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Finasteride is usually only prescribed for men and should not be used by pregnant or potentially pregnant women, as it has been speculated that it could cause severe birth defects in male fetuses.<ref>[http://www.fda.gov/bbs/topics/ANSWERS/ANS00842.html]</ref>
Finasteride is usually only prescribed for men and should not be used by pregnant or potentially pregnant women, as it has been speculated that it could cause severe birth defects in male fetuses.<ref>[http://www.fda.gov/bbs/topics/ANSWERS/ANS00842.html]</ref>



==Antiandrogens==
{{Main|Antiandrogen}}
[[Antiandrogens]] block DHT already produced and present in the blood stream from ''binding'' with hair follicles. Their specificity varies greatly from specific antiandrogens such as finasteride which inhibit the conversion of testosterone to DHT by interfering with 5-alpha-reductase to more broad spectrum antiandrogens ([[fluconazole]], [[spironolactone]], etc.). Although unusual in clinical doses, antiandrogens can have serious side effects including [[gynecomastia]].


==Dutasteride==
==Dutasteride==
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In 2009 a new study result was released including pictures of before and after treatment. In this study six Japanese males with male pattern baldness (androgenetic alopecia) from 23 to 51 years old were enrolled and the subjects applied topical 2% KCZ lotion (Nizoral® cream) every day during or immediately after hair washing with their own un-medicated shampoos. All subjects reported a stop in hair loss and a regrowth of part of their lost hair after three months of continuous use. <ref>[http://www.keepingmyhair.com/japanese-study-nizoral-cream-ie-ketoconazole"]</ref>
In 2009 a new study result was released including pictures of before and after treatment. In this study six Japanese males with male pattern baldness (androgenetic alopecia) from 23 to 51 years old were enrolled and the subjects applied topical 2% KCZ lotion (Nizoral® cream) every day during or immediately after hair washing with their own un-medicated shampoos. All subjects reported a stop in hair loss and a regrowth of part of their lost hair after three months of continuous use. <ref>[http://www.keepingmyhair.com/japanese-study-nizoral-cream-ie-ketoconazole"]</ref>


==Copper peptides==

Copper peptides are applied topically to the scalp, and shorten the resting phase of hairs, resulting in more hair follicles on the scalp being in the growing phase (as opposed to the resting or falling out phase) at one time.{{Dubious|date=October 2008}}<!-- The source is a patent, not a scientific study --> Copper peptides generally have [[superoxide]] [[dismutation]] activity.<ref>[http://www.doctorproctor.com/patents/pro876.html US patent 5,470,876, "Topical SOD for treating hair loss"]</ref>

SOD work by dismuting the superoxide anion into hydrogen peroxide, thereby preventing the converson of the superoxide anion to peroxynitrite (a free-radical) by combining with nitric oxide (a naturally occurring chemical messenger). The double effect of SOD therefore is the reduction in free-radical and increase in nitric oxide. It is thought that a key mechanism of action for minoxidil is the production of [[Nitric oxide]] (NO). Superoxide has an "agonist-antagonist" relationship with Nitric oxide or "Endothelium-derived Relaxing Factor".<ref>[http://www.drproctor.com/Archd.htm "Endothelium-Derived Relaxing Factor and Minoxidil: Active Mechanisms in Hair Growth", ''Archives in Dermatology'', vol 125, August, 1989]</ref>

Various SOD generating products are now available. However, one problem with SOD is the production of Hydrogen Peroxide as a by-product of singlet oxygen (superoxide anion) quenching. In the human body, the enzyme catalase converts the SOD hydrogen peroxide byproduct into water and oxygen.


Nanogen, a UK-based skin research company, is undergoing Phase I trials to ascertain the hair regrowth potential on a new "broad-spectrum" molecule which has been shown in extensive independent laboratory in-vitro testing to have both SOD and Catalase mimetic activity{{Citation needed|date=April 2010}}. The company has not released details of the molecule as it is pending patent but it is copper II based{{Citation needed|date=April 2010}}.


==Herbal Treatment==
==Herbal Treatment==

Revision as of 17:02, 12 April 2010

Just less than half of men are affected by male pattern baldness by age 50, and baldness treatments are estimated to be a US $1 billion per year industry.[1] Since the 1980s, drug therapy has increasingly become a realistic management option for baldness for men and women. Increased understanding of the role of dihydrotestosterone (DHT) in male and female pattern baldness has led to targeted intervention to prevent this hormone from acting on receptors in the scalp.

However, experts warn that many treatments marketed as hair loss cures are ineffective aside from the placebo effect.[2]

Approved treatments

U.S.

There are only two drug treatments approved by the U.S. Food and Drug Administration (FDA) for male baldness: Minoxidil[2] and Finasteride [3]. Finasteride is recommended first for male pattern baldness.[2]

Minoxidil (Rogaine/Regaine)

Minoxidil is a vasodilator and originally was exclusively used as an oral drug (Loniten) to treat high blood pressure. It was discovered, however, to have the side effect of hair growth and reversing baldness, and in the 1980s, Upjohn Corporation received FDA approval to market a topical solution that contained 2% minoxidil to be used to treat baldness and hair loss as Rogaine, marketed as Regaine outside the USA.

Objective evidence shows that minoxidil is effective in both the frontal areas of the scalp and the vertex area in treating male-pattern hair loss. At the conclusion of a 48 week study, improvements were seen in the frontal scalp regions of 51% of men using 5% minoxidil, 42% using 2% minoxidil, and 13% of placebo users. Among these men, moderate to great increases in hair growth were seen in the frontal scalp regions of 19% of men using 5% minoxidil, 10% using 2% minoxidil, and 3% of placebo users.[4]

The method of action for minoxidil is not known, but many speculate that by widening blood vessels and opening potassium channels, it allows more oxygen, blood and nutrients to the follicle. This can also cause follicles in the telogen phase to shed, usually soon to be replaced by new, thicker hairs. As this effect is very temporary and does not seem to change the follicle in any other way, minoxidil needs to be applied regularly (once or twice daily) for hair gained to be maintained.

Finasteride (Propecia)

Finasteride, initially marketed as the brand-name drugs Propecia and Proscar by Merck, belongs to a class of drugs called aza-steroids. Finasteride is a "DHT inhibitor" and was originally approved by the US FDA for the treatment of benign prostatic hyperplasia (BPH). The drug works by binding to 5-alpha-reductase, the enzyme responsible for the conversion of free testosterone to DHT.

Merck sought to find the smallest effective quantity of finasteride and test its long-term effects on 1,553 men between ages 18 and 41 with mildly to moderately thinning hair. Based on their research, 1 mg daily was selected, and after two years of daily treatment, over 83% of the 1,553 men experiencing male hair loss had actually maintained or increased their hair count from baseline. Visual assessments concluded that over 80% had improved appearances.[5]

In 1997, finasteride was approved by the US FDA for the treatment of male pattern baldness. A 5-year study revealed that 9 of 10 men taking finasteride (1 mg daily) experienced visible results (42% of men taking Propecia experienced no further hair loss while 48% experienced no further hair loss and hair regrowth).[6] In clinical studies, finasteride, like minoxidil, was shown to work on both the crown area and the hairline area, but is most successful in the crown area.[7]

Finasteride is usually only prescribed for men and should not be used by pregnant or potentially pregnant women, as it has been speculated that it could cause severe birth defects in male fetuses.[8]


Dutasteride

In 2001, GlaxoSmithKline released another aza-steroid called dutasteride, marketed as Avodart. Like finasteride, dutasteride was originally developed for the treatment of benign prostatic hyperplasia (BPH). It is not currently sold for baldness treatment.

While hair count studies showed that 2.5 mg of dutasteride was about 1.5 times as effective as finasteride for hair regrowth (adding on average 108 versus 72 hair per 1" diameter area), Glaxo stopped FDA hair loss studies after phase II. Although the exact reason was never made public, it was speculated that the product was too similar to finasteride, which itself had not lived up to expectations commercially. As such, the 2.5 mg dosage was not released. The FDA trials for BPH continued, and Avodart became the first drug shown to shrink an enlarged prostate in a clinical study. The .5 mg version of the drug (shown in the same study to add on average 92 hairs to the same area) is increasingly available to hair loss sufferers via the grey-market of online prescription medication, and physicians increasingly willing to prescribe drugs "off-label."

In December 2006, GlaxoSmithKline embarked on a new Phase III, six month study in Korea to test the safety, tolerability and effectiveness of a once-daily dose of dutasteride (0.5 mg) for the treatment of male pattern baldness in the vertex region of the scalp (types IIIv, IV and V on the Hamilton-Norwood scale).[9] GlaxoSmithKline has published the results of the study, concluding

This study demonstrated dutasteride 0.5 mg /day administered for 6 months was well tolerated and slowed the progression of hair loss and increased hair growth in Korean men. For hair counts as assessed by macrophotography in the vertex at 6 months (primary endpoint), the dutasteride 0.5 mg group was significantly superior to the placebo group. The hair count difference at 6 months between dutasteride and placebo group was 7.5 ± 20.4 (95% CI = 0.8, 14.3). The overall incidence of adverse events and adverse drug reactions during treatment was similar in the two groups.. The most commonly reported adverse event in both groups was nasopharyngitis. One serious adverse event was reported during the trial (thyroid cancer in the placebo group).[10]

The future impact that this study will have on the US FDA's approval or disapproval of Avodart for the treatment of male pattern baldness in the United States is yet to be determined.

Ketoconazole

Ketoconazole is a synthetic antifungal drug used to prevent and treat skin and fungal infections, especially in immunocompromised patients such as those with AIDS. Because it is both an anti-fungal, a 5-alpha reductase inhibitor and a hair growth stimulant,[11] it can help to slow the balding process.[12][13] There has been some suggestion that ketoconazole could inhibit testosterone synthesis in utero, which could potentially inhibit genital development of a male fetus. However, this has not been documented in any controlled studies.[14] Ketoconazole has not been FDA-approved for hair loss, though it is used for other scalp conditions.

In 2009 a new study result was released including pictures of before and after treatment. In this study six Japanese males with male pattern baldness (androgenetic alopecia) from 23 to 51 years old were enrolled and the subjects applied topical 2% KCZ lotion (Nizoral® cream) every day during or immediately after hair washing with their own un-medicated shampoos. All subjects reported a stop in hair loss and a regrowth of part of their lost hair after three months of continuous use. [15]


Herbal Treatment

Saw palmetto extract has been suggested as a potential treatment for male pattern baldness. It has been shown to inhibit both isoforms of 5-alpha-reductase without eliminating the cellular capacity to secrete PSA.[16][17]

Spin labels

In animal models, the nitroxide spin labels TEMPO and TEMPOL enhance hair regrowth following radiation. National Cancer Institute-sponsored clinical trials[18] TEMPOL is similarly effective in humans.[19]

Diet and lifestyle

There are a number of genetic factors which determine a person's susceptibility to androgenic alopecia including androgen receptor polymorphisms, 5-alpha-reductase levels in the scalp, androgen receptor density and distribution in the scalp, and other factors some of which may not have been discovered.

Daily, vigorous aerobic exercise (as opposed to short workout periods designed to raise androgen levels and build muscle, or more sporadic exercise) and a diet which is adequate yet more moderate in terms of fat and total calorie intake have been shown to reduce baseline insulin levels as well as baseline total and free testosterone.[20]

Lower insulin levels and reduced stress both result in raised levels of Sex Hormone Binding Globulin (SHBG). SHBG binds to testosterone, and prevents it from circulating free in the blood. Only free testosterone is converted to DHT. It is the level of free androgens and not total androgens which is relevant to the levels of DHT in the scalp and the progression of MPB. In short, aerobic exercise is capable of significantly lowering DHT.[21][22]

Androgenic alopecia has been shown to correlate with metabolic syndrome. Medically increasing androgen levels does not worsen this condition, demonstrating that androgens do not cause metabolic syndrome. Instead, high insulin levels (and possibly chronic inflammation[23]) seem the likely link in the demonstrated correlation between baldness and metabolic syndrome. This reinforces the notion that behaviors which help to keep insulin levels low and reduce chronic inflammation might also help to preserve hair.[24][25]

Hair transplantation

Hair transplantation involves relocating (transplanting) bald resistant hair follicles from the back and sides of the head (the donor areas) to a person’s bald or thinning areas. The transplanted hair follicles will typically grow hair for a lifetime because they are genetically resistant to going bald. In recent years hair transplantation techniques have evolved from using large plugs and mini grafts to exclusively using large numbers of small grafts that contain from between 1 to 4 hairs. The grafting may cause localized loss of existing hair, the graft then typically grows in within a year.

Since hair naturally grows in follicles that contain groupings of 1 to 4 hairs, today’s most advanced techniques transplant these naturally occurring 1–4 hair "follicular units" in their natural groupings. Thus modern hair transplantation can achieve a natural appearance by mimicking nature hair for hair.

Another method is scalp reduction, in which skin in the balding area of the scalp is surgically excised. The left over skin is then pulled together and sutured.

Hair multiplication

Stem cells and dermal papilla cells have been discovered in hair follicles and some researchers predict research on these follicular cells may lead to successes in treating baldness through hair multiplication (HM), also called hair cloning.

HM is being developed by ARI (Aderans Research Institute, a Japanese owned company in the USA).[26][27]

In 2008, Intercytex, a company in Manchester (UK), announced positive results of a Phase II trial for a form of cloning hair follicles from the back of the neck, multiplying them and then reimplanting the cells into the scalp. The initial testing resulted in at least two thirds of male patients regrowing hair. As of 2009, the company estimates this treatment will take "a number of years to complete" Phase III trials before it can go to market.[28] However, after failing to achieve subsequent success in their trials, the company announced discontinuation of its hair multiplication project in January 2010 with intention to sell off its assets and research.[29]

WNT Protein Introduction

In May 2007, U.S. company Follica Inc, announced they have licensed technology from the University of Pennsylvania which can regenerate hair follicles by reawakening genes which were once active only in the embryo stage of human development. Skin apparently can be brought back to this embryonic state when a wound is healing. Hair growth was discovered in the skin wounds of mice when Wnt proteins were introduced to the site. Development of a human treatment is expected to take several years.[30]

Scalp massage

A randomized clinical trial of patients with bald patches on their scalp or skin showed a daily scalp massage with essential oils to be a safe and effective treatment for hair loss resulting from alopecia areata, a condition affected 0.1%–0.2% of humans (mostly women).[31][32]

Low-level laser therapy

Some devices claim to use low-level laser therapy to stimulate hair growth through "Photo-Biostimulation" of the hair follicles. The Hairmax Lasercomb is the only laser phototherapy device to receive FDA clearance for marketing, although the FDA did not determine whether the LaserComb is safe or effective. Instead, it determined that the device is similar to devices sold before 1976. This means that the device can be sold without proof of safety or efficacy. The device's maker also provided the FDA with a results of a trial (co-authored by the device's maker with 3 other authors including dermatologists) that it claims shows that the device is safe and effective. However, there is no evidence that the FDA considered this study it making its ruling. [33]

The Leimo laser is registered with the Therapeutic Goods Administration of Australia as a Class IIa Medical Device. It was approved for safety, but the TGA did not rule on its effectiveness. In 2009 the TGA reprimanded Leimo, stating that there is no evidence that the device would regrow hair, and said that the company must "withdraw any representations that the advertised product can provide benefits such as hair regrowth, reversal of hair loss, or reversal of hair thinning."[34]

Unsaturated fatty acids

Particular unsaturated fatty acids such as gamma linolenic acid are 5 alpha reductase inhibitors if taken internally.[35]

Hedgehog agonists

Through 2006, a drug development company spent $1,000,000 on a hair growth program focused on the potential development of a topical hedgehog agonist for hair growth disorders such as male pattern baldness and female hair loss. The hair loss research program was shut down in May 2007 because the process did not meet the proper safety standards.[36]

Plant remedies

Caffeine

Caffeine has been identified as a stimulator of human hair growth in vitro, and reduced testosterone-induced follicle growth suppression.[37] It has been demonstrated that the addition of caffeine to a shampoo-formulation is effective in administering caffeine to the hair follicles in the scalp.[38] Further research must be done to evaluate the efficacy and adequate dosage of caffeine in the treatment of androgenetic alopecia.

A spray made with coffee beans is claimed to prevent age-related hair loss in women.[39]

Genetic research

In February 2008 researchers at the University of Bonn announced they have found the genetic basis of two distinct forms of inherited hair loss, opening a broad path to treatments for baldness. They found that a gene, P2RY5, causes a rare, inherited form of hair loss called Hypotrichosis simplex. It is the first receptor in humans known to play a role in hair growth. The fact that any receptor plays a specific role in hair growth was previously unknown to scientists and with this new knowledge a focus on finding more of these.

In May 2009, researchers in Japan identified a gene, Sox21, that appears to determine cyclical hair loss in mice. The researchers also believe it may be responsible for hair loss, or alopecia, in people.[40]

See also

Footnotes

  1. ^ Whyche, Stephanie. "The Bald Truth About Hair Loss In Young Men". Retrieved 2006-07-26.
  2. ^ a b c http://www.webmd.com/skin-beauty/guide/hair-loss-treatments.
  3. ^ http://www.fda.gov/cdrh/pdf6/K060305.pdf
  4. ^ [1]
  5. ^ Medscape summary of the full article
  6. ^ Proof of results with PROPECIA
  7. ^ Leyden J, Dunlap F, Miller B; et al. (1999). "Finasteride in the treatment of men with frontal male pattern hair loss". J. Am. Acad. Dermatol. 40 (6 Pt 1): 930–7. doi:10.1016/S0190-9622(99)70081-2. PMID 10365924. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ [2]
  9. ^ [3]
  10. ^ "Study No.: ALO106377" (PDF). Retrieved 2009-11-07.
  11. ^ Jiang, J. Tsuboi, R., Kojima, Y. and Ogawa, H. Topical application of ketoconazole stimulates hair growth in C3H/HeN mice. J Dermatol. 2005 Apr;32(4):243-7.
  12. ^ Hugo Perez BS (2004). "Ketocazole as an adjunct to finasteride in the treatment of androgenetic alopecia in men". Med Hypotheses. 62 (1): 112–115. doi:10.1016/S0306-9877(03)00264-0. PMID 14729013.
  13. ^ Pierard-Franchimont C (1998). "Ketoconazole shampoo: effect of long-term use in androgenic alopecia". Dermatology. 196 (4): 474–477. doi:10.1159/000017954. PMID 9669136. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  14. ^ "Ketoconazole-(P)". Illinois Teratogen Inforamation Service. Retrieved 2006-08-09.
  15. ^ "
  16. ^ Wadsworth TL, Worstell TR, Greenberg NM, Roselli CE (2007). "Effects of dietary saw palmetto on the prostate of transgenic adenocarcinoma of the mouse prostate model (TRAMP)". The Prostate. 67 (6): 661–73. doi:10.1002/pros.20552. PMID 17342743. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ Abe M, Ito Y, Oyunzul L, Oki-Fujino T, Yamada S (2009). "Pharmacologically relevant receptor binding characteristics and 5alpha-reductase inhibitory activity of free Fatty acids contained in saw palmetto extract". Biological & Pharmaceutical Bulletin. 32 (4): 646–50. doi:10.1248/bpb.32.646. PMID 19336899. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  18. ^ report
  19. ^ United States Patent 5,714,482 "Topical spin labels and method"
  20. ^ Daly W, Seegers CA, Rubin DA, Dobridge JD, Hackney AC (2005). "Relationship between stress hormones and testosterone with prolonged endurance exercise". European Journal of Applied Physiology. 93 (4): 375–80. doi:10.1007/s00421-004-1223-1. PMID 15618989. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  21. ^ Barnard RJ, Aronson WJ, Tymchuk CN, Ngo TH (2002). "Prostate cancer: another aspect of the insulin-resistance syndrome?". Obesity Reviews. 3 (4): 303–8. doi:10.1046/j.1467-789X.2002.00081.x. PMID 12458975. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  22. ^ Barnard RJ, Aronson WJ (2005). "Preclinical models relevant to diet, exercise, and cancer risk". Recent Results in Cancer Research. 166: 47–61. doi:10.1007/3-540-26980-0_4. PMID 15648182.
  23. ^ Joffe HV, Ridker PM, Manson JE, Cook NR, Buring JE, Rexrode KM (2006). "Sex hormone-binding globulin and serum testosterone are inversely associated with C-reactive protein levels in postmenopausal women at high risk for cardiovascular disease". Annals of Epidemiology. 16 (2): 105–12. doi:10.1016/j.annepidem.2005.07.055. PMID 16216530. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  24. ^ Cikim AS, Ozbey N, Sencer E, Molvalilar S, Orhan Y (2004). "Associations among sex hormone binding globulin concentrations and characteristics of the metabolic syndrome in obese women". Diabetes, Nutrition & Metabolism. 17 (5): 290–5. PMID 16295051. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  25. ^ Heald AH, Anderson SG, Ivison F; et al. (2005). "Low sex hormone binding globulin is a potential marker for the metabolic syndrome in different ethnic groups". Experimental and Clinical Endocrinology & Diabetes. 113 (9): 522–8. doi:10.1055/s-2005-865807. PMID 16235154. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  26. ^ "Hair Cloning Nears Reality as Baldness Cure". Webmd.com. 2004-11-04. Retrieved 2006-08-10.
  27. ^ "Big Baldness Breakthrough?". Associated Press. 2004-03-15. Retrieved 2006-08-10.
  28. ^ http://www.intercytex.com/icx/products/aesthetic/icxtrc/faqsicxtrc/
  29. ^ http://www.regrowhair.com/hair-loss-blog/intercytex-takes-a-dive-the-end-of-hair-multiplication-cloning-research/
  30. ^ [4] [5] [6] [7] [8][9] [10] [11]
  31. ^ http://www.cancer.org/docroot/ETO/content/ETO_5_3X_Aromatherapy.asp
  32. ^ Hay IC, Jamieson M, Ormerod AD (1998). "Randomized trial of aromatherapy. Successful treatment for alopecia areata". Archives of Dermatology. 134 (11): 1349–52. doi:10.1001/archderm.134.11.1349. PMID 9828867. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  33. ^ http://www.accessdata.fda.gov/cdrh_docs/pdf6/K060305.pdf
  34. ^ http://www.tgacrp.com.au/index.cfm?pageID=13&special=complaint_single&complaintID=1355
  35. ^ Liang T, Liao S (1992). "Inhibition of steroid 5 alpha-reductase by specific aliphatic unsaturated fatty acids". The Biochemical Journal. 285 (2): 557–62. PMC 1132824. PMID 1637346. {{cite journal}}: Unknown parameter |month= ignored (help)
  36. ^ Procter & Gamble (2005). "Curis and Procter & Gamble Enter into R&D Agreement for Hair Growth Program". Retrieved 2006-08-24. {{cite news}}: Unknown parameter |month= ignored (help)
  37. ^ Fischer TW, Hipler UC, Elsner P (2007). "Effect of caffeine and testosterone on the proliferation of human hair follicles in vitro". International Journal of Dermatology. 46 (1): 27–35. doi:10.1111/j.1365-4632.2007.03119.x. PMID 17214716. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  38. ^ Otberg N, Teichmann A, Rasuljev U, Sinkgraven R, Sterry W, Lademann J (2007). "Follicular penetration of topically applied caffeine via a shampoo formulation". Skin Pharmacology and Physiology. 20 (4): 195–8. doi:10.1159/000101389. PMID 17396054.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  39. ^ [12]
  40. ^ [13]

Further reading

  • Leavitt M, Charles G, Heyman E, Michaels D (2009). "HairMax LaserComb laser phototherapy device in the treatment of male androgenetic alopecia: A randomized, double-blind, sham device-controlled, multicentre trial". Clinical Drug Investigation. 29 (5): 283–92. doi:10.2165/00044011-200929050-00001. PMID 19366270.{{cite journal}}: CS1 maint: multiple names: authors list (link)