Separation of growth inhibiting potency from oestrogenicity in different weak oestrogenic drugs of various chemical structures.

Abstract

ABSTRACT It was investigated in the mouse whether in some synthetic weak oestrogens the ability to inhibit sulphate incorporation rate in costal cartilage (and to retard body growth) is strictly bound to oestrogenicity. A new double isotope method was used which permits a correction of the sulphate uptake values in vivo for drug-induced alterations of the size of the exchangeable inorganic sulphate pool of the animals. All drugs were given for 6 days. Oestrogenicity was tested by the uterotrophic assay. Fenocyclin®, TACE® and methallenestril (Vallestril®) all caused a marked and dose-dependent decrease of both the rate of sulphate incorporation and of the size of the sulphate pool. The drugs also caused retardation of the weight-gain of the animals but to varying degrees. The demethylated form of methallenestril was in all respects much more active than the parent compound. The (+)-antipode of the former was less oestrogenic, but a stronger sulphate uptake inhibitor than the (−)-antipode. Sexovid® (cyclofenil; F 6066) and the related substance F 6088 caused a pronounced inhibition of sulphate incorporation without markedly affecting the size of the sulphate pool. The former was stronger weight-gain inhibitor than the latter. For most drugs there was a clear-cut correlation between the sulphation inhibiting potency and the growth retarding potency but some of them (especially Fenocyclin®) were rather weak as weight-gain inhibitors. The potency ratios between sulphate uptake-inhibiting and uterotrophic effects of all studied drugs were much higher than that of oestradiol benzoate. The potency ratio was especially outstanding with Fenocyclin®, Sexovid®, F 6088 and with the (+)-antipode of demethylated methallenestril. It is concluded that the growth retarding and sulphate incorporation-inhibiting properties of weak oestrogens are not strictly bound to classical oestrogenicity.