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Cortisol: cortisone interconversion was studied in human decidua obtained from three groups of patients at term (37-42 weeks): before the onset of labour (at elective Caesarean section), after labour of spontaneous onset, and after labour of induced onset. When intact tissue was incubated with [3H]cortisol or [3H]cortisone in phosphate buffer without added substrate or cofactors, cortisone to cortisol was the dominant conversion. However, when damaged cells or tissue homogenates were used in the same conditions, the dominant direction of the reaction was reversed, with a large increase in oxidative (cortisol to cortisone) activity. Cortisol: cortisone interconversion was similar in the three groups of samples using either intact tissue or homogenates, as was the total 11β-hydroxysteroid dehydrogenase (11β-HSD) activity measured in tissue homogenates in the presence of added substrate (cortisol or cortisone) and cofactors (NADP+ or NADPH). Endogenous cortisol concentrations in decidua were higher than those of cortisone, and the ratio of cortisol to cortisone was similar in the three groups. These findings suggest that there are no changes in human decidual 11β-HSD activity in relation to parturition. Specific activity of 11β-HSD decreased at high protein concentrations, suggesting the presence of some enzyme inhibitor(s) in homogenized decidual tissue.
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ABSTRACT
The effects of an inhibitor of 3β-hydroxysteroid dehydrogenase (epostane) on uterine activity and cervical softening have been studied in eight sheep during late pregnancy. Treatment with epostane led to a rapid decline in the concentration of progesterone measured in utero-ovarian venous plasma, to less than 10% of the pretreatment value within 30 min of bolus injection. This was followed by a significant (P<0·02) increase in the concentrations of metabolites of prostaglandins E and F in utero-ovarian venous plasma and uterine activity similar to that seen in the final stages of normal labour. Measurements of cervical tissue extensibility made ex vivo showed the cervix to have softened considerably. These changes occurred without any significant change in the concentration of oestradiol-17β in utero-ovarian venous plasma. Infusion of mefenamic acid, an inhibitor of prostaglandin synthesis, prevented the changes in uterine activity and cervical softening that occurred after injection of epostane alone. Mefenamic acid also reduced the increase in concentrations of metabolites of prostaglandins E and F in plasma, although the concentration of progesterone in these animals showed the same abrupt fall which occurred in sheep after injection of epostane alone. These results suggest that progesterone withdrawal, in the absence of any subsequent rise in circulating oestrogen concentrations, is sufficient stimulus to induce cervical softening in the ewe. Cervical softening following progesterone withdrawal can be prevented by inhibition of prostaglandin synthesis.
J. Endocr. (1985) 105, 227–233
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Placental tissue was removed from a ewe at 127 days' gestation and, without separating foetal from maternal contributions, incubated as a mince (4 g) with equimolar amounts of [4-14C]androstenedione (2 μCi, 56 mCi/mmol) and [1,2-3H]epitestosterone (15 μCi, 420 mCi/mmol) at 39·5 °C. The reactions were stopped after 2 h by adding acetone and freezing. The non-radioactive carrier steroids, androstenedione, testosterone, epitestosterone, oestrone, oestradiol-17β, oestradiol-17α, testosterone sulphate and epitestosterone sulphate were added in 500 μg amounts.
After mixing, steroids and their conjugates were extracted from the incubation medium with 2 × 100 ml acetone followed by 2 × 100 ml ether: ethanol (3:1, v/v). Nonpolar lipid material was removed by partitioning the pooled, dried extract between 70% (v/v) aqueous methanol and light petroleum (b.p. 40–60 °C). The methanol was evaporated and unconjugated steroids extracted from the aqueous residue with 3 × 30 ml ether before saturating with ammonium
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SUMMARY
Maternal plasma progesterone levels in sheep may fall dramatically during the last few days of gestation and following the administration of glucocorticoids to the foetus. To investigate the mechanism of the fall, metabolism of [3H]pregnenolone and/or [3H]progesterone in vitro by ovine placental tissue was studied in five ewes before and after intra-foetal administration of dexamethasone in a dosage sufficient to induce parturition, and in one ewe after the spontaneous onset of labour at 143 days of gestation. Manual separation of maternal and foetal placental tissues showed that, in 11 out of 12 cases, the foetal and not the maternal placenta produced progesterone from pregnenolone in vitro. Total activities of cholesterol side-chain cleavage enzyme and 3β-hydroxysteroid dehydrogenase in the foetal placenta were not influenced by intra-foetal dexamethasone. Before administration of dexamethasone, homogenates of foetal placenta converted [3H]progesterone to 20α-hydroxy [3H]pregn-4-en3-one in the presence of NADPH. Within 12 h of administration of dexamethasone, and after the natural onset of labour at 143 days, large amounts of 17α,20α-dihydroxy[3H]pregn4-en-3-one were formed from [3H]progesterone. Intra-foetal dexamethasone treatment also induced the formation of 17α,20α-dihydroxy[3H]pregn-4-en-3-one by minced foetal placental tissue incubated with [3H]pregnenolone. This change in steroid metabolism did not occur in foetal placental tissue from a sham-operated animal receiving no dexamethasone. Assay of progesterone in foetal placentae showed that the increased formation of 17α,20αdihydroxypregn-4-en-3-one was unlikely to be caused by a change in the specific activity of added 3H-labelled precursor, although the production of 17α,20α-dihydroxypregn-4-en3-one in vitro increased at a time when both foetal placental and utero-ovarian venous levels of progesterone were decreasing in response to dexamethasone treatment. These observations indicate that intra-foetal dexamethasone treatment induces a placental 17α-hydroxylase enzyme, which is also present in foetal placental tissue after the spontaneous onset of labour at term.
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SUMMARY
Simultaneous measurements of prostaglandin F, total unconjugated oestrogens and progesterone have been made in utero-ovarian venous or posterior vena caval plasma from pregnant ewes during parturition. In all cases, levels of oestrogens and prostaglandin F increased before delivery, after a decrease in the level of progesterone. In four out of six sheep, during both spontaneous and dexamethasone-induced labour, increases in the levels of oestrogens and prostaglandin F occurred in parallel. In the other two animals, levels of prostaglandin F increased before those of oestrogens. The increases in prostaglandin F consistently preceded any measurable increase in uterine activity, suggesting levels were not raised as a consequence of labour. Infusion of oestrogen to two dexamethasone-treated animals resulted in increased utero-ovarian venous prostaglandin F levels within 2–3 h. These findings support previous evidence indicating that levels of prostaglandin F may be controlled by oestrogen and progesterone. Manual examination of the cervix, with associated distension of the vagina, resulted in dramatic increases in the level of utero-ovarian venous prostaglandin F during the last 13 h of gestation, both in dexamethasone-induced labour and in labour of natural onset. Since expulsion of the foetus also results in vaginal distension, this finding raises the possibility that the very high levels of prostaglandin F observed at delivery may be caused by tactile stimulation of the vagina.
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Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Headington, Oxford, 0X3 9DU
(Received 24 April 1974)
Progesterone levels in the blood of pregnant sheep increase with increasing number of foetuses and with gestational age (Bassett, Oxborrow, Smith & Thorburn, 1969), and are thought to be reduced as a result of foetal cortisol secretion preceding parturition (Liggins, 1973). Data presented here suggest that β-adrenergic stimulation may also influence placental progesterone production.
Utero-ovarian venous and intra-amniotic catheters were inserted in four pregnant ewes, gestational ages 119–130 days, 3–4 days before experimentation. Jugular venous catheters were inserted on the day of the experiment, which was carried out on the conscious animals. Progesterone, total unconjugated oestrogens (oestrone + oestradiol-17/β + oestradiol-17α) and prostaglandin F were measured in utero-ovarian or jugular venous plasma by specific radioimmunoassays (Flint, Anderson, Patten & Turnbull, 1974). Neither orciprenaline nor salmefamol cross-reacted at concentrations up to the equivalent of
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SUMMARY
As part of a continuing study of adrenal steroids in relation to breast cancer, various experiments were performed in order to study relationships between androgen and corticosteroid biosynthesis. Chopped tumour tissue from a 'mixed cell' adrenal adenoma (7·4 g.) removed from a patient in Cardiff Royal Infirmary was incubated with [4-14C]pregnenolone and [7α3H]17α-hydroxypregnenolone for periods of time ranging from 30 to 120 min. The results of this work suggest that 17α-hydroxyprogesterone may not be an obligatory intermediate in androgen or cortisol synthesis. Evidence from further experiments with 'normal' human adrenal tissue removed from breast cancer patients using previously established ultramicrochemical techniques indicates that dehydroepiandrosterone (DHA) sulphokinase enzyme system is confined to the zona reticularis of the gland. The conversion of [7α-3H]DHA sulphate, [7α-3H]androstenedione and [7α-3H]testosterone to oestrogens and their conjugates by adrenal homogenates was also investigated. Conversions were extremely low from all precursors.
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This paper reports the metabolism of labelled androstenedione and pregnenolone by the liver of foetal sheep. Isolation of reduction products was a major feature of this study.
The livers were removed from sheep foetuses at (a) 129 days', and (b) 143 days' gestation immediately after Caesarean section under spinal analgesia. The tissue was maintained at 0 °C until incubated 1 h later. Chopped tissue (2 g) was incubated in 24 ml Krebs—Ringer bicarbonate glucose solution at 39–5 °C in 95% O2:5% CO2 with the following: incubation (a), 57·4 nmol each of [4-14C]androstenedione (34·8 mCi/mmol) and [7α-3H]pregnenolone (14·7 Ci/mmol); incubation (b), 57·4 nmol of [4-14C]androstenedione (34·8 mCi/mmol). Reactions were stopped after 2 h with acetone containing 500 μg each of the listed carrier steroids (Table 1). The following were unobtainable as sulphates and were added as free steroids to the conjugate fraction before
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The concentration of thromboxane B2 has been measured in the plasma of women during late pregnancy, during term and pre-term labour, in women with pre-eclampsia and in umbilical cord arterial and venous plasma. In addition, the rates of production of thromboxane B2 in vitro were determined for placental tissues obtained after spontaneous vaginal delivery or elective Caesarean section. The results obtained indicate significant differences during parturition between the sources and controlling mechanisms of thromboxane and prostaglandin production.
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The concentrations of 6-oxo-prostaglandin F1α (6-oxo-PGF1α) have been determined in maternal and foetal plasma from nine chronically catheterized sheep during late pregnancy and parturition. Labour occurred either spontaneously (three sheep) or was induced by continuous intrafoetal infusion of Synacthen (ACTH 1–24; 0·24 mg/24 h; three sheep) or dexamethasone (1 mg/24 h; three sheep). During spontaneous and Synacthen-induced parturition, concentrations of 6-oxo-PGF1α in maternal and foetal plasma remained at basal levels until 24 h before delivery. At varying times during the 24 h before delivery, levels of 6-oxo-PGF1α in maternal and foetal plasma were generally increased. When parturition was induced with dexamethasone, however, no increase was observed in the foetal plasma although the concentration of 6-oxo-PGF1α in maternal plasma was raised close to delivery.
