Premature adrenarche

INTRODUCTION — Adrenarche refers to the progressive maturation of the adrenal cortex that normally becomes manifest after five years of age and is associated with an increased serum dehydroepiandrosterone sulfate (DHEAS) level. Pubarche is the physical manifestation of adrenarche and is characterized by the development of pubic hair, axillary hair, adult apocrine body odor, acne, and increased oiliness of hair and skin.

Pubarche is considered premature if it develops before age eight years in girls and nine years in boys. Premature adrenarche, indicated by a premature elevation of DHEAS levels, is the most common cause of premature pubarche. Premature adrenarche is considered to be a variant of normal development. Premature adrenarche is a diagnosis of exclusion; other causes of pubarche need to be contemplated and excluded. The differential diagnosis includes precocious puberty and other causes of hyperandrogenemia and virilization.

The clinical presentation, evaluation, and differential diagnosis of premature pubarche and premature adrenarche are discussed below. Other UpToDate topic reviews with related information are:

●(See "Physiology and clinical manifestations of normal adrenarche".)

●(See "Normal puberty".)

●(See "Definition, etiology, and evaluation of precocious puberty".)

DEFINITIONS

●Premature pubarche – Premature pubarche is defined as the appearance of sexual pubic or axillary hair before age eight years in girls and age nine years in boys. Adult apocrine odor, mild acne, and increased oiliness of skin and hair may occur.

●Premature adrenarche – Premature adrenarche is an idiopathic condition defined as premature pubarche plus the biochemical demonstration of an adrenal C19 steroid pattern indicative of adrenarche (typically defined as a dehydroepiandrosterone sulfate [DHEAS] concentration above 40 mcg/dL) before age eight years in girls and before nine years in boys (table 1) [1]. In addition to premature pubarche, oily skin or hair, acne (typically microcomedonal), and/or apocrine body odor may occur as clinical manifestations of premature adrenarche.

Although premature adrenarche is typically considered to be a variation in normal maturation, the diagnosis requires exclusion of other causes of adrenal steroid elevations. The adrenarchal steroids are predominantly DHEAS and dehydroepiandrosterone (DHEA), their precursors, their metabolites, and, to a lesser extent, other androgenic steroids. These steroids are collectively referred to as "C19 steroids."

●Virilization – In children, mild virilization manifests as early-onset and/or slow progression of pubic/axillary hair development, acne, and/or hirsutism in both sexes. Moderate to severe virilization is associated with clitoromegaly in girls and penile enlargement in boys. In both sexes, moderate to severe virilization can be accompanied by rapid progression of pubic hair development, cystic acne, accelerated linear growth velocity, and increased muscle mass. Bone age radiographs typically show accelerated skeletal maturation. Bloodwork demonstrates elevated circulating androgen concentrations. Virilization that is present at birth reflects prenatal androgen exposure, which may not be reflected in laboratory tests on the infant.

●Precocious puberty – Precocious puberty refers to precocious gonadarche with associated secondary sex characteristics, ie, breast development before age eight years in girls and testicular enlargement before age nine years in boys. It is usually due to increased gonadotropin-releasing hormone (GnRH) secretion, leading to increased pituitary gonadotropin secretion and gonadal sex steroid hormone secretion. This form of precocious puberty is also known as GnRH-dependent precocious puberty or central precocious puberty (CPP). (See "Definition, etiology, and evaluation of precocious puberty".)

EPIDEMIOLOGY

●Typical timing of pubic hair development – Typical timing and pace of pubic hair development has been reported in several large studies (table 2) [2-6]. These data show differences in timing between populations and variance within each population studied. As an example, a study from Denmark [4] reported much later pubic hair development compared with studies from the United States [5,6]. Studies from the United States also report race- and ethnicity-related differences in onset of pubic hair development and other pubertal milestones. It is important to note that these differences in pubertal timing are smaller than the overall variation between individuals in the population. Clinical decisions should be based on an individual patient's characteristics and family history and less so on racial or ethnic background. (See "Normal puberty", section on 'Typical pubertal timing'.)

●Premature pubarche – Premature pubic hair development (premature pubarche) is more common in girls than in boys; the ratio of affected girls to boys is 4:1 or higher [7-9].

Premature pubarche is commonly encountered in pediatric practice. The Pediatric Research in Office Settings (PROS) study assessed pubertal development in over 17,000 healthy girls in the United States and Puerto Rico in the setting of a pediatric office practice. This cross-sectional study reported that pubic hair development was present in approximately 17 percent of Black girls and approximately 3 percent of White girls under eight years of age [10]. As reported in the PROS study involving 4131 boys, less than 5 percent of those under age nine years had pubic hair development [11]. These data should not be construed as prevalence data, due to the ascertainment bias of an office practice setting [5].

Premature pubarche is unusual before the age of four to five years but can rarely develop earlier [7,12]. Genital/scrotal hair has been described in girls and boys under two years of age. In some instances, this genital/scrotal hair has been associated with exposure to exogenous androgens or intense use of diaper rash prevention cream [13]; dehydroepiandrosterone sulfate (DHEAS) concentrations may be minimally elevated in these children but are typically less than 40 mcg/dL. Usually, the hair growth spontaneously resolves. Nevertheless, longitudinal follow-up is necessary to assess for additional signs of puberty [14].

Risk factors for premature adrenarche:

•Obesity and evidence of insulin resistance have been identified in some but not all populations with premature adrenarche [9,15-18]. In some, insulin resistance is disproportionate to obesity [15,19,20]. In others, insulin resistance can be attributed to obesity [17,21]. How obesity and insulin resistance relate to premature adrenarche is unclear [22]. The molecular basis of the hyperinsulinemia and/or insulin resistance noted in children with premature adrenarche is poorly characterized and is likely to be multifactorial.

•Low birth weight followed by early childhood adiposity rebound has been identified in several cohorts with premature pubarche [23-25], though not in others [26-28].

PATHOPHYSIOLOGY — Premature adrenarche is considered a variation of normal development in which normal adrenarche occurs prematurely [29], which is linked to early maturation of the zona reticularis. At the onset of adrenarche, the 17,20-lyase activity of cytochrome P450c17 increases in conjunction with increased expression of cytochrome b5. Concurrently, expression of two enzymes, sulfotransferase 2A1 and 17-beta-hydrosteroid dehydrogenase type 5, increases, while expression of another enzyme, 3-beta-hydroxysteroid dehydrogenase, decreases. In addition, the enzyme 11-beta-hydroxylase type 1, encoded by CYP11B1, generates 11-beta-hydroxyandrostenedione.

The net result of these changes in enzyme expression leads to an increase in dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS), disproportionate to increases in androstenedione (figure 1). In addition to DHEAS, there is increased secretion and concentrations of other circulating adrenal C19 steroid hormones, including androstenedione, testosterone, 11-beta-hydroxyandrostenedione, and 11-beta-hydroxytestosterone [30]. In peripheral tissues, these adrenal C19 steroids can be converted to other relevant C19 steroids including 11-ketoandrostenedione, 11-ketotestosterone, and, in some target tissues, 11-ketodihydrotestosterone. (See "Physiology and clinical manifestations of normal adrenarche", section on 'Contribution of adrenarchal hormones to bioactive androgens'.)

Excessive adrenal androgens cause the early onset of sexual hair in premature adrenarche. While DHEA and DHEAS have traditionally been considered to be "adrenal androgens," they do not bind to the androgen receptor and have minimal androgenic activity. The zona reticularis secretes 11-beta-hydroxyandrostenedione and 11-beta-hydroxytestosterone. These hormones undergo peripheral conversion to 11-ketoandrostendione and 11-ketotestosterone, respectively. Measurement of these hormones revealed that 11-ketotestosterone is the most abundant circulating bioactive C19 steroid during normal and premature adrenarche [30]. (See "Physiology and clinical manifestations of normal adrenarche", section on 'Regulation of zona reticularis/adrenarchal growth, development, and function'.)

Some retrospective studies have suggested that girls with premature adrenarche develop hyperandrogenism and hirsutism in adulthood. One small prospective study from Finland found decreased sex hormone-binding globulin (SHBG) concentrations and no increased prevalence of ovarian hyperandrogenism [31]. The data on obesity and insulin resistance are mixed, and there may be a slight increase in the prevalence of the mild polycystic ovary syndrome (PCOS) phenotypes that are related to infertility. (See 'Potential adult risks of premature adrenarche' below.)

CLINICAL PRESENTATION — Pubarche is the primary clinical manifestation of adrenarche. Pubarche is characterized by the development of pubic hair or axillary hair. For girls, pubic hair usually begins on the labia majora and spreads onto the mons pubis. For boys, it usually begins at the base of the penis. Other signs of adrenarche such as adult apocrine body odor, acne, and increased oiliness of hair and skin may be present. In some instances, these other signs of androgen action may be the first manifestation of adrenarche [9]. When pubarche is due to premature adrenarche, other signs of secondary sexual development such as breast development, testicular enlargement, and virilization are absent.

Premature adrenarche is substantially more common in girls than in boys [9]. This sexual dimorphism occurs despite similar adrenarchal dehydroepiandrosterone sulfate (DHEAS) levels. Body fat is significantly higher in those with signs of premature adrenarche than in those without and has been speculated to modify peripheral androgen metabolism or action [9].

The specific features associated with premature adrenarche can vary. Stature, height velocity, and bone age may be increased but are usually within the normal ranges [32-35]. One-third of children with premature adrenarche have a bone age advanced by ≥2 years (see 'Bone age radiograph' below). This advancement is typically normal for height age, and predicted adult height and attained adult height are normal for mid-parental height [29,36]. This group has higher adrenarchal androgen (C19 steroid) levels and pubertal onset one to two years earlier compared with children with bone age within one year of chronologic age [28,34]. Some children have atypically high dehydroepiandrosterone (DHEA) responses to adrenocorticotropic hormone (ACTH) stimulation; this has been termed "exaggerated adrenarche" [1].

INITIAL EVALUATION OF PREMATURE PUBARCHE — At a minimum, children with premature pubarche should be evaluated with a medical history including family history, physical examination, and bone age radiograph. Depending on these initial findings, additional studies may be indicated (algorithm 1).

History and physical examination — Evaluation of premature pubarche begins with a thorough medical history and physical examination.

●History – Relevant information includes:

•Age at onset of the specific clinical features such as pubic hair development, axillary hair development, and acne.

•Tempo of pubertal maturation.

•Detailed family history, especially regarding ages of pubertal onset in the child's biologic parents and siblings, including age at menarche for women and age at voice breaking for men. A history of any endocrine or reproductive disorders should be ascertained.

•Possible exogenous androgen exposure, eg, due to use of an androgen-containing cream, gel, or spray or oral anabolic body-building supplement by a caregiver. These androgens may be transferred to the child by skin-to-skin contact or inadvertent ingestion.

●Physical examination – The physical examination should include:

•Accurate determinations of height and weight (anthropometric measurements) and comparison with previous growth parameters to assess for changes in linear growth velocity and rate of weight gain.

•Focused evaluation for pubertal maturation, including sexual maturity rating (also known as Tanner staging) (table 3). (See "Normal puberty", section on 'Sexual maturity rating (Tanner stages)'.)

-For girls, the extent of breast and pubic hair development should be ascertained. The external genitalia should also be examined for clitoromegaly and dulling of the vaginal mucosa. The presence of breast development suggests gonadotropin-releasing hormone (GnRH)-dependent precocious puberty rather than isolated premature adrenarche. Clitoromegaly suggests significant androgen exposure (virilization) such as would be observed with congenital adrenal hyperplasia (CAH).

-For boys, testicular volume, phallic size, and pubic hair development should be assessed. Testicular and/or phallic enlargement is inconsistent with isolated premature adrenarche.

For children with isolated pubarche without other secondary sex characteristics, these anthropometric measurements and sexual maturity rating provide baseline data to monitor pubertal progression. Children with additional secondary sexual characteristics require further evaluation for the possibility of disorders associated with precocious puberty or hyperandrogenism. (See "Definition, etiology, and evaluation of precocious puberty".)

Bone age radiograph — The evaluation for premature pubarche should include a bone age radiograph (algorithm 1).

●Technique – The bone age is determined from a radiograph of the left hand and wrist. For the most commonly used Greulich and Pyle method, the bone age radiograph is compared with an atlas of radiographs from children of known ages. For the Tanner-Whitehouse 2 method, 20 different hand and wrist bones are scored. The bone age is a valuable indicator of the influence of sex steroids (estrogens and androgens) on epiphysial (growth plate) maturation. In addition to sex steroids, other hormones, obesity, genetics, nutritional status, various disease states, and certain medications can influence the tempo of epiphyseal maturation [32,37]. Bone age standards are largely based on hand and wrist radiographs from children of European ancestry from the 1930s to 60s [38,39]. Despite this shortcoming, a bone age radiograph is the single most important diagnostic test for the evaluation of premature pubarche because additional evaluation may be warranted for children with advanced bone maturation (defined as being ≥2 standard deviations (SD) above the child's chronologic age).

●Interpretation:

•A normal or minimally advanced bone age (<2 SD above the child's chronologic age) is found in most children with premature adrenarche. For the Greulich and Pyle method, tables are provided listing SD for each chronologic age and for height prediction for children ≥6 to 7 years old [40].

Repeat bone age radiographs every 6 to 12 months may be useful to assess for accelerating skeletal maturation, prompting additional evaluation in children followed with the provisional diagnosis of isolated premature adrenarche. A follow-up bone age should be repeated if pubertal progression occurs or if height growth velocity accelerates. (See 'Clinical follow-up' below.)

•Markedly advanced bone age (≥2 SD above the child's chronologic age) is found in some children with premature adrenarche. Finding an advanced bone age raises suspicion for other conditions and prompts additional laboratory tests. Laboratory testing is also indicated if the child has signs of virilization or pubertal development, regardless of bone age. (See 'Laboratory tests' below.)

Some experts use bone age >2 SD above the height age (rather than ≥2 SD above the child's chronologic age) as a threshold for moving on to laboratory testing. Calculating height age improves the specificity for distinguishing children with virilizing disorders from those with premature adrenarche and reduces the number of children that require laboratory testing. As an example, in a series of children with premature adrenarche, nearly 30 percent had bone age advancement of ≥2 years (equivalent to ≥2 SD at their average age of seven years) and 10 percent of these had bone age advancement of ≥3 years [33]. Those with ≥2 years bone age advancement were significantly taller by an average of 1.7 SD compared with those with <1 year advanced bone age; they also had significantly higher body mass index (1.69 versus 1.07 SD) and higher dehydroepiandrosterone sulfate (DHEAS; 86 versus 63 mcg/dL), with normal testosterone and 17-hydroxyprogesterone (17OHP) levels.

FURTHER EVALUATION FOR CHILDREN WITH ADVANCED BONE AGE

Referral — Children with premature pubarche and advanced bone age should be referred to a pediatric endocrinologist for the next part of the evaluation, if possible. Specialized expertise is generally needed to accurately interpret the bone age radiograph results, select the appropriate laboratory tests, ascertain whether additional imaging is needed, and determine benefits of medical intervention. The general approach implemented by the specialist is outlined below.

If the evaluation by the specialist determines that the premature pubarche is likely due to premature adrenarche, clinical follow-up can be performed by the specialist or the general pediatrician. (See 'Follow-up' below.)

Laboratory tests — Laboratory tests help distinguish between the diagnostic considerations and are essential for children with advanced bone age (≥2 standard deviations [SD]) and/or rapid height velocity. For practical considerations, the specialist may perform some laboratory testing regardless of bone age results because these results are helpful to reassure the parents regarding the diagnosis (algorithm 1).

The panel of laboratory studies may include:

●Dehydroepiandrosterone sulfate (DHEAS)

●Testosterone

●Androstenedione

●17-hydroxyprogesterone (17OHP), obtained by 8:00 AM

If the physical examination reveals breast development or testicular enlargement, early morning luteinizing hormone (LH; ultrasensitive assay) and follicle-stimulating hormone levels should also be ascertained to assess for gonadotropin-releasing hormone (GnRH)-dependent precocious puberty (also known as central precocious puberty [CPP]).

In the past, steroid hormones had been determined using radioimmunoassays. Methods such as liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-MS) are now commonly utilized. LC-MS/MS and GC-MS provide greater specificity and sensitivity for many hormone determinations [41]. Values for cut-points listed in the following sections are based on normative data using radioimmunoassay results (table 1). Another table (table 4) lists median values and interquartile ranges measured by LC-MS/MS reported by one group of investigators. Results of these tests should be interpreted in view of the assay technique and the reference ranges for each hormone as established by the performing clinical laboratory.

Results are interpreted as follows:

●DHEAS – Girls and boys with premature adrenarche typically have DHEAS concentrations of 40 to 115 mcg/dL (1.1 to 3.1 micromol/L) according to radioimmunoassay (of note, concentrations measured by LC-MS/MS are approximately 45 percent lower [29]). For patients with premature adrenarche, dehydroepiandrosterone (DHEA) and DHEAS concentrations are generally appropriate for the sexual maturity rating (Tanner stage) of pubic hair development. An extremely elevated DHEAS value may direct the diagnostic evaluation to assess for an adrenal androgen-secreting tumor.

●Testosterone and androstenedione – Girls and boys with premature adrenarche typically have testosterone levels ≤20 ng/dL (0.7 nmol/L) (table 1). Higher testosterone and/or androstenedione concentrations warrant additional evaluation for other disorders. Elevated androstenedione prompts consideration of congenital adrenal hyperplasia (CAH). For boys, elevated testosterone concentrations are noted in GnRH-dependent precocious puberty (CPP), androgen-secreting tumors, and familial male-limited precocious puberty due to activating variants in the LH receptor gene. Elevated testosterone concentrations suggest an androgen-secreting tumor. (See 'Other hyperandrogenic causes of premature pubarche' below.)

●17OHP – An early morning baseline measurement of 17OHP is a cost-effective screening test for CAH due to 21-hydroxylase deficiency. CAH is an autosomal recessive disorder characterized by a broad phenotypic spectrum, ranging from classical salt-losing and simple virilizing forms identified during infancy to nonclassic CAH (NCCAH) forms that present with symptoms due to excessive androgen production. A 17OHP level of >200 ng/dL (>6 nmol/L) obtained at 8:00 AM has ≥95 percent sensitivity and specificity for distinguishing CAH due to 21-hydroxylase deficiency from other causes of premature pubarche [42-46]. The early morning timing for this sample is important because 17OHP concentrations show diurnal variation, with the highest concentrations in the morning, similar to cortisol. When the blood sample is obtained in the afternoon, a normal 17OHP value does not exclude CAH. Values are reasonably comparable for the different assay techniques [47]. Nevertheless, it is important to know the normative reference ranges for the clinical laboratory.

Results are interpreted as follows (table 1):

•Normal (<115 ng/dL [3.5 nmol/L]) – This result excludes CAH with >95 percent confidence. These patients should be followed clinically and retested if they have signs of progressive puberty.

•Mildly elevated (between 115 and 200 ng/dL [3.5 to 6 nmol/L]) – This result is atypical but consistent with premature adrenarche [42].

The patient should be followed clinically (ie, for evidence of progressive puberty or virilization) to determine if further testing is indicated. If the bone age becomes accelerated or virilization develops, an adrenocorticotropic hormone (ACTH) stimulation test should be performed. (See 'Additional testing for selected patients' below.)

•Moderately elevated (between 200 and 1000 ng/dL [6 to 30 nmol/L]) – Such values raise the possibility of CAH [42,45,47]. An ACTH stimulation test is recommended and is necessary to confirm the diagnosis. (See 'Additional testing for selected patients' below.)

An 8:00 AM 17OHP level >200 ng/dL (>6.0 nmol/L) measured by radioimmunoassay has approximately 98 percent sensitivity and 96 percent specificity for detecting CAH in children with premature pubarche and in adolescents [42,45].

•Very elevated (≥1000 ng/dL [30 nmol/L]) – This finding is considered to be diagnostic of CAH by evidence-based guidelines [47,48]. Although an ACTH stimulation test is not required to make the diagnosis of CAH in such patients, it may be useful to determine if they are at risk for acute adrenal insufficiency. (See 'ACTH stimulation test' below.)

Additional testing for selected patients

ACTH stimulation test

●Indications – Patients with a random 17OHP concentration ≥200 ng/dL (6 nmol/L), elevated DHEAS >115 mcg/dL, and/or mild-moderately elevated androstenedione and/or testosterone levels should be further evaluated with an ACTH stimulation test (algorithm 2).

An ACTH stimulation test is the definitive test to assess for 21-hydroxyase deficiency and other disorders of adrenal steroidogenesis.

●Technique – To perform the ACTH stimulation test, an early morning baseline blood sample for steroid hormone measurements is obtained, followed immediately by administration of the ACTH (cosyntropin, a synthetic form of ACTH) 250 micrograms given intravenously or intramuscularly. A second blood sample is obtained 30 or 60 minutes later.

In addition to measuring basal and stimulated 17OHP, cortisol levels are measured to assess adrenocortical cortisol reserve. Other hormones including 17-hydroxypregnenolone, DHEA, androstenedione, 11-deoxycortisol, and progesterone can be measured to assess for uncommon types of CAH.

●Interpretation – The peak serum 17OHP response after ACTH stimulation can be interpreted as follows:

•Normal stimulated 17OHP values (eg, peak <335 ng/dL [10 nmol/L]) virtually exclude CAH due to 21-hydroxylase deficiency (table 1). If the child has concerning symptoms (markedly advanced bone age or virilization), he or she should be further evaluated to exclude other types of CAH or an androgen-secreting tumor.

•Intermediate stimulated 17OHP values (eg, peak ≥335 to 999 ng/dL [10 to 30 nmol/L]) are found in carriers for 21-hydroxylase deficiency or in some uncommon types of CAH. When the ACTH-stimulated 17OHP peak value falls within this range, genetic testing is necessary to confirm a definitive diagnosis of heterozygosity for 21-hydroxylase deficiency or another type of CAH [46,48]. Slightly abnormal values for adrenal androgens and their precursors may be found in other genetic disorders affecting the hypothalamic-pituitary-gonadal axis. (See 'Other hyperandrogenic causes of premature pubarche' below.)

•A serum 17OHP peak response ≥1000 ng/dL (30 nmol/L) is considered to be diagnostic of CAH due to 21-hydroxylase deficiency by evidence-based clinical guidelines [47].

●Cortisol – While the ACTH-stimulated cortisol response may be used to assess the adrenal response to stress, the risk for acute adrenal insufficiency is extremely low in individuals with untreated NCCAH [48]. Using newer LC-MS/MS assays, an ACTH-stimulated cortisol response >14 mcg/dL (386 nmol/L) indicates normal adrenal cortisol reserve [47,49,50]. Conversely, an ACTH-stimulated cortisol response below this threshold suggests that supplemental glucocorticoid doses may be beneficial under conditions of physiologic stress (eg, high fever, acute gastroenteritis).

Among individuals with NCCAH receiving glucocorticoid replacement therapy, the highest risk for acute adrenal insufficiency occurs when glucocorticoid replacement therapy is withdrawn abruptly.

Dexamethasone suppression test — The possibility of an androgen-secreting tumor is raised by any of the following [51]:

●Severe or rapid virilization

●Significantly advanced bone age

●Markedly elevated DHEAS (eg, >5 times the age-specific upper limit of normal)

●Moderately elevated testosterone or androstenedione (eg, >2 times the age-specific upper limit of normal)

If Cushing syndrome is suspected, a dexamethasone suppression test may be informative as a screening test (algorithm 3). An overnight low-dose dexamethasone suppression test is helpful to screen for Cushing syndrome [29]. Results can be interpreted as follows:

●If dexamethasone suppresses cortisol (morning cortisol <1.8 mcg/dL), Cushing syndrome is unlikely

●If dexamethasone fails to suppress cortisol (morning cortisol ≥1.8 mcg/dL), evaluation for Cushing syndrome is warranted

●If dexamethasone fails to suppress C19 steroid concentrations (DHEAS, androstenedione, and testosterone), evaluation for an androgen-secreting tumor should be performed (see 'Imaging studies' below)

●In some instances, longer dexamethasone suppression tests may be indicated, eg, dosing for 48 hours (see "Establishing the diagnosis of Cushing syndrome")

Imaging studies — Ultrasonography is often the initial imaging modality to discern among adrenal, testicular, and ovarian tumors.

●The possibility of an adrenocortical tumor is raised by the presence of marked virilization, significantly advanced skeletal maturation, and markedly elevated DHEAS concentrations. Hyperandrogenism (with or without hypercortisolism) should be confirmed by laboratory testing before proceeding to imaging studies.

Adrenal ultrasound is typically the first imaging test. However, ultrasound may fail to identify adrenal tumors smaller than 3 cm. Computed tomography scans can identify smaller lesions and are useful because of speed and high spatial resolution [52]. Magnetic resonance imaging offers several advantages including absence of ionizing radiation and better tissue differentiation [53]. Consultation with a radiologist may help to select the optimal imaging approach.

●Ovarian tumors may also present with marked virilization and advanced skeletal maturation, but DHEAS levels are generally not elevated in childhood in these rare tumors. For suspected ovarian tumors, initial imaging is with pelvic ultrasound. Transvaginal ultrasound studies should be avoided in young girls.

●The possibility of a testicular tumor is raised by virilization in a young boy, with phallic enlargement and, often, testicular asymmetry. In boys with testicular tumors, LH and DHEAS are low (prepubertal) and testosterone is elevated. The initial imaging modality of choice is scrotal ultrasound [54].

Genotyping — The diagnosis of 21-hydroxylase deficiency is generally based on the ACTH-stimulated 17OHP response. However, genotyping may be helpful for genetic counseling and family planning [47,48].

DIAGNOSIS OF PREMATURE ADRENARCHE — Premature adrenarche is suspected when a child presents with isolated pubic and/or axillary hair before age eight years in girls and age nine years in boys. Premature adrenarche is a diagnosis of exclusion.

The diagnosis of premature adrenarche is likely if a focused evaluation finds:

●No evidence of other secondary sex characteristics (eg, breast development or testicular enlargement)

●Typical prepubertal external genitalia

●Slow tempo for progression of pubarche

●Normal height velocity

●Bone age is normal or advanced proportionate to height age

●Laboratory tests (if performed):

•Dehydroepiandrosterone sulfate (DHEAS) concentration that is consistent with sexual maturity rating (also known as Tanner stage) for the extent of pubic hair development. Children with premature adrenarche typically have DHEAS concentrations between 40 and 115 mcg/dL (1.1 and 3.1 micromol/L) when measured by radioimmunoassay and somewhat lower concentrations when measured by LC-MS/MS. (See 'Laboratory tests' above.)

•Testosterone and androstenedione are normal or minimally elevated for age and consistent with sexual maturity rating.

•17-hydroxyprogesterone (17OHP) concentration at 8:00 AM <200 ng/dL (6 nmol/L).

Children failing to fulfill these criteria and/or have other findings may require further evaluation to determine the cause of the premature pubarche. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of premature pubarche includes other benign variants and several pathologic causes. The most common disorder is nonclassic congenital adrenal hyperplasia (NCCAH) (table 5).

Variants of pubarche

●Idiopathic premature pubarche – This diagnosis is made when premature sexual hair is associated with a bone age that is normal for chronologic age and adrenal C19 steroid concentrations (eg, dehydroepiandrosterone sulfate [DHEAS]) are normal for preadrenarchal children. These findings distinguish this condition from premature adrenarche, in which DHEAS concentrations are mildly increased (table 1).

Transient pubic or scrotal hair development may rarely occur in children less than one year of age; growth velocity, hormone concentrations, and bone age radiograph results are normal for chronologic age [1,14].

●Hypertrichosis – Hypertrichosis refers to excessive generalized, fine vellus body hair that occurs in both sexual and nonsexual areas. The consistency of the vellus hair is similar to that of forearm hair. This is a common clinical diagnostic problem because this type of hair can be difficult to distinguish from early stage 2 pubic hair. Therefore, if a child's pubic hair stage is indistinct and there is no other clinical evidence of virilization, the best approach may be a watchful observation period to determine whether the pubic hair becomes coarser and extends over the mons pubis. Hypertrichosis can be familial, ethnic/genetic, or due to exposure to specific medications (such as minoxidil, diazoxide, and phenytoin) [55,56]. Thyroid disorders, anorexia nervosa or other forms of malnutrition, and porphyria can be associated with hypertrichosis [56-58].

●Exaggerated adrenarche – The term "exaggerated adrenarche" has been variously applied but is used here to indicate a clinically extreme type of premature adrenarche [1]. This variant is suggested in children with premature adrenarche who have features that suggest an atypical degree of androgen excess, particularly those with 17-hydroxypregnenolone responses to adrenocorticotropic hormone (ACTH) substantially above those typical of premature adrenarche (up to approximately 3000 ng/dL) (table 1). This diagnosis should only be considered only when virilizing disorders have been excluded.

Other hyperandrogenic causes of premature pubarche

●Virilizing forms of CAHs – The virilizing forms of CAH can present with premature pubarche. These autosomal recessive disorders are associated with impaired cortisol secretion, increased ACTH secretion, and excessive adrenal C19 steroid hormone secretion. Phenotypes range from salt-losing to simple virilizing to nonclassic forms. Newborn girls with severe forms of CAH present with atypical genital appearance.

The most common form of CAH is 21-hydroxylase deficiency due to pathogenic variants in the CYP21A2 gene, which can cause classic (salt-losing or simple virilizing) CAH or NCCAH (mild or late onset) [59,60]. Children with classic CAH (both salt-losing and simple virilizing forms) typically develop virilizing signs and symptoms prior to four years of age if untreated. Children with NCCAH typically present after age four years with premature pubarche or during adolescence with hirsutism and irregular menses. The clinical features of NCCAH cannot be reliably distinguished from those of isolated premature adrenarche [48,61,62]. NCCAH is common, with prevalence ranging from 1 in 200 to 1 in 1000 [63]. Additional features may include tall stature, accelerated linear growth velocity, advanced skeletal maturation, and phallic enlargement (penile enlargement or clitoromegaly).

Uncommon forms of virilizing CAH may be caused by 3-beta-hydroxysteroid dehydrogenase type 2 deficiency (HSD3B2 gene) or 11-beta-hydroxylase deficiency (CYP11B1 gene) [64].

The diagnosis of CAH or NCCAH should be suspected in children with elevated unstimulated morning 17-hydroxyprogesterone (17OHP) levels (≥200 ng/dL [6.0 nmol/L]) [42,45] and is confirmed by a very elevated 17OHP level at baseline or in response to ACTH stimulation (≥1000 ng/dL [30 nmol/L]) [47]. Intermediate ACTH-stimulated 17OHP values (approximately 335 to 999 ng/dL) may be found in heterozygous carriers of 21-hydroxylase variants [65,66] or CAH due pathogenic variants in HSD3B2 [67,68] or CYP11B1 [64,69]. Genetic confirmation may be necessary to confirm a definitive diagnosis of NCCAH [46,48]. (See 'Additional testing for selected patients' above.)

Additional details regarding the diagnosis and management of the various forms of CAH are discussed in separate topic reviews. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Uncommon congenital adrenal hyperplasias".)

●Rare congenital disorders of steroid metabolism

•Cortisone reductase deficiency (MIM #614662) is a rare cause of premature pubarche. It is due to autosomal dominant variants of the HSD11B1 gene that have a dominant negative impact on gene activity in the heterozygous state. "Apparent" cortisone reductase deficiency (MIM #604931, also known as cortisone reductase deficiency type 1) is a rare autosomal recessive cause of premature pubarche associated with pathogenic variants in the H6PD gene. Both disorders may present clinically with hyperandrogenism, manifesting as premature pubarche or with oligomenorrhea, acne, and hirsutism (similar to NCCAH). These disorders share a common mechanism: Both impair the oxidoreduction of cortisone to cortisol, resulting in shorter cortisol half-life and upregulation of ACTH secretion, leading to increased cortisol and adrenal C19 steroid secretion [70]. (See "Uncommon congenital adrenal hyperplasias", section on 'Hexose-6-phosphate-dehydrogenase deficiency (apparent cortisone reductase deficiency)'.)

•Apparent dehydroepiandrosterone (DHEA) sulfotransferase deficiency is caused by loss-of-function variants in the PAPSS2 gene. These pathogenic variants impair the conversion of DHEA to DHEAS, resulting in uniformly low DHEAS concentrations. Premature pubarche and elevated C19 adrenal steroids can occur associated with increased DHEA levels. The phenotype includes androgen excess with or without bone dysplasia. (See "Uncommon congenital adrenal hyperplasias", section on 'PAPSS2 deficiency (apparent DHEA sulfotransferase deficiency)'.)

•Familial glucocorticoid resistance (MIM #615962) is also known as generalized glucocorticoid resistance or Chrousos syndrome. This autosomal dominant disorder, due to pathogenic variants of the NR3C1 gene (that encodes the glucocorticoid receptor), is a rare cause of premature pubarche [71,72]. These variants impair glucocorticoid signaling, resulting in glucocorticoid resistance, loss of negative feedback inhibition, and increased ACTH secretion, leading to compensatory increased cortisol concentrations. Increased ACTH secretion also amplifies mineralocorticoid and adrenal C19 steroid secretion. Characteristic features include fatigue, acne, premature pubarche, irregular menses, infertility, hypertension, hypokalemia, and metabolic alkalosis [73]. Despite elevated cortisol concentrations, affected individuals generally do not have the physical stigmata typical of Cushing syndrome. Diagnostic evaluation includes assessment of two to three consecutive days of urinary free cortisol determinations. In addition, serial overnight dexamethasone suppression tests can be performed. Treatment consists of a high-dose, mineralocorticoid-sparing glucocorticoid such as dexamethasone. (See "The child with tall stature and/or abnormally rapid growth", section on 'Uncommon endocrine causes'.)

●Cushing syndrome – Cushing syndrome refers to states of glucocorticoid excess. In children, the most common cause of Cushing syndrome is exogeneous glucocorticoid treatment. Cushing disease refers to excessive pituitary ACTH secretion, typically due to a pituitary corticotroph adenoma, and is an extremely rare cause of premature pubarche. Other causes of Cushing syndrome include adrenal tumors, bilateral micronodular adrenal hyperplasia, primary bilateral macronodular adrenocortical hyperplasia, and ectopic ACTH secretion. Like Cushing disease, these disorders may be associated with hyperandrogenism. Diagnostic features of Cushing syndrome include elevated late-night salivary cortisol concentrations and failure to suppress cortisol and ACTH during an overnight dexamethasone suppression test (25 mcg/kg, maximum dose 1 mg) [74,75]. (See 'Dexamethasone suppression test' above and "Causes and pathophysiology of Cushing syndrome", section on 'Cushing disease'.)

●Androgen-secreting tumors – Adrenal or gonadal androgen-secreting tumors are extremely rare causes of premature pubarche. Typically, the tempo of pubertal changes is rapid; linear growth velocity and skeletal maturation are accelerated. Androgen-secreting tumors can arise in the adrenal cortex, testicular Leydig cell, or ovary [76]. Their characteristic features and initial evaluation are discussed briefly below and in more detail separately. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Causes of peripheral precocity'.)

•Adrenocortical androgen-secreting tumors are rare and tend to occur in children under five years of age. These tumors usually present with virilization and accelerated skeletal maturation. Although clinical features suggesting hypercortisolism may be inconsistent, most tumors are also associated with hypercortisolism [53]. DHEAS concentration are extremely elevated in over 90 percent of patients [54]. The adrenal tumors can be adenomas or carcinomas.

•Gonadal androgen-secreting tumors are rare. Boys with testicular Leydig cell tumors may present with premature pubarche; phallic enlargement and testicular asymmetry may be present. Ovarian androgen-secreting tumors are usually Sertoli-Leydig cells tumors; girls may develop clitoromegaly [77].

•Tumors that secrete beta-human chorionic gonadotropin (beta-hCG) can develop in the liver, brain, or testes. When these occur in boys, the beta-hCG can stimulate testicular luteinizing hormone (LH) receptors, leading to increased testosterone secretion; in girls, the presence of tumor-produced beta-hCG rarely causes precocious puberty.

●Central precocious puberty (CPP) – Gonadotropin-releasing hormone (GnRH)-dependent precocious puberty, also known as CPP, refers to the premature reactivation of the normally quiescent hypothalamic-pituitary-gonadal axis of early childhood. CPP can usually be distinguished from premature adrenarche because breast development in girls or testicular enlargement in boys is present; these clinical findings associated with CPP typically precede the development of pubic hair. However, isolated pubarche can occasionally be the first sign of CPP in girls or boys [78]. Typically, CPP progresses over time with variable tempos. Secondary CPP can occur in patients with advanced skeletal maturation associated with CAH or adrenal tumors, usually after initiation of treatment [79]. (See "Definition, etiology, and evaluation of precocious puberty".)

Other causes of precocious puberty are discussed separately. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Causes of peripheral precocity'.)

FOLLOW-UP

Counseling — Premature adrenarche is an idiopathic condition that does not require any specific endocrine treatment. Counseling to patients and their parents or caregivers may include the following:

●Premature adrenarche can usually be considered as a variation of normal development. The child can be told that this is a normal event that started a bit early. If the child is uncomfortable with pubic or axillary hairs despite reassurance, the hairs can be trimmed with small scissors. If body odor is upsetting to the child or parent, deodorant can be used sparingly. A hypoallergenic deodorant is preferable to an antiperspirant.

●Premature adrenarche is distinct from central precocious puberty (CPP). Families can be reassured that puberty/menses are not imminent. However, children with premature adrenarche typically begin central puberty (indicated by breast development or testicular enlargement) one to two years earlier than average [28,80].

●The exact underlying basis for normal adrenarche remains unclear. Premature adrenarche is thought to be due to early onset of the normal maturation of the adrenal zona reticularis.

●Some children have idiopathic premature pubarche, which may be due to unusual sensitivity of their hair follicles to normal trace amounts of C19 steroid hormones.

●Children with premature adrenarche may have a slightly increased risk for insulin resistance and obesity in adulthood [29]. To minimize risks for insulin resistance and other potential adult disorders, the best strategy involves helping the child maintain a healthy body weight, practice healthy eating habits, and engage in regular exercise. (See 'Potential adult risks of premature adrenarche' below.)

●Some girls with premature adrenarche may develop polycystic ovary syndrome (PCOS) during late adolescence or adulthood. However, the risk of developing PCOS appears to be low, based on limited longitudinal data. (See 'Potential adult risks of premature adrenarche' below.)

●Girls with premature pubarche due to premature adrenarche may be at risk for anxiety, depression, and eating disorders. A long-term follow-up study reported significantly higher scores on psychological tests for these symptoms in early adulthood (average age 21 years) [81]. Like other early maturing children, they should be considered a psychologically vulnerable population [82].

Clinical follow-up — Children diagnosed with premature adrenarche or premature pubarche should be followed clinically with serial physical examinations (eg, every 6 to 12 months) to monitor for the possibility of precocious puberty or a virilizing disorder. If symptoms do not progress and height velocity remains normal, these children can be reassessed less frequently. The bone age examination can be repeated approximately 6 to 12 months after initial presentation or sooner if the symptoms progress. Laboratory studies may be repeated if symptoms progress.

Potential adult risks of premature adrenarche — The increased prevalence of obesity and evidence of insulin resistance in individuals with premature adrenarche have raised concern about risk for related health problems during adulthood. A retrospective study published in 1993 suggested that premature pubarche/adrenarche was often followed by ovarian hyperandrogenism [83]. Subsequent studies have shown varying results regarding progression from premature adrenarche to ovarian hyperandrogenism [31,81,84,85]. The data regarding obesity and insulin resistance are mixed. Limited available data suggest that the prevalence of mild PCOS phenotypes might be slightly increased. For now, longitudinal follow-up and endorsement of healthy lifestyle choices are prudent therapeutic strategies.

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: Early puberty (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definitions – Premature pubarche is the isolated appearance of sexual hair prior to age eight years in girls and nine years in boys. Premature adrenarche is the most common cause of premature pubarche (often accompanied by seborrhea, axillary hair, microcomedonal acne, and/or adult body odor) and is characterized by increased adrenal steroid C19 secretion by the zona reticularis. The predominant adrenal C19 steroid hormones are dehydroepiandrosterone sulfate (DHEAS) and dehydroepiandrosterone (DHEA). (See 'Definitions' above and 'Pathophysiology' above.)

●Epidemiology – Premature pubarche is more common in girls than in boys. It is seen in up to 15 percent of girls in a primary care setting in the United States, but the prevalence varies between populations and subpopulations (table 2). (See 'Epidemiology' above.)

●Evaluation – Premature adrenarche is a diagnosis of exclusion.

•Initial evaluation – The evaluation includes a focused history and physical examination, looking for evidence of rapid skeletal growth or other secondary sex characteristics, and obtaining a bone age radiograph (algorithm 1). Children with advanced bone age should be further evaluated with a panel of endocrine tests, including DHEAS, testosterone, androstenedione, and 17-hydroxyprogesterone (17OHP). (See 'Initial evaluation of premature pubarche' above.)

•Additional testing – Selected children may require further testing with an adrenocorticotropic hormone (ACTH) stimulation test or dexamethasone suppression test if indicated (algorithm 2 and algorithm 3). (See 'Additional testing for selected patients' above.)

●Diagnosis – The diagnosis of premature adrenarche is confirmed if a focused evaluation finds isolated pubarche with no evidence of other secondary sex characteristics (ie, breast development or testicular enlargement), typical prepubertal external genitalia, slow progression, normal height velocity, and normal or minimally advanced bone age. DHEAS (if measured) is typically between 40 to 115 mcg/dL (1.1 to 3.1 micromol/L), and other laboratory tests are normal for the child’s sexual maturity rating (also known as Tanner stage) (table 1). (See 'Diagnosis of premature adrenarche' above.)

●Differential diagnosis – The differential diagnosis of premature adrenarche includes idiopathic premature pubarche, gonadotropin-releasing hormone (GnRH)-dependent precocious puberty, congenital adrenal hyperplasia (CAH; especially the nonclassic form of 21-hydroxylase deficiency), and rare congenital disorders or tumors associated with clinical features or biochemical evidence of hyperandrogenism (table 5). (See 'Differential diagnosis' above.)

●Follow up – For most children, premature pubarche (whether associated with premature adrenarche or not) can be considered as a benign variation of normal development. These children should be followed clinically with serial physical examinations (eg, initially every six months) to monitor for the possibility of precocious puberty or hyperandrogenism. If there is minimal progression of symptoms and growth velocity remains normal, these children can be reassessed at longer intervals thereafter. (See 'Follow-up' above.)