各種合成 progestin の estrogenic activity および anti-estrogenic activity に関する研究

抄録

In recent years, many potent progestins have been made available for clinical use. In this paper, research on estrogenic and anti-estrogenic activities of progestins is presented.
Estrogenic activities of test compounds were measured by the uterotrophic effect in immature mice⁵⁹⁾ and by vaginal cornification in spayed rats.⁶⁰⁾ From experimental data obtained, synthetic progestins were classified in two groups, namely, estrogenic and nonestrogenic progestins. 17α-ethynyl-19-nortestosterone (ENT), 17α-methyl-19-nortestosterone (MNT), 17α-ethynyl-5 (10) -estrenolone (EEO), 17α-ethynyl-4-estrene-3β, 17β-diol-diacetate (EEDDA) and 17α-ethynyl-estrenol (EEL) which showed marked uterotrophic effects were classified in the former, and progesterone, 6-dehydro-retroprogesterone (Δ⁶RP), 6α-methyl-17α-acetoxyprogesterone (MAP), 6-dehydro-6-methyl-17α-acetoxyprogesterone (Δ⁶MAP), 6-dehydro-6-chloro-17α-acetoxyprogesterone (Δ⁶CAP) and 17α-allyl-estrenol (AlEL) which showed no such effect, in the latter. By vaginal smear test, estrogenic effects were also observed with ENT and MNT. But the cornified cell-appearance induced by ENT was slightly different from that induced by MNT. To clarify these differences, 17α-ethynyl-estradiol (EED) and 17α-methyl-estradiol (MED) were also examined. Similarity of the effects on the cornified cell-appearance was observed between ENT and EED, and between MNT and MED. Since these estrogenic progestins were proved capable of converting into 17α-substituted estradiol in vivo, the resulted compound might be expected to play some role on the estrogenic effect. However, 17α-ethynyl-5α-androstane-17β-ol-3-one, which theoretically did not convert to EED, showed cornification in the Allen-Doisy test. This suggests that estrogenic effects of progestins are due not only to converted estrogen but also to the other metabolites and original compouuds.
Besides estrogenic effects, all tested progestins have inhibitory activities upon estrogen-induced uterine growth in immature mice. Mouse uterus, fully grown by the administration of 0.3μg of estrone, decreased its weight with simultaneous administration of synthetic progestins. The decrease was parallel with the dose of administered progestins.However, when estrogenic progestins were used for the inhibitory agents, maximal effect was obtained with the dose of 30-300μg and a larger dose had no more inhibitory effect. The maximally depressed uterine weight obtained with the combined administration was almost identical with maximally grown uterine weight by a single administration of these estrogenic progestins. (Fig. 8) The depressed uterine weight with large doses of progestin was not affected by the additional 1-3μg of estrone (Table 7). These antagonizing effects were similarly observed in the hexesterol treated mice (Table 6).
Antagonizing effects of estrogenic progestins in the dose of 10-100μg against estrogeninduced vaginal cornification in spayed rat, were not recognized. However, 100μg of nonestrogenic progestins, progesterone and Δ⁶CAP, showed antagonizing effects (Table 11 & 12).
While androgens were also reported to increase the uterine weight of immature mice, uterotrophic activities of estrogenic progestins were compared with that of estrogens and androgens. Histrogically, most remarkable changes were observed in endometrial epithelium. Estrone as well as EED induced high columnar, estrogenic progestins columnar, non-estrogenic progestins and testosterone cuboidal, and estrone in combination with progesterone columnar epithelium (Fig. 5 & 6, Photo. 1-7). Radio-autography of dissected uterus revealed that the ³H-thymidine uptake in the uterus was increased markedly by estrogens,