Adrenarche is the stage in development when the adrenal cortex, specifically the zona reticularis (ZR), undergoes maturation and produces adrenal androgen precursors.1 The chief androgen precursors are dehydroepiandrosterone (DHEA) and androstenedione. Dehydroepiandrosterone sulfate (DHEAS) is produced in the liver and is a useful stable biomarker of adrenal cortex androgenic activity.2 Unlike gonadarche, which is defined as the centrally mediated maturation of the ovaries or testicles and production of the major sex hormones, isolated adrenarche is not a sign of true central puberty.
In-utero, the fetal adrenal gland is disproportionally large. The fetal zone of the adrenal cortex secretes large amounts of DHEA;3 elevated levels of these pre-hormones can be measured in the newborn until late infancy (ie, 9–12 months).4 After birth the fetal zone involutes, and products of the adrenal ZR gradually decrease to low levels.4 Later in childhood, the adrenal cortex develops a definitive ZR.3 Once the ZR develops, it produces more measurable adrenal androgen precursors at approximately age 6 to 8 years, although precursor steroids may be detected in the urine at younger ages.2 Adrenarche is identified clinically as pubarche, which includes the presence of pubic and axillary hair, apocrine body odor, and acne.2
Adrenarche and gonadarche are two independent processes, and the trigger for adrenarche is unknown.1 Premature adrenarche is defined as the presence of pubertal levels of adrenal androgen precursors, traditionally before age 8 years in girls and 9 years in boys. Studies from the Pediatric Research in Office Settings Network have found that black girls and boys, on average, begin to show signs of pubarche 1 year or more before white children.5,6
If signs of gonadarche are also present, the patient does not have premature adrenarche, but rather precocious puberty.2
Premature adrenarche is more commonly seen in girls than boys, at a ratio of 9:1.7 Premature adrenarche is seen with increased frequency in children with certain medical histories or comorbidities. Low birth weight may be associated with increased DHEAS levels in childhood and early puberty.2 However, some studies have shown the incidence of premature adrenarche in children formerly small for gestational age to be equivalent to the general population.2,8 Children who were born preterm may continue to have elevated DHEAS levels into their twenties.2 Children with a history of brain injury have an increased risk of premature adrenarche or precocious puberty.9
Multiple studies have shown that children with premature adrenarche are often taller and heavier than their prepubertal peers.2,3 Overweight or obese children may have increased insulin-like growth factor-1 levels or advanced bone ages that do not portend abnormal stature or full-blown precocious puberty.3 Despite a reduced pubertal growth spurt, their adult height is within 2 standard deviations of their mid-parental height.2 The mean age of menarche for girls with premature adrenarche is no earlier than the general population.2
According to studies of girls in Spain, those with a history of premature adrenarche were more likely to develop functional ovarian hyperandrogenism (FOH) once they reached adolescence.2,8 This may be more prominent in overweight or obese youngsters. Symptoms of FOH include oligomenorrhea, hirsutism, acne, anovulation, and hormonal evidence of hyperandrogenism.2,7 These girls may be diagnosed with polycystic ovary syndrome if these symptoms persist for longer than 3 years after onset of menarche.7
The first symptom of premature adrenarche is typically the appearance of pubic or axillary hair.2 This is often accompanied by the development of apocrine body odor. Acne and increased skin sebum are also often noted.2 A step-by-step evaluation of a child presenting with these symptoms is summarized in Figure 1.
Algorithm for diagnosis of premature adrenarche and other forms of precocious puberty. Therapy for each condition is discussed in the text. Abbreviations: 17-OHP, 17-hydroxyprogesterone; DHEAS, dehydroepiandrosterone sulfate; E2, estradiol; FSH, follicle-stimulating hormone; HCG, human chorionic gonadotropin; LC-MS/MS, liquid chromatography/tandem mass spectroscopy; LH, luteinizing hormone; NCAH, nonclassic congenital adrenal hyperplasia, T, testosterone.
To be diagnosed with premature adrenarche, a child should not have signs of gonadarche, such as testicular enlargement or glandular breast development. Clinicians should perform an adrenal profile by the highly specific method of liquid chromatography/tandem mass spectroscopy (LC-MS/MS). The adrenal profile should consist of DHEAS, androstenedione, testosterone, and 17-hydroxyprogesterone (17-OHP) measured in an early morning (prior to 8 am) blood specimen, when these steroids are at their circadian peak. If the clinician is seeking to rule out central precocious puberty (CPP), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol levels may also be measured, and a bone age X-ray should be performed. Central puberty commences with pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, the rise of FSH and LH from the anterior pituitary, and subsequent rise of estradiol and testosterone from the gonads.10 Endocrine specialty laboratories can provide hormone reference ranges for prepubertal children, which should guide the diagnosis of premature adrenarche and puberty. CPP can be diagnosed in the setting of bilateral testicular enlargement in boys, glandular breast development in girls, and an accompanying pubertal growth spurt.1 A bone age X-ray can identify pubertal bone age advancement.1 Children with premature adrenarche do not typically have bone age advancement, growth spurt, or pubertal range FSH and LH levels.9
It is critical to exclude other pathologic causes of androgen excess.3 These disorders include late-onset or nonclassic congenital adrenal hyperplasia (NCAH),3 genetic conditions such as familial male-limited precocious puberty, androgen-producing tumors in the gonads or adrenal glands, and exogenous androgen exposure.
Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia (CAH) diagnosed outside the newborn period is most often caused by a mild or nonclassic form of 21-hydroxylase deficiency, caused by partial mutations in CYP21A2.11 NCAH, unlike the more severe or classic form of CAH, is not typically identified in the newborn period. The female patient with NCAH does not present with virilized external genitalia, or with an elevated 17-OHP on newborn screen in most cases. Patients with NCAH have residual 21-hydroxylase activity and do not present until later childhood, adolescence, or even until young adulthood.11 Among male and female patients with NCAH diagnosed before age 10 years, 92% present with complaints of premature pubarche.11 They have elevated adrenal steroid levels (specifically 17-OHP and androstenedione) associated with a variable degree of bone age advancement and slightly, but not significantly, shorter adult height compared with mid-parental height.11,12 In adolescence and adulthood, female patients may present with hirsutism, irregular menses, acne, or infertility.11 Male patients with NCAH may be identified due to premature pubarche, acne, an early growth spurt, or subfertility, but the majority are asymptomatic, and found to have NCAH during family screening.11,13
To screen for NCAH caused by 21-hydroxylase deficiency, a serum 17-OHP should be measured by LC-MS/MS on an early morning (ie, prior to 8 am) specimen.11 Normal values are dependent on the child's age, gender, and stage in puberty, and they vary by laboratory. Normal prepubertal children typically have 17-OHP levels of <90-100 ng/dL, whereas normal adolescents or young adults have 17-OHP levels of <200 ng/dL. If the child has a positive screen or a particular concern for NCAH, the next step in evaluation is to perform a cosyntropin (adrenocorticotropin 1–24) stimulation test. Cosyntropin at a dose of 250 mcg is given intramuscularly or intravenously, and serum 17-OHP is measured before and 60 minutes after administration.11 Typically, a stimulated 17-OHP level of >1,000–1,200 ng/dL is consistent with NCAH.11 If the hormonal diagnosis is in doubt, or for purposes of genetic counseling, the diagnosis may be confirmed by genotyping CYP21A2.14
Another rarer form of virilizing nonclassic CAH is 11-beta-hydroxylase deficiency.3 CAH due to 11-beta-hydroxylase deficiency results in increased levels of deoxycorticosterone and 11-deoxycortisol, decreased aldosterone and cortisol, and increased adrenal androgens causing virilization.4 Deoxycorticosterone is a mineralocorticoid, causing patients with severe 11-beta-hydroxylase deficiency to develop low renin hypertension.4 These children are treated with hydrocortisone and may require antihypertensive treatment.
Unlike CAH caused by severe 21-hydroxylase deficiency, in which patients require lifelong treatment with glucocorticoids and mineralocorticoids for survival, not all patients with NCAH require treatment.11 Indications for hydrocortisone treatment include early or rapidly progressive pubarche, bone age advancement, or excessive virilization.11,14 Hydrocortisone can ameliorate signs of androgen excess. Once these children reach adult height, or their symptoms resolve, the hydrocortisone may be tapered and discontinued.14
Certain adrenal or gonadal tumors may produce androgens resulting in premature virilization.1,4 Virilizing adrenal tumors include both adrenocortical adenomas and adenocarcinomas. Adenomas typically secrete cortisol but may also produce mineralocorticoids or androgens; adenocarcinomas commonly secrete multiple hormones.4 Testicular Leydig cell tumors secrete high levels of testosterone.15 Signs of virilizing tumors in young boys include phallic enlargement, erections, body hair, increased muscle mass, and voice deepening.4 Gynecomastia may develop due to aromatization of testosterone to estradiol.16 Boys with adrenal tumors will have no testicular enlargement, whereas boys with Leydig cell tumors may develop asymmetric enlargement of a testis.1,15
Ovarian Sertoli-Leydig cell tumors also produce high levels of androgens and androgen precursors. Girls with virilizing tumors may experience clitoral growth, acne, body hair, voice deepening, and oligo- or amenorrhea.17 These signs tend to be rapidly progressive relative to other causes of early adrenarche.18 If Sertoli-Leydig tumors are not hormone-secreting, abdominal pain or swelling may be the presenting sign.17,18
Germ cells tumors secreting human chorionic gonadotropin (hCG) can also cause a child to virilize prematurely.10 hCG cross-reacts with LH receptors, as the two hormones share an identical alpha subunit.10 Activation of the LH receptor in the testicle will cause the Leydig cells to produce testosterone and virilize a boy while only causing mild testicle growth.10 Girls do not experience signs of puberty, as they require FSH in addition to LH stimulation to secrete estrogen.19 hCG-secreting tumors include hepatomas, hepatoblastomas, choriocarcinomas, and other germ cell tumors.10
In the case of estrogen-, androgen-, or hCG-producing tumors, gonadotropins are suppressed, as the increased sex steroid production is not due to central precocious puberty.15 In addition, midnight salivary cortisol and 24-hour urinary-free cortisol should be checked for Cushing syndrome if suggestive clinical features are observed.4 Ovarian Sertoli-Leydig cells and some germ cell tumors may produce elevated alpha fetoprotein levels.10,20 Imaging should be focused on the likely source of the sex hormone excess. Computed tomography or magnetic resonance imaging of the adrenal gland is recommended if there is no evidence for a gonadal tumor or if the patient has elevated cortisol or signs of Cushing syndrome.4 If the child has an elevated level of hCG, a liver ultrasound should be performed to evaluate for nodules or a mass.10 Other sources of pathologic hCG secretion include the mediastinum and brain.19 A testicular ultrasound would be the appropriate step in a male with testicular asymmetry or mass, or if no other source of androgen excess is detected. A biopsy should be performed on the larger of the asymmetric testes for pathology. Initial treatment for nonhepatic tumor types is surgical resection.4 Isolated estrogen production may be associated with ovarian cysts, of which a small proportion may represent malignancies. Surgical resection is usually indicated, save for those recurrent ovarian cysts attributable to McCune-Albright syndrome caused by Gs-alpha mutations associated with gonadotropin-independent puberty.
Other Differential Diagnoses
Familial male-limited precocious puberty (also known as testotoxicosis) is a rare autosomal dominant condition.1 It is caused by an activating mutation of the LH receptor, causing the testicular Leydig cells to secrete testosterone independent of stimulation from gonadotropins. This causes affected male patients who are age 1 to 4 years to experience rapid virilization, modest bilateral testicular growth, growth acceleration, and bone age advancement.10 They will have pubertal range testosterone levels but prepubertal LH levels.1,10 Treatment is aimed at inhibiting steroidogenesis with ketoconazole, blocking the androgen receptor with bicalutamide, and/or preventing aromatization from testosterone to estrogen with aromatase inhibitors to prevent bone age advancement.10,21
Testosterone preparations are prescribed to male patients by pediatric endocrinologists and adult specialists for various indications, including micropenis, delayed puberty, and testosterone deficiency.22 Testosterone is available as an intramuscular injection, a topical patch, or in gel formulation. Women or children in physical contact with patients using transdermal testosterone (gel or patch) may have high blood testosterone levels with development of pubic hair, acne, phallic or clitoral enlargement, and bone age advancement.7,22 In 2009, the US Food and Drug Administration issued a black box warning for testosterone gels, informing users of the risk of virilization of young children and women who come into contact with these gels.22 Users are instructed to wash their hands immediately after applying the gel and cover the skin where the gel was applied.22 Similar signs of virilization have occurred from oral medications or vitamins contaminated with androgens.23
Premature adrenarche in childhood can be associated with multiple medical conditions in adolescence and in adulthood; however, the majority of such children have no major health problems.7 Those children who have premature pubarche and adrenarche in the setting of overweight and obesity should be educated about incorporating a healthy diet and daily exercise into their routines.2
Once other causes of prepubertal hyperandrogenism have been excluded, the patient can be diagnosed with benign premature adrenarche. Isolated premature adrenarche itself does not require any specific treatment.3 Parents should be informed that the growth of pubic hair may progress. The child should be monitored for other signs of pubertal progression such as breast enlargement in girls before age 8 years or penile/testicular enlargement in boys before age 9 years, which might indicate central precocious puberty.3 Body odor may be managed by frequent bathing and use of a deodorant. Acne may be treated with topical agents.
Adrenarche is a normal process in development, with a variable age at presentation in children. The primary goal in evaluation is to exclude pathologic causes of early onset pubic and axillary hair in young children.
- Palmert MR, Dunkel L, Witchel SF. Puberty and its disorders in the male. In: Sperling MA, ed. Pediatric Endocrinology. 4th ed. Philadelphia, PA: Elsevier Saunders; 2014:697–733.
- Voutilainen R, Jääskeläinen J. Premature adrenarche: etiology, clinical findings, and consequences. J Steroid Biochem Mol Biol. 2015;145:226–236. doi:. doi:10.1016/j.jsbmb.2014.06.004 [CrossRef]
- Utriainen P, Laakso S, Liimatta J, Jääskeläinen J, Voutilainen R. Premature adrenarche – a common condition with variable presentation. Horm Res Paediatr. 2015;83:221–231. doi:. doi:10.1159/000369458 [CrossRef]
- Miller WL, Flück CE. Adrenal cortex and its disorders. In: Sperling MA, ed. Pediatric Endocrinology. 4th ed. Philadelphia, PA: Elsevier Saunders; 2014:471–532.
- Herman-Giddens ME, Steffes J, Harris D, et al. Secondary sexual characteristics in boys: data from the Pediatric Research in Office Settings Network. Pediatrics. 2012;130:e1058–e1068. doi:. doi:10.1542/peds.2011-3291 [CrossRef]
- Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings Network. Pediatrics. 1997;99:505–512. doi:10.1542/peds.99.4.505 [CrossRef]
- Oberfield SE, Sopher AB, Gerken AT. Approach to the girl with early onset of pubic hair. J Clin Endocrinol Metab. 2011;96:1610–1622. doi:. doi:10.1210/jc.2011-0225 [CrossRef]
- Ghizzoni L, Gasco V. Premature pubarche. Horm Res Paediatr. 2010;73:420–422. doi:. doi:10.1159/000308178 [CrossRef]
- Kaplowitz P, Bloch C. Evaluation and referral of children with signs of early puberty. Pediatrics. 2016;137:e20153732. doi:. doi:10.1542/peds.2015-3732 [CrossRef]
- Styne DM, Grumbach MM. Physiology and disorders of puberty. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology. 13th ed. Philadelphia, PA: Elsevier Saunders; 2016:1074–1218.
- Falhammar H, Nordenström A. Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment, and outcome. Endocrine. 2015;50:32–50. doi:. doi:10.1007/s12020-015-0656-0 [CrossRef]
- Muthusamy K, Elamin MB, Smushkin G, et al. Adult height in patients with congenital adrenal hyperplasia: a systematic review and metaanalysis. J Clin Endocrinol Metab. 2010;95:4161–4172. doi:. doi:10.1210/jc.2009-2616 [CrossRef]
- Livadas S, Dracopoulou M, Dastamani A, et al. The spectrum of clinical, hormonal and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene. Clin Endocrinol. 2015;82:543–549. doi:. doi:10.1111/cen.12543 [CrossRef]
- Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:4133–4160. doi:. doi:10.1210/jc.2009-2631 [CrossRef]
- Olivier P, Simoneau-Roy J, Francoeur D, et al. Leydig cell tumors in children: contrasting clinical, hormonal, anatomical, and molecular characteristics in boys and girls. J Pediatr. 2012;161:1147–1152. doi:. doi:10.1016/j.jpeds.2012.05.039 [CrossRef]
- Stephenson AJ, Gilligan TD. Neoplasms of the testis. In: Wein AJ, Kavoussi LR, Partin AW, Peters CA, eds. Campbell-Walsh Urology. 11th ed. Philadelphia, PA: Elsevier Saunders; 2016:784–814.
- Cabrera-Cantú F, Urrutia-Osorio M, Valdez-Arellano F, Rivadeneyra-Espinoza L, Papaqui A, Soto-Vega E. Sertoli–Leydig cell tumor in a 12-year-old girl: a review article and case report. Arch Gynecol Obstet. 2014;290:791–796. doi:. doi:10.1007/s00404-014-3293-6 [CrossRef]
- Bulun SE. Physiology and pathology of the female reproductive axis. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology. 13th ed. Philadelphia, PA: Elsevier Saunders; 2016:589–663.
- Schwabe J, Calaminus G, Vorhoff W, Engelbrecht V, Hauffa BP, Göbel U. Sexual precocity and recurrent beta-human chorionic gonadotropin upsurges preceding the diagnosis of a malignant mediastinal germ-cell tumor in a 9-year-old boy. Ann Oncol. 2002;13:975–977. doi:10.1093/annonc/mdf085 [CrossRef]
- Schultz KAP, Harris AK, Schneider DT, et al. Ovarian sex cord-stromal tumors. J Oncol Pract. 2016;12:940–946. doi:. doi:10.1200/JOP.2016.016261 [CrossRef]
- Lenz AM, Shulman D, Eugster EA, et al. Bicalutamide and third-generation aromatase inhibitors in testotoxicosis. Pediatrics. 2010;126:e728–e733. doi:. doi:10.1542/peds.2010-0596 [CrossRef]
- Cabrera SM, Rogol AD. Testosterone exposure in childhood: discerning pathology from physiology. Expert Opin Drug Saf. 2013;12:375–388. doi:. doi:10.1517/14740338.2013.782000 [CrossRef]
- US Food and Drug Administration. Healthy Life Chemistry by Purity First B-50: FDA health risk warning - undeclared ingredients. http://wayback.archive-it.org/7993/20170406124132/https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm362800.htm. Accessed December 20, 2017.