Steroid Hormones 91 



by the addition of more hydroxyl or carbonyl groups, but, as will 

 become clear below, the rates and directions of certain reactions may 

 be profoundly altered by the presence in the molecule of other groups 

 which may be quite far removed in space. 



The concept which occupies a central position is that of the entire 

 molecule as the reactive entity. This concept is supported by a wide 

 variety of examples of marked alterations of reactivity induced in 

 steroid compounds by the presence of distant functional groups. One 

 such example is that of the effect on the rate of development of color 

 in the Zimmerman reaction of etiocholan-3a-ol-17-one by the introduc- 

 tion of a ketone group at carbon 11. As far as is known, the 11-ketone 

 group does not participate in the reaction, and yet in its presence there 

 is a tenfold increase in the rate of color development. Even more 

 striking is the action of acetic anhydride and pyridine upon the 

 epimers, 3a, 11/i- and 3/3,ll/3-dihydroxyandrostan-17-one. In the for- 

 mer the sole product is the 3-monoacetate, whereas the latter yields 

 predominantly the 3,11-diacetate. Another example is the effect of 

 the presence of an 11-oxygen atom on the in vivo reduction of A 4 -3- 

 ketones of the androstene series. When testosterone or A 4 -androstene- 

 3,17-dionc is given to a human subject, the principal metabolites found 

 in the urine, androsterone and etiocholan-3a-ol-17-one, appear in 

 roughly equal amounts. However, when andrenosterone (A 4 -andro- 

 stcne-3.11,17-trione) is administered, the ratio of androstane to etio- 

 cholane metabolites is more nearly 4. Many other examples of this 

 type of influence have been observed and serve to strengthen the view 

 that the chemical reactivity of the steroids must be considered in terms 

 of the total molecule rather than isolated functional groups. This 

 concept is neither new nor surprising. What is noteworthy is that in 

 the steroids these effects of distant groups upon chemical reactivity are 

 expressed so clearly and unmistakably. This argument leads to the 

 speculation that one must search for the mechanism of action of the 

 steroid hormones not so much in terms of the reactivity of individual 

 function groups but in terms of the behavior which might be expected 

 of the total molecule. The entire molecule of a steroid hormone may 

 thus be dissected into two portions, the nucleus, a lipide backbone, 

 superimposed upon which are centers of unsaturation and oxygen func- 

 tions in highly specific positions and with characteristic configurations 

 and conformations. The introduction of the 4—5 double bond which 

 is so characteristic of the biologically active neutral steroids serves in 

 a sense to increase the rigidity of an already highly rigid molecule. 

 Such a molecule would be highly oriented at any lipide-water interface 



