Male fertility and the effects of dermatological medications, "Beyond the Abstract," by Mona Malakouti, MS, Jillian Wong Millsop, MD, and Jenny Murase, MD

BERKELEY, CA (UroToday.com) - Because many medications are known to temporarily or permanently affect male fertility, it is important to discuss these consequences with men who intend to have children in the near future. The original publication “Dermatological medication effects on male fertility” reviewed available data regarding common dermatologic medications that may affect parameters of male fertility.^[1] A Medline database search was conducted and emphasis placed on recent articles spanning years 2000-2012. Both animal and human studies were reviewed for effects on male fertility of immunosuppressive, retinoid, anti-hormonal, anti-microbial, and anti-histamine agents used in dermatology. As part of “Beyond the Abstract,” we aim to present a review of updated information regarding these agents, limitations faced by the original reviewers, and our recommendations for counseling potential fathers.

Background Regarding Agents with Updated Recommendations

Methotrexate, a folic acid antagonist, is well known for its teratogenic effects in utero. Two potential concerns may arise when considering the use of methotrexate in potential fathers: genotoxic damage to sperm chromosomes present at conception potentially resulting in congenital malformations or abortions, and the exposure of seminal methotrexate to the pregnant partner.^[2] Based on methotrexate’s ability to negatively impact sperm counts and DNA integrity, potential fathers should discontinue methotrexate three months prior to conception in anticipation of a new spermatogenic cycle. Although it is unlikely that trace amounts of methotrexate in seminal fluid may pose a threat to a developing fetus, potential fathers should consider using barrier protection during sexual intercourse should they resume methotrexate during their partner’s pregnancy.

Finasteride, a type 2 5-α reductase inhibitor, blocks the conversion of testosterone to dihydrotesterone (DHT), a potent androgen. For the treatment of benign prostatic hypertrophy, a 5mg/day dose of finasteride is used rather than the 1mg/day dose used to treat androgenic alopecia.^[3] Impaired sperm function was found in males with baseline normal fertility taking the 5mg/day dose. The 1mg/day dose is thought to affect sperm function in males who are subfertile upon initial presentation. However, finasteride was reported to negatively impact sperm integrity in two case reports. In both cases, an increase in the sperm DNA fragmentation index (SDFI) or amount of sperm DNA breaks was observed with chronic use of finasteride 1mg. The first case reported a male whose partner had 4 consecutive abortions.^[4] The second and more recent case, reported a male patient’s inability to conceive for 5 years after taking 1mg of finasteride for 8.5 years.^[5] Upon discontinuation, his wife became pregnant within 8 months, which coincided with a decrease in his SDFI. Eighteen months after restarting the 1mg dose of finasteride, the patient’s SDFI remained at low levels. Based on this observation, the authors of this study suggest that sperm damage results with chronic use of finasteride. Thus, the use of finasteride during conception should be considered for each individual patient with careful consideration of dose, duration of use, and baseline fertility. Short-term use of finasteride at 1mg/day in males with baseline normal fertility may not be problematic. Physicians should consider discontinuing this medication in the event that planned attempts at conception have failed.

Spironolactone is a competitive aldosterone antagonist and potassium-sparing diuretic that is also known to have anti-androgen effects. Spironolactone causes gynecomastia and impotence in a dose-dependent manner. Thus, higher doses of oral spironolactone increase the likelihood of undesirable side effects considering observed alterations in hormone levels as well as depression of spermatogenesis seen with use of the 400 mg dose.^[6] Thus with the limited data available, potential fathers should be counseled on spironolactone’s ability to affect their fertility, especially with oral spironolactone given at higher doses.

Both tetracycline and erythromycin have been shown to impair sperm motility in vitro. Tetracycline is thought to be the most potent in terms of its ability to affect sperm motility, perhaps by way of calcium chelation.^[7] In addition, tetracycline is able to penetrate prostatic and seminal fluid with concentrations approaching levels up to 60% of that seen in the plasma. This is in contrast to erythromycin, which may reach 40% of the plasma concentration and a maximum of 2 micrograms/mL after a single dose of 500 mg in prostatic fluid. Therefore, erythromycin may be less likely to affect mature spermatocytes, warranting its preferential use over tetracycline when appropriate.

Ketoconazole, an antifungal medication, has been shown to inhibit testosterone production by inhibiting the cytochrome p-450 enzymes. Post-marketing data indicates the incidence of erectile dysfunction with doses of ketoconazole higher than 200 mg PO. Oligospermia, impotence, and decreased libido are thought to correlate with ketoconazole serum levels.^[8] Fluconazole has also been shown to decrease testosterone, semen volume and sperm motility with male rabbits.^[9] Miconazole and clotrimazole demonstrated a time and dose-dependent decrease in sperm motility and caused an increased intrasperm calcium concentration when applied to human sperm ejaculates, leading to decreased sperm viability. This study also suggests the potential use of miconazole and clotrimazole for spermicidal purposes.^[10] Based on these studies, potential fathers should consider discontinuing the use of azole antifungals prior to attempts of conception.

Conclusion and Limitations

In dermatology, male patients are often treated for chronic dermatologic conditions requiring medication use for a prolonged period of time. As discussed, many medications have been shown to affect male parameters of fertility. However, it is difficult to formulate definitive guidelines given the lack of quality data. The publications reviewed were mostly case reports or case series that used inconsistent dosing and fertility parameters for these medications. Data from semen analysis are internally limited; many factors can alter semen parameters including age, stress, and timing of semen collection. From our review, dose, duration, and baseline fertility are important considerations in determining how a drug affects male fertility, although these factors were inconsistently evaluated.

As the previous publication concluded, methotrexate is the only agent formally recommended for discontinuation at 3-months prior to conception. Oral retinoids, cyclosporine, azathioprine, and TNF-α inhibitor data do not indicate the need for discontinuation. Oral antibiotics, glucocorticoids, spironolactone, finasteride, chloroquine, ketoconazole, and antihistamines had less available data; thus, physicians must consider the use of these agents on a case-by-case basis. Physicians should consider discontinuation of any of these agents when patients present with multiple failed attempts at conception, since baseline fertility is not analyzed prior to prescribing these agents.

While considering these agents, it is helpful to categorize risk to the fetus, prior to conception, and during pregnancy. Prior to conception, genotoxic damage and decreased sperm counts should be considered. Certain agents such as methotrexate, and possibly finasteride, which have been reported to cause sperm DNA damage, may theoretically result in congenital malformations or spontaneous abortions. Other agents that affect sperm count, motility, or morphology may make successful attempts at conception more unlikely. During pregnancy, men using FDA pregnancy category X agents, including methotrexate, acitretin, and isotretinoin should be counseled regarding the use of barrier protection while engaging in sexual intercourse with their pregnant partners due to the lack of safety information (although the amount of medication in the seminal fluid, and therefore the risk, is thought to be low). Finally, for physicians counseling potential fathers, additional studies are needed to help construct more conclusive guidelines regarding medications and their effect on male fertility.

References:

1. Millsop JW, Heller MM, Eliason MJ, Murase JE. Dermatological medication effects on male fertility. Dermatologic Therapy. Jul 2013;26(4):337-346.
2. Beghin D, Cournot MP, Vauzelle C, Elefant E. Paternal exposure to methotrexate and pregnancy outcomes. Journal of Rheumatology. Apr 2011;38(4):628-632.
3. Samplaski MK, Lo K, Grober E, Jarvi K. Finasteride use in the male infertility population: effects on semen and hormone parameters. Fertility and Sterility. Dec 2013;100(6):1542-1546.
4. Tu HY, Zini A. Finasteride-induced secondary infertility associated with sperm DNA damage. Fertility and Sterility. May 2011;95(6):2125 e2113-2124.
5. Salvarci A, Istanbulluoglu O. Secondary infertility due to use of low-dose finasteride. International Urology and Nephrology. Feb 2013;45(1):83-85.
6. Stripp B, Taylor AA, Bartter FC, et al. Effect of spironolactone on sex hormones in man. Journal of Clinical Endocrinology and Metabolism. Oct 1975;41(4):777-781.
7. Hargreaves CA, Rogers S, Hills F, Rahman F, Howell RJS, Homa ST. Effects of co-trimoxazole, erythromycin, amoxycillin, tetracycline and chloroquine on sperm function in vitro. Human Reproduction. Jul 1998;13(7):1878-1886.
8. Pont A, Graybill JR, Craven PC, et al. High-dose ketoconazole therapy and adrenal and testicular function in humans. Archives of Internal Medicine. Nov 1984;144(11):2150-2153.
9. el-Medany AH, Hagar HH. Effect of fluconazole on the fertility of male rabbits. Arzneimittel-Forschung. 2002;52(8):636-640.
10. Gulati A, Tiwary AK, Jain S, Moudgil P, Gupta A. Intrasperm Ca2+ modulation and human ejaculated sperm viability: influence of miconazole, clotrimazole and loperamide.  Journal of Pharmacy and Pharmacology. Aug 2006;58(8):1145-1151.

Written by:
Mona Malakouti, MS,^a Jillian Wong Millsop, MD,^b and Jenny Murase, MD^c as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

^aChicago Medical School, Rosalind Franklin University of Medicine and Science. University of California, San Francisco, Department of Dermatology.
^bUniversity of California, Davis, Department of Dermatology.
^cUniversity of California San Francisco, Department of Dermatology, and Palo Alto Foundation Medical Group, Department of Dermatology

Corresponding Author:
Jenny E. Murase, MD
Department of Dermatology
Palo Alto Foundation Medical Group
701 East El Camino Real (31-104)
Mountain View, CA 94040
E-mail:

Conflicts of Interest: The authors have no conflicts of interest to disclose. There was no funding provided for the production of this article.

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