Introduction

Androgenetic alopecia (AGA) is the leading cause of the progressive thinning of the scalp. Over 40% of Caucasian men develop hair loss by the age of 40, and, in the world, over 80% of the male population and 50% of the female population are affected by this condition [1]. The transformation of testosterone into dihydrotestosterone, a more active metabolic form also formed at hair follicles level thanks to the intervention of an enzyme called 5-alpha-reductase type 2, acts progressively shortening and thinning hair follicles until their disappearance [2].

Different treatments have been proposed for the treatment of AGA. Currently, two drugs are widely used for the treatment of this condition: minoxidil and finasteride. Unfortunately, the effects of these substances on hair growth are evident only after several months and require daily assumptions. Patients’ compliance decreases with long-term use of these drugs [3]. Platelet-rich plasma injections and hair transplants have also been proposed [4]. Some studies have shown that LLLT (low-level laser therapy) stimulated hair growth in males and females. The wavelengths experimented ranged mainly from orange (635–650 nm) to near-infrared (800–900 nm), but other studies are necessary to determine the most effective wavelength [5,6,7]. To our knowledge, blue light therapy (BLT) has never been proposed for AGA treatment.

This study aims to evaluate the use of BLT in AGA to assess hair growth.

Materials and methods

Twenty male patients aged between 22 and 60 (mean age 38.55 ± 11.68 years old) affected by moderate–severe AGA (with a Norwood-Hamilton score from 3 to 6 [8]) were recruited at the Unit of Dermatology of Magna Graecia University (Catanzaro, Italy). Inclusion criteria were the following: no treatment for AGA or use of anti-androgen drugs in the last 6 months, absence of any autoimmune or systemic condition, and lack of other dermatological conditions interesting the scalp. We treated the patients with BLT (wavelength 417 ± 10 nm, fluence 120 J/cm2, and power intensity 60 mW/cm2 ± 20%). The treatments were performed twice a week for ten consecutive weeks. Each session was characterized by overall exposure to the Blue light of 24 min. Each patient signed informed consent and photo release. The study was approved by the Local Ethical Committee (Comitato Etico Calabria Centro: reference number 37319). As the Norwood-Hamilton scale is non-linear (significant improvements not always correspond to an improvement in the scoring and vice-versa), the primary endpoint was digital photographic evaluation. Researchers took digital photographs before and 1 month after treatment (Nikon D5600, Nikon, Minato City, Tokyo, Japan). Two independent dermatologists ranked the photographic patient results as no improvement (response under 20% or further air loss), good improvement (response from 20 to 50%), and excellent improvement (response over 50%). In case of discrepancies between the physicians, a third dermatologist was called to solve them. Patients were also evaluated with a digital trichoscope to assess hair density and hair shaft width before and 1 month after treatment (Horus HS 1000 trichoscopy system, Adamo SRL, Trapani Italy). Hair shaft width and density were measured in the most advanced part of the hairline and then remeasured in the same spot. Researchers analyzed data for statistical significance with SPSS Statistics version 27.0 (IBM, Armonk, New York). Mean and standard deviations for all groups were calculated. Student’s t test for paired data was used to assess statistical significance. A p-value inferior to 0.05 was considered significant.

Results

The photographic evaluation showed a good improvement in 16 out of 20 patients (80%); 4 patients (20%) reported no change of the condition (Figs. 1, 2 and 3). Mean hair density measured before treatment was 106 ± 66 units/cm2; mean hair density measured after treatment was 117 ± 69 units/cm2. Mean hair density improvement was statistically significant (p = 0.001). The mean hair shaft width measured before treatment was 0.0295 ± 0.017 mm. The mean hair shaft width measured after treatment was 0.034 ± 0.017 mm. Mean hair shaft width improvement was statistically significant (p = 0.009). An increase in hair density and hair shaft width was recorded in 18 (90%) patients after 10 weeks. As expected, the patients that did not show any improvement at photographic evaluation tended to report worsening or stable hair density and hair shaft width (Table 1). Researchers noted no serious adverse events; the only side effect reported in 6 out of 20 patients (30%) was a slight darkening of hair.

Fig. 1
figure 1

Patient 7 before (a) and after treatment (b)

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Fig. 2
figure 2

Patient 13 before (a) and after treatment (b)

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Fig. 3
figure 3

Patient 10 before (a) and after treatment (b)

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Table 1 Patient characteristics
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Discussion

The results observed highlight a positive impact of BLT on hair density and hair shaft width, suggesting this therapeutic option as complementary or a possible alternative to the traditional therapies such as minoxidil or anti-androgens. The exact molecular mechanism underlying light-mediated hair regrowth remains mostly unknown, but the effects of BLT could be mediated by the photolytic generation of NO from nitrosated proteins. Treatment with blue light-emitting diode devices significantly prolonged the anagen phase in hair follicles ex vivo [9]. Recent discoveries opened an exciting field of research: the photoreceptors OPN2 (rhodopsin) and OPN3 (panopsin, encephalopsin) absorbing light in visible blue-green wavelength range are expressed in human skin, human epidermal keratinocytes, mesenchymal components, and in the distinct compartments of the anagen human follicles [7,8,9,10]. The expression of OPN2 and OPN3 was detected in the distinct compartments of skin and anagen hair follicle using real-time qualitative polymerase chain reaction, and immunofluorescence approaches a 453 nm BLT at low radiant exposure that exerts a positive effect on hair growth ex vivo, potentially via interaction with OPN3 [9]. OPN3 and the multimeric tyrosinase/tyrosinase-related protein complex induced after its activation appear as new potential targets for regulating melanogenesis. The melanin synthesis occurs in melanocytes inside melanosomes where melanogenic enzymes (tyrosinase and related proteins) are addressed with specific protein complexes. The melanosomes loaded with melanin are then transferred to keratinocytes [9]. BLT could interact with many enzymes and proteins like light-activated enzyme, cytochrome C oxidase [11], intracellular calcium, and light-gated ion channels [12] and NADPH oxidase, nitrosated proteins [13], and activate secondary messengers, like nitric oxide and other ROS, cAMP, ATP, and Ca2þ [14]. Cytochrome C oxidase plays a role of a light acceptor with absorption bands in red and near-infrared (NIR) range (650–980 nm) and an even higher extinction coefficient in a blue-green spectral range (400–500 nm) [15].

Researchers noted a darkening of the hair in 30% of patients. This side effect could perhaps be explained by the interaction of BLT with the OPN3 photoreceptor. OPN3, highly expressed in human epidermal melanocytes [16], is the critical sensor in melanocytes responsible for hyperpigmentation induced by the shorter wavelengths of visible light [17]. Its mechanism of action seems to generate an increase in melanin synthesis [18]. Regazzetti et al. recently reported that visible blue light stimulates opsin3-regulated calcium-dependent microphthalmia-associated transcription factor activation that increases pigment gene expression: it also causes the clustering of melanogenic enzymes [19]. OPN3 downregulation induces apoptosis of human epidermal melanocytes via mitochondrial pathway: it is a crucial signal responsible for cell survival through a calcium-dependent G protein-coupled signaling mitochondrial pathway [20].

Photobiomodulation has been clinically reported to have a positive impact on many dermatological conditions and hair growth [21, 22]. In particular, BLT has already been used to treat patients with rosacea [23], atopic dermatitis [24], and psoriasis, with variable results. Although photobiomodulation was already proposed for AGA treatment, this study is the first to use a 417 nm diode in the treatment of AGA, with good results.

Conclusions

Our clinical study’s preliminary result seems to confirm the results reported in vitro by other researchers, highlighting the therapeutic effects of BLT in AGA treatment. We provide the first in vivo evidence that BLT has a positive effect on hair growth. Limitations of this study include the small sample size and the lack of a control group. Combining this treatment with other topical and systemic treatments for androgenetic alopecia to enhance its effect is possible. Further studies are needed to clarify the mechanisms of action and to evaluate the clinical effects of BLT better; specifically, a randomized clinical trial on a large number of participants and with the use of videomicroscopy will be necessary to confirm our findings.