University of Illinois at Chicago, Dept of Psychiatry, 912 S Wood St, Chicago, IL 60612, USA.
University of Illinois at Chicago, Dept of Psychiatry, 912 S Wood St, Chicago, IL 60612, USA.
Psychoneuroendocrinology. 2023 Nov;157:106359. doi: 10.1016/j.psyneuen.2023.106359. Epub 2023 Aug 9.
In ovulating psychiatric patients experiencing suicidality, suicidal ideation (SI) often peaks perimenstrually. Our recent double-blind, placebo-controlled, crossover randomized clinical trial (RCT; NCT03720847) showed that perimenstrual administration of estradiol and progesterone (EP) can prevent this peak in SI and depressed mood. In this pre-registered follow-up analysis, we studied how the menstrual cycle and experimental manipulation affected two neurobiological systems associated with the menstrual cycle and suicide risk: GABAergic neuroactive steroids (NAS) and peripheral cytokines.
In 26 psychiatric outpatients with natural menstrual cycles and past-month SI, we analyzed serum samples from three blood draws (midluteal, perimenstrual, midfollicular) per experimental condition (EP vs placebo) timed to a luteinizing hormone-surge ovulation test. Using gas chromatography/mass spectrometry (GC/MS), we measured the progesterone (P4)-derived pregnane NAS (3α,5α)- 3-hydroxypregnan20-one (3α,5α-THP), (3α,5β)- 3-hydroxypregnan-20-one (3α,5β-THP), (3α,5α)- 3,21-dihydroxypregnan-20-one (3α,5α-THDOC), (3α,5α)- 3-hydroxyandrostan-17-one (3α,5α-A), the androstane NAS (3α,5β)- 3-hydroxyandrostan-17-one (3α,5β-A), (3α,5α,17β)-androstane-3,17-diol (3α,5α-A-diol), (3α,5β,17β)-androstane-3,17-diol (3α,5β-A-diol), and their precursor pregnenolone. High sensitivity multiplex assay kits quantified peripheral cytokines IL-1β, IL-6, and TNF-α.
P4-derived NAS fluctuated in parallel with P4 and increased with exogenous perimenstrual administration of EP. Conversely, androstane NAS either did not fluctuate or fluctuated inversely from P4, and these NAS decreased with exogenous EP. Peripheral cytokines did not show cyclical patterns, but each significantly predicted SI, depressed mood, or anxiousness. Concomitant SSRI medication use predicted lower androstane NAS.
While preliminary and exploratory, our findings provide critical descriptive context for future studies. Further, our work presents menstrual cycle-related patterns for ten frequently-studied biomarkers, allowing for improved quality of comparisons involving naturally-cycling populations in research.
在经历自杀意念的排卵期精神病患者中，自杀意念（SI）通常在经前期达到峰值。我们最近的一项双盲、安慰剂对照、交叉随机临床试验（RCT；NCT03720847）表明，经前期给予雌二醇和孕激素（EP）可以预防 SI 和抑郁情绪的这一峰值。在这项预先注册的后续分析中，我们研究了月经周期和实验操作如何影响与月经周期和自杀风险相关的两个神经生物学系统：GABA 能神经活性甾体（NAS）和外周细胞因子。
在 26 名有自然月经周期和过去一个月内有 SI 的精神病门诊患者中，我们分析了每个实验条件（EP 与安慰剂）下三次采血（黄体中期、经前期、卵泡中期）的血清样本，这些采血时间都与促黄体生成素激增排卵试验同步。我们使用气相色谱/质谱法（GC/MS）测量了由孕酮（P4）衍生的孕烷 NAS（3α,5α）-3-羟孕烷-20-酮（3α,5α-THP）、（3α,5β）-3-羟孕烷-20-酮（3α,5β-THP）、（3α,5α）-3,21-二羟孕烷-20-酮（3α,5α-THDOC）、（3α,5α）-3-羟基雄烷-17-酮（3α,5α-A）、雄烷 NAS（3α,5β）-3-羟基雄烷-17-酮（3α,5β-A）、（3α,5α,17β）-雄烷-3,17-二醇（3α,5α-A-二醇）、（3α,5β,17β）-雄烷-3,17-二醇（3α,5β-A-二醇）及其前体孕烯醇酮。使用高灵敏度多重检测试剂盒定量外周细胞因子 IL-1β、IL-6 和 TNF-α。
P4 衍生的 NAS 与 P4 平行波动，并随外源性经前期 EP 给药而增加。相反，雄烷 NAS 要么没有波动，要么与 P4 相反波动，并且这些 NAS 随外源性 EP 而减少。外周细胞因子没有表现出周期性模式，但每个细胞因子都显著预测 SI、抑郁情绪或焦虑。同时服用 SSRI 药物预测较低的雄烷 NAS。
虽然初步和探索性的，但我们的发现为未来的研究提供了重要的描述性背景。此外，我们的工作为十种经常研究的生物标志物提供了与月经周期相关的模式，这使得在涉及自然周期人群的研究中能够提高比较的质量。
