Hormones and the Aging Process. Proceedings of a Conference Held at Arden House, Harriman, New York, 1955 PDF
Preview Hormones and the Aging Process. Proceedings of a Conference Held at Arden House, Harriman, New York, 1955
H O R M O N ES A ND THE A G I NG P R O C E SS Proceedings of a Conference held at Arden House, Ç arriman, New York, 1955 Edited by EARL T. ENGLE GREGORY PINCUS College of Physicians and Surgeons The Worcester Foundation for Colunnbia University Experinnental Biology New York, New York Shrewsbury, Massachusetts 1956 ACADEMIC PRESS INC. · PUBLISHERS · NEW YORK Copyright ©, 1956, by ACADEMIC PRESS INC. 125 EAST 23RD STREET NEW YORK 10, N. Y. All Rights Reserved NO PART OF THIS BOOK MAY BE REPRODUCED IN ANY FORM, BY PHOTOSTAT, MICROFILM, OR ANY OTHER MEANS, WITHOUT WRITTEN PERMISSION FROM THE PUBLISHERS. Library of Congress Catalog Card Number 56-8686 PRINTED IN UNITED STATES OF AMERICA PARTICIPANTS ALEXANDER ALBERT ROY G. HOSKINS Mayo Clinic and Office of Naval Research — Mayo Foundation Medical Sciences Rochester, Minnesota First Naval District Boston, Massachusetts JOSEPH C. AUB Harvard Medical School DWIGHT j. INGLE Massachusetts General Hospital Ben May Laboratory for Boston, Massachusetts Cancer Research HERBERT BRENDLER University of Chicago Department of Urology Chicago, Illinois New York University- JOSEPH W. JAILER Bellevue Medical Center College of Physicians and Surgeons New York, New York Columbia University WILLIAM CONSOLAZIO New York, New York Natioruil Science Foundation Washington, D. C. B. J. KENNEDY The Metabolic Research Unit VICTOR A. DRILL Department of Medicine Division of Biological Research University of Minnesota Medical School G. D. Searle ir Company Minneapolis, Minnesota Chicago, Illinois CHARLES D. KOCHAKIAN LEWIS L. ENGEL Oklahoma Medical Research Harvard Medical School Foundation Massachusetts General Hospital Oklahoma City, Oklahoma Boston, Massachusetts DANIEL LASZLO EARL T. ENGLE Division of Neoplastic Diseases College of Physicians and Surgeons Montefiore Hospital Columbia University New York, New York New York, New York GEORGE C. ESCHER HERTA SPENCER Hormone Therapy Section Division of Neoplastic Diseases Sloan-Kettering Institute Montefiore Hospital for Cancer Research New York, New York New York, New York JAMES H. LEATHEM GILBERT S. GORDAN The Bureau of Biological Research Cerebral Metabolic Laboratory Rutgers University The Langley Porter Clinic New Brunswick, New Jersey University of California Medical School WILLIAM H. MASTERS San Francisco, California Department of Obstetrics and SAMUEL R. HALL Gynecology Public Health Service Washington University School of National Institutes of Health Medicine Bethesda, Maryhnd St. Louis, Missouri OLOF η. PEARSON SAMUEL G. TAYLOR Division of Clinical Investigation, University of Illinois Sloan-Kettering Institute Presbyterian Hospital and Department of Medicine Chicago, Illinois Memorial Center New York, New York PAUL L. WERMER Council on Pharmacy and Chemistry GREGORY PINCUS The Worcester Foundation for American Medical Association Experimental Biology Chicago, Illinois Shrewsbury, Massachusetts RAYMOND E. WESTON RxjLON W. RAWSON The Medical Division Division of Clinical Investigation Montefiore Hospital Sloan-Kettering Institute New York, New York and Department of Medicine Memorial Center New York, New York G. DONALD WHEDON National Institute of Arthritis and ALBERT L. RAYMOND Metabolic Diseases Director of Research National Institutes of Health G. D. Searle h- Company Bethesda, Maryland Chicago, Illinois LEO T. SAMUELS ABRAHAM WHITE Department of Biological Chemistry Department of Biochemistry College of Medicine Albert Einstein College of Medicine University of Utah Yeshiva University Salt Lake City, Utah New York, New York NATHAN W. SHOCK Section on Gerontology IRWIN C. WINTER National Heart Institute Division of Clinical Research National Institutes of Health G. D. Searle it Company Bethesda, Maryhnd Chicago, Illinois PREFACE The problem of the relationship of hormones to the processes of aging is as old as the history of endocrinology itself. In fact the notion that the symptoms of senescence in males may be corrected by testis grafts or by simple testis extracts took a long time to die, and in certain aspects contributed to the discredit of endocrinology. With the development of experimental endocrinology subjected to rigid scientific criteria of proof, and particularly with the development of our knowledge of hormone chemistry and physiology, the opportunity for objective assess ment of the role of hormones in involutional processes has been sub stantially advanced. It was felt by the chairmen of the symposium recorded in this volume that a useful purpose would be served by at tempting to bring together basic biological findings developed during recent years along with specific clinical studies in which the basic studies have found and might find application. Accordingly a con ference was held at Arden House in Harriman, New York, on May 30 and 31, 1955; it was sponsored by G. D. Searle & Company of Skokie, Ilhnois. The members who attended are hsted on preceding pages. The plan of the symposium is evident from the table of contents. For those hormones susceptible of quantitative analysis, an account of the variations in their production with advancing age has been sought. Among the fundamental changes characteristic of the aging process are marked alterations in protein and mineral metabohsm. The tissue wasting and osteoporosis characteristic of aged individuals is a familiar phenomenon. Accordingly some chapters are concerned with the role of hormones in these processes as observed experimentally in animals and in human subjects. In clinical medicine the steroid hor mones, because of their availability as chemicals of known constitu tions and purity, have been extensively employed in certain diseases occurring in older men and women. Consequently, the symposium is concluded with a number of papers describing recent data on experi mental steroid medication in heart disease, osteoporosis, and cancer as well as the use of such medication in senile individuals without specific disease. In assembling the information herein recorded the editors recognize that a comprehensive summary of our knowledge in this field is not attained, nor indeed, has it been sought. Rather it is our aim to present modem experimentation as it is functioning operationally. The problems of the moment, the emphasis in latter-day research, the ideas and methods of the active investigators—these, we hope, are what this book exposes. Certainly experimentation in this diflScult and too neglected field has far from reached its climax, and if these chapters act as stimu lants to obviously needed investigation we shall be happy. We should like to acknowledge the cooperation of Dr. William Jenkins in the management of the conference itself. To Mrs. E. B. RomanoflF we are indebted for the preparation of the index. E. T. ENGLE G. PINCUS March, 1956 Aging and Urinary Steroid Excretion ^ GREGORY Pmcus The Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts I. THE MEASUREMENT OF URINARY STEROID MIXTURES In previous publications (6-8, 11) we have presented data on the urinary outputs of various classes of steroids in a large group of normal, healthy men and women (called the Worcester survey). It is unnecessary here to recount the details of this study, but I should like to recall the age: output relationships for the various classes of compounds studied. These are illustrated in Figs. 1 to 6. Basal output values were sought in the urine specimens collected during the period of sleep (P.M.), and the diurnal rise characteristic of the neutral urinary steroids is found in the values for the specimens collected in the hours following waking (A.M.). It will be seen that the basal output of urinary corticosteroids measured as neutral reducing lipids (Fig. 1) shows no mean change with advancing age, whereas the A.M. values decline at a small (but significant) rate. In these data, as in all neutral steroid measured, an average tendency for men to excrete larger absolute amounts is seen, as indicated by the vertical separation of the lines fitted to the values. Both basal and diurnal output rates of the neutral nonketonic steroids (Fig. 2) decline significantly with age, and at rates exceeding those of the neutral reducing lipid; it should be noted that the group of compounds measured as nonketonic neutral steroid contains substances in large part of adrenal origin. The neutral ketonic steroids, measured either as Zimmerman (Fig. 3) or Pincus reaction (Fig. 4) chromogen, exhibited the most marked decline with age. Using pooled 24- to 48-hour samples we have also measured the androgenic activity of the neutral ketones by bioassay, and the mean data (in terms of androsterone equivalent) are presented in Fig. 5. Here too there is significant output decline with advancing age, but with a tendency for the women's values to level off in the later decades; actually the slope constants for the regression of output on age 1 Investigations described in this paper were aided by grants from the United States Public Health Service (Η-1β59), the American Cancer Society, the Damon Runyon Fund, and G. D. Searle & Co. 1 2 GREGORY PINCUS are higher for these data than for the other neutral steroids. The diflFerence between the sexes in absolute output levels is most marked in these data. A sex difference of another sort is observed when we examine the total estrogen excreted at various ages (Fig. 6); an apparently con stant output at all ages is seen in the men's data, with a steep decline, 2.00rMEUTRAL REDUCING LIPID PM Δ Men 1.80 AM A PM —o Women AM —· ¿ 1.60 CXJ I» 1.40 I ^ 1.20 1.00 .80 40 60 80 Median Age FIG. 1. The relationsliip between median age (abscissa) and the logarithm of the mean output (ordinate) of neutral reducing lipid in urine specimens collected from men and women during the period of sleep (P.M.) and in the several hours following waking (A.M.). From: Recent Progr. Hormone Research 11. followed by a leveHng oflF at about the men's output level, in the women's data. If we assume that the urinary steroid output reflects secretory rates then the following deductions from the foregoing data are permissible: (I) the rate of production of certain steroids, e.g., neutral reducing lipid precursors in both sexes and estrogens in men, changes slightly or not AGING AND URINARY STEROID EXCRETION at all with advancing age; (2) other steroids are produced at dimin ishing rates with advancing age, some decUning rather markedly, e.g., the neutral ketosteroids' precursors in both sexes and the estrogens in women, others less markedly, e.g., the neutral nonketonic steroid pre cursors; (3) the diflFerences between the sexes appear to reside in the NON-KETONIC Sb 40 60 80 Median Age FIG. 2. Data and legends as in Fig. 1, but demonstrating the measurements of neutral nonketonic steroid. From: Recent Progr, Hormone Research 11. absolute output levels of the neutral steroids, which are, on the average, greater in men, at least to the last decades of life, as well as in the androgen output (greater in the men) and total estrogen excreted (greater in the women until the later decades). The assumption that urinary levels reflect secretory levels has been put to test by us in a study of the urinary metabolites of certain steroids administered to elderly subjects (8), with the finding of the expected metabolites and in just about the expected quantities. Such studies require amplification, GREGORY PINCUS particularly in terms of estrogen metabolism, but they are in part con firmed by the finding that ACTH-induced steroid excretion in elderly subjects appears to be quantitatively very similar in young and elderly subjects (3, 5). In short, it would appear that it is the rate of production 2.00 r 17-KS-Z 1.8 Ok . I.60h X 1.40 h o l.20h look 40 60 80 Median Age FIG. 3. Data and legends as in Fig. 1, but demonstrating the measurements of 17-ketosteroids in the ketonic neutral fraction by the Zimmerman reaction (17-K-Z). From: Recent Progr. Hormone Research 11. rather than the rate of catabolism which is significant for the aging process. II. MEASUREMENTS OF INDIVIDUAL URINARY STEROIDS 1. ESTROGENS We may further examine the nature of the age-conditioned changes in excretion of these various classes of steroids by measuring the indi vidual constituents present in the mixtures represented by the foregoing
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