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Jun. 07, 2021
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• Multiple sclerosis predominantly affects women in their childbearing years and fertility is a frequent concern for these patients.
• Infertility is not considered to be more prevalent in patients with multiple sclerosis.
• Fertility can be potentially be affected by different factors, including symptomatic medications and sexual dysfunction.
Multiple sclerosis primarily affects women of childbearing age and the prevalence of this disease has steadily increased in women over the last 5 decades, with a woman to man ratio of approximately 3:1. This trend starts in adolescence and continues up to the sixth decade of life, when the ratio decreases to around 2:1 (19). Over the past 30 years, there has been a clear shift in the treatment paradigm of multiple sclerosis in pregnant women. Decades ago, physicians believed that pregnancy could worsen the natural course of the disease, as it does some other autoimmune illnesses like systemic lupus erythematosus. The 1998 landmark study Pregnancy in Multiple Sclerosis (PRIMS) provided evidence that contradicted the long-held belief that pregnancy was not safe in multiple sclerosis. This large prospective trial was the first to demonstrate an overall decrease in relapse rate during pregnancy, especially in the third trimester, when compared to the year before pregnancy occurred. It simultaneously raised awareness that there can be increased disease activity in the first 3 to 4 months postpartum. Pregnancy is now widely considered an immune system “tolerant” period for multiple sclerosis patients and some data may even suggest a beneficial effect.
• There is no conclusive evidence to support a direct effect of multiple sclerosis on fertility but several studies have reported that women and men with multiple sclerosis have fewer children than healthy controls.
• Potential factors that can affect fertility in patients with multiple sclerosis include sexual dysfunction, endocrine abnormalities, and treatment side effects.
• Cyclophosphamide and mitoxantrone are rarely used in the treatment of multiple sclerosis but they have been shown to directly affect fertility in both men and women.
• Interferon-beta may have a positive impact on the rate of pregnancies, mainly by facilitating embryo implantation.
Fertility is defined as the number of offspring produced, although this term is also often used to describe 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 (37). 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 (32). 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, it remains unclear if multiple sclerosis directly affects fertility. Some studies have noted a higher incidence of childlessness in this population (26; 41; 14) 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 (40). 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 (34). 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% (12). 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 (29). A small study of patients treated with either IFN-B or glatiramer acetate found significantly lower ovarian volume and antral follicle counts versus healthy controls but no consistent alteration in estradiol levels (07). 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. Measurement of anti-Mullerian hormone can provide a menstrual cycle-independent measure of ovarian reserve and is frequently checked as part of an 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 a significantly lower anti-Mullerian hormone level (2.47+/-0.26 ng/ml vs. 3.34+/-0.34 ng/ml) (50). 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 relapsing-remitting multiple sclerosis women to healthy controls and found significantly lower anti-Mullerian hormone levels as well as ovarian volume in relapsing-remitting multiple sclerosis patients with higher disease activity (44). A diminished ovarian reserve remains can present a major challenge for fertility specialists, as these patients often have limited success with assisted reproductive technology (28). 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 antiovarian antibodies. In 85 relapsing-remitting multiple sclerosis females and 63 healthy controls, antiovarian antibodies were not found in either group but the relapsing-remitting multiple sclerosis patients with the lowest anti-Mullerian hormone did have the highest endoglin values (49). The exact role of serum endoglin is unknown in multiple sclerosis but it may shift the balance of Treg/Th17 cells. 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 disability concerns, the ability to care for children in the future, and concerns for 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 (34). 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 relapsing-remitting multiple sclerosis females followed throughout pregnancy found a higher than expected rate for use of artificial insemination compared to the general population (4.9% vs. 0.9%) (23). But 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 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 (21). To date, there have not been any studies to investigate whether multiple sclerosis patients seek assisted reproductive technology more often than expected or if their results with assisted reproductive technology are any more or less successful.
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 (51). 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 (25). On the other hand, men tend to present later in life, with a progressive course, and the disease tends to be more severe (39). 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 antiinflammatory cytokines (31). For example, the placenta-produced estrogen, estriol (E3), peaks during the 3rd trimester and plummets postpartum, correlating with the precipitous drop and rebound of multiple sclerosis relapses. Pregnant animals have a decreased incidence and severity of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (13). Disappointingly, the POPART’MUS trial, which administered both estriol and progestin in postpartum multiple sclerosis patients, showed no differences in relapse rate compared to the placebo group (56). 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 (54). 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 (45).
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 United States cohort group, the risk of multiple sclerosis was increased 2-fold for women with a BMI over 30 at age 18 years (35). The same increased risk was found with a review of the Copenhagen School Health records (36), 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 (53). 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 (27). Obese women undergoing intrauterine insemination require higher doses of gonadotropins and produce fewer follicles compared to normal weight counterparts (48). 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 become an increasing obstacle for the treatment of infertile couples. 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 (57). 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. Lesions in the central nervous system, especially those in the spinal cord, can have direct effects on fertility by leading to erectile or ejaculatory dysfunction. One study of 68 males with multiple sclerosis, who were not receiving disease-modifying drugs for at least 6 months, found lower quality and motility of sperm compared to healthy controls (42). Male multiple sclerosis patients have lower levels of testosterone as well (17). The use of chemotherapeutic agents such as cyclophosphamide and mitoxantrone can also diminish fertility in men.
Disease-modifying drugs and fertility. Overall, disease-modifying drugs are not believed to diminish future fertility. Exceptions in this category are the chemotherapeutic agents cyclophosphamide and mitoxantrone, which have been used in 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 (06). 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 (08). 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. Studies examining coadministration of cyclophosphamide and GnRH agonists in cancer and rheumatologic patients have yielded mixed results and there have not been any trials with multiple sclerosis patients.
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 (38). Interferon-tau, a type I interferon, enhances uterine receptivity in ungulate mammals (17; 03; 38) but the role of interferons in human pregnancy is thus far unknown.
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, impaired ejaculation, 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 (12). 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% (09). 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 transfer to the uterine cavity. Fertility specialists can use various protocols before in vitro fertilization, usually with a GnRH agonist or antagonist. The interchangeable use of an agonist or antagonist can suppress FSH/LH production. GnRH agonists cause an initial surge of LH and FSH, but due to continued binding to GnRH-R, there is a delayed but profound downregulation of FSH and LH. GnRH antagonists directly bind to GnRH-R to block the release of FSH and LH from the pituitary. Retrospectively, physicians noted an increase in multiple sclerosis relapses in women undergoing in vitro fertilization (22; 33). There is also a reported case of tumefactive demyelination in a multiple sclerosis patient shortly after receiving in vitro fertilization (52). In a study of 16 multiple sclerosis patients who underwent 26 in vitro fertilization procedures with GnRH agonists 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. Despite these results, concerns about the role of GnRH agonists are not substantiated and it is possible that results were confounded by the small sample sizes. 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.
The prognosis is very good for most multiple sclerosis patients contemplating having children. Even with the increased postpartum risk described in the PRIMS trial, 72% of the women did not experience a relapse in the postpartum period. Also, assisted reproductive technology has made great advances in fertility treatment, and GnRH antagonists may be the best choice for multiple sclerosis patients. 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 (24); 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.
• Sexual dysfunction in multiple sclerosis can be a direct result of spinal cord lesions, especially in men. Unfortunately, there is no clear characterization of other lesion locations that can affect sexual function.
The pathophysiology of sexual dysfunction is poorly understood for multiple sclerosis patients. Because the exact location of lesions and the extent of disability varies widely for all multiple sclerosis patients, it is difficult to fully relate specific lesions to sexual symptoms. Literature from studies of spinal cord injury patients has been more successful in 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 functioning. 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 (47; 46). 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-L2 as well as sacral somatic fibers (15). Disruptions in these spinal cord pathways due to demyelinating multiple sclerosis lesions could cause sexual dysfunction symptoms in men.
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 (26; 41; 14; 34) but it is unknown if this relates to true infertility or elective nulliparity.
Multiple sclerosis patients should receive the same standard fertility workup as other infertile patients, as the exact role of multiple sclerosis in infertility is still unclear. Neurologists can also help patients by making sure to ask about bowel and bladder function as well as any sexual dysfunction they may be experiencing. Urology referrals may be necessary to aid in the treatment of bladder incontinence and urgency. Patients need to discuss future family planning with their neurologist to allow for adequate time to discontinue disease-modifying drugs. Neurologists should also ask about any previous use of multiple sclerosis drugs, especially the infrequently used chemotherapeutic agents mitoxantrone and cyclophosphamide.
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, multiple sclerosis patients 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 or 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 (16). 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.
• Assisted reproductive technology can be helpful for women with multiple sclerosis experiencing infertility.
• Rates of live births after assisted reproductive technology are similar among women with multiple sclerosis and healthy controls.
• Symptomatic management of sexual, bladder, and bowel dysfunction can improve fertility in patients with multiple sclerosis.
Management of infertility depends on the specific cause, although in some cases a cause is not found. Assisted reproductive technology can be used for multiple sclerosis patients experiencing infertility, but with caution. Patients should carefully discuss their options with the fertility specialist, and it may be advisable to avoid GnRH agonists due to an increased risk of relapse. A Danish cohort study found that rates of live births after assisted reproductive technology were similar between women with multiple sclerosis and healthy controls (24).
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 the multiple sclerosis population. 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 functioning, and psychological status (20). 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 cavernosal 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. But 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 multiple sclerosis patients 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 [PDE5i] performed only slightly better than placebo for improved erections (32.8% vs 17.6%) (43). But 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 males with multiple sclerosis and erectile dysfunction (97% vs 26%) (18). Only 1 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 (Dasqupta et al 2004). 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 (30). It is important to note that all patients received pelvic floor muscle training in the 3 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 with estrogens or combination estrogen and progesterone has never been specifically studied in the female multiple sclerosis population. Supplemental estrogens have been used to treat menopausal symptoms, such as hot flashes and vaginal dryness, but are also the topic of controversy due to possible increased risk of thrombotic events, cardiovascular disease, and cancer. Complicating the issue further, there have been reports of wide variations in actual dosing and consistency with compounded hormone supplements. There is not enough information currently to recommend hormone replacements or supplement therapies for the management of sexual dysfunction in women with multiple sclerosis.
Neurologists heavily rely on the United States Food and Drug Administration classifications for pregnancy risk. Due to lack of safety data regarding disease-modifying drugs, most advise stopping immunomodulating or suppressant medications before conception. Titration off these drugs and decisions as to how long before conception to stop medication depends on the pharmacokinetics of the drug and physician preference. Female multiple sclerosis patients with aggressive or poorly controlled disease should delay pregnancy until their symptoms and disease activity is better controlled. The goal of disease quiescence in the year before pregnancy is important not only because the patient will be off disease-modifying drugs but also because disease activity in the year before pregnancy was a predictor of postpartum relapses in the PRIMS trial (55).
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 (10).
Laura Dresser MD
Dr. Dresser of University of Chicago Medical Center has no relevant financial relationships to disclose.See Profile
Anthony T Reder MD
Dr. Reder of the University of Chicago received honorariums from Bayer, Biogen Idec, Caremark Rx, Genentech, Genzyme, Novartis, Mallinckrodt, Mylan, Serono, and Teva-Marion for service on advisory boards and as a consultant, and stock options from NKMax America for advisory work.See Profile
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This article includes discussion of ulnar neuropathies, Guyon canal neuropathy, ulnar neuropathy at the wrist, and flexor carpi ulnaris exit compression.
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