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A Review on the Effect of Immunosuppressants on Fertility


Affiliations
1 Department of Pharmacy Practice, J.K.K. Nattraja College of Pharmacy, Komarapalayam-638183, Tamil Nadu, India
2 Department of Pharmacology, J.K.K. Nattraja College of Pharmacy, Komarapalayam-638183, Tamil Nadu, India
3 Department of Pharmaceutics, J.K.K. Nattraja College of Pharmacy, Komarapalayam-638183, Tamil Nadu, India
     

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Background: Infertility is defined as not being able to get pregnant (conceive) after one year (or longer) of unprotected sex. Many studies had showed that extensive use of immunosuppressant’s may result in infertility. Immunosuppressive drugs are used in the treatment of inflammatory and autoimmune diseases, as well as in transplantation. Frequently prescribed in young people, these treatments may have deleterious effects on fertility, pregnancy outcomes and the unborn child. Aim: The aim of this study is to review the literatures depicting the about immunosuppressant’s, its impact on fertility and related pregnancy outcomes. Methods: A systematic literature search of the Pub Med database was performed using a combination of relevant terms related to ‘infertility’, 'conception', 'reproduction', 'immunosuppressant’s. Conclusion: From the review of many literatures this study concludes that immunosuppressants has varying effect on pregnancy. Some of the immunosuppressants at therapeutic doses can cause infertility when used for a long time.

Keywords

Fertility, Reproduction, Conception, Immunosuppressants.
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  • Kumar R. Male infertility–Current concepts. Indian Journal of Urology : IJU : Journal of the Urological Society of India. 2011, 27(1):39-40. doi:10.4103/0970-1591.78419.

  • Smith S, Pfeifer SM, Collins JA. Diagnosis and management of female infertility. JAMA. 2003; 290(13): 1767-1770.

  • Doherty CM, Clark MM. Infertility treatment. 1st ed. Czech Republic: Computer Press Brno; 2006; 1-121.

  • Gleicher N, Barad D. Unexplained infertility: does it really exist? Hum Reprod. 2006; 21(8): 1951-1955.

  • Iiristatidis C, Bhattacharya S. Unexplained infertility: does it really exist? Does it matter? Hum Reprod. 2007; 22(8): 2084-2087.

  • Brazdova A. Study of immunological properties of sperm and seminal plasma antigens: anti-seminal and anti-sperm antibodies in female immune infertility. Characterization of targeted proteins. Presented for the Ph.D., Paris. Pierre and Marie Curie university. 2014.

  • Crosignani PC, Collins J, Cooke ID, Diczfalusy E, Rubin B. Recommendations of the ESHRE workshop on 'Unexplained Infertility'. Anacapri, August 28-29, 1992. Hum Reprod. 1993; 8(6): 977-980.

  • Hisatomi A, Fujihira S, Fujimoto Y, Fujii T. Effect of Prograf (FK506) on spermatogenesis in rats.Toxicology.1996; 109(3):75-83.

  • Rovira J, Diekmann F, Ramírez M. Campistol. Sirolimus-associated testicular toxicity: detrimental but reversible. Transplantation,2012; 93: 874-879.

  • Masuda H, Fujihira S, Ueno H, Kagawa H, Katsuoka M. Ultrastructural study on cytotoxic effects of cyclosporine A in spermiogenesis in rats. Medical Electron Microscopy,2003; 36: 183-191.

  • Leroy et al. Immunosuppressive drugs and infertility.Orphanet Journal of Rare Diseases .2015; 10:136.

  • Sands K, Jansen R, Zaslau S, Greenwald D. Review article: the safety of therapeutic drugs in male inflammatory bowel disease patients wishing to conceive. Aliment Pharmacol Ther 2015; 41:821-834.

  • Taffet SL, Das KM. Sulfasalazine. Adverse effects and desensitization.Dig Dis Sci 1983; 28: 833-842.

  • O'Moráin C, Smethurst P, Doré CJ, Levi AJ. Reversible male infertility due to sulphasalazine: studies in man and rat. Gut 1984; 1078-1084.

  • Birnie GG, McLeod TI, Watkinson G. Incidence of sulphasalazineinduced male infertility. Gut 1981; 22: 452-455.

  • Moody GA, Mayberry JF. Perceived sexual dysfunction amongst patients with inflammatory bowel disease. Digestion 1993; 54: 256-260.

  • Toovey S, Hudson E, Hendry WF, Levi AJ. Sulphasalazine and male infertility: reversibility and possible mechanism. Gut 1981; 22:445-451.

  • Fukushima T, Hamada Y, Komiyama M, Matsuno Y, Mori C, Horii. Early changes in sperm motility, acrosome reaction, and gene expression of reproductive organs in rats treated with sulfasalazine. Reprod Toxicol 2007; 23: 153-157.

  • Alonso V, Linares V, Bellés M, Albina ML, Sirvent JJ, Domingo JL, Sánchez DJ. Sulfasalazine induced oxidative stress: a possible mechanism of male infertility. Reprod Toxicol 2009; 27: 35-40.

  • Linares V, Alonso V, Domingo JL. Oxidative stress as a mechanism underlying sulfasalazine-induced toxicity. Expert Opin Drug Saf 2011; 10: 253-263.

  • Wu FC, Aitken RJ, Ferguson A. Inflammatory bowel disease and male infertility: effects of sulfasalazine and 5-aminosalicylic acid on sperm-fertilizing capacity and reactive oxygen species generation. Fertil Steril 1989; 52: 842-845.

  • Hultén L. Proctocolectomy and ileostomy to pouch surgery for ulcerative colitis. World J Surg 1998; 22: 335-341.

  • Cosentino MJ, Chey WY, Takihara H, Cockett AT. The effects of sulfasalazine on human male fertility potential and seminal prostaglandins. J Urol 1984; 132: 682-686.

  • Riley SA, Lecarpentier J, Mani V, Goodman MJ, Mandal BK, Turnberg LA. Sulphasalazine induced seminal abnormalities in ulcerative colitis: results of mesalazine substitution. Gut 1987; 28:1008-1012.

  • Chatzinoff M, Guarino JM, Corson SL, Batzer FR, Friedman LS. Sulfasalazine-induced abnormal sperm penetration assay reversed on changing to 5-aminosalicylic acid enemas. Dig Dis Sci 1988; 33:108-110.

  • Zelissen PM, van Hattum J, Poen H, Scholten P, Gerritse R, te Velde ER. Influence of salazosulphapyridine and 5-aminosalicylic acid on seminal qualities and male sex hormones. Scand J Gastroenterol 1988; 23: 1100-1104.

  • Chermesh I, Eliakim R. Mesalazine-induced reversible infertility in a young male. Dig Liver Dis 2004; 36: 551-552.

  • Shin T, Kobori Y, Suzuki K, Iwahata T, Yagi H, Soh S, Arai G, Okada H. Inflammatory bowel disease in subfertile men and the effect of mesalazine on fertility. Syst Biol Reprod Med 2014; 60: 373-376.

  • Drobnis E.Z., Nangia A.K. (2017) Immunosuppressants and Male Reproduction. In: Impacts of Medications on Male Fertility. Advances in Experimental Medicine and Biology, vol 1034. Springer, Cham.

  • Aguilar-Mahecha A, Hales BF, Robaire B. Chronic cyclophosphamide treatment alters the expression of stress response genes in rat male germ cells. Biol Reprod. 2002;66:1024–1030.

  • Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut 1993;34:1081–1085.

  • Conell WR, Kamm MA, Dickson M, Balkwill AM, Ritchie JK, Lennard-Jones JE. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 1994;342:1249– 1252.

  • Korelitz BI, Mirsky FJ, Fleisher MR, Warman JI, Wisch N, Gleim GW. Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine. Am J Gastroenterol 1999;94:3248–3253.

  • Sulfasalazine or mesalamine, glucocorticoids, and immunosuppressive drugs such as azathioprine (AZA) or 6-mercaptopurine (6-MP) are accepted as standard therapies in IBD.

  • Podolsky DK. Inflammatory bowel disease (second of two parts). N Engl J Med 1991;325:1008–1016. Rutgeerts P. Medical therapy of inflammatory bowel disease. Digestion 1998;59:453–469.

  • Korelitz BI, Present DH. Favorable effect of 6-mercaptopurine on the fistulae of Crohn’s disease. Dig Dis Sci 1985;30:58–64.

  • O’Brian JJ, Bayless TM, Bayless JA. Use of azathioprine or 6-mercaptopurine in the treatment of Crohn’s disease. Gastroenterology 1991;101:39–46.

  • Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut 1993;34:1081–1085.

  • Conell WR, Kamm MA, Dickson M, Balkwill AM, Ritchie JK, Lennard-Jones JE. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 1994;342:1249– 1252.

  • Korelitz BI, Mirsky FJ, Fleisher MR, Warman JI, Wisch N, Gleim GW. Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine. Am J Gastroenterol 1999;94:3248–3253.

  • Kim PS, Zlatanic J, Korelitz BI, Gleim GW. Optimum duration of treatment with 6-mercaptopurine for Crohn’s disease. Am J Gastroenterol 1999;94:3254–3257.

  • Lewis JD, Schwartz JS, Lichtenstein GR. Azathioprine for maintenance of remission in Crohn’s disease: benefits outweigh the risk of lymphoma. Gastroenterology 2000;118:1018–1024.

  • Voogd CE. Azathioprine, a genotoxic agent to be considered non-genotoxic in man. Mutat Res 1989;221:133–152.

  • Brown JH, Maxwell AP, McGeown MG. Outcome of pregnancy following renal transplantation. Ir J Med Sci 1991;160:255–256.

  • Haugen G, Fauchald P, Sodal G, Leivestad T, Moe N. Pregnancy outcome in renal allograft recipients in Norway. The importance of immunosuppressive drug regimen and health status before pregnancy. Acta Obstet Gynecol Scand 1994;73:541–546.

  • Alstead EM, Ritchie JK, Lennard-Jones JE, Farthing MJ, Clark ML. Safety of azathioprine in pregnancy in inflammatory bowel disease. Gastroenterology 1990;99:443–446.

  • Modigliani R. Drug therapy for ulcerative colitis during pregnancy. Eur J Gastroenterol Hepatol 1997;9:854–857.

  • Marion JF. Toxicity of 6-mercaptopurine/azathioprine in patients with inflammatory bowel disease. Inflamm Bowel Dis 1998;4: 116–117.

  • Karbach U, Ewe K, Schramm P. Quality of semen in patients with Crohn’s disease. Z Gastroenterol 1982;20:314–320.

  • Farthing MJ, Dawson AM. Impaired semen quality in Crohn’s disease-drugs, ill health, or undernutrition? Scand J Gastroenterol 1983;18:57–60.

  • Narendranathan M, Sandler RS, Suchindran CM, Savitz DA. Male infertility in inflammatory bowel disease. J Clin Gastroenterol 1989;11:403–406.

  • Rajapakse RO, Korelitz BI, Zlatanic J, Baiocco PJ, Gleim GM. Outcome of pregnancies when fathers are treated with 6-mercaptopurine for inflammatory bowel disease. Am J Gastroenterol 2000;95:684–688.

  • Kane SV. What’s good for the goose should be good for the gander-6-MP use in fathers with inflammatory bowel disease. Am J Gastroenterol 2000;95:581–582

  • Narendranathan M , Sandler RS , Suchindran CM , Savitz DA . Male infertility in inflammatory bowel disease. Journal of Clinical Gastroenterology.1989, 11(4):403-406.

  • Laren JF, Burney Ro, Milki AA, Westphal LM. Effect of methotrexate exposure on subsequent fertility in women undergoing controlled ovarian stimulation. Fertil steril.2009; 92(2): 515-519.

  • Etherington J, Mootoo R, Mathews JA. An audit of the outpatient use of disease modifying and immunosuppressive anti-rheumatic drugs. Br J Rheum.1995; 34(1): 100-103.

  • Angier RB, Boothe JW, Hutchings BL. The structure and synthesis of the liver L. Casei factor. Science.1946; 103(1): 667-669.

  • Seger DR, Smith JM Jr, Haltquist ME. Antagonist for pteroylglutamic acid. J Am Chem Soc.1947; 69(4):2567.

  • Farber S, Diamond LK, Mercer RD, Sylvester RF Jr, Soliff JA. Temporary remission in acute leukaemia in children produced by folic antagonist 4-aminopteroyl-glutamic acid (aminopterin) .N Engl J Med.1948; 238: 787-793.

  • Goldin A. Preclinical methodology for the selection of anticancer agents. In Busch H, ed. Methods in Cancer Research, vol IV. New York, Academic Press, 1968:193–254.

  • AHFS Drug Information.1999;751-759.

  • Gunther E. Andrologic examinations in the antimetabolite therapy of psoriasis. Dermatol Monatsschr 1970;156: 498-502.

  • Grunnet E, Nyfors A, Hansen KB. Studies of human semen in topical corticosteroid–treated and in methotrexate-treated psoriatics. Dermatologica 1977;154:78-84.

  • De Luca M, Ciampo E, Rossi A. Study of the seminal fluid in subjects treated with methotrexate. G Ital Dermatol Minerva Dermatol 1971;46:247-249.

  • Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, Longhi A, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 p -2 protocol: an updated report. J Clin Oncol 2000;18:4016-4027.

  • Siimes MA, Elomaa I, Koskimies A. Testicular function after chemotherapy for osteosarcoma. Eur J Cancer 1990;26:973-975.

  • Yeuhi chen et al. Long-Term Impact of Immunosuppressants at Therapeutic Doses on Male Reproductive System in Unilateral Nephrectomized Rats: A Comparative Study. BioMed Research International. 2013; 2: 1-9.

  • Nakawaga et al. Immunosuppression with tacrolimus improved reproductive outcome of women with repeated implantation failure and elevated peripheral blood TH1/TH2 cell ratios. Am J Reprod Immunol. 2015; 73(4):353-361.


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  • A Review on the Effect of Immunosuppressants on Fertility

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Authors

S. Shenuka
Department of Pharmacy Practice, J.K.K. Nattraja College of Pharmacy, Komarapalayam-638183, Tamil Nadu, India
T. Thiyagarajan
Department of Pharmacology, J.K.K. Nattraja College of Pharmacy, Komarapalayam-638183, Tamil Nadu, India
R. Sambath Kumar
Department of Pharmaceutics, J.K.K. Nattraja College of Pharmacy, Komarapalayam-638183, Tamil Nadu, India

Abstract


Background: Infertility is defined as not being able to get pregnant (conceive) after one year (or longer) of unprotected sex. Many studies had showed that extensive use of immunosuppressant’s may result in infertility. Immunosuppressive drugs are used in the treatment of inflammatory and autoimmune diseases, as well as in transplantation. Frequently prescribed in young people, these treatments may have deleterious effects on fertility, pregnancy outcomes and the unborn child. Aim: The aim of this study is to review the literatures depicting the about immunosuppressant’s, its impact on fertility and related pregnancy outcomes. Methods: A systematic literature search of the Pub Med database was performed using a combination of relevant terms related to ‘infertility’, 'conception', 'reproduction', 'immunosuppressant’s. Conclusion: From the review of many literatures this study concludes that immunosuppressants has varying effect on pregnancy. Some of the immunosuppressants at therapeutic doses can cause infertility when used for a long time.

Keywords


Fertility, Reproduction, Conception, Immunosuppressants.

References