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After an iv injection of [14,15-3H]d,1-norgestrel into 7 women, its disappearance from the plasma and its distribution in the reproductive organs has been investigated. It was found that initially norgestrel disappeared rapidly from the plasma with a half-life of 38.8 min followed by a slower disappearance with a half-life of 45.18 h. The disappearance curve has been analysed on the basis of a biexponential curve representing a two compartmental model. The low metabolic clearance rate of 458.5 1/24 h indicated a more prolonged persistance of norgestrel in the body. Uptake of norgestrel and its metabolites was very high in the endometrium, myometrium, cervix. Fallopian tube, ovary and body fat. Compared to the myometrium, more norgestrel as such was concentrated in the endometrium at 30 min and 12 h after injection of [14,15-3H]d,1-norgestrel. The myometrium on the other hand contained higher amounts of norgestrel at 5 min. The significance and the possible role of localization of norgestrel at multiple sites in the reproductive tract and its contraceptive action are discussed.

Incubation of the 105 000 times g supernatant of rat uterus homogenate with (3H)oestradiol resulted in an oestrogen specific binding of limited capacity to a macromolecule sedimenting in the 8-9S region after density gradient centrifugation. The contraceptive progestins of the 19-nortestosterone series were able to interfere with oestradiol binding in contrast to the hydroxyprogesterone derivatives chlormadinone, medroxyprogesterone and megestrol. The interaction appeared to be competitive. The strongest inhibition of oestradiol binding was observed in the presence of ethinodiol, followed by northinodrel, lynestrenol and norethindrone respectively. Norgestrel was almost inactive. Of the related structures tested oestrenol displayed more activity than norethindrone, nortestosterone and ethisterone were less active and 6alpha-methyllynestrenol showed only border line activity. In comparison with norethinodrel and norethindrone, lynestrenol and oestrenol appeared in vitro to be stronger competitors for oestradiol than in vivo (Part I; Van Kordelaar et al. 1975). This may be due to the great difference in lipophilic character, which is reflected in the RM values of these compounds. From the results obtained it may be concluded, that the presence of a 17alpha-ethynyl substituent promotes receptor binding, whereas the introduction of methyl substituents in the position 6, 10 and 18 causes the opposite effect. The relationship between the various ring A structures and the affinity to the receptor is discussed.