¹Department of Dermatology and Skin Science, The University of British Columbia, Vancouver, BC, Canada
²Vancouver Coastal Health Research Institute, The University of British Columbia, Vancouver, BC, Canada
³Department of Dermatology, New York University, New York, NY, USA

Introduction

Hair loss is a common dermatological problem that affects a large segment of the population both physically and psychologically. There are many causes of hair loss, such as telogen effluvium (thinning of hair as a result of hair follicles perpetually in a resting phase, as opposed to growth phase) and alopecia areata (an inherited autoimmune condition); androgenetic alopecia (AGA) also called male pattern hair loss (MPHL), is the most common. Hair loss can start anytime at or after puberty: many people have hair loss beginning in the late teens due to the effects of androgen hormones on hair follicles.¹ Its occurrence and severity increases with age, with at least 80% of Caucasian men displaying signs of MPHL by age 70.² Because of its considerable psychological impact, many patients seek treatment.³ Currently, only one topical agent is approved for treatment of hair loss in men, although other treatments are being clinically investigated.

Pathogenesis

• The pathophysiology of AGA remains to be fully determined however, as the name implies, androgens and a genetic predisposition appear to be involved.⁴
• Inherited AGA is polygenic with input from either or both parents.
• The androgenic hormones testosterone (T) and dihydrotestosterone (DHT) are the most important in regulating the growth phase duration and hair matrix volume.
  • In men, testosterone is the precursor to DHT. The conversion of T to DHT at the hair follicles is mediated by Type II 5! reductase enzyme.
• DHT, a potent metabolite of testosterone, enlarges follicles in the beard, chest and limbs and miniaturizes follicles in the bitemporal region. In genetically susceptible patients, DHT can cause miniaturisation in the vertex and frontal hairline leading to AGA-patterned thinning.

Clinical Presentation & Diagnosis

• AGA presents with fronto-temporal recession and over the vertex: the occipital scalp is preserved.
• Diagnosis is made based on the clinical history; however a scalp biopsy may be needed in situations where the cause of hair loss is uncertain.
• Telogen effluvium may present like early phase AGA.

Current Topical Treatments

Minoxidil

• Minoxidil is the current topical standard treatment of hair loss. Initially used as an oral antihypertensive medication, its association with hypertrichosis led to its development as a topical therapy for AGA.
• Minoxidil 2% solution was approved by the US FDA for the treatment of MPHL in 1988, and was subsequently approved in 5% strength in a solution format in 1997 and in a foam format in 2006. The 2% solution formulation alone was approved in the US for female pattern hair loss in 1996. Minoxidil 2% solution became available in Canada for the treatment of MPHL in 1986, and the 5% foam in November 2012.⁴
• The content discussed here relates to the branded formulation of minoxidil only and not the compounded or generic formulations.
• The precise mechanism of action of minoxidil is unknown; however it is associated with vasodilation, angiogenesis and enhanced cell proliferation, probably mediated via potassium channel opening.^5,6 Further, it has been seen to prolong duration of anagen of the hair cycle, increase miniaturized hair follicle size, and preserve and thicken preexisting hair.
• Data from a 16-week, randomized, double-blind, placebo controlled (RCT) study of the newly approved minoxidil 5% foam application showed at weeks 8, 12 and 16 the mean increase in target area hair count was significantly greater than placebo (p<0.0001).⁷ At week 16 the percentage change in target area hair count was 13.4% in men treated with minoxidil 5% foam compared with 3% for the placebo arm (21.0 hairs/cm2 vs. 4.3 hairs/cm2, respectively).^7,8 Further, 38.3% of patients in the minoxidil arm demonstrated increased hair growth at week 16, compared with 5.2% in the placebo group (p<0.0001), as rated by an expert panel.⁷
• Data from a 48-week RCT also showed an increase in target area hair count in men treated with minoxidil solution, and that the product reversed hair loss as well as slowed its progression.⁹
• The same study also showed that target area hair counts were greater with the 5% solution compared with the 2% minoxidil solution.
• Minoxidil treatment is life-long: stopping treatment will result in a shedding of all minoxidil-dependent hair growth within 4-6 months after cessation of therapy.⁴
• The recommended dosing of minoxidil 2% solution is twice daily topical application of 1 ml spread evenly over the top of the dry scalp in the hair loss area.
• With minoxidil 5% foam, half a capful is applied twice daily on the dry scalp and left in place for at least four hours. To avoid the drug coming into contact with the face and limit the risk of hypertrichosis in non-scalp body areas, patients should wash their hands with warm water after application.
• Minoxidil has a well-established safety profile. The most frequently reported adverse drug reaction following the short-term, 16-week treatment with minoxidil 5% foam was headache.⁸ The most frequently reported dermatological adverse events were erythema, rash, acne and pruritis. In long-term treatment, the most frequently reported nonserious adverse events were infection and accidental injury.⁸
• The most frequently reported adverse events in the minoxidil 2% solution clinical trials were minor respiratory events, including colds and respiratory infections, rhinitis, sinusitis and coughing. Dermatologic adverse reactions were the next most frequent and included scaling, itching and rash.⁸
• Increased hair shedding is possible in the first 2-6 weeks of treatment, which likely results from inducing anagen from the resting phase.⁸ This may be an indication that minoxidil is effective; patients should be advised not to stop treatment if they experience hair loss for two weeks or less. However, if hair loss continues for longer than two weeks, patients should be advised to stop using the product and talk to their doctor.⁸
• Careful evaluation of the risks and benefits of minoxidil treatment should be considered in patients with pre-existing cardiac, renal or hepatic disease or scalp abnormalities and those receiving potentially interacting drugs concomitantly (e.g., hypotensive agents, such as guanethidine). If minoxidil therapy is initiated in these scenarios, patients should be closely monitored.¹⁰
• Allergic reaction to minoxidil is rare. Constituents of the vehicles may cause skin irritation. Irritant dermatitis to propylene glycol (a component of minoxidil 2% solution vehicle) may occur. Patch testing for propylene glycol can be performed as a precaution. If contact dermatitis results from minoxidil use, treatment should be stopped.
• Minoxidil 5% foam is propylene glycol free. Further, it is aesthetically more pleasing to patients compared to the solution, and thus likely increases compliance.
• Data show patients using the foam product rated it significantly higher compared with the minoxidil solution, finding it easy to apply, quick to absorb and non-drip.¹⁰
• Systemic absorption of minoxidil is weak with only 0.3-4.5% reaching the circulation. It is excreted within four days.

Other Topical Agents

Prostoglandins

• The prostaglandin F2α< analogues latanoprost and bimatoprost are widely used to treat glaucoma.
• Bimatoprost topical solution 0.03% is approved for treating hypotrichosis of the eyelashes by increasing their growth including length, thickness and darkness.
• Topical latanoprost is under investigation for the treatment of AGA.¹¹

Ketoconazole

• Ketoconazole is an imidazole antifungal agent known to be effective for treatment of seborrheic dermatitis and dandruff. It is available as an over-the-counter topical shampoo at a 2% strength.
• Ketaconazole’s action on scalp microflora may benefit patients with AGA-associated follicular inflammation.^12,13
• While the mechanism by which ketoconazole may improve hair growth is unclear, it is known to have anti-inflammatory effects against T-cells which are found in the balding area in patients with AGA.¹⁴
• Further, ketoconazole decreases colonization of the skin by Malassezia.
• Ketoconaole also inhibits steroid synthesis and decreases DHT levels at the hair follicle by affecting androgen receptor activity.¹⁴

Conclusion

AGA is a common issue among men and can significantly affect self-esteem and quality of life, such that they may seek treatment. While different topical agents are currently being investigated for safety and efficacy, only one topical treatment, minoxidil, is currently approved for hair regrowth. The newly approved 5% foam solution has demonstrated patient preference, which in turn may improve compliance. Given its established efficacy and safety profile, minoxidil may be useful in the topical management of AGA in male patients.

References

1. Pray J. et al. US Pharmacist. 2003; 28(8)1.
2. Gan DC, et al. J Investig Dermatol Symp Proc. 2005;10(3):184-9.
3. Budd D. Eur J Dermatol. 2000 Mar;10(2):122-7.
4. Banka N, Dermatol Clin. 2013 Jan;31(1):129-40.
5. Alsantali A, et al. Curr Opin Endocrinol Diabetes Obes. 2009 Jun;16(3):246-53.
6. Messenger AG, et al. Br J Dermatol. 2004 Feb;150(2):186-94.
7. Olsen EA, et al. J Am Acad Dermatol. 2007 Nov; 57(5):767–74.
8. ROGAINE® Canadian Product Monograph
9. Olsen EA, et al. J Am Acad Dermatol. 2002 Sep; 47(3):377-85.10.McEvoy, GK. American Hospital Formulary Service-Drug Information 2002.
10. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2002 (Plus Supplements).
11. Blume-Peytavi U, et al. J Am Acad Dermatol. 2012 May;66(5):794-800.
12. Pierard-Franchimont C, et al. Dermatology. 1998;196(4):474-7.
13. Magro CM. et al. J Drugs Dermatol. 2011 Dec; 10(12):1404-11.
14. Inui S, et al. J Dermatol Sci. 2007 Jan;45(1):66-8.

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

ABSTRACT

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.

Key Words:
androgenetic alopecia, AGA, female pattern hair loss, male pattern hair loss, topicals

Introduction

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

Androgenetic Alopecia

Clinical Presentation

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

Pathogenesis

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.

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.

Conclusion

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.

References

1. 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.
2. 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.
3. Shapiro J. Clinical practice. Hair loss in women. N Engl J Med. 2007 Oct 18;357(16):1620-30.
4. Price VH. Androgenetic alopecia in women. J Investig Dermatol Symp Proc. 2003 Jun;8(1):24-7.
5. 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.
6. Banka N, Bunagan MJ, Shapiro J. Pattern hair loss in men: diagnosis and medical treatment. Dermatol Clin. 2013 Jan;31(1):129-40.
7. 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.
8. Messenger AG, Rundegren J. Minoxidil: mechanisms of action on hair growth. Br J Dermatol. 2004 Feb;150(2):186-94.
9. 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.
10. 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.
11. 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.
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.
13. 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.
14. 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.
15. Law SK. Bimatoprost in the treatment of eyelash hypotrichosis. Clin Ophthalmol. 2010;4:349-58.
16. 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.
17. Jones D. Enhanced eyelashes: prescription and over-the-counter options. Aesthetic Plast Surg. 2011 Feb;35(1):116-21.
18. Poulos GA, Mirmirani P. Investigational medications in the treatment of alopecia. Expert Opin Investig Drugs. 2005 Feb;14(2):177-84.
19. 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.
20. 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.
21. 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.
22. Dill-Muller D, Zaun H. Topical treatment of androgenetic alopecia with spironolactone. J Eur Acad Dermatol Venereol. 1997 Sep;9(Suppl 1):31.
23. Fischer TW, Slominski A, Tobin DJ, et al. Melatonin and the hair follicle. J Pineal Res. 2008 Jan;44(1):1-15.
24. 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.
25. 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.

¹Department of Dermatology and Skin Science, The University of British Columbia, Vancouver, BC, Canada
²Vancouver Coastal Health Research Institute, The University of British Columbia, Vancouver, BC, Canada
³Department of Dermatology, New York University, New York, NY, USA

Introduction

Hair loss is a common dermatological problem that affects a large segment of the population both physically and psychologically. While there are many causes of hair loss, such as telogen effluvium and alopecia areata, androgenetic alopecia (AGA) also called male pattern hair loss (MPHL), is the most common. Hair loss can start anytime at or after puberty. Its occurrence and severity increases with age, with at least 80% of Caucasian men displaying signs of MPHL by age 70.¹ Because of its considerable psychological impact, many patients seek treatment.² Currently, only one topical agent is approved for treatment of hair loss in men, although other treatments are being clinically investigated.

Pathogenesis

• The pathophysiology of AGA remains to be fully determined however, as the name implies, androgens and a genetic predisposition appear to be involved.³
• Inherited AGA is polygenic with input from either or both parents.
• The androgenic hormones testosterone (T) and dihydrotestosterone (DHT) are the most important 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 patients, DHT can cause miniaturisation 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.

Clinical Presentation & Diagnosis

• AGA presents with fronto-temporal recession and over the vertex: the occipital scalp is preserved.
• Diagnosis is made based on the clinical history; however a scalp biopsy may be needed in situations where the cause of hair loss is uncertain.

Current Topical Treatments

Minoxidil

• Minoxidil is the current topical standard treatment of hair loss. Initially used as an oral antihypertensive medication, its association with hypertrichosis led to its development as a topical therapy for AGA.
• Minoxidil 2% solution was approved by the US FDA for the treatment of MPHL in 1988, and was subsequently approved in 5% strength in a solution format in 1997 and in a foam format in 2006. The 2% solution formulation alone was approved in the US for female pattern hair loss in 1996. Minoxidil 2% solution became available in Canada for the treatment of MPHL in 1986, and the 5% foam in November 2012.³
• The content discussed here relates to the branded formulation of minoxidil only and not the compounded or generic formulations.
• The precise mechanism of action of minoxidil is unknown; however it is associated with vasodilation, angiogenesis and enhanced cell proliferation, probably mediated via potassium channel opening.^{4, 5} Further, it has been seen to prolong duration of anagen of the hair cycle, increase miniaturized hair follicle size, and preserve and thicken preexisting hair.
• Data from a 16-week, randomized, double-blind, placebo controlled (RCT) study of the newly approved minoxidil 5% foam application show at weeks 8, 12 and 16 the mean increase in target area hair count was significantly greater than placebo (p<0.0001).⁶ At week 16 the percentage change in target area hair count was 13.4% in men treated with minoxidil 5% foam compared with 3% for the placebo arm (21.0 hairs/cm2 vs. 4.3 hairs/cm2, respectively).^6,7 Further, 38.3% of patients in the minoxidil arm demonstrated increased hair growth at week 16, compared with 5.2% in the placebo group (p<0.0001), as rated by an expert panel.⁶
• Data from a 48-week RCT also showed an increase in target area hair count in men treated with minoxidil solution, and that the product reversed hair loss as well as slowed its progression.⁸
• The same study also showed that target area hair counts were greater with the 5% solution compared with the 2% minoxidil solution.
• Minoxidil treatment is life-long: stopping treatment will result in a shedding of all minoxidil-dependent hair growth within 4-6 months after cessation of therapy.³
• The recommended dosing of minoxidil 2% solution is twice daily topical application of 1 ml spread evenly over the top of the dry scalp in the hair loss area.
• With minoxidil 5% foam, half a capful is applied twice daily on the dry scalp and left in place for at least four hours. To avoid the drug coming into contact with the face and limit the risk of hypertrichosis in non-scalp body areas, patients should wash their hands with warm water after application.
• Minoxidil has a well-established safety profile. The most frequently reported adverse drug reaction following the short-term, 16-week treatment with minoxidil 5% foam was headache.⁷ The most frequently reported dermatological adverse events were erythema, rash, acne and pruritis. In long-term treatment, the most frequently reported nonserious adverse events were infection and accidental injury.⁷
• The most frequently reported adverse events in the minoxidil 2% solution clinical trials were minor respiratory events, including colds and respiratory infections, rhinitis, sinusitis and coughing. Dermatologic adverse reactions were the next most frequent and included scaling, itching and rash.⁷
• Increased hair shedding is possible in the first 2-6 weeks of treatment, which likely results from inducing anagen from the resting phase.⁷ This may be an indication that minoxidil is effective; patients should be advised not to stop treatment if they experience hair loss for two weeks or less. However, if hair loss continues for longer than two weeks, patients should be advised to stop using the product and talk to their doctor.⁷
• Careful evaluation of the risks and benefits of minoxidil treatment should be considered in patients with pre-existing cardiac, renal or hepatic disease or scalp abnormalities and those receiving potentially interacting drugs concomitantly (e.g., hypotensive agents, such as guanethidine). If minoxidil therapy is initiated in these scenarios, patients should be closely monitored.⁹
• Allergic reaction to minoxidil is rare. Constituents of the vehicles may cause skin irritation. Irritant dermatitis to propylene glycol (a component of minoxidil 2% solution vehicle) may occur. Patch testing for propylene glycol can be performed as a precaution. If contact dermatitis results from minoxidil use, treatment should be stopped.
• Minoxidil 5% foam is propylene glycol free. Further, it is aesthetically more pleasing to patients compared to the solution, and thus likely increases compliance.
• Data show patients using the foam product rated it significantly higher compared with the minoxidil solution, finding it easy to apply, quick to absorb and non-drip.⁹
• Systemic absorption of minoxidil is weak with only 0.3 – 4.5% reaching the circulation. It is excreted within four days.

Other Topical Agents

Prostoglandins

• The prostaglandin F2α analogues latanoprost and bimatoprost are widely used to treat glaucoma.
• Bimatoprost topical solution 0.03% is approved for treating hypotrichosis of the eyelashes by increasing their growth including length, thickness and darkness.
• Topical latanoprost is under investigation for the treatment of AGA.¹⁰

Prostoglandins

• Ketoconazole is an imidazole antifungal agent known to be effective for treatment of seborrheic dermatitis and dandruff. It is available as an over-the-counter topical shampoo at a 2% strength.
• Ketaconazole’s action on scalp microflora may benefit patients with AGA-associated follicular inflammation.^11,12
• While the mechanism by which ketoconazole may improve hair growth is unclear, it is known to have anti-inflammatory effects against T-cells which are found in the balding area in patients with AGA.¹³ Further, it decreases colonization of the skin by Malassezia. It also inhibits steroid synthesis and decreases DHT levels at the hair follicle by affecting androgen receptor activity.¹³

Conclusion

AGA is a common issue among men and can significantly affect self-esteem and quality of life, such that they may seek treatment. While different topical agents are currently being investigated for safety and efficacy, only one topical treatment, minoxidil, is currently approved for hair regrowth. The newly approved 5% foam solution has demonstrated patient preference, which in turn may improve compliance. Given its established efficacy and safety profile, minoxidil may be useful in the topical management of AGA in male patients.

References

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5. Messenger AG, et al. Br J Dermatol. 2004 Feb;150(2):186-94.
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7. ROGAINE® Canadian Product Monograph
8. Olsen EA, et al. J Am Acad Dermatol. 2002 Sep; 47(3):377-85.
9. McEvoy, GK. American Hospital Formulary Service-Drug Information 2002. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2002 (Plus Supplements).
10. Blume-Peytavi U, et al. J Am Acad Dermatol. 2012 May;66(5):794-800.
11. Pierard-Franchimont C, et al. Dermatology. 1998;196(4):474-7.
12. Magro CM. et al. J Drugs Dermatol. 2011 Dec; 10(12):1404-11.
13. Inui S, et al. J Dermatol Sci. 2007 Jan;45(1):66-8.