Omar S. Shamsaldeen, MD1; Thamer Al Mubki, MD1,2; Jerry Shapiro, MD, FRCPC1,3
1Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
2College of Medicine, Al Imam Muhammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
3Department of Dermatology, New York University, New York, NY, USA
Hair loss is a widespread complaint that carries a significant psychosocial burden for affected individuals. Androgenetic alopecia (AGA) is the predominant cause of hair loss seen in the dermatology clinic. Although a range of therapies are available, minoxidil remains the only approved topical treatment for AGA. Promising new topical agents are under current investigation.
androgenetic alopecia, AGA, female pattern hair loss, male pattern hair loss, topicals
Hair loss is a common dermatological problem that affects a large segment of the population both physically and psychologically. Although there are many different causes for hair loss, such as telogen effluvium and alopecia areata, androgenetic alopecia (AGA), i.e., male pattern hair loss and female pattern hair loss, is the most prevalent form in both men and women. Onset of AGA can occur anytime at or after puberty, but incidence and severity increases with advancing age in both genders, manifesting in at least 80% of Caucasian men and 40% of women.1 Because of its considerable psychological impact many patients actively search for new treatments.2
Male pattern hair loss (MPHL) affects androgen-sensitive follicles and features fronto-temporal recession and hair loss over the vertex while the occipital scalp is preserved, resulting in a classic M pattern. In women, female pattern hair loss (FPHL) typically presents with diffuse central thinning or frontal accentuation forming a “Christmas tree” pattern. A third and less common presentation is a male-like pattern with fronto-temporal recession/vertex loss, which may indicate excess androgen activity.3 Diagnosis is easily determined from the clinical history, however, a scalp biopsy may be needed in situations where the cause of hair loss is uncertain. Extensive hormonal testing is usually unnecessary unless indicated by signs and symptoms of androgen excess, such as hirsutism, severe unresponsive cystic acne, virilization, or galactorrhea, which may point to the possibility of an underlying endocrine abnormality.4
The pathophysiology of AGA is not yet fully understood, but both genes and androgens appear to be involved. Inheritance is polygenic with input from either or both parents. Women with FPHL are less likely than men to exhibit a clear family history of the disorder.5
The androgens testosterone (T) and dihydrotestosterone (DHT) are the most important factors in regulating the anagen duration and hair matrix volume.
DHT, a potent metabolite of testosterone, enlarges follicles in the beard, chest and limbs, and miniaturizes follicles in the bitemporal region. In genetically susceptible individuals, DHT can cause miniaturization in the vertex and frontal hairline leading to AGA patterned thinning. The conversion of T to DHT occurs at the hair follicles elicited by a type II 5-alpha-reductase enzyme.
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.
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 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 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 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.
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.
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.
Although the clinical diagnosis of AGA can be easily made, the array of topical treatments remains largely investigational and demonstrates variable rates of response. Hence, extensive and well designed studies are needed to confirm their efficacy and safety. Early intervention may be important to limit the associated significant psychological morbidity. Novel and more effective treatments are in persistent demand and may be developed once the pathogenesis of AGA is better understood.
- Gan DC, Sinclair RD. Prevalence of male and female pattern hair loss in Maryborough. J Investig Dermatol Symp Proc. 2005 Dec;10(3):184-9.
- Budd D, Himmelberger D, Rhodes T, et al. The effects of hair loss in European men: a survey in four countries. Eur J Dermatol. 2000 Mar;10(2):122-7.
- Shapiro J. Clinical practice. Hair loss in women. N Engl J Med. 2007 Oct 18;357(16):1620-30.
- Price VH. Androgenetic alopecia in women. J Investig Dermatol Symp Proc. 2003 Jun;8(1):24-7.
- Olsen EA, Messenger AG, Shapiro J, et al. Evaluation and treatment of male and female pattern hair loss. J Am Acad Dermatol. 2005 Feb;52(2):301-11.
- Banka N, Bunagan MJ, Shapiro J. Pattern hair loss in men: diagnosis and medical treatment. Dermatol Clin. 2013 Jan;31(1):129-40.
- Li M, Marubayashi A, Nakaya Y, et al. Minoxidil-induced hair growth is mediated by adenosine in cultured dermal papilla cells: possible involvement of sulfonylurea receptor 2B as a target of minoxidil. J Invest Dermatol. 2001 Dec;117(6):1594-600.
- Messenger AG, Rundegren J. Minoxidil: mechanisms of action on hair growth. Br J Dermatol. 2004 Feb;150(2):186-94.
- Atanaskova Mesinkovska N, Bergfeld WF. Hair: what is new in diagnosis and management? Female pattern hair loss update: diagnosis and treatment. Dermatol Clin. 2013 Jan;31(1):119-27.
- Olsen EA, Whiting D, Bergfeld W, et al. A multicenter, randomized, placebocontrolled, double-blind clinical trial of a novel formulation of 5% minoxidil topical foam versus placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2007 Nov;57(5):767-74.
- Friedman ES, Friedman PM, Cohen DE, et al. Allergic contact dermatitis to topical minoxidil solution: etiology and treatment. J Am Acad Dermatol. 2002 Feb;46(2):309-12.
- Blume-Peytavi U, Hillmann K, Dietz E, et al. A randomized, single-blind trial of 5% minoxidil foam once daily versus 2% minoxidil solution twice daily in the treatment of androgenetic alopecia in women. J Am Acad Dermatol. 2011 Dec;65(6):1126-34 e2.
- Olsen EA, Dunlap FE, Funicella T, et al. A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2002 Sep;47(3):377-85.
- Blume-Peytavi U, Lonnfors S, Hillmann K, et al. A randomized doubleblind placebo-controlled pilot study to assess the efficacy of a 24-week topical treatment by latanoprost 0.1% on hair growth and pigmentation in healthy volunteers with androgenetic alopecia. J Am Acad Dermatol. 2012 May;66(5):794-800.
- Law SK. Bimatoprost in the treatment of eyelash hypotrichosis. Clin Ophthalmol. 2010;4:349-58.
- Higginbotham EJ, Schuman JS, Goldberg I, et al. One-year, randomized study comparing bimatoprost and timolol in glaucoma and ocular hypertension. Arch Ophthalmol. 2002 Oct;120(10):1286-93.
- Jones D. Enhanced eyelashes: prescription and over-the-counter options. Aesthetic Plast Surg. 2011 Feb;35(1):116-21.
- Poulos GA, Mirmirani P. Investigational medications in the treatment of alopecia. Expert Opin Investig Drugs. 2005 Feb;14(2):177-84.
- Sovak M, Seligson AL, Kucerova R, et al. Fluridil, a rationally designed topical agent for androgenetic alopecia: first clinical experience. Dermatol Surg. 2002 Aug;28(8):678-85.
- Pierard-Franchimont C, De Doncker P, Cauwenbergh G, et al. Ketoconazole shampoo: effect of long-term use in androgenic alopecia. Dermatology. 1998;196(4):474-7.
- Inui S, Itami S. Reversal of androgenetic alopecia by topical ketoconzole: relevance of anti-androgenic activity. J Dermatol Sci. 2007 Jan;45(1):66-8.
- Dill-Muller D, Zaun H. Topical treatment of androgenetic alopecia with spironolactone. J Eur Acad Dermatol Venereol. 1997 Sep;9(Suppl 1):31.
- Fischer TW, Slominski A, Tobin DJ, et al. Melatonin and the hair follicle. J Pineal Res. 2008 Jan;44(1):1-15.
- Fischer TW, Burmeister G, Schmidt HW, et al. Melatonin increases anagen hair rate in women with androgenetic alopecia or diffuse alopecia: results of a pilot randomized controlled trial. Br J Dermatol. 2004 Feb;150(2):341-5.
- Orfanos CE, Vogels L. [Local therapy of androgenetic alopecia with 17 alphaestradiol. A controlled, randomized double-blind study (author’s transl)]. Dermatologica. 1980;161(2):124-32.