Lymphocytokaryorrhectic Effects of Adrenocortical Steroids 121 



STRUCTURE ACTIVITY RELATIONSHIPS 



There are marked differences in lymphocytokaryorrhectic capacity of the 

 various adrenal cortical hormones. Cortisol, which is the naturally secreted 

 adrenal hormone of the human, is the most potent. Other less effective hor- 

 mones are cortisone, corticosterone, and dehydrocorticosterone or compound 

 A. 16 None of the other adrenal cortical secretory products appear to have 

 this capacity. Analysis of both the naturally occurring hormones and their 

 analogs which are lacking in one or more substitutions on the gonane nucleus 

 indicates that an unsaturation of the A-ring, a ketone at position 3, either 

 an oxy or hydroxyl substitution at position 1 1 , and a side chain with an 

 alcohol at the 21 position are necessary. Two compounds both lacking a 

 17-hydroxy grouping are corticosterone and 1 1 -dehydrocorticosterone. 1 ' 1 Both 

 of these compounds are effective in suppressing lymphatic tissue growth and 

 bringing about lymphoevtokaryorrhexis. It is interesting in this respect that 

 these compounds have little or no anti-inflammatory activity, and thus there 

 is a separation of anti-inflammatory and lymphocytorrhectic effects. 



MECHANISMS OF HORMONE ACTION 



The effects of Cortisol are direct, i.e., the lymphocytokaryorrhectic activity 

 of this hormone is manifest in vitro and in vivo. Further, these hormones 

 do not act in an all-or-none fashion but in a dose response manner. There- 

 fore, the greater the dose, the greater the degree of lymphocytokaryorrhexis. 

 However, it is interesting that Cortisol among the effective hormones has a 

 greater involutional)- action on the lymph nodes than any of the hormones. 

 The explanation offered for Cortisol activity is that it has a greater capacity 

 to destroy less-matured lymphocytes than its analogs. Thus, there is a qual- 

 itative as well as a quantitative difference in the various adrenocortical 

 steroids which appears to be determined by the degree of maturity of lym- 

 phocytes available for hormone action. The duration of Cortisol action on 

 lymphocytes is short. Radioactive hormone (free 4-C 14 Cortisol) does not 

 remain in lymphatic tissue more than fixe or six minutes following intra- 

 venous administration. However, the major effects of Cortisol on lympho- 

 cytes persist for much longer periods of time than Cortisol, or its metabolic 

 products are present in lymph nodes, spleens, and thymi. 23 This indicates 

 that Cortisol triggers a process in the cell which is self-perpetuating. The 

 lack of necessity for continuously increased hormone concentration at the 

 site of anti-inflammatory or gluconeogenic activity 24 is similar to that found 

 for effects on lymphocytes. 2 ' 5 



It is evident, then, that one way that leukemic lymphocytes can maintain 

 their integrity and continue to multiply is by their capacity to inactivate 

 Cortisol, the normally occurring maturing hormone lor the lymphocyte. It 



