Health Risks Associated with Long-Term Finasteride and Dutasteride Use: It's Time to Sound the Alarm

Abdulmaged M. Traish 대한남성과학회 2020 The World Journal of Men's Health Vol.38 No.3

5α-dihydrotestosterone (5α-DHT) is the most potent natural androgen. 5α-DHT elicits a multitude of physiological actions, in a host of tissues, including prostate, seminal vesicles, hair follicles, skin, kidney, and lacrimal and meibomian glands. However, the physiological role of 5α-DHT in human physiology, remains questionable and, at best, poorly appreciated. Recent emerging literature supports a role for 5α-DHT in the physiological function of liver, pancreatic b-cell function and survival, ocular function and prevention of dry eye disease and kidney physiological function. Thus, inhibition of 5α-reductases with finasteride or dutasteride to reduce 5α-DHT biosynthesis in the course of treatment of benign prostatic hyperplasia (BPH) or male pattern hair loss, known as androgenetic alopecia (AGA) my induces a novel form of tissue specific androgen deficiency and contributes to a host of pathophysiological conditions, that are yet to be fully recognized. Here, we advance the concept that blockade of 5α-reductases by finasteride or dutasteride in a mechanism-based, irreversible, inhabitation of 5α-DHT biosynthesis results in a novel state of androgen deficiency, independent of circulating testosterone levels. Finasteride and dutasteride are frequently prescribed for long-term treatment of lower urinary tract symptoms in men with BPH and in men with AGA. This treatment may result in development of non-alcoholic fatty liver diseases (NAFLD), insulin resistance (IR), type 2 diabetes (T2DM), dry eye disease, potential kidney dysfunction, among other metabolic dysfunctions. We suggest that long-term use of finasteride and dutasteride may be associated with health risks including NAFLD, IR, T2DM, dry eye disease and potential kidney disease.

Impact of Testosterone Deficiency and Testosterone Therapy on Lower Urinary Tract Symptoms in Men with Metabolic Syndrome

Abdulmaged M. Traish,Vanessa Johansen 대한남성과학회 2018 The World Journal of Men's Health Vol.36 No.3

Lower urinary tract function is modulated by neural, vascular and urethral and bladder structural elements. The pathophysiological mechanisms of lower urinary tract symptoms (LUTS) encompass prostate enlargement, alterations in urethra histological structure bladder fibrosis and alterations in pelvic neuronal and vascular networks, The complex pathophysiological relationship between testosterone (T) deficiency (TD) and the constellations LUTS, and metabolic dysfunction manifested in the metabolic syndrome (Met S) remains poorly understood. TD has emerged as one the potential targets by which Met S may contribute to the onset and development as well as worsening of LUTS. Because it has been recognized that treatment of men with Met S with T therapy ameliorates Met S components, it is postulated that T therapy may represent a therapeutic target in improving LUTS. Furthermore, the effect of TD on the prostate remains unclear, and often debatable. It is believed that T exclusively promotes prostate growth, however recent evidence has strongly contradicted this belief. The true relationship between benign prostatic hyperplasia, TD, and LUTS remains elusive and further research will be required to clarify the role of T in both benign prostatic hypertrophy (BPH) and LUTS as a whole. Although there is conflicting evidence about the benefits of T therapy in men with BPH and LUTS, the current body of literature supports the safety of using this therapy in men with enlarged prostate. As the population afflicted with obesity epidemic continues to age, the number of men suffering from Met S and LUTS together is expected to increase.

Androgens Modulate Endothelial Function and Endothelial Progenitor Cells in Erectile Physiology

Abdulmaged M. Traish,Artin Galoosian 대한비뇨의학회 2013 Investigative and Clinical Urology Vol.54 No.11

The incidence of erectile dysfunction (ED) increases with age and cardiovascular disease risk factors, such as hypertension, hyperlipidemia, insulin resistance, obesity, and diabetes. These risk factors are thought to contribute to endothelial dysfunction and atherosclerosis, thus contributing to the pathophysiology of ED. The role of the endothelium in regulating erectile physiology is well established. However, the role of androgens in modulating endothelial function and endothelial repair mechanisms subsequent to vascular injury in erectile tissue remains a subject of intensive research. The clinical and preclinical evidence discussed in this review suggests that androgens regulate endothelial function and also play an important role in the development and maturation of endothelial progenitor cells (EPCs), which are thought to play a critical role in repair of endothelial injury in vascular beds. In this review, we discuss the data available on the effects of androgens on endothelial function and EPCs in the repair of vascular injury. Indeed, more research is needed to fully understand the molecular and cellular basis of androgen action in regulating the development, differentiation, maturation, migration, and homing of EPCs to the site of injury. A better understanding of these processes will be critical to the development of new therapeutic approaches to the treatment of vascular ED.

Diabetes Attenuates Female Genital Sexual Arousal Response via Disruption of Estrogen Action

Abdulmaged M. Traish,Tulay Cushman,Richard Hoyt,Noel N Kim 대한비뇨의학회 2009 Investigative and Clinical Urology Vol.50 No.3

male sexual function, however, the underlying pathophysiological mechanisms remain unknown. To date, limited studies have been published on the effects of type 1 & type 2 diabetes on female genital sexual arousal and how this may impact overall sexual function. The aim of this review is to discuss the effects of diabetes on female sexual function and insights from laboratory studies on the underlying pathophysiology. Materials and Methods: Using PubMed, we reviewed and evaluated the literature published between 1970 and 2009 and data from our laboratories and others investigating the effects of type 1 and type 2 diabetes on genital sexual arousal responses. Results: Women with diabetes experience diminished genital arousal, reduced vaginal lubrication, vaginal atrophy, dyspareunia, and increased vaginal infections. Also, a number of studies using type 1 and type 2 diabetic animal models have reported reduced plasma estradiol levels and marked physiological, biochemical and histological changes in genital tissues. In animal studies, diabetes alters genital tissue structure and attenuates expression of the estrogen, progesterone and androgen receptors and alters vaginal and clitoral hemodynamics. Importantly, treatment of diabetic animals with estradiol in the face of persistent hyperglycemia can restore vaginal structure and sex steroid receptor expression. Conclusions: Type 1 & type 2 diabetic complications produce significant structural and functional disruptions in genital organs and attenuate genital hemodynamics. In the type 2 animal model, estradiol treatment ameliorates diabetic-induced pathophysiological alterations in genital tissues, such as the vagina. This suggests that estrogen supplementation may be beneficial in restoring diabetes-induced genital pathology. male sexual function, however, the underlying pathophysiological mechanisms remain unknown. To date, limited studies have been published on the effects of type 1 & type 2 diabetes on female genital sexual arousal and how this may impact overall sexual function. The aim of this review is to discuss the effects of diabetes on female sexual function and insights from laboratory studies on the underlying pathophysiology. Materials and Methods: Using PubMed, we reviewed and evaluated the literature published between 1970 and 2009 and data from our laboratories and others investigating the effects of type 1 and type 2 diabetes on genital sexual arousal responses. Results: Women with diabetes experience diminished genital arousal, reduced vaginal lubrication, vaginal atrophy, dyspareunia, and increased vaginal infections. Also, a number of studies using type 1 and type 2 diabetic animal models have reported reduced plasma estradiol levels and marked physiological, biochemical and histological changes in genital tissues. In animal studies, diabetes alters genital tissue structure and attenuates expression of the estrogen, progesterone and androgen receptors and alters vaginal and clitoral hemodynamics. Importantly, treatment of diabetic animals with estradiol in the face of persistent hyperglycemia can restore vaginal structure and sex steroid receptor expression. Conclusions: Type 1 & type 2 diabetic complications produce significant structural and functional disruptions in genital organs and attenuate genital hemodynamics. In the type 2 animal model, estradiol treatment ameliorates diabetic-induced pathophysiological alterations in genital tissues, such as the vagina. This suggests that estrogen supplementation may be beneficial in restoring diabetes-induced genital pathology.

The Dark Side of 5α-Reductase Inhibitors’ Therapy: Sexual Dysfunction, High Gleason Grade Prostate Cancer and Depression

Abdulmaged M. Traish,Ashwini Mulgaonkar,Nicholas Giordano 대한비뇨의학회 2014 Investigative and Clinical Urology Vol.55 No.6

With aging, abnormal benign growth of the prostate results in benign prostate hyperplasia(BPH) with concomitant lower urinary tract symptoms (LUTS). Because theprostate is an androgen target tissue, and transforms testosterone into 5α-dihydrotestosterone(5α-DHT), a potent androgen, via 5α-reductase (5α-R) activity, inhibitingthis key metabolic reaction was identified as a target for drug development to treatsymptoms of BPH. Two drugs, namely finasteride and dutasteride were developed asspecific 5α-reductase inhibitors (5α-RIs) and were approved by the U.S. Food and DrugAdministration for the treatment of BPH symptoms. These agents have proven usefulin the reducing urinary retention and minimizing surgical intervention in patients withBPH symptoms and considerable literature exists describing the benefits of theseagents. In this review we highlight the adverse side effects of 5α-RIs on sexual function,high grade prostate cancer incidence, central nervous system function and ondepression. 5α-Rs isoforms (types 1–3) are widely distributed in many tissues includingthe central nervous system and inhibition of these enzymes results in blockade of synthesisof several key hormones and neuro-active steroids leading to a host of adverseeffects, including loss of or reduced libido, erectile dysfunction, orgasmic dysfunction,increased high Gleason grade prostate cancer, observed heart failure and cardiovascularevents in clinical trials, and depression. Considerable evidence exists frompreclinical and clinical studies, which point to significant and serious adverse effectsof 5α-RIs, finasteride and dutasteride, on sexual health, vascular health, psychologicalhealth and the overall quality of life. Physicians need to be aware of such potential adverseeffects and communicate such information to their patients prior to commencing5α-RIs therapy.

Letter to the editor: Questioning the evidence behind the Saturation Model for testosterone replacement therapy in prostate cancer

Abraham Morgentaler,Abdulmaged M. Traish 대한비뇨의학회 2020 Investigative and Clinical Urology Vol.61 No.4

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