Promising Therapies for Treating and/or Preventing Androgenic Alopecia

Kevin J. McElwee, PhD^1,2 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
Conflict of interest disclosure: Authors are part owners of Replicel Life Sciences Inc.

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

1. 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.
2. Shapiro J. Clinical practice. Hair loss in women. N Engl J Med. 2007 Oct 18;357(16):1620-30.
3. Tosti A, Piraccini BM, Iorizzo M, et al. Frontal fibrosing alopecia in postmenopausal women. J Am Acad Dermatol. 2005 Jan;52(1):55-60.
4. 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.
5. Kaufman KD. Androgens and alopecia. Mol Cell Endocrinol. 2002 Dec 30; 198(1-2):89-95.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. Alsantali A, Shapiro J. Androgens and hair loss. Curr Opin Endocrinol Diabetes Obes. 2009 Jun;16(3):246-53.
15. 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.
16. 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.
17. 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.
18. Camacho-Martinez FM. Hair loss in women. Semin Cutan Med Surg. 2009 Mar;28(1):19-32.
19. Rathnayake D, Sinclair R. Male androgenetic alopecia. Expert Opin Pharmacother. 2010 Jun;11(8):1295-304.
20. 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.
21. Banaszek A. Company profits from side effects of glaucoma treatment. CMAJ. 2011 Oct 4;183(14):E1058.
22. 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.
23. 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.
24. 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.
25. 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.
26. Sinclair R, Wewerinke M, Jolley D. Treatment of female pattern hair loss with oral antiandrogens. Br J Dermatol. 2005 Mar;152(3):466-73.
27. 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.
28. 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.
29. 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.
30. Rose PT. The latest innovations in hair transplantation. Facial Plast Surg. 2011 Aug;27(4):366-77.
31. 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.
32. 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.
33. Rogers NE, Avram MR. Medical treatments for male and female pattern hair loss. J Am Acad Dermatol. 2008 Oct;59(4):547-66.

In this issue:

1. Promising Therapies for Treating and/or Preventing Androgenic Alopecia
2. Age-related Percutaneous Penetration Part 2: Effect of Age on Dermatopharmacokinetics and Overview of Transdermal Products
3. Update on Drugs and Drug News - June 2012