SUN-130 - Hypogonadism Due to 5 Alpha Reductase Overexpression

Introduction:
Disorders of androgen metabolism may cause discordant androgen profiles and refractory hypogonadal symptoms despite testosterone replacement. Excessive conversion of testosterone to dihydrotestosterone (DHT) due to increased 5-alpha reductase activity is an uncommon and under recognized mechanism. We report a case illustrating this phenotype and its clinical implications.

Case:
A 66-year-old man with hypogonadism, erectile dysfunction, benign prostatic hyperplasia (BPH), and premature androgenic alopecia presented with persistent symptoms despite androgen replacement therapy. His family history showed premature scalp balding in both his father and brother, both before age 40. Testosterone therapy was complicated by erythrocytosis (hematocrit 55%, hemoglobin 18 g/dL), requiring a switch from injectable to transdermal testosterone due to cardiovascular concerns. Serum testosterone fluctuated between 181 ng/dL and 235 ng/dL while on androgen repletion, but DHT (dihydrotestosterone) concentrations were markedly elevated on repeated measures (peak; 2206.5 pg/mL normal range; 106-719),. Estradiol was also elevated at 83.9 pg/mL (10-42). PSA levels were normal. Both Inhibin B (44 pg/mL), and inhibin A ( < 1 pg/mL) levels were normal suggesting preserved Sertoli cell function. Genetic testing identified multiple X-linked polymorphisms associated with premature androgenic alopecia, as well as variants of unknown significance in FGFR4, ATM, and MTHFR genes. Finasteride 5 mg daily was initiated and post initiation, DHT normalized (628.4) with concomitant normalization of serum testosterone (494-740ng/dl) on topical androgen replacement. The patient’s clinical phenotype suggests excessive peripheral androgen conversion, likely due to increased 5-alpha reductase activity.

Discussion:
This case demonstrates functional hypogonadism driven by disproportionate DHT excess despite testosterone replacement, consistent with pathologic 5-alpha reductase overactivity. Excessive peripheral androgen conversion may reduce effective circulating testosterone while promoting prostate-mediated morbidity and sexual dysfunction. The profound elevation of DHT relative to testosterone, combined with a strong familial and genetic predisposition, underscores a heritable component influencing androgen metabolism. Recognition of this mechanism is critical, as escalating testosterone doses alone may worsen adverse effects. Combined androgen replacement with 5-alpha reductase inhibition may represent a rational therapeutic strategy in select patients with discordant androgen profiles.

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