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STUDY INVOLVING METABOLISM OF 17-KETOSTEROIDS AND 17-HYDROXYCORTICOSTEROIDS OF HEALTHY YOUNG MEN DURING AMBULATION AND RECUMBENCY A DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN NUTRITION IN THE GRADUATE DIVISION OF THE TEXAS WOI\IIAN 'S UNIVERSITY COLLEGE OF HOUSEHOLD ARTS AND SCIENCES BY SANOBER QURESHI I B .Sc. I M.S. DENTON I TEXAS MAY I 1970 ACKNOWLEDGMENTS The author wishes to express her sincere gratitude to those who assisted her with her research problem and with the preparation of this dissertation. To Dr. Pauline Beery Mack, Director of the Texas Woman's University Research Institute, for her invaluable assistance and gui­ dance during the author's entire graduate program, and for help in the preparation of this dissertation; To the National Aeronautics and Space Administration for their support of the research project of which the author's study is a part; To Dr. Elsa A. Dozier for directing the author's s tucly during 1969, and to Dr. Kathryn Montgomery beginning in early 1970, for serving as the immeclia te director of the author while she was working on the completion of the investic;ation and the preparation of this dis- sertation; To Dr. Jessie Bateman, Dean of the College of Household Arts and Sciences, for her assistance in all aspects of the author's graduate program; iii To Dr. Ralph Pyke and Mr. Walter Gilchrist 1 for their ass is­ tance and generous kindness while the author's research program was in progress; To Mr. Eugene Van Hooser 1 for help during various parts of her research program; To Dr. Betty Bohon Alford, Dr. Roman J. Kutskyl Dr. James Hardcastle, and Professor George P. Vose 1 for their invaluable in­ struction and inspiration; To Jessie Ashby 1 for coding and preparing data for statistical ana lysis; To Reba Fry 1 Martin Cucldl and Lenoir 0 'Rear I for their as- sistance in this investigation; To Bill Stover I for the drafting of graphs and figures included in the report; To Dorothy Jones 1 for the typing of this dissertation with pre- cis ion; To my brother 1 Dr. As mat Ullah Qureshi I and to my sisters I Dr. Razia Matin and Miss Shehla Qureshi I for their devotion and iv encouragement, which inspired the author throughout the pursuance of her graduate study; Finally, the author would like to dedicate this dissertation to her parents, Mr. Hifazat Ullah Qureshi and Mrs. Saida Qureshi, who placed educational achievements high in the values of life, and made many sacrifices in order that the author might engage in graduate study. v TABLE OF CONTENTS INTRODUCTION 1 REVIEW 0 F LITERATURE 4 CHEl'v1ISTRY OF STEROID HORMONES 6 Steroisomeris m 10 BIOSYNTHESIS OF STEROIDS 13 Enzyme System 18 THE HYDROXYSTEROID DEHYDROGENASE 19 Hydroxylases and Lyases 19 METABOLISM 21 PHYSIOLOGIC CONSIDERATION OF ANDROGENS 25 Anubolic Effect . 25 Effect on Bone Metabolism 29 Effect on Lipid Me tubolis m 33 GLUCOCORTICOIDS 34 Physiological Considerations 34 Carbohydrate Metabolism 34 Fat Metabolism 37 Protein Metabolism 38 Electrolyte Iviet3.bolis m 39 vi Bone Metabolism . 41 17-KETOSTEROID AND 17 -HYDROXYCORTICOSTEROID EXCRETION 43 17- Ketos teroids 43 17-Hydroxycorticos teroids 47 Stress and Steroid Hormones 48 EFFECT OF IMMOBILIZATION . 52 EXERCISE AND ALTITUDE EFFECTS . 57 THE CIRCADIAN RHYTHM PHENOMENON 59 PLAN OF PROCEDURE 66 PERIODS 0 F THE STUDY DURING THE 196 8 INVESTIGATION 66 SUBJECTS OF THE STUDY. 67 EQUILIBRATION PERIOD . G7 BED REST PERIOD NUMBER ONE G8 INTERIM AMBULATORY PERIOD 69 BED REST PERIOD NUMBER TWO G9 POST-BED REST PERIOD . 70 D IA GRAM I . EXERCISE PROGRi\M FOLLOWED IN BED REST II 0 F THIS INVESTIGATION 72 PERIODS OF THE STUDY DURING THE 1969 INVESTIGATION 74 SUBJECTS OF THE STUDY 74 EQUILIBRATION PERIOD . 75 vii GENERAL PROCEDURE USED IN THE STUDY 76 METHODOLOGY 76 PROCEDURE FOR THE DETERMINATION OF URINARY 17 -KETO­ STEROIDS 76 REAGENTS 77 PROCEDURE 78 CALCULATION 79 PROCEDURE FOR THE DETERMINATION OF URINARY 17 -HY- DROXYCORTICOSTEROIDS 80 CALCULATION 82 STANDARDIZATION 8 2 REAGENTS 83 PRESENT AT I 0 N 0 F FINDINGS WITH DISCUSS I 0 N 84 PART I OF THE STUDY . 84 Comparison of Urinary 17-Ketosteroid Excretion during the Initial Equilibration and the Bed Rest I Periods 85 SUBJECT BB 85 SUBJECT FF 85 SUBJECT HH 86 SUBJECTS BB, FF, HH (Exercising Regularly) 86 viii Comparison of Urinary 17 -Ketosteroid Excretion during the Initial Equilibration and the Bed Rest I Periods 86 SUBJECT AA 86 SUBJECT EE 86 SUBJECT GG 87 SUBJECTS M 1 EE 1 GG (Subjects who Exercised "at Will") 87 ALL SUBJECTS • 87 Comparison of Ambulatory Periods with Each Other 88 SUBJECT BB 88 SUBJECT FF 91 SUBJECT HH 91 SUBJECTS BB 1 FF 1 HI-I (Regular Exercisers) 91 SUBJECT AA 92 SUBJECT EE 92 SUBJECT GG 92 SUBJECTS AA 1 EE 1 GG ("at \Nill" Exercisers) 92 ALL SUBJECTS • 93 COMPARISON OF BED REST I WITH BED REST II • 94 ix SUBJECT BB 94 SUBJECT FF 94 SUBJECT HH 94 SUBJECTS BB 1 FF 1 HH (Who Exercised Regularly) • 97 SUBJECT AA 97 SUBJECT EE 97 SUBJECT GG 97 SUBJECTS AA 1 EE 1 GG (Who Exercised "at Will") • 97 ALL SUBJECTS • 98 COMPARISON Or URINARY EXCRETION OF 17 -KETOSTEROIDS DURING BED REST I AND BED REST II 99 CIRCADIAN PATTERN or URINARY 17-KETOSTEROID EXCRETION DURING BED REST I 101 SUBJECT BB 101 SUBJECT Fr 102 SUBJECT HH 102 SUBJECT AA 105 SUBJECT EE 105 SUBJECT GG 106 ALL SUBJECTS • 106 COMPARISON OF 17 -KETOSTEROIDS WITH INDEPENDENT VARIABLES. 109 X CORRElATION BETWEEN 17-KETOSTEROIDS AND CREATI­ NINE 109 CORRElATION BETWEEN 17 -KETOSTEROIDS AND HY­ DROXYPRO LINE 110 CORRElATION BETWEEN 17-KETOSTEROIDS AND TOTAL CALCIUM 110 CORRELATION BETWEEN 17-KETOSTEROIDS AND URI­ NARY CALCIUM 110 CORRElATION BETWEEN 17-KETOSTEROIDS AND TOTAL NITROGEN 111 CORRElATION BETWEEN 17-KETOSTEROIDS AND 17- l-IYDROXYCORTICOSTEROIDS • 111 CORRElATION BETWEEN 17-KETOSTEROIDS AND CREA­ TINE 111 COMPARISON OF 17-l-IYDROXYCORTICOSTEROIDS WITH INDE­ PENDENT VARIABLES 112 CORRElATION BETWEEN 17-HYDROXYCORTICOSTEROIDS AND CREATININE • 112 CORRELATION BETWEEN 17-HYDROXYCORTICOSTEROIDS AND HYDROXYPROLINE • 112 CORRElATION BETWEEN 17-HYDROXYCORTICOSTEROIDS AND TOTAL CALCIUM 112 xi CORRELATION BETWEEN 17 -HYDROXYCORTICOSTEROIDS AND URINARY CALCIUM 113 CORRELATION BETWEEN 17 -HYDROXYCORTICOSTEROIDS AND TOTAL NITROGEN • 113 CORRELATION BETWEEN 17 -HYDROXYCORTICOSTEROIDS AND CREATINE 113 PART II OF THE STUDY. 114 CIRCADIAN RHYTHM PATTERN OF 17-HYDROXYCORTICOSTER­ OIDS. 114 SUBJECT 1A 117 SUBJECT 2A 117 SUBJECT 3A 117 SUBJECT 4A 118 SUBJECT 6A 118 SUBJECT 7A 118 SUBJECT SA 119 SUBJECT 9A 119 ALL SUBJECTS • 119 SUMMARY AND CONCLUSIONS 124 B I B L I 0 G RA P H Y 127 APPENDIX 143 xii LIST OF TABLES TABLES FOR PART I OF THE STUDY Including Excretion of 17-Ketosteroids by Six Subjects Participating in Two 28-Day Bed Rest and Preliminary and Final Periods in 19 6 8 (Subjects AA I BB I EE I FF I GGI and HH) • 144 TABLE I. URINARY EXCRETION OF 17 -KETOSTEROIDS PER DAY PART A. SUBJECT BB 145 PART B. SUBJECT FF 146 PART C. SUBJECT HH 147 PART D. SUBJECT AA 148 PARTE. SUBJECT EE 149 PART F. SUBJECT GG 150 TABLE II. URINARY 17-KETOSTEROID EXCRETION DURING THREE DAILY PERIODS WHILE BED REST I WAS IN PROGRESS PART A. SUBJECTS BB AND FF 151 PART B. SUBJECTS HH AND AA 152 PART C. SUBJECTS EE AND GG 153 TABLE III. STATISTICAL COMPARISON OF URINARY 17 -KETO­ STEROIDS BETWEEN PAIRS OF THE DIFFERENT PERIODS 0 F THE STUDY PART A. SUBJECT BB 154 PART B. SUBJECT FF 155 PARTC. SUBJECTHH 156 PART D. ALL SUBJECTS EXERCISING REGUlARLY (BB 1 FF 1 HH) 157 xiii TABLE III. (CONTINUED) STATISTICAL COMPARISON OF URI­ NARY 17-KETOSTEROIDS BE1WEEN PAIRS OF THE DIFFERENT PERIODS OF THE STUDY PART E. SUBJECT AA 158 PART F. SUBJECT EE 159 PART G. SUBJECT GG 160 PART H. SUBJECTS EXERCISING "AT WILL" (AA I EE I GG) 161 PART I. ALL SUBJECTS 162 TABLE IV. STATISTICAL COMPARISON 0 F URINARY 17-KETO­ STEROIDS BETWEEN PAIRS OF THE DIFFERENT PERIODS BY GROUPS OF SUBJECTS EXERCISING REGULARLY AND "AT WILL II 163 TABLE V. STATISTICAL ANALYSIS OF URINARY 17 -KETOSTER­ OIDS BE1WEEN GROUPS OF SUBJECTS EXERCISING REGULARLY AND "AT WILL" DURING BED REST ONE AND BED REST 1WO 164 TABLE VI. STATISTICAL COMPARISON OF URINARY 17 -KETO­ STEROID EXCRETION AT DIFFERENT TIMES OF THE DAY PART A. SUBJECTS EXERCISING REGULARLY (BB I FF I AND HH) 165 PART B. SUBJECTS EXERCISING "AT WILL" (AA I EE I AND GG) 166 PART C. ALL SUBJECTS 167 TABLE VII. CORRELATION COEFFICIENT DERIVED BETWEEN 17-KETOSTEROID EXCRETION AND SEVEN INDE­ PENDENT VARIABLES (ALL SUBJECTS) PART A. PRE-BED REST 168 PART B. BED REST ONE • 169 xiv TABLE VIII. CORRELATION COEFFICIENT DERIVED BETWEEN 17 -HYDROXYCORTICOSTEROID EXCRETION AND SEVEN INDEPENDENT VARIABLES (ALL SUBJECTS) PART A. PRE-BED REST 170 PARTB. BEDRESTONE 171 TABLES FOR PART II OF THE STUDY Including Excretion of 17-Hydroxycorticosteroids During Pre-Bed Rest Period by Eight Subjects Participating in a 56- Day Bed Rest Study Conducted in 1969 (Subjects 1A I 2A 1 3AI 4A, 6A, ?A, SA, and 9A) 172 TABLE IX. URINARY 17 -HYDROXYCORTICOSTEROID EXCRETION DURING PRE-BED REST PART A. SUBJECTS 1A, 2A 1 3A, AND 4A • 173 PART B. SUBJECTS 6A, ?A, SA, AND 9A. 174 TABLE X. URINARY EXCRETION OF 17-HYDROXYCORTICO­ STEROIDS DURING PRE -BED REST AT DIFFERENT PERIODS 0 F THE DAY PART A. SUBJECT 1A 175 PART B. SUBJECT 2A 175 PART C. SUBJECT 3A 176 PART D. SUBJECT 4A 176 PARTE. SUBJECT 6A 177 PART F. SUBJECT 7 A 177 PART G.
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    The Hormonal Treatment of Sexual Offenders JOHN McD. W. BRADFORD, MB The hormonal treatment of sexual offenders is part of a pharmacological approach to the reduction of the sexual drive. Sexual drive reduction can also be brought about by stereotaxic neurosurgery and castration. These other methods of sexual drive reduction are closely related to the phar­ macological approach, and all are dependent on the complex interactions between higher central nervous system functions, located in the cortex and limbic systems, and neuroendocrine mechanisms mediated via the hypothalamic pituitary axis, the gonads, and their various feed-back mechanisms. The higher functions of the central nervous system are chan­ neled through the hypothalamic-pituitary axis where complex neurological correlates of behavior are transformed into neuroendocrine responses. Gonatrophin releasing factor (GRF) is released from the hypothalamus irregularly in bursts. The ante rio-pituitary in response releases luteinizing hormone (LH) and follicular stimulating hormone (FSH), also in episodic bursts of secretion. In the normal male, FSH acts on the germinal epithelium of the seminiferous tubules to produce spermatazoa. LH stimulates the Leydig cells to secrete testosterone that is then released into the serum where it forms approximately 95 percent of the plasma testosterone. The other 5 percent in secreted from the adrenal cortex through d4- androstenedione. J During puberty, both sexes show an increase in the volume of gonado­ trophin secretion, and in the male this is associated with increased testos­ terone secretion during sleep. There is an associated circadian rhythm resulting in sleep related increases in gonadotrophic hormone production. J Testosterone in the male regulates spermatogenesis and is responsible for the development of secondary sex characteristics.
  • Steroids an Overview on 5-Reductase Inhibitors

    Steroids an Overview on 5-Reductase Inhibitors

    Steroids 75 (2010) 109–153 Contents lists available at ScienceDirect Steroids journal homepage: www.elsevier.com/locate/steroids Review An overview on 5␣-reductase inhibitors Saurabh Aggarwal a, Suresh Thareja a, Abhilasha Verma a, Tilak Raj Bhardwaj a,b, Manoj Kumar a,∗ a University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India b I. S. F College of Pharmacy, Ferozepur Road, Moga, Punjab 142001, India article info abstract Article history: Benign prostatic hyperplasia (BPH) is the noncancerous proliferation of the prostate gland associated Received 13 July 2009 with benign prostatic obstruction and lower urinary tract symptoms (LUTS) such as frequency, hesitancy, Received in revised form 9 October 2009 urgency, etc. Its prevalence increases with age affecting around 70% by the age of 70 years. High activity of Accepted 20 October 2009 5␣-reductase enzyme in humans results in excessive dihydrotestosterone levels in peripheral tissues and Available online 30 October 2009 hence suppression of androgen action by 5␣-reductase inhibitors is a logical treatment for BPH as they inhibit the conversion of testosterone to dihydrotestosterone. Finasteride (13) was the first steroidal 5␣- Keywords: reductase inhibitor approved by U.S. Food and Drug Administration (USFDA). In human it decreases the 5␣-Reductase inhibitors Androgens prostatic DHT level by 70–90% and reduces the prostatic size. Dutasteride (27) another related analogue ␣ Azasteroids has been approved in 2002. Unlike Finasteride, Dutasteride is a competitive inhibitor of both 5 -reductase Testosterone type I and type II isozymes, reduced DHT levels >90% following 1 year of oral administration. A number BPH of classes of non-steroidal inhibitors of 5␣-reductase have also been synthesized generally by removing 5␣-Dihydrotestosterone one or more rings from the azasteroidal structure or by an early non-steroidal lead (ONO-3805) (261).