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

Abstract

Steroids are important physiological orchestrators of endocrine as well as peripheral and central nervous system functions. One of the key processes for regulation of these molecules lies in their enzymatic processing by a family of 5α-reductase (5α-Rs) isozymes. By catalyzing a key rate-limiting step in steroidogenesis, this family of enzymes exerts a crucial role not only in the physiological control but also in pathological events. Indeed, both 5α-R inhibition and supplementation of 5α-reduced metabolites are currently used or have been proposed as therapeutic strategies for a wide array of pathological conditions. In particular, the potent 5α-R inhibitors finasteride and dutasteride are used in the treatments of benign prostatic hyperplasia (BPH), as well as in male pattern hair loss (MPHL) known as androgenetic alopecia (AGA). Recent preclinical and clinical findings indicate that 5α-R inhibitors evoke not only beneficial, but also adverse effects. Future studies should investigate the biochemical and physiological mechanisms that underlie the persistence of the adverse sexual side effects to determine why a subset of patients is afflicted with such persistence or irreversible adverse effects. Also a better focus of clinical research is urgently needed to better define those subjects who are likely to be adversely affected by such agents. Furthermore, research on the non-sexual adverse effects such as diabetes, psychosis, depression, and cognitive function are needed to better understand the broad spectrum of the effects these drugs may elicit during their use in treatment of AGA or BPH. In this review, we will summarize the state of art on this topic, overview the key unresolved questions that have emerged on the pharmacological targeting of these enzymes and their products, and highlight the need for further studies to ascertain the severity and duration of the adverse effects of 5α-R inhibitors, as well as their biological underpinnings.

Beneficial Effect of a Multifunctional Polyphytocompound in Experimental Prostatic Hyperplasia in Rats

“…Long before surgery may be required, well-known pharmacotherapeutic options are currently employed such as 5-alpha-reductase Inhibitors, alpha-adrenergic antagonists, anticholinergic agents and combination therapy [15,16]. Although these treatments have enabled consistent benefits [17][18][19], their use is associated to a different degree of side effects such as decreased libido, erectile dysfunction gynecomastia and poor ejaculatory function [20][21][22]. This limitation holds particularly relevant when very early cases of BPH are faced or when a tentative "preventive" strategy is planned.…”

Androgen receptor (AR) gene (CAG)n and (GGN)n length polymorphisms and symptoms in young males with long-lasting adverse effects after finasteride use against androgenic alopecia

“…7 Finasteride inhibits 5a-reductase, the enzyme responsible for the reduction of testosterone into dihydrotestosterone. 5 Finasteride against AGA (male pattern hair loss) is used at lower dosage (1 mg/d) than against benign prostatic hyperplasia (5 mg/d). Finasteride inhibits 5a-reductase type 2 and 3 enzymes much more strongly than the type 1 enzyme 8,9 ; therefore, finasteride can affect several different human tissues, 4,5,8,10 such as the prostate, muscle, liver, kidney, brain, mammary gland, frontal cortex, skin, epidermis, pancreas, spleen, heart, testicle, stomach, dermis, small intestine, and adipose tissues.…”

“…5 Finasteride against AGA (male pattern hair loss) is used at lower dosage (1 mg/d) than against benign prostatic hyperplasia (5 mg/d). Finasteride inhibits 5a-reductase type 2 and 3 enzymes much more strongly than the type 1 enzyme 8,9 ; therefore, finasteride can affect several different human tissues, 4,5,8,10 such as the prostate, muscle, liver, kidney, brain, mammary gland, frontal cortex, skin, epidermis, pancreas, spleen, heart, testicle, stomach, dermis, small intestine, and adipose tissues. 8,9,11 Finasteride use has several adverse effects, including erectile dysfunction, loss of libido, and smaller ejaculatory volume.…”

“…8,9,11 Finasteride use has several adverse effects, including erectile dysfunction, loss of libido, and smaller ejaculatory volume. 5,10,12 A meta-analysis on the effects of 5a-reductase inhibitors found a significant pooled relative risk for sexual dysfunction in men with benign prostatic hyperplasia (2.56, 95% CI ¼ 1.48e4.42) but no significant increased risk in men with AGA (1.21, 95% CI ¼ 0.85e1.72). 13 Recently, a clinical study described the main symptoms of subjects with PFS, including loss of penis sensitivity, decreased ejaculatory force, low penile temperature, smaller ejaculatory volume, anhedonia, lack of mental concentration, and loss of muscle tone or mass.…”

“…5 In our previous genetic study, 6 we did not examine the relation of AR (CAG)n and (GGN)n polymorphisms with the single specific symptoms of subjects with PFS. In the present study, we explored this relation by three different questionnaires-the Arizona Sexual Experience Scale (ASEX), 25 the Aging Male Symptom Scale (AMS), 26 and our ad hoc 100-item questionnaire 4 -for the clinical symptoms of 66 men with PFS.…”