Testosterone Versus Clomiphene Treatment of Hypogonadism: A Retrospective Analysis in US Veterans

Male hypogonadotropic hypogonadism is a complex condition with a multifactorial etiology. Although testosterone replacement therapy (TRT) is the only approved treatment for male hypogonadism, clomiphene citrate (CC) is often used as an off-label treatment.

The present study was conducted to objectively compare clinical outcomes, including adverse effects in patients receiving clomiphene citrate and testosterone replacement therapy.

This is a retrospective study of data collected through the Veterans Administration Informatics and Computing Infrastructure. We identified 364,976 patients with hypogonadisma or infertility. After one-to-one propensity matching, we identified 2518 individuals in both clomiphene citrate and testosterone replacement therapy treatment groups. Outcomes included new diagnoses of fractures, osteoporosis, polycythemia, thrombosis, hypertension, pulmonary embolism, coronary artery disease, and cerebrovascular accidents, which were evaluated relative to the two treatments. Survival was plotted for both treatments and analyzed by Kaplan‒Meier statistics.

The incidence of various complications was significantly lower after clomiphene citrate relative to testosterone replacement therapy treatment, including new-onset hypertension (6.04% vs. 10.48%), cerebrovascular accident (0.52% vs. 1.43%), coronary artery disease (1.51% vs. 2.26%), polycythemia (1.07% vs. 2.22%), and osteoporosis (1.15% vs. 2.07%). All-cause mortality was also significantly lower in the clomiphene citrate group (1.83%) relative to testosterone replacement therapy group (10.13%). CC increased testosterone levels relative to baseline in a physiological manner.

TRT was associated with increased mortality relative to CC. Rates of stroke, coronary artery disease, hypertension, osteoporosis, and polycythemia were also greater in patients receiving TRT. Our results also indicate that CC increased testosterone levels relative to baseline in a physiological manner.