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					Human Reproduction Update, Vol.14, No.5 pp. 497–517, 2008 Advance Access publication June 13, 2008

doi:10.1093/humupd/dmn021

Potential significance of physiological and pharmacological glucocorticoids in early pregnancy
Anthony E. Michael1 and Aris T. Papageorghiou2
1

Centre for Developmental and Endocrine Signalling, Academic Section of Obstetrics and Gynaecology, Division of Clinical Developmental Sciences, St George’s University of London, Cranmer Terrace, London SW17 0RE, UK; 2Fetal Medicine Unit, Academic Section of Obstetrics and Gynaecology, Division of Clinical Developmental Sciences, St George’s University of London, Cranmer Terrace, London SW17 0RE, UK Correspondence address. Tel: þ44-20-8725-5961; Fax: þ44-20-8725-5958; E-mail: aemichae@sgul.ac.uk

BACKGROUND: Despite extensive studies of the developmental consequences of increased glucocorticoid exposure in mid- to late pregnancy, relatively little is known regarding the significance of glucocorticoids in early pregnancy. The objective of this review was to consider potential roles for this family of corticosteroids that might relate to early pregnancy. METHODS: Although this is a narrative review, 249 source articles addressing potential effects of glucocorticoids on aspects of early pregnancy and development (published between 1997 and 2007) were identified using a systematic literature search. Additional articles (115) were identified if cited by the primary reference articles identified in the systematic phase of the review. RESULTS: Much of the evidence to implicate glucocorticoids in early pregnancy comes from studies of steroid receptors and the 11b-hydroxysteroid dehydrogenase enzymes, which modulate cortisol action in the endometrium/decidua, trophoblast, placenta and embryo/fetus. The evidence reviewed suggests that in early pregnancy the actions of glucocorticoids are balanced between positive effects that would promote pregnancy (e.g. stimulation of hCG secretion, suppression of uterine natural killer cells, and promotion of trophoblast growth/invasion) versus adverse effects that would be expected to compromise the pregnancy (e.g. inhibition of cytokine-prostaglandin signalling, restriction of trophoblast invasion following up-regulation of plasminogen activation inhibitor-1, induction of apoptosis, and inhibition of embryonic and placental growth). CONCLUSIONS: Glucocorticoids exert many actions that could impact both negatively and positively on key aspects of early pregnancy. These steroids may also be implicated in obstetric complications, including intra-uterine growth restriction, pre-term labour, pre-eclampsia and chorio-aminionitis.
Keywords: cortisol; glucocorticoid; 11b-hydroxysteroid dehydrogenase; placenta; trophoblast

Introduction
Corticosteroid hormones regulate many of the processes required for successful embryo implantation, as well as for the subsequent growth and development of the fetus and placenta. In utero, the endometrium, placenta and embryo/fetus are each exposed to the major physiological glucocorticoid, cortisol, arising from either the maternal or fetal adrenal glands. There are essentially three mechanisms by which the fetus and placenta can be subjected to increased concentrations of active glucocorticoids in utero, these being: (i) administration of synthetic glucocorticoids to the mother (as is common practice in pregnancies at risk of pre-term labour) (ii) elevation of maternal cortisol concentrations (as occurs during maternal stress)

(iii) impaired cortisol metabolism within the decidua, placenta and/or fetus. In recent years there has been interest in the administration of glucocorticoids to improve (i) pregnancy rates in women undergoing assisted conception by in vitro fertilization-embryo transfer (IVF-ET) (Boomsma et al., 2007), and (ii) pregnancy outcomes in women with a history of recurrent miscarriage (Ogasawara and Aoki, 2000; Quenby et al., 2003, 2005). It is known that uterine receptivity during embryo implantation is influenced, at least in part, by growth factors, cytokines and uterine natural killer (NK) cells. Imbalances between these factors have been implicated in implantation failure and recurrent miscarriage. It has been shown that glucocorticoids may have a role in improving the intra-uterine environment (Quenby et al., 2005), and this may be of particular relevance to women with antiphospholipid syndrome.

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Michael and Papageorghiou
Whether this translates to an improvement in clinical outcomes of pregnancy is the aim of ongoing studies. For recurrent miscarriage, this has not been shown and in fact there is a suggestion of increased risks of pregnancy complications (Laskin et al., 1997; Empson et al., 2005). Common medical complications of pregnancy frequently treated by the administration of synthetic glucocorticoids include maternal asthma and rhinitis (Demoly et al., 2003; Namazy and Schatz, 2004; Osur, 2005), although the systemic absorption of inhaled steroids is low and there are a number of studies suggesting no adverse pregnancy effects. A growing body of evidence indicates that increased exposure of the fetus to glucocorticoids in mid- to late pregnancy may result in adverse outcomes, which include: † intra-uterine growth restriction (IUGR) (Reinisch et al., 1978; Benediktsson et al., 1993; Levitt et al., 1996; Lindsay et al., 1996a; Ikegami et al., 1997; Nyirenda et al., 1998; French et al., 1999; Newnham et al., 1999; Huang et al., 1999; Bloom et al., 2001; Langdown and Sugden, 2001; Lesage et al., 2001; Sloboda et al., 2000; Sugden et al., 2001; Welberg et al., 2001; Jensen et al., 2002; Kerzner et al., 2002; Martins et al., 2003; Field et al., 2005, 2006; Kranendonk et al., 2006a; Emgard et al., 2007); † increased risk of pre-term labour (Shams et al., 1998; Langdown and Sugden, 2001; Field et al., 2006); † programming of post-natal hypertension (Tangalakis et al., 1992; Benediktsson et al., 1993; Edwards et al., 1993; Seckl et al., 1995; Levitt et al., 1996; Lindsay et al., 1996a; Dodic et al., 1999; 2002a, b; Doyle et al., 2000; Seckl, 2001; Sugden et al., 2001; Jensen et al., 2002; Trainer, 2002; Banjanin et al., 2004; Jansson and Powell, 2007); † programming of increased post-natal activity in the hypothalamo– pituitary – adrenal axis (Uno et al., 1994; Levitt et al., 1996; Muneoka et al., 1997; Clark, 1998; Lesage et al., 2001; Liu et al., 2001; Bertram and Hanson, 2002; Matthews, 2002; Sloboda et al., 2002; Banjanin et al., 2004; Matthews et al., 2004; Shoener et al., 2006; de Vries et al., 2007); † effects on fetal brain development, associated with alterations in pre-natal and post-natal behaviour (Uno et al., 1994; Muneoka et al., 1997; Rodriguez et al., 1998; Huang et al., 1999; Matthews, 2000; Huang et al., 2001; Welberg et al., 2001; Antonow-Schlorke et al., 2003; Canlon et al., 2003; de Weerth et al., 2003; Matthews et al., 2004; Field et al., 2005; Kranendonk et al., 2006b). These adverse consequences of glucocorticoids in late pregnancy have been the subject of several reviews (Uno et al., 1994; Seckl et al., 1995; Langley-Evans, 1997a; Seckl, 1997, 2001, 2004, 2007; Nyirenda and Seckl, 1998; Clark, 1998; Newnham, 2001; Newnham and Moss, 2001; O’Regan et al., 2001; Fowden and Forhead, 2004; Welberg and Seckl, 2001; Bertram and Hanson, 2002; Matthews, 2002; Trainer, 2002; Matthews et al., 2004; Seckl and Meaney, 2004; Drake et al., 2007; Meaney et al., 2007). In contrast, relatively little is known regarding the significance of glucocorticoids in early pregnancy and most of the available evidence comes from women undergoing assisted reproduction. While a recent Cochrane review concluded that administration of synthetic glucocorticoids prior to or immediately after embryo transfer had no significant effect on the probability of conceiving, when studies involving intracytoplasmic sperm injection (ICSI) were excluded, the six remaining reports of standard in vitro fertilization (IVF) found pregnancy rates to be significantly increased (P ¼ 0.02) (Boomsma et al., 2007), indicating that glucocorticoids may facilitate conception. This review considers the evidence that glucocorticoids can influence several key aspects of early pregnancy, including effects on the maternal immune response, embryo attachment/ implantation, trophoblast outgrowth and invasion, as well as the development of the fetus and associated placenta. Inevitably, much of the experimental evidence comes from studies conducted in animal models, but relevant data from human pregnancies are included wherever available. Evidence is also presented that dysregulation of placental glucocorticoid metabolism might expose the fetus to increased levels of active glucocorticoids in complications of pregnancy, including IUGR, pre-term labour, chorioamnionitis and pre-eclampsia.

Methodology
Although this is a narrative (rather than systematic) review of published evidence, source articles were identified using a systematic literature search. An electronic search strategy was developed for medical literature databases [The Cochrane Library 2006: 2, PubMed (1997 – 2007), Medline (1997 – 2007)], and searches were updated in November 2007 (Table I). After an initial screen based on article titles, the review of abstracts was performed independently by the two authors in order to identify all peer-reviewed publications relating to the role of glucocorticoids in early pregnancy and development. The full text of each article was reviewed if either author opted to include the paper following the abstract review phase. Additional articles were identified for inclusion if cited by the primary reference articles identified in the systematic phase of the review.

Cellular actions of glucocorticoids
Much of the available evidence to implicate glucocorticoids in early pregnancy arises from studies of steroid receptors and/or glucocorticoid metabolism. Hence, this review begins with a brief outline of the cellular mechanisms by which glucocorticoids act and the roles for 11b-hydroxysteroid dehydrogenase (11bHSD) enzymes in modulating glucocorticoid actions. The chronic actions of glucocorticoid are typically mediated via intracellular glucocorticoid receptors (GR) (Funder, 1997; Kino and Chrousos, 2004; Lu et al., 2006). Having bound steroid, activated GR translocate from the cytoplasm into the nucleus where they act as ligand-dependent transcription factors. This involves formation of phosphorylated GR dimers which recruit co-activator or co-repressor proteins, respectively increasing or decreasing the expression of target genes by controlling histone acetylation (Li et al., 2003; Hayashi et al., 2004; Schoneveld et al., 2004). This nuclear mode of action effects lasting changes in cellular function, but takes several hours to elicit a response. One of the proteins up-regulated by glucocorticoids is the serum and glucocorticoid-induced kinase (sgk)-1, a serine-threonine protein kinase which mediates acute regulation of electrolyte and fluid

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Table I. Search strategy for medical literature databases. Corticosteroid.mp. or Adrenal Cortex Hormones/or Glucocorticoid.mp. or Glucocorticoids/cortisol.mp. or Hydrocortisone/or Cortisone Reductase/or Cortisone/or Cortisone.mp. or Hydrocortisone.mp. or Hydrocortisone/or Dexamethasone Isonicotinate/or Dexamethasone/or Dexamethasone.mp. or Prednisone.mp. or Prednisone/or Prednisolone.mp. or Prednisolone/or Betamethasone 17-Valerate/or Betamethasone/or Betamethasone.mp. And Embryo Research/or Embryo Loss/or Embryo.mp. or Embryo Implantation/or Embryo/or Blastocyst Inner Cell Mass/or Blastocyst/or Blastocyst.mp. or Trophoblast.mp. or Trophoblasts/Embryo Implantation, Delayed/or Embryo Implantation/or Placenta/or Placenta Diseases/or Decidua.mp. or Decidua/or Pregnancy/ Number of titles identified by search (all titles/abstracts were reviewed) Number of references obtained for full review Additional/secondary references obtained and reviewed Total number of publications reviewed and cited

4315 249 115 364

balance (Lang et al., 2006). Sgk-1 is expressed in the human endometrium, where it is up-regulated by progesterone in the secretory phase of the cycle and during decidualization (Feroze-Zaidi et al., 2007). In addition, sgk-1 is also expressed in term human cytotrophoblasts where it can be up-regulated by both glucocorticoids and by aldosterone (Driver et al., 2003). GR are expressed at high levels in decidua, chorion, amnion, stromal fibroblasts, vascular smooth muscle cells and endothelial cells from term human placental villi, with moderate expression in term cytotrophoblasts and negligible expression in the term syncytiotrophoblast (Kossmann et al., 1982; Lopez-Bernal et al., 1984; Sun et al., 1996; Weisbart and Huntley, 1997; Driver et al., 2001; Chan et al., 2003; Sun and Myatt, 2003; Lee et al., 2005; Chan et al., 2007; Yang et al., 2007). By differentiating between expression of the vacant, non-phosphorylated form of the GR and the activated, phosphorylated form, (Lee et al., 2005) established that placental GR must be activated by physiological glucocorticoids in utero. While synthetic glucocorticoids can only activate GR, the physiological glucocorticoids, cortisol and corticosterone, can also activate ‘mineralocorticoid receptors’ (MR). Despite their name, MR exhibit little intrinsic specificity, binding aldosterone, cortisol and corticosterone with comparable affinities in vitro (Arriza et al., 1987; Sheppard and Funder, 2001). Since cortisol typically circulates at concentrations 1000-fold greater than aldosterone (nmol/l versus pmol/l, respectively), the MR should be constantly swamped by cortisol, as occurs in the clinical syndrome of apparent mineralocorticoid excess (Ulick et al., 1979; Stewart et al., 1988; Benediktsson and Edwards, 1994; Shimojo and Stewart, 1995; Funder, 1995; Edwards et al., 1996; Mantero et al., 1996; White et al., 1997; Wilson et al., 2001). In the non-pathological state, the 11bHSD enzymes effectively exclude cortisol from the MR, leaving these receptors free to respond appropriately to the renin –angiotensin – aldosterone system (Edwards et al., 1996; White et al., 1997; Krozowski, 1999; Draper and Stewart, 2005). In potential target cells, including cells of the reproductive system, 11bHSD enzymes catalyse the reversible inactivation of cortisol and corticosterone (Edwards et al., 1996; White et al., 1997; Krozowski, 1999; Michael et al., 2003; Draper and Stewart, 2005) (Fig. 1). To date, two 11bHSD isoenzymes have been cloned and characterized. Type 1 11bHSD, which is a relatively low affinity, bidirectional enzyme that usually regenerates cortisol from biologically inert cortisone (Seckl and Walker, 2001), is expressed in the endometrial epithelium (Thompson et al., 2002; McDonald et al., 2006), decidua (Baggia et al.,

Figure 1: Cortisol-cortisone inter-conversion by the cloned hydroxysteroid dehydrogenase (11bhsd) enzymes. The conversion of inert cortisone to active cortisol (which can bind and activate glucocorticoid receptors) is catalysed by type 1 11bHSD (11bHSD1), whereas the metabolism of cortisol to cortisone (which cannot activate glucocorticoid receptors) is mediated via both type 1 and type 2 11bHSD (11HSD2). The pyridine nucleotide cofactors for each isoenzyme are shown in italics.

1990; Arcuri et al., 1996, 1997; Thompson et al., 2002; McDonald et al., 2006), chorion (Li et al., 2006), amnion (Tanswell et al., 1977; Sun and Myatt, 2003), trophoblast (Baggia et al., 1990; Driver et al., 2001; Sun et al., 2002; Li et al., 2006) and placenta (Muneyyirci-Delale et al., 1996; Pepe et al., 1996a, b; Sun et al., 1997a; Yang, 1997; Alfaidy et al., 2001; Thompson et al., 2002; Klemcke et al., 2003). In contrast, type 2 11bHSD, a high affinity enzyme that inactivates cortisol (Agarwal et al., 1994; Albiston et al., 1994; Zhou et al., 1995), has been localized in the endometrium and placenta (Brown et al., 1993; Burton and Waddell, 1994; Krozowski et al., 1995; Stewart et al., 1995; Li et al., 1996; Pepe et al., 1996a; Petrelli et al., 1997; Smith et al., 1997; Sun et al., 1997a; Yang, 1997; Arcuri et al., 1998; Hirasawa et al., 2000; Alfaidy et al., 2001, 2002; Driver et al., 2001; Clarke et al., 2002; Hardy and Yang, 2002; Thompson et al., 2002; Klemcke et al., 2003; Van Beek et al., 2004; Homan et al., 2006). Within the human placenta, there is also substantial metabolism of cortisol (and cortisone) by 5b-reductase, 3a/3bHSD and 20bHSD enzymes to form inactive tetrahydroand hexahydro-steroid metabolites (Pasqualini, 2005).

First clues from IVF
The first evidence to implicate cortisol in early pregnancy was provided by studies of couples undergoing assisted conception by IVF-ET. Eight published studies have reported on the association between the establishment of clinical pregnancies and levels of cortisol– cortisone metabolism within the ovary prior to oocyte retrieval for IVF. These studies have either made direct measurements of ovarian 11bHSD activities in the human granulosa-lutein cells recovered during oocyte collection, or have assessed the

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cortisol:cortisone ratio in follicular fluid as an in vivo index of ovarian cortisol metabolism. Of the eight studies, six reported lower ovarian 11bHSD activities and/or increased cortisol:cortisone ratios in follicular fluid to be associated with an improved probability of achieving pregnancy through IVF-ET (Michael et al., 1993, 1995, 1999; Keay et al., 2002; Lewicka et al., 2003; Thurston et al., 2003). Of the remaining two studies, one was not powered to investigate the link to conception rates (Knaggs et al., 1998) and while the other reported no significant association between levels of cortisol metabolism and pregnancy, the probability of conception was 3-fold higher in those women whose ovarian cells exhibited low rates of cortisol– cortisone metabolism relative to patients with high levels of cortisol oxidation (Thomas et al., 1998). It is important to note that in the studies linking decreased ovarian cortisol metabolism to conception, differences in pregnancy rates were not accompanied by parallel changes in the proportions of oocytes successfully fertilized in vitro nor with numbers of embryos generated for subsequent embryo transfer (Michael et al., 1993, 1995, 1999; Keay et al., 2002; Lewicka et al., 2003; Thurston et al., 2003). Hence, ovarian 11bHSD activities appeared to correlate with the probability of an oocyte, once fertilized, successfully developing and implanting in vivo (Michael, 2003). One mechanism proposed to explain these findings was that decreased glucocorticoid metabolism in the oocyte and/or subsequent embryo would enable cortisol to retain its immunosuppressive actions within the uterus so as to prevent immune rejection of the blastocyst. It was reasoned that if glucocorticoids promote immune tolerance to the embryonic allograft, then this should be most evident for embryos in which the zona pellucida has been compromised, as with ICSI. This prediction was not borne out by the recent Cochrane review. In their meta-analysis of 13 randomized control trials (RCTs) featuring a total of 1759 couples undergoing IVF-ET or ICSI-ET, Boomsma et al. (2007) found no significant effect of synthetic glucocorticoids administered immediately around the time of embryo transfer on conception. However, when ICSI was excluded and a subgroup analysis performed for six RCTs featuring 650 couples treated by IVF-ET alone, the clinical pregnancy rate was significantly increased (odds ratio ¼ 1.50, P ¼ 0.02) by glucocorticoid administration (Boomsma et al., 2007). This clinical finding indicates that glucocorticoids may play positive roles in the establishment of early pregnancy over and above their anticipated effects on immune tolerance of the implanting embryo. by using carbenoxolone to inhibit metabolism of physiological glucocorticoids via the 11bHSD enzymes (Nacharaju et al., 2004). Dexamethasone also stimulated hCG secretion from first trimester cytotrophoblasts (Guller et al., 1994), and when (Mandl et al., 2006) used choriocarcinoma cell lines as in vitro models for first trimester human trophoblast, they found that triamcinolone acetate could double hCG output from GR positive choriocarinoma cell lines (BeWo and JEG3 cells) without effecting hCG production from the GR negative JAR choriocarcinoma cells. Moreover, triamcinolone had no effect on hCG output when experiments were repeated in the absence of serum (Mandl et al., 2006), suggesting that sgk-1 may also be required for the stimulation of hCG production by glucocorticoids.

Blastocyst attachment
Embryo implantation requires a molecular dialogue initiated during blastocyst attachment by cell surface signalling molecules on the trophoblast and endometrium, such as the integrins and fibronectin (Burrows et al., 1996). At physiological concentrations (100 nmol/l), glucocorticoids can suppress the expression of trophoblast integrins (Ryu et al., 1999), hence modulating these initial trophoblast-decidua interactions. The effects of glucocorticoids on fibronectin expression are tissue-specific; while dexamethasone suppresses fibronectin expression in term human cytotrophoblasts and amnion (Guller et al., 1995a, b; Lee et al., 2004), this glucocorticoid acts in synergy with transforming growth factor-b to up-regulate fibronectin in matched samples of chorion and placental mesenchymal cells (Guller et al., 1995a; Lee et al., 2004).

The inflammatory cascade and embryo implantation
Following attachment, successful implantation requires a coordinated sequence of inflammatory events with key roles for pro-inflammatory cytokines, such as interleukin (IL)-1 and tumour necrosis factor (TNF)-a, and for prostaglandins (Chard, 1995; Sharkey, 1998; Kelly et al., 2001; Staun-Ram and Shalev, 2005; Achache and Revel, 2006; Makrigiannakis et al., 2006). Glucocorticoids are known to exert several anti-inflammatory actions which could impair the cytokine-prostaglandin signalling cascade required for implantation.
Glucocorticoid interactions with cytokines

Secretion of hCG
The peri-implantation secretion of hCG from the trophoblast of the early human embryo is pivotal in maintaining progesterone secretion from the corpus luteum until the luteo-placental shift in progesterone synthesis at around 8 weeks of gestation (Hanson et al., 1971; Stevens, 1979). This gonadotrophin may also play local roles in promoting embryo implantation and differentiation (Islami et al., 2001; Licht et al., 2001; Srisuparp et al., 2001; d’Hauterive et al., 2007; Handschuh et al., 2007). The secretion of hCG from human term trophoblast can be stimulated in vitro by up to 10-fold on treatment for 24 to 72 h with synthetic glucocorticoids (dexamethasone and triamcinolone acetate) (Ringler et al., 1989; Guller et al., 1994; Hahn et al., 1999) or

In first trimester human cytotrophoblast cells, cortisol can suppress the synthesis of the pro-inflammatory IL-1b (Librach et al., 1994). Likewise, in term human placental cytotrophoblasts and decidual surface villous explants, physiological concentrations of cortisol and several synthetic glucocorticoids can each inhibit both basal and bacterial lipopolysaccharide (LPS)-stimulated output of the pro-inflammatory cytokines, TNF-a, IL-6 and IL-8 by over 70% (Rosen et al., 1998; Ma et al., 2004, 2006; Xu et al., 2005) without affecting expression of the anti-inflammatory cytokine IL-10 (Xu et al., 2005). The impact on the ratio of proinflammatory to anti-inflammatory cytokines was greater in decidual surface villous explants from placentas delivered at term in pre-eclamptic versus normotensive pregnancies (Xu et al., 2005), indicating that pre-eclampsia may involve altered

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Economopoulos et al., 1996; Whittle et al., 2000, 2001; Sun et al., 2003; Li et al., 2006) and of placental prostaglandin synthase enzymes in the placenta (Zhang et al., 2006). Moreover, glucocorticoids can decrease the expression of prostaglandin dehydrogenase (PGDH), so increasing the functional half-life of prostaglandins in the human chorionic and placental trophoblast (Patel et al., 1999a, b, 2003; Whittle et al., 2001; Patel and Challis, 2002). In the same way that cytokines can modulate the local activity of physiological glucocorticoids, the inter-conversion of cortisol– cortisone within the placenta is also regulated by prostaglandins which up-regulate the expression and reductase activity of type 1 11bHSD in term human placental trophoblasts (Alfaidy et al., 2001) while decreasing the oxidative activity of type 2 11bHSD (Hardy et al., 1999; Hardy et al., 2001) (Fig. 2). In contrast to the negative feedback loop between pro-inflammatory cytokines and glucocorticoids, the reciprocal effects of glucocorticoids on prostaglandin synthesis and of prostaglandins on glucocorticoid metabolism in the placenta establish a positive feed-forward loop which has been implicated in the timing of parturition (Challis et al., 2000; Alfaidy et al., 2001; Michael et al., 2003). While glucocorticoids stimulate prostaglandin synthesis in term placenta and fetal membranes, dexamethasone exerts a conventional anti-inflammatory action to suppress PGHS-2 expression and inhibit prostaglandin synthesis in the first trimester human trophoblast (Imseis et al., 1997). Hence, further studies are required to establish whether the functional interactions between the glucocorticoid, cytokine and prostaglandin systems in the uteroplacental unit differ between early versus late pregnancy.

Figure 2: Regulation of placental glucocorticoid metabolism. Positive effects on enzyme activity and/or protein expression are indicated by positive symbols (solid green arrows), while negative effects are indicated by negative symbols (broken red lines). AA, arachidonic acid; O2, oxygen; PGs, prostaglandins, IL, interleukin; TNF, tumour necrosis factor; PGHS-2, prostaglandin H synthase.

sensitivity of cytokine output to modulation by glucocorticoids. In terms of modulating cytokine actions, glucocorticoids can inhibit the activator protein (AP)-1 and nuclear factor (NF)-kB signalling pathways that typically mediate the cellular responses to pro-inflammatory cytokines (van der Burg and van der Saag, 1996; Barnes, 1998, 2006; Adcock and Caramori, 2001; Hayashi et al., 2004). While glucocorticoids regulate the local synthesis and actions of pro-inflammatory cytokines, these inflammatory mediators can in turn modulate glucocorticoid concentrations within the uteroplacental unit. For example, IL-1b and TNF-a both increase the expression and activity of type 1 11bHSD while suppressing the expression of mRNA transcripts encoding type 2 11bHSD in term human chorionic trophoblasts (Chisaka et al., 2005; Li et al., 2006). This would be expected to increase net regeneration of active cortisol from cortisone, creating a negative feedback loop within the placenta between physiological glucocorticoids and cytokines (Fig. 2). When JEG-3 choriocarcinoma cells were treated with IL-1b and TNF-a, both cytokines up-regulated expression of type 1 11bHSD protein, but exerted inconsistent effects on the expression of type 2 11bHSD in two independent studies (Chisaka et al., 2005; Johnstone et al., 2005), indicating possible differences in the regulation of glucocorticoid metabolism between the term placenta and choriocarcinoma cell lines, commonly used as a model for the early human trophoblast.

Immunosuppression
The immunosuppressant actions of glucocorticoids have long been recognized, and indeed exploited, in clinical medicine. For example, in healthy volunteers, daily oral administration of prednisolone halved the total population of lymphocytes within 7 h of the first glucocorticoid treatment, and reduced the proportion of peripheral NK cells (from 16.5 to 9.5% of lymphocytes) over 3 days (Pountain et al., 1993). In light of their immunosuppressant actions, it has been suggested that glucocorticoids might assist in preventing immune rejection of the implanting embryo (Boomsma et al., 2007). Recent studies have implicated uterine NK cells in recurrent miscarriage. Uterine NK cells constitute a higher proportion of endometrial cells in women with a history of recurrent miscarriage than in endometrial biopsies from women with no history of early pregnancy loss (Quenby et al., 2005; Quenby and Farquharson, 2006). Initial evidence to suggest that synthetic glucocorticoids might influence uterine NK cells was provided by case reports of two individual women who had suffered 10 and 19 recurrent miscarriages, both of whom had successful pregnancies and delivered live infants following oral treatment with methylprednisolone (Ogasawara and Aoki, 2000; Quenby et al., 2003). Subsequent studies established that uterine NK cells are responsive to glucocorticoids in so far as they express GR (Henderson et al., 2003) and the type 1 11bHSD enzyme that modulates access of physiological glucocorticoids to this nuclear receptor (McDonald et al., 2006). In a study of 29 women with a history of recurrent miscarriage and elevated levels of uterine NK cells, oral prednisolone

Glucocorticoid interactions with prostaglandins

In most tissues studied to date, glucocorticoids exert antiinflammatory effects to inhibit the synthesis of prostaglandins and thromboxanes by decreasing the expression and/or actitivity of phospholipase A2 (PLA2), so limiting liberation of arachidonic acid for the prostaglandin H synthase (PGHS), cyclo-oxygenase enzyme (Bailey, 1991; Flower and Rothwell, 1994; Barnes, 1998, 2006). In contrast, in the placenta and fetal membranes, glucocorticoids can paradoxically increase prostaglandin synthesis (Sun et al., 2003; Mirazi et al., 2004; Zhang et al., 2006). This uncharacteristic pro-inflammatory action is achieved, in part, by up-regulating the expression and activities of the PLA2 and PGHS-2 enzymes in human amnion fibroblasts and chorionic trophoblasts (Gibb and Breton, 1993; Zakar et al., 1995;

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administration suppressed uterine NK cells from 14 to 9% of their endometrial biopsies (P , 0.001) (Quenby et al., 2005), and it was argued that this could decrease the likelihood of uterine NK cells mediating immune rejection of the implanting embryo (Quenby et al., 2005; Quenby and Farquharson, 2006). A recent study of 22 early pregnancies found that the mean rate of maternal urinary cortisol excretion in the first 3 weeks following planned conception was increased in 13 women undergoing spontaneous early miscarriage (between Days 13 and 47 after ovulation) as compared to 9 women who successfully carried to term (Nepomnaschy et al., 2006). Elevated urinary cortisol excretion in the 3 weeks post-conception was associated with a 2.7-fold increase in the risk of early miscarriage relative to women where urinary cortisol excretion post-conception was the same as the baseline cortisol excretion level pre-conception. Furthermore, in a prospective case control study, antenatal administration of glucocorticoids to 262 women in the first trimester significantly increased the incidence of miscarriages relative to 728 control patients (from 7.0 to 11.5% of pregnancies) (P ¼ 0.01) (Gur et al., 2004). These findings suggest that physiological glucocorticoids may impede (rather than improve) the early function and implantation of the embryo. A novel factor emerging as relevant to embryo implantation is corticotrophin releasing hormone (CRH) expressed by the embryonic trophoblast and decidua cells. In addition to limiting trophoblast invasion (via down-regulation of carcinoembryonic antigen-related adhesion molecule-1), trophoblastic CRH also exerts an immunosuppressive effect, acting via type 1 CRH receptor to induce apoptosis of activated endometrial T-lymphocytes (Makrigiannakis et al., 2004; Kalantaridou et al., 2007). Although glucocorticoids suppress CRH expression in the hypothalamus and in pituitary corticotrophs, at concentrations as low as 10 nmol/l, glucocorticoids can up-regulate CRH expression in term placental cytotrophoblasts (Jones et al., 1989; Robinson et al., 1988; Makrigiannakis et al., 1996, 1999; Cheng et al., 2000; Gravanis et al., 2001; Nicholson et al., 2004). Hence, cortisol can exert additional indirect effects on endometrial lymphocytes and trophoblast invasion mediated via increased local production of CRH. Degradation of the extracellular matrix during trophoblast invasion also involves urokinase-type plasminogen activator (uPA) which, in common with the tissue-type enzyme (tPA), catalyses the conversion of inactive plasminogen to plasmin. While uPA promotes the plasmin-associated degradation of the extracellular matrix, tPA is required for the plasmin-dependent breakdown of fibrin, essential for efficient vascular exchange in the early placenta (Vassalli et al., 1991; Loskutoff et al., 1993). The activities of both uPA and tPA can be suppressed by plasminogen activator inhibitor (PAI)-1, a 52 kDa serine protease inhibitor secreted by trophoblast and decidual cells (Feinberg et al., 1989; Vassalli et al., 1991; Hofmann et al., 1994). An in vitro study which featured human cytotrophoblasts isolated from term human placental villi and the HTR-8/SV neo cell line derived from first trimester human extravillous trophoblast (EVT) found that both cortisol and dexamethasone could increase expression of PAI-1 (Ma et al., 2002). It has been suggested that over-expression of PAI-1 in the trophoblast prevents tPA from inducing plasmindependent fibrinolysis which could impede placental nutrient transfer in pre-eclampsia and IUGR (Estelles et al., 1994; Grancha et al., 1996). Hence, glucocorticoids may act in the villous trophoblast to increase expression of PAI-1, limiting trophoblast invasion and plasmin-mediated fibrinolysis by inhibiting uPA and tPA, respectively. In addition to affecting the invasive properties of the trophoblast, glucocorticoids have been implicated in the fusion of cytotrophoblast cells to form the syncitiotrophoblast (Morrish et al., 1998, Malassine and Cronier, 2002) and have also been reported to modulate the rate of trophoblast apoptosis. For example, Mandl et al. (2006) found that in the presence of serum, triamcinolone could induce apoptosis in the BeWo choriocarcinoma cell line. Likewise, Crocker et al. (2001) had observed that dexamethasone could induce both apoptosis and necrosis in primary cultures of term human placental trophoblast and in the SGH-PL4 cell line derived from human EVT.

Placental structure and function
As pregnancy progresses, there are major changes in placental structure which are best exemplified in the pregnant sheep which shows progressive haemophagous eversion of the placental cotyledons from predominantly ‘inverted’ into ‘everted’ placentomes. Infusion of glucocorticoids into ewes in either early or late gestation restricts the eversion of the placentomes towards term and decreases the total placental weight (Wintour et al., 1994; Jensen et al., 2002; Ward et al., 2006). Likewise, manipulations of cortisol concentrations in the fetal lamb in late pregnancy can alter the proportion of binucleate cells in the ovine trophectoderm (Ward et al., 2002). Although there are fundamental differences in placental structures between women, sheep and other mammals, these findings establish that glucocorticoids can act in both early and late pregnancy to affect the subsequent growth and development of the placenta. Since the growth potential for the fetus is influenced by the size of the placenta, the impairment of placental growth has been advanced as a potential mechanism to account for IUGR associated with decreased placental metabolism of glucocorticoids and/or antenatal glucocorticoid administration (Hofmann et al., 2001; Seckl and Meaney, 2004). Infusion of betamethasone to

Trophoblast growth and invasion
As noted above, choriocarcinoma cell lines have been studied as in vitro models for first trimester human trophoblast. In the presence of serum, triamcinolone acetate increased proliferation of the GR positive BeWo cell line and up-regulated cyclin B1 in a concentration-dependent manner, suggesting that glucocorticoids could stimulate growth of the early trophoblast (Mandl et al., 2006). At the highest tested concentration of 50 mmol/l, triamcinolone acetate also increased the invasion of a Matrigel matrix by the BeWo cells, accompanied by a concentration-dependent up-regulation in the expression of pro-matrix metalloproteinase (proMMP)-2 (Mandl et al., 2006). This finding was in accord with the increased expression of placental MMP2 observed at term following a single course of antenatal betamethasone (Gharraee et al., 2006). However, these findings contrast with an earlier study of first trimester human cytotrophoblasts which found that dexamethasone (100 nmol/l) suppressed expression of MMP-9 and inhibited the ability of the early cytotrophoblast to invade a Matrigel matrix in vitro (Librach et al., 1994).

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ewes in late pregnancy induced IUGR associated with decreased placental size (Newnham et al., 1999), and in pregnant rats maternal administration of dexamethasone in the second half of gestation produced a 23% decrease in fetal weight that was accompanied by a 51% decrease in placental weight (P , 0.01) (Ain et al., 2005). The impairment of placental growth was characterized by decreased expression of both prolactin-like protein-B and insulin-like growth factor (IGF)-II, particularly in the junctional zone of the rat placenta. The decreased levels of placental Akt phosphorylation observed following in utero exposure to dexamethasone confirmed that signalling through the mitogenic phosphatidylinositol-3 kinase pathway was decreased in the rat placenta by this synthetic glucocorticoid (Ain et al., 2005). Moreover, maternal administration of dexamethasone decreased the phosphorylation of the pro-apoptotic protein, BAD, and increased the cleavage of poly(ADP-ribose) polymerase (Ain et al., 2005): actions which could account for the pro-apoptic action of dexamethasone in the junctional zone of the rat placenta (Waddell et al., 2000). Two of the key molecular pathways involved in placentation are the WNT pathway, implicated in chorioallantoic attachment and branching morphogenesis (Cross et al., 2006), and the peroxisome proliferator-activated receptors (PPARs) which regulate placental growth and vascularity (see Schaiff et al., 2006). In the placenta, WNT ligands activate a signalling pathway that culminates in the nuclear translocation of b-catenin. This then recruits the transcription factors required for trophoblast proliferation and subsequent placental growth (Eberhart and Argani, 2001; Cross et al., 2006). In a study of pregnant rats, Hewitt et al. (2006a) found that administration of dexamethasone in the second half of gestation increased the expression of secreted frizzled-related protein-4 and decreased the nuclear levels of b-catenin, indicating that glucocorticoids can inhibit the WNT signalling pathway crucial for early placentation (Hewitt et al., 2006a). Maternal administration of dexamethasone also suppressed expression of mRNA encoding PPARg in the labyrinthine zone of the rat placenta by 37% (P , 0.05) (Hewitt et al., 2006b). As an orphan nuclear receptor/transcription factor, PPARg appears to be particularly important in the growth/development of the labyrinthine zone of the rat placenta (the site of materno –fetal exchange) during the phase of maximal placental growth (Hewitt et al., 2006b). In order to fulfil its role as the exchange interface between the maternal and fetal circulations, the placenta must be highly vascularized with good uterine and umbilical blood flow accompanied by local angiogenesis. Although glucocorticoids can induce vasoconstriction in sheep uterine arteries (Xiao et al., 2002, 2003; Jellyman et al., 2004), an in vitro study found cortisol, betamethasone and dexamethasone to each dilate human umbilical arteries (Potter et al., 2002). Moreover, Doppler flow studies have found antenatal administration of synthetic glucocorticoids to have no significant effect on the pulsatility index of the uterine artery in women at risk of pre-term labour (Muller et al., 2003; Urban et al., 2005). In terms of potential effects on angiogenesis, glucocorticoids have been reported to inhibit angiogenesis and destabilize microvessels in three different animal tissue models (rabbit cornea, chick chorioallantoic membrane and rat aorta explants in tissue culture) (McNatt et al., 1992; Phillips et al., 1992; Jaggers et al., 1996), as well as in term human placental vein discs (Jung et al., 2001). However, in each of the cited studies, the antiangiogenic effects of glucocorticoids were assessed at high pharmacological concentrations (between 10 mmol/l and 7.6 mmol/l) far in excess of the normal physiological concentration range for cortisol (100 – 600 nmol/l). Nearly 20 years ago, Graf et al. (1989) reported that in vivo administration of dexamethasone and triamcinolone acetate to pregnant rats between Days 16 and 20 of gestation induced major changes in the vascularization of the rat placenta, particularly in the labyrinthine zone (the major site of materno –fetal exchange in rodent placentas). Further studies are required to determine whether physiological concentrations of glucocorticoids can affect human placental vascular supply or angiogenesis in early pregnancy. In a recent review, Jansson and Powell (2007) noted that decreased inactivation of cortisol by the placental type 2 11bHSD enzyme at term was associated with increased placental vascular resistance which the authors contended could programme the increased risk of developing post-natal hypertension in the fetus. Notwithstanding potential effects on the placental vasculature, glucocorticoids can affect the specific placental transport of individual nutrients (Fowden et al., 2006). For example, in pregnant ewes, glucocorticoid administration during either early or late gestation impedes the placental delivery of glucose and lactate to the fetal circulation (Barbera et al., 1997; Moss et al., 2003; Ward et al., 2004, 2006). Results of in vitro studies seem to depend on the steroid concentration and/or the duration of glucocorticoid exposure; Hahn et al. (1999) found that treatment of term human placental trophoblasts with triamcinolone acetate (5 and 50 mmol/l) for 24 h inhibited expression of GLUT-1 and GLUT-3 glucose transporters in a concentration-dependent manner, whereas Ericsson et al. (2005) found no effect of cortisol (tested at 1 mmol/l) over 1 h on glucose transport in villous explants from either first trimester or term human placentas. In contrast, the expression of GLUT-1 and GLUT-3 glucose transporters in the rat placenta can be induced (rather than suppressed) by in vivo administration of glucocorticoids (Langdown and Sugden, 2001). Hence, further studies are required to clarify the molecular effects of glucocorticoids on placental glucose (and lactate) transport at physiological steroid concentrations. Glucocorticoids have also been implicated in the transplacental transport of specific amino acids (Fowden et al., 2006). These effects have been attributed to changes in the local concentration gradients between the maternal, placental and fetal circulations for individual amino acids and/or changes in the expression of placental aminotransferase enzymes (Graf et al., 1989; Timmerman et al., 2001; Fowden et al., 2006). Although an initial investigation of first trimester and term human placental villi found no acute effect of cortisol on glucose or amino acid transport within 1 h (Ericsson et al., 2005), a subsequent study found chronic exposure to cortisol (for 24 h) to stimulate amino acid transport in a concentration-dependent manner by up-regulation of the SNAT2 system A (amino acid) transporters in the BeWo choriocarcinoma cell line (Jones et al., 2006). The precise molecular mechanisms via which glucocorticoids control placental transport of glucose/lactate and amino acids have yet to be determined, but are thought to include changes in expression of IGF-II which is a key regulator of placental growth (Fowden, 2003; Fowden et al., 2006). The expression of the Igf 2 gene is certainly down-regulated following glucocorticoid administration to pregnant rats (Fowden,

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2003; Ain et al., 2005), and steroid-induced suppression of the Igf 2 gene may even mediate the broader effects of glucocorticoids on placental morphology/structure (Fowden et al., 2006). from cortisone (active corticosterone from 11-dehydrocorticosterone in the placentas of rats and mice) (Tanswell et al., 1977; Baggia et al., 1990; Pepe et al., 1996a, b; Sun et al., 1997a, 1998a, 2002; Yang, 1997; Arcuri et al., 1998; Patel et al., 1999b; Driver et al., 2001; Hardy et al., 2001; Alfaidy et al., 2001, 2003; Hardy and Yang, 2002; Thompson et al., 2002; Klemcke et al., 2003; Sun and Myatt, 2003; Van Beek et al., 2004; Li et al., 2006). The expression of type 1 11bHSD increases throughout pregnancy, apparently in response to progesterone (Muneyyirci-Delale et al., 1996; Schoof et al., 2001a; Alfaidy et al., 2003), and can also be up-regulated in term human chorionic trophoblasts by cortisol acting via the nuclear GR (Li et al., 2006) (Table II). As the placenta differentiates, there is progressive up-regulation in expression of the type 2 11bHSD enzyme (Hardy and Yang, 2002) which becomes the major placental isoenzyme, restricting the passage of active glucocorticoids across the placenta into the fetal circulation (Brown et al., 1993; Burton and Waddell, 1994, 1999; Krozowski et al., 1995; Stewart et al., 1995; Pepe et al., 1996a, 1999; Smith et al., 1997; Sun et al., 1997a; Yang, 1997; Sampath-Kumar et al., 1998; Waddell et al., 1998; Arcuri et al., 1999; Alfaidy et al., 2002; Clarke et al., 2002; Thompson et al., 2002; Klemcke et al., 2003; Staud et al., 2006). Hence, if the expression and/or activity of type 2 11bHSD in the placenta is compromised, increased transfer of cortisol across the placenta would induce the differentiation of fetal tissues at the expense of tissue growth. Indeed, this has been advanced as a mechanism to explain the clinical association between decreased activity of type 2 11bHSD in the human placenta and IUGR (Benediktsson et al., 1993; Edwards et al., 1993; Shams et al., 1998; McTernan et al., 2001; Kajantie et al., 2006). However, Newnham et al. (1999) found that while maternal administration caused IUGR, administration of glucocorticoids directly into the fetal circulation did not restrict fetal growth, suggesting that the growth limiting effects are mediated via actions in the uteroplacental unit rather than effects on fetal tissues. Type 2 11bHSD is expressed and functional within the first trimester trophoblast where it has been implicated in successful embryo attachment and implantation (Arcuri et al., 1998). In mid- to late pregnancy, type 2 11bHSD has been co-localized with MR in the fused syncytiotrophoblast (Krozowski et al., 1995; Hirasawa et al., 2000; Driver et al., 2001) and in the invasive EVT (Driver et al., 2001) with no expression in the chorion or amnion (Sun et al., 1997a). In term human trophoblast, expression of type 2 11bHSD is sensitive to the oxygen tension (Alfaidy et al., 2002; Hardy and Yang, 2002; Homan et al., 2006), and is also regulated by nitric oxide, cytokines and steroid hormones (Table II). In a recent study of term placentas from extremely low birth weight infants born weighing ,1 kg at 27 + 2 weeks of gestation, Kajantie et al. (2006) found that antenatal administration of betamethasone was associated with a significant increase in placental type 2 11bHSD activity. Likewise, inhalation of budesonide also increased placental metabolism of cortisol by type 2 11bHSD (Clifton et al., 2006). In contrast, antenatal administration of dexamethasone has been shown to suppress (rather than up-regulate) the expression of type 2 11bHSD in the ovine placenta (Kerzner et al., 2002) and expression of type 2 11bHSD in the ovine placenta decreases at term due to increased fetal output of cortisol (Clarke et al., 2002). These observations emphasize the need to exercise

11bHSD isoenzymes modulate glucocorticoid actions in the decidua and placenta
Studies of enzyme expression in the human endometrium have established that type 1 11bHSD is expressed at its highest levels in the decidua (Lopez-Bernal and Craft, 1981; Giannopoulos et al., 1982; Stewart et al., 1995; Arcuri et al., 1996, 1997; Burton et al., 1996; Petrelli et al., 1997; Sun et al., 1997a; Ricketts et al., 1998; Driver et al., 2001; McDonald et al., 2006) and menstruating endometrium, with no detectable expression in the proliferative or secretory phases of the non-pregnant menstrual cycle (McDonald et al., 2006). In contrast, type 2 11bHSD is highly expressed in both the proliferative and secretory phase endometrium, with expression localized predominantly to the glandular epithelium (Thompson et al., 2002; McDonald et al., 2006). Although type 1 11bHSD is the predominant enzyme expressed in the decidua, there is still marked up-regulation of type 2 11bHSD expression in the decidua relative to the non-pregnant endometrial stroma (McDonald et al., 2006). Hence, within the first trimester decidua, the balance of cortisol– cortisone metabolism favours local synthesis of active cortisol, as opposed to the net inactivation of cortisol in the non-pregnant endometrium. In the decidua of early pregnancy, expression of type 2 11bHSD is accompanied by the expression of both GR and MR (McDonald et al., 2006) such that the type 2 11bHSD enzyme could operate to limit activation of MR (as well as GR) by cortisol. The functional roles for corticosteroid receptors in the decidua have yet to be defined. The expression of both type 1 11bHSD and GR in the human decidua increase dramatically from the first to the third trimester of pregnancy with parallel increases in the rate of decidual cell apoptosis (Chan et al., 2007). This appears to be a causal relationship since cortisol, cortisone and dexamethasone could each induce the expression of both PGHS-2 and the apoptotic enzyme caspase-3 in human decidua (Chan et al., 2007). For the past decade it has been accepted that the two cloned 11bHSD enzymes co-operate in the placenta to modulate transfer of active physiological glucocorticoids from the maternal to the fetal circulations (see Lakshmi et al., 1993; Yang, 1995; Benediktsson et al., 1997; Sun et al., 1998a; Murphy et al., 2006). Several studies have assessed the ability of placental 11bHSD enzymes to metabolize synthetic glucocorticoids either in vitro or in perfused placental lobules. While term human placentas could not metabolize budesonide and fluticasone propionate, they were able to metabolize four synthetic corticosteroids: beclomethasone dipropionate, betamethasone, dexamethasone and prednisolone (Beitins et al., 1972; Anderson et al., 1977; Blanford and Murphy, 1977; Levitz et al., 1978; Smith et al., 1988; Addison et al., 1991, 1993; van Runnard-Heimel et al., 2005; Murphy et al., 2007). Their recent findings prompted (Murphy et al., 2007) to conclude that inhaled steroids used to treat maternal asthma should effectively be excluded from the fetal circulation, and so should not pose a threat to fetal growth. Type 1 11bHSD is expressed specifically in the placental villous endothelial cells, amnion, chorionic and EVT where the enzyme acts predominantly as a reductase to regenerate active cortisol

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Table II. The regulation of cloned 11bHSD enzymes in placenta and decidua. Up-regulate enzyme and/or increase enzyme activity Type 1 11bHSD Dexamethasone Estradiol Sun et al. (2002) Arcuri et al. (1996) Darnel et al. (1999) Sun and Myatt (2003) Chisaka et al. (2005) Johnstone et al. (2005) Li et al. (2006) Alfaidy et al. (2001) Hardy et al. (2001) Arcuri et al. (1996) Darnel et al. (1999) Sun and Myatt (2003) Chisaka et al. (2005) Johnstone et al. (2005) Ma et al. (2003) Koyama and Krozowski (2001) Clarke et al. (2002) Sun et al. (1998b) Pasquarette et al. (1996) Darnel et al. (1999) Van Beek et al. (2004) Arcuri et al. (1996) Darnel et al. (1999) Pepe et al. (2001) Chisaka et al. (2005) Sarkar et al. (2001) Arcuri et al. (1996) Darnel et al. (1999) Tremblay et al. (1999) Chisaka et al. (2005) Down-regulate enzyme and/or decrease enzyme activity No negative regulators reported in the endometrium, decidua or placenta Negative regulators in non-uterine tissues include estradiol, growth hormone, IGF-1 and insulin

IL-1b

PGF2a Progesterone TNF-a

Type 2 11bHSD

Betamethasone Cortisol Cyclic AMP Dexamethasone Estradiol

ATP Cadmium Calcium Dexamethasone Estradiol Hypoxia

IL-1b Noradrenaline Progesterone Retinoic acid TNF-a

IL-1b IL-6 Leukotriene B4 Nitric oxide PGE2 PGF2a PPARd Progesterone TNF-a

Yang et al. (2002) Yang et al. (2006) Hardy et al. (2001) Kossintseva et al. (2006) Kerzner et al. (2002) Sun et al. (1998b) Alfaidy et al. (2002) Hardy and Yang (2002) Homan et al. (2006) Kossintseva et al. (2006) Kossintseva et al. (2006) Hardy et al. (1999) Sun et al. (1997b) Hardy et al. (1999) Hardy et al. (1999) Hardy et al. (2001) Julan et al. (2005) Brown et al. (1996a) Sun et al. (1998b) Kossintseva et al. (2006)

HSD, hydroxysteroid dehydrogenase.

caution in extrapolating findings from animal studies to placental glucocorticoid handling in human pregnancies. The expression and function of type 2 11bHSD in the placenta is also responsive to maternal stress, though it is not yet clear whether placental glucocorticoid metabolism changes simply in response to the elevation in maternal cortisol as opposed to other endocrine regulators, such as prolactin or b-endorphin. A common experimental model to induce maternal stress in pregnant sheep is to restrict maternal nutrient intake. Using this model, Whorwood et al. (2001) found that restriction of nutrient intake in early pregnancy (Days 28– 77 of gestation, where term is 145 days) decreased expression of type 2 11bHSD mRNA. Although restricting nutrient intake by the ewe to 70% of her maintenance diet from Day 27 of gestation to either Day 90 or Day 135 of gestation was associated with a 50% suppression of placental type 2 11bHSD activity (P , 0.001), this was not accompanied by significant changes in the fetal plasma cortisol concentrations (McMullen et al., 2004). As part of their study, McMullen et al. (2004) exposed one group of ewes to the modest nutrient restriction for 30 days prior to mating, but then transferred those ewes to a 100% maintenance diet subsequent to mating for the duration

of pregnancy. This pre-conception restriction of nutrient intake had no lasting effect on placental type 2 11bHSD activity but halved the ratio of cortisol:cortisone in the fetal plasma on Day 135 of gestation, more than 4 months after the maternal stress (McMullen et al., 2004). In a subsequent study, ewes were completely fasted for two days 60 days prior to mating, and then transferred to a diet calculated for each ewe to achieve 15% weight loss from 60 days before through to 30 days after mating. After the initial doubling of maternal cortisol concentrations during the 2 day fast, plasma cortisol levels returned to a lower baseline level in the nutrient restricted ewes (relative to the control ewes). This peri-conception maternal stress decreased ovine placental cortisol metabolism by type 2 11bHSD on Day 50 of gestation (P ¼ 0.01), suggesting that maternal stress in early pregnancy can programme placental cortisol metabolism, modulating subsequent exposure of the fetus and placenta to active glucocorticoids (Jaquiery et al., 2006).

Embryo/fetal growth and development
The strongest evidence to implicate glucocorticoids in the regulation of fetal growth comes from the clinical association

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between IUGR and decreased placental inactivation of cortisol by type 2 11bHSD (Benediktsson et al., 1993; Edwards et al., 1993; Stewart et al., 1995; Shams et al., 1998; Hofmann et al., 2001; McTernan et al., 2001; Murphy et al., 2002, 2006; Kajantie et al., 2003; Seckl and Meaney, 2004). While Rogerson et al. (1997) found no relationship between placental levels of this enzyme and either placental or birth weight in 111 normal births, Struwe et al. (2007) reported decreased levels of both cloned 11bHSD enzymes in placenta delivered with smallfor-gestational-age infants. Moreover, a study of extremely small birth weight infants (born weighing under 1 kg) also found a correlation between placental type 2 11bHSD activities and infant birth weight (Kajantie et al., 2006), while Field et al. (2006) reported an association between elevated cortisol concentrations in maternal urine and decreased birth weight, consistent with decreased placental cortisol metabolism. The relevance of placental glucocorticoid metabolism for fetal growth has been tested in vivo using animal models. In pregnant rats, inhibition of the placental 11bHSD enzymes resulted in a significant reduction in birthweight of the pups (Langley-Evans, 1997b). This has been associated with adult hypertension, hyperinsulinaemia and altered post-natal behaviour in the offspring (Lindsay et al., 1996a, b; Nyirenda et al., 1998; Welberg et al., 2000), suggesting that impairment of placental glucocorticoid metabolism could affect multiple aspects of fetal development, not just growth. In recent studies, glucocorticoid metabolism by type 2 11bHSD in the mouse placenta and fetus has been suppressed using a transgenic strategy, and this also resulted in a significant decrease in mean birth weight (Holmes et al., 2006). In studies of pregnant sheep, McMullen et al. (2004) restricted the nutritional intake of ewes in early, mid and late gestation (Days 28 –45, 46– 90 and 91 –135 of gestation, respectively). The moderate nutrient restriction at each stage of pregnancy did not affect cortisol metabolism in the ovine placental cotyledons, but decreased the ratio of cortisol:cortisone in the fetal plasma at term (McMullen et al., 2004). This implies that the exposure of fetal tissues to cortisol may be determined locally by 11bHSD isoenzymes within the fetus, rather than simply by glucocorticoid metabolism at the materno – fetal interface (Murphy et al., 1981; Stewart et al., 1994, 1995; Langlois et al., 1995; Brown et al., 1996b; Condon et al., 1998; Hirasawa et al., 1999; Hundertmark et al., 2001; Speirs et al., 2004; Thompson et al., 2004; McNeil et al., 2007). In terms of direct evidence for effects of glucocorticoids on human fetal growth, Gur et al. (2004) reported decreased birth weight of infants born to mothers treated with synthetic glucocorticoids in the first trimester of pregnancy. In contrast, a meta-analysis of 5 trials in which 2028 pregnant women were treated with corticosteroids in late pregnancy (22 to 33 weeks of gestation) found no significant effect on birth weight (Crowther and Harding, 2007), indicating that human fetal growth may only be glucocorticoid sensitive in early pregnancy. In experimental studies of pregnant sheep, adrenalectomy accelerated fetal growth and increased birth weight, whereas maternal infusion of betamethasone in late pregnancy decreased birth weight and the size of specific fetal organs (Fowden et al., 1996; Newnham et al., 1999). In a recent study of pregnant pigs, Klemcke et al. (2006) found that suppressing the maternal cortisol concentration on Days 14 –19 of pregnancy (where term is 114 days) resulted in small decreases (8– 12%) in both the average embryonic weight and the total embryonic weight which could be prevented by co-administration of cortisol. Significant biphasic correlations were reported between maternal cortisol concentrations and both the total embryo weight and the total allantoic weight with peak weights observed at a cortisol concentration of 10 ng/ml (equivalent to around 28 nmol/l) (Klemcke et al., 2006). The correlations fitted second-order regressions, suggesting the requirement for an optimal cortisol concentration for maximum embryo growth and allantoic size. In keeping with this model of an optimal cortisol concentration for fetal growth and development, McNeil et al. (2007) reported that small fetal piglets had decreased (rather than increased) plasma cortisol concentrations on Day 45 of gestation. In addition to general effects on fetal growth, there is evidence that glucocorticoids can affect the development of specific fetal organs, of which the best studied are the cardiovascular and central nervous systems (CNSs). Much of the attention has been focused on the development of the cardiovascular system following reports that acute exposure of fetal lambs to dexamethasone for just 48 h in early pregnancy (between Days 22 and 29 of gestation) can programme post-natal hypertension in those lambs which persists for up to 7 years (Dodic et al., 1998, 2001). The actions of dexamethasone in early pregnancy included a 12% increase in fetal cardiac output (Dodic et al., 1999) with steroid-induced left ventricular hypertrophy (Dodic et al., 2001) and proliferation of cardiomyocytes (Giraud et al., 2006). In follow up studies, these authors determined that the developmental consequences of in utero exposure to the pharmacological glucocorticoid dexamethasone were not the same as exposure to cortisol (see Moritz et al., 2005). For example, in the fetal kidney, cortisol selectively increased the expression of the type 1 angiotensin II receptor, whereas dexamethasone also increased the renal expression of the type 2 angiotensin II receptor and angiotensinogen (Moritz et al., 2002). Exposure to dexamethasone in early pregnancy also impaired nephrogenesis in the fetal lamb kidney which persisted as a decreased number of nephrons through to post-natal year 7 (Wintour et al., 2003), and programmed the responses of the peripheral vasculature to known vasoconstrictors and vasodilators in the lambs born to steroid-treated ewes (Roghair et al., 2005; Segar et al., 2006). Hence, a transient increase in glucocorticoids in early pregnancy can produce lasting effects on the structure and function of the cardiovascular system which precede the onset of adult hypertension. The findings of similar studies in pregnant rats indicate important species differences and the need for caution in extrapolating findings from animal studies to human pregnancies. For example, Woods and Weeks (2005) found that while antenatal exposure to dexamethasone in late pregnancy (Days 15– 20 of 22) increased the mean arterial blood pressure in adult rats born to dexamethasone-teated mothers, there was no hypertensive response following in utero exposure to dexamethasone in early pregnancy (Days 1– 10 of gestation) (Woods and Weeks, 2005). In rats, the hypertensive effect of increased glucocorticoid exposure in late pregnancy appears to reflect sclerotic actions of glucocorticoids in the fetal kidney, rather than effects on the cardiac or vascular systems (Ortiz et al., 2001, 2003; Martins et al., 2003; Woods and Weeks, 2005). Actions on the developing CNS may underlie the effects of glucocorticoids on the in utero programming of post-natal behaviour.

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Antenatal treatment of pregnant rats with dexamethasone impaired post-natal learning and cognitive function in their offspring which exhibited increased susceptibility of their cholinergic neurones to neurotoxins (Emgard et al., 2007). Likewise, pharmacological elevation of the physiological glucocorticoid concentration following inhibition of 11bHSD activities in pregnant rats altered the post-natal behaviour, and the hypothalamic expression of GR, in the pups born to carbenoxolone-treated mothers (Welberg et al., 2000). In addition, Holmes et al. (2006) have reported that transgenic mice lacking the type 2 11bHSD enzyme exhibit increased anxiety, consistent with developmental effects of glucocorticoids on the mouse CNS in utero. In marmoset monkeys, prenatal exposure to dexamethasone for 1 week in either early or late pregnancy (Days 42 –48 and 90– 96 of gestation, respectively, where term is 148 days) impaired proliferation of dentate gyrus cells without affecting cell differentiation (Tauber et al., 2006). In terms of assessing CNS function in human neonates, Brazleton scores provide indexes of an infant’s strength and adaptive behavioural responses between 37 weeks of gestation and 2 months of age. Using this scoring system, Field et al. (2006) found that elevated cortisol levels in pregnant women were associated with lower Brazleton habituation scores and higher Brazleton reflex scores in their babies, while de Weerth et al. (2003) found elevated maternal cortisol concentrations in late pregnancy (weeks 37 and 38) to be associated with increased crying, fussing and negative facial expressions in their babies in the first 20 weeks following delivery. In their review, Kapoor et al. (2006) emphasized that the effects of glucocorticoid exposure on brain development and post-natal behaviour are highly sensitive to the gestational age at which the CNS is exposed to glucocorticoids; the maximum impact on brain development/behaviour occurs if the fetus is exposed to elevated glucocorticoid concentrations at the time of maximal brain growth. These authors also commented on the fact that passage of cortisol across the placenta is greater for female fetuses than male fetuses (Kapoor et al., 2006). Since the expression of each of the cloned 11bHSD enzymes in the placenta and decidua is sensitive to sex steroids (Table II), steroid output from the developing fetus could affect the balance between type 1 versus type 2 11bHSD, and hence determine the net inactivation of cortisol within the placenta. While effects of glucocorticoids on the cardiovascular and CNS are the best characterized, the development of other embryonic/fetal organ systems may also be sensitive to glucocorticoids. For example, glucocorticoids have been implicated in regulating the development of the endocrine pancreas (Blondeau et al., 2001; Gesina et al., 2004, 2006; Breant et al., 2006; de Vries et al., 2007) and may programme post-natal insulin secretion and glucose homeostasis (de Blasio et al., 2007; de Vries et al., 2007). metabolism of glucocorticoids within the placenta and associated tissues in the latter stages of pregnancy (Challis et al., 2000; Schoof et al., 2001a; Alfaidy et al., 2003; Ma et al., 2003; Murphy and Clifton, 2003). In terms of direct evidence to support a link between pre-term labour and increased glucocorticoid exposure in early pregnancy, Field et al. (2006) reported a significant association between increased cortisol clearance in maternal urine and pre-term labour. Moreover, the administration of synthetic glucocorticoids in the first trimester of pregnancy doubled the incidence of pre-term delivery (which rose from 10.8 to 22.7%) in the prospective case – control study reported by Gur et al. (2004). While a subsequent meta-analysis, conducted by Rahimi et al. (2006), reported no link between administration of inhaled corticosteroids and incidence of pre-term delivery, the surveyed studies did not assess the impact of glucocorticoids administered in early pregnancy, nor did they take account of variation in the placental metabolism of the different synthetic steroids. Placental CRH has also been implicated in the timing of parturition with plasma CRH concentrations rising at an earlier stage of gestation and to higher levels in pre-term labour (McLean et al., 1995; Wadhwa et al., 1998; Hobel et al., 1999; Erickson et al., 2001; Leung et al., 2001; Beshay et al., 2007; Smith and Nicholson, 2007). In a study of 203 pregnant women for whom plasma CRH and cortisol levels were assessed at 15, 19, 25 and 31 weeks of gestation, the magnitude and timing of the increase in CRH levels was highly predicted by elevated concentrations of cortisol in the maternal plasma in early pregnancy, specifically at 15 weeks of gestation (Sandman et al., 2006). Hence elevated plasma cortisol concentrations in early pregnancy may predict subsequent risk of pre-term labour with an apparent mediatory role for increased placental CRH output.
Chorioamnionitis

Placental glucocorticoid metabolism in complications of pregnancy
Pre-term labour

Increased placental expression of type 1 11bHSD accompanied by decreased placental expression and activity of type 2 11bHSD has been documented in chorioamnionitis (Johnstone et al., 2005). Since glucocorticoids paradoxically increase the net synthesis of active prostaglandins in the human placenta (Whittle et al., 2001; Li et al., 2006) with pro-inflammatory cytokines regulating the expression of both placental 11bHSD isoenzymes (Chisaka et al., 2005; Johnstone et al., 2005; Li et al., 2006) (Fig. 2), it is not yet possible to determine whether changes in placental glucocorticoid metabolism in chorioamnionitis are the cause or consequence of the associated intra-uterine inflammation. A recent meta-analysis of 21 RCTs found that the incidence of chorioamnionitis is not increased by a single maternal course of betamethasone administered across a range of gestational ages (Roberts and Dalziel, 2006), which would seem to imply that changes in glucocorticoid metabolism are more likely to be a consequence of chorioamnionitis than a cause. In pregnancies complicated by chorioamnionitis, decreased expression of sgk-1 in the fetal lungs has been implicated in the dysregulation of pulmonary fluid balance (Wirbelauer et al., 2007).
Pre-eclampsia

As alluded to above, the timing of parturition, both at term and pre-term, has previously been linked to changes in the local

The pathogenesis of pre-eclampsia is increasingly thought to arise from abnormalities in placental implantation or function in the first

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trimester of pregnancy with evidence of increased impedance to uterine artery blood flow, altered maternal serum markers and reduced placental volume as assessed by 3D ultrasound evident long before the onset of the clinical signs (Papageorghiou and Campbell, 2006). Given the importance of glucocorticoids in implantation, trophoblast invasion and placental growth, is there any evidence to implicate glucocorticoids in the aetiology of preclampsia? The majority of published investigations have reported that the expression and/or activity of type 2 11bHSD in human placentas is decreased (typically by 50– 70%) in established preeclampsia relative to placentas from normotensive pregnancies (McCalla et al., 1998; Schoof et al., 2001b; Alfaidy et al., 2002; Causevic and Mohaupt, 2007). Whether such changes pre-date the onset of pre-eclampsia is not known, but in vitro studies conducted using both first trimester placental villous explants (isolated between weeks 5 and 8 of pregnancy) and term human placental trophoblasts have shown that the expression of type 2 11bHSD mRNA and protein are both suppressed by 60% in tissue incubated at low oxygen tensions (either 3 or 1% by volume) when compared with 20% (v/v) oxygen (Alfaidy et al., 2002; Hardy and Yang, 2002). Moreover, the decreased expression of type 2 11bHSD was accompanied by suppression of the net cortisol oxidation by up to 50%, dependent on the gestational age of the trophoblast and the degree of hypoxia (Alfaidy et al., 2002; Hardy and Yang, 2002). Hence the decreased expression and activity of type 2 11bHSD in pre-eclamptic placentas, and the accompanying increase in exposure of the placenta and embryo/fetus to active glucocorticoids, could be a consequence of impaired placental perfusion and hypoxia. Crocker et al. (2003) noted that pre-eclampsia and IUGR were both characterized by increased susceptibility of the placental trophoblast to apoptosis. In light of their earlier finding that glucocorticoids could induce apoptosis in cytotrophoblast and syncytiotrophoblast (Crocker et al., 2001), increased exposure to glucocorticoids following down-regulation of type 2 11bHSD could contribute to the increased rate of trophoblast apoptosis in preeclampsia. Pre-eclampsia is also characterized by increased production of placental CRH (Laatikainen et al., 1991; Goland et al., 1995; Florio et al., 2004) which may also be a reflection of increased local concentrations of active glucocorticoids in pre-eclampsia. Published data relating to dysregulation of glucocorticoid metabolism in pregnancy-induced hypertension (PIH) are equivocal. While Walker et al. (1995) found no difference in urinary ratios of cortisol:cortisone in 12 patients with PIH relative to 16 women with normotensive pregnancies, Heilmann et al. (2001) reported significant increases in the urinary cortisol:cortisone ratios for 59 PIH patients relative to 67 normotensive controls.
Hydatidiform moles

also decreased by .80% in hydatidiform moles relative to normal placentas (Muneyyirci-Delale et al., 2006). Since the abilities of both enzymes to oxidize cortisol were compromised in hydatidiform moles, local exposure of the invasive trophoblast to active cortisol would be increased in molar pregnancies, as in chorioamnionitis and pre-eclampsia.

Conclusions
While glucocorticoids exert predominantly adverse effects on the fetus and placenta in late pregnancy, the effects of these adrenal corticosteroids in early pregnancy are far less well defined. Glucocorticoids can exert a range of positive effects which would be expected to promote establishment of early pregnancy, such as suppression of uterine NK cells and stimulation of hCG secretion, as well as promotion of trophoblast proliferation and invasion (Fig. 3). However, glucocorticoids can also exert a range of adverse effects that would be expected to impede pregnancy, including up-regulation of PAI-1, induction of placental and/or decidual apoptosis and impairment of placental nutrient transport (Fig. 3). Since physiological glucocorticoids have the potential to activate both MR and GR (whereas synthetic glucocorticoids act via the GR only), the divergent actions of cortisol (and corticosterone) in pregnancy may be mediated via different intracellular receptors and signalling pathways. Given the opposing beneficial and adverse actions of glucocorticoids, the apparent lack of effect of glucocorticoid administration on conception rates in the studies included in the meta-analysis reported by Boomsma et al. (2007) could reflect opposing positive versus negative consequences of increased glucocorticoid exposure in early pregnancy, rather than a complete lack of action of these corticosteroids. The one certainty to emerge from this review is that further research is required to elucidate the roles for glucocorticoids in early pregnancy. With such research, the possible relevance of glucocorticoids in the first trimester of pregnancy to

As noted above, pre-eclampsia may have its origins in defective implantation and placentation in early pregnancy (Papageorghiou and Campbell, 2006). However, it has yet to be determined whether the fetus and placenta are exposed to elevated concentrations of active glucocorticoid in early pregnancy, or just in the later stages of gestation. In contrast, hydatidiform moles represent complications of early pregnancy and trophoblast invasion. Hence, it is relevant to this review that a recent study reported that cortisol oxidation by both type 1 and type 2 11bHSD enzymes was

Figure 3: Overview of the possible beneficial and adverse impacts of the physiological glucocorticoid, cortisol, in early pregnancy. Positive effects on enzyme activity and/or protein expression are indicated by solid green arrows, while negative effects are indicated by broken red lines. hCG, human chorionic gonadotrophin; IGF-II, insulin-like growth factor II; MMP-9, matrix metalloproteinase-9; NK, natural killer; PAI-1, plasminogen activator inhibitor-1; PPAR, peroxisome proliferator-activated receptor; proMMP-2, pro-matrix metalloproteinase-2; tPA, tissue plasminogen activator; troph, trophoblast; uPA, urokinase plasminogen activator; CRH, corticotrophin releasing hormone.

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normal embryo implantation and feto–placental development, as well as to the pathogenesis of obstetric complications (e.g. IUGR, pre-term labour and pre-eclampsia) should emerge.
Banjanin S, Kapoor A, Matthews SG. Prenatal glucocorticoid exposure alters hypothalamic-pituitary-adrenal function and blood pressure in mature male guinea pigs. J Physiol 2004;558:305–318. Barbera A, Wilkening RB, Teng C, Battaglia FC, Meschia G. Metabolic alterations in the fetal hepatic and umbilical circulations during glucocorticoid-induced parturition in sheep. Ped Res 1997;41:242– 248. Barnes PJ. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci (Lond) 1998;94:557– 572. Barnes PJ. Corticosteroid effects on cell signalling. Eur Respir J 2006;27: 413– 426. Beitins IZ, Bayard F, Ances IG, Kowarski A, Migeon CJ. The transplacental passage of prednisone and prednisolone in pregnancy near term. J Pediatr 1972;81:936– 945. Benediktsson R, Edwards CR. Apparent mineralocorticoid excess. J Hum Hypertension 1994;8:371–375. Benediktsson R, Lindsay RS, Noble J, Seckl JR, Edwards CRW. Glucocorticoid exposure in utero: new model for adult hypertension. Lancet 1993;341:339– 341. Benediktsson R, Calder AA, Edwards CRW, Seckl JR. Placental 11b-hydroxysteroid dehydrogenase: a key regulator of fetal glucocorticoid exposure. Clin Endocrinol 1997;46:161– 166. Bertram CE, Hanson MA. Prenatal programming of postnatal endocrine responses by glucocorticoids. Reproduction 2002;124:459–467. Beshay VE, Carr BR, Rainey WE. The human fetal adrenal gland, corticotrophin-releasing hormone, and parturition. Semin Reprod Med 2007;25:14– 20. Blanford AT, Murphy BEP. In vitro metabolism of prednisolone, dexamethasone, betamethasone, and cortisol by the human placenta. Am J Obstet Gynecol 1977;127:264– 267. Blondeau B, Lesage J, Czernichow P, Dupouy JP, Breant B. Glucocorticoids impair fetal b-cell development in rats. Am J Physiol Endocrinol Metab 2001;281:E592– E599. Bloom SL, Sheffield JS, McIntire DD, Leveno KJ. Antenatal dexamethasone and decreased birth weight. Obstet Gynecol 2001;97:485–490. Boomsma CM, Keay SD, Macklon NS. Peri-implantation glucocorticoid administration for assisted reproductive technology cycles. Cochrane Database Syst Rev 2007;24:CD005996. Breant B, Gesina E, Blondeau B. Nutrition, glucocorticoids and pancreas development. Horm Res 2006;65(Suppl. 3):98– 104. Brown RW, Chapman KE, Edwards CRW, Seckl JR. Human placental 11b-hydroxysteroid dehydrogenase: evidence for and partial purification of a distinct NAD-dependent iosform. Endocrinology 1993;132:2614–2621. Brown RW, Chapman KE, Kotelevtsev Y, Yau JL, Lindsay RS, Brett L, Leckie C, Murad P, Lyons V, Mullins JJ et al. Cloning and production of antisera to human placental 11b-hydroxysteroid dehydrogenase type 2. Biochem J 1996a;313:1007– 1017. Brown RW, Diaz R, Robson AC, Kotelevtsev YV, Mullins JJ, Kaufman MH, Seckl JR. The ontogeny of 11b-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor gene expression reveal intricate control of glucocorticoid action in development. Endocrinology 1996b;137:794– 797. Burrows TD, King A, Loke YW. Trophoblast migration during human placental implantation. Hum Reprod Update 1996;2:307– 321. Burton PJ, Waddell BJ. 11b-Hydroxysteroid dehydrogenase in the rat placenta: developmental changes and the effects of altered glucocorticoid exposure. J Endocrinol 1994;143:505– 513. Burton PJ, Waddell BJ. Dual function of 11b-hydroxysteroid dehydrogenase in placenta: modulating glucocorticoid passage and local steroid action. Biol Reprod 1999;60:234–240. Burton PJ, Smith RE, Krozowski ZS, Waddell BJ. Zonal distribution of 11b-hydroxysteroid dehydrogenase types 1 and 2 messenger ribonucleic acid expression in the rat placenta and decidua during late pregnancy. Biol Reprod 1996;55:1023– 1028. Canlon B, Erichsen S, Nemlander E, Chen M, Hossain A, Celsi G, Ceccatelli S. Alterations in the intrauterine environment by glucocorticoids modifies the developmental programme of the auditory system. Eur J Neurosci 2003;17:2035–2041. Causevic M, Mohaupt M. 11b-Hydroxysteroid dehydrogenase type 2 in pregnancy and preeclampsia. Mol Aspects Med 2007;28:220– 226. Chan CC, Lao TT, Ho PC, Sung EO, Cheung AN. The effect of mifepristone on the expression of steroid hormone receptors in human decidua and placenta: a randomized placebo-controlled double-blind study. J Clin Endocrinol Metab 2003;88:5846–5850. Chan J, Rabbitt EH, Innes BA, Bulmer JN, Stewart PM, Kilby MD, Hewison M. Glucocorticoid-induced apoptosis in human decidua: a novel role for

Acknowledgements
The authors would like to thank Dr Rachel Webb, Mrs Caroline Michael and Mrs Sarah Winyard for their assistance in the production and editing of this manuscript.

References
Achache H, Revel A. Endometrial receptivity markers, the journey to successful embryo implantation. Hum Reprod Update 2006;12:731–746. Adcock IM, Caramori G. Cross-talk between pro-inflammatory transcription factors and glucocorticoids. Immunol Cell Biol 2001;79:376–384. Addison RS, Maguire DJ, Mortimer RH, Cannell GR. Metabolism of prednisolone by the isolated perfused human placental lobule. J Ster Biochem Mol Biol 1991;39:83 –90. Addison RS, Maguire DJ, Mortimer RH, Roberts MS, Cannell GR. Pathway and kinetics of prednisolone metabolism in the human placenta. J Ster Biochem Mol Biol 1993;44:315–320. Agarwal AK, Mune T, Monder C, White PC. NADþ-dependent isoform of 11b-hydroxysteroid dehydrogenase. Cloning and characterization cDNA from sheep kidney. J Biol Chem 1994;269:25959– 25962. Ain R, Canham LN, Soares MJ. Dexamethasone-induced intrauterine growth restriction impacts the placental prolactin family, insulin-like growth factor-II and the Akt signaling pathway. J Endocrinol 2005;185:253–263. Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS. Cloning and tissue distribution of the human 11b-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol 1994;105:R11– R17. Alfaidy N, Xiong ZG, Myatt L, Lye SJ, MacDonald JF, Challis JR. Prostaglandin F2a potentiates cortisol production by stimulating 11b-hydroxysteroid dehydrogenase 1: a novel feedback loop that may contribute to human labour. J Clin Endocrinol Metab 2001;86: 5585– 5592. Alfaidy N, Gupta S, DeMarco C, Caniggia I, Challis JRG. Oxygen regulation of placental 11b-hydroxysteroid dehydrogenase 2: physiological and pathological implications. J Clin Endocrinol Metab 2002;87:4797–4805. Alfaidy N, Li W, Macintosh T, Yang K, Challis J. Late gestation increase in 11b-hydroxysteroid dehydrogenase 1 expression in human fetal membranes: a novel intrauterine source of cortisol. J Clin Endocrinol Metab 2003;88:5033– 5038. Anderson AB, Gennser G, Jeremy JY, Ohrlander S, Sayers L, Turnbull AC. Placental transfer and metabolism of betamethasone in human pregnancy. Obstet Gynecol 1977;49:471–474. Antonow-Schlorke I, Schwab M, Li C, Nathanielsz PW. Glucocorticoid exposure at the dose used clinically alters cytoskeletal proteins and presynaptic terminals in the fetal baboon brain. J Physiol 2003;547: 117–123. Arcuri F, Monder C, Lockwood CJ, Schatz F. Expression of 11b-hydroxysteroid dehydrogenase during decidualization of human endometrial stromal cells. Endocrinology 1996;137:595– 600. Arcuri F, Battistini S, Hausknecht V, Cintorino M, Lockwood CJ, Schatz F. Human endometrial decidual cell-associated 11b-hydroxysteroid dehydrogenase expression: its potential role in implantation. Early Pregnancy 1997;3:259– 264. Arcuri F, Sestini S, Paulesu L, Bracci L, Carducci A, Manzoni F, Cardone C, Cintorino M. 11b-hydroxysteroid dehydrogenase expression in first trimester human trophoblasts. Mol Cell Endocrinol 1998;141:13–20. Arcuri F, Sestini S, Cintorino M. Expression of 11b-hydroxysteroid dehydrogenase in early pregnancy: implications in human trophoblastendometrial interactions. Semin Reprod Endocrinol 1999;17:53–61. Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE, Evans RM. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science 1987;237:268–275. Baggia S, Albrecht ED, Babischkin JS, Pepe GJ. Interconversion of cortisol and cortisone in baboon trophoblast and decidua cells in culture. Endocrinology 1990;127:1735– 1741. Bailey JM. New mechanisms for effects of anti-inflammatory glucocorticoids. Biofactors 1991;3:97– 102.

509

Michael and Papageorghiou
11b-hydroxysteroid dehydrogenase in late gestation. J Endocrinol 2007;195:7– 15. Chard T. Cytokines in implantation. Hum Reprod Update 1995;1:385– 396. Challis JRG, Matthews SG, Gibb W, Lye SJ. Endocrine and paracrine regulation of birth at term and preterm. Endocr Rev 2000;21:514–550. Cheng YH, Nicholson RC, King B, Chan EC, Fitter JT, Smith R. Glucocorticoid stimulation of corticotropin-releasing hormone gene expression requires a cyclic adenosine 30 ,50 -monophosphate regulatory element in human primary placental cytotrophoblast cells. J Clin Endocrinol Metab 2000;85:1937– 1945. Chisaka H, Johnstone JF, Premyslova M, Manduch Z, Challis JR. Effect of pro-inflammatory cytokines on expression and activity of 11b-hydroxysteroid dehydrogenase type 2 in cultured human term placental trophoblast and human choriocarcinoma JEG-3 cells. J Soc Gynecol Investig 2005;12:303– 309. Clark PM. Programming of the hypothalamo-pituitary-adrenal axis and the fetal origins of adult disease hypothesis. Eur J Pediatr 1998;157:S7– S10. Clarke KA, Ward JW, Forhead AJ, Giussani DA, Fowden AL. Regulation of 11b-hydroxysteroid dehydrogenase type 2 activity in ovine placenta by fetal cortisol. J Endocrinol 2002;172:527– 534. Clifton VL, Rennie N, Murphy VE. Effect of inhaled glucocorticoid treatment on placental 11b-hydroxysteroid dehydrogenase type 2 activity and neonatal birthweight in pregnancies and complicated by asthma. Aust N Z J Obstet Gynaecol 2006;46:136–140. Condon J, Gosden C, Gardener D, Nickson P, Hewison M, Howie AJ, Stewart PM. Expression of type 2 11b-hydroxysteroid dehydrogenase and corticosteroid hormone receptors in early human fetal life. J Clin Endocrinol Metab 1998;83:4490– 4497. Crocker IP, Barratt S, Kaur M, Baker PN. The in-vitro characterization of induced apoptosis in placental cytotrophoblasts and syncytiotrophoblasts. Placenta 2001;22:822–830. Crocker IP, Cooper S, Ong SC, Baker PN. Differences in apoptotic susceptibility of cytotrophoblasts and syncytiotrophoblasts in normal pregnancy to those complicated with preeclampsia and intrauterine growth restriction. Am J Pathol 2003;162:637– 643. Cross JC, Nakano H, Natale DR, Simmons DG, Watson ED. Branching morphogenesis during development of placental villi. Differentiation 2006;74:393–401. Crowther CA, Harding JE. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease. Cochrane Database Syst Rev 2007;3:CD003935. Darnel AD, Archer K, Yang K. Regulation of 11b-hydroxysteroid dehydrogenase type 2 by steroid hormones and epidermal growth factor in the Ishikawa human endometrial cell line. J Ster Biochem Mol Biol 1999;70:203–210. De Blasio MJ, Dodic M, Jefferies AJ, Moritz KM, Wintour EM, Owens JA. Maternal exposure to dexamethasone or cortisol in early pregnancy differentially alters insulin secretion and glucose homeostasis in adult male sheep offspring. Am J Physiol Endocrinol Metab 2007;293:75 –82. de Vries A, Holmes MC, Heijnis A, Seier JV, Heerden J, Louw J, Wolfe-Coote S, Meaney MJ, Levitt NS, Seckl JR. Prenatal dexamethasone exposure induces changes in nonhuman primate offspring cardiometabolic and hypothalamic-pituitary-adrenal axis function. J Clin Invest 2007;117:1058– 1067. de Weerth C, van Hees Y, Buitelaar JK. Prenatal maternal cortisol levels and infant behavior during the first 5 months. Early Hum Dev 2003;74: 139– 151. d’Hauterive SP, Berndt S, Tsamplas M, Charlet-Renard C, Dubois M, Bourgain C, Hazout A, Foidart JM, Geenen V. Dialogue between blastocyst hCG and endometrial LH/hCG receptor: which role in implantation? Gynecol Obstet Invest 2007;64:156–160. Demoly P, Piette V, Daures JP. Asthma therapy during pregnancy. Expert Opin Pharmacother 2003;4:1019– 1023. Dodic M, May CN, Wintour EM, Coghlan JP. An early prenatal exposure to excess glucocorticoid leads to hypertensive offspring in sheep. Clin Sci (Lond) 1998;94:149– 155. Dodic M, Peers A, Coghlan JP, May CN, Lumbers E, Yu Z, Wintour EM. Altered cardiovascular haemodynamics and baroreceptor-heart rate reflex in adult sheep after prenatal exposure to dexamethasone. Clin Sci (Lond) 1999;97:103– 109. Dodic M, Samuel C, Moritz K, Wintour EM, Morgan J, Grigg L, Wong J. Impaired cardiac functional reserve and left ventricular hypertrophy in adult sheep after prenatal dexamethasone exposure. Circ Res 2001;89:623–629. Dodic M, Abouantoun T, O’Connor A, Wintour EM, Moritz KM. Programming effects of short prenatal exposure to dexamethasone in sheep. Hypertension 2002a;40:729–734. Dodic M, Hantzis V, Duncan J, Rees S, Koukoulas I, Johnson K, Wintour EM, Moritz K. Programming effects of short prenatal exposure to cortisol. FASEB J 2002b;16:1017– 1026. Doyle LW, Ford GW, Davis NM, Callanan C. Antenatal corticosteroid therapy and blood pressure at 14 years of age in preterm children. Clin Sci (Lond). 2000;98:137– 142. Drake AJ, Tang JI, Nyirenda MJ. Mechanisms underlying the role of glucocorticoids in the early life programming of adult disease. Clin Sci (Lond) 2007;113:219– 232. Draper N, Stewart PM. 11b-Hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action. J Endocrinol 2005;186:251– 271. Driver PM, Kilby MD, Bujalska I, Walker EA, Hewison M, Stewart PM. Expression of 11b-hydroxysteroid dehydrogenase isozymes and corticosteroid hormone receptors in primary cultures of human trophoblast and placental bed biopsies. Mol Hum Reprod 2001;7: 357–363. Driver PM, Rauz S, Walker EA, Hewison M, Kilby MD, Stewart PM. Characterization of human trophoblast as a mineralocorticoid target tissue. Mol Hum Reprod 2003;9:793– 798. Eberhart CG, Argani P. Wnt signaling in human development: beta-catenin nuclear translocation in fetal lung, kidney, placenta, capillaries, adrenal, and cartilage. Pediart Dev Pathol 2001;4:351– 357. Economopoulos P, Sun M, Purgina B, Gibb W. Glucocorticoids stimulate prostaglandin H synthase type-2 (PGHS-2) in the fibroblast cells in human amnion cultures. Mol Cell Endocrinol 1996;25:141–147. Edwards CRW, Benediktsson R, Lindsay RS, Seckl JR. Dysfunction of placental glucocorticoid barrier: link between fetal environment and adult hypertension. Lancet 1993;341:355–357. Edwards CRW, Benediktsson R, Lindsay RS, Seckl JR. 11b-hydroxysteroid dehydrogenases: key enzymes in determining tissue-specific glucocorticoid effects. Steroids 1996;61:263–269. Emgard M, Paradisi M, Pirondi S, Fernandez M, Giardino L, Calza L. Prenatal glucocorticoid exposure affects learning and vulnerability of cholinergic neurons. Neurobiol Aging 2007;28:112– 121. Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev 2005;2:CD002859. Erickson K, Thorsen P, Chrousos G, Grigoriadis DE, Khongsaly O, McGregor J, Schulkin J. Preterm birth: associated neuroendocrine, medical, and behavioural risk factors. J Clin Endocrinol Metab 2001;86:2544–2552. Ericsson A, Hamark B, Jansson N, Johansson BR, Powell TL, Jansson T. Hormonal regulation of glucose and system A amino acid transport in first trimester placental villous fragments. Am J Physiol Regul Integr Comp Physiol 2005;288:R656–R662. Estelles A, Gilabert J, Keeton M, Eguchi Y, Aznar J, Grancha S, Espna F, Loskutoff DJ, Schleef RR. Altered expression of plasminogen activator inhibitor type 1 in placentas from pregnant women with preeclampsia and/or intrauterine fetal growth retardation. Blood 1994;84:143– 150. Feroze-Zaidi F, Fusi L, Takano M, Higham J, Salker MS, Goto T, Edassery S, Klingel K, Boini KM, Palmada M et al. Role and regulation of the serumand glucocorticoid-regulated kinase 1 in fertile and infertile human endometrium. Endocrinology 2007;148:5020–5029. Feinberg RF, Kao LC, Haimowitz JE, Queenan JT, Jr, Wun TC, Strauss JF, Kliman HJ. Plasminogen activator inhibitor types 1 and 2 in human trophoblasts. PAI-1 is an immunocytochemical marker of invading trophoblasts. Lab Invest 1989;61:20–26. Field T, Diego M, Hernandez-Reif M, Gil K, Vera Y. Prenatal maternal cortisol, fetal activity and growth. Int J Neurosci 2005;115:423– 429. Field T, Hernandez-Reif M, Diego M, Figueiredo B, Schanberg S, Kuhn C. Prenatal cortisol, prematurity and low birthweight. Infant Behav Dev 2006;29:268– 275. Florio P, Imperatore A, Sanseverino F, Torricelli M, Reis FM, Lowry PJ, Petraglia F. The measurement of maternal plasma corticotropinreleasing factor (CRF) and CRF-binding protein improves the early prediction of preeclampsia. J Clin Endocrinol Metab 2004;89:4673– 4677. Flower RJ, Rothwell NJ. Lipocortin-1: cellular mechanisms and clinical relevance. Trends Pharmacol Sci 1994;15:71 –76. Fowden AL. The insulin-like growth factors and feto-placental growth. Placenta 2003;24:803–812.

510

Glucocorticoids and early pregnancy
Fowden AL, Forhead AJ. Endocrine mechanisms of intrauterine programming. Reproduction 2004;127:515–526. Fowden AL, Szemere J, Hughes P, Gilmour RS, Forhead AJ. The effects of cortisol on the growth rate of the sheep fetus during late gestation. J Endocrinol 1996;151:97–105. Fowden AL, Ward JW, Wooding FP, Forhead AJ, Constancia M. Programming placental nutrient transport capacity. J Physiol 2006;572:5– 15. French NP, Hagan R, Evans SF, Godfrey M, Newnham JP. Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol 1999;180:114– 121. Funder JW. Apparent mineralocorticoid excess, 11b-hydroxysteroid dehydrogenase and aldosterone action: closing one loop, opening another. Trends Endocrinol Metab 1995;6:248– 251. Funder JW. Glucocorticoid and mineralocorticoid receptors: biology and clinical relevance. Annu Rev Med 1997;48:231– 240. Gesina E, Tronche F, Herrera P, Duchene B, Tales W, Czernichow P, Breant B. Dissecting the role of glucocorticoids on pancreas development. Diabetes 2004;53:2322– 2329. Gesina E, Blondeau B, Milet A, Le Nin I, Duchene B, Czernichow P, Scharfmann R, Tronche F, Breant B. Glucocorticoid signalling affects pancreatic development through both direct and indirect effects. Diabetologia 2006;49:2939– 2947. Gharraee Z, Beharry KD, Valencia AM, Cho S, Guajardo L, Nageotte MP, Modanlou HD. Effects of antenatal betamethasone on maternal and fetoplacental matrix metalloproteinases 2 and 9 activities in human singleton pregnancies. J Investig Med 2006;54:245–254. Giannopoulos G, Jackson K, Tulchinsky D. Glucocorticoid metabolism in human placenta, decidua, myometrium and fetal membranes. J Steroid Biochem 1982;17:371– 374. Gibb W, Breton R. Studies on the action of dexamethasone on prostaglandin production by freshly dispersed amnion cells. Acta Endocrinol (Copenh) 1993;128:563– 567. Giraud GD, Louey S, Jonker S, Schultz J, Thornburg KL. Cortisol stimulates cell cycle activity in the cardiomyocyte of the sheep fetus. Endocrinology 2006;147:3641– 3642. Goland RS, Tropper P, Warren W, Stark R, Jozak S, Conwell I. Concentrations of corticotropin-releasing hormone in the umbilical cord blood of pregnancies complicated by preeclampsia. Reprod Fertil Dev 1995;7:1227– 1230. Graf R, Gossrau R, Frank HG. Placental toxicity in rats after administration of synthetic glucocorticoids. A morphological, histochemical and immunohistochemical investigation. Anat Embryol (Berl). 1989;180:121– 130. Grancha S, Estelles A, Gilabert J, Chirivella M, Espana F, Aznar J. Decreased expression of PAI-2 mRNA and protein in pregnancies complicated with intrauterine fetal growth retardation. Thromb Haemost 1996;76:761– 767. Gravanis A, Makrigiannakis A, Zoumakis E, Margioris AN. Endometrial and myometrial corticotropin-releasing hormone (CRH): its regulation and possible roles. Peptides 2001;22:785– 793. Guller S, Markiewicz L, Wozniak R, Burnham JM, Wang EY, Kaplan P, Lockwood CJ. Developmental regulation of glucocorticoid-mediated effects on extracellular matrix protein expression in the human placenta. Endocrinology 1994;134:2064– 2071. Guller S, Kong L, Wozniak R, Lockwood CJ. Reduction of extracellular matrix protein expression in human amnion epithelial cells by glucocorticoids: a potential role in preterm rupture of the fetal membranes. J Clin Endocr Metab 1995a;80:2244– 2250. Guller S, Kong L, Wozniak R, Lockwood CJ. Opposing actions of transforming growth factor-b and glucocorticoids in the regulation of fibronectin expression in the human placenta. J Clin Endocr Metab 1995b; 80:3273–3278. Gur C, Diav-Citrin O, Shechtman S, Arnon J, Ornoy A. Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study. Reprod Toxicol 2004;18:93–101. Hahn T, Barth S, Graf R, Engelmann M, Beslagic D, Reul JM, Holsboer F, Dohr G, Desoye G. Placental glucose transporter expression is regulated by glucocorticoids. J Clin Endocr Metab 1999;84:1445–1452. Handschuh K, Guibourdenche J, Tsatsaris V, Guesnon M, Laurendeau I, Evain-Brion D, Fournier T. Human chorionic gonadotropin produced by the invasive trophoblast but not the villous trophoblast promotes cell invasion and is down-regulated by peroxisome proliferator-activated receptor-g. Endocrinology 2007;148:5011– 5019. Hanson FW, Powell JE, Stevens VC. Effects of HCG and human pituitary LH on steroid secretion and functional life of the human corpus luteum. J Clin Endocrinol Metab 1971;32:211–215. Hardy DB, Yang K. The expression of 11b-hydroxysteroid dehydrogenase type 2 is induced during trophoblast differentiation: effects of hypoxia. J Clin Endocrinol Metab 2002;87:3696–3701. Hardy DB, Pereria LE, Yang K. Prostaglandins and leukotriene B4 are potent inhibitors of 11b-hydroxysteroid dehydrogenase type 2 activity in human choriocarcinoma JEG-3 cells. Biol Reprod 1999;61:40 –45. Hardy DB, Dixon SJ, Narayan N, Yang K. Calcium inhibits human placental 11b-hydroxysteroid dehydrogenase type 2 activity. Biochem Biophys Res Comm 2001;283:756–761. Hayashi R, Wada H, Ito K, Adcock IM. Effects of glucocorticoids on gene transcription. Eur J Pharm 2004;500:51– 62. Heilmann P, Buchheim E, Wacker J, Ziegler R. Alteration of the activity of the 11b-hydroxysteroid dehydrogenase in pregnancy: relevance for the development of pregnancy-induced hypertension? J Clin Endocr Metab 2001;86:5222–5226. Henderson TA, Saunders PT, Moffett-King A, Groome NP, Critchley HO. Steroid receptor expression in uterine natural killer cells. J Clin Endocr Metab 2003;88:440– 449. Hewitt DP, Mark PJ, Waddell BJ. Placental expression of peroxisome proliferator-activated receptors in rat pregnancy and the effect of increased glucocorticoid exposure. Biol Reprod 2006a;74:23 –28. Hewitt DP, Mark PJ, Dharmarajan AM, Waddell BJ. Placental expression of secreted frizzled related protein-4 in the rat and the impact of glucocorticoid-induced fetal and placental growth restriction. Biol Reprod 2006b;75:75 –81. Hirasawa G, Sasano H, Suzuki T, Takeyama J, Muramatu Y, Fukushima K, Hiwatashi N, Toyota T, Nagura H, Krozowski ZS. 11b-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor in human fetal development. J Clin Endocrinol Metab 1999;84:1453–1458. Hirasawa G, Takeyama J, Sasano H, Fukushima K, Suzuki T, Muramatu Y, Darnel AD, Kaneko C, Hiwatashi N, Toyota T et al. 11bhydroxysteroid dehydrogenase type II and mineralocorticoid receptor in human placenta. J Clin Endocrinol Metab 2000;85:1306–1309. Hobel CJ, Dunkel-Schetter C, Roesch SC, Castro LC, Arora CP. Maternal plasma corticotropin-releasing hormone associated with stress at 20 weeks’ gestation in pregnancies ending in preterm delivery. Am J Obstet Gynecol 1999;180:257–263. Hofmann GE, Glatstein I, Schatz F, Heller D, Deligdisch L. Immunohistochemical localization of urokinase-type plasminogen activator and the plasminogen activator inhibitors 1 and 2 in early human implantation sites. Am J Obstet Gynecol 1994;170:671–676. Hofmann M, Pollow K, Bahlmann F, Casper F, Steiner E, Brockerhoff P. 11b-hydroxysteroid dehydrogenase (11b-HSD-II) activity in human placenta: its relationship to placental weight and birth weight and its possible role in hypertension. J Perinat Med 2001;29:23– 30. Holmes MC, Abrahamsen CT, French KL, Paterson JM, Mullins JJ, Seckl JR. The mother or the fetus? 11b-hydroxysteroid dehydrogenase type 2 null mice provide evidence for direct fetal programming of behavior by endogenous glucocorticoids. J Neurosci 2006;26:3840–3844. Homan A, Guan H, Hardy DB, Gratton RJ, Yang K. Hypoxia blocks 11b-hydroxysteroid dehydrogenase type 2 induction in human trophoblast cells during differentiation by a time-dependent mechanism that involves both translation and transcription. Placenta 2006;27: 832– 840. Huang WL, Beazley LD, Quinlivan JA, Evans SF, Newnham JP, Dunlop SA. Effect of corticosteroids on brain growth in fetal sheep. Obstet Gynecol 1999;94:213–218. Huang WL, Harper CG, Evans SF, Newnham JP, Dunlop SA. Repeated prenatal corticosteroid administration delays myelination of the corpus callosum in fetal sheep. Int J Dev Neurosci 2001;19:415– 425. Hundertmark S, Buhler H, Fromm M, Kruner-Gareis B, Kruner M, Ragosch V, Kuhlmann K, Seckl JR. Ontogeny of 11b-hydroxysteroid dehydrogenase: activity in the placenta, kidney, colon of fetal rats and rabbits. Horm Metab Res 2001;33:78– 83. Ikegami M, Jobe AH, Newnham J, Polk DH, Willet KE, Sly P. Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs. Am J Respir Crit Care Med 1997;156:178–184. Imseis HM, Zimmerman PD, Samuels P, Kniss DA. Tumour necrosis factor-a induces cyclo-oxygenase-2 gene expression in first trimester trophoblasts: suppression by glucocorticoids and NSAIDs. Placenta 1997;18:521–526. Islami D, Mock P, Bischof P. Effects of human chorionic gonadotropin on trophoblast invasion. Semin Reprod Med 2001;19:49 –53. Jaggers DC, Collins WP, Milligan SR. Potent inhibitory effects of steroids in an in vitro model of angiogenesis. J Endocrinol 1996;150:457– 464.

511

Michael and Papageorghiou
Jansson T, Powell TL. Role of the placenta in fetal programming: underlying mechanisms and potential interventional approaches. Clin Sci (Lond) 2007;113:1– 13. Jaquiery AL, Oliver MH, Bloomfield FH, Connor KL, Challis JR, Harding JE. Fetal exposure to excess glucocorticoid is unlikely to explain the effects of periconceptional undernutrition in sheep. J Physiol 2006;572:109–118. Jellyman JK, Gardner DS, Fowden AL, Giussani DA. Effects of dexamethasone on the uterine and umbilical vascular beds during basal and hypoxemic conditions in sheep. Am J Obstet Gynecol 2004;190:825–835. Jensen EC, Gallaher BW, Breier BH, Harding JE. The effect of a chronic maternal cortisol infusion on the late-gestation fetal sheep. J Endocrinol 2002;174:27 –36. Johnstone JF, Bocking AD, Unlugedik E, Challis JR. The effects of chorioamnionitis and betamethasone on 11b-hydroxysteroid dehydrogenase types 1 and 2 and the glucocorticoid receptor in preterm human placenta. J Soc Gynecol Investig 2005;12:238–245. Jones HN, Ashworth CJ, Page KR, McArdle HJ. Cortisol stimulates system A amino acid transport and SNAT2 expression in a human placental cell line (BeWo). Am J Physiol Endocrinol Metab 2006;291:E596–E603. Jones SA, Brooks AN, Challis JR. Steroids modulate corticotropin-releasing hormone production in human fetal membranes and placenta. J Clin Endocrinol Metab 1989;68:825– 830. Julan L, Guan H, van Beek JP, Yang K. Peroxisome proliferator-activated receptor d suppresses 11b-hydroxysteroid dehydrogenase type 2 gene expression in human placental trophoblast cells. Endocrinology 2005;146:1482– 1490. Jung SP, Siegrist B, Wade MR, Anthony CT, Woltering EA. Inhibition of human angiogenesis with heparin and hydrocortisone. Angiogenesis 2001;4:175– 186. Kajantie E, Dunkel L, Turpeinen U, Stenman UH, Wood PJ, Nuutila M, Andersson S. Placental 11b-hydroxysteroid dehydrogenase-2 and fetal cortisol/cortisone shuttle in small preterm infants. J Clin Endocrinol Metab 2003;88:493– 500. Kajantie E, Dunkel L, Turpeinen U, Stenman U-H, Andersson S. Placental 11bHSD2 activity, early postnatal clinical course and adrenal function in extremely low birth weight infants. Ped Res 2006;59:575–578. Kalantaridou S, Makrigiannakis A, Zoumakis E, Chrousos GP. Peripheral corticotropin-releasing hormone is produced in the immune and reproductive systems: actions, potential roles and clinical implications. Front Biosci 2007;12:572– 580. Kapoor A, Dunn E, Kostaki A, Andrews MH, Matthews SG. Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids. J Physiol 2006;572:31 –44. Keay SD, Harlow CR, Wood PJ, Jenkins JM, Cahill DJ. Higher cortisol:cortisone ratios in the preovulatory follicle of completely unstimulated IVF cycles indicate oocytes with increased pregnancy potential. Hum Reprod 2002;17:2410–2414. Kelly RW, King AE, Critchley HOD. Cytokine control in human endometrium. Reproduction 2001;121:3– 19. Kerzner LS, Stonestreet BS, Wu K-Y, Sadowska G, Malee MP. Antenatal dexamethasone: effect on ovine placental 11b-hydroxysteroid dehydrogenase type 2 expression and fetal growth. Ped Res 2002;52:706–712. Kino T, Chrousos GP. Glucocorticoid and mineralocorticoid receptors and associated diseases. Essays Biochem 2004;40:137– 155. Klemcke HG, Sampath-Kumar R, Yang K, Vallett JL, Christenson RK. 11b-hydroxysteroid dehydrogenase and glucocorticoid receptor mRNA expression in porcine placentae: effects of stage of gestation, breed, and uterine environment. Biol Reprod 2003;69:1945– 1950. Klemcke HG, Vallett JL, Christenson RK. Lack of effect of metyrapone and exogenous cortisol on early porcine conceptus development. Exp Physiol 2006;91:521– 530. Knaggs P, Lambert A, Proudfoot F, Nickson I, Hooper MAK, Lenton E, Robertson WR. A rapid method for the measurement of the oxoreductase activity of 11b-hydroxysteroid dehydrogenase in granulosa-lutein cells from patients undergoing in-vitro fertilization. Mol Hum Reprod 1998;4:147–151. Kossintseva I, Wong S, Johnstone E, Guilbert L, Olson DM, Mitchell BF. Proinflammatory cytokines inhibit human placental 11b-hydroxysteroid dehydrogenase type 2 activity through Ca2þ and cAMP pathways. Am J Physiol Endocrinol Metab 2006;290:E282–E288. Kossmann JC, Bard H, Gibb W. Characterization of specific steroid binding in human amnion at term. Biol Reprod 1982;27:320–326. Koyama K, Krozowski ZS. Modulation of 11b-hydroxysteroid dehydrogenase type 2 activity in Ishikawa cells is associated with changes in cellular proliferation. Mol Cell Endocrinol 2001;183:165–170. Kranendonk G, Hopster H, Fillerup M, Ekkel ED, Mulder EJ, Wiegant VM, Taverne MA. Lower birth weight and attenuated adrenocortical response to ACTH in offspring from sows that orally received cortisol during gestation. Dom Anim Endocrinol 2006a;30:218–238. Kranendonk G, Hopster H, Fillerup M, Ekkel ED, Mulder EJ, Taverne MA. Cortisol administration to pregnant sows affects novelty-induced locomotion, aggressive behaviour, and blunts gender differences in their offspring. Horm Behav 2006b;49:663– 672. Krozowski ZS. The 11b-hydroxysteroid dehydrogenases: functions and physiological effects. Mol Cell Endocrinol 1999;151:121–127. Krozowski ZS, Maguire JA, Stein-Oakley AN, Dowling J, Smith RE, Andrews RK. Immunohistochemical localization of the 11b-hydroxysteroid dehydrogenase type II enzyme in human kidney and placenta. J Clin Endocrinol Metab 1995;80:2203–2209. Laatikainen T, Virtanen T, Kaaja R, Salminen-Lappalainen K. Corticotropin-releasing hormone in maternal and cord plasma in pre-eclampsia. Eur J Obstet Gynecol Reprod Biol 1991;39:19 –24. Lang F, Bohmer C, Palmada M, Seebohm G, Strutz-Seebohm N, Vallon V. (Patho)physiological significance of the serum- and glucocorticoidinducible kinase isoforms. Physiol Rev 2006;86:1151–1178. Langdown ML, Sugden MC. Enhanced placental GLUT1 and GLUT3 expression in dexamethasone-induced fetal growth retardation. Mol Cell Endocrinol 2001;185:109– 117. Langley-Evans SC. Intrauterine programming of hypertension by glucocorticoids. Life Sci 1997a;60:1213–1221. Langley-Evans SC. Maternal carbenoxolone treatment lowers birthweight and induces hypertension in the offspring of rats fed a protein-replete diet. Clin Sci 1997b;93:423–429. Langlois DA, Matthews SG, Yu M, Yang K. Differential expression of 11b-hydroxysteroid dehydrogenase 1 and 2 in the developing ovine fetal liver and kidney. J Endocrinol 1995;147:405–411. Lakshmi V, Nath N, Muneyyirci-Delale O. Characterization of 11b-hydroxysteroid dehydrogenase of human placenta: evidence for the existence of two species of 11b-hydroxysteroid dehydrogenase. J Ster Biochem Mol Biol 1993;45:391–397. Laskin CA, Bombardier C, Hannah ME, Mandel FP, Ritchie JW, Farewell V, Farine D, Spitzer K, Fielding L, Soloninka CA et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med 1997;337:148–153. Lee MJ, Ma Y, LaChapelle L, Kadner SS, Guller S. Glucocorticoid enhances transforming growth factor-b effects on extracellular matrix protein expression in human placental mesenchymal cells. Biol Reprod 2004;70:1246– 1252. Lee MJ, Wang Z, Yee H, Ma Y, Swenson N, Yang L, Kadner SS, Baergen RN, Logan SK, Garabedian MJ et al. Expression and regulation of glucocorticoid receptor in human placental villous fibroblasts. Endocrinology 2005;146:4619– 4626. Lesage J, Blondeau B, Grino M, Breant B, Dupouy JP. Maternal undernutrition during late gestation induces fetal overexposure to glucocorticoids and intrauterine growth retardation, and disturbs the hypothalamo-pituitary adrenal axis in the newborn rat. Endocrinology 2001;142:1692– 1702. Leung TN, Chung TKH, Madsen G, Lam PKW, Sahota D, Smith R. Rate of rise in maternal plasma corticotropin-releasing hormone and its relation to gestational length. Br J Obstet Gynaecol 2001;108:527– 532. Levitt NS, Lindsay RS, Holmes MC, Seckl JR. Dexamethasone in the last week of pregnancy attenuates hippocampal glucocorticoid receptor gene expression and elevates blood pressure in the adult offspring in the rat. Neuroendocrinology 1996;64:412–418. Levitz M, Jansen V, Dancis J. The transfer and metabolism of corticosteroids in the perfused human placenta. Am J Obstet Gynecol 1978;132:363–366. Lewicka S, von Hagens C, Hettinger U, Grunwald K, Vecsei P, Runnebaum B, Rabe T. Cortisol and cortisone in human follicular fluid and serum and the outcome of IVF treatment. Hum Reprod 2003;18: 1613– 1617. Li K, Smith RE, Ferrari P, Funder JW, Krozowski ZS. Rat 11b-hydroxysteroid dehydrogenase type 2 enzyme is expressed at low levels in the placenta and is modulated by adrenal steroids in the kidney. Mol Cell Endocrinol 1996;120:67– 75. Li X, Wong J, Tsai SY, Tsai MJ, O’Malley BW. Progesterone and glucocorticoid receptors recruit distinct coactivator complexes and promote distinct patterns of local chromatin modification. Mol Cell Biol 2003;23:3763– 3773.

512

Glucocorticoids and early pregnancy
Li W, Gao L, Wang Y, Duan T, Myatt L, Sun K. Enhancement of cortisol-induced 11b-hydroxysteroid dehydrogenase type 1 expression by interleukin 1b in cultured human chorionic trophoblast cells. Endocrinology 2006;147:2490– 2495. Librach CL, Feigenbaum SL, Bass KE, Cui TY, Verastas N, Sadovsky Y, Quigley JP, French DL, Fisher SJ. Interleukin-1b regulates human cytotrophoblast metalloproteinase activity and invasion in vitro. J Biol Chem 1994;269:17125–17131. Licht P, Russu V, Lehmeyer S, Wildt L. Molecular aspects of direct LH/hCG effects on human endometrium—lessons from intrauterine microdialysis in the human female in vivo. Reprod Biol 2001;1:10– 19. Lindsay RS, Lindsay RM, Edwards CRW, Seckl JR. Inhibition of 11b-hydroxysteroid dehydrogenase in pregnant rats and the programming of blood pressure in the offspring. Hypertension 1996a;27:1200– 1204. Lindsay RS, Lindsay RM, Waddell BJ, Seckl JR. Prenatal glucocorticoid exposure leads to offspring hyperglycaemia in the rat: studies with the 11b-hydroxysteroid dehydrogenase inhibitor carbenoxolone. Diabetologia 1996b;39:1299– 1305. Liu Y, Li A, Matthews SG. Maternal glucocorticoid treatment programs HPA regulation in adult offspring: sex-specific effects. Am J Physiol Endocrinol Metab 2001;280:E729–E739. Lopez-Bernal A, Craft IL. Corticosteroid metabolism in vitro by human placenta, fetal membranes and decidua in early and late gestation. Placenta 1981;2:279–285. Lopez-Bernal A, Anderson AB, Turnbull AC. The measurement of glucocorticoid receptors in human placental cytosol. Placenta 1984;5:105–116. Loskutoff DJ, Sawdey M, Keeton M, Schneiderman J. Regulation of PAI-1 gene expression in vivo. Thromb Haemost 1993;70:135– 137. Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V, Hochberg RB, McKay L, Renoir JM, Weigel NL et al. International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol Rev 2006;58:782–797. Ma Y, Ryu JS, Dulay A, Segal M, Guller S. Regulation of plasminogen activator inhibitor (PAI)-1 expression in a human trophoblast cell line by glucocorticoid (GC) and transforming growth factor (TGF)-b. Placenta 2002;23:727–734. Ma XH, Wu WX, Nathanielsz PW. Gestation-related and betamethasoneinduced changes in 11b-hydroxysteroid dehydrogenase types 1 and 2 in the baboon placenta. Am J Obstet Gynecol 2003;188:13 –21. Ma Y, Kadner SS, Guller S. Differential effects of lipopolysaccharide and thrombin on interleukin-8 expression in syncytiotrophoblasts and endothelial cells: implications for fetal survival. Ann N Y Acad Sci 2004;1034:236–244. Ma Y, Mor G, Abrahams VM, Buhimschi IA, Buhimschi CS, Guller S. Alterations in syncytiotrophoblast cytokine expression following treatment with lipopolysaccharide. Am J Reprod Immunol 2006;55:12– 18. Makrigiannakis A, Zoumakis E, Margioris AN, Stournaras C, Chrousos GP, Gravanis A. Regulation of the promoter of the human corticotropin-releasing hormone gene in transfected human endometrial cells. Neuroendocrinology 1996;64:85– 92. Makrigiannakis A, Margioris AN, Chatzaki E, Zoumakis E, Chrousos GP, Gravanis A. The decidualizing effect of progesterone may involve direct transcriptional activation of corticotrophin-releasing hormone from human endometrial stromal cells. Mol Hum Reprod 1999;5:789–796. Makrigiannakis A, Zoumakis E, Kalantaridou S, Chrousos G, Gravanis A. Participation of maternal and fetal CRH in early phases of human implantation: the role of antalarmin. Curr Drug Targets Immune Endocr Metabol Disord 2004;4:75– 78. Makrigiannakis A, Minas V, Kalantaridou SN, Nikas G, Chrousos GP. Hormonal and cytokine regulation of early implantation. Trends Endocrinol Metab 2006;17:178–185. Malassine A, Cronier L. Hormones and human trophoblast differentiation: a review. Endocrine 2002;19:3–11. ¨ Mandl M, Ghaffari-Tabrizi N, Haas J, Nohammer G, Desoye G. Differential glucocorticoid effects on proliferation and invasion of human trophoblast cell lines. Reproduction 2006;132:159–167. Mantero F, Palermo M, Petrelli MD, Tedde R, Stewart PM, Shackleton CH. Apparent mineralocorticoid excess: type I and type II. Steroids 1996;61:193– 196. Martins JP, Monteiro JC, Paixao AD. Renal function in rats subjected to prenatal dexamethasone. Clin Exp Pharmacol Physiol 2003;30:32– 37. Matthews SG. Antenatal glucocorticoids and programming of the developing CNS. Pediatr Res 2000;47:291– 300. Matthews SG. Early programming of the hypothalamo-pituitary-adrenal axis. Trends Endocrinol Metab 2002;13:373– 380. Matthews SG, Owen D, Kalabis G, Banjanin S, Setiawan EB, Dunn EA, Andrews MH. Fetal glucocorticoid exposure and hypothalamo-pituitary-adrenal (HPA) function after birth. Endocr Res 2004;30:827–836. McCalla CO, Nacharaju VL, Muneyyirci-Delale O, Glasgow S, Feldman JG. Placental 11b-hydroxysteroid dehydrogenase activity in normotensive and pre-eclamptic pregnancies. Steroids 1998;63:511– 515. McDonald SE, Henderson TA, Gomez-Sanchez CE, Critchley HOD, Mason JI. 11b-hydroxysteroid dehydrogenases in human endometrium. Mol Cell Endocrinol 2006;248:72– 78. McLean M, Bistis A, Davies JJ, Woods R, Lowry PJ, Smith R. A placental clock controlling the length of human pregnancy. Nat Med 1995;1:460– 463. McMullen S, Osgerby JC, Thurston LM, Gadd TS, Wood PJ, Wathes DC, Michael AE. Alterations in placental 11b-hydroxysteroid dehydrogenase (11bHSD) activities and fetal cortisol:cortisone ratios induced by nutritional restriction prior to conception and at defined stages of gestation in ewes. Reproduction 2004;127:717–725. McNatt LG, Lane D, Clark AF. Angiostatic activity and metabolism of cortisol in the chorioallantoic membrane (CAM) of the chick embryo. J Steroid Biochem Mol Biol 1992;42:687– 693. McNeil CJ, Nwagwu MO, Finch AM, Page KR, Thain A, McArdle HJ, Ashworth CJ. Glucocorticoid exposure and tissue gene expression of 11bHSD-1, 11bHSD-2, and glucocorticoid receptor in a porcine model of differential fetal growth. Reproduction 2007;133:653– 661. McTernan CL, Draper N, Nicholson H, Chalder SM, Driver P, Hewison M, Kilby MD, Stewart PM. Reduced placental 11b-hydroxysteroid dehydrogenase type 2 mRNA levels in human pregnancies complicated by intrauterine growth restriction: an analysis of possible mechanisms. J Clin Endocrinol Metab 2001;86:4979– 4983. Meaney MJ, Szyf M, Seckl JR. Epigenetic mechanisms of perinatal programming of hypothalamic-pituitary-adrenal function and health. Trends Mol Med 2007;13:269–277. Michael AE. Life after liquorice: the link between cortisol and conception. Reprod Biomed Online 2003;7:683–690. Michael AE, Gregory L, Walker SM, Antoniw JW, Shaw RW, Edwards CR, Cooke BA. Ovarian 11b-hydroxysteroid dehydrogenase: potential predictor of conception by in-vitro fertilisation and embryo transfer. Lancet 1993;342:711– 712. Michael AE, Gregory L, Piercy EC, Walker SM, Shaw RW, Cooke BA. Ovarian 11b-hydroxysteroid dehydrogenase activity is inversely related to the outcome of in vitro fertilization-embryo transfer treatment cycles. Fertil Steril 1995;64:590–598. Michael AE, Collins TD, Norgate DP, Gregory L, Wood PJ, Cooke BA. Relationship between ovarian cortisol:cortisone ratios and the clinical outcome of in vitro fertilization and embryo transfer (IVF-ET). Clin Endocrinol 1999;51:535– 540. Michael AE, Thurston LM, Rae MT. Glucocorticoid metabolism and reproduction: a tale of two enzymes. Reproduction 2003;126:425–441. Mirazi N, Alfaidy N, Martin R, Challis JR. Effects of dexamethasone and sulfasalazine on prostaglandin E2 output by human placental cells in vitro. J Soc Gynecol Invest 2004;11:22 –26. Moritz KM, Johnson K, Douglas-Denton R, Wintour EM, Dodic M. Maternal glucocorticoid treatment programs alterations in the renin–angiotensin system of the ovine fetal kidney. Endocrinology 2002;143:4455–4463. Moritz KM, Jefferies AJ, Wintour EM, Dodic M. Fetal renal and blood pressure responses to steroid infusion after early prenatal treatment with dexamethasone. Am J Physiol 2005;288:R62– R66. Morrish DW, Dakour J, Li H. Functional regulation of human trophoblast differentiation. J Reprod Immunol 1998;39:179– 195. Moss TJ, Nitsos I, Harding R, Newnham JP. Differential effects of maternal and fetal betamethasone injections in late-gestation fetal sheep. J Soc Gynecol Investig 2003;10:474–479. Muller T, Nanan R, Dietl J. Effect of antenatal corticosteroid administration on Doppler flow velocity parameters in pregnancies with absent or reverse end-diastolic flow in the umbilical artery. Acta Obstet Gynecol Scand 2003;82:794–796. Muneoka K, Mikuni M, Ogawa T, Kitera K, Kamei K, Takigawa M, Takahashi K. Prenatal dexamethasone exposure alters brain monoamine metabolism and adrenocortical response in rat offspring. Am J Physiol Regul Integr Comp Physiol 1997;273:R1669–R1675.

513

Michael and Papageorghiou
Muneyyirci-Delale O, Lakshmi V, McCalla CO, Karacan M, Neil G, Camilien L. Variations in human placental 11b-dehydrogenase and 11-oxoreductase activities of 11b-hydroxysteroid dehydrogenase enzyme during pregnancy. Early Pregnancy 1996;2:201–206. Muneyyirci-Delale O, Nacharaju VL, Sidell J, Neil G, Karacan M, Camilien L, Temkin S, Abulafia O. 11b-hydroxysteroid dehydrogenase activity in pregnancies complicated by hydatidiform mole. Am J Reprod Immunol 2006;55:415–419. Murphy BEP. Ontogeny of cortisol-cortisone interconversion in human tissues: a role for cortisone in human fetal development. J Steroid Biochem 1981;14:811–817. Murphy VE, Clifton VL. Alterations in human placental 11b-hydroxysteroid dehydrogenase type 1 and 2 with gestational age and labour. Placenta 2003;24:739–744. Murphy VE, Zakar T, Smith R, Giles WB, Gibson PG, Clifton VL. Reduced 11b-hydroxysteroid dehydrogenase type 2 activity is associated with decreased birth weight centile in pregnancies complicated by asthma. J Clin Endocr Metab 2002;87:1660– 1668. Murphy VE, Smith R, Giles WB, Clifton VL. Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus. Endocr Rev 2006;27:141–169. Murphy VE, Fittock RJ, Zarzycki PK, Delahunty MM, Smith R, Clifton VL. Metabolism of synthetic steroids by the human placenta. Placenta 2007;28:39– 46. Nacharaju VL, Divald A, McCalla CO, Yang L, Muneyyirci-Delale O. 11b-hydroxysteroid dehydrogenase inhibitor carbenoxolone stimulates chorionic gonadotropin secretion from human term cytotrophoblast cells differentiated in vitro. Am J Reprod Immunol 2004;52:133–138. Namazy JA, Schatz M. Update in the treatment of asthma during pregnancy. Clin Rev Allergy Immunol 2004;26:139– 148. Nepomnaschy PA, Welch KB, McConnell DS, Low BS, Strassmann BI, England BG. Cortisol levels and very early pregnancy loss in humans. Proc Natl Acad Sci USA 2006;103:3938–3942. Newnham JP. Is prenatal glucocorticoid administration another origin of adult disease? Clin Exp Pharmacol Physiol 2001;28:957–961. Newnham JP, Moss TJ. Antenatal glucocorticoids and growth: single versus multiple doses in animal and human studies. Semin Neonatol 2001;6:285– 292. Newnham JP, Evans SF, Godfrey M, Huang W, Ikegami M, Jobe A. Maternal, but not fetal, administration of corticosteroids restricts fetal growth. J Matern Fetal Med 1999;8:81–87. Nicholson RC, King BR, Smith R. Complex regulatory interactions control CRH gene expression. Front Biosci 2004;9:32– 39. Nyirenda MJ, Seckl JR. Intrauterine events and the programming of adulthood disease: The role of fetal glucocorticoid exposure. Int J Mol Med 1998;2:607– 614. Nyirenda MJ, Lindsay RS, Kenyon CJ, Burchell A, Seckl JR. Glucocorticoid exposure in late gestation permanently programmes rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. J Clin Invest 1998;101:2174–2181. Ogasawara M, Aoki K. Successful uterine steroid therapy in a case with a history of ten miscarriages. Am J Reprod Immunol 2000;44:253– 255. O’Regan D, Welberg LL, Holmes MC, Seckl JR. Glucocorticoid programming of pituitary-adrenal function: mechanisms and physiological consequences. Semin Neonatol 2001;6:319– 329. Ortiz LA, Quan A, Weinberg A, Baum M. Effect of prenatal dexamethasone on rat renal development. Kidney Int 2001;59:1663– 1669. Ortiz LA, Quan A, Zarzar F, Weinberg A, Baum M. Prenatal dexamethasone programs hypertension and renal injury in the rat. Hypertension 2003;41:328–334. Osur SL. The management of asthma and rhinitis during pregnancy. J Womens Health (Larchmt) 2005;14:263– 276. Papageorghiou AT, Campbell S. First trimester screening for preeclampsia. Curr Opin Obstet Gynecol 2006;18:594–600. Pasqualini JR. Enzymes involved in the formation and transformation of steroid hormones in the fetal and placental compartments. J Ster Biochem Mol Biol 2005;97:401–415. Pasquarette MM, Stewart PM, Ricketts ML, Imaishi J, Mason JI. Regulation of 11b-hydroxysteroid dehydrogenase type 2 activity and mRNA in human choriocarcinoma cells. J Mol Endocrinol 1996;16:269–275. Patel FA, Challis JRG. Cortisol/progesterone antagonism in regulation of 15-hydroxysteroid dehydrogenase activity and mRNA levels in human chorion and placental trophoblast cells at term. J Clin Endocrinol Metab 2002;87:700– 708. Patel FA, Clifton VL, Chwalisz K, Challis JRG. Steroid regulation of prostaglandin dehydrogenase activity and expression in human term placenta and chorio-decidua in relation to labour. J Clin Endocrinol Metab 1999a;84:291–299. Patel FA, Sun K, Challis JRG. Local modulation by 11b-hydroxysteroid dehydrogenase of glucocorticoid effects on the activity of 15-hydroxyprostaglandin dehydrogenase in human chorion and placental trophoblast cells. J Clin Endocrinol Metab 1999b;84:395–400. Patel FA, Funder JW, Challis JRG. Mechanism of cortisol/progesterone antagonism in the regulation of 15-hydroxyprostaglandin dehydrogenase activity and messenger ribonucleic acid levels in human chorion and placental trophoblast cells at term. J Clin Endocrinol Metab 2003;88:2922– 2933. Pepe GJ, Babischkin JS, Burch MMG, Leavitt MG, Albrecht ED. Developmental increase in expression of the messenger ribonucleic acid and protein levels of 11b-hydroxysteroid dehydrogenase types 1 and 2 in the baboon placenta. Endocrinology 1996a;137:5678–5684. Pepe GJ, Waddell BJ, Burch MG, Albrecht ED. Interconversion of cortisol and cortisone in the baboon placenta at midgestation: expression of 11b-hydroxysteroid dehydrogenase type 1 messenger RNA. J Ster Biochem Mol Biol 1996b;58:403– 410. Pepe GJ, Burch MG, Albrecht ED. Expression of the 11beta-hydroxysteroid dehydrogenase types 1 and 2 proteins in human and baboon placental syncytiotrophoblast. Placenta 1999;20:575–582. Pepe GJ, Burch MG, Albrecht ED. Estrogen regulates 11b-hydroxysteroid dehydrogenase-1 and -2 localization in placental syncitiotrophoblast in the second half of primate pregnancy. Endocrinology 2001;142: 4496– 4503. Petrelli MD, Lim-Tio SS, Condon J, Hewison M, Stewart PM. Differential expression of nuclear 11b-hydroxysteroid dehydrogenase type 2 in mineralocorticoid receptor positive and negative tissues. Endocrinology 1997;138:3077–3080. Phillips GD, Whitehead RA, Knighton DR. Inhibition by methylprednisolone acetate suggests an indirect mechanism for TGF-b induced angiogenesis. Growth Factors 1992;6:77– 84. Potter SM, Dennedy MC, Morrison JJ. Corticosteroids and fetal vasculature: effects of hydrocortisone, dexamethasone and betamethasone on human umbilical artery. Br J Obst Gynaecol 2002;109:1126–1131. Pountain GD, Keogan MT, Hazleman BL, Brown DL. Effects of single dose compared with three days’ prednisolone treatment of healthy volunteers: contrasting effects on circulating lymphocyte subsets. J Clin Pathol 1993;46:1089– 1092. Quenby S, Farquharson R. Uterine natural killer cells, implantation failure and recurrent miscarriage. Reprod Biomed Online 2006;13:24– 28. Quenby S, Farquharson R, Young M, Vince G. Successful pregnancy outcome following 19 consecutive miscarriages: case report. Hum Reprod 2003;18:2562– 2564. Quenby S, Kalumbi C, Bates M, Farquharson R, Vince G. Prednisolone reduces preconceptual endometrial natural killer cells in women with recurrent miscarriage. Fertil Steril 2005;84:980– 984. Rahimi R, Nikfar S, Abdollahi M. Increased morbidity and mortality in acute human organophosphate-poisoned patients treated by oximes: a meta-analysis of clinical trials. Hum Exp Toxicol 2006;25:447–452. Reinisch JM, Simon NG, Karow WG, Gandelman R. Prenatal exposure to prednisone in humans and animals retards intrauterine growth. Science 1978;202:436– 438. Ricketts ML, Verhaeg JM, Bujalska I, Howie AJ, Rainey WE, Stewart PM. Immunohistochemical localization of type 1 11b-hydroxysteroid dehydrogenase in human tissues. J Clin Endocr Metab 1998;83:1325–1335. Ringler GE, Kallen CB, Strauss JF. Regulation of human trophoblast function by glucocorticoids: dexamethasone promotes increased secretion of chorionic gonadotropin. Endocrinology 1989;124:1625– 1631. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006;3: CD004554. Robinson BG, Emanuel RL, Frim DM, Majzoub JA. Glucocorticoid stimulates corticotropin-releasing hormone gene in human placenta. Proc Natl Acad Sci USA 1988;85:5244–5248. Rodriguez JJ, Montaron MF, Petry KG, Aurousseau C, Marinelli M, Premier S, Rougon G, Le Moal M, Abrous DN. Complex regulation of the expression of the polysialylated form of the neuronal cell adhesion molecule by glucocorticoids in the rat hippocampus. Eur J Neurosci 1998;10: 2994– 3006.

514

Glucocorticoids and early pregnancy
Rogerson FM, Kayes KM, White PC. Variation in placental type 2 11b-hydroxysteroid dehydrogenase activity is not related to birth weight or placental weight. Mol Cell Endocrinol 1997;128:103–109. Roghair RD, Lamb FS, Miller FJ, Jr, Scholz TD, Segar JL. Early gestation dexamethasone programs enhanced postnatal ovine coronary artery vascular reactivity. Am J Physiol Regul Integr Comp Physiol 2005;289:R1169–R1176. Rosen T, Krikun G, Ma Y, Wang EY, Lockwood CJ, Guller S. Chronic antagonism of nuclear factor-kappaB activity in cytotrophoblasts by dexamethasone: a potential mechanism for antiinflammatory action of glucocorticoids in human placenta. J Clin Endocrinol Metab 1998;3647– 3652. Ryu JS, Majeska RJ, Ma Y, LaChapelle L, Guller S. Steroid regulation of human placental integrins: suppression of a2 integrin expression in cytotrophoblasts by glucocorticoids. Endocrinology 1999;140: 3904– 3908. Sampath-Kumar R, Matthews SG, Yang K. 11b-hydroxysteroid dehydrogenase type 2 is the predominant isozyme in the guinea pig placenta: decreases in messenger ribonucleic acid and activity at term. Biol Reprod 1998;59:1378– 1384. Sandman CA, Glynn L, Schetter CD, Wadhwa P, Garite T, Chicz-DeMet A, Hobel C. Elevated maternal cortisol early in pregnancy predicts third trimester levels of placental corticotropin releasing hormone (CRH): priming the placental clock. Peptides 2006;27:1457– 1463. Sarkar S, Tsai S-W, Nguyen TT, Plevyak M, Padbury JF, Rubin LP. Inhibition of placental 11b-hydroxysteroid dehydrogenase type 2 by catecholamines via a-adrenergic signalling. Am J Physiol Regul Integr Comp Physiol 2001;281:R1966–R1974. Schaiff WT, Barak Y, Sadovsky Y. The pleiotropic function of PPAR gamma in the placenta. Mol Cell Endocrinol 2006;249:10– 15. Schoof E, Girstl M, Frobenius W, Kirschbaum M, Repp R, Knerr I, Rascher W, Dotsch J. Course of placental 11b-hydroxysteroid dehydrogenase type 2 and 15-hydroxyprostaglandin dehydrogenase mRNA expression during human gestation. Eur J Endocrinol 2001a;145:187–192. Schoof E, Girstl M, Frobenius W, Kirschbaum M, Dorr HG, Rascher W, Dotsch J. Decreased gene expression of 11b-hydroxysteroid dehydrogenase type 2 and 15-hydroxyprostaglandin dehydrogenase in human placenta of patients with preeclampsia. J Clin Endocrinol Metab 2001b;86: 1313– 1317. Seckl JR. Glucocorticoids, feto-placental 11b-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease. Steroids 1997;62: 89–94. Seckl JR. Glucocorticoids programming of the fetus. Mol Cell Endocrinol 2001;185:61– 71. Seckl JR. Prenatal glucocorticoids and long-term programming. Eur J Endocrinol 2004;151:U49–U62. Seckl JR. Glucocorticoids, feto-placental 11b-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease. Steroids 2007;62: 89–94. Seckl JR, Walker BR. 11b-hydroxysteroid dehydrogenase type 1 – a tissue-specific amplifier of glucocorticoid action. Endocrinology 2001;142:1371–1376. Seckl JR, Meaney MJ. Glucocorticoid programming. Ann N Y Acad Sci 2004;1032:63– 84. Seckl JR, Benediktsson R, Lindsay RS, Brown RW. Placental 11b-hydroxysteroid dehydrogenase and the programming of hypertension. J Steroid Biochem Mol Biol 1995;55:447–455. Segar JL, Roghair RD, Segar EM, Bailey MC, Scholz TD, Lamb FS. Early gestation dexamethasone alters baroreflex and vascular responses in newborn lambs before hypertension. Am J Physiol Regul Integr Comp Physiol 2006;291:R481–R488. Schoneveld OJ, Gaemers IC, Lamers WH. Mechanisms of glucocorticoid signalling. Biochim Biophys Acta 2004;1680:114–128. Shams M, Kilby MD, Somerset DA, Howie AJ, Gupta A, Wood PJ, Afnan M, Stewart PM. 11b-hydroxysteroid dehydrogenase type 2 in human pregnancy and reduced expression in intrauterine growth restriction. Hum Reprod 1998;13:799–804. Sharkey A. Cytokines and implantation. Rev Reprod 1998;3:52–61. Sheppard KE, Funder JW. Equivalent affinity of aldosterone and corticosterone for type I receptors in kidney and hippocampus: direct binding studies. J Steroid Biochem 2001;28:737–742. Shimojo M, Stewart PM. Apparent mineralocorticoid excess syndromes. J Endocrinol Invest 1995;18:518– 532. Shoener JA, Baig R, Page KC. Prenatal exposure to dexamethasone alters hippocampal drive on hypothalamic-pituitary-adrenal axis activity in adult male rats. Am J Physiol Regul Integr Comp Physiol 2006;290:R1366– R1373. Sloboda DM, Newnham JP, Challis JR. Effects of repeated maternal betamethasone administration on growth and hypothalamicpituitary-adrenal function of the ovine fetus at term. J Endocrinol 2000;172:79–91. Sloboda DM, Moss TJ, Gurrin LC, Newnham JP, Challis JR. The effect of prenatal betamethasone administration on postnatal ovine hypothalamic-pituitary-adrenal function. J Endocrinol 2002;172:71– 81. Smith R, Nicholson RC. Corticotrophin releasing hormone and the timing of birth. Front Biosci 2007;12:912– 918. Smith MA, Thomford PJ, Mattison DR, Slikker W, Jr. Transport and metabolism of dexamethasone in the dually perfused human placenta. Reprod Toxicol 1988;2:37 –43. Smith RE, Salamonsen LA, Komesaroff PA, Li KXZ, Myles KM, Lawrence M, Krozowski Z. 11b-Hydroxysteroid dehydrogenase type II in the human endometrium: localization and activity during the menstrual cycle. J Clin Endocrinol Metab 1997;82:4252–4257. Speirs HJ, Seckl JR, Brown RW. Ontogeny of glucocorticoid receptor and 11b-hydroxysteroid dehydrogenase type-1 gene expression identifies potential critical periods of glucocorticoid susceptibility during development. J Endocrinol 2004;181:105– 116. Srisuparp S, Strakova Z, Fazleabas AT. The role of chorionic gonadotropin (CG) in blastocyst implantation. Arch Med Res 2001;32:627–634. Staud F, Mazancova K, Miksik I, Pavek P, Fendrich Z, Pacha J. Corticosterone transfer and metabolism in the dually perfused rat placenta: effect of 11b-hydroxysteroid dehydrogenase type 2. Placenta 2006;27:171–180. Staun-Ram E, Shalev E. Human trophoblast function during the implantation process. Reprod Biol Endocrinol 2005;3:56. Stevens VC. Human chorionic gonadotrophin: properties and potential immunological manipulation for clinical application. Clin Obstet Gynaecol 1979;6:549– 566. Stewart PM, Corrie JE, Shackleton CH, Edwards CR. Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle. J Clin Invest 1988;82:340–349. Stewart PM, Murray BA, Mason JI. Type 2 11b-hydroxysteroid dehydrogenase in human fetal tissues. J Clin Endocrinol Metab 1994;78:1529–1532. Stewart PM, Rogerson FM, Mason JI. Type 2 11b-hydroxysteroid dehydrogenase messenger ribonucleic acid and activity in human placenta and fetal membranes: its relationship to birthweight and putative role in fetal adrenal steroidogenesis. J Clin Endocrinol Metab 1995;80:885–890. Struwe E, Berzl GM, Schild RL, Beckmann MW, Dorr HG, Rascher W, Dotsch J. Simultaneously reduced gene expression of cortisol-activating and cortisol-inactivating enzymes in placentas of small-for-gestational-age neonates. Am J Obstet Gynecol 2007;197:43e.1– 43e.6. Sugden MC, Langdown ML, Munns MJ, Holness MJ. Maternal glucocorticoid treatment modulates placental leptin and leptin receptor expression and materno-fetal leptin physiology during late pregnancy, and elicits hypertension associated with hyperleptinaemia in the early-growthretarded adult offspring. Eur J Endocrinol 2001;145:529– 539. Sun K, Myatt L. Enhancement of glucocorticoid-induced 11b-hydroxysteroid dehydrogenases type 1 expression by proinflammatory cytokines in cultured human amnion fibroblasts. Endocrinology 2003;144: 5568–5577. Sun M, Ramirez M, Challis JR, Gibb W. Immunohistochemical localization of the glucocorticoid receptor in human fetal membranes and decidua at term and preterm delivery. J Endocrinol 1996;149:243–248. Sun K, Yang K, Challis JRG. Differential expression of 11b-hydroxysteroid dehydrogenase types 1 and 2 in human placental and fetal membranes. J Clin Endocr Metab 1997a;82:300–305. Sun K, Yang K, Challis JRG. Differential regulation of 11b-hydroxysteroid dehydrogenase type 1 and 2 by nitric oxide in cultured human placental trophoblast and chorionic cell preparation. Endocrinology 1997b; 138:4912– 4920. Sun K, Yang K, Challis JR. Glucocorticoid actions and metabolism in pregnancy: implications for placental function and fetal cardiovascular activity. Placenta 1998a;19:353–360. Sun K, Yang K, Challis JRG. Regulation of 11b-hydroxysteroid dehydrogenase type 2 by progesterone, estrogen, and the cyclic adenosine 50 -monophosphate pathway in cultured human placental and chorionic trophoblasts. Biol Reprod 1998b;58:1379–1384. Sun K, He P, Yang K. Intracrine induction of 11b-hydroxysteroid dehydrogenase type 1 expression by glucocorticoid potentiates

515

Michael and Papageorghiou
prostaglandin production in the human chorionic trophoblast. Biol Reprod 2002;67:1450–1455. Sun K, Ma R, Cui X, Campos B, Webster R, Brockman D, Myatt L. Glucocorticoids induce cytosolic phospholipase A2 and prostaglandin H synthase type 2 but not microsomal prostaglandin E synthase (PGES) and cytosolic PGES expression in cultured primary human amnion cells. J Clin Endocrinol Metab 2003;88:5564– 5571. Tangalakis K, Lumbers ER, Moritz KM, Towstoless MK, Wintour EM. Effect of cortisol on blood pressure and vascular reactivity in the ovine fetus. Exp Physiol 1992;77:709– 717. Tanswell AK, Worthingon D, Smith BT. Human amniotic membrane corticosteroid 11-oxidoreductase activity. J Clin Endocrinol Metab 1977;45:721–725. Tauber SC, Schlumbohm C, Schilg L, Fuchs E, Nau R, Gerber J. Intrauterine exposure to dexamethasone impairs proliferation but not neuronal differentiation in the dentate gyrus of newborn common marmoset monkeys. Brain Pathol 2006;16:209–217. Thomas FJ, Thomas MJ, Tetsuka M, Mason JI, Hillier SG. Corticosteroid metabolism in human granulosa-lutein cells. Clin Endocrinol (Oxf) 1998;48:509–513. Thompson A, Han VKM, Yang K. Spatial and temporal patterns of expression of 11b-hydroxysteroid dehydrogenase types 1 and 2 messenger RNA and glucocorticoid receptor protein in the murine placenta and uterus during late pregnancy. Biol Reprod 2002;67:1708–1718. Thompson A, Han VKM, Yang K. Differential expression of 11b-hydroxysteroid dehydrogenase types 1 and 2 mRNA and glucocorticoid receptor protein during mouse embryo development. J Ster Biochem Mol Biol 2004;88:367–375. Thurston LM, Norgate DP, Jonas KC, Gregory L, Wood PJ, Cooke BA, Michael AE. Ovarian modulators of type 1 11b-hydroxysteroid dehydrogenase (11bHSD) activity and intra-follicular cortisol:cortisone ratios correlate with the clinical outcome of IVF. Hum Reprod 2003;18:1603–1612. Timmerman M, Teng C, Wilkening RB, Chung M, Battaglia FC. Net amino acid flux across the fetal liver and placenta during spontaneous ovine parturition. Biol Neonate 2001;79:54–60. Trainer PJ. Corticosteroids and pregnancy. Sem Reprod Med 2002;20:375–380. Tremblay J, Hardy DB, Pereira LE, Yang K. Retinoic acid stimulates the expression of 11b-hydroxysteroid dehydrogenase type 2 in human choriocarcinoma JEG-3 cells. Biol Reprod 1999;60:541–545. Ulick S, Levine LS, Gunczler P, Zanconato G, Ramirez LC, Rauh W, Rosier A, Bradlow HL, New MI. A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. J Clin Endocrinol Metab 1979;49:757– 764. Uno H, Eisele S, Sakai A, Shelton S, Baker E, DeJesus O, Holden J. Neurotoxicity of glucocorticoids in the primate brain. Horm Behav 1994;28:336–348. Urban R, Lemancewicz A, Przepiesc J, Urban J, Kretowska M. Antenatal corticosteroid therapy: a comparative study of dexamethasone and betamethasone effects on fetal Doppler flow velocity waveforms. Eur J Obstet Gynecol Reprod Biol 2005;120:170–174. van Beek JP, Guan H, Julan L, Yang K. Glucocorticoids stimulate the expression of 11b-hydroxysteroid dehydrogenase type 2 in cultured human placental trophoblast cells. J Clin Endocrinol Metab 2004;89:5614–5621. van der Burg B, van der Saag PT. Nuclear factor-kappa-B/steroid hormone receptor interactions as a functional basis of anti-inflammatory action of steroids in reproductive organs. Mol Hum Reprod 1996;2:433–438. van Runnard Heimel PJ, Schobben AF, Huisjes AJ, Franx A, Bruinse HW. The transplacental passage of prednisolone in pregnancies complicated by early-onset HELLP syndrome. Placenta 2005;26:842– 845. Vassalli JD, Sappino AP, Belin D. The plasminogen activator/plasmin system. J Clin Invest 1991;88:1067– 1072. Waddell BJ, Benediktsson R, Brown RW, Seckl JR. Tissue-specific messenger ribonucleic acid expression of 11b-hydroxysteroid dehydrogenase types 1 and 2 and the glucocorticoid receptor within rat placenta suggests exquisite local control of glucocorticoid action. Endocrinology 1998;139:1517– 1523. Waddell BJ, Hisheh H, Dharmarajan AM, Burton PJ. Apoptosis in rat placenta is zone-dependent and stimulated by glucocorticoids. Biol Reprod 2000;63:1913–1917. Wadhwa PD, Porto M, Garite TJ, Chicz-DeMet A, Sandman CA. Maternal corticotropin-releasing hormone levels in the early third trimester predict length of gestation in human pregnancy. Am J Obstet Gynecol 1998;179:1079– 1085. Walker BR, Aggarwal I, Stewart PM, Padfield PL, Edwards CR. Endogenous inhibitors of 11b-hydroxysteroid dehydrogenase in hypertension. J Clin Endocrinol Metab 1995;80:529–533. Ward JW, Wooding FB, Fowden AL. Ovine feto-placental metabolism. Placenta 2002;23:451–458. Ward JW, Wooding FB, Fowden AL. Ovine feto-placental metabolism. J Physiol 2004;554:529– 541. Ward JW, Forhead AJ, Wooding FB, Fowden AL. Functional significance and cortisol dependence of the gross morphology of ovine placentomes during late gestation. Biol Reprod 2006;74:137– 145. Weisbart M, Huntley FM. The presence of cortisol receptors in the human amnion. J Ster Biochem Mol Biol 1997;63:339–344. Welberg LAM, Seckl JR. Prenatal stress, glucocorticoids and the programming of the brain. J Neuroendocrinol 2001;13:113–128. Welberg LA, Seckl JR, Holmes MC. Inhibition of 11b-hydroxysteroid dehydrogenase, the foeto-placental barrier to maternal glucocorticoids, permanently programs amygdala GR mRNA expression and anxiety-like behaviour in the offspring. Eur J Neurosci 2000;12:1047– 1054. Welberg LAM, Seckl JR, Holmes MC. Prenatal glucocorticoid programming of brain corticosteroid receptors and corticotrophin-releasing hormone: possible implications for behaviour. Neuroscience 2001;104:71– 79. White PC, Mune T, Agarwal AK. 11b-Hydroxysteroid dehydrogenase and the syndrome of apparent mineralcorticoid excess. Endocr Rev 1997;18: 135–156. Whittle WL, Holloway AC, Lye SJ, Gibb W, Challis JR. Prostaglandin production at the onset of ovine parturition is regulated by both estrogen-independent and estrogen-dependent pathways. Endocrinology 2000;141:3783–3791. Whittle WL, Patel FA, Alfaidy N, Holloway AC, Fraser M, Gyomorey S, Lye SJ, Gibb W, Challis JR. Glucocorticoid regulation of human and ovine parturition: the relationship between fetal hypothalamic-pituitaryadrenal axis activation and intrauterine prostaglandin production. Biol Reprod 2001;64:1019– 1032. Whorwood CB, Firth KM, Budge H, Symonds ME. Maternal undernutrition during early to midgestation programs tissue-specific alterations in the expression of the glucocorticoid receptor, 11b-hydroxysteroid dehydrogenase isoforms, and type 1 angiotensin II receptor in neonatal sheep. Endocrinology 2001;142:2854–2864. Wilson RC, Nimkam S, New MI. Apparent mineralocorticoid excess. Trends Endocrinol Metab 2001;12:104–111. Wintour EM, Alcorn D, McFarlane A, Moritz K, Potocnik SJ, Tangalakis K. Effect of maternal glucocorticoid treatment on fetal fluids in sheep at 0.4 gestation. Am J Physiol 1994;266:R1174– R1181. Wintour EM, Moritz KM, Johnson K, Ricardo S, Samuel CS, Dodic M. Reduced nephron number in adult sheep, hypertensive as a result of prenatal glucocorticoid treatment. J Physiol 2003;549:929– 935. Wirbelauer J, Schmidt B, Klingel K, Cao L, Lang F, Speer CP. Serum and glucocorticoid-inducible kinase in pulmonary tissue of preterm fetuses exposed to chorioamnionitis. Neonatology 2007;93:257– 262. Woods LL, Weeks DA. Prenatal programming of adult blood pressure: role of maternal corticosteroids. Am J Physiol Regul Integr Comp Physiol 2005;289:R955– R962. Xiao DL, Huang XH, Bae S, Ducsay CA, Zhang L. Cortisol-mediated potentiation of uterine artery contractility: effect of pregnancy. Am J Physiol Heart Circ Physiol 2002;283:H238–H246. Xiao DL, Huang XH, Pearce WJ, Longo LD, Zhang L. Effect of cortisol on norepinephrine-mediated contractions in ovine uterine arteries. Am J Physiol Heart Circ Physiol 2003;284:H1142–H1151. Xu B, Makris A, Thornton C, Hennessy A. Glucocorticoids inhibit placental cytokines from cultured normal and preeclamptic placental explants. Placenta 2005;26:654–660. Yang K. Co-expression of two distinct isoforms of 11b-hydroxysteroid dehydrogenase in the ovine placenta. J Steroid Biochem Mol Biol 1995;52:337– 343. Yang K. Placental 11 beta-hydroxysteroid dehydrogenase: barrier to maternal glucocorticoids. Rev Reprod 1997;2:129– 132. Yang K, Langlois DA, Campbell LE, Challis JRG, Krkosek M, Yu M. Cellular localization and developmental regulation of 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) gene expression in the ovine placenta. Placenta 1997;18:503– 509. Yang K, Hardy DB, Doumouras MA, van Beek JP, Rocha E. ATP stimulates human placental 11b-hydroxysteroid dehydrogenase type 2 activity by a novel mechanism independent of phosphorylation. J Cell Biochem 2002;84:295– 300.

516

Glucocorticoids and early pregnancy
Yang K, Julan L, Rubio F, Sharma A, Guan H. Cadmium reduces 11b-hydroxysteroid dehydrogenase type 2 activity and expression in human placental trophoblast cells. Am J Physiol Endocrinol Metab 2006;290:E135–E142. Yang Z, Guo C, Zhu P, Li W, Myatt L, Sun K. Role of glucocorticoid receptor and CCAAT/enhancer-binding protein a in the feed-forward induction of 11b-hydroxysteroid dehydrogenase type 1 expression by cortisol in human amnion fibroblasts. J Endocrinol 2007;195:241– 253. Zakar T, Hirst JJ, Mijovic JE, Olson DM. Glucocorticoids stimulate the expression of prostaglandin endoperoxide H synthase-2 in amnion cells. Endocrinology 1995;136:1610– 1619. Zhang Q, Collins V, Chakrabarty K, Wolf RF, Unno N, Howe D, Rose JC, Wu WX. Regulation of membrane-associated prostaglandin E2 synthase 1 in pregnant sheep intrauterine tissues by glucocorticoid and estradiol. Endocrinology 2006;147:3719–3726. Zhou M-Y, Gomez-Sanchez EP, Cox DL, Cosby D, Gomez-Sanchez CE. Cloning, expression and tissue distribution of the rat nicotinamide adenine dinucleotide-dependent isoform of 11b-hydroxysteroid dehydrogenase. Endocrinology 1995;136:3729–3734. Submitted on December 13, 2007; resubmitted on April 11, 2008; accepted on April 24, 2008

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