There has been a global rise in obesity in the last three decades, and at present
one in five women are obese at antenatal booking. Maternal obesity is associated
with an increased risk of adverse pregnancy outcomes, including increased fetal
size and prolonged pregnancy. In the longer-term, offspring of obese are at
increased risk of premature death from a cardiovascular event in their adulthood.
One mechanism that has been linked to these outcomes is fetal exposure to
glucocorticoids in utero.
During normal pregnancy, the maternal hypothalamic pituitary adrenal (HPA)
axis undergoes major changes, resulting in exponentially increasing levels of the
major circulating glucocorticoid cortisol, and other HPA axis hormones, such as
corticotrophin releasing hormone (CRH). Cortisol and CRH are vital for normal
fetal growth and length of gestation, but in excess they are associated with fetal
growth restriction and preterm labour.
In non-pregnant obesity, it is thought that the HPA axis is dysregulated, although
evidence is inconclusive. Little is known about the effects of maternal obesity in
pregnancy on the HPA axis. The work in this Thesis used clinical studies to test
the hypothesis that the HPA axis is dysregulated in obese pregnant women with
altered release, clearance and placental metabolism of cortisol. Associations with
clinical outcomes related to fetal size and length of gestation were also studied.
The HPA axis activity during pregnancy was investigated in a prospective case-control
study cohort. Fasting serum cortisol levels were measured at 16, 28 and
36 weeks of gestation (obese n=276, lean n=135). In a subset (obese n=20, lean
n=20), corticosteroid binding globulin (CBG), CRH, estrogens and progesterone
were measured. Salivary cortisol was measured in samples collected at bedtime, waking and 30 minutes after waking at 16 weeks. Urinary glucocorticoid
metabolites were measured at 19 weeks and 36 weeks (obese n=6, lean n=5) and
non-pregnant (obese n=7, lean n=7) subjects. All circulating hormone levels rose
similarly in obese and lean during pregnancy, but were significantly lower in
obese women. The diurnal rhythm of cortisol was maintained. Urinary
glucocorticoids increased with gestation in lean, but not in obese, indicating a
lesser activation of the HPA axis in obese compared with lean pregnancy. These
findings associated with increased birthweight and longer gestation in obese
pregnancy, suggesting that decreased HPA axis activity may underlie these obese
related adverse pregnancy outcomes.
Whether or not lower glucocorticoids in obese pregnancies are maintained at
delivery was investigated by measuring active glucocorticoids (cortisol and
corticosterone) and their inactive versions (cortisone and 11-
dehydrocorticosterone, respectively) from matched maternal and cord plasma
samples (n=259, BMI 18 – 55 kg/m2). Active glucocorticoids were significantly
higher in maternal than cord blood, and inactive versions were significantly
higher in cord than maternal blood. Increased maternal BMI associated with
lower maternal cortisol, corticosterone and 11-dehydrocorticosterone. Despite
significant correlations between maternal and cord blood glucocorticoid levels,
increased maternal BMI did not associate with lower cord blood glucocorticoids.
This suggests that conditions at delivery may overcome any potential negative
effects of low maternal glucocorticoids on the fetus in the short-term. However,
it may not preclude the longer-term effects of fetal exposure to lower
glucocorticoid levels during obese pregnancy, and offspring follow-up studies
are required.
Potential mechanisms leading to altered HPA axis activity in obese pregnancy
were explored by studying the pulsatile release and placental metabolism of
glucocorticoid hormones. Glucocorticoid pulsatility is thought to be important
for transcriptional regulation of glucocorticoid responsive genes, and disruptions to pulsatility have been reported in some disease processes. Glucocorticoids were
measured in 10-minute serum sampling between 08.00h-11.00h and 16.00h-
19.00h. Peripheral tissue cortisol was measured from 20-minute sampling of
interstitial fluid, over 24-hours, at 16-24 weeks and 30-36 weeks (obese n=7,
lean n=8), and non-pregnant controls (obese n=4, lean n=3). Total circulating
serum cortisol levels were higher in pregnancy than non-pregnancy in lean and
obese, and increased significantly with advancing gestation in lean but not in
obese. Pulsatility of cortisol was demonstrated in interstitial fluid in both non-pregnancy
and pregnancy. In obese pregnancy, interstitial fluid pulse frequency
was lower with advancing gestation. This may be a novel mechanism underlying
the observed decreased HPA axis activity in obese pregnancy.
Placental cortisol metabolism and transport was studied using an ex vivo
placental perfusion model, perfused with a deuterium-labelled cortisol tracer
combined with computational modeling. The findings challenge the concept that
maternal cortisol diffuses freely across the placenta, but confirmed that 11β-
HSD2 acts as major ‘barrier’ to cortisol transfer to the fetus, protecting the fetus
from the high maternal circulating cortisol levels. In addition we showed
preliminary evidence of local cortisol production within the placenta. The model
is able to predict maternal-fetal cortisol transfer and can now be used in future
experimental design.
In conclusion, in obese pregnancy, lower maternal cortisol and urinary clearance
suggested reduced HPA axis activity. Altered glucocorticoid pulsatility may
underlie this change. Future studies of placental cortisol metabolism in maternal
obesity could be conducted using an ex vivo perfusion model. The lower HPA
axis activity in obese pregnancy represents a novel pathway underlying increased
fetal growth