Decreasing allopregnanolone with 5-alpha reductase inhibitors as treatment for pre-menstrual dysphoric disorder

The researchers discuss fluctuations (rather than absolute concentration) of allopregnanolone (5a-THP) as an underlying factor which precipitates pre-menstrual dysphoric disorder.

Dutasteride was used in an attempt to mitigate PMDD symptoms by stabilizing allopregnanolone levels.

Interestingly, irritability, sadness, anxiety, mood swings, food cravings, bloating, decreased sexual interest, and breast pain were assessed prior to treatment and only reductions in irritability, sadness, anxiety, food cravings, and bloating were reported as benefits of dutasteride treatment.

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Premenstrual dysphoric disorder (PMDD) is characterized by distressing mood and behavioral symptoms that occur during the luteal phase of the normal menstrual cycle and disappear within a few days after menses begin (American Psychiatric Association, 1994; American Psychiatric Association, 2013). No abnormalities of ovarian hormone levels consistently identify women with PMDD (Rubinow and Schmidt, 2006). Nonetheless, GnRH agonist-induced ovarian suppression in women with PMDD eliminates symptoms, which can then be precipitated by the administration of physiologic doses of ovarian steroids (Schmidt et al, 1998). Reproductive steroids, therefore, appear to have a role in PMDD.

The ring-A-reduced neurosteroid metabolite of progesterone, allopregnanolone (ie, 3 α -hydroxy-5 α -pregnan-20-one), potentially mediates the symptom precipitating effects of progesterone in PMDD. Allopregnanolone regulates central GABA-A receptor function and hence CNS excitation (Majewska et al, 1986; Paul and Purdy, 1992; Maguire et al, 2005; Shen et al, 2007). In one study, higher plasma levels of allopregnanolone was associated with less severe PMDD symptoms (Wang et al, 1996); however, abnormal plasma allopregnanolone levels have not been consistently observed in PMDD (Schmidt et al, 1994; Wang et al, 1996; Rapkin et al, 1997; Monteleone et al, 2000; Epperson et al, 2002; Lombardi et al, 2004; Schiller et al, 2014). Preclinical studies indicate that the impact of neurosteroids on the GABA receptor is mediated by changes in their levels rather than their absolute concentration. Both increases and decreases in progesterone metabolite neurosteroids induce changes in the alpha 4 subunit conformation of the GABAA R sufficient to produce anxiety-like behaviors (Gulinello et al, 2001; Gulinello and Smith, 2003; Shen et al, 2005). Thus, it is possible that effects of progesterone to precipitate PMDD symptoms (Schmidt et al, 1998) could be mediated by changes in allopregnanolone and/or an abnormal conversion of progesterone to its neurosteroid metabolites.

In this study, we attempted to stabilize allopregnanolone levels in women with PMDD by blocking its formation from progesterone with the 5 α -reductase (type 1 and 2) competitive inhibitor dutasteride. We hypothesized that this would abrogate the luteal phase increase in allopregnanolone levels resulting from increased progesterone secretion (Schmidt et al, 1994) and thus prevent PMDD symptoms. We also examined the effects of dutasteride in control women who did not experience menstrual cycle-related mood or behavioral symptoms.

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