European Journal of Obstetrics & Gynecology and Reproductive Biology
Gene expression patterns of the 11β-hydroxysteroid dehydrogenase 2 enzyme in human placenta from intrauterine growth restriction: the role of impaired feto-maternal glucocorticoid metabolism
Introduction
Intrauterine growth restriction (IUGR) is defined as fetal birthweight at or below the tenth percentile for sex and gestational age [1]. IUGR may result from placental dysfunction, fetal malformation, intrauterine infection or maternal factors. Although the most common etiology for IUGR is thought to be placental dysfunction, its pathology at molecular level remains largely unknown [2], [3]. IUGR is a risk factor for several chronic disorders in adult life, including coronary syndromes, diabetes, and hypertension [4]. According to the concept of fetal programming, these chronic disorders can originate from impaired intrauterine development. Glucocorticoid exposure is thought to be prominent in fetal programming [5], [6].
Both isoenzymes (11β-HSD1; 11β-HSD2) of 11β-hydroxysteroid dehydrogenase (11β-HSD) are important in glucocorticoid metabolism [7] and they are both present in the human placenta. 11β-HSD1 is involved in the conversion of cortisol to cortisone by an NADP(H) dependent reversible process [8], [9]. Even though the enzyme action is bidirectional, under physiological circumstances its dominant function is to help the conversion of the inactive substance cortisone to the biologically active cortisol [10]. In contrast, 11β-HSD2 is an oxidase which is involved in the conversion of cortisol to cortisone in a unidirectional and NAD-dependent manner [11]. During pregnancy, 11β-HSD2 is involved in the development of the placental barrier, which has the basic function of limiting fetal exposure to maternal cortisol [12]. Thus, the main function of 11β-HSD2 is to protect the fetus from the effects of the physiological increase of maternal glucocorticoids during pregnancy [13], [14], [15].
The decrease in transplacental glucocorticoid transport toward the end of pregnancy is an important factor in the normal development of the fetal hypothalamo–pituitary–adrenal axis [16]. The failure of this 11β-HSD2-dependent placental barrier function results in a higher maternal glucocorticoid exposure of the fetus, which increases the risk for IUGR [17], [18].
Previous studies revealed a reverse relationship between the placental level of 11β-HSD2 following delivery and body growth during the first year of life. During pregnancy the high maternal exposure to glucocorticoids leads to growth restriction in the fetus. Growth then accelerates postnatally due to a sudden cessation of the exposure [12]. This effect of glucocorticoid exposure on fetal growth is analogous to the pattern observed in immunosuppressive treatments with steroids in organ transplant recipients [19].
In this study, our primary aim was to describe gene expression patterns of 11β-HSD2 in human placenta from IUGR pregnancies. We also investigated changes in glucocorticoid metabolism in impending fetal asphyxia. As secondary aims, we assessed the relastionships between (1) 11β-HSD2 gene expression and fetal gender, (2) degree of growth restriction and gestational age, (3) gestational age and 11β-HSD gene expression, and (4) 11-βHSD2 gene expression and impending fetal asphyxia in both IUGR and normal pregnancies. Relevant clinical data were also assessed.
Section snippets
Materials and methods
We examined placentas from 101 pregnancies with intrauterine growth restriction treated at the Semmelweis University, Second Department of Gynecology and Obstetrics between January 1, 2010 and January 1, 2011. We compared placental gene expression patterns and clinical characteristics (see below) in the IUGR group to controls gained from 140 pregnancies without IUGR treated at our clinic in the same time period. Diagnosis of IUGR was made on the basis of a standard definition, i.e. birthweight
Results
In the IUGR group (n = 101), fetal gender distribution was 37 male and 64 female (male to female ratio 0.58). In the normal pregnancy group, the male to female ratio was 1.09 (73 males, and 67 females). Median maternal age in the IUGR group was 30.82 ± 4.34, not statistically different from the normal pregnancy group (31.45 ± 3.12, p > 0.05).
In the IUGR group, mean gestational weight gain was 10.9 kg, while in the control group it was 14.8 kg (p < 0.05). Similarly, in the IUGR group BMI increased by 4.0
Comment
In our series, female fetal gender was significantly higher in the IUGR group. There was also a significant difference between the IUGR group and the normal pregnancy group in both gestational weight gain and the degree of BMI change. Specifically, a less than average gestational weight gain (<12.5–13 kg) [1], [3] seemed to predict IUGR. The severity of IUGR was also affected by gestational weight gain, with the most severe form of IUGR (birthweight 0–5 percentile) being more common with either
Acknowledgements
I would like to acknowledge the significant contribution of my colleagues at the 1st and 2nd Department of Obstetrics and Gynecology Semmelweis University in making the study. I would also like to thank the participation of my colleagues at the Nagy Gén Diagnostics and Research Ltd.
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Progesterone partially recovers placental glucose transporters in dexamethasone-induced intrauterine growth restriction
2022, Reproductive BioMedicine OnlineCitation Excerpt :Maternal factors include disorders that result in hypoxia, such as coronary vascular disease and haematological disorders as well as respiratory problems. Another major cause of IUGR development is malfunction of the placental steroid barrier and increase in fetal glucocorticoid exposure (Bamfo and Odibo, 2011; Borzsonyi et al., 2012; Shams et al., 1998). Despite the side effects of glucocorticoids, they are used in clinics as an antenatal intervention for pregnancies with risk of preterm labour to prevent newborn respiratory distress syndrome (Crowther and Harding, 2003).
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2016, PlacentaCitation Excerpt :On the other hand, high levels of maternal blood cortisol may be harmful for the fetus. Indeed, stress during pregnancy is not only known to increase the mother's blood cortisol, it is also linked to a reduction in the expression and activity of the placental 11β-HSD2 [49,52,53], and is associated with fetal growth restriction [54,55], prematurity [56,57] and low birthweight [58,59]. In animal models the effect of PNMS is relatively straightforward to study compared to research in humans, as it is not ethically acceptable to induce stress in a pregnant woman and observe the impact on her child's development.
Regulation of glucocorticoid-related genes and receptors/regulatory enzyme expression in intrauterine growth restriction filial rats
2016, Life SciencesCitation Excerpt :During the 90s up to the 20th century, some scholars have put forward a hypothesis that decreasing the placenta 11β-Hsd2 expression can make the GC enter into the fetal body from the maternal body, causing the occurrence of IUGR and ensuing the risk of adult metabolic syndrome [1,13,21]. To date, a number of animal experiments and clinical investigations have confirmed this hypothesis, further demonstrating that the expression and activity of 11β-Hsd2 is lower in the placenta of a fetus with low birth weight, compared to a normal fetus [3,16,32,34]. In addition to 11β-Hsd2 in the placenta, 11β-Hsd2 in fetal tissues is also closely correlated to adult disease.
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