Inflammatory Bowel Disease Therapies Adversely Affect Fertility in Men- A Systematic Review and Meta-analysis

Author(s): Antara Banerjee, Marco Scarpa*, Surajit Pathak, Patrizia Burra, Giacomo C. Sturniolo, Francesco P. Russo, Ram Murugesan, Renata D'Incá*

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders

Volume 19 , Issue 7 , 2019


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Graphical Abstract:


Abstract:

Background and Aims: Sexual functions are sometimes adversely affected by the therapeutic drugs delivered for treating IBD. Much attention has been focused on pregnancy/sexual issues in women. Relatively less attention has been poured in to address this issue in men. This systematic review assesses the drugs having potential detrimental effects on fertility in men.

Methods: Three databases were searched by two researchers independently for potentially relevant publications between 1964 to 2015 and 249 papers were retrieved. Studies that dealt with sexual problems after IBD drugs administration were included in the purview of this review.

Results: Fourteen studies with 327 human patients and 110 animals were analysed. Sulphasalazine treated patients had lower spermatozoa count, lower sperm motility and higher risk of oligospermia compared to mesalazine treated ones. Biologics seem to be safe to use while attempting to conceive however, proper clinical studies reporting male fertility problems in IBD patients are lacking. Azathioprine caused oligospermia but a meta-analytical approach was not possible due to heterogeneity in studies. Some animal studies showed methotrexate affects abnormal testis structure and spermatogenesis.

Conclusion: This study summarises the current literature and safety issues affecting fertility parameters in men and animals treated with IBD therapeutic drugs, which can further assist clinicians in better management of adult male IBD patients.

Keywords: Inflammatory bowel disease, therapies, male fertility, Ulcerative colitis, azathioprine, oligospermia.

[1]
Ruess, L. Nussbaum, Blask A.R; Bulas, D.I.; Mohan, P.; Bader, A.; Latimer, J.S.; Benny, K. Inflammatory Bowel Disease in Children and Young Adults. Correlation of Sonographic and Clinical Parameters During Treatment. Am. J. Gastroenterol., 2000, 175, 179-184.
[2]
Andres, P.G.; Friedman, L.S. Epidemiology and the natural course of inflammatory bowel disease. Gastroenterol. Clin. North Am., 1999, 28(2), 255-281. vii.
[http://dx.doi.org/10.1016/S0889-8553(05)70056-X] [PMID: 10372268]
[3]
Mahadevan, U.; Sandborn, W.J.; Li, D.K.; Hakimian, S.; Kane, S.; Corley, D.A. Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California. Gastroenterology, 2007, 133(4), 1106-1112.
[http://dx.doi.org/10.1053/j.gastro.2007.07.019] [PMID: 17764676]
[4]
Baumgart, D.C.; Carding, S.R. Inflammatory bowel disease: cause and immunobiology. Lancet, 2007, 369(9573), 1627-1640.
[http://dx.doi.org/10.1016/S0140-6736(07)60750-8] [PMID: 17499605]
[5]
Baumgart, D.C.; Sandborn, W.J. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet, 2007, 369(9573), 1641-1657.
[http://dx.doi.org/10.1016/S0140-6736(07)60751-X] [PMID: 17499606]
[6]
Harrell, L.E.; Hanauer, S.B. Mesalamine derivatives in the treatment of Crohn’s disease. Gastroenterol. Clin. North Am., 2004, 33(2), 303-317. [ix-x.]
[http://dx.doi.org/10.1016/j.gtc.2004.02.010] [PMID: 15177540]
[7]
Singleton, J.W.; Hanauer, S.B.; Gitnick, G.L.; Peppercorn, M.A.; Robinson, M.G.; Wruble, L.D.; Krawitt, E.L. Mesalamine capsules for the treatment of active Crohn’s disease: results of a 16-week trial. Gastroenterology, 1993, 104(5), 1293-1301.
[http://dx.doi.org/10.1016/0016-5085(93)90337-C] [PMID: 8482443]
[8]
Summers, R.W.; Switz, D.M.; Sessions, J.T., Jr; Becktel, J.M.; Best, W.R.; Kern, F., Jr; Singleton, J.W. National Cooperative Crohn’s Disease Study: results of drug treatment. Gastroenterology, 1979, 77(4 Pt 2), 847-869.
[http://dx.doi.org/10.1016/0016-5085(79)90385-8] [PMID: 38176]
[9]
Rutgeerts, P.; Löfberg, R.; Malchow, H.; Lamers, C.; Olaison, G.; Jewell, D.; Danielsson, A.; Goebell, H.; Thomsen, O.O.; Lorenz-Meyer, H. A comparison of budesonide with prednisolone for active Crohn’s disease. N. Engl. J. Med., 1994, 331(13), 842-845.
[http://dx.doi.org/10.1056/NEJM199409293311304] [PMID: 8078530]
[10]
Gross, V.; Andus, T.; Caesar, I.; Bischoff, S.C.; Lochs, H.; Tromm, A.; Schulz, H.J.; Bär, U.; Weber, A.; Gierend, M.; Ewe, K.; Schölmerich, J. Oral pH-modified release budesonide versus 6-methylprednisolone in active Crohn’s disease. Eur. J. Gastroenterol. Hepatol., 1996, 8(9), 905-909.
[PMID: 8889459]
[11]
Schroll, S.; Sarlette, A.; Ahrens, K.; Manns, M.P.; Göke, M. Effects of azathioprine and its metabolites on repair mechanisms of the intestinal epithelium in vitro. Regul. Pept., 2005, 131(1-3), 1-11.
[http://dx.doi.org/10.1016/j.regpep.2005.03.001] [PMID: 16122821]
[12]
Sandborn, W.; Sutherland, L.; Pearson, D.; May, G.; Modigliani, R.; Prantera, C. Azathioprine or 6-mercaptopurine for inducing remission of Crohn’s disease. Cochrane Database Syst. Rev., 2000, (2)CD000545
[PMID: 10796557]
[13]
Pearson, D.C.; May, G.R.; Fick, G.; Sutherland, L.R. Azathioprine for maintaining remission of Crohn’s disease. Cochrane Database Syst. Rev., 2000, (2)CD000067
[PMID: 10796482]
[14]
Levi, A.J.; Fisher, A.M.; Hughes, L.; Hendry, W.F. Male infertility due to sulphasalazine. Lancet, 1979, 2(8137), 276-278.
[http://dx.doi.org/10.1016/S0140-6736(79)90292-7] [PMID: 88609]
[15]
Jason, M.M.D.; Kane, S.V.; Feagins, L.A. Fertility and Contraception in Women With Inflammatory Bowel Disease. Gastroenterol. Hepatol., 2016, 12(2), 101-109.
[16]
Shin, T.; Okada, H. Infertility in men with inflammatory bowel disease. World J. Gastrointest. Pharmacol. Ther., 2016, 7(3), 361-369.
[http://dx.doi.org/10.4292/wjgpt.v7.i3.361] [PMID: 27602237]
[17]
Dejaco, C.; Mittermaier, C.; Reinisch, W.; Gasche, C.; Waldhoer, T.; Strohmer, H.; Moser, G. Azathioprine treatment and male fertility in inflammatory bowel disease. Gastroenterology, 2001, 121(5), 1048-1053.
[http://dx.doi.org/10.1053/gast.2001.28692] [PMID: 11677195]
[18]
Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement., PLoS Med, 2009, 21, 6(7), e1000097
[19]
Scarpa, M.; Castagliuolo, I.; Castoro, C.; Pozza, A.; Scarpa, M.; Kotsafti, A.; Angriman, I. Inflammatory colonic carcinogenesis: a review on pathogenesis and immunosurveillance mechanisms in ulcerative colitis. World J. Gastroenterol., 2014, 20(22), 6774-6785.
[http://dx.doi.org/10.3748/wjg.v20.i22.6774] [PMID: 24944468]
[20]
Angriman, I.; Scarpa, M.; Castagliuolo, I. Relationship between pouch microbiota and pouchitis following restorative proctocolectomy for ulcerative colitis., World J Gastroenterol, 2014, 7,20(29), 9665-9674.
[http://dx.doi.org/10.3748/wjg.v20.i29.9665]
[21]
Zelissen, P.M.; van Hattum, J.; Poen, H.; Scholten, P.; Gerritse, R.; te Velde, E.R. Influence of salazosulphapyridine and 5-aminosalicylic acid on seminal qualities and male sex hormones. Scand. J. Gastroenterol., 1988, 23(9), 1100-1104.
[http://dx.doi.org/10.3109/00365528809090175] [PMID: 2907823]
[22]
Farthing, M.J.; Dawson, A.M. Impaired semen quality in Crohn’s disease--drugs, ill health, or undernutrition? Scand. J. Gastroenterol., 1983, 18(1), 57-60.
[http://dx.doi.org/10.3109/00365528309181559] [PMID: 6144170]
[23]
Mahadevan, U.; Terdiman, J.P.; Aron, J.; Jacobsohn, S.; Turek, P. Infliximab and semen quality in men with inflammatory bowel disease. Inflamm. Bowel Dis., 2005, 11(4), 395-399.
[http://dx.doi.org/10.1097/01.MIB.0000164023.10848.c4] [PMID: 15803031]
[24]
Birnie, G.G.; McLeod, T.I.; Watkinson, G. Incidence of sulphasalazine-induced male infertility. Gut, 1981, 22(6), 452-455.
[http://dx.doi.org/10.1136/gut.22.6.452] [PMID: 6114898]
[25]
Riley, S.A.; Lecarpentier, J.; Mani, V.; Goodman, M.J.; Mandal, B.K.; Turnberg, L.A. Sulphasalazine induced seminal abnormalities in ulcerative colitis: results of mesalazine substitution. Gut, 1987, 28(8), 1008-1012.
[http://dx.doi.org/10.1136/gut.28.8.1008] [PMID: 2889648]
[26]
Burnell, D.; Mayberry, J.; Calcraft, B.J.; Morris, J.S.; Rhodes, J. Male fertility in Crohn’s disease. Postgrad. Med. J., 1986, 62(726), 269-272.
[http://dx.doi.org/10.1136/pgmj.62.726.269] [PMID: 2872665]
[27]
O’Moráin, C.; Smethurst, P.; Doré, C.J.; Levi, A.J. Reversible male infertility due to sulphasalazine: studies in man and rat. Gut, 1984, 25(10), 1078-1084.
[http://dx.doi.org/10.1136/gut.25.10.1078] [PMID: 6148293]
[28]
Di Paolo, M.C.; Paoluzi, O.A.; Pica, R.; Iacopini, F.; Crispino, P.; Rivera, M.; Spera, G.; Paoluzi, P. Sulphasalazine and 5-aminosalicylic acid in long-term treatment of ulcerative colitis: report on tolerance and side-effects. Dig. Liver Dis., 2001, 33(7), 563-569.
[http://dx.doi.org/10.1016/S1590-8658(01)80108-0] [PMID: 11816545]
[29]
Ludvigsson, J.F.; Ludvigsson, J. Inflammatory bowel disease in mother or father and neonatal outcome. Acta Paediatr., 2002, 91(2), 145-151.
[http://dx.doi.org/10.1111/j.1651-2227.2002.tb01686.x] [PMID: 11952000]
[30]
Kjaergaard, N.; Christensen, L.A.; Lauritsen, J.G.; Rasmussen, S.N.; Hansen, S.H. Effects of mesalazine substitution on salicylazosulfapyridine-induced seminal abnormalities in men with ulcerative colitis. Scand. J. Gastroenterol., 1989, 24(7), 891-896.
[http://dx.doi.org/10.3109/00365528909089231] [PMID: 2572047]
[31]
Shrestha, S.; Dhungel, S.; Saxena, A.K.; Bhattacharya, S.; Maskey, D. Effect of methotrexate (MTX) administration on spermatogenesis: an experimental on animal model. Nepal Med. Coll. J., 2007, 9(4), 230-233.
[PMID: 18298010]
[32]
Masuda, H.; Fujihira, S.; Ueno, H.; Kagawa, M.; Katsuoka, Y.; Mori, H. Ultrastructural study on cytotoxic effects of cyclosporine A in spermiogenesis in rats. Med. Electron Microsc., 2003, 36(3), 183-191.
[http://dx.doi.org/10.1007/s00795-003-0213-4] [PMID: 14505063]
[33]
Saxena, A.K.; Dhungel, S.; Bhattacharya, S.; Jha, C.B.; Srivastava, A.K. Effect of chronic low dose of methotrexate on cellular proliferation during spermatogenesis in rats. Arch. Androl., 2004, 50(1), 33-35.
[http://dx.doi.org/10.1080/01485010490250533] [PMID: 14660169]
[34]
Narendranathan, M.; Sandler, R.S.; Suchindran, C.M.; Savitz, D.A. Male infertility in inflammatory bowel disease. J. Clin. Gastroenterol., 1989, 11(4), 403-406.
[http://dx.doi.org/10.1097/00004836-198908000-00011] [PMID: 2760429]
[35]
Timmer, A.; Bauer, A.; Kemptner, D.; Furst, A.; Rogler, G. Determinants of male sexual function in infl ammatory bowel disease: a survey-based cross-sectional analysis in 280 men. Inflamm. Bowel Dis., 2007, 13, 1236-1243.
[http://dx.doi.org/10.1002/ibd.20182] [PMID: 17508419]
[36]
Timmer, A.; Bauer, A.; Dignass, A.; Rogler, G. Sexual function in persons with inflammatory bowel disease: a survey with matched controls. Clin. Gastroenterol. Hepatol., 2007, 5(1), 87-94.
[http://dx.doi.org/10.1016/j.cgh.2006.10.018] [PMID: 17234557]
[37]
Heetun, Z.S.; Byrnes, C.; Neary, P.; O’Morain, C. Review article: Reproduction in the patient with inflammatory bowel disease. Aliment. Pharmacol. Ther., 2007, 26(4), 513-533.
[http://dx.doi.org/10.1111/j.1365-2036.2007.03397.x] [PMID: 17661756]
[38]
Correia, L.M.; Bonilha, D.Q.; Ramos, J.D.; Ambrogini, O.; Miszputen, S.J. Treatment of inflammatory bowel disease and pregnancy: a review of the literature. Arq. Gastroenterol., 2010, 47(2), 197-201.
[http://dx.doi.org/10.1590/S0004-28032010000200016] [PMID: 20721468]
[39]
Tavernier, N.; Fumery, M.; Peyrin-Biroulet, L.; Colombel, J.F.; Gower-Rousseau, C. Systematic review: fertility in non-surgically treated inflammatory bowel disease. Aliment. Pharmacol. Ther., 2013, 38(8), 847-853.
[http://dx.doi.org/10.1111/apt.12478] [PMID: 24004045]
[40]
Sauk, J.; Kane, S. The use of medications for inflammatory bowel disease during pregnancy and nursing. Expert Opin. Pharmacother., 2005, 6(11), 1833-1839.
[http://dx.doi.org/10.1517/14656566.6.11.1833] [PMID: 16144504]
[41]
Taffet, S.L.; Das, K.M. Sulfasalazine. Adverse effects and desensitization. Dig. Dis. Sci., 1983, 28(9), 833-842.
[http://dx.doi.org/10.1007/BF01296907] [PMID: 6136396]
[42]
Feagins, L.A.; Kane, S.V. Sexual and reproductive issues for men with inflammatory bowel disease. Am. J. Gastroenterol., 2009, 104(3), 768-773.
[http://dx.doi.org/10.1038/ajg.2008.90] [PMID: 19223893]
[43]
Kornbluth, A.; Sachar, D.B. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am. J. Gastroenterol., 2010, 105(3), 501-523.
[http://dx.doi.org/10.1038/ajg.2009.727] [PMID: 20068560]
[44]
Rosenblatt, E.; Kane, S. Sex-Specific Issues in Inflammatory Bowel Disease. Gastroenterol. Hepatol. (N. Y.), 2015, 11(9), 592-601.
[PMID: 27482181]
[45]
Puchner, R.; Danninger, K.; Puchner, A.; Pieringer, H. Impact of TNF-blocking agents on male sperm characteristics and pregnancy outcomes in fathers exposed to TNF-blocking agents at time of conception. Clin. Exp. Rheumatol., 2012, 30(5), 765-767.
[PMID: 22935608]
[46]
Ramonda, R.; Foresta, C.; Ortolan, A.; Bertoldo, A.; Oliviero, F.; Lorenzin, M.; Pizzol, D.; Punzi, L.; Garolla, A. Influence of tumor necrosis factor α inhibitors on testicular function and semen in spondyloarthritis patients. Fertil. Steril., 2014, 101(2), 359-365.
[http://dx.doi.org/10.1016/j.fertnstert.2013.10.048] [PMID: 24332378]
[47]
Paschou, S.; Voulgari, P.V.; Vrabie, I.G.; Saougou, I.G.; Drosos, A.A. Fertility and reproduction in male patients with ankylosing spondylitis treated with infliximab. J. Rheumatol., 2009, 36(2), 351-354.
[http://dx.doi.org/10.3899/jrheum.080554] [PMID: 19040305]
[48]
Lautenschläger, C.; Schmidt, C.; Fischer, D.; Stallmach, A. Drug delivery strategies in the therapy of inflammatory bowel disease. Adv. Drug Deliv. Rev., 2014, 71, 58-76.
[http://dx.doi.org/10.1016/j.addr.2013.10.001] [PMID: 24157534]
[49]
Colombel, J.F.; Sands, B.E.; Rutgeerts, P.; Sandborn, W.; Danese, S.; D’Haens, G.; Panaccione, R.; Loftus, E.V., Jr; Sankoh, S.; Fox, I.; Parikh, A.; Milch, C.; Abhyankar, B.; Feagan, B.G. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut, 2016, 0, 1-13.
[PMID: 26893500]


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Article Details

VOLUME: 19
ISSUE: 7
Year: 2019
Published on: 10 October, 2019
Page: [959 - 974]
Pages: 16
DOI: 10.2174/1871530319666190313112110
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