European Journal of Obstetrics & Gynecology and Reproductive Biology
Abnormal fetomaternal glucocorticoid metabolism in the background of premature delivery: placental expression patterns of the 11β-hydroxysteroid dehydrogenase 2 gene
Introduction
Preterm delivery is defined as birth of an infant before the 37th gestational week. The occurrence of preterm delivery is 12–13% in the United States, 5–9% in Western Europe, and 9–10% in Hungary [1], [2]. Almost 75% of perinatal mortality and about half of long-term postnatal mortality is associated with preterm delivery [3]. Both genetic and environmental factors can play a role in preterm delivery. Due to the high heterogeneity of these factors, it is often difficult to identify the exact mechanism. Several epidemiological studies revealed the importance of genetic factors in the background of preterm deliveries [4], [5]. Among these, some studies point to the role of genes involved in cholesterol metabolism [5], infection and inflammation [6], [7].
It has been shown that both in the case of humans and in several animal species, glucocorticoids play a prominent role in fetal programming [8], [9]. The main tenet behind the concept of fetal programming is that susceptibility to certain diseases starting in adulthood may develop during the intrauterine phase.
Both isoenzymes (11β-HSD1; 11β-HSD2) of 11β-hydroxysteroid dehydrogenase (11β-HSD) are important in glucocorticoid metabolism [10] 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. 11β-HSD1 is primarily secreted by the chorionic membrane. 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 [11], [12], [13]. In contrast, 11β-HSD2 is an oxidase which is involved in the conversion of cortisol to cortisone in a unidirectional and NAD-dependent manner [14]. The enzyme is present in relatively high concentrations in the brain, kidney and spleen, but it is less abundant in the liver and in fat tissue. 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 [15], [16]. Thus, the main function of 11β-HSD2 is to protect the fetus from the effects of the physiological increase of maternal glucocorticoids during pregnancy [17], [18], [19].
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 [20]. The failure of this 11β-HSD2-dependent placental barrier function results in a higher maternal glucocorticoid exposure of the fetus, which increases the risk of intrauterine growth restriction. On the other hand, a low level exposure to maternal glucocorticoids is essential for intrauterine development of fetal organs [18], [21]. Impaired 11β-HSD2 enzyme activity is partly responsible for reduced birthweight after preterm delivery [22].
Amniotic 11β-HSD1 is involved in the induction of delivery through a feedback mechanism. Cortisol both stimulates prostaglandin production and inhibits prostaglandin breakdown. Through the former effect, it activates 11β-HSD1 [23]. During the course of normal pregnancy, the placental expression of 11β-HSD1 rises [24].
Preterm infants, especially those with very low birthweight, experience a greater exposure to maternal glucocorticoids before delivery. It is important to keep in mind that this excessive glucocorticoid exposure may be further affected by prophylactic steroids given to accelerate fetal lung maturation in cases of impending preterm delivery [25], [26].
In this study, our primary aim was to investigate gene expression patterns of the 11β-hydroxysteroid dehydrogenase isoenzyme 2 in placental samples obtained after preterm delivery. Secondary aims included the clarification of relationships between 11β-HSD2 gene expression and fetal gender as well as 11β-HSD2 gene expression and gestational age. Relevant clinical data were also assessed.
Section snippets
Patient population
Between January 1, 2010 and January 1, 2011 we examined placentas from 104 pregnancies that ended in preterm delivery at the Semmelweis University, Budapest. We compared placental gene expression patterns and several clinical characteristics (as described below) in the preterm delivery group to full term pregnancy controls gained from 140 normal pregnancies (without any pathological condition during the pregnancy) in the same time period. Preterm delivery was diagnosed on the basis of
Clinical data (Table 1)
In the preterm delivery group, distribution of fetal gender was as follows: 49 males, 55 females (M:F 0.89); in the control group 73 males, 67 females (M:F 1.09). Median maternal age in the preterm delivery group was 30.7 ± 5.20 years vs. 31.4 ± 3.12 years. Median gestational age at the time of preterm delivery was 32.8 ± 3.7 weeks. In the preterm delivery group gestational weight gain was found to be 11.6 ± 4.6 kg. Pre-gestational body mass index (BMI), which had been hypothesized to be a predictor of
Comments
Under physiological conditions, the placenta starts producing a great quantity of 11β-HSD2 toward the end of the gestational period. This helps in the development of a placental barrier, which defends the fetus from excessive maternal cortisol exposure [27]. Our results confirm those of Johnstone et al. [12], that in cases of preterm delivery, impaired function of this placental barrier due to decreased 11β-HSD2 gene activity may be an important etiological factor. Excessive glucocorticoid
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