Multiple sclerosis and the menstrual cycle

Summary

Multiple sclerosis is an autoimmune, inflammatory, and neurodegenerative disease of the central nervous system. MS typically affects young adults between the ages of 20 and 40 years and the disease is more prevalent among women. The course of MS, whether relapsing-remitting or primary progressive, is now well and extensively mapped. With the use of highly effective therapies, we try to influence the disease as therapeutically as possible. Even in cases when patients are clinically and radiologically stable, may still experience some minor fluctuations in their health status, especially transient worsening of subjectively perceived symptoms, such as fatigue or dizziness. One of the factors that may affect the condition of MS patients to a small extent is the menstrual cycle. In this review paper, we will discuss how the menstrual cycle can affect MS, and on the other hand, how MS affects the menstrual cycle.

Keywords:

Multiple sclerosis – menstrual cycle

This is an unauthorised machine translation into English made using the DeepL Translate Pro translator. The editors do not guarantee that the content of the article corresponds fully to the original language version.

 

Introduction

Multiple sclerosis is one of the most common neurological diseases affecting young adults between the ages of 20-40, with a higher incidence in women, at a ratio of 3 : 1 [1].

During this period, women experience physiological fluctuations in their sex hormones, both due to possible pregnancy and breastfeeding, but also due to the slight hormonal changes that occur periodically during the menstrual cycle. How hormonal changes affect pregnancy and the subsequent postpartum period has been consistently mapped [2-5].

Recently, the therapy of MS has shifted significantly and with the use of high-efficacy therapies (HET) we aim to achieve not only clinical but also radiological stability of the disease (maintaining the concept of NEDA -⁠ no evidence of disease activity). Nevertheless, occasionally patients experience minor fluctuations in symptoms, which may be caused by e.g. excessive mental or physical activity, concurrent illness or menstrual cycle [6].

The aim of this review is to focus on how MS affects the menstrual cycle and how hormonal fluctuations during menstruation can affect MS symptoms.

 

Menstruation

The reproductive system of a woman, unlike that of a man, shows regular cyclical changes that can be considered as periodic preparation for pregnancy and fertilization. This is the menstrual cycle and its most prominent feature is the periodic vaginal bleeding during which the uterine lining is shed (menstruation). The cycle length in healthy women is approximately 28 days from the start of one menstrual period to the start of the next. It begins at puberty, ranging from 10 to 16 years of age (average 12.4 years), and ends at menopause at an average age of 51 years [6].

The menstrual cycle is conventionally divided into two phases, follicular and luteal, followed by menstrual bleeding. During the follicular phase, estrogen levels gradually rise until secretion of luteinizing hormone (LH) from the pituitary gland induces ovulation. If fertilisation does not occur within 24 h after ovulation, the estrogen level drops again. LH also induces the conversion of ovarian granulosa cells from androgen-converting cells to progesterone-producing cells, leading to an increase in progesterone levels during the luteal phase. If implantation does not occur, progesterone levels drop after 14 days and menstrual bleeding occurs [6].

The moderate influence of MS symptoms during the menstrual cycle may occur at several levels, both on an immunological basis and through other mechanisms such as regulation of receptor expression, modulation of muscle contraction and influence on behavioural aspects [7].

 

The effect of the menstrual cycle on the immune system

The effect of the menstrual cycle on the immune system and its influence on the course of autoimmune diseases (e.g. rheumatoid arthritis) was described in a review study by Oertelt-Prigione et al. in 2011 [8].

The menstrual cycle can directly influence not only the number of immune cells, but can also modulate their activity during the 4-week cycle.

Periods with high estrogen levels (first half of the cycle) appear to be protective because they lead to an anti-inflammatory response by inhibiting the production and signaling of pro-inflammatory cytokines (tumor necrosis factor alpha [TNFa ], interleukins [IL-1 and IL-6]), inhibiting natural killer (NK) cells, and inducing the expression of anti-inflammatory cytokines (IL-4, IL-10). Conversely, lower estrogen and higher progesterone levels in the second half of the cycle stimulate TNF-a , IFN-g , IL-1 and NK cell activity, which may promote a pro-inflammatory environment [8].

 

The effect of the menstrual cycle on neurological diseases

Multiple sclerosis is not one of the only neurological diseases in which there may be fluctuations in symptoms during menstruation.

The topic of the influence of the menstrual cycle on neurological diseases is comprehensively addressed in the review studies by Roeder et al. 2021 [9] and Migdalia et al. 2022 [10]. The conclusions of the studies suggest that ovarian steroid hormones (estrogen and progesterone) also affect CNS functioning, which may influence the susceptibility, severity and course of many neurological diseases [9,10].

The menstrual cycle is controlled within the hypothalamus-pituitary-ovarian axis. Gonadotropin-releasing hormone of the hypothalamus promotes the release of follicle-stimulating hormone (FSH) and LH from the anterior pituitary gland. FSH and LH act on the ovary to stimulate the release of estrogen and progesterone, which act by feedback to the pituitary gland [11].

An example is the premenstrual estrogen decline that can trigger migraine attacks due to estrogen's effects on prostaglandin, serotoninergic, dopaminergic, and calcitonin gene-related peptide (CGRP) activity. Migraine is present in up to 22% of migraineurs during menstruation. Migraine attacks during menstruation are more likely to be without aura compared to attacks outside of menstruation and can be more severe, painful, disabling, nausea-inducing, longer lasting and are more commonly associated with allodynia [11].

In seizure disorders such as epilepsy, a decrease in progesterone in the premenstrual period and an increased estrogen to progesterone ratio in the periovulatory and luteal phases may increase the predisposition to seizure activity. Thus, progesterone exerts some degree of antiseizure activity by increasing GABAergic activity, whereas estrogen may be potentially epileptogenic through its influence on glutamatergic pathways [12].

Symptoms of Parkinson's disease and dystonia may also be perimenstrually exacerbated by the effect of estrogens on dopaminergic activity [13].

Hormone therapy is currently highly debated as a potential part of a comprehensive treatment for patients with certain neurological diseases (e.g. menstrual cycle-related migraines or catamenial epilepsy). However, the conclusions of the studies are still quite diverse and no clear recommendations for clinical practice have emerged yet [14,15].

 

The effect of menstruation on MS

The results of studies that have looked at the effect of menstruation on MS in the past are inconclusive. One of them is the 2002 study by Zorgdrager et al. which prospectively followed 56 patients with relapsing-remitting MS. It showed that approximately 45% of patients experienced a slight worsening of MS symptoms before menstruation and, conversely, a return to improvement with the onset of menstrual bleeding [16]. Patients were followed up regularly for 2 years not only clinically but also by means of summary questionnaires. On average, 3 days before menstruation, patients experienced worsening of motor (30%) and sensory (13%) symptoms, deterioration of balance (12%), vision (10%) and sphincter dysfunction (7%) [16].

In contrast, a later study by Holmqvist et al. in 2009 did not confirm the effect of menstruation on MS symptoms [17]. In this prospective study, 63 women with MS who had regular spontaneous menstrual cycles or were taking combined oral contraceptives were asked to assess their MS symptoms every day for three cycles. Symptom scores were analyzed in relation to different phases of the spontaneous menstrual cycle or the contraceptive-controlled cycle. The study showed a worsening of MS symptoms in women using combined oral contraceptives during a 7-day interval without contraceptive use, i.e. during menstrual bleeding. The results of the study did not confirm any significant differences in symptom scores between phases of the menstrual cycle in women not using combined hormonal contraception [17].

During the menstrual cycle, body temperature fluctuates physiologically. Due to progesterone released from the corpus luteum after ovulation, there is a slight increase in basal body temperature (on average 0.5-1.0°C) during the luteal phase compared to the previous follicular phase [18].

Heat intolerance is frequently described in MS patients (60-80% of cases), in which an increase in body temperature (whether due to endogenous or exogenous causes) of only ~0.5 °C can cause a temporary worsening of MS symptoms [18].

How an increase in body temperature during menstruation can affect MS symptoms was investigated in a 2006 study by Wingerchuk et al. It describes 3 women with relapsing-remitting MS who regularly experienced worsening MS symptoms during the premenstrual period, especially worsening fatigue, paresthesia of the limbs, and more frequent urination. This worsening was attributed to a slight increase in body temperature (on average 0.5 °C) in the premenstrual (luteal) phase compared to the menstrual and follicular phases [19]. This study also included brain MRI scans including contrast agent application at different phases of the cycle. The MRI findings were stationary, the objective findings assessed by the Kurtzke Expanded Disability Status Scale were also stationary, and only the measurement of walking speed by the Timed 25-Foot Walk (T25FW) test showed a slight deterioration (mean 1.1 s) in the luteal phase compared with the follicular phase [19].

In 2020, 2 papers were published describing the effect of the menstrual cycle on anxiety, pain, and fatigue [20], as well as on semi-sensation, balance, and dual motor tasks [21] in a small cohort of 14 women with MS. The studies demonstrated differences in pain perception and semi-motility in the early follicular phase and the luteal phase, and also showed a relationship between pain and performance on a dual motor task in the early follicular phase. However, due to the low number of participants, no clear conclusions can be drawn from these studies and it is more a reflection on whether to consider the menstrual cycle phase in the physiotherapy of MS patients.

In 2023, a prospective pilot study was published to describe whether MS symptoms change with the phase of the menstrual cycle and whether variations in these symptoms affect the use of oral contraceptives. The study followed 47 patients over a 6-month period. The severity of MS symptoms did not clearly vary with menstrual cycle in participants with endogenous cycles. However, fatigue and daily complaints were less variable in participants using continuous oral contraceptives than in patients using cyclic contraception or in MS patients not using contraception [22].

So far, only one published study has looked at the effect of the menstrual cycle on laboratory parameters. The study compared leukocyte levels in 41 MS patients on fingolimod therapy compared to 33 healthy controls. The results showed that fingolimod-treated patients with relapsing-remitting MS had decreased total leukocyte, neutrophil and lymphocyte levels, but these changes were not related to menstrual cycle phase. Leukocyte levels in healthy subjects were significantly lower in the proliferative phase than in other phases of the menstrual cycle. The results showed that the menstrual cycle does not affect lymphocyte levels in MS patients treated with fingolimod, and therefore, the determination of lymphocyte levels can be performed at any phase of the menstrual cycle [23].

 

Effect of MS on the menstrual cycle

The menstrual cycle begins in women between the ages of 10 and 16 (average 12.4 years). We know that MS is more common in women than in men. However, this is only true if the first symptoms of MS appear after the age of 12 years (the ratio of women to men with MS with onset in childhood before the age of 12 years is 1.2 : 1), suggesting a key role for the hormonal changes that occur with the onset of puberty and the beginning of the menstrual cycle [24].

However, the biological basis of the effect of puberty on the risk of developing MS has not yet been fully elucidated. Hormonal changes may therefore influence the development of MS. In addition, it is known that puberty also involves substantial maturational changes in the brain, such as an increase in white and grey matter volume, which may also play an important role in neurological modulation. Moreover, puberty appears to be a key period when some well-known risk factors for MS, such as overweight, vitamin D deficiency and Epstein-Barr virus infection, may become apparent due to rapid developmental changes. Finally, it is also likely that metabolic factors such as childhood nutrition and changes in the gut microbiome may lead to earlier menarche and altered immunological modulation, thereby contributing to the risk of developing MS [24].

The results of epidemiological studies that have investigated the relationship between the onset of the menstrual cycle and the development of MS are rather contradictory. Although some studies have linked earlier age at menarche with increased risk of MS [25-27], others have not confirmed this association [28,29].

Based on a population-based case-control study in Israel, which included 241 cases and 964 controls, it was found that women with MS have significantly shorter actual menstrual periods (menstrual length usually lasts about 3-5 days) compared to healthy controls. However, no differences in the average length of the menstrual cycle were observed [30].

A multicentre retrospective study conducted in 2015-2016 yielded interesting results. That study showed that patients experienced an increase (from 21% to 40%) in menstrual bleeding irregularity after a diagnosis of MS [31]. Until diagnosis, these women had menstrual periods as frequent as healthy controls. A general association between depressive symptoms and irregular menstrual cycles may be offered as an explanation, as many patients with newly diagnosed MS experience depressive or anxiety symptoms more frequently (their prevalence is 2-3 times more frequent than in the general population) [32].

Premenstrual syndrome (PMS) involves clinically significant somatic and psychological symptoms during the luteal phase of the menstrual cycle that lead to significant discomfort and impairment of functional abilities. These symptoms subside within a few days after the onset of menstruation. The overall prevalence of women of reproductive age affected by PMS worldwide is 47.8%. Of these, approximately 20% of women have symptoms severe enough to interfere with their daily activities, and the rest have mild to moderate symptoms. Symptoms of PMS include changes in appetite, weight gain, abdominal pain, back pain, low back pain, headaches, breast swelling and tenderness, nausea, constipation, anxiety, irritability, anger, fatigue, restlessness, mood changes and crying [33].

A 2018 study by Mirmosayyeb et al. showed that MS patients also reported more premenstrual symptoms (e.g., breast tenderness, headache, acne, increased limb pain, lower abdominal tenderness, fatigue, low mood, tension, anger, preference for solitude, low self-esteem) before, during, and after menstruation compared with healthy controls [31]. Although it appears that MS may have an effect on perimenstrual symptoms, it should be considered that some perimenstrual symptoms are interrelated with MS, which may account for the higher frequency of these symptoms in MS patients. These symptoms include weakness, fatigue, decreased ability to move, anxiety, and others [31]. PMS may also exacerbate depression and anxiety, which are more common in MS patients than in the general population.

A very effective pharmacological therapy for PMS is selective serotonin reuptake inhibitors (SSRIs) and/or hormonal contraceptives. Non-pharmacological treatments include aerobic exercise, consumption of complex carbohydrates and frequent meals, relaxation training, regular sleep and cognitive behavioural therapy [32-34].

 

Use of hormonal contraception in patients with MS

Many MS patients take some type of hormonal contraceptive for a long time.

In the treatment of MS with some immunomodulatory drugs, contraception is generally recommended for women of childbearing age (e.g. fingolimod, ponesimod, ozanimod, teriflunomide, cladribine), and at the same time, contraception is also suitable for timing pregnancy until the period of clinical stabilisation of the disease. More detailed recommendations on the use of hormonal contraception specifically for women with MS were made according to a large review study from 2017. The study shows that most contraceptive methods appear to be safe for women with MS based on current evidence. The only limitation is the use of combined hormonal contraception in MS patients with advanced disability associated with long-term immobility, due to concerns about possible venous thromboembolism [35].

The use of hormonal contraceptives may be appropriate for patients not only to reduce PMS symptoms but also to modify the irregularity of the menstrual cycle [36].

 

Menopause and MS

It is estimated that 30% of the current MS population is made up of women at or after menopause.

Menopause involves a number of physiological changes that affect women with MS in the reproductive, immunological and neurological domains.

Menopause in women with MS, as in healthy women, begins around the age of 51 and follows the same gynaecological course. Menopause and its impact on MS is discussed in detail in the publication by Zapletal et al. 2022. The basic recommendations are then summarized in the Clinical Guidelines for the Diagnosis and Treatment of MS and Neuromyelitis Optica and its Broader Spectrum Diseases, version 3.0 [3,37].

In essence, it can be said that the natural course of menopause in women with MS is often associated with progression of neurological findings.

The management of pharmacological therapy of menopausal symptoms in women with MS includes early initiation of hormone replacement therapy, while regular physical activity and psychotherapeutic support are appropriate non-pharmacological interventions [38].

 

Conclusion

In this review we have tried to summarize the currently available information on MS and menstruation.

If patients observe regularly fluctuating transient worsening of MS symptoms, it is advisable to advise them to notice when their problems are more pronounced and when they hardly or not at all notice them. As part of this process, patients themselves often become aware of the connection between these problems and the menstrual cycle.

If this is indeed the case, it is advisable to target coping strategies that can help the patient. These include scheduling more challenging tasks and activities into the phase of the cycle when patients do not experience worsening symptoms, as well as a healthy diet, regular aerobic activity and sufficient sleep.

If non-pharmacological methods are not effective, pharmacological therapy (e.g. antidepressant medication or hormonal contraceptives) may be used.

 

Conflict of interest

The authors declare that they have no conflict of interest in relation to the subject of the study.