What is hyperandrogenism in a female of reproductive age?

Hyperandrogenism in Reproductive-Age Females

Hyperandrogenism is a clinical and biochemical condition characterized by excessive androgen (male sex hormone) levels in women, manifesting as hirsutism, acne, androgenic alopecia, menstrual irregularities, and in severe cases, virilization. 1, 2

Definition and Core Pathophysiology

Hyperandrogenism represents excessive levels of androgens either systemically or in peripheral tissues, affecting 5-10% of reproductive-age women. 3 The condition arises from:

• Ovarian overproduction of androgens, driven by accelerated GnRH pulsatility causing excessive LH secretion, which stimulates ovarian theca cells to overproduce testosterone while FSH-granulosa cell function becomes impaired. 4
• Peripheral androgen metabolism, where testosterone converts to the more potent dihydrotestosterone (DHT) via 5α-reductase enzyme in target tissues like skin and hair follicles. 5
• Metabolic amplification, particularly through hyperinsulinemia, which directly stimulates ovarian androgen production and suppresses sex hormone-binding globulin (SHBG), increasing free testosterone levels. 4

Clinical Manifestations

Cutaneous and Hair Changes

• Hirsutism (excessive terminal hair growth in male-pattern distribution) is the most common clinical diagnostic criterion, present in up to 80% of hyperandrogenic women, assessed using standardized scoring systems. 1, 3
• Acne, particularly persistent or severe forms resistant to standard dermatologic treatments. 1
• Androgenic alopecia (male-pattern hair loss), which may occur with or without hirsutism. 1, 3
• Clitoromegaly indicates more severe androgen excess. 1

Reproductive and Metabolic Signs

• Oligomenorrhea or amenorrhea (infrequent or absent menstrual periods). 1
• Infertility or difficulty conceiving. 1
• Acanthosis nigricans (dark, velvety skin patches indicating insulin resistance). 1
• Truncal obesity with central weight distribution. 1

Virilization Features

Virilization is uncommon and suggests androgen-secreting tumors, including: 2, 3

• Deepening of voice. 1
• Increased muscle mass. 2
• Severe clitoral enlargement. 2

Diagnostic Approach

First-Line Laboratory Testing

Total testosterone (TT) and free testosterone (FT) measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) are the first-line tests for diagnosing biochemical hyperandrogenism. 6, 1

• TT sensitivity: 74%, specificity: 86%. 6
• FT sensitivity: 89%, specificity: 83%. 6
• Timing matters: Measure testosterone in the morning due to diurnal variation. 1
• Free testosterone should be assessed by equilibrium dialysis, ammonium sulfate precipitation, or calculated using free androgen index (FAI = TT/SHBG ratio) when LC-MS/MS is unavailable. 6, 1

Second-Line Testing

If TT or FT are not elevated but clinical suspicion remains high: 6, 1

• Androstenedione (A4): sensitivity 75%, specificity 71%. 6
• DHEAS: sensitivity 75%, specificity 67%. 6
• Note: These have poorer specificity than testosterone measurements. 6

Additional Screening Tests

• TSH to exclude thyroid disease. 1
• Prolactin to rule out hyperprolactinemia. 1
• Fasting glucose and 2-hour oral glucose tolerance test for diabetes/insulin resistance screening. 1
• Fasting lipid panel for cardiovascular risk assessment. 1

Common Causes

Polycystic Ovary Syndrome (PCOS)

PCOS accounts for 95% of hyperandrogenism cases, affecting 10-13% of women globally. 1 Hyperandrogenism is present in 75% of PCOS cases and serves as both a diagnostic criterion and central pathogenic driver. 6, 4

Other Causes to Exclude

• Nonclassic congenital adrenal hyperplasia. 1
• Cushing's syndrome. 1, 2
• Androgen-secreting tumors (ovarian or adrenal), particularly if testosterone levels are very high (>150-200 ng/dL) or symptoms develop rapidly. 1
• Hyperprolactinemia. 1
• Exogenous androgen use (medications or supplements). 1

Critical Clinical Caveats

Rapid-onset or severe virilization demands immediate aggressive workup for androgen-secreting tumors rather than PCOS. 4, 2, 3 Key red flags include:

• Markedly elevated DHEAS (>600 μg/dL) suggesting adrenal source. 1
• Very high total testosterone levels. 1
• Rapid symptom progression. 4

Avoid direct immunoassay methods for free testosterone due to poor accuracy at low serum concentrations; LC-MS/MS is superior for all androgen measurements. 6, 1

SHBG fluctuations (affected by age, weight, oral contraceptives) can influence TT and FAI results, making free testosterone assessment critical. 6, 1

Weight gain is a major trigger for PCOS development and worsening hyperandrogenism in genetically susceptible women. 4