SAT-175 - When Low Testosterone Is Not Hypogonadism: A Case of Markedly Reduced SHBG in A Young Man

Background
Interpretation of testosterone levels can be challenging in the setting of altered sex hormone - binding globulin (SHBG). Markedly low SHBG may lead to spuriously low total and calculated free testosterone levels, potentially resulting in misdiagnosis of hypogonadism and inappropriate testosterone therapy. Direct measurement of free testosterone is essential in such cases.

Case Presentation
A 23-year-old male with no significant past medical history was referred for evaluation of low testosterone after presenting with fatigue, weight gain and gynecomastia. Physical examination was significant for absence of firm, rubbery glandular tissue under the areola. Initial laboratory evaluation demonstrated persistently low total testosterone (130–209 ng/dL; reference 175–781 ng/dL), low calculated free testosterone (3.5–5.8 ng/dL; reference 4.9–19.0 ng/dL), and markedly reduced SHBG (9.5–10.5 nmol/L; reference 13.3–89.5 nmol/L). An extensive endocrine workup revealed normal luteinizing hormone, follicle-stimulating hormone, estradiol, prolactin, ferritin, thyroid-stimulating hormone, insulin-like growth factor-1, and human chorionic gonadotropin levels.
Despite biochemical findings suggestive of hypogonadism, the patient had normal libido, preserved virilization, normal erectile function, absence of testicular atrophy, and no history of delayed puberty. Given the discordance between laboratory results and clinical findings, total and free testosterone were re-measured using equilibrium dialysis, which demonstrated normal androgen levels.
These findings confirmed preserved biologically active testosterone, indicating that low total and calculated free testosterone values were attributable to markedly reduced SHBG rather than true gonadal dysfunction.
The patient was diagnosed with pseudohypogonadism due to low SHBG and did not require testosterone therapy. Evaluation for contributory conditions revealed overweight status with hypertriglyceridemia but no insulin resistance. Workup for gynecomastia and obstructive sleep apnea was ongoing, and referral for genetic testing for a pathogenic SHBG variant was initiated.

Conclusion
This case highlights a critical diagnostic pitfall in the evaluation of male hypogonadism. In patients with markedly low SHBG, total and calculated free testosterone measurements may be misleading. Direct assessment of free testosterone using equilibrium dialysis is essential to avoid misdiagnosis and inappropriate testosterone therapy. Clinicians should interpret testosterone levels within the broader clinical and biochemical context, particularly in young patients with preserved androgenic features.

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