Neuroactive Steroids and Seizure Control during Pregnancy in Women with Epilepsy

描述（由申请人提供）：癫痫是一种常见疾病，影响美国约130万育龄妇女。怀孕期间的癫痫发作可能会增加母亲和胎儿的风险。这些风险必须与抗癫痫药物（AED）的已知致畸作用相平衡。在怀孕期间，性类固醇激素雌二醇和孕酮急剧增加。性类固醇激素和能够改变神经活动的代谢副产物被归类为神经活性类固醇（NAS）。动物模型证实NAS 17 <$-雌二醇（EST）、孕酮（PROG）和别孕烯醇酮（ALLO）对癫痫发作活动的调节。在女性中，这些NAS的波动与非妊娠状态下的癫痫发作控制有关，在月经周期的某些时间癫痫发作恶化（月经性癫痫）。人体研究表明，随着EST/PROG比值升高和PROG水平下降或降低，癫痫发作频率增加。这还没有在癫痫妇女怀孕期间进行研究。这项拟议的研究将利用在妇女和性别问题研究专门中心项目资助期间从135名癫痫妇女在怀孕不同阶段收集的血清样本（n=810份样本）。这些妇女前瞻性地登记，跟踪癫痫发作和药物治疗。在每个妊娠期的多个时间点采集血浆样本。基于入组的变量点（< 20周妊娠），我们增加了妊娠晚期的观察/样本。将在妊娠中期和妊娠晚期分析癫痫发作频率，并与每例受试者的非妊娠基线进行比较。与R 03机制一致，本申请将通过测量神经活性类固醇EST、PROG和ALLO来扩展这些现有数据/样本的分析。工作假设是：1）在怀孕期间，EST和PROG浓度的变化影响癫痫发作控制; 2）孕酮代谢物ALLO介导PROG的降低癫痫发作的作用。将分析以下与妊娠期间癫痫发作频率变化的关系：EST/PROG比值、PROG上升率和ALLO上升率。此外，考虑到分娩和分娩是癫痫发作增加的特别脆弱的时间;将比较围产期癫痫发作的女性和未发生癫痫发作的女性之间的ALLO和PROG水平。这项研究最终可以更好地了解NAS对妊娠期间癫痫发作控制的调节。从这项研究中获得的见解可以为NAS类似物的进一步开发提供动力，治疗益处扩展到所有性别和所有年龄段。妊娠期间，补充孕酮治疗可降低胎儿宫内AED暴露水平，改善癫痫发作控制，降低解剖学和神经发育致畸性。 公共卫生相关性：在怀孕期间治疗患有癫痫的妇女需要控制母亲的癫痫发作而不使发育中的胎儿暴露于比必要更多的抗惊厥药物的不稳定平衡。在怀孕期间，性类固醇激素及其代谢副产物的增加可能直接影响癫痫发作的控制;这项研究将分析在怀孕期间癫痫妇女已经获得的血液样本，以检查癫痫发作增加的妇女是否有神经活性类固醇水平的改变。这些发现可能会导致开发新的治疗策略，为妇女在怀孕期间癫痫，如使用补充孕酮，以改善母亲和儿童的健康结果。

DESCRIPTION (provided by applicant): Epilepsy is a common disorder, affecting approximately 1.3 million women of child-bearing age in the United States. Seizures during pregnancy can cause increased risks to both the mother and fetus. These risks have to be balanced against the known teratogenic effects of antiepileptic drugs (AEDs). During pregnancy, the sex steroid hormones estradiol and progesterone increase dramatically. Sex steroid hormones and the metabolic byproducts that are capable of modifying neural activity are classified as neuroactive steroids (NAS). Animal models demonstrate modulation of seizure activity by the NAS 17¿-estradiol (EST), progesterone (PROG), and allopregnanolone (ALLO). In women, fluctuations in these NAS have been implicated in seizure control in the non-pregnant state, with worsening seizures at certain times of the menstrual cycle (catamenial epilepsy). Human studies have demonstrated an increase in seizure frequency with elevated EST/PROG ratios and with declining or low PROG levels. This has not been studied during pregnancy in women with epilepsy. This proposed study will utilize serum samples (n=810 samples) already collected from 135 women with epilepsy during different stages of pregnancy during a Specialized Center of Research in Women and Gender Issues program project grant. These women were enrolled prospectively with tracking of seizures and medications. Collection of plasma samples occurred at multiple points in each trimester. Based on variable points of enrollment (< 20 weeks gestation), we have increased observations/samples in the later trimesters of pregnancy. Seizure frequency will be analyzed during the second and third trimesters of pregnancy and compared to the nonpregnant baseline for each subject. Consistent with the R03 mechanism, the current application will extend the analysis of these existing data/samples via measurement of the neuroactive steroids EST, PROG, and ALLO. The working hypotheses are 1) during pregnancy, changing concentrations of EST and PROG influence seizure control; 2) the progesterone metabolite, ALLO, mediates the seizure-reducing effect of PROG. The following will be analyzed in relationship to change in seizure frequency during pregnancy: EST/PROG ratio, the rate of rise of PROG, and the rate of rise of ALLO. Additionally, given that labor and delivery is a particularly vulnerable time for increased seizures; ALLO and PROG levels will be compared between women who had peripartum seizures and those who did not. This study can ultimately lead to a better understanding of the NAS regulation of seizure control during pregnancy. Insights gained from this study could provide the impetus for further development of NAS analogs, with treatment benefits extending to both genders and across all ages. During pregnancy, treatment with supplemental progesterone could allow for decreased levels of fetal exposure to AEDs in utero, with improved seizure control and reduced anatomical and neurodevelopmental teratogenicity. PUBLIC HEALTH RELEVANCE: Treating women with epilepsy during pregnancy requires a precarious balance of controlling the mother's seizures without exposing the developing fetus to more anticonvulsant medication than necessary. During pregnancy, the rising sex steroid hormones and their metabolic byproducts may directly influence seizure control; this study will analyze blood samples already obtained in women with epilepsy during pregnancy to examine whether women with increased seizures have alterations in neuroactive steroid levels. These findings could lead to the development of novel treatment strategies for women with epilepsy during pregnancy, such as use of supplemental progesterone, to improve mother and child health outcomes.