Clinical manifestations

Presentation and course

Fertility is often defined as the potential to conceive and carry a pregnancy to term. Infertility is defined as the failure to conceive after 12 months of regular unprotected intercourse in women under the age of 35 years, or 6 months in women over the age of 35. According to the National Survey of Family Growth, the prevalence of infertility among women aged 15 to 49 years is 13.1% in the United States (46). Any number of factors can impair a couple’s ability to conceive, such as disruption of any of the steps from ovulation, sperm reaching the egg, fertilization, or implantation in the uterus. Although infertility is commonly viewed as a “female” issue, about 20% of cases are considered to be solely due to male factors and up to 40% of cases are due to both male and female factors (40). This article will consider fertility in both women and men with multiple sclerosis. It is important to note that most of the multiple sclerosis studies cited here include mostly patients with relapsing-remitting disease, with very few progressive cases.

To date, there is limited, and sometimes contradictory, evidence regarding the direct impact of multiple sclerosis on fertility. Some studies have noted a higher incidence of childlessness in this population (33; 50; 17), but it is unknown if this relates to true infertility or elective nulliparity. A small retrospective French study found no difference in the number of spontaneous pregnancies per woman and time to pregnancy between women with multiple sclerosis and the general population, but only 57% of women had complete data (49). In contrast, a study from Denmark reported that women and men with multiple sclerosis had fewer children than matched controls (IRR=0.63 and IRR=0.69, respectively), and this difference was more pronounced after disease diagnosis as compared to disease onset (43). Houtchens and colleagues analyzed data from an administrative claims database and found that women with multiple sclerosis had lower live birth rates and were more frequently diagnosed with infertility (29). An analysis of infertile men also found a higher risk (HR 1.91) of multiple sclerosis as well as other autoimmune diseases compared to fertile men and controls (05).

Multiple disease-related factors can potentially impact fertility in men and women with multiple sclerosis including sexual dysfunction, endocrine abnormalities, and treatment effects. Sexual dysfunction in multiple sclerosis can be primary, as a result of direct damage to the central nervous system, secondary to other disease factors, such as bladder dysfunction or muscle spasticity, or tertiary due to psychosocial effects. In any case, the prevalence of sexual dysfunction in women with multiple sclerosis can be as high as 40% to 80% (15). The impact of multiple sclerosis therapies on fertility is not fully understood. Overall, the amount of information is scarce but older agents are better understood. Although rarely used in current practice, some medications used to treat aggressive or progressive forms of multiple sclerosis, such as cyclophosphamide and mitoxantrone, have gonadotoxic effects.

Endocrine factors could also be responsible for decreased fertility in both men and women with multiple sclerosis. In a study of sex hormones throughout the menstrual cycle in women of reproductive age with multiple sclerosis, 36.4% had abnormal hormone levels, with the most common alteration being low 17-B-estradiol (36). A small study of patients treated with either interferon-beta or glatiramer acetate found significantly lower ovarian volume and antral follicle counts versus healthy controls, but no consistent alteration in estradiol levels (08). It is important to note that the literature has been conflicting on alterations in other sex hormones such as LH levels and FSH levels compared to healthy controls, and most of these studies were relatively small (08; 36). Measurement of anti-Mullerian hormone can provide a menstrual cycle-independent measure of ovarian reserve and is frequently checked as part of any infertility workup. Anti-Mullerian hormone in women is secreted by ovarian granulosa cells soon after birth and until menopause, when levels drop due to exhaustion of growing follicles. One study compared women with relapsing-remitting multiple sclerosis with healthy controls and found that multiple sclerosis patients had significantly lower anti-Mullerian hormone levels (2.47+/-0.26 ng/ml vs. 3.34+/-0.34 ng/ml) (60). The study also found that not currently being treated with a disease-modifying drug was a predictor of a very low anti-Mullerian hormone level (< 0.4 ng/ml). This study, although small, suggests untreated multiple sclerosis itself, rather than disease-modifying drugs, may be related to decreased fertility in women with multiple sclerosis. Another study compared 25 women with relapsing-remitting multiple sclerosis to healthy controls and found significantly lower anti-Mullerian hormone levels and ovarian volume in women with relapsing-remitting multiple sclerosis and higher disease activity (54). A diminished ovarian reserve can present a major challenge for fertility specialists, as these patients often have limited success with assisted reproductive technology (35). Some cases of female infertility are thought to be auto-antibody driven, and these women have low estrogen levels and amenorrhea, as well as adrenocortical or steroidogenic cell autoantibodies, including anti-ovarian antibodies. In 85 women with relapsing-remitting multiple sclerosis and 63 healthy controls, antiovarian antibodies were not found in either group (59). This study found that patients with multiple sclerosis had higher levels of endoglin compared to healthy-controls, levels were highest among those with the lower levels of anti-Mullerian hormone. The exact role of serum endoglin is unknown in multiple sclerosis, but it may shift the balance of Treg/Th17 cells towards a proinflammatory profile. Autoimmune diseases known to increase the risk of infertility due to premature ovarian failure include Sjögren disease, systemic lupus erythematosus, and myasthenia gravis. It is unknown exactly how nonendocrine autoimmune diseases disrupt ovarian functioning, and attempts to relate this to specific autoantibodies have been inconsistent. Traditionally, multiple sclerosis is considered a disease of abnormal inflammation and demyelination within the central nervous system, but there is also systemic inflammation that precedes and coincides with multiple sclerosis exacerbations.

Family planning decisions in patients with multiple sclerosis can be complex, and many times they are heavily weighted toward patient’s concerns about risk of acquiring further disability, the ability to care for children in the future, and disease progression due to discontinuation of disease-modifying therapies. A Danish study found that women with multiple sclerosis and higher disability scores had fewer children compared to healthy controls (43). This finding supports the idea that disability can play an important role in family planning in patients with multiple sclerosis. Young couples consider cost as well; quotes for healthcare cost burden range from $8,528 to $54,244 per multiple sclerosis patient per year in the United States (01).

One way to examine infertility in multiple sclerosis would be to analyze whether multiple sclerosis patients use assisted reproductive technology more frequently than other patients. A Finnish study of 61 women with relapsing-remitting multiple sclerosis followed throughout pregnancy found a higher than expected rate of use of artificial insemination compared to the general population (4.9% vs. 0.9%) (30). However, artificial insemination might be used for any number of male or female fertility issues, so it is unclear if this increase is related to multiple sclerosis alone. Another Danish cohort specifically looked at men registered for in vitro fertilization (IVF) and compared them to the Danish Multiple Sclerosis Registry and found that men specifically diagnosed with male factor infertility had a higher risk of prevalent and incident multiple sclerosis (24). To date, there have not been any studies to investigate whether multiple sclerosis patients seek assisted reproductive technology more often. A retrospective cohort study based on a nationwide Danish health registry analyzed outcomes of embryo transfers from 1995 to 2017 in women with multiple sclerosis and found that the chance of live birth was comparable to women without multiple sclerosis (31).

Estrogen and multiple sclerosis. Multiple sclerosis has long been recognized as a predominantly female disease, and similar trends have been seen in many other autoimmune conditions. In contrast to the increasing female predominance in adult multiple sclerosis, pediatric disease shows an almost equal ratio of females to males in prepubertal patients (61). Early menarche is associated with a higher incidence of multiple sclerosis; in fact, the risk of multiple sclerosis falls by 13% for each year of menarche delay. In addition, women with multiple sclerosis tend to present earlier and have more frequent relapses and inflammatory lesions in the relapsing form of the disease as compared to men (32). On the other hand, men tend to present later in life, with a progressive course, and the disease tends to be more severe (48). This female preponderance and the differential incidence with puberty suggest a hormonal effect on development and disease progression.

Moreover, researchers have proposed a potential neuroprotective role for estrogens. This effect is likely mediated by inhibition of proinflammatory cytokines, NK cell activation, and induction of anti-inflammatory cytokines (39). For example, the placenta-produced estrogen, estriol (E3), peaks during the third trimester and plummets postpartum, correlating with the drop and rebound of multiple sclerosis relapses, respectively. Pregnant animals have a decreased incidence and severity of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (16). Disappointingly, the POPARTMUS trial, which administered both estriol and progestin in postpartum multiple sclerosis patients, showed no differences in relapse rate compared to the placebo group (66). Results from a phase 2 trial combining 8 mg oral estriol and glatiramer acetate in female multiple sclerosis patients have been more encouraging, with a small reduction in annualized relapse rate (0.25 vs. 0.37 in placebo group) with a planned power threshold of p < 0.10 (64). Estriol patients without enhancing lesions had less cortical grey matter atrophy, and there was an association between higher estriol concentrations and better PASAT scores. These results are supported by a smaller study that found a decrease in MRI enhancement in nonpregnant multiple sclerosis patients taking estriol alone (55).

Obesity, multiple sclerosis, and fertility. Obesity has gained attention as a risk factor for multiple sclerosis as well as a separate component of female infertility. In a cohort study conducted in the United States, the risk of multiple sclerosis was increased 2-fold for women 18 years of age or older and with a BMI over 30 (44). The same increased risk was found with a review of the Copenhagen School Health records (45), further supporting a possible association between teenage obesity and the risk of multiple sclerosis in women. Obesity is correlated with anovulation and menstrual irregularities in otherwise healthy women, and the metabolic syndrome is seen frequently in polycystic ovarian syndrome. Obesity reduces the probability of success for spontaneous conception even in women who have normal ovulatory cycles (63). Even with medication to induce ovulation, obesity can damper the success of advanced reproductive therapies. Obese women have a decreased rate of success when undergoing assisted reproductive therapies (34). Obese women undergoing intrauterine insemination require higher doses of gonadotropins and produce fewer follicles compared to normal weight counterparts (58). It is unknown how much obesity is contributing to overall fertility rates for multiple sclerosis patients, but as obesity rates increase it will likely continue to be an obstacle for the treatment of couples suffering from infertility. Obesity has also been found to be a risk factor for infertility in males, and studies have shown that obese men have lower sperm count and quality. A study from a Swedish-based cohort showed that the risk of incident multiple sclerosis was higher in patients with higher BMI, independent of physical fitness (67). Therefore, male obesity is also a major concern for infertility rates in patients with multiple sclerosis.

Male fertility and multiple sclerosis. Unfortunately, there is insufficient information about the effects of multiple sclerosis on male fertility and it remains largely understudied. Two population registries from Sweden and Denmark showed a lower number of pregnancies in female partners of men with multiple sclerosis. The Swedish registry found that men with newly-diagnosed multiple sclerosis were less likely to have had children in the five years preceding diagnosis (26). The Danish population registry found that the male partners of couples treated for male infertility had a higher prevalence of multiple sclerosis compared to male partners of couples treated for infertility not due to male factors (24).

Fertility in men with multiple sclerosis can be affected by three main mechanisms: 1) erectile and/or ejaculatory dysfunction due to direct impact of the disease; 2) hypogonadism, either of central or peripheral etiology (central hypogonadism can be the result of lesions affecting the hypothalamus-pituitary-testis axis, whereas peripheral hypogonadism is the result of chronic inflammation and autoimmunity); and 3) possible gonadotoxic effects of symptomatic or disease-modifying therapy for multiple sclerosis (41).

Fifty percent to 90% of men with multiple sclerosis report sexual complaints throughout the course of their disease; this is more common in patients with higher disability (06). Lesions in the central nervous system, especially those in the spinal cord, can have direct effects on sexual function in men by leading to erectile or ejaculatory dysfunction. Autonomic dysfunction caused by suprasacral, parasympathetic, or peripheral autonomic lesions can lead to sexual dysfunction. In addition, some symptomatic medications commonly used in multiple sclerosis can also cause erectile and/or ejaculatory dysfunction, especially benzodiazepines and tricyclic antidepressants. Oxidative stress and chronic inflammation have been linked to infertility in men, leading to alterations in semen parameters. One study of 68 males with multiple sclerosis, who were not receiving disease-modifying drugs for at least six months, found lower quality and motility of sperm compared to healthy controls (51). As noted above, men with multiple sclerosis can also present with hypogonadism, which manifests with lower serum levels of testosterone, LH, and FSH (20; 51).

Disease-modifying drugs and fertility. Overall, disease-modifying drugs are not believed to diminish future fertility, with the exception of the chemotherapeutic agents cyclophosphamide and mitoxantrone, which have been used in the past for treatment of aggressive and progressive forms of multiple sclerosis. Cyclophosphamide is an alkylating chemotherapy agent that binds DNA and interferes with cell replication and has well-known gonadotoxicity and fertility risks, as germinal cells have high mitotic activity. In mouse studies, cyclophosphamide disrupted female germ cells, especially if given within a week of conception. Infertility seems to be related to older age at dosing of cyclophosphamide and to higher cumulative dosages. In a trial with pulse cyclophosphamide for systemic lupus erythematosus, rates of sustained amenorrhea were increased for patients over the age of 25 years (04). As many as 50% to 90% of men can also have transient or permanent azoospermia with cyclophosphamide use (07). Mitoxantrone, an anthracenedione chemotherapeutic agent, also disrupts DNA synthesis and has FDA approval for secondary progressive or relapsing progressive forms of multiple sclerosis. It also has a dose-dependent effect on fertility that increases with age and is associated with amenorrhea in about 26% of multiple sclerosis patients (09). Various methods have been used to allow chemotherapy-exposed patients to conceive, including freezing of eggs or sperm before treatment. Some clinicians propose adding an estroprogestinic drug during treatment to suppress the ovarian cycle and hopefully protect future fertility. The FEMIMS study found that women given an estroprogestinic combined with mitoxantrone had a lower incidence of amenorrhea following treatment. Some clinicians propose adding an estroprogestinic drug during treatment to suppress the ovarian cycle and hopefully protect future fertility. The FEMIMS study found that women given an estroprogestinic agent combined with mitoxantrone had a lower incidence of amenorrhea following treatment (09).

On the contrary, interferon-beta has been proposed to have a positive impact on fertility through the facilitation of implantation and potentially affecting estrogen levels. There are anecdotal reports of patients who had failed assisted reproductive technology trials but became pregnant soon after resuming interferon-beta therapy (47). Interferon-tau, a type I interferon, enhances uterine receptivity in ungulate mammals (20; 03; 47) but the role of interferons in human pregnancy is thus far unknown.

A prospective case-control study conducted in Catania, Italy analyzed the impact of natalizumab and ocrelizumab in fertility on male patients with relapsing-remitting multiple sclerosis (13). It found no differences between cases and healthy controls with respect to gonadal steroid levels (total testosterone, luteinizing hormone and follicle stimulating hormone) and sperm parameters (seminal fluid levels, total sperm count, and total and progressive motility). Measurements were conducted before starting treatment and after one year of therapy.

Sexual dysfunction and multiple sclerosis. Sexual dysfunction can have a profound impact on fertility as well as quality of life and relationships in patients with multiple sclerosis. It can be classified into primary, secondary, or tertiary. Primary sexual dysfunction is directly caused by spinal cord and brain lesions leading to erectile dysfunction, ejaculatory dysfunction, or decreased lubrication. Impaired ability to achieve orgasms and anorgasmia can occur due to lesions in the brainstem or spinal cord and autonomic pathways. Secondary sexual dysfunction occurs as a result of indirect factors such as fatigue, weakness, bowel or bladder dysfunction, as well as from concurrent use of several symptomatic medications. Psychosocial factors such as depression, body image, or societal perception, lead to tertiary sexual dysfunction (15). These difficulties are seldom brought up by patients. In a review of articles concerning sexual disorders among women with multiple sclerosis, the prevalence ranged from 34% to 85% (10). As mentioned above, the medications used to treat multiple sclerosis symptoms can interfere with sexual function. Loss of desire and orgasmic dysfunction is a well-described side effect of SSRIs used to treat depression and may warrant discontinuation or switch to drugs with fewer sexual side effects like bupropion. Muscle relaxants used to treat spasticity may also worsen multiple sclerosis fatigue or contribute to weakness at higher doses. Anticholinergic medications like tricyclic antidepressants or urinary urgency medications can cause decreased vaginal lubrication and pain during intercourse.

Assisted reproductive technology and multiple sclerosis. Assisted reproductive technology includes the use of procedures such as artificial insemination or in vitro fertilization, usually coupled with fertility-promoting medications. In vitro fertilization is a procedure where fertility medications are given to stimulate the ovaries and produce follicles, which are then retrieved and fertilized in the laboratory to later be transferred to the uterine cavity. Fertility specialists can use various protocols before in vitro fertilization, usually with a GnRH agonist or antagonist. These medications suppress FSH and LH production. GnRH agonists cause an initial surge of LH and FSH, but due to continued binding to GnRH receptors, there is a delayed but profound downregulation of FSH and LH. GnRH antagonists directly bind to GnRH receptors to block the release of FSH and LH from the pituitary. A study analyzing data from an administrative claims database in the United States found that women with multiple sclerosis had lower live birth rates and were more frequently diagnosed with infertility; nonetheless, they were less likely to undergo fertility treatments compared to healthy controls (29). Historically, there has been a fear that fertility treatments may increase risk of relapse. The effects of reproductive technologies on disease activity in patients with multiple sclerosis have been investigated over the years, with largely conflicting results.

Retrospectively, physicians noted an increase in multiple sclerosis relapses in women undergoing in vitro fertilization (27; 42). There is also a reported case of tumefactive demyelination in a multiple sclerosis patient shortly after receiving in vitro fertilization (62). In a study of 16 multiple sclerosis patients who underwent 26 in vitro fertilization procedures with GnRH agonists, researchers isolated monocytes and CD4+ T cells from the same patients and found that assisted reproductive technology greatly enhanced the production of pro-inflammatory cytokines like IFN-gamma, IL-8, and IL-12 and surprisingly increased the anti-inflammatory TGF-beta. The study also found increased production of CXCL-12 (C-X-C motif chemokine 12 or SDF-1), which induces peripheral blood mononuclear cell migration across the blood-brain barrier. Interestingly, the same robust increase in multiple sclerosis relapse after GnRH agonists does not appear to be shared with GnRH antagonists. A multicenter retrospective study conducted by Dr. Bove and colleagues in the United States followed 65 women with multiple sclerosis and clinically isolated syndrome undergoing fertility treatments (25). They found no evidence of increased relapse risk. In this cohort, 43% of women were receiving disease modifying therapy.

Overall, the choice to use GnRH agonists or antagonists usually depends on physician preference or previous response to in vitro fertilization regimens. Multiple sclerosis patients about to undergo assisted reproductive technology should carefully discuss their options with the fertility specialist.

A retrospective cohort study based on a nationwide Danish health registry analyzed outcomes of embryo transfers from 1995 to 2017 in women with multiple sclerosis and found that the chance of live birth was comparable to women without multiple sclerosis (31).

Prognosis and complications

The prognosis is very good for most patients with multiple sclerosis who are trying to conceive and those who become pregnant. Even with the increased relapse risk in the postpartum period described in the PRIMS trial, 72% of the women did not experience a relapse after delivery. Also, assisted reproductive technology has made great advances in fertility treatment. A large cohort study of Danish women who underwent assistive reproductive technology found that the proportion of live births did not significantly differ between those diagnosed with multiple sclerosis and healthy controls (31); this is in opposition to rates of live births in women suffering from other autoimmune diseases such as rheumatoid arthritis, Crohn disease, and ulcerative colitis.

Biological basis

Etiology and pathogenesis

The pathophysiology of sexual dysfunction in patients with multiple sclerosis is poorly understood. Because the exact location of lesions and the extent of disability varies widely for all patients with multiple sclerosis, it is difficult to fully relate specific lesions to sexual symptoms. Literature from studies of patient with spinal cord injury have been more successful at describing and isolating specific forms of sexual dysfunction due to damaged spinal cord pathways. Overall, a complete spinal level injury is more likely to cause sexual dysfunction, and lesions to the lower spinal cord are more likely to compromise sexual function. Preserved pinprick and light touch between levels T11 through L2 can be predictive of genital responses in spinal cord injury for both males and females (57; 56). The pathophysiology of male sexual dysfunction has been better elucidated in spinal cord injury literature. It is known that normal male sexual function relies heavily on coordinated interactions between the somatic and autonomic nervous systems. Sympathetic as well as parasympathetic fibers are involved in male arousal and ejaculation. Erections require S2 to S4 parasympathetic fibers, and the ejaculatory reflex involves thoracolumbar sympathetic fibers from T10 to L2 as well as sacral somatic fibers (18). Disruptions in these spinal cord pathways due to demyelinating lesions could cause sexual dysfunction in men.

Epidemiology

The exact incidence or prevalence of infertility among patients with multiple sclerosis is still a matter of debate. Some studies have reported that women and men with multiple sclerosis have fewer children (33; 50; 17; 29; 43), but it is unknown if this relates to true infertility or elective nulliparity.

Differential diagnosis

Patients with multiple sclerosis should receive the same standard fertility workup as other patients without demyelinating diseases, as the exact role of multiple sclerosis in infertility is still unclear. As a general rule, patients with multiple sclerosis should be referred to a fertility specialist if they are unable to conceive after 3 to 6 months of consistent attempts. This recommendation is mostly based on limited data regarding fertility and multiple sclerosis, as well as with a goal to minimize time off therapy and risk of relapse. Neurologists can also help patients by inquiring about bowel, bladder, and sexual dysfunction, as they can all contribute directly or indirectly to infertility. Family planning should be addressed frequently during visits for patients of childbearing age, to allow for adequate time to adjust disease-modifying drugs. Neurologists should also inquire about any previous use of chemotherapeutic agents, such as mitoxantrone and cyclophosphamide.

Diagnostic workup

The typical infertility workup involves a thorough history and examination for both female and male patients and is usually completed by a trained fertility specialist. Infertility specialists will screen for a history of pregnancy complications, miscarriages, smoking, previous chemotherapy or gonadotoxic medications, family history, and description of menstrual cycle issues. Although it is important for physicians to note the clinical history of multiple sclerosis and use of disease-modifying drugs and treatments for multiple sclerosis symptoms, patients with multiple sclerosis should undergo the same infertility testing as other couples. Infertility testing usually includes a semen analysis for men, blood tests of thyroid function, FSH, and estradiol levels, and a hysterosalpinography of the fallopian tubes and uterine cavity for women. The fertility specialist may elect to pursue further testing with laparoscopy to look for pelvic pathology, pelvic ultrasound, or antimüllerian hormone to measure ovarian reserve.

Neurologists should identify multiple sclerosis-specific causes of sexual dysfunction during the clinical interview, including an assessment of bowel and bladder control. Patients may feel more comfortable filling out a questionnaire, and the Multiple Sclerosis Intimacy and Sexuality Questionnaire is one such tool that assesses primary, secondary, and tertiary factors of sexual dysfunction in men and women (19). Overall, the biggest barrier to treatment is poor identification of those with sexual dysfunction, so it is important for physicians to screen patients appropriately and make them aware of treatments. It is also vital to gauge patient expectations for treatment and, when appropriate, refer them to urologists.

Management

Management of infertility depends on the specific cause, although in some cases a cause is not found. Assisted reproductive technology can be used for patients with multiple sclerosis experiencing infertility. A Danish cohort study found that rates of live births after assisted reproductive technology were similar between women with multiple sclerosis and healthy controls (31).

Sexual dysfunction management should also be directed toward the suspected cause of symptoms. Vaginal dryness or pain can be aided by lubricants or topical estrogens. Removal of medications, such as anticholinergic and antidepressant drugs, may also be necessary to help sexual dysfunction. Therapy may be recommended for psychosocial aspects of sexual dysfunction, as well as for depression.

Bladder and bowel dysfunction. Bowel and bladder dysfunction are frequently seen but often ignored in patients with multiple sclerosis. Urinary urgency is typically treated with anticholinergic medications, which are available in both immediate-release as well as extended-release formulations. For patients with refractory symptoms, another option is intravesical botulinum toxin injections. A small study found that the use of onabotulinum toxin A intravesical injections in 31 women with multiple sclerosis significantly improved urinary symptoms, sexual function, and psychological status (23). For patients with persistent urinary retention, clean intermittent catheterization is often necessary to fully empty the bladder and prevent urinary tract infections.

Bowel dysfunction includes symptoms of constipation as well as bowel incontinence. Constipation is typically managed with bulking agents, adequate hydration, and a high fiber diet. Laxatives may be used for more refractory cases including osmotic or stimulant laxatives but may produce incontinence. Bowel incontinence remains a difficult symptom to treat and inquiry into the underlying cause is necessary, as chronic constipation and fecal impaction can cause overflow incontinence which would only worsen with antimotility agents. Typically, a more structured bowel regimen is recommended to decrease the unpredictability of bowel movements.

Phosphodiesterase V inhibitors. Medications such as PDE-5 inhibitors are widely used in men to manage erectile dysfunction due to various conditions, including spinal cord injuries. Phosphodiesterase V inhibitors block the enzyme that breaks down nitric oxide-cyclic guanosine monophosphate (cGMP). With increased cGMP, there is increased cavernous blood flow and smooth muscle relaxation in the penis, leading to increased erectile function. Researchers were optimistic that the same mechanism could allow women to benefit from PDE-5 inhibitors through increased clitoral blood flow. However, a large, double-blinded study of 781 women with female sexual arousal disorder found no difference between sildenafil and placebo in sexual satisfaction and global efficacy questionnaires (02). The use of PDE5i in patients with multiple sclerosis has mainly been studied in male populations with positive but conflicting results. In a double-blinded study of men with multiple sclerosis and erectile dysfunction in Iran, sildenafil performed only slightly better than placebo in improving erections (32.8% vs. 17.6%) (52). However, a similarly designed double-blinded study in the United Kingdom and the United States found a 4-fold increase in improved erections for sildenafil in men with multiple sclerosis and erectile dysfunction (97% vs. 26%) (21). Only one trial has been performed with sildenafil in women with multiple sclerosis and sexual dysfunction. There was a statistically significant increase in lubrication but no change in quality-of-life measures (14). These results in women are representative of the overall disappointing PDE5i results for female sexual dysfunction.

Pelvic floor muscle training. Pelvic floor muscle training or rehabilitation is a series of pelvic exercises, sometimes combined with biofeedback and electrical stimulation, to help improve tone and muscle control. Several randomized controlled trials have found benefits for women with stress incontinence, but there is not enough evidence currently to support use for sexual dysfunction. One small study of women with multiple sclerosis found benefit for pelvic floor muscle training with or without electrical stimulation, and at the end of 12 weeks saw a statistically significant improvement in lubrication, arousal, and satisfaction (38). It is important to note that all patients received pelvic floor muscle training in the three groups studied, and the perceived benefit was equivalent in groups given sham neuromuscular electrical stimulation and true intravaginal neuromuscular electrical stimulation.

Hormone replacement and hormone supplements. Hormone replacement therapy has been used to treat systemic symptoms of menopause, specifically vasomotor symptoms. There is not enough information currently to recommend systemic hormone replacement for management of isolated sexual dysfunction in women. Nonetheless, if used for systemic vasomotor symptoms, hormone replacements can have indirect effects on sexual function by improving vaginal dryness, fatigue, and insomnia. Local/vaginal estrogen therapy is indicated for the management of genitourinary syndrome of menopause, by improving vaginal dryness, local pH, and restoring vaginal and urethral endothelium thickness (53).

Testosterone replacement therapy is also used in the treatment of sexual dysfunction in men. Clinical trials and observation studies support its use for patients with confirmed hypogonadism (total testosterone less than 12 nM), although overall clinical efficacy is considered limited, especially in cases of complicated vasculogenic erectile dysfunction (11).

Special considerations

Pregnancy

According to a retrospective U.S. administrative claims study, there has been a significant increase in pregnancy rates among women with multiple sclerosis, which indicates that more women and neurologists are becoming comfortable with preconception planning in multiple sclerosis (28). Careful pregnancy planning is advised in patients receiving disease modifying therapies, as discontinuation or adjustment will be required in preparation for pregnancy. Neurologists should discuss pregnancy planning with women of childbearing potential frequently during visits, including effects of medication on pregnancy. Women with aggressive or poorly controlled disease should be encouraged to delay pregnancy until their symptoms and disease activity is better controlled. The goal of disease quiescence in the year before pregnancy is important because it is a predictor of risk of postpartum relapses in the PRIMS trial (65). Further discussion about specific disease modifying therapies and their management in pregnancy and preconception is beyond the scope of this review.

Anesthesia

Patients and their obstetricians should be reassured that labor and delivery can be treated similarly to any other patient. Multiple sclerosis is not a contraindication to epidural anesthesia or cesarean delivery. Postprocedure care does not differ in this patient population. Multiple sclerosis patients do not have higher rates of complications during labor and delivery (12).