Reduced Glucocorticoid Action in Obese Pregnancy is Associated with Increased Birthweight

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 72-87-HPA Axis
Basic
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-80
James Richard O'Reilly*1, Simon C Riley1, Hilary O D Critchley1, Maria Bowman2, Roger Smith2, Jane E Norman1, Brian R Walker1, Jonathan Robert Seckl1, Amanda Jane Drake1 and Rebecca M Reynolds1
1University of Edinburgh, Edinburgh, United Kingdom, 2Hunter Medical Research Institute, Australia
Background: Between 18 and 38% of US women are obese at antenatal booking. Maternal obesity increases risk of pregnancy complications including high birthweight. Glucocorticoids are key regulators of fetal growth and development and increased fetal exposure to glucocorticoids lowers birthweight. We therefore hypothesised that fetal exposure to glucocorticoids is decreased in maternal obesity with resultant increased birthweight. We compared glucocorticoid levels during pregnancy and placental glucocorticoid sensitivity in obese and lean women.

 Methods: Serum cortisol levels were measured at 16, 28 and 36 weeks gestation in n=173 class III obese (BMI 44.0±4.5kg/m2) and n=107 lean (BMI 22.8±1.6kg/m2) pregnant women. Serial corticosteroid binding globulin (CBG) and corticotrophin releasing hormone (CRH) concentrations were measured in a subset (n=39 lean, 26 obese). Free cortisol levels were calculated using Coolen’s equation. Salivary cortisol was measured in samples collected at bed-time, waking and 30 minutes after waking. 11b-hydroxysteroid dehydrogenase type 2 (11βHSD2), which inactivates cortisol, and glucocorticoid receptor (GR) mRNAs were measured in first trimester (n=34) and term (n=56) placental samples. DNA methylation of key regions controlling GR and 11βHSD2 expression was measured by pyrosequencing. Ethical approval and informed consent was obtained.

 Results: Cortisol, CRH and CBG levels were lower throughout pregnancy in obese women (all p<0.05). Cortisol levels rose similarly during pregnancy in both obese and lean groups and the diurnal rhythm of cortisol was maintained. CBG levels also increased during pregnancy, although this change was lower in obese (1.21-fold (±0.32) vs 1.56-fold (±0.38), p<0.01). In obese, lower free cortisol at 16 weeks gestation was associated with higher birthweight after adjustment for confounders (r=-0.46, p<0.05). Placental expression of 11βHSD2 increased in association with increasing obesity in early pregnancy (r=0.46, p<0.01) and was highest in term placentas in obese women with macrosomic (>4000g) offspring (p<0.05). Placental expression of GR also increased in association with increasing obesity in early pregnancy (r=0.45, p<0.01), but was lowest in term placenta from obese women with macrosomic offspring (p<0.05). Methylation of the 1C promoter of GRwas lower in placentas of macrosomic offspring of obese women compared to lean (p<0.05).

 Conclusions: The combination of lower CRH and CBG with associated lower circulating and bioavailable cortisol, together with a more effective placental barrier preventing maternal to fetal glucocorticoid transfer, may contribute to attenuated feto-placental glucocorticoid action and thus higher birthweight in the offspring of obese women.

Nothing to Disclose: JRO, SCR, HODC, MB, RS, JEN, BRW, JRS, AJD, RMR

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Tommy's , Sir Jules Thorn Charitable Trust, British Heart Foundation