Androgen Receptor Dysfunction (Answer: A)
The most likely cause of this patient's condition is androgen receptor dysfunction (partial androgen insensitivity syndrome), which classically presents with gynecomastia, sparse body hair, elevated testosterone, elevated LH, normal FSH, and severe oligospermia. 1, 2
Clinical Reasoning and Hormone Pattern Analysis
This patient's hormone profile is pathognomonic for androgen resistance:
- High testosterone with high LH indicates the pituitary is appropriately responding to perceived androgen deficiency by increasing LH secretion, which drives Leydig cells to produce more testosterone 1, 2
- Normal FSH distinguishes this from primary seminiferous tubule damage, where FSH would be markedly elevated (typically >7.6 IU/L and often much higher) 3
- The combination of elevated testosterone, elevated LH, and normal FSH is the classical hormonal signature of partial androgen insensitivity syndrome (PAIS) 1, 2
Why Other Options Are Incorrect
Damage to Seminiferous Tubules (Option B)
- Primary seminiferous tubule damage presents with elevated FSH (typically >7.6 IU/L), often with testicular atrophy and low-normal testosterone 3
- The normal FSH in this patient excludes significant primary seminiferous tubule dysfunction 3
- While severe oligospermia is present, the hormone pattern does not support this diagnosis 3
Ejaculatory Duct Obstruction (Option C)
- Obstructive azoospermia presents with normal FSH, normal testicular size, and normal testosterone levels 3
- Patients typically have low ejaculate volume (<1.5 mL) and acidic semen pH 3
- The presence of gynecomastia, sparse body hair, and elevated LH exclude this diagnosis 3
Exogenous Androgen Use (Option D)
- Exogenous testosterone causes suppression of both LH and FSH through negative feedback on the hypothalamus and pituitary 3, 4
- This patient has elevated LH, which is incompatible with exogenous androgen use 3
- Exogenous testosterone would not cause gynecomastia in the setting of high testosterone unless aromatization is excessive, but the elevated LH excludes this 3
Impaired Leydig Cell Function (Option E)
- Primary Leydig cell failure presents with low testosterone, elevated LH, and elevated FSH 3
- This patient has high testosterone, indicating intact Leydig cell function with appropriate response to elevated LH 1, 2
Pathophysiology of Androgen Receptor Dysfunction
In PAIS, mutations in the androgen receptor gene prevent normal androgen signaling despite adequate or elevated testosterone levels 1, 2:
- The hypothalamus and pituitary sense inadequate androgen effect and increase LH secretion 1, 2
- Leydig cells respond normally to LH, producing supranormal testosterone levels 1, 2, 5
- FSH remains relatively normal because Sertoli cell function is less dependent on androgen signaling 1
- Gynecomastia develops due to the imbalance between ineffective androgen action and normal or elevated estrogen (from aromatization of high testosterone) 1, 6, 2
- Severe oligospermia occurs because spermatogenesis requires normal androgen receptor function within the testes 2, 5
Clinical Confirmation and Management
Genetic testing for androgen receptor gene mutations confirms the diagnosis, though mutations are found in less than one-third of PAIS cases 2:
- Novel mutations continue to be identified, including thermolabile receptor variants 5
- Some affected men retain fertility despite androgen resistance, though severe oligospermia is common 5
- Gynecomastia due to PAIS will not resolve spontaneously and surgery for breast reduction should be recommended 1
Critical Diagnostic Pitfall
The key distinguishing feature is the combination of high testosterone with high LH—this pattern immediately suggests androgen resistance rather than primary gonadal failure or hypothalamic-pituitary dysfunction 1, 2. Normal FSH further supports preserved Sertoli cell function despite impaired spermatogenesis from androgen receptor dysfunction 1.