INTRODUCTION — A number of antiinflammatory and immunosuppressive drugs have improved the treatment of rheumatoid arthritis (RA), spondyloarthritis (SpA), systemic lupus erythematosus (SLE), and other rheumatic disorders. These conditions often impact reproductive-aged individuals. Much of the available data on the effects of antiinflammatory and immunosuppressive drugs on reproductive function and pregnancy are based upon maternal exposures. Less attention has been paid to the impact of these drugs on male reproductive function, particularly spermatogenesis and risk of teratogenicity in offspring.
The reproductive impact of antiinflammatory and immunosuppressive drugs in men with rheumatic disease will be reviewed here, including:
●Impact on spermatogenesis
●Risk of teratogenicity in offspring (from sperm deoxyribonucleic acid [DNA] damage or drug exposure during intercourse)
●Guidance for the discontinuation of cyclophosphamide and thalidomide when planning pregnancy
The impact of these agents on female reproduction and the effects of specific cytotoxic agents on gonadal function in adult men are discussed in detail elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation" and "Effects of cytotoxic agents on gonadal function in adult men".)
EFFECTS ON MALE GONADAL FUNCTION — Infertility in men with rheumatic disorders can be due to disease activity and rarely to medication exposure [1]. Drug-induced infertility in men results from the toxic effects of the medication on the testes or the suppressive effects of the medications on the hypothalamic-pituitary-gonadal axis. The testes contain two anatomical units: the seminiferous tubules, composed of germ cells and Sertoli cells, and the interstitium, containing Leydig cells that produce testosterone. (See "Male reproductive physiology" and "Causes of male infertility".)
Spermatogenesis is much more likely to be disrupted than testosterone production because the actively proliferating germinal epithelium of the testes is more sensitive to damage (eg, from cytotoxic drugs) than are the Leydig cells. Sperm concentration, motility, and morphology are all surrogate markers that reflect fertility. The magnitude of the effect on sperm production is drug-specific and dose- and duration-dependent. Additional factors that may influence gonadal function in patients receiving these medications include effects of the underlying disease (eg, chronic kidney or pulmonary disease). (See "Effects of cytotoxic agents on gonadal function in adult men" and 'Adverse effects on spermatogenesis' below.)
Adverse effects on spermatogenesis — Only two commonly used antirheumatic drugs, cyclophosphamide and sulfasalazine (SSZ), have been shown to adversely affect spermatogenesis. The antirheumatic agent with the most deleterious effect on male fertility is the alkylating agent (cyclophosphamide), which can induce irreversible or prolonged oligozoospermia or azoospermia, compromising fertility (see 'Cyclophosphamide' below). SSZ can cause reversible azoospermia or oligospermia and adversely impact sperm quality. (See 'Sulfasalazine' below.)
It is likely that the number of men with rheumatic diseases affected by drug-induced infertility has declined over time as cyclophosphamide use for severe and organ-threatening manifestations of systemic lupus erythematosus (SLE), systemic vasculitis, and several other conditions has increasingly been replaced with other agents including mycophenolate mofetil (MMF) and rituximab. Similarly, the use of SSZ for conditions such as rheumatoid arthritis (RA) and spondyloarthritis (SpA) has become less common with the availability of similarly or more effective and well-tolerated biologic agents. (See 'Cyclophosphamide' below and "Effects of cytotoxic agents on gonadal function in adult men" and 'Sulfasalazine' below.)
When cyclophosphamide is being administered to men, patients should be referred for cryopreservation of semen containing viable sperm for subsequent use in assisted reproductive technologies (ART) such as in vitro fertilization. (See 'Preservation of fertility' below and "Effects of cytotoxic agents on gonadal function in adult men".)
Limited data do not suggest that other antirheumatic drugs impact spermatogenesis. (See 'Generally presumed safe' below and 'Limited data' below.)
Cyclophosphamide — Cyclophosphamide is a cytotoxic alkylating agent, which can cause irreversible azoospermia that may induce permanent infertility. These effects are dose-related; cumulative cyclophosphamide doses of 6 to 10 grams are likely to result in oligospermia and often in irreversible azoospermia. Repeated exposure may be more harmful than single exposure at the same total dose.
Thus, male patients receiving doses in this range should be counseled about cryopreservation of sperm. (See 'Preservation of fertility' below and "Effects of cytotoxic agents on gonadal function in adult men".)
Detailed information regarding these and other adverse effects, use, and monitoring of this medication is presented elsewhere. (See "Effects of cytotoxic agents on gonadal function in adult men", section on 'Chemotherapeutic agents associated with infertility' and "General toxicity of cyclophosphamide in rheumatic diseases".)
Sulfasalazine — SSZ has been used since its development in the 1940s as an agent for the treatment of RA and inflammatory bowel disease (IBD). Specific details regarding the use and monitoring of this medication are presented elsewhere. (See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis" and "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease".)
SSZ, which possesses both antiinflammatory properties mediated by its 5-aminosalicylic acid moiety and antibacterial characteristics associated with its sulfapyridine moiety, has been associated with reversible azoospermia or oligospermia in some men, along with reduced sperm motility and an increased proportion of abnormal forms. However, we do not routinely discontinue SSZ in men who are pursuing fertility. In men taking SSZ in whom attempts at pregnancy have not been successful, we obtain a semen analysis, and if abnormal, we suggest stopping the medication for three months to allow for recovery of spermatogenesis [2-4].
No known impact on spermatogenesis — Small cohorts, case series, and case reports of men receiving a range of medications for the treatment of rheumatic disease have not demonstrated any negative impact on their fertility [5,6].
Generally presumed safe — Several drugs do not appear to have a negative impact on gonadal function:
●TNF inhibitors – Although data are limited, paternal exposure to tumor necrosis factor (TNF) inhibitors does not appear to have a negative impact on spermatogenesis. Two early case series suggested that TNF inhibitors may impact sperm production and motility [7,8], but subsequent larger studies suggest that TNF inhibitors do not impair sperm production or function [9-12]. Studies have included patients receiving adalimumab, etanercept, and infliximab; there are no data for certolizumab pegol or golimumab. In a prospective study of 20 patients with active ankylosing spondylitis who were initially tested before starting TNF inhibitors, there were no adverse effects on sperm concentration or quality (motility and morphology) after 3 to 6 months of therapy, or after 12 months in the 6 patients retested [12]. In another study of semen samples from a cohort of 26 patients with SpA, abnormalities in sperm, including poor motility, were more pronounced in patients with active SpA who were not receiving TNF inhibitors than in TNF inhibitor-treated patients and in healthy men [9]. Sperm concentration and morphology did not differ between treated and non-treated groups.
●Azathioprine – Monotherapy with azathioprine (AZA) does not appear to reduce male fertility. In a study of 18 men treated with AZA (1.5 to 2 mg/kg/day) for at least three months for IBD, semen analyses were normal before and after 11 to 49 months of treatment [13]. AZA and its metabolite, 6-mercaptopurine, have been widely used in organ transplantation and for IBD, in addition to their uses in patients with rheumatic disease. (See "Fertility, pregnancy, and nursing in inflammatory bowel disease", section on 'Azathioprine and mercaptopurine'.)
●Methotrexate – No reduction in fertility of men taking methotrexate (MTX) in doses used to treat rheumatic diseases (up to 30 mg once per week) has been observed [5,6,14].
●NSAIDs, including aspirin – The effects of nonsteroidal antiinflammatory drugs (NSAIDs) and salicylates have been evaluated in a number of studies [5,12,15-18]. While aspirin in doses greater than 2.6 grams a day can impede spermatogenesis, lower doses do not. In one case series of men exposed to greater than one nonsteroidal tablet a day, lower sperm counts were reported; however, these results are confounded by the fact that these men were being evaluated at an infertility clinic. Subsequent case series have not shown this effect.
●Mycophenolate mofetil – MMF is an inhibitor of purine biosynthesis for which there have been no reports of impaired spermatogenesis [19].
●Cyclosporine – Cyclosporine is a calcineurin inhibitor for which there have been no reports of impaired spermatogenesis [20].
Additional commonly used medications whose reproductive impact has not been studied include hydroxychloroquine and intravenous immune globulin (IVIG); however, male infertility has not been reported with these agents despite their multiple decades of availability and use.
Limited data — There is insufficient evidence and reported experience related to the effects of the following biologic agents and targeted synthetic disease-modifying antirheumatic drugs (DMARDs; ie, Janus kinase [JAK] inhibitors) on male gonadal function, but the sum of available data regarding targeted biologic agents such as antibodies suggests they do not have adverse effects on fertility.
●Certolizumab
The effects of JAK inhibitors (tofacitinib, baricitinib, upadacitinib, peficitinib) and apremilast on fertility are unknown.
TERATOGENICITY — Male factor teratogenicity can occur by a direct drug effect on sperm development or with seminal fluid exposure during intercourse. However, limited data in men suggest that paternal use of antirheumatic drugs other than cyclophosphamide and potentially thalidomide do not cause congenital anomalies, unlike the greater potential for teratogenic effects of some of these agents in pregnant women (see "Safety of rheumatic disease medication use during pregnancy and lactation"). Moreover, the risk of withdrawing therapy may be substantial. Therefore, in patients with active disease, the author suggests that male patients remain on their medications, with the exception of cyclophosphamide and thalidomide, while attempting conception. (See 'Drugs to avoid' below and 'Generally presumed safe' below.)
Drugs to avoid — Two medications, cyclophosphamide and thalidomide, which are sometimes used in rheumatic disease patients, should not be used by the male partner when a couple is pursuing pregnancy, because of their known teratogenic risks. (See 'Cyclophosphamide' below and 'Thalidomide' below.)
Cyclophosphamide — There are limited data on the risk of teratogenicity in offspring of men with rheumatologic disorders (eg, systemic lupus erythematosus [SLE] and systemic vasculitis) treated with cyclophosphamide, in part due to the drug's adverse impact on spermatogenesis. [6]. An increased risk of congenital anomalies in their offspring has not yet been demonstrated [6]. However, there is concern for potential teratogenicity as cyclophosphamide use in men with cancer results in significant sperm DNA damage [21]. In animals, exposure to cyclophosphamide also induces genetic damage [22-24].
In view of the indirect data from male animal models and men with cancer that demonstrate sperm DNA damage with cyclophosphamide use, we suggest that men should discontinue this medication for at least three months to allow for a full cycle of spermatogenesis before attempting conception. Our approach is consistent with published guidelines [25].
Thalidomide — There are no data on paternal exposure to thalidomide in men with rheumatic diseases; it is used rarely for these conditions, but has been employed in patients with refractory cutaneous lupus and cutaneous sarcoid, mucocutaneous manifestations of Behçet syndrome, and to an even more limited extent in several forms of inflammatory arthritis [26-28]. Nonetheless, given the high rate of teratogenicity after maternal exposure [29] and the presence of drug in the semen of men who have been treated with this agent [30], we recommend discontinuing thalidomide for four weeks prior to attempting conception. Some experts recommend the use of barrier contraception in men who are taking this agent [30,31]. The manufacturer and US Food and Drug Administration (FDA) recommend that males taking thalidomide (even those vasectomized) must use a latex or synthetic condom during any sexual contact with females of childbearing potential and for up to 28 days following discontinuation of therapy; and that males taking thalidomide must not donate sperm [32]. Some clinicians suggest continued condom use for 12 weeks after thalidomide is discontinued to allow for a full cycle of spermatogenesis.
Generally presumed safe — Paternal use of most antirheumatic drugs is generally considered to be safe (eg, without demonstrated evidence of risk to the fetus that exceeds the 3 to 5 percent risk of congenital anomalies observed in the general population), although data are generally limited [5,6]. Paternal use of these agents is also generally consistent with available expert guidelines that indicate that paternal exposure to these medications is compatible with pregnancy [25,33,34]. The agents in this category include:
●Methotrexate – Paternal exposure to methotrexate (MTX) around the time of conception does not appear to have adverse consequences for pregnancy outcomes. In a prospective cohort of 113 pregnancies in which there was paternal exposure to low-dose MTX (up to 30 mg once weekly) around the time of conception, there was no increase in the rate of major congenital anomalies or spontaneous abortion with 412 nonexposed control pregnancies [35]; neither gestational age at delivery nor birth weights differed between groups. These findings are consistent with other smaller series [36,37]. However, a National Birth Registry reported two cases of orofacial defects among 50 pregnancies associated with paternal exposure to MTX (in the three months prior to conception) [38]. In another study, which included 49 fathers taking MTX for inflammatory arthritis at the time of conception, no increase in the risk of congenital anomalies was identified in the offspring [39].
●Mycophenolate mofetil – Mycophenolate mofetil (MMF), an inhibitor of purine biosynthesis, does not appear to have an adverse effect on spermatogenesis or on fertility. In a study of 350 pregnancies fathered by 230 men, in which 155 were treated with MMF, there was no increase in the rate of major congenital anomalies [19]. These findings, observed in men who received solid organ transplants, have been supported by those of other studies that were also performed in transplantation patients [40,41].
●Leflunomide – Leflunomide (LEF) is an antimetabolite that inhibits dihydroorotate dehydrogenase, the enzyme that catalyzes the rate-limiting step in pyrimidine biosynthesis [42-47]. We are unaware of studies that have directly examined its safety with respect to male gonadal function. Likewise, other than one report of a healthy baby born whose father was on LEF during conception, there are no available data on male-mediated fetal toxicity.
●Other agents have also been widely used without evidence raising concerns about teratogenicity:
•Sulfasalazine (SSZ)
•Glucocorticoids
•Azathioprine (AZA)
•Tumor necrosis factor (TNF) inhibitors (other than golimumab)
Limited data on glucocorticoids suggest that these medications do not increase the risk of teratogenicity. In a large cohort study from Denmark, there were 2380 paternal exposures of glucocorticoids in the three months before conception and no increased risk of congenital anomalies, preterm birth, or small-for-gestational-age infants was observed [48].
Limited evidence — There is a paucity of information regarding the safety of a number of agents, with systematic reviews [6,12], 2016 guidelines from the United Kingdom [25], and the 2020 guidelines from the American College of Rheumatology [34] suggesting that IVIG, tacrolimus, and the monoclonal antibodies below are unlikely to be harmful:
●Intravenous immune globulin (IVIG)
Information regarding potential teratogenicity of the Janus kinase (JAK) inhibitors (tofacitinib, baricitinib, upadacitinib, peficitinib) is unavailable.
MANAGEMENT OF MEN STARTING THERAPY
Preservation of fertility — A number of strategies have been explored to preserve fertility in men receiving cytotoxic medications, including semen cryopreservation, which is well-established as an effective approach, and the use of gonadotropin-releasing hormone (GnRH) agonists to suppress the pituitary-gonadal axis, which has not shown benefit in human studies [49].
Cryopreservation of sperm — We recommend cryopreservation of sperm in all men who plan to start treatment with cyclophosphamide, the one drug with the potential to cause permanent azoospermia. However, this approach has some limitations. Among men who are starting cytotoxic chemotherapy, only 50 percent are offered sperm banking, in spite of guidelines that recommend that all men should be offered this service. Moreover, many insurance companies will not cover the monthly cost of maintaining the specimen. (See "Effects of cytotoxic agents on gonadal function in adult men".)
Hormonal suppression — Studies using GnRH agonists to reversibly suppress the hypothalamic-pituitary-testicular axis have demonstrated no definitive benefit either in preserving spermatogenesis or in accelerating its recovery. We suggest not using this approach. (See "Effects of cytotoxic agents on gonadal function in adult men".)
Assisted reproductive technologies (ART) — With the advent of in vitro fertilization with intracytoplasmic sperm injection (ICSI), viable pregnancies occur with sperm concentrations that are much lower than normal. Even men with azoospermia should be evaluated to see if there are spermatozoa that could be extracted directly from the testis for ICSI. ART can be pursued for many drugs (with the exception of cyclophosphamide and thalidomide) while the patient is on or off therapy. (See "Intracytoplasmic sperm injection" and "Treatments for male infertility", section on 'Retrieval of sperm'.)
Sulfasalazine-related infertility — Men may continue sulfasalazine (SSZ) while pursuing pregnancy. In men taking SSZ in whom attempts at pregnancy have not been successful, we obtain a semen analysis, and if abnormal, we suggest stopping the medication for three months to allow for recovery of spermatogenesis. (See 'Sulfasalazine' above.)
Avoid teratogenicity — As noted above, the two drugs with potential teratogenicity are cyclophosphamide and thalidomide. The approach to avoiding harmful fetal effects in men receiving either drug while pursuing fertility include:
●Cyclophosphamide – We suggest, consistent with expert guidelines [25], that men discontinue this medication for at least three months to allow for a full cycle of spermatogenesis before attempting conception. (See 'Cyclophosphamide' above.)
●Thalidomide – Given the high rate of teratogenicity after maternal exposure to thalidomide and the presence of the drug in the semen of men who have been treated with the drug, we recommend discontinuing thalidomide for four weeks prior to attempting conception. Available guidelines suggest that after stopping the drug, men must use a latex or synthetic condom during any sexual contact with women of childbearing potential for up to four weeks; and they must not donate sperm [32]. Some clinicians suggest continued condom use for 12 weeks after thalidomide is discontinued to allow for a full cycle of spermatogenesis. (See 'Thalidomide' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Male infertility (The Basics)")
●Beyond the Basics topics (see "Patient education: Treatment of male infertility (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Patients considering use of cyclophosphamide should be advised regarding strategies for preservation of fertility. We suggest that all men who plan to undergo therapy with cyclophosphamide be counseled about obtaining a semen sample for cryopreservation prior to initiating therapy. The use of gonadotropin-releasing hormone (GnRH) agonists during cyclophosphamide treatment has not been shown either to preserve spermatogenesis or to accelerate its recovery. (See 'Preservation of fertility' above and "Effects of cytotoxic agents on gonadal function in adult men".)
●There is a relative paucity of data regarding the effects on male gonadal function of most antiinflammatory and immunosuppressive drugs used in the treatment of rheumatic diseases. We suggest that cyclophosphamide be discontinued for a minimum of three months before attempting pregnancy (Grade 2C). Cyclophosphamide, an alkylating agent, is associated with a high risk of irreversible azoospermia and should therefore be used with caution in patients anticipating future attempts at pregnancy. (See 'Cyclophosphamide' above.)
●Sulfasalazine (SSZ) can reversibly induce oligospermia or azoospermia, as well as abnormal sperm function. In men taking SSZ in whom attempts at pregnancy have not been successful, we obtain a semen analysis, and if abnormal, we suggest stopping the medication for three months to allow for recovery of spermatogenesis (Grade 2C). (See 'Sulfasalazine' above.)
●Thalidomide is used rarely for rheumatic diseases; it is highly teratogenic after maternal exposure and the drug is present in the semen of men being treated with this agent. We recommend discontinuing thalidomide for four weeks prior to attempting conception (Grade 1C). Some experts and regulators recommend the use of barrier contraception (ie, a latex or synthetic condom) in men who are taking this agent, including those vasectomized, and for up to 28 days following discontinuation of therapy. Some clinicians also suggest continued condom use for 12 weeks after thalidomide is discontinued to allow for a full cycle of spermatogenesis. (See 'Thalidomide' above.)
●Paternal exposure to several drugs, including methotrexate (MTX), mycophenolate mofetil (MMF), leflunomide (LEF), azathioprine (AZA), and cyclosporine, has not been associated with adverse effects on male gonadal function or increased fetal risk. Hydroxychloroquine and intravenous immune globulin (IVIG) are widely used and are not known to have adverse effects on male gonadal function. (See 'No known impact on spermatogenesis' above and 'Generally presumed safe' above.)
●The impact of most biologic agents on male gonadal function is unknown, but targeted biologic agents such as antibodies are not known to have adverse effects on fertility or to result in adverse pregnancy outcomes. These medications include tumor necrosis factor (TNF) inhibitors, anakinra, rituximab, abatacept, and tocilizumab. The effects of the Janus kinase (JAK) inhibitors on fertility and on the fetus are unknown. (See 'Generally presumed safe' above and 'No known impact on spermatogenesis' above.)
