After injection of [4-14C]norethisterone or norgestrel labelled with 14C in the ethynyl group into rabbits, 45 % and 57\m=.\4% of the radioactivity was excreted in the urine, mostly within 2 days. Although small amounts of radioactivity were excreted in the expired air of rabbits receiving norgestrel, little metabolism of the ethynyl group occurred. Radioactivity in plasma declined quickly after injection and 24 hr. later less than 0\m=.\5 % of the dose remained in the circulation. Up to 5 hr. after injection large amounts of radioactivity were found in liver, kidney, intestine and bile; a large proportion of the dose appeared to undergo an entero-hepatic circulation. Although the concentration in fat and muscle was low the total amount in these tissues may approach 5%. The uterus contained a high concentration of radioactivity suggesting that this tissue may bind the progestins or their metabolites. By 24 hr. the amount of radioactivity in the tissues had markedly decreased. Small amounts of radioactivity crossed the placenta of pregnant animals near term and small amounts were found in the foetus and amniotic fluid. Within 3 hr. of the injection at least half of the radioactivity in the tissues was in a conjugated form and considerable metabolism of the injected progestins had occurred. Little, if any, norethisterone or norgestrel was present in the tissues. The metabolites of norethisterone were mainly polar compounds showing that hydroxylation of the steroid had occurred, whereas the metabolites of norgestrel appeared to be similar to the compounds produced by partial or complete reduction of the \g=a\,\g=b\-unsaturated ketone grouping in ring A.

SUMMARY After the administration of [4-14C]lynestrenol (17α-ethynyl-19-nor-androst-4-en-17β-ol) to 7 human subjects 31·–57·6% of the dose, whether administered orally or i.v., was excreted in the urine within 5 days. The biological half-life of radioactivity was 26·5 hr. After acid and enzymatic hydrolysis, 58·7 and 45·6% respectively of the urinary radioactivity was extractable. About 10% of the urinary metabolites were excreted as sulphate conjugates. A mean value of 1·75% of the administered dose was converted to phenolic compounds. The metabolites in the free fraction and enzymehydrolysed extract of urine were almost entirely polar compounds, whereas 70% of the metabolites in the sulphate fraction were much less polar. The chromatographic evidence showed that hydroxylation of lynestrenol must have occurred at two points in the molecule. Plasma radioactivity decreased more rapidly than after administration of norethisterone.

After the administration of norethisterone to seven human subjects 37\m=.\4 % to 80\m=.\6 % of the dose was excreted in the urine within 5 days. About half of the urinary radioactivity was extractable after acid or enzymatic hydrolysis and about 80 % was extracted by using a serial hydrolytic and extraction procedure. About 15 % of the urinary radioactivity was present as sulphate conjugates. About 5 % of the urinary radioactivity was present in acidic or phenolic compounds. No metabolism ofthe ethynyl group seemed to occur and the Girard reaction showed that about half of the urinary metabolites were ketonic. The metabolites in the glucuronide fraction of urine were predominantly more polar on paper chromatography than tetrahydronorethisterone, whereas in the sulphate fraction most of the metabolites had a polarity similar to the simple reduction products of norethisterone. Two days after injection the plasma still contained about 5 % of the administered dose.

The excretion of pregnanediol, pregnanetriol and the 6-oxygenated metabolites of progesterone by fifteen women has been measured throughout pregnancy. During the first trimester the level of excretion of the 6-oxygenated metabolites varied from 0\m=.\4to 2\m=.\2 mg./day and at the end of pregnancy the range was from 3\m=.\5to 11\m=.\6 mg./day. During the last 6 weeks of pregnancy, pregnanediol excretion was relatively constant, whereas in seven of the patients the excretion of the 6-oxygenated metabolites continued to increase. Except at the end of pregnancy there was a close correlation between the 6-oxygenated metabolites and pregnanediol excretion. The results suggest that the 6-oxygenated metabolites and pregnanediol have the same precursor and that little, if any, of a 6-oxygenated progesterone is secreted during pregnancy.There appears to be little increase in pregnanetriol excretion during pregnancy; six of the subjects showed a significantly higher excretion in the third trimester compared with the first trimester of pregnancy, but the values were not outside the normal range for non-pregnant subjects. The specificity of the method of Fotherby & Love (1960) for the estimation of pregnanetriol was examined when applied to pregnancy urine. Between 1\m=.\1and 2\m=.\4 % of administered progesterone was excreted as the 6-oxygenated metabolites. In only one of five subjects was pregnanetriol excretion increased after progesterone administration.

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