Stimulation of 16α-Hydroxylation of Dehydroisoandrosterone Sulfate by Diethylstilbestrol

Abstract

The conversion of dehydroisoandrosterone sulfate (DS) to 16a-hydroxydehydroisoandrosterone-3-sulfate (16aH0DS) was studied in patients with prostatic cancer, before and after one month of treatment with either diethylstilbestrol (DES) or 6ot-methyl-17-acetoxyprogesterone (Provera®). A mixture of 3 H-16a-HODS and 14 C-DS was administered intravenously in each experiment and the 3 H/ 1 4 C ratio in 16a-H0DS isolated from pooled urine, collected for 3 days following the injection, was measured. The conversion of blood-borne DS to blood-borne 16a-HODS was found to be high (11 to 46%) before treatment and to about double as a result of the administration of DES. No changes occurred during treatment with medroxyprogesterone acetate. It is concluded from these results that 16<x-hydroxylation is a quantitatively important path of metabolism of DS in men and that the enzymatic activity can be increased by estrogenic compounds. (/ Clin Endocrinol Metab 37: 867, 1973) T HE quantitative aspects of the metabolism of dehydroisoandrosterone (D) and dehydroisoandrosterone sulfate (DS) in man have been extensively investigated by tracer methods (1-5). Administration of labeled intermediates (androstenedione, testosterone, androstenediol, androstenediol sulfate) in the formation of urinary metabolites (conjugated androsterone, etiocholanolone, testosterone, androstandiols, etiocholanediols, androstenediols) served to evaluate the importance of various paths of metabolism of D and DS. It was apparent from these studies that a significant fraction of blood-borne DS was eliminated via unknown pathways. Estimation of the importance of a route involving 16a hydroxylated compounds was therefore of interest.Madden et al. (6) have indicated that the large part of the markedly increased metabolism of DS during pregnancy (7) is due to conversion of DS to 16o-H0DS. Although hydroxylation of DS at C-16 is a process known to occur in the human fetus (8,9), these authors indicated that the increased Received June 25, 1973. •Present address: Mount Sinai School of Medicine, conversion of DS to 16a-HODS induced by the pregnant state can be observed postpartum. Therefore, it is likely that one of the hormones whose levels are increased during pregnancy is responsible for the induction of the 16a-hydroxylase activity. Engel (10) stated several years ago that estradiol increases the levels of the hepatic enzyme which converts estrone or estradiol to estriol.The aim of the studies described in this article was to estimate the extent of conversion of DS to 16a-H0DS in man and to test the hypothesis that either estrogens or progesterone were responsible for the increased 16a-hydroxylation of DS noted during pregnancy. For this purpose, subjects suffering from prostatic cancer who were scheduled for treatment with either diethylstilbestrol (DES) or 6a-methyl-17-acetoxyprogesterone (Provera®) were studied. Each of these volunteers received intravenously a mixture of 14 C-DS and 3 H-16a-HODS before and after 1 month of treatment. The metabolite 16a-HOD...

Feto-Placental Steroid Metabolism in Growth Retarded Human Fetuses

“…Nothing is known about the control of this enzyme in the fetus. The activity of this enzyme in women in late pregnancy is increased, probably as a result of the high circulating estrogen levels (24). However, in the human fetus, placental sulfatase deficiency, leading to very low circulating fetal E, and E2 levels, is not associated with low hepatic l6a-hydroxylase activities (25).…”

16β-hydroxylation of dehydroepiandrosterone sulphate by homogenates of human foetal liver

“…It has been suggested (Ingelman-Sundberg et al, 1975) that the purpose of the steroid sulphatehydroxylating system in human foetal liver is to 1976 16fl-HYDROXYLATION OF DEHYDROEPIANDROSTERONE SULPHATE provide a detoxification mechanism for biologically active steroids that cannot be excreted. This teleological argument is not convincing when one considers that 16-hydroxylation is not unique to the foetal compartment; it is also quantitatively important in the adult (Baulieu et al, 1965;Laatikainen, 1970;Gurpide et al, 1973;Seth & Pennington, 1973) and perhaps the demonstration of the mineralocorticoid action of 16,B-hydroxydehydroepiandrosterone (Liddle & Sennett, 1975) heralds reassessment of its role in human metabolism.…”

Dehydroepiandrosterone Sulfate in Postmenopausal Women: Lack of Influence of Parity

“…They showed that this differ ence had been present for more than 10 years after the last delivery and suggested that it may reflect a persist ing increase in maternal hepatic 16a-hydroxylase activ ity, induced by pregnancy. Decreased peripheral DHAS levels and increased 16a-hydroxylase activity have also been reported during oral estrogen treatment [4][5][6][7].…”