Jerry Shapiro – Skin Therapy Letter

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

STL Pharmacist Volume 7 Number 1 — Mon, 01 Jul 2013 00:44:58 +0000

Omar S. Shamsaldeen, MD1 and Jerry Shapiro, MD, FRCPC^1,2,3

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.

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

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

Topical Agents for Hair Growth Promotion: What Is Out There?

STL Volume 18 Number 4 — Sat, 01 Jun 2013 20:12:09 +0000

Omar S. Shamsaldeen, MD¹; Thamer Al Mubki, MD^1,2; Jerry Shapiro, MD, FRCPC^1,3

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

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

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.

Androgenetic Alopecia: A Review of Topical Agents for Hair Growth Promotion (Family Practice)

STL FP Volume 9 Number 1 — Wed, 01 May 2013 18:12:30 +0000

Omar S. Shamsaldeen, MD1 and Jerry Shapiro, MD, FRCPC^1,2,3

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.

Conclusion

References

Gan DC, et al. J Investig Dermatol Symp Proc. 2005;10(3):184-9.
Budd D. Eur J Dermatol. 2000 Mar;10(2):122-7.
Banka N, Dermatol Clin. 2013 Jan;31(1):129-40.
Alsantali A, et al. Curr Opin Endocrinol Diabetes Obes. 2009 Jun;16(3):246-53.
Messenger AG, et al. Br J Dermatol. 2004 Feb;150(2):186-94.
Olsen EA, et al. J Am Acad Dermatol. 2007 Nov; 57(5):767–74.
ROGAINE® Canadian Product Monograph
Olsen EA, et al. J Am Acad Dermatol. 2002 Sep; 47(3):377-85.
McEvoy, GK. American Hospital Formulary Service-Drug Information 2002. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2002 (Plus Supplements).
Blume-Peytavi U, et al. J Am Acad Dermatol. 2012 May;66(5):794-800.
Pierard-Franchimont C, et al. Dermatology. 1998;196(4):474-7.
Magro CM. et al. J Drugs Dermatol. 2011 Dec; 10(12):1404-11.
Inui S, et al. J Dermatol Sci. 2007 Jan;45(1):66-8.

Promising Therapies for Treating and/or Preventing Androgenic Alopecia

STL Volume 17 Number 6 — Fri, 01 Jun 2012 21:07:51 +0000

Kevin J. McElwee, PhD^1,2 and Jerry Shapiro, MD, FRCPC^1,2,3

ABSTRACT

Androgenetic alopecia (AGA) may affect up to 70% of men and 40% of women at some point in their lifetime. While men typically present with a distinctive alopecia pattern involving hairline recession and vertex balding, women normally exhibit a diffuse hair thinning over the top of their scalps. The treatment standard in dermatology clinics continues to be minoxidil and finasteride with hair transplantation as a surgical option. Here we briefly review current therapeutic options and treatments under active investigation. Dutasteride and ketoconazole are also employed for AGA, while prostaglandin analogues latanoprost and bimatoprost are being investigated for their hair growth promoting potential. Laser treatment products available for home use and from cosmetic clinics are becoming popular. In the future, new cell mediated treatment approaches may be available for AGA. While there are a number of potential treatment options, good clinical trial data proving hair growth efficacy is limited.

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

Hair Loss

Hair loss comes in many forms and it is an increasingly common complaint of dermatology clinic patients. While there are many potential diagnoses, the most frequently encountered are androgenetic alopecia (male pattern baldness [MPB]; female pattern hair loss [FPHL]), telogen effluvium, or alopecia areata. Several forms of scarring alopecia also seem to be becoming more common in dermatology clinics. However by far, the near universal hair loss complaint is androgenetic alopecia (AGA) in men and women. The population frequency of AGA varies with ethnicity, but as a rough generalization up to 70% of men and 40% of women will experience some degree of AGA in their lifetime. While the condition is a widespread experience, negative image perceptions¹ mean affected individuals can be highly motivated to seek diagnosis and treatment.

Androgenetic Alopecia

Clinical Presentation

In most men, AGA develops with a distinctive “patterned” hair line recession. In women, the presentation may be less clear; typically women will develop a diffuse thinning over the top of the scalp yielding a “Christmas tree” pattern with more thinning towards the front, though the frontal hairline is maintained.² Occasionally men may develop a female presentation of hair loss and women, primarily those experiencing excess androgen activity, may develop a more male-like hair loss pattern. Also of note, frontal fibrosing alopecia in women, a scarring alopecia with hairline recession, has been frequently misdiagnosed as AGA.³ Diffuse AGA may be difficult to distinguish from telogen effluvium. Indeed, telogen effluvium may spur AGA onset and the increased shedding of telogen effluvium can be an early phase characteristic of AGA. Where diagnosis is in doubt, a biopsy may clarify.⁴

Biochemistry

Research on subjects with androgen insensitivity syndromes, or ⁵α reductase deficiency, implies that AGA is induced via activation of androgen receptors in hair follicles by dihydrotestosterone (DHT). DHT binds to androgen receptors with five times the tenacity of testosterone and consequently has greater downstream activation potency.⁵ Two distinct forms of 5α reductase (types 1 and 2) differ in their tissue distribution; type 2 is most active in hair follicles, but both likely contribute to AGA. The primary precursor of DHT in men is testosterone, but dehydroepiandrosterone (DHEA) and other weaker androgens, are the precursors for DHT in women. The intracellular signaling cascade after androgen receptor binding is poorly understood, but receptor binding leads to increased production of cytokines, such as TGFbeta1 and 2, which promote telogen and dermal papilla cell senescence.^6,7 The density of androgen receptors in hair follicles varies with location. Occipital hair follicles, with a low number of androgen receptors, have little or no response to DHT. Consequently, hair loss is mostly restricted to the scalp vertex and fronto-temporal areas.

Genetics and Diagnostic Tests

AGA susceptibility is largely determined by genetics, though the environment may also play a minor role. Androgen receptor polymorphisms probably make the key determination for androgen responsiveness, but 5α reductase, aromatase, and sex hormone binding globulin (SHBG) genes may also contribute along with other hormone metabolism associated genes.⁸ While the complete genetic picture is not clear, at least one company claims to have a gene polymorphism based diagnostic test (HairDX™) that will predict the chances of future AGA development.^9,10 For young patients concerned about hair loss this test may help to define the value of early treatment initiation. Perhaps of more immediate practical significance, a test that predicts responsiveness to treatment with finasteride is also available.¹¹ In women, serum ferritin levels may also be assessed to determine iron deficiency, thyrotropin levels may be evaluated to rule out thyroid dysfunction, and free testosterone is assessed when androgen excess is suspected. If serum ferritin is low, iron supplementation has been recommended as an enabler of response to other treatments.²

Current and Future Treatments

Drug therapies specifically approved for treating AGA are limited to minoxidil and finasteride. Both can be used in combination.¹² Several other drugs are also used off label (see below) and a plethora of treatments with unsubstantiated hair growth claims can be obtained over the counter. Recently, a review and development of evidence-based guidelines for the treatment of AGA in men and women was published, which may assist with treatment decisions.¹³

Minoxidil

Minoxidil (Rogaine®) was originally an antihypertensive therapy but was subsequently developed as a topical treatment (available in 2% and 5% solutions) for hair loss. Minoxidil use is associated with vasodilation, angiogenesis, and enhanced cell proliferation, probably mediated via potassium channel opening.¹⁴ Side effects include contact dermatitis and a transient shedding during the first ~4 months of use. Use of 5% minoxidil in a commercially available foam vehicle that does not contain propylene glycol (potential irritant), reduces the incidence of pruritus.¹⁵ Several products that include minoxidil, sometimes combined with other active ingredients such as tretinoin, are available from different manufacturers in the US.

Finasteride

Finasteride (Propecia®) is the most common treatment approach for MPB. It is a synthetic type II 5α reductase inhibitor that reduces the conversion of testosterone to DHT.¹⁶ Improvement in hair count and thickness is possible, with responsiveness improving over 6 months to 1 year with 1 mg daily intake.¹⁷ Adverse sexual events have been reported more frequently with finasteride. Finasteride has significant, adverse consequences for the development of male embryos and, as such, it is not officially approved for use in women. However, in combination with an effective oral contraceptive, finasteride is being prescribed off label. Small scale studies suggest it may be effective in women where androgen activity is involved in FPHL.¹⁸

Dutasteride

Dutasteride (Avodart®), a type I and II 5α reductase inhibitor, is on hold in Phase III trials for AGA.¹⁹ It is currently approved for treatment of benign prostatic hyperplasia. Phase II studies for AGA demonstrated a dose-dependent increase in hair growth. The efficacy of dutasteride 2.5 mg/day was superior to that of finasteride 5 mg/day.²⁰ Side effects are similar to finasteride.

Prostaglandin Analogues

The prostaglandin F2α analogues latanoprost and bimatoprost are used in treating ocular hypertension and glaucoma. A noted side effect was increased eyelash hair growth, a feature that has been investigated in several small scale studies. Bimatoprost (Latisse®) is now available as a treatment for eyelash growth.²¹ More recently, latanoprost (Xalatan®) has been investigated for its potential to promote scalp hair growth. Latanoprost significantly increased hair density compared with baseline and placebo and may also encourage pigmentation.²²

Ketoconazole

A topical shampoo containing 2% ketoconazole (Nizoral®) is available over the counter while higher concentrations are available by prescription only. As an imidazole anti-fungal agent, ketoconazole is effective for the treatment of dermatitis and dandruff, and its action on scalp microflora may benefit those with AGA associated follicular inflammation.^23,24 However, ketoconazole is also an anti-androgen and has been suggested to improve hair growth in AGA through androgen dependent pathways.²⁵ Ketoconazole shampoo is typically utilized in conjunction with other AGA treatments.

Anti-androgens

Several synthetic anti-androgens can be used as inhibitors of 5α reductase activity and can also block androgen receptor binding. The efficacy of topical anti-androgen compounds for AGA has been investigated in some small studies,¹⁸ but this approach is not generally considered.¹³ More commonly, anti-androgens are combined with estrogens for the treatment of FPHL. Treatment approaches using oral anti-androgens are significantly more popular in Europe than North America. Cyproterone acetate, available in Canada but not in the US, has been used for FPHL to some effect. However, spironolactone is typically the preferred oral anti-androgen for hair loss in North America.²⁶

Estrogens

Estrogens are indirect anti-androgens, and are sometimes used for the treatment of androgenetic alopecia in women in the form of a birth control pill. When used systemically, estrogens increase SHBG production, which binds to androgens, including testosterone, reducing their bioavailability. Topical estrogen compounds are also commercially available in Europe.¹³ Hair follicles have estrogen receptors and it is believed that topical compounds may act on the hair follicles as direct hair growth promoters as well as by antagonizing androgen activity. However, large clinical studies demonstrating efficacy are lacking and topical treatment is not generally available in North America.

Laser Treatment

Laser/light treatment for hair loss has become very popular in the last few years; it has also been promoted as a preventative measure against AGA. Several different manufacturers provide lasers and light sources of varying wavelengths and with different suggested modes of use. While some laser machines are designed for use at home on a daily basis, others are only available through clinics for weekly or monthly use. Whilst there is evidence that laser light can stimulate hair growth at some wavelengths,²⁷ the biological mechanism by which it occurs has not been defined. With one exception,²⁸ clinical data from large scale, placebo controlled trials is lacking. While lasers may be options that patients wish to independently explore, so far they have not become a significant treatment approach in most dermatology clinics.²⁹

Surgical Treatment

The hair follicles on the scalp occiput are relatively androgen resistant. This enables their transplantation to balding areas to provide a permanent treatment for AGA. Significant advances have been made in surgical hair restoration techniques. Follicular unit transplantation (FUT) is widely available from transplant clinics in North America and beyond. More recently, specialized techniques have been developed involving individual hair follicle and unit extraction (FUE) to avoid scarring from strip graft harvesting. Hand held motorized devices are now available for the extraction of grafts and most recently robots capable of automated hair follicle extraction have been developed and are commercially available.³⁰ Hair transplant costs vary from $5,000 to $20,000 per session and sometimes more depending on the number of grafts and the surgeon. One or two sessions may be required depending on the extent of hair loss. Surgical treatment is limited by the hair density in the donor region and the reluctance of some patients to undergo what is a fairly invasive procedure.

Cell Mediated Treatment

Several companies and academic research groups are focused on the development of cell mediated treatments for AGA. Two main approaches are under investigation: the direct injection of cultured cells or the use of cell secreted factors as a hair growth promoting product. It has been shown that cells from the hair follicle mesenchymal tissue can be cultured and then used to induce new hair follicle formation from epithelial tissue. The injected cells can also migrate to resident hair follicles to increase their size.31 Alternatively, cells are cultured and the culture supernatant is processed to produce a compound rich in hair growth promoting factors, such as Wnt proteins, for use in treatment. These cell mediated treatment approaches are still in Phase I or II trials, but may be available in a few years. Also of note, currently gaining popularity in the marketplace is platelet rich plasma (PRP) isolated from whole blood. Platelets have multiple growth factors associated with them as well as other potentially stimulatory mediators. Some hair transplant surgeons use this product to encourage transplanted graft growth.³⁰ PRP is also available from some clinics as a standalone treatment for AGA, though so far there is only one small published study in support of this approach.³²

Alternative Treatments

Numerous products marketed direct to the consumer contain blends of herbal, vitamin and mineral components, though independent data supporting their claims as hair growth promoters are absent. Some of the more common herbs that patients may take include saw palmetto (Serenoa repens), black cohosh (Actaea racemosa), dong quai (Angelica sinensis), false unicorn (Chamaelirium luteum), chaste berry (Vitex agnuscastus), and red clover (Trifolium pratense) which are claimed to have anti-androgenic or estrogen promoting activity. Other products may contain biotin, caffeine, melatonin, copper complexes, and various proprietary compounds with diverse purported modes of action.^13,33

Conclusion

Overall, there are a number of treatment options currently available to people with AGA, though the clinical data supporting their use is often very limited. Finasteride and minoxidil are still the most common therapeutic drugs prescribed for AGA. New treatment approaches are under active investigation.

References

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.
Tosti A, Piraccini BM, Iorizzo M, et al. Frontal fibrosing alopecia in postmenopausal women. J Am Acad Dermatol. 2005 Jan;52(1):55-60.
Sinclair R, Patel M, Dawson TL, Jr., et al. Hair loss in women: medical and cosmetic approaches to increase scalp hair fullness. Br J Dermatol. 2011 Dec;165(Suppl 3):12-8.
Kaufman KD. Androgens and alopecia. Mol Cell Endocrinol. 2002 Dec 30; 198(1-2):89-95.
Inui S, Itami S. Molecular basis of androgenetic alopecia: From androgen to paracrine mediators through dermal papilla. J Dermatol Sci. 2011 Jan; 61(1):1-6.
Winiarska A, Mandt N, Kamp H, et al. Effect of 5alpha-dihydrotestosterone and testosterone on apoptosis in human dermal papilla cells. Skin Pharmacol Physiol. 2006;19(6):311-21.
Yip L, Rufaut N, Sinclair R. Role of genetics and sex steroid hormones in male androgenetic alopecia and female pattern hair loss: an update of what we now know. Australas J Dermatol. 2011 May;52(2):81-8.
Ellis JA, Stebbing M, Harrap SB. Polymorphism of the androgen receptor gene is associated with male pattern baldness. J Invest Dermatol. 2001 Mar;116(3):452-5.
Hillmer AM, Hanneken S, Ritzmann S, et al. Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia. Am J Hum Genet. 2005 Jul;77(1):140-8.
Keene S, Goren A. Therapeutic hotline. Genetic variations in the androgen receptor gene and finasteride response in women with androgenetic alopecia mediated by epigenetics. Dermatol Ther. 2011 Mar-Apr;24(2):296-300.
Arca E, Acikgoz G, Tastan HB, et al. An open, randomized, comparative study of oral finasteride and 5% topical minoxidil in male androgenetic alopecia. Dermatology. 2004;209(2):117-25.
Blumeyer A, Tosti A, Messenger A, et al. Evidence-based (S3) guideline for the treatment of androgenetic alopecia in women and in men. J Dtsch Dermatol Ges. 2011 Oct;9(Suppl 6):S1-57.
Alsantali A, Shapiro J. Androgens and hair loss. Curr Opin Endocrinol Diabetes Obes. 2009 Jun;16(3):246-53.
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.
Drake L, Hordinsky M, Fiedler V, et al. The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia. J Am Acad Dermatol. 1999 Oct;41(4):550-4.
Mella JM, Perret MC, Manzotti M, et al. Efficacy and safety of finasteride therapy for androgenetic alopecia: a systematic review. Arch Dermatol. 2010 Oct;146(10):1141-50.
Camacho-Martinez FM. Hair loss in women. Semin Cutan Med Surg. 2009 Mar;28(1):19-32.
Rathnayake D, Sinclair R. Male androgenetic alopecia. Expert Opin Pharmacother. 2010 Jun;11(8):1295-304.
Olsen EA, Hordinsky M, Whiting D, et al. The importance of dual 5alphareductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride. J Am Acad Dermatol. 2006 Dec;55(6):1014-23.
Banaszek A. Company profits from side effects of glaucoma treatment. CMAJ. 2011 Oct 4;183(14):E1058.
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.
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.
Magro CM, Rossi A, Poe J, et al. The role of inflammation and immunity in the pathogenesis of androgenetic alopecia. J Drugs Dermatol. 2011 Dec; 10(12):1404-11.
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.
Sinclair R, Wewerinke M, Jolley D. Treatment of female pattern hair loss with oral antiandrogens. Br J Dermatol. 2005 Mar;152(3):466-73.
Lee GY, Lee SJ, Kim WS. The effect of a 1550 nm fractional erbium-glass laser in female pattern hair loss. J Eur Acad Dermatol Venereol. 2011 Dec; 25(12):1450-4.
Leavitt M, Charles G, Heyman E, et al. HairMax LaserComb laser phototherapy device in the treatment of male androgenetic alopecia: A randomized, double-blind, sham device-controlled, multicentre trial. Clin Drug Investig. 2009;29(5):283-92.
Avram MR, Leonard RT, Jr., Epstein ES, et al. The current role of laser/light sources in the treatment of male and female pattern hair loss. J Cosmet Laser Ther. 2007 Mar;9(1):27-8.
Rose PT. The latest innovations in hair transplantation. Facial Plast Surg. 2011 Aug;27(4):366-77.
McElwee KJ, Kissling S, Wenzel E, et al. Cultured peribulbar dermal sheath cells can induce hair follicle development and contribute to the dermal sheath and dermal papilla. J Invest Dermatol. 2003 Dec;121(6):1267-75.
Takikawa M, Nakamura S, Nakamura S, et al. Enhanced effect of platelet-rich plasma containing a new carrier on hair growth. Dermatol Surg. 2011 Dec; 37(12):1721-9.
Rogers NE, Avram MR. Medical treatments for male and female pattern hair loss. J Am Acad Dermatol. 2008 Oct;59(4):547-66.

Management of Hirsutism

STL Volume 14 Number 7 — Tue, 01 Sep 2009 19:00:33 +0000

A. Alsantali, MD and J. Shapiro, MD, FRCPC

Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

ABSTRACT
Hirsutism is a relatively common condition affecting about 5%-10% of women of childbearing age. Herein, we present an overview of hirsutism with emphasis on its etiology and therapeutic options.

Key Words:
antiandrogens, hirsutism, insulin-sensitizing agents, oral contraceptives, PCOS, polycystic ovary syndrome

Hirsutism is defined as excessive terminal hair growth in women, which has a typical male pattern distribution. It should be differentiated from hypertrichosis, a generalized excessive hair growth that may be hereditary or result from some drugs, such as cyclosporine. Hirsutism is a relatively common disorder that affects about 5%-10% of women of reproductive age.¹ Unwanted hair growth can be associated with significant psychosocial consequences that negatively affect patients’ quality of life.

Causes

More than 70% of hirsutism is caused by polycystic ovary syndrome (PCOS).² PCOS is the most common endocrinopathy in females, affecting 5%-10% of women of childbearing age.² According to the Rotterdam criteria for diagnosis of PCOS,³ the diagnosis could be achieved if 2 of the following 3 criteria are present:

Oligo- or anovulation (menstrual cycles longer than 35 days or fewer than 10 menses a year).
Clinical (hirsutism, acne, androgenetic alopecia) or biochemical evidence of hyperandrogenism.
Polycystic ovaries (=12 follicles in each ovary measuring 2-9mm in diameter and/or increased ovarian volume to >10ml) on ultrasound examination.

Other less common causes include idiopathic hirsutism (i.e., with no other clinical or biochemical abnormalities) (23%), nonclassic adrenal hyperplasia (4.3%), ovarian or adrenal androgen secreting tumors (0.2%), Cushing’s syndrome, acromegaly, hyperprolactinemia, and drugs.

Diagnostic Approach

Clinical history, thorough physical examination and laboratory investigations can be crucial in the correct evaluation of hirsutism. The history should include the onset and progression of hirsutism, the pattern of menstruation, weight gain, and the use of androgenic drugs, such as anabolic and androgenic steroids, and valproic acid.

A rapid progression of hirsutism and evidence of virilization (e.g., clitoromegaly, an increase in muscle mass, and a deepening of the voice) can be noted with rare androgen secreting tumors.

The severity of hirsutism can be measured objectively using the Ferriman-Gallwey hirsutism scoring system.⁴ A score of 8 or more has been used to define the presence of hirsutism. As the response of a pilosebaceous follicle to androgen varies considerably, the hirsutism score does not correlate well with the androgen level.

A thorough abdominal and pelvic examination may rarely show a palpable ovarian mass.

According to the Endocrine Society Clinical Practice Guidelines,⁵ testing for androgen is recommended in women with moderate-to-severe hirsutism or hirsutism of any degree when it is associated with any of the following: sudden onset, rapid progression menstrual irregularity, infertility, central obesity, clitoromegaly, or acanthosis nigricans. The initial tests for hirsutism should include early morning plasma total testosterone and free testosterone. If testosterone levels are more than 1.5-2 times the upper normal limit, or if a history of rapid virilization is found, dehydroepiandrosterone sulphate (DHEA-S) and androstenedione should be measured to identify an adrenal or ovarian source of hyperandrogenemia.

In patients with a positive family history of congenital adrenal hyperplasia or in members of high risk ethnic groups such as Ashkenazi Jews, Hispanics, and Slavics, measurement of an early morning follicular phase level of 17-hydroxyprogesterone is recommended.
If there are features of Cushing’s syndrome, thyroid dysfunction, acromegaly or hyperprolactinemia, an endocrine workup should be carried out accordingly. Transvaginal ultrasonographic imaging of the ovaries is recommended for patients with either menstrual disturbances or clinical or biochemical hyperandrogenism.

Treatment

The therapeutic options of hirsutism can be divided into systemic, topical, and dermato-cosmetic therapies. Patients should be informed that the response to systemic agents is slow; occurring over 3-6 months after therapy has begun.

Systemic Treatment

Oral Contraceptives

Oral contraceptive (OC) agents are considered to be the first-line therapy for hirsutism in premenopausal women.⁵ This treatment option has the advantage of regulating the menstrual cycle and providing contraception. Oral contraceptive pills commonly contain ethinyl estradiol (EE), in combination with a progestin. The most androgenic progestins are norgestrel and levonorgestrel, whereas the least androgenic progestins are norgestimate and desogestrel. Other progestins, such as cyproterone acetate and drospirenone, work as androgen receptor antagonists. The recommended OC includes a combination of EE with either 2mg of cyproterone acetate (Diane-35®, Schering) or 3mg drospirenone (Yasmin®, Bayer Healthcare).

The mechanisms by which OCs improve hirsutism include the suppression of luteinizing hormone secretion, resulting in the inhibition of ovarian androgen biosynthesis, stimulation of sex hormone binding globulin production (effectively decreasing serum free androgen concentrations), and a mild reduction in adrenal androgen synthesis. OCs should not be prescribed to women with a history of venous thrombosis.

Antiandrogens

Spironolactone (Aldactone®, Pfizer), an aldosterone antagonist, has several actions including inhibition of the androgen receptor, suppression of adrenal androgen biosynthesis, and inhibition of the 5á-reductase enzyme. A recent Cochrane review of trials comparing spironolactone 100mg/d with placebo showed a significant subjective improvement in hair growth (odds ratio 7.18, 95% confidence interval [CI] 1.96 to 26.28). The Ferriman-Gallwey score, however, did not validate these findings (weighted mean difference 7.20, 95% CI -10.98 to -3.42).6 Spironolactone is generally well tolerated with few side-effects, such as menorrhagia, lethargy and stomach upset. A clinically significant hypotension and increased serum potassium levels are rare if spironolactone has been used at doses of 100mg/day. In the first months of treatment, measurements of blood pressure and serum potassium levels every 4 weeks are recommended. Spironolactone should not be prescribed to patients with renal insufficiency or hyperkalemia. As spironolactone usually causes feminization of the male fetus as well as menstrual alterations, it is best to add oral contraceptive pills.

Cyproterone acetate (CA) is a progestin with antiandrogenic activity that interferes with the binding of dihydrotestosterone to the androgen receptor and inhibits the secretion of gonadotropin, thereby reducing ovarian and adrenal androgen production. CA (2mg) combined with EE has been shown to be more effective than placebo, but not better than other antiandrogens.7 A small randomized controlled study⁸ showed that CA when combined with EE at a dosage of 0.01mg/d for the first week, 0.02mg/d for the second week, 0.01mg/d for the third week, followed by a pause of 7 days, and 12.5mg CA/d added during the first 10 days of every month for 12 months seems to be the most effective treatment to reduce the hirsutism score when compared with flutamide 250mg/d, finasteride 5mg/d, and ketoconazole 300mg/d. The recommended dose is 12.5-100mg/d added to the first 10 days of each calendar pack of oral contraceptives. Side-effects of CA include weigh gain, loss of libido, depression, headache, mastodynia, and feminization of the male fetus.

Flutamide is a pure nonsteroidal antiandrogen that acts as an androgen receptor blocker. Studies have shown that flutamide 250-500mg/d is more effective than finasteride⁹ and triptorelin,¹⁰ a long acting gonadotropin-releasing hormone antognist. A systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the efficacy of different antiandrogens for the treatment of hirsutism reported that when compared with metformin, flutamide reduced the hirsutism score by 5 (95% CI 3.0-7.0; I²=0%). Spironolactone reduced the score by 1.3 (95% CI 0.03-2.6).¹¹ Due to its propensity for severe hepatotoxicity, which is occasionally fatal, flutamide should not be used as first-line therapy for hirsutism.

Finasteride is a potent inhibitor of the type 2 isoenzyme of 5-á-reductase, which blocks the conversion of testosterone to 5-á-dihydrotestosterone. Finasteride has been shown to lower hirsutism scores by 30%-60% in addition to reducing the average hair diameter.¹² In comparative studies, finasteride demonstrated efficacy similar to that of other antiandrogens with fewer adverse effects.¹³ Other trials suggested that spironolactone and flutamide were more effective than finasteride.^14,15 In women with hirsutism, finasteride is used in doses of 2.5-7.5mg/d. Doses of 2.5mg and 5mg seem to be equally effective.¹⁶ As with the other antiandrogens, the use of finasteride requires a reliable method of contraception in order to avoid a pregnancy given the potential risk of feminization of the male fetus.

Insulin-Sensitizing Drugs

Metformin lowers hepatic glucose production and decreases insulin levels. Thiazolidinediones (rosiglitazone and pioglitazone) sensitize end organs to insulin through their action on the peroxisome-proliferator-activated receptor-ã. Meta-analyses of RCTs of insulin sensitizers for the treatment of hirsutism concluded that insulin sensitizers provide limited or no improvement for women with hirsutism.¹⁷

Gonadotropin-Releasing Hormone (GnRH) Agonists

GnRH agonists suppress luteinizing hormone, and to a lesser degree follicle stimulating hormone secretion, leading to a decline in ovarian androgen production. GnRH agonist therapy seems to have no therapeutic advantage over OC and antiandrogens.^18,19 As GnRH agonist therapy is expensive, requires injections, and estrogen needs to be added to the therapy, its use should be reserved for severe forms of hyperandrogenemia, such as patients with ovarian hyperthecosis who have a suboptimal response to OCs and antiandrogens.

Glucocorticoids

Glucocorticoids can be prescribed to women who:

have hirsutism that is due to nonclassic congenital adrenal hyperplasia
have a suboptimal response to OCs and/or antiandrogens
exhibit poor tolerance to OCs
are seeking ovulation induction.

Topical Treatment

Eflornithine hydrochloride cream 13.9% (Vaniqa®, Skin Mediea) has been approved by the US FDA for the reduction of unwanted facial hair in women. Noticeable results take about 6-8 weeks. Adverse effects include itching and skin dryness.

Direct Hair Removal Methods

A wide range of hair removal methods have been advocated over the years with varying degrees of success. These modalities can be divided into temporary methods of hair removal and permanent methods of hair reduction. Temporary methods of hair removal include plucking, waxing, shaving and chemical depilatory agents. Although not a method of hair removal, bleaching serves to lighten the color of the external hair shafts so that they are less noticeable. Permanent methods of hair reduction include photoepilation (using laser and intense pulse light [IPL]) and electrolysis. Photoepilation seems to be superior to the conventional methods, such as shaving, waxing and electrolysis. A Cochrane review of photoepilation of unwanted hair growth showed that alexandrite and diode lasers are more effective, whereas little evidence was obtained for the effect from IPL, Nd:YAG, or ruby lasers.²⁰ However, some longer wavelength lasers (Nd:YAG), or IPL, appear to provide benefits in patients who have darker skin types and therefore have less risk of burning and dyspigmentation. Paradoxical hypertrichosis is a possible, but rare, adverse effect of photoepilation, particularly in dark-skinned individuals.^21,22

Conclusion

Hirsutism is usually a benign, but extremely distressing condition. Although several treatment options exist, we recommend the use of OCs with antiandrogenic activity as first-line therapy for the majority of premenopausal women. An antiandrogen can be added if the response to OCs is suboptimal after 6 months of use. Laser/photoepilation are the preferred direct hair removal methods. Logical combinations tailored to the individual clinical profile can accomplish the best results in most patients.

References

Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 352(12):1223-36 (2005 Mar).
Carmina E, Rosato F, Janni A, et al. Extensive clinical experience: relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism. J Clin Endocrinol Metab 91(1):2-6 (2006 Jan).
Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 19(1):41-7 (2004 Jan).
Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 21:1440-7 (1961).
Martin KA, Chang RJ, Ehrmann DA, et al. Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93(4):1105-20 (2008 Apr).
Brown J, Farquhar C, Lee O, et al. Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. Cochrane Database Syst Rev (2):CD000194 (2009 Apr).
Van der Spuy ZM, le Roux PA. Cyproterone acetate for hirsutism. Cochrane Database Syst Rev (4):CD001125 (2003).
Venturoli S, Marescalchi O, Colombo FM, et al. A prospective randomized trial comparing low dose flutamide, finasteride, ketoconazole, and cyproterone acetate-estrogen regimens in the treatment of hirsutism. J Clin Endocrinol Metab 84(4):1304-10 (1999 Apr).
Falsetti L, Gambera A, Legrenzi L, et al. Comparison of finasteride versus flutamide in the treatment of hirsutism. Eur J Endocrinol 141(4):361-7 (1999 Oct).
Pazos F, Escobar-Morreale HF, Balsa J, et al. Prospective randomized study comparing the long-acting gonadotropin-releasing hormone agonist triptorelin, flutamide, and cyproterone acetate, used in combination with an oral contraceptive, in the treatment of hirsutism. Fertil Steril 71(1):122-8 (1999 Jan).
Swiglo BA, Cosma M, Flynn DN, et al. Clinical review: antiandrogens for the treatment of hirsutism: a systematic review and meta-analyses of randomized controlled trials. J Clin Endocrinol Metab 93(4):1153-60 (2008 Apr).
Townsend KA, Marlowe KF. Relative safety and efficacy of finasteride for treatment of hirsutism. Ann Pharmacother 38(6):1070-3 (2004 Jun).
Wong IL, Morris RS, Chang L, et al. A prospective randomized trial comparing finasteride to spironolactone in the treatment of hirsute women. J Clin Endocrinol Metab 80(1):233-8 (1995 Jan).
Erenus M, Yucelten D, Durmusoglu F, et al. Comparison of finasteride versus spironolactone in the treatment of idiopathic hirsutism. Fertil Steril 68(6):1000-3 (1997 Dec).
Unluhizarci K, Ozel D, Tanriverdi F, et al. A comparison between finasteride, flutamide, and finasteride plus flutamide combination in the treatment of hirsutism. J Endocrinol Invest 32(1):37-40 (2009 Jan).
Bayram F, Müderris II, Güven M, et al. Comparison of high-dose finasteride (5 mg/day) versus low-dose finasteride (2.5 mg/day) in the treatment of hirsutism. Eur J Endocrinol 147(4):467-71 (2002 Oct).
Cosma M, Swiglo BA, Flynn DN, et al. Clinical review: insulin sensitizers for the treatment of hirsutism: a systematic review and meta-analyses of randomized controlled trials. J Clin Endocrinol Metab 93(4):1135-42 (2008 Apr).
Heiner JS, Greendale GA, Kawakami AK, et al. Comparison of a gonadotropin-releasing hormone agonist and a low dose oral contraceptive given alone or together in the treatment of hirsutism. J Clin Endocrinol Metab 80(12):3412-8 (1995 Dec).
Carmina E, Lobo RA. Gonadotrophin-releasing hormone agonist therapy for hirsutism is as effective as high dose cyproterone acetate but results in a longer remission. Hum Reprod 12(4):663-6 (1997 Apr).
Haedersdal M, Gotzsche PC. Laser and photoepilation for unwanted hair growth. Cochrane Database Syst Rev (4):CD004684 (2006 Oct).
Alajlan A, Shapiro J, Rivers JK, et al. Paradoxical hypertrichosis after laser epilation. J Am Acad Dermatol 53(1):85-8 (2005 Jul).
Radmanesh M. Paradoxical hypertrichosis and terminal hair change after intense pulsed light hair removal therapy. J Dermatolog Treat 20(1):52-4 (2009).

Treatments for Unwanted Facial Hair

STL Volume 10 Number 10 — Thu, 01 Dec 2005 23:00:37 +0000

J. Shapiro, MD, FRCPC and H. Lui, MD, FRCPC

Hair Research and Treatment Centre, and Division of Dermatology, University of British Columbia, Vancouver, British Columbia, Canada

ABSTRACT

Twenty-two percent of women in North America have unwanted facial hair, which can cause embarrassment and result in a significant emotional burden. Treatment options include plucking, waxing (including the sugar forms), depilatories, bleaching, shaving, electrolysis, laser, intense pulsed light (IPL), and eflornithine 13.9% cream (Vaniqa®, Barrier Therapeutics in Canada and Shire Pharmaceuticals elsewhere). Eflornithine 13.9% cream is a topical treatment that does not remove the hairs, but acts to reduce the rate of growth and appears to be effective for unwanted facial hair on the mustache and chin area. Eflornithine 13.9% cream can be used in combination with other treatments such as lasers and IPL to give the patient the best chance for successful hair removal.

Key Words:
eflornithine, unwanted facial hair, hair removal

Unwanted facial hair (UFH) in women is a common problem, and is most often a result of ethnic background or heredity. In a small percentage of women, it may be caused by androgen overproduction, increased sensitivity to circulating androgens, or other metabolic and endocrine disorders. Approximately 22% of women are affected by the presence of UFH growth on the mustache and chin area, and this can be a source of distress, leading to anxiety, depression and a reduced quality of life.¹

It is very important to determine the underlying causes. Most are ethnic or hereditary; however, one must rule out any signs of androgen excess, e.g., an increase in body hair, irregular menstrual cycles, acne, alopecia, and seborrhea.

Polycystic Ovary Syndrome (PCOS) is the most common cause of androgen excess, and 70%-80% of patients with androgen excess demonstrate hirsutism, though this sign may be less prevalent among women of Asian extraction. There is a strong familial predilection for hirsutism, primarily because the underlying endocrine disorders in this population and the factors regulating the development of hair growth have a strong genetic component.²

Patients should be adequately advised of the available treatment modalities for hair removal. No single method of hair removal is appropriate for all body locations or patients, and the one adopted will depend on the character, area and amount of hair growth, as well as on the patient’s age and their personal preference.³

Technique	Body Area	Advantages	Disadvantages
Plucking	Face Eyebrows Bikini area	Inexpensive Regrowth can take weeks	Painful Slow
Waxing	Face Eyebrows Groin Trunk Extremities	Regrowth can take weeks	Painful Slow Risk of folliculitis
Depilatories	Extremities Groin Face	Quick	Can be irritating Regrowth in days
Shaving	All areas	Easy Inexpensive	Quick regrowth Risk of folliculitis Time consuming
Electrolysis	All areas, but usually the face	May give permanent removal	Painful Repeat treatments needed Very time consuming Expensive Risk of scarring and skin pigment changes
Laser and Intense Pulsed Light (IPL)	All areas	May give permanent hair reduction Efficient	Painful Repeat treatments needed Dark hair required Expensive Risk of scarring and skin pigment changes Rare reports of paradoxical hypertrichosis⁵
Eflornithine 13.9% cream	Face Neck	On stopping, regrowth can take 2 months Minimal adverse effects Can be used in conjunction with other treatments	Must be continued indefinitely to prevent regrowth
Antiandrogens and oral contraceptives	Inhibits androgen driven hair in all areas		Takes months to show benefit Some adverse effects Long-term treatment required
Table 1: Advantages and disadvantages of hair removal techniques

Treatment options for removing excess facial hair are limited and can vary in effectiveness, the degree of discomfort, and cost. Current methods for removing this unwanted hair include such over-the-counter methods as plucking, waxing (including the sugar forms), depilatories, shaving, and home electrolysis. Hair removal methods that could take place in a doctor’s office include laser, and intense pulsed light (IPL). An additional modality is a topical cream that inhibits hair growth: eflornithine 13.9% cream (Vaniqa®, Barrier Therapeutics in Canada and Shire Pharmaceuticals elsewhere).¹

These methods are temporary with the time of regrowth ranging from a few days to a few months. For hirsutism associated with PCOS, treatments include oral contraceptives and/or antiandrogens, such as spironolactone, cyproterone acetate, flutamide and finasteride.⁴

Eflornithine HCl 13.9% Cream

Eflornithine HCl 13.9% cream is an irreversible inhibitor of ornithine decarboxylase, an enzyme that has been associated with the prolongation of the anagen or growth phase of the hair.⁶ Consequently, it reduces the rate of hair growth for all hairs. It appears to be effective regardless of whether the unwanted facial hair is hereditary or is due to medical conditions such as an androgen excess disorder, e.g., PCOS. After 24 weeks of treatment in clinical trials, it was shown to be effective on the chin and upper lip.⁷

Eflornithine, also known as difluoromethylornithine or DFMO, was synthesized in the 1970s as a potential anticancer drug. In 1980, Bacchi, et al. reported that this drug was effective in the treatment of African trypanosomiasis in a mouse model,⁸ and this finding later led to clinical studies in humans. In 1990, the US FDA granted marketing approval and orphan drug status for eflornithine to treat this disease. Clinical observations identified hair loss as a side-effect of eflornithine therapy and led to the development of Vaniqa®, which gained US regulatory approval in July 2001, as the first and only prescription cream clinically proven to slow the growth of unwanted facial hair in women.⁹

Pharmacokinetics

In an open-label, multiple-dose study of 10 women with excessive facial hair, Malhotra, et al. determined percutaneous absorption and the pharmacokinetics of eflornithine following topical treatment with eflornithine HCl 13.9% cream. The mean percutaneous absorption was minimal and most of what was absorbed was excreted unchanged in the urine without being metabolized by the body. The steady-state peak serum concentration was < 10.44ng/ml. Trough plasma concentrations reached steady state (4.61-5.5ng/ml) after 4 days of twice-daily topical treatment. Multiple dosing had no apparent effect on disposition kinetics.¹⁰

Combination Therapy

It is a common misconception that eflornithine 13.9% cream competes with other methods of hair removal and therefore should not be used in combination with them, particularly laser and IPL treatments. However, that is not the case. Eflornithine 13.9% cream can slow hair growth and may reduce the frequency of the need for hair removal by other means.^11,12 It is also useful in treating hair that is unresponsive to laser therapy, such as white or vellus hairs.

Studies have shown that the two processes can be started simultaneously, and eflornithine treatment can continue right through laser treatments.¹
According to Azziz,² treatment should be undertaken using combination therapy, to possibly include:

hormonal suppression, e.g., oral contraceptives, long-acting gonadotropin-releasing hormonal analogues and insulin sensitizers
peripheral androgen blockade, e.g., spironolactone, cyproterone acetate, flutamide, or finasteride
mechanical/cosmetic amelioration and destruction of the unwanted hairs, e.g., electrolysis, lasers, IPL, depilatories, shaving, waxing
application of eflornithine 13.9% topical cream.

Adverse Events for Eflornithine

Skin-related side-effects such as stinging, burning and tingling are seen occasionally, particularly when eflornithine is applied to broken or abraded skin.13 Eflornithine offers a low degree of percutaneous absorption and low systemic exposure to eflornithine, offering a favorable clinical safety profile with minimal side-effects.^11,14 This drug is classified as a pregnancy category C agent, so risk to the fetus cannot be ruled out.

Patient Communication

The results of therapy may not always be satisfactory, so it is very important to advise the patient of the available treatment modalities for temporary or permanent hair reduction. No single method is appropriate for all body locations or patients. The one adopted will depend on the character, area and amount of hair growth as well as on the patient’s age and personal preferences.

Conclusion

Unwanted facial hair can cause embarrassment and lead to anxiety and depression. There are a limited number of treatments available that vary in efficacy, degree of discomfort, and cost. Eflornithine 13.9% cream, by itself or in combination with other treatments, has been shown to be effective for the treatment of UFH. Future experience will dictate the most effective niche for Vaniqa® within this family of treatments.

An adaptation of this article was recently published in Skin Therapy Letter – Family Practice Edition 1(2):6-7.

References

Dawber RP. Guidance for the management of hirsutism. Curr Med Res Opin 21(8):1227-34 (2005 Aug).
Azziz R. The evaluation and management of hirsutism. Obstet Gynecol 101 (5 Pat 1):995-1007 (2003 May).
Trueb RM. Causes and management of hypertrichosis. Am J Clin Dermatol 3(9):617-27 (2002).
Archer JS, Chang RJ. Hirsutism and acne in polysystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 18(5):737-54 (2004 Oct).
Alajlan A, Shapiro J, Rivers JK, MacDonald N, Wiggin J, Lui H. Paradoxical hypertrichosis after laser epilation. J Am Acad Dermatol 53(1):85-8 (2005 Jul).
Hynd PI, Nancarrow MJ. Inhibition of polyamine synthesis alters hair follicle function and fiber composition. J Invest Dermatol 106(2):249-53 (1996 Feb).
Hickman JG, Huber F, Palmisano M. Human dermal safety studies with eflornithine HCL 13.9% cream (Vaniqa), a novel treatment for excessive facial hair. Curr Med Res Opin 16(4):235-44 (2001).
Coyne PE. The eflornithine story. J Amer Acad Dermatol 45(5):784-6 (2001 Nov).
Pepin J, Milord F, Guern C, Schechter PH, Difluoromethylornithine for arseno-resistant Trypanosome brucei gambiense sleeping sickness. Lancet 2:1431-3 (1987).
Malhotra B, Noveck R. Behr D, Palmisano M. Percutaneous absorption, and pharmacokinetics of eflornithine HCl 13.9% cream in women with unwanted facial hair. J Clin Pharmacol 41(9):972-8 (2001 Sep).
Tan E, Hamzavi I, Shapiro J, Lui H. Combined treatment with laser and topical eflornithine is more effective than laser treatment alone for removing unwanted facial hair – a placebo controlled trial. Presented at: The 4th Intercontinental Meeting of Hair Research Societies; June 17-19, 2004; Berlin, Germany. Abstract #P10.144.
Smith SR, Piacquadio D, Beger B. A randomized, double-blind, vehicle controlled, bilateral comparison study of the efficacy and safety of eflornithine HCl 13.9% cream in combination with laser in the treatment of unwanted facial hair in women. Presented at: The 61st Annual Meeting of the American Academy of Dermatology; March 21-26, 2003; San Francisco, CA. Abstract #P649.
Shapiro J, Lui H. Vaniqa – Eflornithine 13.9% Cream. Skin Therapy Lett 6(7):1-2,5 (2001 Apr).
Shenenberger DW, Utecht LM. Removal of unwanted facial hair. Am Fam Physician 66(10):1907-11 (2002 Nov).

Excessive Facial Hair

STL FP Volume 1 Number 2 — Sat, 01 Oct 2005 22:56:07 +0000

J. Shapiro, MD, FRCPC and H. Lui, MD, FRCPC

Hair Research and Treatment Centre, and Division of Dermatology, University of British Columbia, Vancouver, British Columbia, Canada

Hirsutism

Excessive facial hair in women, or hirsutism, is a common problem that may be caused by androgen overproduction, increased sensitivity to circulating androgens, or other metabolic and endocrine disorders. Approximately 80% of women are affected by the presence of
excessive hair growth in areas usually recognized as places where male secondary sexual characteristics occur. This can be a source of distress, leading to anxiety, depression and a reduced quality of life.

Differential Diagnosis

It is very important to determine the etiology of this condition. Diagnostic evaluation of the potentially hirsute patient first involves confirmation of the presence of hirsutism and then exclusion of associated or etiological abnormalities and disorders. Investigate or rule
out underlying conditions that produce excess androgens using tests such as:

Serum testosterone
Serum DHEA (Dehydroepiandrosterone)
Rule out testosterone secreting tumors.

Hair Removal Techniques

Technique	Body Area	Advantages	Disadvantages
Plucking	Face Eyebrows	Inexpensive Regrowth can take weeks	Painful Slow
Waxing	Face Eyebrows Groin Trunk	Regrowth can take weeks	Painful Slow Risk of folliculitis
Depilatories	Extremities Groin Face	Quick	Can be irritating Regrowth in days
Shaving	All areas	Easy Inexpensive	Quick regrowth Risk of folliculitis Time consuming
Electrolysis	All areas, but usually the face	May give permanent removal	Painful Very time consuming Expensive Risk of scarring and skin pigment changes
Laser and Intense Pulsed Light (IPL)	All areas	May give permanent hair reduction Efficient	Painful Repeat treatments needed Dark hair required Expensive Risk of scarring and skin pigment changes Rare reports of paradoxical hypertrichosis [Alajlan A, et al. J Am Acad Dermatol 53(1):85-8 (2005 Jul).]
Eflornithine 13.9% cream	Face Neck	Regrowth can take weeks Minimal adverse effects Can be used in conjunction with other treatments	Must be continued indefinitely to prevent regrowth
Antiandrogens and oral contraceptives	Inhibits androgen		Takes months to show benefit Some adverse effects
Table 1: Methods for removing unwanted hair

Treatment Options

Current methods for removing unwanted hair include plucking, waxing (including the sugar forms), depilatories, shaving, electrolysis, laser, intense pulsed light (IPL), and eflornithine 13.9% cream. All these methods are temporary with the time of regrowth ranging from a few days to a few months. Short of surgical removal of the hair follicle, the only permanent treatment is electrolysis. However, the practice of electrolysis lacks standardization. For hirsutism associated with Polycystic Ovary Syndrome (PCOS), treatments include oral contraceptive pills or antiandrogens, such as spironolactone, flutamide and finasteride.

Patients should be adequately advised of the available treatment modalities for hair removal. No single method of hair removal is appropriate for all body locations or patients, and the one adopted will depend on the character, area and amount of hair growth as well as on the age of the patient and their personal preference.

Women and Hirsutism

Women who have hirsutism will need to be evaluated to rule out causes of elevated androgens. PCOS needs to be excluded if there are suspicious clinical features. Medications such as spironolactone and oral contraceptives, e.g., cyproterone acetate + ethinyl estradiol, can be of value.

Ornithine Decarboxylase (ODC)

ODC is an enzyme that has been associated with the prolongation of the anagen or growth phase of the hair. Thus, when ODC is decreased, the length of time the hair is in the growth phase is also reduced.

Eflornithine HCl 13.9%, rather than removing the hair, is an irreversible inhibitor of ODC, thus it reduces the rate of hair growth. It appears to be effective regardless of whether the unwanted facial hair is hereditary or whether it is due to medical conditions such as an androgen excess disorder, e.g., PCOS.

Combination Therapy

Eflornithine 13.9% cream can slow hair growth and thus reduce the frequency of the need for hair removal by other means, such as lasers and IPL treatments. Studies have shown that the two processes can be started simultaneously, and eflornithine treatment can continue right through laser treatments. [Dawber RP. Curr Med Res Opin 21(8):1227-34 (2005 Aug).] Treatment should be undertaken using combination therapy to possibly include:

hormonal suppression, e.g., oral contraceptives, long-acting gonadotropin-releasing hormonal analogues and insulin sensitizers
peripheral androgen blockade, e.g., spironolactone, flutamide, cyproterone acetate or finasteride
mechanical/cosmetic amelioration and destruction of the unwanted hairs, e.g., electrolysis, lasers, IPL, depilatories, shaving, waxing, etc.
application of eflornithine 13.9% topical cream.[Azziz R. Obstet Gynecol 101 (5 Pat 1):995-1007 (2003 May).]

Paradoxical hypertrichosis has, however, been reported in a small number of patients receiving laser or IPL treatment for excess hair
removal. [Alajlan A, et al. J Am Acad Dermatol 53(1):85-8 (2005 Jul).]

Conclusion

Hirsutism can cause embarrassment and lead to anxiety and depression. There are a limited number of treatments available that vary in efficacy, degree of discomfort and cost. It is very important to make sure that the patient is aware of all the available treatment modalities, since no one method is effective for all patients or body locations, and results from therapy may not always be satisfactory.

This article has been adapted from an article by Drs. Shapiro and Lui to be published in the November 2005 issue of Skin Therapy Letter®.

Once Daily Application of a Combination of Calcipotriol and Betamethasone Dipropionate (Dovobet®, Daivobet®) for the Treatment of Psoriasis

STL Volume 8 Number 7 — Mon, 01 Dec 2003 22:56:56 +0000

H. Lui, MD FRCPC, J. Shapiro, MD, FRCPC

Psoriasis Phototherapy Centre, Division of Dermatology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada

ABSTRACT

This new compound product containing 50µg/gm calcipotriol and 0.5mg/gm betamethasone dipropionate was recently introduced in Canada for the treatment of psoriasis. Clinical trials demonstrated that this compound was more active than either agent used alone. Recent changes in the product monograph involving the reduction in dose to once daily use has raised questions about the relevance of some previous comparisons of twice daily Dovobet*. Pooling the available data from 5,500 patients in clinical trials for Dovobet* will allow an inter-trial comparison of the various treatment arms, demonstrating that Dovobet*, when applied once daily is significantly more effective than with twice daily applications of either its individual components used alone.

Key Words: psoriasis, calcipotriol,betamethasone dipropionate

Calcipotriol and corticosteroids are both established treatments for psoriasis.¹ Recently, studies have reported that combination therapy applied twice daily with 50µg/gm calcipotriol and 0.5mg/gm betamethasone dipropionate (Dovobet*, LEO Pharma) is significantly more effective than either monotherapy with each component or the vehicle.^2-4 In Europe, this product is marketed as Daivobet®.

Once-Daily Dovobet*

In an international, multicenter, prospective, randomized, double-blind, vehicle-controlled, parallel group, 4 week study, Guenther, et al, demonstrated that there was no statistically significant difference in the mean percentage change in the Psoriasis Area and Severity Index (PASI) from baseline to end of treatment between once daily vs. twice daily use of this compound (-5.4%, p=0.052).⁵ There are a number of advantages for reducing the applications to once-daily from twice daily, including reduced cost to the patient, and improved patient compliance. However, the most important is the need to reduce long-term exposure to steroids for psoriasis patients. The irreversible side-effects and tachyphylaxis that are associated with topical steroids should be avoided whenever other proven and safer alternatives exist, since psoriatic patients often self medicate for long periods of time without physician supervision and monitoring.

A recent change in the product monograph involving the reduction in dose to once daily use, raises questions about the relevance of some previous studies that compared twice daily Dovobet* to twice daily use of calcipotriol (Dovonex®, LEO Pharma) or betamethasone dipropionate (Diprosone®, LEO Pharma).⁶ These trials all explored the use of Dovobet* for treating large numbers of adult patients with psoriasis. All studies involved the maximal use of 100gm of ointment per week for 4 weeks, had virtually identical inclusion/exclusion criteria, and assessed patients on the basis of the percentage reduction in their Psoriasis Area and Severity Index (PASI) scores. In most cases, a similar group of investigators and site staff was used in the various trials. Together, these factors suggest that a pooling of data to allow the inter-trial comparison of various treatment arms will yield reliable results (see Tables 1 and 2 for meta-analyses of the data).

Comparators	n	Mean % decrease from baseline at week 4
Dovobet*, once daily	1285	69.7 ± 24.3
Betamethasone dipropionate, twice daily	362	61.3 ± 27.9
Calcipotriol, twice daily	919	56.1 ± 27.9

Table 1: Pooled results used to compare once daily Dovobet* with twice daily monotherapies.⁶

The mean difference between treatment groups is provided in Table 2, along with their 95% Confidence Intervals. In both comparisons, the once daily use of Dovobet* demonstrates statistically significant improvement over the twice daily marketed comparator product.

Comparators	Mean % Difference in PASI reduction	95% Confidence Interval	p-value
Dovobet*, q.d. vs. betamethasone dipropionate, b.i.d.	-8.4	-11.3 to -5.4	<0.001
Dovobet*, q.d. vs. calcipotriol, b.i.d.	-14.4	-17.3 to-11.4	<0.001

Table 2: Mean differences between treatment groups.⁶

Treatment Regimen

One potential treatment approach for using Dovobet* and Dovonex® to treat psoriasis includes “jump starting” the patient with once-daily Dovobet*, followed by a gradual transition within 4 weeks to Dovonex® or emollients for maintenance. Dovobet* can subsequently be reintroduced on weekends as an intermittent pulse therapy when partial relapse or flares occur.

Side-effects

All trials using the twice daily application of Dovobet* demonstrated fewer reported side-effects than with calcipotriol alone.⁷ Once daily applications mean that patients have less exposure to the drugs and presumably less chance developing side-effects, especially those associated with steroids.

Conclusion

Dovobet*, when applied only once daily, is as effective as twice daily applications, and significantly more effective than twice daily applications of calcipotriol or betamethasone dipropionate. In addition, the once-daily application of a single combination ointment is more patient-friendly and likely to encourage compliance.

* registered trademark of LEO Pharmaceutical Products used under the license by LEO Pharma Inc., Thornhill, Ontario, Canada.

References

Greaves MW, Weinstein, GD. Treatment of psoriasis. N Engl J Med 1995 Mar; 332(9):581-8.
van Rossum MM, van Erp PE, van de Kerkhof PC. Treatment of psoriasis with a new combination of calcipotriol and betamethasone dipropionate: a flow cytometric study. Dermatology 203(2):148-52 (2001).
Douglas WS, Poulin Y, Decroix J, et al. A new calcipotriol/betamethasone formulation with rapid onset of action was superior to monotherapy with betamethasone dipropionate for calcipotriol in psoriasis vulgaris. Acta Derm Venereol 82:131-5 (2002).
Guenther L, van de Kerkhof PC, Snellman E, et al. Efficacy and safety of a new combination of calcipotriol and betamethasone dipropionate (once or twice daily) compared to calcipotriol (twice daily) in the treatment of psoriasis vulgaris: a randomized, double-blind, vehicle-controlled clinical trial. Br J Dermatol 147(2):316-23 (2002 Aug).
Guenther L, Cambazard F, Van De Kerkhof PGM, et al. Efficacy and safety of a new combination of calcipotriol and betamethasone dipropionate (once or twice daily) compared to calcipotriol (twice daily) in the treatment of psoriasis vulgaris: a randomized, double-blind, vehicle-controlled clinical trial. Br J Dermatol 147:316-23 (2002).
Data on file, LEO Pharma.
Poulin Y. Calcipotriol and betamethasone dipropionate (Dovobet*, Daivobet®): A new formulation for the treatment of psoriasis. Skin Therapy Lett 7(6):1-3 (2002 Jun).

Vaniqa – Eflornithine 13.9% Cream

STL Volume 6 Number 7 — Sun, 01 Apr 2001 21:07:23 +0000

J. Shapiro, MD, FRCPC and H. Lui, MD, FRCPC

Hair Research and Treatment Centre, and Division of Dermatology, University of British Columbia, Vancouver, British Columbia, Canada

ABSTRACT

Eflornithine HCl 13.9% cream is the first topical prescription treatment to be approved by the US FDA for the reduction of unwanted facial hair in women. It irreversibly inhibits ornithine decarboxylase (ODC), an enzyme that catalyzes the ratelimiting step for follicular polyamine synthesis, which is necessary for hair growth. In clinical trials eflornithine cream slowed the growth of unwanted facial hair in up to 60% of women. Improvement occurs gradually over a period of 4–8 weeks or longer. Most reported adverse reactions consisted of minor skin irritation.

Key Words:
eflornithine, ornithine decarboxylase inhibitor, reduction of unwanted facial hair in women

The first topical prescription treatment for the reduction of unwanted facial hair in women, eflornithine HCl 13.9% cream (Vaniqa, Bristol-Myers Squibb), was approved by the US FDA in August 2000. This product is an irreversible inhibitor of ornithine decarboxylase (ODC), an enzyme that is critical for the biosynthesis of cationic polyamines, which are necessary for cell growth. Vaniqa appears to be effective regardless of whether the unwanted facial hair is hereditary or whether it is due to medical conditions such as an androgen excess disorder, e.g., polycystic ovarian syndrome.

The Hair Growth Cycle

All hair undergoes an intrinsic, rhythmic, cyclical growth pattern consisting of three phases. Periods of growth (anagen) are followed by periods in which the bulbar portion of the follicle is almost totally degraded through apoptosis (catagen), which is then followed by the resting phase (telogen). The duration of anagen on the face is usually 16 weeks, whereas on the scalp it typically continues for 150 weeks. Catagen lasts for 1 week on both the scalp and face, and telogen lasts for 6 weeks on the face, and 12 weeks on the scalp. Each hair follicle consists of a permanent and non-permanent portion with the lowermost aspect of the permanent portion located at the level of the insertion of the arrector pili muscle, also known as the “follicular bulge”.

The rate of growth for hair is approximately 0.44mm/day on the scalp, and 0.27mm/day for beards. Seasonal variation does exist with a higher rate of growth in the summer (July/August), as compared to the winter months (Jan/Feb). This variability correlates with fluctuations in androgen levels where higher levels of testosterone occur during the summer months.

In principle, there are three ways to slow down hair growth: 1) decrease the anagen phase, 2) delay the onset of anagen following the telogen phase, or 3) prolong telogen. While neither the telogen phase, nor the onset of anagen can yet be prolonged pharmacologically, the anagen phase can be reduced.

Ornithine Decarboxylase

ODC is an enzyme that is key to the formation of cationic polyamines, which in turn are necessary for cellular migration, differentiation and proliferation. Polyamines are low molecular weight, aliphatic, non-protein, nitrogenous bases that are predominantly found in proliferating tissues.

The Polyamine Pathway

L-Ornithine → Putrescine → Spermidine → Spermine
Ornithine decarboxylase

ODC activity and its biosynthetic products, putrescine and spermidine are usually low in normal resting cells, but high in proliferating cells, such as within anagen follicles. As well, ODC and putrescine were found to be higher in psoriatic skin, and putrescine is twice as high in the serum of psoriatic patients.¹

In terms of hair growth, investigators reported that ODC activity increased in rodent skin within four hours after hair plucking. This is much sooner than the earliest reported increases in matrix cell labeling indices after hair plucking,^2–4 which implies that ODC activity increases prior to the onset of increased mitotic activity. In embryonic human epidermis, ODC was found to be expressed in the ectodermal cells at sites where follicles develop, and to persist in cells at the leading edge of the follicular placode. ODC is abundantly expressed in the proliferating bulb cells of anagen follicles, and entry of the follicle into catagen is accompanied by a down-regulation of ODC expression, which persists until the next follicular growth cycle is initiated. In animal vibrissae, ODC is expressed in a group of outer root sheath cells near the follicle bulge, which is the putative site of hair follicle stem cells.^5,6 ODC activity is particularly high at the level of the bulb.

Increased ODC activity, has thus been associated with prolongation of anagen, and conversely, when ODC is decreased, anagen is reduced, thereby slowing hair growth. ODC activity is also reduced during the telogen phase.⁷

Pharmacokinetics

The mean percutaneous absorption for eflornithine 13.9% cream is less than 1%, and the steady-state peak serum concentration is less than 10ng/ml. It is not metabolized and is excreted unchanged in the urine. The time required to reach steady-state is 4 hours. The plasma half-life is 8 hours.⁸

Outcome	Eflornithine	Vehicle
Clear/almost clear	5%	0
Marked improvement	27%	8%
Improved	26%	26%
No improvement	42%	66%

Table 1: 58% of Vaniqa group demonstrated improvement versus 34% of placebo (p <.001)

Clinical Trial Results⁹

Two multi-center, double-blinded, vehicle controlled, randomized studies were carried out in the US and Europe. The first trial was conducted in 10 US centers: n=285 (189 Vaniqa cream/96 vehicle), and second took place at 8 centers in the US and 1 in Europe: n=309 (206 Vaniqa/103 vehicle). All ethnic groups and skin types were included, and all women were removing at least 5 hairs/cm² on the chin and upper lip at least twice/week prior to study entry.

The treatment regimen consisted of twice daily application of the creams for 24 weeks, followed by 8 weeks of no treatment.

Patients were seen at baseline, day 2, and weeks 2, 4, 8, 12, 16, 20, 24, and 32. At all visits a clinical assessment, self-assessment, video imaging, photographs and safety data were taken. Efficacy was determined by a Physician’s Global Assessment using a 4- point scale: clear to almost clear, marked improvement, improved, no improvement. All clinical assessments were made 48 hours after shaving. Statistically and clinically significant improvement was noted in the eflornithine group as compared to the vehicle control group at 8 weeks and continued for 24 weeks. However, hair regrowth approached pretreatment levels within 8 weeks of treatment withdrawal.

The subject self-assessment showed marked improvement with the use of Vaniqa. The mean overall level of discomfort or bother was reduced by 33% for the eflornithine group after 24 weeks based on a self-assessment questionnaire and a visual analog scale. There were no significant differences for patients using the placebo vehicle in this same period of time.¹⁰

Adverse Events

Skin related side effects such as stinging, burning and tingling occurred in a few patients, particularly when eflornithine was applied to broken or abraded skin. Only 2% discontinued eflornithine due to an adverse reaction in the United States. This drug is classified as a Pregnancy Category C agent, so risk to the fetus cannot be ruled out.

Dosage and Cost

Vaniqa is supplied in a 30gm tube, and should be applied twice daily. The area should not be washed for 4 hours after application, but cosmetics and sunscreens can be applied over treated areas once the cream has dried. The cost is $50.00 USD for a 30gm tube.

Conclusion

Eflornithine HCl 13.9% cream, used twice daily is effective for unwanted facial hair in women and complements other current hair removal methods by slowing the rate of hair regrowth. In order to prevent regrowth, eflornithine treatment must be continued indefinitely.

References

Lowe NJ. Epidermal ornithine decarboxylase, polyamines, cell proliferation, and tumor promotion. Arch Dermatol 116(7):822–5 (1980 Jul).
Morrison DM, Goldsmith LA. Ornithine decarboxylase in rat skin. J Invest Dermatol 70(6):309–13 (1978 Jun).
Ogawa H, Hattori M. Regulation mechanisms of hair growth. Curr Probl Dermatol 11:159–70 (1983).
Probst E, Krebs A. Ornithine decarboxylase activity in relation to DNA synthesis in mouse interfollicular epidermis and hair follicles. Biochim Biophys Acta 407(2):147–57 (1975 Oct).
Nancarrow MJ, Nesci A, Hynd PI, Powell BC. Dynamic expression of ornithine decarboxylase in hair growth. Mech Dev 84(1–2):161–4 (1999 Jun).
Nancarrow MJ, Powell BC, Hynd PI. Expression of ornithine decarboxylase during embryonic development of wool follicles. Exp Dermatol 8(4):326–8 (1999 Aug).
Hynd PI, Nancarrow MJ. Inhibition of polyamine synthesis alters hair follicle function and fiber composition. J Invest Dermatol 106(2):249–53 (1996 Feb).
Malhotra B. Percutaneous absorption, pharmacokinetics and dermal safety of eflornithine 15% cream in hirsute women. At: American Academy of Dermatology Annual Meeting (2000), San Francisco, California.
Schrode K. Randomized double blind vehicle controlled safety and efficacy evaluation of eflornithine 15% cream in the treatment of women with excessive facial hair. At: American Academy of Dermatology Annual Meeting (2000), San Francisco, California.
Huber F. Outcome of a quality of life assessment used in clinical trials for hirsute women treated with topical eflornithine 15% cream. At: American Academy of Dermatology Annual Meeting (2000), San Francisco, California.

Jerry Shapiro – Skin Therapy Letter

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

Introduction

Pathogenesis

Clinical Presentation & Diagnosis

Current Topical Treatments

Minoxidil

Other Topical Agents

Prostoglandins

Ketoconazole

Conclusion

References

Topical Agents for Hair Growth Promotion: What Is Out There?

Introduction

Androgenetic Alopecia

Clinical Presentation

Pathogenesis

Topical Treatments

Minoxidil

Prostaglandins

Fluridil

Ketoconazole

Spironolactone

Melatonin

Estrogens

Conclusion

References

Androgenetic Alopecia: A Review of Topical Agents for Hair Growth Promotion (Family Practice)

Introduction

Pathogenesis

Clinical Presentation & Diagnosis

Current Topical Treatments

Minoxidil

Other Topical Agents

Prostoglandins

Prostoglandins

Conclusion

References

Promising Therapies for Treating and/or Preventing Androgenic Alopecia

Hair Loss

Androgenetic Alopecia

Clinical Presentation

Biochemistry

Genetics and Diagnostic Tests

Current and Future Treatments

Minoxidil

Finasteride

Dutasteride

Prostaglandin Analogues

Ketoconazole

Anti-androgens

Estrogens

Laser Treatment

Surgical Treatment

Cell Mediated Treatment

Alternative Treatments

Conclusion

References

Management of Hirsutism

Causes

Diagnostic Approach

Treatment

Systemic Treatment

Topical Treatment

Conclusion

References

Treatments for Unwanted Facial Hair

Eflornithine HCl 13.9% Cream

Pharmacokinetics

Combination Therapy

Adverse Events for Eflornithine

Patient Communication

Conclusion

References

Excessive Facial Hair

Hirsutism

Differential Diagnosis

Hair Removal Techniques

Treatment Options

Women and Hirsutism

Clinical Trial Results⁹