Sulfasalazine and 5-aminosalicylates (5-ASAs) have been used for the initial treatment of IBD and for long-term maintenance of disease remission[28]. These drugs have anti-inflammatory activity.

Levi et al[29] first reported 4 cases of male infertility associated with sulfasalazine in 1979. In all 4 cases, discontinuation of sulfasalazine led to successful conception. Subsequent studies showed that this medication causes reversible non-dose-dependent quantitative and qualitative abnormalities of sperm in > 80% of men[28,30,31]. Birnie et al[32] examined 21 men with CD who received sulfasalazine and found that 18 of them had abnormal semen analysis results and 15 had oligozoospermia. Another study by Moody et al[4] showed that 25% of men with IBD had no children, compared with 15% of men in the general population. They also found that 60% of male IBD patients who had no children were taking sulfasalazine. Sulfasalazine is a molecule that has two components: 5-ASA and sulfapyridine. The sulfapyridine metabolite is thought to be responsible for adverse effects on sperm, causing impaired sperm maturation or oxidative stress production[33-36]. However, Wu et al[37] found no correlation between reactive oxygen species production and sperm density, sperm motility, or hamster oocyte penetration capacity. The adverse effects of sulfasalazine on sperm have been shown to be fully reversible after discontinuation[29,31,33,36,38]. Restoration of semen quality and fertility has also been shown after switching to a different 5-ASA compound without the sulfapyridine component, such as mesalazine (also called mesalamine)[39,40]. Zelissen et al[41] evaluated semen quality in 11 patients with IBD during sulfasalazine treatment and 4 mo after replacing sulfasalazine with an oral slow-release preparation of 5-ASA, and observed significant improvements in sperm count, morphology, and motility during 5-ASA treatment in comparison with sulfasalazine treatment. Notably, 3 pregnancies occurred during the study period.

On the other hand, there is a case report of mesalazine-induced oligozoospermia in a young man with UC. In that case, semen analysis results returned to near normal and pregnancy occurred after mesalazine treatment was stopped, but the patient’s semen parameters worsened after resuming mesalazine[42]. Moreover, we have reported a retrospective study of the negative influence of mesalazine on fertility in men with IBD[43]. In this study, 7 of 1225 male subfertile patients had received mesalazine. In 6 of them, mesalazine was discontinued and sperm motility and total motile sperm count were significantly improved. After discontinuation of mesalazine, 4 of the 6 patients achieved pregnancy with their partners. However, mesalazine should be discontinued in only patients with stable disease, and it is possible that low IBD activity itself might have contributed to the improved semen analysis results in the patients who discontinued mesalazine.

With respect to pregnancy complications, Moody et al[4] suggested an increased risk of congenital malformations in children born to men on sulfasalazine, but a meta-analysis examining the risk of adverse pregnancy outcomes in women with IBD after exposure to 5-ASAs including sulfasalazine showed no significant increase in congenital abnormalities, stillbirths, spontaneous abortions, preterm deliveries, or low birth weight[44].

From the evidence accumulated to date, discontinuation of sulfasalazine is recommended for prospective fathers, but not discontinuation of 5-ASA compounds lacking the sulfapyridine moiety.

Corticosteroids are potent anti-inflammatory agents used for moderate to severe relapses of both CD and UC, but they have no role in maintenance therapy. Corticosteroids inhibit several inflammatory pathways by suppression of interleukin transcription; induction of I-kappa B, which stabilizes the nuclear factor kappa B complex; suppression of arachidonic acid metabolism; and stimulation of apoptosis of lymphocytes within the lamina propria of the gut[45].

Limited data are available on the effects of corticosteroids therapy on fertility for men with IBD. Lerman et al[46] found a reversible reduction in fertility in rats exposed to corticosteroids in spite of no changes in sperm count and motility. In a study of 5 endurance-trained men, Roberts et al[47] showed that an increase in endogenous steroids might be correlated with a subsequent decrease in sperm concentration 74 d later. In contrast, in a study of 70 men with CD and a group of age-matched controls, Burnell et al[48] found no correlation between male infertility and steroid use. In a study of IBD patients undergoing azathioprine (AZA) treatment, the additional administration of corticosteroids had no negative influence on seminogram findings[49]. Definite conclusions regarding the effects of corticosteroids on male fertility cannot be drawn at present because of insufficient data.

AZA and its active metabolite 6-mercaptopurine (6-MP) are widely used as adjunctive therapy in IBD and as corticosteroid-sparing therapies although they are unapproved therapies for IBD[47].

In a study of 18 men with IBD who received AZA, no worsening of semen analysis results was found, and 6 of the men fathered children during the study period[49]. In a survey of 164 male renal transplant recipients, Xu et al[50] concluded that long-term treatment with cyclosporine, AZA, and corticosteroid had no obvious effect on fertility.

A study of male mice exposed to 6-MP showed no reduction in sperm quantity or quality, but a significantly increased incidence of abortion was noted. The authors suggested that this indicated occult sperm damage[51]. In a study of male patients with IBD who were treated with 6-MP, Rajapakse et al[52] revealed that the incidence of pregnancy-related complications was significantly increased when the father had used 6-MP within 3 mo of conception. Another study showed that paternal use of AZA or 6-MP before conception was associated with an increased, but not statistically significant, risk of congenital abnormalities[16,53]. Conversely, Francella et al[54] found no significant difference in pregnancy outcomes for both men and women taking 6-MP as compared with controls. Teruel et al[55] evaluated the outcomes of pregnancies in which the father was exposed to thiopurines at the time of conception, and found no significant difference in unsuccessful pregnancies, namely, spontaneous abortions, ectopic pregnancies, anembryonic pregnancies, or fetal deaths. They concluded that routine alteration of treatment regimens was not recommended for men taking thiopurines when attempting to conceive. According to a review by Akbari et al[56] concerning the effects of thiopurines on birth outcomes, thiopurine exposure in men with IBD at the time of conception was not associated with congenital abnormalities[28].

In summary, thiopurines do not appear to deteriorate semen quality. Some studies have suggested that paternal thiopurine treatment is associated with an increased risk of pregnancy complications, but in most past studies, paternal thiopurine exposure was not related to congenital abnormalities. Regarding the use of thiopurines in male IBD patients who wish to conceive, Sands et al[28] proposed that health care providers should inform them that there is a possibility of an increased risk of congenital defects and pregnancy complications although fertility does not seem to be affected.

Methotrexate (MTX) is positioned as a second-line immunosuppressive agent used in patients resistant or intolerant to AZA or 6-MP. Polyglutamated metabolites of MTX act through the inhibition of dihydrofolate reductase, and the inhibition of cytokine and eicosanoid synthesis are thought to play a role[45].

MTX is known to have teratogenic effects in women, and it is classified by the American Foods and Drug Administration under Pregnancy Category X, which means that it is contraindicated during pregnancy[7]. However, data are scarce on the effect of MTX on male fertility. Studies of animals exposed to MTX showed altered spermatogenesis, cytotoxicity, and degeneration of spermatocytes, Sertoli cells, and Leydig cells[15,28,57,58]. In 1980, Sussman et al[59] reported severe oligozoospermia after MTX administration but a return to normal sperm concentrations after discontinuation of MTX. The antifolate mechanism of MTX, which results in decreased DNA synthesis rates and subsequent inhibition of cellular proliferation, likely causes reversible oligozoospermia[28]. El-Beheiry et al[60] investigated the effects of MTX on fertility potential in 26 male psoriatic patients. They showed no abnormalities in semen analysis, testicular histology, or spermatogenic function observed using radioactive phosphorus, although a longer follow-up was required to rule out the possible teratogenic effects of the drug.

There have been no reports of MTX-induced adverse pregnancy outcomes in men exposed to the drug. Recently, Weber-Schoendorfer et al[61] performed a prospective observational cohort study involving 113 pregnancies where the father was treated with low-dose MTX around the time of conception. As compared with 412 pregnancies without MTX exposure, no increase was observed in the rate of major birth defects or the risk of spontaneous abortion. Further, gestational age at delivery and birth weights did not differ significantly between the groups. Given these results, they concluded that it seems reasonable not to postpone family planning in the case of unavoidable paternal MTX therapy.

However, the active metabolites of MTX could remain in cells or tissues for several months after discontinuation[16]. Furthermore, MTX seems to be associated with erectile dysfunction[62-64]. In most of the literature reviews, discontinuation of MTX was recommended at least 3-4 mo before a planned conception for men with IBD[7,15,16].

Ciclosporin (CsA) is a calcineurin inhibitor used for treating severe IBD. It prevents clonal expansion of T cell subsets with a rapid onset of action. Tacrolimus is another calcineurin inhibitor, and is often preferred in transplant recipients[45]. CsA and tacrolimus differ in their chemical structure: Tacrolimus is a macrocyclic lactone, while CsA is a cyclic endecapeptide. However, they act in a similar manner as calcineurin inhibitors.

In a review, Sands et al[28] introduced one study using male mice exposed to CsA, and remarked on the presence of abnormal sperm, oligozoospermia, decreased motility, decreased testicular weight, and decreased testosterone concentrations. A study in rats found that CsA had a deleterious effect on spermiogenesis by directly impairing spermiogenic cell development and by impeding Sertoli cell function[65]. In humans, small studies have not found an association between CsA use and male fertility[16,66-68]. There have been no reports of adverse pregnancy outcomes in partners of men receiving CsA.

Three biological agents are used for the treatment of IBD, namely, infliximab (IFX), adalimumab, and certolizumab. All agents are monoclonal antibodies against tumor necrosis factor-alpha (anti-TNF). IFX is a chimeric anti-TNF antibody, consisting of 75% human IgG and 25% murine component. Adalimumab and certolizumab are humanized anti-TNF antibodies. These agents are indicated in CD resistant to standard immunosuppression therapy. IFX is also indicated in UC and fistulating CD[45].

Few studies have examined the effects of anti-TNF on male fertility. IFX is the most studied of the three agents[28]. One animal study using analogous anti-TNF agents revealed no adverse effect on male fertility[7,69]. In a study of 10 men (8 with IBD, 2 with indeterminate colitis), Mahadevan et al[70] showed a significant increase in semen volume one week after IFX infusion and a trend toward decreased sperm motility. In contrast, in a study of 26 men with spondyloarthritis, Villiger et al[71] showed no statistically significant difference in sperm quality between healthy controls and patients treated with anti-TNF. They recommended the continuation of anti-TNF treatment when fatherhood was planned. Further, in a prospective study of 10 men with spondyloarthritis and 20 healthy male controls, Ramonda et al[72] found a statistically significant decrease in sperm aneuploidies and normal hormone levels after a 12-mo anti-TNF regimen and concluded that anti-TNF agents appeared to be safe for testicular function and male fertility.

Exposure to anti-TNF agents in men prior to a planned conception does not seem to cause embryo toxicity. One study that investigated medical records of men with ankylosing spondylitis reported that 4 patients had fathered 6 healthy children during IFX treatment[73]. A systematic review by Puchner et al[74] did not found any documentation of miscarriages or physical abnormities associated with anti-TNF treatment and paternity. Instead, an improvement in sperm motility and vitality during anti-TNF treatment was shown in that review. The authors suggested that the improvement might be due to a decrease in disease activity.

Active disease seems to affect male reproductive and sexual function[15,16]. The presence of pro-inflammatory cytokines, including TNF, in the male urogenital tract could lead to cytokine-mediated antifertility effects. Furthermore, inflammation is associated with elevated levels of reactive oxygen species and oxidative stress, both of which have a negative effect on male fertility[75]. Regarding sexual function, Timmer et al[76] showed that men with IBD in remission or with mild disease activity had similar rates of erectile dysfunction as compared with controls, whereas men with severe IBD activity had higher rates. Thus, control of IBD activity is recommended for men planning to conceive.

Poor nutritional status in men with IBD might cause infertility. El-Tawil suggested a possible relation between decreased testicular function and zinc deficiency, which has been found in up to 70% of patients with CD[77]. To date, no other studies have specifically addressed the contribution of nutritional status to male infertility in IBD, but Feagins et al[15] proposed that optimizing nutritional status is important for men with IBD who are attempting to father children.

There are several studies that implicate a negative effect of alcohol consumption on the course of IBD[78]. Swanson et al[79] showed that alcohol resulted in exacerbation of gastrointestinal symptoms in patients with non-active UC and CD. Jowett et al[80] indicated that alcohol consumption increased the risk of disease exacerbation in patients with UC. Thus, alcohol use could activate the disease in the patients with IBD. Moreover, past studies implicated alcohol use in decreasing sperm quality and fertility in men[15,81-83]. Alcohol is considered as one of factors that might be contributing to male infertility in men with IBD.

Smoking is the most researched environmental factor associated with IBD. It has been observed that smoking has a varying impact on CD and UC, contributing to an increased risk for individuals with CD and a protective role in individuals with UC[1]. The mechanism of these paradoxical effects of smoking on CD and UC is not well understood. It is hypothesized that nicotine and oxidative stress play some role[1,84].

Even if smoking protects against UC, smoking itself impairs fertilization capacity[83]. Tobacco combustion produces many chemical compounds with potential deleterious effects on male germ cells[85]. The toxins originating from cigarette smoke can decrease sperm mitochondrial activity and damage the chromatin structure in human sperm[83]. From a recent meta-analysis of 20 studies with 5865 participants, smoking was found to be a significant risk factor for decreased semen parameters in men[86]. Therefore, smoking cessation is expected to have a positive influence on semen quality and consequently male fertility.

Past studies showed lower birth rates to men after IBD diagnosis than before diagnosis compared with controls[5,48]. These results meant that IBD men might consider voluntary childlessness apart from physiological factors that could reduce fertility[87]. This voluntary childlessness appears to result from concerns about adverse reproductive outcomes that may not be justified, or patients’ fear of transmitting the disease[7,88]. In a questionnaire survey, Mountifield et al[88] concluded that patients require accurate counseling addressing fertility and pregnancy outcomes in IBD to assist in their decision making.