Clomiphene Citrate

Clomiphene may offer alternative for treating low testosterone

Data show long-term use is associated with sustained symptom improvement

Evidence continues to accumulate that clomiphene citrate (Clomid), approved in the U.S. for the treatment of ovulatory dysfunction in women, may be an effective therapeutic option for men with hypogonadism.

The most recent studies of the effects of the agent in older men were presented at the 2010 AUA annual meeting in San Francisco by Darren Katz, MD, a former urology research fellow at Memorial Sloan-Kettering Cancer Center in New York who is now the urology registrar at the Monash Medical Center, Melbourne, Australia.

"The take-home is that clomiphene citrate may provide an efficacious alternative to testosterone," Dr. Katz told Urology Times. "It can be used in older men and it can be used long term. It is a well-tolerated drug."

Dr. Katz rests his conclusions on data from two studies on which he served as first author. One study looked at the agent in older men, and the other examined the long-term efficacy of the agent in men, more than half of whom were followed to 36 months.

Clomiphene is finding increased use as a therapy for younger men due to the absence of concerns about testicular atrophy, said Dr. Katz, who worked on the study with John P. Mulhall, MD, and colleagues.

The Sloan-Kettering team decided to look at the effects of the drug in an older cohort of 96 men aged 50 to 70 years (mean, 61.7) with documented hypogonadism. Significant percentages of the cohort presented with co-morbidities. More than one-third (36%) had hypertension, 14% had diabetes, and 39% had dyslipidemia. At baseline, 74 (77%) of the men had abnormal bone density.

Comorbidities influence response.

Dr. Katz noted that the number of comorbidities, along with age and luteinizing hormone (LH) levels, were factors influencing response to clomiphene. Younger men, men with low baseline LH levels, and those with fewer comorbidities were more likely to achieve testosterone levels ≥400 ng/dL.

The agent was initially administered at 25 mg every other day and titrated to 50 mg every other day if required. Those patients showing inadequate responses to the 50-mg dose were switched to testosterone supplementation.

Administration of clomiphene brought testosterone levels to >400 ng/dL in 76% of the cohort after a mean follow-up of 26 months.

The percentage of men with abnormal bone density dropped from 77% of the cohort to 56%. Scores on the Androgen Deficiency in Aging Males (ADAM) test dropped from 7..5 to 4.3.

"The ADAM scores showed a significant subjective improvement. About half the patients improved in three of the ADAM symptom domains," Dr. Katz said. The ADAM questionnaire presents subjects with 10 symptom-based questions. A score of 0 to 1 would represent the fewest symptoms.

Long-term advantages, disadvantages

The long-term effects of clomiphene were identified in the second study, which followed 46 men for 12 months, 37 men for 24 months, and 29 for 36 months. The men in this study were younger (mean age, 44-18 years). Benefits seen at 36 months included a continuing improvement in both testosterone levels and bone density, and sustained elevations of LH that continued throughout the trial. In addition, there was a significant increase in estradiol, from 37.16 pg/mL at baseline to 50.30 pg/mL at 36 months. By controlling this we can keep estradiol in check using anastrozole and thereby eliminate this concern.

ADAM scores improved from 7.2 at baseline to 3.2 at 12 months before rising and stabilizing at 52.5 at 24 months. The drug was well tolerated, with no men ceasing the drug due to side effects.