Plasma osmolality affects ACTH and cortisol regulation besides magnocellular vasopressin

The recently published article entitled "Disrupted ACTH and cortisol response to osmotic and non-osmotic stress in patients with arginine vasopressin deficiency," authored by Nikaj et al. evaluated the HPA axis response to osmotic and non-osmotic stimuli in patients with AVP deficiency (AVP-D) and with primary polydipsia (PP). Patients with AVP-D showed increased plasma ACTH and cortisol concentrations, in response to arginine stimulation, compared to patients with PP. The authors attributed altered ACTH and cortisol responses in AVP-D patients mainly to non-osmotic stress. However, PP patients may also show impaired osmolality and psychological comorbidities, which would be better assessed if there was a healthy control group in the study. We raised this aspect because data from our previous published study (Elias et al.), evaluating the interaction of plasma osmolality and plasma AVP, as well as plasma ACTH and cortisol responses to human CRH alone and combined with osmotic stimulus or isotonic volume loading in patients with AVP-D and healthy controls, showed a significant correlation between plasma osmolality and the ACTH response to hCRH across both healthy and AVP-D subjects during tests. Moreover, the enhanced ACTH and cortisol responses to hCRH with increasing pOsm were also observed in both healthy controls and patients with AVP-D. These findings suggest that the acute rise in plasma osmolality amplifies the ACTH and cortisol responses to hCRH, involving factors beyond magnocellular AVP. Importantly, Itagaki. et al. also demonstrated a positive correlation between plasma ACTH and plasma osmolality in AVP-D patients subjected to hypertonic saline infusion. In conclusion, while Nikaj. et al.'s study provides confirmation of the HPA axis activity in AVP-D patients, it seems unlikely that disruption of HPA axis regulation in these patients is due to impaired feedback regulation between AVP and CRH.