Hair Loss: Established Treatments and Emerging Therapies

Marc Avram, MD

Nikhil Shyam, MD

Hair loss, or alopecia, affects a significant proportion of the world’s population and can have numerous psychological and social consequences. Alopecia is known to be associated with depression, introversion, and lower self-esteem. While there are several different types of hair loss, they are broadly categorized into two forms: nonscarring (preservation of hair follicles) and scarring (loss of follicular ostia). The most common type of hair loss is androgenetic alopecia (AGA) and affects 80% of men and 50% of women in the course of their lifetime.¹^,²^,³

ANDROGENETIC ALOPECIA

AGA is an androgen-dependent loss of hair that occurs in genetically predisposed men and women. Androgens, specifically dihydrotestosterone (DHT), have been shown to play an important role in the progression of AGA. Testosterone is converted to DHT by the type II isoenzyme of 5-alpha reductase that is expressed in the dermal papillae of hair follicles. Elevated levels of DHT result in many of the classic features of AGA including miniaturization of terminal hairs to vellus-like hairs and a prolonged telogen phase with shortening of the anagen growth phase.⁴^,⁵^,⁶ Several androgen receptor
polymorphisms have been noted, highlighting a polygenetic condition as well as an autosomal dominant inheritance.⁷^,⁸ Several studies have also reported single-nucleotide polymorphisms at different genomic loci associated with hair loss, including the AR/EDA2R locus and 20p11 locus.⁹ Clinically, men and women often exhibit different patterns of hair loss that have been described as male pattern hair loss (MPHL) and female pattern hair loss (FPHL), respectively. However, overlap in terms of distribution of hair loss may occur as well.

Male Pattern Hair Loss

Androgen-dependent hair loss is well established in men and typically presents with gradual thinning of hairs in the vertex scalp along with recession of the frontotemporal hairline. Typically, the occipital and parietal scalp remain unaffected. Classically, the Hamilton-Norwood scale (Figure 6.1) is utilized to describe the severity of MPHL.

Diagnosis is usually made through clinical history and physical exam with notable decreased density of hairs in the bitemporal and vertex scalp with prominent sparing of occipital and parietal areas.

Female Pattern Hair Loss

The role of androgens in the progression of FPHL is less well established. However, there is a strong genetic predisposition with 40% to 54% of patients reporting family history of pattern hair loss. The frequency of FPHL increases with age with 12% of women reporting symptoms by age 29%, 25% by 49 years, and >50% by 79 years.¹⁰

While FPHL and MPHL share a similar pathology resulting in progressive follicular miniaturization of terminal to vellus hairs and decreased anagen growth phase, the etiology of FPHL remains unclear. Interestingly, unlike MPHL, miniaturization in FPHL is not uniform and intense with relatively few areas of complete alopecia. While androgens are a primary driver of MPHL, many women with FPHL do not have elevated androgens. However, a genetic predisposition may exist whereby normal circulating levels of androgens act on follicular receptors that are highly sensitized. In addition, androgen-independent pathways may also exist that have yet to be elucidated.¹¹^,¹²^,¹³

Polycystic ovarian syndrome and metabolic syndrome are the two most commonly associated comorbidities noted with FPHL. The association of decreased iron levels and thyroid disorders has also been associated with FPHL. Some studies have shown that antiandrogen therapy is more efficacious in patients with ferritin levels >40 µg/L.¹⁴^,¹⁵

The diagnosis of FPHL is largely based on clinical history and physical exam. Details including when the hair loss started, whether it was gradual or sudden onset, and any associated physical, mental, or emotional stressors within the prior 3 to 6 months of hair loss are important to rule out acute and chronic telogen effluvium. Details regarding possible signs of hyperandrogenism including hirsutism, menstrual irregularities, acne, infertility, and ovarian abnormalities should be ascertained as positive findings and may necessitate laboratory workup. The physical exam is usually notable for widening of the central part with diffuse reduction in hair density over the frontal scalp (Figure 6.2). If there is any question regarding the diagnosis of hair loss, a scalp biopsy can provide valuable information.

FIGURE 6.1 The Hamilton-Norwood scale of male pattern hair loss.

FIGURE 6.2 Ludwig scale classification of female pattern hair loss.

ESTABLISHED TREATMENTS OF ANDROGENETIC ALOPECIA

First-Line Treatments

Currently, the only US Food and Drug Administration (FDA)-approved drugs for pattern alopecia are minoxidil for men and women and finasteride for men alone. The only FDA-cleared device is low-level light therapy, also known as photobiomodulation therapy (PBMT). A recent meta-analysis on the treatment for AGA published in the Journal of the American Academy of Dermatology in 2017 supported these findings.¹⁶

Minoxidil

Minoxidil is a potent vasodilator that was initially approved for hypertension by the FDA in 1979. The topical formulations of 2% and 5% were eventually approved for the treatment of AGA in men in 1988 and 1991, respectively. In 1991, the FDA approved 2% minoxidil for FPHL and most recently approved 5% minoxidil foam for once daily application in 2014.

Minoxidil is a prodrug that is converted to minoxidil sulfate by sulfotransferase enzymes in the outer root sheath of hair follicles. It functions through opening potassium channels and stimulates hair growth by increasing the anagen phase of the hair cycle. It also improves perifollicular angiogenesis. The recommended treatment dose is 1 mL of the 2% solution twice daily to the affected areas (males can use the 5% solution as well) or 1 mL of the 5% foam once daily to affected areas. A minimum period of 12 months of treatment is required to determine efficacy. Clinically, approximately 40% of patients show significant improvement after 3 to 6 months of treatment. However, response is only sustained with continuous treatment and cessation of medication may induce telogen effluvium within 4 to 6 months. In addition, patients may experience transient shedding during the first few months of treatment. While generally well tolerated, few patients may develop an allergic or irritant contact dermatitis, which is related to propylene glycol that is present in the solution formulation but not the foam.

Finasteride

In terms of systemic treatment, finasteride is the only FDA-approved medication for the treatment of AGA in men and was approved in 1997. Finasteride inhibits the type II 5-alpha reductase enzyme thereby preventing the conversion of testosterone to the more potent DHT. Clinically, the drug is administered orally at a dose of 1 mg daily for the treatment of MPHL. Studies have shown that consistent use of the medication for 5 years may decrease hair loss by about 50% to 90% with notable increases in hair diameter and growth rate.¹⁷ Hair regrowth is more likely in those who are younger and have milder hair loss. However, similar to minoxidil, the efficacy of finasteride is dependent on its continued use. Importantly, while clinical improvement may be seen as early as 3 months, consistent use of the medication for 6 to 12 months is necessary in order to evaluate for nonresponders (20%-30%).

The use of finasteride in women is not FDA approved and is contraindicated in pregnant women due to risk of feminization of the male fetus. While Shum et al. found 1.25 mg/day of finasteride improves FPHL in women with hyperandrogenism, there was no improvement in those without elevated androgens.¹⁸ Additionally, Price et al. showed that 1 mg/day of finasteride taken for 12 months was ineffective in postmenopausal women with FPHL.¹⁹ While some clinicians prescribe 1 to 5 mg of finasteride daily in postmenopausal women, its efficacy is highly variable. Larger, randomized controlled studies are required to determine the dosage and efficacy of finasteride in FPHL.

Post-Finasteride Syndrome

While finasteride is FDA approved for men and treatment is generally well tolerated, several side effects have been reported. These most commonly include decreased libido, erectile dysfunction, and decreased ejaculate volume that occur in approximately 1% to 4% of men. Prostate-specific antigen (PSA) levels may be reduced by approximately 50% during treatment due to decrease in DHT levels. This could mask an early diagnosis of prostate cancer and a baseline PSA is recommended in men older than 50 years prior to treatment initiation.²⁰^,²¹ Other reported adverse events include gynecomastia, impotence, anxiety, depression, and memory disturbances. While these side effects generally resolve following cessation of the medication, there are growing reports of persistence of many of these symptoms post discontinuation in what has been referred to as a “post-finasteride syndrome.” The most frequent symptoms reported include sexual dysfunction and psychological impairments including depression. Recent evidence suggests that finasteride may affect the metabolism of steroids in the brain and induce γ-aminobutyric acid imbalances, which could account for the symptoms noted in post-finasteride syndrome.²² However, further research is required to understand this syndrome as well as potential risk factors for patients who may develop these symptoms. Prior to initiation of finasteride, it is important all patients are informed of the risks regarding post-finasteride syndrome in addition to a low risk of gynecomastia, reversible sexual side effects, and the effect finasteride has on PSA and prostate cancer.

Photobiomodulation Therapy

PBMT, also known as low-level light therapy or low-level laser therapy, is a relatively new FDA-cleared treatment for AGA but has its origins in the 1960s. Dr Endre Mester first noted the beneficial effects of accelerated hair growth in mice following use of a low-power 694-nm ruby laser in 1967.²³ The initial skepticism due to lack of studies with PBMT has gradually dissipated over the last decade with more evidence demonstrating its efficacy in the treatment of hair loss.

The FDA first cleared a PBMT device for the treatment of AGA in males in 2007. Subsequently, the direct-consumer market for hair loss devices has grown rapidly with an increasing number of FDA-cleared PBMT devices including combs, headbands, caps, and helmets. These devices are cost-effective and have an excellent safety profile.
Currently, there are 29 FDA-cleared devices for the treatment of AGA in men and women (Fitzpatrick I-IV) with 13 of these devices commercially available for home-use treatment. All PBMT devices contain either diode lasers or light-emitting diodes (LEDs) which emit light continuously or in short, rapid pulses. Compared with lasers, LED devices may be more appealing as they are easier and safer to use with less risk of burns, as they emit noncoherent light. They can also deliver energy to a wider area of the scalp and are less expensive. Most devices use wavelengths between 650 and 700 nm and contain anywhere between 7 and 272 diode lasers/LEDs conferring a total power output between 35 and 1360 mW.²⁴ The specifics of each FDA-cleared device for home-use is listed in Table 6.1.

There are no head-to-head studies comparing the efficacy between various PBMT devices. Patient preference is most important when selecting the appropriate device
including design, ease of use, and affordability. Office-based PBMT devices such as Capillus272^TM OfficePro (Capillus LLC, Miami, FL) and the Sunetics Clinical Laser (Sunetics International Marketing Group LLC, Dallas, TX) are useful for patients who may not wish to purchase a device or who feel uncomfortable operating an at-home device.

TABLE 6.1 FDA-Cleared Lasers for Home Use

PBMT Device	Device Design	Light Parameters	Treatment Regimen	Approximate Retail Price
HairMax Prima 7 Laser Comb	Comb	7 LDs; 655 + 10nm CW	15 min; 3 times a week	$295
HairMax Ultima 9 Laser Comb	Comb	9 LDs; 655 + 10nm CW	15 min; 3 times a week	$395
HairMax Ultima 12 Laser Comb	Comb	12 LDs; 655 + 10nm CW	8 min; 3 times a week	$495
NutraStim Laser Hair Comb	Comb	12 LDs; 655 + 10nm CW	8 min; 3 times a week	$279
Theradome LH80 PRO	Helmet	80 LDs; 678 + 8nm CW	20 min; 2 times a week	$895
iRestore Hair Growth System	Helmet	21 LDs; 650 + 10nm CW 30 LEDs; 660 + 5nm PE	25 min; every other day	$595
iGrow Hair Growth System	Helmet	21 LDs; 655nm CW 30 LEDs; 655nm PE	25 min; every other day	$695
Capillus82 Laser Cap	Sports cap	82 LDs;	30 min; 3-4 times a week	$799
Capillus202 Laser Cap	Sports cap	202 LDs; 650nm PE	30 min; 3-4 times a week	$1999
Capillus272 Pro Laser Cap	Sports cap	272 LDs; 650nm PE	30 min; 3-4 times a week	$3000
LaserCap LCPRO	Sports cap	224 LDs; 650nm PE	36 min; every other day	$3000
HairMax LaserBand 41	Headband; moved by user every 30 s	41 LDs; 655 + 10nm CW	3 min; 3 times a week	$595
HairMax LaserBand 82	Headband; moved by user every 30 s	82 LDs; 655 + 10nm CW	90 s; 3 times a week	$795
CW, continuous wave; LD, laser diodes; LED, light-emitting diodes; PE, pulsed emission. From Dodd EM, Winter MA, Hordinsky MK, Sadick NS, Farah RS. Photobiomodulation therapy for androgenetic alopecia: A clinician’s guide to home-use devices cleared by the Federal Drug Administration. J Cosmet Laser Ther. 2018;20(3):159-167. Adapted by permission of Taylor & Francis Ltd, www.tandfonline.com.