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Partners Multiple Sclerosis Center, Department of Neurology, Brigham and Women׳s Hospital, Brookline, MA 02445, USAHarvard Medical School, Boston, MA 02115, USACenter for Neurologic Diseases, Harvard Medical School, 77 Avenue Louis Pasteur, NRB168, Boston, MA 02115, USA
Partners Multiple Sclerosis Center, Department of Neurology, Brigham and Women׳s Hospital, Brookline, MA 02445, USAHarvard Medical School, Boston, MA 02115, USACenter for Neurologic Diseases, Harvard Medical School, 77 Avenue Louis Pasteur, NRB168, Boston, MA 02115, USAMassachusetts General Hospital Biostatistics Center, Boston, MA 02114, USA
Partners Multiple Sclerosis Center, Department of Neurology, Brigham and Women׳s Hospital, Brookline, MA 02445, USAHarvard Medical School, Boston, MA 02115, USACenter for Neurologic Diseases, Harvard Medical School, 77 Avenue Louis Pasteur, NRB168, Boston, MA 02115, USA
Partners Multiple Sclerosis Center, Department of Neurology, Brigham and Women׳s Hospital, Brookline, MA 02445, USAHarvard Medical School, Boston, MA 02115, USACenter for Neurologic Diseases, Harvard Medical School, 77 Avenue Louis Pasteur, NRB168, Boston, MA 02115, USA
We leveraged a patient-powered research platform to rapidly test a research hypothesis.
•
Prospectively collected MS severity scores were more severe after menopause.
•
Women with early, surgical menopause had worse MS severity scores.
•
These findings require validation in clinical cohorts.
Abstract
Background
Many women with multiple sclerosis (MS) are postmenopausal, yet the impact of menopause on MS symptoms is unknown.
Objective
To investigate 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.
), and therefore the loss of ovarian sources of estradiol occurring at menopause could be hypothesized to result in either reduced inflammation, or worse clinical decline (
Patient-reported reproductive histories have yielded insights important to the care of patients with MS, such as a need for counseling surrounding reproductive decision-making (
). Respondents also differed in their perceptions of the effect of hormone replacement therapies (HRT) on MS course: while in the earliest study, 75% patients reported that HRT led to symptomatic improvement {
), we hypothesized that MS severity would be worse in women who have gone through menopause, even accounting for disease duration. We leveraged the frequent sampling of data from a large online population of individuals motivated to contribute to research in order to investigate the effect of menopausal status on a patient-reported disease severity score.
2. Materials and methods
2.1 Data source
PatientsLikeMe (www.patientslikeme.com; PLM) is an online structured research platform, whose members reporting MS are largely comparable in demographic and disease characteristics to a large referral center and a large online patient registry (
Evaluation of an online platform for multiple sclerosis research: patient description, validation of severity scale, and exploration of BMI effects on disease course.
Evaluation of an online platform for multiple sclerosis research: patient description, validation of severity scale, and exploration of BMI effects on disease course.
). We emailed them an invitation to complete an online reproductive questionnaire (Appendix 1) in June 2012. An automated reminder message was sent three days later. Members elected to respond (N=513), opt out (N=112), or not respond (N=317); response rate among members who opened their emails was 54%. After 15 days, the survey was closed.
2.3 Reproductive variables
Menopausal status was categorized as “cycling”, “perimenopausal” (last menses 3–12 months prior to survey), or “postmenopausal” (either no menses in prior 12 months, or loss of menses due to surgical intervention). Menopause type was categorized as resulting from (1) natural physiology, (2) surgical intervention (hysterectomy and/or bilateral oophorectomy), or (3) chemotherapy or radiation. Menopause age was defined using the Stages of Reproductive Aging +10 Workshop convention as: “age at last menses beyond which no menses occurred for one year (natural), or date of surgery (surgical)” (
). HRT use was categorized dichotomously as “ever” vs. “never” use, as systemic (patch+oral) vs. local (gel, cream and ring), and whether initiated within 3 years of menopause or thereafter, a time period even more restrictive than the typical 5-year perimenopausal “window of opportunity” (
In the MS Rating Score (MSRS, free under Creative Commons License), patients rate their disability on a 0–4 scale in 7 areas (walking, use of upper extremities, speech disturbance, vision, dysphagia, cognitive or affective disturbance, and sensory disturbance; Appendix 2). Composite scores range from 0 to 28. The patient-reported MSRS has shown high internal consistency, concordant validity with the Patient Determined Disease Steps (PDSS), and demonstrated adequate known-groups validity (
). In a clinic population, the MSRS has demonstrated good correlations with physician-derived EDSS (MSRS composite score rs=0.61, MSRS walking domain rs=0.74) (
Evaluation of an online platform for multiple sclerosis research: patient description, validation of severity scale, and exploration of BMI effects on disease course.
Ethical approval for this study was obtained from the Partners Healthcare Human Research Committee Institutional Review Board.
2.6 Statistical analysis
We compared demographic and menopausal characteristics according to menopausal type using t-tests and the ANOVA procedure. We estimated age at natural menopause using a Kaplan–Meier curve; cycling or perimenopausal subjects were censored at date of questionnaire and surgical or chemotherapy induced menopausal subjects were censored at the date of menopause.
We assessed whether disease severity was associated with menopausal status by performing a linear regression comparing MSRS at last data entry across three menopausal groups (premenopausal, natural menopause, and surgical menopause). This regression model adjusted for patient age, disease type (progressive onset vs. relapsing onset vs. unknown) and disease duration. In the post-menopausal women, a second linear regression model including age at menopause was added to the model with the other predictors. Women reporting menopause induced by chemotherapy were excluded due to potential confounding, as chemotherapy can be used to treat aggressive MS and can also result in menopause (
). Perimenopausal subjects (N=7) were also excluded.
We tested the hypothesis that HRT protects against disease worsening after menopause by adding a main effect of HRT use (systemic HRT started perimenopausally vs. never) to the model. Statistical analyses were performed using R version 3.0.2 (http://www.r-project.org).
3. Results
3.1 Respondent characteristics
Our 513 respondents were similar to non-respondents in terms of disease type, race and age at symptom onset (p>0.25), but were older at survey completion (p<0.001) (Appendix 3).
Over half of respondents were post-menopausal (52.4%) (Table 1). Menopause was natural in only 44.8% respondents. Surgical menopause occurred at a younger age than natural menopause (p<0.0001), and was associated with higher rates of HRT use (p=0.0065), of longer duration (10.8 (N=51) vs. 4.7 years (N=30), p<0.001). The median age at natural menopause, calculated using a Kaplan–Meier curve, was 51.6 years (95% CI: 51.1, 52.8).
Table 1Demographic, disease and menopause characteristics of study subjects.
For HRT use, 3 natural menopause subjects, 7 surgical menopause subjects and 1 chemotherapy menopause subject did not complete the HRT questions. For HRT use within 3 years of menopause, 1 additional subject from each menopause group did not complete the question.
Perimenopausal women were excluded from this Table (N=7), as were women who had missing responses regarding their reproductive status (N=74).
a PP=primary progressive MS, PR=progressive relapsing MS, RR=relapsing remitting MS, and SP=secondary progressive MS.
b For HRT use, 3 natural menopause subjects, 7 surgical menopause subjects and 1 chemotherapy menopause subject did not complete the HRT questions. For HRT use within 3 years of menopause, 1 additional subject from each menopause group did not complete the question.
The mean (SD) MSRS at the time of the questionnaire was higher in the surgical menopause group (13.1 (5.4)) than in the natural menopause (9.6 (5.1)) or cycling (8.9 (5.5)) groups (age, disease duration and category-adjusted difference for surgical menopause vs. cycling=3.28; 95% CI: 1.64, 4.91, p<0.0001; surgical vs. natural menopause=3.44; 95% CI: 1.80, 5.08, p<0.0001) (Fig. 1). Interestingly, we found associations of menopausal status with MS symptoms for the global MSRS score as well as for individual MSRS domains, even those not typically overlapping with menopausal symptoms (Table 2). When we excluded from the surgical menopause group women who had undergone hysterectomy without oophorectomy, the findings were unchanged. HRT use did not modify the association between menopausal status and global MSRS (p=0.43).
Fig. 1Boxplot comparing MSRS scores across three subject groups: women who underwent natural menopause (N=80), women who underwent surgical menopause (N=94), and cycling women (N=186).
Table 2Menopausal features are associated with prospectively collected disease severity scores (MSRS) (N=351).
Reproductive status
Estimate
P-value
MSRS TOTAL
Cycling
Reference
Natural menopause
−0.16
0.87
Surgical menopause
3.28
0.0001
MSRS DOMAINS
Walking
Cycling
Reference
Natural menopause
0.30
0.12
Surgical menopause
0.17
0.31
Using arms or hands
Cycling
Reference
Natural menopause
0.23
0.20
Surgical menopause
0.56
0.0004
Vision
Cycling
Reference
Natural menopause
−0.21
0.25
Surgical menopause
0.40
0.015
Speech
Cycling
Reference
Natural menopause
−0.25
0.15
Surgical menopause
0.43
0.004
Swallowing
Cycling
Reference
Natural menopause
−0.08
0.60
Surgical menopause
0.38
0.007
Thinking, memory or cognition
Cycling
Reference
Natural menopause
−0.14
0.46
Surgical menopause
0.64
0.0002
Numbness, tingling, burning sensation or pain
Cycling
Reference
Natural menopause
−0.005
0.98
Surgical menopause
0.69
0.0001
As subjects contribute scores prospectively to PLM, the score most recently entered was selected.
NB: Subjects with menopause induced by factors other than surgery (N=17) were excluded. Subjects who had never entered an MSRS score or were missing disease duration were also excluded (N=64).
Multivariate regression models adjusted for age at survey, disease type and disease duration. A positive estimate indicates a more severe MSRS score.
In the post-menopausal women, we further sought to distinguish the effects of menopausal type (surgical vs. natural) from early age at menopause, which is a feature of surgical menopause. When age at menopause was included in the model along with the other predictors described above, earlier age at menopause was associated with worse disease severity across most MSRS domains; menopausal type was no longer statistically significant in this model (Table 3).
Table 3Age at menopause reveals more significant associations with prospectively collected disease severity scores (MSRS) than menopausal type (N=169).
Outcome
Variable
Model 1
Model 2
Estimate
P-value
Estimate
P-value
MSRS TOTAL
Age at menopause
−0.22
0.0001
−0.25
<0.0001
Menopause type
Natural
Reference
Surgical
0.73
0.48
MSRS DOMAINS
Walking
Age at menopause
−0.029
0.010
−0.013
0.17
Menopause type
Natural
Reference
Surgical
−0.50
0.017
Using arms or hands
Age at menopause
−0.046
<0.0001
−0.037
<0.0001
Menopause type
Natural
Reference
Surgical
−0.26
0.20
Vision
Age at menopause
−0.027
0.029
−0.037
0.0002
Menopause type
Natural
Reference
Surgical
0.30
0.17
Speech
Age at menopause
−0.026
0.018
−0.039
<0.0001
Menopause type
Natural
Reference
Surgical
0.37
0.068
Swallowing
Age at menopause
−0.018
0.11
−0.027
0.003
Menopause type
Natural
Reference
Surgical
0.25
0.23
Thinking, memory or cognition
Age at menopause
−0.032
0.005
−0.046
<0.0001
Menopause type
Natural
Reference
Surgical
0.39
0.061
Numbness, tingling, burning sensation or pain
Age at menopause
−0.045
0.0002
−0.050
<0.0001
Menopause type
Natural
Reference
Surgical
0.17
0.44
As subjects contribute scores prospectively to PLM, the score most recently entered was selected.
Multivariate regression models adjusted for age at survey, disease type and disease duration. Here, Model 1 includes both menopausal age and type. Model 2 includes only menopausal age. A positive estimate indicates a more severe MSRS score.
In this study, we assessed the impact of menopause on disease severity in an online patient powered research network, and found that postmenopausal status was associated with worse reported disease severity, even when adjusted for disease duration and type. Additionally, earlier age at menopause, which is often a consequence of surgical menopause, appeared to have a strong association with worse disease severity.
In prior cross-sectional studies, differing patient perceptions of the effect of menopause, and of use of HRT, on MS course have been reported (
). This study has improved upon prior study designs, as the primary outcome was the MSRS, a prospectively collected disease severity score that has shown reasonable correlation with EDSS. We also found that menopausal status was associated with individual MSRS domains that do not typically overlap with menopausal symptoms, such as vision and use of arms. This suggests that the effects of menopause on MS may not be entirely due to menopausal symptoms themselves (
), but rather to an impact of menopause on neurologic function.
Mechanistically, our findings could be explained by the loss of the neuroprotection afforded by estradiol as levels decline after menopause. In animal models of MS, estrogens have been noted to have neuroprotective effects (
), and in healthy women declines in estradiol at menopause (particularly the sudden declines after surgical menopause) have been linked with longitudinal cognitive decline (
). Other hormonal changes associated with menopause, such as weight gain and changes in vitamin D regulation, could also have physiologic consequences.
Study strengths included use of a detailed questionnaire with complex branching that limited errors in reporting, and inclusion of MSRS entered prospectively by subjects blinded to study hypotheses. Additionally, we were able to supplement the questionnaires with an open-ended field that yielded qualitative information about a research area that is poorly understood, and that highlights new avenues of inquiry.
This study highlights a promising aspect of patient-powered research in its unique ability to measure MS outcomes in a real world and dynamic sample of MS patients. While the patient-reported nature of the data may not provide an ideal measure of MS progression, this likely does not limit the generalizability of our findings, relative to other patient-reported measures. Additionally, similar mean ages at survey response and at natural menopause may mitigate the potential for differential recall among the participants. The response rate, while 54% for PLM active online users, is consistent with the response rate of similar large MS-based reproductive questionnaires (45%) (
The first limitation of this study is that, while we previously reported that PLM subjects are broadly similar in demographic and disease characteristics to MS patients from a large referral center and a large online patient registry (
Evaluation of an online platform for multiple sclerosis research: patient description, validation of severity scale, and exploration of BMI effects on disease course.
), we could not validate respondents׳ clinical diagnoses or reproductive histories. The older average age of respondents perhaps reflected more free time, or a broader non-response bias inherent to most survey-based research (
), and this likely reflected a response bias. It is also possible that additional bias was introduced by the varying amounts of missing data among respondents. The fact that menopausal age was associated with MSRS suggests our findings are physiologically plausible, because of the cascade of physiologic changes resulting from early loss of ovarian function (
), even if the magnitude of their effect may be overestimated here. Because we categorized women undergoing hysterectomy, but with preserved ovaries as postmenopausal, we may have attenuated the association between menopause, and/or surgical menopause, and MS outcomes. Additionally, the exclusion of subjects with chemotherapy-induced menopause limited our ability to determine menopausal age, or whether menopause impacts disease course (
). Lastly, we could not assess the role of potential confounders, such as MS treatment, vitamin D status, education, or co-morbidities on disease severity.
Contrary to studies of healthy cognitive aging and dementia (
), we did not observe any protective effects of HRT on MSRS, though our study was not designed specifically to detect one. A longitudinal observation period and a larger sample size are likely required to assess for neuroprotective effects of HRT.
Given an aging population and a median age of individuals currently living with MS very close to menopausal age in many cohorts, our study is the first online study of a real world MS community, which suggests that potentially modifiable changes occurring at menopause might impact the trajectory of many patients with MS. These findings warrant further validation and investigation in other community-based and clinic cohorts.
Author declaration
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.
We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In doing so we confirm that we have followed the regulations of our institutions concerning intellectual property.
We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). She is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author and which has been configured to accept email from rbove @partners.org.
Signed by all authors as follows on August 5, 2014
This research was supported by the National Multiple Sclerosis Society/American Brain Foundation Clinician Scientist Award FAN 1761-A-1 (RB). PLD is a National MS Society Harry Weaver Neuroscience Scholar Award Recipient.
Financial disclosures
Dr. Bove reports no disclosures.
Dr. Healy has received research support from Merck Serono and Novartis.
Ms. Secor reports no disclosures.
Dr. Vaughan is an employee of PatientsLikeMe and holds stock options in the company.
Dr. Katic is an employee of PatientsLikeMe and holds stock options in the company.
Dr. Chitnis has served as a consultant for Biogen-Idec, Sanofi Aventis, Novartis and Alexion, and has received grant support from Merck-Serono and Novartis for unrelated activities.
Dr. Wicks is an employee of PatientsLikeMe and holds stock options in the company.
Dr. De Jager has received research support and speaker honoraria from Biogen-Idec and consultation fees from Teva Neuroscience.
The PatientsLikeMe R&D team has received research support from Abbvie, Acorda, AstraZeneca, Avanir, Biogen, Boehringer Ingelhim, Bristol-Myers Squibb, Genentech, Genzyme, Janssen, Merck, Novartis, Otsuka, Sanofi, and UCB.
PatientsLikeMe provided no financial support to the investigative team from Brigham & Women׳s Hospital.
Conflict of interest
The authors declare that there is no conflict of interest.
Acknowledgments
The authors are grateful to the patient members of PatientsLikeMe׳s MS community, who contributed their data, time, and feedback to this project.
Evaluation of an online platform for multiple sclerosis research: patient description, validation of severity scale, and exploration of BMI effects on disease course.
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