Popular selective serotonin reuptake inhibitor may reduce male fertility potential

San Francisco-A recent prospective clinical trial found that the antidepressant paroxetine (Paxil) is associated with a five-fold increase in the risk of abnormal sperm DNA fragmentation as measured by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) score. Standard semen parameters are not affected.

"This is a preliminary study that raises awareness of the problem," said Cigdem Tanrikut, MD, assistant professor of surgery, Massachusetts General Hospital, Harvard Medical School, Boston, and Cornell Institute for Reproductive Medicine, New York. "We need larger-scale studies and randomized, placebo-controlled trials with other agents to further explore these findings."

Major depressive disorders affect about 10% of U.S. men, Dr. Tanrikut reminded the 2008 American Society for Reproductive Medicine annual meeting. Antidepressants are the most common form of therapy, and selective serotonin reuptake inhibitors (SSRIs) such as paroxetine are the most common agents used.

The current study enrolled 35 healthy men between the ages of 19 and 58 years. Two semen analyses and the Brief Sexual Function Inventory (BSFI) were performed before paroxetine dosing began. Men in the study were not taking any other prescription drug products. Volunteers were also eliminated if they were taking any herbal or non-prescription drugs known to affect semen factors or sexual function. All were screened for post-traumatic stress disorder and other mental conditions.

Participants took paroxetine for 5 weeks: 10 mg daily during the first week, 20 mg daily during week 2, 30 mg daily during weeks 3 and 4, and 20 mg daily during week 5. The dosing regimen was designed to minimize withdrawal symptoms, Dr. Tanrikut said.

Repeat semen analyses were done at weeks 2 and 4, then again 1 month after halting paroxetine. BSFI was repeated at week 4 and 1 month after paroxetine was stopped. TUNEL assays were performed on semen samples taken at baseline and at week 4 to evaluate sperm DNA fragmentation. Standard semen parameters included semen volume, sperm concentration, motility, and morphology.

"There were no statistically significant changes in mean values for standard semen parameters," Dr. Tanrikut noted.

Researchers saw no significant changes in endocrine studies of FSH, LH, and prolactin. Testosterone and estradiol levels decreased significantly and TUNEL results showed significant changes.

Mean DNA fragmentation at baseline was 13.8% compared to 30.3% at week 4 (p=.0002). At baseline, 9.7% of men in the study had a TUNEL score ≥30 compared to 50% at week 4 (p=.001). Dr. Tanrikut noted that a TUNEL score of 30 or higher is generally accepted as indicating abnormal sperm DNA fragmentation. Abnormal sperm DNA integrity is associated with a lower likelihood of intrauterine insemination success and may have an adverse effect on in vitro fertilization-intracytoplasmic sperm injection results.

The overall odds ratio of having abnormal DNA fragmentation while taking paroxetine was 9.33 (95% confidence interval: 2.3-37.9). Multivariate analysis that corrected for age and body mass index showed an odds ratio of 11.12 (p=.0003) in favor of abnormal DNA fragmentation while taking paroxetine. Further analyses suggested that higher BMI may have a negative impact on sperm DNA fragmentation, but the association did not reach statistical significance.

"This five-fold increase in sperm DNA fragmentation is troubling," Dr. Tanrikut said. "It suggests an adverse fertility effect. We are planning a randomized, placebo-controlled trial with other SSRIs."

In addition, the study confirmed the association between paroxetine and erectile dysfunction. Researchers had anticipated ED problems with some men in the study, Dr. Tanrikut said. BSFI scores put ED at 35% in this particular population. Further, 47% of men reported ejaculatory difficulties while taking paroxetine.

"The majority of men had a least partial recovery of sexual function within 1 month after halting medication," she reported.