Posted 19 March 2012 - 07:53 PM
Finasteride is the first 5á-reductase inhibitor that received clinical approval for the treatment of human benign prostatic hyperplasia (BPH) and androgenetic alopecia (male pattern hair loss). These clinical applications are based on the ability of finasteride to in- hibit the Type II isoform of the 5á-reductase enzyme, which is the predominant form in human prostate and hair follicles, and the concomitant reduction of testosterone to dihyd- rotestosterone (DHT). In addition to catalyzing the rate-limiting step in the reduction of testosterone, both isoforms of the 5á-reductase enzyme are responsible for the reduction of progesterone and deoxycorticosterone to dihydroprogesterone (DHP) and dihydrode- oxycorticosterone (DHDOC), respectively. Recent preclinical data indicate that the subse- quent 3á-reduction of DHT, DHP and DHDOC produces steroid metabolites with rapid non-genomic effects on brain function and behavior, primarily via an enhancement of ã-aminobutyric acid (GABA)ergic inhibitory neurotransmission. Consistent with their ability to enhance the action of GABA at GABAA receptors, these steroid derivatives (termed neuroactive steroids) possess anticonvulsant, antidepressant and anxiolytic effects in addition to altering aspects of sexual- and alcohol-related behaviors. Thus, finasteride, which inhibits both isoforms of 5á-reductase in rodents, has been used as a tool to manip- ulate neuroactive steroid levels and determine the impact on behavior. Results of some preclinical studies and clinical observations with finasteride are described in this review article. The data suggest that endogenous neuroactive steroid levels may be inversely re-lated to symptoms of premenstrual and postpartum dysphoric disorder, catamenial epi- lepsy, depression, and alcohol withdrawal.
INTRODUCTION
Rapid membrane effects of steroid hormones provide a mechanism by which steroids can influence brain function and behavior in addition to their classic genomic actions. The pioneering studies of Hans Seyle first described the neuroactive properties of several steroidal compounds (128). The time course for action of the steroidal compounds was consistent with the idea that steroid metabolism produced the neuroactive compound(s). After the initial demonstration that the synthetic steroid alphaxalone potentiated GABA- gated chloride currents (67), strong evidence indicated that steroid metabolites have rapid membrane actions via an interaction with ligand-gated ion channels (8,13,93,102,123). Based on this evidence and consensus in the field, the term “neuroactive steroids” refers to the rapid membrane actions of steroids and their derivatives.
The progesterone metabolite allopregnanolone (3á,5á-THP or tetrahydroprogesterone) is the most potent endogenous positive modulator of GABAA receptors yet identified. Fluctuations in endogenous levels in vivo occur within the range of concentrations that po- tentiate GABAergic inhibition in vitro (8), and clinical and animal research show that these fluctuations can contribute to diverse disorders such as premenstrual and postpartum dysphoric disorder (37), catamenial epilepsy (68), depression (148), and alcohol with- drawal (118). The inverse relationship between endogenous 3á,5á-THP levels and anxiety, depression and seizure susceptibility is consistent with 3á,5á-THP’s pharmaco- logical profile, since exogenous administration produces anxiolytic, anticonvulsant and antidepressant effects (53,72).
Generally speaking, the two-step metabolism of testosterone, progesterone and deoxy- corticosterone yields neuroactive compounds through the actions of the enzymes 5á-re- ductase and 3á-hydroxysteroid dehydrogenase (20,94). The 5á-reduction of testosterone, progesterone and deoxycorticosterone (to produce DHT, DHP, and DHDOC, respectively) is unidirectional. In contrast, the 3á-reduction of DHT, DHP, and DHDOC (to produce androstanediol, 3á,5á-THP and tetrahydrodeoxycorticosterone or 5á-THDOC, respec- tively) is a reversible reaction. Hence, use of a 5á-reductase inhibitor can be considered a blockade of the rate-limiting step to the two-step production of neuroactive steroid metab- olites (see Fig. 1). Since androstanediol, 3á,5á-THP and 5á-THDOC all have higher po- tency at GABAA receptors than at androgen, progesterone or corticosteroid receptors, re- spectively, it is possible that inhibition of 5á-reductase would have consequences on central nervous system (CNS) inhibitory tone and resultant behavioral processes.
POTENTIAL IMPACT
ON BRAIN FUNCTION AND BEHAVIOR
Depression
This section will highlight preclinical research involving animal models of anxiety and depression and clinical investigations with findings relevant to depression.
Preclinical studies on anxiety- and depression-related behaviors
Numerous studies have documented that systemic administration of 3á,5á-THP pro- duces anxiolytic (53,75,111,155) and antidepressant effects (79). Co-administration of a 5á-reductase inhibitor (different than finasteride) with progesterone blocked its anxiolytic effect, providing evidence that the anxiolytic effect of progesterone was due to its metab- olism to 3á,5á-THP (12). Likewise, a similar strategy demonstrated that the anxiolytic effect of testosterone was mediated by its 5á-reduced metabolites (30). Microinjection studies have targeted the amygdala and hippocampus, brain regions thought to be relevant in anxiety and depression. Bilateral infusion of 3á,5á-THP into the dorsal hippocampus (11) or amygdala (14) produced anxiolytic effects, and intracerebroventricular adminis- tration of 3á,5á-THP generated antidepressant effects (72). In contrast, both systemic and intrahippocampal administration of finasteride increased depression- and anxiety-like be- haviors in rats (50,51). A subsequent study determined that finasteride increased depres- sion- and anxiety-like behaviors in rats when administered into the amygdala (152). Therefore, bi-directional manipulation of endogenous 3á,5á-THP levels in the amygdala and hippocampus ( with exogenous 3á,5á-THP or progesterone, ̄ endogenous synthesis with finasteride) produced opposite effects in animal models of anxiety and depression. These findings suggest that 3á,5á-THP levels may be inversely related to mood states.
Animal models of postpartum dysphoric disorder document that withdrawal from high levels of progesterone increased anxiety and seizure susceptibility concomitant with a re- duction in GABAA receptor function, and that blocking progesterone metabolism (and consequently, 3á,5á-THP formation) reduced these symptoms of “progesterone with- drawal” (129,130). The results from a recent mouse model of premenstrual dysphoric dis- order indicated that 3 daily injections of finasteride significantly decreased hippocampal 3á,5á-THP levels. This reduction in 3á,5á-THP levels was associated with a decrease in sensitivity to the anxiolytic effect of pregnanolone (3á,5â-THP), the 5â-isomer of 3á,5á- THP that also is a positive modulator of GABAA receptors with slightly less potency than 3á,5á-THP (131). While the array of symptoms and hormonal correlations reported for premenstrual dysphoric disorder in females suggest a diverse etiology, it has been sug- gested that the extent or rate of change in 3á,5á-THP levels might be more important than the absolute levels of this neuroactive steroid with regard to its contribution to dysphoric symptoms (39,131).
An inverse relationship between endogenous 3á,5á-THP levels and symptoms of anxiety andGor depression was reported in cohorts of male subjects with depression (148) or in the early phase of alcoholic withdrawal (118). Treatment with drugs that restored
CNS Drug Reviews, Vol. 12, No. 1, 20063á,5á-THP levels to those found in control subjects significantly reduced the symptoms of anxiety and depression in both the depressed and alcoholic subjects (119,120,134). Spe- cifically, drugs clinically employed for the treatment of depression, such as the selective serotonin reuptake inhibitors fluoxetine and paroxetine (63) and the atypical, third-gener- ation antidepressant mirtazepine (127), were found to increase 3á,5á-THP levels, albeit via different effects on the 3á-hydroxysteroid dehydrogenase enzyme. Whereas fluoxetine and paroxetine favor the enzymatic reduction of DHP (to form 3á,5á-THP), mirtazepine inhibits the oxidation of 3á,5á-THP (to form DHP). In summary, preclinical studies with finasteride and other drugs that alter 3á,5á-THP biosynthesis support a role for endog- enous 3á,5á-THP in maintaining normal GABAergic brain function, and suggest that al- terations in endogenous 3á,5á-THP levels could contribute to symptoms of anxiety and depression (84).
