650 



PHYSIOLOGY OF GONADS 



urine and are known to be estrogen metab- 

 olites (Marrian and Bauld, 1955). 



H. TRANSPORT, CONJUGATION, AND EXCRETION 



Steroids circulate in the blood in part as 

 free steroids and in part conjugated with 

 sulfate or glucuronic acid (c/. review by 

 Roberts and Szego, 1953b j . The steroids are 

 generally conjugated by the hydroxy 1 group 

 at carbon 3 with inorganic sulfate or with 

 glucuronic acid. In addition, either the con- 

 jugated or nonconjugated forms may be 

 bound to certain of the plasma proteins such 

 as the ^-globulins (Levedahl and Bernstein, 

 1954) . There is evidence of specific binding 

 of certain steroids with particular proteins, 

 e.g., the binding of Cortisol to "transcortin" 

 (Daughaday, 1956). Between 50 and 80 per 

 cent of the estrogens in the blood are pres- 

 ent closely bound to plasma proteins. A 

 similar large fraction of the other steroid 

 hormones is bound to plasma proteins ; pre- 

 sumably this prevents the hormone from be- 

 ing filtered out of the blood as it passes 

 through the glomerulus of the kidney. The 

 steroids excreted in the urine are largely in 

 the conjugated form, as sulfates or glucu- 

 ronides. 



The liver plays a prime role in the catab- 

 olism of the steroids. It is the major site 

 of the reductive inactivation of the steroids 

 and their conjugation with sulfate or glucu- 

 ronic acid. These conjugated forms are more 

 water-soluble and the conjugation probably 

 promotes their excretion in the urine. Rather 

 large amounts of certain steroids, notably 

 estrogens, are found in the bile of certain 

 species. These estrogens are free, not con- 

 jugated; the amount of estrogens present 

 in the bile suggests that this is an im- 

 portant pathway by which they are ex- 

 creted. It has been suggested that the bac- 

 teria of the gastrointestinal tract may 

 degrade the steroids excreted in the bile and 

 further that there is an "enterohepatic cir- 

 culation" of steroids with reabsorption 

 from the gut, transport in the portal system 

 to the liver, and further degradation within 

 the liver cells. 



III. Effects of Sex Hormones on 

 Intermediary Metabolism 



The literature concerning the effects of 

 hormones on intermediary metabolism is 



voluminous and contains a number of con- 

 tradictions, some of which are real and 

 some, perhaps, are only apparent contradic- 

 tions. Evidence that a hormone acts at one 

 site does not necessarily contradict other 

 evidence that that hormone may act on a 

 different metabolic reaction. From the fol- 

 lowing discussion it should become evident 

 that there may be more than one site of 

 action, and more than one mechanism of 

 action, of any given hormone. 



The hormones are so different in their 

 chemical structure, proteins, peptides, 

 amino acids, and steroids, that it would 

 seem unlikely, a priori, that they could all 

 influence the cellular machinery by com- 

 parable means. The basic elements of an 

 enzyme system are the protein enzyme, its 

 cofactors and activators, and the substrates 

 and products. A hormone might alter the 

 over-all rate of an enzyme system by alter- 

 ing the amount or activity of the protein 

 enzyme, or by altering the availability to 

 the enzyme system of some cofactor or sub- 

 strate molecule. Some of the mechanisms 

 of hormone action which have been pro- 

 posed are these. (1) The hormone may alter 

 the rate at which enzyme molecules are 

 produced de novo by the cell. (2) The hor- 

 mone may alter the activity of a preformed 

 enzyme molecule, i.e., it may convert an 

 inactive form of the enzyme to an active 

 form. (3) The hormone may alter the per- 

 meability of the cell membrane or the 

 membrane around one of the subcellular 

 structures within the cell and thus make 

 substrate or cofactor more readily available 

 to the enzyme. Or, (4) the hormone may 

 serve as a coenzyme in the system, that is, 

 it may be involved in some direct fashion 

 as a partner in the reaction mediated by the 

 enzyme. Each of these theories has been 

 advanced to explain the mode of action of 

 the sex hormones. 



The problem of the hormonal control of 

 metabolism has been investigated at a vari- 

 ety of biologic levels. The earliest experi- 

 ments were done by injecting a hormone 

 into an intact animal and subsequently 

 measuring the amount of certain constitu- 

 ents of the blood, urine, or of some tissue. 

 There are several difficulties with such ex- 

 periments. All of the homeostatic mecha- 

 nisms of the animal operate to keep condi- 



