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Hypertensive Disorders of Pregnancy (HDsP) remain leading causes of maternal and perinatal morbidity and mortality. Growing evidence suggests the involvement of epigenetic factors, such as gene-specific and global DNA methylation changes, both in the etiology and as an effect of HDsP. In this study, we investigated the potential association between placental DNA methylation status in selected CpGs of HSD11B2 cortisol level controlling gene, RUNX3 tumor suppressor gene, and long interspersed nucleotide element-1 (LINE-1) repetitive elements and HDsP-preeclampsia (PE), gestational hypertension (GH), and chronic hypertension (CH). Methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ) were used to analyze placental DNA methylation. Plasma and urine cortisol and cortisone levels were measured using high performance liquid chromatography with fluorescence detection (HPLC-FLD), whereas serum progesterone level was determined by electrochemiluminescence immunoassay. The mean percentage of HSD11B2, RUNX3, and LINE-1 methylation was not altered in the placentas of patients with HDsP, as compared to the controls. However, among patients from PE, GH, and CH groups, several significant correlations were observed between the methylation status of HSD11B2, RUNX3, or LINE-1 and children's birth weight, gestational age at delivery, mother's age, and body mass index as well as hormones levels. These results indicate lack of association between methylation status of HSD11B2, RUNX3, or LINE-1 repetitive elements and HDsP. However, association of these parameters with some clinical variables may suggest the role of placental DNA methylation in fetal development and should be further explored.

ObjectivesThe aim of the study was to analyze the plasma and urinary cortisol (F) and cortisone (E) levels in normotensive and hypertensive pregnant women. The parameters known to reflect the function of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) were calculated to verify the changes in glucocorticoid balance over the course of gestational hypertension (GH) and pre-eclampsia (PE).Materials and MethodsThis retrospective case-control study included women in the third trimester of pregnancy, diagnosed with: GH (n = 29), PE (n = 26), or chronic hypertension (CH; n = 22). Normotensive women in their third trimester of pregnancy were also included (controls; n = 43). The plasma and urinary F and E levels were measured with the HPLC-FLD method. The 11β-HSD2 function was estimated by calculating the following ratios: plasma F/E and urinary free F to urinary free E (UFF/UFE). A statistical analysis was performed based on case-control structure.Results and DiscussionPE was characterized by lower plasma F levels (639.0 nmol/L), UFF/Cr levels (3.80 μg/mmol) and F/E ratio (3.46) compared with that of the controls (811.7 nmol/L, 6.28 μg/mmol and 5.19, respectively) with marked abnormalities observed in the changes of F/E and UFF/UFE ratios with advancing gestation. GH patients showed significant disparities in the urinary steroid profile with lower UFF/UFE ratio (0.330 vs. 0.401) compared with the normotensive controls and abnormal changes in the UFF/UFE throughout pregnancy. The observed tendency towards lower F/E and UFF/UFE ratios in PE and GH patients may reflect more intensive F metabolism over the course of those disorders. In the normal pregnancy group, the plasma F/E and UFF/UFE ratios tended to present inverse correlations with advancing gestation. This trend was much less marked in PE and GH patients, suggesting that the abnormalities in 11β-HSD2 functions progressed with the GA. The birth weights of neonates born from pre-eclamptic pregnancies were lower than those from uncomplicated pregnancies, although only when the babies were born prematurely. Children born at term to normotensive mothers or mothers suffering from PE had comparable birth weights.

Supplemental Digital Content is Available in the Text. Baseline mechanical pain threshold does not predict analgesic response to pregabalin in painful chemotherapy-induced peripheral neuropathy caused by docetaxel, paclitaxel, or oxaliplatin.

PurposeThe diminished function of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) was found in placentae from preeclamptic pregnancies. Here, we examine the overall maternal glucocorticoid balance in pregnancy-related hypertension. We aim to answer the question if the functions of primary enzymes involved in cortisol metabolism: 11β-HSD1 and 11β-HSD2 and 5-reductases (both 5α- and 5β) are altered in the course of hypertensive pregnancy.MethodsWe determined plasma and urinary cortisol and cortisone as well as their urinary tetrahydro- and allo-tetrahydrometabolites, both in free and conjugated forms in samples obtained from 181 Polish women in the third trimester of pregnancy. We compared steroid profiles in women with preeclampsia (PE), gestational hypertension (GH), chronic hypertension (CH) and in normotensives (controls).ResultsWe found significant differences in glucocorticoid balance in pregnancy-related hypertension. Plasma cortisol to cortisone was significantly lower in PE than in controls (3.00 vs. 4.79; p < 0.001). Increased function of renal 11β-HSD2 in PE and GH was manifested by significantly lower urinary free cortisol to cortisone ratio (0.169 and 0.206 vs. 0.277 in controls; p < 0.005). Markedly enhanced metabolism of cortisol was observed in pregnancy-related hypertension, with no significant alterations in CH, and the changes were more clearly expressed in PE than in GH.ConclusionsThe glucocorticoid balance in PE and GH is shifted towards decreasing cortisol concentration either due to intensified conversion to cortisone or enhanced production of tetrahydro and allo-tetrahydrometabolites.

Preeclampsia is a serious medical problem affecting the mother and her child and influences their health not only during the pregnancy, but also many years after. Although preeclampsia is a subject of many research projects, the etiology of the condition remains unclear. One of the hypotheses related to the etiology of preeclampsia is the deficiency in placental 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), the enzyme which in normal pregnancy protects the fetus from the excess of maternal cortisol. The reduced activity of the enzyme was observed in placentas from pregnancies complicated with preeclampsia. That suggests the overexposure of the developing child to maternal cortisol, which in high levels exerts proapoptotic effects and reduces fetal growth. The fetal growth restriction due to the diminished placental 11β-HSD2 function may be supported by the fact that preeclampsia is often accompanied with fetal hypotrophy. The causes of the reduced function of 11β-HSD2 in placental tissue are still discussed. This paper summarizes the phenomena that may affect the activity of the enzyme at various steps on the way from the gene to the protein.

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