Studie: http://www.sciencedirect.com/science/article/pii/S0015028211000161
Finasteride-induced secondary infertility associated with sperm DNA damage (2011)
Case report
A 48-year-old man with no prior medical or urologic history presented for evaluation of secondary infertility of 4 years’ duration. His wife had experienced four consecutive spontaneous abortions (after documented biochemical and/or clinical pregnancy) and to date they did not have a full-term pregnancy or live birth. His wife was 37 years old and had normal menses and a normal exam by her gynecologist.
The patient’s medications included zopiclone (a mild sleeping pill) and finasteride 1 mg for treatment of androgenic hair loss, which he had been taking for many years. The patient was a nonsmoker and consumed one glass of wine per day for many years. He had no history of exposure to hazardous materials, radiation, or heat. There was no history of sexually transmitted diseases or erectile dysfunction. Physical examination was unremarkable, with bilateral testes measuring 18 mL and normal location and firmness. The penis, epididymides, and vas deferens were normal. There were no varicoceles.
Semen analysis done a year before confirmed a normal volume of 1.6 mL, sperm concentration 53 × 106/mL, and motility 58%. The patient had a normal 46,XY karyotype. The sperm DFI was 30% at this time and was unchanged when repeated 2 months later. The patient was advised to stop finasteride. Three months later, the DFI decreased to 21% and subsequent DFI after another 3 months improved to 16.5%.
The Ethics Review Board at our institution approved the study. All information remained confidential.
Result(s)
The sperm DFI done a year earlier was 30%. This value was unchanged when repeated 2 months later. The patient was advised to stop finasteride. Three months after discontinuing the finasteride, the DFI decreased to 21% and subsequent DFI after another 3 months improved to 16.5%. To date, there is still no documented full-term pregnancy or live birth.
Conclusion(s)
The significant reduction in DFI within 3 months of finasteride cessation and continued improvement
suggests a causal link between finasteride and sperm DNA damage. We hypothesize that low-dose finasteride may exert a negative influence on sperm DNA integrity, resulting in increased pregnancy losses. We suggest that in infertile men using finasteride, sperm DFI should be measured in addition to semen parameters, and a trial of discontinuation of finasteride may be warranted.
Discussion
Most reports of finasteride-associated infertility have studied the effects of finasteride on spermatogenesis in relation to semen parameters (1). The current literature does not report on the association between finasteride and sperm DNA damage. To our knowledge, the present case represents the first report of low-dose finasteride associated with increased sperm DNA fragmentation potentially contributing to recurrent pregnancy losses in the context of an otherwise normal semen analysis.
Finasteride is a 5-alpha reductase inhibitor that blocks the conversion of testosterone to its more potent form, dihydrotestosterone (DHT). In the United States and Canada, it is used at a higher dose (5 mg) for the treatment of benign prostatic hyperplasia and lower dose (1 mg) for the treatment of androgenic hair loss. Earlier studies have shown that high-dose finasteride has been associated with a reversible decrease in sperm concentration and motility in normal men (2). Despite the decrease, the average sperm concentration was still adequate for normal fertility. The authors concluded that testosterone was essential for spermatogenesis and that DHT played no major role.
There have been only a few case reports and one randomized controlled trial on the effect of low-dose finasteride on spermatogenesis and infertility [1] and [3]. Amory et al. (2) randomized 99 men with normal semen parameters to receive dutasteride 0.5 mg, finasteride 5 mg, or placebo for 1 year. The outcome of the study showed that among young healthy men, finasteride 5 mg had a mild effect on spermatogenesis. Recent case reports have documented that finasteride 1 mg was associated with partially reversible impaired spermatogenesis in subfertile men or men with other contributing factors to infertility. In one case report of three patients, two patients had a varicocele and the third was obese (1). In another series of two patients, the authors suggested a causal relationship between the discontinuation of finasteride and the significant improvement in semen parameters within 3 months (3).
A systematic review of 11 studies demonstrated that the sperm DFI, an estimate of sperm DNA breaks, was significantly associated with increased risk for spontaneous abortions after IVF and intracytoplasmic sperm injection (ICSI) (4). A cutoff DFI of 27%–30% used by multiple studies has shown a statistically significant relationship with increased pregnancy losses. It has been theorized from animal studies that this association could be due to abnormal embryo development and impaired embryo implantation. The present case illustrates a patient on finasteride 1 mg for several years with normal semen parameters. This is in keeping with the fact that DHT is not as greatly affected by low doses of finasteride and that testosterone plays a more crucial role in spermatogenesis. It is possible that the high DFI (30%) contributed to the recurrent pregnancy losses in this couple, as has been observed for other couples undergoing IVF and ICSI. The significant reduction in DFI within 3 months of finasteride cessation and continued improvement thereafter suggests a causal link between finasteride and sperm DNA damage. We recognize that having a pretreatment sperm DFI would strengthen our observation, but sperm DFI, as measured by the sperm chromatin structure assay, exhibits a low degree of biologic variability, and there were no other factors that could explain the substantial drop in sperm DFI. We hypothesize that low-dose finasteride may exert a negative influence on sperm DNA integrity resulting in increased pregnancy losses. Future studies should be done to investigate the relationship between finasteride and sperm DNA damage. We suggest that in infertile men using finasteride with normal semen parameters, a sperm DNA fragmentation index should be measured and a trial of discontinuation of finasteride may be warranted.
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