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 to 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.

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.)

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.)

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), increased growth velocity; in peri-menarcheal girls: rapid onset hirsutism, moderate to severe inflammatory acne. ^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 menarche. Primary amenorrhea at 15 yr or > 3 yr post-thelarche should raise concerns. ^dACTH stimulation test: Cosyntropin 250 mcg IV. Draw serum 17OHP (consider also DHEA, 17OH-Pregnenolone, A4, T) at baseline and 60 minutes^,. ^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^,.