Approach to the patient with delayed puberty

INTRODUCTION — Delayed puberty is defined clinically as the absence of the first signs of pubertal development beyond the normal range for the population. In the United States, this has generally been taken to mean the absence of breast development by age 12 to 13 years in females or absence of testicular enlargement by age 13 to 14 years in males. However, the timing of pubertal onset varies substantially within and across different populations and the family history and population background should be incorporated into decisions regarding the evaluation and therapy of pubertal disorders.

The most common cause of delayed puberty is a functional delay in production of gonadotropin-releasing hormone (GnRH) from the hypothalamic neuronal networks that initiate the episodic or pulsatile release of the GnRH and activate the hypothalamic-pituitary-gonadal axis. This delay may be due to individual genetic variations, known as constitutional delay of growth and puberty (CDGP), or other functional defects, such as undernutrition or chronic illness. Other causes of delayed puberty include a variety of hypothalamic, pituitary, and gonadal disorders.

The evaluation and management of an adolescent with delayed puberty is thus essentially an exercise in excluding pathologic causes, as discussed in this topic review. Other clinical presentations of hypogonadism are discussed elsewhere:

●(See "Evaluation and management of primary amenorrhea".)

●(See "Evaluation and management of secondary amenorrhea".)

●(See "Clinical features and diagnosis of male hypogonadism".)

DEFINITIONS

Delayed puberty — Delayed puberty is defined clinically by the absence or incomplete development of secondary sexual characteristics by an age 2 to 3 standard deviations above the mean age of onset of puberty, ie, by an age at which 97 to 99 percent of children of that sex and culture have begun sexual maturation. In the United States, this corresponds to an upper limit of 12 to 13 years for breast development in females [1-4] and of 13 to 14 years for testicular enlargement in males [1,5-7]. The age for undertaking a clinical evaluation for delayed puberty, like that for precocious puberty, depends on individual factors including family history and body weight. Onset of pubic hair is not usually included in this definition, because this is typically a sign of adrenarche rather than true puberty. (See "Normal puberty".)

However, there are wide ranges within and across populations as to the order and temporal sequences that occur during puberty, especially in females. In females, this range is due in part to the fact that some features of the earliest elements of sexual maturation (pubic hair, axillary hair and odor, and acne) are manifestations of adrenal androgen secretion (termed adrenarche). Clinical adrenarche typically occurs approximately six months after the start of true puberty (ie, ovarian maturation that is followed by breast development, which results from estradiol secretion by the ovaries). Hence, some females have early breast development but little else for some time, whereas others follow closely the typical sequence of events described by Tanner [8,9].

Stalled puberty — Puberty can be considered "stalled" if it was not completed within approximately four years of its onset. Approximately 95 percent of healthy children complete their full pubertal development within four years [10]. In the clinical setting, an evaluation may be initiated before this threshold is reached if there is no evidence of pubertal progression for a sustained period of time (eg, for two or more years).

EPIDEMIOLOGY — By definition, delayed puberty occurs in approximately 5 percent of apparently healthy individuals in a given population. The relative frequency of various causes of delayed puberty was described in a retrospective study of adolescents presenting to an academic center for delayed puberty [11]:

●Secondary (hypogonadotropic) hypogonadism:

•Constitutional delay of growth and puberty (CDGP) – 53 percent of subjects (63 percent of males and 30 percent of females)

•Functional hypogonadotropic hypogonadism – 19 percent

•Other causes of hypogonadotropic hypogonadism (eg, isolated gonadotropin-releasing hormone [GnRH] deficiency, including Kallmann syndrome, or a central nervous system tumor) – 12 percent

●Primary hypogonadism – 13 percent

●Unclassified – 3 percent

ETIOLOGY — It is useful to classify hypogonadism pathophysiologically according to the circulating levels of the gonadotropins, which are luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (table 1):

Primary hypogonadism — Primary hypogonadism is characterized by small gonadal size, low serum concentrations of gonadal steroids, and high serum concentrations of LH and FSH. This may be caused by a variety of gonadal diseases including Turner syndrome, Klinefelter syndrome, gonadal injury from chemotherapy, radiotherapy, autoimmune or post-infectious injury, cryptorchidism, or disorders of testosterone biosynthesis in males. Rarely, it is caused by defects in the molecular structure of LH and FSH or defects in their membrane receptors on gonadal cells. (See "Causes of primary hypogonadism in males" and "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)".)

Secondary (hypogonadotropic) hypogonadism — Secondary hypogonadism is characterized by low serum concentrations of gonadal steroids and low or normal serum LH and FSH concentrations. This family of disorders is characterized either by deficient gonadotropin-releasing hormone (GnRH) secretion or by pituitary disease. Both lead to deficient secretion of LH and FSH from the anterior pituitary, which results in deficient gonadal steroid secretion and deficient gametogenesis. This category is sometimes called "central" hypogonadism.

Causes of secondary hypogonadism include:

Constitutional delay of growth and puberty — Constitutional delay of growth and puberty (CDGP) is the most common cause of delayed puberty and is due to a transient functional defect in production of GnRH from the hypothalamus, caused by individual genetic variations in the ensemble of hypothalamic and pituitary genes controlling sexual maturation. CDGP tends to have familial patterns of inheritance, often following an autosomal dominant pattern such that family members from multiple generations often have a history of "late blooming," with an onset of puberty and pubertal growth spurt that are delayed compared with their peers. (See "Causes of short stature", section on 'Constitutional delay of growth and puberty'.)

Isolated gonadotropin-releasing hormone deficiency — Isolated GnRH deficiency, also known as idiopathic hypogonadotropic hypogonadism or congenital hypogonadotropic hypogonadism, can be caused by a variety of genetic mutations. Approximatively 50 percent of patients have associated anosmia (absent sense of smell), known as Kallmann syndrome. Other congenital anomalies including midline defects (cleft lip/palate), neurosensory hearing loss, synkinesia (alternating mirror movements), unilateral renal agenesis, or skeletal defects including syndactyly and ectrodactyly (lobster claw deformity) can be associated with isolated GnRH deficiency at variable frequency. The clinical presentation of these genetic defects varies considerably depending on the causative gene but may include microphallus and/or cryptorchidism in males at birth, a consequence of GnRH deficiency in utero, and absent or stalled pubertal development in males and females [12,13]. These disorders may have different familial patterns of inheritance, although many cases appear to be sporadic because of the variable clinical presentation and/or inability to obtain a detailed family history. The hypogonadism is usually permanent but may be reversible later in life in approximately 10 to 15 percent of patients [14]. Genetics and other details are discussed separately. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Genetics'.)

Isolated GnRH deficiency is initially a diagnosis of exclusion but, in approximately 50 percent of patients with Kallmann syndrome, can be confirmed by identification of mutations in specific genes. In patients with unexplained hypogonadotropic hypogonadism, a presumptive diagnosis of isolated GnRH deficiency can be made in patients with suggestive physical features (microphallus and/or cryptorchidism, anosmia, unilateral renal agenesis, synkinesia, or skeletal defects) or a family history of isolated GnRH deficiency or those in which puberty has not begun by age 17 years. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Diagnosis'.)

In patients under 17 years old who lack any of these characteristic phenotypic features, it may be difficult to distinguish isolated GnRH deficiency from CDGP. Furthermore, these classes of delayed pubertal disorders are likely to have some degree of genetic overlap. This is suggested by the observation of higher rates of CDGP in families with isolated GnRH deficiency [15] and reports that some cases of apparent CDGP are associated with heterozygous mutations in a gene associated with isolated GnRH deficiency [16].

Other forms of functional hypogonadotropic hypogonadism — This may be associated with an underlying medical condition such as poor nutrition (including anorexia nervosa), chronic illness (eg, inflammatory bowel disease, celiac disease), hypothyroidism, and excessive exercise. Affected patients typically have delayed but spontaneous pubertal development.

Hypothalamic or pituitary disease — Hypothalamic or pituitary disorders, such as malformations, hemochromatosis, injury, or tumors (especially craniopharyngioma) can cause secondary hypogonadism.

EVALUATION — Although measurement of serum gonadotropin levels and gonadal sex steroid levels can usually differentiate primary from secondary hypogonadism, making a definitive diagnosis of a specific cause of delayed puberty associated with secondary hypogonadism during adolescence can be difficult. Because most of these disorders have in common a decrease in gonadotropin-releasing hormone (GnRH) secretion and/or its action, no single test except for serial observations over time reliably distinguishes patients with constitutional delay of growth and puberty (CDGP), who will eventually progress spontaneously through puberty, from patients with other causes of delayed puberty, particularly those with isolated GnRH deficiency [17-19]. In addition, because some cases of well-documented isolated GnRH deficiency undergo spontaneous reversals after being treated with sex steroids, these distinctions between CDGP and isolated GnRH deficiency are becoming less absolute [14]. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Reversal of IHH'.)

As a result, the first step in the evaluation is a complete history and physical examination to determine whether further biochemical testing or imaging studies are needed.

History — Key questions to ask during the history are:

●Is pubertal development totally absent, or did it start and then "stall"? – Assessment of the patient's growth pattern up to the time of evaluation is critical, with review of the height-for-age growth chart and calculation of height velocity (cm/year), compared with their peers of the same chronologic age (figure 1A-B). Similarly, ask whether there have been any signs of pubertal development, such as some initial breast development or tenderness in females, that subsequently disappeared. Isolated androgen-mediated sexual characteristics (such as pubic and/or axillary hair, acne, and apocrine odor) may be the first signs of puberty but usually reflect adrenarche. (See "Causes of short stature".)

Patients with CDGP have delayed (not stalled) pubertal development, with slow progression of skeletal growth, adrenarche, gonadal maturation, and bone age that is delayed compared with their peers. In contrast, adolescent-aged patients with tumors in the hypothalamic-pituitary region may present with stalled pubertal development.

●Does the patient have nutritional habits or a medical illness or engage in intense exercise that delayed the onset or slowed the tempo of puberty? – Undernutrition or high-intensity exercise (eg, long-distance running) are common causes of pubertal delay in otherwise healthy adolescents. Delays in sexual maturation and height velocity often can be the first clinical signs of underlying disorders, such as inflammatory bowel disease, hypothyroidism, or psychosocial deprivation [20]. Patients with inflammatory bowel disease often have gastrointestinal symptoms such as loose or bloody stools or abdominal pain, but the symptoms may be subtle. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children" and "Growth failure and pubertal delay in children with inflammatory bowel disease", section on 'Clinical manifestations'.)

Chronic opioid use is associated with hypogonadism. (See "Causes of secondary hypogonadism in males", section on 'Opioids'.)

●Does the patient have any congenital abnormalities or neurologic symptoms? – Some patients with isolated GnRH deficiency have associated anomalies including microphallus, cryptorchidism, midline defects, synkinesia, and/or renal agenesis [21]. Neurologic symptoms such as headache, visual disturbances, dyskinesia, seizures, and intellectual disability may also occur and, if present, strongly suggest a central nervous system disorder. (See 'Hypothalamic or pituitary disease' above and "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Congenital abnormalities'.)

●Is there a family history of delayed or absent puberty? – A family history of delayed puberty is common in both CDGP and isolated GnRH deficiency, and, in some cases, the disorders may have similar genetic mechanisms (see 'Isolated gonadotropin-releasing hormone deficiency' above). In CDGP, parents or siblings give a history of being "late bloomers," with a late growth spurt or late puberty compared with their peers. This typically has an autosomal dominant mode of inheritance, with or without incomplete penetrance [22]. Isolated GnRH deficiency can be inherited in an autosomal dominant, autosomal recessive, or X-linked recessive manner. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)".)

●Does the patient have a normal sense of smell? – Absent sense of smell (anosmia) strongly suggests Kallmann syndrome, which is a subtype of isolated GnRH deficiency [23-25]. (See 'Isolated gonadotropin-releasing hormone deficiency' above.)

Physical examination — Careful assessments of height, weight, arm span, and secondary sex characteristics are the most relevant aspects of the physical examination. Early signs of sexual development unnoticed by the patient (such as testicular growth) may permit reassurance and avoidance of a costly evaluation in the otherwise normal child. Serial measurements of height and testicular size or breast development made over one or two years will help to confirm the presence or absence of pubertal changes and their progression as well as clarify the diagnosis.

Both standing height and arm span should be measured to determine if the body proportions are eunuchoid, indicated by an arm span exceeding the height by more than 5 cm. This finding suggests delayed epiphyseal closure secondary to hypogonadism (eg, due to Klinefelter syndrome). Increased arm span is also a feature of Marfan syndrome, but Marfan syndrome is not associated with hypogonadism. The height should be plotted on growth charts that include normal growth patterns with centiles or standard deviation scores (figure 2A-B) to place the current height in the proper developmental context and to allow comparison with both current and subsequent bone age determination. The height velocity should be carefully documented for at least six months or longer, if possible.

Secondary sexual characteristics should be staged according to the sexual maturity ratings, also known as Tanner staging (picture 1 and picture 2A-B) [26]. In males, testicular size should be measured by a Prader orchidometer (picture 3). Particular attention also should be paid to the symmetry of the testes since gonadal tumors can occur in several intersex disorders presenting at puberty with asymmetrical gonadal development and defects in sexual maturation; suspected abnormalities should be further evaluated by ultrasonography. (See "Normal puberty", section on 'Sexual maturity rating (Tanner stages)' and 'Additional testing' below.)

The earliest signs of pubertal development are a testicular volume of greater than or equal to 4 mL in males (figure 3) (corresponding to approximately 2.0 to 3.1 cm in testicular length) and the appearance of breast buds in females. If either of these features is present, the patient and family can be reassured that puberty will most likely progress. However, longitudinal follow-up is essential since some children exhibit some initial signs of pubertal development, but then pubertal progression stops or stalls. This pattern may occur in some children with genetic causes of isolated GnRH deficiency.

All females should be carefully evaluated for features associated with Turner syndrome (table 2). In some individuals with Turner syndrome, the presenting feature is delayed pubertal development, usually with longstanding short stature and generally without other obvious clinical features of Turner syndrome (see "Clinical manifestations and diagnosis of Turner syndrome", section on 'Typical features'). As a result, any female with unexplained significant pubertal delay and primary hypogonadism (elevated levels of luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) should have genetic testing for Turner syndrome. (See 'Additional testing' below.)

Initial testing — For patients with some signs of pubertal development (eg, breast buds by age 12 years in females or testicular enlargement by age 14 years in males) and no evidence of underlying disease, general laboratory screening is appropriate but not essential. These patients should be followed clinically at three- to six-month intervals and tested if puberty does not progress.

Patients with absent, stalled, or very delayed puberty should undergo a bone age determination and the additional laboratory testing as described below.

Bone age — A radiograph of the left hand and wrist to evaluate bone age should be obtained at the initial visit to assess skeletal maturation and then repeated over time if needed. This provides valuable information about the relationship between chronologic age and skeletal maturation and the potential for future skeletal growth and also allows a preliminary prediction of adult height. These results are useful when making decisions about possible interventions (eg, whether or not to initiate hormonal therapy for patients with CDGP). However, the bone age does not help to distinguish between different causes of delayed puberty.

Patients with CDGP typically have bone ages delayed by approximately 20 percent compared with chronologic age. Skeletal development progresses slowly without the presence of pubertal levels of gonadal steroids because sex steroids are required for epiphyseal closure.

General laboratory tests — Children with delayed puberty should be evaluated for the possibility of nutritional disorders, celiac disease, or occult chronic illnesses (eg, chronic inflammatory bowel disease, anorexia nervosa, or hepatic disease) that may affect hypothalamic GnRH secretion [27] by performing the following tests:

●Complete blood count, erythrocyte sedimentation rate or C-reactive protein, blood urea nitrogen, creatinine, and liver function tests (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]).

●Tissue transglutaminase-immunoglobulin A antibodies (tTG-IgA) to screen for celiac disease. Celiac disease is common and occasionally presents with delayed growth and puberty, with few or no other symptoms. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children" and "Diagnosis of celiac disease in children".)

Endocrine tests — The hormonal evaluation should include the following tests:

●LH, FSH, estradiol, and testosterone – Random (unstimulated) measurements of serum LH and FSH, together with estradiol (females) or testosterone (males), should be obtained to distinguish between primary and secondary hypogonadism. These measurements should be interpreted based upon the normative data provided by the testing laboratory.

•Elevated serum LH and FSH concentrations with subnormal testosterone or estradiol for age indicate primary hypogonadism. These hormones are usually sufficiently elevated by adolescence to be easily distinguished from normal adolescents without hypogonadism. This is particularly true for FSH levels, which provide the greatest discrimination in this age group. Females with elevated gonadotropins should be further evaluated for Turner syndrome. (See 'Additional testing' below.)

•Low or normal serum LH and FSH values in the setting of low levels of testosterone or estradiol in the adolescent age range are consistent with either CDGP or isolated GnRH deficiency. This pattern is also be seen with other forms of functional hypogonadotropic hypogonadism (eg due to medical illness) or hypothalamic-pituitary disorders. (See 'Other forms of functional hypogonadotropic hypogonadism' above and 'Hypothalamic or pituitary disease' above.)

GnRH stimulation testing is not recommended, because it does not help distinguish between CDGP and isolated GnRH deficiency, with significant overlap of LH and FSH responses between the two groups of patients [28-30]. Several reports have suggested that stimulation tests with other GnRH agonists, such as buserelin, are better at differentiating between these groups of patients [31,32]. In most cases, however, the distinction between CDGP and isolated GnRH deficiency remains ambiguous and the disorders typically can be distinguished only with "tincture of time" and serial observations. In some patients, therapy may be initiated prior to determining the diagnosis. (See 'Therapy' below.)

●Prolactin – A random measurement of serum prolactin should be obtained to detect hyperprolactinemia, which can present clinically as "stalled" puberty. An elevated prolactin level can result from a lactotroph adenoma (prolactinoma) or from any hypothalamic or pituitary disorder that interrupts hypothalamic inhibition of prolactin secretion. Patients with hyperprolactinemia (unless clearly related to a prolactin-raising medication) should be further evaluated by imaging of the hypothalamus and the pituitary region by head magnetic resonance imaging (MRI). (See "Causes of hyperprolactinemia" and "Causes, presentation, and evaluation of sellar masses".)

●Insulin-like growth factor 1 (IGF-1) – Measurement of IGF-1 is often suggested to help exclude the possibility of growth hormone deficiency as a cause of the delayed puberty. The growth hormone deficiency may be isolated or associated with other pituitary hormone deficiencies. The results should be compared with the normal range for the child's pubertal stage (and/or bone age) rather than chronologic age. Growth hormone deficiency is unlikely if the IGF-1 result is normal. However, a low IGF-1 level does not mean that the patient has growth hormone deficiency, as low levels are seen in many other disorders, including undernutrition, hypothyroidism, renal failure, and other chronic illnesses. (See "Diagnosis of growth hormone deficiency in children", section on 'IGF-1 and IGFBP-3'.)

●Thyroid function tests – Tests for hypothyroidism, which delays puberty by as yet unknown mechanisms, should be obtained, particularly if height velocity has suddenly slowed and the bone age is significantly delayed. Both thyroid-stimulating hormone (TSH) and free thyroxine (T4) should be measured. Serum TSH is elevated in primary hypothyroidism but is usually normal or low in secondary hypothyroidism (ie, due to hypothalamic or pituitary disease). As a result, serum free T4 should be measured to assess for central hypothyroidism. (See "Laboratory assessment of thyroid function".)

Additional testing — Depending upon the clinical findings and the results of the hormonal testing, additional evaluation may include the following:

Patients with high LH and FSH — Patients with elevated gonadotropins have primary hypogonadism. A karyotype or comparative genomic hybridization array should be performed in every patient with primary hypogonadism to evaluate the possibility of Turner syndrome in females and Klinefelter syndrome in males. Increasingly, whole-exome/whole-genome sequencing are used to investigate these structural defects, with improvements in cost, interpretation, and turnaround time. Turner syndrome may present with delayed puberty/primary amenorrhea or, in some cases, stalled puberty (especially in those with Turner mosaic genotype). Klinefelter syndrome rarely presents with delayed puberty; more typical presenting features are incomplete puberty and other physical findings that suggest the diagnosis (cryptorchidism, testes smaller than 5 mL in volume, and/or gynecomastia). (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Diagnosis' and "Causes of primary hypogonadism in males", section on 'Klinefelter syndrome'.)

Patients with low or normal LH and FSH — Patients with low or normal LH and FSH have secondary or hypogonadotropic hypogonadism. Additional evaluation in these patients depends upon their clinical presentation:

●Head MRI with emphasis on the sellar region should be obtained if associated neurologic symptoms or signs suggest a process involving the brain (eg, headaches, visual disturbances, and/or midline defects) or if the laboratory studies are consistent with hypothalamic or pituitary disease (eg, hyperprolactinemia, central adrenal insufficiency, and/or central hypothyroidism). If a sellar mass is identified, the patient should be further evaluated for pituitary hormone deficiencies. In addition, clinicians may request special imaging (with thin cuts through the olfactory region) to assess the presence or hypoplasia/absence of the olfactory bulb, nerves, and tracts, which can provide insight into the possibility of Kallmann syndrome. (See "Clinical manifestations and evaluation of hyperprolactinemia", section on 'Laboratory/imaging tests' and "Diagnostic testing for hypopituitarism" and "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Diagnosis'.)

●Tests of olfactory function ("smell kit") can be used for patients who report anosmia to point toward a diagnosis of Kallmann syndrome. (See 'Isolated gonadotropin-releasing hormone deficiency' above.)

●Genetic testing panels may be appropriate if isolated GnRH deficiency is strongly suspected because of anosmia or associated congenital anomalies (eg, midline defects [cleft lip/palate], neurosensory hearing loss, synkinesia, unilateral renal agenesis, or skeletal defects including syndactyly). By contrast, in patients without these features, genetic testing usually is not warranted during adolescence. This is because a majority of patients with secondary hypogonadism and no other abnormalities will have CDGP. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Diagnosis'.)

●Stimulation testing with kisspeptin is a promising approach to help distinguish between patients with CDGP and isolated GnRH deficiency/Kallmann syndrome. In a pilot study of 17 children with delayed or stalled puberty, a rise in LH of 0.8 mIU/mL or greater after kisspeptin stimulation predicted pubertal progression by 18 years of age [33]. Kisspeptin appears to have a role in activating GnRH secretion at puberty. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Genetics' and "Normal puberty", section on 'Physiology of pubertal onset'.)

●Serum inhibin B can be used as a biochemical index of gonadal function in males. For individuals with secondary (hypogonadotropic) hypogonadism with no clear cause, a very low level of inhibin B is more likely to be associated with isolated GnRH deficiency with absent puberty than CDGP [34]. In a study of 82 male adolescents with delayed puberty and genital stage 1, a cutoff for inhibin B of <35 pg/mL showed a sensitivity and specificity of 100 percent for distinguishing GnRH deficiency from CDGP [34]. In a second study of 170 adolescents with delayed puberty, a cutoff for inhibin B of <61 ng/L (pg/mL) had a sensitivity of 90 percent and a specificity of 83 percent for detecting congenital GnRH deficiency [35]. However, inhibin B levels are not useful to distinguish between CDGP and partial isolated GnRH deficiency. For males, serial measurements of inhibin B can help to monitor pubertal progression, as a supplement to measurements of testicular volume, because inhibin B and testicular size are well correlated [34]. For females, there is no such clinical correlation.

●Evaluation for iron overload in patients with risk factors, by measuring serum transferrin saturation and ferritin, can be done in clinically appropriate situations. Iron overload can cause secondary (hypogonadotropic) hypogonadism. Risk factors include:

•Children with a history of blood transfusion therapy (eg, those with hemoglobinopathies).

•Males or females with risk factors for juvenile hereditary hemochromatosis, which include a family history of consanguinity or iron overload, or unexplained liver or cardiac disease. Juvenile hemochromatosis is rare but has been most commonly reported in Italy. In contrast with other forms of hereditary hemochromatosis, it can present in adolescents or young adults. (See "HFE and other hemochromatosis genes", section on 'Hemojuvelin (HJV)' and "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Indications for testing'.)

THERAPY

Patients with specific cause of delayed puberty — If a specific underlying disorder can be identified (table 1), therapy should be targeted at that disorder. As examples, thyroid hormone replacement in hypothyroidism, effective treatment of inflammatory bowel disease, dopamine agonist treatment of lactotroph adenomas, and excision of craniopharyngiomas can result in prompt initiation or resumption of sexual maturation in the appropriate clinical circumstances.

For patients with primary gonadal failure, such as Turner or Klinefelter syndrome, sex hormone therapy is a component of management. (See "Management of Turner syndrome in children and adolescents" and "Testosterone treatment of male hypogonadism".)

Patients with presumed constitutional delay of growth and puberty — A majority of patients with pubertal delay will have secondary hypogonadism without evidence of underlying disease. For this group of patients, the most likely causes are either constitutional delay of growth and puberty (CDGP) or isolated gonadotropin-releasing hormone (GnRH) deficiency. Distinguishing between these disorders is often impossible during the initial evaluation, unless specific associated features of isolated GnRH deficiency are present. In many cases, the diagnosis is resolved only with serial observations. (See 'Isolated gonadotropin-releasing hormone deficiency' above and "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Diagnosis'.)

In view of these diagnostic difficulties, the initial therapeutic approach is similar for both disorders [36,37]. The two major options are "watchful waiting," with reassurance and psychological support for the patient and family, or short-term hormonal therapy, with testosterone in males and estradiol in females.

Hormonal therapy

Indications and goals — Short-term hormonal therapy may be appropriate for males older than 14 years, or females older than 12 years who show few or no signs of puberty, and if the pubertal delay is severe or if the patient's psychosocial concerns about the delay play a prominent role that cannot be resolved by reassurance and education alone. The short-term use of exogenous testosterone in males or estradiol in females does not appear to have any long-term sequelae, except that the hormone-induced skeletal maturation might result in some loss of adult height.

Short-term therapeutic goals include:

●Attainment of age-appropriate secondary sex characteristics to ameliorate the patient's concern about their appearance relative to peers. In some cultures, this can be a particular problem for males in communal settings that require disrobing, such as in showers and gym classes, but one that occurs to some degree in both males and females.

●Induction of a growth spurt without inducing premature epiphyseal closure. This goal requires frequent (eg, every six months) longitudinal monitoring of bone age during therapy.

●Potential induction of a "reversal" of their GnRH deficiency, whether congenital or functional; sex steroid hormone therapy has been demonstrated to induce puberty even in some cases in which the GnRH deficiency has a genetic etiology [14]. However, the therapy should be stopped periodically for three to six months to determine if spontaneous puberty has been initiated. During these intervals, serum testosterone and testicular sizes should be followed carefully at two- to three-monthly intervals as markers of pubertal progression.

For patients who exhibit isolated GnRH deficiency that does not "reverse" spontaneously, the long-term goals of therapy are to maintain the serum concentrations of sex steroids within the normal adult range and, eventually, to induce fertility if and when the patient desires. (See "Induction of fertility in males with secondary hypogonadism" and "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)".)

Testosterone therapy — Testosterone can be administered by several routes, and the patient's preference should be considered. The most reliable and well-tested approach is to use intramuscular (IM) injections of testosterone esters [38-47]. The use of testosterone gel transdermally seems appealing because of its efficacy and convenience in adult males with hypogonadism, but it has not yet been approved or even widely studied in males younger than age 18 years. An oral preparation of testosterone undecanoate is available in some countries, but it must be taken twice a day and is not approved for males under age 18. (See "Testosterone treatment of male hypogonadism", section on 'Choice of testosterone regimen'.)

Testosterone doses should initially be initiated at relatively low levels (eg, 50 mg of IM testosterone enanthate or testosterone cypionate once a month). Such a dose (approximately 15 to 25 percent of the adult dose) is usually sufficient to achieve early virilization and growth over time (ie, three to six months), without unduly advancing epiphyseal maturation (bone age). (See "Testosterone treatment of male hypogonadism".)

One approach is to administer testosterone enanthate or cypionate (50 mg IM once monthly) for six months and then reassess endogenous gonadal function and size six months later. In many patients, this therapy is associated with pubertal development, indicated by testicular enlargement and increasing testosterone concentrations after the cessation of therapy. Testicular enlargement and increasing testosterone concentrations demonstrate that follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are present in sufficient quantities and also excludes testicular pathology. It is unclear whether the pubertal development is spontaneous or is triggered by the testosterone exposure. Controlled studies in this area are difficult to conduct but do support the notion that testosterone exposure may hasten the hypothalamic GnRH secretion required for puberty.

Although exogenous sex steroid administration accelerates epiphyseal maturation [45], most studies indicate that judicious treatment with low doses of sex steroids for limited periods of time does not adversely affect adult height [37-40,43,46]. The use of relatively low doses of testosterone, and treating for limited periods of time, maximizes the likelihood that a male will reach his "predicted" final height.

In one report, for example, 15 males with CDGP were treated with testosterone enanthate (50 mg/month) for a mean of 1.2 years [37]. Mean height velocity increased from the 3^rd percentile for mean bone age to above the 90^th percentile, and mean testicular volume rose from 5.9 to 11.3 mL during therapy. The increase in testicular volume during the course of testosterone therapy was accompanied by endogenous GnRH secretion and the occurrence of spontaneous puberty. Skeletal maturation increased only in the males with an initial bone age below the group mean. After cessation of therapy, bone age and sexual development proceeded normally and the males ultimately achieved their predicted mean height. Similar results have been reported in other studies [38,43,46]. Thus, it is unusual for a male with CDGP to require more than two three- to six-month courses of testosterone therapy before spontaneous puberty occurs.

In contrast, most males with other forms of hypogonadotropic hypogonadism demonstrate little or no pubertal development with low-dose testosterone, and pubertal progress usually stops with cessation of therapy. After the age of 18 years in those patients without any organic or obvious pathologic causes, isolated (congenital) GnRH deficiency is the most likely diagnosis. However, approximately 10 percent of patients with isolated GnRH deficiency appear to undergo a spontaneous reversal following even a brief course of sex steroid exposure. This reversal is heralded by testicular enlargement, or the ability to sustain a normal testosterone concentration off of treatment or following a missed prescription refill [14].

Estradiol therapy — In females, estradiol may be given orally or transdermally. Initial doses are lower than those used for replacement therapy in adults. Guidelines suggest starting with very low doses of estradiol and gradually increasing the dose. Our approach, using the transdermal 17-beta estradiol patch, is as follows:

●Start with a transdermal matrix 17-beta estradiol patch that is designed to deliver 25 mcg/day. Cut into quarters to deliver approximately 6.25 mcg/day per piece. For all doses, wear the patch continuously and change the patch as directed on the manufacturer's insert (typically twice weekly).

●Month 6 – Increase to one-half patch (12.5 mcg/day of 17-beta estradiol).

●Month 12 – Increase to three-fourth quarters patch (18.75 mcg/day of 17-beta estradiol).

●Month 18 – Increase to full patch (25 mcg/day of 17-beta estradiol).

●Month 24 – Continue estradiol and add cyclic progestin 200 mg, given on days 1 to 12 of the calendar month (if breast development is adequate).

In individuals with Turner syndrome, estradiol therapy is typically started at age 11 to 12 years. In this case, some experts use even lower initial doses (eg, cutting a smaller portion of the patch and wearing this only at night). (See "Management of Turner syndrome in children and adolescents", section on 'Induction of puberty'.)

The initial estradiol doses used are below those required to induce menstruation. We add cyclic progestin therapy after two years of estradiol or when breakthrough bleeding occurs on unopposed estradiol. Our first choice for progestin therapy is oral micronized progesterone 200 mg days 1 to 12 of the calendar month. The progestin should not be added until there is substantial breast development that is not solely confined to the areolae and full contour breast growth has plateaued, because premature initiation of progestin therapy can compromise ultimate breast growth.

Once breast growth has plateaued during serial evaluation and menstruation has been established, estradiol therapy can be discontinued intermittently for one- to three-month periods to determine if spontaneous menstruation occurs, which should happen in females with CDGP. If spontaneous menstruation occurs, the estradiol therapy is stopped.

Patients who do not develop spontaneous menstruation and who are older than age 18 years likely have isolated (congenital) GnRH deficiency. In this case, full adult replacement therapy with both estrogen and progesterone should be initiated. Doses and principles of therapy are similar to those for women with primary ovarian insufficiency. Additional details on progestin therapy and maintenance hormone therapy are found separately. (See "Management of primary ovarian insufficiency (premature ovarian failure)".)

Growth hormone therapy — The value of growth hormone therapy in patients without documented growth hormone deficiency is controversial. Serum growth hormone and insulin-like growth factor 1 (IGF-1) concentrations are usually low for chronologic age in patients with CDGP (but not if corrected for the normal range for bone age) and increase in response to testosterone or estrogen therapy. Patients with isolated (congenital) GnRH deficiency are typically not growth hormone-deficient and do not benefit from growth hormone therapy, since sex steroids will prompt normal increases in their growth axis. Although the administration of growth hormone is less likely to induce epiphyseal closure than sex steroids and may therefore add to adult height, children with delayed puberty grow well when treated with sex steroids alone.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Normal puberty and puberty-related disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Late puberty (The Basics)")

SUMMARY

●Definition – Delayed puberty is defined clinically by the absence or incomplete development of secondary sexual characteristics by an age 2 to 3 standard deviations above the mean age of onset of puberty, ie, by an age at which 97 to 99 percent of children of that sex and culture have initiated sexual maturation. In the United States, this corresponds to an upper limit of 12 to 13 years for females (for breast development) and of 13 to 14 years for males (for testicular enlargement). (See 'Delayed puberty' above.)

●Categories and causes – Primary hypogonadism is characterized by low levels of gonadal hormones and high levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Secondary hypogonadism is characterized by low levels of gonadal hormones and low to normal concentrations of LH and FSH and typically is caused by impaired secretion of hypothalamic gonadotropin-releasing hormone (GnRH).

Causes of delayed puberty are listed in the table (table 1). Common causes of secondary hypogonadism are:

•Constitutional delay of growth and puberty (CDGP) – This is the most common cause of delayed puberty; it is a transient defect in production of GnRH from the hypothalamus due to physiologic individual variation. Patients with CDGP have delayed (not stalled) growth, adrenarche, sexual development, and bone age.

•Isolated (congenital) GnRH deficiency – This can be difficult to distinguish from CDGP between 14 to 16 years. Some patients with isolated GnRH deficiency have anosmia or other associated congenital anomalies, including midline defects (cleft lip/palate), neurosensory hearing loss, synkinesia, unilateral renal agenesis, or skeletal defects including syndactyly and ectrodactyly. (See 'Etiology' above.)

●Evaluation – The most valuable components of an assessment are a focused history and physical examination as well as observation over time. (See 'Evaluation' above.)

•History – Determine whether pubertal development is totally absent or had started but then "stalled," and solicit information about underlying chronic disease, congenital anomalies (especially midline craniofacial defects or anosmia), and family history of pubertal development. (See 'History' above.)

•Physical examination – Determine sexual maturity rating (Tanner stage) of pubertal development (picture 1 and picture 2A-B). Calculate the height velocity from serial measurements of height over six months or more. (See 'Physical examination' above.)

Patients with absent, stalled, or very delayed puberty should undergo further testing:

•Bone age – Bone age determination provides valuable information about the relationship between chronologic age and skeletal maturation. Children with CDGP typically have bone ages approximately 20 percent younger than their actual age. (See 'Bone age' above.)

•Laboratory tests – These should evaluate for endocrine causes of delayed puberty and screen for nutritional disorders or occult chronic illnesses that may affect hypothalamic GnRH secretions. (See 'General laboratory tests' above and 'Endocrine tests' above.)

•Additional tests – In selected patients, head MRI or evaluation for iron overload are appropriate. Patients with primary hypogonadism (elevated LH and FSH) should undergo diagnostic testing for Turner syndrome (females) or Klinefelter syndrome (males). (See 'Additional testing' above.)

●Treatment

•If a specific underlying disorder can be identified (table 1), therapy should be targeted at that disorder. (See 'Patients with specific cause of delayed puberty' above.)

•In most patients with secondary hypogonadism and no other abnormalities, the distinction between CDGP and isolated (congenital) GnRH deficiency remains uncertain between 14 and 16 years old and can be resolved only with serial observations. Short-term hormonal therapy may be appropriate when the pubertal delay is severe or the patient's psychosocial concerns about the delay play a prominent role that cannot be addressed by reassurance and education alone. (See 'Patients with presumed constitutional delay of growth and puberty' above.)