This article is an update of the currently available options for medical therapies to treat androgenetic alopecia in men and women. Emerging novel therapeutic modalities with potential for treating these patients are discussed. Because androgenetic alopecia is progressive in nature, stabilization of the process using medical therapy is an important adjunct to any surgical hair-restoration plan.
Key points
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Topically applied minoxidil results in increased hair weight with a less dramatic increase in hair counts, suggesting that its therapeutic effect is primarily due to increasing the diameter of existing hairs.
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Finasteride is a type II 5α-reductase inhibitor that decreases serum and scalp levels of dihydrotestosterone. Administered orally at a dose of 1 mg daily, it is by far the most effective FDA-approved treatment of male pattern hair loss.
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Although a small number of men claim that they have suffered permanent sexual dysfunction despite discontinuation of finasteride, most large, double-blind, placebo-controlled studies do not confirm the claims of persistent sexual dysfunction. In a subset of men, however, prolonged sexual side effects lasting weeks to months have been reported and patients should be advised to report promptly any side effects.
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The optimal frequency, power, and duration of low-level light therapy for treating pattern hair loss have yet to be determined. Current treatment protocols are determined on an empiric basis. Theoretically, it is possible that too high a dose could result in a reversal of therapeutic benefit.
Introduction
The introduction of minoxidil in the late 1970s and systemic 5α-reductase inhibitor therapy in the late 1990s each provided, for the first time, an effective means for halting the progression of male pattern baldness and, in some cases, achieving regrowth. Medical therapy is most effective when started in the early phases of pattern hair loss and patients may elect to be treated solely with nonsurgical modalities. Undoubtedly, as long as surgical hair restoration is limited by a finite donor supply, medical therapy will play a central role as an adjunct to surgical treatment by preventing loss of surrounding native hair and thus enhancing the overall aesthetic result.
Introduction
The introduction of minoxidil in the late 1970s and systemic 5α-reductase inhibitor therapy in the late 1990s each provided, for the first time, an effective means for halting the progression of male pattern baldness and, in some cases, achieving regrowth. Medical therapy is most effective when started in the early phases of pattern hair loss and patients may elect to be treated solely with nonsurgical modalities. Undoubtedly, as long as surgical hair restoration is limited by a finite donor supply, medical therapy will play a central role as an adjunct to surgical treatment by preventing loss of surrounding native hair and thus enhancing the overall aesthetic result.
Minoxidil
Minoxidil was originally developed as an antihypertensive agent that attracted interest as a potential hair loss therapy when patients receiving this drug via the oral route were noted to develop generalized hypertrichosis. This observation led to its topical formulation, which has become a first-line treatment of pattern hair loss in men and women. Topically applied minoxidil is currently available as an over-the-counter preparation in either a 2% or 5% solution, or as a 5% foam.
Mechanism of Action of Minoxidil
Minoxidil’s mechanism of action was originally thought to be secondary to vasodilation but, recently, it has been linked to the opening of potassium channels. In the stump-tail macaque, minoxidil was shown to increase follicle size in histologic sections as well as the percentage of anagen follicles. These findings have been confirmed in clinical studies of male-pattern hair loss (MPHL). Topically applied minoxidil increases hair weight with a less dramatic increase in hair counts, suggesting that its therapeutic effect is primarily due to increasing the diameter of existing hairs. In MPHL, the 5% concentration is superior in efficacy to 2%, with 45% more hair growth after 48 weeks of treatment. It should be noted that, although the package label states that minoxidil is indicated for treatment of the vertex, in the authors’ experience it is effective for treating the top scalp and frontal areas.
Side Effects of Minoxidil
The most commonly observed side effect is allergic or irritant contact dermatitis. This is predominately in reaction to propylene glycol, which is used to enhance minoxidil solubility in the liquid vehicle. It should be noted that, although less frequent, true allergic reactions to minoxidil also occur. Irritant contact dermatitis occurs less frequently with the 2% compared with the 5% solution. Patients exhibiting this type of reaction can be switched to the 5% foam vehicle, which is formulated without propylene glycol. If reactions persist, contact allergy to minoxidil is likely and, therefore, all minoxidil preparations should be discontinued. In the absence of contact reactions, compliance issues may arise either from the cosmetic appearance of the hair following application (which may influence the choice of foam or liquid) or from the need for twice daily use. Compounding tretinoin into a minoxidil solution may increase its efficacy and improve compliance because once daily application of 5% minoxidil with 0.01% tretinoin was shown to be equal in efficacy to twice-daily 5% minoxidil alone.
Minoxidil Use in Females
For women, minoxidil is marketed only as a 2% solution because the 5% solution is associated with a greater incidence of hypertrichosis. In a study of 1333 women with female-pattern hair loss (FPHL), 4% developed hypertrichosis outside the area of application. This was more frequent with the 5% solution than the 2% solution and generally resolved 1 to 3 months after discontinuation. A more recent study showed equal efficacy in women who applied the 2% solution twice daily compared with a single daily application of the 5% foam, with the latter resulting in less pruritus and flaking. There is increasing evidence that FPHL is associated with a significant inflammatory component and a formulation of 5% minoxidil with 0.025% retinoic acid and 0.05% betamethasone dipropionate has been shown to be effective in treating women with FPHL ( Fig. 1 ). It should be noted that minoxidil might be harmful in women who are pregnant or breastfeeding.
Finasteride
Finasteride is a type II 5α-reductase inhibitor that decreases serum and scalp levels of dihydrotestosterone (DHT). It is administered orally at a dose of 1 mg daily and is by far the most effective FDA-approved treatment of MPHL. It acts predominantly by increasing hair diameter and growth rate, although increased hair counts are also observed to a lesser degree. In 1553 men, daily treatment with 1 mg finasteride resulted in stabilization of pattern hair loss in 51% and regrowth in 48% of subjects. The first signs of efficacy are usually seen at 3 months when men who complain of increased hair shedding during their hair loss process begin to notice improvement in this parameter. To assess fully stabilization and/or regrowth, 12 months of therapy are required.
Side Effects of Finasteride
Finasteride was evaluated for safety in a large clinical trial of subjects with MPHL. The most common drug-related side effects were decreased libido (1.9%), erectile dysfunction (1.4%), and decreased ejaculate volume (1.0%). Resolution of these side effects occurred in those men who discontinued the drug and in many of those who continued therapy. In the authors practice, we have observed resolution of side effects in some patients simply by prescribing every-other-day dosing. In a dose-ranging study of men ages 18 to 36 years, 0.2, 1, and 5 mg daily were shown to be effective compared with placebo. Doses of 1 and 5 mg daily had similar efficacy, whereas 0.2 mg daily showed 70% to 90% of the effect seen with 1 mg, depending on the parameter being measured. The effectiveness of lower doses may serve as a rationale for decreasing daily dosage or frequency of administration in patients who develop side effects. Postmarketing side effects reported include breast tenderness and/or enlargement, breast nodules, depression, allergic reactions, testicular pain, and rare cases of male breast cancer. Although a small number of men claim that they have suffered permanent sexual dysfunction despite discontinuation of the drug, most large, double-blind, placebo-controlled studies do not confirm the claims of persistent sexual dysfunction. In a subset of men, however, prolonged sexual side effects lasting weeks to months have been reported and patients should be advised to report promptly any side effects.
Men older than age 45 should be advised that finasteride affects the results of prostate-specific antigen testing and, therefore, should report the use of this medication to their physician. In the 7-year prostate cancer prevention trial, men older than age 55 taking finasteride 5 mg daily (5 times the daily dose of Propecia) had an overall decrease in the incidence of prostate cancer, but those who did develop prostate cancer had a higher proportion of histologically high-grade tumors. It has not been clearly established whether this effect was due to histologic grading artifacts that have been observed with androgen deprivation therapy or to increased sampling density bias from reducing prostate volume, or if 5α-reductase inhibitors may increase the risk of developing high-grade prostate cancer. Additional validation is necessary to draw firm conclusions. Women should not handle crushed or broken finasteride tabs when they are pregnant or trying to become pregnant because of the possibility of percutaneous absorption and subsequent risk to the male fetus.
Finasteride Use in Females
Finasteride therapy for FPHL was first evaluated in a large well-controlled study of postmenopausal women in which a 1 mg daily dose was shown to have no effect. Although a handful of case reports have demonstrated stabilization of hair loss with some regrowth using higher doses than what is used in men (2.5–5 mg daily), the limited clinical studies available show varying results. Thirty-seven premenopausal women with no evidence of hyperandrogenism were treated with 2.5 mg of finasteride orally plus an oral contraceptive agent containing ethinyl estradiol and drospirenone for 12 months. Scalp photography showed improvement in 62% of the subjects, of which half were slightly improved and half were moderately to greatly improved. Thirty-five percent of the study subjects had stabilization of their hair loss. In addition, there was a statistically significant increase in the hair density score in 12 subjects. No adverse reactions to the drug were reported. In a separate study of 87 normoandrogenic premenopausal and postmenopausal women, 5 mg of finasteride daily for 12 months showed a statistically significant improvement in hair density and hair thickness on phototrichogram. In addition, 81.4% improved on global photographic assessment. Although finasteride would be expected to be particularly effective in women with hyperandrogenism, a study of 48 premenopausal women with documented hyperandrogenism showed that finasteride 5 mg daily did not result in a statistically significant improvement as measured by Ludwig score and subjective assessment of clinical improvement. Finasteride is not approved by the FDA for the treatment of FPHL and, therefore, is prescribed off label. Pregnancy must be ruled out before instituting therapy and women should be maintained on strict birth contraception during treatment.
Other Antiandrogens for Female Hair Loss
Other antiandrogens for systemic use in FPHL include spironolactone and cyproterone acetate (the latter not available in the United States). Spironolactone requires 6 to 12 months to exhibit a therapeutic effect and treatment is generally initiated with a low dose of 25 to 50 mg daily, which is then gradually increased to a maintenance dose of 100 to 200 mg daily, which is the dose required to attain a therapeutic benefit. In a study of 80 FPHL subjects, 200 mg daily of spironolactone was equivalent to 100 mg daily of cyproterone acetate, resulting in 44% of subjects experiencing regrowth, 44% with stabilization, and 12% with further hair loss. It should be noted that spironolactone may elevate serum potassium levels and regular monitoring is necessary. In addition, patients should be advised to adhere to strict, effective birth contraception while taking antiandrogens because they pose a risk to the fetus.
Dutasteride
Dutasteride inhibits both type I and type II 5α-reductase and was approved by the FDA in 2002 for the treatment of benign prostatic hyperplasia at a dose of 0.5 mg per day. Since then, dutasteride has been used off label for the treatment of MPHL and FPHL. Compared to finasteride, dutasteride is 3 times more potent for inhibiting type II 5α-reductase and 100 times more potent for inhibiting the type I enzyme in vitro. In a study of 416 men ages 21 to 45 years, various doses of dutasteride were compared with finasteride 5 mg or placebo for 24 weeks of treatment. Finasteride 1 mg was not available at the time of the study and previous data showed that 1 and 5 mg of finasteride were equal in efficacy for treatment of MPHL. All dutasteride doses tested (0.05, 0.1, 0.5, 2.5 mg) and finasteride 5 mg were significantly better than placebo at 12 and 24 weeks, but only dutasteride at a 2.5 mg daily dose was statistically superior to finasteride with respect to hair counts. There was no significant difference in adverse events, but it is noteworthy that 9 of 71 subjects treated with dutasteride 2.5 mg daily developed decreased libido, whereas only 1 of 68 subjects treated with dutasteride 0.5 mg complained of this side effect. Because scalp DHT suppression most likely correlates with clinical efficacy, we might speculate that a dutasteride 0.5 mg daily dose should be superior to finasteride as reflected by the 51% scalp DHT reduction observed with dutasteride 0.5 mg compared with the 32% suppression of finasteride. Although dutasteride 2.5 mg showed a 79% reduction, the frequency of sexual side effects cited above suggests that, from a risk benefit ratio, 0.5 mg daily may be the optimal dose. In fact, this dose was evaluated in a phase III 6 month trial of 153 men ages 18 to 49 years that showed a statistically significant improvement compared with placebo with regard to hair counts, self-assessment scores, and photographic assessment.
Side Effects of Dutasteride
Sexual dysfunction was reported in 4.1% of the subjects in the treatment group compared with 2.7% of those receiving placebo. Unfortunately, the study did not evaluate sperm parameters; concern in this regard has been raised by a study that showed decreased sperm counts after 26 weeks of treatment with dutasteride 0.5 mg daily in 27 subjects, with 2 subjects developing greater than 90% reduction in sperm count that, after 24 weeks of discontinuing therapy, improved by only 20%. This brings to light concern with dutasteride side effects because the half-life of the drug is 4 to 5 weeks compared with the half-life of finasteride, which is only 6 to 8 hours. Therefore, any side effects that occur secondary to dutasteride may take much longer to resolve than with finasteride. Additionally, this drug should be used with caution in men with MPHL due to concerns of infertility. The authors suggest that dutasteride should be reserved for cases of MPHL that are refractory to finasteride therapy. We have observed stabilization of hair loss in such patients with a 0.5 mg daily dose ( Fig. 2 ). Of the first three such patients treated, all in their early twenties, two developed profoundly decreased sperm counts that gradually returned to normal after discontinuing the drug. A case report describes a patient who was experiencing decreased response to finasteride after 4 years of therapy and experienced an increase in hair density 3 months after the addition of dutasteride at 0.5 mg weekly. The extended half-life of dutasteride serves as a rationale for intermittent dosing even though the optimal frequency interval has not been determined.
