madman
Super Moderator
Health Risks Associated with Long-Term Finasteride and Dutasteride Use: It's Time to Sound the Alarm
Traish AM. World J Mens Health. 2020 Jan;38:e17. https://doi.org/10.5534/wjmh.200012
Health Risks Associated with Long-Term Finasteride and Dutasteride Use: It’s Time to Sound the Alarm
5α-dihydrotestosterone (5α-DHT) is the most potent natural androgen. 5α-DHT elicits a multitude of physiological actions, in a host of tissues, including the 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 the liver, pancreatic b-cell function, 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 the long-term treatment of lower urinary tract symptoms in men with BPH and in men with AGA. This treatment may result in the development of non-alcoholic fatty liver diseases (NAFLD), insulin resistance (IR), type 2 diabetes (T2DM), dry eye disease, and 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.
1. Finasteride and dutasteride induce liver lipid accumulation and steatosis
2. Finasteride and dutasteride induce insulin resistance and type 2 diabetes
3. Finasteride and dutasteride impair ocular function and cause the development of dry eye disease
4. Adverse effects of finasteride and dutasteride on kidney function
DISCUSSION
Inhibition of 5α-dihydrotestosterone biosynthesis induces a novel form of androgen deficiency independent of testosterone levels T
T is synthesized and secreted by the testis and circulates in plasma as free (unbound) T or bound to sex hormone-binding globulin and serum albumin. The unbound fraction of T, known as biologically available free T, enters target and nontarget cells by passive diffusion through the phospholipid plasma membrane (Fig. 6). In androgen target cells, T is further metabolized to 5α-DHT via 5α-Rs. In target cells, both T and 5α-DHT interact with the AR; however, 5α-DHT binds to the AR with approximately 10-fold higher affinity compared with T [35]. This large difference in the affinity of T and 5α-DHT for AR makes 5α-DHT the critical physiological androgen modulator in many tissues, and therefore, inhibition of its biosynthesis may result in a novel state of androgen deficiency. The wide expression and distribution of 5α-Rs in many tissues and organs [2] suggests that although T is the main circulating androgen, its conversion to the high-affinity 5α-DHT in many of these tissues is responsible for regulating tissue and cellular metabolism and function. The binding of 5α-DHT to AR results in the activation and transformation of the AR into a higher affinity complex for DNA and induces its translocation from the cytoplasm to the nucleus where it interacts with the androgen response elements. This high-affinity binding to a specific DNA sequence, results in recruitments of AR co-activators or co-repressors, resulting in regulating specific gene expression. This results in changes in cellular metabolism and function.
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 a more potent natural ligand than T. SHBG: sex hormone binding globulin
In addition to the well-recognized role of 5α-DHT and not total T in prostate growth and function, several other examples exist, which illustrate the key physiological role of 5α-DHT and not total T in mediating tissues function and metabolism. One such example is the role of 5α-DHT in maintaining erectile physiology [36]. It is now well-established that men treated with finasteride or dutasteride for BPH or AGA experience a greater risk of erectile dysfunction, loss of libido, and ejaculatory dysfunction [1,7,37-39]. These observations are strongly supported by studies in animal models, which demonstrated that finasteride and dutasteride, by inhibiting the biosynthesis of 5α-DHT, impair corpus cavernosum growth and trabecular smooth muscle relaxation, endothelial function, increased connective tissue deposition and result in erectile dysfunction, even in the presence of physiological levels of total T [36,40-42]. Erectile dysfunction was attributed to a reduction in intracellular 5α-DHT levels which were deemed essential for maintaining tissue function and metabolism even in the presence of physiological levels of T [43]. In addition, 5α-DHT is deemed critical for activating gene expression of neuronal and endothelial nitric oxide synthases, which are critical physiological mediators of penile erection [36,40-42]. These findings clearly demonstrate that 5α-DHT and not total T levels are critical for maintaining erectile physiology. A second example for the critical role of 5α-DHT is derived from the studies on fertility. Reduction of spermatogenesis progression is impaired in men lacking 5α-R type 2 isozyme [44], suggesting that 5α-DHT is critical for spermatogenesis, as well as the structure of seminiferous tubules/spermatocytes and Sertoli cells are affected by the loss of 5α-DHT since they Sertoli cells support germ cells’ development and the structure of the seminiferous tubules concomitant with the maintenance of the blood-testis barrier [45,46]. A third example of the relevance of 5α-DHT instead of total T is the effects of 5α-DHT on scalp hair growth. In absence of 5α-DHT baldness, a pattern was observed in men as determined in men with mutations in the 5α-R type 2 gene resulting in no expression of 5a-R type 2 enzyme [44,47] even though there were no changes in total T levels. In the scalp, the presence of 5α-DHT induces hair miniaturization by converting terminal hairs into vellus hairs [48-50]. This specific 5α-DHT-mediated biological event prompted the development of finasteride for the treatment of AGA [51,52]. A fourth example is the recent observations that the treatment of animals with finasteride or dutasteride results in dry eye disease within a very short period of time [19,23]. This illustrates the role of 5α-DHT on the lacrimal and meibomian gland's structure and function and on the overall ocular function.
To date, the role of 5α-DHT in human physiology is not fully appreciated. The role of 5α-DHT in the growth of the prostate is the one area where an agreement on a role for this potent androgen. However, recent literature supports a role for 5α-DHT in liver function [12,14- 16], b-cell function [53,54] and in ocular [27] and kidney function [18]. This introduces a new paradigm that, while T is the most circulating androgen, its derivative, 5α-DHT, is the most potent androgen and has a multitude of physiological action that is now being recognized. Therefore, inhibition of 5α-DHT biosynthesis by synthetic inhibitors acting via a mechanism-based (irreversible) inhibition of 5α-RS (suicide substrates) induce a novel form of tissue-specific androgen deficiency and results in pathophysiological conditions that are not fully recognized.
It is worth noting that finasteride has been shown to inhibit both 5α-R types 1 and 2 in rats [55], monkeys [56], and humans [57]. While the affinity and selectivity of finasteride towards 5α-R type 2 are far greater than that for 5α-R type 1, the long-term administration of finasteride (5 mg) in BPH patients and 1 mg in AGA patients would be expected to bring about sufficient drug plasma levels to inhibit of both 5α-R types 1 and 2. In addition, since finasteride and dutasteride act via a mechanism-based inhibition (slow dissociation rate) rendering the reaction nearly irreversible, once bound to the active site, finasteride and dutasteride are tightly bound to the enzyme resulting in the inactivation of the enzyme. Furthermore, with the advent use of dutasteride which inhibits both types, this drug brings about complete inhibition of both isozymes. Finally, both finasteride and dutasteride are believed to inhibit 5α-R type 3 which is expressed in a host of tissues. Thus, the long-term administration of these drugs may bring about pathophysiological harm in some tissues that have yet to be recognized.
Although many clinical studies claimed that finasteride and dutasteride ‘are safe and tolerable’ [7], new emerging evidence suggests that finasteride and dutasteride induce metabolic dysfunction, such as hyperglycemia [16], IR [13,16], liver fat accumulation [12,14], liver steatosis and liver fibrosis [12,14], and T2DM [17]. It should be noted that many reported clinical trials failed to incorporate specific measures of metabolic dysfunction (e.g., liver lipid accumulation; hyperglycemia, IR) as primary or secondary endpoints, in order to evaluate the effects of these drugs on metabolic dysfunction [9,10].
Here we advance the concept that blockade of the 5α-R enzymatic activities by such irreversible inhibitors results in a state of a new form of androgen deficiency, independent of circulating T levels. This new form of androgen deficiency has not been recognized before, simply, it is thought that as long as T levels are in the physiological range, androgen sufficiency is considered normal. Because finasteride and dutasteride are often prescribed to treat LUTS in men with BPH and male pattern hair loss in men with AGA for prolonged periods of time, it is postulated that men treated with these drugs are in a state of androgen deficiency and are at high risk of developing NAFLD IR, T2DM, dry eye disease, potential kidney dysfunction, among other metabolic dysfunctions. For these reasons, we believe that the clinical community should recognize these new potential health risks associated with these drugs and we believe “it’s time to sound the alarm” on these drugs.
