11 



SOME PROBLEMS OF THE METABOLISM AND 



MECHANISM OF ACTION OF STEROID 



SEX HORMONES 



Claude A. Villee, Ph.D. 



ASSOCIATE PROFESSOR OF BIOLOGICAL CHEMISTRY, 

 HARVARD UNIVERSITY 



I. Introduction 643 



II. The Biosynthesis op Steroids 643 



A. Cholesterol 644 



B. Progesterone 644 



C. Androgens 645 



D. Estrogens 647 



E. Biosynthesis of Other Steroids 647 



F. Interconversions of Steroids 647 



G. Catabolism of Steroids (548 



H. Transport, Conjugation, and Excre- 

 tion 650 



III. Effects of Sex Hormones on Inter- 



mediary Metabolism 650 



A. Estrogens 652 



B. Androgens 659 



C. Progesterone 660 



IV. References 661 



I. Intro<luction 



The chemical structure of the sex hor- 

 mones, their isohition from biologic ma- 

 terials, and many of their chemical proper- 

 ties were fully described in the previous 

 edition of Sex and Internal Secretions (W. 

 M. Allen, 1939; Doisy, 1939; Koch, 1939). 

 The major steroid sex hormones were iso- 

 lated and identified 20 to 30 years ago. 

 Estrone, in fact, was crystallized from preg- 

 nancy urine by Doisy, Veler and Thayer 

 (1929) before the true structure of the ster- 

 oid nucleus was known. The isolation, iden- 

 tification, and chemical synthesis of estra- 

 diol, progesterone, and testosterone were 

 accomplished during the 1930's. Additional 

 substances with androgenic, estrogenic, or 

 progestational activity have subsequently 

 been isolated from urine or from tissues but 

 these are probably metabolites of the major 



sex steroids. The steroids are now routinely 

 synthesized from cholesterol or from plant 

 sterols. It would be possible to carry out 

 the total synthesis of steroids from simple 

 precursors but this is not commercially 

 practicable. 



The two decades since the previous edi- 

 tion have been marked by major advances 

 in our understanding of the intermediary 

 metabolism of steroids — the synthesis of 

 cholesterol from two-carbon units, the con- 

 version of cholesterol to pregnenolone and 

 progesterone, and the derivation of corti- 

 coids, androgens, and estrogens from proges- 

 terone. These advances were made possible 

 by the development of vastly improved 

 methods for the isolation and identification 

 of steroids: chromatography on paper or 

 columns, counter-current distribution, label- 

 ing with radioactive or heavy isotopes, 

 infrared spectroscopy, and so on. There have 

 been concomitant increases in the informa- 

 tion regarding the sites and mechanisms of 

 action of these biologically important sub- 

 stances and the means by which they stimu- 

 late or inhibit the growth and activity of 

 particular tissues of the body. The following 

 discussion will attempt to present a general 

 picture of these two fields and not an ex- 

 haustive citation of the tremendous body of 

 relevant literature. 



II. The Biosynthesis of Steroids 



When the steroid hormones were first dis- 

 covered it was generally believed that each 



643 



