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Methods and Results of Aromatization Studies in Vivo1

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[CANCER RESEARCH (SUPPL.) 42, 3307S-3311s, August 1982] 0008-5472/82/0042-OOOOS02.00 Methods and Results of Aromatization Studies in Vivo1 Christopher Longcope Department of Obstetrics/Gynecology and Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605 Abstract peripheral extraglandular tissues, aromatization by these tis sues was not established until the work of MacDonald ef al. In order to characterize aromatization in vivo, an androgen (18) and Longcope ef al. (15). These workers administered and an estrogen, labeled with different radioactive isotopes, radiolabeled androgens to normal subjects and after extensive are administered simultaneously, either as a pulse alone or as purification procedures found radiolabeled estrogens in the a pulse followed by a constant infusion of the same radiolabeled urine and blood. Studies since then have been directed at steroids. Subsequently, blood samples are obtained at varying time intervals and analyzed for the 3H/14C ratio in nonme- determining the importance of peripheral aromatization as a source of estrogens, the tissues involved in the reaction, dis tabolized unconjugated estrogen, and/or all urine is collected for 96 hr and analyzed for the 3H/14C ratio in an estrogen ease states which alter the rate of aromatization, and the controlling mechanisms of the reaction. These studies have conjugate. The fraction of androgen (An) entering the blood been carried out using analysis in either blood or urine, and I which is converted to and measured as a specific estrogen (Es) in the blood ((P]BBEs)is calculated from will review briefly the 2 techniques involved and then present and discuss the results. (3H-Es/14C-Es)B (3H-An/14C-Es),„, Methods where (3H-Es/14C-Es)B is the ratio of radioactivities in the Analysis in Blood (2, 6, 15, 16). The subjects were given an i.v. specific estrogen in blood; (3H-An/14C-Es)lnj is the ratio of priming dose of an 3H-labeled androgen and a 14C-labeled estrogen in 0.9% NaCI solution followed by a constant i.v. infusion for 2 to 4 hr of radioactivities administered. The fraction of androgen admin the same radiolabeled steroids. During the course of the infusion, blood istered which is converted to a specific estrogen in the body samples were obtained from a vein in the arm opposite to the infusion. and measured as a specific estrogen conjugate in the urine ([P]BMES)iscalculated from In certain experiments, blood samples were obtained from multiple veins and an artery in order to establish tissue aromatization rates. (3H-Es/14C-Es)M The samples were analyzed for radioactivity as specific androgens and estrogens by standard methods involving solvent extraction fol (3H-An/'4C-Es>n, lowed by extensive purification procedures consisting of multiple chro- where (3H-An/14C-Es)M is the ratio of radioactivities in the matographies and derivative formation until radiochemical purity was achieved. The radioactivity in the samples was then measured by liquid specific estrogen conjugate. Irrespective of the method used, scintillation spectrometry, and the results were corrected for losses the aromatization of androstenedione is greater than the aro through the procedure. matization of testosterone; aromatization in normal men is The amount of radioactivity administered as 3H-labeled androgen greater than that in normal young women; aromatization in which enters the blood as the specific estrogen during the infusion is postmenopausal women is greater than that in premenopausal calculated as women. 3H-Es x Aromatization occurs in many tissues but especially in adi pose tissue and muscle, and to a lesser extent in brain, kidney, where 3H-Es is the concentration of 3H in the specific estrogen and and skin. The liver appears to be a relatively minor site for MCREs is the metabolic clearance rate of the specific estrogen. The aromatization in normal subjects. fraction of 3H-labeled androgen administered which is aromatized to In certain diseases, e.g., hepatic cirrhosis and obesity, aro the specific estrogen [P]BB'ESiscalculated as matization rates are increased compared to those rates in normal individuals. rplBBE5 = 3H-Es x In men and postmenopausal women, peripheral aromatiza where rAn is the rate of infusion of 3H-labeled androgen. This can also tion of androgen is a major source of circulating estrogens. The peripheral aromatization of an androgen does not appear be expressed as to be influenced by luteinizing hormone, follicle-stimulating (3H-Es/'4C-Es)B hormone or adrenocorticotropic hormone or by substrate or (3H-An/'4C-Es),„, product concentration. Blood flow through peripheral tissues may play a major role in control of this physiologically important where (3H-Es/14C-Es)B is the 3H/14C ratio of radioactivity administered reaction. as the specific estrogen in the blood and (3H-An/14C-Es)ini is the 3H/ 14Cratio of administered radioactivity, both androgen and estrogen. This method gives the fractional rate of aromatization of androgen Although there were indications from the early work of Leach to estrogen where the estrogen must enter the blood pool of circulating et al. (10) that androgens could be aromatized to estrogens by unmetabolized estrogen, i.e.. Chart 1, Step 2. Inherent in the technique 1 Presented at the Conference "Aromatase: New Perspectives for Breast is the establishment of radiochemical purity as noted and also the Cancer," December 6 to 9, 1981, Key Biscayne. Fla. This work was supported achievement of an isotopie steady state for the androgen and estrogen in part by USPHS Grants NICHHD 15443 and NICHHD 08610. radioactivity in the blood during the infusion. AUGUST 1982 3307s Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1982 American Association for Cancer Research. C.Longcope With this type of analysis, the production rates of androgens and from androgen in peripheral tissues. However, [p]EMEsis a measure of estrogens are determined at the same time as the fractional aromati Step 1 which represents all the estrogen formed from androgen in the zation rates are calculated. Therefore, the mass of androgen aroma tissues, whether it enters the blood (Step 2) or is conjugated to ECon¡ tized to estrogen and the importance of this aromatization can be (Step 3) before it enters the blood. Therefore, determined. Analysis in Urine (17, 18). The subjects received radiolabeled = [p]eSEs androgens and estrogens either as a pulse or as a priming dose, If Step 3 is nonexistent, then [P]BME°willbe equal to[p]ßBEs.However, followed by a constant infusion of the same radiolabeled steroids. if Step 3 is present, then [P]BBESwill be smaller than [p]auiEs bV an Following the administration of radioactivity, all urine was collected for 3 to 5 days and pooled. An aliquot equal to 50 to 100% of the urine amount equal to Step 3. An additional cause for a discrepancy between [P]BMESand [p]EBEs was extracted with an organic solvent to remove any free steroid, and the urine was then subjected to /3-glucuronidase hydrolysis. After would occur if an isotopie steady state were not reached for estrogen hydrolysis, the urine was extracted with organic solvent, and the in the blood during the infusion of androgen. In such a situation, unconjugated steroids were purified by multiple chromatographies and M&E' > [p]ESE5 derivative formation. Because the amounts of radioactivity involved are larger than in the blood specimens, most procedures have included Since urine is collected until essentially all radioactivity as estrogen is crystallization to constant specific activity for final purification. excreted, [P]BMESwill be independent of the isotopie steady state in The fractional rate of aromatization was calculated as blood for estrogen. _ (3H-Es/'4C-Es)M With this type of analysis, blood samples must still be analyzed to (3H-An/"C-Es),n, provide the data necessary for calculating blood production rates of androgens. These production rates will be needed to determine the where (3H-Es/MC-Es)M was the ratio of radioactivity as 3H to 14Cin the mass of androgen converted to estrogen using the [P]BMESvalues. urinary estrogen conjugate. As shown in Chart 1, [P]BBESis a measure of Step 2 which represents Results all the unconjugated estrogen entering the blood after its aromatization Overall Aromatization. As shown in Table 1, the mean values for aromatization in men are greater than are the respective mean values in women, and in either sex the mean value for TISSUE [pies51 is greater than that for [pJBiP- It should be noted that these studies were all done in subjects who were within 20% of their ideal weight. These values are not different from the [P]BM' and [p]eM2 values reported by MacDonald ef al. (1 8). The similarity of the values in these normal subjects indicates that the previously mentioned step (Chart 1, Step 3) is not of major importance. In addition, Steps 1 and 2 appear to be relatively rapid, and an isotopie steady state was obtained during the infusion for the radiolabeled estrogen in the blood. The sex difference in [pleif1 values can be removed if the [P]BBEIvalues are normalized for body weight (Table 1). The mean values of [piel2, however, remain significantly different for men and women even if normalized for body weight. There fore, we conclude that the sex hormone-binding globulin of testosterone may, in part, play a role in the difference in [p]eiP values between men and women which cannot be ex plained by differences in body weight and/or composition. BB An The actual mass of androgen aromatized to a specific estro URINE gen (Pen'Es)can be calculated as Chart 1. Peripheral aromatization as measured by analysis in blood and analysis in urine. Radiolabeled androgen (An) is infused into blood and trans [p]EKiE ported into tissues where it is aromatized to estrogen (Es) (Step 1).
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