the 2011 Japanese Endocrine Society Meeting and the 2011 Asahikawa Winter Conference on Molecular Medicine with support from Japan Chemical Research Pharmaceuticals; and payment for participating in a symposium sponsored by Sandoz at the 2011 Annual Meeting of the European Society of Pediatric Endocrinology, as well as for a Grand Rounds lecture at McGill University sponsored by Eli Lilly. Dr. Dunkel reports receiving lecture fees from Pfizer and payment for participating in a symposium sponsored by Sandoz at the 2011 Annual Meeting of the European Society of Pediatric Endocrinology. No other potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
An audio version of this article is available at NEJM.org.
Source Information
From the Division of Endocrinology, the Hospital for Sick Children, and the Departments of Pediatrics and Physiology, University of Toronto — both in Toronto (M.R.P.); and the Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London (L.D.).
Address reprint requests to Dr. Palmert at the Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada, or at mark.palmert@sickkids.ca; or to Dr. Dunkel at the Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Sq., London EC1M 6BQ, United Kingdom, or at l.dunkel@qmul.ac.uk.
Key Clinical Points
DELAYED PUBERTY
• Delayed puberty is diagnosed when there is no testicular enlargement in boys or breast development in girls at an age that is 2 to 2.5 SD later than the mean age at which these events occur in the population (traditionally, 14 years in boys and 13 years in girls).
• Constitutional delay of growth and puberty (CDGP) is the single most common cause of delayed puberty in both sexes, but it can be diagnosed only after underlying conditions have been ruled out.
• The cause of CDGP is unknown, but most patients with CDGP have a family history of delayed puberty.
• Management of CDGP may involve expectant observation or therapy with low-dose sex steroids.
• When treatment is given, the goals are to induce the appearance of secondary sexual characteristics or the acceleration of growth and to mitigate psychosocial difficulties associated with pubertal delay and short stature.
• The routine use of growth hormone, anabolic steroids, or aromatase inhibitors is not currently recommended.
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I. Baus, P.-M. Holterhus. (2013) Vorzeitige und verzögerte Pubertät beim Mädchen. Gynäkologische Endokrinologie 11:1, 11-18
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Anjali Santhakumar, Margaret Miller, Richard Quinton. (2013) Pubertal Induction in Adult Males with Isolated Hypogonadotropic hypogonadism using Long-Acting Intramuscular Testosterone Undecanoate 1g depot (Nebido ® ). Clinical Endocrinologyn/a-n/a
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- Comments (1)
Statistics smooth
The summed curve of out of phase sine curves is a flat line. Similarly no child's growth follows the average curves. Perhaps growth charts should include a few individuals' lines to reassure patents.