A B S T R A C T The continuous infusion of 3H-6,7-estrone and 3H-6,7-estradiol has been used to study the metabolic clearance rate (MCR), the interconversions, and the red cell uptake of these steroids in normal males and females. The whole blood MCR of estrone is 1,990 + 120 liters per day/ m2 (SE) in males and 1,910 + 100 liters per day/M2 in females. The whole blood MCR of estradiol is 1,600 + 80 liters per day/M2 in males and 1,360 + 40 liters per day/M2 in females. The values in females do not vary significantly when studied in the follicular or luteal phase of the cycle. At least 35%o of the total estrone metabolism in both sexes is extrasplanchnic and at least 25%o of the total estradiol metabolism in males, and 15%o in-females is extrasplanchnic. The [p] BB21 [transfer constant of estradiol. to estrone, which is equivalent to the fraction of the precursor (estradiol) converted to the product (estrone) when both the infusion of the precursor and the measurement of the product aire in peripheral blood] is 15%o; and the [p]BB"2 [transfer constant of estrone to estradiol, which is equivalent to the fraction of the precursor (estrone) converted to product (estradiol) when both the infusion of the precusor and the measurement of the product are in peripheral blood] is 5%o in both INTRODUCTIONThe metabolic clearance rate (MCR) of a substance, defined as that volume of blood from which it is totally and irreversibly cleared in unit time, is a concept which has been applied to studies of the metabolism of aldosterone, cortisol, progesterone, and the androgens (1-5). In this manner, information has been obtained concerning splanchnic and extrasplanchnic metabolism. In addition, the use of the continuous infusion technique has provided data on the interconversion of androstenedione and testosterone (3,4,6) and on the uptake of steroid hormones into red cells (2).Previous studies of the metabolism of estrone and 17,8-estradiol in nonpregnant humans have provided some data concerning the half-lives of these steroids in plasma (7) and the red cell binding of estrone (8). The major studies have been concerned with urinary metabolites and with the radioactivity appearing in these metabolites after administration of the labeled hormone (9-11). In-The Journal of Clinical Investigation Volume 47 1968 93 formation obtained in this manner however does not always reflect the dynamics of the circulating hormone (4, 12, 13). Therefore, we felt that a study of the metabolic clearance rates and the interconversion of estrone and 17fl-estradiol in blood would provide a fuller picture of the metabolism of these steriods. The plasma MCR of testosterone is much lower than the hepatic plasma flow. This difference indicates incomplete splanchnic extraction for this steroid (3,4,6). However, the plasma MCR of androstenedione is greater than hepatic plasma flow (3, 4, 6). Bardin and Lipsett (13) have reported that the plasma MCR of testosterone is greater for males than for females, and the difference is significant after correction...

Methods suitable for the estimation of urinary metabolites of aldosterone and of cortisol are described. The excretion of 3H and of 14C in various urinary fractions after the simultaneous injection of 7-3H aldosterone and 4-14C cortisol have been investigated, and the secretion rates of these steroids were estimated. Factors affecting the accuracy of the methods and their suitability for routine use are discussed. Considerable difference was found in the pattern of excretion of 3H and of 14C. In particular, a much larger proportion of the injected tritium was released on extraction at pH. 1. Further, while the total excretion of glucuronide as a percentage of the injected dose was greater for 14C than for 3H, about 72 % of the total tritium in the glucuronide fraction of the first 24 hour urine collection was eluted as a single chromatographic peak, whereas about 60 % of the 14C in the glucuronide fraction was eluted as tetrahydrocortisone, tetrahydrocortisol and allotetrahydrocortisol combined. Excretion values for aldosterone released at pH 1 were obtained for nine normal men after addition of tritiated aldosterone to the urine, and for five normal women and one normal man after injection of the isotope. Excretion values for cortisol metabolites are reported for six normal subjects after injection of 4-14C cortisol. Secretion rates for cortisol were calculated for six normal subjects from the specific activity of the tetrahydro metabolites. The values were 12.2 to 20.5, mean 17.2 mg/d, and agreed with those reported by other workers. The secretion rates for aldosterone, based on the specific activity of the aldosterone released at pH 1 were 50 to 118, mean 77 μg/d.

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Three androgen epoxides, 17beta-hydroxy-4beta,5-oxido-5beta-androstan-3-one (II), 3beta,19-dihydroxy-5,6beta-oxido-5beta-androstan-17-one 3-acetate (VIII), and 19-hydroxy-4beta,5-oxido-5beta-androstane-3,17-dione (V), were synthesized and subsequently evaluated as potential precursors in the biosynthesis of estrogens by incubation with human placental microsomes. One of these epoxides (V) was converted into 17beta-estradiol, whereas the other two were metabolized to unidentified products. The possible intermediacy of an androgen epoxide in the biosynthesis of estrone and of 17beta-estradiol is discussed and a mechanism is proposed for the aromatization process.

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