Genetic SHBG Deficiency Unmasks the Discrepancy Between Biochemical and Clinical Hypogonadism

Near-absent serum SHBG influences calculated free testosterone, complicating the evaluation of suspected hypogonadism. We report a 50-year-old man with longstanding low total testosterone (147.1 ng/dL [SI: 5.1 nmol/L], reference range: 289-866 ng/dL [SI: 10.0-30.0 nmol/L]). Further laboratory testing revealed a suppressed SHBG of 2 nmol/L (reference range: 14-72 nmol/L) and remarkably normal calculated free testosterone (between 5.0 and 6.0 ng/dL [SI: 0.174-0.210 nmol/L], reference range: 4.9-15.7 ng/dL [SI: 0.160-0.700 nmol/L]). Direct equilibrium-dialysis measurement, however, revealed low free testosterone (2.9 ng/dL [SI: 0.099 nmol/L], reference range: 4.9-15.8 ng/dL [SI: 0.170-0.546 nmol/L]), establishing the diagnosis of biochemical hypogonadism. Genetic analysis demonstrated compound heterozygosity for the SHBG variants c.554C > T (p.Pro185Leu), which impairs steroid binding and increases clearance, and c.670G > A (p.Gly224Arg), which prevents secretion. This double hit explains the paradox of marked biochemical abnormalities in the absence of clinical hypogonadism. The case underscores not only the limitations of calculated, and even directly measured, free testosterone when SHBG is profoundly low but also the importance of integrating genetic analysis and clinical context into the diagnostic process. This case suggests that in rare cases of genetic SHBG deficiency, male reproductive function may remain intact despite profoundly low circulating SHBG levels. Clinicians should recognize that SHBG genetic variants may cause aberrant biochemical findings that mimic hypogonadism, which should be included in the differential diagnosis when evaluating patients with unexplained hormonal abnormalities.