Is It Time to Rethink HRT?

PHOENIX — The overlapping symptoms of menopause and multiple sclerosis (MS) in aging women may warrant hormone replacement therapy (HRT), says one expert, who argues that the potential benefits in easing the combined symptom burden outweigh the therapy’s modest risks.

It is suspected but not proven that menopause increases the risk and severity of menopausal symptoms such as urinary dysfunction, vasomotor dysregulation, disturbed sleep, and anxiety, but it is known that HRT offers benefit against these, said Kate Petheram, MD, a consultant neurologist for the Royal Sunderland Hospital, Sunderland, UK.

In women with MS, “there is a clear benefit from controlling symptoms associated with menopause even if we do not know yet whether the benefit involves reducing symptoms driven by MS,” Petheram reported.

The modest amount of attention paid to the overlap between symptoms of MS and menopause is an important issue for a disease with a 3:1 female to male ratio, said Petheram, in a May 29 presentation at the Consortium of Multiple Sclerosis Centers (CMSC) 2025 Annual Meeting. 

WHI: Flawed Data

Speaking at a symposium dedicated to the topic, Petheram noted that her audience was almost entirely female: a pattern she has observed in previous iterations of the same talk. She urged all neurologists to recognize the interplay between menopause and MS, emphasizing that 30% of people with MS are peri- or postmenopausal women.

In the UK, as in the US, prescriptions for HRT plummeted following the 2002 publication of the Women’s Health Initiative (WHI): a study involving more than 16,000 participants that was halted after 5.2 years of follow-up. 

At the time, a widely used combination of conjugated equine estrogen and medroxyprogesterone was linked to several risks — including breast cancer, cardiovascular disease, and stroke — that were deemed to outweigh its symptomatic benefits. 

Subsequent data have refuted most of those claims, said Petheram, who described the WHI study design as flawed. In fact, current evidence suggests HRT lowers cardiovascular risk.

While it does increase the risk of breast cancer, she noted that the increase is modest — and importantly, the risk of dying from breast cancer is not significantly elevated.

Yet the reexamination of the evidence has never received the attention needed to shift perceptions shaped by the original WHI study, said Petheram. She described a “loss of confidence” in HRT that has been only modestly reversed in the UK and not at all in the US. Drawing on published data, she noted that HRT use among menopausal women remains below 5% in the US, compared to 15% in the UK. 

This poses a particular challenge for women with MS, given the overlap between menopausal symptoms and MS-related complaints. While some issues — such as anxiety and sleep disturbances — may be managed with other therapies, HRT remains one of the most effective treatments for vasomotor symptoms, sexual dysfunction, and urinary complaints.

An Effective Option

Both historical and emerging evidence suggest that HRT can reduce symptoms shared by MS and menopause, Petheram said. In the observational Nurses’ Health Study — a 2016 analysis published in Neurology, for example — women with MS who began HRT 3-10 years after their final menstrual period showed significant improvements across multiple validated quality-of-life measures compared to those who did not use HRT.

“Menopausal women do well on HRT, and they do less well when they quit,” said Petheram, citing multiple studies, including several published in recent years. While she acknowledged that HRT is not a panacea, she emphasized that it remains the only therapy that effectively targets the wide range of symptoms common to both MS and menopause.

The ability to address a wide range of symptoms is a significant advantage. Citing fatigue, mood disorders, and sexual and urinary issues as the most common overlapping complaints, Petheram noted that HRT offers additional documented benefits — such as improved bone health — that are meaningful not only to aging women in general, but especially to those with MS.

This message is starting to gain traction in the UK, but Jennifer Graves, MD, PhD, director of the Neuroimmunology Research Program at the University of California, San Diego, acknowledged that it will be a tougher sell in the US without targeted education to overcome longstanding biases.

“The WHI is still being taught in some medical schools,” she said. While she agreed that some of the most serious risks linked to HRT in the WHI have since been rescinded — warranting a reassessment of the benefit-to-risk ratio — she also emphasized that aging and menopause in women with MS remain largely overlooked. 

“We need greater awareness of the challenges of menopause in women with MS and I think this involves better educating clinicians about how aging, menopause, and MS intersect,” Graves said. 

Petheram clarified that she doesn’t prescribe HRT to women with MS, but she does discuss the overlap between menopausal and MS symptoms — explaining both the potential benefits and risks to help patients make informed decisions. She believes all neurologists should take responsibility for understanding the interaction between menopause and MS in order to better manage overlapping symptoms.

Petheram reports financial relationships with Novartis, Merck, Roche, Sanofi, and Biogen. Graves reports no relevant financial conflicts of interest.