New trends in the treatment of androgenetic alopecia

Introduction

Androgenetic alopecia (AGA) is the most common type of non-cicatricial alopecia located on the scalp over the galea aponeurotica/epicranial aponeurosis. The condition’s aetiology is multifactorial, with genetic predisposition and androgen influence being the most significant factors [1, 2]. The development of the condition results in shortening of the anagen and prolongation of the telogen phase, gradual miniaturisation of the hair follicle, and complete involution (fig. 1) [3–5]. Topical minoxidil and oral finasteride are the treatments approved by the US Food and Drug Administration. Other popular methods include platelet-rich plasma and fibrin, low-level laser therapy, microneedling, oral minoxidil and injectable 5α-reductase inhibitors. Due to a very high demand from affected patients and market expectations, the research regarding enrichment of the available therapies is carried out. In the study, six procedures worth discussing are analysed.

Minoxidil

The drug was originally used as a hypotensive agent in cardiology, but has attracted attention because of its potential for the treatment of androgenetic alopecia due to its ability to induce hypertrichosis. It regulates K+ channels, which stimulates cell proliferation and influences the cell cycle. Additionally, it has anti-inflammatory effects and can stimulate neoangiogenesis by increasing the expression of vascular endothelial growth factor (VEGF) [6–8]. Although the effects of minoxidil are well-known, its mechanism of action is not fully understood yet. Minoxidil is a prodrug that is converted into its active form, minoxidil sulphate, by sulfotransferase (SULT) within the outer root sheath of the hair follicle (fig. 2) [7, 9, 10]. Approximately 60% of the population has low SULT1A1 activity (follicular variant), which indicates weaker hair regrowth and poorer therapeutic effect [11]. This suggests that higher concentrations of minoxidil solution may be necessary. Currently, a 2% or 5% solution is registered as the first-line therapy. However, solutions ranging from 1% to 15% are also available (tab. 1).
The efficacy of higher concentrations of minoxidil is disputed by the authors]. Although most studies have found higher efficacy with increased concentrations, some have not. The differences in study conditions, patients, and duration of follow-up seem to be key factors (tab. 2).
The low-dose oral form of minoxidil treatment (LDOM) is currently experiencing a resurgence (tab. 1). The initial dose ranges from 0.25 to 5 mg/day, which is significantly lower than the therapeutic range for hypertension (above 10 mg/day) [12–16]. This form of drug application is becoming increasingly popular for several reasons. It is more convenient to use and ensures correct application of the drug as there is no possibility of missing a certain part of the scalp. Additionally, it does not cause local adverse effects such as irritation or allergic contact dermatitis, which are mainly caused by propyl glycol. Despite the possibility of adverse effects such as dizziness, fluid retention, tachycardia, headache, periorbital oedema and insomnia, only 1.7% of patients required treatment discontinuation due to their severity. In most cases, reducing the initial dose was enough to completely resolve the symptoms or make them tolerable for the patient. Due to safety reasons, the suggested starting dose for women is 0.5 mg/day, with an increase of 0.25 mg every 3 months, up to a maximum of 2.5 mg/day. Men, on the other hand, can start from a dose of 2.5 mg/day, with an increase of 1.25 mg (up to maximum of 5 mg/day) [7, 16, 17].

5a-reductase inhibitors

For the treatment of androgenetic alopecia in men, finasteride is the only drug approved at a dose of 1 mg/day [18]. As a type II 5a-reductase inhibitor, it irreversibly binds to the enzyme that converts testosterone to dihydrotestosterone, reducing its blood concentration by approximately 60%. Dutasteride, another 5a-reductase inhibitor, has a more potent effect as it inhibits both type I and type II enzymes. Studies comparing 0.5 mg dutasteride daily with 1 mg finasteride daily have shown an advantage for the former [2, 19–21].
The most common adverse effect of both oral forms of the drugs is a reversible sexual dysfunction, which includes impaired libido, erectile dysfunction, and ejaculatory disorders. There was no statistically significant difference found between the two 5a-reductase inhibitor agents [22]. The half-life of finasteride is approximately 5 hours, while that of dutasteride is approximately 5 weeks. It may be perceived that the cumulative toxicity of dutasteride is higher than that of finasteride. However, a study demonstrated that serum concentrations of dutasteride remained stable with daily dosing over a period of 6 months. Additionally, the effects of 5a-reductase inhibitors on serum and semen composition were investigated for 1 year of daily therapy, and it was concluded that none of the drugs had an effect on sperm morphology. Teratogenic potential is a concern for patients of childbearing age. Finasteride and dutasteride require volumes of 750 ml and 186 ml of semen, respectively, to induce a teratogenic effect [19].
Although oral 5a-reductase inhibitors are generally well tolerated, in some patients they may associate with the above-mentioned side effects. Alternative, topical formulations may be helpful for these individuals. Over the years, studies have compared the efficacy of this therapy against placebo, oral forms of 5a-reductase inhibitors and topical minoxidil (tab. 3) [23–27].
Another increasingly popular alternative to the 5a-reductase inhibitor is injectable route. These can take the form of mesotherapy or a long-acting injectable formulation. Due to the half-life and possible pain associated with intradermal delivery of the drug in the form of mesotherapy, dutasteride is the most common choice. Research on the use of injectable dutasteride has been ongoing since 2009 [28]. Algorithms under study involve the use of a 0.005–0.05% solution at intervals ranging from 1 week to 3 months in both male and female populations [29]. A potential breakthrough in AGA therapy could be the use of loaded microspheres for subcutaneous administration. Due to the lower number of treatments and potential toxicity, papers discuss the use of finasteride in this form of treatment.
Based on an animal model, two groups were identified; the study compared the effects of subcutaneously administered finasteride-loaded microspheres (0.1 ml, 15 mg/ml) on the first day of the experiment with orally applied finasteride (0.1 ml, 0.1 mg/ml) once daily for 56 days. The results showed that the microspheres-treated group had similar values for follicular number, follicular length, anagen/telogen ratio, and hair bulb diameter to those of the orally applied finasteride group [30]. A theoretical drug dose for humans was developed based on animal models and observations of the pharmacokinetics and dynamics of the long-acting injectable formulation of finasteride. The most optimal starting dose was set at 16.80 mg. These conclusions could serve as the foundation for developing a registered medicinal product [31].

Tretinoin

Recent reports suggest that tretinoin, specifically all-trans retinoic acid, a metabolite of retinol, may be useful as an adjunct to the treatment of AGA. Tretinoin is commonly used as a topical treatment for acne vulgaris as it prevents the accumulation of keratinised epidermal cells in the adnexal duct. This unclogs the sebaceous gland outlet, inhibits the formation of inflammatory foci, and prevents the formation of comedones. Furthermore, tretinoin prevents the excessive accumulation of inflammation-causing lipids and fatty acids in the sebaceous glands. It also stimulates epidermal cell mitosis, which accelerates turnover time. The ability of tretinoin to enhance the activity of topical minoxidil was observed by Bazzano et al. in 1986. It was found that similar results could be achieved using a once-daily therapy that combines topical minoxidil 5% with tretinoin 0.01%, compared to monotherapy with topical minoxidil 5% applied twice a day [6, 32]. However, this practice did not become part of the standard procedure due to an unknown mechanism by which tretinoin affects the metabolism of minoxidil and its irritating effect on the skin. Clinicians were hesitant to use this algorithm due to these two aspects. As a result, they replaced it with methods that are fully understood and accepted by the community. It is known now that the formation of an active form of minoxidil, minoxidil sulphate, which causes vasodilation and hair growth, requires the enzyme SULT 1A1 [7]. Tretinoin increases the secretion of this enzyme. Regarding oral minoxidil, which is primarily activated by SULT enzymes in the liver and platelets, the addition of topical tretinoin is unlikely to have a significant impact [33].

Botulinum toxin

The pathogenesis of AGA strongly suggests dihydrotestosterone as the main factor. However, researchers are investigating new biological, histological, or metabolic aspects that may contribute to and accelerate its development. One such aspect is the activity of the muscles attached to the galea aponeurotica/epicranial aponeurosis. Chronic muscle contraction causes localized pressure on the blood vessels that supply oxygen and nutrients to the area affected by AGA. The literature notes a correlation between the contraction of the occipitalis and frontalis muscles and the distribution of AGA symptoms [34]. Therefore, it seems reasonable to consider the use of botulinum toxin and its inhibitory effect on neurotransmitters in the neuromuscular junction. The literature presents treatment algorithms that use 50 to 150 units of botulinum toxin type A, which are administered to 30 selected sites in the frontalis, temporalis, periauricularis, and occipitalis muscles. Alternatively, 30 units can be administered directly to sites affected by AGA [35, 36].

microRNA

The aetiology of AGA is thought to be influenced by Dickkopf-related protein 1 (DKK1) on the Wnt/β-catenin pathway [37]. Regulating Wnt family proteins may promote hair regeneration and growth. Micro-RNAs can regulate gene expression to aid in this process. To produce a microRNA-based drug, several conditions must be fulfilled, including identifying a suitable microRNA to regulate the hair growth cycle, determining the method of drug delivery, identifying its vector, and achieving initial stabilization [38]. A significant development in the field of vaccinology has been the creation of a commercially available microRNA-based vaccine for COVID-19. The development of a microRNA-based drug could potentially be a significant advancement in the pharmacotherapy of AGA. MicroRNA plays a crucial role in regulating various biochemical pathways, including osteogenesis, wound healing, and carcinogenesis. Currently, seven microRNAs show the most promise: miR-29, miR-31, miR-103/107, miR-152, miR-203, and miR-218 [37].

Osteopontin

Excessive hair growth is often observed in melanocytic skin nevi in humans, indicating increased hair stem cell activity. Osteopontin, a signalling molecule of nevi, is overexpressed in human hairy nevi and stimulates new growth of human hair follicles [39–41]. It is produced by non-proliferating, aging melanocytes as a signalling molecule, which causes the reduced hair follicles to activate their stem cells, resulting in the growth of longer and thicker hair. In this case, the accumulation of ageing cells, resulting from genotoxic stress or the passage of time, can significantly increase the activity of neighbouring intact stem cells and stimulate hair regeneration. Studies on mouse models have demonstrated that injecting osteopontin or inducing its genetic overexpression leads to significant hair growth. Therefore, it seems that osteopontin may be a sufficient factor for inducing hair regeneration and growth [39, 41, 42].

Discussion

For patients who do not respond to standard preparations, a solution of minoxidil at higher concentrations may be a viable alternative. Although the oral form has a systemic effect, it has been demonstrated to be safe and has minimal side effects with regular monitoring and patient feedback. To avoid the subjectively reported discomfort associated with the solution, the oral form should be considered as the first-line therapy. Finasteride and dutasteride are both effective in treating AGA. However, dutasteride, which inhibits two subtypes of the enzyme 5a-reductase, is more effective in reversing miniaturisation compared to finasteride. In South Korea and Japan, dutasteride has been approved for treating AGA at an oral dose of 0.5 mg since 2009. Both drugs have a similar safety profile and do not pose major concerns regarding teratogenicity, fertility, or sexual side effects. For patients experiencing sexual side effects, topical finasteride may be a viable option due to its lower likelihood of causing systemic side effects by reducing DHT levels. Further research is required before the injectable formulation, whether in mesotherapy or long-acting formulation, can be considered as an alternative to the first-line therapy. According to experts worldwide, both minoxidil and 5a-reductase inhibitors are the best studied substances and should play a primary role in the treatment of AGA. The use of tretinoin and botulinum toxin as treatments for AGA are promising, but should only be used as an adjunct to methods with well-established efficacy. The potential use of osteopontin or microRNA drugs in the future has the potential to revolutionise AGA treatment, but further clinical trials involving humans are required.

Funding

No external funding.

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

References