dutasteride and Diabetes-Mellitus

Benign prostatic hyperplasia (BPH), benign prostatic enlargement (BPE) and lower urinary tract symptoms (LUTS) belong to the most frequent diseases in ageing men. Beyond the 6th decade of life, more than 30% of men suffer from moderate to severe LUTS requiring intervention. The pathophysiology of BPH/BPE is still incompletely understood. The dominant role of the androgen system and the androgen receptor is well defined. Androgen receptors are expressed in BPH tissue in which they are activated by the potent androgen dihydrotestosterone. Synthesis of dihydrotestosterone is under control of the 5α-reductase enzyme, activity of which is antagonized by finasteride and dutasteride. More recently, the impact of prostatic inflammation and metabolic parameters particularly for the development of BPE and LUTS has increasingly been recognized. A better understanding of the pathophysiology is a prerequisite for the development of novel, more effective medical treatment options.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; 5-alpha Reductase Inhibitors; Aging; Diabetes Mellitus; Dihydrotestosterone; Dutasteride; Dyslipidemias; Finasteride; Humans; Inflammation; Lower Urinary Tract Symptoms; Male; Metabolic Syndrome; Prostatic Hyperplasia; Receptors, Androgen

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.

Topics: 5-alpha Reductase Inhibitors; Alopecia; Animals; Central Nervous System; Cholestenone 5 alpha-Reductase; Cognition Disorders; Depression; Diabetes Mellitus; Dutasteride; Finasteride; Humans; Male; Prostatic Hyperplasia; Prostatic Neoplasms; Psychoses, Substance-Induced; Sexual Dysfunction, Physiological; Steroids

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.

Topics: 5-alpha Reductase Inhibitors; Animals; Azasteroids; Diabetes Mellitus; Dutasteride; Finasteride; Glucocorticoids; Humans; Insulin Resistance; Metabolic Syndrome; Mineralocorticoids; Obesity; Vascular Diseases