The aim of this project was to investigate the possible mechanism(s) underlying the
attenuated hypothalamic-pituitary-adrenal (HPA) axis response to stressors during
pregnancy at the level of the anterior pituitary. We found that the reduced HPA axis
activity during pregnancy was not due to changes in the sensitivity of corticotrophs in
the anterior pituitary, but to the decreased secretion particularly of vasopressin and
possibly corticotropin-releasing hormone (CRH) from the hypothalamus. The reduced
CRH and vasopressin secretion during pregnancy is a result of action of neurosteroid
metabolites of progesterone as a 5a-reductase inhibitor reversed the attenuated
adrenocorticotrophic hormone (ACTH) secretory response to stress.
By in situ hybridisation, we found a progressive decrease in proopiomelanocortin
(POMC) mRNA expression in the anterior pituitary during pregnancy. However, there
was no change in ACTH content. Compared with expression in the anterior pituitary
of virgin rats, in late pregnancy (day 21), CRH receptor subtype 1 (CRHR1) mRNA
expression was not changed, vasopressin receptor subtype lb (VlbR) mRNA
expression was reduced, and glucocorticoid receptor (GR) mRNA was increased. We
also measured large conductance potassium channel (BK) and the splice variant of the
BK channel, STREX, mRNA expression and found no change during pregnancy.
Corticotropin-releasing hormone binding protein (CRHBP) mRNA expression was
elevated by 30 min restraint stress in the anterior pituitary, but there were no
differences between virgin and pregnant rats.
In vivo, a CRHR1 antagonist, antalarmin, decreased ACTH secretion in response to
swimming stress in both virgin and pregnant rats. However, a Vla/b receptor
antagonist decreased the ACTH response to this stressor in virgin rats only.
Exogenous vasopressin or CRH injection alone increased ACTH secretion more in
virgin than in pregnant rats. Injection of CRH and vasopressin together had a similar
stimulatory action on ACTH secretion in virgin and pregnant rats. Thus the attenuated
ACTH stress response during pregnancy is primarily a result of reduced vasopressin
secretion during stress.
To investigate whether corticotroph sensitivity to CRH and vasopressin is modulated
during pregnancy, we incubated anterior pituitary cells with different concentrations
of CRH, vasopressin, a combination of CRH and vasopressin, or cAMP. We found a
dose related augmentation of CRH stimulation of ACTH secretion by vasopressin.
The sensitivity of corticotrophs to CRH was greater in pregnancy and the
augmentation by vasopressin of the effects of a low concentration of CRH was greater
for corticotrophs from pregnant than from virgin rats. A greater effect of cAMP
suggests changes in post receptor signalling mechanisms in pregnancy.
GABAergic mechanisms inhibit the HPA axis via GABAa receptors on CRH
neurones and their inputs. Alloprcgnanolone, the neurosteroid metabolite of
progesterone, acts as a major GABAa receptor allosteric modifier, so enhancing the
action of GABA. To investigate such a possible enhanced GABAergic action by
allopregnanolone on CRH and vasopressin secretion during pregnancy, we prevented
the inhibitory action of the metabolic product of progesterone by blocking production
via 5a-reductase with 4-MA. 4-MA prevented the attenuated ACTH secretory
response to swimming stress in pregnant rats and had no effect directly on the
The reduced stress- induced ACTH response during pregnancy is predominantly the
consequence of reduced vasopressin release, with secondary changes in corticotrophs.
The central changes may be due to the inhibitory action of allopregnanolone on CRH
and vasopressin secretion from the hypothalamus.