The hair growth cycle is a complex, tightly regulated process consisting of four primary phases, involving growth, transition, resting, and shedding, called anagen, catagen, telogen, and exogen, respectively [28]. The anagen phase is characterized by active cell proliferation within the hair bulb, leading to the production of the hair shaft [29]. In the scalp, the anagen phase typically lasts between two to eight years and determines the final length of the hair [29]. The catagen phase follows, lasting approximately 2 to 3 weeks, during which hair growth ceases, and the hair follicle undergoes apoptosis-driven regression [30]. The telogen phase lasts about two to three months, involving resting of the old hair and simultaneous new hair development at the hair follicle base [31]. Lastly, the exogen phase describes the termination of telogen and initiation of anagen phase, of which new hair grows upward, pushing the old hair out and culminating in shedding [28].

In androgenetic alopecia (AGA), the normal hair cycle is disrupted, leading to progressive miniaturization of hair follicles and altered cycling dynamics. In AGA affected areas, increased AR density enhances DHT binding, resulting in the prolonged activation of androgen-responsive genes responsible for regulating hair follicle cycling [26]. Androgen-mediated signaling shortens the anagen phase while increasing the duration of the telogen phase, leading to progressive follicular miniaturization [32][33]. Successive cycles result in the substitution of terminal hairs for thinner, less pigmented vellus hairs, which lack the robustness of healthy scalp hair [23]. The reduced duration of the anagen phase limits hair shaft elongation and contributes to the visible thinning characteristic of AGA.

Hair follicle miniaturization is the defining pathological feature of androgenetic alopecia (AGA), and involves the progressive reduction in hair follicle size, leading to the transformation of thick terminal hairs into fine, short vellus hairs [34]. This miniaturization process is largely driven by inflammatory and microenvironmental changes, but is best understood as a result of increased follicular sensitivity to DHT. DHT binds to ARs in the dermal papilla cells of the hair follicle, initiating signaling pathways that induce apoptosis of follicular cells and trigger the premature entry into the catagen phase [34]. The miniaturization process in AGA is often accompanied by DHT mediated perifollicular fibrosis, which creates a rigid extracellular matrix around the follicle, impairing its ability to regenerate and enter the anagen phase effectively [35]. This process results in shorter, thinner hair shafts and an overall reduction in hair density [35]. Over successive cycles, the eventually follicle’s ability to regenerate diminishes, leading to baldness and thinning.

As mentioned previously, sebaceous glands are highly sensitive to androgens and play a significant role in the pathophysiology of AGA. These glands secrete sebum to lubricate the scalp and hair, helping to seal in moisture and prevent skin desiccation [36]. In AGA, sebaceous glands undergo morphological changes, exhibiting increased ductal branching and lobulations, or altered lipid metabolism [37]. Although sebaceous glands in miniaturized follicles may appear disproportionately enlarged, this phenomenon is not due to true glandular hypertrophy, but instead as a result of shrinkage of the surrounding hair follicle [33][37].

In AGA-affected scalps there is increased binding affinity of sebaceous gland cells for DHT, which leads to upregulated sebum production [37]. Excess sebum can create an occlusive environment around hair follicles, promoting microinflammation and oxidative stress, further accelerating follicular miniaturization [37]. Additionally, the sebaceous glands in AGA patients express significantly higher levels of ARs compared to non-AGA scalps, making them more responsive to circulating androgens [38]. Understanding the role of sebaceous gland alterations in AGA underscores the importance of addressing glandular changes. By targeting both the follicular and glandular components, clinicians can optimize treatment outcomes and improve scalp health in AGA patients.

Lipidomics has allowed for novel ways to investigate AGA. There are significant changes in lipid content and metabolism in AGA, relative to healthy controls [39]. Variants of phosphatidylcholine (PC), the most biologically active phospholipid considered to possess regenerative and antioxidant effects, were noted to be significantly decreased in AGA [39][40]. Autophagy plays a key role in initiating hair follicle activation and is initiated by phosphatidylethanolamine (PE), another phospholipid also found to be significantly decreased in AGA [37]-[41]. Amongst PE and PC, phosphatidylglycerol (PG) and phosphatidylinositol (PI), related to inflammatory response reduction and hair follicle regeneration respectively, were also significantly reduced in AGA patients [39][42][43]. Furthermore, triglyceride metabolites were found to be significantly increased in the scalp of male AGA patients, relative to female AGA patients, indicating the role sex may play in lipid metabolism [39]. Subsequently, lipidomics has considerable potential to identify key diagnostic biomarkers aiding in AGA diagnosis and characterization.

Although AGA. is typically classified as a non-inflammatory, non-scarring form of hair loss, histological evidence of inflammation has been reported. Mononuclear cells and lymphocytic infiltrates have been observed in nearly half of male AGA scalp samples [44]. Mast cell degranulation and fibroblast activation within hair follicle fibrous shifts has also been observed [44]. Moreover, T cell infiltrates are prominent in the region of the follicular bulge, a critical source of hair follicle stem cells [45]. Perifollicular infiltration of lymphocytes and mast cells, promote fibrosis and compromise follicle function, contributing to hair follicle miniaturization in AGA [44]. Critically, the hair bulge of human anagen hair follicles represents a site of relative immune privilege [46]. However, disruption of hair follicle immune privilege in AGA can be characterized by upregulation of MHC-1 and II expression, rendering hair follicles susceptible to inflammatory attack, and ultimately culminating in hair loss [46].

Macroscopic Patterns and Microscopic Progression in AGA

AGA follows a characteristic and progressive pattern of hair loss that macroscopically varies between males and females [2][4]. Macroscopically, AGA typically begins at the frontal hairline, temples, and vertex of the scalp, gradually progressing to a receding hairline and thinning at the crown, which may eventually merge into larger bald areas [2]. In men, this is commonly classified using the Norwood-Hamilton scale, while the Ludwig scale is used for women, where diffuse thinning over the crown occurs while maintaining the frontal hairline [4].

Microscopically, AGA shows certain distinct alterations. Notably, AGA is characterized by miniaturization of hair follicles within scalp follicular units [34]. Terminal hair follicles progressively transform into finer, shorter vellus hairs, due to the effects of DHT and altered hair cycle dynamics [34]. This miniaturization results in a decrease in hair shaft diameter and length, leading to the clinical appearance of thinning hair [34]. Miniaturization is accompanied by a reduced number of terminal hairs within each follicular unit, with affected areas showing a higher proportion of vellus hairs compared to unaffected scalp regions [44]. In AGA, the follicular microenvironment also displays fibrotic changes, further contributing to disease progression. Increased extracellular matrix deposition and reduced vascularization in the scalp regions of AGA-affected individuals prevents nutrients from being delivered to hair follicles [23]. Over time, the accumulation of DHT-mediated perifollicular fibrosis and reduced vascularization further limits follicular regeneration, exacerbating hair loss [23].

Topical minoxidil is amongst the most frequent therapies currently employed for AGA with proven efficacy, which works by enhancing blood supply in the scalp and thereby stimulating hair growth [47]. Minoxidil induces opening of potassium channels, thereby resulting in subsequent vasodilation and improved supply of oxygen and nutrition to miniaturized follicles [48]. This drug works by prolonging the growth phase of the hair cycle, which enables follicles to produce a thicker and healthier hair strand [48]. It is available in 2% and 5% formulation; effective in both men and women [33][35]. Minoxidil is applied to the scalp, making this a rather convenient and noninvasive treatment; however, it needs to be used continuously to sustain any response [33]. The discontinuation of therapy generally results in resumption of miniaturization of hair follicles, highlighting the need for long-term compliance [33]. Most patients tolerate minoxidil well, though some develop scalp irritation, dryness, or even unwanted excessive hair growth on the face, which may be disturbing for some individuals [33].

Topical antibiotics and antifungals are not primary therapies for AGA, but do play an adjunctive role in the treatment of AGA, particularly in the presence of comorbid seborrheic dermatitis [49]. Antibiotics, such as clindamycin, are effective in reducing inflammation by targeting bacterial overgrowth that may contribute to localized irritation [47]. Ketoconazole, an antifungal, is an effective treatment for seborrheic dermatitis produced by the yeast Malassezia [47]. Ketoconazole also inhibits the action of DHT on the scalp, thereby reducing sebum production [47][50]. By reducing fungal colonization and sebum production, ketoconazole helps develop a more hospitable scalp for hair growth [47][50]. Regular use of ketoconazole reduces itching, flaking, and erythema and serves as an effect adjunct to other active treatments of AGA [50].

Finasteride forms the backbone of the management of AGA, due to its primary action against DHT production. Finasteride is a selective type II 5α-reductase inhibitor, preventing the conversion of testosterone into DHT [34]. In fact, several studies have identified that with continued therapy, finasteride significantly improves hair density and thickness, especially over the crown and mid-scalp areas [34]. It is taken orally in a standard dosage of 1 mg daily and is approved by the FDA for the treatment of male pattern hair loss [34]. Adverse effects include impaired libido, erectile dysfunction, and gynecomastia, which, although no doubt distressing, are relatively uncommon and usually reversible on cessation [34][51]. Due to its teratogenic effects, finasteride is contraindicated in women of childbearing age [34]. Nonetheless, finasteride remains one of the most effective pharmacological options available for arresting the progression of AGA and promoting hair regrowth in affected individuals.

Dutasteride is a 5-alpha reductase inhibitor, similar to finasteride, but it inhibits both type I and type II isoforms of the enzyme, making it a significantly more potent effector [51][52]. Dutasteride’s broader mechanism of action leads to greater suppression of DHT production, increasing hair count and shaft thickness in more advanced, or treatment-resistant, cases of AGA [51]-[53]. However, dutasteride is associated with a higher side effect profile, including: sexual dysfunction, mood changes, and hormonal imbalances [53]. While highly effective, dutasteride’s use requires careful patient selection and monitoring, as the potential side effects can outweigh the benefits in some individuals [53]. In women, dutasteride is rarely used due to its teratogenic risks and systemic hormonal effects.

Spironolactone represents the most common oral antiandrogen for female patients with AGA, especially when associated with signs of hyperandrogenism like in PCOS [54]. Spironolactone exerts an antiandrogenic effect via AR blockade and via suppression of testosterone synthesis, effectively slowing balding and promoting follicular regrowth [55]. It has been administered in dosages ranging from 50 - 200 mg/day, depending on the severity of hair loss and the underlying hormonal profile of the patient [55]. Its use warrants caution, given the possibilities for side effects such as menstrual irregularities, mammary tenderness, dizzy spells, and hyperkalemia [55]. Spironolactone is also contraindicated in pregnancy, due to its teratogenic properties [55]. Despite these precautions, spironolactone remains a safe and effective option for many women with AGA, offering a targeted approach to managing androgen-mediated hair loss.

Prostaglandin analogues, such as latanoprost and bimatoprost, are an innovative class of treatments originally developed for managing glaucoma [56]. These agents have been found to stimulate hair growth by extending the anagen phase and increasing hair follicle size, resulting in thicker and darker hair strands [57]. Bimatoprost, in particular, is FDA-approved for enhancing eyelash growth and is being explored for its potential in treating scalp hair loss [57]. Topical application of prostaglandin analogues allows for localized effects with minimal systemic absorption, reducing the risk of side effects [57][58]. Early clinical studies have shown promising results, with increased hair density and improved hair quality in treated areas. However, these treatments are still in the experimental stage for AGA, and more extensive research is needed to establish their long-term safety and efficacy. Side effects, though rare, may include localized irritation or darkening of the skin around the application site [56][59]. Prostaglandin analogues represent an exciting frontier in AGA management, offering a novel mechanism of action that complements existing therapies.

Photobiomodulation (PBM), commonly known as low-level light therapy (LLLT), has emerged as a non-pharmaceutical intervention for AGA by leveraging specific wavelengths of red (620 - 700 nm) and near-infrared (700 - 1440 nm) light to stimulate cellular processes [65][66]. These wavelengths are absorbed by chromophores within cells, triggering the production of nitric oxide (NO) and modulation of reactive oxygen species (ROS), which in turn activate redox-sensitive signaling pathways that enhance cellular proliferation, migration, and differentiation in hair follicle and perifollicular cells [65][66]. This process helps to counteract oxidative stress and inflammation, which are key contributors to follicular miniaturization in AGA.

PBM utilizes a variety of cellular pathway signalling mechanisms. A primary mechanism underlying PBM’s efficacy is the activation of mitochondrial cytochrome c oxidase, which boosts adenosine triphosphate (ATP) synthesis, thereby increasing cellular energy and supporting follicular regeneration [67]. Additionally, PBM has been shown to upregulate the Wnt/β-catenin signaling pathway, a key driver of hair follicle development and growth, while downregulating the transforming growth factor-beta (TGF-β) pathway, which contributes to follicular miniaturization and hair loss [67]. By promoting Wnt/β-catenin signaling, PBM encourages hair follicle stem cell activation, thereby extending the anagen (growth) phase of the hair cycle [67].

The therapeutic potential of PBM is supported by clinical evidence, demonstrating significant improvements in hair density and shaft diameter among patients receiving LLLT compared to controls [68]. This suggests that PBM not only prevents further hair loss but also actively contributes to hair regrowth by improving follicular function. Furthermore, PBM has been shown to enhance cell viability, proliferation, and migration in dermal papilla cells, reinforcing its role in stimulating hair growth [67]. These effects help maintain a functional hair follicle niche, ensuring continuous hair regeneration. By improving mitochondrial function, modulating critical signaling pathways, and fostering a healthier follicular microenvironment, PBM presents a promising, safe, and non-invasive strategy for managing AGA [65][67]. The multifaceted OBM mechanism of action positions it as an effective alternative or adjunct therapy to conventional AGA treatments.

Platelet-rich plasma (PRP) therapy has gained attention as a non-pharmaceutical treatment for androgenetic alopecia (AGA) [68][69]. PRP is an autologous preparation of plasma with a high concentration of platelets and associated growth factors, such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) [69]. These growth factors are believed to promote hair growth by enhancing cellular proliferation, differentiation, and angiogenesis in hair follicles [69]. Additionally, PRP acts to support the release of growth factors that stimulate the proliferation of dermal papilla cells, prolong the anagen phase of the hair cycle, and enhance vascularization around hair follicles, leading to increased hair density and thickness [70]. Treatment with PRP leads to significant increases in hair count, hair density, and the percentage of anagen hairs, relative to controls, highlighting PRP’s role in follicular regeneration [69]-[72]. Ultimately, PRP therapy presents a promising, safe, and effective treatment modality for AGA, with mounting clinical evidence supporting its efficacy in improving hair growth parameters.

Stem cell therapy leverages the regenerative potential of various stem cell types to promote hair follicle restoration. Mesenchymal stem cells (MSCs), particularly those derived from adipose tissue and hair follicles, secrete growth factors and cytokines that stimulate dermal papilla cell proliferation, prolong the anagen phase of the hair cycle, and enhance vascularization in the perifollicular region [72][73]. For example, MSC suspension, derived from autologous hair follicles, has been observed to contribute to notable increases in terminal hair proportion and shaft diameter, particularly benefiting patients with advanced follicular miniaturization [73]. Autologous micrografts containing adipose tissue-derived stem cells (ADSC) have also exhibited a significant increase in mean hair density improvement at 23 and 24 weeks post-treatment, with no severe side effects observed [72][74].

In particular, ADSC-Exosome therapy serves as a promising treatment for AGA due to its potential to enhance hair follicle regeneration through multiple molecular pathways. Exosomes are small extracellular vesicles that facilitate intercellular communication by transferring proteins, lipids, and RNA, thereby influencing key biological processes in recipient cells [75][76]. One of the primary mechanisms through which ASC-Exosomes promote hair growth is the activation of the Wnt/β-catenin signaling pathway, a critical regulator of hair follicle development and stem cell activity [75]-[77]. By increasing the expression of β-catenin and other hair growth-associated genes such as alkaline phosphatase (ALP) and versican (VCAN), ASC-Exosomes stimulate the proliferation and differentiation of dermal papilla cells, key contributors to hair follicle maintenance and growth [76][77]. ADSC-Exosomes carrying miR-122-5p effectively counteracted DHT-induced follicular suppression while simultaneously enhancing β-catenin expression and VCAN levels [76]. Additionally, ADSC exosomes have been shown to inhibit the TGF-β/SMAD3 pathway, which is implicated in hair follicle miniaturization and AGA progression [76]. Notably, ADSC-Exosomes carrying microRNA-122-5p have also been found to antagonize the inhibitory effects of DHT on hair follicles by downregulating TGF-β1/SMAD3 signaling, thereby fostering a pro-growth follicular environment [78]. Another essential mechanism involves enhanced angiogenesis, wherein exosomes promote vascularization around hair follicles, ensuring adequate nutrient and oxygen supply for sustained hair growth [75].

Stem cell therapy, especially utilizing ADSC-Exosomes, exhibits substantial clinical evidence to back its efficacy in AGA treatment. Collectively, current literature indicates that stem cell therapy offers a promising and effective approach for AGA management, with substantial improvements in hair density, follicular health, and overall patient satisfaction.

Despite the availability of various treatments for AGA, several issues persist that limit their effectiveness and patient satisfaction. 5-alpha reductase inhibitors, such as finasteride and dutasteride, are effective, but are associated with concerns about sexual adverse effects, which can deter patients from long-term use [34][51][53]. Topical finasteride offers a safer alternative with fewer systemic effects, but its efficacy compared to oral formulations remains under investigation [78]. Oral minoxidil, although effective, is not FDA-approved for AGA and can cause side effects like hypertrichosis, dizziness, and lower limb edema, which may limit its use [79]. PRP therapy shows promise, but the heterogeneity in treatment protocols and lack of standardized procedures make it difficult to compare results across studies and establish definitive efficacy [78][80]. LLLT is another non-pharmaceutical option with demonstrated efficacy, but the evidence is limited, and its effectiveness compared to other treatments or as an adjunct therapy is not well established. Emerging treatments, such as pyrilutamide and GT20029, are still in the investigational stages, and their long-term safety and efficacy need further validation [81]. Additionally, mesotherapy with dutasteride and scalp threading are newer approaches with limited evidence supporting their effectiveness, highlighting the need for more robust clinical trials [82][83]. While the pipeline for new treatments is promising, the current landscape of AGA therapy is marked by limitations in efficacy, safety concerns, and a lack of standardized treatment protocols.