Metabolism of Synthetic Steroids by the Human Placenta
Introduction
Pregnant women with asthma are at increased risk of poor pregnancy outcomes [1], including preterm delivery [2], pre-eclampsia [3] and low birth weight [4] independent of prematurity [5]. The mechanisms contributing to these outcomes are unknown, but may include poorly controlled asthma [5] or its treatment with inhaled or oral corticosteroids [6]. While there is little evidence in the literature to suggest that inhaled corticosteroids (ICS) are harmful to the fetus [7], [8], non-adherence to ICS medication by pregnant women with asthma for fear of its effect on the fetus remains a major clinical problem [9], [10].
Glucocorticoids are essential for the development and maturation of fetal organs before birth and late pregnancy is characterised by a rise in cortisol levels, which parallels the increased maturity of fetal organs [11]. However, glucocorticoids have potentially adverse effects on the fetus and have been linked to altered fetal programming. Women using prednisone during pregnancy have been reported to have an increase in still-birth, fetal distress, placental insufficiency [12] and low birth weight neonates [13]. Antenatal dexamethasone treatment has been associated with a reduction in birth weight, by as much as 161 g in infants delivered between 30 and 32 weeks [14]. While recent evidence from randomised controlled trials suggests that there is no additional decrease in fetal growth when repeated courses of antenatal steroids are used compared to single doses [15], French et al. found that repeated courses of betamethasone were associated with a 9% reduction in birth weight and a 4% reduction in head circumference in preterm infants born prior to 33 weeks of gestation [16].
Two isoforms of 11β-hydroxysteroid dehydrogenase (11β-HSD) have been cloned and characterised in humans which interconvert glucocorticoids with their 11-keto metabolites (Fig. 1). The type 1 enzyme (11β-HSD1) is NADP(H) dependent, acting primarily as an oxoreductase, converting cortisone to cortisol. The main functional isozyme in the placental syncytiotrophoblast is 11β-HSD2, a high affinity, NAD dependent, uni-directional enzyme, catalysing only the dehydrogenase reaction, converting cortisol to cortisone [17]. In the placenta 11β-HSD2 protects the fetus from the potentially harmful effects of endogenous maternal glucocorticoids [18], by acting as a barrier to protect the fetus from the much higher levels of cortisol found in the mother [19].
Several studies have described a relationship between reduced activity of 11β-HSD2 and reduced birth weight or intrauterine growth restriction [20], [21]. We have previously found that asthmatic women who do not use inhaled steroids for treatment have smaller female neonates at term [22]. This late gestation reduction in fetal growth was associated with a significant decrease in 11β-HSD2 activity [22], [23].
It is thought that synthetic steroid derivatives, such as dexamethasone and betamethasone are not extensively metabolised by 11β-HSD2. In bronchial epithelial cells, Feinstein and Schleimer found that the addition of the 11β-HSD inhibitor, glycyrrhetinic acid, had no effect on the anti-inflammatory activity of beclomethasone dipropionate (beclomethasone), fluticasone propionate (fluticasone) or budesonide, suggesting that they were not metabolised by 11β-HSD2 [24]. However, in another study using BEAS-2B cells derived from the bronchial epithelium, the addition of the 11β-HSD inhibitor, carbenoxolone, resulted in an increased potency of dexamethasone by approximately 10-fold [25]. Orsida et al. have suggested that the presence of 11β-HSD2 activity in the lung may serve to re-activate synthetic steroids used as anti-inflammatory agents in diseases such as asthma [26]. Information about the metabolism of synthetic steroid derivatives by 11β-HSD2 is therefore conflicting.
No studies have been published regarding the placental metabolism of synthetic steroids used for asthma treatment during pregnancy such as beclomethasone, budesonide and fluticasone. If these steroids reach the placenta but are not metabolised into inactive forms, they may have adverse effects on fetal development and may contribute to reduced fetal growth in asthmatic women using inhaled or oral corticosteroid medication. We have studied metabolism of the synthetic steroids in placentae collected from non-asthmatic women, since changes in enzyme activity were previously observed in some women with asthma [22], [23]. The effect of inhaled steroid use in vivo has been investigated in women with asthma, compared to women without asthma, by examining fetal growth and markers of fetal hypothalamic–pituitary–adrenal (HPA) axis function, including cortisol and estriol concentrations in cord blood. Estriol is a derivative of dehydroepiandrosterone sulfate (DHEA-S), derived from the fetal adrenal and produced by the placenta [27]. Less than 10% of circulating estriol is derived from the mother, estriol had been used as an indicator of fetal adrenal function and fetal well-being [27], [28]. In this paper, we hypothesise that beclomethasone, budesonide, fluticasone, dexamethasone, betamethasone and prednisolone are converted into their 11-keto metabolites by the placental enzyme 11β-HSD2 and that the use of inhaled steroids by pregnant women with asthma has no effect on fetal growth and development.
Section snippets
Materials and methods
The studies were approved by the Hunter Area Health Service and University of Newcastle Human Research Ethics Committees. Pregnant women with and without asthma were recruited at the John Hunter Hospital antenatal clinics as part of a prospective cohort study, according to a previously described protocol [22], [23], [29]. We have previously reported some maternal characteristics, maternal corticosteroid use and some placental and fetal outcomes for a number of these subjects [22], [23], [29],
ICS use for asthma during pregnancy
Table 1 gives the median dose of ICS used in each trimester of pregnancy in the four groups (oral steroids + ICS, beclomethasone alone, budesonide alone and fluticasone alone). ICS dose was significantly lower in the beclomethasone group compared to the oral steroid + ICS group in all trimesters (Kruskal–Wallis test and Dunn's multiple comparisons test, P < 0.01) and compared to the fluticasone group in the first trimester (Kruskal–Wallis test and Dunn's multiple comparisons test, P < 0.05). In the
Discussion
In this study, we have demonstrated using an in vitro enzyme assay and TLC method that placental 11β-HSD2 metabolises the synthetic steroids beclomethasone, prednisolone, dexamethasone and betamethasone, but not budesonide or fluticasone. This is the first study to examine placental metabolism of beclomethasone, budesonide and fluticasone, drugs commonly used to treat pregnant women with asthma. We have previously measured placental 11β-HSD2 activity (using cortisol as the substrate) in samples
Acknowledgements
We thank the staff of the antenatal clinic and delivery suite at John Hunter Hospital for assistance with recruitment and collection of placental samples.
Funding was provided by the National Health and Medical Research Council (ID 252438), Asthma Foundation of NSW, Hunter Medical Research Institute, NSW Health. Dr Vanessa Murphy was the recipient of a National Health and Medical Research Council (NHMRC) Dora Lush (Biomedical) Postgraduate Scholarship and a Hunter Medical Research Institute/Port
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