Non-PCOS Hyperandrogenic Disorders in Adolescents

Abstract

Hyperandrogenism—clinical features resulting from increased androgen production and/or action—is not uncommon in peripubertal girls. Hyperandrogenism affects 3–20% of adolescent girls and often is associated with hyperandrogenemia. In prepubertal girls, the most common etiologies of androgen excess are premature adrenarche (60%) and congenital adrenal hyperplasia (CAH) (4%). In pubertal girls, polycystic ovary syndrome (PCOS) (20–40%) and CAH (14%) are the most common diagnoses related to androgen excess. Androgen-secreting ovarian or adrenal tumors are rare (0.2%). Early pubic hair, acne, and/or hirsutism are the most common clinical manifestations, but signs of overt virilization in adolescent girls—rapid progression of pubic hair or hirsutism, clitoromegaly, voice deepening, severe cystic acne, growth acceleration, increased muscle mass, and bone age advancement past height age—should prompt detailed evaluation. This article addresses the clinical manifestations of and management considerations for non-PCOS related hyperandrogenism in adolescent girls. We propose an algorithm to aid diagnostic evaluation of androgen excess in this specific patient population.

Introduction

Hyperandrogenism is defined as clinical and/or biochemical features of increased androgen production and/or action, and is common in adolescent girls and women. Hyperandrogenism affects 3–20% of adolescents^1–3, depending on the population studied, and may be attributed to polycystic ovary syndrome (PCOS) in 20–40%^1,2,4. The estimated prevalence of non-PCOS-related hyperandrogenism is 3–16%, while the estimated prevalence of non-PCOS-related biochemical hyperandrogenemia is 3–7%^1–3,5.

All hyperandrogenism—whether related to PCOS or otherwise—is important to address. Clinical hyperandrogenism (e.g., hirsutism) is commonly an important concern to patients and may negatively impact psychological and social wellbeing. Moreover, non-PCOS-related hyperandrogenism may indicate (or contribute to) risks of elevated body mass index (BMI), metabolic syndrome, and dysglycemia⁶, much like the well-known association of PCOS with features of metabolic syndrome⁷. A number of conditions other than PCOS should be considered in each adolescent presenting with hyperandrogenism, in large part because treatment approaches and comorbidities may differ from those of PCOS. Herein we review the clinical manifestations, diagnosis, and management of non-PCOS-related hyperandrogenism in adolescent girls.

Clinical Manifestations

Hirsutism is defined as excess growth of dark and/or coarse terminal hair in a male-like distribution, and must be distinguished from hypertrichosis, the presence of generalized excessive fine vellus hair growth⁸. The modified Ferriman-Gallwey scoring system is the most common tool to assess hirsutism in women. This system involves grading terminal hair growth by assigning a score—ranging from 0 (absence) to 4 (extensive)—for 9 different body sites: upper lip, chin, chest, upper and lower back, upper and lower abdomen, arm, and thigh (Fig. 1)⁹. A cut-off sum of scores ≥4–6 has been suggested to define hirsutism in adult women by the 2018 International PCOS Consensus Guideline, based on the 85th percentile of scores and cluster analysis in relation to PCOS features¹⁰. Limitations include its subjective nature with high inter-observer variability; lack of scoring for other androgen-sensitive areas (e.g., sideburns, buttocks, and perineum); and inability to capture the impact of severe focused hirsutism. Additionally, it is difficult to score women with blond hair or prior cosmetic surgery¹⁰. Importantly, normal scores differ according to ethnicity and have not been established in adolescents, who likely have lower scores for degree of hyperandrogenemia due to limited exposure time. Therefore, the precise role of Ferriman-Gallwey scoring in adolescents remains uncertain.

Figure 1.

Modified Ferriman-Gallwey grading system for terminal hair growth at androgen-sensitive sites. (Reprinted with permission from Yildiz BO, Bolour S, Woods K, Moore A, Azziz R. Visually scoring hirsutism. Hum Reprod Update. 2010;16(1):51–64.)

Acne is common in adolescents, and androgen excess may contribute to acne via stimulation of sebaceous gland growth and sebum production. However, other non-androgen-related factors—such as colonization with Propionibacterium acnes and tissue inflammatory response—contribute to acne, which may explain the poor correlation between acne symptom severity and androgen levels¹¹.

At the extreme, markedly elevated serum androgen concentrations can lead to virilization, suggested by rapid progression of pubic hair or hirsutism, clitoromegaly, voice deepening, severe cystic acne, growth acceleration, increased muscle mass, frontal balding, and bone age advancement past height age¹².

Defining Hyperandrogenemia in Adolescents

The steroidogenic pathways for the androgens considered most relevant to clinical androgen excess are illustrated in Fig 2. ^13,14 The first androgens to increase in girls are adrenal cortical androgens, predominantly dehydroepiandrosterone sulfate (DHEA-S), due to increases in 17,20-lyase and sulfotransferase activities and a decrease in 3β-hydroxysteroid dehydrogenase (3βHSD) activity, as part of adrenarche. Adrenarche is independent from gonadotropin secretion¹⁵ and is characterized biochemically by a distinct rise of DHEA-S to levels ≥ 40 – 60 mcg/dL around age 6 – 8 yr^16,17. Adrenarche manifests clinically as the development of pubic hair (pubarche), axillary hair, apocrine odor, oily skin, and often acne.

Figure 2.

Steroidogenic pathways for clinically relevant androgen production in girls. (Adapted with permission from Rosenfield RL. Normal and premature adrenarche. Endocr Rev. 2021 Mar 31:bnab009. Online ahead of print. Available at: https://academic.oup.com/edrv/advance-article/doi/10.1210/endrev/bnab009/6206746. Accessed May 25, 2021; and from Turcu AF, Rege J, Auchus RJ, Rainey WE. 11-Oxygenated androgens in health and disease. Nat Rev Endocrinol. 2020 May;16(5):284–296.)

Levels of testosterone (T) also increase throughout puberty in normal girls¹⁸, including prior to thelarche¹⁹. The precise source of such T increases are unclear, but may be of adrenal origin early in puberty, with increasing ovarian contribution by mid- to late puberty²⁰. It has been recently recognized that 11-oxygenated C19 androgens—generated in part via aldo-keto reductase family 1 member C3 (AKR1C3) activity in the adrenal gland and adipose tissue—are important contributors to androgen excess in adolescent girls and women. Such androgens include 11-ketotestosterone (11-KT), which binds and activates the androgen receptor with the same affinity as T. 11-KT levels are elevated in girls with premature adrenarche, congenital adrenal hyperplasia (CAH), PCOS, and obesity^21–24.

Several practical considerations pertain to the assessment of serum androgen levels in adolescent girls. Assessments must consider the patient’s age and pubertal (Tanner) stage. The absence of normal adolescent references ranges for many assays has made determination of hyperandrogenemia in adolescents especially challenging. Serum T levels are much lower in girls compared to women and especially men, and commercial T assays have historically been beset by poor analytical sensitivity and poor specificity at low concentrations. Although some RIA testosterone assays may perform well at low levels²⁵, liquid chromatography-tandem mass spectrometry is largely viewed as the assay method of choice when available.

Nearly 98% of circulating testosterone is bound to sex hormone binding globulin (SHBG) or albumin, and the unbound (“free”) T is felt to be the biologically active fraction of circulating T. Indeed, free T—measured via equilibrium dialysis techniques or calculated using total T and SHBG levels—has ~50% greater sensitivity to detect hyperandrogenemia compared to total T alone and is widely considered to be the best single indicator of hyperandrogenism²⁶. Testosterone levels may vary according to time of day, being higher in the morning, in addition to cycle stage in post-menarcheal girls, being higher during mid-cycle²⁶. Whenever an accurate assessment of ovarian androgens is required, hormonal contraceptives should be withdrawn 2–3 months before testing because they can suppress ovarian androgen production (via gonadotropin suppression) and because estradiol can increase the production of SHBG by the liver²⁶.

Premature Adrenarche

Premature adrenarche is defined clinically as idiopathic pubarche before age 8 yr in girls (9 yr in boys)²⁷, based on the original clinical observations of Marshall and Tanner. (Although studies of 24-hr urinary androgen metabolites suggest that adrenarche may begin as early as age 3 yr²⁸, pubarche typically occurs much later.) Premature adrenarche is the most common etiology of androgen excess in prepubertal children, affecting 61% of referred children. It occurs mostly in girls—79% of those with premature adrenarche—and is associated with elevations in DHEA-S in 85%, androstenedione (A4) in 26%, and T in 9%⁴. Clinical signs of premature adrenarche also include increased height growth and moderately advanced bone age (≤ + 2 SD, correlated to height age)²⁷, but girls are not at risk for short stature^30,31. Premature adrenarche is unrelated to breast development or gonadotropin release¹⁷; some, but not all, studies suggest earlier age of menarche, but within the range of ages considered normal.

Although DHEA-S is a weak androgen, it may be converted to more potent A4 and T by non-adrenal tissues¹². A4 and T are moderately elevated for age, but normal for pubic hair stage²⁷. DHEA-S levels may be higher than expected even for pubic hair stage²⁷, but are usually suppressible by dexamethasone³⁰. Importantly, premature adrenarche should not be associated with clitoral enlargement, voice deepening, cystic acne, hirsutism, breast development, vaginal bleeding, bone age greater than height age, or androgen (i.e., A4 or T) levels elevated for pubic hair stage^12,27. Premature adrenarche is also a diagnosis of exclusion. Providers should consider central or peripheral precocious puberty, virilizing adrenal or gonadal tumor, non-classical congenital adrenal hyperplasia, or exogenous androgen exposure as differential diagnoses.

Several risk factors are associated with early adrenarche. Race is associated with earlier adrenarche, as more black girls have pubic hair at ages 6 and 8 (9.5% and 34.3%) compared to white girls (1.4% and 7.7%)³³. Nutritional status also contributes to adrenarche, and weight gain, obesity, and insulin resistance in childhood put girls at risk for premature adrenarche^34–37.

Premature adrenarche is no longer considered a benign variant of normal puberty, as it portends future metabolic and reproductive endocrine risk. Girls with premature adrenarche in the U.S., Finland, and Spain may demonstrate signs of insulin resistance and metabolic syndrome, including acanthosis nigricans, hyperinsulinemia, dyslipidemia, increased waist circumference, and increased fat mass (with or without elevated BMI)^38–42. Such metabolic abnormalities may persist into adulthood. For example, Finnish women with history of premature adrenarche exhibited more acanthosis nigricans, decreased insulin sensitivity, elevated hemoglobin A1c (HbA1c), and larger central fat depots compared to BMI-matched controls⁴³.

Likewise, premature adrenarche is a risk factor for the development of PCOS. Catalan girls with premature adrenarche demonstrated peripubertal worsening of hyperandrogenemia—including ovarian hyperandrogenemia—along with metabolic derangements, leading to a higher prevalence of ovulatory dysfunction by 3 years after menarche^44–46. Similarly, irregular menses, hirsutism, hyperandrogenemia, and exaggerated androgen responses to acute gonadotropin releasing hormone (GnRH) agonist stimulation testing developed in half of such girls by late puberty, suggesting the development of PCOS⁴⁷. The precise nature of the relationship between premature adrenarche and PCOS is unclear. The relationship may possibly reflect a more general exaggeration of androgen steroidogenesis—including in the ovary—related to inherited enzyme abnormalities or steroidogenesis-modifying factors such as hyperinsulinemia^48,49. In addition, early hyperandrogenemia may predispose girls to neuroendocrine dysfunction (e.g., luteinizing hormone [LH] excess) during the pubertal transition, which may promote ovarian dysfunction⁴⁸.

Since the consequences of premature adrenarche are primarily metabolic with an increased risk of PCOS, healthy lifestyle and maintenance (or achievement) of normal body weight should be encouraged. No specific pharmacological treatment is recommended, however. In Catalan girls with premature adrenarche, metformin was associated with less adiposity, later ages of thelarche and menarche, slowed bone maturation with better height, less hirsutism and oligomenorrhea, lower androgen levels, and lower risk of adolescent PCOS^50–52. Nonetheless, additional longitudinal studies in other populations are needed to assess whether this or other pharmacological treatments for premature adrenarche are helpful.

Non-Classical Congenital Adrenal Hyperplasia

Nonclassical congenital adrenal hyperplasia (NCCAH) accounts for 6% of children and adolescents (4% prepubertal; 14% pubertal) presenting with androgen excess, compared to 2–5% of women ^4,7,53. Although the overall contribution to girls presenting with androgen excess is relatively low, NCCAH is the most common autosomal recessive endocrine disorder. Incidence rates of NCCAH are known to vary widely in different ethnic populations, occurring in approximately 0.1% of Caucasians, less commonly in African populations, and more commonly in Yugoslav (1.6%), Hispanic (1.9%), and Ashkenazi Jewish (3.7%) populations^54,55. Because of these known genetic differences in prevalence, NCCAH will not be applicable to many populations internationally.

NCCAH represents a mild form of CAH: such patients are not born with genital ambiguity, and they are not clinically cortisol deficient because ACTH elevations can adequately compensate for the mild enzymatic defect⁵⁶. Clinical findings may start from age 5 yr but usually emerge in late childhood, adolescence, and adulthood⁵⁷. In 220 women with NCCAH, only 11% had symptoms—primarily premature pubarche—before age 10 ⁵⁸. Hyperandrogenemia (elevated A4 in 86%, T in 50%, DHEA-S in 33%) constitutes the main basis for symptoms⁴. Other than premature pubarche, clinical findings in girls may include labial adhesion, perianal hair, clitoromegaly, increased bone age, early apocrine odor, greasy hair, acne, and a short height prediction versus mid-parental target height⁵⁷. During adolescence and adulthood, NCCAH may manifest as hirsutism (59–78%), anovulatory menstrual dysfunction (55%), acne (33%), decreased fertility (12%), and androgenic alopecia^59,60. Indeed, NCCAH may masquerade as PCOS—NCCAH is an important exclusion criterion for PCOS—and 56%-73% of such patients otherwise appear to meet criteria for PCOS^53,61.

Since the most common form of CAH is caused by 21OH deficiency, screening for NCCAH is done via basal (unstimulated) serum 17OHP levels drawn at 8 am during the follicular phase of the menstrual cycle (when applicable)⁶². Levels < 200 ng/dL (6 nmol/L) exclude NCCAH with 95% specificity and sensitivity, while levels > 1000 ng/dL (45 nmol/L) are diagnostic⁶⁰. Afternoon 17OHP measurements can yield false negative results in 2–9% of patients with NCCAH, and luteal phase 17OHP may be > 200 ng/dL in approximately 50% of healthy females without NCCAH^61–63. When basal 17OHP is 200–1000 ng/dL, an ACTH stimulation test should be performed with 17OHP drawn before and 60 minutes after cosyntropin (synthetic ACTH) 250 mcg IV⁵⁷. ACTH stimulation testing should also be considered in girls with premature adrenarche if bone age-to-height age ratio is > 1, if basal androgen levels are elevated (DHEAS > 130 mcg/dL, T > 35 ng/dL), or if there are atypical features such as cystic acne or virilization^12,27. ACTH-stimulated 17OHP > 1000 ng/dL (30 nmol/L) confirms NCCAH, although lower levels do not completely exclude NCCAH (or carrier status for classical CAH)⁶². Some experts suggest also measuring 17-OH pregnenolone, 11-deoxycortisol, cortisol, DHEA, and A4 during the ACTH stimulation test to detect rare forms of CAH or other virilizing disorders¹². While genetic testing is not a primary diagnostic tool for NCCAH at this time, it may be helpful for diagnosis if ACTH responses are indeterminate or to inform genetic counseling^62,64.

Patients with NCCAH are treated according to their symptoms. Glucocorticoids are used to treat girls with NCCAH if they have early, rapid progression of pubarche with advanced bone age that will adversely affect adult height, or if they develop symptoms of overt virilization suggesting more severe enzymatic dysfunction⁶². When needed, early initiation of glucocorticoids (i.e., one year prior to puberty, bone age < 9 yr) can protect genetically-determined height potential⁶³. Hydrocortisone, which is preferred over prednisone or dexamethasone due to their growth limiting effects, is administered at a dose of 6–15 mg/m²/day, divided into 3 doses⁶⁰. Hydrocortisone may be discontinued when such girls reach adult height, especially if there are no findings of hyperandrogenism. While adolescents with irregular menses and acne may benefit from continued low dose glucocorticoid therapy, glucocorticoids can have undesirable long-term effects, and they are unlikely to improve hirsutism⁶². Accordingly, women with NCCAH and patient-important hyperandrogenism are often treated with oral contraceptives with or without spironolactone, with glucocorticoid therapy reserved for recalcitrant symptoms or infertility^62,66–68. When used for NCCAH-related infertility, glucocorticoids that are inactivated by placental 11β-hydroxysteroid dehydrogenase 2 (e.g., prednisone, prednisolone, or hydrocortisone) are recommended⁶⁸. Glucocorticoid stress dosing for major surgery or serious illness/injury is not required for NCCAH patients unless cortisol response to ACTH stimulation is < 14–18 mcg/dL or if the patient develops iatrogenic adrenal insufficiency from chronic glucocorticoid treatment^62,69,70.

Androgen-secreting tumors

Androgen-secreting tumors are rare, occurring in 0.2% of children and adolescents (and 0.2% of women) with symptoms of androgen excess^4,7,53, and may arise from the ovaries or adrenal glands. Androgen-secreting ovarian tumors include Leydig-Sertoli cell tumors, other steroid cell tumors, and ovarian thecomas; and adrenal adenomas and carcinomas may secrete androgens. Such neoplasms should be considered in patients with rapidly progressive symptoms (over weeks or months) and/or virilization⁷¹. Symptoms of virilization include enlargement of the clitoris (transverse diameter >10 mm), increased muscularity, deepening of the voice, severe cystic acne or seborrhea, and male-pattern balding^71,72.

Androgen-secreting tumors should be considered when the serum testosterone is > 150 – 200 ng/dL (5–7 nmol/L, or 2–3 times the upper limit of normal)^71,72 or when DHEA-S is > 700 mcg/dL (>19 mmol/L)^26,73. Elevated testosterone (often with elevated androstenedione) without an elevation of DHEAS suggests an ovarian source^71,72. Small ovarian tumors can demonstrate episodic secretion of androgens, and repeat androgen measurements may be required when index of suspicion remains high⁷¹. Androgen suppression by combined oral contraceptive pills (OCPs) has been suggested as a way to assess for functional ovarian hyperandrogenism, but case reports suggest that OCPs can normalize androgen levels in some cases of androgen-secreting ovarian tumors^71,73. Elevated DHEA-S suggests an adrenal source, but an androgen-secreting adrenal tumor is unlikely if DHEA-S can be suppressed to normal levels with dexamethasone^12,73.

Imaging is reserved for patients with a high index of suspicion based on clinical and biochemical data, since discovery of incidentalomas is not uncommon (especially in the adrenal gland)⁷⁴. The adrenal glands are easily visible by CT or MRI⁷¹. For ovarian tumors, transvaginal ultrasound is often the first modality used in adult women, but MRI may be better suited for adolescents to avoid vaginal manipulation in young patients and to visualize small or isoechoic Sertoli-Leydig cell tumors^71,75.

Other Rare Causes of Hyperandrogenism

Rare causes of hyperandrogenism should be considered in the setting of unexplained androgen excess, but other symptoms usually predominate in such conditions. Central precocious puberty may present with premature pubarche, representing 2.5% of cases of androgen excess, but would also be associated with breast development^4,12. Cushing’s syndrome occurs in 0.2% in children and adolescents with androgen excess⁴ and should be considered in adolescent girls with a PCOS-like phenotype, particularly if they have other symptoms that increase pretest probability (e.g., growth retardation, hypertension, proximal muscle weakness, wide violaceous striae)⁷⁶. Progressive virilization at the time of puberty can be a sign of a disorder of sexual development, including 5α-reductase deficiency⁷⁷. Acromegaly-related insulin resistance and compensatory hyperinsulinemia can lead to hyperandrogenism and may be associated with tall stature in girls who are still growing⁷⁸. Exogenous androgens may lead to hyperandrogenism in adolescents, especially with exposure to topical testosterone (e.g., male contacts) or nutritional supplements.

Obesity-related hyperandrogenemia

Hyperandrogenemia may be associated with obesity in peripubertal girls, even prior to thelarche, with observed elevations of serum A4, T, and free T levels^18,79. According to one study, approximately 60% of obese girls exhibit elevated morning free T levels⁸⁰. The development of hyperandrogenemia in pre- and early pubertal girls with obesity may suggest an adrenal source, as significant ovarian androgen production is presumably absent in such girls. Increased central activation of the hypothalamic-pituitary-adrenal axis and direct activity of leptin or insulin on adrenal steroidogenesis have also been proposed as potential mechanisms for obesity-related hyperandrogenemia in early puberty⁷⁹. By late puberty, girls with obesity demonstrate 4-fold higher post-dexamethasone levels of free T and 2-fold higher A4 and free T responses to cosyntropin, suggesting both ovarian and adrenal contributions to obesity-associated hyperandrogenemia in later puberty²⁰.

In prepubertal obese girls, weight loss of at least 0.5 BMI SDS is associated with improved insulin resistance and decreased A4 and T levels⁷⁹. However, the relationship between obesity and androgen excess may be bidirectional. For example, testosterone administration can promote visceral fat accumulation and insulin resistance in adolescent female nonhuman primates in the setting of high-fat/calorie diet^81,82.

Androgen excess as possible precursor to PCOS

Despite decades of intensive research, the etiology of PCOS remains enigmatic. For many women with PCOS, initial symptoms manifested during or shortly after puberty, and peripubertal hyperandrogenemia has been linked to the eventual development of full-blown PCOS. For example, as described above, girls with exaggerated adrenarche appear to be at higher risk for PCOS⁴⁸. In addition, some evidence suggests a high prevalence of secondary PCOS—manifesting as ovarian hyperandrogenemia and LH excess—in women with virilizing CAH⁸³.

We and others have raised concerns that peripubertal obesity-associated hyperandrogenemia may put girls at risk for adult PCOS^84,85. This putative pathway toward PCOS may be different than for other girls at risk for PCOS. Compared to daughters of women with PCOS, premenarcheal girls with obesity-related androgen excess have lower SHBG and lower anti-Mullerian hormone⁸⁶, suggesting a distinct phenotype with increased androgen bioavailability and fewer abnormalities of ovarian folliculogenesis.

While peripubertal androgen excess may simply represent an early marker of nascent PCOS, a number of findings indicate that androgen excess may also actively contribute to its development. Perhaps the most robust evidence that androgens contribute to the development of PCOS comes from animal studies. In rodents, sheep, and non-human primates, experimental prenatal androgenization is associated with numerous PCOS-like characteristics in adulthood, including ovulatory dysfunction, endogenous hyperandrogenemia, polyfollicular ovaries, and neuroendocrine abnormalities⁸⁷. Peripubertal androgen administration in female rats also yields a number of PCOS-like features including ovulatory dysfunction, polyfollicular ovaries, increased adiposity, and insulin resistance⁸⁷.

Although mechanisms are likely multifactorial, androgen excess may encourage the development of PCOS through neuroendocrine mechanisms⁸⁸. For example, prenatally-androgenized animals exhibit neuroanatomical and functional neuronal changes that contribute to GnRH neuronal hyperactivity^89–91. Peripubertal hyperandrogenemia may impair negative feedback suppression of LH (GnRH) pulse frequency as it does in adult PCOS⁹², since elevated fasting insulin levels are associated with similar impairment in adolescents^93,94. Such effects of androgen excess on GnRH release may be especially relevant during critical developmental windows such as fetal development and puberty. Additional effects of peripubertal hyperandrogenemia—e.g., on adiposity, insulin resistance, and follicular dynamics—may be pertinent to the development of PCOS as well⁸⁷.

Clinical Strategies

An algorithm to evaluate adolescent girls with symptoms of androgen excess is proposed in Fig 3. Any underlying medical condition related to hyperandrogenism should be treated according to pathology, as discussed above.

Figure 3.

Diagnostic algorithm for adolescent hyperandrogenism. BA = bone age; HA = height age; 17OHP = 17 hydroxyprogesterone; T = testosterone; DHEA-S = dehydroepiandrosterone sulfate; DHEA = dehydroepiandrosterone; A4 = androstenedione; PCOS = polycystic ovary syndrome; 21-OH def = 21-hydroxylase deficiency; 3βHSD def = 3β-hydroxysteroid dehydrogenase deficiency; CAH = congenital adrenal hyperplasia; NCCAH = nonclassical congenital adrenal hyperplasia; DSD = disorder of sexual development; SRY = sex-determining region of the Y chromosome. ^aIn any girl: clitoromegaly, voice deepening, frontal balding, rapid development of symptoms; in pre-menarcheal girls: moderate to severe comedonal acne (≥ 10 lesions)¹², increased growth velocity; in peri-menarcheal girls: rapid onset hirsutism, moderate to severe inflammatory acne⁹⁹. ^bGirls should be monitored for clinical worsening or development of irregular menses. ^cIrregular menses is defined as >90 day cycle length for any one cycle at > 1 yr after menarche; < 21 day or > 45 day cycle length at > 1 to < 3 yr after menarche; < 21 day or > 35 day cycle length at ≥ 3 yr after menarche⁹⁹. Primary amenorrhea at 15 yr or > 3 yr post-thelarche should raise concerns⁹⁹. ^dACTH stimulation test: Cosyntropin 250 mcg IV. Draw serum 17OHP (consider also DHEA, 17OH-Pregnenolone, A4, T) at baseline and 60 minutes^12,27. ^eAssessment for cortisol excess/dexamethasone suppression test: Obtain 24 hr urine for free cortisol or 3 midnight salivary cortisol levels. First, consider a low dose dexamethasone suppression test. Draw at 8 am baseline T, cortisol, DHEA-S, other elevated androgens/precursors. Give dexamethasone 1 mg orally at midnight. Drawn 8 am repeat serum levels. For more definitive test, if androgen levels are not suppressed to normal levels by low dose dexamethasone test, give dexamethasone 1 mg BID × 5 days or 1 mg/m2 divided 3–4 times daily × 4 days with last dose morning day 5, as a definitive test to assess for an adrenal tumor^12,73.

The Endocrine Society recommends treating patient-important hirsutism, defined as hirsutism causing patient distress⁶⁶. The degree of hirsutism may not correlate well with serum androgen levels because the response of androgen-dependent follicles is variable within and among persons⁶⁶. Initial measures for hirsutism may include shaving, plucking, waxing, or depilatory creams. While these measures work well for many, they can occasionally result in scarring, rashes, folliculitis, or hyperpigmentation.

First line pharmacologic treatment is combined oral contraceptives, which suppress ovarian androgen production and stimulate SHBG production⁶⁶. However, OCPs may not fully lower non-ovarian androgen production and should not be used in girls who still have growth potential, due to the risk for premature fusion of growth plates, or in girls with medical contraindications for use of OCPs. Pharmacological interventions impact growth at the hair root, but patients may start noticing changes within 6 months and can expect to experience maximal effect after about 9 months⁹⁵. If patient-important hirsutism persists after 6 months of OCP therapy, anti-androgen therapy with spironolactone may be added⁶⁶. Finasteride—a 5α-reductase inhibitors—is less or equally effective compared to spironolactone^26,66 but may have undesirable side effects, and flutamide is not recommended due to potentially serious hepatotoxicity. Cyproterone acetate (CPA)—a progestin that blocks the androgen receptor and 5α-reductase—is used in countries outside the U.S. and may be cycled with ethinyl estradiol (ethinyl estradiol 20–50 mcg/day × 3 weeks, CPA 50–100 mg/day during first 10 days of cycle) or combined in an oral contraceptive pill (2 mg CPA plus 35 mcg ethinyl estradiol)⁶⁶. Drosperinone is another progestin with antiandrogen activity: when given at a dose of 3 mg within a combined oral contraceptive pill, its antiandrogen potency equates to approximately 25 mg spironolactone or 1 mg CPA⁶⁶. Eflornithine—which inhibits a key step in hair growth—can be used topically to slow hair growth and is safe when combined with other therapies.

For patients with NCCAH, glucocorticoid therapy alone is unlikely to improve hirsutism, but may be added to oral contraceptives for recalcitrant symptoms, with or without spironolactone, at doses of prednisone 4–6 mg/day or dexamethasone 0.25 mg/day, titrated to prevent suppression of DHEA-S below 70 mcg/dL^62,66–68. GnRH agonists are reserved for patients with severe ovarian hyperandrogenism for whom OCPs and antiandrogens are ineffective. GnRH agonists reversibly produce severe hypogonadotropic hypogonadism, but concomitant estradiol and progesterone therapy can be used to mitigate adverse effects of hypoestrogenism and bone loss^26,66. Additionally, direct hair removal methods (e.g., electrolysis or photoepilation with laser or intense pulsed light) may be recommended after or alongside pharmacological treatment in women with patient-important hirsutism⁶⁶.

Given the association of peripubertal obesity in girls with hyperandrogenemia in most studies^18,96,97, weight reduction via lifestyle interventions may help lower androgen levels in peripubertal girls with obesity⁹⁶ and adolescents with PCOS^79,98. These results are likely the result of improved insulin sensitivity and may help girls with non-PCOS hyperandrogenemia, such as premature adrenarche, obesity-related hyperandrogenemia, and idiopathic hyperandrogenemia. Metformin has demonstrated reproductive and metabolic benefits in some studies of girls with premature adrenarche^50–52, but is not recommended as a specific treatment for hirsutism due to lack of efficacy⁶⁶.

Conclusions

Several diagnoses other than PCOS need to be considered in the evaluation of peripubertal girls with androgen excess. Most prepubertal girls presenting with symptoms of androgen excess will have premature adrenarche (61%), but NCCAH occurs in 6% of all peripubertal adolescents; thus, evaluation should include a morning serum 17OHP level. Signs of virilization or markedly elevated androgen levels should raise concern for an androgen-secreting tumor. During later puberty, ovarian androgen overproduction may emerge in girls at risk (e.g., daughters of women with PCOS, girls with obesity, girls with a history of premature adrenarche), and symptoms of PCOS may manifest across adolescence. NCCAH can closely mimic PCOS in older girls and should remain on the differential diagnosis. Hyperandrogenemia without other reproductive manifestations in adolescence may progress to PCOS in adulthood. Treatment strategies should be patient-focused and consider the underlying cause of androgen excess when known. Oral contraceptive pills are generally considered the first-line pharmacological therapy for hirsutism, but should not be used in girls who are still growing. Lifestyle interventions are important to improve androgen overproduction related to hyperinsulinemia and obesity.