1. INTRODUCTION:

Hair is an epidermal appendage that plays a crucial role in enhancing the overall aesthetic appeal of the human body. Hair loss, dandruff, infestation of lice, split ends, and graying of hair are among the various hair-related issues encountered by individuals¹. Where most people in today's culture are greatly distressed by hair loss. Given the importance of hair to most people's identities, society strongly encourages the research of alopecia².

Alopecia research will also contribute to a better knowledge of the basic biology of the hair follicle. As a result, gaining a better knowledge of the pathophysiology and potential treatments for alopecia will be a welcome step forward³.

Alopecia is a medical condition characterized by partial or complete hair loss involving a combination of multiple environmental and genetic factors, it is also considered as an immune-mediated skin condition characterized by the rapid hair loss on the scalp, beard, and, in some cases, brows, eyelashes, and body hair⁴. Accordingly, Alopecia can be broadly divided into a few major types such as Alopecia areata, Androgenetic alopecia, Alopecia totalis and Alopecia universalis. Alopecia is known as the Baldness where Areata gives the idea of Patchy. This patchy baldness can appear anywhere on the body, including the scalp, the beard area, brows, and eyelashes, which shows localized bold spots on these areas⁵. Androgenetic alopecia is the type which is caused because of excessive Androgens⁶. Alopecia totalis is the complete loss of hair in the scalp while Alopecia universalis is the loss of hair on scalp and body⁷.

The study of Alopecia has paved the way for the study of hair follicle morphology which mainly comprises of three concentric regions: the medulla, cortex, and cuticle. Regular hair growth pattern comprises the Anagen, Catagen, and Telogen phases. Normally, the average life span of a hair shaft is about 3.5-4 years. Generally, around 100 hairs shed per day but if more than 100 shed per day, it can be due to factors like stress, medications, hormonal changes, hair styling and pregnancy ⁸. Due to these reasons, people have mainly focused on various remedies for different patterns of hair loss ⁹. So, as a result, many chemical remedies are used against hair loss. Minoxidil, Finasteride therapy, Dutasteride are few of them¹⁰. But with the use of these chemical remedies, many patients have experienced with several side effects such as Irritant contact dermatitis, Hypertrichosis, cancers ¹¹, and reduced libido, gynecomastia were mainly seen in males due to treatments with Finasteride ¹². So as a result, many plant based treatments against alopecia are being experimented. Proanthocyanidins extracted from grape seed extracts ¹³, Salvia plebeia leaf extract ¹⁴, Sophora flavescens root extract ¹⁵, Carthamus tinctorius L. floret extract ¹⁶, Phyllanthus emblica L¹⁷ are some of the plants that were experimented against anti alopecia properties which had shown a great level of success. So, the aim of this review article is to understand the prevailing treatment modalities for Alopecia and their side effects and to study about the natural substituents to treat Alopecia with fewer or no side effects.

2. HAIR MORPHOLOGY:

Hair is one of the most vital structures in the body of an organism that has many functions such as providing protection and insulation. Each individual hair shaft is made up of 3 concentric regions: Cuticle, Medulla, and the Cortex. Cuticle is the outermost layer seen in a hair shaft which is made up of layers of keratinized cells that provides protection for the hair ¹⁸. Medulla is the vacuolated innermost cell layer containing transparent cells (contain glycogen-rich vacuoles and medullary granules that contain citrulline), and air spaces that vary among a population ¹⁹. The cortex, which constitutes most of the hair fiber composition, contains the bulk and plays a vital role in the physical and mechanical qualities of hair²⁰. The spatial distribution of the 12 types of keratins and keratin-associated proteins forms the primary structure of the cortex²¹. The nerves for hair follicles arise from the dermis or subcutaneous tissue and ascend from the dermal network to innervate the hair follicle from the bulb to the epidermis, which includes afferents and autonomic sympathetic nerves²².

Figure 1: Anatomy of Hair follicle

3. HAIR GROWTH CYCLE:

Hair is an integral constituent of the integumentary system which penetrates the dermal layer, where it resides in the hair follicle ²³. A human hair shaft has an average life cycle of about 3.5 years, where an average person has roughly 100,000+ scalp hair shafts, each resting at a different stage of the hair growth cycle. The growth stages of a hair can be divided into 3 phases as the Anagen, Catagen and the Telogen phases ²⁴. During the first stage of the Anagen phase (Active Growth phase), the hair follicle begins to grow back to full size and expand deeper into the skin, where then the follicle reaches its maximal length and volume. Following the Anagen phase is the Catagen phase or the involution phase ²⁵. At the onset of the catagen phase, melanocytes' ability to produce pigment stops, differentiation and proliferation of hair matrix keratinocytes drastically decline, and hair shaft generation is finished. Therefore, the hair follicle starts to shrink due to the apoptosis of cells and the keratogenous zone of the hair bulb and eventually stops its development, reducing its diameter ²⁶. So, the catagen phase is considered as the shortest phase of the hair growth cycle and the phase where the club hair is formed ²⁷. The next is the Telogen or the resting phase, where the metabolic and proliferative activity of the hair follicle begins to decline and a shortage of Inner Root Sheath and melanocytes that produce pigment take place. The hair falls out after the completion of this resting stage, and a few weeks later, the hair follicle restarts the growth phase by activating stem cells ²⁸. This hair growth cycle, as well as the hair follicle growth and morphogenesis, are complicated and are coordinated processes that rely on the interaction of various signals and stimuli that form within specialized epithelial and stromal cells ²⁹.

4. DIFFERENTIAL DIAGNOSIS Of HAIR LOSS:

Hair loss is a common issue that affects many men and women throughout their lives due to reversible changes that take place in the hair-growth cycle and other several different factors ³⁰, which is not life threatening but can have negative consequences like psychological effects on patients. Scarring and nonscarring alopecia are the two most frequent types of hair loss, where scarring alopecia is uncommon and has several causes. Furthermore, hair loss can be classified as either focal or diffused type. Non scarring (ex: Alopecia areata) and scarring alopecia are classified as Focal alopecia while Alopecia totalis and universalis are categorized under diffused type Alopecia ³¹. Considering Alopecia totalis and Alopecia universalis, they are significantly more resistant to treatment than Alopecia areata, with those individuals far less likely to experience significant hair regrowth ³².

4.1 Alopecia areata:

Alopecia areata (AA) is the 2^nd most common type of non-scarring hair loss that affects males and females equally after Androgenetic alopecia ³³. AA characterized by smooth bald patchy areas of nonscarring hair loss that range from single oval patches to several patches ³⁴ that is believed to have a genetic predisposition with a polygenic inheritance pattern³¹. In AA, an infiltrate assaults the pigment-producing Hair Follicle (HF) during abrupt precipitation of the anagen stage III hair follicles at the site of disease activity, resulting in increased hair loss ³⁵ . The existence of active perifollicular infiltrates of Mono Nuclear Cells (MNCs) composed of CD4⁺ and CD8⁺ lymphocytes around affected anagen hair bulbs ³⁶, as well as the potential of T cells to transfer AA from affected scalp to human scalp explants in mice with severe combined immunodeficiency conditions, indicates that AA to be an Autoimmune disease ³⁷. Also, AA has been reported to be strongly linked to two Human Leukocyte Antigens (HLA) genes, DQB1*03 and DRB1*1104 ³⁸. Patients reported with AA may normally be healthy however, atopy, lupus erythematosus, thyroid disorders, allergic rhinitis, and vitiligo are more prevalent among them ³⁹.

4.2 Androgenetic alopecia:

Androgenetic alopecia (AGA) is the most common type of hair loss that is mainly seen in males than in females who are at their 50s or younger ⁴⁰. AGA is a hereditary hair thinning caused by androgens due to a combination of endocrine factors and polygenic inheritance ^41,42. Hair loss affects androgen-sensitive follicles, beginning with bitemporal recession and progressing to vertex and frontal thinning. Dihydrotestosterone (DHT) is considered as the main androgen that is responsible for AGA ⁴³. DHT is derived by the activity of 5 alpha reductase enzyme (2 isoforms of type 1 and type 2) upon the male androgen Testosterone ⁴⁴, where it results in miniaturizing the hair follicles by acting on DHT receptors ⁴⁵. Patients with AGA have had higher 5a-reductase levels, lower estrogen synthetase levels, and more androgen receptors ⁴⁶ compared to the healthy people⁴⁷.

The various clinical patterns of AGA reflect quantitative variations in the amounts of 5 alpha reductase, androgen receptors, and estrogen synthetase, which transforms testosterone into estradiol in various regions of the scalp at various ages.⁴⁵.

5. TREATING ALOPECIA WITH SYNTHETIC DRUGS:

With the increased incidents of different types of Alopecia, people are becoming more demanding of effective treatments that target the specific key phase in hair follicle cycling which is mainly the Anagen phase and on the enzymes that convert Androgens to its products that promote miniaturizing of the hair follicles ⁴⁸. Up to date, the FDA has approved Minoxidil and Finasteride in treating alopecia, but still with side effects. The other novel chemical treatments include Dutasteride, and JAK (Janus Kinase) inhibitors ⁴⁹.

5.1 Minoxidil (MXD):

Minoxidil is a Piperidino-pyrimidine derivative (C₉H₁₅N₅O), a prodrug which undergoes biotransformation into Minoxidil Sulfate within the body which is believed to be the active form responsible for promoting hair growth. MXD was originally used to treat hypertension due to its capacity to open K⁺ channels on the smooth muscles of the peripheral artery, inducing hyperpolarization of the cell membrane. So, since K+ activity plays a major role in the progression of the G1stage of the cell cycle, MXD was later used to treat Alopecia by promoting Anagen phase ⁵⁰. MXD works in promoting hair growth by; activating K⁺ channels that allow the cell cycle to advance to the G1 stage; hence plays a crucial role in early cell proliferation by boosting the Anagen phase ⁵¹, acting as a potent arteriolar vasodilator, hyperpolarizing the cell membrane, and thereby boosting blood flow to hair follicles. Also, it extends the Anagen phase of hair follicles by activating beta-catenin and enhancing follicle growth and development, resulting in larger follicles and a higher percentage of active growth follicles ⁵². Initially MXD was found in its solution form which contained Propylene glycol (PG), that was used as the vehicle to efficiently transport MXD by making it soluble into the hair follicles, ethanol, and water ⁵³. But with the use of this, patients had shown local irritations which was due to PG. This had therefore led the way for the development of PG free MXD Form (MF) which had shown less irritations and higher drug efficiency ⁵⁴. Although MXD has vasodilator properties, its mode of action in hair loss involves a direct stimulatory effect on dermal papillae or follicular hair matrix cells ⁵⁵. Since MXD's beneficial effect on hair development is primarily attributable to its metabolite, minoxidil sulfate, patients with increased enzyme activity shows a better and a positive response to topical MXD mainly because Minoxidil sulfation in the human scalp is primarily mediated by two phenol sulfotransferases, ^56,57. MXD is also regarded as a generalist medication that can help men, women, and children with AGA and AA. However, it is most effective in treating women with AGA. In AGA, MXD enhances the Anagen phase or the growth phase by inducing the beta catenin activity and enlarges the miniaturized hair follicles that was caused due to DHT. Because it does not rely on a hormonal component or the inhibitor action of 5 alpha-reductase, topical MXD is the only medicine available for encouraging hair growth in women with AGA ⁵⁸. MXD can also influence hair follicles in androgen and non-androgen dependent areas, promoting regeneration and increasing the length and thickness of anagen follicles while decreasing telogen follicles ^59,60. Though MXD is used against Alopecia as an off- label drug ⁶¹, it had failed as a Monotherapy in treating AA, therefore is given with other medications ^54,62. The most effective MXD solution is 5% in promoting hair growth in people with scarring alopecia and severe AA ⁶³ but not in patients with Alopecia universalis or Alopecia totalis ⁶⁴. But, with the use of MXD, many side effects were observed, such as irritant contact dermatitis with typical symptoms of itching and scaling, Allergic contact dermatitis because of PG or minoxidil itself (Therefore, the PG vehicles were substituted with butylene glycol, glycerin, or polysorbate) ⁶⁵, Hypertrichosis which was dependent on minoxidil concentration ⁶⁶, mutagenic and carcinogenic effects due to inducing cell division and increasing the possibility of DNA damage with the increase of the dose and the duration of application which was studied using SKH1 hairless mice ⁵⁴. And with the systematic administration of MXD, cardiovascular defects and Sodium and water retention defects were also reported ⁶⁷.

5.2 Finasteride:

Finasteride is a type II 5-alpha Reductase Inhibitor (5-ARI) that belongs to the Azasteroid family ⁶⁸, which is a competitive inhibitor of type II alpha reductase which blocks the conversion of Testosterone to Dihydrotestosterone (DHT) in the scalp and serum ⁶⁹. Humans have two isoenzymes of the 5-alpha reductase enzyme ⁷⁰. Type I 5-alpha reductase was found abundant in the skin and the outer sheath of the hair follicle, whereas Type II 5-alpha reductase was found most actively in the dermal papillae and the inner root sheath of the hair follicle ⁷¹, which has been suggested as the main cause of Androgenetic alopecia, primarily in men ⁶⁸. The only 2 drugs that are approved by the FDA against AGA are Minoxidil for both men and women and Finasteride for men only ⁷². AGA that is caused due to high DHT levels, results in miniaturization of hair follicles and causes alterations in the hair growth cycle as aforementioned which therefore will ultimately result in empty hair follicles. In a short amount of time, Finasteride could reduce serum and scalp Dihydrotestosterone levels by more than 60%. Where it shows no affinity for the androgen receptor and hence has no effect on the functions of testosterone; it also has no androgenic, estrogenic, progestational, or other steroidal actions ^73,74. But with the use of this drug many men had shown adverse effects such as erectile dysfunctions, decreased libido, and ejaculatory dysfunctions. But however, these were observed to be reduced within months to weeks with the continuation of treatment ⁷³. Finasteride is an orally given medication with the potential for transdermal absorption. As a result, pregnant, expecting moms, and breastfeeding women are at danger since it might cause abnormalities in the developing fetus ⁷⁵.

5.3 Dutasteride:

Dutasteride is another medicine that has a similar function to finasteride in that it inhibits both type I and type II 5-alpha reductase enzymes. However, this has a greater inhibitory effect on the activity of Type II 5-alpha reductase than on the activity of Type I 5-alpha reductase. However, due to its side effects, the FDA has not cleared this for clinical use ⁷⁶.

6. NATURAL SUBSTANCES WITH ANTI-ALOPECIA PROPERTIES:

With the adverse effects observed with the use of synthetic drugs against Alopecia, many herbal prospective has been experimented by research. As a result, the search for natural products that promote hair growth is never-ending where, a number of herbs with a track record of success in the treatment of alopecia were investigated in order to address the issue of hair loss which has several advantages, such as patient compliance, less side effects, and the presence of more than one mechanism of action in treating different types of Alopecia ⁷⁷. Herbs used to treat Alopecia provide nutritional support, DHT blockers, 5-reductase blockers, aromatherapy, and improved scalp blood circulation with less inflammations and side effects when compared to synthetic drugs ¹⁷. Mineral deficiency impairs the ability to regulate blood circulation, which supports healthy hair development, as well as thyroid hormones, which prevent dry hair. Vitamins A and B (especially B6, B3, B5, and folic acid) are beneficial to hair follicles because they keep the hair root moisturized. While Vitamin C and E acts as an antioxidant, promoting effective circulation in the scalp by increasing oxygen intake in the blood, and thus plays an important role in hair development and prevention. Vitamin E, specifically alpha tocopherol, serves as the primary lipophilic antioxidant within plasma, membranes, and various bodily tissues ⁷⁸where Vitamin E was found to repair damaged hair, reduce hair breakage, give shine and elasticity to hair, and nourishes and moisturize the scalp by preserving its protective lipid bilayer ⁷⁹.It was also found that Coenzyme Q10 (CQ-10) is also an essential vitamin that provides the ingredients needed for healthy hair development ¹⁷.So, natural, and herbal hair loss treatments are easily purchased in both domestic and foreign markets in a range of pharmaceutical forms with various modes of action, including androgen antagonists, nutritional supplements, vasodilators, 5-reductase inhibitors, or dihydrotestosterone blockers ⁸⁰.

6.1 Grape Seed:

Grape seeds (Vitis vinifera L.) belong to the family of Vitaceae that has many biologically important substituents like anthocyanins, flavan‐3‐ols, flavonoids like catechin, vitamin E (α‐tocopherol), B4 and B6 procyanidins, petiole, linoleic acid, polyphenols, unsaturated fatty acids, and phytosterols in which catechins, epicatechins, trans-resveratrol, and procyanidin B1 are the most active components ⁸¹. Proanthocyanidins which are mainly focused here are phenolic oligomers and polymers found in grape seeds that are related to catechin and epicatechin. The discovery of proanthocyanidins to have capillary protecting benefits, radical scavenging activity ⁸², anti-tumor promoting activity ⁸³, anti-fungal activity, and anti-hypertensive effects has made proanthocyanidins a highly active component out of all ⁸⁴. The study of hair follicle morphology in a proanthocyanidins-containing medium revealed that proanthocyanidins' mode of action involves the inhibition of cell differentiation and prolonged maintenance of the anagen phase of the hair growth cycle. It was also assumed that proanthocyanidins had a growth effect on the outer root sheath cells, transitioning the bulb region from the telogen phase to the anagen phase of the hair follicular growth cycle. Additionally, it was shown that epicatechin did not process any hair growth action, indicating that the oligomeric forms of proanthocyanidins are more necessary for hair growth ⁸⁰.

According to a research paper that includes an experiment which used C3H mice to test the hair follicle proliferation activity with the use of proanthocyanidins extracted from grape seeds versus the widely used Minoxidil, has given the following results with the application of 1% Minoxidil, the vehicle, and 3% Proanthocyanidins within in 19 days. No side effects were observed in the group of mice applied with 3% Proanthocyanidins ⁸⁵. According to the results of this investigation, proanthocyanidins derived from grape seeds exhibit similar hair cycle converting and hair follicle cell development activities to MXD.

Table 1: Results of the experiment done using C3H mice to test the hair follicle proliferation activity with the use of proanthocyanidins extracted versus Minoxidil.

Group of mice	Percentage of hair growth observed
Control (only vehicle)	30-40 %
1 % Minoxidil	90 - 100 %
3 % Proanthocyanidins	80 - 90 %

Figure 1: Mice treated with vehicle (A), 1% Minoxidil (B), 3% Proanthocyanidins (C)⁸⁵

6.2 Salvia plebeian:

Slavia plebeia (SP), that is also known as Sage weed, includes flavonoids, rosmarinic acid, and 2-hydroxy-5-methoxybiochanin A, which has been shown to promote hair growth, reduce hair regression, and induce early hair anagen phase. According to one study, SP extract affects hDPC (human Dermal Papillae Cells) function in the telogen phase skin via ERK (Extracellular signal-regulated kinase) and Akt (Ak strain transforming) signaling pathways, as well as by activating beta-catenin which is a main component of Cadherin protein complex ⁸⁶. But still, it is also necessary to investigate the active SP extract constituents responsible for these effects, as well as if SP extract encourages the growth of additional hair follicle cell types. In this study, male C57BL/6 mice were treated with a DMSO vehicle, 3% MXD, and S.plebeia extract. Within 21 days of the daily application of SP extract to the shaved dorsal skin of mice, hair regeneration was observed. All groups displayed black pigmentation, indicating that within 1 week, hair follicles had transitioned from the telogen to the anagen phase. According to the study, only the mice treated with minoxidil, and SP extract groups were observed to have newly regrown hairs on their back skin. It was recorded that in the SP extract and minoxidil groups, the dorsal skin hair had fully regenerated after two weeks, whereas bare patches on the back of the depilated areas were found in the vehicle group ⁸⁷.

6.3 Carthamus tinctorius:

With the increased side effects of using Finasteride, which is a DHT blocker, researchers have investigated experiments on Thai plants which have had 5 alpha reductase inhibitory action. According to published data, the most effective growth promoter activity and a potent 5 alpha reductase inhibitory action⁸⁸ with an equivalent 5 alpha reductase activity to Finasteride was found to be in the floret extract prepared using Carthamus tinctorius / Safflower that belonged to the Asteraceae family⁸⁹.

Another study claimed that the C. tinctorius floret contained several flavonoids, and hydroxysafflor yellow A where the primary function of hydroxysafflor yellow A was to stimulate hair growth through a synergistic interaction ⁹⁰. With the animal studies done, it was further demonstrated that Carthamus tinctorius has the potential in increasing the expression of hair growth-promoting genes such as vascular endothelial growth factor and keratinocyte growth factor, as well as dermal papilla cells and HaCaT which are the immortalized human keratinocytes⁹⁰. Also, with the suppression of the expression of transforming growth factor-1 (TGF-1), a gene associated with hair loss ⁹¹, Carthamus tinctorius has reached a high standard in mainly treating Androgenetic alopecia patients with less or no side effects and inflammations.

6.4 Sophora flavescens:

Sophora flavescens (S. flavescens) is a plant that has been widely used in traditional medicine. Its parts are used to treat various medical complications, and the root extract of S. flavescens has the potential to be a successful treatment for hair loss⁹². The active compounds of S. flavescens consist of Leguminosae-specific pterocarpan derivatives capable of stimulating the proliferation of primary human Hair Keratinocytes. Local application of an extract from the desiccated roots of the S. flavescens plant accelerated the transition of hair follicles from the telogen to the anagen phase in mice. During studies, it was determined that the action of S. flavescens extract on hair development was mediated by the modulation of growth factors such as IGF-1 and Keratinocyte Growth Factor (KGF) found in dermal papilla cells ⁹³.

In addition, it has been discovered that root extract from S. flavescens significantly inhibits the effect of 5 - alpha reductase type II, likely due to the presence of prenylflavonoids, prenylflavones, and pterocarpans ⁹³. Further researchers have investigated the efficacy of the growth-promoting activity of S. flavescens extract, which depends primarily on the transformation of vellus hairs into dense terminal hairs, which in turn lengthens the anagen phase of the hair growth cycle in treating Androgenetic alopecia ⁹⁴.

Figure 3: C57BL/6 mice with the treatment with the vehicle (DMSO), 3% MXD and Salvia plebeia⁸⁷

6.5 Aroma Therapy:

Aromatherapy uses essences and essential oils that are often massaged into the skin and made from plants, flowers, and wood resins⁹⁵. Typically, essential oils like thyme, rosemary, lavender, evening primrose oil, and cedrus are blended with carrier oils including jojoba, grape seed, almond, lemon, and soy oils. In a randomized, double-blind, controlled study, Hay et al. has examined the effectiveness of aromatherapy in the treatment of 86 patients with Alopecia areata using thyme, rosemary, lavender, and cedarwood essential oils where they discovered that the improvement rate was 44%, which was comparable to, if not more beneficial than, conventional therapies ⁹⁵.

Table 2: Results of the experiment performed by Hay at el

Therapy	Effectiveness
Placebo	15% of 41 patients
Aromatherapy	44% of 43 patients

According to the study with twelve weeks of topical aromatherapy done by Ibrahm Ozmen, a relatively good response rate was found out for Aromatherapy with only one negative effect. However, it was discovered that aromatherapy was both safe and far more efficient than a placebo (when used in conjunction with carrier oils) for the treatment of localized Alopecia areata ⁹⁶. However, the scientific evidence supporting its purported ability to promote hair growth is currently inadequate ⁹⁵.

Table 3: Results obtained from the 12-week study performed by Ibrahim Ozmen

Group

Efficacy

Aromatherapy

75% of 43 patients

Placebo

(same carrier oils with the aromatherapy)

30% of 41 patients

In summary, this thorough assessment of the differential diagnosis, pharmaceutical agents, their side effects, and herbal compounds for managing alopecia offers significant perspectives on the advancing realm of therapeutic alternatives since the economic perspective of these herbal cosmetics has a captivating propensity at present⁹⁷. Also, this article explains that synthetic drugs and herbal remedies exhibit the potential of treating and tackling alopecia. But still, scientific inquiry and rigorous clinical examinations are essential to improve the therapeutic approach for this complex pathological state to enhance the overall well-being of individuals.

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Received on 23.11.2023 Revised on 13.05.2024

Accepted on 28.09.2024 Published on 05.12.2024

Available online on December 28, 2024

Research J. Topical and Cosmetic Sci. 2024; 15(2):107-116.

DOI: 10.52711/2321-5844.2024.00018