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Propecia-induced spermatogenic failure: a report of two cases
CASE REPORT Propecia-induced spermatogenic failure: a report of two cases Kimberly E. Liu, M.D.,a Saleh Binsaleh, M.D.,b Kirk C. Lo, M.D.,b and Keith Jarvi, M.D.a,b a
Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Toronto, Reproductive Biology Unit, Mount Sinai Hospital, Toronto, ON, Canada; and b Divison of Urology, Department of Surgery, Murray Koffler Urologic Wellness Centre, Mount Sinai Hospital, University of Toronto, Toronto ON M5T 3L9 Murray Koffler Urologic Wellness Centre, Mount Sinai Hospital, Toronto, Ontario, Canada
Objective: To describe the results of two cases of azoospermia and severe oligospermia in men during and after cessation of finasteride 1 mg. Design: Case report. Setting: Tertiary-care hospital-based clinic for andrology/male infertility. Patient(s): Two patients with azoospermia and severe oligospermia using finasteride 1 mg for hair loss. Intervention(s): Discontinuation of finasteride. Main Outcome Measure(s): Improvement in sperm concentration. Result(s): Patient A had documented azoospermia over 1 year and was initially booked for a testicular biopsy. Six months after discontinuation of finasteride 1 mg daily he showed improvement in sperm concentration to 5.5 106/mL. Patient B had severe oligospermia with a sperm concentration of 4 106/mL. Sperm concentration improved to 6.6 then 18.7 106/mL at 3 and 6 months after stopping finasteride. Conclusion(s): We report two cases of infertile patients with azoospermia or severe oligospermia who showed significant improvements in sperm concentrations 6 months after the discontinuation of finasteride. In one case, improvement in semen parameters prevented the need for testicular biopsy and corrected the azoospermia. Stopping finasteride in the infertility population may improve semen parameters, and may allow for less invasive fertility treatments. (Fertil Steril 2008;90:849.e17–e19. 2008 by American Society for Reproductive Medicine.) Key Words: Spermatogenesis, finasteride, azoospermia, oligospermia
Finasteride 1 mg is currently marketed in the United States and Canada under the trade name ‘‘Propecia’’ for the treatment of androgenic hair loss in men. Finasteride is a 5-alpha reductase inhibitor that is also used for the treatment of benign prostatic hyperplasic at higher doses (5 mg). Finasteride blocks the conversion of testosterone to dihydrotestosterone (DHT), a more potent androgen. Although testosterone has been shown to be crucial for spermatogenesis, studies from men with DHT suppression suggest it is not essential for spermatogenesis (1). However, previous studies have shown that finasteride 5 mg daily has a reversible negative effect on total sperm counts (2). The investigators could only find one study in the literature on the effect of finasteride 1 mg on spermatogenesis (3). This study was performed in healthy men with normal sperm parameters, and did not show an effect on semen parameters. We did not find any studies published on the effects of finasteride 1 mg daily on men with reduced fertility. Received June 13, 2007; revised and accepted August 8, 2007. Conflict of interest: none. Submitted for ASRM 2007. Reprint requests: Keith Jarvi, M.D., Joseph & Wolf Lebovic Centre, 60 Murray Street, 6th Floor, Toronto ON M5G 1X5, Canada (FAX: 416-586-8354; E-mail: [email protected]).
0015-0282/08/$34.00 doi:10.1016/j.fertnstert.2007.08.026
MATERIALS AND METHODS A retrospective chart review was performed on two patients who attended the Murray Koffler Urologic Wellness Center at the Mount Sinai Hospital in Toronto, Ontario, Canada. Both patients presented with azoospermia or severe oligospermia during an infertility workup. Occurrence of these two cases in the clinical setting prompted a further review of the charts and a review of the literature. RESULTS Patient A was 34-year-old male with a 3-year history of primary infertility. On medical history, he had had two previous episodes of genital herpes. The patient’s medications included valacyclovir and finasteride 1 mg daily, which he had been taking for 2 years. He was a nonsmoker. Initial examination confirmed normal testicular volumes (20 cc), bilateral palpable vas deferens, and absence of varicocele. Four semen analysis reports over a 1-year period confirmed normal semen volume cryptazoospermia, with only rare sperm found in the centrifuged semen specimen. Initial blood work results included FSH 3.6 IU/L, LH 6.7 IU/L, and an elevated total testosterone 30 nmol/L. Genetic testing including karyotype, cystic fibrosis screening, and Y-chromosome microdeletions
Fertility and Sterility Vol. 90, No. 3, September 2008 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.
849.e17
were all normal. The patient was thought to have obstructive azoospermia, and surgery including a testicular biopsy with possible vasoepididymostomy was planned. Before proceeding to surgery, the patient was asked to discontinue the finasteride. Three months after stopping the medication, the sperm concentration was 0.3 106/mL. Surgery was therefore postponed to allow for further improvement. After 4 further months, sperm concentrations had increased to 5.5 106/mL. Testosterone levels normalized to 15 nmol/L. Surgery was cancelled and the patient was advised to bank sperm samples. Patient B was a 32-year-old male with severe oligospermia who had been on finasteride for 3 years. Initial semen analysis was volume 1.4 mL, sperm count 4 106/mL, 14% motility, and 5% normal morphology. Initial investigations and examination showed a small right hydrocoele with normal testicular size. A postejaculatory urine sample was negative for sperm. Initial blood work was normal: FSH 6.4 IU/L, LH 4.2 IU/L, testosterone 18 nmol/L. The patient was advised to stop finasteride. Three months later, semen analysis had improved: volume 2.2 mL, 6.6 106/mL, 42% motility, and 15% normal morphology. Subsequent semen analysis 5 and 7 months after stopping finasteride showed greater improvements to 18 106/mL, 24% motility, 5% normal morphology, and 24 106/mL, 25% motility, 5% normal morphology.
Higher doses of finasteride used to treat benign prostatic hyperplasia have been associated with a reversible decrease in total sperm counts and sperm motility in humans (2). There has only been one previous study on the effect of 1 mg of finasteride in young healthy men (3). In this study, 181 men were randomized to finasteride 1 mg or placebo for 1 year. There were no differences seen in sperm concentration, motility, or morphology between groups. Of the 79 men screened by semen analysis, all had normal semen parameters with no history of infertility. There have been no previous studies looking at the effects of finasteride in infertile men or men with oligospermia. However, there has been one other case report showing improvement in semen parameters in three infertile men after discontinuation of finasteride taken for hair loss (7). Finasteride’s effects on spermatogenesis could be secondary to changes in androgen levels. Patient A exhibited an elevated testosterone level while on finasteride, which was consistent with an elevation in testosterone levels seen in Overstreet’s study (3). Although DHT was not thought to have a significant impact on spermatogenesis (8), this study suggests that decreased local DHT levels may play a role in spermatogenesis in men with preexisting subfertility.
DISCUSSION We have presented two cases of infertile men who had severe oligospermia or azoospermia while taking finasteride 1 mg for hair loss. In both cases, significant improvements in sperm concentration were seen within 6 months after discontinuation of the medication. In the first case, the use of finasteride was associated with a reversible azoospermia. In his particular case, discontinuation of the drug and the resultant improvement in sperm concentration prevented the need for invasive scrotal surgery. In both cases, semen parameters, although dramatically improved, did not return to normal, indicating that the finasteride was unlikely to be the sole cause of the subfertility. Although in patient B random variation in semen analysis results cannot be completely discounted because only one semen analysis was performed before discontinuing finasteride, the three semen analysis after the drug was stopped showed a continual upward trend in sperm concentration from 4 million/mL to 6 million/mL to 18 and 24 million/mL as time away from the drug increased, which suggests an effect from the finasteride.
Finasteride 1 mg, or Propecia, is a commonly used medication for hair loss in reproductive-aged young men. Therefore, it is important to understand its potential effects on spermatogenesis and fertility. Although this dose of finasteride did not appear to cause a reduction in sperm concentration in young, healthy, men with normal sperm concentrations, we report two cases of infertile men with significant improvements in sperm concentrations within 6 months after discontinuation of the drug. Neither patient had ever had a semen analysis before being on Propecia; therefore, we can only draw conclusions from the effects of withdrawing the drug, not the effects of starting the medication. Although the effects therefore cannot be absolutely attributable to Propecia, as other variables or random variation can lead to significant changes in semen analysis results, in both patients the temporal association with resolution within 3–6 months after the discontinuation of the medication suggests a causal relationship. In both cases, these improvements allowed for less invasive fertility therapy, in one case avoiding the need for surgery, and in the other case allowing for adequate sperm concentrations for intrauterine inseminations instead of in vitro fertilization. We suggest that in infertile men with severe oligospermia or azoospermia using finasteride a trial of discontinuation of the medication is warranted, and may prevent the need for more invasive fertility treatments.
In rat studies, finasteride has been shown to decrease fertility (4). However, this effect was felt to be secondary to inadequate copulatory plug formation, secondary to the drug’s effects on seminal vesicles and the prostate (4, 5). Further studies did not show an effect on spermatogenesis (6). Therefore, the effects of finasteride on fertility seen in rats were felt to be a species specific.
1. Katz MD, Kligman I, Cai LQ, Zhu YS, Fratianni CM, Zervoudakis I, et al. Paternity by intrauterine insemination with sperm from a man with 5alpha-reductase-2 deficiency. N Engl J Med 1997;336:994–7. 2. Amory JK, Wang C, Swerdloff RS, Anawalt BD, Matsumoto AM, Bremner WJ, et al. The effect of 5{alpha}-reductase inhibition with
849.e18
Liu et al.
Propecia-induced spermatogenic failure
REFERENCES
Vol. 90, No. 3, September 2008
dutasteride and finasteride on semen parameters and serum hormones in healthy men. J Clin Endocrinol Metab 2007;92:1659–65. 3. Overstreet JW, Fuh VL, Gould J, Howards SS, Lieber MM, Hellstrom W, et al. Chronic treatment with finasteride daily does not affect spermatogenesis or semen production in young men. J Urol 1999;162:1295–300. 4. Wise LD, Minsker DH, Cukierski MA, Clark RL, Prahalada S, Antonello JM, et al. Reversible decreases of fertility in male SpragueDawley rats treated orally with finasteride, a 5 alpha-reductase inhibitor. Reprod Toxicol 1991;5:337–46. 5. Cukierski MA, Sina JL, Prahalada S, Wise LD, Antonello JM, MacDonald JS, et al. Decreased fertility in male rats administered the 5
Fertility and Sterility
alpha-reductase inhibitor, finasteride, is due to deficits in copulatory plug formation. Reprod Toxicol 1991;5:353–62. 6. Rhoden EL, Gobbi D, Menti E, Rhoden C, Teloken C. Effects of the chronic use of finasteride on testicular weight and spermatogenesis in Wistar rats. BJU Int 2002;89:961–3. 7. Glina S, Neves PA, Saade R, Netto NR Jr, Soares JB, Galuppo AG. Finasteride-associated male infertility. Rev Hosp Clin Fac Med Sao Paulo 2004;59:203–5. 8. George FW, Johnson L, Wilson JD. The effect of a 5 alpha-reductase inhibitor on androgen physiology in the immature male rat. Endocrinology 1989;125:2434–8.
849.e19
Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Toronto, Reproductive Biology Unit, Mount Sinai Hospital, Toronto, ON, Canada; and b Divison of Urology, Department of Surgery, Murray Koffler Urologic Wellness Centre, Mount Sinai Hospital, University of Toronto, Toronto ON M5T 3L9 Murray Koffler Urologic Wellness Centre, Mount Sinai Hospital, Toronto, Ontario, Canada
Objective: To describe the results of two cases of azoospermia and severe oligospermia in men during and after cessation of finasteride 1 mg. Design: Case report. Setting: Tertiary-care hospital-based clinic for andrology/male infertility. Patient(s): Two patients with azoospermia and severe oligospermia using finasteride 1 mg for hair loss. Intervention(s): Discontinuation of finasteride. Main Outcome Measure(s): Improvement in sperm concentration. Result(s): Patient A had documented azoospermia over 1 year and was initially booked for a testicular biopsy. Six months after discontinuation of finasteride 1 mg daily he showed improvement in sperm concentration to 5.5 106/mL. Patient B had severe oligospermia with a sperm concentration of 4 106/mL. Sperm concentration improved to 6.6 then 18.7 106/mL at 3 and 6 months after stopping finasteride. Conclusion(s): We report two cases of infertile patients with azoospermia or severe oligospermia who showed significant improvements in sperm concentrations 6 months after the discontinuation of finasteride. In one case, improvement in semen parameters prevented the need for testicular biopsy and corrected the azoospermia. Stopping finasteride in the infertility population may improve semen parameters, and may allow for less invasive fertility treatments. (Fertil Steril 2008;90:849.e17–e19. 2008 by American Society for Reproductive Medicine.) Key Words: Spermatogenesis, finasteride, azoospermia, oligospermia
Finasteride 1 mg is currently marketed in the United States and Canada under the trade name ‘‘Propecia’’ for the treatment of androgenic hair loss in men. Finasteride is a 5-alpha reductase inhibitor that is also used for the treatment of benign prostatic hyperplasic at higher doses (5 mg). Finasteride blocks the conversion of testosterone to dihydrotestosterone (DHT), a more potent androgen. Although testosterone has been shown to be crucial for spermatogenesis, studies from men with DHT suppression suggest it is not essential for spermatogenesis (1). However, previous studies have shown that finasteride 5 mg daily has a reversible negative effect on total sperm counts (2). The investigators could only find one study in the literature on the effect of finasteride 1 mg on spermatogenesis (3). This study was performed in healthy men with normal sperm parameters, and did not show an effect on semen parameters. We did not find any studies published on the effects of finasteride 1 mg daily on men with reduced fertility. Received June 13, 2007; revised and accepted August 8, 2007. Conflict of interest: none. Submitted for ASRM 2007. Reprint requests: Keith Jarvi, M.D., Joseph & Wolf Lebovic Centre, 60 Murray Street, 6th Floor, Toronto ON M5G 1X5, Canada (FAX: 416-586-8354; E-mail: [email protected]).
0015-0282/08/$34.00 doi:10.1016/j.fertnstert.2007.08.026
MATERIALS AND METHODS A retrospective chart review was performed on two patients who attended the Murray Koffler Urologic Wellness Center at the Mount Sinai Hospital in Toronto, Ontario, Canada. Both patients presented with azoospermia or severe oligospermia during an infertility workup. Occurrence of these two cases in the clinical setting prompted a further review of the charts and a review of the literature. RESULTS Patient A was 34-year-old male with a 3-year history of primary infertility. On medical history, he had had two previous episodes of genital herpes. The patient’s medications included valacyclovir and finasteride 1 mg daily, which he had been taking for 2 years. He was a nonsmoker. Initial examination confirmed normal testicular volumes (20 cc), bilateral palpable vas deferens, and absence of varicocele. Four semen analysis reports over a 1-year period confirmed normal semen volume cryptazoospermia, with only rare sperm found in the centrifuged semen specimen. Initial blood work results included FSH 3.6 IU/L, LH 6.7 IU/L, and an elevated total testosterone 30 nmol/L. Genetic testing including karyotype, cystic fibrosis screening, and Y-chromosome microdeletions
Fertility and Sterility Vol. 90, No. 3, September 2008 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.
849.e17
were all normal. The patient was thought to have obstructive azoospermia, and surgery including a testicular biopsy with possible vasoepididymostomy was planned. Before proceeding to surgery, the patient was asked to discontinue the finasteride. Three months after stopping the medication, the sperm concentration was 0.3 106/mL. Surgery was therefore postponed to allow for further improvement. After 4 further months, sperm concentrations had increased to 5.5 106/mL. Testosterone levels normalized to 15 nmol/L. Surgery was cancelled and the patient was advised to bank sperm samples. Patient B was a 32-year-old male with severe oligospermia who had been on finasteride for 3 years. Initial semen analysis was volume 1.4 mL, sperm count 4 106/mL, 14% motility, and 5% normal morphology. Initial investigations and examination showed a small right hydrocoele with normal testicular size. A postejaculatory urine sample was negative for sperm. Initial blood work was normal: FSH 6.4 IU/L, LH 4.2 IU/L, testosterone 18 nmol/L. The patient was advised to stop finasteride. Three months later, semen analysis had improved: volume 2.2 mL, 6.6 106/mL, 42% motility, and 15% normal morphology. Subsequent semen analysis 5 and 7 months after stopping finasteride showed greater improvements to 18 106/mL, 24% motility, 5% normal morphology, and 24 106/mL, 25% motility, 5% normal morphology.
Higher doses of finasteride used to treat benign prostatic hyperplasia have been associated with a reversible decrease in total sperm counts and sperm motility in humans (2). There has only been one previous study on the effect of 1 mg of finasteride in young healthy men (3). In this study, 181 men were randomized to finasteride 1 mg or placebo for 1 year. There were no differences seen in sperm concentration, motility, or morphology between groups. Of the 79 men screened by semen analysis, all had normal semen parameters with no history of infertility. There have been no previous studies looking at the effects of finasteride in infertile men or men with oligospermia. However, there has been one other case report showing improvement in semen parameters in three infertile men after discontinuation of finasteride taken for hair loss (7). Finasteride’s effects on spermatogenesis could be secondary to changes in androgen levels. Patient A exhibited an elevated testosterone level while on finasteride, which was consistent with an elevation in testosterone levels seen in Overstreet’s study (3). Although DHT was not thought to have a significant impact on spermatogenesis (8), this study suggests that decreased local DHT levels may play a role in spermatogenesis in men with preexisting subfertility.
DISCUSSION We have presented two cases of infertile men who had severe oligospermia or azoospermia while taking finasteride 1 mg for hair loss. In both cases, significant improvements in sperm concentration were seen within 6 months after discontinuation of the medication. In the first case, the use of finasteride was associated with a reversible azoospermia. In his particular case, discontinuation of the drug and the resultant improvement in sperm concentration prevented the need for invasive scrotal surgery. In both cases, semen parameters, although dramatically improved, did not return to normal, indicating that the finasteride was unlikely to be the sole cause of the subfertility. Although in patient B random variation in semen analysis results cannot be completely discounted because only one semen analysis was performed before discontinuing finasteride, the three semen analysis after the drug was stopped showed a continual upward trend in sperm concentration from 4 million/mL to 6 million/mL to 18 and 24 million/mL as time away from the drug increased, which suggests an effect from the finasteride.
Finasteride 1 mg, or Propecia, is a commonly used medication for hair loss in reproductive-aged young men. Therefore, it is important to understand its potential effects on spermatogenesis and fertility. Although this dose of finasteride did not appear to cause a reduction in sperm concentration in young, healthy, men with normal sperm concentrations, we report two cases of infertile men with significant improvements in sperm concentrations within 6 months after discontinuation of the drug. Neither patient had ever had a semen analysis before being on Propecia; therefore, we can only draw conclusions from the effects of withdrawing the drug, not the effects of starting the medication. Although the effects therefore cannot be absolutely attributable to Propecia, as other variables or random variation can lead to significant changes in semen analysis results, in both patients the temporal association with resolution within 3–6 months after the discontinuation of the medication suggests a causal relationship. In both cases, these improvements allowed for less invasive fertility therapy, in one case avoiding the need for surgery, and in the other case allowing for adequate sperm concentrations for intrauterine inseminations instead of in vitro fertilization. We suggest that in infertile men with severe oligospermia or azoospermia using finasteride a trial of discontinuation of the medication is warranted, and may prevent the need for more invasive fertility treatments.
In rat studies, finasteride has been shown to decrease fertility (4). However, this effect was felt to be secondary to inadequate copulatory plug formation, secondary to the drug’s effects on seminal vesicles and the prostate (4, 5). Further studies did not show an effect on spermatogenesis (6). Therefore, the effects of finasteride on fertility seen in rats were felt to be a species specific.
1. Katz MD, Kligman I, Cai LQ, Zhu YS, Fratianni CM, Zervoudakis I, et al. Paternity by intrauterine insemination with sperm from a man with 5alpha-reductase-2 deficiency. N Engl J Med 1997;336:994–7. 2. Amory JK, Wang C, Swerdloff RS, Anawalt BD, Matsumoto AM, Bremner WJ, et al. The effect of 5{alpha}-reductase inhibition with
849.e18
Liu et al.
Propecia-induced spermatogenic failure
REFERENCES
Vol. 90, No. 3, September 2008
dutasteride and finasteride on semen parameters and serum hormones in healthy men. J Clin Endocrinol Metab 2007;92:1659–65. 3. Overstreet JW, Fuh VL, Gould J, Howards SS, Lieber MM, Hellstrom W, et al. Chronic treatment with finasteride daily does not affect spermatogenesis or semen production in young men. J Urol 1999;162:1295–300. 4. Wise LD, Minsker DH, Cukierski MA, Clark RL, Prahalada S, Antonello JM, et al. Reversible decreases of fertility in male SpragueDawley rats treated orally with finasteride, a 5 alpha-reductase inhibitor. Reprod Toxicol 1991;5:337–46. 5. Cukierski MA, Sina JL, Prahalada S, Wise LD, Antonello JM, MacDonald JS, et al. Decreased fertility in male rats administered the 5
Fertility and Sterility
alpha-reductase inhibitor, finasteride, is due to deficits in copulatory plug formation. Reprod Toxicol 1991;5:353–62. 6. Rhoden EL, Gobbi D, Menti E, Rhoden C, Teloken C. Effects of the chronic use of finasteride on testicular weight and spermatogenesis in Wistar rats. BJU Int 2002;89:961–3. 7. Glina S, Neves PA, Saade R, Netto NR Jr, Soares JB, Galuppo AG. Finasteride-associated male infertility. Rev Hosp Clin Fac Med Sao Paulo 2004;59:203–5. 8. George FW, Johnson L, Wilson JD. The effect of a 5 alpha-reductase inhibitor on androgen physiology in the immature male rat. Endocrinology 1989;125:2434–8.
849.e19