All women with multiple sclerosis should start hormone replacement therapy at menopause unless contraindicated: No

Multiple sclerosis (MS) is a lifelong condition that typically manifests from a young age and persists throughout one’s life. With approximately two-thirds of individuals affected by MS being women, most women diagnosed with MS will undergo menopause after their MS diagnosis.

Natural menopause represents an irreversible interruption of menstruation, signifying the latter phase of ovarian physiology. It typically manifests in the sixth decade of life with the median age being around 51 years. There is currently no evidence suggesting that MS affects the timing of menopause.

The hormonal shift that marks a natural transition in a woman’s life can influence various health aspects, including the course of MS. Toward the end of the reproductive years, progesterone and estradiol levels decline starting 2 years before and continuing about 2 years after the final menstrual period. During menopause, women can experience vasomotor symptoms, including hot flashes which can trigger Uthoff’s phenomenon, as well as sweating, mood changes, and cognitive disorders. Symptoms of MS and menopause can frequently overlap, including disturbances in cognition, mood, sleep, and bladder function, which can create challenges in distinguishing the likely cause of symptoms to be treated. ¹

Changes that affect women with MS occur through at least three physiological mechanisms are reproductive, immunological, and neurological. Immunological changes occur due to age-associated immunosenescence and inflammaging, leading to alterations in the immune system’s function and thereby affecting MS disease development.

A change of the disease course occurs in women around the menopausal age, characterized by fewer relapses and increased disability progression. ² A recent longitudinal study involving women with MS and healthy controls has shown that the anti-Mullerian hormone typically considered to be an objective indicator of ovarian aging is associated with greater total gray and cortical gray matter loss, independent of chronological age and disease duration, indicating the potential influence oh hormonal changes on neurodegeneration. ³

Several studies have reported a worsening of MS symptoms at menopause. If worsening of MS symptoms during menopause is mediated by fall in estrogen production, hormone therapy might mitigate these symptoms. For general menopausal symptoms, hormone replacement therapy (HRT) can be highly effective, but its role in managing MS-related symptoms during menopause is less clear, with some studies suggesting transient symptom exacerbation or improvement in specific cases. A survey of 95 postmenopausal using self-administered questionnaires have examined the association between the influence on menopause including hormone therapy on MS disease, indicated improved physical quality of life with significantly better patient-reported physical functioning scores. ⁴

Several studies utilizing the MS animal model experimental autoimmune encephalomyelitis have demonstrated a therapeutic effect of testosterone and estriol, showing both hormones to induce anti-inflammatory and neuroprotective effects ⁵

HRT typically consists with an estrogen, such as estradiol paired with a progestogen. Therefore, HRT could beside alleviate menopausal symptoms and prevent bone density loss and also be beneficial on symptom exacerbation and long-term outcomes of MS; however, there is no evidence that HRT has a beneficial effect on MS disease activity. A study utilizing nationwide Danish registry data revealed no overall association between HRT and disability accrual, although a trend toward increased risk of disability with longer hormone use was noted. In addition, there was a 20% increased risk of recurrent relapses among current hormone users compared to non-users, although the clinical significance of this finding was minimal. ⁶ In another study examining the impact of menopause on disease severity in a well-described clinic-based cohort, involving 124 women followed for a mean of 10.4 years through their menopausal transition, a possible worsening of MS disability after menopause was observed. However, there was no significant effect of HRT exposure on MS disability, although HRT utilization remained low in this cohort. ⁷

Despite estrogen’s known immunomodulatory effects, the direct influence of HRT on MS progression and relapse rates remains uncertain. HRT carries risks, including increased chances of thromboembolic events, stroke, and breast cancer. Women with MS may have an elevated risk of cardiovascular comorbidities. Given that hormones used in HRT are linked to higher risks of cardiovascular diseases in the broader population consideration should be given to the woman’s overall 10-year cardiovascular risk which depends on blood pressure, smoking status, cholesterol levels, and age and increased risk of thromboembolic disease (e.g. obesity, history of venous thrombosis). ⁸

The occurrence of breast cancer is directly proportional to the absolute amount of hormone and dose of progestogen and is highest during continuous treatment. The increased occurrence is highest during hormone treatment and decreases after discontinuation an approximately 20% increased occurrence compared to women who have not used hormone treatment during menopause. ⁹

Moreover, recent studies have linked HRT exposure around menopause onset to an increased risk of dementia and Alzheimer’s disease, adding another layer of consideration. ¹⁰ While hot flashes and other menopausal symptoms can significantly impact quality of life, although they are often transient. Systemic hormone therapy with estrogen or estrogen in combination with progestin should only be considered for persistent, moderate to severe symptoms that affect quality of life.

However, the potential influence of exogenous hormones on the course of MS remains a topic of high interest, warranting large randomized clinical trials to determine their true effect. Given the risks associated with long-term or high-dose hormone therapy, routine administration is not recommended.

In conclusion, the decision to use HRT in women with MS during menopause should be individualized, considering the individual’s symptom profile, health risks, and preferences. While hormone therapy may be appropriately given within the window of the menopausal transition for debilitating symptoms, its long-term effects on neuroprotection in MS are unknown.