A single study that described the use of finasteride in the treatment of balding in stumptail macaques was identified. In this 20-week study (Diani AR et al. J CLIN Endocrinal Metab 1992; 74:345-50), 21 adult male balding stumptail macaques were assigned to one of four groups to receive once- daily therapy with topical minoxidil 2% (n=5), topical vehicle alone (n=6), oral finasteride 0.5 mg plus topical minoxidil (n=5), or oral finasteride 0.5 mg plus topical vehicle (n=5). The response to therapy was assessed by shaving the hair from a one square inch area of the balding scalp and weighing it. Significant augmentation of hair growth was observed in the group receiving minoxidil alone. Finasteride plus vehicle increased hair weight in four out five subjects. The mean increase in this group was statistically significant only when the data from the one nonresponder were deleted. In recipients of finasteride plus minoxidil, an additive effect was observed; and the mean increases in hair weight were significantly greater than that observed in the other three treatment groups.
Mellin TN et al (J Steroid Biochem Molec Biol 1993; 44: 121-31) conducted in vitro studies of the ability of finasteride and there 4 azastreroids to inhibit 5 alpha-reductase activity in isolated hair follicles taken from a 46-year-old man with male pattern baldness (MPB), as well as in human foreskin homogenate and in human prostate tissue taken from patients with BPH. The 5 alpha-reductase inhibitory activity of finasteride was 20 times greater in prostate tissue than in hair follicles. The authors concluded that the “weak activity (of finasteride) against the hair follicle enzyme suggests it may not be an effective agent for treating MPB.”
Dallob AL et al (J Clin Endocrinol Metab 1994; 79:703-706) conducted a double-blind, placebo-controlled pilot study in which the effect of finasteride on scalp skin levels of DHT and testosterone (t) were analyzed in 17 men with male pattern baldness who were scheduled to undergo hair transplantation. Patients were randomized to receive either finasteride 5 mg/day (n=8), or placebo (n=9) for 28 days. At baseline, bald scalp skin had significantly higher concentrations of DHT than did hairy scalp skin, and baseline T levels did not differ between the two types of scalp skin. At four weeks, the mean decrease in balding scalp skin DHT concentration for patients receiving finasteride, was significantly lower compared to the results for the placebo group. T concentrations in bald scalp skin after four weeks of finasteride had variable changes, but None were significant compared to placebo. The DHT/T ratio was significantly decreased in patients receiving finasteride, but remained unchanged in the placebo group. The authors concluded that this data suggest that oral finasteride may have some utility in the treatment of male pattern baldness; however further studies are needed.
ABSTRACT
The effects of the 5a-reductase inhibitor, finasteride, on scalp skin testosterone (T) and dihydrotestosterone (DHT) levels were studied in patients with male pattern baldness. In a double blind study, male patients undergoing hair transplantation were treated with oral finaseride (5mg/day) or placebo for 28 days. Scalp skin biopsies were obtained before and after treatment for measurement of T and DHT by high pressure liquid chromatography-RIA. In 10 male subjects studied at baseline, mean (+*SEM) DHT levels were significantly higher in bald (7.37+* 1.24pmol/g) compared to hair-containing (4.20+* 0.65 pmol/g) scalp, whereas there was no difference in mean T levels at baseline. In bald scalp from 8 patients treated with finasteride, the mean DHT concentration decreased from 6.40+* 1.07 pmol/g at baseline to 3.62+* 0.38 pmol/g on day 28. Scalp T levels increased in 6 of 8 subjects treated with finasteride. Finasteride decreased the mean serum DHT concentration from 1.36 +* 0.18 nmol/L (n=8) at baseline to 0.46 +* 0.10 nmol/L on day 28 and had no effect on serum T. There were no significant changes in scalp or serum T or DHT in placebo-treated patients.
In this study, male subjects treated with 5 mg/day finasteride for 4 weeks had significantly decreased concentrations of DHT in bald scalp, resulting in a mean level similar to the baseline levels found in hair containing scalp. (J Clin Endocrinol Metab 79: 703-706, 1994).
The progressive loss of scalp hair in male pattern baldness is under androgen control. Hypogonadol men do not become bald, and hairloss can be induced by testosterone (T) in these individuals. Male pseudohermaphrodites with 5a-reductase deficiency do not exhibit male pattern baldness, suggesting that dihydrotestosterone (DHT) is the active androgen in the development of hairloss. Increased information of 5a-reduced metabolites of T has been shown in bald scalp compared to that in hairy scalp. Topical administration of the 5a-reductase inhibitor and antiandrogen N,N-diethyl-4-methyl-3-oxo-4-aza-5a-androstane-17B carboxamide prevented the development of baldness in the stumptail macaque, an animal model of male pattern baldness.
Recently, two isoenzymes of 5a-reductase have been identified in human tissue. The type 1 isoenzyme is found in scalp skin, whereas 5a-reductase type 2 is the predominant form in prostate. These isoenzymes can be distinguished by differences in pH optima, substrate Km, and sensitivity to inhibitors. Male pseudohermaphrodites are deficient in 5a-reductase type 2, and it has been proposed that the activity of this isoenzyme may be involved in the progression of hairloss. Finasteride is a 4-azasteroid inhibitor of 5a-reductase, devoid of antiandrogen activity. It is a potent inhibitor of human 5a-reductase type 2, with very little activity against the type 1 isoenzyme in vitro. This drug has been shown to be effective in the treatment of benign prostatic hyperplasia. At the therapeutic dose of 5mg/day, finasteride treatment lowers serum DHT levels in men by 65-80% compared to baseline values and decreases intraprostatic levels of DHT by 85% compared to the effect of placebo. In mature male stumptail macaques, an increase in hair weight was found in most finasteride-treated animals, whereas all control animals exhibited hairloss.
The present study was designed to evaluate the effects of finasteride treatment on scalp DHT and T concentrations in patients with male pattern baldness to investigate the use of 5a-reductase inhibitors in the treatment of this disorder.
DISCUSSION
In this study, baseline DHT concentrations were significantly higher in bald scalp skin than in samples of hairy scalp from the same patients (P<0.01). This observation is consistent with previous studies showing increased 5a-reductase activity in bald scalp. Although samples of bald and hairy scalp were similar in thickness, hairy scalp typically contained a small amount of blood contamination (5 to 15% by weight) that was not seen in bald scalp. This contamination may result in a 5-15% underestimation of the DHT concentration in hairy scalp, but would not fully account for the difference observed between bald and hairy scalp. Finasteride treatment (5 mg/day for 28 days) significantly decreased mean DHT levels in bald scalp compared to placebo (P<00.01). After 28 days of treatment. The mean (+*sem) concentration of DHT in bald scalp (3.62 +* 0.38 pmol/g; n=8) was approximately equal to the mean level found in hair-containing scalp from untreated subjects (4.20 +* 0.65 pmol/g; n=10).
Scalp skin 5a-reductase activity is thought to be due to the presence of the type 1 isoenzyme. It has been shown that although immunoblotting only detected 5a-reductase type 1 in scalp, there was detectable enzyme activity at pH 5, consistent with the presence of the type 2 isoenzyme. No difference in 5a-reductase type 1 expression was seen between bald and hairy scalp.
The effect of finasteride on lowering of scalp skin DHT could be mediated through one or a combination of mechanisms. The DHT concentration in full thickness scalp samples may be dependent in part on circulating levels of DHT, because scalp skin is highly vascularized. Finasteride may exert part of its effect on scalp levels by lowering serum DHT. Residual DHT in scalp after finasteride treatment may represent the local activity of the 5a-reductase type 1 isoenzyme, which is less effectively inhibited by this drug. Alternatively, it is possible that finasteride can effectively inhibit 5a-reductase type 1 in vivo after chronic treatment. Although finasteride is a more potent inhibitor of 5a-reductase type 2, inhibition of type 1 is seen at higher concentrations in vitro.
The effect of oral finasteride on the scalp skin DHT concentration suggests possible utility in the treatment of male pattern baldness. It is not known whether complete inhibition of both isoenzymes
is necessary to promote hair growth. N,N-Diethyl-4-methyl-3-oxo-4-aza-5a-androstane-17B carboxamide, shown to prevent hairloss in the stumptail macaque model, is an equipotent inhibitor of 5a-reductasetype 1 and type 2. Finasteride, a type 2 inhibitor, has also shown activity in this model.
Further studies on the effects of 5a-reductase type 1 and 2 inhibitors on scalp DHT levels and hair growth will help define the role that these isoenzymes play in male pattern baldness. Prolonged exposure to decreased levels of DHT may be necessary for clinical efficacy. In the stumptail macaque, significant changes in hair weight were seen after 8-12 weeks of finasteride treatment. In man, 6 months of dosing were required to achieve maximum prostate shrinkage. In the present study, patients were treated with finasteride for only 4 weeks, and it is not known whether peak effects of the drug were achieved. It is also not known whether a decrease in DHT alone is sufficient for the prevention of male pattern baldness.
