The Mechanism by which Foetal Cortisol Controls the Onset of Parturition in the Sheep

Abstract

The sheep is one of the few species in which there is good evidence that the foetus is involved in determining the length of pregnancy. Parturition in the sheep is prevented by foetal hypophysectomy (Liggins etal., 1967; Comline etal., 1970; Bosc, 1972) or adrenalectomy (Drost & Holm, 1968), and can be induced prematurely by intrafoetal administration of ACTH* or glucocorticoid (Liggins et al., 1967). The foetal adrenal hypertrophies towards the end of pregnancy, doubling in weight during the last 2 weeks (Comline & Silver, 1961), and its ability to respond to ACTH with increased cortisol output also increases during this time (Bassett & Thorburn, 1973). High concentrations of ACTH have been reported in foetal plasma near term (Rees et al., 1973, although it is not clear that the increase precedes the onset of 1abour.Thereisadramaticand sustained increase in the concentration of cortisol in the foetal plasma during the last week of pregnancy (Bassett & Thorburn, 1969; Comline et al., 1970). In addition to these events in the foetus, important endocrine changes occur in the mother before parturition. Placental progesterone production declines, leading to a decrease in the maternal peripheral plasma progesterone concentration (Bassett et a[., 1969; Fylling, 1970), and maternal plasma concentrations of oestrogens, both unconjugated and sulpho-conjugated, rise (Challis, 1971 ; Currie et al., 1973). Uterine prostaglandin production increases, and high concentrations of prostaglandin FIG appear in the uterine venous effluent (Liggins & Grieves, 1971 ; Thorburn et al., 1972). These changes can be monitored in the foetus and mother by the use of indwelling vascular catheters implanted at surgery some weeks before delivery. Investigation of the temporal interrelationships between these endocrine changes has shown that the progesterone concentration in maternal plasma falls at about the same time as that of cortisol in foetal plasma rises, 3-7 days before delivery. Oestrogen concentrations in plasma increase later, generally about 24-48 h before delivery, and are accompanied by rising uterine venous concentrations of prostaglandin F (Thorburn et al., 1972). These changes precede the onset of uterine contractions (Rawlings W Flint et al., 1974). Since oestrogen administration stimulates uterine prostaglandin production in a number of species (including the sheep) both during pregnancy and otherwise, it has been suggested (Liggins et al., 1973) that the elevated oestrogen concentration in maternal plasma is responsible for the increased concentration of prostaglandin F. Prostaglandins cause marked increases in uterine contractility in sheep at term (M. D. Mitchell, A. P. F. Flint & A. C. Turnbull, unpublished work), as in other species, and it is probable that the oestrogens, which themselves cause labour when administered to pregnant sheep (Hindson et al., 1967), act through prostaglandin synthesis. These endocrine events play an important part in controlling the onset of labour in sheep. The foetal cortisol surge is a necessary prelude to parturition at term: foetal hypophysectomy prevents delivery. Involvement of various maternal organs has been ruled out by extirpation : parturition occurs normally after maternal hypophysectomy (Denamur & Martinet, 1961 ; Bosc, 1972), ovariectomy or adrenalectomy (Thompson & Wagner, 1974). The fall in the progesterone concentration in maternal plasma is also a pre-requisite for normal labour. Labour induced with foetal glucocorticoid can be blocked by the simultaneous administration of large doses of progesterone to the ewe (Liggins et al., 1972); and induction of labour with oestrogens (when there is no fall in progesterone concentration) is associated with failure of the cervix to dilate. There