June 22, 2009 — The selective serotonin-reuptake inhibitor (SSRI) paroxetine (Paxil, GlaxoSmithKline) may affect male fertility through its effects on sperm DNA, according to a small study by Weill Cornell Medical Center researchers. In the study of 35 healthy volunteers without psychiatric disorders, the antidepressant induced abnormal sperm DNA fragmentation in more than 40% of participants.
"Sperm DNA fragmentation is thought to be a very sensitive measure of sperm abnormality, independent of sperm counts or standard sperm tests, and predicts natural fertility as well as fertility with the most advanced forms of assisted reproduction, such as in vitro fertilization," said senior author Peter Schlegel, MD, chair of the department of urology and professor of reproductive medicine at Weill Cornell Medical Center, in New York City. "What the study tells us is that paroxetine could have an effect on fertility that will not show up in standard sperm tests — and cause an increase in genetic damage to sperm," he said.
Their report is published June 10 online in Fertility and Sterility.
Dr. Schlegel noted that because the study did not show any changes in the conventional measures of sperm quality — including sperm volume, concentration, motility, and morphology — their paper suggests that men on SSRIs might have a reduced ability to conceive. "A man could have his fertility affected and still could have what look like normal sperm counts," he said. He advises that men on SSRIs who are interested in conceiving talk to their physicians about other treatment options for depression.
Effects Reversed After Withdrawal
In the study, paroxetine was administered to participants for 5 weeks at escalating doses. Semen analyses were performed at the end of weeks 2 and 4 and again a month after stopping the medication. Sperm DNA fragmentation — defined as missing pieces of code in sperm DNA — was measured with an assay called deoxyuride-50-triphosphate biotin nick end labeling (TUNEL). The men also completed the Brief Sexual Function inventory test at baseline and after the fourth week. Hormonal status, including testosterone levels, was also evaluated in the fourth week after the subjects initiated antidepressant therapy.
In addition to problems in sperm DNA fragmentation, the men also experienced significant sexual dysfunction. At baseline, only 9.7% of patients had a TUNEL score of 30% or less, a cutoff point thought to signal abnormal DNA in sperm. At week 4, however, 50% of patients had a TUNEL score of 30% or less (P = .001). Up to 35% of men in the study also experienced worsening erectile function after starting antidepressant therapy (P < .003), and 47% reported significant declines in ejaculatory function (P < .002). However, normal sexual function as well as normal sperm DNA fragmentation returned 1 month after paroxetine was discontinued.
There was also a significant 28% decrease in testosterone levels in men who took paroxetine (844 ng/dL vs 605 ng/dL; P = .015), although the decreased values remained in the normal range. In healthy men, this decline in serum testosterone levels would have little effect, but for men with compromised fertility, this decline could have negative effects on sperm-cell development, the authors write in their paper.
Coauthor and researcher Cigdem Tanrikut, MD, acknowledged that the study had several limitations. The men were not blinded to the fact that they were taking antidepressants, nor was there any placebo group. Fertility itself was not directly assessed in the study. "Yet the marked changes in sperm DNA integrity strongly suggest a potential negative impact on fertility," said Dr. Tanrikut, adjunct assistant professor of urology and reproductive medicine at Weill Cornell Medical College. In addition, the use of normal healthy volunteers eliminated the chance that the DNA damage — or the sexual dysfunction associated with the antidepressant — might have been caused by comorbid depression or anxiety.
Because sperm DNA returned to normal so quickly, the study suggests that SSRIs may cause problems in sperm transport, rather than production. "If the [DNA] changes were mediated by an effect on sperm production, those changes would have taken months to be reflected in semen analyses," Dr. Tanrikut said. Dr. Schlegel also noted that sperm transmission as well as ejaculation occurs through nerves that can be mediated by serotonin. "Serotonin drives how these nerves work," he said.
Findings "Not Robust"
The authors plan larger-scale randomized placebo-controlled trials with other SSRIs — research that may be necessary to confirm their findings, according to Richard Balon, MD, professor of psychiatry at Wayne State University in Detroit, Michigan, who specializes in research on sexual dysfunction. "These are interesting findings, but they are not robust," he said. As well as the small size of the study, he noted that tests of conventional semen parameters did not show any effect from paroxetine. He also pointed out that many of the men who had abnormal sperm DNA fragmentation were obese, and although the authors could find no correlation in their statistical analysis, it could have possibly influenced the results, Dr. Balon said.
"There are some interesting findings in the study — including the sexual dysfunction found in healthy volunteers taking SSRIs, as well as the decreases in testosterone levels," he said. "But the findings need follow-up and confirmation," he added.
The study was funded by the Frederick J. and Theresa Dow Wallace Fund of the New York Community Trust and the Brady Urology Foundation. Drs. Tanrikut and Balon reported no relevant financial disclosures. Dr. Schlegel is a member of the medical advisory board for Theralogix.
Fertil Steril.2009: Published online June 10, 2009. Abstract
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Cite this: New Study Shows the SSRI Paroxetine May Affect Sperm DNA and Male Fertility - Medscape - Jun 22, 2009.