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Symptoms of multiple sclerosis during use of combined hormonal contraception
European Journal of Obstetrics & Gynecology and Reproductive Biology, October 2015, Pages 1 - 4
The incidence and disease course of multiple sclerosis (MS) is influenced by sex steroids, and several studies have shown less disease activity during high estrogen states. We have previously shown variation in symptom experience related to the estrogen/progestogen phase in women using combined hormonal contraceptives (CHC) in a small sample. The aim of this study was to confirm these results in a larger sample.
Self-assessment of symptoms of MS in relation to CHC cycle by 22 female MS patients. A symptom diary based on a validated instrument for cyclical symptoms was used. Mean symptom scores for high and low estrogen/progestogen phases were compared.
The women scored four out of ten symptoms significantly higher during the pill-free week than during the CHC phase (p < .05).
Women with MS report more pronounced symptoms during the pill-free, low-estrogen/progestogen phase of CHC use. Future studies should investigate, with a prospective, controlled design, the effects that continuous-use regimens of CHC have in women with MS.
Keywords: Multiple sclerosis, Combined hormonal contraceptives, Symptom experience.
Both the incidence and disease course of multiple sclerosis (MS) are influenced by sex steroids. The prevalence has been reported to be two to three times higher in women than in men  and the course of the disease differs between the sexes  and .
During pregnancy, relapses of MS tend to decrease, whereas the post-partum period is associated with a higher relapse rate , , and . D’Hooghe et al. also showed a possibly favorable effect of childbirth on long-term progression of MS  and . During pregnancy, 17β-estradiol (E2) and estriol (E3) reach high serum concentrations. In women with MS, treatment with E3 has been associated with a reduction in lesions on MRI scans  and  and favorable effects of E2 and ethinylestradiol (EE) have been shown in animal models , , , , and .
Retrospectively, women with MS reported more MS symptoms in the premenstrual phase  and  and had exacerbations of MS starting pre-menstrually  . However, no symptom variation in relation to the menstrual cycle was shown in a prospective study  .
The low potency E3, which is produced mainly during pregnancy, has been suggested to be 8–10 times less potent than E2, the estrogen mainly produced by the ovaries. EE, which is commonly used in hormonal contraceptives, has been suggested to be about 100–500 times more potent than E2  . Consequently, possible effects of estrogens on MS symptoms should be most evident during use of combined hormonal contraceptives containing EE.
Two cohort studies found no effect of hormonal contraceptives on the incidence of MS, although the type of hormonal contraceptive was not specified  and . In a case–control study, the incidence of MS was lower among users than non-users of combined hormonal contraception (CHC)  . Women with MS, who used hormonal contraceptives after disease onset, had a more benign disease course than women who did not  and . However, a higher risk of reaching a more severe state of MS among users of hormonal contraceptives has been reported in a subgroup of women with progressive onset MS  . In both these studies, the type of hormonal contraception is vaguely defined. We have previously shown a higher age at onset of MS among women who had been using CHC before the disease than among non-users  .
In a previous study  , we found that women with MS using CHC had higher symptom scores during the low-estrogen phase than during CHC use, although the number of women included in the study was low. The aim of this study was to investigate whether the symptom score differed between high and low estrogen phases during CHC use in a larger sample.
The Swedish national MS register is a nationwide quality register that includes the majority of all patients with MS in Sweden, presently about 13,000. The register includes data on age at onset of the first symptoms possibly related to the disease, characterization of onset, and age at final diagnosis. Moreover, the neurologists prospectively register data about the patients’ status, use of medication and EDSS (Expanded Disability Status Scale)  scores at each visit. At inclusion in the register the patients are asked to consent to participate in scientific studies including questionnaires, and to the use of their data in the register. We previously conducted a study on women included in the MS register living in one of five Swedish counties  . In all, 521 women, 18–45 years old, who had answered the previous study questionnaire, were asked in a letter if they were using CHC (pills, transdermal or vaginal administration) and, if they were, if they could participate and fill out a symptom diary during the course of three CHC cycles. Since the response rate and the use of CHC among the responders were very low we also asked women with MS who were participating in a parallel study of immunological changes during CHC cycles to fill out the symptom diary. No woman who had participated in the previous study, which had used a similar method to that of the present study, was asked to participate  .
The symptom diary was based on the Cyclicity Diagnoser (CD)  , which is a validated instrument for monitoring cyclical symptom changes in relation to the menstrual cycle. The CD was originally designed for studies of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD), and in the present study our modified version of the CD included ten symptoms of MS (visus impairment, double vision, vertigo, weakness, urinary symptoms, bowel symptoms, walking impairment, stiffness, coordination impairment and numbness) chosen by a neurologist at the Department of Neurology at the University Hospital of Linköping, Sweden. Symptoms of MS varies between patients  . The original symptom diary used in our earlier study  was designed to include symptoms of impaired motor, sensory visual, and autonomic functions. In this study we excluded tiredness, mood symptoms and behavioral symptoms from the original symptom diary, since these could be related to sex hormone cyclicity without influence from MS, even though fatigue is a very common symptom of MS. The women were asked to grade each symptom from 1 to 8 (no to maximal symptom experience). In the statistical analysis we calculated the mean score for each of the 10 symptoms and compared the means of tablet day 15–21 (high estrogen/progestogen phase) with day 22–28 (low estrogen/progestogen phase) over three cycles. The hypothesis was tested using a Wilcoxon's matched-pair signed rank test in IBM SPSS 21.0.
This study was approved by the Regional Ethics Committee in Linköping (no. M127-09) and the Ethics Committee of the Swedish National MS Register.
Out of 521 women, 240 responded. Of these, 17 used CHC and were eligible for the study, agreed to participate and filled out the symptom diaries. One woman was excluded because of a clinical exacerbation during the study period. From the parallel, immunological study six of the 12 CHC users sent in a complete symptom diary. Thus, in total, diaries from 22 women with MS using CHC were included in the statistical analyses ( Fig. 1 ). These 22 women had a median age of 34 years, range 24–44 and a median EDSS at the last visit before inclusion of 1.75, range 0–5. All women included in the statistical analyses were on a 21/7 regimen of CHC. Fourteen of the women were on monophasic regimens taking 30 μg EE daily, one woman was on a monophasic regimen taking 35 μg EE daily, five women were on triphasic regimens taking 30–40 μg EE daily. One woman used a vaginal ring and one woman used a transdermal patch as administrational routes of CHC. Seven different progestogens were used in combination with EE. No woman used CHC with E2 as the estrogen compound.
The women scored four out of ten symptoms higher during the pill-free week than during the CHC-phase ( Table 1 ). The scores for vertigo, weakness, urinary symptoms, and stiffness were significantly higher during the seven days without CHC (p < .05).
|Days 15–21||Days 22–28||p|
This prospective study based on daily symptom scoring found that women with MS scored four out of ten symptoms significantly lower during the last week on CHC than during the pill-free week. Moreover, the same trend was present for three other symptoms.
In the present study, we analyzed data from three times as many women as we did in the previously published study  , and found significantly higher symptom scores for four typical MS symptoms during the pill-free phase. This is in line with and confirms our previous results. It indicates that EE and/or progestogens might bring the immune system towards a lower disease activity. Several different formulations of combined hormonal contraception were used. Unfortunately the numbers were too small to perform subgroup analyses but there were no big differences according to the EE exposition in the groups using combined hormonal contraception. The main problem with this study is that only a small number of the women who were asked to participate were using CHC. Of the 240 women who responded to the invitation to participate, only 17 (7.1%) were CHC users. The median age of the 22 women whose diaries were analyzed was 34. A Swedish study on contraceptive use  indicates that the prevalence of CHC use at 34 years of age is 12%, which partly explains the low number of women included in the study. It is also possible that women with MS are prescribed CHC to a lower extent than healthy women because of hesitation from the prescribers and the partly unknown effects of sex steroids on the disease. However, we cannot exclude the possibility that there was selection bias.
In general, the women had low symptoms scores reflecting a low disease activity.
The majority of the patients were on immunomodulatory therapy, which may have affected the results. It would not have been ethical to suggest a change in this medication. The use of these drugs was, however, unchanged during the study period but a general reduction of disease activity is possible. It can be speculated that the findings would have been even more pronounced if the women did not use immunomodulatory drugs.
Our findings suggest that sex steroids in CHC could influence the experience of MS symptoms in women with MS, which seems reasonable as the incidence and course of MS has been shown to be influenced by sex. Moreover, sex steroids have also been shown to affect the immune system and probably the immunopathology of MS , , , , , , , , , and .
Contraception is a very important issue for most women, including women with chronic diseases such as MS. Hormonal contraception has also been described as having numerous effects on the risk and course of several different diseases  . In an earlier small study  , we found that women with MS using CHC scored some symptoms higher during the low-estrogen/progestogen phase than during the pill-free week. These results were confirmed in the present study.
Women with no hormonal contraception did not experience any differences in MS symptoms between different phases of the menstrual cycle. Worsening of MS symptoms in the luteal phase of the menstrual cycle has been suggested to be caused by the increased body temperature during the luteal phase, and such symptoms have been called pseudoexacerbations  . The luteal phase is a high-progesterone, high-estrogen part of the menstrual cycle and in the present study we found that symptom scores rose when the women shifted from an extremely high estrogen/progestogen state to a low level. The differences found between natural cycles and CHC cycles might be due to differences in both dose and duration of the exposition of the sex steroids.
Estrogens, and especially EE, have beneficial effects on the mouse model of MS, Experimental Allergic Encephalitis (EAE), and possibly also on MS , , , and . Because of this, we speculate that the lower symptom scores during the EE/progestogen phase CHC-phase in the present study may be due to the effects of EE. A positive effect of CHC on MS incidence and on the course of the disease has also been shown in some other , , , and  but not all studies , , and . The diversity in the results of previous studies may be due, at least in part, to retrospective design and recall bias. In the present study the symptom scores as well as the intake of the pills were prospectively registered and thus the data have a high reliability.
A problem with many studies on the effects of hormonal contraceptives on MS is that the type of contraceptive is not specified. Progestin-only hormonal contraceptives do not contain any estrogen, which seems to have important effects on MS. As progestogens theoretically may also affect the disease, it is of great importance that future studies specify which type of hormonal contraception is used by the women studied. There is also a possibility that the steroid hormones have effects on the symptoms studied independent of an effect on MS but that was not the subject of this study and impossible to state with the design we used and hence not studied.
Although the number of patients was low, our results are in line with and strengthen the results from our earlier study and indicate that women with MS using CHC experience lower symptom activity during a high estrogen/progestogen state than during the pill-free week. If this is the case these women should possibly have even fewer symptoms if they were using their CHC continuously with a longer time between the pill-free phases. Future studies should investigate, with a prospective, controlled design, the effects that continuous-use regimens of CHC have on women with MS.
Financial support was received from the County Council of Östergötland, Sweden, and the County Council of Västernorrland, Sweden.
Conflict of interest
The authors report no conflict of interest.
Authors wish to acknowledge Gunn Johansson, Department of Neurology, University Hospital of Linköping, Sweden, and Therese Pollack, Department of Neurology, Karolinska University Hospital of Solna, Sweden for technical assistance.
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a Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, S-581 85 Linköping, Sweden
b Department of Obstetrics & Gynecology, County Hospital Sundsvall, Sweden
⁎ Corresponding author at: Department of Obstetrics & Gynecology, County Hospital, SE-85186 Sundsvall, Sweden. Tel.: +46 60181000; fax: +46 60181557.
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