5α-Reductase inhibitors alter steroid metabolism and may contribute to insulin resistance, diabetes, metabolic syndrome and vascular disease: a medical hypothesis

Abstract

5α-reductases, a unique family of enzymes with a wide host of substrates and tissue distributions, play a key role in the metabolism of androgens, progestins, mineralocorticoids and glucocorticoids. These enzymes are the rate-limiting step in the synthesis of a host of neurosteroids, which are critical for central nervous system function. Androgens and glucocorticoids modulate mitochondrial function, carbohydrate, protein and lipid metabolism and energy balance. Thus, the inhibition of these regulatory enzymes results in an imbalance in steroid metabolism and clearance rates, which leads to altered physiological processes. In this report, we advance the hypothesis that inhibition of 5α-reductases by finasteride and dutasteride alters not only steroid metabolism but also interferes with the downstream actions and signaling of these hormones. We suggest that finasteride and dutasteride inhibit 5α-reductase activities and reduce the clearance of glucocorticoids and mineralocorticoids, potentiating insulin resistance, diabetes and vascular disease.

Finasteride, not tamsulosin, increases severity of erectile dysfunction and decreases testosterone levels in men with benign prostatic hyperplasia

“…This finding suggests that inhibition of 5α-Rs in liver brings about biochemical changes in liver function and may represent alterations in liver metabolism [90][91][92]. In addition, finasteride inhibits not only type 2 but also type 1 5α-reductase, albeit at a slower rate, suggesting that this drug may alter liver function via inhibition of 5α-reductases types 1 and 2 [93][94].…”

Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?

“…Since no treatment of hypogonadism were implemented in the BPH patients in such studies, it remains difficult to ascertain the nature of the adverse sexual side effects. Although review of the literature reported serious concerns about the potential side effect of 5α-RIs therapy [23], such concerns were not heeded. In fact, many continue to argue that since clinical trial reports did not show significant adverse effects, the drug is deemed safe and effective.…”

“…GCs are metabolized by reduction of the A ring via 5α-Rs and then cleared via specific pathways involving conjugation and excretion. The principal urinary metabolites of cortisol and cortisone are tetrahydrocortisol and tetrahydrocortisone, cortols and cortolones [23].…”

“…5α-and 5β-Rs, 6β -hydroxylases, 20-reductases, and 11 β-hydroxy-steroid dehydrogenases (11β-HSD) are key enzymes involved in GCs metabolism and clearance mechanisms [23]. The majority of cortisol is inactivated, principally via the A-ring reduced metabolites, on a single pass through the liver [24].…”

“…An editorial following the report by Belknap [89] has highlighted the need to re-think the safety of these drugs [90]. The following section summarizes preclinical and clinical evidence documenting how finasteride and dutasteride may impair sexual function, including sexual desire, erectile, ejaculation and orgasmic function [23,[91][92][93][94][95].…”