5α-Reductases In Human Physiology: an Unfolding Story

      ABSTRACT

      Objective

      5a-reductases are a family of isozymes expressed in a wide host of tissues including the central nervous system (CNS) and play a pivotal role in male sex ual differentiation, development and physiology.

      Methods

      A comprehensive literature search from 1970 to 2011 was made through PubMed and the relevant information was summarized.

      Results

      5a reductases convert testosterone, proges terone, deoxycorticosterone, aldosterone and corticoste rone into their respective 5a-dihydro-derivatives, which serve as substrates for 3a-hydroxysteroid dehydrogenase enzymes. The latter transforms these 5a-reduced metabo lites into a subclass of neuroactive steroid hormones with distinct physiological functions. The neuroactive steroid hormones modulate a multitude of functions in human physiology encompassing regulation of sexual differen tiation, neuroprotection, memory enhancement, anxiety, sleep and stress, among others. In addition, 5a -reductase type 3 is also implicated in the N-glycosylation of pro teins via formation of dolichol phosphate. The family of 5a-reductases was targeted for drug development to treat pathophysiological conditions, such as benign prostatic hyperplasia and androgenetic alopecia. While the clinical use of 5a-reductase inhibitors was well established, the scope and the magnitude of the adverse side effects of such drugs, especially on the CNS, is still unrecognized due to lack of knowledge of the various physiological functions of this family of enzymes, especially in the CNS.

      Conclusion

      There is an urgent need to better under stand the function of 5a-reductases and the role of neuro active steroids in human physiology in order to minimize the potential adverse side effects of inhibitors targeting 5a-reductases to treat benign prostatic hyperplasia and androgenic alopecia. (Endocr Pract. 2012;18:965-975)
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