Topical Agents for Hair Growth Promotion

What Is Out There?

Omar S. Shamsaldeen, MD; Thamer Al Mubki, MD; Jerry Shapiro, MD, FRCPC

Disclosures

Skin Therapy Letter. 2013;18(4) 

In This Article

Topical Treatments

Minoxidil

Minoxidil is the current standard treatment for hair loss. It was initially used as an oral antihypertensive medication, but because of minoxidil's side effect of hypertrichosis it was subsequently developed as a topical treatment in 2% strength for hair loss. US FDA approval for the treatment of MPHL was granted to the 2% formulation in 1988 and the 5% in 1997, but only the 2% strength was approved for FPHL in 1997.[6]

The precise mechanism by which minoxidil induces hair growth is unknown. However, its vasodilatory, angiogenic, and enhanced cell proliferative effects are thought to be responsible. Minoxidil is an adenosine-triphosphate-sensitive potassium channel opener reported to stimulate the production of vascular endothelial growth factor, a possible promoter of hair growth.[7] Minoxidil prolongs duration of anagen of the hair cycle and increases miniaturized hair follicle size in addition to its significant ability to maintain and thicken preexisting hair.[8]

Minoxidil's efficacy in pattern hair loss has been proven in doubleblind, placebo-controlled trials. In men with MPHL, minoxidil showed a rapid increase in hair count and weight peaking at 16 weeks. The average increase in target area hair count is about 8% with minoxidil 2% lotion and 10–12% with the 5% formulation. About 60% of men demonstrated improvement with the 5% formulation and 40% with the 2% formulation compared with 23% of placebo.[6]

In women with FPHL treated with minoxidil 2% solution, a 10–16% increase in regrowth compared with controls was shown, while greater effects may be derived at the higher 5% concentration.[9] This treatment is life-long and stopping minoxidil will shed all minoxidil-dependent hair growth within 4 to 6 months.[6]

The recommended dosing of either 2% or 5% minoxidil solution is twice daily application of 1 ml (25 drops) spread evenly over the entire top of the dry scalp. For the 5% foam formulation, half a capful is applied twice daily on the dry scalp and left in place for at least 4 hours. To minimize the risk of hypertrichosis of the face, especially in women, hands should be washed with warm water after application. The minoxidil 5% foam has only just recently become available in Canada as of November 2012.

Minoxidil has a well-established safety profile.[10] Adverse effects are very infrequent and include skin irritation, contact dermatitis, facial hypertrichosis, scale, dryness, tachycardia, and transient increased hair shedding, which is more prominent in the first 4 weeks and results from induction of anagen from the resting phase. This may be viewed as an indication of minoxidil's efficacy, as such, patients should be advised to continue with treatment even if this side effect occurs.

Constituents of the vehicle (e.g., propoylene glycol and minoxidil) can cause irritant contact dermatitis, allergic contact dermatitis, or exacerbation of seborrheic dermatitis, which are more common with the 5% solution. An allergic reaction to minoxidil itself is very rare; the more common contactant inducing pruritus and scaling of the scalp is propylene glycol.[11] The 5% foam vehicle is propylene glycol free and, hence, reduces the potential for irritation and improves cosmetic acceptability.[12] Patch testing for propylene glycol can be performed. If positive, a less irritating butylene glycol vehicle can be substituted. If the contact dermatitis is due to minoxidil, then treatment with this agent may have to be abandoned.

The side effect of hypertrichosis is more frequently seen in female patients who already have hirsutism. It mostly affects the forehead, malar areas and sides of the face, but is totally reversible with cessation of the drug.

Systemic absorption of minoxidil is weak, with only 0.3–4.5% reaching the circulatory system, and excreted within 4 days. No changes in blood pressure or other hemodynamic effects were shown with minoxidil use,[13] however, caution should be exercised in patients with cardiovascular disease. Minoxidil has been assigned to pregnancy category C. Although there is no evidence of teratogenicity in rats and rabbits, studies are lacking in humans and it is secreted in human milk, therefore, use in pregnant or nursing women should be avoided.

Prostaglandins

Latanoprost and bimatoprost are prostaglandin analogues widely used to treat glaucoma and recently they have been investigated for eyelash alopecia. Studies have demonstrated variable success when used as eye drops to stimulate eyelash growth in alopecia areata.[14] Although their mechanism of action is not fully understood, these compounds likely work by interacting with the prostaglandin receptors in the hair follicle and inducing anagen (growth phase) in telogen (resting phase) follicles.[15]

The rationale for use in alopecia areata was predicated on bimatoprost's history of drug discovery. When administered as an eye drop for glaucoma, eyelash growth was noted in 42.6% of patients treated once daily for a year.[16,17] Initially, this effect was regarded as an adverse event, but the potential aesthetic benefits of eyelash growth were quickly recognized, leading to the development of bimatoprost for hypotrichosis of the eyelashes and culminating in US FDA approval for this indication in 2008.

A 24 week double-blind, randomized pilot study of 16 men with mild AGA showed a significant increase in hair density (terminal and vellus hairs) on the treated site with latanoprost 0.1% compared to baseline and the placebo-treated area.[14] Treatment was well tolerated, although erythema at the application site was observed in 5 patients.

More data is required to determine the optimal concentrations of these prostaglandin analogues. Bimatoprost may eventually be more effective at the right titrated concentration.[14]

Fluridil

Fluridil is a synthetic novel topical antiandrogen that is similar in structure to flutamide. Fluridil is a highly hydrophobic, systemically non-resorbable compound that demonstrates local tolerance and degrades into inactive metabolites without systemic antiandrogenic effects.[18,19] In a double-blind, placebocontrolled study of 43 men with AGA, application of fluridil for 3 months resulted in increased anagen percentage from 76% to 85% in the fluridil treated group, and at 9 months to 87%, with no change in the placebo group. Sexual function, libido, hematology and blood chemistry values were normal over the duration of the investigation.[19] Fluridil is being used throughout Europe but is still awaiting approval in the US.

Ketoconazole

Ketoconazole is an imidazole antifungal agent known to be effective for the treatment of seborrheic dermatitis and dandruff.[20] In a 21 month study comparing topical ketoconazole to minoxidil, the effect of ketoconazole 2% shampoo was compared to that of an unmedicated shampoo used in combination with or without minoxidil 2% therapy. Hair density and size as well as proportion of anagen follicles were improved almost similarly by both ketoconazole and minoxidil regimens.[20] The mechanism by which ketoconzole improves hair growth is unclear, but may be attributable to anti-inflammatory effects against T cells that are found in the balding area in AGA and activity against microflora of the skin by Malassezia. It also inhibits steroid synthesis and decreases DHT levels at the hair follicle by affecting androgen receptor activity.[21]

Spironolactone

Spironolactone is an aldosterone receptor blocker that reduces enzyme activity in the biosynthesis of testosterone. In a clinical study of 60 female patients with AGA, topical spironolactone 1% was found to be effective in promoting hair growth without hypotonia or hormonal disorders reported.[22] However, larger studies are necessary to determine the antiandrogenic properties of topical spironolactone and its potential utility for FPHL.

Melatonin

Melantonin has long been known to modulate hair growth. Animal testing has shown that melatonin stimulates the anagen phase of hair growth.[23] In a double-blind, randomized, placebocontrolled study 40 women with diffuse alopecia (n=28) or AGA (n=12) were treated topically for 6 months with 1 ml daily of 0.1% melatonin-alcohol solution versus vehicle. Trichograms were used to determine efficacy in the frontal and occipital scalp areas. At the end of the study, the AGA group demonstrated a statistically significant increase in anagen hairs in the occiput region compared to placebo (mean 78 to 82 hairs), but no difference was shown with placebo in the frontal area.[24] The group with diffuse alopecia showed a substantial increase in frontal hair. Plasma melatonin levels were elevated under treatment with melatonin, but did not exceed the physiological night peak.

Estrogens

Systemic estrogens increase production of the glycoprotein sex hormone-binding globulin (SHBG), leading to a decrease in free testosterone. A 6 month study of a topical 17α-estradiol 0.025% preparation applied by 7 women with FPHL reported stabilization of hair loss and/or increased telogen hair shedding compared to 2 female control subjects.[25] More studies are warranted to validate the use of topical estrogens in AGA.

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