Effect of Finasteride, an Inhibitor of the Enzyme 5alpha-Reductase, in the Nervous System

Program: Abstracts - Orals, Poster Previews, and Posters
Session: SUN 203-235-Steroid Hormone Actions, Biosynthesis and Metabolism (posters)
Bench to Bedside
Sunday, April 3, 2016: 1:15 PM-3:15 PM
Exhibit/Poster Hall (BCEC)

Poster Board SUN 226
Roberto Cosimo Melcangi*, Donatella Caruso, Marzia Pesaresi, Simone Romano, Silvia Diviccaro and Silvia Giatti
Università degli Studi di Milano, Milano, Italy
Finasteride is a commercially available 5alpha-reductase (5alpha-R) reversible inhibitor. This molecule blocks the conversion of progesterone and testosterone into dihydroprogesterone and dihydrotestosterone, respectively. These neuroactive steroids, as well as their further metabolites, are important mediators for many physiological processes in the nervous system, affecting mood, behavior, reproduction, and cognition (1, 2). Moreover, neuroactive steroids act as protective agents in different experimental models of neurodegeneration (1, 2). Therefore, the enzymatic conversion mediated by 5alpha-R exerts a crucial role in the nervous system. However, despite of the wide therapeutic use of this inhibitor (e.g., human benign prostatic hyperplasia and androgenic alopecia), the effects of finasteride per se in the nervous system have been poorly explored. This aspect could be important, particularly because observations performed in a subset of man taking finasteride for androgenic alopecia show sexual dysfunction as well as anxious/depressive symptomatology. Very important, these side-effects were also reported in a subset of patients after discontinuation of the therapy (3). Interestingly, these patients also showed altered neuroactive steroid levels in plasma and cerebrospinal fluid (CSF) in comparison to healthy individuals (4, 5).

On this basis, we have evaluated in male rats the effects of a subchronic treatment with low doses of finasteride (i.e., 3mg/kg/day for 20 days) and the consequences of its withdrawal (i.e., evaluated 1 month after the last treatment) on neuroactive steroid levels assessed by liquid chromatography tandem mass spectrometry in plasma, CSF, cerebellum, cerebral cortex and hippocampus. Moreover, the expression of androgen, estrogen and progesterone receptors as well as of GABA-A receptor subunits (i.e., alpha 2, alpha 4, beta 3, delta and gamma 2) in brain areas were analyzed. Data obtained indicate that, after subchronic treatment, depending on the compartment considered, alteration in the levels of neuroactive steroids was observed. Moreover, increased expression of androgen receptor in the cerebral cortex and beta3 subunit of GABA-A receptor in the cerebellum was reported. Interestingly, at the withdrawal some of these effects persisted and different changes in neuroactive steroid levels, and in the expression of receptors were also detected. Altogether these findings suggest that the block of the enzyme 5alpha-reductase by finasteride treatment may have broad consequences for the nervous system.

(1) Melcangi et al., Cell Mol Life Sci 2008; 65:777-797.  (2) Giatti et al., J Steroid Biochem Mol Biol 2015; 153:127-134. (3) Traish et al., Rev Endocr Metab Disord, 2015; DOI 10.1007/s11154-015-9319-y. (4) Melcangi et al., J Sex Med 2013; 10: 2598-2603. (5) Caruso et al., J Steroid Biochem Mol Biol 2015; 146: 74-79.

Nothing to Disclose: RCM, DC, MP, SR, SD, SG

*Please take note of The Endocrine Society's News Embargo Policy at https://www.endocrine.org/news-room/endo-annual-meeting/pr-resources-for-endo

Sources of Research Support: Post-Finasteride Foundation