Androgenic Alopecia Treatment Review
Androgenic Alopecia Treatment Review
Abstract
Androgenic alopecia (AGA), commonly known as male pattern baldness (MPB), is a hereditary condition
characterized by hair follicles that are sensitive to androgens. This article focuses on examining the recent
advancements in the comprehension and management of AGA. The genetic factors and pathophysiology of
AGA, including the role of dihydrotestosterone (DHT) and the androgen receptor gene, are discussed. The
consequences of hair loss on self-esteem and identity, as well as on mental health, are examined. Diagnostic
methods, such as the hair-pull test and trichoscopy, are discussed. The article also presents the Hamilton-
Norwood classification, which is the most commonly employed system for classifying MPB. The article then
delves into the various treatment options available, including topical minoxidil, oral finasteride, platelet-
rich plasma therapy, low-level light therapy, hair transplant, and other alternative treatments. The efficacy
and combination therapies for these treatments are examined. Additionally, emerging treatments such as
caffeine-based solutions and prostaglandin inhibitors are discussed. By examining the recent advancements
in AGA treatment, this article provides a comprehensive overview for healthcare professionals to make
informed decisions when selecting the best treatment options for their patients.
Methodology
Working in collaboration with other authors of this paper, we searched articles on PubMed Central,
MEDLINE, and Google Scholar indexed journals in May 2023. The keywords from our research topic
Review
Genetics and AGA
AGA is a complicated condition that is impacted by a combination of environmental and genetic factors.
Genes related to the androgen receptor and 5-AR have been identified as significant players in AGA. Recent
genome-wide studies have found strong associations between AGA and the androgen receptor gene, as well
as the ectodysplasin A2 receptor on the X chromosome [6]. Existing research has identified several genes,
such as PGD2, neurotrophin-3 protein, PGDS, BMP2, BDNF, ephrinA3, neural growth factor-β, GSN, and
ASS1, to show varying levels of expression in both, scalp biopsies and cell cultures from the dermal papilla,
of individuals suffering with AGA; nonetheless, more research is necessary to authenticate these
findings [7]. AGA, despite its connection to the activity of androgenic hormones and genetic predisposition,
also involves familial clustering. However, it can manifest in multiple family members without following a
single-gene inheritance pattern, making it a complex trait [6].
Pathophysiology
The hair follicle experiences three primary stages in its lifecycle. During the anagen (growth) stage, the hair
follicle undergoes an active phase where it assumes a structure resembling an onion and functions to
generate the hair strand. It is followed by the catagen phase, which lasts for a few weeks, where the hair shaft
loses 1/6th of its diameter by apoptosis-driven regression. This is followed by the telogen or dormant phase,
where there is no hair growth [8]. AGA occurs due to the gradual reduction in the length of consecutive
growth phases of hair (anagen phases) and the gradual shrinking of hair follicles that are genetically
susceptible, triggered by androgens. Additionally, the process involves the substitution of thick, dark hairs
(terminal hairs) with thin, lightly colored hairs (vellus hair) [9]. The conversion of testosterone to DHT is
primarily carried out by the enzyme 5-AR, and DHT plays a crucial role in the development of AGA in males.
5-AR exists in three different forms: types I, II, and III. The skin, encompassing the sebaceous glands and
hair follicles, primarily has the type 1 enzyme [10]. In about two-thirds of biopsy cases, there is an observed
presence of a relatively moderate perifollicular lymphohistiocytic inflammatory infiltrate surrounding the
infundibulum. However, this finding lacks specificity since it is also observed in approximately one-third of
normal control cases [11]. A recent development in our understanding of hair follicle regeneration and hair
shaft growth involves the recognition of the vital role played by the Wnt/β-catenin signaling pathway in
maintaining the properties of dermal papilla cells (DPC) that are necessary for these processes. Additionally,
it has been found that androgens and ligand-activated androgen receptors can have a negative impact on the
Wnt/β-catenin signaling pathway, as shown in Figure 1. More precisely, increased expression of glycogen
synthase kinase 3 beta by androgens is what obstructs this pathway [12]. One distinguishing feature of AGA
is the perceived enlargement of sebaceous glands in relation to the size of miniaturized hair follicles.
However, it is important to note that this observation is not indicative of true sebaceous hyperplasia, as the
sebaceous glands maintain their normal size and structure and their enlargement is only apparent [13].
Another hypothesis regarding AGA suggests that the disappearance of the arrector pili muscle is a
contributing factor. The smooth muscle plays a role in regulating body temperature and sebum production
while also serving as a link between the hair follicle and the upper layers of the skin. Researchers have put
forward the idea that the loss of the arrector pili muscle could be linked to the permanent development of
AGA [14].
Image credits: Parth S. Bajoria, Priyansh Patel, and Prathma Anandbhai Dave
Consequences of AGA
It is clear that the development of AGA is dependent on factors such as age, lifestyle, and hormonal
disorders. AGA tends to affect more individuals with advanced age and stressful lifestyles. Hair is a crucial
part of an individual’s appearance, and losing hair can create a feeling of looking older and losing
confidence. There are plenty of other psychological effects that follow, which are shown in Figure 2 [15].
Image credits: Parth S. Bajoria, Priyansh Patel, and Prathma Anandbhai Dave
Diagnosis
The diagnosis of AGA involves assessing the patient's medical history, clinical findings, duration and
location of hair loss, shedding or thinning of hair, and reviewing family history, current medications, and
conducting basic laboratory tests to exclude other possible causes of hair loss [3]. Evaluation of AGA is
usually done by pull test or trichoscopy. To identify ongoing hair loss, the hair-pull test is conducted by
gently pulling 50-60 hairs near the scalp using the middle finger, index finger, and thumb. If six or more
hairs are detached during this process, it suggests that there is ongoing hair loss [5]. Trichoscopy is a non-
invasive technique used to examine the hair and scalp, which provides valuable information about various
characteristics. The most commonly observed trichoscopic features in AGA include variations in hair
Classification
Devised by Dr. James Hamilton and later revised by Dr. O'Tar Norwood, the Hamilton-Norwood classification
is a commonly employed system for classifying MPB. It consists of seven stages (types I-VII) that depict the
progression of hair loss in men, from minimal to extensive [17]. Figure 3 shows a brief description of each
stage.
Image credits: Parth S Bajoria, Priyansh Patel, and Prathma Ananbhai Dave
Treatment
Treating AGA is challenging due to its chronic nature and the interplay of genetic and environmental
factors. While the Food and Drug Administration (FDA) has approved only topical minoxidil and oral
finasteride, several non-FDA-approved treatments have shown effectiveness. Further research is needed to
explore these newer treatments, which are mentioned below [3].
Non-medical Treatment
The most straightforward and convenient approach for addressing mild male AGA is through camouflage.
This involves adopting hair styling techniques to conceal the balding scalp, utilizing electrostatically-held
small fibers, and dyeing the scalp to match the hair color. These affordable measures can yield cosmetically
pleasing outcomes. Additionally, modern wigs offer the ability to style and wash and provide a natural
appearance [18].
Minoxidil: Topical minoxidil (2% or 5%) was the first FDA-approved drug for the treatment of AGA. It is
available as a topical solution as well as foam preparation; however, the foam preparation is associated with
lesser local reactions such as erythema or pruritus as per Hasanzadeh et al. [19]. Multiple studies have
reported that combination therapy is more efficacious than 5% topical minoxidil alone. Faghihi et al.
conducted a study on 50 participants for about 12 months and suggested that adding low-level light therapy
to topical minoxidil therapy was more effective than minoxidil therapy alone [20], whereas Pakhomova et al.
conducted a study on 69 men divided into three groups of topical minoxidil therapy alone, platelet-rich
plasma (PRP) alone and PRP+minoxidil therapy. Her study concluded that combination therapy was highly
efficacious as compared to either monotherapy and that PRP monotherapy was more efficacious than topical
minoxidil in most aspects [21]. Mirmirani et al. conducted a prospective pilot study that was placebo-
controlled and double-blinded. The study evaluated the efficacy of minoxidil topical foam 5% compared to a
placebo in 16 men diagnosed with type IV or V AGA and concluded that minoxidil was equally effective in
the treatment of both, the frontal and the vertex of the scalp, which are the most commonly affected areas in
men with AGA, although there is a variation in regional gene expression profile of these areas [22]. Sakr et
al. concluded after a 32-week pilot study that the use of a multimodal minoxidil formulation containing
diclofenac and tea tree oil, demonstrated greater efficacy, stability, and safety for treating AGA by promoting
earlier responses, potentially due to diclofenac's anti-inflammatory effects on scalp and hair follicles and tea
tree oil's ability to eliminate microbial or fungal presence in follicles [23].
5-AR inhibitors: Oral finasteride was the other drug approved by FDA to be used for AGA. To minimize the
systemic effects associated with its use, the use of topical finasteride has been suggested in recent years as it
selectively targets 5-AR inhibition in the scalp. Piraccini et al. supported this finding with their study on 458
patients although the increase in hair count between oral and topical formulation groups was similar [1]. As
with minoxidil, combination therapy generates superior outcomes in patients taking oral finasteride. Van
Neste et al. supported this in their study of 22 patients and concluded that the use of oral finasteride along
with topical 5% minoxidil (applied at a volume of 1 mL once a day) led to an improvement in the growth of
underactive hair follicles although it did not result in an increase in the speed of hair growth [24].
Dutasteride is a second-generation drug of the same class. It shares a similar side-effect profile as finasteride
although it is more efficacious as per Shanshanwal et al. [10].
PRP therapy: PRP is derived from whole blood by centrifugation. Gressenberger et al. conducted a pilot study
on 30 male patients and said that PRP did not significantly improve hair growth as a monotherapy [25].
Singh et al. studied 80 patients using double-blinded randomized controlled trials (RCTs) and concluded that
PRP, along with topical minoxidil 5%, was more efficacious than either PRP or topical minoxidil alone and
also PRP demonstrated quicker results compared to topical minoxidil [26] as did Pakhomova et al.
suggest [22].
Platelet lysate (PL): PRP and PL are produced in a similar manner, but PL undergoes an additional step that
increases the concentration of growth factors in the serum. It is faster acting as compared to PRP. Guan et al.
studied 107 AGA patients and said that PL was as efficacious as PRP in terms of increasing hair count,
diameter, and absolute anagen counts, making it ideal to replace PRP [27].
Low-level light therapy (LLLT): LLLT or photobiomodulation delivered via caps or helmets has been claimed
to prevent MPHL, as well as FPHL. In a 26-week-long study of four RCTs, Jimenez et al. concluded that the
increase in terminal hair count by LLLT was similar to the results observed in short-term trials of a 5%
minoxidil topical solution and a daily dose of one mg of finasteride, but less effective compared to longer-
term trials lasting at least one year [28]. Blum et al. in their study on 119 subjects with the cold X5 hair laser
said that chronic therapy leads to hair growth [29].
Miscellaneous Treatments
Treatment for AGA usually continues for an individual’s entire life and therefore taking into account the
risk/benefit profile of a drug takes prime importance. Specifically, 0.2% topical caffeine-based solutions are
typically safe with very minimal adverse effects for long-term treatment of AGA, and they are not inferior to
topical 5% minoxidil therapy as per Dhurat et al. [9]. Prostaglandins (PGs) play a crucial role in the hair
follicle cycle, with PGE2-promoting hair growth and PGD2 inhibiting it. Hossein Mostafa et al. compared
topical cetirizine 1% (a PGD2 inhibitor) with minoxidil 5% and found that cetirizine had fewer side effects.
Both groups showed increased hair density after 16 weeks, but the minoxidil group had greater improvement
[30]. Adipose tissue-derived stem cells (ADSCs) release growth hormones that promote cell development,
and Tak et al. suggested that applying ADSC-cetirizine solution directly to the scalp, along with finasteride
or minoxidil, could be a viable alternative treatment for AGA [31]. Botulinum toxin (BT) derived from
Clostridium botulinum blocks acetylcholine release, relaxing muscles, improving blood flow, increasing
oxygen, reducing DHT activation, and promoting hair regrowth. Zhou et al. studied the safety and
effectiveness of BT type A and concluded that BT type A given along with finasteride has higher efficacy as
compared to BT type A injections alone [2]. Pekmezci et al. studied herbal shampoo and solutions containing
anti-androgenic, anti-inflammatory, anti-oxidative, and angiogenic properties, on 120 subjects and
Surgical Treatment
Hair transplantation, commonly used for medical treatment failure/resistant AGA, is a surgical procedure
that implants new hairs into areas with significant hair loss, providing a natural look and permanent results
with over 90% graft survival. It can be classified as follicular unit transplantation (FUT) or follicular unit
extraction (FUE) and robotic techniques are also available, albeit with higher costs and maintenance
demands [34]. The major treatments are discussed and compared in Table 1.
Contact/Irritant
The Influx of calcium ions up- dermatitis,
1 mL applied twice a day.
regulates ATP-synthase, pruritus, skin First-line FDA-approved therapy. Easy
Available in 2% and 5%
Minoxidil which enhances the process irritation and to use. Loss of results on
topical as well as foam
of stem cell differentiation and erythema, facial discontinuation [18]. Cost-efficient.
preparation [3].
promotes hair growth [18]. hypertrichosis
[34].
Erectile
FDA-approved. Good compliance due
dysfunction,
to a once-daily oral regimen. Cessation
Oral Highly selective and binds reduced libido,
1 mg once daily [3]. of therapy leads to the loss of observed
Finasteride irreversibly to type-II 5-AR [3]. orthostatic
results [19] and the reversal of any side
hypotension, and
effects that may have occurred [3].
dizziness [34].
Contact
dermatitis, skin Lesser systemic side effects than oral
Topical Highly selective and binds
0.25% spray or 1% gel [3]. irritation, sexual counterparts [18]. Variable response to
Finasteride irreversibly to type-II 5-AR [3].
side effects therapy.
(rarely) [3,18].
Erectile
Acts as an inhibitor of both the dysfunction,
2.5 or 5 mg once daily Higher efficacy than finasteride [18].
Dutasteride iso-enzymes of 5-AR (types I reduced libido,
[34]. Used off-label.
and II) [3]. gynecomastia
[18].
Limitation
Most of the clinical trials were of short duration, and a few were conducted on small sample sizes. Hence,
larger and longer studies are further required. We omitted articles in languages other than English and also
omitted animal studies. Only articles published in the last decade were considered so there might be other
relevant studies that are published before this decade. Only literature found on PubMed was reviewed, and
other databases were not explored. Only clinical trials were included to make results in the study. Results
from other types of studies were excluded. Moreover, the lack of research evidence regarding the use of
nutritional supplements and dietary options in the treatment of AGA and the management of environmental
risk factors associated with AGA also needs to be addressed.
Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the
following: Payment/services info: All authors have declared that no financial support was received from
any organization for the submitted work. Financial relationships: All authors have declared that they have
no financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: All authors have declared that there are no
other relationships or activities that could appear to have influenced the submitted work.
Acknowledgements
1st Author - BPS, 2nd Author - DPA, 3rd Author - RRK, 4th Author - TC, 5th Author - MN, 6th Author - GSK,
7th Author - PP. BPS and PP contributed equally to the work and should be considered co-first authors. BPS
and PP were involved in drafting the concept of the Abstract and the Discussion; wrote the Discussion;
performed the literature search and quality appraisal of the finalized studies; and conceived the overall
structure, framework, and concept of the study. They also drafted and edited images and formatted, edited,
and helped draft the final manuscript. DPA was involved in writing the Abstract, extracted and analyzed the
data from the finalized studies, and helped draft the images and draft the final manuscript. RRK was
involved in drafting the design of the Introduction and quality assessment of studies; conceived the overall
structure, framework, and concept of the study; and helped draft the final manuscript. TC was involved in
writing the Introduction and drafting the structure of the Discussion, extracted and analyzed data from the
finalized studies, and helped draft the final manuscript. MN extracted and analyzed data from the finalized
studies, helped draft the concept and design for the Conclusion, wrote the Conclusion, and helped draft the
final manuscript. GSK and PP were involved in the literature search; drafted the concept and design for the
Conclusion; conceived the overall structure, framework, and concept of the study; and helped draft the final
manuscript. All authors have read and approved the final manuscript. All authors agree to be accountable for
all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work
are appropriately investigated and resolved.
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