Androgenetic alopecia (“AGA”) is the most prevalent type of progressive hair loss, causing tremendous psychological and social stress in patients. However, AGA treatment remains limited in scope. The pathogenesis of androgenetic alopecia is not completely understood but is known to involve a hair follicle miniaturization process in which terminal hair is transformed into thinner, softer vellus-like hair. This process is related to the dysregulation of the Wnt/β-catenin signaling pathway, which causes premature termination of the anagen growth phase in hair follicles. Historically used for wound healing, platelet rich plasma (“PRP”) has recently been at the forefront of potential AGA treatment. PRP is an autologous preparation of plasma that contains a high number of platelets and their associated growth factors such as EGF, IGF-1, and VEGF. These factors are known to individually play important roles in regulating hair follicle growth. However, the clinical effectiveness of PRP is often difficult to characterize and summarize as there are wide variabilities in the PRP preparation and administration protocols with no consensus on which protocol provides the best results. This study follows the previous review from our group in 2018 by Cervantes et al. to analyze and discuss recent clinical trials using PRP for the treatment of AGA. In contrast to our previous publication, we include recent clinical trials that assessed PRP in combination or in direct comparison with standard of care procedures for AGA such as topical minoxidil and/or oral finasteride. Overall, this study aims to provide an in-depth analysis of PRP in the treatment of AGA based on the evaluation of 17 recent clinical trials published between 2018 and October 2021. By closely examining the methodologies of each clinical trial included in our study, we additionally aim to provide an overall consensus on how PRP can be best utilized for the treatment of AGA.
Hair follicles cycle through three primary phases of catagen, telogen, and anagen: former two phases encompass hair follicle regression and shedding while the latter represents the formation and growth of new hair. Hair growth is a highly regulated process that is directly dependent on the β-catenin signaling pathway, which is activated by Wnt ligands. Although there are 19 distinct Wnt genes within the human genome, some Wnt gene have been characterized to play different roles in hair follicle biology. The β-catenin signaling pathway exhibits crosstalk with receptors from other signaling pathways such as the estrogen receptor alpha (ERα), Retinoic Acid Receptor (RAR), and the androgen receptor (AR). Specifically, the crosstalk between the β-catenin pathway and the androgen signaling pathway represents a significant mechanism through which androgens such as DHT (dihydrotestosterone) can induce AGA (androgenetic alopecia), also known as male pattern baldness.
Although the majority of people experience some form of hair loss in their life time, AGA represents the most prevalent type of progressive hair loss, causing tremendous psychological and social stress in patients. Given that the pathogenesis of AGA is driven by potent androgens such as DHT, current standard of care treatments for AGA include finasteride, which inhibit the conversion of testosterone to DHT. Another standard of care treatment for AGA is minoxidil, which is hypothesized to promote the delivery of nutrients and oxygen to hair follicles, thereby shortening the telogen phase. However, these treatments remain limited in scope, and novel treatments that are more effective and act more quickly are needed for the treatment of AGA. Although initially studied for its potential in promoting wound healing, PRP (platelet rich plasma) has been extensively studied in many recent clinical trials for its potential to promote hair growth and to reverse the signs of AGA. PRP is prepared from whole blood by extracting and condensing the fraction of plasma that is rich in platelets. By doing so, PRP thereby contains a higher concentration of platelet-associated growth factors such as EGF, IGF-1, and VEGF, each has been characterized to play an important role in promoting and maintaining hair growth.
In this review, we begin by introducing the molecular mechanisms behind the pathogenesis of androgen-driven hair loss. Special emphasis is placed on the discussing the Wnt/β-catenin signaling pathway, the biology of androgen signaling, and how the two pathways converge. We then provide a brief introduction to hematology, leading into a deeper discussion on how PRP is extracted and produced as well as the clinical implications that come with different methodologies of PRP production. We also briefly discuss how the growth factors found within PRP impact hair follicle biology. Most importantly, we provide an in-depth analysis of all clinical trials published between 2018 and October 2021 that studied PRP as a treatment for AGA. Lastly, we provide a general consensus on how PRP can be best used for treating AGA and provide our observations regarding the clinical contexts in which PRP may be most effective.
Hair is one of the primary characteristics of mammals and exerts many important physiological functions. Terminal hair, which is found on the scalp, is the subject of extensive research in dermatology because its abundance and health directly impacts the psychological well-being of many in our society. To generate hair strands, each hair follicle cycles through three primary phases: catagen, telogen, and anagen. During the catagen phase, the hair follicle regresses via apoptosis and sheds the old hair. After lying dormant during the telogen phase, the hair follicle re-enters the anagen growth phase to re-initiate the formation of new hair. This process is carefully coordinated by the interactions between the ectoderm- and mesoderm-derived cells within each hair follicle and have previously been reviewed.
Two distinct parts exist within each hair follicle: the upper portion that does not regress during the hair cycle, and the lower portion which undergoes regression and remodeling during each cycle. The anatomy of the upper portion includes the infundibulum, the opening of the hair canal to the skin, at the top; the sebaceous gland just below the infundibulum; the isthmus, where the arrector pili muscle inserts into the hair outer root sheath; and the bulge region, which contains hair follicle stem cells and is just above the junction between the upper and lower portions of the hair follicle. The lower cycling portion includes two key components: the anagen bulb and the dermal papilla. During each hair cycle, stem cells from the bulge region migrate toward the anagen bulb at the deepest level of the lower portion and give rise to activated matrix keratinocytes that colonize the matrix area, which later forms the hair shaft and parts of the root sheaths of hair. In contrast to these cells of the ectodermal lineage, the dermal papilla is a cluster of mesodermal fibroblasts that exist below the matrix keratinocytes and form the core of the anagen bulb. Migration of the aforementioned epithelial stem cells that give rise to the activated matrix keratinocytes depend on molecular signals from the dermal papilla. Indeed, the size and shape of the hair strand depend on the number of dermal papilla cells within the anagen bulb. Insufficient accumulation of dermal papilla cells within the anagen bulb would fail to stimulate new hair generation regardless of keratinocyte numbers. The Wnt/β-catenin pathway is the primary signaling pathway through which dermal papilla dictates hair bulb size and hair shaft diameter.
The biochemistry of the canonical Wnt/β-catenin signaling pathway has been previously reviewed. Briefly, β-catenin is constitutively phosphorylated by glycogen synthase kinase 3B (GSK-3B) and targeted for proteasomal degradation in the absence of the Wnt ligand. Once the Wnt ligand binds Frizzled, a G-protein Coupled Receptor, and the Low-Density Lipoprotein-Related Protein (LRP); GSK-3B becomes inactivated and ceases to phosphorylate β-catenin. Upon translocation into the nucleus, β-catenin is recruited to chromatin with the transcription factors T-cell Factor/Lymphoid Enhancer Factor (TCF/LEF) and initiates transcriptional activation of genes.
The role of β-catenin in regulating hair follicle formation was uncovered in 1998 when the ectopic expression of a degradation-resistant truncated β-catenin in mice keratinocytes promoted de novo hair follicle morphogenesis. This was followed soon after by another study which found that β-catenin signaling in chicken skin regulates the development of feather buds. Skin-specific ablation of β-catenin in mice abrogates the formation and development of hair, as keratinocytes that originate from the stem cell population of the hair follicle bulge lose the ability to form hair. Furthermore, transient activation of the β-catenin pathway in keratinocytes can induce progression from the telogen to the anagen phase, leading to active hair growth. Wnt/β-catenin signaling is therefore indispensable for the formation of hair follicles as well as the promotion of hair growth.
Later studies sought to elucidate the cell type-specific roles of Wnt/β-catenin signaling within the hair follicle. It was discovered that β-catenin deletion in dermal papilla cells within fully formed hair follicles reduced the proliferation of stem cells that give rise to the matrix keratinocytes within the anagen bulb. This led to thinner and shorter hair as well as premature anagen termination/catagen induction. Additionally, the absence of β-catenin signaling in dermal papilla cells abrogated the regeneration of hair follicles. Unsurprisingly, the continuous ectopic expression of β-catenin in the dermis produced larger hair follicles and accelerated the differentiation of hair follicle components. Additionally, it was found that epidermal Wnt ligands were required for β-catenin signaling in dermal papilla cells. The result was corroborated by another study showing that the ablation of Wnt ligand secretion specifically within the epidermal compartment of the hair follicle during telogen inhibited the anagen induction and resulted in hair cycle arrest. This is attributed to the downregulation of β-catenin signaling in both dermal papilla cells as well as in the matrix keratinocytes, thereby showing that epidermal Wnt ligands are required for activating β-catenin in both comp
