Zeydan Burcu, Atkinson Elizabeth J, Weis Delana M, Smith Carin Y, Gazzuola Rocca Liliana, Rocca Walter A, Keegan Brian Mark, Weinshenker Brian G, Kantarci Kejal, Kantarci Orhun H
Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA.
Brain Commun. 2020 Nov 17;2(2):fcaa185. doi: 10.1093/braincomms/fcaa185. eCollection 2020.
Being a woman is one of the strongest risk factors for multiple sclerosis. The natural reproductive period from menarche to natural menopause corresponds to the active inflammatory disease period in multiple sclerosis. The fifth decade marks both the peri-menopausal transition in the reproductive aging and a transition from the relapsing-remitting to the progressive phase in multiple sclerosis. A short reproductive period with premature/early menopause and/or low number of pregnancies may be associated with an earlier onset of the progressive multiple sclerosis phase. A cross-sectional study of survey-based reproductive history in a multiple sclerosis clinical series enriched for patients with progressive disease, and a case-control study of multiple sclerosis and age/sex matched controls from a population-based cohort were conducted. Menarche age, number of complete/incomplete pregnancies, menopause type and menopause age were compared between 137 cases and 396 control females. Onset of relapsing-remitting phase of multiple sclerosis, progressive disease onset and reaching severe disability (expanded disability status scale 6) were studied as multiple sclerosis-related outcomes ( = 233). Menarche age was similar between multiple sclerosis and control females ( = 0.306). Females with multiple sclerosis had fewer full-term pregnancies than the controls ( < 0.001). Non-natural menopause was more common in multiple sclerosis (40.7%) than in controls (30.1%) ( = 0.030). Age at natural menopause was similar between multiple sclerosis (median, interquartile range: 50 years, 48-52) and controls (median, interquartile range: 51 years, 49-53) ( = 0.476). Nulliparous females had earlier age at progressive multiple sclerosis onset (mean ± standard deviation: 41.9 ± 12.5 years) than females with ≥1 full-term pregnancies (mean ± standard deviation: 47.1 ± 9.7 years) ( = 0.069) with a pregnancy-dose effect [para 0 (mean ± standard deviation: 41.9 ± 12.5 years), para 1-3 (mean ± standard deviation: 46.4 ± 9.2 years), para ≥4 (mean ± standard deviation: 52.6 ± 12.9 years) ( = 0.005)]. Menopause age was associated with progressive multiple sclerosis onset age ( = 0.359, < 0.001). Duration from onset of relapses to onset of progressive multiple sclerosis was shorter for females with premature/early menopause ( = 26; mean ± standard deviation: 12.9 ± 9.0 years) than for females with normal menopause age ( = 39; mean ± standard deviation: 17.8 ± 10.3 years) but was longer than for males (mean ±standard deviation: 10.0 ± 9.4 years) ( = 0.005). There was a pregnancy-dose effect of age at expanded disability status scale 6 (para 0: 43.0 ± 13.2 years, para 1-3: 51.7 ± 11.3 years, para ≥4: 53.5 ± 4.9 years) ( = 0.013). Age at menopause was associated with age at expanded disability status scale 6 ( = 0.229, < 0.003). Premature/early menopause or nulliparity was associated with earlier onset of progressive multiple sclerosis with a 'dose effect' of pregnancies on delaying progressive multiple sclerosis and severe disability. Although causality remains uncertain, our results suggest a beneficial impact of oestrogen in delaying progressive multiple sclerosis. If confirmed in prospective studies, our findings have implications for counselling women with multiple sclerosis about pregnancy, surgical menopause and menopausal hormone therapy.
身为女性是多发性硬化症的最强风险因素之一。从初潮到自然绝经的自然生育期与多发性硬化症的活动性炎症疾病期相对应。五十岁左右标志着生殖衰老中的围绝经期过渡以及多发性硬化症从复发缓解期向进展期的转变。生育期短、过早绝经和/或怀孕次数少可能与进展性多发性硬化症阶段的较早发病有关。对一个以进展性疾病患者为主的多发性硬化症临床系列中基于调查的生殖史进行了横断面研究，并对来自人群队列的多发性硬化症患者和年龄/性别匹配的对照进行了病例对照研究。比较了137例病例和396例对照女性的初潮年龄、完整/不完整怀孕次数、绝经类型和绝经年龄。将多发性硬化症复发缓解期的发病、进展性疾病发病以及达到严重残疾（扩展残疾状态量表6级）作为与多发性硬化症相关的结局进行研究（n = 233）。多发性硬化症女性和对照女性的初潮年龄相似（P = 0.306）。患有多发性硬化症的女性足月妊娠次数少于对照组（P < 0.001）。非自然绝经在多发性硬化症患者中（40.7%）比对照组（30.1%）更常见（P = 0.030）。多发性硬化症患者自然绝经年龄（中位数，四分位间距：50岁，48 - 52岁）与对照组（中位数，四分位间距：51岁，49 - 53岁）相似（P = 0.476）。未生育女性进展性多发性硬化症发病年龄（平均值±标准差：41.9±12.5岁）早于有≥1次足月妊娠的女性（平均值±标准差：47.1±9.7岁）（P = 0.069），呈现妊娠剂量效应[未生育（平均值±标准差：41.9±12.5岁），1 - 3次妊娠（平均值±标准差：46.4±9.2岁），≥4次妊娠（平均值±标准差：52.6±12.9岁）（P = 0.005）]。绝经年龄与进展性多发性硬化症发病年龄相关（P = 0.359，P < 0.001）。过早/早期绝经的女性从复发开始到进展性多发性硬化症发病的持续时间（n = 26；平均值±标准差：12.9±9.0岁）短于绝经年龄正常的女性（n = 39；平均值±标准差：17.8±10.3岁），但长于男性（平均值±标准差：10.0±9.4岁）（P = 0.005）。在扩展残疾状态量表6级时存在妊娠剂量效应（未生育：43.0±13.2岁，1 - 3次妊娠：51.7±11.3岁，≥4次妊娠：53.5±4.9岁）（P = 0.013）。绝经年龄与扩展残疾状态量表6级时的年龄相关（P = 0.229，P < 0.003）。过早/早期绝经或未生育与进展性多发性硬化症的较早发病相关，妊娠对延迟进展性多发性硬化症和严重残疾有“剂量效应”。尽管因果关系仍不确定，但我们的结果表明雌激素在延迟进展性多发性硬化症方面有有益影响。如果在前瞻性研究中得到证实，我们的发现对于为患有多发性硬化症的女性提供关于妊娠、手术绝经和绝经激素治疗的咨询具有重要意义。
