5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder

Abstract

Changes in neurosteroid levels during the luteal phase of the menstrual cycle may precipitate affective symptoms. To test this hypothesis, we stabilized neurosteroid levels by administering the 5α-reductase inhibitor dutasteride to block conversion of progesterone to its neurosteroid metabolite allopregnanolone in women with premenstrual dysphoric disorder (PMDD) and in asymptomatic control women. Sixteen women with prospectively confirmed PMDD and 16 control women participated in one of two separate randomized, doubleblind, placebo-controlled, cross-over trials, each lasting three menstrual cycles. After one menstrual cycle of single-blind placebo, participants were randomized to receive, for the next two menstrual cycles, either double-blind placebo or dutasteride (low-dose 0.5 mg/ day in the first eight PMDD and eight control women or high-dose 2.5 mg/day in the second group of women). All women completed the daily rating form (DRF) and were evaluated in clinic during the follicular and luteal phases of each menstrual cycle. Main outcome measures were the DRF symptoms of irritability, sadness, and anxiety. Analyses were performed with SAS PROC MIXED. In the low-dose group, no significant effect of dutasteride on PMDD symptoms was observed compared with placebo (ie, symptom cyclicity maintained), and plasma allopregnanolone levels increased in women with PMDD from follicular to the luteal phases, suggesting the absence of effect of the lowdose dutasteride on 5α-reductase. In contrast, the high-dose group experienced a statistically significant reduction in several core PMDD symptoms (ie, irritability, sadness, anxiety, food cravings, and bloating) on dutasteride compared with placebo. Dutasteride had no effect on mood in controls. Stabilization of allopregnanolone levels from the follicular to the luteal phase of the menstrual cycle by blocking the conversion of progesterone to its 5α-reduced neurosteroid metabolite mitigates symptoms in PMDD. These data provide preliminary support for the pathophysiologic relevance of neurosteroids in this condition.

Premenstrual Dysphoric Disorder Symptoms Following Ovarian Suppression: Triggered by Change in Ovarian Steroid Levels But Not Continuous Stable Levels

“…Additionally it is possible given the findings by Segebladh (28) that low dose estradiol alone could be employed for some women with PMDD with proper monitoring of the endometrium. Finally, preliminary findings from a small trial of the 5-alpha reductase inhibitor dutasteride suggested that preventing the luteal phase increase in allopregnanolone levels mitigates symptoms in PMDD (16). Thus, treatment strategies to attenuate or eliminate the change in estradiol and progesterone (or their metabolites) could effectively target the hormonal trigger in this condition.…”

“…Second, re-exposure to physiologic doses of either estradiol or progesterone (but not placebo) for four weeks duration resulted in a recurrence of PMDD symptoms after 2–3 weeks of exposure in women with PMDD whose symptoms remitted after GnRH agonist treatment (controls who participated in an identical hormone manipulation study were not symptomatic) (14). Finally, inhibition of the luteal phase increase in the progesterone metabolite allopregnanolone with dutasteride, a 5alpha-reductase inhibitor, mitigated symptom emergence in PMDD (16). …”

Treatment of Premenstrual Dysphoric Disorder: Therapeutic Challenges

“…The rapid efficacy of selective serotonin reuptake inhibitors (SSRIs) in PMDD may be due in part to their ability to increase ALLO levels in the brain and enhance GABA A receptor function with a resulting decrease in anxiety. A recent study with a 5α-reductase inhibitor dutasteride, that blocks the conversion of progesterone to ALLO, reported that dutasteride 2.5 mg daily decreased several premenstrual symptoms [7]. A preliminary unpublished study reported a decrease in premenstrual symptoms with isoallopregnanolone, an ALLO antagonist [6].…”

“…Future studies are indicated to systematically compare the efficacy and predictors of response to symptom-onset, luteal phase, and continuous daily SSRI dosing in women with PMDD. It is possible that the irritability/ anger/mood swings subtype of PMDD is differentially responsive to treatments that lead to a quick change in ALLO availability or function, for example, symptomonset SSRI [11] or dutasteride [7]. Women with prominent depressive symptoms or physical symptoms may require longer duration of SSRI treatment during the cycle [5].…”

“…the amygdala) and blunted top-down inhibition from frontocingulate cortical regions [8]. The differential sensitivity is likely in part genetically determined, with possible genetic polymorphisms in genes coding for serotonergic and BDNF function [8], type 1 5α-reductase [7], or the estrogen receptor alpha 1 [5].…”