DISPOSICIONES GENERALES DE LAS COOPERATIVAS DE TRABAJO ASOCIADO

The role of oxytocin in stimulating uterine contractions during parturition is well established (Campbell and Lasley 1985) as is its role in the milk-ejection reflex (see review by Cowie et al.

1980). Galactopoietic responses to oxytocin have been observed, which are not likely to have been responses to increased milk removal (see Cowie and Tindal 1971). The release of this

hormone during parturition, combined with evidence of galactopoietic activity, warrants consideration of the possibility that oxytocin has a role in the initiation of lactogenesis.

1.7.1 PLASMA CONCENTRATIONS OF OXYTOCIN

Oxytocin is secreted into the blood in response to the suckling or milking stimulus in all species so far studied (Cowie et al. 1980) including the ewe (Cowie and Tindal 1971). A transient release of oxytocin was detected during suckling in the ewe. Peak activity observed was 114 µU/ml plasma which fell to a very low level within 2 min after the start of suckling (Fitzpatrick 1961). However, prior to the development of RIA's for oxytocin (first publications in 1970) the bioassays employed were slow and suffered problems of poor specificity, sensitivity, and precision (Cowie and Tindal 1971). Thus, such reports of oxytocin concentrations are unreliable, but they are included here due to the lack of other reported values in sheep. Similar values were reported in machine-milked cows and hand-milked goats, but it is interesting to note that no release was detected in a high proportion of individuals (Cowie and Tindal 1971). The half-life of oxytocin in the ewe is less than 1 min according to Schmidt (1971), but Wachs et al. (1984), using a highly specific RIA, reported a "rapid" half-life of 3.87 min and a "slow" half-life of 25.5 min (representing the initial phase and terminal phase of elimination, respectively). These values indicate the need for speed and accuracy during blood sampling in order to measure, or indeed to detect, oxytocin release.

There appear to be no reported measurements of oxytocin concentrations in relation to lactogenesis in sheep, but Rice et al. (1984) stated that levels are elevated in the latter stage of delivery. Oxytocin is also released during second stage labour in the goat (Fitzpatrick and Walmsley 1965). According to Thorburn et al. (1977) both PGF2α and oxytocin were elevated in response to vaginal distension in goats. Since each is believed to stimulate the release of the other, a positive feedback cascade may exist between these substances (and also with oestrogen; see section 1.4.3). Release of oxytocin caused by vaginal distension was enhanced by oestrogen (confirmed by Liggins et al. 1972) and inhibited by progesterone. Thorburn et al.

(1977) suggested that PGF2α was a prerequisite to parturition and that, in normal circumstances, oxytocin has an important role in augmenting second stage labour.

Thus, the available evidence, although limited, indicates that plasma oxytocin concentrations are elevated at a time when they could contribute to the initiation of lactogenesis.

1.7.2 ROLE OF OXYTOCIN IN LACTOGENESIS

There appear to have been no direct studies of the effect of endogenous oxytocin on lactogenesis, probably because there are no known means of specifically inhibiting or stimulating the release of oxytocin. Lowering plasma oxytocin levels using antibodies to oxytocin does not appear to have been attempted. Removal of the sources of endogenous oxytocin would

necessitate ablation of not only the posterior pituitary gland, but also the corpus luteum since the latter is also a potential source of oxytocin (at least during the oestrous cycle) (Rice et al. 1984). Removal of the former could make interpretation of results difficult since, in addition to the well established hormones it secretes, it also contains (at least in the rat) a potent, unidentified PRL- releasing factor (PRF) (Hyde et al. 1987). Removal of the corpus luteum by ovariectomy would necessitate replacement with ovarian steroids, which could themselves affect lactogenesis. Enucleation of the corpus luteum, leaving the ovary, should be possible and would not require progesterone replacement if performed during late pregnancy. However, this would still leave the pituitary source.

Clinical use of oxytocin provides limited information. Although obstetricians frequently use oxytocin to induce and assist labour (Campbell and Lasley 1985), initiation of lactation in women did not appear to coincide with the release of oxytocin (Peterson and Bowes 1983). The presence in the plasma of pregnant women of an oxytocinase, which remains until very shortly after parturition, may provide circumstantial evidence for a lactogenic role of oxytocin in women, but the presence of this enzyme in other species has not been clearly demonstrated (Campbell and Lasley 1985).

Indirect evidence for a role in lactogenesis might arise from reported galactopoietic responses to oxytocin. However, results indicating that oxytocin stimulated increased milk production during established lactation are equivocal. Delouis and Denamur (1967) showed that injection of oxytocin into ewes milked during late pregnancy led to the secretion of copious quantities of milk. Recently, Nostrand et al. (1991) reported that cows which received 20 i.u. of oxytocin at each milking produced significantly more milk during the declining phase of lactation than control cows. Such differences were not detected in early lactation. These observations must be interpreted with care because they do not necessarily indicate direct effects of oxytocin. The galactopoietic effects may have been due to increased milk removal, or were perhaps mediated through the effects of other hormones such as PRL or prostaglandin. It is likely that these were not direct effects of oxytocin, since Linzell and Peaker (1971a) found, in the goat, that hourly massage of the gland without milk removal had no effect, while increasing the frequency of milking increased the rate of milk secretion in that gland (see also Wilde and Peaker 1990).

1.7.3 MECHANISM OF OXYTOCIN ACTION

Intravenous injection of oxytocin caused sharp increases in jugular plasma concentrations of PRL in the goat (Cowie 1969), but doses of 5-80 i.u. produced no PRL response in cows (Karg and Schams 1974). The suggestion that oxytocin may stimulate the release of anterior pituitary hormones via retrograde flow in the pituitary stalk cannot be dismissed (Cowie et al. 1980). However, the specific oxytocin receptor antagonist ornithine vasotocin completely abolished the PRL-releasing effect of oxytocin in perifused anterior pituitary cells, yet failed to reduce the PRF

activity of posterior pituitary extracts, indicating that oxytocin is not the PRF (Hyde et al. 1987). Furthermore, since removal of the neuro-intermediate lobe of rats did not alter plasma PRL levels during late pregnancy or lactation, it is probable that the neuro-intermediate lobe is not involved in control of PRL release at these times (Grattan and Averill 1991).

Oxytocin binding to receptors in mammary tissues has been observed in the rat (Cowie et al.

1980; Tucker 1981). Binding is principally to myoepithelial cells but effects have also been reported on secretory epithelial cells. There is evidence from the lactating rat and rabbit that binding is to the plasma membrane of the mammary gland cells. Furthermore oxytocin has been reported to have effects on milk protein secretion from epithelial cells (see Cowie et al. 1980) and it has been suggested that oxytocin may increase membrane permeability, thereby increasing the supply of nutrients to the alveolar cells (see Cowie et al. 1980). Thus, there is very limited evidence that oxytocin has a direct effect on mammary epithelial cell secretory activity.