REVIEWARTICLE

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

Jerry Shapiro1 and Keith D. Kaufman21Division of Dermatology, University of British Columbia,Vancouver General Hospital,Vancouver, British Columbia, Canada; 2Merck ResearchLaboratories, Rahway, New Jersey, USA

Finasteride, a type 2-selective 5a-reductase inhibitor,was approved in 1997 as the rst oral pharmacologictherapy for the treatment of men with androgeneticalopecia (AGA; male pattern hair loss). Originally de-veloped for the treatment of men with benign prostatichyperplasia (BPH) at a dose of 5 mg/day, nasteride hasa well-established, excellent safety prole. Subsequentstudies demonstrated that nasteride was an eectivetreatment for men with AGA at an optimal dose of

1 mg/day. This report summarizes the publishedpeer-reviewed literature on the use of nasteride in thetreatment of men with AGA, including the data onlong-term (5 years) use of nasteride in a placebo-con-trolled clinical trial environment. Key words: type 2 5a-reductase/nasteride/dihydrotestosterone/androgenetic alopecia/male pattern hair loss. JID Symposium Proceedings 8:20 ^23,2003

INITIAL CLINICAL STUDIES WITH FINASTERIDE INMEN WITH ANDROGENETIC ALOPECIA

Drake et al (1999) reported on the biochemical ecacyof nasteride in men with androgenetic alopecia(AGA), demonstrating that median scalp dihydro-testosterone 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 withplacebo. Median serum DHT levels decreased 71% and 72%, re-spectively, compared to a 1% increase with placebo. This studyalso demonstrated that at doses as low as 0.05 mg daily, nasteridesignicantly decreased scalp DHT, although only dosesX0.2 mgwere near-maximally eective in decreasing both scalp andserum DHT.Roberts et al (1999) reported on clinical dose-ranging studies

with nasteride at doses of 5, 1, 0.2 and 0.01 mg/day in men withAGA.These studies demonstrated that nasteride treatment led toboth an increase in hair count and cosmetic improvement in hairgrowth, establishing for the rst time the proof of concept forthe ecacy of nasteride in the treatment of men with AGA.The ecacy of nasteride 1 mg was similar to the ecacy ob-served with the 5-mg dose but was signicantly greater than theecacy observed with lower doses (0.2 mg and 0.01mg) of nas-teride. The 1-mg dose was generally well tolerated by patients,and its safety prole was similar to that seen with lower doses ofnasteride or placebo. The 1-mg dose was thus chosen as optimalfor further study in subsequent Phase III studies in men withAGA.

PHASE III STUDIES WITH FINASTERIDE IN MEN WITHANDROGENETIC ALOPECIA

Three double-blind, randomized, placebo-controlled Phase IIIstudies of nasteride were conducted in 1879 men ages 18^41years with mild to moderate AGA (Kaufman et al, 1998; Leydenet al, 1999). Two of the studies enrolled men with predominantlyvertex hair loss (n1553; Kaufman et al, 1998) and one study en-rolled men with predominantly frontal (anterior mid-scalp) hairloss (n 326; Leyden et al, 1999). Finasteride 1 mg or matchingplacebo tablets were taken once daily for 24 months in the vertexstudies and for 12 months in the frontal study. All three studiesdemonstrated that nasteride treatment led to a signicant im-provement in hair growth and slowing of further hair loss pro-gression, while placebo-treated men showed signicant hair loss.In the Phase III vertex hair loss studies, treatment with naster-

ide 1 mg/day produced clinical benet relative to baseline or pla-cebo for all four predened endpoints: hair counts obtained in adened, representative area of scalp hair loss; patient self-adminis-tered assessment of hair growth; investigator clinical assessmentof hair growth; and blinded assessment of standardized clinicalphotographs by an expert panel of dermatologists (global photo-graphic assessment).The assessment of standardized clinical photographs by the ex-

pert panel demonstrated that improvement in hair growth oc-curred in 48% of nasteride-treated men at one year, comparedwith 7% of men receiving placebo. The benet of nasteride in-creased further at two years: 66% of men were rated as havingimproved hair growth based on assessment of standardized clini-cal photographs, compared with 7% of men receiving placebo.The nasteride-related improvements in hair growth, based on

assessment of standardized clinical photographs, were associatedwith increased hair density, based on hair counts obtained in astandardized, 1-inch diameter, circular target area centered at theanterior leading edge of the vertex bald spot. Treatment with -nasteride led to an 11% mean increase in hair count compared tobaseline at 1 year, and this improvement was maintained at2 years. In contrast, men treated with placebo were documented

Reprint requests to: Keith D. Kaufman, Clinical Research RY34-A248,Merck Research Laboratories, 126 E. Lincoln Ave., Rahway, NJ 07065,USA; E-mail: keith_kaufman@merck.comAbbreviations: AGA, androgenetic alopecia; DHT, dihydrotestosterone;

PSA, prostate-specic antigen; BPH, benign prostatic hyperplastic

Accepted for publication February 1, 2003

0022-202X/03/$15.00 . Copyrightr 2003 by The Society for Investigative Dermatology, Inc.20

by hair count to have sustained progressive hair loss over 2 years.The net improvement in hair count (nasteride vs. placebo) wasthus 14% at 1year and 16% at 2 years. Only 17% of men receivingnasteride lost hair based on hair count during the 2-year studies,compared with 72% of men receiving placebo. These data de-monstrated that nasteride slowed the progression of hair loss.Despite mean hair counts being stable between years 1 and 2 fornasteride-treated patients, assessment of standardized clinicalphotographs demonstrated further improvement in these menbetween years 1 and 2. This nding indicated that treatment withnasteride produced further improvements in hair quality be-tween the rst and second year. The clinical relevance of theseimprovements was supported by the improvements reported bypatients based on a self-administered hair growth questionnaire.Analysis of this validated instrument indicated that the majorityof men reported slowing of scalp hair loss, increased scalp hairgrowth, improved appearance of scalp hair, and increased satisfac-tion with the appearance of scalp hair by 2 years, and thesechanges were superior to those reported by men treated with pla-cebo. Analysis of the investigators clinical assessment of patientsscalp hair also conrmed that nasteride treatment improvedscalp 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 nasteride to treat-ment with placebo and showed loss of the benet achieved in therst year by hair count and standardized clinical photography.Other subjects were randomly crossed over from treatment withplacebo to treatment with nasteride after 1year and showed sig-nicant gains. For subjects treated continuously with nasteride1 mg, hair count increases above baseline were maintainedthroughout the 2 years of the studies.The Phase III vertex hair loss studies demonstrated that nas-

teride 1 mg/day has an excellent safety prole. As in all clinicalstudies with nasteride, a marked and persistent suppression ofserum DHT levels was observed in nasteride-treated subjects,but this was not associated with signicant changes in serum go-nadotropins (luteinizing hormone (LH) and follicle-stimulatinghormone (FSH)). These data are consistent with previous dataon the lack of eect of nasteride on the hypothalamic pitui-tary-gonadal axis in young men. As expected, based on the pre-viously reported experience with nasteride, a few men in thevertex hair loss studies experienced reversible impairment of sex-ual function. Drug-related adverse events reported by X1% ofmen receiving nasteride 1 mg in the rst year were decreasedlibido (reported by 1.8% of men on nasteride vs. 1.3% on place-bo), erectile dysfunction (reported by 1.3% of men on nasteridevs. 0.7% on placebo) and ejaculation disorder (1.2% of men onnasteride vs. 0.7% on placebo). Approximately 1% (1.2%) ofmen receiving nasteride discontinued treatment due to these ad-verse events (compared with 0.9% of men in the placebo group)with resolution occurring after discontinuation of drug. No othersignicant adverse eects of nasteride were observed in the pa-tient population evaluated in these clinical studies. This excellentsafety prole is consistent with prior experience with nasterideat ve times the dose used in these studies, and has been well-documented in large clinical trials and postmarketing surveil-lance in men with benign prostatic hyperplasia (BPH) for nearly10 years. A modest reduction in serum prostate-specic antigen(PSA) was also observed in nasteride-treated subjects. In lightof the well-known inhibitory eect of nasteride on the growthof the prostate gland in men with BPH, this decrease in PSAwasnot unexpected. For men in whom serum PSA is used as part of ascreening evaluation for prostate cancer, guidelines have beenpublished for interpretation of PSA levels in men receiving nas-teride treatment.The Phase III frontal hair loss study was conducted in parallel

with the Phase III vertex hair loss studies in order to evaluate theecacy of nasteride 1 mg primarily in the anterior mid-scalparea, as opposed to the vertex. The frontal hair loss study usedsimilar endpoints to those used in the vertex studies and demon-strated signicant improvements in all predened ecacy mea-

sures with nasteride compared with placebo. Treatment withnasteride signicantly improved anterior mid-scalp hair countsand led to cosmetic improvement noted by patients, investigators,and the expert panel reviewing standardized clinical photographs.Based on the ndings from the Phase III vertex and frontal

hair loss studies, it can be concluded that nasteride is generallywell tolerated and leads to improvements in hair growth in menwith AGA, and slows the further progression of hair loss that oc-curs without treatment. Continued daily use of 1-mg oral nas-teride is needed for sustained benet. Based on hair counts, nofurther hair loss was observed in 83% of nasteride-treated menwith vertex hair loss after 2 years and in 70% of nasteride-treat-ment men with frontal hair loss after 1 year. Based on standar-dized clinical photography, the chances of mild to moderatevisible regrowth are 61% on the vertex (with an additional 5%achieving great visible regrowth) after 2 years and 37% on thefrontal area after 1year.

5-YEAR PLACEBO-CONTROLLED EXTENSIONS TOPHASE III VERTEX STUDIES

The previously described 2-year Phase III vertex hair loss studieswere extended for up to 5 years of placebo-controlled observa-tions (Finasteride Male Pattern Hair Loss Study Group, 2002).The results of these 5-year studies demonstrated that long-termtreatment with nasteride led to durable improvements in scalphair compared to treatment with placebo in men with AGA.Hair counts, which increased with nasteride treatment during

the rst year of the study, remained above baseline over 5 years.In contrast, men treated with placebo progressively lost hair over5 years, conrming the eect of continued miniaturization ofscalp hair that is the hallmark of this disorder.Thus, the treatmenteect of nasteride on hair count relative to placebo increasedprogressively over time, leading to a net improvement for nas-teride-treated men of 277 hairs in the target area compared toplacebo at 5 years. Most (65%) nasteride-treated men had in-creases in hair count at 5 years, compared to none of the placebo-treated men, but even for those nasteride-treated men with alower hair count at ve years compared to baseline, the averagemagnitude of loss was less than that observed in the placebogroup. These data support that the progression of hair loss ob-served in placebo-treated men was signicantly reduced by treat-ment with nasteride.Similarly, expert panel review of standardized clinical photo-

graphs conrmed the benet of nasteride treatment: 90% of -nasteride-treated men either maintained (no further visible hairloss from baseline), or sustained visible improvement in, scalp cov-erage over 5 years, while 75% of placebo-treated men sustainedvisible deterioration in scalp coverage (Fig 1). The investigators as-sessments also demonstrated a sustained benet of nasteride treat-ment over 5 years. Although there was no further improvementreported for nasteride-treated subjects between 2 and 5 years bythis assessment, there was signicant deterioration reported forplacebo-treated subjects during the same time period. Thus, thetreatment eect of nasteride, compared to placebo, as assessed bythe investigators increased between 2 and 5 years, indicatingfurther separation between the treatment groups over time.Analysis of the patient self-assessment data demonstrated the

relevance of the benet of nasteride from the patients perspec-tive. Men treated with nasteride had a more positive self-assess-ment of their hair growth and satisfaction with their appearancethan men treated with placebo, with the majority of nasteride-treated men reporting satisfaction with the overall appearance oftheir scalp hair at 5 years (Fig 2). Consistent with the ndings ofthe Phase III frontal hair loss study, patients satisfaction with theappearance of their frontal hairline was improved by treatmentwith nasteride in the vertex hair loss studies at 5 years.No new side-eects were reported from these long-term clin-

ical trials, and the incidence of side-eects reported in the rstyear decreased with continued use.

FINASTERIDE IN MEN WITH ANDROGENETIC ALOPECIA 21VOL. 8, NO. 1 JUNE 2003

In summary, the results of the two 5-year Phase III vertex hairloss studies conrm and extend the ndings from the published2-year results of these studies. Long-term treatment with nas-teride was generally well tolerated and led to signicant and dur-able improvements in hair growth while slowing the furtherprogression of hair loss that occurred without treatment in menwith AGA.

STUDIES EXAMINING MECHANISM(S) UNDERLYINGFINASTERIDES BENEFICIAL EFFECTS ON HAIR

GROWTH IN MEN WITH ANDROGENETIC ALOPECIA

A number of clinical studies have been conducted to examinethe mechanism(s) by which nasteride may produce its benecial

eects on hair growth in men with AGA. Whiting et al (1999)conducted a histologic study of scalp biopsies taken from men atbaseline and after 12 months of treatment with either nasteride1 mg or placebo. This study demonstrated that treatment with -nasteride led to a signicant increase in terminal anagen hairsafter 12 months compared to placebo. Histologically, a trend to-wards a decrease in vellus-like miniaturized hairs and an increasein the terminal to vellus ratio was observed in the nasteridegroup compared to the placebo group, suggesting reversal of theminiaturization process with nasteride.A second study by Van Neste et al (2000) using the phototri-

chogram method provided direct evidence that treatment withnasteride 1mg promotes the conversion of hairs into the anagenphase. This study enrolled 212 men ages 18^40 years with AGA,randomized to either nasteride 1 mg or placebo daily for48 weeks. Macrophotographs were taken to measure both totaland anagen hair counts in a 1-cm2 target area of the vertex scalp.At 48 weeks, treatment with nasteride signicantly increasedboth total and anagen hair counts and improved the anagen/telo-gen ratio, resulting in a net improvement in the anagen/telogenratio of 47% compared to placebo.

EFFECTS OF FINASTERIDE IN WOMEN WITHANDROGENETIC ALOPECIA

In contrast to all of the studies described above, which were con-ducted in men with AGA, a study of nasteride in postmenopau-sal women with AGA showed no benet (Price et al, 2000). In this1-year, double-blind, randomized, placebo-controlled trial, 137postmenopausal women (41^60 years of age) with AGA receivednasteride 1 mg/day or placebo. Ecacy was evaluated by scalphair counts, patient and investigator assessments, ratings of stan-dardized clinical photographs by an expert panel, and histologicanalysis of scalp biopsies. Although nasteride was generally welltolerated, after 1year of treatment there was no signicant dier-ence in the change in hair count between the nasteride and pla-cebo groups, and decreases in hair count in the frontal/parietalscalp were observed in both treatment groups. Similarly, patient,investigator, and standardized clinical photographic assessmentsdid not demonstrate improvement in slowing hair loss, increasinghair growth, or improving the appearance of scalp hair in nas-teride-treated subjects compared with the placebo group. Thesendings were conrmed by histologic analysis of scalp biopsiesfrom women participating in the trial (n 94; Whiting et al,1999; Price et al, 2000), which also showed no improvement.

CONCLUSION

5a-reductase inhibitors were developed approximately 20 yearsago. Their subsequent use as tools to understand both androgenbiology and disease pathophysiology has led to an understandingof the key role DHT plays in the pathophysiology of AGA inmen. Finasteride was the rst, highly specic inhibitor of thehuman type 2 5a-reductase enzyme developed for clinical use.Accumulated data from multicenter clinical trials have establishednasterides importance as a treatment for men with androgen-dependent disorders, including AGA. Finasterides mechanism ofaction, which leads to reduced levels of DHT when the drug isadministered orally, represents a rational approach to the treat-ment of men with AGA. Because it is a systemic medication,nasteride is delivered to the entire scalp, including the aectedareas.The clinical studies demonstrated responsiveness to naster-ide treatment across a broad range of men with AGA, those withmild to moderate degrees of hair loss in the vertex and anteriormid-scalp areas. No signicant clinical or laboratory adverseeects have been observed with nasteride that preclude itslong-term use by men. Moreover, nasteride is not a new drug,and worldwide experience with a higher dose of nasteride overmany years in the treatment of men with BPH conrms the

Figure1. Finasteride treatment led to no further visible hair lossfrom baseline in the majority of men over 5 years of observation,based on expert panel review of standardized clinical photographsfor the cohort of patients in the combined Phase III vertex hair lossstudies who entered the last (fth) placebo-controlled extensionstudies. Conversely, most (75%) men treated with placebo sustainedfurther visible hair loss at 5 years.

Figure 2. Finasteride treatment led to a more positive self-assess-ment of scalp hair appearance compared with placebo over 5 yearsof observation. One-year and 5-year data are shown for the percent ofmen who self-reported their degree of satisfaction with the overall appear-ance of their scalp hair compared with baseline for the cohort of patients inthe combined Phase III vertex hair loss studies who entered the last (fth)placebo-controlled extension studies.

22 SHAPIROAND KAUFMAN JID SYMPOSIUM PROCEEDINGS

long-term safety of the compound. The eectiveness of naster-ide in the treatment of men with androgen-dependent disorders,including AGA, has prompted the development of other inhibi-tors of 5a-reductase, as well as increasing research in modulatorsof androgen action, for potential use in treating men with thesedisorders.

The authors wish to thank DrAlan Meehan, Merck & Co., Inc., for his assistance inthe preparation of this manuscript.

REFERENCES

Drake L, Hordinsky M, Fiedler V, et al: The eects of nasteride on scalp skin andserum androgen levels in men with androgenetic alopecia. J Am Acad Dermatol41:550^554, 1999

Finasteride Male Pattern Hair Loss Study Group: Long-term (5-year) multinationalexperience with nasteride 1 mg in the treatment of men with androgeneticalopecia. J Eur Dermatol 12:38^49, 2002

Kaufman KD, Olsen EA,Whiting D, et al: Finasteride in the treatment of men withandrogenetic alopecia. J Am Acad Dermatol 39:578^589, 1998

Leyden J, Dunlap F, Miller B, et al: Finasteride in the treatment of men with frontalmale pattern hair loss. J Am Acad Dermatol 40:930^937, 2002

Price VH, Roberts JL, Hordinsky M, et al: Lack of ecacy of nasteride in postme-nopausal women with androgenetic alopecia. J Am Acad Dermatol 43:768^776,2000

Roberts JL, Fiedler V, Imperato-Mcginley J, et al: Clinical dose ranging studies withnasteride, a type 2 5a-reductase inhibitor, in men with male pattern hair loss.J Am Acad Dermatol 41:555^563, 1999

Van Neste D, Fuh V, Sanchez-Pedreno P, et al: Finasteride increases anagen hair inmen with androgenetic alopecia. Br J Dermatol 143:804^810, 2000

Whiting DA,Waldstreicher J, Sanchez M, Kaufman KD: Measuring reversal of hairminiaturization in androgenetic alopecia by follicular counts in horizontalsections of serial scalp biopsies: Results of nasteride 1 mg treatment of menand postmenopausal women. J Invest Dermatol Symposium Proceedings 4:282^284,1999

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