madman
Super Moderator
5-alpha reductase inhibitors use in prostatic disease and beyond (2023)
Bodie Chislett, David Chen, Marlon L. Perera, Eric Chung, Damien Bolton, Liang G. Qu
Abstract
5-alpha reductase inhibitors (5-ARIs) are commonly used and widely available, with benefits observed from their effect on androgen signaling. Their effect relies on the inhibition of the 5-alpha reductase enzyme which aids in the conversion of testosterone to dihydrotestosterone. 5-ARIs have increasing clinical relevance outside of benign prostatic hyperplasia (BPH). Such development requires clinicians to have an updated review to guide clinical practices. This review details the pharmacology and mechanisms of action for 5-ARIs and how this relates to multiple clinical indications. Of note, is the debunked association between finasteride and increased risk of high-grade prostate cancer. Furthermore, adverse effects of 5-ARI use are detailed in this review, with specific mentions of the post-finasteride syndrome. In addition to overviews pertaining to BPH and prostate cancer, much attention has also been focused on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The androgen axis may be associated with increased virulence for SARS-CoV-2 in men, with some reporting a correlation between the severity of illness and androgenic alopecia. Since these observations, the role of antiandrogens, including 5-ARIs, has been explored further in SARS-CoV-2. Increasing understanding of pathological processes involving the androgen axis in which 5-ARIs work, has led to increasing clinical indications for 5-ARIs. Several novel off-label indications have been suggested including its potential role in the pathogenesis of SARS-CoV-2, but to date, these claims have not been substantiated. Previously held truths regarding the role of 5-ARIs and prostate carcinogenesis have been contested, inadvertently leading to the re-exploration of 5-ARIs utility in prostate cancer. With growing evidence of pathological processes involving the androgen axis, 5-ARIs are likely to become increasingly more used. This review serves as a timely update of 5 ARIs pharmacology, current indications, and potential future directions.
Introduction
5-alpha reductase inhibitors (5-ARIs) are commonly used and widely available, with benefits observed from their effect on androgen signaling. Initially licensed for use in benign prostatic hyperplasia (BPH), finasteride and dutasteride are the two major 5-ARIs that are commercially available and in use today (1,2). Their effect relies on the inhibition of the 5-alpha reductase (5α-reductase) enzyme which aids in the conversion of testosterone to dihydrotestosterone (DHT)(3).
Since its introduction, the clinical indication for 5-ARIs has grown from BPH to include androgenetic alopecia (AGA) and hirsutism (1). As more pathological processes are identified as being mediated by DHT, the clinical indications and utility of 5-ARIs expand. The relationship between 5-ARIs and prostate cancer is of particular interest due to the androgen-driven nature of prostate carcinogenesis (3,4). Other new associations have been observed between 5-ARIs and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), including reduced disease severity and mortality (5,6).
With new developments and increasing clinical indications, an up-to-date review of 5-ARIs is warranted, helping to inform clinical practice. This narrative review addresses the mechanism of action of 5-ARIs, potential adverse effects, and current clinical indications including indications within and outside of urology.
Pharmacology
Finasteride was first licensed by the United States Food and Drug Administration (US FDA) in 1992 (1,7). It competitively inhibits the type II 5α-reductase enzymes isoenzyme, suppressing serum DHT by approximately 70% from baseline (3). Dutasteride, the first dual 5α-reductase type I and type II isoenzyme inhibitor, was approved for use a decade later and is estimated to lower serum DHT by approximately 90% (8)
5α-reductase is a nuclear-bound steroid intracellular enzyme that converts the androgen testosterone into DHT. 5-ARIs are chemically 4-azasteroids that competitively bind 5α-reductase intracellularly, primarily in the prostate stroma, leading to the peripheral inhibition of testosterone conversion into its more potent metabolite. DHT is observed as having a greater affinity than testosterone to androgen receptors (AR) in the prostate gland. A hormonal mediator, DHT modulates genes responsible for cell proliferation and can lead to hyperplasia.
5α-reductase exists as two isoenzymes, type I and type II, primarily found within the prostate stroma. Type II isoenzymes are estimated to account for two-thirds of serum DHT production and can be found outside prostate tissue, including seminal vesicles, epididymides, hair follicles, and the liver (1). Finasteride selectively inhibits type II isoenzyme and reduces serum DHT by 65% within the first 24 hours (1). Dutasteride inhibits type I and type II and was observed to reduce serum DHT by 90% after two weeks of regular dosing (2). DHT suppression through inhibition of 5α-reductase leads to an increase of serum testosterone of 15% and 19% for finasteride and dutasteride respectfully (1,2)
5-ARIs are absorbed well orally, with a mean bioavailability of approximately 60–65% from a 1 mg dosage (1,2). With 90% of the circulating drug being protein-bound, 5-ARIs are predominantly metabolized hepatically by the cytochrome P450 enzyme. It is estimated that between 32–46% of the drug is excreted in the urine, with the remaining 51–64% excreted in feces. The half-life of 5-ARI is approximately 6 hours in young, healthy males, increasing to 8 hours in septuagenarians (1,2).
Adverse effects
Both finasteride and dutasteride are generally well-tolerated medications, with most adverse effects reported as mild and transient (2). The most frequently reported adverse effects are related to sexual dysfunction, mainly decreased sexual libido, impotence, and ejaculatory disorders. Increasing post-market reports of sexual and depressive side effects prompted many countries to change the labeling to include these adverse side effects. Despite a growing body of literature to support the existence of adverse sexual side effects, the validity of a causal relationship between 5-ARIs and all its reported adverse effects remains unclear, with only observation studies available (9-13). The Proscar Long-Term Efficacy and Safety Study (PLESS), reported a marginal effect with 3.7% of patients treated with finasteride ceasing the medication due to adverse sexual side effects, compared to 2.1% of patients taking a placebo (14). A more substantial effect was observed in a meta-analysis by Liu et al., where men taking 5-ARIs for BPH had a 156% increased risk of experiencing sexual side effects (9). This study also observed dutasteride as having a greater incidence of adverse sexual side effects than finasteride. Most literature suggests these symptoms tend to resolve within 1 month of ceasing the medication.
Several other adverse effects have been described, including depression, cardiovascular disease, and metabolic syndrome. Suggestions of an increase in the incidence of male breast cancer and dementia have not been supported by current literature (15,16). The association of 5-ARIs and depressive symptoms was first highlighted in the Prostate Cancer Prevention Trial (PCPT) (4). The PCPT however was not designed or powered to assess an association between depressive symptoms and 5-ARIs, failing to establish a causal relationship. Other studies attempting to correlate depressive symptoms and 5-ARIs have similar flaws, highlighted in a comprehensive clinical review by Saengmearnuparp et al. (17). It is reported 5-ARIs may increase insulin resistance, leading to high rates of diabetes, metabolic disease, and cardiovascular disease (18).
While only observation human data exists, these claims were supported by the pre-clinical findings in rodents by Livingstone et al., where the absence of type I 5α-reductase isoenzyme was associated with hepatic steatosis and insulin resistance (19). This is in contrast to a previous publication by Hsieh et al., where they report no association between 5-ARIs and cardiovascular events during a follow-up of over 1,400 men over 5 years (20). This data however failed to examine markers of metabolic disease. Longer follow-up may be required. Currently, there remains no well-established relationship between 5-ARIs and metabolic syndrome or cardiovascular disease.
A growing chorus of consumers has reported persistent adverse side effects from 5-ARIs, despite the discontinuation of the medication. These persistent symptoms have been labeled post-finasteride syndrome (PFS), embodying a constellation of sexual, physical, and neuropsychiatric symptoms that developed during or after the use of 5-ARIs. Consequently, several countries, including the US FDA, have amended warnings to include the possibility of persistent side effects (21). The pathological mechanism of PFS is unclear, though it is theorized 5-ARIs inhibit the synthesis of neurosteroids known to affect mood, cognition, and libido (17). Current literature is conflicting regarding the existence of PFS, along with the dosing and duration required to be at risk. The PLESS study showed 15% of patients taking finasteride experienced sexual side effects within the first 12 months, compared to 7% in the placebo group. During the remaining 3 years of follow-up, there was no difference in reported sexual side effects between groups (14). However, only 50% of people taking finasteride reported resolution of their adverse sexual side effects following discontinuation, compared to 41% in the placebo group. A recent meta-analysis on adverse side effects of 5-ARIs did not assess persistent symptoms. Current evidence in support of PFS consists of case reports, surveys, or low-volume observation data. It is, for this reason, that the existence, incidence, and mechanism of PFS remain debated (13,21,22). To establish the existence of PFS, quality prospective data, including placebo trials, is required.
*Benign prostatic hyperplasia
*Prostate cancer
*SARS-CoV-2
*Other non-urological indications for 5-ARIs
Conclusions
Since their introduction in 1992 for the management of BPH, the clinical indications for 5-ARI have expanded to areas such as androgenic alopecia and hirsutism. This can be attributed to the increasing understanding of pathological processes involving the androgen axis in which 5-ARIs work. Several novel off-label indications have been suggested including its potential role in the pathogenesis of SARS-CoV-2, but to date, these claims have not been substantiated. Previously held truths regarding the role of 5-ARIs and prostate carcinogenesis have been contested, inadvertently leading to the re-exploration of 5-ARIs utility in prostate cancer. Other future directions will continue to be elucidated, as the implications of 5-ARIs in androgen signaling continue to be explored.
Bodie Chislett, David Chen, Marlon L. Perera, Eric Chung, Damien Bolton, Liang G. Qu
Abstract
5-alpha reductase inhibitors (5-ARIs) are commonly used and widely available, with benefits observed from their effect on androgen signaling. Their effect relies on the inhibition of the 5-alpha reductase enzyme which aids in the conversion of testosterone to dihydrotestosterone. 5-ARIs have increasing clinical relevance outside of benign prostatic hyperplasia (BPH). Such development requires clinicians to have an updated review to guide clinical practices. This review details the pharmacology and mechanisms of action for 5-ARIs and how this relates to multiple clinical indications. Of note, is the debunked association between finasteride and increased risk of high-grade prostate cancer. Furthermore, adverse effects of 5-ARI use are detailed in this review, with specific mentions of the post-finasteride syndrome. In addition to overviews pertaining to BPH and prostate cancer, much attention has also been focused on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The androgen axis may be associated with increased virulence for SARS-CoV-2 in men, with some reporting a correlation between the severity of illness and androgenic alopecia. Since these observations, the role of antiandrogens, including 5-ARIs, has been explored further in SARS-CoV-2. Increasing understanding of pathological processes involving the androgen axis in which 5-ARIs work, has led to increasing clinical indications for 5-ARIs. Several novel off-label indications have been suggested including its potential role in the pathogenesis of SARS-CoV-2, but to date, these claims have not been substantiated. Previously held truths regarding the role of 5-ARIs and prostate carcinogenesis have been contested, inadvertently leading to the re-exploration of 5-ARIs utility in prostate cancer. With growing evidence of pathological processes involving the androgen axis, 5-ARIs are likely to become increasingly more used. This review serves as a timely update of 5 ARIs pharmacology, current indications, and potential future directions.
Introduction
5-alpha reductase inhibitors (5-ARIs) are commonly used and widely available, with benefits observed from their effect on androgen signaling. Initially licensed for use in benign prostatic hyperplasia (BPH), finasteride and dutasteride are the two major 5-ARIs that are commercially available and in use today (1,2). Their effect relies on the inhibition of the 5-alpha reductase (5α-reductase) enzyme which aids in the conversion of testosterone to dihydrotestosterone (DHT)(3).
Since its introduction, the clinical indication for 5-ARIs has grown from BPH to include androgenetic alopecia (AGA) and hirsutism (1). As more pathological processes are identified as being mediated by DHT, the clinical indications and utility of 5-ARIs expand. The relationship between 5-ARIs and prostate cancer is of particular interest due to the androgen-driven nature of prostate carcinogenesis (3,4). Other new associations have been observed between 5-ARIs and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), including reduced disease severity and mortality (5,6).
With new developments and increasing clinical indications, an up-to-date review of 5-ARIs is warranted, helping to inform clinical practice. This narrative review addresses the mechanism of action of 5-ARIs, potential adverse effects, and current clinical indications including indications within and outside of urology.
Pharmacology
Finasteride was first licensed by the United States Food and Drug Administration (US FDA) in 1992 (1,7). It competitively inhibits the type II 5α-reductase enzymes isoenzyme, suppressing serum DHT by approximately 70% from baseline (3). Dutasteride, the first dual 5α-reductase type I and type II isoenzyme inhibitor, was approved for use a decade later and is estimated to lower serum DHT by approximately 90% (8)
5α-reductase is a nuclear-bound steroid intracellular enzyme that converts the androgen testosterone into DHT. 5-ARIs are chemically 4-azasteroids that competitively bind 5α-reductase intracellularly, primarily in the prostate stroma, leading to the peripheral inhibition of testosterone conversion into its more potent metabolite. DHT is observed as having a greater affinity than testosterone to androgen receptors (AR) in the prostate gland. A hormonal mediator, DHT modulates genes responsible for cell proliferation and can lead to hyperplasia.
5α-reductase exists as two isoenzymes, type I and type II, primarily found within the prostate stroma. Type II isoenzymes are estimated to account for two-thirds of serum DHT production and can be found outside prostate tissue, including seminal vesicles, epididymides, hair follicles, and the liver (1). Finasteride selectively inhibits type II isoenzyme and reduces serum DHT by 65% within the first 24 hours (1). Dutasteride inhibits type I and type II and was observed to reduce serum DHT by 90% after two weeks of regular dosing (2). DHT suppression through inhibition of 5α-reductase leads to an increase of serum testosterone of 15% and 19% for finasteride and dutasteride respectfully (1,2)
5-ARIs are absorbed well orally, with a mean bioavailability of approximately 60–65% from a 1 mg dosage (1,2). With 90% of the circulating drug being protein-bound, 5-ARIs are predominantly metabolized hepatically by the cytochrome P450 enzyme. It is estimated that between 32–46% of the drug is excreted in the urine, with the remaining 51–64% excreted in feces. The half-life of 5-ARI is approximately 6 hours in young, healthy males, increasing to 8 hours in septuagenarians (1,2).
Adverse effects
Both finasteride and dutasteride are generally well-tolerated medications, with most adverse effects reported as mild and transient (2). The most frequently reported adverse effects are related to sexual dysfunction, mainly decreased sexual libido, impotence, and ejaculatory disorders. Increasing post-market reports of sexual and depressive side effects prompted many countries to change the labeling to include these adverse side effects. Despite a growing body of literature to support the existence of adverse sexual side effects, the validity of a causal relationship between 5-ARIs and all its reported adverse effects remains unclear, with only observation studies available (9-13). The Proscar Long-Term Efficacy and Safety Study (PLESS), reported a marginal effect with 3.7% of patients treated with finasteride ceasing the medication due to adverse sexual side effects, compared to 2.1% of patients taking a placebo (14). A more substantial effect was observed in a meta-analysis by Liu et al., where men taking 5-ARIs for BPH had a 156% increased risk of experiencing sexual side effects (9). This study also observed dutasteride as having a greater incidence of adverse sexual side effects than finasteride. Most literature suggests these symptoms tend to resolve within 1 month of ceasing the medication.
Several other adverse effects have been described, including depression, cardiovascular disease, and metabolic syndrome. Suggestions of an increase in the incidence of male breast cancer and dementia have not been supported by current literature (15,16). The association of 5-ARIs and depressive symptoms was first highlighted in the Prostate Cancer Prevention Trial (PCPT) (4). The PCPT however was not designed or powered to assess an association between depressive symptoms and 5-ARIs, failing to establish a causal relationship. Other studies attempting to correlate depressive symptoms and 5-ARIs have similar flaws, highlighted in a comprehensive clinical review by Saengmearnuparp et al. (17). It is reported 5-ARIs may increase insulin resistance, leading to high rates of diabetes, metabolic disease, and cardiovascular disease (18).
While only observation human data exists, these claims were supported by the pre-clinical findings in rodents by Livingstone et al., where the absence of type I 5α-reductase isoenzyme was associated with hepatic steatosis and insulin resistance (19). This is in contrast to a previous publication by Hsieh et al., where they report no association between 5-ARIs and cardiovascular events during a follow-up of over 1,400 men over 5 years (20). This data however failed to examine markers of metabolic disease. Longer follow-up may be required. Currently, there remains no well-established relationship between 5-ARIs and metabolic syndrome or cardiovascular disease.
A growing chorus of consumers has reported persistent adverse side effects from 5-ARIs, despite the discontinuation of the medication. These persistent symptoms have been labeled post-finasteride syndrome (PFS), embodying a constellation of sexual, physical, and neuropsychiatric symptoms that developed during or after the use of 5-ARIs. Consequently, several countries, including the US FDA, have amended warnings to include the possibility of persistent side effects (21). The pathological mechanism of PFS is unclear, though it is theorized 5-ARIs inhibit the synthesis of neurosteroids known to affect mood, cognition, and libido (17). Current literature is conflicting regarding the existence of PFS, along with the dosing and duration required to be at risk. The PLESS study showed 15% of patients taking finasteride experienced sexual side effects within the first 12 months, compared to 7% in the placebo group. During the remaining 3 years of follow-up, there was no difference in reported sexual side effects between groups (14). However, only 50% of people taking finasteride reported resolution of their adverse sexual side effects following discontinuation, compared to 41% in the placebo group. A recent meta-analysis on adverse side effects of 5-ARIs did not assess persistent symptoms. Current evidence in support of PFS consists of case reports, surveys, or low-volume observation data. It is, for this reason, that the existence, incidence, and mechanism of PFS remain debated (13,21,22). To establish the existence of PFS, quality prospective data, including placebo trials, is required.
*Benign prostatic hyperplasia
*Prostate cancer
*SARS-CoV-2
*Other non-urological indications for 5-ARIs
Conclusions
Since their introduction in 1992 for the management of BPH, the clinical indications for 5-ARI have expanded to areas such as androgenic alopecia and hirsutism. This can be attributed to the increasing understanding of pathological processes involving the androgen axis in which 5-ARIs work. Several novel off-label indications have been suggested including its potential role in the pathogenesis of SARS-CoV-2, but to date, these claims have not been substantiated. Previously held truths regarding the role of 5-ARIs and prostate carcinogenesis have been contested, inadvertently leading to the re-exploration of 5-ARIs utility in prostate cancer. Other future directions will continue to be elucidated, as the implications of 5-ARIs in androgen signaling continue to be explored.
