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5-alpha-reductace inhibitors- a new hope in dermatology?
Boaz Amichai, MD, Marcelo H. Grunwald, MD, and Richard Sobel, MD
Androgens, testosterone, and, in particular, dihydrotestosterone are prerequisites
for sexual hair and sebaceous gland development (1). In conjunction with other regulatory
factors such as insulin-like growth factors, androgens cause the prepubertal pilosebaceous
unit in androgen-dependent areas to differentiate either into a terminal hair follicle
or into a sebaceous fillicle in which the sebaceous component proliferates and the
hair remains fine (2). Androgens, particularly dihydrotestosterone, appear to play
a major role in the pathogenesis of male-pattern baldness, hirsutism, acne, male
pseudohermaphroditism, and benign prostatic hyperplasia. Antiandrogens reverse this
process, causing pilosebaceous units to revert toward the vellus state. The conversion
of testosterone to dihydrotestosterone is a key reaction for androgen activity. (3,4)
Finasteride is one of the 5-alpha-reductase inhibitors that have been recently
developed. These drugs selectively block androgen activity in the prostate and skin
and are potentially useful in treating male-pattern baldness, hirsutism, and acne.
5-alpha-reductase
5-alpha-reductase is associated with the nuclear membrane and is found in high concentrations
in male reproductive tissues, skin, and liver. Two isoenzymes (type 1 and 2) of 5-alpha-reductase
have been identified in human tissue, these enzymes have only 50% homology in amino
acid sequences. The gene for the type 1 isoenzyme is located on the short arm of
chromosome 5, while the gene for the type 2 isoenzyme is located on the short arm
of chromosome 2. Mutation of type 2 results in male pseudohermaphroditism. (3,5-7)
The type 1 isoenzyme is found in scalp skin, while the type 2 isoenzyme is found
in prostate. Eicheler et al. Found type 1 isoenzyme in the nuclei of cells in all
layers of the epidermis, in basal and glandular cells of sebaceous glands, in hair
follicles (papilla, matrix cells, inner and outer root sheat, and arrector pili),
and in eccrine and apocrine sweat glands. The type 2 isoenzyme is located in the
cytoplasm of epidermal keratinocytes and in the inner root sheath of hair follicles.
Controverial results have been published about distribution and expression of type
1 isoenzyme in bald and hairy scalp. Several studies showed increased 5-alpha-reductase
activity in bald scalp, while others showed no difference in 5-alpha-reductase type
1 isoenzyme expression. Enhanced 5-alpha-reductase activity has been found in the
skin of hirsute women.
Thigpen et al, in a recent study, described the ontologic expression pattern of the
two isoenzymes. The expression of the type 1 isoenzyme begins at birth in the liver;
in the scalp and skin two waves of expression were found. The first wave begins and
birth and ends around age 2-3 years. The second wave begins during puberty and continues
throughout life. The type 2 isoenzyme is found in normal prostate at all ages, it
is also present in the adult male reproductive system and in fetal genital skin.
The type 2 isoenzyme is found in the skin and scalp from the birth to the age 2-3
years.
Congenital 5-alpha-reductase deficiency
In male pseudohermaphroditism there is congenital 5-alpha-reductase type 2 isoenzyme
deficiency due to a gene defect. In those patients the type 1 isoenzyme is normal.
Although type 1 isoenzyme is the dominant form of enzyme in adult scalp and the type
2 is dominant in prostate and genital tissue, in male pseudohermaphroditism patients’
virilization of the external genitalia occurs during puberty, although secondary
sexual hair remains sparse and they seldom suffer from male-pattern baldness or acne.
These findings support the hypothesis that both isoenzymes influence skin and genitalia.
Finasteride
Finasteride selectively blocks the production of dihydrotestosterone by a competitive
inhibition of 5-alpha-reductase, and does not act on the androgen receptor. Finasteride
is a potent inhibitor of the type 2 isoenzyme and is less effective against the type
1 isoenzyme. Finasteride is well absorbed after oral administration, with a mean
serum half-life of 6-8 h. Its biologic half-life is much longer, leading to a low
serum concentration of dihydrotestosterone until 2 weeks after withdrawl of the drug.
Approximately 90% of circulating finasteride is bound to plasma proteins. Finasteride
is excreted in the stool and urine.
Side effects
Finasteride is generally well tolerated and safe, and the adverse reactions are mild
and transient. Patients with benign prostatic hyperplasia treated with the recommended
dose of 5 mg daily reported impotence (3-4%) and ejaculation disorders (4.4%) [Dr.
Felman is using 1mg doses with MUCH less incidence of side effects] Finasteride has
no effects on serum lipids and bone density, and has no adverse hormonal effects
in healthy men. No interaction with other drugs ahs been reported, although in women
treated with both finasteride and oral contraceptive there was a marked increase
of serum cholesterol levels. In hirsute women treated by finasteride, slight but
significant increases were seen in the levels of both serum gonadotropins and testosterone.
The drug is contraindicated in pregnancy because it may cause abnormalities of the
external genitalia of the male fetus.
5-alpha-reductase inhibitors in dermatology
The role of 5-alpha-reductase inhibitors is not yet fully understood. Based on the
pathophysiology of male pseudohermaphroditism it seems that hirsutism, baldness,
and acne may respond to treatment with 5-alpha-reductase inhibitors.
Male-pattern baldness
Most of the studies concerning male-pattern baldness have been made in animals. Diani
et al. Found that 20 days of 5mg/day finasteride given to male macaque monkeys resulted
in increased hair weight. Finasteride given to male and female macaque monkeys was
found to reverse the balding seen with age in both sexes. On the other hand, 1 year
of treatment with MK386, an inhibitor of 5-alpha-reductase type 1, did not cause
in increase in hair weight. In humans, Dallob et al. Found that men treated with
5 mg/day of finasteride for 4 weeks had significantly decreased concentration of
dihydrotestosterone in bald scalp, resulting in a mean level similar to the baseline
levels found in hairy scalp.
From the Department of Dermatology
and Endocrine Unit, Soroka Medical Center, Beer-Sheva, Isreal.
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