Influence of labor on direct and indirect determinants of placental 11beta-hydroxysteroid dehydrogenase activity

Abstract

Purpose: Labor is a complex process involving multiple para-, auto- and endocrine cascades. The interaction of cortisol, corticotropin-releasing hormone (CRH) and progesterone is essential. The action of cortisol on the human feto-placental unit is regulated by 11beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2/HSD11B2) that converts cortisol into inactive cortisone. The majority of studies on the assessment of placental 11β-HSD2 function determined indirect activity parameters. It remains elusive if indirect measurements correlate with enzymatic function and if these parameters are affected by potential confounders (e.g., mode of delivery). Thus, we compared determinants of indirect 11β-HSD2 tissue activity with its direct enzymatic turnover rate in placental samples from spontaneous births and cesarean (C)-sections.

Methods: Using LC-MS/MS, we determined CRH, cortisol, cortisone, progesterone and 17-hydroxy(OH)-progesterone in human term placentas (spontaneous birth vs. C-section, n = 5 each) and measured the enzymatic glucocorticoid conversion rates in placental microsomes. Expression of HSD11B1, 2 and CRH was determined via qRT-PCR in the same samples.

Results: Cortisol-cortisone ratio correlated with direct microsomal enzymatic turnover. While this observation seemed independent of sampling site, a strong influence of mode of delivery on tissue steroids was observed. The mRNA expression of HSD11B2 correlated with indirect and direct cortisol turnover rates in C-section placentas only. In contrast to C-sections, CRH, cortisol and cortisone levels were significantly increased in placental samples following spontaneous birth.

Conclusion: Labor involves a series of complex hormonal processes including activation of placental CRH and glucocorticoid metabolism. This has to be taken into account when selecting human cohorts for comparative analysis of placental steroids.

Keywords: 11beta-hydroxysteroid dehydrogenase; CRH; LC–MS/MS; Mode of delivery; Placenta.

Fig. 1

Pearson correlation of direct and indirect measures of HSD11B2 activity. A Expected and observed Pearson correlation coefficients are presented for correlation of HSD11B2 mRNA expression (qRT-PCR), 11β-HSD2 activity directly measured by microsomal turnover and cortisol/cortisone ratios (LC–MS/MS). “+” represents a positive correlation, “−”a negative correlation. Pearson correlation coefficients of measures in placentas from spontaneous birth are marked red and those from cesarean section (C-section) black. B Dot blot diagrams are presented of spontaneous birth and C-section cases (n = 5 each), for measures of HSD11B2 mRNA and activity levels (a), HSD11B2 mRNA and cortisol/cortisone ratios (b) and 11β-HSD2activity and cortisol/cortisone ratios (c). Three placental samples per case were analyzed from different placental regions (central, medial, distal) and are represented by dots with matching color