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Effects of GABA active steroids in the female brain with a focus on the premenstrual dysphoric disorder
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.ORCID iD: 0000-0002-4988-1967
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
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2018 (English)In: Journal of neuroendocrinology (Print), ISSN 0953-8194, E-ISSN 1365-2826, Vol. 30, no 2, article id e12553Article in journal (Refereed) Published
Abstract [en]

Premenstrual dysphoric disorder (PMDD) afflicts 3%-5% of women of childbearing age, and is characterised by recurrent negative mood symptoms (eg, irritability, depression, anxiety and emotional lability) during the luteal phase of the menstrual cycle. The aetiology of PMDD is unknown, although a temporal association with circulating ovarian steroids, in particular progesterone and its metabolite allopregnanolone, has been established during the luteal phase. Allopregnanolone is a positive modulator of the GABA(A) receptor: it is sedative in high concentrations but may precipitate paradoxical adverse effects on mood at levels corresponding to luteal phase concentrations in susceptible women. Saccadic eye velocity (SEV) is a measure of GABA(A) receptor sensitivity; in experimental studies of healthy women, i.v. allopregnanolone decreases SEV. Women with PMDD display an altered sensitivity to an i.v. injection of allopregnanolone compared to healthy controls in this model. In functional magnetic resonance imaging (fMRI) studies, women with PMDD react differently to emotional stimuli in contrast to controls. A consistent finding in PMDD patients is increased amygdala reactivity during the luteal phase. Post-mortem studies in humans have revealed that allopregnanolone concentrations vary across different brain regions, although mean levels in the brain also reflect variations in peripheral serum concentrations. The amygdala processes emotions such as anxiety and aggression. This is interesting because allopregnanolone is detected at high concentrations within the region into which marked increases in blood flow are measured with fMRI following progesterone/allopregnanolone administration. Allopregnanolone effects are antagonised by its isomer isoallopregnanolone (UC1010), which significantly reduces negative mood symptoms in women with PMDD when administered s.c. in the premenstrual phase. This was shown in a randomised, placebo-controlled clinical trial in which the primary outcome was change in symptom scoring on the Daily Rating of Severity of Problems (DRSP): the treatment reduced negative mood scores (P<.005), as well as total DRSP scores (P<.01), compared to placebo in women with PMDD. In conclusion, the underlying studies of this review provide evidence that allopregnanolone is the provoking factor behind the negative mood symptoms in PMDD and that isoallopregnanolone could ameliorate the symptoms as a result of its ability to antagonise the allopregnanolone effect on the GABA(A) receptor.

Place, publisher, year, edition, pages
2018. Vol. 30, no 2, article id e12553
Keywords [en]
GABA, neuroactive steroids, premenstrual dysphoric disorder
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
URN: urn:nbn:se:umu:diva-145601DOI: 10.1111/jne.12553ISI: 000425521300018OAI: oai:DiVA.org:umu-145601DiVA, id: diva2:1194178
Conference
9th International Meeting on Steroids and Nervous System, FEB 11-15, 2017, Torino, ITALY
Available from: 2018-03-29 Created: 2018-03-29 Last updated: 2018-06-09Bibliographically approved

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Bixo, MarieJohansson, MajaTimby, ErikaMichalski, LouiseBäckström, Torbjörn

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