Rheumatology-led pregnancy clinic: men perspective

Erectile dysfunction is the most common form of sexual impairment reported in men, and causes them to feel frustrated, shocked, stressed and get overwhelmed with the feeling of emasculation. In standard outpatient rheumatology practice, erectile dysfunction represents a major hurdle to having a healthy marital relationship [2]. In an earlier report [17] a patient described erectile dysfunction as “a shock and a threat to his sense of masculinity.” The research work revealed that while a cohort of the male patients related their sexual dysfunction to having intense pain during sexual activity, others saw it as a side effect of medications they are taking. None of the participants included in that study [17] had been given information regarding the risks of erectile dysfunction as a side effect of prescribed medications or that it may be related to their disease activity. These factors add to the stress and anxiety the patient may feel with a net result of impaired sexual health.

Considering the pathophysiology, erectile dysfunction in ARDs has been linked to endothelial dysfunction. Strong evidence accrued in the last years endorses the concept that erectile function is an exceptional surrogate marker of systemic health in general and vascular performance in particular [18]. This has been described by the equation: endothelial dysfunction = erectile dysfunction (ED = ED, and vice versa) [19]. High levels of pro inflammatory cytokines, specifically TNF-α involved in most of the ARDs pathogenesis, have been suggested to be related to sexual dysfunction and fatigue [20, 21]. In a study of 383 males without rheumatic disease, Matos et al. [22], found that there was a significant link between erectile dysfunction and high levels of TNF- α. It is worth mentioning that the pro-inflammatory cytokines are also closely linked to levels of serum testosterone. Earlier data revealed that hypogonadal males tend to have higher concentration levels of TNF-α, IL-6, and IL-1β as a result of impaired suppression. This ultimately worsens the endothelial dysfunction, with consequent further impairment of erectile function [23]. Therefore, the use of anti-TNF medications could help with improving erectile dysfunction [22, 24].

Another factor that plays an important role in erectile dysfunction among men with ARDs is the presence of associated comorbidities. A close link between cardiovascular risk and erectile dysfunction has been reported [2, 23]. Unfortunately, this is not usually considered in the same context as the more traditional cardiovascular conditions which include hypertension, ischemic heart disease, dyslipidaemia, diabetes mellitus and insulin resistance/metabolic syndrome complex. The good news is that there are now established, regularly updated specific guidelines for the treatment of men with erectile dysfunction who are known to have cardiovascular disease [25].

Lastly, while it is extremely rare that methotrexate therapy induces erectile dysfunction, however, it has been reported that intramuscular methylprednisolone injections given to men have a strong correlation with erectile dysfunction [2].

The potential of decreased fertility is not unusual concern among ARD patients whether males or females [26, 27]. Several research studies addressed this problem in association with individual rheumatic diseases including rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, gout, Behçet disease, and dermatomyositis [28‐31]. In men living with ARDs, the potential of impaired reproduction has been linked to both the disease directly as well as the medical therapy. The testicular tissue has been identified as the main pathological site [28]. A systematic review was carried out by Tiseo et al [32], to assess the potential alteration of male fertility in different rheumatic diseases. Results revealed that the frequency and severity vary among the different rheumatic diseases. 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 revealed that gonadal dysfunction was observed as consequence of disease activity and antisperm antibodies.

Immunologic Infertility, characterized by the presence of antisperm antibody (ASA), has also been reported in men living with ARDs [28]. With the presence of multiple antisperm antibody, this may induce the immobilization and agglutination of spermatozoa, blocking sperm-egg interaction. This can also impede implantation or cause the arrest of the development of the embryo [33, 34]. In rheumatoid arthritis patients with difficulty to conceive, gonadal impaired function with elevated LH/FSH, has been linked to having a higher incidence of ASA [35]. However, although ASA has been found to be present in as many as 42% of male patients with SLE, the real significance of this in infertile men remains controversial and at present there is no standardized treatment regimen [36]. Another point to consider in immunologic infertility, men who present with severally compromised spermatogenesis, kariotype should be evaluated to complete the fertility analysis as aneuploidies are frequent and may also contribute for fertility impairment in SLE patients [37].

On another front, another main factor for gonadal dysfunction is drug treatment. Some drugs, such as nonsteroidal anti-inflammatory drugs in women, and sulfasalazine/methotrexate in men can cause reversible infertility, whereas after treatment with alkylating agents such as cyclophosphamide-CYC and chlorambucil, irreversible infertility has, on occasions, been observed in both genders. Therefore, alkylating agents should be used at the lowest possible dose and alternative therapies, such as azathioprine or mycophenolate mofetil, need to be considered when fertility is an issue [38].

There are variations in the concerns regarding the medications used for men living with ARDs. This can be stratified into those men who are planning for a family and those whose sexual partner is pregnant. The concerns prior to conception focus on the effects the medication may have on the man’s fertility as well as the possibility of medication associated teratogenicity. Unfortunately, published information looking at these issues is scarce. Meanwhile, stopping paternal medication needs to be carefully considered, weighing this up with the effect this may have on the disease activity. Concerns after the man’s partner become pregnant includes consideration of whether his medication is present in the seminal fluid, can transfer through the vaginal mucosa to cross the placenta and be teratogenic. As seminal concentrations of medications and volumes transferred are small, hence, post-conception exposure of the embryo or fetus is likely to be minimal [39]. Reassurance can be given when the man’s partner is pregnant, and that there is low risk associated the ARDs treatment. This suggestion has been supported by the findings of the Norwegian birth data and DMARD registry studies. These revealed that there was no risk identified of preterm delivery, low birth weight or congenital abnormalities when evaluating risk of paternal DMARD exposure near conception in comparison to the reference population [40]. This patient cohort included those taking MTX, sulfasalazine, leflunomide, azathioprine, hydroxychloroquine, and TNF inhibitors. A summary of drug compatibility with paternal exposure is shown in Table 1.

Though the package insert of methotrexate advises the user to wait for at least 3 months (a period which corresponds to the length of the spermatogenic cycle (74 days) [43]), after discontinuing the medication before trying to conceive [36]. However, recent data from a prospective cohort study on paternal MTX exposure, reassuringly, revealed that there was no increase in spontaneous abortions, major birth defects, low birth weight, or low gestational age at delivery [44, 45].

As far as sulfasalazine is concerned, it has been reported to be associated with decreased sperm count, motility, and abnormal sperm morphology [46]. Therefore, male patients could be advised to stop sulfasalazine, particularly if their disease is well controlled or there has been some difficulty with fertility. Temporary stoppage of sulfasalazine therapy in such cases may help to achieve successful conception.

In the case of azathioprine/mercaptopurine paternal exposure before conception, there has been no association with congenital abnormalities [44, 47]. In the study done by Teruel and colleagues [48], assessment of pregnancy outcomes among men with IBD who had taken azathioprine for 3 months prior to conception, did not reveal any significant difference in time to conception, spontaneous abortions or birth weight in comparison to those who did not.

Regarding leflunomide, there is only limited data for paternal exposure to the medication; however, there was an earlier case report of pregnancy outcome of a normal-term pregnancy in the partner of one man who continued to take leflunomide throughout the pregnancy [49].

In SLE and vasculitis, it is more common to use cyclophosphamide to suppress the inflammatory process. Cyclophosphamide has been reported to have negative impact on sperms [50]. Analysis of published data revealed that there was almost universal agreement of reduced sperm counts among men taking cyclophosphamide therapy. The pattern of affection included both azoospermia and teratospermia which was reported whether during or after treatment. On a time-scale, sperm counts tend to drop within the first 3 weeks of therapy, but normally the fall is noted after four months of therapy. Studies which monitored patients after stopping cyclophosphamide therapy reported some improvement in sperm counts over time, although this was not universal [47, 48]. A mean recovery time of 31 months was reported in one study [51] and successful conceptions were reported in five cases [52].

Regarding biologic therapy, the available data regarding the TNF inhibitors and their impact on spermatogenesis is conflicting. One study reported that ten men treated with Infliximab for IBD were found to have an increase in semen volume compared to their figures recorded prior to therapy [50]. However, there was reduction in the percentage of sperm motility as well as the normal oval forms in this cohort of patients [53]. In comparison, there was one case report of oligoasthenozoospermia in a man treated with Adalimumab [54]. When treatment with Adalimumab was stopped sperm morphology and concentration returned to normal; however, the sperm motility remained low. On assessment of men living with spondyloarthritis and receiving anti-TNF therapy, there were no differences in sperm concentration, morphology, or quality reported on comparing patients treated with anti-TNF therapy to healthy controls [55]. This study supports the continued use of anti-TNF therapy in patients who are trying for pregnancy with their partner.

In general, poor pregnancy outcomes have not been reported among fathers who have been diagnosed to have one of the ARDs [36]. However, considering medical management and its impact on the birth outcomes, there may be some implications to be considered.

Limited data in men suggests that although male factor teratogenicity can occur by direct drug effect on sperm development or with seminal fluid exposure during intercourse, paternal use of antirheumatic drugs other than cyclophosphamide [66] and potentially thalidomide [67, 68] do not cause congenital anomalies. This is unlike in pregnant women where there is greater potential for teratogenic effects from some antirheumatic drugs. It is therefore suggested that male patients with active disease remain on their antirheumatic medications, the exception being in the use of cyclophosphamide and thalidomide, while attempting conception. In such patients, the risk of stopping medications may have a substantial effect.

Due to the multiplicity and complexity of forms of sexuality expression among men living with ARDs, the approach of this cohort with sexual dysfunction involves broad aspects and hard-to-approach themes, whose handling requires the formation of bonds and an environment enabling the understanding of the physical complaints aspects and beyond, in particular, the emotional and social factors [72, 73].

The rheumatology-led pregnancy clinic represents the main gate for the appropriate patients’ care delivered by a multidisciplinary team. Such approach permits the set-up and initiation of actions at different levels of complexity in health care. In this perspective, the psychologist would be the most appropriate speciality to provide management for the emotional problems, related to the illness process, and the implications of these issues on the affective and sexual relationship with the patient [73, 74]. Interventions to control pain and increase mobility and muscle strength, providing improved physical capacity for the patient, are held by the physical therapist, and this process is monitored by a physical education professional [75]. This will facilitate the improvement of objective symptoms linked to the disease, such as fatigue, pain and joint movement restrictions. Guidelines on the organization of the routine and protection of joints during activities of daily living, as well as the indication of assisted technology to modify objects and environments, are demands met by occupational therapists. Simple baseline measurements and investigations can be initiated in the rheumatology clinic and give guidance to the next step of management [76].

Different ways have been described discussing how to handle sexual function and sexual relationship problems in ARDs patients. Examples are, finding the best possible conditions to facilitate sexual arousal, best, least painful, position for making love or how to handle hand pain. These examples are in line with the strategies for self-management which Helland et al. [73] have described. These suggestions included being creative during the sexual act, adapting positions and movements; using alternative locations; using painkillers or pillows; ignoring restrictions; initiating less strenuous sexual activity; postponing sexual activity until flares have passed and having sex despite a lack of desire. Treating health care professionals/rheumatology nurses, should leave the door open for the patient to confer any worries or future plans, he might have. With this in the background, it has been suggested to include self-management strategies in the standard clinical care of ARDs patients. In a study carried out by Stoffer et al. [77] as well as in earlier research (National Rheumatoid Arthritis Society) [78], the cohort of patients included in these works, raised their concerns that the their treating healthcare professionals did not include any form of evaluation or interventions in relation to their sex life. According to Matheson et al. [79], when managing inflammatory arthritic conditions, it is vital to involve the partner in any discussion, to be able to provide comprehensive supportive care for patients as well as their families. To achieve this, it is important to pay attention to any sexual difficulties the patient might have or develop during the clinical follow-up visits. Also, whenever appropriate, to offer sexual counseling to the patient and his partner [80].

Though significant percentage of men living with ARD or receiving medical management for their disease, have reported negative impact of their disease or medication on their sexual health, yet, in majority the cases, the patients have not raised this problem for discussion with their treating health professional [25, 81]. In fact, in standard clinical practice, most of the time, sexual problems are ignored. Furthermore, patients with inflammatory arthritis in general and men in particular, vary in their preference of health professional with whom to discuss these issues [2], suggesting all health care professionals whether rheumatologists or rheumatology nurses involved in men care should attain better knowledge and understanding of how inflammatory arthritis can impact on both family planning and sexual function.

Sexual dysfunction is closely related to disease activity, its medical therapy and associated comorbidities. Table 2 depicts an approach to assessment of the male sexual health problems and its associated comorbidities which can be implemented in standard practice. To facilitate the process of early detection, it is advisable that a standard core theme should be implemented, bearing in mind how such a sensitive and private problem can be handled in standard clinical practice. In a study using a multidimensional PROMs questionnaire [2], which included questions regarding sexual dysfunction, the individual patient had the opportunity to highlight these problems. This helped both the patient and healthcare physician to bridge the gap and open this sensitive topic.

Panush et al. [82] described a strategy to approach and offer guidance on sexual function, called as PLIS-SIT (permission, limited information, specific strategies and intensive therapy). Permission consists in questioning the patient about his/her sexual dysfunction, taking the liberty and showing openness to dialog. The second step is to search and provide information about sexual dysfunction. The third phase is to develop specific strategies for each problem. In case of arthritic men who develop impotence, usually of psychogenic origin, phosphodiesterase inhibitors may be used, with “A” level of evidence in cases of organic, psychogenic and pharmacological erectile dysfunction [83]. The fourth step involves referring the patient to the sex therapist, in case of failure of other strategies.