Premature ovarian failure and the menopause

Are premature ovarian failure and the menopause important to people with MS?

If you have your menopause before the age of 40 it is considered premature and hence abnormal. If you are older than 40 it is considered normal.

Premature menopause is one of the main reasons women with MS are turning down the option of being treated with HSCT. The chemotherapy they use for myeloablation is toxic to ovaries. Our London based haematologists are quoting a figure of ~45% risk of premature ovarian failure (POF) from HSCT. The latter is age dependent; the older you are the higher the risk. 

If future pregnancy is an issue post-HSCT you can have your eggs harvested and frozen down. However, this takes time. From experience, this delays HSCT by 3-4 months and the cost of storage of the eggs and fertility treatment is not necessarily covered by the NHS. In England, this comes down to your Clinical Commissioning Group (CCG) and what its fertility policy is. Unfortunately, the level of fertility treatment offered is very much a ‘postcode lottery’ and is determined by each individual CCG. Some CCGs may not fund treatment if, for example, you have existing children – even if they are not from the current relationship, don’t live with you and/or are grown up. Some may fund if one partner has no children. You can find out the situation in your area at the Fertility Fairness website. 

Menopausal symptoms, post HSCT and chemotherapy, can be treated with by hormone replacement therapy (HRT).

Menopause is important for pwMS. Several studies show that in women with MS, menopause is associated with worsening disability. The average change in disability is very small but significant. The results, however, suggest this observation has a biological basis and can, therefore, potentially be manipulated to treat MS; i.e. by giving HRT. Whether these observations are due to a loss of the neurotrophic effects of oestrogen on the brain and nervous system or ageing is a moot point. The first study below did not find any impact of HRT on disability, but too few women were on HRT to be able to see a reliable effect on the outcome. We know from the dementia field that HRT is likely to delay the onset of dementia, therefore I would not be surprised if HRT had an impact on brain health in MS. 

Do you think we should do a study of HRT in women with progressive MS? Or should we simply offer women with MS the option of starting HRT? The latter has been difficult in view of some of the negative effects of HRT, i.e. an increased incidence of cardiovascular events, breast cancer and deep vein thrombosis. However, it is reassuring that a recent large meta-analysis published in JAMA did not show an increase in all-cause mortality (death) as a result of HRT. Therefore, you can now go onto HRT without having to worry about reducing your lifespan. However, you still need to be aware of a slightly higher risk of breast and endometrial cancer and thrombotic events on HRT compared to not being on HRT.

Another issue is that a lot of the symptoms due to the menopause can be confused with MS-related symptoms, for example, fatigue, low mood and brain fog. Menopause is known to worsen MS-related symptoms (study 2 below). This is another reason to potentially go onto HRT. Menopausal brain fog is covered in a recent New York Times article (The Brain Fog of Menopause). 

Finally, it is important to know that menopausal age is not affected by MS (study 3 below). However, long-term methylprednisolone and IFNβ-1b treatments may change menopausal age in a dose-dependent manner. I am not sure if these observations are clinically significant.

I am often asked what would I do if I had MS and I was a woman. If I didn’t have any contra-indications to HRT I wouldn’t hesitate in starting HRT. HRT is anti-ageing, it may modify the course of MS and it will counteract the worsening MS symptoms associated with the menopause mentioned in study 2 below. 

As I am not a woman, what would you do?

Common contraindications to HRT:
  1. Pregnancy
  2. Undiagnosed abnormal vaginal bleeding
  3. Active thromboembolic disorder or acute-phase myocardial infarction
  4. Suspected or active breast or endometrial cancer
  5. Active liver disease with abnormal liver function tests
  6. Porphyria cutanea tarda

Study 1: CLIMB Study

Bove et al. Exploration of changes in disability after menopause in a longitudinal multiple sclerosis cohort.Mult Scler. 2015. pii: 1352458515606211.

BACKGROUND: Onset of multiple sclerosis (MS) is typically in early adulthood. The impact, if any, of menopause on the MS course is unknown.

OBJECTIVE: Our objective was to determine whether menopause is associated with changes in MS severity in a longitudinal clinical cohort.

METHODS: Responses from an ongoing reproductive questionnaire deployed in all active female. CLIMB observational study participants with a diagnosis of clinically isolated syndrome (CIS) or MS were analyzed when the response rate was 60%. Reproductive data were linked with clinical severity measures that were prospectively collected every six months, including our primary measure, the Expanded Disability Status Scale (EDSS).

RESULTS: Over one-half of the respondents (368 of 724 women) were post-menopausal. Median age at natural menopause was 51.5 years. In our primary analysis of 124 women who were followed longitudinally (mean duration 10.4 years) through their menopausal transition (natural or surgical), menopause represented an inflection point in their EDSS changes (difference of 0.076 units; 95% CI 0.010-0.14; p = 0.024). These findings were not explained by vitamin D levels, nor changes in treatment or smoking status over this period. There was no effect of hormone replacement therapy (HRT) exposure, but HRT use was low.

CONCLUSIONS: We observed a possible worsening of MS disability after menopause. Larger cohorts are required to assess any HRT effects.

Study 2: PatientsLikeMe

Bove et al. Patients report worse MS symptoms after menopause: findings from an online cohort. Mult Scler Relat Disord. 2015 Jan;4(1):18-24.

BACKGROUND: Many women with multiple sclerosis (MS) are postmenopausal, yet the impact of menopause on MS symptoms is unknown.

OBJECTIVE: To investigate the patient-reported impact of menopause in a large online research platform, PatientsLikeMe (PLM).

METHODS: A detailed reproductive history survey was deployed to PLM members, and responses were linked to PLM׳s prospectively collected patient-reported severity score (MS Rating Scale, MSRS). The MSRS has previously shown good correlation with physician-derived EDSS scores.

RESULTS: Of the 513 respondents, 55% were postmenopausal; 54% of these reported induced menopause. Median age at natural menopause was 51. Surgical menopause occurred at an earlier age (p<0.001) and was associated with more hormone replacement therapy use (p=0.02) than natural menopause. Postmenopausal status, surgical menopause, and earlier age at menopause were all associated with worse MSRS scores (p≤0.01) in regressions adjusting for age, disease type and duration.

CONCLUSION: Postmenopausal patients in this study reported worse MS disease severity. Further, this study highlights a utility for online research platforms, which allow for rapid generation of hypotheses that then require validation in clinical settings.

Study 3: MS and menopause

Türk Börü et al. Effects of multiple sclerosis and medications on menopausal age. J Int Med Res. 2018 Mar;46(3):1249-1253.

Objectives: We aimed to determine whether multiple sclerosis (MS) and methylprednisolone and disease-modifying drugs have an effect on menopausal age. 

Methods: A total of 86 patients and 98 healthy subjects were included in this study. The natural menopausal age of the patients and healthy subjects were compared. The cumulative dosages of methylprednisolone, beta interferons (IFNβs), and glatiramer acetate were calculated. The effects of the Expanded Disability Status Scale (EDSS), duration of the disease, and cumulative dosage of medications on menopausal age were evaluated. 

Results: The patients’ mean menopausal age was 45.3 ± 4.8 years and healthy subjects’ menopausal age was 46.8 ± 4.3 years, with no significant difference between the two groups. The cumulative dosage of methylprednisolone showed an effect on menopausal age. There was a significant inverse correlation between menopausal age and dosage of IFNβ-1b, while the disease duration and EDSS score showed no correlation with menopausal age. 

Conclusions: We conclude that menopausal age is not affected by MS. However, long-term methylprednisolone and IFNβ-1b treatments may change menopausal age in a dose-dependent manner.

One thought on “Premature ovarian failure and the menopause”

  1. Very interesting and thanks for posting. This is a real dilemma for me as I know hrt can help my menopause symptoms. However, as I have an ongoing lower lymphocyte count, I worry about having enough defences to combat cancer. As taking hrt gives you a slightly higher risk of contracting cancer, I don't want to risk it. However, am I causing my ms to worsen by not taking hrt. I'm on fingolimod and at a steady 0.4 to 0.5 lymphocyte count.Although it fell in the summer to 0.3 and I had the most painful attack of shingles. It's a damned if you do and damned if you don't situation.

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