Topical Alternatives for Hair Loss: Beyond the Conventional

ABSTRACT

Topical hair growth supplements in the form of hair growth serums, oils, and shampoos have flooded the cosmeceutical market. The gullible masses are targeted with sponsored marketing gimmicks through social media platforms. This review article brings to light the most hyped active ingredients or peptides in these products along with their clinical evidence available in the literature. The topical actives include Redensyl, Procapil, Capixyl, Baicapil, AnaGain, onion juice, coffee extract, saw palmetto extract, pumpkin seed oil (PSO), and rosemary oil. PubMed, Google Scholar, and Google databases were searched with the keywords: topical, hair growth, hair loss, and the respective active agents. Twenty-four relevant articles and technical files were extracted and reviewed. They have been studied mostly as combined formulations with other agents in randomized controlled trials or prospective cohort studies and have shown promising results. However, most of the studies have limited sample size, lack of comparison with standard therapies, nonuniformity between study groups, nondisclosure of the type of alopecia treated, and conflicts of interest. These topicals with their less significant side effect profile may find their use as an add-on therapy or as an alternative in patients not tolerating standard therapies. In this fast-growing commercialized world, it is imperative that we remain vigilant and understand the pros and cons of these products and ultimately guide our patients to the right track.

INTRODUCTION

Hair loss or hair fall is an omnipresent concern seen among patients visiting a dermatologist. The medical treatment includes both topical and oral medications depending on the cause and severity of the condition. The patients are often prejudiced with the possible side effects of approved drugs such as minoxidil and finasteride or have experienced these side effects firsthand. Therefore, patients seek safe, natural ingredients to attenuate their hair loss. There is a growing interest in these alternatives among patients and with the strong claims made by manufacturers, patients are often misguided. The vast number of cosmeceutical products available over the counter makes it even more difficult for clinicians to recommend the right product. Hence, there is a need to review these active ingredients to understand their potential and limitations in treating hair loss and make further evidence-based decisions.

The common actives or peptides that promote hair growth are described as follows and are summarized in Table 1. The literature search was done in PubMed, Google Scholar, and Google databases. The search keywords included topical, hair growth, hair loss, and the respective active agents. A total of relevant 24 research articles and technical files in the English language were reviewed.

Table 1.

Summary of the reviewed topical agents

Topical agent	Parent company	Constituents	Mechanism of action	Studies	Highest level of evidence*	Market formulations
Redensyl (1%–3%)	Givaudan, Switzerland	DHQG EGCG2 Glycine Zinc	Decreases stem cell apoptosis (BCL2 activation), initiates anagen phase (beta-catenin activation) Reduces IL-8 and free radicals Component of keratin-associated proteins Cofactor for cystine incorporation in hair keratin	Proof-of-concept RCT (redensyl) RCTs (combined formulations: Redensyl+sepicontrol A5; redensyl+procapil+capixyl vs. minoxidil 5%)	2 (combined formulation)	Hair lotion, hair serum, eyelash growth serum, active mascara, eyebrow enhancers
Procapil (3%)	Sederma, France	Peptide Biotinyl-GHK Apigenin, a citrus extract Oleanolic acid, extracted from roots of Loveyly Hemsleya	Increases adhesion proteins for hair anchoring Vasodilation effect Inhibits production of DHT via 5α-reductase	Proof-of-concept clinical trial (procapil) RCT (redensyl + procapil + capixyl) versus minoxidil 5% Prospective cohort study (combined formulation: Oleanolic acid, apigenin, biotinyl tripeptide-1, diaminopyrimidine oxide, adenosine, biotin, and ginkgo biloba	2 (combined formulation)	Hair lotion, serum, shampoo
Capixyl (intensive treatment: 5%, Preventive care: 0.5%–2.5%)	Lucas Meyer Cosmetics, US	Acetyl tetrapeptide-3 Biochanin A (red clover extract)	5 α reductive inhibitor Increases ECM proteins for hair anchoring	Proof-of-concept RCT RCT (combined formulation: Biochanin A, acetyl tetrapeptide-3, and ginseng extracts versus minoxidil 3%) RCT (Redensyl + Procapil + capixyl) versus minoxidil 5%)	2 (combined formulation)	Hair lotion, serum, shampoo
Anagain (2%, 4%)	Mibelle biochemistry, Switzerland	Pea sprouts: Biotin, L-arginine and isoflavones	Increases noggin, a protein that limits the telogen phase and FGF-7, promoting matrix keratinocyte growth for a new anagen phase	Proof-of-concept cohort study Prospective cohort study	3	Hair serum, lotion, oil
Baicapil (2%–4%)	Provital.S.A., Barcelona	Baicalin derived from Chinese skull cap (Scutellaria baicalensis) roots; Soy (Glycine max L.) and wheat (Triticum vulgare) sprouts rich in sugars	Provides ATP through oxidative glycolysis; induces TERT to activate stem cells; protects mitochondria DNA, stem cells and and fibroblasts from oxidative stress	Proof-of-concept RCT	No published studies	Hair lotion serum, shampoo
Onion juice			Induces an immunological reaction, possibly as a mild form of dermatitis that stimulates hair re-growth through antigenic competition	RCT in patchy alopecia areata	2	Hair lotion, serum, shampoo
Coffee extract (0.5%–3%)		Caffeine	Inhibits phosphodiesterase which increases cAMP levels to increase cell proliferationn; vasodilation	RCT	2	Hair shampoo, serum, oil
PSO		Phytosterols	Phytosterols, especially β-sitosterol inhibits 5 α-reductase	Prospective cohort study (as niosomes)	3	Hair oil
SP extract		Fatty acids, phytosterols	Blocks both isoforms of 5α reductive Activates 3α-hydroxysteroid - dehydrogenase, an enzyme converting DHT to its weaker metabolite, androstanediol	RCT Prospective cohort study	2	Hair serum, oil, shampoo
Rosemary oil		1,8-cineplex, Borneo, bornyl acetate, camphor, alpha pinene and beta pinene	Anti-spasmodic activity of camphor leading to increased scalp perfusion Antioxidant properties	RCT in AGA (vs. 2% minoxidil)	2	Hair serum, oil

*According to Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence, Level 1 - Systematic review of randomized trials or n-of-1 trials; Level 2 - Randomized trial or observational study with dramatic effect; Level 3 - Nonrandomized controlled cohort/follow-up study; Level 4 - Case-series, case-control studies, or historically controlled studies; Level 5 - Mechanism-based reasoning. BCL-2 - B cell lymphoma 2; RCTs - Randomized controlled trials; IL - Interleukin; ATP - Adenosine triphosphate; TERT - Reverse transcriptase; DNA - Deoxyribonucleic acid; cAMP - Cyclic adenosine monophosphate; AGA - Androgenetic alopecia; DHT - Dihydrotestosterone; ECM - Extracellular matrix; DHQG - Dihydroquercetin-glucoside; EGCG2 - Epigallocatechin-glucoside; GHK - Gly-His-Lysine; FGF-7 - Fibroblast growth factor-7; PSO - Pumpkin seed oil; SP - Saw palmetto

REDENSYL

Redensyl is made of:

1. Dihydroquercetin-glucoside sourced from larch tree, a stabilized polyphenol which activates the division of hair follicle stem cells. It guards the stem cells from apoptosis (BCL2 activation) and initiates the anagen phase (beta-catenin activation), while boosting the metabolism of dermal papilla (DP) fibroblasts

2. Epigallocatechin-glucoside derived from green tea leaves, a stabilized EGCG derivative that reduces inflammation (reduction of IL-8) and captures free radicals[1]

3. Glycine, a major component of keratin-associated proteins, which promotes hair growth[2]

4. Zinc, a cofactor for enzymes that incorporates cystine in keratin for a stronger hair shaft.[3]

Evidence

Clinical assessment was done in a double-blind placebo-controlled trial which involved 26 males with grade 3–4 androgenetic alopecia (AGA). Fifty percent of volunteers received the placebo and 50% received 3% Redensyl applied once a day for 3 months. Eighty-five percent of volunteers showed clinical improvements as an average of +9% of anagen hair, −17% of telogen hair, +8% increase in hair density corresponding to + 10,000 new hairs.[4] (Pilot clinical Trial).

In a randomized, single-blinded, vehicle-controlled study of combined Redensyl and Sepicontrol A5 in AGA, 41 patients were randomized to apply the active lotion or the control, twice daily for 24 weeks. The median anagen-to-telogen ratio in the active group increased from 2.25 to 4.00 to 6.02 at weeks 0, 12, and 24 which was significantly more than the control group. Mild scalp pruritus was observed in both groups.[5]

(Sepicontrol A5 is a Cinnamomum zeylanicum bark extract. It suppresses expression of 5α-reductase, steroid receptor coactivator, estrogen receptor α, and androgen receptor.[6])

PROCAPIL

Procapil is an anti-hair loss complex that targets 5α-reductase, inadequate blood perfusion, and failing anchorage of the hair in the DP.[7] It consists of 3 active substances:

1. Biotinyl-GHK (gly-his-lysine), a matrikine, which helps anchoring of the hair through adhesion proteins such as vimentin, desmogleins, desmocollins, laminin 5, and collagen IV and also promotes keratinocytic multiplication

2. Apigenin, a citrus extract flavonoid with vasodilatory effect

3. Oleanolic acid, extracted from roots of Lovely hemsleya, which inhibits the production of dihydrotestosterone (DHT) via 5α−reductase.

Evidence

A placebo-controlled pilot clinical trial confirmed the marked anti-hair loss activity of the complex which was applied as 3% alcohol lotion twice a day for 4 months. Thirty-five male subjects presenting with more than 20% of their hair in the telogen phase were included. Out of the 18 volunteers in the procapil group, 67% showed significant improvement in the mean anagen/telogen ratio.[7]

In a 6-month open-label study, a topical hair lotion containing oleanolic acid, apigenin, biotinoyl tripeptide-1, diaminopyrimidine oxide, adenosine, biotin, and Ginkgo biloba which was prescribed once daily was assessed in 56 patients of AGA and telogen effluvium (TE). In the TE subgroup, there was a significant increase in total hairs, and in the AGA subgroup, there was a significant increase in both total hairs and anagen hairs. The patients reported a decrease in hair loss (79%), heightened confidence (86%), and less apparent scalp (79%). No adverse events were observed.[8]

Diaminopyrimidine oxide, chemically related to minoxidil, acts against perifollicular fibrosis.[9] Adenosine promotes the expression of several growth factors.[10] Biotin is a vitamin that assists in numerous metabolic reactions involved in fatty acid synthesis.[11] Ginkgo biloba has antioxidant properties and also enhances microcirculation.[12]

CAPIXYL

Capixyl contains biomimetic peptide acetyl tetrapeptide-3 and a red clover extract rich in biochanin A. It increases extracellular matrix proteins such as collagen type III and anchoring fibers such as laminin and collagen VII in DP for increased hair anchoring. Capixyl decreases pro-inflammatory cytokines such as IL-8, 1α. The capacity of biochanin A to inhibit 5-α reductase activity, thereby preventing hair miniaturization is comparable with EGCG.[13]

Evidence

In a test protocol that included 30 men with AGA, 15 were treated with the capixyl lotion (5%) and 15 with a placebo which was applied daily as 20 drops for a period of 4 months. Capixyl increased the anagen/telogen ratio by 46% compared to a reduction of 33% with the placebo.[13]

In a 24-week, triple-blinded, randomized controlled study conducted in male and female subjects (n = 32) with mild-to-moderate AGA, the participants were instructed to apply 1 mL of a herbal extract containing biochanin A, acetyl tetrapeptide-3, and ginseng extracts or 3% minoxidil solution twice daily. The combination group showed a comparable efficacy to 3% minoxidil. No local adverse reactions were observed.[14]

A randomized controlled trial (RCT) compared the safety and efficacy of a combination treatment Redensyl, Capixyl, and Procapil (RCP) versus 5% minoxidil solution in 106 adult male patients with AGA. The patients applied 1 mL of either solution to their scalp twice a day for 24 weeks. Patients who received the combination treatment had a significantly higher researcher score (minoxidil group 25.5% vs. RCP group 64.7%), better photographic evaluation score (minoxidil: 60% vs. RCP: 88.9%), and higher self-evaluation score.[15]

ONION JUICE

Garlic as folk medicine has been tried in topical therapy for alopecia areata. Garlic and onion belong to the same genus Allium and there are many similarities in their chemical constituents, particularly allicin.[16]

Onion can induce allergic contact dermatitis in susceptible individuals.[17] However, recent studies showed that onion extract can inhibit allergic reactions by inducing an immunological reaction, possibly as a mild form of dermatitis that stimulates hair re-growth through antigenic competition.[18] The generation of nonspecific T-suppressor cells in the lymphocytic infiltrate of alopecia areata that lacks suppressor T cells, is likely to inhibit the ongoing autoimmune reaction. Onion is rich in sulfur and phenolic compounds which can cause irritant contact dermatitis.[19]

Evidence

In a study that assessed the effectiveness of topical crude onion juice in the treatment of patchy alopecia areata in comparison with tap water, the onion juice-treated group (n = 23) and the control group (n = 15) were advised to apply the treatment twice daily for 2 months. Hair regrowth was seen in 17 patients (73.9%) at 4 weeks and in 20 patients (86.9%) at 8 weeks in the active group. In the control group, only 2 patients (13%) showed hair regrowth at 8 weeks. No significant side effects were noted in the crude onion-treated group apart from mild erythema in 14 patients (60.8%). However, some patients disliked the unpleasant odor of onion. Ten patients followed up monthly for 6 months and hair regrowth was maintained with no relapse.[20]

COFFEE EXTRACT

Caffeine, derived from coffee, is a central nervous system stimulant that reduces fatigue and drowsiness. Caffeine has shown beneficial effects in patients suffering from AGA. It counteracts DHT-induced miniaturization of the hair follicle through inhibition of phosphodiesterase which increases cyclic adenosine monophosphate levels in cells and thereby enhances cell proliferation.[21]

Evidence

In a double-blinded controlled clinical trial to determine the effects of caffeine on hair growth, 40 Korean men and women were enrolled into the control group (vehicle shampoo daily) and the test group (0.5% caffeine shampoo daily). In the test group, a significant improvement was noted after 8 and 24 weeks. Comparison of hair density changes between the groups revealed significant differences after 8, 16, and 24 weeks.[22]

Caffeine also produced lengthening of hair in ex vivo culture. There was an increase in DP cell proliferation and the expression of growth factors, vascular endothelial growth factor, and keratinocyte growth factor. The potassium channel opening assay indicated that caffeine may improve nutrition by promoting vasodilation. The inner portion of hair follicles revealed more Ki-67-positive cells in the caffeine-treated group.[22]

PUMPKIN SEED OIL

The fatty acids, tocopherols, and sterols in PSO provide positive benefits against hypertension, carcinogenic diseases, and diabetes.[23,24,25] It also shows antibacterial, antioxidant, anti-inflammatory, and wound-healing properties. It has also been reported to be effective for symptomatic benign prostatic hyperplasia. Its antiandrogenic benefits have been suggested to be due to phytosterols, especially β-sitosterol which inhibit 5 α-reductase.[26]

Evidence

In a study that assessed the anti-hair loss effects of topical PSO-loaded noisome, 42 subjects with hair loss were assigned to use the serum twice daily for 8 weeks. The difference in the number of fallen hairs was significantly altered to 23.57% ±1.29% and 44.42% ±1.22% after 4 and 8 weeks, respectively. The anagen-to-telogen ratio was significantly increased by 1.4-fold compared to the pretreatment conditions.[27,28]

SAW PALMETTO EXTRACT

Saw palmetto (SP) is derived from the berries of the Serenoa repens dwarf tree, native to the sub-tropical, Southeastern United States. SP extract consists of fatty acids, phytosterols such as β-sitosterol, β-carotene, Vitamin E derivatives, and polysaccharides.[29] It is a competitive, nonselective inhibitor of both isoforms of 5α-reductase, blocking nuclear uptake of DHT and decreasing DHT binding capacity to androgen receptors. SP also increases the activity of 3α-hydroxysteroid dehydrogenase, an enzyme converting DHT to its weaker metabolite, androstanediol.[30]

Evidence

An RCT tested the efficacy of a topical SP-containing lotion twice daily, alone, and in addition to a tablet containing gelatin-cystine 4 times a day, in 60 men and women with AGA over a period of 50 weeks. The SP-containing topical demonstrated a mean increase in hair count of 17% by week 10 and 27% by week 50, as compared to 6% and 14% among the vehicle group at weeks 10 and 50, respectively. The combined use of topical SP and oral gelatin-cystine supplement caused a further increase of approximately 50% in all hair growth parameters when compared to the use of either agent alone. Topical SP was well tolerated.[31,32]

A 24-week, prospective cohort study demonstrated the efficacy of a topical SP-containing lotion applied to the entire scalp daily for the treatment of AGA in 50 men. There was an increase in hair count after 12 and 24 weeks compared to baseline by 3.4 and 4.9%, respectively, while terminal hair count increased by 21.4 and 74.1%, respectively. Median AGA Norwood Hamilton stage changed from 4 at baseline to 3 at 24 weeks.[33]

ANAGAIN

Anagain is a water-soluble extract prepared from edible organic pea sprouts (Pisum sativum L.). Pea sprouts are a rich source of various nutrients such as biotin, L-arginine, and isoflavones.[34]

Evidence

Analysis of gene expression in hair bulbs treated with anagain showed an increase of two DP signaling molecules:

1. Noggin, a protein that limits the telogen phase

2. Fibroblast growth factor-7 (FGF-7), which promotes the proliferation activity of the matrix keratinocytes at the beginning of a new anagen phase.[35]

The effects of anagain on hair growth were evaluated on 20 volunteers suffering from mild to moderate hair loss. Four percent of anagain gel was applied to their scalps twice a day for 3 months. Anagain significantly decreased the density of telogen hair and increased the density of anagen hair, thereby improving the A/T ratio.[36]

In a study by Grothe et al., 2% pea sprout extract was applied on the scalp of 10 volunteers. It increased the expression of FGF-7 and noggin, by 56% and 85%, respectively. Furthermore, an interventional nutrition study of 21 volunteers proved that pea sprout extract is also effective as a dietary supplement (100 mg). No adverse events were reported.[37]

BAICAPIL

Baicapil is a combination of

1. Baicalin derived from Chinese skull cap (Scutellaria baicalensis) roots

2. Soy (Glycine max L.) and wheat (Triticum vulgare) sprouts rich in sugars.

Growing follicles use glucose around twice as fast than resting follicles to obtain energy in the form of ATP.[38] Baicapil provides additional sugars to the growing follicles. It also induces TERT (telomerase reverse transcriptase) which activates stem cells and initiates a new anagen phase.[39] The same induction provides mitochondrial DNA protection against oxidative stress and reactive oxygen species in stem cells and fibroblasts, thereby preserving them from senescence.[40] The cumulative effect is a longer anagen phase leading to hair growth and greater hair density.

Evidence

The in vivo efficacy was demonstrated in 61 volunteers. Half of them applied a lotion with 3% of Baicapil and the other half a placebo for 6 months. Baicapil increased anagen hair by an average of 12.7% more as compared to 2% in the placebo group which was statistically significant. There was a 68.6% increase in the anagen-to-telogen ratio with Baicapil and only a 3.6% increase in the placebo group.[41]

ROSEMARY OIL

Rosmarinus officinalis L. is a perennial herb native to the Mediterranean region. Its pharmacological activities include antioxidant, cholagogue, antiviral, antifungal, antibacterial, hepatoprotective, neuroprotective, and smooth muscle relaxant properties.[42,43] The leaves and branchlets of rosemary contain around 0.5%–2.5% v/w essential oils. The major volatile components of rosemary oil include 1,8-cineplex, Borneo, bornyl acetate, camphor, alpha-pinene, and beta-pinene.[44] The spasmolytic activity of rosemary leading to relaxation of scalp vessels and enhanced perfusion is accounted mainly by camphor. The free radical scavenging and lipid peroxidation inhibitory properties also contribute to the anti-hair loss effect.[45] This oil, in addition, nourishes and conditions the hair strands giving a soft and silky appearance.

Evidence

In a randomized controlled study, 100 patients with AGA were assigned to apply rosemary oil or minoxidil 2% for a period of 6 months. Both groups experienced a significant increase in hair count at the 6-month endpoint compared with the baseline and 3-month endpoint. No significant difference was found between the study groups regarding hair count either at month 3 or 6. Scalp itching, however, was more frequent in the minoxidil group at both assessed endpoints.[45]

CONCLUSION

Almost all current formulations containing the active peptides also contain other vitamins, minerals, or chemical additives, making it challenging to discern the exact extent of contribution. Among the studies presented, there were methodological flaws such as limited sample size, lack of representative sample, lack of appropriate comparison groups, qualitative over quantitative measures of hair regrowth, and conflicts of interest in the form of sponsorship by pharmaceutical companies. In some of the studies conducted, the exact type of alopecia treated is not disclosed and only male patients were included. There is a lack of head-to-head comparison with the standard methods of treatment. Therefore, more well-designed comparative studies are needed to ascertain the real-world benefits of these agents in hair loss. Nevertheless, these relatively newer agents with their lack of significant side effects may find their place in those patients who suffer from adverse effects of standard therapies and who are apprehensive of them. Another advantage would be their potential usefulness as an add-on therapy or as a maintenance agent. It is imperative that physicians recognize these agents and understand their benefits, limitations, and potential adverse effects as evidence-based treatment is the best we can do for our patients.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.