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RESEARCH |
School of Women's and Infants' Health, M550, King Edward Memorial Hospital, The University of Western Australia, 374 Bagot Road, SUBIACO, Perth, Western Australia 6008, Australia1 School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Perth, Western Australia 6009, Australia2 Department of Physiology, Monash University, Melbourne, Victoria 3800, Australia
Correspondence should be addressed to J J Henderson; Email: jhenderson{at}meddent.uwa.edu.au
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Abstract |
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Introduction |
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High circulating progesterone levels inhibit milk production during pregnancy (Kuhn 1969). The withdrawal of progesterone at the end of pregnancy in the presence of high levels of prolactin and cortisol triggers the onset of copious milk secretion (secretory activation) (Neville et al. 2002, Pang & Hartmann 2007). Secretory activation occurs normally at parturition in sheep and within 2 days after birth in most women but is delayed when the postnatal withdrawal of progesterone is incomplete or absent (Hartmann et al. 1973, Neifert et al. 1981). In women, delay has also been attributed to excessive activation of the hypothalamic–pituitary–adrenal axis occurring during stressful labour and delivery (Chen et al. 1998, Grajeda & Pérez-Escamilla 2002). Furthermore, experiments in mice have suggested that premature secretory activation impacts adversely on subsequent mammary secretion (Gorska et al. 2003). We hypothesised that antenatal treatment with exogenous glucocorticoids causes premature secretory activation during pregnancy and that this precocious lactation results in impaired milk secretion after parturition.
The objective of this study was to investigate, in sheep, the effects of a single dose of antenatal glucocorticoids on secretory activation before and after parturition.
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Results |
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Postnatal increases in the concentration of lactose in milk (indicating the onset of mammary secretion) tended to be delayed in both the BETA and MPA groups (Table 2). Milk lactose levels on the first and second postnatal days were lower in the BETA and MPA groups than in the SALINE group and a wide range of milk lactose concentration was found in the BETA group on all five postnatal days. After adjustment for pregnancy length and postnatal day, this difference approached statistical significance (P=0.076). Postnatal lactose concentration in maternal plasma was also significantly reduced, after statistical adjustment for pregnancy length and postnatal day, in the BETA group (P=0.001) but not the MPA group (P=0.826) when compared with the SALINE group (Fig. 1).
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Discussion |
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The onset of copious milk secretion is inhibited during pregnancy and normally occurs after the withdrawal of progesterone close to parturition (Hartmann et al. 1973, Neville et al. 2002). We observed rapid increases in maternal plasma lactose levels, indicating premature onset of mammary secretion (Arthur et al. 1991, McNeill et al. 1998), soon after treatment at 125 days of pregnancy with betamethasone, but not in sheep treated with either saline or MPA alone. The rise in lactose was preceded by a sudden decrease in progesterone concentration, suggesting that the precocious onset of secretion was caused by the removal of the normal progesterone inhibition of lactation.
The administration of glucocorticoids to pregnant ewes has been found to induce premature parturition (Nathanielsz et al. 1988, Jobe et al. 2003). This is prevented by the prior administration of the progestagen MPA, which is assumed to compensate for the rapid withdrawal of progesterone that follows glucocorticoid administration (Liggins et al. 1972). Glucocorticoid administration in sheep causes a fall in progesterone levels by inducing the up-regulation in the placenta of 17
-hydroxylase and shifting placental steroidogenesis in favour of increased oestradiol secretion at the expense of progesterone secretion (Challis et al. 2000).
While there are differences in the origin and function of progesterone during pregnancy and parturition between rats, ewes and women, progesterone withdrawal is a common trigger for secretory activation in all three species (Kuhn 1969, Turkington & Hill 1969, Hartmann et al. 1973). Our finding that MPA pretreatment did not prevent the premature stimulation of secretory activation, although glucocorticoid-induced premature parturition was inhibited, suggests that there are differences in function between placental and mammary progesterone receptors in sheep.
In primates such as humans, where 17-hydroxylase is not present in the placenta, glucocorticoids do not exert the same function during parturition. There is evidence, however, of a functional withdrawal of progesterone prior to parturition caused by a change in the dominance of specific progesterone receptor isoforms in myometrium and fetal membrane tissues (Haluska et al. 2002). It is unclear whether the differences in response to progesterone observed between placental and mammary tissues also occur in humans. In a parallel study, we observed a slight delay in secretory activation in the mothers of very preterm infants who had received antenatal glucocorticoids at least 3 days before delivery (Henderson et al. 2008). The findings from the present sheep study are consistent with the changes observed in women suggesting that further research using a sheep model of secretory activation is warranted. Future research is indicated to investigate possible changes in intracellular signalling, including the role of activated glucocorticoid receptor, in lactocytes that have been prematurely stimulated by antenatal glucocorticoid treatment.
We cannot explain why the progesterone concentration decreased on day 130 in the MPA and SALINE groups. However, the fall in these groups was not sufficient to induce a lactogenic effect in the mammary gland (Fig. 2). Furthermore, the ewes treated with betamethasone had a significantly greater and sustained depression of progesterone up until term.
Elevated levels of endogenous glucocorticoids are required for the onset of secretory activation after parturition. Our finding of a transient suppression of maternal plasma cortisol concentration immediately after betamethasone administration is consistent with previous reports (Kutzler et al. 2004a, 2004b). This reduction was not sufficient to inhibit the onset of secretory activation probably because of the presence of high levels of synthetic glucocorticoids.
Maternal plasma prolactin concentration was generally low at all gestational ages in saline and MPA-treated sheep and the decrease in all groups at 143 days was consistent with previous findings (Cowie et al. 1980). Prolactin normally has a seasonal variation in pregnant sheep and tends to have very low levels until a few days before parturition (Cowie et al. 1980). The finding of a transient surge soon after betamethasone administration has not been observed previously but supports our speculation that betamethasone treatment caused a temporary withdrawal of the progesterone inhibition of secretory activation, allowing other lactogenic hormones to up-regulate temporarily. Prolactin is essential for the expression of milk protein genes and has a synergistic action with activated glucocorticoid receptor (Rosen et al. 1999). Glucocorticoids have been reported to stimulate prolactin up-regulation in vitro and the glucocorticoid receptor is involved in this process (Fu & Porter 2004).
The variation in the concentration of lactose in milk in the first 2 days post partum indicates that change from colostrum to copious milk secretion was delayed in BETA sheep. This may be explained by the differences in the timing of parturition. In addition, decreased levels of lactose in milk and increased levels of lactose in maternal plasma in the MPA group on the first day post partum suggest a delay in the onset of copious milk secretion in these sheep. We speculate that the delay in the MPA sheep is caused by a delayed closure of the tight junctions between lactocytes under the influence of the long-acting progestagen (Nguyen & Neville 1998).
Increased rates of pregnancy loss and longer lengths of pregnancy in betamethasone-treated sheep are consistent with previous reports and fetal growth restriction has also been reported previously after betamethasone treatment (Newnham et al. 1999, Moss et al. 2001, Jobe et al. 2003). The present study is the first to show an adverse effect of maternal glucocorticoid treatment on postnatal weight gain, although high neonatal lamb mortality rates after antenatal treatment with repeated doses of betamethasone have been reported previously (Moss et al. 2001). Our findings of adverse effects on postnatal weight gain contrast with those of a study in which no effect on postnatal growth was observed after multiple courses of low-dose maternal dexamethasone (Kutzler et al. 2004a, 2004b). This difference may be explained by our use of a higher dose of synthetic glucocorticoids. We used a betamethasone dose of 0.5 mg/kg maternal weight, which is the minimal dose that causes clinically relevant improvement in neonatal pulmonary function in sheep (Moss et al. 2001). No persistent improvement in postnatal lung function has been found with lower maternal doses of betamethasone (0.2 mg/kg; Rebello et al. 1996).
Our findings do not exclude the possibility that the effect of betamethasone on postnatal secretory activation was moderated by its indirect effects on the lambs. Morbidity associated with the relatively low birth weights may have resulted in inadequate suckling, possibly influencing supply. Cross-fostering, used in rodents to eliminate such neonatal confounding (Wlodek et al. 2003), is not feasible in sheep. However, the onset of copious milk secretion occurs independently of milk removal in all species (Kulski et al. 1978, Neville et al. 2001), and our finding of reduced concentration of lactose in milk and postpartum maternal plasma in the BETA group supports the conclusion that secretory activation was delayed in these sheep.
We did not find a difference in mammary gland weight after milk was removed on day 5 post partum, suggesting that the structural development of the gland is near completion at 125 days of pregnancy when betamethasone was administered, and that the changes we observed during pregnancy and after parturition were solely due to functional and not structural changes. We suggest that the premature stimulation of secretion by the lactocytes was followed by loss of function in the absence of milk removal during pregnancy. Mammary gland involution has been shown to commence within 4 days of cessation of milk removal when lactation is established (Tatarczuch et al. 1997, Neville & Morton 2001). This process, which is triggered by milk stasis (Marti et al. 1977), results in rapid reductions in the synthesis of major milk components such as lactose (Neville et al. 1991). Our findings of a return to baseline levels of lactose in the BETA maternal plasma 9 days after treatment suggest that involution commenced in these sheep during pregnancy and that this was followed by impaired secretory activation at parturition. This finding confirms studies using mice, which show that premature secretory activation disrupts subsequent milk secretion after parturition (Gorska et al. 2003).
Our ewes received betamethasone treatment at 80% of pregnancy in accordance with our study treatment protocols. Anticipated preterm delivery in women is treated clinically with glucocorticoids as early as 24-week gestational age (60% of pregnancy). It remains to be investigated whether the effects we have observed would be so great after treatment at earlier gestational ages.
There is recent evidence that neonatal benefits of antenatal glucocorticoid therapy may not persist if delivery occurs more than 7 days after treatment (McLaughlin et al. 2003). An increase in perinatal mortality has been reported in studies that investigated the effects of betamethasone after prolonged intervals between treatment and delivery in preterm infants (Liggins & Howie 1972, McLaughlin et al. 2003) and sheep (Moss et al. 2001). This is supported by our finding that lactation is also compromised when delivery is delayed after glucocorticoid treatment in sheep.
Since own mother's milk confers considerable nutritional and immunological advantages to the preterm infant (Gartner et al. 2005), these findings indicate that the effect of glucocorticoid treatment on secretory activation requires further research in both sheep and women.
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Materials and Methods |
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Sheep management and sample collection
Pregnant merino ewes carrying single fetuses of known gestational age were maintained in open pasture and allowed to feed ad libitum. To minimise transport-induced stress, injections and procedures were performed in an adjacent facility. The ewes were randomised to receive a single i.m. injection of either betamethasone (Celestone Chronodose; Schering Plough, North Ryde, NSW, Australia; 0.5 mg/kg; BETA group; n=12) or physiological saline (SALINE group; n=12) at 125 days of pregnancy. To prevent glucocorticoid-induced pregnancy loss, an i.m. injection of a progesterone derivative, (MPA, 150 mg, Pharmacia & Upjohn), was given to BETA ewes at 118 days (Nathanielsz et al. 1988, Jobe et al. 2003). SALINE ewes received i.m. saline at 118 days. Because the effects of MPA on lactation are unknown, a third group was given MPA at 118 days and saline at 125 days (MPA group; n=12). We included the MPA group to control for the potential of the progestational activity of MPA to independently disrupt the timing of secretory activation (Jeppsson 1981).
Maternal blood samples (10 ml) were collected into heparinised tubes by jugular venipuncture before treatment and at 126, 127, 128, 130, 132, 134, 136 and 143 days of pregnancy and 1, 2 and 5 days after parturition. Plasma was separated and stored at –20 °C. The ewes were transferred to individual pens at 143 days of pregnancy where they had unlimited access to water and chaff; pellets (Econosheep; Milne Feeds, Perth, Western Australia, Australia) were fed daily. The normal length of pregnancy in Western Australian merino sheep is 
150 days.
After spontaneous delivery, lambs were housed with their mothers and were able to suckle ad libitum. Samples of mammary secretions (5 ml) were collected in the early morning (0900 h) from all the ewes daily from birth until day 5 and stored at –20 °C. Lamb weights were measured at birth and on postnatal day 5. Milk volume was measured on day 5 by hand milking after a 4-h separation of the ewes from the lambs (McCance 1959). To minimise variation, only one person milked the ewes (J J H) and the method was the same for all the ewes. Mammary glands were milked until no further milk could be obtained (10–15 min). The ewes were then killed by lethal injection of pentobarbitone (75–100 mg/kg) and the mammary glands were removed and weighed.
Concentration of lactose in maternal plasma
Secretory activation was determined by assaying the concentration of lactose in both milk and maternal plasma. Lactose is the principal carbohydrate in milk and the onset of mammary secretion is accompanied by rapid increases in the concentration of lactose in milk and maternal plasma (Hartmann et al. 1973, McNeill et al. 1998). Plasma samples were deproteinised and the bioluminescence technique of Arthur et al. (1989) was used to measure lactose concentration. Lactose was hydrolysed with β-galactosidase (Boehringer Mannheim, North Ryde, NSW, Australia) to galactose and glucose; NADH was produced by incubating galactose with the enzyme β-galactose dehydrogenase (Boehringer Mannheim). NaOH solution was used to stop the reaction and stabilise NADH. The bioluminescence was then measured on a plate luminometer (Microlite ML 2250 Microtiter Plate Luminometer; Dynatech Laboratories, Chantilly, VA, USA) using a luciferase reagent as described previously (Arthur et al. 1989). We did not correct for galactose that was present in the plasma as the concentration was consistently below 2 µM. Intra- and inter-assay coefficients of variation were respectively 6% and 10% and the detection limit was 1.62 µM.
Concentration of lactose in milk
The concentration of lactose in milk was measured using a modification of a method described previously (Kuhn & Lowenstein 1967). Milk samples were thawed at 37 °C, mixed and centrifuged in microcentrifuge tubes at 10 000 g for 5 min and the fat layer was removed by slicing the tube below the layer. Lactose was hydrolysed with β-galactosidase using the method described above. Glucose was then measured by incubating at room temperature for 45 min with a glucose reagent containing glucose oxidase (Sigma), peroxidase (Sigma) and reduced ABTS (2,2'-azino-di-(3-ethyl-benzthiazolinsulphonate)-6-sulphonate; Boehringer Mannheim) in a phosphate buffer. The resulting absorbance was read at 405 nm using a Titertek Multiscan MCC/340 (Flow Laboratories, McLean, VA, USA). Intra- and inter-assay coefficients of variation were respectively 2% and 6% and the detection limit was 3.17 mM.
Concentration of progesterone in maternal plasma
Progesterone concentration in maternal plasma was measured in duplicate using a double-antibody RIA, described previously, with tracer containing 1,2,6,7-3[H]progesterone (Amersham Pharmacia Biotech; Gales et al. 1997). All samples were processed in a single assay with a minimum detection limit of 0.13 ng/ml and a mean intra-assay coefficient of variation of 6.17%.
Concentration of cortisol in maternal plasma
Cortisol concentration in maternal plasma was measured using Gamma Coat Cortisol 125I RIA Kit (DiaSorin, Stillwater, MN, USA; Kerzner et al. 2002). Duplicates of standards and samples were incubated with cortisol tracer in antibody-coated tubes (rabbit anti-cortisol serum-coated tubes). After incubation at 37 °C for 45 min, the contents of each tube were decanted and the tubes were counted on a gamma counter. The antiserum had 100% cross-reactivity to cortisol, 0.2% to dexamethasone and <0.1% to progesterone. The mean intra- and inter-assay coefficients of variation were 5.7% and 3.7% respectively.
Concentration of prolactin in maternal plasma
Prolactin concentration in maternal plasma was measured with a homologous double-antibody RIA as described previously (Miller et al. 1995). Standard (NIADDK-oPrl-I-2) and antiserum (R160) were kindly donated by Mr Avenell (CSIRO Division of Animal Production, Prospect, NSW, Australia). Samples were assayed in duplicates of 10 µl aliquots and the limit of detection was 0.12 ng/ml. The assay included six replicates of three control samples containing 9.75, 4.95 and 1.11 ng/ml, which were used to estimate the intra-assay coefficients of variation (4%, 2.5% and 4.6%).
Statistical analysis
The primary outcome was concentration of lactose in maternal plasma during pregnancy. Based on an estimated plasma concentration of 6 µM during pregnancy (McNeill et al. 1998), a sample size of 12 sheep per group was selected to detect a difference between group means of plasma lactose concentration of 1 S.D. with a power of 80% and a type 1 error rate of 5%. Plasma lactose, progesterone, cortisol and prolactin values were log transformed and ANOVA for repeated measures was performed. Lamb weight gain, milk volume and concentration of milk lactose were summarised using non-parametric methods (median, range). Postnatal outcomes were compared after adjustment for pregnancy length, birth weight and day of measurement where appropriate. All analyses were performed with the Statistical Analysis System (SAS) statistical software package (SAS Version 8, Cary, NC, USA).
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Declaration of interest |
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TopAbstractIntroductionResultsDiscussionMaterials and MethodsDeclaration of interestFundingAcknowledgementsReferences |
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Funding |
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TopAbstractIntroductionResultsDiscussionMaterials and MethodsDeclaration of interestFundingAcknowledgementsReferences |
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Acknowledgements |
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TopAbstractIntroductionResultsDiscussionMaterials and MethodsDeclaration of interestFundingAcknowledgementsReferences |
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Received 24 March 2008
First decision 14 May 2008
Revised manuscript received 25 June 2008
Accepted 28 July 2008
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References |
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