VA National Center for PTSD Women's Health Science Division, Boston, MA, 02130, United States; VA Boston Healthcare System, Boston, MA, 02130, United States; Boston University School of Medicine, Boston, MA, 02118, United States.
VA National Center for PTSD Women's Health Science Division, Boston, MA, 02130, United States; VA Boston Healthcare System, Boston, MA, 02130, United States; Boston University School of Medicine, Boston, MA, 02118, United States.
Psychoneuroendocrinology. 2019 Apr;102:95-104. doi: 10.1016/j.psyneuen.2018.11.027. Epub 2018 Nov 22.
Allopregnanolone and pregnanolone (together termed allo + pregnan) are neurosteroid metabolites of progesterone that equipotently facilitate the action of gamma-amino-butyric acid (GABA) at GABA receptors. The adrenal steroid dehydroepiandrosterone (DHEA) allosterically antagonizes GABA receptors and facilitates N-methyl-D-aspartate (NMDA) receptor function. In prior research, premenopausal women with posttraumatic stress disorder (PTSD) displayed low cerebrospinal fluid (CSF) levels of allo + pregnan [undifferentiated by the gas chromatography-mass spectrometry (GC-MS) method used] that correlated strongly and negatively with PTSD reexperiencing and negative mood symptoms. A PTSD-related decrease in the ratio of allo + pregnan to 5α-dihydroprogesterone (5α-DHP: immediate precursor for allopregnanolone) suggested a block in synthesis of these neurosteroids at 3α-hydroxysteroid dehydrogenase (3α-HSD). In the current study, CSF was collected from unmedicated, tobacco-free men with PTSD (n = 13) and trauma-exposed healthy controls (n = 17) after an overnight fast. Individual CSF steroids were quantified separately by GC-MS. In the men with PTSD, allo + pregnan correlated negatively with Clinician-Administered PTSD Scale (CAPS-IV) total (ρ=-0.74, p = 0.006) and CAPS-IV derived Simms dysphoria cluster (ρ=-0.71, p = 0.01) scores. The allo+pregnan to DHEA ratio also was negatively correlated with total CAPS (ρ=-0.74, p = 0.006) and dysphoria cluster (ρ=-0.79, p = 0.002) scores. A PTSD-related decrease in the 5α-DHP to progesterone ratio indicated a block in allopregnanolone synthesis at 5α-reductase. This study suggests that CSF allo + pregnan levels correlate negatively with PTSD and negative mood symptoms in both men and women, but that the enzyme blocks in synthesis of these neurosteroids may be sex-specific. Consideration of sex, PTSD severity, and function of 5α-reductase and 3α-HSD thus may enable better targeting of neurosteroid-based PTSD treatments.
所有孕烷醇酮和孕烷醇（统称 allo + 孕烷）是孕酮的神经甾体代谢物，可等效促进 γ-氨基丁酸（GABA）在 GABA 受体上的作用。肾上腺类固醇脱氢表雄酮（DHEA）变构拮抗 GABA 受体并促进 N-甲基-D-天冬氨酸（NMDA）受体功能。在之前的研究中，患有创伤后应激障碍（PTSD）的绝经前妇女的脑脊液（CSF）中 allo + 孕烷水平较低[使用气相色谱-质谱（GC-MS）方法未区分]，与 PTSD 再体验和负性情绪症状呈强烈负相关。 allo + 孕烷与 5α-二氢孕酮（5α-DHP：allopregnanolone 的直接前体）的比值降低表明这些神经甾体的合成在 3α-羟甾脱氢酶（3α-HSD）处受阻。在当前的研究中，从经过一夜禁食的未接受药物治疗的无吸烟的 PTSD 男性（n = 13）和创伤暴露的健康对照者（n = 17）中采集 CSF。通过 GC-MS 分别单独定量个体 CSF 类固醇。在 PTSD 男性中，allo + 孕烷与临床医生管理的 PTSD 量表（CAPS-IV）总分（ρ=-0.74，p=0.006）和 CAPS-IV 衍生的 Simms 烦躁集群（ρ=-0.71，p=0.01）呈负相关。 allo + pregna 与 DHEA 的比值也与总 CAPS（ρ=-0.74，p=0.006）和烦躁集群（ρ=-0.79，p=0.002）呈负相关。 5α-DHP 与孕酮的比值降低表明 allopregnanolone 合成在 5α-还原酶处受阻。这项研究表明，CSF allo + 孕烷水平与男性和女性的 PTSD 和负性情绪症状呈负相关，但这些神经甾体合成中的酶阻滞可能是性别特异性的。因此，考虑性别、PTSD 严重程度以及 5α-还原酶和 3α-HSD 的功能，可能会更好地针对基于神经甾体的 PTSD 治疗。
