Department of Psychiatry, University of Illinois at Chicago College of Medicine, Chicago, IL, United States.
Department of Psychiatry & Behavioral Sciences, The Johns Hopkins University School of Medicine, 550 N. Broadway Street, Baltimore, MD, United States.
Psychoneuroendocrinology. 2024 Nov;169:107145. doi: 10.1016/j.psyneuen.2024.107145. Epub 2024 Jul 24.
Premenstrual dysphoric disorder (PMDD) is characterized by severe affective symptoms during the luteal phase of the menstrual cycle. There is some evidence of altered interactions between the hypothalamic pituitary gonadal (HPG) and hypothalamic pituitary adrenal (HPA) axes in PMDD. There is also evidence that similar affective disorders such as major depression and perinatal depression are associated with dysregulation in immune factors, but this has not been characterized in PMDD.
The goals of this exploratory study were to identify 1) whether HPA-HPG axis interactions and immune markers differ between PMDD patients and controls across the menstrual cycle; 2) how luteal phase sertraline treatment impacts stress and inflammatory markers.
Participants were females age 18-50 with regular menstrual cycles, not using psychotropic or hormonal medications, and were assigned to a control group or PMDD group based on prospective daily symptom ratings and clinical interview. Blood was drawn in the follicular and luteal phases, during laboratory sessions involving a mildly stressful task. In a second luteal phase, PMDD participants received open-label sertraline (50 mg/d) from ovulation to menses. Serum cortisol and ACTH were measured via ELISA and operationalized as area under the curve with respect to ground (AUCg), and peak level following laboratory task. Serum TNF-α, IL-6, CXCL-8, and IL-1β were measured using multiplex kits. Serum allopregnanolone (ALLO) was measured by gas chromatography/mass spectroscopy. To characterize HPA-HPG axis interactions across the menstrual cycle in PMDD participants and controls, multilevel linear models predicted cortisol and ACTH from the interaction of cycle phase (controlling for sertraline treatment), ALLO, and group. To determine the effects of sertraline treatment on inflammatory markers and how groups might differ in cyclical change on each marker, multilevel linear models predicted inflammatory markers from cycle phase (controlling for sertraline treatment) and group. A final set of exploratory models tested whether inflammatory markers predict premenstrual symptom score severity.
The sample included n=77 participants (41 controls, 36 PMDD); 28 participants with PMDD completed sertraline treatment. Group x phase x ALLO interactions showed that higher ALLO levels predicted lower cortisol peak in the treated luteal phase (interaction between phase and ALLO, p=0.042), and there was a higher cortisol peak in the treated luteal phase than the untreated luteal phase (p=0.038). CXCL-8 was significantly associated with premenstrual symptom severity after controlling for group and cycle phase (p=0.011). There were no main effects of group, phase, or ALLO on cortisol AUCg, ACTH AUCg, IL-6, CXCL-8, IL-1β, nor TNF-α (p's>0.05).
Serum markers of HPA axis and immune function did not vary by menstrual cycle phase nor PMDD status. However, sertraline treatment in the luteal phase was associated with higher ALLO levels predicting lower cortisol peak in response to mild laboratory stress, suggesting that sertraline treatment may normalize HPG-HPA axis interactions among individuals with PMDD. Greater premenstrual symptomatology was associated with higher levels of the inflammatory marker CXCL-8, but further research is needed into the potential role of inflammation in PMDD.
经前期烦躁障碍（PMDD）的特征是在月经周期的黄体期出现严重的情感症状。有一些证据表明，PMDD 患者的下丘脑-垂体-性腺（HPG）和下丘脑-垂体-肾上腺（HPA）轴之间的相互作用发生了改变。也有证据表明，类似的情感障碍，如重度抑郁症和围产期抑郁症与免疫因子的失调有关，但这在 PMDD 中尚未得到描述。
本探索性研究的目的是确定 1）在整个月经周期中，PMDD 患者和对照组之间的 HPA-HPG 轴相互作用和免疫标志物是否存在差异；2）黄体期舍曲林治疗如何影响应激和炎症标志物。
参与者为年龄在 18-50 岁之间、月经周期规律、不使用精神药物或激素药物的女性，并根据前瞻性每日症状评分和临床访谈被分配到对照组或 PMDD 组。在卵泡期和黄体期采集血液，在此期间参与者要参与一个轻度应激的实验室任务。在第二个黄体期，PMDD 参与者从排卵到月经开始接受开放标签舍曲林（50mg/d）治疗。通过 ELISA 测量血清皮质醇和促肾上腺皮质激素（ACTH），并以 AUCg（相对于基础）和实验室任务后峰值水平来表示。使用多重试剂盒测量血清 TNF-α、IL-6、CXCL-8 和 IL-1β。通过气相色谱/质谱法测量血清孕烷二醇（ALLO）。为了描述 PMDD 患者和对照组在整个月经周期中 HPA-HPG 轴的相互作用，使用多水平线性模型预测了皮质醇和 ACTH 与周期阶段（控制舍曲林治疗）、ALLO 和组之间的相互作用。为了确定舍曲林治疗对炎症标志物的影响，以及两组在每个标志物的周期性变化上可能存在的差异，使用多水平线性模型预测了炎症标志物与周期阶段（控制舍曲林治疗）和组之间的关系。最后一组探索性模型测试了炎症标志物是否可以预测经前期症状评分的严重程度。
该样本包括 n=77 名参与者（41 名对照组，36 名 PMDD）；28 名 PMDD 患者完成了舍曲林治疗。组 x 期 x ALLO 相互作用表明，较高的 ALLO 水平预测了治疗黄体期皮质醇峰值的降低（期与 ALLO 之间的相互作用，p=0.042），并且治疗黄体期的皮质醇峰值高于未治疗黄体期（p=0.038）。在控制了组和周期阶段后，CXCL-8 与经前期症状严重程度显著相关（p=0.011）。组、期或 ALLO 对皮质醇 AUCg、ACTH AUCg、IL-6、CXCL-8、IL-1β和 TNF-α均无主要影响（p＞0.05）。
血清 HPA 轴和免疫功能标志物的变化与月经周期阶段或 PMDD 状态无关。然而，黄体期舍曲林治疗与较高的 ALLO 水平相关，这表明 HPG-HPA 轴相互作用可能在 PMDD 患者中得到了正常化。更高的经前期症状与更高水平的炎症标志物 CXCL-8 相关，但需要进一步研究炎症在 PMDD 中的潜在作用。
