Advances in the treatment of male androgenetic alopecia. A brief review of finasteride studies

ARTICLE

Male androgenetic alopecia is a common condition, which eventually affects at least half the world's adult male population. It is an inherited condition, which is thought to be dominantly inherited, with variable penetrance [1-4]. The gene or genes have not yet been identified. Its presumed androgen dependance is based on the observation that it is prevented by early castration but can develop if the castrate is treated with androgen replacement [5]. Furthermore, males who lack the enzyme type 2 5alpha-reductase do not produce much dihydrotestosterone (DHT) and do not become bald [6, 7].

The characteristic balding of the crown, as evidenced by bitemporal recession of hair and vertex baldness, is diagnostic of male pattern alopecia [8]. The underlying change responsible for the balding process is a progressive miniaturization of terminal hairs on the crown [9-11]. Although the traditional view of miniaturization has been that of a gradual, step wise progression, there is mounting evidence that the process can occur, or be reversed, abruptly [12], perhaps in one hair growth cycle.

The first drug approved for the treatment of male pattern alopecia, over a decade ago, by the US Food and Drug Administration was topical minoxidil [13]. Its mechanism of action is still unclear, but it has no apparent effect on androgen metabolism. Although minoxidil has a definite effect in initiating and prolonging the anagen phase of the hair growth cycle, its visible effects on hair growth are often not striking. In general, it is better at preserving than restoring hair.

In more recent years finasteride, a potent inhibitor of type 2 5alpha-reductase, was developed. It directly affects androgen metabolism by reducing the amount of DHT converted from testosterone. Finasteride was designed to resemble the structure of testosterone, so as to block the production of DHT and mimic the biochemical profile of type 2 5alpha-reductase deficiency. In that capacity, it was expected to shrink benign prostatic hyperplasia and regrow miniaturized hairs in male androgenetic alopecia. Oral finasteride 5 mg daily was first developed and approved for the treatment of benign prostatic hyperplasia [14]. Based on its positive therapeutic effects and safety profile, finasteride was then studied extensively in the treatment of men with male pattern baldness.

Studies of finasteride in the treatment of androgenetic alopecia

Proof of the concept that inhibition of 5alpha-reductase would improve hair growth in male androgenetic alopecia was obtained in Phase II studies. A small pilot study in males aged 18 to 35 years with mild to moderate androgenetic alopecia, comparing oral finasteride 5 mg daily to placebo, showed a definite finasteride benefit. Subsequent dose ranging studies indicated that oral finasteride 1 mg daily was an optimal dose for hair growth [15]. Patients in the phase II study were given the option of continuing an open label study for another five years on finasteride 1 mg daily and a significant number remained in the study. The continued benefit of finasteride was shown over time.

Two similar pivotal Phase III vertex studies comparing finasteride 1 mg daily to placebo in 1,553 men aged 18 to 41 years, with mild to moderate androgenetic alopecia, were conducted in US and international sites for one year, with yearly continuations. The results of the two studies were similar and were combined [16]. Progress was measured from baseline by hair counts recorded by macrophotography with a final magnification of 5.84:1 of a clipped 2.54 cm diameter circular area, marked by a tattoo, and by global photography, investigator assessment and patient questionnaires. The macrophotographic magnification of 5.84:1 was chosen deliberately to show up terminal, but not vellus, hairs for image analysis. All these data sets were interpreted by assessors who were blinded to the treatment given. At one year, the mean increase of 86 terminal hairs over the 876 hairs at baseline represented a 10% gain for finasteride patients. Adding this to the mean decrease of 21 hairs in placebo patients made a difference between finasteride and placebo patients of 107 hairs, representing a 12% gain for finasteride. With global photography, finasteride patients showed increased hair growth in 48% of patients (comprising 30% mild, 16% moderate and 2% dense increase) versus 7% of placebo patients. Eighty-five percent of the placebo patients showed no change and 8% were worse. Investigator assessments and patient assessments also favored finasteride over placebo. Questions to patients covered efficacy of treatment and satisfaction with the appearance of the hair. After one year, the study design was changed, so that 45 of the 50% of patients on finasteride continued with the drug and 5% went on placebo. Also, 45 of the 50% of patients on placebo went on finasteride, leaving 5% on placebo. In this way, the natural progress of the disease could be compared with progress on continuous, intermittent, or discontinued finasteride. After two years, hair counts in patients continuously on finasteride remained at the one year level, but counts in placebo patients continued to decrease to 138 hairs less than finasteride patients, representing a net gain for finasteride of 16% over placebo. Furthermore, global photography showed increased hair coverage in 66% of finasteride patients (comprising 30% mild and 36% moderate or dense increase) versus 7% of placebo patients. Those patients who stopped finasteride lost the hair that they had gained, and the placebo patients who started finasteride later grew hair, but did not reach the same degree of improvement as seen in patients who initiated therapy one year earlier. Extension studies continued in consenting patients for a total of five years. The four-year results are currently available. The mean hair count showed some decline from the peak effect observed at one and two years in the finasteride patients, although the benefit was maintained in the majority of patients. However, placebo patients continued to lose hair to the extent of 216 hairs less than finasteride patients, a net gain for finasteride of nearly 25% over placebo. The global photographs at four years showed that 55% of the finasteride patients were improved, 36% unchanged, and 8% worse, versus 29% of the placebo patients unchanged and 71% worse. These results showed that long-term finasteride produced visible regrowth in up to 66% of patients and prevented hair loss in 91% of patients.

A phase III frontal hair loss study was conducted on 291 male patients aged 18 to 41 years [17]. Hair counts were evaluated using macrophotography of 1 cm² circular clipped areas, and global photographs of the frontal and mid scalp areas. During the first year, the 50% of patients on finasteride showed a 10% improvement in terminal hair count, whereas the placebo patients lost hair. After one year, all patients were given finasteride and the patients already on finasteride maintained their improvement and the patients previously on placebo gained hair. These results demonstrated the ability of finasteride to regrow frontal hair in androgenetic alopecia.

A phase III phototrichogram study was conducted on 212 men aged 18 to 40 years, with mild to moderate vertex hair loss [18]. The special feature of this study was macrophotography of a clipped circular area on the vertex. The area was then re-clipped close to the skin and re-photographed two days later, thus recording growth only in anagen hairs. Total hair counts, anagen, and telogen counts, and the anagen to telogen ratio could then be calculated. Macrophotographs were taken at baseline, 24 and 48 weeks. They showed that in finasteride patients total hair counts, anagen counts, and anagen to telogen ratios increased, but telogen counts decreased. Placebo patients did not show improvement. This study provided further confirmation that finasteride can regrow terminal hairs in male pattern alopecia.

In a single US center, a phase III hair weight study was conducted on 66 men, ages 18 to 40 years, with mild to moderate androgenetic alopecia. Hairs were clipped in a small, marked area, and weighed at baseline and every 6 weeks for a total of 96 weeks. Hair weight is a non-invasive measure of hair growth that integrates changes in total numbers of hairs, thickness of hairs, and length of hairs (i.e. growth rate of hairs) [19, 20]. Finasteride taken for 96 weeks maintained a mean increase in hair weight from baseline of 22%, while placebo-treated subjects showed a mean decrease in hair weight from baseline of ­ 14%, resulting in a net increase in percent change in hair weight for the finasteride group compared to the placebo group of 36%. Hair weight studies confirmed that frontal hair regrowth does occur with finasteride treatment as shown previously by the frontal hair loss study.

In one US pivotal study center, a scalp biopsy study was conducted on a cohort of 26 men aged 18 to 41, with mild to moderate vertex alopecia [21]. The objective was to confirm the effectiveness of finasteride histologically with serial follicular counts showing regrowth of miniaturized into terminal hairs and increased terminal to vellus hair ratios. Punch biopsies of 4 mm diameter were taken adjacent to the shaved hair count area at baseline, one year and five years. At 12 months, the finasteride patients showed a mean increase of 29% in terminal hairs, a mean decrease of 7% in miniaturized or vellus hairs, and an increased terminal to vellus ratio, as compared to placebo patients. These results confirmed that finasteride is capable of reversing miniaturization of scalp hairs in androgenetic alopecia, in a single cycle.

Adverse affects were not a major problem in any of these studies [16]. In the phase III studies, the complaints of decreased libido, erectile dysfunction, and ejaculation disorder occurred in only 0.5% of men on finasteride as compared to placebo. These adverse effects disappeared in men who stopped the drug and in most men who continued finasteride. In the third and fourth years of the pivotal studies, these symptoms were rare and occurred to a similar extent in placebo and finasteride patients. Finasteride 1 mg produces small decreases in prostate volume and serum PSA levels in young men. In older men, it is recommended that the measured PSA value in a patient on finasteride be doubled to calculate the corrected value. Finasteride has no long-term deleterious effects on semen production, spermatogenesis, bone mineral density, markers of bone turnover, or fasting lipid levels.

A pilot study of finasteride 1 mg versus placebo was conducted in 136 postmenopausal women aged up to 60 years with mild to moderate female pattern androgenetic alopecia [21]. Progress was recorded by hair counts of macrophotographs and by global photography. No improvement in the hair loss was noted in patients after 12 months of finasteride. No significant side effects were seen. Scalp biopsies were taken at baseline and after one year of treatment; follicular counts confirmed the lack of efficacy of finasteride in these patients.

CONCLUSION

Evaluation of finasteride: conclusions

* Long term data:

Finasteride provides continued benefit both as a restorative and a preservative.

Progressive hair loss without treatment indicates that prevention of further loss by finasteride implies hair regrowth.

There is a strong indication for prescribing finasteride for early cases of male androgenetic alopecia before much hair has been lost.

The safety profile of finasteride is excellent.

* Phototrichogram study:

Finasteride increases anagen hairs and decreases telogen hairs in vertex hair loss.

* Hair weight study:

Finasteride increases hair thickness and growth rate in frontal hair loss.

* Scalp biopsy data:

Follicular counts indicate that finasteride increases terminal hairs while decreasing miniaturized hairs, thereby reversing miniaturization in one hair cycle.

* Finasteride in women:

Finasteride does not improve hair loss in postmenopausal women. Its lack of effect is confirmed by scalp biopsy data.

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