|
Testosterone is made from cholesterol in several tissues, including
the testes, ovaries, and adrenal glands, and is thereafter secreted
into the blood stream. The hormone enters target tissues and
activates the androgen receptor, a transcription factor that
induces the expression of genes involved in virilizing the male
(Figure 1). Working with Dr. Stefan Andersson in the Department
of Obstetrics and Gynecology at UT Southwestern, we isolated
the gene encoding the last enzyme in the testosterone biosynthetic
pathway (17β-HSD type 3) and showed that genetic loss of
this enzyme in humans causes feminization in males.
In addition to a role in the formation of the male phenotype, testosterone
is a precursor for the synthesis of two other steroid hormones,
dihydrotestosterone and estradiol (Illustration 1). Dihydrotestosterone
is the most potent naturally occurring androgen, and is made from
testosterone by two enzymes, termed steroid 5α-reductase type 1 and
steroid 5α-reductase type 2. The Russell lab isolated genes
encoding these two enzymes and showed that genetic loss of 5α-reductase
type 2 in humans causes an unusual male birth defect in which the external
genitalia and prostate gland fail to form. Adult males with this genetic
disease also do not develop male pattern baldness, the gradual loss of
hair that occurs with aging in men. The observations that loss of steroid 5α-reductase
type 2 prevented both prostate growth and baldness led to the development of drugs
(Proscar, Propecia, Merck and Co.) that inhibit the enzyme and are prescribed
for benign prostatic hyperplasia and baldness. Based on the results from the
cloning studies indicating the presence of two steroid 5α-reductase enzymes,
and the observation that the Merck drugs inhibited only one of these (the type 2 enzyme),
scientists at the Glaxo Welcome company developed a drug that inhibits both enzymes (Dutasteride),
which is thought to be more efficient in treating prostate growth and baldness.
|
