Low baseline FSH predicts successful clomiphene Tx

March 1, 2009

Researchers are trying to identify which oligospermic men will respond to the drug clomiphene citrate.

San Francisco-Clomiphene citrate (Clomid, Milophene, Serophene) has been shown to improve semen parameters in some men, but it has not been clear which subgroups of infertile men are most likely to benefit. New research appears to point to one important predictor of response to the drug.

Clomiphene is indicated for the treatment of ovulatory dysfunction in women desiring pregnancy, and it is widely used off-label as empiric therapy to treat men with idiopathic oligospermia to enhance semen parameters and improve the likelihood of pregnancy.

"If you know someone is not going to be a responder, you can counsel the couple to move on to some other assisted reproductive technology and save them some time, money, and the potential side effects of therapy," said Adam Nicholson, MD, a urology resident at the University of Minnesota, Minneapolis, working with Antoine A. Makhlouf, MD, PhD.

Dr. Nicholson and colleagues conducted a retrospective chart review from 2003 to 2008 and found 32 men with idiopathic oligospermia who had been treated with clomiphene by UM urologists. They located and abstracted data on pre- and post-treatment semen parameters, follicle stimulating hormone (FSH) levels, and testosterone levels. Results of the study were presented at the American Society of Reproductive Medicine annual meeting.

The patient population was representative of idiopathic oligospermia, Dr. Nicholson said. Mean age of these men was 35 years; mean FSH, 4.7 IU/L; mean testosterone, 287.1 ng/dL. Semen parameters were somewhat better than expected in this population, he noted, because an outlier pushed the mean sperm concentration to 24.4. Excluding the outlier gave a concentration of about 10. Other semen parameters, including volume, total count, motility, and morphology were poor, as would be expected in men with low sperm counts.

Chart review indicated that the men were given clomiphene, 12.5 mg daily, which was increased to 25 mg or 50 mg daily as needed to boost testosterone into the normal range of 400 to 500 ng/dL. Therapy was then continued for 4 months, at which time a semen analysis was obtained to determine whether the patient had responded to treatment.

"Our endpoint was a change in sperm count," Dr. Nicholson said. "Anyone who improved by 50% or more, we counted as a responder in this analysis."

The review did not include data on pregnancy outcomes among couples in which the man had been treated with clomiphene.

Drug therapy produced significant increases in FSH, testosterone, and a positive, but not statistically significant trend toward improved sperm concentration and motility, Dr. Nicholson said. Ten of the 32 patients (31%) responded with a greater than 50% increase in sperm concentration. Binary logistic regression modeling showed that baseline FSH and testosterone levels were the best predictors for response. All but one of the responders had baseline FSH levels below 5.5 and testosterone levels below 350, but low baseline FSH emerged as the only statistically significant predictor of response (p=.038).

"Lower FSH was the real predictor of who would respond," Dr. Nicholson said. "If testosterone was suboptimal, but FSH was higher than 5.5, the man was not likely to respond and the couple should be counseled accordingly."

The rate of increase in FSH or testosterone level during clomiphene treatment and the final values of the two hormones were not at all predictive of response, he added.

Dr. Nicholson said the numbers are small and retrospective data lack the predictive power of randomized, prospective trials.

"We would be happier if we could see hundreds of patients in this kind of analysis, rather than tens of patients," he said. "But randomized, controlled trials are always going to be difficult in this population. Offering a couple who desperately want to have a baby the chance to take a placebo is really not a very attractive option."