46 



Gregory Pincus and Anne P. Merrill 



potent ovulation inhibitors following oral ingestion. In this connection it 

 should be noted that, in addition to finding them more potent as oral than as 

 parenteral progestins, Saunders and Drill (11) were unable to find evidence 



Table 2. The Relative Effecttveness of Certain Steroids by Parenteral and Oral 

 Routes as Ovulation Inhibitors and as Progestins 



* SQ = by subcutaneous injection; O = by gavage. 

 t From Miyake and Pincus (4). 



of direct effect on the endometrium with intrauterine implants. Their trans- 

 formation to active progestins somewhere outside the uterus is indicated by 

 this evidence as well as by our data on the oral : subcutaneous ratio. 



If this in vivo conversion to a potent progestin be accepted, then it may be 

 asked if the unknown conversion product is also responsible for the ovulation 

 inhibition. The fact is that a number of highly potent progestins are also 

 rather potent ovulation inhibitors on injection (e.g. LIII, XLI and related 

 compounds). Presumably their reduced activity by mouth is due to some 

 inactivation process in the gut or in the liver. We have considered the 

 possibility that norethynodrel (LXII) and norethindrone (XLVI) are con- 

 verted to estrogenic compounds which in turn are the active ovulation 

 inhibitors. The rather unremarkable record of the estrogens as ovulation 

 inhibitors in our tests (see Fig. 1) has led us to discount this possibility. We 

 have, in fact, tested the 3-methyl ether of ethinyl estradiol subcutaneously at 

 dosages of 10, 5, 1 and 0.1 mg and have had no significant inhibition of 

 ovulation. However, 17a-ethinyl estradiol itself is the probable estrogenic 

 metabolite, and we have not as yet tested this compound as an ovulation 

 inhibitor in the rabbit. 



Before concluding this presentation, I should like to exhibit data which we 

 have obtained on the ovaries of rats receiving norethynodrel. These are 

 presented in Tables 3 and 4, in which the numbers of corpora lutea, of various 

 folhcle types, and of primordial ova per unit area are given for control and 

 for norethynodrel-injected rats. The rats were injected daily for fourteen days 

 and sacrificed at the fifteenth day. In both groups of animals there was con- 

 sistent reduction over the control values only in the number of corpora lutea. 



