madman
Super Moderator
Abstract
Background
Androgenetic alopecia (AGA) is a common skin disease characterized by gradually miniaturized hair follicles, which manifests as progressive hair thinning and produces a bald appearance. Currently, finasteride is approved by the Food and Drug Administration (FDA) for the treatment of AGA, but its efficacy remains poor in some patients.
Summary
Compared to finasteride, oral dutasteride has better efficacy and similar tolerability, and most adverse events are mild and reversible, making it an effective option for AGA, but its sexual adverse events and potential psychiatric risks still need to be concerned. Mesotherapy with dutasteride and microneedling combined with dutasteride solution can reduce adverse events caused by oral medication and exhibit certain efficacy, but standardized treatment protocols and large-scale clinical trials are still needed in the future. Liposomes or nanoparticles of dutasteride are under development and may become an efficient topical formulation.
Key Messages
We have summarized the efficacy and adverse events of dutasteride in treating AGA under different administration methods and the promise of novel topical drug carriers.
Introduction
Androgenetic alopecia (AGA) is a common disease of multifactorial inheritance characterized by progressive hair loss. In male patients, AGA manifests itself as a receding frontal hairline and (or) progressive reduction and thinning of hair on the scalp, also known as male pattern baldness [1]. In female patients, AGA is characterized by progressive reduction and thinning of hair without receding of the frontal hairline, also known as female pattern hair loss[2]. The prevalence of AGA was reported to be 50% in Caucasian men and 19% in Caucasian women[3, 4]. In China, the prevalence of male AGA was 21.3%, while for females, it was 6.0% [5]. The prevalence of AGA was 14.6% in African men and 3.5% in African women [6]. Asian and African populations had a lower prevalence than Caucasians. The results above indicate that there are racial differences and regional differences in the prevalence of AGA.
The primary pathogenesis of AGA is that 5α-reductase converts testosterone into dihydrotestosterone (DHT), which binds to the androgen receptor, thus inhibiting the Wnt/β-cyclin signaling pathway, and reducing the role of papilla cells in inducing and sustaining hair growth[7]. Eventually, genetically susceptible hair follicles are gradually miniaturized and terminal hairs grown from them are replaced by vellus hairs[8]. At the same time, the dynamics of the hair cycle change: the duration of the anagen phase gradually decreases, while the telogen phase increases. The duration of the anagen phase determines the length of the hair, so the new anagen hairs become shorter, gradually producing a bald appearance[9].
There are three isozymes of 5α-reductase: type I, type II, and type III. Type I and type II have been isolated from the scalp of AGA patients[10]. Type III mRNA expression has also been detected in anagen hairs [11]. Dutasteride and finasteride are both 5α-reductase inhibitors (5ARIs). Currently,only two drugs, topical minoxidil and oral finasteride, have been approved by the FDA for the treatment of AGA. The FDA has approved a dose of 0.5 mg/d of dutasteride for the treatment of benign prostatic hyperplasia (BPH) [12], but for male patients with AGA, only South Korea and Japan have approved the use of dutasteride [13][14]. Finasteride selectively inhibits type II 5α-reductase, while dutasteride inhibits type I and type II 5α-reductase. Finasteride (5 mg/d) can reduce scalp DHT by approximately 41%, while dutasteride (0.5 mg/d) can reduce scalp DHT by approximately 51% [15]. Another study measured the concentration of medication and DHT in the hair and found that finasteride and dutasteride reduced hair DHT levels by approximately 64% and 92%, respectively[16].Therefore, for patients with AGA who do not respond well to finasteride, dutasteride may be a better option.
Results
Pharmacology of dutasteride
Dutasteride can form a stable enzyme complex with 5α-reductase isozymes, thus inhibiting the conversion of testosterone to DHT. Dutasteride at a dose of 0.5 mg/d can reduce serum DHT levels by approximately 92%, while finasteride at 5 mg/d can reduce serum DHT levels by approximately 73%[15]. Due to the participation of 5α-reductase in the synthesis of neurosteroids such as 3α,5αtetrahydroprogesterone (3α,5α-THP) and tetrahydrodeoxycorticosterone (THDOC), dutasteride can also have inhibitory effects on their production[17].
Absorption
After taking a 0.5 mg soft capsule, the maximum blood concentration (Cmax) of dutasteride is averaged at 1.27 ng/ml, occurring between 1-3 hours. Absolute bioavailability in healthy individuals is approximately 60% (range: 40%-94%) [18].
Distribution
Dutasteride is widely distributed in the human circulation and has a high binding affinity to plasma albumin (99%) and α-1 acid glycoprotein (96.6%) [18].
Metabolism and Excretion
Dutasteride is extensively metabolized in the liver by the cytochrome P450 (CYP) isoenzymes CYP3A4 and CYP3A5. There are 5 metabolites in human serum: 3 main metabolites (4'-hydroxydutasteride, 1,2-dihydroxydutasteride, 6-hydroxydutasteride) and 2 minor metabolites (6,4'-dihydroxydutasteride, 15-hydroxydutasteride). Due to its long half-life, dutasteride remains detectable in serum (>0.1 ng/mL) for 4-6 weeks after discontinuation of therapy. The terminal elimination half-life of dutasteride in steady state is approximately five weeks[18]. Men treated with dutasteride should not donate blood until at least six months after discontinuation of the drug to prevent the use of dutasteride in pregnant women receiving blood transfusions[15]. Feces is the main mode of excretion of dutasteride and its metabolites[18].
Efficacy and adverse events of oral dutasteride
1. Efficacy
There are four double-blind, randomized, placebo-controlled trials [15, 19-21] and one prospective, evaluator-blinded, open-label, randomized controlled trial [22] using average changes in target are a hair count as the efficacy endpoint. To compare the efficacy of different trials, we standardized the units for average changes in target area hair count before and after 24 weeks of treatment to "number of hairs/cm2" (shown in Table 1). At week 24, the increase in hair count in the 0.5 mg dutasteride group was superior to the finasteride group [15, 19, 22], while the 0.1 mg dutasteride group was similar to the finasteride group [15, 19], and the treatment groups were significantly better than the placebo group [15, 19-21]. For the increase in the placebo group in Table 1, the researchers believed that it may be related to the season; Many of the subjects in that trial were enrolled in early spring, and the percentage of scalp anagen hair peaked at more than 90% in March and then gradually declined [20]. In terms of global photographic assessment, the panel of experts (composed of dermatologists) evaluated scalp vertex and frontal photographs before and after 24 weeks, and concluded that the 0.5 mg dutasteride group was superior to the finasteride group [15, 19, 22] and that all treatment groups were superior to placebo group[15, 19-21]. In terms of subjects’ self assessments, the researchers scored using the Hair Growth Index and Hair Growth Satisfaction Scale or similar questionnaires. In the 24th week, several studies suggested that the 0.5 mg dutasteride group was superior to the finasteride group[19, 22], and only one study found it not superior to the finasteride group[15], in which the finasteride group received a dose of 5 mg/d. The other studies used a dose of 1 mg/d. Each treatment group was superior to the placebo group [15, 19-21].
In a prospective open-label study of 120 AGA patients treated with 0.5 mg dutasteride for 52 weeks, the average hair count, hair width and global photographic assessment (vertex and frontal of the scalp) improved from baseline at weeks 26 and 52, and the proportion of patients with improvement ranged from 76% to 85%. The improvements in hair width and terminal hair count at week 52 continued compared with week 26 [23]. In a retrospective study of 26 male patients with AGA who took 0.5 mg dutasteride orally for more than 52 weeks, 84.62% of the patients self-reported improvement or maintenance [24]. Another retrospective study included 42 patients with AGA who only took dutasteride 2-7 times a week for at least 12 months, and researchers found that efficacy was associated with a higher frequency of medication through a comparison of overall hair appearance[25].
A 6-month retrospective study included 246 patients with AGA who received 1 mg finasteride and 249 patients who received 0.5 mg dutasteride orally. By evaluating photos before and after treatment, the researchers concluded that dutasteride was superior to finasteride in improving the overall appearance of hair [26]. In another retrospective study with an observation period of more than three years, researchers concluded that the 0.5 mg dutasteride group (n=250) was superior to 1 mg finasteride group (n=285) in improving the clinical grade of AGA in men (Basic and specific classification) [27]. Furthermore, a retrospective study included 99 male AGA patients who used dutasteride for more than five years. The researchers scored clinical photos of the frontal and vertex of the scalp, concluding that using 0.5 mg of dutasteride for at least 5 years is a safe and effective treatment that can provide good results for male AGA patients [28].
A study included 35 patients with AGA who did not show a significant clinical improvement after six months of finasteride treatment (1 mg/d). They received treatment with dutasteride at a dose of 0.5mg/d for six months. Compared to finasteride treatment, hair density and thickness increased by 10.3% (9 /cm2) and 18.9% (10μm), respectively. However, the study did not include a control group that continued to take finasteride[29].
2. Adverse events
2.1. Sexual adverse events
Since DHT plays a key role in erectile physiology, including activation of nitric oxide synthase and increased blood flow to penile tissue, inhibition of 5α-reductase by finasteride or dutasteride leads to erectile dysfunction. Furthermore, deficiency or reduced levels of DHT can cause the death of smooth muscle cells in the penile trabeculae, accompanied by increased deposition of connective tissue, resulting in structural changes in the penile tissue and hindering its compliance, ultimately leading to erectile dysfunction[30].
Four randomized, double-blind, placebo-controlled trials [15, 19, 20, 31] were conducted to compare the incidence of sexual adverse events (AEs) between treatment groups and placebo groups, one of which was unblinded after 24 weeks and changed to open-label dutasteride [31] (shown in Table 2). Sexual AEs included altered libido, impotence, ejaculation disorders, breast enlargement and breast tenderness[19]. The incidence of sexual AEs in the dutasteride group appeared to be similar to the finasteride group [15, 19], while the incidence of sexual AEs in the placebo group was similar to or lower than that in the treatment group[15, 19, 20, 31].
An open-label prospective 52-week study enrolling 120 patients with AGA taking 0.5 mg of oral dutasteride showed an overall incidence of 17% of drug-related AEs. Sexual AEs (15.8%) were the most common drug-related AEs, particularly erectile dysfunction and decreased libido. The incidence of most sexual AEs was high in the first six months and decreased in the subsequent six months. Of the 19 patients (15.8%) who reported AEs of sexual dysfunction, 6 patients (5%) were relieved during the 52-week treatment period; 13 patients (10.8%) achieved a recovery during the 6-month follow up period after discontinuation of treatment [23]. A single-center retrospective study lasting more than 12 months found that among 307 patients with AGA aged 18 to 79 years who were treated with dutasteride, sexual AEs occurred in 20 cases (6.5%) when the dose ranged from 1 to 7 tablets per week. Among the 12 patients who took 0.5 mg of finasteride 2-3 times a week, no sexual AEs were reported. Researchers suggest that this dose regimen can be used for patients with AGA who were concerned about sexual AEs [25].
In a 48-week study, the first 24 weeks were a randomized, double-blind, placebo-controlled study, and the last 24 weeks were open-label 0.5 mg dutasteride treatment. During the double-blind period, the incidence of sexual AEs in the dutasteride group (16%) was approximately twice that of the placebo group (8%); during the open-label period, the overall incidence of sexual AEs was lower (5%)[31]. All AEs were mild to moderate in severity and were considered related to treatment. Most sexual AEs occurred within the first three months of dutasteride treatment and resolved during or after study treatment. The mean International Index of Erectile Function (IIEF) Questionnaire-Erectile Function domain scores remained stable in the placebo group during the first 24 weeks, while the dutasteride group showed a trend toward worse erectile function from baseline to double blind weeks 12 and 24 [31]
In a 1-year randomized, double-blind, placebo-controlled trial, 99 healthy men were randomized to dutasteride (0.5 mg), finasteride (5 mg) or placebo orally once daily. At 26 weeks, total sperm counts in the dutasteride and finasteride groups decreased by 28.6% and 34.3%, respectively, compared to baseline. At 52 weeks, the total sperm count decreased by 24.9% and 16.2%, the semen volume decreased by 29.7% and 14.5%, and the sperm concentration decreased by 3.2% and 7.4%, respectively. Sperm motility was significantly reduced by 6% to 12% during both treatment and follow-up. Neither treatment had any effect on sperm morphology. The decrease in semen parameters was reversible after discontinuation of the drug[32].
2.2. Mental adverse events
5α-reductase is involved in the production of neurosteroids [17]. Animal studies have shown that in the brain, 5α-reductase catalyzes progesterone into 5α-dihydroprogesterone (5α-DHP), which is further catalyzed by 3α-hydroxysteroid dehydrogenase (3α-HSD) into the potent neurosteroid 3α,5α-tetrahydroprogesterone (3α, 5α-THP). Neurosteroids have been shown to promote sexual maturation, antidepressant, and anxiolytic effects in animal studies [33]. 5ARIs can reduce neurosteroid production[34, 35].
In an open-label prospective study lasting 52 weeks, 120 patients with AGA received oral 0.5 mg dutasteride. The researchers used the Columbia Suicide Severity Rating Scale to assess suicidal tendencies. At week 52, a patient had suicidal ideation and two patients had depressive symptoms ,which were considered as possibly AEs related to suicide [23]. A single-center retrospective study lasting 12 months found that among 307 patients with AGA aged 18 to 79 who received oral dutasteride treatment, three patients experienced mood disorders[25].
A meta-analysis has found that 5ARIs can increase the risk of developing depression, especially inpatients with risk factors or a history of depression. Clinicians should consider this information carefully[36]. Another cohort study has shown that male patients aged 50 to 90 who undergo 5ARIs treatment may have an increased risk of developing depression, with no difference in risk between finasteride and dutasteride. Furthermore, neither of these medications has been associated with suicide[37].
2.3. Other adverse events
In a case report, a 25-year-old man had taken 0.5 mg of dutasteride every other day to treat hair loss. After nine months, the patient developed cerebral venous thrombosis. The patient had no other prothrombotic conditions and was not taking any medications that could cause thrombosis. It is speculated that elevated estrogen levels caused by dutasteride may have led to the formation of the thrombus[38]. Two reviews proposed that DHT plays an essential role in liver physiology, pancreatic β-cell function and survival, eye function, prevention of dry eye, and kidney physiology. Therefore, inhibition of 5α-reductase with dutasteride or finasteride to reduce DHT biosynthesis may lead to non-alcoholic fatty liver disease, insulin resistance, type 2 diabetes mellitus, dry eye, potential renal dysfunction, and other metabolic dysfunctions[39, 40].
Efficacy and adverse events of mesotherapy with dutasteride
Microneedle combined with dutasteride solution
Dutasteride in patients with female pattern hair loss
Transdermal drug delivery system of dutasteride
Limitation
We selected only the PubMed database as the source of our literature. Due to economic and technical constraints, a very small number of citations were not available in full text for deeper analysis.
Conclusion
The efficacy of oral dutasteride is better than finasteride, and their tolerability is similar. Most adverse events are mild and reversible. It is an effective option for the treatment of AGA. Mesotherapy with dutasteride can be effective in patients with AGA, but standardized treatment protocols and large-scale clinical trials are needed to further validate its efficacy and safety. Microneedling combined with dutasteride solution also has its own unique efficacy for treating AGA. Liposomes or lipid nanoparticles of dutasteride are still under development and may become a more optimized topical agent in the future.
Background
Androgenetic alopecia (AGA) is a common skin disease characterized by gradually miniaturized hair follicles, which manifests as progressive hair thinning and produces a bald appearance. Currently, finasteride is approved by the Food and Drug Administration (FDA) for the treatment of AGA, but its efficacy remains poor in some patients.
Summary
Compared to finasteride, oral dutasteride has better efficacy and similar tolerability, and most adverse events are mild and reversible, making it an effective option for AGA, but its sexual adverse events and potential psychiatric risks still need to be concerned. Mesotherapy with dutasteride and microneedling combined with dutasteride solution can reduce adverse events caused by oral medication and exhibit certain efficacy, but standardized treatment protocols and large-scale clinical trials are still needed in the future. Liposomes or nanoparticles of dutasteride are under development and may become an efficient topical formulation.
Key Messages
We have summarized the efficacy and adverse events of dutasteride in treating AGA under different administration methods and the promise of novel topical drug carriers.
Introduction
Androgenetic alopecia (AGA) is a common disease of multifactorial inheritance characterized by progressive hair loss. In male patients, AGA manifests itself as a receding frontal hairline and (or) progressive reduction and thinning of hair on the scalp, also known as male pattern baldness [1]. In female patients, AGA is characterized by progressive reduction and thinning of hair without receding of the frontal hairline, also known as female pattern hair loss[2]. The prevalence of AGA was reported to be 50% in Caucasian men and 19% in Caucasian women[3, 4]. In China, the prevalence of male AGA was 21.3%, while for females, it was 6.0% [5]. The prevalence of AGA was 14.6% in African men and 3.5% in African women [6]. Asian and African populations had a lower prevalence than Caucasians. The results above indicate that there are racial differences and regional differences in the prevalence of AGA.
The primary pathogenesis of AGA is that 5α-reductase converts testosterone into dihydrotestosterone (DHT), which binds to the androgen receptor, thus inhibiting the Wnt/β-cyclin signaling pathway, and reducing the role of papilla cells in inducing and sustaining hair growth[7]. Eventually, genetically susceptible hair follicles are gradually miniaturized and terminal hairs grown from them are replaced by vellus hairs[8]. At the same time, the dynamics of the hair cycle change: the duration of the anagen phase gradually decreases, while the telogen phase increases. The duration of the anagen phase determines the length of the hair, so the new anagen hairs become shorter, gradually producing a bald appearance[9].
There are three isozymes of 5α-reductase: type I, type II, and type III. Type I and type II have been isolated from the scalp of AGA patients[10]. Type III mRNA expression has also been detected in anagen hairs [11]. Dutasteride and finasteride are both 5α-reductase inhibitors (5ARIs). Currently,only two drugs, topical minoxidil and oral finasteride, have been approved by the FDA for the treatment of AGA. The FDA has approved a dose of 0.5 mg/d of dutasteride for the treatment of benign prostatic hyperplasia (BPH) [12], but for male patients with AGA, only South Korea and Japan have approved the use of dutasteride [13][14]. Finasteride selectively inhibits type II 5α-reductase, while dutasteride inhibits type I and type II 5α-reductase. Finasteride (5 mg/d) can reduce scalp DHT by approximately 41%, while dutasteride (0.5 mg/d) can reduce scalp DHT by approximately 51% [15]. Another study measured the concentration of medication and DHT in the hair and found that finasteride and dutasteride reduced hair DHT levels by approximately 64% and 92%, respectively[16].Therefore, for patients with AGA who do not respond well to finasteride, dutasteride may be a better option.
Results
Pharmacology of dutasteride
Dutasteride can form a stable enzyme complex with 5α-reductase isozymes, thus inhibiting the conversion of testosterone to DHT. Dutasteride at a dose of 0.5 mg/d can reduce serum DHT levels by approximately 92%, while finasteride at 5 mg/d can reduce serum DHT levels by approximately 73%[15]. Due to the participation of 5α-reductase in the synthesis of neurosteroids such as 3α,5αtetrahydroprogesterone (3α,5α-THP) and tetrahydrodeoxycorticosterone (THDOC), dutasteride can also have inhibitory effects on their production[17].
Absorption
After taking a 0.5 mg soft capsule, the maximum blood concentration (Cmax) of dutasteride is averaged at 1.27 ng/ml, occurring between 1-3 hours. Absolute bioavailability in healthy individuals is approximately 60% (range: 40%-94%) [18].
Distribution
Dutasteride is widely distributed in the human circulation and has a high binding affinity to plasma albumin (99%) and α-1 acid glycoprotein (96.6%) [18].
Metabolism and Excretion
Dutasteride is extensively metabolized in the liver by the cytochrome P450 (CYP) isoenzymes CYP3A4 and CYP3A5. There are 5 metabolites in human serum: 3 main metabolites (4'-hydroxydutasteride, 1,2-dihydroxydutasteride, 6-hydroxydutasteride) and 2 minor metabolites (6,4'-dihydroxydutasteride, 15-hydroxydutasteride). Due to its long half-life, dutasteride remains detectable in serum (>0.1 ng/mL) for 4-6 weeks after discontinuation of therapy. The terminal elimination half-life of dutasteride in steady state is approximately five weeks[18]. Men treated with dutasteride should not donate blood until at least six months after discontinuation of the drug to prevent the use of dutasteride in pregnant women receiving blood transfusions[15]. Feces is the main mode of excretion of dutasteride and its metabolites[18].
Efficacy and adverse events of oral dutasteride
1. Efficacy
There are four double-blind, randomized, placebo-controlled trials [15, 19-21] and one prospective, evaluator-blinded, open-label, randomized controlled trial [22] using average changes in target are a hair count as the efficacy endpoint. To compare the efficacy of different trials, we standardized the units for average changes in target area hair count before and after 24 weeks of treatment to "number of hairs/cm2" (shown in Table 1). At week 24, the increase in hair count in the 0.5 mg dutasteride group was superior to the finasteride group [15, 19, 22], while the 0.1 mg dutasteride group was similar to the finasteride group [15, 19], and the treatment groups were significantly better than the placebo group [15, 19-21]. For the increase in the placebo group in Table 1, the researchers believed that it may be related to the season; Many of the subjects in that trial were enrolled in early spring, and the percentage of scalp anagen hair peaked at more than 90% in March and then gradually declined [20]. In terms of global photographic assessment, the panel of experts (composed of dermatologists) evaluated scalp vertex and frontal photographs before and after 24 weeks, and concluded that the 0.5 mg dutasteride group was superior to the finasteride group [15, 19, 22] and that all treatment groups were superior to placebo group[15, 19-21]. In terms of subjects’ self assessments, the researchers scored using the Hair Growth Index and Hair Growth Satisfaction Scale or similar questionnaires. In the 24th week, several studies suggested that the 0.5 mg dutasteride group was superior to the finasteride group[19, 22], and only one study found it not superior to the finasteride group[15], in which the finasteride group received a dose of 5 mg/d. The other studies used a dose of 1 mg/d. Each treatment group was superior to the placebo group [15, 19-21].
In a prospective open-label study of 120 AGA patients treated with 0.5 mg dutasteride for 52 weeks, the average hair count, hair width and global photographic assessment (vertex and frontal of the scalp) improved from baseline at weeks 26 and 52, and the proportion of patients with improvement ranged from 76% to 85%. The improvements in hair width and terminal hair count at week 52 continued compared with week 26 [23]. In a retrospective study of 26 male patients with AGA who took 0.5 mg dutasteride orally for more than 52 weeks, 84.62% of the patients self-reported improvement or maintenance [24]. Another retrospective study included 42 patients with AGA who only took dutasteride 2-7 times a week for at least 12 months, and researchers found that efficacy was associated with a higher frequency of medication through a comparison of overall hair appearance[25].
A 6-month retrospective study included 246 patients with AGA who received 1 mg finasteride and 249 patients who received 0.5 mg dutasteride orally. By evaluating photos before and after treatment, the researchers concluded that dutasteride was superior to finasteride in improving the overall appearance of hair [26]. In another retrospective study with an observation period of more than three years, researchers concluded that the 0.5 mg dutasteride group (n=250) was superior to 1 mg finasteride group (n=285) in improving the clinical grade of AGA in men (Basic and specific classification) [27]. Furthermore, a retrospective study included 99 male AGA patients who used dutasteride for more than five years. The researchers scored clinical photos of the frontal and vertex of the scalp, concluding that using 0.5 mg of dutasteride for at least 5 years is a safe and effective treatment that can provide good results for male AGA patients [28].
A study included 35 patients with AGA who did not show a significant clinical improvement after six months of finasteride treatment (1 mg/d). They received treatment with dutasteride at a dose of 0.5mg/d for six months. Compared to finasteride treatment, hair density and thickness increased by 10.3% (9 /cm2) and 18.9% (10μm), respectively. However, the study did not include a control group that continued to take finasteride[29].
2. Adverse events
2.1. Sexual adverse events
Since DHT plays a key role in erectile physiology, including activation of nitric oxide synthase and increased blood flow to penile tissue, inhibition of 5α-reductase by finasteride or dutasteride leads to erectile dysfunction. Furthermore, deficiency or reduced levels of DHT can cause the death of smooth muscle cells in the penile trabeculae, accompanied by increased deposition of connective tissue, resulting in structural changes in the penile tissue and hindering its compliance, ultimately leading to erectile dysfunction[30].
Four randomized, double-blind, placebo-controlled trials [15, 19, 20, 31] were conducted to compare the incidence of sexual adverse events (AEs) between treatment groups and placebo groups, one of which was unblinded after 24 weeks and changed to open-label dutasteride [31] (shown in Table 2). Sexual AEs included altered libido, impotence, ejaculation disorders, breast enlargement and breast tenderness[19]. The incidence of sexual AEs in the dutasteride group appeared to be similar to the finasteride group [15, 19], while the incidence of sexual AEs in the placebo group was similar to or lower than that in the treatment group[15, 19, 20, 31].
An open-label prospective 52-week study enrolling 120 patients with AGA taking 0.5 mg of oral dutasteride showed an overall incidence of 17% of drug-related AEs. Sexual AEs (15.8%) were the most common drug-related AEs, particularly erectile dysfunction and decreased libido. The incidence of most sexual AEs was high in the first six months and decreased in the subsequent six months. Of the 19 patients (15.8%) who reported AEs of sexual dysfunction, 6 patients (5%) were relieved during the 52-week treatment period; 13 patients (10.8%) achieved a recovery during the 6-month follow up period after discontinuation of treatment [23]. A single-center retrospective study lasting more than 12 months found that among 307 patients with AGA aged 18 to 79 years who were treated with dutasteride, sexual AEs occurred in 20 cases (6.5%) when the dose ranged from 1 to 7 tablets per week. Among the 12 patients who took 0.5 mg of finasteride 2-3 times a week, no sexual AEs were reported. Researchers suggest that this dose regimen can be used for patients with AGA who were concerned about sexual AEs [25].
In a 48-week study, the first 24 weeks were a randomized, double-blind, placebo-controlled study, and the last 24 weeks were open-label 0.5 mg dutasteride treatment. During the double-blind period, the incidence of sexual AEs in the dutasteride group (16%) was approximately twice that of the placebo group (8%); during the open-label period, the overall incidence of sexual AEs was lower (5%)[31]. All AEs were mild to moderate in severity and were considered related to treatment. Most sexual AEs occurred within the first three months of dutasteride treatment and resolved during or after study treatment. The mean International Index of Erectile Function (IIEF) Questionnaire-Erectile Function domain scores remained stable in the placebo group during the first 24 weeks, while the dutasteride group showed a trend toward worse erectile function from baseline to double blind weeks 12 and 24 [31]
In a 1-year randomized, double-blind, placebo-controlled trial, 99 healthy men were randomized to dutasteride (0.5 mg), finasteride (5 mg) or placebo orally once daily. At 26 weeks, total sperm counts in the dutasteride and finasteride groups decreased by 28.6% and 34.3%, respectively, compared to baseline. At 52 weeks, the total sperm count decreased by 24.9% and 16.2%, the semen volume decreased by 29.7% and 14.5%, and the sperm concentration decreased by 3.2% and 7.4%, respectively. Sperm motility was significantly reduced by 6% to 12% during both treatment and follow-up. Neither treatment had any effect on sperm morphology. The decrease in semen parameters was reversible after discontinuation of the drug[32].
2.2. Mental adverse events
5α-reductase is involved in the production of neurosteroids [17]. Animal studies have shown that in the brain, 5α-reductase catalyzes progesterone into 5α-dihydroprogesterone (5α-DHP), which is further catalyzed by 3α-hydroxysteroid dehydrogenase (3α-HSD) into the potent neurosteroid 3α,5α-tetrahydroprogesterone (3α, 5α-THP). Neurosteroids have been shown to promote sexual maturation, antidepressant, and anxiolytic effects in animal studies [33]. 5ARIs can reduce neurosteroid production[34, 35].
In an open-label prospective study lasting 52 weeks, 120 patients with AGA received oral 0.5 mg dutasteride. The researchers used the Columbia Suicide Severity Rating Scale to assess suicidal tendencies. At week 52, a patient had suicidal ideation and two patients had depressive symptoms ,which were considered as possibly AEs related to suicide [23]. A single-center retrospective study lasting 12 months found that among 307 patients with AGA aged 18 to 79 who received oral dutasteride treatment, three patients experienced mood disorders[25].
A meta-analysis has found that 5ARIs can increase the risk of developing depression, especially inpatients with risk factors or a history of depression. Clinicians should consider this information carefully[36]. Another cohort study has shown that male patients aged 50 to 90 who undergo 5ARIs treatment may have an increased risk of developing depression, with no difference in risk between finasteride and dutasteride. Furthermore, neither of these medications has been associated with suicide[37].
2.3. Other adverse events
In a case report, a 25-year-old man had taken 0.5 mg of dutasteride every other day to treat hair loss. After nine months, the patient developed cerebral venous thrombosis. The patient had no other prothrombotic conditions and was not taking any medications that could cause thrombosis. It is speculated that elevated estrogen levels caused by dutasteride may have led to the formation of the thrombus[38]. Two reviews proposed that DHT plays an essential role in liver physiology, pancreatic β-cell function and survival, eye function, prevention of dry eye, and kidney physiology. Therefore, inhibition of 5α-reductase with dutasteride or finasteride to reduce DHT biosynthesis may lead to non-alcoholic fatty liver disease, insulin resistance, type 2 diabetes mellitus, dry eye, potential renal dysfunction, and other metabolic dysfunctions[39, 40].
Efficacy and adverse events of mesotherapy with dutasteride
Microneedle combined with dutasteride solution
Dutasteride in patients with female pattern hair loss
Transdermal drug delivery system of dutasteride
Limitation
We selected only the PubMed database as the source of our literature. Due to economic and technical constraints, a very small number of citations were not available in full text for deeper analysis.
Conclusion
The efficacy of oral dutasteride is better than finasteride, and their tolerability is similar. Most adverse events are mild and reversible. It is an effective option for the treatment of AGA. Mesotherapy with dutasteride can be effective in patients with AGA, but standardized treatment protocols and large-scale clinical trials are needed to further validate its efficacy and safety. Microneedling combined with dutasteride solution also has its own unique efficacy for treating AGA. Liposomes or lipid nanoparticles of dutasteride are still under development and may become a more optimized topical agent in the future.
