Androgens in Health and Disease.pdf - E Library

Chapter 4/Dihydrotestosterone and 5α-Reductase 83
lowest in the occipital area (81). No genetic polymorphisms in the two genes that encode
5α-reductase enzymes have been found to explain an inherited predisposition for AGA
(82), although polymorphisms in the androgen receptor have been implicated (83).
Five milligrams of finasteride daily was found to reduce the concentration of DHT in
scalp biopsy samples from men with AGA (84). Subsequently, a number of carefully
performed randomized controlled trials have demonstrated the efficacy of finasteride in
reversing alopecia in a subset of men with AGA (17,85–90). Approximately half of treated
men enjoy a significant improvement in hair counts when treated with finasteride (85).
Improvements in scalp hair counts persist for 5 yr or more with continued treatment (90).
Dose ranging studies suggest that 1 mg finasteride daily is the optimal dose (88). Finasteride
treatment appears to decrease apoptosis of hair follicles by downregulating caspases and
upregulating inhibitors of apoptosis (91). The net result is an increase in anagen hair
follicles (89). Finasteride does not affect spermatogenesis or sexual function in these
studies (92,93). Finasteride does not increase hair growth or slow progression of hair
thinning in postmenopausal women with AGA (94). It remains to be seen whether
dutasteride, an inhibitor of both 5α-reductase isozymes, will be more effective than
finasteride in men with AGA or whether it will be effective in treating women with AGA.
Finasteride has also been used to treat hirsutism in women. In one study, 5 mg
finasteride daily was compared with 100 mg spironolactone daily in 14 hirsute women
(95). Although only finasteride had a significant impact on serum hormones, both treatments
were effective in decreasing anagen hair diameter in this small study. Similarly,
another study compared 5 mg finasteride daily with treatment with spironolactone (100 mg
daily), flutamide (250 mg daily), or placebo in 40 hirsute women. Finasteride, spironolactone,
and flutamide were all shown to be more effective than placebo after 6 mo of followup
(96). Concern remains regarding the possible feminization of male fetuses during the
first trimester of pregnancy; therefore, fertile women treated with inhibitors of the type II
5α-reductase, such as finasteride or dutasteride, should be counseled to use effective
means of contraception (oral contraceptives or intrauterine devices).
Acne
Acne vulgaris occurs commonly during puberty, when it is present in 50% of pubertal
girls and as many as 85% of pubertal boys (97). Acne is multifactorial, although it is
believed that increases in sebum production contribute to its development (98). Androgen
stimulates sebum production, cellular proliferation of sebaceous glands, and an
increase in intracellular lipid content (99). Similarly, androgenic progestins increase
sebum production. Estradiol reduces sebum production.
The predominant form of 5α-reductase in sebaceous glands is type I (80). Finasteride
is a selective inhibitor of the type II isozyme and would not be expected to have significant
effects on acne. Indeed, usual doses of finasteride (1–5 mg daily) do not significantly
reduce sebum DHT (100). Dual-type inhibitors, such as dutasteride, or a selective
inhibitor of type I 5α-reductase may be useful therapies for acne. Concerns regarding
feminization of male fetuses in fertile women reduce enthusiasm for an inhibitor of the
type II isozyme for the treatment of acne in young women.
SUMMARY
Dihydrotestosterone plays a critical role in the normal development and differentiation
of external male genitalia and the prostate gland. DHT is metabolized from T