Amin J, Huang B, Yoon J, et al. Update 2014: advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD. Inflamm Bowel Dis. 2015;21:445–52.

Article  PubMed  Google Scholar 

Lee MN, Kang B, Choi SY, et al. Relationship between azathioprine dosage, 6-thioguanine nucleotide levels, and therapeutic response in pediatric patients with IBD treated with azathioprine. Inflamm Bowel Dis. 2015;21:1054–62.

Article  CAS  PubMed  Google Scholar 

Timmer A, McDonald JW, Tsoulis DJ, et al. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2012;9:CD000478.

Google Scholar 

Chande N, Patton PH, Tsoulis DJ, et al. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev. 2015;10:CD000067.

Torres J, Bonovas S, Doherty G, et al. ECCO guidelines on therapeutics in Crohn’s disease: medical treatment. J Crohns Colitis. 2020;14:4–22.

Article  PubMed  Google Scholar 

van Gennep S, de Boer NK, D’Haens GR, et al. Thiopurine treatment in ulcerative colitis: a critical review of the evidence for current clinical practice. inflamm Bowel Dis. 2017;24:67–77.

Article  PubMed  Google Scholar 

Gearry RB, Barclay ML, Burt MJ, et al. Thiopurine drug adverse effects in a population of New Zealand patients with inflammatory bowel disease. Pharmacoepidemiol Drug Saf. 2004;13:563–7.

Article  CAS  PubMed  Google Scholar 

Van Dieren JM, Hansen BE, Kuipers EJ, et al. Meta-analysis: inosine triphosphate pyrophosphatase polymorphisms and thiopurine toxicity in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther. 2007;26:643–52.

Article  PubMed  Google Scholar 

Chaparro M, Ordas I, Cabre E, et al. Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients. Inflamm Bowel Dis. 2013;19:1404–10.

Article  PubMed  Google Scholar 

Chang JY, Cheon JH. Thiopurine therapy in patients with inflammatory bowel disease: a focus on metabolism and pharmacogenetics. Dig Dis Sci. 2019;64:2395–403.

Article  PubMed  Google Scholar 

Yang SK, Hong M, Baek J, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014;46:1017–20.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Moriyama T, Nishii R, Perez-Andreu V, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet. 2016;48:367–73.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther. 2019;105:1095–105.

Article  CAS  PubMed  Google Scholar 

Kakuta Y, Kawai Y, Okamoto D, et al. NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study. J Gastroenterol. 2018;53:1065–78.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yang JJ, Landier W, Yang W, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol. 2015;33:1235–42.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Chang JY, Park SJ, Jung ES, et al. Genotype-based treatment with thiopurine reduces incidence of myelosuppression in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2020;18(2010–8): e2.

Google Scholar 

Asada A, Nishida A, Shioya M, et al. NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease. J Gastroenterol. 2016;51:22–9.

Article  CAS  PubMed  Google Scholar 

Kakuta Y, Naito T, Onodera M, et al. NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD. Pharmacogenomics J. 2016;16:280–5.

Article  CAS  PubMed  Google Scholar 

Warner B, Johnston E, Arenas-Hernandez M, et al. A practical guide to thiopurine prescribing and monitoring in IBD. Frontline Gastroenterol. 2018;9:10–5.

Article  CAS  PubMed  Google Scholar 

Nakase H, Uchino M, Shinzaki S, et al. Evidence-based clinical practice guidelines for inflammatory bowel disease 2020. J Gastroenterol. 2021;56:489–526.

Article  PubMed  PubMed Central  Google Scholar 

Imai T, Kawahara M, Tatsumi G, et al. Thiopurine use during pregnancy has deleterious effects on offspring in Nudt 15(R138C) knock-in mice. Cell Mol Gastroenterol Hepatol. 2021;12:335–7.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tatsumi G, Kawahara M, Imai T, et al. Thiopurine-mediated impairment of hematopoietic stem and leukemia cells in Nudt 15(R138C) knock-in mice. Leukemia. 2020;34:882–94.

Article  CAS  PubMed  Google Scholar 

Yang L, Boyd K, Kaste SC, et al. A mouse model for glucocorticoid-induced osteonecrosis: effect of a steroid holiday. J Orthop Res. 2009;27:169–75.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Shin SC, Kang YM, Jin YW, et al. Relative morphological abnormalities of sperm in the caudal epididymis of high- and low-dose-rate gamma-irradiated ICR mice. J Radiat Res. 2009;50:261–6.

Article  PubMed  Google Scholar 

Takeda N, Yoshinaga K, Furushima K, et al. Viable offspring obtained from Prm1-deficient sperm in mice. Sci Rep. 2016;6:27409. https://doi.org/10.1038/srep27409.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yoshida S. From cyst to tubule: innovations in vertebrate spermatogenesis. Wiley Interdiscip Rev Dev Biol. 2016;5:119–31.

Article  PubMed  Google Scholar 

Weinbauer GF, Nieschlag E. Gonadotrophin control of testicular germ cell development. Adv Exp Med Biol. 1995;377:55–65.

Article  CAS  PubMed  Google Scholar 

Migrenne S, Moreau E, Pakarinen P, et al. Mouse testis development and function are differently regulated by follicle-stimulating hormone receptors signaling during fetal and prepubertal life. PLoS ONE. 2012;7: e53257. https://doi.org/10.1371/journal.pone.0053257.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Patel H, Bhartiya D. Direct action of FSH on testicular stem cells. Stem Cell Res Ther. 2019;10:261.

Article  PubMed  PubMed Central  Google Scholar 

Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol. 2015;12:720–7.

Article  PubMed  Google Scholar 

van den Heuvel TR, Wintjens DS, Jeuring SF, et al. Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort. Int J Cancer. 2016;139:1270–80.

Article  PubMed  Google Scholar 

Oatley JM, Reeves JJ, McLean DJ. Biological activity of cryopreserved bovine spermatogonial stem cells during in vitro culture. Biol Reprod. 2004;71:942–7.

Article  CAS  PubMed  Google Scholar 

Habas K, Brinkworth MH, Anderson D. In vitro responses to known in vivo genotoxic agents in mouse germ cells. Environ Mol Mutagen. 2017;58:99–107.

Article  CAS  PubMed  Google Scholar 

Kotaja N, De Cesare D, Macho B, et al. Abnormal sperm in mice with targeted deletion of the act (activator of cAMP-responsive element modulator in testis) gene. Proc Natl Acad Sci U S A. 2004;101:10620–5.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Simsek M, Lambalk CB, Wilschut JA, et al. The associations of thiopurines with male fertility and paternally exposed offspring: a systematic review and meta-analysis. Hum Reprod Update. 2018;24:192–206.

Article  CAS  PubMed  Google Scholar 

Ligumsky M, Badaan S, Lewis H, et al. Effects of 6-mercaptopurine treatment on sperm production and reproductive performance: a study in male mice. Scand J Gastroenterol. 2005;40:444–9.

Article  CAS  PubMed  Google Scholar 

Karl PI, Katz R, Daum F, et al. 6-Mercaptopurine and spermatogenesis in the young rat. Dig Dis Sci. 1991;36:1569–73.

Article  CAS  PubMed  Google Scholar 

de Boer NK, de Meij T, van Bodegraven AA. Thiopurines during pregnancy in inflammatory bowel disease: is there a risk for the (unborn) child? Expert Rev Gastroenterol Hepatol. 2013;7:669–71.

Article  PubMed  Google Scholar 

Coelho J, Beaugerie L, Colombel JF, et al. Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines: cohort from the CESAME Study. Gut. 2011;60:198–203.

Article