Female Gender and Reproductive Factors Affecting

Review Gynecol Obstet Invest 2013;75:73–84 DOI: 10.1159/000346319

Received: August 2, 2012 Accepted after revision: December 5, 2012 Published online: January 18, 2013

Female Gender and Reproductive Factors Affecting Risk, Relapses and Progression in Multiple Sclerosis M.B. D’hooghe a, b T. D’Hooghe c J. De Keyser b, d a

National Center for Multiple Sclerosis, Melsbroek , b Department of Neurology UZ Brussels, Center for Neurosciences, Vrije Universiteit Brussel (VUB), Brussels, and c Department of Obstetrics and Gynecology, Leuven Fertility Center, UZ Gasthuisberg, Leuven, Belgium; d Department of Neurology, University Medical Center Groningen, Groningen, The Netherlands

Abstract Multiple sclerosis (MS), a chronic inflammatory demyelinating and degenerative disease of the central nervous system, is a frequent cause of neurological disability in young adults. Female predominance has increased over the last decades. Although female gender carries a higher risk of developing relapsing remitting MS, being female and at child-bearing age also appears to provide some protection against cognitive decline and against progressive onset MS, an adverse predictive factor when considering long-term disability in MS. The risk of MS in women has been associated with an earlier age at menarche. In most studies, parity did not impact MS risk. However, the recently published association of higher parity and offspring number with a reduced risk of a first demyelinating event suggests a potential suppressive effect. Pregnancy in MS patients has been associated with a reduced relapse rate and a reduction of neurological symptoms, especially in the third trimester. Despite the increased relapse risk in the postpartum period, there is no indication of an adverse effect of childbirth on the long-term course of MS. Fertility treatment in MS has been associated with an

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increased relapse risk in the following 3-month period, especially when the procedure did not result in pregnancy and gonadotrophin-releasing hormone agonists were used. Altogether, there is substantial evidence to support a regulatory role of sex steroid hormones in MS. In the absence of correlations with single hormone blood levels, we can only speculate about the underlying mechanisms. In conclusion, the increased MS risk in women and the changes in relapse and progression risk in association with reproductive events suggest significant and complex interactions between immune, neuroendocrine and reproductive systems in MS. Copyright © 2013 S. Karger AG, Basel

General Introduction on Multiple Sclerosis

Genes and Environment Multiple sclerosis (MS), the most frequent cause of chronic disability in young adults, is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). The age at onset peaks at 29 in women and 30 in men and most frequently ranges between 20 and 50. Women are affected about twice as often as men or even more [1]. The sequence of events that initiates the disease remains largely unknown. Complex interactions between Marie B. D’hooghe, MD Multiple Sclerosis Center Vanheylenstraat 16 BE–1820 Melsbroek (Belgium) E-Mail marie.dhooghe @ mscenter.be

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Key Words Multiple sclerosis ⴢ Female gender ⴢ Pregnancy ⴢ Menarche ⴢ Oral contraceptives

Relapses and Progression Based on the time course over which first symptoms develop, MS can be classified as relapsing remitting or primary progressive MS (table 1). The clinical picture of MS is characterized by an impressive variability in type, symptoms, course and severity of MS. In the majority of patients, the disease starts with a first demyelinating event and continues with a relapsing remitting course. Relapses present as a focal or multifocal CNS dysfunction, usually developing over hours to days and resolving either partially or completely over weeks. They reflect acute inflammatory events, thought to be autoimmune in nature and driven by autoreactive T cells that cross the blood-brain barrier [11]. Demyelination, a variable degree of remyelination and axonal damage, in relation to the degree of inflammation has been described [12–14]. Although relapses are unpredictable, evidence 74

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suggests that relapses can be triggered by infections, stressful life events and the postpartum period [15]. Following a variable period of time, the majority of patients convert to a secondary progressive phase. Axonal degeneration is thought to underlie this process of slow accumulation of disability. A minority of subjects, those with primary progressive MS, start with a gradually increasing neurological disability. They are older at onset, have less inflammatory white matter lesions and a higher proportion is male [16]. Functional impairments gradually increase over months to years and, apart from minor fluctuations, do not reverse [17]. Clinical Disability and Milestones Chronic disability in MS may be the result of two distinct clinical phenomena: relapses and progression. Although early relapses contribute to early disease progression, the long-term effect of relapses appears to be minimal [18]. According to natural history studies of MS, the total number of relapses is not related to long-term disability [19]. Clinical neurological disability can be measured with the Expanded Disability Status Scale (EDSS) [20]. Lower scores reflect lower disability and scores 64 primarily reflect ambulation-related disability. EDSS 4 corresponds to limited walking but without aid (500 m) and EDSS 6 signifies walking with unilateral aid (100 m). The time interval between the onset of MS and the point of reaching EDSS 4 or EDSS 6 and the age of reaching these milestones of disability have been used to measure long-term disability in natural history studies. The similar course in primary progressive and secondary progressive MS, irrespective of relapses and the similar ages at which the milestones of disability are reached, support the notion of the progressive phase falling within a single disease entity regardless of whether it occurs from onset or after a relapsing remitting phase [16]. Different factors are known to predict the time to reach these milestones. Gender, age at onset, course at onset, degree of recovery from the first relapse, time to second relapse and the number of relapses in the first years affect the time from onset to EDSS 4 or 6 [21, 22]. Male gender, older age at onset and progressive onset MS are predictors of an unfavorable outcome [23]. Focal White Matter versus Diffuse CNS Pathology Focal demyelinated plaques in the white matter (WM), visible with the naked eye, are considered to be the pathological hallmark of MS. Microscopically, many types of D’hooghe /D’Hooghe /De Keyser


genetic and environmental factors contribute to the etiology of MS [2–4]. There is a marked aggregation of MS in families with an increased recurrence risk correlating with the degree of kinship. The association with the human leukocyte antigen (HLA) gene cluster in chromosome 6p21, housing class I and II major histocompatibility complex molecules, is probably related to the role of these molecules in antigen presentation to T lymphocytes [5]. A threefold increased risk was found in HLA-DR2, now HLA-DRB1-positive individuals, corresponding to 20–40% of the genetic risk for MS. The HLA-DRB1*1501 haplotype, but also other haplotypes have been associated with the MS risk. The maternal parent-of-origin effect in MS, the higher frequency of HLA-DRB1*15 in female patients with MS and the increased penetrance of HLA-DRB1*15 over time in females in multigenerational MS pedigrees, suggest gender-specific epigenetic interactions might be the driving forces behind the MHC haplotypic associations [6]. The risk of developing MS has been negatively correlated with levels of vitamin D and sun exposure and has been positively correlated with Epstein-Barr virus serology, infectious mononucleosis at adolescent age and smoking [7, 8]. Over the past few decades, the prevalence of MS has invariably increased with repeated surveys in the same area. Both a longer survival and a changing incidence have been observed [9, 10]. While the male incidence has remained constant, the female incidence of disease onset has almost doubled in Denmark since 1970 [9]. The involvement of factors related to Western lifestyle has been proposed.

Table 1. Clinical differences between relapsing remitting MS and primary progressive MS

lesions have been demonstrated [24]. Because of its high sensitivity for the detection of these lesions in the WM, conventional magnetic resonance imaging (MRI) has become an established tool in the diagnosis of MS [25]. Multisequence protocols typically include T2-weighted images (T2w) and gadolinium (Gd)-enhanced T1-weighted (T1w) images. However, focal hyperintense areas on T2w images in the periventricular, juxtacortical and infratentorial WM, although suggestive for MS, lack specificity and reflect a broad spectrum of changes. Gadoliniumenhancing lesions on T1w images correspond to acute focal inflammatory lesions with disruption of the bloodbrain barrier. The enhancement is usually transient and resolves after 2–6 weeks [26]. In relapsing onset MS, the burden of visible lesions on T2w images of the brain is at most moderately correlated with neurological disability [27]. In progressive onset MS, spinal cord involvement is usually more extensive than abnormalities in the brain. When using more advanced MRI techniques, widespread abnormalities have been found in the normal appearing white and gray matter in MS of both relapsing onset and progressive onset groups. Cortical lesions and pathological processes beyond the focal lesions are usually missed with standard MRI [26]. Whole-brain atrophy correlates better with disability but measurements of atrophy are not yet used in clinical practice. In conclusion, MS pathology is characterized by focal lesions as well as diffuse pathology, in both the white and gray matter. Conventional MRI of brain and spinal cord mainly reveals focal lesions in the WM which do not represent all aspects of disease pathology. Treatment There is no cure for MS. In relapsing MS, high doses of intravenous or oral methylprednisolone speed up recovery from relapses [28]. Corticosteroids, as part of the steFemale Gender and Reproductive Factors in Multiple Sclerosis

Primary progressive MS

over hours to days 85% 2–3:1 optic nerve, brainstem, spinal cord moderate often yes (fewer relapses) 23.1 (20.1–26.1)

over months to years 15% 1:1 spinal cord small extensive no (disability not affected) 7.1 (6.3–7.9)

roid family, have a sterol skeleton which they share with sex steroid hormones and synthetic steroid compounds used in contraception or hormonal replacement therapy. All currently used immunotherapeutic agents are nonantigen-specific immunosuppressants or immunomodulators. Treatments with ␤-interferons, glatiramer acetate, natalizumab [29] or fingolimod [30] primarily reduce the frequency of relapses and focal inflammatory activity on MRI. Reduced disability progression, mainly in the context of relapses, has been demonstrated with some of the drugs described [31]. However, suppression of MRI-detectable inflammation does not fully translate into a comparable slowing of the rate of brain atrophy [32]. Currently, no therapies are known to prevent the progression of disability, independently of relapses, in secondary progressive MS. Similarly, no drugs have been shown to be effective in primary progressive MS.

Female Gender in MS: MS Risk versus Progression from Onset

The incidence of MS in women is at least twice as high as in men. The female:male ratio by year of birth has been increasing for at least 50 years and now exceeds 3.2:1 in Canada [33]. Female predominance is very pronounced in patients with onset after the age of 11 or 12 years [34–36] and has been higher in adolescent-onset MS (!16 years) compared to adult-onset MS [35, 36]. The female:male ratio then declines with age and is lowest in late-onset MS, after age 50 [37], when male excess or reduced female predominance has been found [37, 38]. Compared to men, women have a slightly mean younger age at onset [37] and more often have a relapsing remitting course at onset. These factors, as well as female gender, are associated with a better prognosis in the long term. Recent epidemiological data suggest that women Gynecol Obstet Invest 2013;75:73–84

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Time course of first symptoms Prevalence Female:male ratio Presenting symptoms Brain lesions Spinal cord lesions Immunomodulatory treatment response Median time from onset to EDSS 6, years (95% CI) [17]

Relapsing remitting MS

Reproductive Events

A number of studies have addressed MS variables in relation to reproductive events. Based on criteria developed by the American Academy of Neurology for prognostic questions [44], we assessed the methodological 76


Table 2. Classification of studies (A) and levels of evidence (B)

A Class I and II High-quality studies

Prospective data collection. Retrospective study of a broad spectrum of patients with the defined outcome compared to a broad spectrum of controls Population-based study or representative population study Low or moderate risk of bias Masked or independent assessment of the outcome and prognostic factor Class III and IV Retrospective study of a narrow spectrum of Low-quality patients with the defined outcome compared to studies a narrow spectrum of controls Patients recruited from referral centers Case series without controls High or very high risk of bias

B Strong Moderate Limited Inconclusive

Consistent findings (≥80%) in at least two high-quality cohorts One high-quality cohort and consistent findings in one or more low-quality cohorts Findings of one cohort or consistent findings in one or more low-quality cohorts Inconsistent findings irrespective of study quality

quality of the reviewed studies using the qualification of evidence scheme. All studies were classified into either high-quality studies or low-quality studies (table 2A). The strength of evidence was based upon criteria used in a systematic review of prognostic factors of whiplash-associated disorders (table 2B) [45]. An overview of the most important findings is given in table 3 [46–75]. Age at Menarche: Risk and Progression A population-based study clearly demonstrated an association between earlier age at menarche and an increased risk of MS in women [46]. As opposed to the findings in an earlier survey in a small number of female patients with relapsing remitting MS [76], no correlation between age at menarche and age at onset of disease was found. In men, there was no effect of the age at puberty on the risk of MS [46]. More recently, a higher age at menarche has been associated with a reduced risk to reach the milestone of EDSS 6, requiring aid to walk 100 m, in progressive onset MS [47]. No similar association was found in relapsing onset MS. The significance of this association remains unclear. Common underlying mechanisms might be involved or one event might induce the other (menarche or D’hooghe /D’Hooghe /De Keyser


have a few more years before reaching the first benchmark of disability (requiring aid to walk 100 m) than men [22, 38]. However, the increased time to reach the milestone of requiring aid to walk 100 m in women has been found to be restricted to adult-onset MS and was not present in late-onset MS, when the incidence of progressive disease onset increases [38]. This MS subtype, which starts with slowly progressive neurological symptoms, is widely recognized to be predictive of a shorter time to reach the milestones of progression in MS than the MS subtype which starts with relapses [19, 21, 39, 40]. Based on the available study results, gender does not seem to exert independent effects on morphological changes of the brain [40]. However, recent data on cognitive functions and functional reorganization in the brain show that male MS patients had functional changes and reduced visuospatial memory when compared to male controls, whereas female MS patients did not. As both groups of patients were carefully matched with controls, gender-specific functional network changes could be related to worse cognitive functioning in male MS patients [41]. Therefore, gender-related differences in functional reorganization have been proposed with a potential neuroprotective role of sex steroids in women. More recently, male sex was found to be an important predictor of a worse cognitive performance and of higher regional atrophy [42]. It has also been suggested that treatment with interferon in secondary progressive MS could be more beneficial in preventing disability progression in women than in men [43]. In conclusion, female gender appears to be a risk factor for an earlier presentation of MS with relapsing onset but somehow protects against progressive onset MS and cognitive decline. The increasing incidence in women during the last decades in combination with the reduced risk of progression at onset, at least when the disease starts during reproductive years, might contain clues to the underlying mechanisms of MS. Risk factors for relapsing disease reflecting focal inflammatory lesions might be different from risk factors for progressive disease reflecting diffuse neurodegeneration.

Table 3. Classification of levels of evidence Finding

Rating of studies

Evidence classification

– Earlier age at menarche increases MS risk – Earlier age at menarche increases risk of reaching EDSS 6 in progressive onset MS

– One case-control study [46]

– Moderate evidence

– One cross-sectional study [47]

– Limited evidence

Premenstrual period increases relapse risk in subgroup of patients

One cohort study [48]

Limited evidence

Oral contra- – Oral contraceptives do not ceptives substantially affect MS risk – Clinical disability progression

– Two high-quality cohort studies and one high-quality case-control study [49–51] – One study found no effect [52] A pilot study reported a beneficial association in relapsing MS [53] Another study found increased progression in progressive onset MS [47]

– Strong evidence

Pregnancy

Reduced relapse risk, especially during third trimester

One high-quality cohort study [54] and consistent findings in several low-quality studies [55] One prospective cohort study did not find a reduced relapse rate during pregnancy [56]

Moderate evidence

Postpartum period

– Two- to threefold increased relapse risk in 3-month period – Increased MS risk in 6-month period following childbirth

– Two high-quality cohort studies [54, 56] Consistent findings in MR study [57] – One high-quality cohort study [51] Consistent findings in MR study [58]

– Strong evidence

Breastfeeding

No increased short-term risk of relapse

A prospective study did not find a relationship of breastfeeding with postpartum relapses [59] Consistent findings in several case series [54, 60, 61] Two cohort studies found exclusive breastfeeding to be associated with a reduced relapse risk [62, 63]

Strong evidence against an increased relapse risk during exclusive breastfeeding

Long-term effects of childbirth

Clinical disability progression in association with childbirth

Inconsistent findings, ranging from no effect [52, 56, 64, 65] to a mild, beneficial effect on relapses and progression [47, 56, 66-69]

Strong evidence against an adverse effect on disability progression in MS

Parity

Reduced MS risk in association with increasing parity

One high-quality case-control study [66] Two high-quality cohort studies [50, 51] did not find this One high-quality case-control study [70] found a reduced risk of first demyelinating event in association with increasing parity

Inconclusive evidence

Assisted reproductive technology (ART)

Increased relapse risk during the 3-month period following ART treatment with gonadotropin releasing hormone agonists

One high-quality cohort study [71] found a sevenfold increase in risk of MS relapse and a ninefold increased risk of enhanced disease activity on MRI One systematic study [72] and consistent findings in several low-quality cohort studies [73–75] found an increased relapse risk, especially when ART failed

Moderate evidence

Menstrual cycle

– Inconclusive evidence

– Moderate evidence

MS). The substantial increase in gonadal hormone secretion around puberty is driven by the hypothalamic-pituitary-gonadal (HPG) axis. At that time there are also considerable changes in the hormones released by hypothalamic-pituitary-adrenal (HPA) axis, the primary neuroendocrine axis that mediates hormonal stress response. Animal studies have shown substantial transitions in stress reactivity during pubertal maturation, with sex

differences [77]. Gonadal hormones might be involved in programming the HPA axis, leaving traces on later function. In view of the link between the HPG axis and the HPA axis and taking into account the dysregulated HPA axis in MS [78], the association of a lower age at menarche with the risk and progression of MS might imply a role for the neuroendocrine axis in disease etiology and progression.

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Age at menarche

Fertility and Endocrine Patterns The issue of fertility has not been studied extensively. The frequency of childlessness in the female MS population might be higher than in the general population [66]. This might be related to postponing pregnancy or to concerns about a higher risk for transmitting disease [84]. Compared to controls, significantly higher levels of gonadotrophins and significantly lower estrogen levels were found in the early follicular phase of the menstrual cycle of 14 women with MS with regular cycles [85], which could result in menstrual irregularity and infertility [84]. A higher incidence of hyperprolactinemia and signs of hyperandrogenism have also been reported. 78


These alterations could contribute to the slightly higher incidence of oligo/amenorrhea observed in women with MS [86]. Oral Contraceptives, MS Risk and Progression OC, a source of exogenous sex hormones for many women, does not substantially affect the MS risk [87]. A slightly elevated relative risk for MS has been found among women using OC for 6–7 years or more compared to those who never used OC, suggesting a possibly increased risk of MS in long-term OC users [50]. Based upon a reduced incidence of MS in recent OC users, a delay in the age at onset of MS in association with use of OC, has also been proposed, suggesting some protective effect [51, 88]. In a prospective study in 7 women taking combined OC, higher symptom scores for weakness, numbness and tiredness were observed during the pill-free interval, with lower scores being present during the 3 weeks of pill taking [80]. It remains to be established whether these symptoms might be related to diffusion and metabolic changes in the female human hypothalamus during the pill-free interval, as demonstrated by MRI studies in women without MS [89]. Effects of OC use on the long-term course of MS have not been studied very well. In an older study of 446 women, no substantial influence of OC has been reported on the degree of disability after a certain period [52]. In a recent cross-sectional study, the use of OC, especially when taken as a teenager, were associated with an increased risk of progression to EDSS 6 in progressive onset MS, but not in relapsing onset MS [47]. These findings suggest OC use at a young age might matter when considering disease progression. In an exploratory study of women with relapsing onset MS and a mean disease duration of 6.2 years, OC use after disease onset was associated with a milder disease, as measured with the EDSS and the MS severity score, when compared with OC use before disease onset and never using OC [53]. The study design and small sample size in each category do not allow to make firm conclusions. Furthermore, MS may start biologically several years before clinical onset and the onset of MS may change contraceptive behavior. Distinguishing between OC use before or after clinical onset may not be very informative. At present, except for a possible delay of clinical onset in relapsing onset MS, there are no conclusive clinical data to suggest a beneficial effect of OC use on the course and progression of MS. These findings are in contrast D’hooghe /D’Hooghe /De Keyser


Menstrual Cycle and MS Activity The premenstrual period has been associated with an increased relapse risk in a subgroup of patients irrespective of oral contraceptive (OC) use [48, 79]. However, a worsening of symptoms during this period has also been described [79] and the difference between relapses and pseudorelapses may not be evident [11]. In a recent prospective study, there was an absence of significant differences in MS symptom scores according to the phase of the menstrual cycle in women with regular, natural cycles [80]. In a serial MRI study in 8 women with MS, enhancing lesions, suggestive of acute, focal inflammation were found to be positively related to the actual progesterone/ 17␤-estradiol ratio during the luteal phase [81]. In contrast, in another MRI study of the menstrual cycle in 30 MS patients, a positive correlation was found between the number of enhancing lesions, and high estradiol and low progesterone levels, whereas a low level of both hormones was associated with less inflammatory activity [82]. More recently, serum testosterone levels in women with relapsing MS appeared to be lower during the follicular and luteal phase than in controls. Women with abnormally low testosterone concentrations had more enhancing lesions than women with normal testosterone concentrations. On the other hand, higher testosterone concentrations were significantly associated with the likelihood of irreversible tissue injury and clinical disability [83]. In conclusion, there is no consistent pattern of clinical changes during the menstrual cycle. A subgroup might have an increased relapse risk during the follicular phase. Serum levels of single hormones have not consistently been associated with either enhanced or reduced MS activity. These findings suggest the effects of gonadal hormones are complex and may be different in the context of inflammation or irreversible tissue injury.

Effect of Pregnancy and Postpartum Period on MS Risk A lower risk of MS has been reported in nulliparous women when compared to parous women [66]. However, other studies did not find changes in MS risk in relation to pregnancy or parity [50, 51]. Very recently, an Australian case-control study reported a substantially reduced risk of a first demyelinating event among women with higher parity and higher offspring number [70]. The associations were not present in men and persisted after adjusting for confounding factors. There was no association with the time since last birth. In view of the consistency and magnitude of the association, the authors proposed a cumulative beneficial effect of pregnancy. Childbirth has also been associated with a delay in the age at onset of MS, suggesting a protective effect [88]. On the other hand, the risk of MS has been found to be increased in the 6 months after giving birth [51, 92]. Similarly, an increased risk for conversion from a radiologically isolated syndrome to a clinical event and new MRI activity has been reported during follow-up of women with pregnancies compared with non-pregnant controls [58]. Based on the available data, a beneficial effect of pregnancy and parity on the risk of inflammatory demyelinating events remains possible. The postpartum period might trigger inflammatory events in women, who already have an increased risk. Female Gender and Reproductive Factors in Multiple Sclerosis

Effect of Pregnancy and Postpartum Period on MS Activity Pregnancy in MS is associated with a reduction of neurological symptoms and an improvement of the quality of life. These changes are most obvious during the third trimester, when compared to the first trimester [93]. During pregnancy, especially during the third trimester, the relapse risk is substantially reduced and followed by a threefold increase in the 3-month postpartum period [54]. Compared to a mean relapse rate of 0.7 8 0.9 in the pre-pregnancy year, a decrease by two thirds to 0.2 8 1.0 was observed during the third trimester (p ! 0.001). By contrast, the 3-month postpartum period was characterized by an increase in the rate up to 1.20 8 2.0 (p ! 0.001). Thereafter, the relapse rate stabilized towards the reference period rate [54, 94]. Clinical predictors of a relapse during the postpartum period were an increased relapse rate in the year before or during pregnancy and a higher EDSS at the onset of pregnancy. Still, 72% of the women did not experience a relapse during this period [57, 94]. In serial MRI studies in 28 Finnish patients, increased inflammatory disease activity was observed during the postpartum period [57]. Pregnancy has been shown to change the expression of four inflammation-related genes in patients with MS, which resulted in a temporary loss of the MS signature [95]. Downregulation of three of these genes encoding negative regulators of inflammation has been inversely correlated with relapse rate and EDSS in men and women in the initial phase of relapsing remitting MS [96]. With regard to the long-term consequences of pregnancy and childbirth in MS, all studies agree on the absence of an adverse effect, which is reassuring [47, 56, 64– 68, 97, 98]. In a recent hospital-based cohort of Dutch patients, parity did not influence the risk of secondary progression in MS [65]. Remarkably, a reduced conversion to progressive disease [66] as well as a shift in the time to reach the milestones of disease progression has been reported in women with MS who get children after MS onset compared to women who did not [64, 66–68]. In all but one [64] of these studies, this association persisted after correction for age at onset. Furthermore, regardless of the timing of birth, all women with relapsing onset MS and children had a reduced time to reach EDSS 6 when compared with women without children [47, 68]. Similar results were obtained with the age at EDSS 6 analysis. As women who had children before MS onset had a significantly higher age at onset in different studies [64, 68, 88], a delay in the age at onset as the result of childbirth cannot be excluded. Gynecol Obstet Invest 2013;75:73–84

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with the overwhelming evidence of neuroprotective effects of sex steroids and OCs in the context of autoimmune diseases in experimental studies [90]. The increased risk of progression in women with progressive onset MS in association with OC use and in association with an earlier age at menarche, suggests the neuroendocrine axis might play a role in the neurodegenerative component of the disease. Because the pathophysiology of neurodegeneration in MS is not very well understood, we can only speculate about possible mechanisms. Several studies have suggested a dysregulated HPA axis in MS with hypercortisolemia, in relation to the course and clinical type of MS [78, 91]. Whether these changes are adaptive or related to the cause of neurodegeneration remains to be determined. In view of the activation of the HPG axis and HPA axis before and during puberty and the interplay between both axes, exposure to female hormones at a young age may affect a delicate endogenous hormonal balance in the CNS via interaction with hormone receptors or interference with hormone synthesis or metabolism.

Effect of MS in Mother on Newborns

An increased risk of operative delivery and a reduced birth weight in the newborn has been observed [99]. A significantly lower mean birth weight in term births was found in mothers with manifest MS, when compared to pre-MS or between onset and the diagnosis of MS, after adjusting for gestation in weeks, mother’s age, time period and caesarean section [100]. However, the rate of birth complications and interventions did not differ between the three groups. A recent study did not find significant differences in mean birth weight and gestational age of babies born to mothers with or without MS. Women with MS were not at a greater risk of adverse delivery outcomes which provides reassurance that maternal MS in general is not associated with adverse neonatal and delivery outcomes [101]. However, in this study, MS mothers were more often overweight and obese. In view of the limited number of women with higher disability (EDSS 66), no general conclusions can be made and an increased risk of adverse delivery outcome cannot be excluded. Epidural Anesthesia No controlled studies in MS patients exist. General anesthesia and epidural anesthesia with low concentration of local anesthetics are considered to be relatively safe [102]. The relapse incidence in women who received epidural anesthesia for vaginal delivery did not significantly differ from that in women who received local infiltration [103]. However, all women with postpartum relapses in this study had received epidural concentrations of bupivacaine 10.25%. Based on these data, it is not possible to exclude that higher concentrations of bupivacaine might adversely affect the relapse risk. In more recent studies, women with or without epidural analgesia did not differ in their risk of postpartum relapses [54, 94]. 80


Lactation Most studies, retrospective and prospective, did not find an altered risk or timing of relapses in the postpartum period in relation to breastfeeding [54, 59–61, 94]. The lower relapse rate in the year before and during pregnancy in women who breastfed in a large prospective study suggested a milder MS form in these women [54, 94]. In one small prospective study, exclusive breastfeeding for at least 2 months postpartum was associated with a strongly reduced relapse rate compared with no breastfeeding or starting supplemental formula feedings within 2 months [62]. A German cohort study also reported some beneficial effect of exclusive breastfeeding on postpartum relapse [63]. However, a recent, larger prospective study did not confirm a relationship of breastfeeding with postpartum relapses [59]. Taken together, breastfeeding probably does not change the relapse risk in MS. However, patients with a more benign course may be more inclined to give exclusive breastfeeding. Assisted Reproductive Technology There are no randomized, controlled trials studying the effect of treatment with assisted reproductive technology (ART) in female MS patients. However, a single relapse has been observed within 3 months following administration of either luteinizing hormone-releasing hormone (LHRH) agonists or LHRH antagonists, initially in 5 of 6 MS patients and consequently in 23 MS patients who underwent 78 hormonal stimulations [73–75]. No patient had a relapse 3 months before treatment, whereas 12 patients suffered from a single relapse within 3 months after ART. The relapse rate increased significantly from 0.62 8 0.1 before to 0.95 8 0.12 after ovarian stimulation, independent of the hormonal approach or the time interval between the stimulations. None of the patients who became pregnant had a relapse [75]. A recent systematic study of the relationship between in vitro fertilization (IVF) and risk of subsequent relapse in 32 women and 70 IVF treatments confirmed an increased relapse rate during the 3-month period following IVF compared with the same period before IVF [72]. An association with the use of gonadotropin-releasing (GnRH) agonists and IVF failure was found. Remarkably, the annualized relapse rate before IVF was higher in the IVF failure group than in the IVF success group, suggesting that patients with increased relapse rates may have been more prone to IVF failure [72]. A recent prospective study found ART using LHRH agonists to be associated with a sevenfold increase in risk of MS relapse and a ninefold increase in D’hooghe /D’Hooghe /De Keyser


In conclusion, the association of pregnancy with a reduced relapse rate, reduced neurological symptoms and an improved quality of life suggests reduced inflammatory MS activity during pregnancy, especially during the third trimester. These effects are likely to be related to changes in sex steroid hormones, obvious candidates to explain effects on inflammation. The association of childbirth with a reduced risk to reach EDSS 6 needs to be carefully interpreted. However, a favorable long-term effect cannot be excluded. Sex steroid hormones, but also changes in lifestyle related to childbirth might be involved [68].

Treatment Studies with Estriol, Progestins and Testosterone

Based on the findings during pregnancy, non-pregnant women have been treated for 6 months with estriol at a pregnancy dose. In 6 female patients with relapsing remitting MS, median total number and volume of acute inflammatory lesions on MRI were reduced by 80% during treatment, returned to baseline when off treatment and decreased again during the retreatment extension [104]. Levels of interferon-␥ were also significantly reduced. In the 4 patients with secondary progressive MS, no obvious estriol effects were found. A double-blind, placebo-controlled study of progestins combined with a low dose of transdermal estradiol (POPART’MUS), immediately after delivery and continuously during 3 months postpartum, was started several years ago to prevent postpartum relapses in women with MS [105]. The results have not been published yet but appear to be negative (oral communication by S. Vukusic, at ECTRIMS, October 2012, Lyon, France).

Menopause

Little information is available on the effects of menopause and hormone replacement therapy in postmenopausal women. A worsening of MS symptoms at the time of menopause was reported by 40%, whereas 56% reported no change and 5% a decrease in symptoms [106]. An earlier study reported worsening symptoms in 54% and an improvement in 75% of those who had tried hormone replacement therapy [107].

Concluding Remarks

Implications for Clinical Practice MS frequently affects women of child-bearing age and leads to dilemmas surrounding fertility and pregnancy. Limited data about menstrual cycles, endocrine patterns Female Gender and Reproductive Factors in Multiple Sclerosis

and fertility in MS are available. When considering ART treatment with hormone-releasing hormone (LHRH) agonists or LHRH antagonists, women with MS should be informed about the possibility of an increased relapse risk, especially if the procedure includes the administration of LHRH agonists. There are currently no reasons to believe that pregnancy and childbirth in MS adversely affect the longterm outcome of MS. Especially during the third trimester, the relapse rate is reduced and neurological symptoms improve. Notwithstanding the increased relapse risk during the postpartum period, the majority of women with MS do not relapse. Judging this risk may influence the choice for breastfeeding. Patients with a higher relapse rate before pregnancy could choose to restart immunomodulatory treatment after delivery and decline breastfeeding. Breastfeeding and epidural anesthesia do not obviously affect the relapse risk. Despite some reports of an increased risk of operative delivery and a reduced birth weight in the newborn of MS mothers, a recent study did not observe significant differences in neonatal and delivery outcomes between mothers with or without MS. Data on OCs and hormone replacement therapy are too limited to make any firm conclusions. Implications for Research Women have a higher risk to develop MS than men in combination with a reduced risk of progression at onset, at least during reproductive years. Although exposure, exposure to female steroid hormones increases the susceptibility for relapses (inflammation), at the same time it provides some protection against progression (neurodegeneration). A younger age at menarche increases the risk of MS in women. Also, a younger age at menarche and early exposure to OCs have been associated with increased progression in progressive onset MS. These observations indicate the neuroendocrine axis might be involved in MS. The absence of associations of disease activity with single hormone blood levels suggest relative effects of steroid hormones might matter. Alternatively, a shift from systemic to local steroid synthesis with autonomous regulation of steroids within the target tissues, including the brain, might be involved. Such a change in balance has been demonstrated in animals during certain life periods. Local steroid production may be regulated by local HPA and HPG axis homologues and become important when systemic steroid levels are low [108]. Local steroid synthesis has also been found in humans. The term Gynecol Obstet Invest 2013;75:73–84

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the risk of enhanced disease activity on MRI, with corresponding changes in immune response regulation [71]. In conclusion, there is increasing evidence to support an increased MS relapse risk following ART. Direct effects of GnRH agonists, changes in estrogen levels, temporary cessation of immunomodulatory treatment and stress induced by IVF might be involved [72, 75].

neurosteroids is used to define steroid hormones like estrogens, androgens and progestagens that are synthesized de novo or metabolized within the CNS. They are known for their neurotransmitter modulatory activity and neurotrophic as well as neuroprotective actions. In particular, progesterone and its metabolites appear to promote myelination and neural repair [109]. The reduced allopregnanolone levels and reduced mRNA expression of its synthetic enzymes in the normal appearing WM of MS patients when compared with controls, seems to support the hypothesis of a dysregulated neurosteroid synthesis in MS [110, 111]. Whether these changes are mediated by the neuroendocrine axis in MS remains to be studied. Further work is needed to establish the role of neurosteroids and the neuroendocrine axes in MS. Differential effects on inflammation and neurodegeneration are possible. It also remains to be established whether a substantial reduction of inflammation prevents neurodegeneration in MS. A dissociation of these processes, at least partially, has been proposed. Longitudinal studies in women with MS are needed to confirm the associations of progression with age at men-

arche, OCs and pregnancies. Information on age at menarche, menstrual cycles, use, type/duration of OCs, other contraceptives, fertility treatment, pregnancies, age at menopause and type/duration of hormonal substitution should be collected prospectively in relation to the onset type of MS and the progression of disability. The inclusion of an earlier milestone, like EDSS 4, may be more informative when studying disability progression in relation to relapses or slow progression. Finally, epidemiological studies in MS should take gender and onset type of MS into account, as risk factors may be different in men and women.

General Conclusion

Based on epidemiological studies and observational data, there is substantial evidence to support an influence of sex steroids on the risk of developing MS and MS progression. Associations of disease progression with age at menarche and changes in the HPA axis suggest a role for the neuroendocrine axis in MS, yet to be clarified.

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