Effects of GABA active steroids in the female brain with focus on the premenstrual dysphoric disorder

Abstract

PMDD (premenstrual dysphoric disorder) afflicts 3-5% of women of childbearing age, and is characterized by recurrent negative mood symptoms, e.g. irritability, depression, anxiety and emotional lability during the luteal phase of the menstrual cycle. The etiology of PMDD is unknown, but a temporal association with circulating ovarian steroids, in particular progesterone and its metabolite allopregnanolone, during the luteal phase has been established.

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, intravenous allopregnanolone decreases SEV. Women with PMDD display an altered sensitivity to an intravenous injection of allopregnanolone in comparison with healthy controls in this model.

In fMRI studies, women with PMDD react differently to emotional stimuli in contrast with 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, but mean levels in the brain also reflect variations in peripheral serum concentrations. The amygdala processes emotions such as anxiety and aggression, which is interesting since 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 antagonized by its isomer isoallopregnanolone (UC1010), which significantly reduces negative mood symptoms in women with PMDD when administered subcutaneously in the premenstrual phase. This was shown in a randomized, placebo-controlled clinical trial in which the primary outcome was change in symptom scoring on the DRSP (Daily Rating of Severity of Problems): the treatment reduced negative mood scores (p<0.005) as well as total DRSP scores (p<0.01) 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 due to its ability to antagonize the allopregnanolone effect on the GABA_A receptor.

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