Use of Finasteride in the Treatment of Men With Androgenetic Alopecia (Male Pattern Hair Loss)

reported on the biochemical efficacy of finasteride in men with androgenetic alopecia (AGA), demonstrating that median scalp dihydrotestosterone DHT levels were decreased by 64% and 69% after 42 days of treatment at doses of 1 mg and 5 mg, respectively, compared to a 13% decrease with placebo. Median serum DHT levels decreased 71% and 72%, respectively, compared to a 1% increase with placebo. This study also demonstrated that at doses as low as 0.05 mg daily, finasteride significantly decreased scalp DHT, although only doses ≥0.2 mg were near-maximally effective in decreasing both scalp and serum DHT.

reported on clinical dose-ranging studies with finasteride at doses of 5, 1, 0.2 and 0.01 mg/day in men with AGA. These studies demonstrated that finasteride treatment led to both an increase in hair count and cosmetic improvement in hair growth, establishing for the first time the proof of concept for the efficacy of finasteride in the treatment of men with AGA. The efficacy of finasteride 1 mg was similar to the efficacy observed with the 5-mg dose but was significantly greater than the efficacy observed with lower doses (0.2 mg and 0.01 mg) of finasteride. The 1-mg dose was generally well tolerated by patients, and its safety profile was similar to that seen with lower doses of finasteride or placebo. The 1-mg dose was thus chosen as optimal for further study in subsequent Phase III studies in men with AGA.

Three double-blind, randomized, placebo-controlled Phase III studies of finasteride were conducted in 1879 men ages 18–41 years with mild to moderate AGA (;Leyden et al, 1999). Two of the studies enrolled men with predominantly vertex hair loss (n=1553;) and one study enrolled men with predominantly frontal (anterior mid-scalp) hair loss (n=326; Leyden et al, 1999). Finasteride 1 mg or matching placebo tablets were taken once daily for 24 months in the vertex studies and for 12 months in the frontal study. All three studies demonstrated that finasteride treatment led to a significant improvement in hair growth and slowing of further hair loss progression, while placebo-treated men showed significant hair loss.

In the Phase III vertex hair loss studies, treatment with finasteride 1 mg/day produced clinical benefit relative to baseline or placebo for all four predefined endpoints: hair counts obtained in a defined, representative area of scalp hair loss; patient self-administered assessment of hair growth; investigator clinical assessment of hair growth; and blinded assessment of standardized clinical photographs by an expert panel of dermatologists (global photographic assessment).

The assessment of standardized clinical photographs by the expert panel demonstrated that improvement in hair growth occurred in 48% of finasteride-treated men at one year, compared with 7% of men receiving placebo. The benefit of finasteride increased further at two years: 66% of men were rated as having improved hair growth based on assessment of standardized clinical photographs, compared with 7% of men receiving placebo.

The finasteride-related improvements in hair growth, based on assessment of standardized clinical photographs, were associated with increased hair density, based on hair counts obtained in a standardized, 1-inch diameter, circular target area centered at the anterior leading edge of the vertex bald spot. Treatment with finasteride led to an 11% mean increase in hair count compared to baseline at 1 year, and this improvement was maintained at 2 years. In contrast, men treated with placebo were documented by hair count to have sustained progressive hair loss over 2 years. The net improvement in hair count (finasteride vs. placebo) was thus 14% at 1 year and 16% at 2 years. Only 17% of men receiving finasteride lost hair based on hair count during the 2-year studies, compared with 72% of men receiving placebo. These data demonstrated that finasteride slowed the progression of hair loss. Despite mean hair counts being stable between years 1 and 2 for finasteride-treated patients, assessment of standardized clinical photographs demonstrated further improvement in these men between years 1 and 2. This finding indicated that treatment with finasteride produced further improvements in hair quality between the first and second year. The clinical relevance of these improvements was supported by the improvements reported by patients based on a self-administered hair growth questionnaire. Analysis of this validated instrument indicated that the majority of men reported slowing of scalp hair loss, increased scalp hair growth, improved appearance of scalp hair, and increased satisfaction with the appearance of scalp hair by 2 years, and these changes were superior to those reported by men treated with placebo. Analysis of the investigators' clinical assessment of patients' scalp hair also confirmed that finasteride treatment improved scalp hair growth compared to treatment with placebo.

Some subjects in the vertex hair loss studies were randomly crossed over after 1 year from treatment with finasteride to treatment with placebo and showed loss of the benefit achieved in the first year by hair count and standardized clinical photography. Other subjects were randomly crossed over from treatment with placebo to treatment with finasteride after 1 year and showed significant gains. For subjects treated continuously with finasteride 1 mg, hair count increases above baseline were maintained throughout the 2 years of the studies.

The Phase III vertex hair loss studies demonstrated that finasteride 1 mg/day has an excellent safety profile. As in all clinical studies with finasteride, a marked and persistent suppression of serum DHT levels was observed in finasteride-treated subjects, but this was not associated with significant changes in serum gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)). These data are consistent with previous data on the lack of effect of finasteride on the hypothalamic pituitary-gonadal axis in young men. As expected, based on the previously reported experience with finasteride, a few men in the vertex hair loss studies experienced reversible impairment of sexual function. Drug-related adverse events reported by ≥1% of men receiving finasteride 1 mg in the first year were decreased libido (reported by 1.8% of men on finasteride vs. 1.3% on placebo), erectile dysfunction (reported by 1.3% of men on finasteride vs. 0.7% on placebo) and ejaculation disorder (1.2% of men on finasteride vs. 0.7% on placebo). Approximately 1% (1.2%) of men receiving finasteride discontinued treatment due to these adverse events (compared with 0.9% of men in the placebo group) with resolution occurring after discontinuation of drug. No other significant adverse effects of finasteride were observed in the patient population evaluated in these clinical studies. This excellent safety profile is consistent with prior experience with finasteride at five times the dose used in these studies, and has been well-documented in large clinical trials and postmarketing surveillance in men with benign prostatic hyperplasia (BPH) for nearly 10 years. A modest reduction in serum prostate-specific antigen (PSA) was also observed in finasteride-treated subjects. In light of the well-known inhibitory effect of finasteride on the growth of the prostate gland in men with BPH, this decrease in PSA was not unexpected. For men in whom serum PSA is used as part of a screening evaluation for prostate cancer, guidelines have been published for interpretation of PSA levels in men receiving finasteride treatment.

The Phase III frontal hair loss study was conducted in parallel with the Phase III vertex hair loss studies in order to evaluate the efficacy of finasteride 1 mg primarily in the anterior mid-scalp area, as opposed to the vertex. The frontal hair loss study used similar endpoints to those used in the vertex studies and demonstrated significant improvements in all predefined efficacy measures with finasteride compared with placebo. Treatment with finasteride significantly improved anterior mid-scalp hair counts and led to cosmetic improvement noted by patients, investigators, and the expert panel reviewing standardized clinical photographs.

Based on the findings from the Phase III vertex and frontal hair loss studies, it can be concluded that finasteride is generally well tolerated and leads to improvements in hair growth in men with AGA, and slows the further progression of hair loss that occurs without treatment. Continued daily use of 1-mg oral finasteride is needed for sustained benefit. Based on hair counts, no further hair loss was observed in 83% of finasteride-treated men with vertex hair loss after 2 years and in 70% of finasteride-treatment men with frontal hair loss after 1 year. Based on standardized clinical photography, the chances of mild to moderate visible regrowth are 61% on the vertex (with an additional 5% achieving great visible regrowth) after 2 years and 37% on the frontal area after 1 year.

The previously described 2-year Phase III vertex hair loss studies were extended for up to 5 years of placebo-controlled observations (). The results of these 5-year studies demonstrated that long-term treatment with finasteride led to durable improvements in scalp hair compared to treatment with placebo in men with AGA.

Hair counts, which increased with finasteride treatment during the first year of the study, remained above baseline over 5 years. In contrast, men treated with placebo progressively lost hair over 5 years, confirming the effect of continued miniaturization of scalp hair that is the hallmark of this disorder. Thus, the treatment effect of finasteride on hair count relative to placebo increased progressively over time, leading to a net improvement for finasteride-treated men of 277 hairs in the target area compared to placebo at 5 years. Most (65%) finasteride-treated men had increases in hair count at 5 years, compared to none of the placebo- treated men, but even for those finasteride-treated men with a lower hair count at five years compared to baseline, the average magnitude of loss was less than that observed in the placebo group. These data support that the progression of hair loss observed in placebo-treated men was significantly reduced by treatment with finasteride.

Similarly, expert panel review of standardized clinical photographs confirmed the benefit of finasteride treatment: 90% of finasteride-treated men either maintained (no further visible hair loss from baseline), or sustained visible improvement in, scalp coverage over 5 years, while 75% of placebo-treated men sustained visible deterioration in scalp coverage (Figure 1). The investigators' assessments also demonstrated a sustained benefit of finasteride treatment over 5 years. Although there was no further improvement reported for finasteride-treated subjects between 2 and 5 years by this assessment, there was significant deterioration reported for placebo-treated subjects during the same time period. Thus, the treatment effect of finasteride, compared to placebo, as assessed by the investigators increased between 2 and 5 years, indicating further separation between the treatment groups over time.

Analysis of the patient self-assessment data demonstrated the relevance of the benefit of finasteride from the patient's perspective. Men treated with finasteride had a more positive self-assessment of their hair growth and satisfaction with their appearance than men treated with placebo, with the majority of finasteride-treated men reporting satisfaction with the overall appearance of their scalp hair at 5 years (Figure 2). Consistent with the findings of the Phase III frontal hair loss study, patients' satisfaction with the appearance of their frontal hairline was improved by treatment with finasteride in the vertex hair loss studies at 5 years.

No new side-effects were reported from these long-term clinical trials, and the incidence of side-effects reported in the first year decreased with continued use.

In summary, the results of the two 5-year Phase III vertex hair loss studies confirm and extend the findings from the published 2-year results of these studies. Long-term treatment with finasteride was generally well tolerated and led to significant and durable improvements in hair growth while slowing the further progression of hair loss that occurred without treatment in men with AGA.

A number of clinical studies have been conducted to examine the mechanism(s) by which finasteride may produce its beneficial effects on hair growth in men with AGA. Whiting et al (1999) conducted a histologic study of scalp biopsies taken from men at baseline and after 12 months of treatment with either finasteride 1 mg or placebo. This study demonstrated that treatment with finasteride led to a significant increase in terminal anagen hairs after 12 months compared to placebo. Histologically, a trend towards a decrease in vellus-like miniaturized hairs and an increase in the terminal to vellus ratio was observed in the finasteride group compared to the placebo group, suggesting reversal of the miniaturization process with finasteride.

A second study by using the phototrichogram method provided direct evidence that treatment with finasteride 1 mg promotes the conversion of hairs into the anagen phase. This study enrolled 212 men ages 18–40 years with AGA, randomized to either finasteride 1 mg or placebo daily for 48 weeks. Macrophotographs were taken to measure both total and anagen hair counts in a 1-cm² target area of the vertex scalp. At 48 weeks, treatment with finasteride significantly increased both total and anagen hair counts and improved the anagen/telogen ratio, resulting in a net improvement in the anagen/telogen ratio of 47% compared to placebo.

In contrast to all of the studies described above, which were conducted in men with AGA, a study of finasteride in postmenopausal women with AGA showed no benefit (). In this 1-year, double-blind, randomized, placebo-controlled trial, 137 postmenopausal women (41–60 years of age) with AGA received finasteride 1 mg/day or placebo. Efficacy was evaluated by scalp hair counts, patient and investigator assessments, ratings of standardized clinical photographs by an expert panel, and histologic analysis of scalp biopsies. Although finasteride was generally well tolerated, after 1 year of treatment there was no significant difference in the change in hair count between the finasteride and placebo groups, and decreases in hair count in the frontal/parietal scalp were observed in both treatment groups. Similarly, patient, investigator, and standardized clinical photographic assessments did not demonstrate improvement in slowing hair loss, increasing hair growth, or improving the appearance of scalp hair in finasteride-treated subjects compared with the placebo group. These findings were confirmed by histologic analysis of scalp biopsies from women participating in the trial (n=94;^;), which also showed no improvement.

5α-reductase inhibitors were developed approximately 20 years ago. Their subsequent use as tools to understand both androgen biology and disease pathophysiology has led to an understanding of the key role DHT plays in the pathophysiology of AGA in men. Finasteride was the first, highly specific inhibitor of the human type 2 5α-reductase enzyme developed for clinical use. Accumulated data from multicenter clinical trials have established finasteride's importance as a treatment for men with androgen-dependent disorders, including AGA. Finasteride's mechanism of action, which leads to reduced levels of DHT when the drug is administered orally, represents a rational approach to the treatment of men with AGA. Because it is a systemic medication, finasteride is delivered to the entire scalp, including the affected areas. The clinical studies demonstrated responsiveness to finasteride treatment across a broad range of men with AGA, those with mild to moderate degrees of hair loss in the vertex and anterior mid-scalp areas. No significant clinical or laboratory adverse effects have been observed with finasteride that preclude its long-term use by men. Moreover, finasteride is not a new drug, and worldwide experience with a higher dose of finasteride over many years in the treatment of men with BPH confirms the long-term safety of the compound. The effectiveness of finasteride in the treatment of men with androgen-dependent disorders, including AGA, has prompted the development of other inhibitors of 5α-reductase, as well as increasing research in modulators of androgen action, for potential use in treating men with these disorders.