1. INTRODUCTION:

Androgenic alopecia (AGA) is the most prevalent cause of hair loss in both genders¹. It may influence a variety of psychological and social experiences, develops common aesthetically and psychosocially painful condition and impact the individual’s quality of life ^2–5. Follicular miniaturization is the histological feature of AGA. Four most common forms of alopecia are androgenetic alopecia, alopecia areata, alopecia totalis and alopecia universalis. AGA produces patterned hair loss, beginning with bitemporal recession of the frontal hair line, followed by diffuse thinning over the vertex^6,7. The age of onset is generally the 3rd and 4th decades, however the hair loss starts soon after puberty and continues increasingly ^8–11.

Bitemporal recession affects 98.6% of men and 64.4% of women, whereas mid-frontal hair loss affects nearly two thirds of women over the age of 80 years, and three quarters of men over 80 years have mid-frontal and vertex hair loss^12,13.

Genetically predisposed men initially develop bitemporal recession, then diffuse frontal loss and there after a bald patch over the vertex of the scalp occurs. Ultimately, all the hair over the crown is lost ¹⁴. With each new cycle, hair follicles (HFs) are regenerated and follicular stem cells are responsible for this and recapitulate many of the signals of embryologic development. Various factors can influence and alter the regenerating HFs with advancing age ¹³. AGA is caused by an alteration in hair cycle dynamics viz., decreases in anagen phase duration and increase in the telogen phase ¹⁶. Gradual conversion of terminal hairs into vellus hairs happens in a highly predictable manner, shed the scalp and leads to baldness. While some degree of androgen-dependent hair loss is ubiquitous after adolescence ¹⁷.

Fig. 1- Various causes of AGA

1.1 Patterns of hair loss:

In androgenetic alopecia, the pigmented, long and terminal hairs on the scalp are replaced by short, pale, vellus hairs. Hamilton graded (Fig. 2) this progression from type I, pre-pubertal scalp with terminal hair on the forehead and all over the scalp, through gradual regression of the frontal hairline and thinning on the vertex, to type VII where the bald areas join together to leave hair only around the back and sides of the head ^18,19.

Fig. 2- Norwood- Hamilton scale of male pattern baldness²⁰

2. EPIDEMIOLOGY:

AGA also known as male pattern hair loss is the most well recognized cause of hair thinning. There is no clear demographic data, but it is stated that up to 50% of men will notice some degree of AGA by age 50 and a similar proportion of women by the age of 60 are affected by this condition. 87% of the Indian patients were affected compared with 61% of the Chinese ^8,13,21. In the United States, about half of men and women show some expression of this trait by the age of 40. In Caucasoid men, the lifetime incidence might approach 100%. A community-based study was conducted recently in Singapore, in that study, it was estimated that AGA at 63% was gradual increase in age from 32% among young adults 17–26 years old to 100% among those in their 80s^9,22. Another study done in the Korean population, the prevalence of AGA in men at all ages was 14.1%. However, there was a steady increase with advancing age from 2.3% in the third decade of life to 46.9% in the seventh decade and beyond^14,23. Hamilton et. al., 1951 observed various patterns of the baldness. He observed that the transformation of type I AGA (normal pubertal scalp pattern) to type II AGA occurs in 96% of men after puberty. He also mentioned Pattern Type V-VII in 58% of men over 50 years of age, in which baldness is increasing at 70 years of age. Postmenopausal women had an increased incidence of AGA, with 63% having Caucasian men were affected by AGA four times more than black men and were also more commonly affected than Japanese and Chinese^24,25.

2.1 Genetic factor: Genetic factors modify the amplitude of the hair follicles (HF) response to circulating androgens. Those with a strong preinclination go bald in their teenage years, while those with a mild predisposition may not go bald until they are in their 60s or 70s. There are less than 15% of men with little or no baldness in their age of 70. According to Osborne (1916), the baldness gene behaved in an autosomal dominant manner in men and an autosomal recessive fashion in women ²⁶. Happle and Küster showed that, if the number of afflicted family members is raised then baldness risk also increases. Furthermore, they noticed that inherited features attributable to single gene errors seldom have a frequency larger that 1:1000, while polygenic disorders are far more prevalent, as is the case with AGA ^26–28.

2.2 Hormonal Factor:

It is suggests that testosterone or its some metabolites are necessary for baldness and confirmed that deficiency of 5α-reductase and androgen insensitivity syndrome does not go bald. Type-I 5α-reductase has been observed in sebaceous glands, HFs, epidermis, apocrine sweat glands and eccrine sweat glands. In skin, the activity of type-1 5α-reductase is greater in the sebaceous glands and compared to non-acne-prone regions, is much more in the face and scalp. It is also present in the liver, adrenals and kidneys. The type-2 enzyme is located in the dermal papilla, the inner layer of the outer root sheath, the sebaceous ducts and proximal inner root sheath of scalp HFs. It is also found in the liver, prostate and testes. 17beta- and 3beta-hydroxysteroid dehydrogenases (HSD), with type-2 5α-reductase inside the dermal papilla, serve a pivotal function in the intrafollicular conversion of testosterone to DHT. Androgen stimulation of cultured beard dermal papilla cells (DPC) resulted to higher transcription of insulin-like growth factor 1 (IGF-1) and accelerated proliferation of co-cultured keratinocytes. Androgen stimulation of DPC generated from balding scalp resulted to inhibition of proliferation of co-cultured keratinocytes. This growth inhibition of keratinocytes was mediated by transforming growth factor-beta1 (TGF-beta1) generated from DPC from men with       AGA ²⁷.

3. ANATOMY OF HAIR FOLLICLE:

The hair follicle can be divided into three regions:lower segment (bulb and suprabulb), middle segment (isthmus) and upper segment (infundibulum). From the base of the lower segment, this channel extends to the conjunction of the erector pili muscle (which is also known as an arrector pili muscle). The middle segment is a small section that extends from the inclusion of erector pili muscles to the entrance of the sebaceous gland duct. The upper section extends from the entrance to the sebaceous gland duct to the follicular holes ^29–32. Fig.3 shows anatomical structure of hair.

Fig. 3: An illustration of the anatomicalstructure of hair

During the continuation of the follicles the size of HFs varies significantly. Under hormonal influences, the vellus HFs in the male beard area usually thicken and darken at puberty. There are two types of hair prensent in human body i.e. terminal hairs and vellus hairs. Terminalhairs are androgen-independent hairspresent in eyebrows, lashes and vellus hairs sre hormone-dependent hairs situted on scalp, beard, chest, axilla, pubic region. These hairs are (> 0.03 mm), long (> 2 cm), thick pigmented and usually contain a medullary cavity. These hairs also extend morethan 3 mm into the hypodermis^33,34.

Dermal papilla cells (DPCs) play a key part in the orientation and maintenance of growth of epithelium and produce the growth factors which mediate the growth stimulating signals of androgens that operate in a signaling cascade fashion on the other follicle cells ^18,35. The growth factors released via the hair folicles and DPCs have an autocrine influence on the dermal papilla itself and a paracrine effect on the HFs epithelial cells. They include insulin like growth factor 1 (IGF-1), vascular endothelial growth factor, basic fibroblast growth factor, and all are responsible for stimulation of hair growth ^36–39.

3.1 Hair cycle:

The first phase is the anagen phase which is the active growth phase and lasts for 2-6 years. The distinguishing characteristic of this phase is that anagen not only shows the growth of hair shaft but also most of the epithelial HFs compartments undergo proliferation process, with the hair matrix keratinocytes located around the dermal papilla showing the highest proliferative activity and the newly formed hair shaft is pigmented by the follicle pigmentary unit. The second phase is the short catagen transition phase¹⁸.During the catagen stage, HFs enter a continuous process which is highly controlled in manner that is characterized by a burst of programmed cell death (apoptosis) in the majority of follicular keratinocytes. This phase lasts only 2 weeks and is manifested by the upward movement of the dermal papilla within the connective tissue sheath of the follicle⁴⁰.This is followed by the telogen phase (resting phase). In this phase, the hair shaft matures into a club hair, which is held tightly in the bulbous base of the follicular epithelium, before it is eventually shed from the follicle, usually as a result of combing or washing. In a normal adult scalp, the anagen phase lasts from two to as long as 7 years. At the end of resting phase, a new hair starts to grow in the follicle to maintain the cycle as shown in Fig. 4 ^33,41–44.

Fig. 4-Various phases of hair growth cycle

4. Androgen, Its Metabolites and Androgenic Receptor:

4.1 Androgen: Androgens (andro inGreek means male/man) is a male sex hormone conventionally considered as male sex steroids which maintains the male characteristics ⁴⁵. Hamilton suggested that androgens, genetic and age factors are mutual interplay in the origin of AGA¹⁴. Through the attachment of androgen with Androgen Receptor (AR), which is a ligand-induced nuclear receptor, activation is followed by another functions as transcription ⁴⁶. In man, the primary androgen is testosterone produced by the leydig cells of the testes, and released into circulation ^45,47. Androgen plays an important role in skin, by regulating sebum production and secretion, hair growth and some physiological effects such as wound healing and cutaneous barrier formation. It is responsible for development and maintenance of long terminal hairs e.g. scalp hairs, eyelashes and eyebrows throughout life and have protective functions³.

4.2 Androgen metabolites: Enzymes, which are responsible for biosynthesis of androgen, are localized in the inner mitochondrial membrane⁴⁸. In secreting glands, androgenic hormones are synthesized and released into the bloodstream and bind globular proteins to be transported to their target organs⁴⁹. The most important protein for androgen binding is sex-hormone binding globulin (SHBG). About 70% of testosterone binds with SHBG and 19% to albumin. Remaining unbound testosterone are circulated in the blood stream ^26,28. Pregnenolone is made by conversion of cholesterol which is an androgens, made up of 21-carbon steroid substrate (Fig. 4). The action of the enzyme C_17-20lyase cleaves distal carbon moieties at the C-17 position via α-hydroxylation, leaving a 19-carbon steroid with a C-17 ketone in the distal ring. These "17-ketosteroids" make up a group of androgen such as dehydroepiandrosterone (DHEA), that are weak in nature and have quite low affinity for the androgen receptor. These weak androgens can be converted or reversibly converted (some reactions are reversible) into the more potent androgens such as testosterone, via the enzymatic reaction within tissues, including skin, which have greater affinity for the androgen receptor. Testosterone is the major circulating androgen. In cytoplasm 5α-reductase enzyme are present which converts testosterone into the more potent androgen DHT when it reaches in the skin through capillary blood⁴⁵. DHT is approximately fivefold more potent than testosterone on the basis of affinity with AR and is responsible for the pathogenesis of several disorders, including benign prostatic hyperplasia, prostate cancer, vulgaris, acne, hirsutism and AGA⁴⁶.

In skin, mainly three enzymes are responsible for conversion of weak androgens to more potent androgen that are 3P-hydroxysteroid dehydrogenase-A5- A4-isomerase (3P-HSD), 17P-hydroxysteroid dehydrogenase (17P-HSD), and 5α-reductase. This is the principal pathways involved in activation of androgen. The weak androgens dehydroepiandrosterone (DHEA), dehydro epiandrosterone-sulfate (DHEA-S), and androstenedione are converted peripherally to the more potent androgens testosterone and DHT^50,51. Once formed, potent androgens, such as testosterone and DHT, are either removed by conversion back to the weaker 17-ketosteroids, or they can be metabolized by other enzymatic pathways, which converts androgens to estrogenic compounds, and 3a-hydroxysteroid dehydrogenase (3a-HSD). In the continuous process of the enzymatic reaction steps are followed by glucuronidation or sulfation to form androgen conjugates that are more rapidly cleared from the circulation⁵².Androgen metabolism in the pilosebaceous units starts from the desulfation of DHEA-S to DHEA by steroid sulfate synthase in dermal papilla. Next, 3β-hydroxysteroid dehydrogenase—Δ5→4—isomerase (3β-HSD) type 1 converts DHEA into androstenedione in the sebaceous glands and dermal papilla^53,54. Subsequently, androstenedione is converted into testosterone by 17β-hydroxysteroid dehydrogenase (17β-HSD). Human sebaceous glands provide the cellular machinery needed to transcribe the genes for 17β-HSD types 1–5. 17β-HSD types 1, 3, and 5 support the formation of more active androgens, whereas the oxidative reaction induced by 17β-HSD types 2 and 4 deactivates them, indicating the possible role of sebaceous glands in the regulation of local androgen metabolism. Alternatively, DHEA can be converted into androstenediol and testosterone by 17β-HSD and 3β- HSD respectively in the pilosebaceous unit ^45,49,55.

Fig. 5- Androgen metabolites

4.3 Androgenic receptor: The action of androgens (testosterone and DHT) on skin is essentially mediated via the AR, a ligand dependent nuclear transcription factor and member of the steroid hormone nuclear receptor super family ^3,56. AR is 110-kDa ligand-inducible nuclear receptor that regulates the expression of target genes through binding to an androgen response element (ARE). The AR consists of three basic functional domains: the N- terminal transcription regulation domain, the DNA-binding domain (DBD) and the ligand-binding domain. The most variable part is N-terminal domain whereas most highly conserved region is the DBD among the different members of the steroid hormone nuclear receptor family. DBD and ligand-binding domain are linked by a hinge region. The ligand binding interacts with the N-terminus of the AR to stabilize bound androgens^21,57,58.

Fig. 6: Schematicrepresentation of hair follicle miniaturization process

5. TREATMENT:

Currently permitted treatment options frequently demand a high degree of compliance over extended periods of time to achieve effectiveness ^59-62. Approved medications for AGA include finasteride and topical minoxidil. Treatment for AGA is mostly based on experience as randomized, controlled clinical researches are limited. Unfortunately, adverse effects of medications and lack of perseverance are the most prevalent factors for noncompliance. Therefore, new medications with lesser side effects and easier to use are needed to enhance patient compliance ^63-65. Additionally, improved models for drug testing have to be devised as well as better, more focused drug delivery systems to minimize the side-effect profile ^59–61

5.1 Approved drug:

5.1.1 5-α reductase enzyme inhibitor: Finasteride and Dutasteride are the drugs available in the market with this category. A synthetic type II-5α reductase inhibitor can reduce the conversion of testosterone to DHT. If it is taken over 6 months to 1 year, with dose of 1 mg daily, it can improve the hair count and thickness, with improved responsiveness. The efficacy of Dutasteride 2.5 mg/day was superior to that of Finasteride 5 mg/day^62,63.Finasteride’s most severe adverse effects are sexual dysfunction, mental issues and increased risk of high-grade prostate cancer in males and its administration is restricted in pregnancy or women with personal or family history of breast or ovarian cancer. On continuous oral administration for long term, there can be loss of hairs, which was gained within 12 months. But finasteride is reported to be less effective on large bald spots^64,65.

5.1.2 Minoxidil:

Minoxidil was originally used as an antihypertensive and improved the blood circulation in particular area of HFs but it was consequently used as a topical treatment (available in 2% and 5% solutions) for hair loss. Minoxidil use is associated with angiogenesis, vasodilation, enhanced cell proliferation, probably mediated via potassium channel opening. Minoxidil produces some side effects as it comes in contact with skin and it may cause dermatitis and a transitory shedding in first 4 months of use. Use of 5% minoxidil in a commercially available foam vehicle that does not contain propyleneglycol (potential irritant), reduces the incidence of pruritus. Minoxidil can cause irritation and/or allergy at the site of application and is typically required to be administered twice daily for extended durations of time. Women can use the 5 % solution once a day getting the same outcomes, while males might also apply it once a day if combined with topical tretinoin 0.01 %^6,66,67.

5.2 Other drugs:

5.2.1 Antioxidant- Oxidative stress was supposed to be one of the important causative agents of androgenic alopecia, characterized by excessive scalp hair thinning. Hence, it can be suggested that the utilization of antioxidant molecules with some functional excipients can arrest the progression of this disease. Melatonin nanovesicles using an antioxidant bilayer forming agent was reported to be effective in the treatment of oxidative based diseases such as AGA⁶⁸. The two major kinds of radicals or reactive oxygen species and reactive nitrogen species are superoxide radical, hydrogen peroxide (H₂O₂) and hydroxyl radical and the reactive nitrogen species include nitric oxide and its metabolites. Consumption of exogenous antioxidants in the diet becomes crucial to mitigate the hazardous effect of diminished antioxidants and increased free radicals in disease circumstances ^69–71.

5.2.2 Caffeine- Caffeine is shown to inhibit 5-α reductase which is responsible for testosterone conversion to DHT ^35,72. It also inhibits phosphodiesterase (PDE) that is responsible for degradation of cyclic adenosine monophosphate (cAMP). This increases intracellular levels of cAMP and stimulates cellular metabolism. Furthermore, caffeine causes vasodilation and, thereby, increases blood supply to the follicles⁷³. The caffeine-induced inhibition of PDE enzymes raises intracellular cAMP concentrations, resulting in stimulatory effects on cell metabolism and proliferation. Hence, caffeine has a strong potential to be effective in people suffering from hair loss that results from early end of the hair development phase. ^74,75.

5.2.3 Valproic acid- It can activate the Wnt/β-catenin pathway, which is associated with hair growth cycle and anagen induction. In patients with moderate AGA, it was evaluated by photoyrichogram analysis and for primary end-point for efficacy, i.e., change in hair count during treatment⁷⁶.In an in vitro study, VPA was found to have an inhibitory effect on GSK-3b in neuronal cells, implying that it promotes hair growth via b-catenin stabilisation. In fact, in an in vitro culture model, VPA stimulated human hair growth. It was recently reported that topical application of VPA to C3H mice significantly increased hair growth and b-catenin expression in the skin. The mechanism of VPA-induced biotin deficiency is unknown, but impaired liver function may result in low serum biotinidase activity or inhibit carboxylase activity ^77,78

5.2.4 Roxithromycin- On the basis of its properties to inhibit of apoptosis of keratinocytes, it has recently been explored for AGA (via suppressing the production of oxygen reactive species) and suppression of the androgenic receptor in human dermal fibroblasts⁷⁹. Recent experimental data shows that apoptosis seems to be crucial event in control of the hair cycle. In the catagen stage of hair cycle, HFs undergo a highly controlled process of involution, which is marked by a burst of apoptosis. Among the rising number of cytokines that govern HF cycle, IFN- is implicated as an in vitro powerful catagen inducer by activation of apoptosis in HF keratinocytes. it is uncertain if the anti-androgenetic action of RXM shown invitro only in cells grown very sensitive to androgen may beapplicable to the favourable impact of topical RXM on AGA. Microninflammation caused by microbial toxin or antigennear the infundibulum of HFs is often mentioned as the etiology of AGA. Because of the anti-inflammatory effect by regulating immune cells, topical RXM may contribute to restoration of hair growth by down-regulating local inflammation in AGA^80–82.

5.2.5 Spironolactone- Spironolactone has antiandrogenic properties and has therefore gained attention for treating androgenic alopecia. Spironolactone is typically the preferred oral anti-androgen for hair loss ⁸³.Spironolactone reduces 5-alpha reductase activity via enhanced clearance of testosterone related to elevated liver hydroxylase activity. In addition, it raises the level of steroid hormone binding globulin (SHBG), thereby creating a sink that decreases circulating free testosterone as more is bound by the increased quantity of SHBG. The consequent impact of lowering free testosterone in circulation is an elevated estrogenic state, which can lead to gynecomastia or diminished libido, especially when greater dosages of oral spironolactone are taken. Spironolactone also operates locally by competing with dihydrotestosterone (DHT) for cutaneous androgen receptors, hence reducing testosterone and DHT binding ^84,85.

5.2.6 Cyproterone acetate-Cyproterone acetate (CPA)can be used as inhibitors of 5-α reductase activity and can also block AR binding. More commonly, anti-androgens are combined with estrogens for the treatment of female pattern hair loss alopecia^62,64. Van der Spuy et al. found that CPA at a dose of 2 mg/day was more effective than placebo but not any other antiandrogen (ketoconazole, spironolactone, flutamide, finasteride and gonadotropin-releasing hormone agonists).CPA (50-100 mg) mixed with EE (30-35 g) was found to be more fast and effective than flutamide, ketoconazole, and finasteride by Venturoli et al. ⁸⁶.

5.2.7 Ketoconazole- A topical shampoo is available in market (2%) with OTC, while higher concentrations are available by prescription only. Mainly it is effective for the treatment of dermatitis and dandruff, and its action on scalp microflora may benefit with AGA and can improve hair growth through androgen dependent pathways⁸⁷.The most frequently proposed mechanism of action for topical KCZ in androgenetic alopecia (AGA) is through its established anti-androgenic characteristics. Aldhalimi et al., on the other hand, revealed that it was also effective on the androgen-insensitive coat hairs of mice. This finding suggests that topical KCZ may function through both androgen-dependent and androgen-independent pathways, which calls for additional research ^88,89.

5.3 Herbal products:

Minerals including calcium, iron, copper, chromium, iodine, zinc, and magnesium are required for healthy hair development. Mineral insufficiency reduces the ability to control blood circulation, which promotes healthy hair growth, and thyroid hormones, which prevent dry hair and hair loss, as well as colour deficiencies in hair. Iron is hazardous to the body in excess. B vitamins (particularly B6, B3, B5, and folic acid), biotin (anti-oxidant, biotin sources include whole grains, egg yolks, liver, rice, and milk). Vitamin A is essential for overall health. Vitamin E functions as an antioxidant that promotes effective circulation in the scalp through enhanced oxygen uptake in the blood, and thus plays a vital role in encouraging hair development and preventing hair loss. The numerous herbs that provide nutritional support are presented in table 3.^90–92

5.4 Laser Treatment: Laser/light treatment for hair loss has become very popular in the last few years for dermatological diseases and as well, itis promoted as a preventative measure against AGA. In this treatment lasers and light sources are used which vary in the wavelengths and several different manufacturers provide different modes of use. Some laser machines are designed for daily use at home,whereas some types are available only for clinical uses for weekly or monthly intervals ^62,93.

5.5 Surgical Treatment: Surgical treatment is well known options for the treatment of AGA andincludes scalp reduction and hair transplant procedures. Hair transplantation is ultimate option for patients who have a donor with much more density of hair. Transplantation of grafts/follicles are done into the scalp under local anaesthetic condition. In North America follicular unit transplantation (FUT) is widely available. More recently, follicle and unit extraction (FUE) have been developed, it is a specialized techniques involving individual hair treatment to avoid scarring from strip graft harvesting^27,62.

5. CONCLUSION:

There are several dermatological abnormalities and diseases related to the skin and HF i.e. alopecia, acne and some skin cancer. Alopecia is commonly known as hair loss and result from a reduction of hair density. Even though alopecia is a non-life-threatening disorder, it can have severe implications in terms of quality of life and mental trauma. Scientific advances have facilitated the understanding of multifaceted sequence and progression of androgenic alopecia. 5α-reductase enzyme can block the conversion of testosterone to dihydrotestosterone. Because of the presence of enzyme in the prostate gland it can reached on the gland via the systemic circulation and produces some disabilities i.e. decreases the libido and sexual abilities. Thus, the primary challenge remains to formulate the topical formulation, which can avoid the systemic side effects. Several phytochemicals have also been reported for their hair-growth promoting activity and treatment of androgenic alopecia.

6. CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

7. ACKNOWLEDGEMENT:

The authors are thankful to the University Institute of Pharmacy, Pandit Ravishankar Shukla University, Raipur for the infrastructural facilities. The authors extend special thanks to the Librarian, Pt. Sundarlal Sharma Library of the University for e-resources available through UGC-INFLIBNET.

REFERENCES:

1. Mazzarella, F., Loconsole, F., Cammisa, A., Mastrolonardo, M. and Vena, G. A. Topical finasteride in the treatment of androgenic alopecia. Preliminary evaluations after a 16-month therapy course. Journal of Dermatological Treatment. 1997; 8: 189–192.

2. Sinclair, R. D. and Sinclair, R. D. Male androgenetic alopecia. (2017) doi:10.1517/14656561003752730.

3. Ceruti, J. M., Leirós, G. J. and Balañá, M. E. Androgens and androgen receptor action in skin and hair follicles. Molecular and Cellular Endocrinology. 2018; 465: 122–133.

4. Ă, S. P. et al. Therapeutic considerations related to finasteride administration in male androgenic alopecia and benign prostatic hyperplasia. 2017; 65.

5. Khan, M. Z. U. et al. Finasteride Topical Delivery Systems for Androgenetic Alopecia. Current Drug Delivery. 2018; 15: 1100–1111.

6. Ateeq Ahmad, S. S. A New Topical Formulation of Minoxidil and Finasteride Improves Hair Growth in Men with Androgenetic Alopecia. Journal of Clinical and Experimental Dermatology Research. 2015; 6: 6–11.

7. Kaufman, K. D. and Francisco, S. Changes in hair weight and hair count in men with androgenetic alopecia after treatment with finasteride, 1 mg, Daily. 2002: 517–523 doi:10.1067/mjd.2002.120537.

8. Esen Salman, K., Kucukunal, N. A., Kivanc Altunay, I. and Aksu Cerman, A. Frequency, severity and related factors of androgenetic alopecia in dermatology outpatient clinic: Hospital-based cross-sectional study in Turkey. Anais Brasileiros de Dermatologia. 2017; 92: 35–40.

9. Tang, P. H., Chia, H. P., Cheong, L. L. and Koh, D. A community study of male androgenetic alopecia in Bishan, Singapore. Singapore Medical Journal. 2000; 41: 202–205.

10. Neste, D. V. A. N., Fuh, V. and Wolff, H. Finasteride increases anagen hair in men with androgenetic alopecia. 2000: 804–810.

11. Sintov, A., Serafimovich, S. and Gilhar, A. New topical antiandrogenic formulations can stimulate hair growth in human bald scalp grafted onto mice. 2000; 194: 125–134.

12. Avital, Y. S., Morvay, M., Gaaland, M. and Kemny, L. Study of the international epidemiology of androgenetic alopecia in young caucasian men using photographs from the internet. Indian Journal of Dermatology. 2015; 60: 419.

13. Mirmirani, P. Maturitas Age-related hair changes in men : Mechanisms and management of alopecia and graying. Maturitas. 2015; 80: 58–62.

14. Gan, D. C. C. and Sinclair, R. D. Prevalence of male and female pattern hair loss in Maryborough. The journal of investigative dermatology. Symposium proceedings / the Society for Investigative Dermatology, Inc. [and] European Society for Dermatological Research. 2005; 10: 184–189.

15. Kaliyadan, F., Nambiar, A. and Vijayaraghavan, S. Androgenetic alopecia : An update. 2013; 79.

16. Lolli, F. et al. Androgenetic alopecia : a review. Endocrine. 2017; 9–17. doi:10.1007/s12020-017-1280-y.

17. Cranwell, W., Hons, M., Hons, B. and Sinclair, R. Male Androgenetic Alopecia. 2018; 1–30.

18. Chueh, S. C. et al. Therapeutic strategy for hair regeneration: Hair cycle activation, niche environment modulation, wound-induced follicle neogenesis, and stem cell engineering. Expert Opinion on Biological Therapy. 2013; 13: 377–391.

19. Randall, V. A. Molecular Basis of Androgenetic Alopecia. Aging Hair. 2010 doi:10.1007/978-3-642-02636-2.

20. Otberg, N., Finner, A. M. and Shapiro, J. Androgenetic Alopecia. Endocrinology and Metabolism Clinics of North America. 2007; 36: 379–398.

21. Cloke, B. and Christian, M. The role of androgens and the androgen receptor in cycling endometrium. Molecular and Cellular Endocrinology. 2012; 358: 166–175.

22. Sehgal, V. N., Aggarwal, A. K., Srivastava, G. and Rajput, P. Male Pattern Androgenetic Alopecia. 2006.

23. Davis, D. S. and Callender, V. D. International Journal of Women’s Dermatology Review of quality of life studies in women with alopecia. International Journal of Women’s Dermatology. 2018; 4: 18–22.

24. Sinclair, R. D., Perera, E., Sinclair, R. and Alexander, S. Androgenetic Alopecia. 2015. doi:10.3109/9781439808078-33.

25. Lee, W. S. et al. Guidelines for management of androgenetic alopecia based on BASP classification – the Asian consensus committee guideline. 2013; 1026–1034. doi:10.1111/jdv.12034.

26. Tru, R. M. Molecular mechanisms of androgenetic alopecia. 2002; 37: 981–990.

27. Ellis, J. A., Sinclair, R. and Harrap, S. B. Androgenetic alopecia : Pathogenesis and potential for therapy Androgenetic alopecia : pathogenesis and potential for therapy. 2016 doi:10.1017/S1462399402005112.

28. Trüeb, R. M. Inflammatory Phenomena and Fibrosis in Androgenetic Alopecia Androgenetic. in 16th Annual Meeting European Hair Research Society Barcelona. 2012: 21–23.

29. Ebling, F. J. G. 8 Hair follicles and associated glands as androgen targets. Clinics in Endocrinology and Metabolism. 1986; 15: 319–339.

30. Mak, W. C. et al. Triggering of drug release of particles in hair follicles. Journal of Controlled Release. 2012; 160: 509–514.

31. Patzelt, A. and Lademann, J. Drug delivery to hair follicles. Expert Opinion on Drug Delivery. 2013; 10: 787–797.

32. Lademann, J. et al. Hair follicles - A long-term reservoir for drug delivery. Skin Pharmacology and Physiology. 2006; 19: 232–236.

33. Stenn, K. S., Prouty, S. M. and Seiberg, M. Molecules of the cycling hair follicle - a tabulated review. Journal of Dermatological Science. 1994; 7.

34. Botchkareva, N. V., Ahluwalia, G. and Shander, D. Apoptosis in the hair follicle. Journal of Investigative Dermatology. 2006; 126: 258–264.

35. Fischer, T. W. et al. Differential effects of caffeine on hair shaft elongation, matrix and outer root sheath keratinocyte proliferation, and transforming growth factor-β2/insulin-like growth factor-1-mediated regulation of the hair cycle in male and female human hair follicle. British Journal of Dermatology. 2014; 171: 1031–1043.

36. S, I., C, T. and S, I. Acceleration of Hair Growth Rate by Topical Liposomal Cepharanthine in Male Androgenetic Alopecia. Hair Therapy and Transplantation. 2016; 6: 6–7.

37. Soma, T., Ogo, M., Suzuki, J., Takahashi, T. and Hibino, T. Analysis of apoptotic cell death in human hair follicles in vivo and in vitro. Journal of Investigative Dermatology. 1998; 111: 948–954.

38. itami1990.pdf.

39. Robinson, H. N. and Martin, N. F. Topical treatment of acne WItH Cephalosporns. 1995.

40. Paus, R. and Cotsarelis, G. The biology of hair follicles. New England Journal of Medicine. 1999; 341: 491–497.

41. Wosicka, H. and Cal, K. Targeting to the hair follicles: Current status and potential. Journal of Dermatological Science. 2010; 57: 83–89.

42. Alonso, L. and Fuchs, E. The hair cycle. 2006: 391–393.

43. Ford, S. J. et al. Structural and Functional Analysis of Intact Hair Follicles and Pilosebaceous Units by Volumetric Multispectral Optoacoustic Tomography. Journal of Investigative Dermatology. 2016; 136: 753–761.

44. Amin, S. S. and Sachdeva, S. Alopecia areata: A review. Journal of the Saudi Society of Dermatology and Dermatologic Surgery. 2013; 17: 37–45.

45. Schiffer, L., Arlt, W. and Storbeck, K. H. Intracrine androgen biosynthesis, metabolism and action revisited. Molecular and Cellular Endocrinology. 2018; 465: 4–26.

46. Pretorius, E. et al. 11-Ketotestosterone and 11-ketodihydrotestosterone in castration resistant prostate cancer: Potent androgens which can no longer be ignored. PLoS ONE. 2016; 11: 1–17.

47. Storbeck, K. H. et al. 11β-Hydroxydihydrotestosterone and 11-ketodihydrotestosterone, novel C19 steroids with androgenic activity: A putative role in castration resistant prostate cancer? Molecular and Cellular Endocrinology. 2013; 377: 135–146.

48. Anuka, E., Gal, M., Stocco, D. M. and Orly, J. Expression and roles of steroidogenic acute regulatory (StAR) protein in ‘non-classical’, extra-adrenal and extra-gonadal cells and tissues. Molecular and Cellular Endocrinology. 2013; 371: 47–61.

49. Manenda, M. S., Hamel, C. J., Masselot-Joubert, L., Picard, M. È. and Shi, R. Androgen-metabolizing enzymes: A structural perspective. Journal of Steroid Biochemistry and Molecular Biology. 2016; 161: 54–72.

50. Zouboulis, C. C. et al. PNAS-2002-Zouboulis-. 2000;99: 7148-53.

51. Zouboulis, C. C. Acne and sebaceous gland function. Clinics in Dermatology. 2004; 22: 360–366.

52. Kaufman, K. D. Androgen metabolism as it affects hair growth in androgenetic alopecia. 1996; 14

53. Hoffman, R. M. The hair follicle and its stem cells as drug delivery targets. Expert Opinion on Drug Delivery. 2006; 3: 437–443.

54. Li, L. et al. Selective induction of apoptosis in the hamster flank sebaceous gland organ by a topical liposome 5-α-reductase inhibitor: A treatment strategy for acne. Journal of Dermatology. 2010; 37: 156–162.

55. Leyden, J. et al. Finasteride in the treatment of men with frontal male pattern hair loss. 1999: 930–937.

56. Janne, O. A., Palvimo, J. J., Kallio, P. and Mehto, M. Androgen Receptor and Mechanism of Androgen Action. 1993.

57. Mendonca, B. B. et al. Reprint of “Steroid 5α-reductase 2 deficiency”. Journal of Steroid Biochemistry and Molecular Biology. 2017; 165: 95–100.

58. Li, J. and Al-Azzawi, F. Mechanism of androgen receptor action. Maturitas. 2009; 63: 142–148.

59. Kelly, Y., Blanco, A. and Tosti, A. Androgenetic Alopecia: An Update of Treatment Options. Drugs. 2016; 76: 1349–1364.

60. Singal, A., Sonthalia, S. and Verma, P. Female pattern hair loss. Indian Journal of Dermatology, Venereology and Leprology. 2013; 79: 626–640.

61. Srulevich, M. Medical management of benign prostatic hypertrophy in older men. Clinical Geriatrics. 2009; 17: 28–32.

62. McElwee, K. J. and Shapiro, J. S. Promising therapies for treating and/or preventing androgenic alopecia. Skin Therapy Letter. 2012; 17: 1–4.

63. Kaufman, K. D. et al. Finasteride in the treatment of men with androgenetic alopecia. Journal of the American Academy of Dermatology. 1998; 39: 578–89.

64. Guo, H., Gao, W. V., Endo, H. and McElwee, K. J. Experimental and early investigational drugs for androgenetic alopecia. Expert Opinion on Investigational Drugs. 2017; 26; 917–932.

65. Yu, M. et al. Hair follicles and their role in skin health. Expert Review of Dermatology. 2006; 1: 855–871.

66. Kumar, P., Singh, S., Handa, V. and Kathuria, H. Oleic Acid Nanovesicles of Minoxidil for Enhanced Follicular Delivery. Medicines. 2018; 5: 103.

67. Usmania, Ajay Bilandi, M. K. K. Minoxidil Emulgel for Androgenic Alopecia : A Literature Review Including Patents. 2017; 5: 49–58.

68. Hatem, S. et al. Melatonin vitamin C-based nanovesicles for treatment of androgenic alopecia: Design, characterization and clinical appraisal. European Journal of Pharmaceutical Sciences. 2018; 122.

69. Olubukola Sinbad, O., Folorunsho, A. A., Olabisi, O. L., Abimbola Ayoola, O. and Johnson Temitope, E. Vitamins as Antioxidants. Journal of Food Science and Nutrition Research. 2019; 2: 214–235.

70. Koca, R., Armutcu, F., Altinyazar, H. C. and Gürel, A. Evaluation of lipid peroxidation, oxidant/antioxidant status, and serum nitric oxide levels in alopecia areata. Medical Science Monitor. 2005; 11: 296–299.

71. Fernández, E., Martínez-Teipel, B., Armengol, R., Barba, C. and Coderch, L. Efficacy of antioxidants in human hair. Journal of Photochemistry and Photobiology B: Biology. 2012; 117: 146–156.

72. Otberg, N. et al. Follicular penetration of topically applied caffeine via a shampoo formulation. Skin Pharmacology and Physiology. 2007; 20: 195–198.

73. Ramezani, V. et al. Formulation and optimization of transfersome containing minoxidil and caffeine. Journal of Drug Delivery Science and Technology. 2018; 44: 129–135.

74. Daniels, G., Akram, S., Westgate, G. E. and Tamburic, S. Can plant-derived phytochemicals provide symptom relief for hair loss? A critical review. International Journal of Cosmetic Science. 2019; 41: 332–345.

75. Michael, J., Nadine, V., Maike, K. and Adolf, B. Erratum: Caffeine and Its Pharmacological Benefits in the Management of Androgenetic Alopecia: A Review. Skin Pharmacol Physiol. 2020; 33: 93-109 DOI: 10.1159/000508228).

76. Sonthalia, S., Daulatabad, D. and Tosti, A. Hair Restoration in Androgenetic Alopecia : Looking Beyond Minoxidil , Finasteride and Hair Transplantation. 2016; 2: 1–13.

77. Jo, S. J. et al. Topical valproic acid increases the hair count in male patients with androgenetic alopecia : A randomized , comparative , clinical feasibility study using phototrichogram analysis. Journal of Dermatology. 2014; 41: 1–7.

78. Ashique, S., Sandhu, N. K., Haque, S. N. and Koley, K. A Systemic Review on Topical Marketed Formulations , Natural Products, and Oral Supplements to Prevent Androgenic Alopecia : National Institutes of Health. Natural Products and Bioprospecting. 2020; 10: 345–365.

79. Sonthalia, S., Daulatabad, D. and Tosti, A. Journal of Cosmetology and Trichology Hair Restoration in Androgenetic Alopecia : Looking Beyond Minoxidil, Finasteride and Hair Transplantation. 2016; 2: 1–13.

80. Ito, T. et al. Roxithromycin antagonizes catagen induction in murine and human hair follicles: Implication of topical roxithromycin as hair restoration reagent. Archives of Dermatological Research. 2009; 301: 347–355.

81. Csongradi, C., du Plessis, J., Aucamp, M. E. and Gerber, M. Topical delivery of roxithromycin solid-state forms entrapped in vesicles. European Journal of Pharmaceutics and Biopharmaceutics. 2017; 114: 96–107.

82. Wosicka-fra, H. et al. Roxithromycin-loaded lipid nanoparticles for follicular targeting. 2015; 495; 807–815.

83. Shamma, R. N. and Aburahma, M. H. Follicular delivery of spironolactone via nanostructured lipid carriers for management of alopecia. International Journal of Nanomedicine. 2014; 9: 5449–5460.

84. Kim, G. K. and Del Rosso, J. Q. Oral spironolactone in post-teenage female patients with acne vulgaris: Practical considerations for the clinician based on current data and clinical experience. Journal of Clinical and Aesthetic Dermatology. 2012; 5: 37–50.

85. Abdel-Raouf, H., Aly, U. F., Medhat, W., Ahmed, S. S. and Abdel-Aziz, R. T. A. A novel topical combination of minoxidil and spironolactone for androgenetic alopecia: Clinical, histopathological, and physicochemical study. Dermatologic Therapy. 2021; 34: 0–2.

86. Lumachi, F. and Basso, S. M. M. Medical Treatment of Hirsutism in Women. Current Medicinal Chemistry. 2010; 17: 2530–2538.

87. Perez, B. S. H. Ketocazole as an adjunct to finasteride in the treatment of androgenetic alopecia in men. 2004: 112–115 doi:10.1016/S0306-9877(03)00264-0.

88. Jiang, J., Tsuboi, R., Kojima, Y. and Ogawa, H. Topical Application of Ketoconazole Stimulates Hair Growth in C3H / HeN Mice. The Journal of Dermatology. 2005; 32: 243–247.

89. El-garf, A., Mohie, M. and Salah, E. Trichogenic effect of topical ketoconazole versus minoxidil 2 % in female pattern hair loss : a clinical and trichoscopic evaluation. Biomedical Dermatology. 2019; 3: 1–8.

90. Kaushik, R., Institutions, R., Gupta, D. and Institutions, R. Alopecia : Herbal remedies. International Journal of Pharmaceutical Sciences and Research. 2014; 2: 1631–1637.

91. Ramkar, S. et al. Nano-Lipidic Carriers as a Tool for Drug Targeting to the Pilosebaceous Units. CPD. 2020; 26: 3251–3268.

92. Ramkar, S. and Suresh, P. K. Finasteride-loaded nano-lipidic carriers for follicular drug delivery: preformulation screening and Box-Behnken experimental design for optimization of variables. Heliyon. 2022; 8: e10175.

93. Knorr, F. et al. Follicular transport route - Research progress and future perspectives. European Journal of Pharmaceutics and Biopharmaceutics. 2009; 71: 173–180.

Received on 12.07.2023 Revised on 04.05.2024

Accepted on 06.10.2024 Published on 24.12.2024

Available online from December 27, 2024

Research J. Pharmacy and Technology. 2024;17(12):6137-6145.

DOI: 10.52711/0974-360X.2024.00931