PROGESTATIONAL ACTIVITY OF CERTAIN 19-NOR STEROIDS AND PROGRESTERONE DERIVATIVES¹

Abstract

Seven 19-norsteroids, 17a:-ethinyl-19-nortestosterone (I), 17a-ethinyl-5(10)estraenolone (II), 17a-ethyl-19-nortestosterone (III), 17a-methyl-19-nortestosterone (IV), 17a:-propyl-l9-nortestosterone (V), 17a-butenyl-19-nortestosterone (VI), and 17a-allyl-19-nortestosterone (VII), and two progesterone derivatives-17a-hydroxyprogesterone-17-acetate (VIII) and 17a-hydroxy-6a-methyl-progesterone acetate (IX) have been administered subcutaneously or orally into Clauberg rabbits to demonstj-ate their progestational activity by estimation of endometrial carbonic anhydrase content and measurement of the uterine G/M ratio.The increase of endometrial carbonic anhydrase content induced by treatment with each compound correlates well with that of the G/M ratio which measures uterine proliferation. Similarly, the relative potencies by the enzyme test correspond to those obtained by the G/M assay either in subcutaneous treatment or in oral administration.The relationship between the progestational activity and the length of .17side-chain in the 17-substituted-19-nortestosterones found by Saundcrs et al.(3) seems to be applicable to the potencies obtained by subcutaneous injection but not to those found on oral administration. Among the 17-substituted-19nortestosterones, the allyl-compound is the most active in the subcutaneous assay, but the most active by oral route is the ethyl-compound.Three 19-norsteroids, I, II and IV are much more active by the oral route than by the subcutaneous route, while the others are quite opposite. The progestational activity of progesterone administered either parenterally or orally is increased by 17a-acetoxylation ; and further increase is obtained by 6a-methylation of this acetate ester.

Onset of Synthesis of Progesterone by Ovine Placenta

“…Pregnancy maintenance in ovariectomized ewes In the study of Alexander & Williams (1968), the lowest dose of progesterone maintaining pregnancy in 100% of ovariectomized ewes was 1 -05 mg/kg per week and in certain bioassays the progestagenic activity of MPA is 30-to 40-fold greater than that of progesterone (Miyake & Pincus, 1958;Illingworth & Deanesly, 1972). The mean body weight of sheep in this study was 65 kg, thus the estimated maintenance dose of MPA was 1-7-2-3 mg/week.…”

Placental production of progesterone in ovariectomized goats treated with a synthetic progestagen to maintain pregnancy

“…Some inhibition of LH release might be expected if the progestational effect of circulating MPA was greater than that normally exerted in pregnancy by progesterone. The potency of MPA has been quoted as 30-40 times greater than that of progesterone in the rat and guinea-pig (Miyake & Pincus, 1958;Illingworth & Deanesly, 1972); if this is also true for the goat, then the circulating MPA concentration (which reached 0-6-0-8 ng/ml; Text- fig. 4) is equivalent to a concentration of progesterone of 18-36 ng/ml, which is above the normal range (Table 1).…”

Maintenance of Pregnancy by Synthetic Progestagens in Guinea-Pigs Ovariectomized Before Implantation; Progesterone-Binding Protein and Placental Progesterone Secretion

“…MAP was described as 30-40 times as active as progesterone using the rabbit endometrium (Miyake & Pincus, 1958;Edgren et al 1968), and for main¬ tenance of pregnancy in the guinea-pig, MAP also seems to be about 30 times as active as progesterone. MGA, three to four times as active as MAP in the McPhail test (Duncan, Lyster, Hendrix, Clark & Webster, 1964), was about as active as MAP in the present experiments.…”