Clomiphene Linked to Lower Mortality Than TRT in Vets With Hypogonadism

A retrospective cohort study links clomiphene citrate (CC) to significantly lower mortality rates when compared with testosterone replacement therapy (TRT) in male veterans with hypogonadism or infertility. CC is not approved by the US Food and Drug Administration (FDA) for hypogonadism but is often used off label. Patients taking clomiphene also had significantly lower risk of diseases of the circulatory system, brain, and bones. 

The study tracked matched cohorts of 2518 patients taking CC or TRT for a mean 3.5 years. All-cause mortality was lower in the CC group (1.83%) than the TRT group (10.13%, P < .001), reported researchers at the Kansas City Veterans Affairs Medical Center and University of Missouri-Kansas City School of Medicine, et al in Andrology.

The researchers also reported that outcomes were better in the CC group than the TRT group for new-onset hypertension (6.04% vs 10.48%, P < .001), cerebrovascular accident (0.52% vs 1.43%, P < .001), coronary artery disease (1.51% vs 2.26%, P < .048), polycythemia (1.07% vs 2.22%, P < .001), and osteoporosis (1.15% vs 2.07%, P = .009), respectively. 

“It seems like clomiphene is a good medication to be used long term, but we still need more investigation into this,” endocrinologist Mariana Garcia-Touza, MD said in an interview with Federal Practitioner. 

TRT is a common therapy for male hypogonadism, although the study notes it is linked to thickened blood, breast growth, infertility, fluid retention, obstructive sleep apnea, and cardiovascular and prostate problems. Guidelines recommend against its use in patients with prostate cancer, at high cardiovascular risk, and those trying to have children.

CC is a selective estrogen receptor modulator and used off-label to treat male hypogonadism because it can boost the production of testosterone. The study notes how many Veterans health Administration patients have low testosterone, with previous research reporting the rate among veterans aged ≥ 60 years at 34%. 

Garcia-Touza was especially interested in any effect clomiphene has on bones: “We’ve been hearing that it probably affects the bone and can cause osteoporosis, but no one has looked into it.”

The study tracked veterans from December 1990 to September 2024; follow-ups lasted up to 34 years. Patient mean ages were 46.5 and 47.5 years for the HRT and CC groups, respectively. Hypogonadism was the treatment indication for 98.4% and 64.5% and infertility was the indication for 1.6% and 35.5% for the HRT and CC groups, respectively. About 70% of both groups were White. 

There were no statistically significant gaps between the groups regarding hip fractures, pulmonary embolism, thrombosis, and vertebral fractures. Garcia-Touza said the all-cause mortality gap the study reported was surprising, although the study did not control for factors that may have differed between the groups.

“This needs to be more carefully examined to see if this is a real finding or if there is some bias in the study that is causing it,” she said.

Moving forward, Garcia-Touza said she hopes to launch a prospective study of TRT vs CC.

Parviz K. Kavoussi, MD, a reproductive urologist at the University of Texas at Austin who was not involved in the study, said in an interview the study’s findings highlight the importance of monitoring patients on TRT for an increase in hematocrit. 

“Not all testosterone replacement therapies are created equal from this standpoint,” he said, noting that risk depends on the delivery method. “There are multiple modalities — topical gels, patches, nasal gels, intramuscular injections, subcutaneous pellets, subcutaneous autoinjector pens, and oral testosterone pills. Each of these has a defined percentage risk of secondary erythrocytosis, with some being significantly higher than others.”

As for other potential risks from TRT such as a possible higher mortality rate, Kavoussi noted that a landmark 2023 trial of middle-aged and older men convinced the FDA to no longer require testosterone products to include a black-box warning about cardiovascular disease. 

Regarding the question of whether clomiphene works as well as testosterone, Kavoussi noted his group’s research has found clomiphene can normalize testosterone levels biochemically. However, “where clomiphene typically falls short in data and in clinical practice is the level of symptomatic improvement in testosterone deficiency symptoms that patients can achieve in comparison to exogenous testosterone replacement.” 

No funding was reported, and the authors – including Garcia-Touza – had no disclosures. Kavoussi discloses relationships with Halozyme and Verity.