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Multiple Sclerosis in relation to sex steroid exposure
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Multiple sclerosis (MS) is a potentially severe chronic inflammatory disease of the central nervous system (CNS) and is usually diagnosed between 20 and 40 years of age. The incidence of MS is two to three times higher among women and the type and course of the disease often differ between the sexes. Sex steroids, especially estrogens, have been shown to influence the immunopathology involved in MS and the mouse model experimental allergic encephalomyelitis (EAE), as well as radiological and clinical signs of the disease. The ovarian cycle and hormonal contraception result in fluctuations in sex steroid concentrations that could possibly affect MS. The incidence of MS in women is highest at an age when a reliable contraceptive method is an important matter but the effects of estrogen-containing combined hormonal contraceptives (CHC) on MS have not been thoroughly studied. The general aim of the research for this thesis was to investigate how fluctuations in sex steroid exposure during the menstrual cycle and use of CHC affect MS in a clinical context.

Paper I is based on female MS patients with or without hormonal contraception. Symptoms were reported prospectively in an MS-symptom diary. In contrast with results from previous retrospective studies, 16 women without hormonal contraception reported fewer complaints regarding one out of 13 symptoms during the low estrogen/progesterone phase of the menstrual cycle. Seven women who used CHC experienced three of the symptoms significantly more strongly during the low estrogen/progestogen, pill-free period. In paper II 22 women with MS who used CHC reported higher scores for four out of 10 symptoms during the “pill-free” week, i.e. during the low-estrogen/progestogen phase using a modified symptom diary. Women with MS who did not use hormonal contraception reported no differences in symptom scores between high and low estrogen/progesterone phases. Paper III included 770 women who answered a questionnaire that was designed to investigate whether longer periods of high estrogen concentration such as CHC-use and pregnancies delay the onset of MS. The mean age at MS onset was significantly higher among women who had been using COC before their first MS symptom (26 vs 19 years, p<0.001) and the longer the women had been using COC the higher the mean age at MS onset. The number of children born before the first symptom of MS was positively correlated with age at MS onset (r=0.6; p<0.001). Paper IV aimed to investigate if peripheral blood levels of cytokines, chemokines, and transcription factors for different T helper (Th) cell subsets change in relation to high and low estrogen/progestogen states in women with MS and healthy controls with and without CHC using multiplex bead technology and qPCR. Expression of the B cell-associated chemokine CXCL13 was generally higher in high the estrogen/progestogen phase than in the low estrogen/progestogen phase and the expression of the transcription factors showed a general activation of peripheral blood T cells during high estrogen and progestogen phases in women with MS as well as in healthy women.

The clinical implication of these and other studies is that there is probably no reason for avoiding CHC as a contraceptive method in women with MS. It is also probably beneficial for women with MS to use CHC regimens with longer estrogen periods and fewer pill-free intervals. Future studies should investigate the outcomes of such regimens on relapse rate, MRI lesions, disease activity related cytokines and chemokines in CSF and peripheral blood and the women’s experiences of their symptoms.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. , 83 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1415
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-108888DOI: 10.3384/diss.diva-108888ISBN: 978-91-7519-257-4 (print)OAI: oai:DiVA.org:liu-108888DiVA: diva2:733624
Public defence
2014-09-11, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2014-07-10 Created: 2014-07-10 Last updated: 2014-07-11Bibliographically approved
List of papers
1. Symptoms of multiple sclerosis in women in relation to cyclical hormone changes.
Open this publication in new window or tab >>Symptoms of multiple sclerosis in women in relation to cyclical hormone changes.
2009 (English)In: The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception, ISSN 1473-0782, Vol. 14, no 5, 365-370 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: To prospectively investigate if women with multiple sclerosis (MS) experience changes in MS-symptoms in relation to cyclical hormonal changes. METHODS: Sixty-three women with MS, either with regular, spontaneous menstrual cycles or taking combined oral contraceptives (COCs), were asked to score their MS symptoms every day during three cycles. Symptom scores were analysed in relation to different phases of the spontaneous menstrual- or pill-driven cycle. RESULTS: Twenty-three women completed the score record. Among the 16 women who were not using a COC there were no significant differences in symptom scores between the phases of the menstrual cycle. The seven women taking a COC reported significantly higher symptom score points for weakness, numbness and tiredness during the pill-free interval compared with the phase during which they took the COC daily. CONCLUSIONS: This prospective study appears to contradict earlier retrospective studies regarding variations in MS symptoms in relation to the menstrual cycle in women who are not using a COC. The lower symptom scores during the three weeks of pill taking suggest a positive effect of the steroids on the manifestations of MS. Further studies concerning both short- and long-term effects of OC-use on MS symptoms are needed.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53085 (URN)10.3109/13625180903137329 (DOI)19916763 (PubMedID)
Available from: 2010-01-15 Created: 2010-01-15 Last updated: 2014-07-10
2. Symptoms of Multiple Sclerosis during use of Combined Hormonal Contraception
Open this publication in new window or tab >>Symptoms of Multiple Sclerosis during use of Combined Hormonal Contraception
2015 (English)In: European Journal of Obstetrics, Gynecology, and Reproductive Biology, ISSN 0301-2115, E-ISSN 1872-7654, Vol. 193Article in journal (Refereed) Published
Abstract [en]

Objective: 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 earlier shown variation in symptom experience related to estrogen/progestogen phase in women using combined hormonal contraceptives (CHC) in a small sample. The aim of this study was confirm these results in a larger sample.

Design: Self-assessment of symptoms of MS in relation to CHC cycle or menstrual cycle. Sample: Twenty-three female MS patients using CHC. Control groups were female MS patients without hormonal contraception and healthy women with CHC and without hormonal contraception.

Methods: All women filled out a symptom diary based on a validated instrument for cyclical symptoms.

Main Outcome measures: Mean scores for high and low estrogen/progestogen phases were compared.

Results: The women with MS using combined hormonal contraceptives scored all symptoms higher during the pill-free week than during the CHC-phase and the scores for vertigo, weakness, urinary symptoms and stiffness were significantly higher during the seven days without CHC (p < 0.05). No such relation was found in the group of women with MS not using any hormonal contraception. Women without MS did not report any symptoms at all.

Conclusion: Women with MS report more pronounced symptoms during the lowestrogen/ progestogen phase of CHC use. Future studies should investigate, with a prospective, controlled design, which effects continuous-use regimens of CHC have in women with MS.

Place, publisher, year, edition, pages
Elsevier, 2015
Keyword
Multiple Sclerosis, Combined Hormonal Contraceptives, Symptom experience
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-108886 (URN)10.1016/j.ejogrb.2015.06.030 (DOI)000361777400001 ()
Note

Funding: County Council of Ostergotland, Sweden; County Council of Vasternorrland, Sweden

Available from: 2014-07-10 Created: 2014-07-10 Last updated: 2017-12-05Bibliographically approved
3. Age at onset of multiple sclerosis is correlated to use of combined oral contraceptives and childbirth before diagnosis
Open this publication in new window or tab >>Age at onset of multiple sclerosis is correlated to use of combined oral contraceptives and childbirth before diagnosis
2010 (English)In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 94, no 7, 2835-2837 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to evaluate whether age of onset of multiple sclerosis is related to use of combined oral contraceptives and/or timing of childbirth. The results showed that use of combined oral contraceptives and childbirth before the first multiple sclerosis symptom was correlated to a higher mean age at the onset of the disease.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam., 2010
Keyword
Multiple sclerosis, estrogen, combined oral contraceptives
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-63156 (URN)10.1016/j.fertnstert.2010.06.045 (DOI)000284573700084 ()
Note
Original Publication: Per Holmqvist, Mats Hammar, Anne-Marie Landtblom and Jan Brynhildsen, Age at onset of multiple sclerosis is correlated to use of combined oral contraceptives and childbirth before diagnosis, 2010, Fertility and Sterility, (94), 7, 2835-2837. http://dx.doi.org/10.1016/j.fertnstert.2010.06.045 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/Available from: 2010-12-13 Created: 2010-12-13 Last updated: 2017-12-11
4. T cell subset-associated transcription factors, cytokines and chemokines in relation to the menstrual cycle and use of combined hormonal contraceptives in women with multiple sclerosis and healthy controls
Open this publication in new window or tab >>T cell subset-associated transcription factors, cytokines and chemokines in relation to the menstrual cycle and use of combined hormonal contraceptives in women with multiple sclerosis and healthy controls
Show others...
2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Study question: Do peripheral blood levels of cytokines, chemokines, and transcription factors for different T helper (Th) cell subsets change in relation to high and low estrogen/progestogen states in women with multiple sclerosis (MS) and healthy controls with and without combined hormonal contraceptives (CHC)?

Summary answer: Our findings indicate a general activation of peripheral blood T cells and B cells during high estrogen/progestogen phases with higher levels of transcription factors associated with both Th1 (TBX21) and Th2 (GATA3) subsets of T cells and the B cell-associated chemokine CXCL13.

What is known already: There are some indications that sex steroids may positively affect MS clinically and immunologically.

Study design, size, duration: A total of 60 women were included. Paired blood samples were drawn in high and low estrogen/progestogen phases during the same cycle in women using or not using CHC.

Participants/materials, setting, methods: Participants were female MS patients and healthy controls with and without CHC. Concentrations of cytokines and chemokines were measured using multiplex bead technology and expression of transcription factors in blood cells was determined by qPCR. Owing to possible differences in cell composition, expression of Th-associated transcription factors were normalized to the T cell-specific transcription factor CD3E.

Main results and the role of chance: Sixty women were included but 13 women dropped out, leaving 47 women to the statistical analyses. In healthy controls using CHC, both TBX21, and GATA3 expression was higher in the high estrogen/progestogen phase than in the low estrogen/progestogen phase. TBX21 expression in high estrogen/progestogen phase differed significantly between groups with the highest levels in healthy controls without CHC. In all MS patients as well as in healthy controls using CHC, the concentrations of CXCL13 was significantly higher in the high estrogen/progestogen phase compared to the low estrogen/progestogen phase.

Limitations, reasons for caution: The low number of participants. A majority of the MS patients were using immunomodulatory drugs which may have interfered with the results. The study design makes it impossible to differ between estrogenic and progestogenic effects.

Wider implications of the findings: Our findings show that high and low levels of estrogens and/or progestogens differently affect immune parameters related to Th cell subsets as well as B cells. The differences between high- and low estrogen/progestogen phases were most obvious in women using CHC indicating that CHC is more potent than 17β-Estradiol/progesterone in inducing immune changes in both MS patients and healthy women.

Study funding/competing interest(s): This study was funded by the County Councils of Östergötland and Västernorrland, Sweden. No author have any conflicts of interest to declare.

Keyword
Multiple Sclerosis, Combined Hormonal Contraceptives, Symptom experience
National Category
Obstetrics, Gynecology and Reproductive Medicine Basic Medicine
Identifiers
urn:nbn:se:liu:diva-108887 (URN)
Available from: 2014-07-10 Created: 2014-07-10 Last updated: 2015-04-01Bibliographically approved

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