In recent years, the topic of hair loss has frequently been trending on social media, attracting widespread attention from netizens. Hair loss has become a prevalent issue, with a trend of occurring at younger ages, and young and middle-aged individuals have become the main force of the "hair loss army."

Different causes lead to different types of hair loss, and common hair loss types include androgenetic alopecia (AGA), alopecia areata, trichotillomania, telogen effluvium, and senile alopecia. Among them, AGA is the most common type of hair loss, with the main pathological feature being progressive miniaturization of hair follicles. The primary causative factor is genetics, and its incidence and prevalence are closely related to age and gender. Drug therapy is the most widely used and effective treatment method for AGA, spanning the entire treatment process. Currently, only minoxidil and finasteride have been approved by the FDA for the treatment of AGA.

As AGA becomes more prevalent, drugs for treating AGA are also being continuously developed. Research strategies for AGA drugs mainly focus on developing drugs that target single or multiple targets. Different targets have different strategic drugs, and some antagonists and promoters have performed well in treating AGA.

1. 5α-Reductase Inhibitors

Testosterone is the main androgen in the blood, which can be converted into dihydrotestosterone (DHT), the primary pathogenic androgen for AGA, under the catalysis of 5α-reductase. Therefore, inhibiting 5α-reductase is a major target in the treatment of AGA. There are three types of 5α-reductase in the human body, among which type II 5α-reductase is widely distributed in the prostate, hair follicles (innermost layer of the outer root sheath), and surrounding hair follicle tissues, making it most relevant to AGA. Many drugs achieve the purpose of treating hair loss by inhibiting the action of 5α-reductase. Studies have shown that plants and substances with anti-5α-reductase activity can also promote hair growth, such as bayberry bark, white cedar seeds, and epigallocatechin gallate (EGCG) found in green tea.

Finasteride is a type II 5α-reductase inhibitor that competitively inhibits the activity of type II 5α-reductase. By reducing the activity of type II 5α-reductase and thereby lowering the expression level of DHT, it can significantly improve hair loss and is also used to treat prostatic hyperplasia. However, its side effects primarily include sexual dysfunction in males, such as erectile dysfunction, reduced semen volume, decreased libido, and gynecomastia. While the reduction in DHT contributes partially to these symptoms, the additional conversion of testosterone to estradiol also contributes to these side effects. After discontinuing the use of finasteride, the therapeutic effects may reverse, and the side effects will gradually decrease over several years.

Dutasteride, an analog of finasteride, is also a second-generation 5α-reductase inhibitor that inhibits both type I and type II 5α-reductases. Compared to finasteride, dutasteride has a 3-fold increase in potency for inhibiting type I 5α-reductase and a 100-fold increase in potency for inhibiting type II 5α-reductase. Clinical trials have shown that dutasteride is superior to finasteride in increasing hair count and improving hair follicle miniaturization, while showing similar side effects, mainly sexual dysfunction.

2.Androgen Receptor (AR) Antagonists

One of the causes of AGA is the overexpression of androgen receptors (AR) in the scalp hair follicles, making them abnormally sensitive to androgens. With the deepening of research on AR, many innovative small-molecule drugs have emerged, and some have already entered clinical trial stages. The treatment of AGA through the AR target primarily involves drugs competing with AR to bind, reducing AR's sensitivity to androgens, and thus achieving the goal of treating hair loss.

Spironolactone is a non-steroidal anti-androgen drug that blocks androgen receptors in target tissues and reduces testosterone levels, thus exerting an anti-androgen effect, primarily used for the treatment of female AGA. Studies have found that topical application of spironolactone has a high permeability rate to active sites, with the advantage of reducing the adverse reactions associated with oral spironolactone. A combination of 1% spironolactone and 5% minoxidil topical gel is effective for both male and female AGA and can enhance treatment efficacy.

Cyproterone acetate directly blocks androgen receptor activity, reduces testosterone levels, and can be used to treat female androgenic disorders such as acne, seborrhea, mild hirsutism, and AGA by inhibiting the release of luteinizing hormone and follicle-stimulating hormone. The most significant side effects of cyproterone acetate are thromboembolism, breast tenderness, headache, and nausea, but they tend to decrease over time with continued treatment.

Regarding the AR target, various other compounds have been discovered to have inhibitory effects on it, potentially becoming starting points for new drug development. CB0301, a new type of topical anti-androgen drug developed by Canadian company Cassiopea, does not cause systemic adverse reactions and has an activity roughly equivalent to cyproterone acetate. Suzhou Kaituo Pharmaceutical has independently developed drugs KX-826 and GT20029, both of which have received approval from the US FDA to conduct clinical trials. KX-826 (Forrestane) is an AR antagonist with the same mechanism of action as CB0301. The small molecule GT20029 belongs to a targeted protein degradation chimera, whose mechanism of action involves binding AR protein to E3 ubiquitin ligase. Once AR protein is ubiquitinated, it will be degraded by the ubiquitin-proteasome pathway, achieving the effect of inhibiting the binding of AR to androgens. In addition, anti-androgen drugs such as RU58841, flutamide, and flurandrenolide also have certain efficacy in the treatment of AGA.

3.Botulinum toxin type A (BTX-A)

Research has shown that there are hemodynamic abnormalities in the hair loss areas of patients with alopecia, including microvascular dysfunction and reduced blood flow. Therefore, improving blood supply to the scalp may stimulate hair growth. Botulinum toxin type A (BTX-A), a highly effective neurotoxin, selectively blocks the release of acetylcholine and many other neurotransmitters at the neuromuscular junction. It has been widely used in dermatology clinics for reducing wrinkles, facial muscle regulation, hyperhidrosis, correction of masseter hypertrophy, and gastrocnemius hypertrophy. When BTA is injected into the scalp, it may relax the muscles around the head, increase blood flow and oxygen concentration in the hair loss areas, further inhibit the activation of DHT, and ultimately reduce the occurrence of hair loss. Additionally, high concentrations of oxygen can stimulate hair follicles to enter the growth phase, leading to hair regeneration.

4.Prostaglandins and Prostaglandin Analogues

Prostaglandins (PGs) are important regulators of hair growth, and thus PGE2 and PGF2a analogues and agonists can be used to treat alopecia. Research has found that prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) in the hair follicle unit can stimulate hair growth, while prostaglandin D2 (PGD2) has been found to limit hair growth and induce miniaturization of hair follicles. Furthermore, the PGF2α analogue latanoprost has been approved for promoting eyebrow and eyelash growth by improving local blood circulation. In vitro studies have shown that levocetirizine hydrochloride can inhibit the PGD2-GPR44 pathway, activate the AKT signaling pathway, and thereby promote the proliferation and growth of human hair papilla cells.

5.Wnt Pathway Modulators

The Wnt signaling pathway plays a crucial role in regulating hair growth, and abnormal regulation of Wnt can lead to hair loss. Increasing evidence suggests that hair follicle development, formation, and hair growth rely on the activation of Wnt/β-catenin signaling. Not only can Wnt proteins in the epidermis trigger hair follicle growth, but also the maintenance and growth of hair follicles require the communication of Wnt/β-catenin signaling pathways between skin and epidermal cells. Therefore, activating the Wnt/β-catenin signal is a potential treatment for AGA. SM04554 is a small molecule that can activate the Wnt pathway, and currently, a Phase III clinical trial of SM04554 for the treatment of hair loss is ongoing. Previous Phase II clinical studies showed that SM04554 can promote hair growth and/or hair follicle formation.

6.Other Drugs

Minoxidil is a long-lasting drug among the multi-target drugs for treating AGA. Initially, minoxidil was used to treat hypertension, but later it was discovered to increase hair growth and has been approved as one of the drugs for treating AGA. The exact mechanism of minoxidil is not fully understood, but it has multiple functions, including: ① increasing blood circulation by inducing vasodilation and overexpression of vascular endothelial growth factor; ② increasing the mitosis of hair matrix keratinocytes, promoting hair growth and increasing hair diameter; ③ extending the hair follicle growth phase; ④ stimulating hair follicles to initiate a new growth cycle, etc. Adverse reactions include scalp dryness, hypertrichosis, and contact dermatitis. Clinically, solutions containing minoxidil in concentrations of 2% and 5% are mainly used, but increasing the concentration has shown adverse reactions such as irritation or allergic rhinitis. Some researchers compared the therapeutic effects of 10% minoxidil and 5% minoxidil solutions and found that 5% minoxidil had slightly better therapeutic effects, while 10% minoxidil was more irritating.

Currently, existing hair loss treatment methods cannot fully meet clinical needs in terms of effectiveness, safety, and practicality. The prevention and treatment of hair loss, as well as hair regeneration, remain one of the challenges faced by both clinical and basic research. The precise mechanism of hair loss is still unclear, and there are certain limitations with single-target drugs. Multi-target drugs and methods have become new treatments and approaches for hair loss due to their comprehensive therapeutic effects and low side effects.

References

[1] Wu Wei, Zhao Hongwei. Advances in Drug Treatment and New Drug Research for Androgenetic Alopecia [J]. Tissue Engineering and Reconstructive Surgery, 2021, 17(05): 445-449.

[2] Liu Sixu, Zheng Rong, Liao Yujie, Liu Yuxin, Xia Zanxian, Wu Wei. Research Progress on Related Targets of Androgenetic Alopecia [J]. Chinese Journal of Aesthetic and Plastic Surgery, 2022, 33(01): 26-28.

[3] Wu Wei, Zhang Ying, Zhang Mei, Zhao Hongwei, Liu Chi. Advances in Drug Research for Androgenetic Alopecia [J]. Chinese Journal of Aesthetic and Plastic Surgery, 2022, 33(05): 308-311.

[4] Yan Jing, Wang Ruichuan, Sun Yifeng, Deng Ningning, Chen Yuanyuan, Wu Junying, Chu Wenzhu, Ma Zhihong. Research Progress in the Treatment of Androgenetic Alopecia [J]. Chinese Medical Cosmetology, 2022, 12(04): 61-65. DOI: 10.19593/j.issn.2095-0721.2022.04.015.

About the Author

Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.