Evaluation of platelet‐rich plasma plus basic fibroblast growth factor combined with minoxidil in the treatment of androgenetic alopecia: A randomized controlled trial

Abstract

Background

Platelet‐rich plasma plus basic fibroblast growth factor (PRPF) has been confirmed to be a safe and valuable therapy for androgenetic alopecia (AGA). However, the efficacy of PRPF combined with minoxidil treatment remains unknown.

Objective

To assess the efficacy of combined PRPF and minoxidil treatment for AGA.

Methods

In this prospective, randomized controlled trial, 75 patients with AGA were randomly divided into three groups and were administered the following treatments: Group 1, direct intradermal PRPF injection; Group 2, topical minoxidil 5% twice daily; and Group 3, PRPF injection combined with minoxidil. The PRPF injection was performed three times, 1 month apart. Hair growth parameters were evaluated using a trichoscope until the sixth month of the study. Patient satisfaction and side effects were recorded during the follow‐up.

Results

All patients showed improvements (p < 0.05) in hair count, terminal hair, and decrease in telogen hair ratio after treatment. The efficacy of PRPF complex therapy revealed significant improvements (p < 0.05) in hair count, terminal hair and growth rate, compared with monotherapy.

Limitations

Small sample size, short follow‐up time and lack of quantification of GFs in PRPF.

Conclusion

The effect of complex therapy exceed both the effects of PRPF monotherapy and minoxidil treatment, which can be a beneficial AGA treatment strategy.

Abbreviations

• AGA
• androgenetic alopecia
• ANOVA
• Repeated-measures analysis of variance
• ATP
• adenosine triphosphate
• BFGF
• basic fibroblast growth factor
• EGF
• epidermal growth factor
• GF
• growth factors
• HF
• hair follicle
• IGF
• insulin-like growth factor
• PRP
• platelet-rich plasma
• PRPF
• platelet-rich plasma plus fibroblast growth factor
• VEGF
• vascular endothelial growth factor

INTRODUCTION

Androgenetic alopecia (AGA) is a common type of progressive hair loss. Until recently, the main treatment for AGA has been medication such as topical minoxidil and oral finasteride, but these medications may have adverse effects. Therefore, adjuvant therapy and improved treatment modalities are needed to achieve better outcomes. Platelet-rich plasma (PRP), an autogenous solution extracted from blood, centrifuged and filtered, and containing a high concentration of platelets and their bioactive growth factors (GFs), has been used to treat AGA in increasing numbers over the last decade.

Basic fibroblast growth factor (bFGF), also known as FGF2, is a member of FGF family. Previous studies have shown that bFGF increased the size of hair shaft and promote cell proliferation and cycle progression. However, some studies have shown that compared with other GFs, the amount of bFGF in PRP was often less. It is important to note that bFGF has been approved by the State Food and Drug Administration (SFDA) for many clinical use. Therefore, adding bFGF to PRP should improve the efficacy of PRP. A previous study has demonstrated that PRP plus bFGF (PRPF) is effective in treating wrinkles. In addition, our research found that PRPF had better efficacy in AGA treatment than PRP alone, which introduces a new method for AGA treatment. Numerous studies and meta-evidence-based medicine have shown that, compared with PRP/minoxidil single treatment, the complex therapy has a higher improvement rate in AGA. Regarding PRPF, it is necessary to use minoxidil in combination to achieve better results. However, there is a lack of relevant clinical studies. Therefore, we conducted a randomized controlled study to explore the clinical efficacy of PRPF monotherapy, minoxidil monotherapy, and their complex therapy, which aimed to provide a theoretical basis for finding effective and safe treatments in future clinical practice.

METHODS

Study design

This study was designed as a randomized controlled trial based on the principles of the Declaration of Helsinki. The study was approved by the local medical ethics committee, and informed consent for treatment was obtained from all patients before enrollment.

Participants

This study was conducted in the Plastic and Aesthetic Department of Nanfang Hospital, Southern Medical University. The same clinician enrolled patients of AGA from April 2021 to December 2021. Randomization assignments to any one of the three treatments were made sequentially according to a randomization table prepared by the research designers. All patients included in this study (n = 75) were randomly divided into three groups as follows: Group 1, 25 patients received monotherapy (direct intradermal PRPF injection); Group 2, 25 patients received classical therapy (topical minoxidil 5% was recommended twice daily); and Group 3, 25 patients received minoxidil combined with intradermal PRPF injection. The patients in Groups 1 and 2 received three PRPF treatment sessions at 1-month intervals. Detailed parameters of these three groups are shown in Table . A family history of AGA was recorded in all (75) of the patients included in this study. The exclusion criteria are introduced in Supplementary Methods . Except for the two designers of research, other researchers, including all outcome assessors were blinded to the treatment, and blinding was maintained until all data were analyzed.

Treatment protocol

PRP was prepared first following the manufacturer's protocol of the Tricell system (Supplementary Methods ). For PRPF preparation, 200 micrograms of bFGF (SL Pharm, Beijing, China) was diluted with normal saline, and 20 μg of bFGF was added per 1 mL of PRP. Before treatment, all patients in three groups were marked with a dot tattoo within the hair loss area. Lidocaine cream was smeared on the treatment area, lasting for 40 min, and cleansed with 70% alcohol, after which, harvested PRPF was injected at a dose of 0.05–0.1 mL/cm² using a 30-G needle according to the divided group. The depth of intradermal injections was approximately 1.5–2.5 mm deep. The center of injections region was ≥12 cm distance from lateral angle of the eye and ≥9 cm distance from top of the ear.

Assessment criteria

Trichoscopy and global photographs were performed in four stages: T0, beginning of the study; T1, 1 month; T3, 3 months; and T6, 6 months. The 2 cm diameter circle centered on the marked tattoo was evaluated, and trichoscope photos were taken 3 days after hair shaving to assess hair growth rate and telogen hair ratio. This effect was reflected in the assessment of hair count, terminal hair count, vellus hair ratio, hair density, mean thickness, hair growth rate, telogen hair ratio, and global appearance. Patient satisfaction with the treatment and its side effects were also recorded, and the questionnaire was administered at T0 and T6. Please refer to Supplementary Methods and for patients' satisfaction scores and questionnaires.

Statistical analysis

Repeated-measures analysis of variance (ANOVA) was used to determine the mean differences between hair parameters before and after treatment. The mean differences among the three groups were also examined using ANOVA. A post-hoc Bonferroni correction was applied to correct for the family wise error rate. The mean differences in the questionnaire results of the three groups were analyzed using the Wilcoxon rank test. Statistical analyses were performed using SPSS Statistics 23 and R software. For all tests, results with p < 0.05 were considered statistically significant.

RESULTS

Hair density and hair thickness

As shown in Table  and Figure , the total mean hair count and density in all three groups increased significantly after 6 months treatment. At T6, the mean hair count increased by almost 31.28 hairs in PRPF group, 11.32 hairs in minoxidil group, and 41.96 hairs in complex therapy group (p < 0.05). The effects of PRPF monotherapy exceeded the effects of minoxidil treatment (p < 0.05). Both parameters of hair count and density suggested the effect of complex therapy exceeded both the effects of PRPF monotherapy (p < 0.05) and minoxidil treatment (p < 0.05). Nevertheless, the mean thickness showed no significant difference at T3 but declined in both the PRPF and complex therapy groups at T6.

TABLE 1 Relevant change of hair growth parameters at 1 month, 3 months, and 6 months.

Parameter	Time	Group I	Group II	Group III	Group I vs. Group II	Group I vs. Group III	Group II vs. Group III
Mean ± SD	p	Mean ± SD	p	Mean ± SD	p	p	p	p
Hair count	T0	118.12 ± 24.84	-	126.68 ± 15.33	-	117.88 ± 18.33	-	<0.05	<0.05	<0.05
T1	126.04 ± 22.98	<0.05	126.36 ± 16.47	>0.05	134.56 ± 17.67	<0.05
T3	143.08 ± 24.02	<0.05	133.88 ± 19.23	>0.05	153.24 ± 21.43	<0.05
T6	149.40 ± 28.01	<0.05	138.00 ± 17.35	<0.05	159.84 ± 22.19	<0.05
Hair density	T0	135.15 ± 28.42	-	144.94 ± 17.54	-	134.87 ± 21.56	-	<0.05	<0.05	<0.05
T1	144.21 ± 26.30	<0.05	144.58 ± 18.85	>0.05	153.96 ± 20.21	<0.05
T3	163.71 ± 27.50	<0.05	153.18 ± 22.00	<0.05	175.33 ± 24.52	<0.05
T6	170.94 ± 32.05	<0.05	157.89 ± 19.86	<0.05	182.89 ± 25.39	<0.05
Vellus hair	T0	21.92 ± 7.57	-	22.52 ± 9.01	-	24.64 ± 11.81	-	>0.05	>0.05	>0.05
T1	20.20 ± 11.30	>0.05	23.92 ± 13.07	>0.05	23.92 ± 11.36	>0.05
T3	21.80 ± 9.77	>0.05	23.64 ± 10.75	>0.05	24.44 ± 12.00	>0.05
T6	21.68 ± 11.59	>0.05	22.04 ± 13.01	>0.05	20.20 ± 13.96	>0.05
Terminal hair	T0	99.24 ± 24.47	-	100.80 ± 21.30	-	103.20 ± 16.76	-	<0.05	>0.05	<0.05
T1	107.24 ± 26.32	<0.05	101.88 ± 25.27	>0.05	109.52 ± 21.54	>0.05
T3	119.52 ± 25.98	<0.05	110.24 ± 22.60	<0.05	124.24 ± 19.73	<0.05
T6	125.88 ± 24.15	<0.05	109.52 ± 20.13	<0.05	130.16 ± 22.32	<0.05
Vellus hair ratio (%)	T0	0.19 ± 0.07	-	0.19 ± 0.09	-	0.19 ± 0.07	-	>0.05	>0.05	>0.05
T1	0.16 ± 0.09	>0.05	0.20 ± 0.12	>0.05	0.18 ± 0.09	>0.05
T3	0.16 ± 0.08	>0.05	0.18 ± 0.08	>0.05	0.16 ± 0.07	>0.05
T6	0.15 ± 0.07	>0.05	0.19 ± 0.08	>0.05	0.13 ± 0.08	>0.05
Mean thickness (μm)	T0	80.00 ± 10.00	-	70.50 ± 10.05	-	80.00 ± 10.00	-	>0.05	<0.05	<0.05
T1	80.05 ± 10.50	>0.05	70.50 ± 0.02	>0.05	80.50 ± 10.50	>0.05
T3	80.00 ± 10.00	>0.05	70.00 ± 20.50	>0.05	80.50 ± 10.00	>0.05
T6	70.50 ± 10.50	<0.05	70.50 ± 20.00	>0.05	70.50 ± 10.50	<0.05
Telogen hair ratio (%)	T0	33.03 ± 4.15	-	31.63 ± 4.82		34.17 ± 5.59	-	<0.05	>0.05	<0.05
T1	27.39 ± 3.30	<0.05	30.12 ± 5.01	<0.05	27.58 ± 4.29	<0.05
T3	22.36 ± 3.23	<0.05	27.18 ± 4.91	<0.05	22.01 ± 3.41	<0.05
T6	21.50 ± 3.42	<0.05	26.49 ± 4.62	<0.05	19.76 ± 2.42	<0.05
Hair growth rate (mm/day)	T0	0.70 ± 0.01	-	0.70 ± 0.07		0.72 ± 0.07	-	<0.05	<0.05	<0.05
T1	0.74 ± 0.11	<0.05	0.67 ± 0.12	>0.05	0.91 ± 0.10	<0.05
T3	0.79 ± 0.12	<0.05	0.69 ± 0.14	>0.05	1.01 ± 0.12	<0.05
T6	0.83 ± 0.12	<0.05	0.72 ± 0.13	>0.05	1.06 ± 0.12	<0.05

Terminal and vellus hair

Changes in terminal hair in the PRPF and complex therapy groups showed a sustained increase after treatment (p < 0.05). However, in the minoxidil group, the index of terminal hair began to increase 3 months after treatment (p < 0.05), and the vellus hair ratio in the PRPF group decreased at T1, T3, and T6 (p < 0.05). Nevertheless, the mean vellus hair ratio showed no significant change in the minoxidil and complex therapy groups (p > 0.05). It is worth noting that only significant improvements in terminal hair count were found in PRPF group versus minoxidil group (p < 0.05) and complex therapy group versus minoxidil group (p < 0.05).

Telogen hair ratio and hair growth rate

The telogen hair ratio in all three observation groups decreased significantly, particularly in the complex therapy group. At the last visit, the mean ratio decreased by almost 11.53% in the PRPF group, 5.14% in the minoxidil group, and 14.41% in complex therapy group (p < 0.05). Through the comparative analyses, we found the effects of PRPF monotherapy exceeded the effects of minoxidil treatment (p < 0.05), and the effect of complex therapy exceeded both the effects of PRP monotherapy (p < 0.05) and minoxidil treatment (p < 0.05).

Regarding hair growth rate, this index in PRPF and complex therapy groups was augmented with significance in T1, T3, and T6. Hair growth rate had increased from 0.70 ± 0.01 mm/day at T0 to 0.83 ± 0.12 mm/day at T6 in the PRPF group (p < 0.05) and 0.72 ± 0.07 mm/day at T0 to 1.06 ± 0.12 mm/day at T6 in the complex therapy group (p < 0.05). However, there were no notable differences in hair growth rate in the minoxidil group. At T6, the hair growth rate of the complex therapy group was significantly higher than that of both PRPF therapy (p < 0.05) and minoxidil treatment (p < 0.05).

Variation for photographs at baseline and 6 months follow-up

Representative images of patients in each group before and after treatment are shown in Figure . A significant improvement in hair density compared with the two single therapy groups was observed in the complex therapy group, as determined by TrichoScan (Figure ).

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[IMAGE OMITTED. SEE PDF]

Patient satisfaction and adverse effects

Most of the patients with AGA in the complex therapy group, with a mean score of 3.88, and the PRPF group, with a mean score of 3.2, were satisfied by the results at T6, and they were encouraged to continue treatment. Nevertheless, the mean patient satisfaction score in the minoxidil group was only 2.64. To better evaluate the subjective feelings of patients during treatment, we used a questionnaire survey before and after treatment. As shown in Table , significant improvements in questionnaire responses for complex therapy treatment were observed for 6 of 16 questions, and the degree of improvement was significantly better than that for PRPF/minoxidil single treatment (e.g., impact of hair loss on social well-being, concern about bare spots, concern about continuation of hair loss, etc.). As for adverse effect, four patients (16%) in the minoxidil group experienced itchy scalp symptoms during treatment. Only three (12%) patients in the PRPF group and two (8%) patients in the complex therapy group experienced an adverse effect after PRPF injection, with minimal pain, redness, and pinpoint bleeding after instant PRPF injection. No other major side effects were reported during the treatment.

DISCUSSION

Owing to the limited effective treatment of AGA, PRP is gradually becoming an effective alternative therapy. Many clinical studies have shown that PRP is beneficial for treating hair loss. However, there has been no unified standard for the preparation process of PRP. Due to the multifold enrichment of platelets that secrete GFs after PRP injection, the heterogeneity of GFs may lead to inconsistent clinical responses.

Various GFs in PRP have been found to regulate the growth cycles and morphological changes in hair follicles (HFs), and studies have shown that bFGF can promote hair growth. Recently, researchers have shown that the combination of bFGF and 5% minoxidil improved treatment efficiency and patient satisfaction in the treatment of male patients with AGA. Additionally, our team conducted a randomized controlled clinical study, which confirmed that PRPF was more effective than PRP in promoting hair growth. Our study, in conjunction with previous studies, lay a foundation for the clinical application of PRPF in AGA.

It has already confirmed that PRP combined with minoxidil treatment enhances the functions of HFs, and it is currently the recommended treatment for AGA. Our team further confirmed that PRPF was more effective than PRP in promoting hair growth. Therefore, we assessed the efficacy of PRPF and minoxidil complex therapy in AGA. The results again showed better improvement in treatment efficiency and patient satisfaction with PRPF than those with minoxidil. It also demonstrated the high clinical efficacy of complex therapy and its advantages over single treatment with PRPF or minoxidil. PRPF complex therapy dramatically increased hair count, promoted hair regrowth, and improved hair loss, with a statistically higher efficacy than treatment with PRPF or minoxidil alone.

PRPF complex therapy showed better efficacy than monotherapy in this study, which emphasized the importance of combination therapy for AGA. Except for higher bFGF concentrations, PRPF has the same biological characteristics as PRP. PRPF contains various GFs, such as epidermal growth factor (EGF), FGF, insulin-like growth factor (IGF), and vascular endothelial growth factor (VEGF) at supraphysiological concentrations. Each of these GFs activates important biological mechanisms that promote hair growth by either directly affecting the Wnt/β-catenin signaling pathway or establishing a permissive microenvironment for healthy HFs to take root. Specifically, FGF can promote the induction of anagen phase in HFs by β-catenin signaling activation. Further, bFGF can promote hair growth by increasing the size of HFs and promoting the proliferation of DP cells in mice. Chi Liu et al. have confirmed that combination of bFGF and minoxidil improved treatment efficiency and patient satisfaction in AGA. Consistently, PRPF acts synergistically with topical minoxidil to promote hair growth in AGA in our study.

Up to now, the mechanism by which minoxidil promotes hair growth has not yet been fully elucidated. Studies have shown that minoxidil, by activating potassium channels, can increase blood flow to the scalp and promote the transition of HFs to the active anagen phase. Minoxidil requires sulfotransferase catalysis to form minoxidil sulfate, and it works to promote HF growth by increasing blood flow and allowing more nutrients to be delivered to the HF, thus stimulating the hair growth cycle. Platelets have exhibit minoxidil sulfotransferase activity. PRPF not only provides a large number of GFs to promote hair growth but might also promote the production of active metabolite of minoxidil. Meanwhile, by increasing the blood flow to the scalp, minoxidil provides HF with more oxygen and adenosine triphosphate (ATP) for hair growth. PRPF and minoxidil potentiate each other's actions when used in combination. Moreover, complex therapy allows AGA patients to achieve more significant results in a shorter treatment period, which may increase patient confidence and compliance during treatment. To date, AGA treatment has been recommended as hybrid therapy, and the combination of PRPF and topical minoxidil can be considered a promising treatment strategy.

There are still several parts in this study that need to be improved in the future. Firstly, sample size needs to be increased and the follow-up time needs to be extended. In addition, considering the heterogeneity in GFs and resultant yield of PRP, GFs quantification analysis of PRPF need to be performed in our further study.

CONCLUSION

Significant increase in hair count, hair density and hair growth rate were observed after PRPF therapy than minoxidil treatment. Moreover, the combination of PRPF and topical minoxidil achieved a better improvement in efficacy and patient satisfaction beyond the monotherapy. This study provided further evidence that treatment with PRPF is efficient and safe, and emphasized the importance of combination therapy for AGA.

AUTHOR CONTRIBUTIONS

Shulian Wu, Yong Miao, Qian Qu and Zhiqi Hu designed the research study. Shulian Wu, Shizhao Liu and Qing Guan carried out global and trichoscope photography. Shulian Wu, Shizhao Liu and Damao Dai conducted the questionnaire survey. Shulian Wu, Shizhao Liu, Weijie Liu and Qian Qu analyzed the data. Shulian Wu and Qian Qu wrote the paper.

FUNDING INFORMATION

This trial was funded by the Natural Science Foundation of China (Grant No.81772104, No.81701929), the Natural Science Foundation of Guangdong Province (Grant No.2017A030310120, No.2019A1515012170), and Medical Scientific Research Foundation of Guangdong Province (Grant No. C2019112).

CONFLICT OF INTEREST STATEMENT

The authors have declared that no conflict of interest exists.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT

All procedures in this study were reviewed and approved by research ethics board at Nanfang Hospital, Southern Medical University (approval code: NFEC-2019-212), and participants provided informed consent explaining therapeutic approaches in this study, their benefits, and possible adverse effects.

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