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The pharmacological effect of 2-hydroxyoestradiol (2-OHE₂) and 4-OHE₂ on concentrations of LH in the chronically castrated rat have been compared with that of oestradiol in order to determine whether the in-vivo activity is altered by insertion of a hydroxyl group at position 2 or 4 of the aromatic A ring; these derivatives are naturally occurring oestrogen metabolites. Four groups of six adult male rats were used 4 weeks after bilateral orchidectomy. The right jugular vein was exposed under ether anaesthesia and a basal blood sample taken (10.00 h) immediately before an intravenous injection of vehicle alone (0·1 ml ethanol with 0·01 % ascorbic acid), oestradiol, 2-OHE₂ or 4-OHE₂ (10 µg of each in 0·1 ml vehicle). Blood was taken from each animal at 2, 4, 6, 8 and 24 h after treatment and serum assayed for LH. Baseline LH levels were similar in the four groups. At 2 h there was no change in 2-OHE₂-treated rats but there was a significant decrease of serum levels of LH in rats treated with oestradiol and 4-OHE₂ compared with vehicle-treated controls. The decrease in LH was quantitatively similar in oestradiol- and 4-OHE₂-treated groups and was sustained at 4, 6 and 8 h, returning to control values at 24 h. In subsequent experiments the effects of lower doses of these two steroids were compared and the potency of 4-OHE₂ was estimated to be about 25% that of oestradiol. In a further experiment, 2-OHE₂ (100 µg) had no effect when given alone, but when injected i.v. immediately before treatment with 1 µg oestradiol, it was able to inhibit the suppression of LH by oestradiol. In conclusion, 4-OHE₂ had a potent effect in lowering plasma LH levels whereas 2-OHE₂, even at a high dose (100 µg), did not suppress LH but it was able to inhibit the effect of oestradiol. These differences in biological activity may reflect more rapid metabolism of 2-OHE₂ or differences in binding properties of these catechol oestrogens to the oestrogen receptor.