Department of Clinical Experimental Research, Glostrup Research Institute, Rigshospitalet, Glostrup, Denmark.
Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University Hospital, Lund, Sweden.
J Headache Pain. 2020 Nov 10;21(1):131. doi: 10.1186/s10194-020-01197-0.
Migraine occurs 2-3 times more often in females than in males and is in many females associated with the onset of menstruation. The steroid hormone, 17β-estradiol (estrogen, E2), exerts its effects by binding and activating several estrogen receptors (ERs). Calcitonin gene-related peptide (CGRP) has a strong position in migraine pathophysiology, and interaction with CGRP has resulted in several successful drugs for acute and prophylactic treatment of migraine, effective in all age groups and in both sexes.
Immunohistochemistry was used for detection and localization of proteins, release of CGRP and PACAP investigated by ELISA and myography/perfusion arteriography was performed on rat and human arterial segments.
ERα was found throughout the whole brain, and in several migraine related structures. ERβ was mainly found in the hippocampus and the cerebellum. In trigeminal ganglion (TG), ERα was found in the nuclei of neurons; these neurons expressed CGRP or the CGRP receptor in the cytoplasm. G-protein ER (GPER) was observed in the cell membrane and cytoplasm in most TG neurons. We compared TG from males and females, and females expressed more ER receptors. For neuropeptide release, the only observable difference was a baseline CGRP release being higher in the pro-estrous state as compared to estrous state. In the middle cerebral artery (MCA), we observed similar dilatory ER-responses between males and females, except for vasodilatory ERβ which we observed only in female arteries.
These data reveal significant differences in ER receptor expression between male and female rats. This contrasts to CGRP and PACAP release where we did not observe discernable difference between the sexes. Together, this points to a hypothesis where estrogen could have a modulatory role on the trigeminal neuron function in general rather than on the acute CGRP release mechanisms and vasomotor responses.
偏头痛在女性中的发病率比男性高 2-3 倍，在许多女性中与月经初潮有关。甾体激素 17β-雌二醇（雌激素，E2）通过结合和激活几种雌激素受体（ER）发挥作用。降钙素基因相关肽（CGRP）在偏头痛病理生理学中具有重要地位，与 CGRP 的相互作用导致了几种用于偏头痛急性和预防性治疗的成功药物，这些药物在所有年龄段和性别中均有效。
免疫组织化学用于检测和定位蛋白质，通过 ELISA 研究 CGRP 和 PACAP 的释放，并用大鼠和人动脉段进行肌电图/灌注血管造影术。
ERα 在整个大脑和几个与偏头痛相关的结构中均有发现。ERβ 主要存在于海马体和小脑。在三叉神经节（TG）中，ERα 存在于神经元的核内；这些神经元在细胞质中表达 CGRP 或 CGRP 受体。G 蛋白 ER（GPER）在大多数 TG 神经元的细胞膜和细胞质中被观察到。我们比较了来自雄性和雌性的 TG，发现雌性表达的 ER 受体更多。对于神经肽释放，唯一可观察到的差异是发情前期的 CGRP 释放基线高于发情期。在大脑中动脉（MCA）中，我们观察到雄性和雌性之间的 ER 反应性扩张存在相似的差异，除了我们仅在雌性动脉中观察到的血管扩张性 ERβ。
这些数据显示雄性和雌性大鼠之间 ER 受体表达存在显著差异。这与 CGRP 和 PACAP 释放形成对比，我们没有观察到性别之间的明显差异。总的来说，这表明雌激素可能对三叉神经神经元功能具有调节作用，而不是对急性 CGRP 释放机制和血管运动反应具有调节作用。
