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Current Research of David Russell lab
Of the half-gram or so of cholesterol that is actively metabolized in the human body each day, approximately 90% is converted into bile acids (please see Current Research). The other 10% is converted into steroids, which include male hormones such as the androgen testosterone, and their counterparts, the female hormones or estrogens. In past research, the Russell lab studied enzymes that synthesize and break down androgens as well as other classes of steroid hormones.
Illustration of Biosynthesis of Bile Acids From Cholesterol
Figure 1
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.

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