madman
Super Moderator
Abstract
Background and Objectives: Finasteride 1 mg/day is indicated for androgen-dependent conditions such as male androgenetic alopecia (AGA).
Methods: The literature is comprehensively summarized on the pharmacodynamics, pharmacokinetics, mechanism of action, and metabolism of finasteride. Pairwise and network meta-analyses were performed to assess the efficacy of finasteride reported in clinical trials. The adverse events profile is described along with the post-marketing reports.
Results and Conclusion: Finasteride 1 mg/day significantly increased total hair count compared to placebo after 24 weeks (mean difference = 12.4 hairs/cm 2 , p<0.05), and 48 weeks (mean difference = 16.4 hairs/cm 2 , p<0.05). The efficacy of the two doses of finasteride (5 mg/day and 1 mg/day) and topical finasteride (1% solution) were not significantly different. The most commonly reported sexual events include erectile dysfunction and decreased libido. Increasing patient complaints and analysis of the FAERS database led to the inclusion of depression in the FDA label in 2011, as men were found to be at risk of suicide due to the persistent sexual side effects commonly termed as post-finasteride syndrome. Finasteride is shown to be reasonably tolerated in both men and women; however, patients need to be educated about the possible short- and long-term side effects.
1. Introduction
Androgenetic alopecia (AGA) is the most common non-scarring hair loss in men. It can usually be classified according to the Norwood Hamilton scale, but there are exceptions (1,2). Hair loss may significantly impair quality of life resulting in passive psychological effects (3). In genetically predisposed men, androgens have an effect on hair follicles where they may transform terminal hair into vellus-like miniaturized hair, leading to gradual hair loss (4–6). The conversion of testosterone to dihydrotestosterone (DHT) is mediated by the enzyme 5α-reductase (5AR) (4) (Figures 1 and 2).
Finasteride is an oral pharmacologic therapy developed for the treatment of AGA, designed to inhibit the 5AR enzyme (7). Three multi-center (the USA and 16 countries), phase III trials established the efficacy of finasteride in improving hair growth in men with pattern baldness (4,7–9). We review the role of androgens and the enzyme 5AR in hair loss, the 5AR inhibitor therapy (finasteride), its mechanism of action, pharmacokinetics, efficacy, and safety in treating pattern hair loss, along with post-marketing experience.
2. Androgens and 5α reductase (5AR)
The enzyme 5AR family (types I, II, and III) participates in bile, androgen, and estrogen metabolism (10). Three distinct 5AR isoenzymes, type I, II, and III are found across mammalian species and influence progesterone, corticosteroid, and androgen metabolism (11,12). The physiological distribution of 5AR isoenzymes is listed in Table 1. The Type I isoform is found predominantly in the liver, sebaceous glands in the skin, including the scalp, and to a lesser extent in the male reproductive organs such as the prostate; type II is abundantly expressed in the prostate and hair follicles, and to a lesser extent in the liver (13–15); while the data on the localization of the type III enzyme is limited, it is expressed in prostate basal epithelial cells (12). Genes for 5AR type I and II were expressed in cultured dermal papilla cells from beard and scalp hair follicles (16). The type I isoenzyme is responsible for about 1/3rd of circulating DTH and type II is responsible for 2/3rds of circulating DTH (7).
*It was shown that men who had a genetic deficiency of the type II isoenzyme did not develop AGA (4). Additionally, men with pattern baldness had elevated type II 5AR activity and increased DHT levels in the scalp (4). Taken together, these findings provide a rationale for the role of the type II isoenzyme and the androgen DHT in AGA.
3. Finasteride – 5 AR inhibitor
Finasteride originated as a chemopreventive for prostate cancer in the 1930s and 1940s by Charles B Huggins, leading to the discovery of the link between the physiological role of testosterone and prostate growth (17,18). It was later developed as MK-906 (now finasteride), which was approved by the FDA in 1992 for the treatment of benign prostatic hyperplasia (BPH) as ‘Proscar’ (19). Merck obtained FDA approval under the name ‘Propecia’ for the treatment of pattern hair loss or AGA in 1997 (20,21). Finasteride, a synthetic 4-aza-3-oxosteroid compound is the active ingredient in ‘Propecia’ with a molecular weight of 372.55 (7,22). The optimum oral dosage suggested for the treatment of male pattern hair loss is 1 mg/day (7).
4. Mechanism of action
Finasteride inhibits type II 5AR isoenzyme 100-fold more selectively over type I isoenzyme (7). The NAPDH-mediated irreversible inhibition leads to finasteride being reduced to dihydrofinasteride, thereby blocking the peripheral conversion of testosterone to DHT at the dermal papillae level (7,23) (Figure 2). Therefore, this leads to a significant reduction in scalp and serum DHT levels (7).
Finasteride reduces serum DHT levels by about 70% after administration of a single oral dose (24). Preliminary studies showed that finasteride 5 mg/day suppressed scalp DHT concentrations significantly compared to placebo (25). Thereafter, in a scalp DHT dose-ranging study (5, 1, 0.2 mg/day finasteride) demonstrated a reduction in scalp DHT levels by about 65% at doses ≥ 0.5 mg/day after 6 weeks of treatment (25,26). DHT levels are not reduced completely due to the residual conversion of testosterone through type I 5AR (4,7). DHT levels are shown to return to normal within 2 weeks of treatment discontinuation (27).
5. Metabolism
Finasteride is metabolized extensively in the liver, primarily by the cytochrome P450 3A4 (CYP 3A4) enzyme subfamily of hepatic drug-metabolizing enzymes (7,20). The biotransformation of finasteride occurs in two pathways: phase I and phase II metabolism (28) (Figure 3). During phase I, finasteride is metabolized to ω-hydroxyfinasteride (major metabolite) through hydroxylation of the t-butyril group (29).
The phase I metabolites are further reduced to hydroxyfinasteride glucuronide and carboxylic acid metabolites through glucuronidation, known as phase II metabolism (30). The end products being finasteride carboxylic acid glucuronide and hydroxyfinasteride glucuronide (18). The final metabolites are highly hydrophilic and possess ≤20% of the 5AR inhibitory activity of finasteride (7). The documentation of the two phases of finasteride metabolism and identification of several minor metabolites in vitro suggest that there may be alternative pathways of finasteride metabolism yet to be discovered.
6. Bioavailability
Propecia may be orally administered with or without meals as the bioavailability is not affected by food (7). The mean bioavailability of finasteride 1mg tablets is 65% (range: 26-170%) in a study conducted in 15 healthy young male volunteers (7). Multiple studies have calculated the percentage bioavailability of finasteride between 63% to 80% (29,31). Finasteride reaches a steady-state in plasma within 2 hours of administration, with a peak concentration of 9.2 ng/mL (range: 4.9-13.7 ng/mL) (7). Finasteride is absorbed completely in 6-8 hours post-administration (32). The circulating finasteride is bound to the plasma proteins (89.8-91.3%) and slowly accumulates after multiple doses (7,33).
The mean terminal half-life of finasteride is 5-6 hours in men 18-60 years age and approximately 8 hours in mean aged 70 years and above (7). Following oral administration of finasteride, it was reported that approximately 39% of the metabolites were excreted through urine and 57% excreted through feces (7).
7. Effect of Finasteride on Pregnancy
9. Formulations – Oral vs Topical
10. Efficacy
11. Safety and Adverse events
11.1 Prostate Cancer
11.2 Sexual dysfunction
12. Post-marketing reports
12.1 Finasteride and FAERS
12.2 Post finasteride syndrome (PFS)
Several groups around the world have coined the term “Post finasteride syndrome (PFS)” in a subset of men who used finasteride, who experienced persistent sexual dysfunction (decreased libido and ejaculation disorder) and psychological effects (increased depression, anxiety, and suicidal ideas) after cessation of therapy, irrespective of age, drug, or duration of treatment (81,83). Men using finasteride for more than 205 days had a higher risk for persistent erectile dysfunction (76,84).
The association of sexual and nonsexual side effects in former finasteride users may be due to the fact that finasteride irreversibly inhibits 5AR with a slow rate of dissociation, probably leading to a long-lasting effect on the body, regardless of the time and dose of administration (83). Additionally, an alteration in the brain neurosteroids such as progesterone and dihydro-progesterone could possibly contribute to the persistent psychological effects, as the inhibition of 5AR is a rate-limiting step in the production of neurosteroids (76,85). Preclinical animal studies showed that finasteride lowered plasma and hippocampal neurosteroids and increased depression (86,87).
13. Conclusion
Finasteride was the first selective type II 5ARI introduced for BPH, which was later FDA approved for male AGA. It has been used off-label to treat female pattern baldness, especially in post-menopausal women due to the potential risk to the male fetus in pregnant and nursing women. Physicians should educate patients, especially men and women in the reproductive age, about potential adverse events of finasteride such as sexual dysfunction and psychological effects. Clinical trials have proven the efficacy of oral finasteride significantly improves the progression of hair loss in men with a reversal of the miniaturization process. There may be a significant increase in the total and terminal anagen hairs; and an improved anagen/telogen ratio, compared to placebo, after 12 months of finasteride therapy. The topical formulations of finasteride have to be examined in more detail for efficacy and safety.
Background and Objectives: Finasteride 1 mg/day is indicated for androgen-dependent conditions such as male androgenetic alopecia (AGA).
Methods: The literature is comprehensively summarized on the pharmacodynamics, pharmacokinetics, mechanism of action, and metabolism of finasteride. Pairwise and network meta-analyses were performed to assess the efficacy of finasteride reported in clinical trials. The adverse events profile is described along with the post-marketing reports.
Results and Conclusion: Finasteride 1 mg/day significantly increased total hair count compared to placebo after 24 weeks (mean difference = 12.4 hairs/cm 2 , p<0.05), and 48 weeks (mean difference = 16.4 hairs/cm 2 , p<0.05). The efficacy of the two doses of finasteride (5 mg/day and 1 mg/day) and topical finasteride (1% solution) were not significantly different. The most commonly reported sexual events include erectile dysfunction and decreased libido. Increasing patient complaints and analysis of the FAERS database led to the inclusion of depression in the FDA label in 2011, as men were found to be at risk of suicide due to the persistent sexual side effects commonly termed as post-finasteride syndrome. Finasteride is shown to be reasonably tolerated in both men and women; however, patients need to be educated about the possible short- and long-term side effects.
1. Introduction
Androgenetic alopecia (AGA) is the most common non-scarring hair loss in men. It can usually be classified according to the Norwood Hamilton scale, but there are exceptions (1,2). Hair loss may significantly impair quality of life resulting in passive psychological effects (3). In genetically predisposed men, androgens have an effect on hair follicles where they may transform terminal hair into vellus-like miniaturized hair, leading to gradual hair loss (4–6). The conversion of testosterone to dihydrotestosterone (DHT) is mediated by the enzyme 5α-reductase (5AR) (4) (Figures 1 and 2).
Finasteride is an oral pharmacologic therapy developed for the treatment of AGA, designed to inhibit the 5AR enzyme (7). Three multi-center (the USA and 16 countries), phase III trials established the efficacy of finasteride in improving hair growth in men with pattern baldness (4,7–9). We review the role of androgens and the enzyme 5AR in hair loss, the 5AR inhibitor therapy (finasteride), its mechanism of action, pharmacokinetics, efficacy, and safety in treating pattern hair loss, along with post-marketing experience.
2. Androgens and 5α reductase (5AR)
The enzyme 5AR family (types I, II, and III) participates in bile, androgen, and estrogen metabolism (10). Three distinct 5AR isoenzymes, type I, II, and III are found across mammalian species and influence progesterone, corticosteroid, and androgen metabolism (11,12). The physiological distribution of 5AR isoenzymes is listed in Table 1. The Type I isoform is found predominantly in the liver, sebaceous glands in the skin, including the scalp, and to a lesser extent in the male reproductive organs such as the prostate; type II is abundantly expressed in the prostate and hair follicles, and to a lesser extent in the liver (13–15); while the data on the localization of the type III enzyme is limited, it is expressed in prostate basal epithelial cells (12). Genes for 5AR type I and II were expressed in cultured dermal papilla cells from beard and scalp hair follicles (16). The type I isoenzyme is responsible for about 1/3rd of circulating DTH and type II is responsible for 2/3rds of circulating DTH (7).
*It was shown that men who had a genetic deficiency of the type II isoenzyme did not develop AGA (4). Additionally, men with pattern baldness had elevated type II 5AR activity and increased DHT levels in the scalp (4). Taken together, these findings provide a rationale for the role of the type II isoenzyme and the androgen DHT in AGA.
3. Finasteride – 5 AR inhibitor
Finasteride originated as a chemopreventive for prostate cancer in the 1930s and 1940s by Charles B Huggins, leading to the discovery of the link between the physiological role of testosterone and prostate growth (17,18). It was later developed as MK-906 (now finasteride), which was approved by the FDA in 1992 for the treatment of benign prostatic hyperplasia (BPH) as ‘Proscar’ (19). Merck obtained FDA approval under the name ‘Propecia’ for the treatment of pattern hair loss or AGA in 1997 (20,21). Finasteride, a synthetic 4-aza-3-oxosteroid compound is the active ingredient in ‘Propecia’ with a molecular weight of 372.55 (7,22). The optimum oral dosage suggested for the treatment of male pattern hair loss is 1 mg/day (7).
4. Mechanism of action
Finasteride inhibits type II 5AR isoenzyme 100-fold more selectively over type I isoenzyme (7). The NAPDH-mediated irreversible inhibition leads to finasteride being reduced to dihydrofinasteride, thereby blocking the peripheral conversion of testosterone to DHT at the dermal papillae level (7,23) (Figure 2). Therefore, this leads to a significant reduction in scalp and serum DHT levels (7).
Finasteride reduces serum DHT levels by about 70% after administration of a single oral dose (24). Preliminary studies showed that finasteride 5 mg/day suppressed scalp DHT concentrations significantly compared to placebo (25). Thereafter, in a scalp DHT dose-ranging study (5, 1, 0.2 mg/day finasteride) demonstrated a reduction in scalp DHT levels by about 65% at doses ≥ 0.5 mg/day after 6 weeks of treatment (25,26). DHT levels are not reduced completely due to the residual conversion of testosterone through type I 5AR (4,7). DHT levels are shown to return to normal within 2 weeks of treatment discontinuation (27).
5. Metabolism
Finasteride is metabolized extensively in the liver, primarily by the cytochrome P450 3A4 (CYP 3A4) enzyme subfamily of hepatic drug-metabolizing enzymes (7,20). The biotransformation of finasteride occurs in two pathways: phase I and phase II metabolism (28) (Figure 3). During phase I, finasteride is metabolized to ω-hydroxyfinasteride (major metabolite) through hydroxylation of the t-butyril group (29).
The phase I metabolites are further reduced to hydroxyfinasteride glucuronide and carboxylic acid metabolites through glucuronidation, known as phase II metabolism (30). The end products being finasteride carboxylic acid glucuronide and hydroxyfinasteride glucuronide (18). The final metabolites are highly hydrophilic and possess ≤20% of the 5AR inhibitory activity of finasteride (7). The documentation of the two phases of finasteride metabolism and identification of several minor metabolites in vitro suggest that there may be alternative pathways of finasteride metabolism yet to be discovered.
6. Bioavailability
Propecia may be orally administered with or without meals as the bioavailability is not affected by food (7). The mean bioavailability of finasteride 1mg tablets is 65% (range: 26-170%) in a study conducted in 15 healthy young male volunteers (7). Multiple studies have calculated the percentage bioavailability of finasteride between 63% to 80% (29,31). Finasteride reaches a steady-state in plasma within 2 hours of administration, with a peak concentration of 9.2 ng/mL (range: 4.9-13.7 ng/mL) (7). Finasteride is absorbed completely in 6-8 hours post-administration (32). The circulating finasteride is bound to the plasma proteins (89.8-91.3%) and slowly accumulates after multiple doses (7,33).
The mean terminal half-life of finasteride is 5-6 hours in men 18-60 years age and approximately 8 hours in mean aged 70 years and above (7). Following oral administration of finasteride, it was reported that approximately 39% of the metabolites were excreted through urine and 57% excreted through feces (7).
7. Effect of Finasteride on Pregnancy
9. Formulations – Oral vs Topical
10. Efficacy
11. Safety and Adverse events
11.1 Prostate Cancer
11.2 Sexual dysfunction
12. Post-marketing reports
12.1 Finasteride and FAERS
12.2 Post finasteride syndrome (PFS)
Several groups around the world have coined the term “Post finasteride syndrome (PFS)” in a subset of men who used finasteride, who experienced persistent sexual dysfunction (decreased libido and ejaculation disorder) and psychological effects (increased depression, anxiety, and suicidal ideas) after cessation of therapy, irrespective of age, drug, or duration of treatment (81,83). Men using finasteride for more than 205 days had a higher risk for persistent erectile dysfunction (76,84).
The association of sexual and nonsexual side effects in former finasteride users may be due to the fact that finasteride irreversibly inhibits 5AR with a slow rate of dissociation, probably leading to a long-lasting effect on the body, regardless of the time and dose of administration (83). Additionally, an alteration in the brain neurosteroids such as progesterone and dihydro-progesterone could possibly contribute to the persistent psychological effects, as the inhibition of 5AR is a rate-limiting step in the production of neurosteroids (76,85). Preclinical animal studies showed that finasteride lowered plasma and hippocampal neurosteroids and increased depression (86,87).
13. Conclusion
Finasteride was the first selective type II 5ARI introduced for BPH, which was later FDA approved for male AGA. It has been used off-label to treat female pattern baldness, especially in post-menopausal women due to the potential risk to the male fetus in pregnant and nursing women. Physicians should educate patients, especially men and women in the reproductive age, about potential adverse events of finasteride such as sexual dysfunction and psychological effects. Clinical trials have proven the efficacy of oral finasteride significantly improves the progression of hair loss in men with a reversal of the miniaturization process. There may be a significant increase in the total and terminal anagen hairs; and an improved anagen/telogen ratio, compared to placebo, after 12 months of finasteride therapy. The topical formulations of finasteride have to be examined in more detail for efficacy and safety.
