Abstract
PurposeLabor 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.MethodsUsing 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.ResultsCortisol–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.ConclusionLabor 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.
Highlights
Labor strongly influences the human placental transcriptome [1,2,3] and post-transcriptional modifications like the phosphorylation of central signaling nexus, e.g., mammalian target of rapamycin [4]
corticotropin-releasing hormone (CRH) further controls fetal organ maturation by regulating placental 11beta-hydroxy-steroid dehydrogenase type 2 (11β-HSD2/HSD11B2) expression, and inducing fetal adrenocorticotropic hormone (ACTH) release [12]. This comprises a feedback loop that essentially depends on the rate of materno-fetal cortisol transport, which in turn is limited by the enzymatic activity of placental 11β-HSD2 [9] converting cortisol (F) to cortisone (E) and corticosterone (B) to dehydrocorticosterone (A)
We analyzed the correlation of direct and indirect measures of 11β-HSD2 activity in placentas from spontaneous and C-section births
Summary
Labor strongly influences the human placental transcriptome [1,2,3] and post-transcriptional modifications like the phosphorylation of central signaling nexus, e.g., mammalian target of rapamycin (mTOR) [4] It is further associated with progressive oxidative stress consistent with ischemia–reperfusion injury and induces the release of angiogenic, proinflammatory cytokines and pro-apoptotic factors in the human placenta [3]. CRH further controls fetal organ maturation by regulating placental 11beta-hydroxy-steroid dehydrogenase type 2 (11β-HSD2/HSD11B2) expression, and inducing fetal adrenocorticotropic hormone (ACTH) release [12]. This comprises a feedback loop that essentially depends on the rate of materno-fetal cortisol transport, which in turn is limited by the enzymatic activity of placental 11β-HSD2 [9] converting cortisol (F) to cortisone (E) and corticosterone (B) to dehydrocorticosterone (A)
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