Male fertility potential alteration in rheumatic diseases: a systematic review

ABSTRACT Background Improved targeted therapies for rheumatic diseases were developed recently resulting in a better prognosis for affected patients. Nowadays, patients are living longer and with improved quality of life, including fertility potential. These patients are affected by impaired reproductive function and the causes are often multifactorial related to particularities of each disease. This review highlights how rheumatic diseases and their management affect testicular function and male fertility. Materials and Methods A systematic review of literature of all published data after 1970 was conducted. Data was collected about fertility abnormalities in male patients with systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, ankylosing spondylitis, Behçet disease and gout. Two independent researchers carried out the search in online databases. Results A total of 19 articles were included addressing the following diseases: 7 systemic lupus erythematosus, 6 Behçet disease, 4 ankylosing spondylitis, 2 rheumatoid arthritis, 2 dermatomyositis and one gout. Systemic lupus erythematosus clearly affects gonadal function impairing spermatogenesis mainly due to antisperm antibodies and cyclophosphamide therapy. Behçet disease, gout and ankylosing spondylitis patients, including those under anti-TNF therapy in the latter disease, do not seem to have reduced fertility whereas in dermatomyositis, the fertility potential is hampered by disease activity and by alkylating agents. Data regarding rheumatoid arthritis is scarce, gonadal dysfunction observed as consequence of disease activity and antisperm antibodies. Conclusions Reduced fertility potential is not uncommon. Its frequency and severity vary among the different rheumatic diseases. Permanent infertility is rare and often associated with alkylating agent therapy.


INTRODuCTION
There are 1.3 million adults affected by rheumatoid arthritis (RA) and up to 322.000 by systemic lupus erythematosus (SLE) in United States (1). Improved targeted therapies for rheumatic diseases have been developed recently resulting in better prognosis. In this context health-related quality of life became a major concern, including reproductive issues (2).
Decreased fertility potential is not unusual among patients of both genders with rheumatic diseases, particularly in women (3,4) with many articles addressing in RA, SLE, ankylosing spondylitis (AS), dermatomyositis (DM), Behçet disease (BD) and gout (5)(6)(7)(8). Drug treatment is probably the main factor for gonadal dysfunction (9). Some drugs can cause reversible infertility, such as nonsteroidal antiinflammatory drugs in women and sulfasalazine/methotrexate in men whereas irreversible infertility is occasionally observed after treatment with alkylating agents (cyclophosphamide-CYC and chlorambucil) in both genders (10). When fertility is an issue, alkylating agents should be used at lowest possible dose and alternative therapies (such as azathioprine or mycophenolate mofetil) must be considered.
The reproduction potential of these male patients is impaired by the disease directly in the testicular tissue or by immunosuppressive therapy (11). The evaluation of male subjects should rely on careful medical history, complete physical examination, semen analysis and sexual hormone profile.
The objective of this systematic review of the literature on rheumatic disease male fertility potential is to provide a better understanding to urologists, andrologists, infertility specialists and rheumatologists of the underlying contributing factors involved, as well as discuss how fertility potential is endangered by diseases management.

sEaRCH sTRaTEgy aND sElECTION CRITERIa
It was conducted a computerized search of English and non-English language articles published after 1970 listed in the electronic databases of SCOPUS, PUBMED/MEDLINE and Cochrane Library. Two independent researchers (MC, BT) conducted the search during May-July 2014. The following terms were used: 'systemic lupus erythematosus', 'ankylosing spondylitis', 'dermatomyositis', 'rheumatoid arthritis', 'Behçet disease', 'gout', 'male infertility', 'pregnancy rate', 'sperm', 'semen', 'spermatozoa', 'sperm quality' and 'rheumatic disease' . The search was performed in English language but articles yielded in other languages were not excluded. The authors graded the abstract of each study identified by the search to determine eligibility. If these criteria remained unclear from the abstract, the full article was retrieved for clarification.
Data extraction was carried out by the investigators using a standardized data collection form with subsequent discussion with all authors. Peer-reviewed observational controlled and non-controlled studies (case-control and co-hort studies) were selected. All studies were referral centre-, hospital-or population-based studies. The data collected in the selected articles were all related to fertility abnormalities in male patients with SLE, RA, DM, AS, BD and gout. We excluded articles that were case reports and those that did not evaluated male patients.

REsulTs
The article flow through the selection phase is summarized in Figure-1. An initial search of online databases yielded 136 publications from PUBMED/MEDLINE, 112 reviews from Cochrane Library, 136 from Web of Science, and 162 from Scopus. After excluding duplicated publications and applying exclusion criteria, 19 relevant articles were included with the following diseases: 7 SLE, 2 DM, 2 RA, 4 AS, 6 BD and one with gout. There was one article evaluating simultaneously two diseases and another addressing three ( Figure-1).

Systemic lupus erythematosus
Publications selected focused on four aspects of male fertility in SLE: gonadal dysfunction, testicular alterations induced by immunosuppressive treatment, presence of anti-sperm antibody and genetic abnormalities (Table-1).
A global gonadal function evaluation was performed by our Group (12) assessing sex hormone profile, semen analysis and antisperm analysis (ASA). Thirty-five patients compared to paired controls had lower testicular volumes, total sperm count and total motile sperm count associated with CYC use.
We investigated Sertoli cell function analyzing inhibin B levels and semen abnormalities in SLE patients. Lower inhibin B level was correlated with diminished sperm count, concentration and total motility count and with elevated FSH and LH levels (13). In addition, it was observed that 20% of SLE patients had erectile dysfunction, 36% of testicles were below the normal volume range and 48% had semen analysis abnormalities associated with CYC therapy (14). The same gonadotoxic effect of CYC was also reported in four patients with juvenile SLE (15).
Serum IgG ASA targeting the sperm head and/or midpiece was reported in 15% and antisperm deoxyribonucleic acid antibodies were found in 42% of SLE patients, indicating that autoimmunity is another contributing factor in these patient's (16). This finding was confirmed in 8 patients evaluated by Shiraishi et al. (17).

Dermatomyositis
The two publications addressing DM patient's fertility are illustrated in Table-2   sperm count and lower normal sperm morphology percentage. Disease activity seemed to be a relevant factor in four patients and CYC in one of them (20).

Rheumatoid arthritis
Two publications assessed fertility on RA patients (Table-3). Gordon et al. (21) evaluated 31 patients with RA, 33 with AS and 95 healthy controls. Patients with RA had lower serum testosterone levels and higher FSH and LH levels than controls. Ten patients (33%) admitted periods of erectile dysfunction while 15 (50%) also referred decreased libido when suffering from arthritis. Four patients referred difficulty to conceive, among them, two did not seek medical assistance for infertility. Nineteen males had successfully fathered children and the others were still singles.
In 2008, Shiraishi et al. (17) evaluated 32 RA patients and found one with serum ASA. The patient was 74 years old and the disease onset was at the age of 60 years. He had already 2 children before being diagnosed with the disease so the relation between fertility status and the presence of the antibody could not be addressed nor its relation with the disease.

Ankylosing spondylitis
Four publications were selected regarding the AS association with male fertility. The major aspects of each paper are summarized in Table-4. A total of 33 AS patients were evaluated in 1986, reporting four patients with erectile dysfunction and 11 with decreased libido. Only one male with AS had an infertile marriage and did not seek for medical assistan-ce. Thirteen patients were singles and all other had constituted their families without problems (21). Varicocele was an additional and frequent finding in AS males (40%), of another cohort, and its impact in male fertility remains to be determined, since only mild sperm abnormalities was observed in these patients (22).
Regarding to biological therapy, Paschou et al. (7), in 2009, assessed AS patients who were treated with infliximab and reviewed their medical records. They found that all of them had successfully fathered at least one children even one patient that also received small doses of methotrexate. Reinforcing this finding, our group evaluated 20 AS patients under TNF blockage and compared to 24 normal controls and showed no difference in sex hormone, inhibin B levels and seminal analysis (23).

Behçet disease
There were six papers addressing BD and its relationship with male fertility. They are summarized in Table- Alkylating agents may induce sperm abnormalities in BD patient's, as reported in ten men using chlorambucil that had impairment of semen production: 7 with oligospermia and 3 with azoospermia (27).
A recent study evaluated fertility outcome of a larger retrospective cohort of BD patient's compared to a control Group (28). They observed that 23 out of 130 subjects had infertility and the most common etiology was varicocele. In contrast, none of the 14 men with BD assessed for ASA had antisperm antibodies (17).

Gout
There is only one report addressing gout and fertility in males (Table-5). In a large study with 540 young patients with gout, fertility status was preserved in patients treated with colchicine and none presented fertility issues during 20 years of follow-up (29).  Note: bD = Behçet disease; FsH = follicle-stimulating hormone; CyC = cyclophosphamide; as = ankylosing spondylitis; asa = antisperm antibody; FMF = familial mediterranean fever

DIsCussION
SLE is an uncommon disease in men. It affects males in a sex ratio of 1:9 (30), suggesting that sex hormones could modify susceptibility or reduce the expression of SLE (11). Infertility is an important issue for them nowadays due to better prognosis and quality of life. Six publications reported impaired testicular function and decreased semen production in SLE patient's and their possible association with disease and treatment (11-14, 31, 32). The underlying mechanism for disease in-duced damage to the testis is not completely elucidated although some authors showed that there is immunopathologic lesion of the testis (and excurrent ducts) occurring through T cell-mediated mechanisms triggered by antigens or pathogens that disrupt testicular immune privilege (33,34). Testicular aggression by alkylating agents has been described since 1972 showing that it impairs the sperm production presenting spermatogenesis abnormalities and Sertoli cell dysfunction (35)(36)(37).
Although semen analysis is considered the hallmark of male infertility evaluation, standard seminal parameters do not detect abnormalities in up to 20% of subfertile males (38). The routine measurements do not reveal seminal defects at molecular levels that might be induced by reactive oxygen species, which are associated with male infertility (39,40). The 2010 World Health Organization guidelines have reduced the reference limits for seminal parameters and fail to satisfy clinical and statistical standards and pose the risk of misclassifying a subject's true fertility status (41,42). The introduction of new biomarkers of spermatic function in the clinical practice will allow a more precise evaluation of the real impact of rheumatic disease on male fertility potential. Unfortunately, to date, there is no available information in the literature and these aspects were not covered in the present review.
Autoimmunity also affects fertility by the presence of ASA. Immunologic infertility is characterized by the presence of antibodies against spermatozoa in the serum and/or in the seminal plasma or on the sperm surface (43). The presence of multiple ASA can lead to the immobilization and/or agglutination of spermatozoa, which blocks sperm-egg interaction. They can also prevent implantation or arrest embryo development (44,45). In SLE patient's ASA have been found in up to 42% of the patient's. However, the real significance of ASA in infertile men is controversial and currently there is no standardized treatment regimens (46). Lastly, aneuploidies are frequent and may also contribute for fertility impairment in SLE patient's; therefore kariotype should be evaluated to complete the fertility analysis of these patient's, especially in those with severally compromised spermatogenesis (47).
The incidence of DM is 1.5 to 0.7 per 100.000 per person-years and there is a trend to affect more women than males in a 1.9 ratio (48,49). The fertility evaluation of this particular Group has limited publications. The most important contributing factors of infertility in male DM are disease activity and CYC use (6), generally associated with high doses of this alkylating agent (5,50).
Several large Scandinavian cohorts and a cohort study in the United States demonstrate that women with RA have smaller families and are slower to conceive compared with other wo-men (51). Even though female infertility has been extensively explored in past years, the evaluation of male fertility was overlooked. The few publications available show gonadal impaired function with elevated LH/FSH, patients with difficult to conceive and also a higher incidence of ASA (17,21). A more extensive evaluation of this set of patients is necessary to have a clear sense of RA real impact on male fertility.
Most physicians agree that diseases such as RA and AS can cause significant limitations in sexual activity due to diminished desire and impaired mechanical capacity (52,53). In spite of that, evaluation of sex hormonal levels, seminal analysis and varicocele have shown that AS disease and treatment do not have a major impact in male fertility (7,(21)(22)(23).
BD is a multisystemic vasculitis with musculoskeletal, muco-cutaneous, ocular, gastrointestinal and neurological findings. The disease is frequently seen in the Mediterranean basin and the Far East. Young adults in their 20s and 30s are typically affected, during their reproductive years, with no gender predilection. However, males usually have a more severe course of the disease and are prone to present eye and other major organ involvement (28). The available literature about BD relationship with infertility is not robust. The disease itself seems to have no impact on fertility potential, but alkylating agents use is associated with its decrement (26,27). The aggression to testicular tissue by colchicine reported by some authors in BD (25) was not confirmed in a large gout study (28).
Gout is induced by the deposition of monosodium urate crystals in synovial fluid and other tissues associated with hyperuricemia (54). Patient's with gout are usually older and fertility often is not an issue, as most of them had already constituted their families. Although there is a concern about colchicine impairing reproductive function, decreased fertility has not been found in these patient's (29).
And finally, the modern view of male fertility evaluation gives a new meaning to the term "male infertility management", which goes beyond the simple identification and elimination of the cause. The andrologist's therapeutic strategies have changed from a recent past of only attempting to achieve a simple increase in the sperm concentration. We are moving forward and now our main target is to improve the "quality" of spermatozoa and/or preserve fertility (55). This approach is thus especially recommended for patients with rheumatic diseases, often not considered potentially fertile.

CONClusIONs
Rheumatic diseases comprise a heterogeneous Group of diseases with distinct aspects regarding male infertility. SLE clearly affects gonadal function impairing spermatogenesis due to ASA and CYC therapy. Fertility seems to be not affected in BD and AS patients, including patients under anti-TNF therapy. The fertility potential of DM patients may be affected by the disease activity and by alkylating agents. There are also few data regarding RA, however male gonad may be affected by the disease activity and ASA. Gout patients usually do not have any conception desire at the time of disease manifestation and there are no reports of fertility impairment.
A multidisciplinary Group is essential to assess male reproductive health in rheumatic disease patients with a special focus on improving the fertile potential and sexual dysfunction to minimize the disease and treatment damage. This study was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP#2014/14806-0 to CAS), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ#301411/2009-3 to EB, and#302724/2011-7 to CAS), Federico Foundation (to EB, and CAS) and by Núcleo de Apoio à Pesquisa "Saúde da Criança e do Adolescente" da USP (NAP-CriAd) to CAS.