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Review Article Types of Hair Loss and Treatment Options,Including the Novel Low-Level Light Therapyand Its Proposed MechanismMahyar Ghanaat, MD evaluated based on the Ludwig scale, which ranges from I-III Abstract: Androgenetic alopecia (AGA) is the most common form
(Fig. 2).4 These classification systems differ based on the fact of hair loss in men, and female pattern hair loss (FPHL) is the most that hair loss and thinning in men most commonly occurs in common form of hair loss in women. Traditional methods of treating an orderly fashion and involves the temporal and vertex re- hair loss have included minoxidil, finasteride, and surgical trans- gion while sparing the occipital region; diffuse thinning and plantation. Currently there is a myriad of new and experimental loss of density with a normal distribution and maintenance of treatments. In addition, low-level light therapy (LLLT) has recently the frontal hairline is often seen in women.2,4,5,9,10 been approved by the United States Food and Drug Administration The term AGA pertains to the pathophysiology of MPHL, (FDA) for the treatment of hair loss. There are several theories and in which there is an induction of hair loss due to the effects minimal clinical evidence of the safety and efficacy of LLLT, al- of androgens such as testosterone (T) and its derivative di- though most experts agree that it is safe. More in vitro studies are hydrotestosterone (DHT) in genetically susceptible individu- necessary to elucidate the mechanism and effectiveness at the cel- als.2 Recently, authors have argued against the use of the term lular level, and more controlled studies are necessary to assess the AGA in women, as the role of androgens in FPHL is debat- role of this new treatment in the general population.
able.4,7,11,12 Testosterone is a lipophilic compound that dif- Key Words: fibroblast, hair growth, hair loss, low level laser ther-
fuses the cell membrane. It is converted into its more active apy, low-level light therapy form, DHT, by the cytoplasmic enzyme 5-alpha reductase(5-AR).2,4 There are two types of 5-AR. Type 1 is found in Types and Epidemiology of Hair Loss keratinocytes, fibroblasts, sweat glands, and sebocytes, and Male pattern hair loss (MPHL), also known as androge- Type 2 is found in skin and the inner root sheath of hair netic alopecia (AGA), is the most common form of hair loss follicles.4,13,14 Androgens play an important role in the con- in men.1–3 Similarly, female pattern hair loss (FPHL) is the trol of hair. During puberty, due to a surge in T, there is an most common form of hair loss in women.4 The incidence induction of pubic hair growth and a decrease in follicle size and prevalence of MPHL is dependent on age and race. Chi- in the bitemporal region.8 Also, castrated men are not known nese, Japanese, and African American people are affected to develop MPHL.2,7 However, there is no correlation be- less than Caucasians.2,5 Its incidence increases by age.5 Prev- tween T levels and MPHL.2 The role of DHT was first no- alence values have variable ranges from 16 –96%, depending ticed in pseudohermaphrodites lacking this enzyme, who did on the age group and whether or not mild forms of MPHL are not develop MPHL.2,7 DHT then binds the nuclear androgen included (Table 1).2,6,7 Prevalence values for FPHL are com- receptor (AR) that regulates gene expression.2,7 Although the parable to MPHL (Table 2).8 The severity of MPHL is based exact genes involved in hair loss are not known with cer- on the Norwood Hamilton Classification, which takes into tainty, some of the proposed genes responsible for hair growth account bitemporal and vertex hair loss (Fig. 1).2 FPHL is (mainly studied in knockout and transgenic mice) are desmo- From the Department of Dermatology, SUNY Downstate Medical Center, Brooklyn, NY.
• Low-level light therapy (LLLT) appears safe and ef- Reprint requests to Mahyar Ghanaat, BS, MD, SUNY Downstate Medical Center, Box #50, 450 Clarkson Avenue, Brooklyn, NY 11230. Email: fective for the treatment of hair loss.
• LLLT may serve as an adjunct to other treatment No authors have any financial support and proprietary interest.
Accepted October 22, 2009.
• More cellular and human research is necessary to elu- Copyright 2010 by The Southern Medical Association cidate the mechanism of LLLT.
Southern Medical Journal • Volume 103, Number 9, September 2010

Ghanaat • Low-Level Light Therapy in Hair Loss Table 1. Prevalence of male pattern hair loss
Not including Type II frontal Hamilton37 Including Type II frontal recession in Hamilton'sdata37 Including Type II frontal recession in Norwoods'data38 62% in 20–40 yr olds Have bitemporal recession 54% of those ⬎30 yrs old Have androgenetic alopecia 53% of 40–49 yr olds Have Type III or greater 42% of 18–49 yr olds Have Type III or greater 16% of 18–29 yr olds Have Type III or greater Moderate to severe hair loss Rhodes study including all types of hair loss 30% by 30, 50% by 50, and White men See references for full citation. glein, activin, epidermal growth factor (EGF), fibroblastgrowth factor (FGF), lymphoid-enhancer factor-1 (LEF-1),and Sonic Hedgehock.15 Besides patterned baldness, there are several other forms of hair loss, which include alopecia areata (AA), telogen ef-fluvium (TE), and several androgen-related female alopecias.
AA is an autoimmune inflammatory condition which mayaffect the hair of the head, face, and body.16 Although mostcommonly thought of as an acquired disorder, congenitalcases have been described.17 It has an incidence of 0.1– 0.2%,and affects 1–2% of men and women.16,18 Hair involvementin AA is often patchy. Two variants of AA are alopecia totalis, a total loss of scalp hair, and alopecia universalis, total Norwood Hamilton classification. Reprinted with per-
mission from Endocrinol Metab Clin North Am 2007;36:381,
loss of scalp and body hair.16 AA is linked to several human 2007 Elsevier Inc. All rights reserved.
leukocyte antigen (HLA) alleles, such as HLA-AI, HLA-HLA-B26, HLA-DQ1, and HLA-DQ3.16 Although most com-monly treated by an injection of intralesional corticosteroids, and systemic corticosteroids, minoxidil for moderate cases, an- other treatment modalities are used.16 These include topical thralin, contact sensitizers (when more than half the scalp isaffected), psoralen plus ultraviolet A (PUVA), cyclosporine, ta-crolimus, and biologics.16,18,19 Biologics include agents such as Table 2. Prevalence of female pattern hair loss
alefacept, efalizumab, etanercept, infliximab, and adalimumab.
Of these, alefacept seems to be most promising, while adali-mumab and infliximab have been reported to induce AA.20 12% of those 20–29 yr old Dinh and Sinclair4 Telogen effluvium (TE) is abnormal hair cycling caus- ⬎50% in those ⬎80 yr old Dinh and Sinclair4 ing excessive loss of telogen hair.12 It is likely the most common cause of alopecia in children.12 Some of the com- mon causes include acute severe illness, surgery, iron de- 10% of premenopausal women ficiency anemia, thyroid disease, malnutrition, chronic ill- 50–75% of women ⬎65 yr old ness, and medications such as oral contraceptives, lithium, See References for full citation. and cimetidine.12,19 A good illness and medication history 2010 Southern Medical Association

have shown the same efficacy with the 5% solution, yet ahigher rate of hypertrichosis with topical application.8,19 Mi-noxidil is effective in adolescents.12 Finasteride is an oral agent, which is a competitive 5-AR inhibitor with more affinity for Type II 5-AR.8,11,13 Thus, itinhibits the conversion of T to its more active form of DHT.2,4Given its systemic nature, potential side effects of finasterideinclude erectile dysfunction, gynecomastia, and loss of li-bido.1 Like minoxidil, this is an ongoing therapy. Finasterideis only approved for men 18 years of age or older.12 Whereas minoxidil and finasteride are temporizing mea- Fig. 2 Ludwig classification. Reprinted with permission from
surements and require continuous administration, hair resto- Clin Interv Aging 2007;2:190, 2007 Dove Medical Press Ltd.
ration may serve as a definitive treatment.2,9 This procedure All rights reserved.
is based on the fact that occipital hair follicles are not andro-gen dependent, and that transplanted hair maintains donor is necessary to make the diagnosis, as well as laboratory dominance.9,22 Follicular units are acquired from the occipital studies such as complete blood count (CBC), thyroid func- scalp and transplanted into the frontal scalp in a cosmetically tion tests, and syphilis titers.12,19 acceptable manner.9,22 This procedure should ideally be per- Androgen-related female alopecias include a variety of formed on individuals who have reached a plateau in balding types of hypergonadism. Polycystic ovarian syndrome and have realistic expectations.9,22 Side effects are usually (PCOS) is a common cause of hypergonadism which could minor and include postoperative pain, delayed hair growth, cause amenorrhea, hirsutism, and FPHL.14 Some antiandro- and, rarely, infection.9 Periorbital and frontal swelling may gen medications that may be helpful for FPHL include cypro- also occur.22 Some argue that the future procedure of hair terone acetate, spironolactone, and flutamide.10 However, one cloning may dramatically improve this process.23 study argues that 88% of FPHL will not improve with oral In addition, there are a variety of off-label and investi- gational drugs that are used or considered in the treatment ofhair loss. Dutasteride is a dual Type I and II 5-AR inhibitor.4,7 Traditional Treatment Options Latanoprost is a prostaglandin mainly used for glaucoma, The two medications approved for MPHL by the United which was observed to stimulate eyelash and eyebrow States Food and Drug Administration (FDA) are 5% minoxi- growth.7 The antifungal agent ketoconazole may also pro- dil and finasteride.2,3,19 Two percent minoxidil is the only mote hair growth, perhaps by inhibiting inflammation and approved medication for FPHL.3,10 Minoxidil is an antihy- serving as an antiandrogen.7 Other investigational drugs in- pertensive medication with peripheral vasodilator properties, clude fluridil, a topical antiandrogen; naminidil, which works and the side effect when taken systemically is hypertricho- through the potassium (K) channel; P-45, which may inhibit sis.1,11 After application, minoxidil is converted to minoxidil interleukin 4 (I-L4)-induced CD23 expression; PSK 3841, a sulfate, a potassium channel opener which relaxes vascular topical nonsteroidal androgen antagonist; and lemuteporfin smooth muscle and increases blood flow.6 It was first sus- (QLT 0074), a photosensitizer to be used with photodynamic pected that this increased blood flow is the mechanism by therapy.3 Other agents include antiandrogen oligonucleo- which minoxidil affects hair loss, but this may not be the tides—which are deoxyribonucleic acid (DNA) that pairs case.11 In vitro studies of hair growth have shown that hair with complementary ribonucleic acid (RNA)—KF19418, cultures grown in the presence of minoxidil maintain mor- LGD1331, steroid sulfatase inhibitors, and thymosin beta 4, phology, whereas controls undergo kinking and necrosis.21 A which stimulates hair growth via stem cell migration.3 Gene common side effect of minoxidil is contact dermatitis, which delivery through liposome technology has also showed some can initially be managed by switching to a 2% solution or the foam preparation, which lacks propylene glycol (an irritatingsubstance).2 Corticosteroids may also be beneficial to im-prove pruritic side effects.11 One drawback with minoxidil Low-Level Light Therapy treatment is that it requires twice daily application indefi- In 2007, low-level light therapy (LLLT) was approved nitely to maintain results.1,2,6 Shin et al6 have proposed that by the FDA as a treatment for hair loss.23 LLLT is also combination of minoxidil with tretinoin once a day makes no known as low level laser therapy, red light therapy, cold laser, significant difference in efficacy or side effect profile (as soft laser, biostimulation, and photobiomodulation.24–26 Most opposed to minoxidil twice a day), and may improve patient experts agree that LLLT is safe for the treatment of hair loss, compliance. Tretinoin increases the absorption of minoxidil.6 but more studies are needed to confirm its therapeutic ef- Two percent minoxidil is approved for women, as studies fects.24 LLLT was discovered in the 1960s and first used by Southern Medical Journal • Volume 103, Number 9, September 2010

Ghanaat • Low-Level Light Therapy in Hair Loss the National Aeronautics and Space Administration (NASA) One study reported a failure in treatment of AA.32 However, to accelerate wound healing in space.25 Since then, LLLT has the researchers used a small dose (630 nm at 37 J/cm2 for 7.5 been used to reduce neurogenic pain, reduce inflammation, min) only once a month.32 In addition, they reported success- and promote wound healing.25–27 Other uses include non- ful treatment in beard AA after only three sessions in three melanoma skin cancer and its precursors, acne vulgaris, pho- patients.32 Sobanko and Alster25 propose that better under- torejuvenation, hidradenitis suppurativa, and psoriasis.28 It standing of the mechanisms of LLLT will help resolve some may also prove helpful in killing bacteria, fungi, and vir- of these questions. Some negative results are also attributed uses.28 LLLT has also been used to achieve attenuation of to poor design and use of very low doses.33 Unresolved ques- retinal toxicity in methanol-poisoned rats.27 The role of LLLT tions regarding the properties of light being used include: in hair growth was discovered accidentally in 1967.26 In an wavelength, laser vs noncoherent, dose, pulsed vs continuous attempt to test if LLLT causes cancer in shaved mice, re- wave (CW), and polarization status.26 All of these conditions searchers discovered that these mice did not develop cancer, and cell culture condition will determine the effect of LLLT.33 but instead grew hair.26 Usually wavelengths in the 600-1000 nm range and powers Before describing the mechanisms of LLLT, a brief dis- from 5–500 mW are used.25 Evans and Abrahamse33 studied course into its terminology will be taken. The term "laser" the effect of light with wavelengths of 638.2, 830, and 1064 refers to the fact that monochromatic light is used.27 This is nm at 5, 10, and 16 J/cm2 intensities to compare control vs in contrast to light emitting diode (LED). The term "low wounded fibroblasts. They found the most stimulatory effect level" alludes to the fact there is a specific wavelength of on wounded fibroblasts using 5 J/cm2 of 632.8 nm light.33 light that has optimal therapeutic effects, and any level higher They also found the dose of 16 J/cm2 to cause DNA damage or lower than this may not be proficient.26 This therapeutic and reversible cell damage (in most instances).33 Similarly, in window ranges roughly from 600 to less than 1,400 nm, and assessing free radical formation, Haywood et al34 found no is close to the absorption spectrum of hemoglobin and water, detectable free radicals after exposure of human skin biopsy respectively.26 Furthermore, respiratory chain components to 694 nm light at 11–14 J/cm2 in 0.9 ms pulses using electron (mainly cytochrome c) have a similar absorption spec- spin resonance spectroscopy.
trum.26 This low level results in a negligible change intissue temperature.25 LLLT appears safe and effective for the treatment of hair The Mechanism of LLLT loss in theory and through minimal observational studies, but There are several theories that explain the mechanisms of more clinical and in vitro studies are needed. Proposed in LLLT: cytochrome c oxidase-mediated increase in adenosine vitro studies may include the effect of LLLT on fibroblast triphosphate (ATP) production, the singlet oxygen hypothe- function in controlled settings. Factors such as growth rate sis, the redox properties alteration hypothesis, and nitrous and apoptotic rate may be assessed. Similar in vitro studies oxide (NO) hypothesis.26 Cytochrome c oxidase is part of the may be carried out with intact hair follicles. Finally, random- respiratory chain that ultimately results in ATP production. It ized double blind multicenter trials are needed to truly assess is hypothesized that the light absorbed by this moiety may safety and efficacy; one such trial has found promising results ultimately result in increased ATP production, which may thus far.35 Another study of seven patients did not reveal alter cell metabolism.26 This is a concept similar to photo- statistical significance, and proposed that some individuals synthesis in plants. Singlet oxygen hypothesis stems from the may be more responsive to this treatment.36 fact that radiation used in high doses to kill cancer cellscauses a paradoxical cell proliferation in low doses.26 Theredox properties alteration hypothesis proposes that enzymes other than cytochrome c are induced to produce superoxide 1. Bienova´ M, Kucerova´ R, Fiura´skova´ M, et al. Androgenetic alopecia and anion.26 The NO hypothesis proposes that LLLT may unin- current methods of treatment. Acta Dermatovenerol Alp Panonica Adriat2005;14:5– 8.
hibit the effect of NO on cytochrome c.26 2. Otberg N, Finner AM, Shapiro J. Androgenetic alopecia. Endocrinol There have been several studies to evaluate the effects of Metab Clin North Am 2007;36:379 –398.
LLLT. Increase in ATP synthesis, proton electrochemical po- 3. Poulos GA, Mirmirani P. Investigational medications in the treatment of tential, and oxygen uptake have all been shown in rat liver alopecia. Expert Opin Investig Drugs 2005;14:177–184.
mitochondria.26,29,30 LLLT has been shown to increase pro- 4. Dinh QQ, Sinclair R. Female pattern hair loss: current treatment con- collagen synthesis in fibroblasts.25,26 However, numerous hu- cepts. Clin Interv Aging 2007;2:189 –199.
man and animal studies have shown inconsistent results, 5. Stough D, Stenn K, Haber R, et al. Psychological effect, pathophysiol- mainly due to lack of coherence in protocols.25 Some also ogy, and management of androgenetic alopecia in men. Mayo Clin Proc relate the variability in results across studies to the fact that the effect of LLLT depends on the physiologic state of cells.31 6. Shin HS, Won CH, Lee SH, et al. Efficacy of 5% minoxidil versus 2010 Southern Medical Association

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Southern Medical Journal • Volume 103, Number 9, September 2010

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