Abstract
Although multiple low-level laser therapy (LLLT) devices have received FDA clearance for safety, LLLT effect on hair loss diseases is still a matter of debate for male and female pattern hair loss (MPHL, FPHL). Completed clinical trials of LLLT use for MPHL and/or FPHL demonstrated improvement precisely measured hair parameters such as density and width. However, improvement in hair appearance was insufficiently demonstrated. Moreover, no study compared LLLT and conventional drugs such as topical minoxidil, oral finasteride, and dutasteride. Therefore, at present, LLLT should be considered as an adjunctive therapy to these treatments. Further, if patients dislike currently available medical treatments, LLLT may be offered as an alternative method. Additionally, our basic research revealed that HGF, leptin, and VEGF-A secreted from dermal papilla cells mediate the red light effect on hair growth.
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1 LLLT and Paradoxical Hypertrichosis
In 1968 Mester et al. examined the carcinogenic potential of a low-power ruby laser (694 nm) using mice. Although there was no carcinogenesis, incidentally finding of hair growth was noted [1]. More recently in humans, undesirable hair growth was observed around treated areas after the laser-assisted hair removal, and this phenomenon has been known as “paradoxical hypertrichosis” [2]. This fact suggested the potential photobiostimulation of hair growth by low-level laser therapy (LLLT). Many basic and clinical studies of LLLT on hair growth have been reported, and several LLLT devices have received FDA 510 (k) clearance [3, 4]. In spite of this clearance for safety and efficacy, LLLT effect on hair loss diseases is still a matter of controversy especially for male pattern hair loss or androgenetic alopecia (MPHL) and female patter hair loss (FPHL). In this review, the randomized controlled trials (RCTs) are surveyed, and the question “Does LLLT work?” is discussed.
2 Clinical Trials of LLLT for Hair Loss Diseases
As of the date of this publication, five RCTs of LLLT use for MPHL have been published. Two utilized a comb device [3, 5] and three used a helmet/cap [6,7,8].
2.1 Effect of LLLT on Hair Density and Thickness
Jimenez et al. [5] designed the largest study of LLLT thus far. Four multicenter prospective randomized, double-blinded studies were performed. In the trials #1 and #2, FPHL patients were treated with a 9-beam (655 nm) (#1, n = 53; sham = 25) or a dual 12-beam (6–655 nm, 6–635 nm) (#2, n = 42; sham = 21). In the trials #3 and #4, MPHL patients were treated with a 7-beam (655 nm) (#3, n = 33; sham = 16) or a 9- (655 nm) or 12-beam (6–655 nm, 6–635 nm) (#4, 9-beam, n = 25; 12-beam, n = 28; sham = 26) laser combs. The subjects applied the device three times a week. The irradiation periods were 15 min for the 7-beam, 11 min for the 9-beam, and 8 min for the 12-beam device. The treatment was continued for 26 weeks. Scalp assessment, global and macro digital imaging after hair clipping, and computer-aided hair counts were carried out. All four studies showed significant terminal hair density increase by LLLT compared with the sham treatments. Global photographs to show hair volume increase were provided only in a female subject. The result of self-assessment did not always reach statistical significance. Laser comb-related adverse events were dry skin (5.1%), pruritus (2.5%), scalp tenderness (1.3%), irritation (1.3%), and a warm sensation at the treated site (1.3%). However, there were no serious adverse events that resulted in discontinuation of the treatments.
Leavitt et al. [3] reported similar results by comparing the laser comb (n = 71) and sham device (n = 39). The LLLT showed significant terminal hair density increase compared with the sham after 26 weeks.
Kim et al. [6] evaluated a helmet-type LLLT device consisting of LEDs (630 nm) and laser diodes (650 nm) for MPHL and FPHL at two research centers. Treatments were performed once a day for 24 weeks. The duration of each treatment was 18 minutes, and its irradiation energy was 47.90 J/cm2. LLLT significantly increased hair density and thickness (n = 15) compared with the sham treatment (n = 14). The investigator global assessment (excellent, good, slight, no change, worse) was good or excellent in 26.7% in the treatment group, but no sham group subjects were rated good or excellent, demonstrating significant positive effect on hair appearance (p = 0.002, Wilcoxon ran sum test). However, the global photographs were not provided.
Similarly, two other trials reported by the same author showed significant hair growth in MPHL [7] and FPHL [8] by the helmet/cap devices containing laser diodes and LEDs (both, 655 nm).
Together, these five RCTs demonstrated significant hair regrowth by LLLT. Therefore, LLLT is a well-evidenced and safe treatment for MPHL and FPHL. These evaluations primarily examined precise objective hair parameters such as density and width. However, the subjective effect on hair appearance was demonstrated only by global photographs of one case by Jimenez et al. [5] and by global point assessment by Kim et al. [6]. Moreover, no study compared LLLT and conventional drugs such as topical minoxidil [9, 10], oral finasteride [11, 12], and dutasteride [13]. Therefore, at present, LLLT should be considered as an adjunctive therapy to these treatments. Further, if patients dislike currently available medical treatments, LLLT may be offered as an alternative method.
3 Potential Mechanism of LLLT/LED Effect
For LLLT to be effective, light must penetrate the skin and reach hair follicles. Therefore, red or near-infrared lights (600–950 nm) are appropriate for hair treatments. In general, light must reach receptors in the cells, known as photoacceptors or chromophores [14]. Cytochrome C oxidase, which catalyzes the final step in the mitochondrial electron transfer chain, is a potential photoacceptor of red or near-infrared lights [15]. However, the mechanism downstream from the photoacceptor is not clear, and the search continues for potential mediators to exert the biological functions of red or near-infrared lights, particularly using LED [16]. First, to examine effect of LED light on hair growth, the dorsa hairs of 7-week-old female BL-6 mice were shaved off. Starting the next day (day 1), red LED light (638 nm/1.0 J/cm2) was irradiated for 20 minutes three times a week. Thereafter, we took photos of the dorsa skin and measured the percentage of hair regrowth. No LED light was irradiated elsewhere for a control. At days 18 and 22, hair regrowth areas were significantly increased by red LED light irradiation when compared to controls. In addition, the dorsa skin of the red LED irradiation group at day 22 was colored black, indicating anagen induction. Furthermore, we searched molecular mechanisms of LED stimulation on hair growth using cultured normal human dermal papilla cells irradiated with red (638 nm/1.5 J/cm2) LED. RNA samples were extracted from the cells and subjected to semiquantitative RT-PCR for various growth factors and cytokines. Analysis revealed mRNA of HGF, leptin, and VEGF-A was increased. Then, we confirmed the enhanced production of these factors by red LED light at the protein level from cultured normal human dermal papilla. The conditioned media of dermal papilla cells irradiated with red LED were harvested and used to measure the protein levels of the cytokines by ELISA. We found that HGF, leptin, and VEGF-A were significantly increased, agreeing with previous observations: (1) upregulation of HGF reportedly accelerates hair growth and retards entry to catagen in hair cycling [17, 18], (2) leptin induces the anagen phase of hair cycle [19], and (3) VEGF-A induces perifollicular angiogenesis, accelerating hair regrowth [20].
Recently, the wavelength-dependent effects of hair growth were examined using laser diodes with wavelengths of 632, 670, 785, and 830 nm in Sprague-Dawley rats. Results revealed that LLLT with a 830-nm wavelength induced greater stimulation of hair growth than the other wavelengths examined [21]. Accordingly, LLLT of longer wavelengths than utilized today may have more potent effects on hair growth.
4 Conclusion
The stimulatory effect of LLLT/LED has been convincingly demonstrated by several RCTs, but its potency has not been definitively established. At present, LLLT should be considered as an adjunctive or alternative therapy to conventional treatments. Therefore, further basic and clinical studies are needed for refinement of the devices and light sources.
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Inui, S. (2018). LLLT: Does It Work?. In: Pathomvanich, D., Imagawa, K. (eds) Practical Aspects of Hair Transplantation in Asians. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56547-5_69
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