madman
Super Moderator
What’s New in Therapy for Male Androgenetic Alopecia? (2022)
David Saceda‑Corralo · Miguel Domínguez‑Santas · Sergio Vañó‑Galván · Ramon Grimalt
Abstract
Male androgenetic alopecia is a common condition and represents a major concern for patients who experience this condition. While there are different treatments to stop hair loss and improve hair density, the 5-alpha reductase inhibitors have been demonstrated to be effective in improving androgenetic alopecia in men and can maintain a positive response for many years. Oral finasteride 1 mg is a US FDA-approved option, but dutasteride 0.5 mg has been proven to induce better responses, especially in the frontal area. Both have been shown to be safe in clinical trials but there is widespread concern about sexual adverse effects among patients. The use of topical finasteride has increased during the last few years as a useful option to avoid systemic therapy. The efficacy of topical finasteride 0.25% daily has been demonstrated in clinical trials, with a less marked decrease in serum dihydrotestosterone levels than with oral intake. Mesotherapy with dutasteride has also become more widespread recently, although evidence of its effectiveness is limited to retrospective studies in real clinical practice. The use of oral minoxidil in androgenetic alopecia has not been approved by the FDA, however, several clinical studies have shown that it is an effective treatment option. The initial dose recommended to treat male hair loss is 2.5 mg daily, although the dose is frequently increased to 5 mg daily. The main adverse effect of oral minoxidil is hypertrichosis, followed by dizziness or lower limb edema, which are much less common. Platelet-rich plasma is a non-pharmacological option to treat male androgenetic alopecia, with some clinical trials demonstrating an improvement in hair count after several months. Among the published studies, the main limitation to comparing its efficacy is the heterogeneity of the procedure. The most frequent regimens propose treatment every 4 weeks for 3 months initially to assess the individual response. Another treatment alternative is the use of light devices with wavelengths of between 630 and 660 nm, known as low-level laser therapy. These devices can be used at home every day for 15–30 min. Their efficacy has been shown in a limited number of clinical trials; however, there is a lack of evidence about the efficacy of these devices compared with other medical options or as a complementary therapy in hair loss. The pipeline of potential new treatments for male androgenetic alopecia is strong. Pyrilutamide and GT20029 are being studied as topical antagonists of the androgen receptor, while cetirizine is another topical option with some initial promising results. Furthermore, according to isolated studies with heterogeneous treatment schemes, the use of botulinum toxin in the scalp might improve androgenetic alopecia, and lastly, scalp threading might increase the total hair count as growth factors are released during implantation.
Introduction
Androgenetic alopecia (AGA) is the most frequent cause of hair loss in men and women. According to epidemiological studies, 80% of Caucasian men and 40–50% of women will develop AGA over the course of their lifetime [1]. AGA is characterized by a decrease in hair density in androgenetic areas of the scalp due to progressive miniaturization of the hair follicle. The etiopathogenesis is multifactorial and complex [2].
The objective of this review was not to make a systematic review of the published evidence in male AGA but to compile the most interesting, updated options for this condition.
2 Oral 5‑Alpha Reductase Inhibitors
Androgens play an important role in androgenetic hair loss. The influence of testosterone is especially relevant in men and is still controversial in women [3, 4]. The activity of the 5-alpha-reductase (5-AR) enzyme converts free testosterone into 5-alpha-dihydrotestosterone. Later, it binds to the androgen receptor in the dermal papilla of the hair follicle and activates the genes responsible for gradual hair loss; this occurs in genetically susceptible people. After several hair cycles, the duration of the anagen phase shortens, and the matrix size decreases, resulting in clinically evident miniaturized hairs [4].
Peripheral antiandrogens, such as 5-AR inhibitors, have been proven to be effective in stopping this mechanism and also in reversing hair thinning. Oral finasteride, which inhibits the type II enzyme, is a US FDA-approved drug to treat AGA, while oral dutasteride inhibits both types I and II enzymes and has already been approved for the treatment of AGA in Japan and South Korea.
*The systemic use of 5-AR inhibitors has been related to sexual adverse effects (AE), including sexual impotence, ejaculation disorders, and decreased libido.
*Despite the evidence-based data, these AEs represent a primary concern for patients considering treatment, and the possibility of sexual AEs due to a nocebo effect must be considered. Most of these patients have a resolution of sexual AEs after discontinuation of 5-AR inhibitors, although some studies describe a group of patients with persistent sexual dysfunction after stopping treatment [14]. This condition, termed post-finasteride syndrome, is still a controversial issue in the medical community.
3 Oral Minoxidil
Topical minoxidil is an FDA-approved treatment for AGA in men. Applied on the scalp, the minoxidil molecule is converted into minoxidil sulfate by sulfotransferase enzymes located in the outer root sheath of the hair follicle.
*Oral minoxidil is approved as an antihypertensive, with doses ranging between 10 and 40 mg daily [22]. The most frequent AEs are hypertrichosis, tachycardia, and lower-limb edema.
4 Topical Finasteride
Finasteride is an FDA-approved treatment for male AGA. Clinical studies of oral finasteride 1 mg daily demonstrated that treatment stopped hair loss and improved hair density compared with placebo. There is also sufficient data to confirm a sustained effect for 5–10 years after the start of treatment [35]. Finasteride is generally well tolerated but the use of 5-AR inhibitors is associated with sexual AEs. Oral finasteride has also been related to an increased risk of depression. A population-based, retrospective, matched cohort study was designed to evaluate whether 5-AR inhibitors were associated with an increased risk of depression or committing suicide. While the suicide risk did not vary, there was an increase in the incidence of depression in the 5-AR inhibitor cohort [36]. Topical use of finasteride may reduce or avoid these systemic AEs while maintaining clinical efficacy.
5 Platelet‑Rich Plasma
Platelet-rich plasma (PRP) has been accepted as a potential therapy for hair loss and consists of autologous blood-derived plasma with increased platelet concentrations. The patient’s own blood is centrifuged to obtain this product. The platelets contain multiple growth factors and once activated, they are released into the scalp after local injection. Some of these growth factors are the vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β, epithelial growth factor (EGF), and insulin-like growth factor (IGF) [43].
6 Low‑Level Laser Therapy
Low-level laser therapy (LLLT) is a non-invasive therapy for treating hair loss. It has been demonstrated that low fluences of light devices can induce hair thickening and longer anagen phases [48]. LLLT may have anti-inflammatory properties, as was observed in the treatment of other cicatricial alopecias [49]. The use of LLLT in clinical practice is not well standardized. The devices used vary from helmets or caps to combs [50, 52]. According to the evidence, it is recommended to use wavelengths of between 630 and 660 nm, for 15–30 min, and with a periodicity between daily or three times per week [53]. In fact, one of the limitations found in this meta-analysis was the high heterogeneity among clinical trials. Despite the continuing controversy, LLLT is one of the male AGA treatments that have more available published evidence for its use [53].
7 New Emerging Therapies
New investigational drugs are being developed for AGA. Although some preliminary results are promising, we advise caution and waiting for new data.
Topical antiandrogens can be useful in the management of AGA. Besides topical finasteride, antagonists of androgen receptors such as pyrilutamide have been developed. This drug has been evaluated in phase I clinical trials for AGA in men and the results are not available yet [54]. If it is shown to be safe and effective, its topical administration would open the doors to the use of direct androgen receptor antagonists in men. Further interesting research is focused on GT20029, a molecule that will be evaluated in phase I clinical trials [55]. It would be the first topical drug that uses the PROTAC (Proteolysis Targeting Chimera) technology for hair loss. It captures the androgen receptor and induces its degradation through ubiquitin-mediated proteolysis.
Another potentially effective topical option is cetirizine. A study in 85 male patients showed that topical cetirizine 1% might induce an improvement of total hair density compared with placebo after 6 months [56]. The possible explanation for these results is that cetirizine may reduce the levels of prostaglandin D2, which is supposed to stop hair loss in AGA. However, the study had significant limitations, as the control group was much smaller than the treatment group and it was clearly not randomized. In addition, the presentation of the results was confusing and there are no other studies supporting this therapy.
The pathway of prostaglandin synthesis has captured the interest of researchers in the last few years. A prostaglandin D2 inhibitor, setipiprant, was a very interesting option for the treatment of AGA. A phase III clinical trial comparing it with placebo and finasteride has recently finished [57]. Male patients with grade III or higher AGA took 1g of setipiprant every 12 hours for 24 weeks. The outcomes at week 24 and week 32 showed that setipiprant was not better than placebo in AGA.
Botulinum toxin (BT) is a well-known treatment in aesthetic dermatology. In the last few years, it has been proposed as a treatment option in AGA. There are a couple of hypotheses about how it might work in hair loss. Firstly, the block of presynaptic release of acetylcholine may induce a relaxation of scalp muscles that promotes a local increase of blood flow with an increase of oxygen and a decrease of DHT. Secondly, BT has been demonstrated to reduce the gene transcription of TGF-β that is induced after the activation of the androgen receptor by DHT [58]. TGF-β is a promoter of follicular fibrosis associated with miniaturization in AGA. Two studies propose injections in 30 different sites of 5 IU of BT (a total of 150 IU) with different treatment regimens. First, Freund et al. treated 40 subjects every 6 weeks and observed an increase in total hair count of 18% after 1 year [59]. Second, Singh et al. performed the injections every 4 weeks for 6 months in 10 patients [60]. They observed a clinical improvement in 7 patients. Further research is needed to consider BT as a useful treatment in AGA.
Finally, an interesting non-medical treatment for AGA has arisen with scalp threading. Scalp micro needling releases growth factors, e.g. platelet-derived growth factor, and it is believed that the use of polydioxanone (PDO) threads can induce the same effect. A pilot study showed an increase in total hair counts at 12 weeks in 5 patients [61]. Further research will elucidate if it is an effective treatment for AGA
8 Conclusions
The options for treatment in male AGA have multiplied in recent years. According to the published evidence, oral dutasteride and oral minoxidil are probably some of the most effective medical treatments available. However, their use is limited as neither are FDA-approved options for hair loss. For patients concerned about AEs produced by oral medication, topical finasteride is very useful. Mesotherapy with dutasteride, PRP, and LLLT remain complementary options for patients who are receiving other concomitant treatments.
David Saceda‑Corralo · Miguel Domínguez‑Santas · Sergio Vañó‑Galván · Ramon Grimalt
Abstract
Male androgenetic alopecia is a common condition and represents a major concern for patients who experience this condition. While there are different treatments to stop hair loss and improve hair density, the 5-alpha reductase inhibitors have been demonstrated to be effective in improving androgenetic alopecia in men and can maintain a positive response for many years. Oral finasteride 1 mg is a US FDA-approved option, but dutasteride 0.5 mg has been proven to induce better responses, especially in the frontal area. Both have been shown to be safe in clinical trials but there is widespread concern about sexual adverse effects among patients. The use of topical finasteride has increased during the last few years as a useful option to avoid systemic therapy. The efficacy of topical finasteride 0.25% daily has been demonstrated in clinical trials, with a less marked decrease in serum dihydrotestosterone levels than with oral intake. Mesotherapy with dutasteride has also become more widespread recently, although evidence of its effectiveness is limited to retrospective studies in real clinical practice. The use of oral minoxidil in androgenetic alopecia has not been approved by the FDA, however, several clinical studies have shown that it is an effective treatment option. The initial dose recommended to treat male hair loss is 2.5 mg daily, although the dose is frequently increased to 5 mg daily. The main adverse effect of oral minoxidil is hypertrichosis, followed by dizziness or lower limb edema, which are much less common. Platelet-rich plasma is a non-pharmacological option to treat male androgenetic alopecia, with some clinical trials demonstrating an improvement in hair count after several months. Among the published studies, the main limitation to comparing its efficacy is the heterogeneity of the procedure. The most frequent regimens propose treatment every 4 weeks for 3 months initially to assess the individual response. Another treatment alternative is the use of light devices with wavelengths of between 630 and 660 nm, known as low-level laser therapy. These devices can be used at home every day for 15–30 min. Their efficacy has been shown in a limited number of clinical trials; however, there is a lack of evidence about the efficacy of these devices compared with other medical options or as a complementary therapy in hair loss. The pipeline of potential new treatments for male androgenetic alopecia is strong. Pyrilutamide and GT20029 are being studied as topical antagonists of the androgen receptor, while cetirizine is another topical option with some initial promising results. Furthermore, according to isolated studies with heterogeneous treatment schemes, the use of botulinum toxin in the scalp might improve androgenetic alopecia, and lastly, scalp threading might increase the total hair count as growth factors are released during implantation.
Introduction
Androgenetic alopecia (AGA) is the most frequent cause of hair loss in men and women. According to epidemiological studies, 80% of Caucasian men and 40–50% of women will develop AGA over the course of their lifetime [1]. AGA is characterized by a decrease in hair density in androgenetic areas of the scalp due to progressive miniaturization of the hair follicle. The etiopathogenesis is multifactorial and complex [2].
The objective of this review was not to make a systematic review of the published evidence in male AGA but to compile the most interesting, updated options for this condition.
2 Oral 5‑Alpha Reductase Inhibitors
Androgens play an important role in androgenetic hair loss. The influence of testosterone is especially relevant in men and is still controversial in women [3, 4]. The activity of the 5-alpha-reductase (5-AR) enzyme converts free testosterone into 5-alpha-dihydrotestosterone. Later, it binds to the androgen receptor in the dermal papilla of the hair follicle and activates the genes responsible for gradual hair loss; this occurs in genetically susceptible people. After several hair cycles, the duration of the anagen phase shortens, and the matrix size decreases, resulting in clinically evident miniaturized hairs [4].
Peripheral antiandrogens, such as 5-AR inhibitors, have been proven to be effective in stopping this mechanism and also in reversing hair thinning. Oral finasteride, which inhibits the type II enzyme, is a US FDA-approved drug to treat AGA, while oral dutasteride inhibits both types I and II enzymes and has already been approved for the treatment of AGA in Japan and South Korea.
*The systemic use of 5-AR inhibitors has been related to sexual adverse effects (AE), including sexual impotence, ejaculation disorders, and decreased libido.
*Despite the evidence-based data, these AEs represent a primary concern for patients considering treatment, and the possibility of sexual AEs due to a nocebo effect must be considered. Most of these patients have a resolution of sexual AEs after discontinuation of 5-AR inhibitors, although some studies describe a group of patients with persistent sexual dysfunction after stopping treatment [14]. This condition, termed post-finasteride syndrome, is still a controversial issue in the medical community.
3 Oral Minoxidil
Topical minoxidil is an FDA-approved treatment for AGA in men. Applied on the scalp, the minoxidil molecule is converted into minoxidil sulfate by sulfotransferase enzymes located in the outer root sheath of the hair follicle.
*Oral minoxidil is approved as an antihypertensive, with doses ranging between 10 and 40 mg daily [22]. The most frequent AEs are hypertrichosis, tachycardia, and lower-limb edema.
4 Topical Finasteride
Finasteride is an FDA-approved treatment for male AGA. Clinical studies of oral finasteride 1 mg daily demonstrated that treatment stopped hair loss and improved hair density compared with placebo. There is also sufficient data to confirm a sustained effect for 5–10 years after the start of treatment [35]. Finasteride is generally well tolerated but the use of 5-AR inhibitors is associated with sexual AEs. Oral finasteride has also been related to an increased risk of depression. A population-based, retrospective, matched cohort study was designed to evaluate whether 5-AR inhibitors were associated with an increased risk of depression or committing suicide. While the suicide risk did not vary, there was an increase in the incidence of depression in the 5-AR inhibitor cohort [36]. Topical use of finasteride may reduce or avoid these systemic AEs while maintaining clinical efficacy.
5 Platelet‑Rich Plasma
Platelet-rich plasma (PRP) has been accepted as a potential therapy for hair loss and consists of autologous blood-derived plasma with increased platelet concentrations. The patient’s own blood is centrifuged to obtain this product. The platelets contain multiple growth factors and once activated, they are released into the scalp after local injection. Some of these growth factors are the vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β, epithelial growth factor (EGF), and insulin-like growth factor (IGF) [43].
6 Low‑Level Laser Therapy
Low-level laser therapy (LLLT) is a non-invasive therapy for treating hair loss. It has been demonstrated that low fluences of light devices can induce hair thickening and longer anagen phases [48]. LLLT may have anti-inflammatory properties, as was observed in the treatment of other cicatricial alopecias [49]. The use of LLLT in clinical practice is not well standardized. The devices used vary from helmets or caps to combs [50, 52]. According to the evidence, it is recommended to use wavelengths of between 630 and 660 nm, for 15–30 min, and with a periodicity between daily or three times per week [53]. In fact, one of the limitations found in this meta-analysis was the high heterogeneity among clinical trials. Despite the continuing controversy, LLLT is one of the male AGA treatments that have more available published evidence for its use [53].
7 New Emerging Therapies
New investigational drugs are being developed for AGA. Although some preliminary results are promising, we advise caution and waiting for new data.
Topical antiandrogens can be useful in the management of AGA. Besides topical finasteride, antagonists of androgen receptors such as pyrilutamide have been developed. This drug has been evaluated in phase I clinical trials for AGA in men and the results are not available yet [54]. If it is shown to be safe and effective, its topical administration would open the doors to the use of direct androgen receptor antagonists in men. Further interesting research is focused on GT20029, a molecule that will be evaluated in phase I clinical trials [55]. It would be the first topical drug that uses the PROTAC (Proteolysis Targeting Chimera) technology for hair loss. It captures the androgen receptor and induces its degradation through ubiquitin-mediated proteolysis.
Another potentially effective topical option is cetirizine. A study in 85 male patients showed that topical cetirizine 1% might induce an improvement of total hair density compared with placebo after 6 months [56]. The possible explanation for these results is that cetirizine may reduce the levels of prostaglandin D2, which is supposed to stop hair loss in AGA. However, the study had significant limitations, as the control group was much smaller than the treatment group and it was clearly not randomized. In addition, the presentation of the results was confusing and there are no other studies supporting this therapy.
The pathway of prostaglandin synthesis has captured the interest of researchers in the last few years. A prostaglandin D2 inhibitor, setipiprant, was a very interesting option for the treatment of AGA. A phase III clinical trial comparing it with placebo and finasteride has recently finished [57]. Male patients with grade III or higher AGA took 1g of setipiprant every 12 hours for 24 weeks. The outcomes at week 24 and week 32 showed that setipiprant was not better than placebo in AGA.
Botulinum toxin (BT) is a well-known treatment in aesthetic dermatology. In the last few years, it has been proposed as a treatment option in AGA. There are a couple of hypotheses about how it might work in hair loss. Firstly, the block of presynaptic release of acetylcholine may induce a relaxation of scalp muscles that promotes a local increase of blood flow with an increase of oxygen and a decrease of DHT. Secondly, BT has been demonstrated to reduce the gene transcription of TGF-β that is induced after the activation of the androgen receptor by DHT [58]. TGF-β is a promoter of follicular fibrosis associated with miniaturization in AGA. Two studies propose injections in 30 different sites of 5 IU of BT (a total of 150 IU) with different treatment regimens. First, Freund et al. treated 40 subjects every 6 weeks and observed an increase in total hair count of 18% after 1 year [59]. Second, Singh et al. performed the injections every 4 weeks for 6 months in 10 patients [60]. They observed a clinical improvement in 7 patients. Further research is needed to consider BT as a useful treatment in AGA.
Finally, an interesting non-medical treatment for AGA has arisen with scalp threading. Scalp micro needling releases growth factors, e.g. platelet-derived growth factor, and it is believed that the use of polydioxanone (PDO) threads can induce the same effect. A pilot study showed an increase in total hair counts at 12 weeks in 5 patients [61]. Further research will elucidate if it is an effective treatment for AGA
8 Conclusions
The options for treatment in male AGA have multiplied in recent years. According to the published evidence, oral dutasteride and oral minoxidil are probably some of the most effective medical treatments available. However, their use is limited as neither are FDA-approved options for hair loss. For patients concerned about AEs produced by oral medication, topical finasteride is very useful. Mesotherapy with dutasteride, PRP, and LLLT remain complementary options for patients who are receiving other concomitant treatments.
