The hypothalamo-pituitary-adrenal (HPA) axis is hyporesponsive during late
pregnancy to emotional, physical and metabolic signals. This is due to reduced
responsiveness of the parvocellular paraventricular nucleus (pPVN) corticotrophin
releasing hormone (CR11) and arginine vasopressin (AVP) neurones. Major
adjustments in metabolic regulation during late pregnancy will help ensure a
successful outcome. These include increased appetite and reduced energy
expenditure during exposure to a stress, to which reduced neuroendocrine stress
responses may contribute. Glucocorticoids have a key role in mobilising energy in
response to acute stress, and have longer-term actions in the regulation of fat storage.
investigated the relationship between the HPA axis and endocrine factors relating to
adipose tissue storage and appetite regulation during late pregnancy in rats. The
responsiveness of the hypothalamic neurones regulating ACTH and hence
corticosterone responses to insulin induced hypoglycaemia (IIH) and the orexigenic
peptides NPY, orexin and ghrelin was investigated with particular focus on the
mechanisms involved in restraining these responses during late pregnancy.
IIH increased ACTH secretion similarly in both virgin and pregnant rats. Unlike
most stressors IIH did not stimulate parvocellular CRH mRNA expression in pPVN
neurones but it did increase AVP mRNA expression.
The responsiveness of the HPA axis to the orexigenic peptides ghrelin, orexin and
NPY given by i.e.v. injection was markedly reduced during late pregnancy. This was
at least partly a result of reduced activation of the pPVN neurones, as revealed by
reduced stimulation of Fos expression in the pPVN compared with virgin rats given
these peptides. ACTH secretory responses were also strongly attenuated in late
pregnant rats. In contrast all three orexigenic peptides increased food intake to a
similar level in both virgin and pregnant rats. Thus neuroendocrine stress responses
to central administration of orexin, NPY and ghrelin are absent during late pregnancy
whilst ingestive behavioural responses remain intact. Changes in brain circuitry
regulating appetite during late pregnancy were shown by increased Fos activation in
the lateral hypothalamic area (LPIA), ventromedial hypothalamus (VMH) and
dorsomedial hypothalamus (DMH). Supraoptic and magnocellular PVN oxytocin
responses to centrally administered NPY were reduced during late pregnancy.
Endogenous opioids are involved in the attenuation of HPA axis responses to orexin
and NPY during late pregnancy since pre-treatment with the opioid receptor
antagonist naloxone reinstated the ACTH response and restored CRH and AVP
mRNA responses. Naloxone administration revealed that endogenous opioids
facilitate NPY-induced feeding in both virgin and late pregnant rats, but more
importantly in late pregnant rats. Naloxone restored a Fos response in the PVN and
SON in response to NPY in late pregnant rats indicating that oxytocin neurone
responses to NPY are suppressed by endogenous opioids.
Basal blood glucose levels were lower in late pregnant rats than in virgins. Ghrelin
increased blood glucose levels similarly in both virgin and pregnant rats, whilst NPY
and orexin increased blood glucose in only the virgin rats.
In conclusion, neuroendocrine stress responses to orexin, ghrelin and NPY are
reduced in pregnant rats, and this was shown for orexin and NPY to be due to
endogenous opioid restraint. Endogenous opioid mechanisms have opposite effects
on neuroendocrine stress responses and feeding, which will enhance energy
availability for the fetuses at this time. Intact FIPA axis responses to IIH will ensure
continued glucose supply.