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The binding characteristics, content and intracellular distribution of cytosolic and nuclear progesterone receptors have been investigated, using [3H]progesterone as ligand, in the rat uterus bearing a unilateral intra-uterine device (IUD) during the oestrous cycle and from days 3 to 6 of pregnancy. The dissociation constants of nuclear and cytosolic progesterone-receptor complexes for IUD-containing and control uterine horns were similar. Cytosolic receptor concentrations in the IUD-containing uterus were always lower but changed in a manner similar to the control during the periods studied. Nuclear receptor concentrations in the control horn reflected changes in hormone levels during the oestrous cycle although concentrations measured were greater than previously reported. However, in IUD-containing uteri the pattern was completely reversed with minimal levels at pro-oestrus. Nuclear receptor concentrations were little different in both horns during early pregnancy. Total progesterone receptor synthesis determined between metoestrus and pro-oestrus in IUD-containing horns was significantly less than that of control horns. This correlated with the attenuated rise of nuclear oestrogen receptor levels previously observed between these times in IUD-containing uterine horns.

Intravenous glucose tolerance tests, and estimations of prothrombin time, and plasma coagulation factors VII and X, were made on 12 women receiving 200 mg norethisterone oenanthate intramuscularly as a contraceptive. These estimations were made before, and at 2 and 12 weeks after, a single injection of norehisterone oenanthate. There was no significant effect on the intravenous glucose tolerance, prothrombin time, or on plasma coagulation factors VII and X, further confirming the safety of norehisterone oenanthate when used as a short-term injectable contraceptive.

The prostaglandins PGE1, PGE2, PGD2, PGF2 alpha, U46619 and 6 beta-PGI1 were administered as bolus injections both separately and in combination with angiotensin II into the fetal circulation of isolated human placental cotyledons perfused in vitro. PGF2 alpha and PGD2 caused small dose-dependent increases in fetal perfusion pressure when compared with U46619 which acted as an extremely potent vasoconstrictor of the fetal-placental vasculature. PGE1 caused very small dose-dependent decreases in fetal perfusion pressure when injected on its own. In combination with angiotensin II, PGE1, PGD2 and 6 beta-PGI1 caused significant, dose-related attenuations of the angiotensin II vasoconstrictive response whereas PGE2, PGF2 alpha and U46619 potentiated the response. Injections of angiotensin II after the infusion of indomethacin into the fetal circulation resulted in a potentiation of angiotensin II induced vasoconstriction. The results indicate that prostaglandins exert their effects on the fetal-placental circulation by modulating the actions of angiotensin II.

Production of prostacyclin (PGI2) in vitro by human placental cells from pregnancies complicated by fetal growth retardation was significantly reduced compared with that in placental cells from normal pregnancies of either matched gestation or at term. This appeared to be due to a reduction of synthesis of PGI2 rather than to any alteration in the rate of its enzymic metabolism. Addition of oestradiol and progesterone increased PGI2 production by cells from pregnancies with fetal growth retardation in a similar manner to that by cells from first trimester pregnancies, implying that the placental cells are not irreversibly damaged by ischaemia. The decreased PGI2 production by cells of trophoblastic origin may be an aetiological factor in the thrombotic occlusion of the uteroplacental circulation which impairs fetal growth.

The presence of an intra-uterine device in the rat results in a lower nuclear concentration of the oestrogen receptor in the treated horn at pro-oestrus when it is compared with the contralateral control horn. This effect was also seen after the administration of hyperphysiological doses of oestradiol and when the horn was exposed in vitro to high concentrations of oestradiol. The cyclic changes during the oestrous cycle in the activity of the oestrogen-induced enzyme peroxidase were similar in the treated and control horns. These observations have discounted the possibility that the relatively lower nuclear receptor content in the treated horn at pro-oestrus was due to a decreased exposure to oestrogen. A significantly lower nuclear content was also observed in the treated horn on days 4 and 5 of pregnancy. This was not associated with a deficiency in cytosol receptor content which increased concurrently with that of the control horn in the 6 days of pregnancy that were studied. The proportional content of the putative cytosol factor implicated in receptor translocation was similar in both horns, increasing on days 4 and 6 in concert with reported changes in 'induced protein' synthesis. There appeared to be reduced levels of nuclear receptor at a time when blastocyst implantation normally occurs.

Saline extracts were made from portions of 17 normal placentae and from 8 placentae from pregnancies complicated by fetal growth retardation, but not hypertension. The ability of these extracts to inhibit urokinase-induced fibrinolysis was measured using a fibrin plate technique. Placental extracts from pregnancies complicated by fetal growth retardation exhibited greater inhibition of urokinase-induced fibrinolysis. There was no evidence of disseminated intravascular coagulation in these patients, but certain coagulation factors in the peripheral blood were raised.

Secondary ADP induced platelet aggregation was inhibited in 17 patients after the administration of oral prostaglandin E2 tablets for the induction of labour. Primary ADP induced aggregation was shown to be inhibited by oral prostglandin E2 when the platelets responded to the lower concentration of 0-5 mug/ml of ADP. This inhibition was not detectable when the higher concentration of 1-0 mug/ml ADP was necessary. There would appear to be a decreased risk of thrombosis initiated by platelet aggregation as a result of using oral PGE2 tablets for inducing labour.

The effects of the lipoxygenase products of arachidonic acid, 5- and 12-hydroxyeicosatetraenoic acid (5- and 12-HETE) and leukotriene B4 (LTB4), on the spontaneous contractility of lower uterine segment human myometrial strips obtained prior to labour have been studied in vitro. 5-HETE gave a dose- dependent (10-500ng) increase in both the rate of contractions and overall contractility of myometrial strips while 12-HETE and LTB4 had no effect at the same concentrations. Prostaglandin F2 alpha (50ng) contracted all myometrial strips in a similar pattern to 5-HETE but was approximately 10 times more potent. The effect of 5-HETE may be direct or perhaps indirect via interaction with the cyclo-oxygenase pathway. The findings do not disprove the contention that the onset of parturition may be characterised by a switch in arachidonic acid metabolism in intra-uterine tissues from lipoxygenase to cyclo-oxygenase products.

The status of oestrogen and progesterone receptors has been measured in 147 primary breast tumours. In addition to the measurement of cytoplasmic oestrogen receptors, the ability of these receptors to bind to oligo(dT)-cellulose has been assessed. This indicates the capability for activation of cytoplasmic receptors to a form able to bind in the nuclear compartment in vivo and thus be part of a functional receptor pathway. All the receptor concentrations measured were increased in the postmenopausal group of patients. All nuclear oestrogen receptors in this group were available for labelling at 4 degrees C, in contrast to the premenopausal group. The apparent functionality of the oestrogen receptor pathway could be equally assessed either by the co-presence of cytosol progesterone receptor with nuclear oestrogen receptor (30 or 4 degrees C) or with activated cytosol oestrogen receptor. The presence of activated cytosol oestrogen receptor was as reliable (80%) as the presence of either nuclear oestrogen receptor at 30 (83%) or 4 degrees C (81%) in predicting the response of breast tumours to endocrine therapy.

The activation of the rat uterine oestrogen receptor has been measured in vitro by its binding to oligodeoxythymidylate cellulose (oligo(dT] and was found to be sensitive to the time and temperature of prior incubation of cytosol with oestradiol. The presence of 20 mM dithiothreitol promoted receptor activation and was partially inhibited by 10 mM molybdate; molybdate also inhibited the time- and temperature-dependent activation of receptor. The nucleotides GTP, ATP, ADP, CTP and UTP all promoted receptor activation; the effect of GTP was significantly greater than that of ATP. It is unlikely that phosphate donation is involved in receptor activation as the effects of GTP could be reproduced by p[NH]ppG (guanosine 5'-[beta, gamma-imido]triphosphate), while PPi was also effective in activating receptor. The results provide evidence for the distinct regulation of the oligonucleotide- and ligand-binding domains, since manipulations which promoted binding to oligo(dT) did not affect either ligand binding capacity or the rate constant and composition the biphasic dissociation of the ligand receptor complex.