Said I. Hakky

Preliminary studies on the isolation and characterization of predominant prostatic proteins

The increasing incidence of prostate cancer demands that we give our full attention not only to the etiology and prevention of this common type of cancer, but also to the diagnosis and prognostic course of this disease. In an effort to develop new prostatic tumor markers that could be useful to the physician at the current state of our knowledge in the diagnosis and prognosis of this disease, our laboratories have undertaken an effort to isolate and characterize the nature of the major proteins in the normal prostate and in prostatic neoplasia.

In vitro studies on the inhibition of testosterone synthesis in the human testis by atamestane

In view of the well established clinical results of the deprivation of androgens through orchiectomy in prostatic cancer and the structural similarities of 4-androsten-3,17-dione and atamestane (1-methyl-ADD), we studied the influence of 1-methyl-ADD on the conversion of 4-androsten-3,17-dione to testosterone by the 17 beta-hydroxysteroid reductase enzyme in human testicular tissue. Our studies, presented in this manuscript, demonstrate that 1-methyl-ADD is a competitive inhibitor of 4-androsten-3,17-dione in its reduction to testosterone by the 17 beta-hydroxysteroid reductase enzyme in the human testis.

A study of androgen biosynthesis by the human testis in vitro

The biosynthetic pathways in human testicular tissue have been studied extensively in our laboratory without the use of radioisotopes. Experiments were conducted with normal testicular tissue from patients undergoing orchiectomy for prostatic cancer. These studies have shown that the preferred pathway of testosterone biosynthesis is influenced by the nature and concentration of cofactor added to the incubation medium. Four enzymes are involved in the transformation of pregnenolone to testosterone, that is, 3 beta-hydroxysteroid dehydrogenase, 17 alpha-hydroxylase, C17-C20 lyase and 17 beta-hydroxysteroid oxidoreductase. Our studies show that the 4-ene pathway predominates in the biosynthesis of testosterone from pregnenolone. Analysis of several samples of human testicular vein blood supports the contention that 4-androsten-3,17-dione is the immediate precursor of testosterone.

Testicular androgens in prostate cancer patients treated with a luteinizing hormone releasing hormone agonist

Luteinizing hormone releasing hormone agonists have been shown to reduce the levels of androgens in the peripheral circulation and to reduce prostate volume. The objective of this study was to quantify testicular function in patients with metastatic carcinoma of the prostate treated with a luteinizing hormone releasing hormone agonist, leuprolide, by analysis of spermatic vein blood for testosterone and androstenedione, and by determination of the maximum velocity of the 17 beta-hydroxysteroid oxidoreductase enzyme in testicular tissue in vitro. A chemical analysis of the spermatic vein blood of 19 patients with a median age of 78 years revealed the presence of significantly high levels of testosterone and androstenedione, 20.7 +/- 1.9 micrograms % and 6.7 +/- 0.7 micrograms %, respectively. These androgens could not be detected in patients treated with leuprolide before orchiectomy. Patients treated with leuprolide for several months followed by a period of no treatment before orchiectomy secreted testosterone and androstenedione levels comparable to the control group. The maximum velocity of the 17 beta-hydroxysteroid oxidoreductase enzyme in vitro in the testes of the leuprolide treated patients was significantly inhibited. Enzyme activity returned to normal levels when leuprolide treatment was followed by a recovery period of no treatment before orchiectomy.