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

Abstract

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 β-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.

Keywords: 5-alpha reductase inhibitors; Diabetes mellitus; Dry eye syndromes; Hypogonadism; Kidney diseases; Non-alcoholic fatty liver disease.

Fig. 1. Cumulative incidence of type 2 diabetes mellitus in Taiwanese National Health Insurance Research Database cohort over study period: main cohort (adjusted) and adjusted for propensity score. Data from Wei et al (BMJ 2019;365:l1204) [17].

Fig. 2. Tear film break up time (TBUT) changes in the four groups at different time points (^*p<0.05, ^**p<0.01 vs. baseline within the same group). Con: control, Sal: physiological saline, Fin: oral finasteride, Bp: oral finasteride and Bidens pilosa L. ^ap<0.05 within the group Con at the same time point. ^bp<0.05 within the group Fin at the same time point. Data from Zhang et al (Cell Physiol Biochem 2016;39:266–77) [19].

Fig. 3. Lacrimal gland histopathology (H&E, ×400). (A) Lacrimal gland from the control group; (B) Lacrimal gland from the oral finasteride group. A large number of lymphocytes had infiltrated the interlobular space and surrounded the acinar and ductal cells as indicated by the black arrow. Data from Zhang et al (Cell Physiol Biochem 2016;39:266–77) [19] with original copyright holder's permission.

Fig. 4. Representative microphotography showing terminal deoxynucleotidyl transferase dUTP nick end labeling reaction (A, C) and proliferating cell nuclear antigen-positive cells (B, D) in control (A, B) and finasteride-treated (C, D) rats. Red filled arrows indicate positive signaling in nuclei of proximal convoluted tubule (PCT); blue empty arrows indicate positive signaling in nuclei of the distal convoluted tubule (DCT). Slides were rinsed in phosphate buffer saline and labeled with streptavidin conjugated with horseradish peroxidase. To visualize the effect of the reaction (places of DNA split), 3,3′-diaminobenzidine was added. Positive staining was defined microscopically (Leica DM5000B, Germany) through visual identification of brown pigmentation of the cell nucleus. Scale bar from objective magnification ×40 (A, B; C, D) is 100 mm. RC: renal corpuscle. Data from Baig et al (Int J Environ Res Public Health 2019;16:E1726) [18].

Fig. 5. Visualization of collagen fibers type I (black filled arrows) and type III (blue empty arrows) in control (A, B) and in finasteride-treated rats' kidneys that exhibited well visible tubulointerstitial fibrosis (C, black filled arrows and blue empty arrows) and glomerulosclerosis (D, black filled arrows). Sirius Red staining, polarized microscopy. Scale bar: 100 mm. Data from Baig et al (Int J Environ Res Public Health 2019;16:E1726) [18].

Fig. 6. Universal genomic molecular mechanism of androgen action. One key biochemical reaction in this sequence of pathways is the transformation of testosterone (T) to 5α-dihydrotestosterone (5α-DHT) via 5α-reductases (5α-Rs). This pathway is critical in the function of androgen receptor, since 5α-DHT is more potent natural ligand than T. SHBG: sex hormone binding globulin.