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

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 41; no. 4; pp. 1093 - 1102
• Main Authors: Martinez, Pedro E, Rubinow, David R, Nieman, Lynnette K, Koziol, Deloris E, Morrow, A Leslie, Schiller, Crystal E, Cintron, Dahima, Thompson, Karla D, Khine, Khursheed K, Schmidt, Peter J
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01-03-2016
• Subjects: 5-alpha Reductase Inhibitors - administration & dosage; Adult; Androsterone - blood; Cholestenone 5 alpha-Reductase - physiology; Double-Blind Method; Dutasteride - administration & dosage; Female; Humans; Luteal Phase - blood; Middle Aged; Original; Pregnanolone - blood; Pregnenolone - blood; Premenstrual Dysphoric Disorder - blood; Premenstrual Dysphoric Disorder - enzymology; Premenstrual Dysphoric Disorder - psychology; Severity of Illness Index; Single-Blind Method
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2015.246

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, double-blind, 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 low-dose 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.