Androgenetic alopecia: An update.

Background
Androgenetic alopecia (AGA) is a common patterned hair loss affecting men and women.1 It is influenced by genetics and sensitivity to androgens.2 Prevalence differs by gender and race, with >50% of older men and 15% of postmenopausal women affected. However, hair thinning can start as early as puberty.3 AGA's impact on appearance and psychosocial experiences can affect the quality of life (QOL).4 Despite numerous models exploring AGA pathogenesis, there are only 2 FDA approved treatments (finasteride and minoxidil).5
Balding has been observed throughout history, with Aristotle noting its absence in women and eunuchs.6,7 Darwin believed baldness was a secondary sexual characteristic. He reasoned that while hair is a common feature in most adult humans, males tend to experience hair loss more frequently than females.8 Osborn discovered that baldness follows a dominant inheritance pattern.9 Hamilton and Orentreich linked genetic predisposition, androgens and age to baldness.2,10
AGA progresses differently in males and females, with different classification scales.11 While the cause may be similar in both genders, the evidence for androgens is stronger in males and there are variations in hair loss patterns.12
This review discusses AGA's history, causes, diagnosis, management, and recent advancements in research and clinical approaches.

AGA etiology

Androgens and androgen receptors
Androgens are important hormones for the growth and development of the human body. They function through intracellular signalling pathways, with testosterone being the main and most active androgen in males.13 Testosterone is converted by type 2, 5-alpha reductase (SRD5A2) into dihydrotestosterone (DHT), leading to AGA. Excessive DHT shrinks hair follicles, replacing terminal hairs, with vellus hairs (Fig 1).14
Androgen receptors (ARs) in hair follicles bind to DHT, changing protein shape, and initiating a signalling cascade (Fig 2).15 Occipital hairs are less sensitive due to AR methylation, protecting them from miniaturization and loss. AR has a strong affinity for DHT compared to testosterone, explaining their binding strength.16

The role of genetics
AGA susceptibility is primarily influenced by hereditary factors, contributing to around 80% of the predisposition to baldness.17 AGA follows a polygenic model, characterized by varying expression levels, which accounts for the diverse range of clinical phenotypes and initial variations observed in individuals affected by this condition.18
Modifications of the androgen receptor (AR) genes on the Xq12 chromosome lead to AGA,19 through increased AR gene activity in hair follicles triggered by dihydrotestosterone (DHT) binding. The mechanism of AR-mediated hair loss remains unknown.20 However, gene polymorphisms in the AR gene consistently correlate with AGA susceptibility in men21 and are implicated in FPHL.22 Variation of the AR gene accounts for about 40% of the heritability of AGA in men,23 and variation in the DNA responsible for hair loss is close to the AR locus in regions responsible for the regulatory effect of AR, including the Ectodysplasin A2 Receptor (EDA2R).24 Studies have provided partial insight into the intricate heritability of AGA, revealing a reciprocal interplay between genetics and androgens, as evidenced by the development of alopecia in individuals from families with bald adult males upon androgenic therapy.10,20

The role of steroid 5-alpha reductase (SRD5A) enzyme
The SRD5A enzyme is a full membrane-embedded protein with 5 members: SRD5A type 1 to type 3, the glycoprotein synaptic 2 (GSPN2) and GSPN2- like.25 SRD5A1 predominates in the liver, skin, and scalp, and metabolises neurosteroids. SRD5A2 is expressed in hair follicles, the prostate, and the genitourinary tract, and has high specificity for steroids containing the Δ4,3-keto configuration, like testosterone. SRD5A2 was characterised based on its ability to convert Δ4,3-keto steroids into metabolites with distinct predetermined roles26 and is the one associated with AGA. SRD5A3 functions in protein N-linked glycosylation and is expressed in malignant human prostate tissues, prostate cancer, and breast cancer.27
SRD5A mediates 3 metabolic pathways; bile acid biosynthesis, androgen, and oestrogen metabolism. In androgen metabolism, SRD5A reduces Δ4,5 bond in substrates using NADPH, for example, SRD5A1 converts testosterone to DHT causing BPH and SRD5A2 is involved in AGA. These 2 iso-enzymes reduce the Δ4 group (double bond) of C-19 and C-21 steroids into 5α-stereoisomers – DHT (Fig 3).28

AGA management

Diagnosis
Male and female pattern hair loss have similarities but also significant differences in their presentation and treatment. The pattern of hair loss and the response to treatment vary between genders. Advanced ADA is a clinical diagnosis. However, assessing patients for early AGA involves invasive and noninvasive methods such as scalp dermoscopy, hair/scalp examination, pull tests, trichograms, and scalp biopsies.29
Histologically, AGA is characterized by follicular miniaturization, perifollicular inflammation, fibrosis in the pilosebaceous unit angiofibrotic tracts, follicular stelae and signs of follicle destruction or hair shaft damage.30 Evaluation is critical to exclude other scalp conditions, like seborrheic dermatitis, which can aggravate AGA and result in smooth and shiny skin.31
The management of AGA involves FDA-approved and nonapproved treatments, which are reported to effectively slow down the progression of hair loss. It's important to note that discontinuing treatment may result in a rapid progression of hair loss.

Treatment
Despite the widespread occurrence of AGA, effectively managing and treating the condition remains challenging, leading many individuals to seek medical help. Various options, including lifestyle adjustments, hair care practices, and medications are available, but only 2 drugs, oral finasteride (for men) and topical minoxidil (for both men and women), are FDA-approved for AGA treatment. Off-label use of topical minoxidil for AGA exists, but its effectiveness and safety require further investigation to assess potential benefits and risks.32

Finasteride
Finasteride – a competitive and specific SRD5A2 inhibitor – is an FDA-approved drug used to treat adult men with mild to moderate AGA at an oral dosage of 1 mg/day, thereby decreasing serum, prostate, and scalp DHT by 60% to 70%.33 Finasteride preferentially inhibitions SRD5A2 by forming a stable complex with the enzyme in the presence of NADPH (Fig 4). SRD5A2 inhibitors prevent the hydride transfer from NADPH to testosterone responsible for converting testosterone to DHT. The SRD5A2 and finasteride complex have a half-life (t1/2) of approximately 31 days, and DHT takes about 14 days to increase after the discontinuation of finasteride. Hair regrowth stops within 12 months of stopping systemic finasteride.34 A systematic review of randomized controlled trials (RCTs) recommended a combination therapy of minoxidil 2% and systemic finasteride 1 mg, citing its superiority to monotherapies.35
Topical finasteride, not FDA-approved but found to be effective, is recommended for females to avoid hormonal side effects.36 It reduces hair loss, improves hair growth and lowers DHT levels.37 While finasteride has shown positive effects, there have been reported drawbacks, leading to a decline in its prescription.38 Studies suggest higher doses may be more effective for female pattern hair loss,39 but caution is required due to the risk of teratogenicity in premenopausal women.40
Finasteride side effects may result from interactions with proteins beyond SRD5A2 inhibition. Recent research discovered that finasteride can bind and inhibit phenylethanolamine N-methyltransferase, an enzyme that controls epinephrine production. This interaction might contribute to systemic side effects like sexual and psychological symptoms.41

Minoxidil
Topical minoxidil is the main treatment for AGA and is also used off-label for other forms of hair loss. It was repurposed as a hair loss treatment when hypertensive patients on oral treatment experienced increased hair growth as a side effect.42 Topical minoxidil is thought to dilate scalp blood vessels, promoting hair growth by improving nutrient delivery to hair follicles.43 It is available in different forms, such as solutions, foam, and shampoo, with the 5% solution being more effective than the 2% solution.44
Recent studies have shown that low-dose oral minoxidil (2.5-5 mg/day for male and 0.25-1.25 mg daily for female AGA) can be safe and effective but should be used with caution in individuals at risk for cardiovascular events.45, 46, 47

Laser therapy
In 1967, a study showed that low-level light/laser therapy (LLLT) using a ruby laser promoted hair growth in mice. LLLT devices were later FDA-cleared in 2007 for men and 2011 for women as a potential treatment for hair loss. LLLT stimulates hair growth by influencing the hair cycle using specific wavelengths between 650 nm and 1200 nm,48 with LLLT red or near-infrared light ranging between 600 and 950 nm and fluences between 2 and 10 Joules per square centimetres (J/cm2), over 15-20 minutes, 3 times a week for 6 months.49
Recent reviews of randomized trials have found that LLLT can increase hair diameter or density compared to sham devices, with minor side effects like dry skin and scalp irritation reported. These findings support the use of LLLT as a treatment option for AGA. However, challenges exist in standardizing treatment parameters, study designs, and assessing long-term outcomes in LLLT studies.50,51

Hair transplantation
Hair follicle transplantation is a surgical procedure that involves removing and transplanting hair follicles from non-androgen sensitive areas to areas affected by AGA. The transplanted follicles do not miniaturize, grow in groups of 1 to 4 hairs and are harvested as units. In 2009, the FDA-approved a robotic hair restoration device to assist surgeons. Later in 2011, the ARTAS system was also approved to harvest curly hair in black men.52 ARTAS robotic hair transplant is a minimally invasive hair restoration system that uses artificial intelligence technology to restore hair faster and more precisely than traditional hair restoration methods.

Non–FDA-approved AGA treatments

Off-label medications and hormonal therapies
Dutasteride is an effective off-label drug for AGA and inhibits SRD5A2,53 and was more effective than finasteride in a meta-analysis of 24 weeks of treatment with comparable side effects.54 In Japan and South Korea, oral dutasteride (0.5 mg/d) has been approved for male AGA.55
Other treatment options for AGA include oral cyproterone and spironolactone, sometimes used off-label in females.56 Cyproterone blocks the androgen receptor, while spironolactone slows androgen production by blocking androgen receptors in target tissues and decreasing testosterone production in the adrenal gland. Flutamide, a nonsteroidal antiandrogen that binds to the AR and blocks the action of testosterone, is not commonly used in the treatment of AGA in either males or females due to adverse side effects, such as liver toxicity.57,58

Phytomedicine
Phytomedicine, the use of plant-based products for medicinal purposes, is popular for treating AGA and can be used as a complementary or alternative treatment. Plants like Serenoa repens, Panax ginseng, Curcuma aeruginosa, Cucurbita pepo and Trifolium pratense59; palm extract (tocotrienol/tocopherol complex), horsetail and ashwagandha have been reported to treat AGA. Although high quality evidence from controled studies are needed these plants are reported to inhibit 5-alpha-reductase, lower cortisol levels, reduce inflammation, promote homeostasis, and maintain collagen stores.60

Injectables
Platelet-rich plasma (PRP) refers to a naturally derived mixture of platelets in a concentrated plasma solution, typically containing over 1,000,000 platelets per microliter or 2-7 times the concentration found in regular blood.61 The application of PRP has been shown to stimulate hair growth, enhance cell survival, and extend the active growth phase (anagen) of the hair cycle.62 It enhances grafting and improves follicular unit survival,63 resulting in hair density and thickness, according to recent meta-analyses of 30 articles with 687 patients using various injection methods.64 However, the efficacy of PRP compared to other treatments for androgenetic alopecia (AGA) remains uncertain due to a lack of standardized protocols, long-term follow-up outcomes, and limited clinical evidence.65

Exosomes
Mesenchymal stem cell-derived exosomes hold great promise in the field of hair restoration, as they contain cytokines and growth factors that promote hair growth.66,67
Research suggests that exosomes derived from dermal papilla cells can accelerate hair follicle growth, delay regression, and reduce hair loss and inflammation in preclinical models.68
Although no clinical trials have been completed yet, anecdotal evidence and case reports suggest promising results69 and initial studies indicate increased hair thickness and density after exosome therapy in individuals with pattern baldness.70
A Korean pilot study showed that exosome therapy improved hair thickness (increased from 57.5 to 64.0 mm, P ≤ .001) and hair density (increased from 105.4 to 122.7 counts/cm2, P ≤ .001) after 12 weeks.71,72 However, further research is needed to assess exosomes' biodistribution, pharmacokinetic profile, and safety.73

Adjuvant therapy
Microneedling, a minimally invasive cosmetic procedure, stimulates the release of growth factors and stem cells, promoting collagen formation and improving topical treatment absorption,74 leading to improved hair density and thickness.75 Case studies demonstrate its effectiveness when combined with therapies like PRP and minoxidil for patients unresponsive to conventional treatments, resulting in improved hair density and thickness.76 Reported side effects include pain, bruising, and folliculitis.77

Camouflage techniques
Camouflage techniques can be helpful in disguising hair loss and boosting self-confidence.78 These methods include temporary solutions like wigs, hair-thickening fibres, and pigmented powders79 as well as semi-permanent options such as scalp micro-pigmentation, which creates the appearance of closely shaved hair follicles through tattooing.80

Future prospects
The discovery of SRD5A2's structure (Fig 5) in 2020 has opened new possibilities for developing more effective AGA treatments. Understanding its function and interactions allows researchers to identify drug targets and design drugs specifically targeting the protein. This breakthrough has the potential to enhance drug efficacy and safety. It also has implications for treating other diseases. The discovery represents a milestone in AGA treatment and promises a brighter future for patients.

New treatments
New insights into AGA's pathogenesis have led to new research prospects. Promising treatments are being developed, including clascoterone, an FDA-approved topical androgen receptor inhibitor initially used for acne. Recent studies indicate clascoterone's potential effectiveness in treating AGA.81 Patients treated with clascoterone 7.5% twice daily for 6 months experienced reduced hair loss and improvement compared to the placebo group and their baseline.82,83
Other upcoming treatments for AGA include Janus kinase inhibitors, which block the immune system response causing hair loss, and stem cell therapies that stimulate hair growth.

Conclusion
Androgenetic alopecia (AGA) poses significant challenges for individuals, particularly among younger males, females, and those seeking treatment. Although limited treatment options currently exist, ongoing research and expanding knowledge about its underlying mechanisms and potential interventions offer hope for improving outcomes for those affected by this condition. As we continue to learn more about AGA and the structure of SRD5A2, we can work toward developing better targeted approaches to managing and treating this common and distressing condition.

Conflicts of interest
None disclosed.