Male sexual and reproductive health in multiple sclerosis: a scoping review

Sexual and reproductive health is severely affected by MS [10‐12]. Causes of sexual dysfunction are multifactorial and may be a consequence of neurologic dysfunction, inflammation, hormonal imbalances, and/or due to cognitive dysfunction and mood disorders, which are prevalent in MS [10]. Clinical approaches in MS define primary sexual dysfunction as related to reproductive system dysfunction, secondary as related to disability due to motor impairment, fatigue, or associated bladder and bowel dysfunction, and tertiary as related to psychological and social factors [13]. Sexual dysfunction and impaired reproductive health lead to increased burden of disease, with direct impact on physical health, mental health, and quality of life in MS [12, 14, 15]. Despite the recognized value of sexual and reproductive health in MS, data on these domains are sparse, mostly based on cross-sectional or retrospective studies, and from periods before the availability of newer high-efficacy DMTs [14‐22]. Newer DMTs such as B-cell-depleting drugs have different safety profiles than predecessors, and their teratogenic potential is mostly unknown or investigated with ongoing monitoring [21]. In addition, the longitudinal effects of common MS comorbidities on sexual and reproductive health in MS populations remain severely understudied.

The incidence of MS is greatest between the ages of 20 and 40 years [23], which coincides with the age period of optimal fertility, and, thus, family planning should be a part of standard MS care [24]. Studies suggest female infertility may be more common in MS, but causes are not well understood, and recent findings are conflicting [17‐19]. Robust data on infertility in males with MS (MwMS) are lacking, but fewer pregnancies in women with MwMS partners compared to the general population have been reported [18, 25]. Similar to females with MS (FwMS), sexual dysfunction is very common in MwMS, with 50% experiencing ejaculatory or orgasmic dysfunction and 40–75% experiencing erectile dysfunction [26‐30]. Timely use of effective DMTs is increasingly encouraged to maintain remission, despite known and unknown teratogenic potential [19‐22]. Most FwMS discontinue DMT as part of pregnancy planning, though trends over the last decade show an increase in continued use [19]. There are knowledge gaps in MS care regarding the effects of DMT use on sexual and reproductive health in MwMS.

Following recent reviews focused on female reproductive and sexual health in MS [20, 24, 31], we conducted a scoping review to evaluate the available literature on male reproductive and sexual health in MS. Such a comprehensive summary will facilitate current knowledge synthesis and identify existing gaps in the literature, which will guide next steps in enhancing MS clinical care and research related to male sexual and reproductive health in MS.

To address the stated objective, we conducted a focused scoping review using the PRISMA-ScR Checklist as a methodological guideline [32, 33]. Candidate publications were identified in PubMed database with the use of keyword “multiple sclerosis” and selected keywords (“sexual health”, “reproductive health”, “family planning”, “male fertility”, “male infertility”, “sexual dysfunction”, “erectile dysfunction”), as respective combinations with the logical operator “AND”. Following the initial title and abstract identification, full papers were read for those passing the screening. Secondary sources, which were otherwise not detected with the earlier search, were sporadically identified in retrieved papers and additionally considered for inclusion in the final review based on their relevance. Final included sources had to meet eligibility criteria and were classified by topic, study design, year of publishing, number of male participants, and study population country and continent of recruitment. Specific data on DMTs were not part of this review. Search was performed between July 15th, 2023 and July 24th, 2023. The methodological flowchart with results is presented as Fig. 1.

Studies available via PubMed database published in English between January 1st, 2002, and July 1st, 2023 were included in the initial screening. The initial date was chosen as a time point after the International Panel on MS Diagnosis presented the recognized diagnostic standard in 2001, which notably integrated magnetic resonance imaging and enabled greater diagnostic accuracy for MS [34]. The final date was chosen as the beginning of the month closest to the time when the literature search was performed. The defined period, spanning more than 2 decades, was also deemed appropriate to assess the overall trends in publishing regarding topics investigated. To broaden the assessed literature, the initial screening included studies regardless of methodology. The final bibliography for the scoping review was manually compiled of original investigations with a focus on MwMS. Duplicates were excluded, as well as reviews, case reports or case series, in vitro or animal studies, and studies that did not report male-stratified findings. The senior author reviewed and approved the final bibliography.

Descriptive analysis was performed for the articles included in the scoping review. Main results are presented in table form and discussed.

Information on study types, topics of studies, and geographical locations where studies were conducted is displayed in the Supplemental Table 1. Four main study topics emerged following final review: sexual dysfunction covering multiple domains of sexual health, erectile dysfunction as a specific topic of interest, fertility, and family planning. Most studies were cross-sectional (21/34, 62%) and from Europe (22/34, 65%). Sexual dysfunction in a broader sense was the most frequently addressed topic (20/34, 58%), followed by studies focused on erectile dysfunction (7/34, 21%), fertility (5/34, 15%), and family planning (2/34, 6%). Cohort studies (N = 9) were more common than clinical trials (N = 2) or case–control studies (N = 2). Of the two clinical trials, both investigated treatment for erectile dysfunction. Three studies were international: a clinical trial, a prospective cohort, and a cross-sectional study. Temporal trend showed that half of the included studies (17/34, 50%) were published after 2017 (Fig. 2), with at least one publication every year since 2017. Conversely, there were years between 2002 and 2017 which did not yield any studies for the final scoping review literature (Fig. 2).

A summary of studies focused on sexual dysfunction is provided in Table 1. Cross-sectional studies were the most used methodology (16/20, 80%), and three studies were based on cohorts (3 prospective and 1 retrospective). More than half of the studies were European (12/20, 60%) and a fifth were North American (4/20, 20%). The largest study was based on North American Research Committee on Multiple (NARCOMS) Registry and included 1568 male participants [29], while the smallest included 12 male participants [35]. Most studies used standardized questionnaires such as MS Quality of Life [26, 30, 36‐38], MS Intimacy and Sexuality Questionnaire [29, 35, 39‐46], Sexual Quality of Life Questionnaire for men [35, 44, 47, 48], and International Index of Erectile Function [44, 47, 48], but other methods also included original surveys created by the investigators [46, 49], or other validated forms [38, 39, 46, 49‐51]. Serum laboratory tests [42] and magnetic resonance imaging (MRI) [35] were uncommon across studies. Based on instruments applied, sexual dysfunction was predominantly determined as a composite qualitative outcome comprising a sexual quality of life metric in combination with measurements of erectile dysfunction and issues with libido, orgasm, or ejaculation. Across studies, the reported prevalence of sexual dysfunction was 35–72% (Table 1). Common associated factors were depression [36, 38], older age [36, 38, 44, 47], and disability due to MS [36, 38, 43, 44, 50]. Additional factors which were reported as associated with sexual dysfunction in individual studies were fatigue [30, 36] and smoking [44]. A cohort study including 27 MwMS determined a continued decrease in sexual activity and worsening sexual function over a 6-year period [49]. The study also reported that those affected were more willing to discuss sexual dysfunction with their partners than with their treatment team (33% vs 7%) [49], but a later cross-sectional study noted that the presence of family or friends during a clinical encounter can be a barrier to help seeking for sexual dysfunction [46]. In the same study, 6/20 MwMS reported that other MS symptoms overshadow their sexual problems, and 5/20 felt there was insufficient time to discuss sexual function during the encounter [46]. In a cross-sectional study of 50 MwMS investigating serum sex hormone profiles including 17-beta estradiol, progesterone, androstenedione, dehydroepiandrosterone-sulfate, total testosterone, estrone, prolactin, sex hormone-binding globulin, inhibin B, and anti-Mullerian hormone, there were no substantial differences in those with or without sexual dysfunction, except for lower levels of inhibin B in those with sexual dysfunction [42]. No specific brain or spinal cord MRI findings were found to be associated with the severity of sexual dysfunction [35].

A summary of studies focused on erectile dysfunction is provided in Table 2. More than half of the included studies were cross-sectional (4/7, 57%), two were clinical trials, and one was a case–control study. Besides the case–control study based on a national database (38,139 cases with erectile dysfunction and 262,848 controls) [52], the second largest study was a randomized double-blind placebo-controlled clinical trial including 217 participants [53]. All studies included the International Index of Erectile Function questionnaire as the main assessment method, with the addition of quality of life [27, 53‐55] or urinary tract function [27, 54, 56] metrics in some. In cross-sectional studies assessing the prevalence of erectile dysfunction in MwMS, the values were 45% [28] and 74% [27]. Depression, urinary tract symptoms, and greater disability due to MS were factors associated with erectile dysfunction in MS [27, 54, 56]. Diagnosis of MS was shown to be associated with erectile dysfunction in the large Taiwanese case–control study based on their national insurance database [52]. Phosphodiesterase-5 inhibitors (sildenafil, tadalafil), were shown to be effective for erectile dysfunction in MS leading to improvement in sexual quality of life in two clinical trials [53, 55]. In an international multi-center randomized controlled trial assessing sildenafil (104 subjects) against placebo (113 subjects), after 3 months, 90% of those using sildenafil (25–100 mg dose) reported improvement in erectile function and quality of life in comparison to 24% in the placebo group, a result which was sustained in the 48-week open label extension [53]. In an Italian single-arm prospective study assessing tadalafil, 70 of 92 participants noted improvement in erectile function and quality of life as measured at 3 months [55]. Both trials supported phosphodiesterase-5 inhibitors as safe pharmacological interventions with caveats regarding exclusion criteria, notably uncontrolled cardiovascular comorbidities and major psychiatric disorders [53, 55].

Four cohort studies (3 retrospective and 1 prospective) and a case–control study were focused on fertility as the main topic (Table 3). The prospective cohort study was the smallest (32 participants), but included longitudinal serum sex hormone profiles and sperm analysis [57]. It demonstrated no changes in measured hormonal or sperm parameters over a 12-month follow-up period in those treated with natalizumab or ocrelizumab. The larger retrospective study [58], based on the pooled data from Danish national registries for infertility and multiple sclerosis (24,011 with male-factor infertility, 49 MwMS), showed that male infertility was associated with a presence of diagnosis of MS (odds ratio 1.6), but not with subsequent new diagnosis of MS. In a similar manner, a Swedish case–control study (497 MwMS and 1081 controls) showed there was an association between MS diagnosis in men and being childless for the 5 years preceding index MS clinical symptom with an odds ratio 0.6 for a diagnosis of MS for those with children when compared to being childless [18]. A prior Danish national retrospective cohort based on a sample of 2,240,000 men (3426 MwMS) showed a reduced risk of MS diagnosis in men who had a child, with more children further decreasing the risk of MS diagnosis [25]. However, these case–control studies might reflect changes in sexual behaviors that might lead to conception in the prodromal period for MS. Finally, in a cohort treated with mitoxantrone (238 participants, 80 MwMS), there were no differences in number of pregnancies or rates of abortion or miscarriages between FwMS and partners of MwMS [59].

Two cross-sectional studies focused on family planning [60, 61] and both were based on original surveys. The first, based on 102 MwMS in Denmark, reported information about fetal risk with use of DMT was commonly obtained from MS treatment team (40% of respondents), but a majority of participants did not know if their current DMT had direct teratogenic effects (74%), or if DMT of male partners with MS may be associated with teratogenicity in case of conception with a female partner without MS [61]. In the second study, in an international sample of 61 MwMS, 49% reported their MS diagnosis did not have an impact on their desire to have children, 8% decided not to have children due to their diagnosis, and 25% reported changing their plans significantly [62].

Prevalence of sexual dysfunction in global male populations increases with age, especially after the age of 40 years and even more after age of 70 years, but a majority (> 50%) still retain sexual desire [64]. Erectile dysfunction affects 20% of otherwise healthy 50-year-old men, but the prevalence doubles in those with hypertension, obesity, and diabetes [65]. In contrast to a general male population, a much greater proportion of MwMS are affected with erectile dysfunction or loss of libido (40–75%) [26‐30]. In the Taiwanese case–control study, the association between erectile dysfunction and a diagnosis of MS remained evident even when controlling for age, socio-economic status, and comorbidities [52]. Although erectile function and libido are the most commonly considered factors associated with male sexual health, etiology of sexual dysfunction in MS is complex, and postulated factors have been clinically organized into a tripartite hierarchical model [13]. For MwMS, our summary identified erectile dysfunction as the most common factor categorized as a component of primary sexual dysfunction, disability due to MS categorized as secondary, and depression categorized as tertiary. Specific hormonal or neuroimaging findings pointing to sexual dysfunction in MwMS have not been identified, aside from a potential role of lower levels of inhibin B [42]. A prior electrophysiologic study based on volunteer sample of 29 MwMS reported neurogenic causes as more frequent than isolated psychological (26 vs. 3 participants), though the latter was also recognized as a potential co-factor when the former is present [66]. Besides optimizing prevention and management of comorbidities found to impact sexual health in the general male population, our review highlights reduction of the burden of motor disability due to MS and improving mental health as additional intervention targets to ameliorate sexual dysfunction in MwMS. In review of the epidemiologic evidence, there were only two clinical trials focused on erectile dysfunction in MwMS. Most of the observational studies on sexual dysfunction were cross-sectional (14/20), which precluded inferences about longitudinal relationships between associated factors. Despite general study design limitations, including modest sample sizes, similar manifestations and related symptoms or comorbidities were reported across studied populations.

There is a major knowledge gap regarding DMT use in the context of reproductive health in MwMS population [61], which possibly has a direct impact for about a third of MwMS who change their plans regarding having children following an established diagnosis of MS [62]. Sexual health is an integral part of reproductive health, but fertility and fecundity also depend on male factors such as sperm quality. Exact pathophysiologic mechanisms of male-factor infertility in MS remain to be determined, though up to 40% of causes of male-factor infertility are elusive even in general population-based studies [67]. Scandinavian population-based studies showed an association between male diagnosis of MS and fewer offspring, and may be indicative of increased infertility but it may also reflect altered sexual behaviors [18, 25, 58]. Most of the observational studies on these topics were retrospective (4/7) and based on specific European populations (4/7 Scandinavian countries, 2/7 Italy), which limits generalizability.