Androgenetic Alopecia: A Review of Topical Agents for Hair Growth Promotion

Omar S. Shamsaldeen, MD1 and Jerry Shapiro, MD, FRCPC<sup>1,2,3

1</sup>Department 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.

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