PTSD in women is associated with a block in conversion of progesterone to the GABAergic neurosteroids allopregnanolone and pregnanolone measured in plasma

•There is a PTSD-related block in ALLO synthesis at 3α-HSD.•The present study confirmed this finding in plasma.•Ability to measure ALLO in plasma is important for use in clinical care. There is a need to identify new and more effective treatments for posttraumatic stress disorder (PTSD). Allopregnan...

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Published in:	Psychoneuroendocrinology Vol. 93; pp. 133 - 141
Main Authors:	Pineles, S.L., Nillni, Y.I., Pinna, G., Irvine, J., Webb, A., Arditte Hall, K.A., Hauger, R., Miller, M.W., Resick, P.A., Orr, S.P., Rasmusson, A.M.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-07-2018
Subjects:	Allopregnanolone Neurosteroid Posttraumatic stress disorder Pregnanolone Progesterone PTSD PTSD Neurosteroid Posttraumatic stress disorder Progesterone Pregnanolone Allopregnanolone
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Summary:	•There is a PTSD-related block in ALLO synthesis at 3α-HSD.•The present study confirmed this finding in plasma.•Ability to measure ALLO in plasma is important for use in clinical care. There is a need to identify new and more effective treatments for posttraumatic stress disorder (PTSD). Allopregnanolone and its stereoisomer pregnanolone (together termed ALLO) are metabolites of progesterone that positively and allosterically modulate GABA effects at GABAA receptors, thereby reducing anxiety and depression. Previous research revealed that women with PTSD had low cerebrospinal fluid (CSF) ALLO levels and a low ratio of ALLO to the allopregnanolone precursor 5α-DHP, consistent with deficient activity of the ALLO synthetic enzyme 3α-hydroxysteroid dehydrogenase (3α-HSD). The current study examined ALLO and the ratio of ALLO to 5α-DHP in plasma at rest and in response to psychophysiological stressors in trauma-exposed, medication-free women with and without PTSD. Participants were examined twice in random order during the early follicular phase (eFP) and mid-luteal phase (mLP) of the menstrual cycle. Plasma neurosteroids were measured using gas chromatography-mass spectrometry. Results indicate that the ALLO to 5α-DHP ratio in plasma increases between the eFP and mLP. In addition, women with PTSD have a lower ratio of ALLO to 5α-DHP than trauma-exposed healthy women, as well as blunted increases in this ratio in response to a moderately stressful laboratory procedure, i.e., differential fear conditioning, across the menstrual cycle. Clinically feasible testing for 3α-HSD dysfunction is critical to translating this line of research into clinical care. Measurement of this ratio in plasma could facilitate patient stratification in clinical treatment trials, as well as precision medicine targeting of treatments that address ALLO synthesis deficits in women with PTSD.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0306-4530 1873-3360
DOI:	10.1016/j.psyneuen.2018.04.024