What is the recommended evaluation and initial management for a 13-year-old female with irregular menstrual cycles, hirsutism, acne, fatigue, and normal serum testosterone?

Evaluation and Management of a 13-Year-Old with Irregular Menses, Hirsutism, Acne, and Fatigue

Initial Assessment

This 13-year-old requires a focused hormonal workup despite normal testosterone, because hirsutism combined with irregular menses signals potential hyperandrogenism that may not be captured by total testosterone alone. 1

The key clinical features—irregular menses, hirsutism, acne, and fatigue—suggest either polycystic ovary syndrome (PCOS) or functional hypothalamic amenorrhea (FHA), but normal total testosterone does not exclude hyperandrogenism because free testosterone and other androgens may be elevated. 2, 3

Critical History Elements

• Document menstrual pattern precisely: age at menarche, cycle length, duration of irregularity (oligomenorrhea is defined as cycles >35 days apart). 1

• Assess energy availability: calculate if she consumes >30 kcal/kg fat-free mass/day, document hours per week of exercise (>10 hours/week intense training warrants evaluation for Female Athlete Triad), and screen for restrictive eating patterns or weight loss >5% over 6 months. 1, 4

• Quantify hyperandrogenic symptoms: use Ferriman-Gallwey scoring for hirsutism, document acne severity and distribution, and assess for androgenetic alopecia. 1, 5

• Evaluate fatigue context: distinguish between constitutional symptoms versus signs of thyroid dysfunction, anemia, or depression. 1

Physical Examination Priorities

• Calculate BMI: obesity (BMI >25 kg/m²) points toward PCOS, whereas low BMI (<18.5 kg/m²) favors FHA. 1, 4

• Perform Tanner staging: assess breast and pubic hair development to determine pubertal progression. 1

• Measure waist-to-hip ratio: ratio >0.9 suggests truncal obesity associated with PCOS. 1

• Examine for acanthosis nigricans: indicates insulin resistance commonly seen in PCOS. 1

Laboratory Evaluation

Order a comprehensive hormonal panel because normal total testosterone does not exclude hyperandrogenism—free testosterone, DHEA-S, and androstenedione are frequently elevated even when total testosterone is normal. 2, 3, 5

Mandatory First-Line Tests

• Pregnancy test: must be performed first to exclude pregnancy as a cause of amenorrhea. 1

• FSH and LH (drawn on cycle days 3-6 or any time if amenorrheic): LH/FSH ratio >2 strongly suggests PCOS, while ratio <1 is seen in 82% of FHA cases. 1, 4

• Prolactin (single morning resting sample, avoid post-stress or post-exercise collection): elevated levels >20 µg/L suggest hyperprolactinemia. 1

• TSH and free T4: thyroid dysfunction is a reversible cause of menstrual irregularity and fatigue. 1

Critical Androgen Testing (Despite Normal Total Testosterone)

• Free testosterone: more sensitive indicator of hyperandrogenism than total testosterone; salivary testosterone shows the highest correlation with hirsutism severity. 3, 5

• DHEA-S: age-adjusted thresholds (age 13-19: >3800 ng/mL warrants investigation); elevated in functional adrenal hyperandrogenism and may be the only abnormal androgen in adolescent acne. 1, 6

• Androstenedione: levels >10.0 nmol/L warrant investigation for adrenal or ovarian neoplasms; often elevated in PCOS even when testosterone is normal. 1, 5

• Sex hormone-binding globulin (SHBG): low levels increase bioavailable testosterone and correlate negatively with hirsutism score. 5

Additional Testing Based on Clinical Context

• Mid-luteal progesterone (if cycles present): <6 nmol/L indicates anovulation seen in PCOS or hypothalamic amenorrhea. 1

• Fasting glucose and insulin: glucose >7.8 mmol/L suggests diabetes; glucose/insulin ratio >4 indicates insulin resistance. 1

• 17-OH progesterone: if DHEA-S elevated, screen for non-classical congenital adrenal hyperplasia (accounts for 1.8% of cases). 1

Diagnostic Algorithm

If LH/FSH Ratio >2 and Elevated Androgens (Free Testosterone, DHEA-S, or Androstenedione)

Diagnosis: PCOS (accounts for 51% of anovulatory oligomenorrhea in reproductive-age women). 7

• PCOS in adolescents requires hyperandrogenism (clinical or biochemical) plus persistent oligomenorrhea (>6 months). 2

• Do not order pelvic ultrasound if gynecologic age <8 years post-menarche because multi-follicular ovaries are normal in this developmental stage and lead to false-positive PCOS diagnoses. 4

If LH/FSH Ratio <1, Low Estradiol (<30 pg/mL), and Thin Endometrium (<5 mm)

Diagnosis: Functional Hypothalamic Amenorrhea (accounts for 20-35% of secondary amenorrhea). 4

• Triggered by low energy availability, excessive exercise, eating disorders, or psychological stress. 4

• Hirsutism in FHA may reflect adrenal androgen excess (elevated DHEA-S) rather than ovarian hyperandrogenism. 3, 6

If Normal Hormones but Persistent Hirsutism and Acne

Diagnosis: Idiopathic hyperandrogenism or peripheral androgen sensitivity. 2, 3

• Free testosterone and DHEA-S may be the only elevated androgens. 3, 6

• Skin sensitivity to normal androgen levels can produce hirsutism without systemic hyperandrogenism. 5

Management Strategy

For PCOS

• Combined oral contraceptives (ethinylestradiol plus progestin): suppress ovarian androgen production and increase SHBG, reducing free testosterone. 2, 7

• Metformin: if insulin resistance present (glucose/insulin ratio >4 or acanthosis nigricans). 1

• Topical acne therapy: benzoyl peroxide with topical retinoid (adapalene) as first-line; avoid topical antibiotics as monotherapy due to resistance risk. 2

• Lifestyle modification: weight loss of 5-10% improves insulin sensitivity and androgen levels in overweight adolescents. 1

For Functional Hypothalamic Amenorrhea

• Increase caloric intake to achieve >30 kcal/kg fat-free mass/day as primary therapy. 4

• Reduce exercise volume if >10 hours/week of intense training. 4

• Nutritional counseling by sports dietitian experienced with energy availability assessment. 4

• If amenorrhea persists >6 months despite addressing stressors: initiate transdermal estradiol 100 µg patch twice weekly with cyclic micronized progesterone 200 mg for 12 days/month (not oral contraceptives, which provide supraphysiologic doses and inferior bone protection). 4

• Obtain DXA scan for bone mineral density if amenorrhea extends beyond 6 months, as 90% of peak bone mass is attained by age 18. 4

For Acne Management (Regardless of Etiology)

• Topical retinoid (adapalene) plus benzoyl peroxide: addresses comedonal and inflammatory acne. 2

• Oral antibiotics (doxycycline or minocycline) for moderate-to-severe inflammatory acne, always combined with benzoyl peroxide to prevent bacterial resistance. 2

• Avoid isotretinoin in this setting because it can paradoxically worsen hirsutism and menstrual irregularity by altering adrenal hormone levels and decreasing SHBG. 8

Critical Pitfalls to Avoid

• Do not rely on total testosterone alone: free testosterone, DHEA-S, and androstenedione are frequently elevated when total testosterone is normal in adolescent hyperandrogenism. 3, 5, 6

• Do not order pelvic ultrasound in early post-menarchal adolescents (<8 years gynecologic age) because polycystic ovarian morphology is present in 17-22% of normal adolescents. 4

• Do not assume amenorrhea in athletes or stressed adolescents is benign: other pathology must be excluded even when clinical picture suggests FHA. 4

• Do not overlook eating disorders: adolescents frequently minimize or deny disordered eating behaviors; ask specific questions about restrictive eating, purging, and body image. 1, 4

• Do not prescribe oral contraceptives as first-line for FHA: this masks the problem without addressing underlying energy deficit and provides false reassurance. 4

• Do not delay bone density assessment: DXA scanning is indicated regardless of age if amenorrhea extends beyond 6 months. 4

Referral Indications

• Refer to endocrinology if: prolactin >100 µg/L, total testosterone >5 nmol/L (suggests tumor), rapid virilization, or persistently abnormal hormones despite treatment. 1

• Refer to gynecology if: structural abnormalities on imaging, persistent oligomenorrhea >6 months despite initial management, or infertility concerns. 7

• Refer to eating disorder team if: significant weight loss, BMI <18.5 kg/m², or positive screening for disordered eating. 4