SYSTEMATIC REVIEW article

Front. Pharmacol., 06 May 2021

Sec. Drugs Outcomes Research and Policies

Volume 12 - 2021 | https://doi.org/10.3389/fphar.2021.642980

Platelet-Rich Plasma in Female Androgenic Alopecia: A Comprehensive Systematic Review and Meta-Analysis

    SZ

    Shuying Zhou 1

    FQ

    Fei Qi 2

    YG

    Yue Gong 1

    CZ

    Chenxi Zhang 1

    SZ

    Siqi Zhao 2

    XY

    Xutong Yang 2

    YH

    Yanling He 2*

  • 1. Department of Dermatology, The 305 Hospital of PLA, Xicheng, China

  • 2. Capital Medical University, Beijing Chaoyang Hospital, Beijing, China

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Abstract

Introduction: The population of young women who suffered from female pattern hair loss (FPHL) or female androgenic alopecia (AGA) is gradually increasing. Platelet-rich plasma is a novel and promising therapeutic method as a nonsurgical treatment for FPHL.

Objective: To summarize different preparation methods of PRP and treatment regimes in FPHL, qualitatively evaluate the current observations, and quantitively analyze the efficacy of PRP in FPHL treatment.

Methods: Six databases, MEDLINE, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, LILACS, and CNKI, were searched with terms “platelet-rich plasma,” synonyms for AGA and FPHL. Meta-analysis was conducted with enrolled observational studies and randomized controlled trials separately.

Results: We evaluated 636 studies and 12 trials from all searched databases. A total of 42 studies of 1,569 cases, including 776 female participants covering 16 randomized controlled trials and 26 observational trials, were included for qualitative synthesis study and systematic review. PRP showed positive efficacy in treating FPHL in hair density compared to the control groups with odds ratio (OR) 1.61, 95% CI 0.52–2.70, and compared to baseline with OR 1.11, 95% CI 0.86–1.37.

Conclusion: PRP showed excellent efficiency as a novel therapy of FPHL through hair density evaluation. Further studies are needed to define standardized protocols, and large-scale randomized trials still need to be conducted to confirm its efficacy.

Introduction

Female pattern hair loss (FPHL), with an alternative name female androgenic alopecia (AGA), is the most common type of hair loss affecting 6.0% of Chinese women, among which 3.6% were under 40-year-old (Wang et al., 2010). FPHL is characterized by progressive follicular miniaturization and the accompanying conversion of terminal follicles into vellus-like follicles (Trueb, 2002). Patients may present with hair density reduction, hair thinning, and widening of the area especially on the center of the scalp (Olsen, 2001). Those changes may lead to serious psychological impacts (van Zuuren et al., 2012) on one’s self-esteem, interpersonal relationships, and the social status (Cash, 2001). Although multiple nonsurgical therapeutic methods like topical minoxidil, oral finasteride, and low-level laser comb had been introduced to FPHL treatment, more large-scale–randomized controlled trials still need to be investigated to confirm their efficacy (van Zuuren et al., 2016). Despite decreased number of more actively proliferating progenitor cells, the current studies have presented an unaltered number of hair follicle stem cells in a hair loss scalp (Garza et al., 2011). Hence the application of autologous stem cells including autologous micro-grafts enriched of human follicle cells (HF-MSCs) as well as platelet-rich plasma has been explored and gradually been introduced to clinical use (Gentile et al., 2019).

Platelet-rich plasma (PRP) is a preparation of an enriched platelet autologous plasma in which the concentration of platelet is above normal contained in the whole blood (Wu et al., 2016). Platelets are able to secrete growth factors, adhesion molecules, and chemokines. After being activated, those effective factors interact with the local environment and promote cell differentiation, proliferation, and regeneration (Weibrich et al., 2002; Davì and Patrono, 2007; Sánchez-González et al., 2012). Published data also highlighted that PRP contains major growth factors, including basic fibroblast growth factor (bFCF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), transforming growth factor-β (TGF-β), and insulin-like growth factor-1 (IGF-1) (Cervelli et al., 2012). In the past decade, PRP has been studied and widely used in alopecia, acne scarring, skin rejuvenation, chronic wounds, and vitiligo (Hesseler and Shyam, 2019). Comparing with traditional nonsurgical therapies and the surgical approaches such as hair transplantation, PRP is believed as a promising treatment of AGA with lower cost and fewer adverse effects. However, only a limited number of publications focus on the utilization of PRP in AGA treatment, and few studies or reviews about the application of PRP in FPHL have been performed.

In this study, we summarized different PRP preparation methods, reviewed the various treatment regime in FPHL that are reported in the previous studies, qualitatively evaluated the current observations, and quantitively analyzed the efficacy of PRP in FPHL treatment. This work may offer a reference to the clinical workers and associated FPHL patients.

Methods

This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (http://www.prisma-statement.org) and Meta-analysis Of Observation Studies in Epidemiology (MOOSE) statement (Stroup et al., 2000).

Literature Screening

Two investigators independently conducted a systematic search of studies published before October 29, 2020, using the databases MEDLINE via PubMed, embase, Web of Science via Ovid, Cochrane Central Register of Controlled Trials (CENTRAL), LILACS, and CNKI. The strategy of search terms was composed of at least one term from two search blocks: the term “platelet-rich plasma” and synonyms for androgenic alopecia (AGA) and female pattern hair loss (FPHL). All synonyms were found based on MESH and ENTRÉE (Supplementary Material S1).

Study Selection

Original studies include observational studies (i.e., case series, cross-sectional, case-control, and cohort) and randomized trials of platelet-rich plasma (PRP), and AGA in woman patients in English, German, Swedish, Norwegian, Spanish, Danish, Turkish, and Chinese were all eligible for inclusion. Exclusion criteria were reviews, studies only included male patients, abstracts, unpublished studies, and lack of raw data. Conference reports were also excluded for insufficient details for analysis. Two reviewers screened the titles and abstracts of the identified studies. If the information provided in the abstracts was not sufficient to access the eligibility, a full-text evaluation was conducted. All observational studies and randomized trials will be recruited for qualitative analysis, and only randomized controlled trials will be analyzed quantitively and enrolled in the meta-analysis in this work. Two authors also evaluated the quality of the included studies independently. Any disagreement was resolved through discussion or decided by a third person.

Data Extraction

Two reviewers completed the data extraction work independently with the following information: author, year of publication, journal name, country, methods of PRP preparation, treatment regime, and the number of cases/controls (total, exposed, nonexposed). In case of disagreement, a third person conducted a further assessment.

Endpoint Definition

The efficacy of PRP was evaluated by an increase in hair density, increment of hair count, improvement in the hair-pull test, satisfaction of patients from the questionaries, and changes of hair thickness compared with photos taken before and after the treatment sections. Given that various test methods were taken through the studies we included, only the most widely used methods would be set at the endpoints for all-pooled studies.

To access the safety of PRP, all-side effects, including local injection pain, headache, increasing scalp sensitivity, and any allergic effects, would be recorded.

Data Analysis

We conducted the meta-analysis with Stata statistical software 15.0 (Metrika Consulting, Stockholm, Sweden) using the “metan” command. A random-effect analysis with the method of Dorsmanin and Laird (Higgins et al., 2020) was taken, given the considerable heterogeneity. We chose 95% confidence intervals (CI) and I (Trueb, 2002) to access statistical heterogeneity (Higgins et al., 2003; Cook and Reed, 2015): 30–60% as moderate heterogeneity, 50–90% substantial heterogeneity, greater than 75% considerable heterogeneity (Higgins et al., 2020). Funnel plots and Egger tests were performed for publication bias assessment with asymmetry in the funnel plot and a p-value that was less than 0.1. Eggers’s test would overrule visual inspection if results diverged between the two methods above.

Clinical heterogeneity was measured by stratification, for example, subgroup analysis of the study types, i.e., randomized controlled trials and observational trials. The observational trials were further stratified into case series, cohort studies, cross-sessional studies, and case-control studies. We also conducted a subgroup analysis based on different endpoint definitions, e.g., hair density, hair count, and increment in hair density. Subgroup analysis with different PRP preparation methods and PRP concentrations were only performed with sufficient data.

The quality of each study was evaluated based on Joanna Briggs Institute Critical Appraisal tools for case-series studies (Munn et al., 2020), Newcastle-Ottawa Scale (Stang, 2010) for cohort studies and case-control studies, and Cochrane Risk of Bias Tool for Randomized Controlled Trials (Higgins et al., 2011). Three groups of study quality were defined: high, middle, and low. Rovis was used for the presentation of the quality of each study (McGuinness and Higgins, 2020).

Results

Literature Search

We found 636 literature and 12 trials from databases and three additional references by reference screening. Six hundred and three studies were excluded for reasons including duplicated, male patients only, and not in human subjects (Figure 1).

FIGURE 1

FIGURE 1

The process of literature screening.

Although only the PRP effect on a female would be evaluated in this study and given only a few pure women studies were found, studies involved in both female and male patients would also be pooled in this work. A total of 42 studies, 1,569 cases including 776 female participants covering 16 randomized controlled trials and 26 observational trials, were included for qualitative synthesis study and systematic review.

Study Characters

Studies with various group settings were enrolled (Table 1). Eight out of 16 randomized controlled trials investigated the effect of PRP comparing with placebo, in which 6 of which were done in half-headed comparation. Four studies evaluated the differences of the effect of PRP combination therapy with topical minoxidil, oral finasteride, laser, and polydeoxyribonucleotide (PDRN), while the other four accessed the different efficacy from treating strategy, i.e., PRP concentration, centrifugation protocol, treatment sessions, and treatment doses. The risk of bias of all-eight–randomized placebo-controlled trials was graded by two reviewers (Figures 2, 3).

TABLE 1

Author/yearCountryTrial charactersSubject charactersObjectives
Abaroa 2016MexicoRCT10 males and 6 femalesEfficacy of APRP
Alves 2016SpainRCT23 males and 12 femalesEfficacy of APRP with half-headed
Alves 2018SpainRCT13 males and 11 femalesEfficacy of APRP combines with topical minoxidil and oral finasteride, half-headed
Anitua 2017SpainUCT13 males and 6 femalesEfficacy of APRP
Bruce 2019USARCT20 femalesEfficacy of APRP with half-headed
Butt G 2020PakistanRCT17 males and 5 femalesEfficacy of APRP with SVF-PRP
Butt G 2019PakistanUCT20 males and 10 femalesEfficacy of APRP with minoxidil
Dina 2019USACase report2 femalesEfficacy of APRP
Dubin 2020USARCT30 femalesEfficacy of APRP with placebo
El-husseiny 2020EgyptUCT13 males and 10 femalesEfficacy of APRP in double-spin and single-spin, half-headed
Garg 2017IndiaUCT65 males and 50 femalesEfficacy of APRP
Gentile a 2020ItalyUCT15 femalesEfficacy of APRP combined with microneedling technique, low-level laser therapy
Gentile b 2020ItalyUCT63 males and 27 femalesEfficacy of APRP activated APRP compared with nonactivated PRP
Gentile 2018ItalyUCT18 males and 5 femalesEfficacy of APRP
Gkini 2014GreeceUCT20 males and 2 femalesEfficacy of APRP
Hausauer 2018USARCT29 males and 10 femalesEfficacy of APRP with half-headed
Ho 2020USAUCT24 femalesEfficacy of APRP with minoxidil
Juhasz 2020USAUCT74 females and 30 malesEfficacy of APRP
Kang 2014South KoreaRCT15 males and 11 femalesEfficacy of APRP with placebo
Laird 2018SpainPatients survey41 femalesEfficacy of APRP
Lee 2015South KoreaRCT40 femalesEfficacy of APRP plus PDNR and PDNR monotherapy
Makki 2020EgyptUCT13 males and 37 femalesEfficacy of APRP
Paththinige 2018Siri lankaUCT27 males and 1 femalesEfficacy of APRP
Puig 2016USARCT16 femalesEfficacy of APRP with placebo
Qu 2019ChinaUCT51 males and 37 femalesEfficacy of APRP
Rossano 2017ItalyUCT25 males and 16 femalesEfficacy of APRP
Schiavone 2018ItalyUCT102 males and 66 femalesEfficacy of APRP
Schiavone 2014ItalyUCT42 males and 22 femalesEfficacy of APRP
Sclafani 2014USAUCT9 males and 6 femalesEfficacy of APRP
Shapiro 2020USARCT18 males and 17 femalesEfficacy of APRP with half-headed
Siah 2020United KingdomRCT1 males and 9 femalesEfficacy of APRP
Singhal 2015IndiaUCT1 males and 2 femalesEfficacy of APRP
Starace 2019ItalyUCT10 femalesEfficacy of APRP
Takikawa 2011JapanRCT16 males and 10 femalesEfficacy of APRP with D/P MPS
Tan 2019SingaporeRCT33 males and 22 femalesEfficacy of APRP with half-headed
Tawfik 2018EgyptRCT13 femalesEfficacy of APRP with placebo
Zolfaghari 2020IranUCT4 males and 9 femalesEfficacy of APRP
Zhang 2018ChinaRCT28 males and 32 femalesEfficacy of APRP with placebo
Navarro 2015SpainUCT50 males and 50 femalesEfficacy of APRP
DeVasconcelos 2015BrazilUCT9 males and 7 womenEfficacy of APRP
Yang 2020ChinaRCT27 males and 5 femalesEfficacy of APRP with minoxidil
Zhang 2020ChinaRCT36 males and 34 femalesEfficacy of APRP with lacer and placebo

The study characters.

RCT, randomized controlled trials; UCT, uncontrolled clinical trials; APRP, autogenous platelet-rich plasma; SVF, stromal vascular fraction; PDNR, polydeoxyribonucleotide; D/P MPs, dalteparin and prota-mine microparticles; USA, the United States of America.

FIGURE 2

FIGURE 2

The Risk of Bias evaluation of randomized trials.

FIGURE 3

FIGURE 3

Summary of Risk of Bias in Randomized Controlled Trials.

Observation studies including 21 case series, 2 case reports, one patient survey, one treatment protocol, and one treatment experience were enrolled, while one case series containing only one female patient was abandoned. Quality of the total 20 case series was accessed, three of which were excluded for high risk after evaluation (Figure 4).

FIGURE 4

FIGURE 4

Risks of Bias evaluation of case series.

Study Subjects

Among all 42 studies, we only found seven studies that recruited only female participants. The mean age of the total-enrolled patients was above 18 years old and between 25 and 35 years old. Most female patients had a history of AGA for at least 3–5 years with type I to III FPHL on Ludwig scale (Harrison, 2017) or 1–5 on Sinclair score system (Kasprzak et al., 2019). Patients who had previous hair transplantation, a drug-taking history that could cause hair loss or any inflammations, scars, or erythema on the scale were excluded. Laboratory tests, including hemoglobin, platelet count, serum ferritin, liver function, thyroid function, and female hormone profile, were checked for excluding any other autoimmune or systematic diseases that could cause hair loss. Acute or chronic infections should also be tested before using PRP.

Platelet-Rich Plasma Preparation

The methods of PRP preparation vary in studies (Table 2). PRP kits were commonly used from a different company and centrifugation protocol. The choices of activators and anticoagulation vary depending on PRP kits and study purposes. In all-enrolled studies, calcium gluconate in a 10:1 ratio and sodium citrate were mainly added as activators and anticoagulants, respectively. Moreover, platelet concentration differs from 1.5 times to seven-fold as whole blood according to the PRP preparation protocols.

TABLE 2

Author/yearBlood drawnCentrifugation protocolActivatorsAnticoagulantPlatelet concentration
Abaroa 201620–30 mlDouble-spin method, 20–30 ml of cititrated blood, centrifuged at 1,800 rpm for 10 min, abandon buffy coat, 3,000 rpm for 10 minCalcium gluconate in a 10:1 ratio6.8% sodium citrate200–400% over basal blood
Alves 201618 ml460 g for 8 min0.15 ml 10% calcium chloride immediately before application2 ml of 3.8% sodium citrateApprocimately 3 times higher than whole blood
Alves 201818 ml460 g for 8 minPRP kits2 ml of 3.8% sodium citrateApprocimately 3 times higher than whole blood
Anitua 201718 ml580 g for 8 minPRGF activbitor9 ml tubes 3.8% sodium citrate
Bruce 201960 mlDual spin centrifugation, 1,500 rpm for 10 min, removal of red cell layer, additional centrifugation at 3,500 rpm for 10 min, G force 684, and radius of 508 ml citrate dextrose solution A
Butt G 20209 ml650 g for 10 minPRP kit (tray life tube gel) comprising a mixture of polymers that sepatated plasma and sodium citrate
Butt G 20199 ml1,000 rpm for 10 minPRP kit (tray life tube gel) comprising a mixture of polymers that sepatated plasma and sodium citrate
Dina 20199 ml1,100 g for 6 min0.5 m calcium chlorideSodium citrate
Dubin 202022 mlEclipse PRP system 3500 revolutions per minute for 10 min
El-husseiny 202010 mlDouble-spin: 800D at 1,12 g (100 rpm) for 10 min, plasma for 448 g units (2,000 rpm) for 10 min, single-spin: 1,372 g units (3,500 rpm) for 10 min1 ml calcium gluconate (1:9)Tri-sodium citrate
Garg 201713.5 mlREMI [centrifuged for 4 min at 3,000 rpm (revolutions per minute)]Y cell bio kit1.5 ml of ACD-A solutionIt gives 5–7 times the concentration of the baseline platelet count
Gentile a 202055 mlThree different kit: C-Punt, i-stem, MAG-18
Gentile b 202055 ml or 18 ml for APRP, ANAPRP for 18 mlA-PRP:C-PunT prepration system, 1,200 rpm per 10 min, followed 1,200 rpm for 5 min, MAG-18 PRP kit, 3,000 rpm for 6 min, then 3,000 rpm for 2 min, AA-PRP: Cascade-selphyl, 1,100 g per 10 minCalcium gluconate in a 10:1 ratioSodium citrate (ACD)
Gkini 201416 mlRegenKit-BCT-3, 1,500 g for 5 minCalcium gluconateDodium citrate solution5.8 times as whole blood
Hausauer 201822 ml3,500 revolutions per minute for 10 minEclipsePRP kits4 to 6 times the platelet concentration of whole blood
Ho 20208 ml1,500 g 5 minRegenKit-BCT1.5 times, total 5 ml
Juhasz 20208 or 16 ml1,500 g 5 minregenkit-BCT1.6 times, total 5 ml
Kang 201460 mlSmartPRePSodium citrate solution
Laird 20188 mlDouble-spin cycle20 mg of acell MatriStem micro matrix + 1cc of 10% calcium gluconateDextrose solution A
Lee 201560 mlSmartPReP4% sodium citrate solution
Makki 202010 ml400 g for 10 min, upper part for 800 g 10 min
Paththinige 201818 mlMale 3,000 rpm 4 min, female 3,000 rpm for 3 min; fastened PRP kit was for 3,200 rpm, 6 minCalcium gluconate in a 10:1 ratioSodium citrate
Puig 201660 ml2.75 to 3.4 times
Qu 201940 ml3,300 rpm for 4 min, then 3,200 rpm for 3 minTricell kit
Rossano 201716 ml1,500 g 5 minRegenKit-BCT-3, calcium gluconate per 0.9 ml of PRP 1:10 ratioSodium citrateMean platelet counts were1,9*105 in whole blood and 5.5*105 platelets/µl in PRP, 5 TIMES, 0.1ml/m2
Schiavone 201860–120 mlSoft-spin, 1,500r 5 minGLO PRP kit, and C-PunTACD-A4.5 fold
Sclafani 201418 ml1,100 g for 6 minCalcium chlorideThixotropic separator gel
Shapiro 202010 ml1,500 g 5 minThicotropic gel for separating
Siah 202020 ml300 g 18C, 5 min, 700 g for 17 min
Starace 201910 ml2,500 rpm for 10 minACD-A acid-citrate-dextrose
Takikawa 201115 ml1,700 r, 15 min, then 3,000 rpm in 5 min0.2% sodium citratePlatelet concentration in PRP (88.2 7 21.7 ? 104/1 mL, n = 15 persons) was significantly higher than that in whole blood (14.4 7 3.8 ? 104/1 mL, n = 15 persons)
Tawfik 201810 ml1,200 g for 15 min, then 200 g for 10 min1:9 ratio, 0.1 ml calcium gluconate per 0.9 ml of PRPSodium citrate
Zolfaghari 202040 mlWomen: 1,400 r 14 m, men 1,600 r, then 4 min at 4,000 rpmPRGF activbitor3.8% sodium citrate
Zhang 201816 ml1,500 G, 3,000 r, 10 min
Navarro 201518 ml580 g for 8 minPRGF activbitor3.8% sodium citrate
Zhang 202030 ml3,000 r/min, 10 min10% calciun choliradeSodium citrate6.34 ± 0.4 fold

Preparation of PRP in studies.

Treatment Strategy

Despite all studies performed intradermal injections on the local alopecia area for AGA treatment, the whole procedure diverged (Table 3). 70% alcohol, spirit, or 0.1% octenidine hydrochloride spray were used for cleaning the local skin, and local anesthesia with the help of 2% lidocaine with 0.001% epinephrine were commonly used. two studies used anesthesia cream, one used soft head message, and one conducted cold air anesthesia before injections.

TABLE 3

Author/yearPRP-injected (total, each injection) injection detailsTreatment session arrangementAnesthesia
Abaroa 2016Total 3–5 ml to right half of the scales, intradermally, each puncture was made in spaces of 1cm, apply 0.2 ml in each puncture for 15 to 20 puncturesTwice a week for three weeksAt 72-h intervals over a three-week periodNot mentioned
Alves 20164 selected areas with 30-G needle, about 0.15 ml/cm21 month from each other for 3 monthsNone
Alves 20184 selected areas with 30-G needle, about 0.15 ml/cm21 month from each other for 3 monthsNone
Anitua 20173–4 cm3 of freshly activated RPGF injected to the hair-depleted area, with a 30-G needleEvery months for 3 sessions, 2 additional reminer injection doses were administered at months 4 and 7 after the start pointNot mentioned
Bruce 2019The patient’s scalp was cleaned with 70% alcohol, and a grid was marked with dots approximately 1–2 cm apart, covering the affected area. A total of 5 ml of PRP was injected using a 30-gauge needle, approximately 0.1 ml per injection site and 50 injection points in the grid. The needle was angled close to 90°, targeting the transition between the dermis and subcutaneous layerCold air
Butt G 20203 ml PRP at 0.5 interval intradermally with insulin syringes2 sessions each after 4 weeksLocal anesthetic gel, 1 h before giving injections
Butt G 2019Cleaned with spirit, 1 cm distance using nappage technique for 1.5–2.5 mm deep in the skinRepeated after 4 weeksLocal anesthetic gel, 1 h before giving injections
Dina 20194–5 ml of PRP to the scalp vertex and temporal hairline3 treatments, spaced 4 weeks apartNot mentioned
Dubin 20204.0 ml of PRP was injected 3–8 mm below the skin surface into the subdermal plane via a 30-gauge 0.5-inch needle. Each injection was comprised of 0.2 ml of PRP and spaced 1–2 cm apartAt week 0, 4, 8Not mentioned
El-husseiny 2020Multiple small ingections in a linear pattern 1 cm apart over the right half of the scalp, intradermally3 treatments3 weeks apartNot mentioned
Gentile a 20200.2 ml*cm2 with a 30-G needle and10 ml luer lock syringe for 5 mm deepNot mentioned
Gentile b 20200.2 ml*cm2 with 0.5 mm sterilemicro-needling procedureRepeated every 15 days for three timesNone
Gkini 2014Cleaned using 0.1% octenidine hydrochloride spray, PRP for 0.05–0.1 ml/cm2 with a 27-G needle for 1.5–2.5 mm deep3 treatment sessions with an interval of 3 weeks, a booster in 6 mLocal anethesia
Hausauer 20180.2–0.5 ml, half-inch needle every 2–3 cm at balding areas with a 32-gauge needle, half-inch needle deep subdermallygroup1: Received 4 total injections, the first 3 at monthly intervals and the last 3 months later, group2: Received 2 total injections, one at baseline and one at 3 months23% topical lidocaine or 7% tetracaine ointment
Ho 20200.1 ml PRP and spaced 1 cm apart for approximately 1 cm deepMonthly for four additional months for four followed by maintenance injections every 3–6 monthsNot mentioned
Juhasz 20200.1 ml PRP and spaced 1 cm apart for approximately 1 cm deep2 PRP sessions completed at 4–6 weeks intervals
Kang 2014Cleaned with 70% alcohol and interfollicular injection3 months interval2% lidocaine with 0.001% epinephrine 3–5 ml injection
Laird 2018Using microneedle on the treatment area with derma rollar for a 22-G gauge needle deep dermis/upper cutis2% lidocaine with 0.001% epinephrine 3–5 ml injection
Lee 2015Cleaned with 70% alcohol, intra-perifollicular injectionPDNR weekly for 12 weeks2% lidocaine with 0.001% epinephrine 3–5 ml injection
Makki 2020Cleaned and sterilized with spirit and povidone-iodine, 1 cm distance using nappage technique with the insulin syringe4 times at 4 weeks intervalTopical anesthesia
Paththinige 2018Loaded with 1 ml syringes before injection, cleaned with 70% alcohol, nappage technique (injections 1 cm apart, in a linear manner). 1.5–2.5 mm deep, with a 25-G needle4 treatment sessions with initial three treatments in an interval of 3 weeks and a booster session performed at 14 weeks from the baseline treatment (2 months after the 3rd treatment session)Local anethesia cream
Puig 2016Anesthetized using a ring block method:achieved by injecting a 50:50 mixture of 2% lidocaine and 0.5% bupivicaine
Qu 2019With a 30-G needleWith a 1-month interval for 6 consecutive sessionsNot mentioned
Rossano 2017Clean with 0.1% citidine chloride spray, injected with a 27-G needle and 1 ml syringes for 1.5–2.5 mm deep in the skin4sessions of PRP application each 40–60 daysNot mentioned
Schiavone 20181–2 mm deep2 injection regimen with a 3-month interval between the 2 interventionsNot mentioned
Schiavone 20144 injections would be on the vertices of a square with sides = 1 cm. The amount injected, per each injection, was approximately 0.2–0.3 ml. With a 22–24G needle for 1 mm deep2 injection regimen with a 3-month interval between the 2 interventionsNot mentioned
Sclafani 20140.1 ml per injection spot, separate by 5–8 mm intradermallyEvery 4weeks for 3 treatment sessionsNot mentioned
Shapiro 20203–4 mm deep for 0.1–0.2 ml per injection/cm21-month intervals for 3 month with a final follow-up visit three months after the last treatmentNot mentioned
Siah 20203 cm2 area with a volume of 0.1 ml/cm25 injections with a 2-week intervalNot mentioned
Singhal 20158–12 ml of total volume3 months at an interval of 2–3 weeks. The treatment is repeated every 2 weeks for four sessionsNot mentioned
Starace 20191 ml per injection point, with a 25G needleEvery 2 weeks for a total of 4 sessionsAnethesia cream
Takikawa 2011A 25G needle5 injections at 0,2,4,6,9 weeksNot mentioned
Tan 20194 treatment sessions total 3 weeks apart for 9 weeksNot mentioned
Zhang 20184 injections would be on the vertices of a square with sides = 1 cm. The amount injected, per each injection, was approximately 0.2–0.3 mlOnce a month, for 4 timesNot mentioned
Navarro 2015A 30-G needle for total 2.5–3 ml, with a mesotherapy gun2 treatment sessions with 1 month of time period between themSoft head message
DeVasconcelos 2015Intradermally at a dose of 0.2 ml of on each point of the affexted region, with spaces of approximately 2 cm between these points with a 26G 1/2 needle3 injextions at 21 intervalsNot mentioned
Yang 2020Inject with a 3 mm interval
Zhang 202035 spot for 0.1 ml each spotOnce a month for 4timesNot mentioned

Treatment protocols.

The majority of studies selected 22- to 30-G gauge needles with insulin syringes to perform the procedure, while sterilemicro-needling and DHN1 mesotherapy gun were also used in independent studies. Nappage technique (Modarressi, 2013) was taken by most studies with 1 to 3 cm distance between each injection point. 1cc PRP was injected within each grided injection point. The depth of intradermal injections was approximately 1.5–2.5 mm deep, but 0.5 mm deep for the sterilemicro-needling procedure. Intrafollicular injections and intra-perifollicular injections were also carried in several studies.

For treatment schedules, normally 3–5 treatment sessions with 4–6 intervals were performed. And the time of follow-up was commonly from 12 weeks to 9 months depending on the growth period of hairs (Lee et al., 2020).

Outcome Evaluation Methods and Adverse Effects

In addition to Ludwig and Sinclair scale, endpoints evaluation methods included biopsy with ki-67 immunochemistry stain, photographic evaluation, hair density, hair count, global photographs, and phototrichogram analysis (Ueki et al., 2003), physician global assessment score (PhGAS), patient global assessment score (PaGAS), and pull test. The satisfaction questionnaires and scales were taken from the perspective of patients and other observers were also used to evaluate the efficacy of PRP in some of the recruited studies (Table 4).

TABLE 4

Author/yearOutcomes result and measurementAdverse eventsOutcomes on molecular levels
Abaroa 2016Biopsy and photographs at week 12Not mentionedNot mentioned
Alves 2016Global photographs and phototrichogram analysis (vertex, grontal, and occipital)Not mentionedNot mentioned
Alves 2018Global photographs and phototrichogram analysis (vertex, grontal, and occipital)Not mentionedNot mentioned
Anitua 2017Phototrichogram analysis using the TrichoScope ASG and the TrichoSciencePro hair and scalp diagnostic software, for women, mild scalp and crown region, hair density, hair diameterm terminal/vellus-like hair ratio and thin/regular/thick hair shafts among terminal follicles, and standardized global macrophotographs, self-assessment questionnaire and rated satisfaction following a likert scale, biosy from 6 volunteers, with ki-67Not mentionedMeasuring TGFβ1, PDGF-AB, EGF, VEGF, TSP-1 and Ang-1 increasing by ELISA
Bruce 2019TrichoScan analysis and TrichoScan digital image analysis, hair count, hair density, cumulative thickness. QOL questionaireweeks 4,8 and 12 of PRP treatmentNot mentioned
Butt G 2020Macroscopic photographs, pull test, trichoscopic photomicrographs, physician glob asseement score (PhGAS), patient global assessment score (PaGAS), hair densityNot mentionedNot mentioned
Butt G 2019Macroscopic photographs, pull test, trichoscopic photomicrographs, physician glob asseement score (PhGAS), patient global assessment score (PaGAS)Not mentionedNot mentioned
Dubin 2020Hair density, caliber and blinded global photographic assessmentIn PRP, mild headache 50%, scalp tightness 50%, swelling29, redness 14%, post-injection bleeding 7%, and tingling 7%Not mentioned
El-husseiny 2020Patients' global photographs, Lugwig's and Sinclair's grading, questionaire of satisfacition, improvement in hair density, hair quality and pain injection and infection11 headache, all reported mild pain during injectionsNo significant difference was found between the median concentrations (ng/L) of VEGF in both nonactivated and activated single- and double-spin prepared PRP measuring by ELISA
Garg 2017Parameters which were observed on video-microscopy are hair count, diameter of hair, change in texture, multiplicity of hair, perifollicular halo, perifollicular pigmentation, increase in telogen hair and increase in vellus hair countNot mentionedNot mentioned
Gentile a 2020Photography, physician's and patient's global assessment scale, and standardized phototrichogramsNot mentionedNot mentioned
Gentile b 2020Hair density by trichoscan, bioposi on anti-ki-67, anti-CD31Not mentionedNot mentioned
Gkini 2014Hair density and patients' satisfaction, hair-pull test, dermoscopic photomicrographs, macroscopic photographs and a satisfaction questionnaire25% mild pain after application, 60% scalo sensitivityNot mentioned
Hausauer 2018Folliscope and global photography, hair count, hair density, shaft caliber, Norwood-Hamilton or ludwig scale were determined, patient's satisfiactionNot mentionedNot mentioned
Ho 2020Hair density and diameter using folliscopeNot mentionedNot mentioned
Juhasz 2020Hair densityNot mentionedNot mentioned
Kang 2014Phototrichogram scalp on hair numbers, thickness with follioscopeNot mentionedFlow cytometry was performed using PRP preparation and an equal amount of peripheral blood in two healthy volunteers. One participant presented 6.7 cells ⁄ lL of CD34 + cells in peripheral blood, whereas those in the autologous PRP preparation were 31.1 cells ⁄ lL
Laird 2018SatisfactionNot mentionedNot mentioned
Lee 2015Hair density, hair count, hair thicknessNot mentionedWestern blot analyses of PDGF-A revealed significant differences between PRP-treated skin samples and control skin samples
Makki 2020Photographs, quartile grading scale with two dermatologists, hair parameters, and hair density, patients satisfactionLocal injection painNot mentioned
Paththinige 2018Hair density, hair count under dermoscopic photographsNot mentionedNot mentioned
Puig 2016Hair count through photography, hair mass index (measured using the cohen hair check system); and patient surveryNot mentionedNot mentioned
Qu 2019Global macroscopic photographs, standardized phototrichograms, hair-pull test and satisfaction questionaireMild pain when injection, headacheNot mentioned
Rossano 2017Gene typeNot mentionedIt showed a negative correlation. IL-1a could be used as a prognostic value for PRP efficacy in female pattern hair loss
Schiavone 2018Photographs by global physician assessment (GPA) score and questionairesBruise after 48–72 h and spontaneously resolved in the fourth to fifth postop dayNot mentioned
Schiavone 2014Photographs by global physician assessment (GPA) score and questionairesNot mentionedNot mentioned
Sclafani 2014Hair densityNoNot mentioned
Shapiro 2020Hair densityNoNot mentioned
Siah 2020Dermatoscope, photography, hair density counting and hair caliber measurementAt week8, treatment site having a higher hair density 129.3 comparing to placebo site 115.3PDGF-BB was the highest concentration of growth factor injected, and VEGF was tested for the lowest growth factor concentration
Singhal 2015Hair count, hair thickness, hair root strength, and overall alopecia3 mild head painNot mentioned
Starace 2019Pull test, blobal photographs, and trichoscan, hair measurementNot mentionedNot mentioned
Takikawa 2011Histological examNot mentionedNot mentioned
Tan 2019Folliscope, questionnaireNot mentionedNot mentioned
Tawfik 2018Hair growth, hair density, hair diameter, photography, hair-pull test, patient's satisfaction scale, standardized phototrichograms, and patient’s satisfactionNot mentionedNot mentioned
Zhang 2018Biopsy ki-67, hair densityNot mentionedNot mentioned
Navarro 2015Trichogram, photograpy, anagen, telogenNot mentionedNot mentioned
DeVasconcelos 2015Mann-whitnety testNoNot mentioned
Yang 2020Dermascopy and photographNot mentionedNot mentioned
Zhang 2020Photographs, satisfaction questionaireNot mentionedNot mentioned
Zolfaghari 2020Hair number and thicknessNot mentionedMeasuring TGFβ1, TGFβ2, PDGF, EGF, VEGF, and HGF increasing by ELISA

Outcomes measurement and adverse events in enrolled studies, and the evaluation of growth factors.

All-included studies showed positive responses and an improvement compared with the baseline; a few pooled patients reported adverse effects, including bruise and mild pain on injection sites after 48–72 h, which would resolve spontaneously in the 4th or 5th postoperation day. Mild headache and scalp sensitivity were also reported in a few studies.

Labs

Apart from clinical evaluation, 7 out of 42 studies also did an assessment on platelet-rich growth factors (PRGF) (Table 4). 6 out of 7 focused on hair follicles regenerative factors including VEGF, PDGF, IGF, TGF-β, and HGF through enzyme-linked immunosorbent assay (ELISA), Western blot for mRNA expression, flow cytometry on CD34+, and animal models. One study reveals a negative correlation between individual genetic inflammatory profile and efficacy of PRP, which was different from PRP in males (Rossano et al., 2017).

Subgroup Meta-Analysis

PRP efficacy compared to placebo. Only endpoints evaluated in the same measurement methods would be pooled in the meta-analysis. Using the random-effects model, PRP showed positive efficacy in the treatment of FPHL in hair density comparing to the control groups with odds ratio [OR] 1.61; 95% CI 0.52–2.70 (Figure 5).

FIGURE 5

FIGURE 5

PRP efficacy compared to the baseline.

PRP efficacy compared to the baseline. Only studies with high quality would be pooled in the analysis. Using a random-effects model, PRP showed effectiveness and improvements on hair density comparing to baseline with OR 1.11; 95% CI 0.86–1.37 (Figure 6).

FIGURE 6

FIGURE 6

PRP efficacy compared to placebo.

Meta-analysis with other evaluation methods was not conducted due to limited studies.

Heterogeneity

In general, a meta-analysis of PRP efficacy comparing to the placebo had considerable statistical heterogeneity (I (Trueb, 2002) >75%), while a smaller substantial heterogeneity exists when comparing to the baseline. Visual inspection of funnel plots and Eggers tests were consistently in agreement with publication bias (Figure 7). Funnel plot that comparing with placebo suggested a tendency toward lack of large studies with both positive and negative results, two of the enrolled small studies showed little association (Figure 8). For the funnel plot in the baseline of the comparison group, a tendency toward a lack of small studies with negative and positive results was indicated (Figure 9).

FIGURE 7

FIGURE 7

Begg’s funnel plot of studies compared the efficacy complared to placebo.

FIGURE 8

FIGURE 8

Begg’s funnel plot of studies compared the efficacy complared to the baseline.

FIGURE 9

FIGURE 9

Funnel plot of studies compared the efficacy complared to the baseline.

Discussion

Our study demonstrated an effective response and relative safety for the application of PRP in the treatment of FPHL with the meta-analysis for RCT and observation studies. Especially for those patients with negative response to the tropical use of minoxidil, PRP offered an alternative treatment option. We only used hair density as an endpoint to perform meta-analysis for the diversity of endpoint settings among the enrolled studies, while hair density is the most commonly used one. This result is in accordance with previous systemic review (Torabi et al., 2020).

The major strengths of the study suggested a positive efficacy of PRP for female AGA and elucidated different PRP preparing methods and treatment regimes. Although there were several systemic reviews (Torabi et al., 2020) and meta-analysis on the application of PRP in AGA treatment (Evans et al., 2020), one mainly focus on female patients remain scarce.

In the author’s opinion, the need for larger scale randomized–controlled trials and extensive meta-analysis precedes a considerable heterogeneity challenge. Heterogeneity anticipated was mainly because of female’s nationalities and races, the difference treatment regime, PRP preparation methods, injection details, and PRP concentration. Subgroup analysis according to the different patient’s races and nationalities were not included in this study for the limited-published data and only a few studies included races information. Lower heterogeneity showed when studies of low quality were abandoned suggesting methodological heterogeneity contributed. Although efforts had been made to accommodate this issue, limited number of studies just based on women patients impeded methods like subgroup analysis, which resulted in a challenge to interpret the efficacy of PRP on female patients. As some studies measured patients of both gender but without separated data for female patients, we cannot prove strong evidence for the treating efficacy.

Selection bias is possibly addressed by group settings among studies. The prevalence of AGA is known to vary from the races (Paik et al., 2001; Gan and Sinclair, 2005; Khumalo et al., 2007). Enrolled studies were conducted by different countries, while all-pooled female participants were diverse in races. Subgroups regarding to ethnicity were not included in this study for the limited-enrolled studies. Whether divergences exist in the efficacy of PRP through races remain unclear. Besides, the majority of randomized studies were set in half-headed. Patients received PRP on half-scalp and placebo on the other half. Both injected spots showed improvement of hair growth or hair density. Although PRP-injected site showed a more obvious effect, the improvement of hair density on the placebo-injected sites may result in a smaller difference between PRP and placebo. Besides, whether PRP had a growth effect on the opposite side of the scalp remains obscure.

In aggregate, our study showed an efficacy of PRP in the therapy of FPHL through hair density evaluation. Although the mechanism of action on hair follicles is still under debate, it has proved to be a promising option for FPHL treatment. Given that current treatments differ from methodology and treatment technique, further studies are needed to define standardized protocols and large-scale–randomized trials still need to be conducted to confirm its efficacy.

Statements

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material; further inquiries can be directed to the corresponding author.

Author contributions

SZ and FQ contributed equally to this work. SZ and FQ did the conceptualization, CZ and YH screening the literatures, FQ and YG evaluated the quality of the included studies, SZ made the decision when any disagreement occurs. SZ and XY extracted the data. FQ and CZ did the meta-analysis and formal analysis, SZ and FQ wrote the original draft, SZ and YH reviewed and editing the draft. YH and CZ did the supervision of the whole work.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2021.642980/full#supplementary-material.

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Summary

Keywords

platelet-rich plasma, female androgenic alopecia, female pattern hair loss, systematic review, meta-analysis

Citation

Zhou S, Qi F, Gong Y, Zhang C, Zhao S, Yang X and He Y (2021) Platelet-Rich Plasma in Female Androgenic Alopecia: A Comprehensive Systematic Review and Meta-Analysis. Front. Pharmacol. 12:642980. doi: 10.3389/fphar.2021.642980

Received

18 December 2020

Accepted

19 March 2021

Published

06 May 2021

Volume

12 - 2021

Edited by

Pietro Gentile, University of Rome Tor Vergata, Italy

Reviewed by

Kurt Neumann, Independent Researcher, Kerékteleki, Hungary

Raja Ahsan Aftab, Taylor’s University, Malaysia

Updates

Copyright

*Correspondence: Yanling He,

†These authors have contributed equally to this work

This article was submitted to Drugs Outcomes Research and Policies, a section of the journal Frontiers in Pharmacology

Disclaimer

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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