Overview
Definition:
Hyperandrogenism in children refers to a state of excessive androgen production or action, leading to virilization and other symptoms
Investigations often focus on 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone sulfate (DHEAS) to identify specific etiologies.
Epidemiology:
Prevalence varies by etiology
congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most common genetic cause of hyperandrogenism
Polycystic ovary syndrome (PCOS) is the most common cause in adolescent girls, though less common in prepubertal children.
Clinical Significance:
Accurate workup is crucial for timely diagnosis and management of conditions like CAH, which can be life-threatening if untreated
It also helps in differentiating other causes of precocious puberty and virilization, impacting growth, fertility, and psychological well-being.
Clinical Presentation
Symptoms:
In prepubertal children: Premature adrenarche or pubarche
Clitoromegaly
Acne
Hirsutism
Advanced bone age
Growth spurt acceleration
In adolescent females: Irregular menses
Hirsutism
Acne
Polycystic ovaries on ultrasound
In males: Premature pubarche
Androgenic effects may be less apparent due to endogenous production.
Signs:
Clitoromegaly
Hirsutism (Ferriman-Gallwey score > 8)
Acne
Androgenic alopecia
Deepening of voice
Increased muscle mass
Advanced bone age
Palpable masses (rare, suggest tumor).
Diagnostic Criteria:
No single criterion exists
diagnosis relies on clinical suspicion, hormonal assays, and exclusion of other causes
Elevated androgen levels, particularly 17-OHP or DHEAS, in conjunction with clinical signs of virilization prompt further investigation.
Diagnostic Approach
History Taking:
Detailed birth history (congenital anomalies, maternal virilization)
Age of onset of pubertal signs
Menstrual history in adolescents
Family history of endocrine disorders or infertility
Medications
Symptoms of adrenal insufficiency (salt-wasting crises).
Physical Examination:
Assess Tanner staging for pubic hair and genitalia
Measure height and weight
Assess for clitoromegaly, hirsutism (Ferriman-Gallwey score), acne, alopecia, voice changes, and muscle development
Palpate abdomen for masses
Assess for signs of Cushing's syndrome or hypothyroidism.
Investigations:
Initial screening: Total testosterone (elevated in most androgen excess states)
17-hydroxyprogesterone (17-OHP): Basal 17-OHP is essential for CAH screening, especially in neonates or children with signs of virilization
A morning fasting sample is preferred
Levels >200 ng/dL (6 nmol/L) are suggestive of 21-hydroxylase deficiency, especially non-classical forms
Levels >1000 ng/dL (30 nmol/L) strongly suggest classical CAH
DHEAS: A marker of adrenal androgen production
Elevated in adrenal hyperplasia and adrenal tumors
Levels >7 µg/mL (15 µmol/L) in prepubertal children or >10 µg/mL (25 µmol/L) in adolescents suggest adrenal source
Other tests: ACTH stimulation test (confirms 21-hydroxylase deficiency if 17-OHP response is exaggerated)
Androstenedione, FSH, LH, prolactin, TSH, cortisol
Imaging: Pelvic ultrasound (PCOS, ovarian tumors), adrenal CT/MRI (adrenal tumors).
Differential Diagnosis:
Congenital adrenal hyperplasia (21-hydroxylase deficiency, 11β-hydroxylase deficiency, 3β-hydroxysteroid dehydrogenase deficiency)
Polycystic ovary syndrome (PCOS)
Premature adrenarche
Idiopathic hirsutism
Androgen-secreting tumors (ovarian or adrenal)
Cushing's syndrome
Exogenous androgen intake
Peripheral conversion of androgens.
Management
Initial Management:
For suspected CAH, especially salt-wasting forms, immediate stabilization with hydrocortisone and fludrocortisone is critical
For other causes, management is directed at the underlying etiology.
Medical Management:
For confirmed CAH: Glucocorticoids (hydrocortisone: 10-20 mg/m²/day divided into 3 doses
or dexamethasone in severe cases) to suppress ACTH and adrenal androgen production
Mineralocorticoids (fludrocortisone: 0.05-0.1 mg/day) for salt-wasting forms
Anti-androgens (spironolactone, cyproterone acetate) may be used in adolescents with PCOS or non-classical CAH if symptomatic despite glucocorticoids
Metformin may be used for insulin resistance in PCOS.
Surgical Management:
Surgical intervention is indicated for androgen-secreting tumors
Varies from adrenalectomy to ovarian tumor resection.
Supportive Care:
Psychological support for children and families regarding body image changes and long-term management
Nutritional counseling
Monitoring for growth, bone age, and pubertal progression
Regular follow-up with an endocrinologist.
Complications
Early Complications:
Adrenal crisis (especially in salt-wasting CAH)
Dehydration
Electrolyte imbalances
Failure to thrive.
Late Complications:
Infertility
Menstrual irregularities
Hirsutism and acne (persistent)
Osteoporosis
Psychological distress
Cushingoid features with excessive steroid therapy
Short stature (if bone age advances too rapidly).
Prevention Strategies:
Adequate and timely glucocorticoid and mineralocorticoid replacement in CAH
Careful monitoring of steroid doses to avoid over- or under-treatment
Early diagnosis and management of PCOS or other androgen excess conditions
Regular monitoring of bone age and growth velocity.
Prognosis
Factors Affecting Prognosis:
Genotype and phenotype of CAH
Age at diagnosis
Adherence to treatment
Presence of adrenal tumors
Management of associated conditions like PCOS.
Outcomes:
With appropriate treatment, classical CAH can be managed to prevent adrenal crises and allow near-normal growth and development
Fertility rates can be good
Non-classical CAH symptoms often improve with treatment
Prognosis for virilization and reproductive health depends on the underlying cause and management effectiveness.
Follow Up:
Lifelong follow-up is generally required for CAH
Regular monitoring of hormonal levels, growth, bone age, and clinical signs of hyperandrogenism is essential
Adolescents require careful transition to adult endocrine care.
Key Points
Exam Focus:
17-OHP is the primary screening test for 21-hydroxylase deficiency CAH
DHEAS is a marker of adrenal androgen excess
Elevated 17-OHP in neonates can also be due to transient neonatal hyperprolactinemia or stress
Non-classical CAH often presents with milder symptoms and later onset
Differentiate between adrenal and ovarian sources of hyperandrogenism based on hormone profiles and imaging.
Clinical Pearls:
Always consider CAH in any child with significant virilization, regardless of age
Perform basal 17-OHP early in the morning
If 17-OHP is borderline, an ACTH stimulation test is confirmatory
Remember that normal testosterone can mask significant androgen excess from other sources.
Common Mistakes:
Delayed diagnosis of CAH, especially salt-wasting forms
Misinterpreting borderline 17-OHP levels without confirmatory testing
Inadequate glucocorticoid or mineralocorticoid replacement in CAH
Failing to investigate for androgen-secreting tumors in cases of rapid or severe virilization.