Menopause

Is it MS or the menopause?

“I am a woman with MS and have started going through the menopause. My last menstrual period was four months ago and have frequent hot flushes. All of a sudden my MS seems to have worsened. I am more fatigued, my sleep is disrupted, my bladder problems are worse, my mood is all over the place and my walking has deteriorated. Is this my MS or is simply the menopause? “

In my experience, the menopause seems to change things for women with MS. There is little doubt that in healthy women the menopause is associated with a well-defined syndrome or constellation of symptoms. Some women cope very well with the menopause and others don’t. There are several symptomatic treatments that can be prescribed to deal with specific menopausal symptoms or you can take hormone replacement therapy (HRT), which really delays the menopause as it replaces the hormones your ovaries make as they fail. 

Recently there has been a backlash against HRT by the medical community when HRT was shown to increase your chances of developing breast cancer and your chances of having a heart attack or stroke by a similar amount. However, these risks need to be put in the context of the benefits of HRT and the fact that both breast cancer and cardiovascular risks can be derisked with screening. 

It was therefore very reassuring when a very large and definitive meta-analysis showed that the all-cause mortality was not increased by HRT (see below). In other words, the benefits and risks of HRT in terms of life expectancy or survival balance each other off. Based on this I think HRT is safe provided you participate in the national breast cancer and cardiovascular screening programmes.

It is important to realise that the type of breast cancers that occur as a result of HRT is usually hormone-responsive and hence have a better prognosis. In terms of the cardiovascular risks associated with HRT, your GP should make sure these are managed, i.e. if you are a smoker you need to stop smoking or at least go onto safer nicotine replacement therapies, you need to make sure your blood pressure and cholesterol levels are checked and if appropriate screened for diabetes. Your GP will also weigh you and ask about your activity levels and family history. Most UK GPs will plug all this information into one of the online cardiovascular risk calculators to see if you need treatment with a statin. 

All this of the above should happen anyway regardless of whether or not you have MS. What about if you have MS? 

Is the menopause different in women who have MS? 

In my experience, the menopause is likely to cause more problems in MSers because of reduced brain reserve and the presence of many MS-related comorbidities. I suspect a lot of the problems the MSers describes above are due to the menopause interacting with MS, that is both together. 

We now know from several studies that menopause affects the natural history of MS. The menopause seems to be a turning point; the replace rate goes down after the menopause and you are more likely to have worsening disability. One could argue that this could simply be due to ageing rather than the menopause. However, there is compelling data that HRT is anti-ageing and many animal studies showing that oestrogens are neuroprotective. 

HRT in menopausal women reverses many of the symptoms and signs of the menopause, i.e. weight gain, hot flushes, depression, insomnia, dry vagina, hair and skin thinning, loss of breast tissue, urinary symptoms and reduced libido. HRT is anti-ageing when it comes to the skin, brain, reproductive system (vagina and breast) and bone health. The latter is very important for women with MS;  MSers tend to have more fragile bones (osteopaenia) and are more likely to fall and suffer fractures. Therefore anything that improves bone health should help MSers overall.  

So when it comes to advising my patients with MS about HRT it is a no-brainer. If you have MS and are menopausal the arguments for starting HRT are quite compelling. However, like everything else in medicine is should be about choice and informed consent. What I am finding is that many GP’s are reluctant to prescribe and monitor HRT in my patients because of the ‘hassle factor’. It is easier for them not to prescribe HRT. I deplore this behaviour; in my opinion, every woman living in the UK who is menopausal should have the right to go onto HRT and at the same time they should have the right to say no thanks I want to age naturally, but they need to be given the choice. So don’t take no for an answer and challenge your GP if they refuse to consider you for HRT. 

In my practice, I also see a lot of women using natural HRT products independent of their GPs. Many of these products contain natural oestrogens and hence are working via the same mechanism as HRT. If you go this ‘natural’ HRT route you still need to make sure you enrol in the national screening programmes for cardiovascular disease and breast cancer. 

I suspect this post will generate a lot of questions and discussion. The three papers below are at least some food for thought.

#1 – Menopause and MS

Baroncini et al. Impact of natural menopause on multiple sclerosis: a multicentre study. J Neurol Neurosurg Psychiatry. 2019 Jun 12. pii: jnnp-2019-320587.

Objective: To study the effect of natural menopause on multiple sclerosis clinical course.

Methods: This was an observational, retrospective, multicentre, cohort study. Menopause onset was defined by the final menstrual period (FMP) beyond which no menses occurred for 12 months. We included multiple sclerosis (MS) patients with FMP occurred after 2005 and a recorded follow-up of at least 2 years pre-FMP and post-FMP. We excluded patients with primary progressive course, iatrogenic menopause and with other confounders that could mask menopause onset. We compared relapse-rate and expanded disability status scale (EDSS) scores pre-FMP and post-FMP, searching for possible interactions with age, disease duration, cigarette smoking and nulliparity status.

Results: 148 patients were included (mean observation: 3.5 years pre-FMP and post-FMP). Most patients (92%) received disease-modifying therapies, mainly first-lines. After menopause the annualised relapse rate (ARR) significantly decreased (from 0.21±0.31 to 0.13± 0.24; p=0.005), while disability worsened (increase of mean 0.4 vs 0.2 points after menopause; p<0.001). Older age and long-lasting disease were associated with ARR reduction (p=0.013), but not with disability worsening. Cigarette smokers showed a trend to a higher disability accumulation after menopause (p=0.059).

Conclusion: Natural menopause seems to be a turning point to a more progressive phase of MS. Relapse rate is also reduced after menopause, but this effect could be driven most by ageing and shifting to progressive phase in patients with long-lasting disease. Cigarette smoking could speed up disability progression after menopause.

#2 – HRT and mortality

Manson et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women’s Health Initiative Randomized Trials. JAMA. 2017 Sep 12;318(10):927-938.

IMPORTANCE: Health outcomes from the Women’s Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality.

OBJECTIVE: To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women’s Health Initiative hormone therapy trials.

DESIGN, SETTING, AND PARTICIPANTS: Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014.

INTERVENTIONS: Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median).

MAIN OUTCOMES AND MEASURES: All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization.

RESULTS: Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials.

CONCLUSIONS AND RELEVANCE: Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years.

#3 – HRT and breast cancer

Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological. Lancet August 29, 2019. DOI:https://doi.org/10.1016/S0140-6736(19)31709-X

Background: Published findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence.

Methods: Principal analyses used individual participant data from all eligible prospective studies that had sought information on the type and timing of MHT use; the main analyses are of individuals with complete information on this. Studies were identified by searching many formal and informal sources regularly from Jan 1, 1992, to Jan 1, 2018. Current users were included up to 5 years (mean 1·4 years) after last-reported MHT use. Logistic regression yielded adjusted risk ratios (RRs) comparing particular groups of MHT users versus never users.

Findings: During prospective follow-up, 108 647 postmenopausal women developed breast cancer at mean age 65 years (SD 7); 55 575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1–4 (oestrogen-progestagen RR 1·60, 95% CI 1·52–1·69; oestrogen-only RR 1·17, 1·10–1·26), and were twice as great during years 5–14 (oestrogen-progestagen RR 2·08, 2·02–2·15; oestrogen-only RR 1·33, 1·28–1·37). The oestrogen-progestagen risks during years 5–14 were greater with daily than with less frequent progestagen use (RR 2·30, 2·21–2·40 vs 1·93, 1·84–2·01; heterogeneity p<0·0001). For a given preparation, the RRs during years 5–14 of current use were much greater for oestrogen-receptor-positive tumours than for oestrogen-receptor-negative tumours, were similar for women starting MHT at ages 40–44, 45–49, 50–54, and 55–59 years, and were attenuated by starting after age 60 years or by adiposity (with little risk from oestrogen-only MHT in women who were obese). After ceasing MHT, some excess risk persisted for more than 10 years; its magnitude depended on the duration of previous use, with little excess following less than 1 year of MHT use.

Interpretation: If these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.

CoI: multiple