Version July 2025
INTRODUCTION —
Delayed puberty is defined as the absence of clinical signs of pubertal development by the expected age of pubertal onset for a given population. In the United States, this has traditionally been taken to mean the absence of breast development by age 13 years in females or the absence of testicular enlargement by age 14 years in males. However, the timing of pubertal onset varies substantially within and across different populations and is determined by both genetic and environmental factors.
The evaluation and management of the pediatric patient with delayed puberty is reviewed here. Normal puberty and related conditions are discussed elsewhere.
●(See "Normal puberty".)
●(See "Evaluation and management of primary amenorrhea".)
●(See "Evaluation and management of secondary amenorrhea".)
●(See "Clinical features and diagnosis of male hypogonadism".)
DEFINITIONS
Normal puberty — Puberty refers to the physical changes that occur in response to sex steroids secreted by the gonads (testosterone produced by the testes and estradiol produced by the ovaries). Although the average age at which puberty begins (8 to 13 years in females, 9 to 14 years in males) has gotten somewhat younger over the past century, the sequence of events that occur in puberty is relatively consistent [1-3]. (See "Normal puberty", section on 'Secondary sex characteristics (Tanner stages)'.)
Delayed puberty — Delayed puberty is usually identified when individuals do not develop secondary sex characteristics (eg, breast development in females, voice change and facial hair growth in males) at the same time as peers. Because the average age of pubertal onset varies between subgroups in the population, we define delayed puberty as the absence of breast development by age 12 to 13 years in females or the absence of testicular enlargement (≥4 mL in volume) by age 13 to 14 years in males.
However, pubertal timing differs among ethnic groups in the United States [1-6]. In one longitudinal cohort, the average onset of breast development in females based on provider examination occurred at age 8.8 years in Black children compared with 9.3 years in Hispanic children, 9.7 years in non-Hispanic White children, and 9.7 years in Asian children [2]. Similar differences occurred in a longitudinal cohort of males, with the provider-reported onset of testicular enlargement ≥3 mL at 9.71 years in Black children, 9.63 years in Hispanic children, and 9.95 years in non-Hispanic White children [3].
Development of pubic hair is not usually included in this definition because this can be a sign of adrenarche (physiologic production of adrenal androgens) rather than true puberty. (See "Physiology and clinical manifestations of normal adrenarche", section on 'Clinical manifestations of adrenarche'.)
Stalled puberty — Puberty is considered "stalled" if not completed within approximately four years of its onset (a time when 95 percent of youth will have completed pubertal development) or if pubertal development has not progressed within two years [7]. Disorders associated with alterations in reproductive function may present with either delayed puberty or stalled puberty. As an example, some individuals with Turner syndrome present with stalled puberty after spontaneous breast development, while others may not experience spontaneous breast development. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Delayed, stalled, or absent puberty'.)
Hypogonadism — Hypogonadism refers to inadequate or absent production of gonadal sex steroids (ie, estradiol testosterone from the testes or from the ovary). This results in delayed or absent development of the physical changes associated with puberty. Hypogonadism is classified based on whether it is the result of gonadal disease (primary or hypergonadotropic hypogonadism) (see 'Primary (hypergonadotropic) hypogonadism' below) or alterations in the structure or function of the hypothalamus or pituitary gland (secondary or hypogonadotropic hypogonadism). (See 'Secondary (hypogonadotropic) hypogonadism' below.)
EPIDEMIOLOGY —
Delayed puberty occurs in approximately 2 to 5 percent of adolescents [8,9].
In retrospective studies of adolescents evaluated for delayed puberty, the relative frequency of the various causes was [8-13]:
●Primary hypogonadism – 5 percent of males and 15 to 25 percent of females.
●Secondary hypogonadism – 85 to 95 percent of males and 75 to 85 percent of females.
•Transient forms
-Constitutional delay of growth and puberty (CDGP) – 60 to 80 percent of males and 30 to 55 percent of females.
-Functional hypogonadotropic hypogonadism (FHH) – 10 to 20 percent of males and 20 to 30 percent of females.
•Permanent forms – 10 percent of males and 10 to 20 percent of females.
ETIOLOGY
Primary (hypergonadotropic) hypogonadism — Primary hypogonadism refers to gonadal hypofunction due to gonadal disease. The gonadotroph cells of the pituitary gland respond appropriately to the deficiency of testosterone or estradiol by secreting large amounts of gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Because gonadotropin levels are (appropriately) elevated on serum measurements, primary hypogonadism is sometimes described as "hypergonadotropic hypogonadism." Importantly, elevated FSH and LH do not cause hypogonadism but represent an appropriate response to inadequate production of testosterone/estradiol by the ovaries/testes. (See 'Initial tests' below.)
Primary hypogonadism is usually permanent. It may be caused by congenital or acquired disorders (table 1).
●Males – Although Klinefelter syndrome is the most common cause of primary hypogonadism in males, most patients with this diagnosis do not experience delayed or stalled puberty [14]. Other causes of primary hypogonadism include exposure to gonadotoxic agents (eg, chemotherapy), cryptorchidism infection, trauma, and disorders of testosterone biosynthesis (table 2). (See "Clinical features, diagnosis, and management of Klinefelter syndrome" and "Causes of primary hypogonadism in males".)
●Females – In females, Turner syndrome is the most common congenital cause of primary hypogonadism [15]. However, up to 30 percent of individuals with Turner syndrome experience some breast development followed by stalled or incomplete pubertal progression rather than absent puberty [16]. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Delayed, stalled, or absent puberty'.)
Exposure to gonadotoxic therapies is the most common iatrogenic cause of primary hypogonadism in females. Other causes of primary hypogonadism in females (also known as primary ovarian insufficiency) more often present after puberty with secondary amenorrhea (table 3). (See "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)".)
Secondary (hypogonadotropic) hypogonadism — Secondary hypogonadism refers to gonadal hypofunction resulting from inadequate production of the hypothalamic (gonadotropin-releasing hormone [GnRH]) or pituitary (FSH and LH) hormones that stimulate gonadal secretion of testosterone or estradiol. Because the gonadotropins are not elevated on serum measurements, secondary hypogonadism may also be called "hypogonadotropic hypogonadism." (See 'Initial tests' below.)
Secondary hypogonadism may be transient or permanent.
Transient forms — Reversible causes of secondary hypogonadism in males and females include constitutional delay of growth and puberty (CDGP) and functional hypogonadotropic hypogonadism (FHH).
●CDGP – CDGP (commonly known as "late blooming") is the most frequent cause of delayed puberty. In individuals with CDGP, puberty begins later than is typical but before age 18 years. Patients with CDGP may demonstrate a history of reduced linear growth velocity beginning in childhood. (See "Causes of short stature", section on 'Constitutional delay of growth and puberty'.)
CDGP is caused by a delayed physiologic rise in hypothalamic GnRH secretion. It is highly heritable, with affected families often reporting that individuals in multiple generations have a history of delayed puberty [17,18]. However, the genetic background of CDGP remains incompletely understood. Rarely, CDGP occurs in carriers of recessive pathogenic variants that cause permanent hypogonadotropic hypogonadism in homozygous individuals [19]. In most cases, however, CDGP is thought to be polygenic, resulting from variants of small effect occurring in multiple genes [17-20].
●FHH – The second most common cause of delayed puberty is FHH. In FHH, there is no structural or genetic cause of abnormalities in the hypothalamic-pituitary-gonadal (HPG) axis. In FHH, failure to progress through puberty occurs because of a hypermetabolic state (eg, systemic illnesses such as poorly controlled diabetes or severe hypothyroidism) and/or inadequate caloric assimilation for energy expenditure (eg, restrictive eating disorder, excessive exercise, celiac disease). (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Causes of secondary (hypogonadotropic) hypogonadism in males".)
Permanent forms — Hypogonadotropic hypogonadism is considered permanent if patients have no spontaneous pubertal development by 18 years of age. These conditions result from structural or functional abnormalities of the hypothalamus or pituitary gland.
●Developmental or acquired abnormalities of the central nervous system (CNS) – Hypothalamic or pituitary disorders may be associated with multiple pituitary hormone deficits and may present in association with multisystem disorders.
Acquired disorders include tumors (especially craniopharyngioma), hypothalamic/pituitary surgery or irradiation, infiltrative disorders (eg, histiocytosis), and hemochromatosis. (See "Causes of hypopituitarism" and "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Hypothalamic-pituitary dysfunction'.)
Inherited abnormalities in the hypothalamus and pituitary gland may be caused by pathogenic variants in genes associated with pituitary development (eg, LHX4, PROP1). Congenital hypopituitarism may be associated with a small phallus and/or cryptorchidism. These and other congenital disorders are discussed in detail separately. (See "Causes of hypopituitarism", section on 'Genetic diseases'.)
●Idiopathic hypogonadotropic hypogonadism (IHH) – IHH encompasses a family of genetic disorders that are associated with defects in the production and/or action of hypothalamic GnRH. It may also be referred to as isolated GnRH deficiency or as congenital hypogonadotropic hypogonadism.
IHH may present either with normal olfaction (normosmic) or with hyposmia/anosmia. Normosmic forms of GnRH deficiency may be suspected in otherwise healthy patients who do not have evidence of spontaneous pubertal development by age 18 years. The clinical presentation with hyposmia/anosmia is referred to as Kallmann syndrome, which is diagnosed in approximately half of patients with GnRH deficiency. Isolated GnRH deficiency may also be associated with other features (eg, midline defects [cleft lip/palate], neurosensory hearing loss, unilateral renal agenesis, synkinesia [alternating mirror movements], and small phallus [length or width <2 standard deviations below the mean for age] or cryptorchidism [undescended testes]).
CDGP and isolated GnRH deficiency likely have some degree of genetic overlap as suggested by higher rates of CDGP in families with isolated GnRH deficiency [21,22]. In addition, some cases of apparent CDGP are associated with heterozygous pathogenic variants in a gene associated with isolated GnRH deficiency [23]. Some patients with well-documented isolated GnRH deficiency undergo spontaneous entry into puberty (in their 20s and, rarely, beyond) after initiation of treatment with sex steroids. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Clinical presentation' and "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Reversal of IHH'.)
EVALUATION
Initial approach for all patients — The evaluation of patients with delayed puberty includes a thorough history, with determination of pubertal timing for birth parents, and physical examination with pubertal (Tanner) staging (ie, breast examination in females, testicular examination in males). In addition, clinicians should review all available growth charts (or measurements, if not plotted on growth charts), ideally from infancy to adolescence. This information will help determine whether further biochemical testing or imaging studies are needed to evaluate for underlying causes of delayed puberty. (See "Measurement of growth in children" and "Normal growth patterns in infants and prepubertal children".)
History — We obtain a detailed family, medical, and psychosocial history, focusing on the following:
●Pubertal development – We ask about physical changes associated with early puberty (eg, breast development and growth acceleration in females or testicular growth; body, axillary, and pubic hair; and odor development in males) to determine whether pubertal changes started. At times, early pubertal changes may not be noticed by patients/caregivers. (See "Normal puberty" and 'Physical examination' below.)
●Psychosocial distress – Patients (and caregivers) may report significant distress at being behind their peers in pubertal development. If distress is present, we attempt to understand the cause.
●Family history of delayed puberty – A family history of delayed puberty supports a diagnosis of constitutional delay of growth and puberty (CDGP) or isolated gonadotropin-releasing hormone (GnRH) deficiency, although other disorders must be excluded first. The absence of a family history does not exclude CDGP or isolated GnRH deficiency. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)".)
●Medical history and symptoms of systemic disease – Acute or chronic systemic disease can cause functional hypogonadotropic hypogonadism (FHH), which may delay the onset of puberty or cause slow progression of pubertal changes. In some cases, delayed pubertal development is the presenting sign of chronic disease or undernutrition, with additional symptoms only evident upon further discussion with the patient or family [24]. Some conditions (eg, sickle cell disease, celiac disease, inflammatory bowel disease) are commonly associated with delayed puberty.
●Neurologic symptoms – Neurologic symptoms (eg, headache, visual disturbances, seizure) strongly suggest a central nervous system (CNS) disorder. The presence or absence of these clinical findings is an important clinical discriminator between CDGP and structural CNS or pituitary lesions causing hypogonadotropic hypogonadism [25]. Other symptoms that are concerning for a structural hypothalamic or pituitary lesion include an abrupt decrease in linear growth velocity with preservation of weight gain and symptoms of diabetes insipidus. (See "Clinical manifestations and diagnosis of central nervous system tumors in children", section on 'Common presenting signs and symptoms' and "Diagnosis of growth hormone deficiency in children", section on 'Imaging' and "Craniopharyngioma", section on 'Clinical presentation'.)
●Multisystem and syndromic phenotypes
•Patients with idiopathic hypogonadotropic hypogonadism (IHH) may have syndromic features in addition to hypogonadotropic hypogonadism, the most common being hyposmia/anosmia and craniofacial malformations (cleft lip/palate). CHARGE (Coloboma, Heart defects, Atresia choanae, Growth retardation, Genital abnormalities, Ear abnormalities) syndrome is associated with features of isolated GnRH deficiency as well as other congenital anomalies. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Congenital abnormalities'.)
•Females with Turner syndrome may present with delayed puberty in combination with short stature and other characteristic features (table 4). (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Most common features'.)
•Prader-Willi syndrome is associated with hypogonadotropic hypogonadism and delayed puberty but is typically diagnosed in early childhood due to other characteristic features [26]. (See "Prader-Willi syndrome: Clinical features and diagnosis", section on 'Clinical manifestations'.)
●Nutrition and exercise – Caloric restriction and/or high-intensity exercise are common causes of pubertal delay in otherwise healthy adolescents. We ask patients with delayed puberty about daily eating and exercise habits and attempts to lose weight. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations".)
●Medication and substance use – Additionally, we ask patients about current and previous medication. Gonadotoxic therapies (eg, alkylating agents used in chemotherapy) can cause hypergonadotropic hypogonadism, whereas glucocorticoids and opioids may be associated with hypogonadotropic hypogonadism. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Gonadal dysfunction' and "Causes of secondary (hypogonadotropic) hypogonadism in males", section on 'Suppression of gonadotropins'.)
Review of growth — A review of the patient's height and weight trends up to the time of the evaluation may provide insight into the etiology of pubertal delay. We review growth charts, evaluating trends in height velocity (increased or decreased) and comparing the patient's height velocity (cm/year) to that of peers (figure 1A-B). We also assess whether the patient's height trends have been consistent with midparental target-height percentiles. (See "Measurement of growth in children" and "Diagnostic approach to children and adolescents with short stature", section on 'Prediction of adult height' and "Diagnostic approach to children and adolescents with short stature", section on 'Is the child's growth within the range for the family?'.)
In patients with CDGP, childhood growth will typically show slower growth velocity than in peers and height percentiles below what would be expected based on midparental height throughout childhood. By contrast, patients with an underlying illness causing delayed growth and puberty (eg, celiac disease) will generally grow at a percentile consistent with midparental height for most of childhood, with growth deceleration or cessation when the illness develops. (See "Diagnostic approach to children and adolescents with short stature", section on 'Is there evidence of delayed or accelerated growth?'.)
Physical examination — The physical examination should focus on determining whether the child/adolescent has started puberty and on features that may suggest an etiology for delayed puberty.
The presence, timing, and progression of pubertal development can help distinguish between stalled and absent puberty. Early signs of pubertal development (such as testicular enlargement >4 mL) may be missed by the patient/caregiver. Identification of pubertal onset may avoid an unnecessary evaluation in an otherwise healthy child.
Before beginning an examination for breast development or testicular enlargement, we provide an explanation of the purpose and a description of how the examination will be performed to patients and caregivers. We provide patients and caregivers with the opportunity to ask questions and inform them that they can terminate the examination at any time. We discuss the need for chaperones during the examination, as addressed in detail elsewhere. (See "Normal puberty", section on 'Pubertal changes' and "The pediatric physical examination: The perineum", section on 'Use of chaperones'.)
Pubertal staging of breast tissue and testicular volume is conducted according to sexual maturity ratings (also known as Tanner staging.) (figure 2 and picture 1) [27]. (See "Normal puberty", section on 'Secondary sex characteristics (Tanner stages)'.)
●Height, weight, and arm span – Careful assessments of height, weight, and arm span are important. Standing height should be plotted on growth charts that include normal growth patterns for sex (figure 3A-B) to compare with norms for age and predicted midparental height. If possible, the height velocity should be carefully documented for at least six months or longer. (See "Diagnostic approach to children and adolescents with short stature", section on 'Is the child short?'.)
An arm span exceeding height by more than 5 cm is associated with delayed epiphyseal closure (eg, due to Klinefelter syndrome or isolated GnRH deficiency). (See "Clinical features and diagnosis of male hypogonadism", section on 'Physical findings'.)
●Females – In females, initial pubertal development may be characterized by enlargement or tenderness of the areola (figure 2). Pubic/axillary hair, apocrine odor, and acne are not signs of puberty in females but usually reflect the onset of adrenarche. (See "Normal puberty", section on 'Pubertal changes' and "Physiology and clinical manifestations of normal adrenarche", section on 'Overview'.)
●Males – In males, the first sign of puberty is testicular enlargement (>4 mL). Testicular size should ideally be measured using a Prader orchidometer (picture 2 and table 5). If testicular asymmetry or masses are noted or if the clinician cannot palpate testes on physical examination, a prompt testicular ultrasound should be obtained, with referral to pediatric urology as needed. (See "Causes of painless scrotal swelling in children and adolescents" and "Undescended testes (cryptorchidism) in children: Clinical features and evaluation", section on 'Evaluation'.)
A small phallus, small testes, and cryptorchidism are suggestive of abnormalities of testosterone secretion (eg, Klinefelter syndrome) or IHH [28]. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Physical findings'.)
Axillary hair/acne/odor may be the earliest reported signs of puberty but almost certainly represent adrenarche in the absence of testicular enlargement [29]. (See "Normal puberty", section on 'Pubertal changes'.)
●Has puberty started? – If breast development is noted in females or testicular volumes ≥4 mL are present in males, puberty has begun. If the development is recent, we provide reassurance that puberty will most likely progress and do not typically pursue laboratory testing and imaging. However, we counsel patients that lack of progression of pubertal development warrants additional evaluation.
Laboratory testing and imaging
Initial tests — For patients who either have no evidence of pubertal development or who have evidence of stalled puberty, we measure the following tests [30]. Although these tests may not definitively establish the cause of delayed puberty, they can exclude some causes and may be used as a baseline for monitoring.
●Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) as well as testosterone or estradiol – We measure LH and FSH as well as estradiol or total testosterone in the morning (ideally 8 to 9 AM) to capture the early morning surge in pubertal hormones. If available, we prefer to use ultrasensitive assays for LH, estradiol, and testosterone.
●Bone age – At the initial visit, we obtain a bone age radiograph of the left hand and wrist, which can then be repeated over time as needed. This provides valuable information about the relationship between chronologic age and skeletal maturation as well as the potential for future skeletal growth; this also allows for a preliminary prediction of adult height.
●Additional testing – Based on patients' clinical history, additional testing may be warranted, including tissue transglutaminase immunoglobulin A (IgA; celiac disease), inflammatory markers/complete blood count (inflammatory diseases such as Crohn disease), thyroid-stimulating hormone (TSH; thyroid disorders), and prolactin (hyperprolactinemia). While some clinicians perform all of these tests at the initial visit, these conditions represent uncommon causes of delayed puberty [8,31], and extensive testing in otherwise asymptomatic patients with delayed puberty appears to have limited value [30].
Interpretation of results
FSH and LH in reference range for pubertal stage — When FSH and LH (and testosterone or estradiol) concentrations are within the reference ranges for early puberty, the patient has begun puberty. Usually, this is an indication that physical development will occur soon after. Ongoing monitoring may be indicated to ensure that puberty is progressing as expected.
High FSH and LH for pubertal stage — FSH and LH above the reference ranges for early puberty with testosterone or estradiol below or within reference range for early puberty is consistent with primary (hypergonadotropic) hypogonadism. A karyotype should be performed in every patient with primary hypogonadism to evaluate for sex chromosome aneuploidies, such as those causing Turner syndrome and Klinefelter syndrome. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Confirmatory diagnostic testing'.)
Testing for other causes of premature ovarian insufficiency (eg, fragile X premutation) may be warranted in some cases. Additional evaluation for hypergonadotropic hypogonadism is reviewed separately. (See "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)" and "Causes of primary hypogonadism in males".)
Low FSH and LH for pubertal stage — FSH and LH below the reference range for early puberty with testosterone or estradiol below or within reference range is consistent with secondary (hypogonadotropic) hypogonadism. In patients with these laboratory findings, we use history and physical examination to determine whether to perform additional laboratory evaluation and imaging [30].
●Symptoms/signs of chronic inadequate caloric intake or underlying illness – For some patients, the history and/or physical examination will suggest an underlying disease causing delayed puberty. As an example, a patient who reports restrictive eating or excessive exercise likely has FHH. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations", section on 'Inadequate caloric intake and assimilation'.)
In other patients, the clinical presentation may suggest the need for further laboratory testing. As an example, we perform condition-specific laboratory testing for celiac disease in a patient with clinical findings suggestive of this diagnosis (eg, unintentional weight loss or difficulty gaining weight, particularly when accompanied by symptoms such as abdominal pain/distension, diarrhea, or constipation). (See "Diagnosis of celiac disease in children", section on 'Indications for testing'.)
Additional testing may be needed if pubertal delay persists despite treatment of the underlying condition. (See 'When cause is known or suspected' below.)
●Neurologic symptoms – In clinically stable patients with neurologic symptoms (eg, headache, visual disturbances such as bitemporal hemianopsia, seizures), magnetic resonance imaging (MRI) of the brain is usually the next step in the evaluation. The specific imaging studies are often guided by consultation with appropriate clinical teams (eg, neurology, neurosurgery, ophthalmology). If a mass is identified. the patient should be further evaluated for pituitary hormone deficiencies (eg, diabetes insipidus, central adrenal insufficiency), which, undiagnosed and/or untreated, may lead to acute clinical decompensation. (See "Clinical manifestations and diagnosis of central nervous system tumors in children", section on 'Endocrinopathies' and "Causes, presentation, and evaluation of sellar masses", section on 'Other benign tumors'.)
Pituitary adenomas rarely present with isolated delayed puberty. However, if patients demonstrate symptoms suggestive of pituitary hormone excess (eg, galactorrhea suggestive of hyperprolactinemia), we perform a laboratory evaluation and imaging as indicated to evaluate for pituitary adenoma. (See "Clinical manifestations and evaluation of hyperprolactinemia", section on 'Laboratory/imaging tests'.)
●No symptoms/signs of chronic inadequate caloric intake or underlying illness – If clinical evaluation does not clearly suggest an etiology, the most likely cause of delayed puberty is CDGP. However, the presence of hyposmia/anosmia, syndromic features, small phallus, small testes, or cryptorchidism are highly suggestive of IHH. In this setting, we suggest referral to an endocrinologist for further evaluation. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Clinical presentation'.)
●Distinguishing between CDGP and IHH – In the absence of clinical findings other than delayed puberty, drawing a distinction between these entities may be challenging [32]. The timing of adrenarche may provide additional information; individuals with CDGP may be more likely to have delayed adrenarche, but this is not always the case [8]. Ongoing monitoring will eventually distinguish between CDGP and IHH. Specifically, if spontaneous puberty has not begun by age 16 in males or 15 in females, the diagnosis of IHH is more likely. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Differential diagnosis' and 'When cause is unknown or CDGP is suspected' below.)
Additional testing to distinguish between CDGP and IHH is usually limited to specialty centers. Emerging data suggest that basal serum FSH, inhibin B, and/or anti-Müllerian hormone (AMH) may be useful tests to distinguish between CDGP and IHH [32-34]. In a case-control study of 65 male adolescents (ages 13 to 18 years) with delayed puberty, median basal serum LH, FSH, AMH, and inhibin B were lower in patients with IHH than in those with CDGP [34]. Furthermore, combining these measurements showed high accuracy for distinguishing between CDGP and IHH. Of note, none of the participants with IHH experienced testicular volume ≥6 mL during the study period.
The kisspeptin stimulation test has shown promise for identifying patients with IHH. In a longitudinal cohort study, individuals who exhibited LH response of ≥0.8 mIU/mL to an intravenous kisspeptin bolus subsequently progressed through puberty [35].
Finally, genetic testing may be a valuable tool in cases with additional phenotypic features suggestive of IHH. Identifying a pathogenic (or likely pathogenic) variant known to be causative of IHH increases the likelihood of that diagnosis [36,37]. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Approach to genetic testing'.)
Bone age — Bone age provides valuable information about the relationship between chronologic age and skeletal maturation and the potential for future skeletal growth while allowing for a preliminary prediction of adult height. While bone age does not help to distinguish between different causes of delayed puberty, results can inform treatment decisions (eg, whether or not to initiate hormonal therapy for patients with CDGP). (See "Diagnostic approach to children and adolescents with short stature", section on 'Bone age determination'.)
MANAGEMENT OF SECONDARY (HYPOGONADOTROPIC) HYPOGONADISM
The most common causes of secondary (hypogonadotropic) hypogonadism are constitutional delay of growth and puberty (CDGP) and functional hypogonadotropic hypogonadism (FHH). In many cases, the cause of delayed puberty will become evident based on the findings of the initial clinical evaluation (see 'Evaluation' above). Abnormalities in the central nervous system (CNS) may be diagnosed.
When cause is known or suspected
●FHH – Treatment of patients with FHH (ie, hypogonadism due to an underlying illness or inadequate caloric intake) begins with treatment of the primary illness (table 1). The treatment for such disorders is discussed in disease-specific treatment topics. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children", section on 'Non-gastrointestinal manifestations' and "Causes of primary amenorrhea", section on 'Functional hypothalamic amenorrhea'.)
If the unexpected pubertal delay persists after appropriate treatment of the underlying disease, additional testing may be needed. In some cases, hormonal treatment may be considered (eg, in patients with hypogonadism due to restrictive eating disorders). (See "Functional hypothalamic amenorrhea: Evaluation and management", section on 'Estrogen replacement'.)
●Anatomic lesions of the hypothalamus and pituitary gland – Secondary hypogonadism due to congenital abnormalities of the pituitary gland and hypothalamus (eg, hypoplastic pituitary, optic nerve hypoplasia) are usually permanent. Although CNS tumors may cause transient secondary hypogonadism that resolves when treatment is instituted, surgical resection may cause permanent hypogonadotropic hypogonadism due to disruption of the hypothalamus or pituitary gland. Management is discussed below. (See 'Management of primary hypogonadism and permanent secondary hypogonadism' below.)
When cause is unknown or CDGP is suspected — Constitutional delay of growth and puberty (CDGP) is the most common diagnosis in patients with hypogonadotropic hypogonadism, but it is a diagnosis of exclusion. Serial evaluations over time can distinguish between FHH, CDGP, and isolated gonadotropin-releasing hormone (GnRH) deficiency without associated features [13]. As an example, FHH related to undernutrition may not be obvious at the initial clinical evaluation but may become evident if the patient loses weight on subsequent visits. Additionally, idiopathic hypogonadotropic hypogonadism (IHH) may only be distinguished from CDGP when patients fail to enter puberty by age 18, although additional testing may clarify the diagnosis. (See 'Low FSH and LH for pubertal stage' above.)
There are no clinical practice guidelines to direct treatment, and practice patterns vary significantly among pediatric endocrinologists [38]. Our approach is outlined here.
Counseling on options — We engage in a discussion with patients and caregivers to individualize treatment decisions. Supportive management (watchful waiting) over time is a reasonable option for most younger adolescents (eg, <13 years for females, <14 years for males) (see 'Watchful waiting' below). Supportive management is also appropriate for older adolescents with CDGP, although short-term treatment with gonadal steroids (testosterone or estradiol) may be used in some cases. (See 'Short-term sex steroid treatment in select patients' below.)
The decision to pursue one option over the other is based on individual patient/caregiver concerns related to delayed puberty. For example, increased rates of anxious and depressive symptoms have been reported in males with delayed puberty during adolescence [39,40]. However, data are inadequate to support consistent improvements in psychosocial outcomes in patients treated with testosterone. If the patient is experiencing distress, it is important to ascertain if this is primarily related to specific aspects of delayed puberty (eg, short stature, lower muscle mass relative to peers) or other factors (eg, bullying), which may be better addressed through psychosocial support. Limited data described below may be useful during discussion and shared clinical decision-making. (See 'Outcomes of watchful waiting' below and 'Outcomes of short-term hormone therapy' below.)
Watchful waiting — Watchful waiting is an acceptable initial option for most patients with CDGP. This approach involves regular monitoring (eg, examination every 6 to 12 months) for signs of pubertal development in combination with reassurance and psychological support for the patient and caregivers. If there is no evidence of puberty after one year, we reassess gonadotropins and testosterone or estradiol and pursue additional testing based on clinical presentation.
If there is no evidence of pubertal development on examination and by laboratory assessment of gonadotropins after one year of monitoring, we engage the patient and caregivers in a discussion of the benefits and risks of continued watchful waiting compared with a short course of testosterone in males or estradiol in females [39,41]. Generally, a referral to a specialist (ie, a pediatric endocrinologist) is warranted if hormone therapy is being considered and/or if there are no signs of puberty by age 15 in females and 16 in males. (See 'Counseling on options' above.)
Outcomes of watchful waiting — Predictive modeling has identified the likelihood of endogenous puberty occurring within one year of consultation without treatment. In a retrospective cohort study of patients seen for delayed puberty in a pediatric endocrine clinic, most adolescents with CDGP started puberty spontaneously within one year [13].
As examples:
●The probability of entering puberty in the next year for males ages 13.5, 14, 15, and 16 years was 38, 55, 64, and 68 percent, respectively.
●For 16.5-year-old males, the likelihood of entering puberty spontaneously was lower (ie, 48 percent), likely because of an increased incidence of permanent GnRH deficiency in this population.
●The probability of entering puberty in the next year for females ages 12, 13, and 15.5 years was 40, 62, and 74 percent, respectively.
Short-term sex steroid treatment in select patients — Short-term treatment with testosterone or estradiol in individuals with CDGP has been offered as a means to induce the physical changes associated with puberty and, in some cases, trigger endogenous puberty (often referred to "jump-starting" puberty) [42-53].
For many providers, the decision to offer this treatment is based on a desire to alleviate the psychosocial distress that accompanies pubertal delay for some patients. However, available data in CDGP do not support the improved efficacy of short-term hormone therapy when compared with watchful waiting in addressing psychosocial distress or other meaningful clinical outcomes. Furthermore, adolescent patients may find the burden of medical treatment, serial examinations, and laboratory testing to be an additional source of distress. In all cases, the care of patients being treated with testosterone or estradiol for delayed puberty should be overseen by a pediatric endocrinologist.
Patient selection — In patients for whom no other cause of delayed puberty has been identified after comprehensive evaluation, we will consider a short course of testosterone (in males) or estradiol (in females) for patients with all of the following:
●No evidence of pubertal development by at least age 14 years old in males or age 13 years in females after at least six months of monitoring (or if no pubertal progression at least two years after puberty began)
●Distress attributed to delayed puberty
●Clinicians have completed comprehensive counseling about all management options for delayed puberty with the patient and caregivers, and the benefits of sex steroid treatment are likely to outweigh the potential burdens of therapy (see 'Counseling on options' above and 'Outcomes of short-term hormone therapy' below)
Before initiating hormone therapy, we perform a baseline bone age radiograph, which is then monitored regularly.
Although there is currently no consensus about the optimal regimen for short-term testosterone or estradiol therapy in this setting, commonly used regimens are as follows [32,41,54].
Short-term testosterone
●Formulation – Pediatric endocrinologists typically use intramuscular (IM) testosterone due to greater familiarity with this formulation. Other forms of testosterone (eg, subcutaneous or transdermal) may be considered based on patient preference, clinician experience, and local regulatory approval [55,56]. As an example, some clinicians use subcutaneous regimens rather than IM administration of testosterone as subcutaneous testosterone may be less painful and may be administered at home (after appropriate training by qualified clinicians). Although no randomized trials have been conducted, indirect evidence from adult males with hypogonadism and transgender young adults suggests that subcutaneous testosterone regimens have similar efficacy to IM treatment for pubertal induction [57-59]. (See "Testosterone treatment of male hypogonadism", section on 'Subcutaneous injection'.)
●Administration – Potential regimens are as follows:
•IM testosterone (most common) – 50mg of IM testosterone cypionate or enanthate may be administered once every three to four weeks for a duration of four to six months. We do not use higher doses of testosterone to avoid suppressing endogenous GnRH in patients who begin puberty during treatment. (See "Normal puberty", section on 'Physiology and endocrinology of puberty'.)
•Subcutaneous testosterone – Subcutaneous testosterone has been used for short-term therapy in the management of presumed CDGP, although there are limited data on outcomes of this approach [55]. One potential regimen may include 25 mg of subcutaneous testosterone given every other week for four to six months. (See 'Testosterone' below.)
●Monitoring and treatment outcomes – After four to six months of treatment, we assess the patient's response. We ask about physical changes (eg, onset of virilization, linear growth) and side effects (eg, acne, injection-related discomfort) and assess for improvement in symptoms of distress (if present). We perform a complete physical examination and review of growth to assess change from baseline. In most cases, we perform laboratory testing (testosterone, follicle-stimulating hormone [FSH], luteinizing hormone [LH]) to assess endogenous gonadal function and a bone age radiograph to assess remaining growth potential. (See 'Physical examination' above and 'Review of growth' above.)
Because treatment with exogenous testosterone will not lead to testicular enlargement, testicular growth during treatment suggests that endogenous puberty has begun. (See "Normal puberty", section on 'Changes in children assigned male at birth'.)
•If testicular enlargement has occurred, we do not resume testosterone therapy. We generally monitor for ongoing pubertal progression and growth. We request that patients return in three to four months for assessment. (See "Normal puberty", section on 'Changes in children assigned male at birth'.)
•If there is no evidence of testicular growth during four to six months of exogenous testosterone therapy, we assess for potential causes of delayed puberty not previously identified (see 'Initial approach for all patients' above). If no other cause for delayed puberty is identified, we again discuss management options, including watchful waiting or repeating the course of testosterone treatment. The treatment plan is individualized based on clinician, patient, and caregiver preferences. (See 'Counseling on options' above.)
Short-term estradiol — There are no data on optimal regimens for females with CDGP receiving short-term hormone therapy for the treatment of delayed puberty. Clinical experience is limited, in part because females are less frequently referred to endocrinologists for delayed puberty, although clinicians also report a greater reluctance to treat females with delayed puberty [38,60].
●Formulation – For females with delayed puberty, transdermal 17-beta estradiol is preferred for both short-term treatment and long-term pubertal induction given the ease of titrating the dose at low levels. Additionally, data in adults support a lower risk of thrombosis using transdermal estradiol compared with oral estradiol formulations [61-63]. However, other formulations (eg, oral estradiol) may be used based on provider and patient preference.
●Administration – For regimens using a transdermal 17-beta estradiol patch, the patch should be worn continuously and changed as directed by the manufacturer's insert (typically twice weekly). (See "Management of Turner syndrome in children and adolescents", section on 'Estradiol therapy'.)
One potential regimen involves cutting transdermal estradiol patches into smaller sections to allow for the administration of very low doses:
•Begin with a transdermal 17-beta estradiol patch that is designed to deliver 0.025 mg/day and cut into quarters to deliver approximately 0.00625 mg/day per piece. (See "Management of Turner syndrome in children and adolescents", section on 'Estradiol therapy'.)
•Continue 0.00625 mg/day (one-quarter of a patch, changed biweekly or weekly) for four to six months. If no breast development is noted by month 4, increase to one-half of a patch (0.0125mg/day) and continue at this dose.
•After six months (at an estradiol dose sufficient to induce breast development), discontinue estradiol patch.
●Monitoring and treatment outcomes – Patients may be assessed two to three months after completion of the six-month course of estradiol. The visit should focus on physical changes and side effects of estradiol treatment (eg, nausea, skin irritation at patch sites) and improvement in symptoms of distress (if present). We perform a complete physical examination and review of growth to assess change from baseline. In most cases, we perform laboratory testing for biochemical evidence of advancing puberty (estradiol, LH, and FSH), and a bone age radiograph to assess remaining growth potential. (See 'Physical examination' above and 'Review of growth' above.)
Although breast development will occur with adequate doses of exogenous estradiol treatment, it will only continue after treatment discontinuation if endogenous estradiol production has begun.
•If breast development has continued after discontinuation of the estradiol patch, we generally recommend that patients return three to four months later, at which time we monitor for ongoing pubertal progression and growth. (See "Normal puberty", section on 'Changes in children assigned female at birth'.)
•If breast development has not continued after discontinuation, we assess for potential causes of delayed puberty not identified on initial evaluation (see 'Initial approach for all patients' above). If no other cause for delayed puberty is identified, we again discuss management options, including watchful waiting or repeating the course of estradiol treatment. The treatment plan is individualized based on clinician, patient, and caregiver preferences. As an example, some clinicians may elect to treat again with a higher dose of estradiol (eg, half of a patch, 0.0125 mg/day), but this must be balanced with the potential for early fusion of the growth plates. (See 'Counseling on options' above.)
Outcomes of short-term hormone therapy — Available data on the outcomes of hormone therapy for patients with CDGP are limited to studies of testosterone in males, likely because of referral bias for males with delayed puberty [38,64].
Data do not support a clear benefit for the efficacy of short-term hormone therapy in addressing psychosocial distress or other meaningful clinical outcomes when compared with watchful waiting.
●Psychosocial distress – Short-term exogenous testosterone therapy will induce the physical changes of puberty in males with CDGP, as shown by observational studies demonstrating greater improvements in growth and sexual maturation parameters among males with CDGP who received testosterone therapy compared with untreated controls [43-53]. In one such study, 19 males treated with testosterone for delayed puberty and 11 untreated controls were asked to complete a survey retrospectively reflecting on their experience with treatment. Of these, 18 (95 percent) of the treated group indicated that they believed treatment was helpful, although only 14 (74 percent) would have chosen to be treated again. Of the untreated group, only one patient indicated that he would have preferred to receive testosterone treatment [46].
Another study of 22 males with CDGP demonstrated an improved perception of physical appearance in those who received testosterone treatment, although the small number of participants and absence of an untreated control group are insufficient to determine the efficacy of hormonal treatment compared with supportive counseling in alleviating psychosocial distress [39,45,56,65]. Finally, one retrospective study reporting a benefit for psychosocial health in male patients with CDGP treated with testosterone compared with untreated controls was limited by the inconsistent methodology used to assess psychosocial outcomes [45].
●Growth – Data do not support sustained improvements or impairments in height attainment among male patients with CDGP treated with short-term testosterone [44-49]. Although growth velocity temporarily increases with treatment, in retrospective studies and a randomized trial, short-term testosterone treatment did not improve adult height when compared with watchful waiting in patients with CDGP [49,66-68]. Several retrospective studies conducted in the 1980s identified an association between later puberty and decreased adult height compared with predicted height. However, additional data suggest that height deficits exist primarily in the subgroup of patients with slow growth velocity before puberty [39,43,68-71].
●Onset of puberty – Observational studies have supported sustained pubertal development among males with CDGP after short-term treatment with testosterone (commonly known as "jump-starting" puberty) when compared with untreated controls [44,46,52,53]. However, the data are insufficient to determine whether short-term testosterone treatment triggered endogenous testosterone or if onset of puberty occurred independent of testosterone treatment. As an example, in an observational study of seven males with CDGP treated with testosterone therapy for four months, all participants exhibited an increase in testicular volume, indicating spontaneous pubertal onset in the first four months after stopping testosterone [72]. Other studies are limited by use of treatment protocols that are no longer used (eg, long-term testosterone regimens, addition of aromatase inhibitors [52,53]). In another observational study of 22 males intermittently treated with testosterone for 15 to 21 months, testicular volume increased in all participants, and in 12 patients, endogenous testosterone increased to late pubertal levels. However, 10 participants had less robust increases in endogenous testosterone (eg, levels consistent with early puberty) [73].
MANAGEMENT OF PRIMARY HYPOGONADISM AND PERMANENT SECONDARY HYPOGONADISM —
Hypogonadism is usually permanent in patients with primary (hypergonadotropic) hypogonadism and those with secondary (hypogonadotropic) hypogonadism due to known structural abnormalities of the hypothalamus or pituitary gland (eg, interrupted pituitary stalk, tumor, central nervous system [CNS] surgery) or hypothalamic dysfunction (idiopathic hypogonadotropic hypogonadism [IHH]/Kallmann syndrome). Therefore, patients with these diagnoses require exogenous testosterone or estradiol to both initiate and progress through puberty, which should be overseen by a pediatric endocrinologist. Individual diagnoses may require specific therapeutic approaches as discussed elsewhere. (See "Management of primary ovarian insufficiency (premature ovarian failure)", section on 'Suggested estrogen regimens' and "Clinical features, diagnosis, and management of Klinefelter syndrome", section on 'Testosterone therapy'.)
Sex steroids for pubertal induction — The initial goal of sex steroid treatment in individuals with permanent hypogonadism is to approximate the timing and tempo of endogenous puberty [74]. In patients diagnosed in childhood with disorders associated with hypogonadism (eg, Turner syndrome), pubertal induction may begin if no pubertal development has begun at ages that are typical for pubertal onset in the general population (eg, age 11 in females, 12 in males).
Initial doses of testosterone or estradiol are low and are gradually increased over the course of several years, although higher initial doses may be used for patients with stalled pubertal development. The management of permanent hypogonadism involves long-term hormone replacement to prevent health consequences associated with sex steroid deficiency (eg, osteoporosis and cardiovascular disease). (See "Testosterone treatment of male hypogonadism" and "Management of primary ovarian insufficiency (premature ovarian failure)", section on 'Importance of estrogen therapy'.)
Testosterone — For males with permanent hypogonadism, titration of testosterone is based on age at initiation, height potential, and monitoring of effects. The goal is to mimic the normal pubertal tempo, following physical signs of puberty, bone age, and testosterone levels. (See 'Monitoring and treatment outcomes' below.)
●Age at initiation – Males with a known cause of permanent hypogonadism diagnosed in childhood undergo pubertal induction at the average age of onset of puberty for males, which is approximately 12 years of age. For males with a known cause of permanent hypogonadism diagnosed after presenting with delayed puberty (after age 13 years), testosterone is initiated at the time of diagnosis.
Testosterone dosing is generally the same in both groups. However, in males with older ages of presentation, the dose is increased more frequently to facilitate more rapid progression of puberty.
●Formulation – Generally, intramuscular (IM) testosterone is used because it is the most well-studied formulation for pubertal induction. However, some experts use subcutaneous testosterone regimens for pubertal induction, although they have not been studied for this purpose in hypogonadal adolescent patients. Most data on safety and efficacy are from the treatment of transgender young adults or adults with hypogonadism [41,56].
●Administration – Potential regimens are as follows:
•IM testosterone – IM testosterone cypionate or enanthate is started at 50 mg, given IM once every four weeks, and then increased by 50 mg monthly every four to six months only after assessing a serum testosterone level midway between doses to prevent excessive dosing. Once the dose is 150 mg monthly for four to six months, the dose is increased to 150 mg every two weeks. Although this is the final adult dose for some patients, others may require 200 mg every two weeks. The goal is to achieve a testosterone level in the middle of the reference range for adult males.
•Subcutaneous testosterone – Subcutaneous testosterone is started at 20 to 25 mg every other week for four to six months, then increased to 20 to 25 mg weekly for four to six months after confirming that a serum testosterone level midway between doses is within the expected range for the pubertal stage. This dose is continued for four to six months. The same procedure is followed, with the next dose increase to 30 to 40 mg weekly and then 50 mg weekly. The final dose may be 50 to 70 mg weekly. To prepare testosterone enanthate for subcutaneous injection, the clinician or patient draws up the dose in a 1 mL syringe, which is then administered with a 25G 5/8-inch needle.
The testosterone dose in both IM and subcutaneous regimens may be increased less frequently (every 6 to 12 months) for patients in whom measured serum levels are above the reference range for pubertal stage or in whom bone age has rapidly advanced (with potential compromise of adult height).
Testosterone gel is used less often. This is largely because most pediatric clinicians are less comfortable with its use and there are limited data on the efficacy of this formulation for pubertal induction in patients with constitutional delay of growth and puberty (CDGP) [25,41,75-77]. However, one additional concern in adolescent patients is the potential for transdermal transfer to others. If used, patients should take appropriate measures to prevent this (eg, apply at night and avoid overnight contact with other individuals, ensure that testosterone gel dries completely) [56,78].
We do not use other testosterone formulations (eg, long-acting IM testosterone undecanoate) or oral testosterone for adolescent patients. The latter does not have regulatory approval in the United States for this age group [55].
Estradiol — Much of the data on the safety and efficacy of estradiol replacement regimens in permanent hypogonadism are adapted from data in patients with Turner syndrome. (See 'Monitoring and treatment outcomes' below.)
●Age at initiation – Females with a known cause of permanent hypogonadism diagnosed in childhood undergo pubertal induction at the average age of onset of puberty for females, which is approximately 11 years of age. For females with a known cause of permanent hypogonadism diagnosed after presenting with delayed puberty (after age 12 years), estradiol is initiated at the time of diagnosis.
Estradiol dosing is generally the same in both groups. However, in females with older ages of presentation, the dose is increased more frequently to facilitate more rapid progression of puberty.
●Formulation – For females with permanent hypogonadism, transdermal 17-beta estradiol is also preferred for long-term pubertal induction given the ease of titrating the dose at low levels. Additionally, data in adults support a lower risk of thrombosis using transdermal estradiol compared with oral estradiol formulations [61-63]. However, other formulations (eg, oral estradiol) may be used based on provider and patient preference. Titration of estradiol is based on age at initiation, height potential, and monitoring of effects.
●Administration – For regimens using a transdermal 17-beta estradiol patch, the patch should be worn continuously and changed as directed by the manufacturer's insert (typically twice weekly). (See "Management of Turner syndrome in children and adolescents", section on 'Estradiol therapy'.)
•A sample transdermal regimen, in which the patch is cut to deliver lower doses of estradiol, would be as follows:
-Begin with a transdermal 17-beta estradiol patch that is designed to deliver 0.025 mg/day and cut into quarters to deliver approximately 0.00625 mg/day per piece.
-Four to six months after start – Increase to one-half patch (0.0125 mg/day).
-8 to 12 months after start – Increase to full patch (0.025 mg/day).
-12 to 16 months after start – Increase to next dose strength (0.0375 mg/day).
-16 to 20 months after start – Increase to next dose strength (0.050 mg/day).
-24 to 28 months after start – Increase to next dose strength (0.075 mg/day).
When breakthrough bleeding occurs or at months 24 to 28, we add progesterone to avoid unopposed endometrial estradiol exposure. We prefer cyclic micronized progesterone 200 mg given on days 1 to 12 of the calendar month. However, some clinicians may use medroxyprogesterone acetate at a dose of 5 to 10 mg on days 1 to 12 of the calendar month.
-28 to 32 months after start – Increase to next dose strength (100 mcg/day).
The dose may be increased at approximately four to six-month intervals after ensuring that a serum estradiol level measured two days after patch change is within normative ranges for the pubertal stage. The estradiol dose may be increased less frequently (every 6 to 12 months) for patients in whom measured serum levels are above the reference range for the pubertal stage, in whom bone age has rapidly advanced (with potential compromise of adult height), or in patients experiencing side effects (eg, headaches, nausea). (See 'Monitoring and treatment outcomes' below.)
Monitoring and treatment outcomes — Patients being treated with testosterone or estradiol for pubertal induction should be monitored with a clinic visit approximately every four to six months. The following data should be reviewed by the pediatric endocrinologist supervising treatment:
●Patient satisfaction with treatment and side effects. Side effects of testosterone treatment include acne and injection site reactions. Side effects of estradiol treatment include nausea and skin irritation at the patch site.
●Pubertal development based on chaperoned physical examination.
●Growth velocity and growth percentile, as determined by measurements of height.
●Serum testosterone (level should be obtained between IM doses) and estradiol (level should be obtained approximately two days after new patch is placed), targeting ranges that are appropriate for the pubertal stage.
●Growth potential based on bone age (should be assessed every 6 to 12 months).
Medication doses are adjusted to optimize patient satisfaction and growth. Treatment is continued throughout adulthood in males and at least until a typical age for menopause in females. Management of hormone replacement therapy for hypogonadotropic hypogonadism in adulthood is discussed elsewhere. (See "Testosterone treatment of male hypogonadism" and "Evaluation and management of secondary amenorrhea", section on 'Low or normal serum FSH'.)
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 5th to 6th 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 10th to 12th 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 AND RECOMMENDATIONS
●Definition – Delayed puberty is defined clinically by the absence or incomplete development of secondary sex characteristics by 12 to 13 years of age in females and 13 to 14 years of age in males.
●Causes – Delayed puberty is caused by inadequate production of gonadal hormones (estradiol or testosterone). This may be due to abnormalities of the gonad (primary hypogonadism) or inadequate production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH; secondary hypogonadism) (table 1).
•Primary (hypergonadotropic) hypogonadism – A minority of patients with delayed puberty (<25 percent) have primary hypogonadism. Laboratory testing will show elevated LH and FSH above the expected range for early puberty with low or inappropriately normal testosterone or estradiol, which is usually irreversible. Exposure to gonadotoxic agents may cause acquired primary hypogonadism in all patients. Turner syndrome and Klinefelter syndrome represent the most common congenital causes in females and males, respectively. Notably, Turner syndrome presents with some pubertal development in two-thirds of patients, and Klinefelter syndrome rarely presents with delayed puberty. (See 'Primary (hypergonadotropic) hypogonadism' above and "Causes of primary hypogonadism in males" and "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)".)
•Secondary (hypogonadotropic) hypogonadism – Most patients (>75 percent) with delayed puberty will have secondary hypogonadism. Laboratory testing will show LH or FSH below the expected range for the pubertal stage with low or normal testosterone or estradiol. This may be reversible or irreversible. The most common cause of reversible secondary hypogonadism (and of delayed puberty overall) is constitutional delay of growth and puberty (CDGP). CDGP is a highly heritable transient delay in onset of gonadotropin-releasing hormone (GnRH) secretion and pubertal development. It is commonly known as "late blooming." Other reversible causes include functional hypogonadotropic hypogonadism (FHH), in which delayed onset of puberty is the result of chronic disease or undernutrition. Irreversible causes include structural or functional abnormalities of the hypothalamus or pituitary gland and idiopathic hypogonadotropic hypogonadism (IHH). (See 'Secondary (hypogonadotropic) hypogonadism' above.)
●Evaluation – The assessment begins with a focused history, symptom review, physical examination with pubertal staging, and review of growth patterns and weight. (See 'Initial approach for all patients' above.)
We measure estradiol (in females) and testosterone (in males) as well as LH and FSH. We perform a bone age radiograph to assess height potential and to measure the progression of skeletal maturation. (See 'Laboratory testing and imaging' above.)
Additional testing is performed based on the results of this evaluation. (See 'Interpretation of results' above.)
If the evaluation is unrevealing, CDGP is most likely. It is a diagnosis of exclusion, made only after other underlying causes of delayed puberty have been ruled out. CDGP may be difficult to distinguish from isolated GnRH deficiency. Syndromic features, anosmia, small phallus, small testes, and cryptorchidism in males are suggestive of isolated GnRH deficiency rather than CDGP. (See 'Low FSH and LH for pubertal stage' above.)
●Management – The approach to management is based on the suspected cause of delayed puberty.
•Most forms of secondary hypogonadism (transient) – The most common forms of secondary hypogonadism are transient. In these cases, endogenous puberty will occur after appropriate management.
-FHH – When delayed puberty is thought to be a result of underlying illness or undernutrition, the diagnosis is FHH. Treatment is directed at addressing the underlying condition. (See 'When cause is known or suspected' above.)
-Suspected CDGP – For adolescents with suspected CDGP, the two primary management options are supportive monitoring ("watchful waiting") or short-term therapy with sex steroids (testosterone [in males] or estradiol [in females]). Decisions about management should be made only after a discussion addressing patients' and caregivers' goals and the likelihood that each intervention will achieve the desired outcomes. (See 'Counseling on options' above.)
-Supportive management (watchful waiting) over time is a reasonable option for most younger adolescents (eg, <14 years for males and <13 years for females) and older adolescents who are not experiencing distress. (See 'Watchful waiting' above.)
-For adolescent males ≥14 years and females ≥13 years with suspected CDGP who have had no pubertal progression after 6 to 12 months of supportive monitoring (or stalled puberty) and ongoing psychosocial distress that cannot be alleviated with behavioral health interventions, we suggest short-term therapy with testosterone (in males) or estradiol (in females) (Grade 2C). Treatment should be conducted under the supervision of a pediatric endocrinologist.
These medications will lead to the development of some secondary sex characteristics. Referral to a pediatric endocrinologist is also warranted if endogenous puberty has not begun by age 16 in males or 15 in females. (See 'Short-term sex steroid treatment in select patients' above.)
•Primary hypogonadism and permanent forms of secondary hypogonadism – Permanent forms of hypogonadism require testosterone or estradiol therapy to induce puberty and then maintain adult levels of testosterone or estradiol. Ongoing treatment is needed to minimize sequelae of hypogonadism (eg, osteoporosis). Females also will require cyclic progesterone. (See 'Management of primary hypogonadism and permanent secondary hypogonadism' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Nelly Pitteloud, MD, and William F Crowley, Jr, MD, who contributed to earlier versions of this topic review.
