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A Thesis by Morry Givner Subrnitted to the Faculty of Graduate Studies

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A Thesis by Morry Givner Subrnitted to the Faculty of Graduate Studies ESTROGEN METABOLISM 1N HUMAN SUBJECTS A Thesis by Morry Givner Subrnitted to the Faculty of Graduate Studies and Research in partial fulfillment of the Requirements for the degree of Master of Science. McGill University August 1956. Montreal, Quebec ACKNOWLEDGEMENTS Grateful acknowledgement is expressed to my research director, Dr. W.S. Bauld for encouragement and supervision during this course of study. The author wishes to express his gratitude to Dr. 1. G. Milne of the McGill University Clinic of The Montreal General Hospital for his co-operation in the selection of subjects and his many valuable suggestions. To Dr. E. H. Bensley, 1 wish to express my appreciation for his valuable suggestions. Finally, thanks are offered to Mrs. A. Alfh.eim for her excellent technical assistance, which was neoessary for this work. TABLE OF CONTENTS ESTROGEN EXCRETION IN PATIENTS WITH PREVIOUS MYOCARDIAL INFARCTION I. Introduction: A. Reasons for the Investigation P.l B. Survey of Previous Investigations on Estrogen Metabolism P.4 C. The relationship of Estrogens to Coronary Artery Disease P.lO II. Methode: A. Experimental Procedure for the Study of Patients with Previous Myocardial Infarction P.13 B. Method for Estrogen Analysis P.13 III. Resulta P.16 IV. Discussion P.24 v. Summary P.26 Table of Contents {Contfd) ESTROGEN METABOLISM IN VARIOUS GYNECOLOGICAL AND ENDOCRINOLOGICAL DISORDERS I. Experimental P.27 ll. Discussion P.27 Ill. Summary P.28 A METHOD FOR THE DETERMINATION OF ESTRONE IN HUMAN URINE 1. Introduction P.29 ll. Methods P.29 Ill. Resulta P.32 IV. Discussion P.33 V. Summary P.33 GENERAL SUMMARY P.34 REFERENCES APPENDIX LIST OF FIGURES Figure 1. Total Blood Cholesterol of Normal and Myocardial Infarction Subjects Figure 2. Estrogen Excretion in Normal and Myocardial Infarction Subjects Figure 3. Long Term Study on a Subject with Myocardial Infarction Figure 4. Estrogen Excretion in a Subject with Infarction and Normal Estriol : Estrone Ratio 1. INTRODUCTION A. Rea sons for the Investigation. This phase of the investigation was concerned with a study of the urinary excretion of estriol, estrone and estradiol -17Jl following the intramuscular injection of estradiol -17J3 in men with myocardial infarction. The resulta were compared with those of a control group of male subjects with no clinical evidence of this disease. The study was undertaken for the reasons set forth below. {1) Rarity of myocardial infarction in females before the menopause. Myocardial infarction is rare in women before the menopause but postmenopausal women show a high incidence of this disease. The evidence supporting this statement is of two types: (a) Clinical evidence - Oliver and Boyd(49) have studied the sex and age distribution of 1000 consecutive cases of coronary artery disease. From Table 1, we see that the clinical manifestations of coronary artery disease are nineteen times more common in men under the age of 35 and fifteen times more common under the age of 40. In the menopausal and postmenopausal years, the ratio drops to 7:1 to 5:1 to 2:1. TABLE 1 Sex and Age Distribution of 1000 Consecutive Cases of Coronary Disease; Oliver and Boyd(49) . Age Number of Cases (Year) Men Women Men : Women Under 35 19 1 19:1 35-39 44 3 15:1 40-49 188 26 7:1 50-59 256 53 5:1 60-69 195 86 2:1 Over 70 68 61 1:1 - 2 - (b) Pathological evidence - It is recognized, however, that there is considerable limitation in the clinical and electrocardiographie diagnosis of myocardial infarction. However, the striking sex differences in myocardial infarction ls supported by the pathological findings of Schlesinger and ZoU (59), the resulta of the ir injections and dissections are presented in Table n. TABLE IT Incidence of Coronary Arter_y Occlusion in Men and Women at Varying Ages; Schlesinger and zou(o9) Age Total Number Hearts with Occlusion {Year) Sex of Hearts Number Per cent 20-39 M 44 1 2.3 F 19 1 5.3 40-59 M 85 20 23.5 F 56 2 3.6 60-79 M 115 43 37.4 F 65 21 32.3 80 on M 9 4 44.4 F 7 2 28.6 Here the resulte are striking. Between the ages of 40 and 59 there are six to seven times more coronary occlusions in males than in females. However, between 60 and 79 the incidence is approximately the same. (2) Lack of evidence relating sex and atherosclerosis. A detailed study by Sjovall and wihman(60) of 1380 individuals at post- mortem revealed that there are no significant differences between the sexes in so far as general:ized atherosclerosis is concerned. The resulte of their study are indicated in Table III. Even when the study is restricted to the coronary vessels {see Table IV), the difference between males and females in the various age groups is not marked. - 3 - TABLE ID Extent of Total Atherosclerosis in Males and Females at Various Ages. Values are expressed as indices derived by combining sepa.rate obser­ vations on the aorta and its main branches; Sjovall and Wihman(60) Age Stockholm Lund (Year) Men Women Mëiï Women 1-20 0.3 0.5 0 0.2 21-30 1.3 1.2 0.6 0.5 31-40 3.5 2.3 2.7 1.9 41-50 8.0 5.6 3.5 5.0 51-60 10.5 10.0 8.4 9.3 61-70 15.7 13.3 13.0 15.0 71-80 16.6 18.5 19.0 23.0 81-90 21.7 20.0 20.8 25.5 TABLE IV Extent of Coronary Atherosclerosis in Males and Females at Various Ages. Values are indices derived by combining observations in severa! locations in ail individuals of the groups; Ackerman, Dry, and Edwards(l) Age (Year) Men 1.56 1.74 2.46 2.21 2.32 2.29 Women 1.13 1.30 1.48 1.69 1.99 2.03 Thus, in the ages from 30-39 the degree of coronary atherosclerosis in men is only 1.4 times that in women. However, from Table 1 we saw that the clinical manifestations of coronary artery disease are 15 times more com.mon in men under the age of 40. (3) Estrogen as a possible mechanism of protection. The increase in the incidence of myocardial infarction after a natural meno- pause, and prematurely following an artificial menopause suggests develop- ment of this disease may be accelerated by changes in the hormonal equilibrium(49). Clinicat coronary artery occlusion is commonly associated with abnormal circulating lipids and lipoproteins(46)' (51). Fig.l shows the plasma total cholesterol in normal subjects and those with coronary artery disease. FJG.I MEAN PL A$ MA TOTAL CHOLESTEROL VALUES CCORONARY ARTERY DISEASE AND CONTROL GROUPs). ~. ~ 275 (!) ~ -z ..J 0 ~ w t- U) 1&1 ..J CORONARY ARTERY 0 % OISEASE GROUP (6') u c 2 U) c ..J Q. _, c t- 0 t- 150 30 40 5 60 70 -39 -49 -&9 -69 -79 AGE GROUPS - 4 - The administration of estrogen effects changes in the circulating lipids(50). The evidence of these changes, which will be covered in detail in a subsequent section, emphasizes the importance of hormonal factors in the pathogenesis of the disease. (4) Availability of a method. The avàilability of a method(7) for the investigation of estrogen metabolism enabled us to determine the response to exogenous estrogen in men with myocardial infarction. Women were not used in this investigation because of cyclic variations in urinary estrogens. (5) Edinburgh. Study. In a preliminary study on estrogen metabolism in men with myocardial infarction, Bauld(6) found an elevated estriol : estrone ratio. These findings prompted this investigation. B. Survey of Previous Investigations on Estrogen Metabolism. This investigation has been confined to the changes in the urinary excretion of estriol, estrone and estradiol -17J3 following the- injection of estradiol -17f3. Consequently this survey will not include a review of the etudies of the formation of estrogens from acetate, testosterone- - 4..C14, or the anabolic interrelationships with other steroid hormones so ably shown by Heard et al. (26-28). Moreover, the survey will be restricted to estrogen metabolism in the human because of the difference in estrogens in different species of animais. For example, estriol has only been isolated from hum an sources, estradiot -17p is a product of rabbit and equine metabolism and naphtholic estrogens are peculiar to equine species{54). Moreover, the importance of the gastrointestinal tract as a site of estrogen interconversions varies widely with the species of the experimental animal. Heard et al. (26) using Estrone -16-c14 in mice f01m.d the gastrointestinal tract a major pathway of excretion (20. 55% of the total dose administered). V/hen this compolm.d was administered to a pregnant mare, only traces of radio- - 5 - activity were fmmd in the feces(26). Gallagher and Beer(lO) found only 0. 05-4.0 per cent of the ·injected radioactivity in human feces after the administration of Estradiol -17,4-16-c14. (1) Resulte of isolation etudies. Table V shows the ·classical isolation etudies of estrogens from human sources. TABLE V Isolation of Estrogens from Humans Estrogen Source Reference Estriol Urine - pregnant Marrian(39) 1930 Meconium Doisy et al. (34) 1956 Estrone Urine - pregnant Doisy(24) 1929 Urine - pregnant Butenandt(16) 1929 Urine - pregnant Laqueur et al. (35) 1930 Estradiol -17J3 Urine - pregnant Huffman et al. {32) 1940 Placenta Huffman et al. (33) 1940 q • Estranediol A Urine - nonpregnant Marker et al. (38) 1938 Estranediol B Urine - nonpregnant Marker et âl. (38) 1938 16 - epiestriol Urine - pregnant Marrian & Bauld(41) 1954 16-p-Hydro?,CYestrone*.
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