^oo Conditions for Tumorigenesis 



pluristratified insular metaplasia of the endometrium can be produced in the 

 guinea pig with less than forty injections of i fig. of estradiol when it is given 

 as an ester. Certain esters, especially the 17-caprylate, are more active than 

 others; with the 17-caprylate or the i7-benzoate-3-n-butyric ester of estradiol 

 one may sometimes observe beginning metaplasia with one-tenth these 

 quantities. 



The threshold for fibromatogenic action seems to be higher than that for 

 the beginning proliferation or metaplasia of the uterine epithelium. Small 

 parametral fibroids sometimes appear, however, when only forty injections 

 of 1 fjig. of esterified estradiol have been given; some animals will show ab- 

 dominal fibroids with less than forty injections of 2 /xg. of estradiol given as 

 17-caprylate (Lipschiitz, Vargas, Baeza-Rosales and Baeza-Herrera^"). The first 

 signs of a fibrous tumorigenic reaction on the spleen, or what we called the 

 "tumoral seed" (Vargas and Lipschiitz"^), may become evident with as little as 

 ten injections of 1 fig. of estradiol given as the 17-caprylate in the course of 

 twenty-one days. 



When similar quantities of free and esterified estradiol are administered 

 under similar timing conditions (three injections weekly in the course of three 

 months), differences become evident: esterification with caprylic acid in posi- 

 tion 17, for example, enhances the fibromatogenic action of estradiol one hun- 

 dred to two hundred times; a dose of 2 to 5 /xg. of the caprylate is enormously 

 superior to 200 to 400 /xg. of free alpha-estradiol.The fibromatogenic minimum 

 of the 17-caprylate of estradiol is, in fact, greater than the sarcomatogenic mini- 

 mum of certain hydrocarbons, but the enhancement of the power of an estrogen 

 to induce tumors by simple esterification has an analogy in the carcinogenic 

 hydrocarbons, where methylation, for instance, may confer the highest car- 

 cinogenic capacity; 1 : 2-benzanthracene is almost devoid of carcinogenic action, 

 whereas its 5: 10-dimethyl derivative is highly active (Bachmann and co- 

 workers*"). 



2. The Tumorigenic Timing Conditions. Why is the tumorigenic capacity of 

 estrogens so considerably enhanced by esterification? At the beginning of our 

 work the assumption was tentatively made that a certain threshold, or tumori- 

 genic level, of folliculinemia must be attained and continuously maintained 

 for tumorigenesis to occur (Lipschiitz"). The free hormone is rapidly absorbed 

 and inactivated in the body so that the concentration of the hormone in the 

 blood is subject to considerable fluctuation when injections are given thrice 

 weekly. Under these conditions, great quantities of the hormone would be 

 necessary to maintain the concentration of hormone in the blood at the tumori- 

 genic level. On the other hand, absorption of the esterified hormone is gen- 

 erally considered to be slow, a circumstance favoring the maintenance of 

 folliculinemia at the tumorigenic level, even when smaller quantities are in- 

 jected. Later we found that differences in the tumorigenic faculty of the free 

 hormone and the esterified one did not always parallel differences in the rate of 

 absorption. The dipropionate of estradiol is much more tumorigenic than the 



