What defines perimenopause, menopause and post-menopause?1

Menopause is defined as the permanent cessation/absence of menses for 12 months, determined retrospectively (without other pathological causes). Perimenopause is defined as the menopausal transition and first 12 months following the final menses, and post-menopause refers to the phase beginning 12 months following the final menstrual period (extending to the end of life).

How does menopause differentially impact women with multiple sclerosis (MS)?

Menopause is common in women with multiple sclerosis (MS), with most women diagnosed with MS prior to menopause and approximately 30% of the MS population being peri- or postmenopausal. The typical age of menopause onset in women with MS does not differ from the general population. There is substantial overlap between menopausal and MS symptoms, including cognitive dysfunction, fatigue, mood disturbances, sleep disruption, sexual dysfunction and bladder issues, making symptom attribution challenging and necessitating careful clinical assessment to distinguish between MS progression and menopausal transition.2-4

How does menopause impact MS disease course?

Sex hormones, particularly estrogen and progesterone, may play a role in modulating neuroinflammation and neuroprotection. Estrogen depletion at menopause may contribute to increased neurodegeneration and altered immune responses, potentially influencing MS disease activity and progression. Immunological and neurological changes at the time of menopause, including immunosenescence, are potentially relevant to MS pathophysiology and may contribute to some of the observed clinical changes during this period.2,3,5,6

The impact of menopause on MS disease course remains an area of active investigation. Some studies suggest a transient worsening of MS symptoms and (possible) inflection point in disability progression during the menopausal transition, while others do not confirm a significant change in relapse rates or long-term disability trajectory. The evidence is inconsistent, and the relationship between menopause and MS progression is still debated.3,5-7

Most disease-modifying therapies (DMTs) do not appear to alter the age of menopause onset, and current evidence does not suggest significant interactions between DMTs and hormone therapy, but vigilance is warranted.2,3 However, more advanced treatments for MS, including autologous hematopoietic stem cell transplant (AHSCT)/low-dose chemotherapeutic agents, commonly induce premature ovarian insufficiency and/or early menopause (with rates approaching 80% depending on age and regimen intensity) due to gonadotoxic effects.8 Recovery of menses is possible in a subset of patients (with estimated rates of around 25%), with younger age being the strongest predictor of recovery.9,10 Some studies have suggested that menopausal symptoms may be milder in women who have undergone HSCT compared to naturally menopausal women.11

How should neurological symptoms be assessed in women entering/in/post-menopause?

A comprehensive evaluation should address the full spectrum of overlapping symptoms: vasomotor (hot flashes, night sweats), genitourinary (vaginal dryness, urinary symptoms), mood (depression, anxiety), sleep disturbances, cognitive changes, pain and sexual dysfunction. It is critical to differentiate between symptoms attributable to menopause and those due to MS progression, as management strategies may differ. Tools such as symptom diaries, validated questionnaires, and structured interviews can aid in this distinction.1-3,12,13

How should neurological symptoms be managed in women entering/in/post-menopause?

Non-pharmacologic interventions include lifestyle modifications (exercise, weight management), behavioral therapies, sleep hygiene and cognitive behavioral therapy, all of which can improve quality of life and address both menopausal and MS-related symptoms, and should be implemented where applicable.2,12,13 Multidisciplinary care is optimal, particularly partnership with obstetrics-gynecology or urogynecology providers who possess expertise in menopause.

The Cleveland Clinic offers many unique offerings to aid in the care of women throughout the menopausal transition. The Center for Specialized Women’s Health specializes in interdisciplinary mid-life women’s health-related issues, including consultations specifically for menopausal evaluation and treatment. Information or appointments can be obtained by calling 216.444.4437. The Neurological Institute also houses a section for Women’s Neurology, comprised of physicians from all neurological subspecialties with an interest and advanced knowledge in caring for women with neurological disease throughout the lifespan. The Mellen Center also offers a shared medical appointment with a focus on navigating menopause with MS.

How should menopausal symptoms be assessed in women with MS?

Women with MS should undergo screening and evaluation for menopausal symptoms, the same as women within the general population. Women with MS are often overlooked in this regard, as disability can deter care. Women with MS should be made aware that adaptive equipment (i.e. examination tables) and providers trained in the management of women with neurological disease exist. Comprehensive evaluation of symptoms should be encouraged.

How should the use of pharmacological therapies be approached in this population?

In short, the use of pharmacologic therapies should be individualized. Hormone therapy (HT), including systemic estrogen (with or without progestogen), is the most effective treatment for vasomotor symptoms, but its use requires consideration of risks (e.g., thromboembolism, breast cancer) and benefits. For example, certain patients with MS may be at a higher risk for thromboembolic events secondary to mobility status, though generally these treatments are considered safe for women with MS and should be utilized when indicated. Current evidence does not demonstrate a clear impact of HT on MS disease course, and data specific to MS are limited. Local (vaginal) estrogen is effective for genitourinary syndrome of menopause (GSM) and is considered safe. In all patients, contraindications to HT must be assessed prior to initiation.1,3,5-7,14,15

Nonhormonal options for treatment of vasomotor symptoms include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), gabapentin and paroxetine. These may also provide secondary benefits for mood and sleep disturbances, which are common in MS.1,12,14,15 Nonhormonal moisturizers, ospemifene and prasterone (dehydroepiandrosterone) are options for treatment of vaginal dryness and dyspareunia. Nonhormonal moisturizers are noninferior to estrogen-based therapies for mild symptoms.1,12,14

Are there special considerations for treatment of women with MS during the menopausal transition and post-menopausal stage of life?

Screening for osteoporosis, cancer and cardiovascular risk is essential, as both MS and menopause increase these risks. Shared decision-making and individualized care, considering comorbidities and patient preferences, are paramount.2,3,5,7,12,14,15

How common is female sexual dysfunction in MS?

Female sexual dysfunction is highly prevalent in MS, with reported rates ranging from 40% to over 75% of patients. The impact is multidimensional, affecting quality of life, intimate relationships and psychological well-being. Sexual dysfunction in MS is classified as primary (direct neurological impairment affecting sexual response), secondary (physical symptoms such as fatigue, spasticity or bladder dysfunction that indirectly impair sexual function) and tertiary (psychosocial factors including depression, anxiety and relationship issues).16-19

What are the risk factors and contributing mechanisms to sexual dysfunction in MS patients?

Key risk factors and mechanisms include neurological impairment (lesion location and disease burden), higher disability status, bladder and bowel dysfunction, depression, anxiety, fatigue, hormonal changes and side effects of medications. These factors often coexist and interact, necessitating a comprehensive approach to management.17-19

How should symptoms of female sexual dysfunction be screened for and assessed?

Routine, active screening for sexual dysfunction is essential in women with MS, as the condition is frequently underdiagnosed. A multidisciplinary evaluation, including neurological, urological, gynecological and psychological perspectives, is optimal for comprehensive care.16,17,19,23

Validated tools such as the Multiple Sclerosis Intimacy and Sexuality Questionnaire-19 (MSISQ-19)20,21 and the Female Sexual Function Index (FSFI)22 may be used for structured assessment, but are not routinely implemented at the Mellen Center.

How should symptoms of female sexual dysfunction be managed?

Management should be coordinated among neurology, gynecology, urology, physiotherapy and mental health professionals. This team-based approach addresses the complex interplay of neurological, physical and psychosocial contributors to sexual dysfunction in MS.19,23-26

Sexual therapy, including cognitive behavioral therapy (CBT), mindfulness-based interventions, and patient education, has demonstrated benefit for sexual dysfunction in MS, and have the capacity to target both psychological and relational aspects.18,27-29 Pelvic floor muscle training (PFMT), physiotherapy and adjunctive techniques (such as biofeedback, neuromuscular electrical stimulation, yoga and aquatic exercise) have shown improvements in arousal, lubrication, satisfaction and overall sexual function. These interventions may be delivered alone or in combination, and the involvement of pelvic floor physiotherapists is increasingly recognized as important.24-27,30 Assistive devices may be considered for select patients.24,27

Pharmacologic options with some evidence in MS-related sexual dysfunction include: sildenafil and tadalafil (phosphodiesterase-5 inhibitors) for treatment of issues with arousal; flibanserin and bremelanotide for hypoactive sexual desire in premenopausal women OR transdermal testosterone cream in postmenopausal women; lubricants, moisturizers, topical vaginal estrogen, prasterone inserts and oral ospemifene for treatment of dyspareunia or vaginal dryness; beta-3 agonists, amitriptyline, hydroxyzine, intravesical dimethyl sulfoxide and onabotulinum toxin A when bladder dysfunction is a contributing factor. Hormonal status should be evaluated, as alterations in estrogen and androgen levels may contribute to dysfunction and guide therapy.17,24,27 Lastly, it is important to acknowledge and treat MS-related sequelae (such as spasticity and neuropathic pain), which may indirectly impair sexual function. Again, the evidence base for pharmacologic interventions remains limited, and individualized risk-benefit assessment is necessary.

References

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