Oxytocin levels in response to CRH administration in hypopituitarism and hypothalamic damage: a randomized, crossover, placebo-controlled trial

Abstract

Increasing evidence supports the presence of oxytocin deficiency (OXT-D) in patients with hypopituitarism and hypothalamic damage (HHD), that might be associated with neuropsychological deficits and sexual dysfunction, leading to worse quality of life (QoL). Therefore, identifying a provocative test to diagnose an OXT-D will be important. Corticotropin-releasing hormone (CRH) is a candidate for such a test as it increases oxytocin secretion in animal models. This study aimed to examine the effects of CRH on oxytocin release in HHD compared to healthy controls (HC) and to describe the psychopathology, sexual function and QoL and their associations with oxytocin. This is a single-blind, randomized, placebo-controlled, proof-of-concept study (NCT04902235) with crossover assignment (CRH vs. placebo). Nineteen HHD patients (10 females) and 20 HC (11 females) completed two visits, receiving CRH or placebo in random order and completed validated questionnaires to assess psychopathology, sexual function and QoL. Samples were collected over 120 min to assess oxytocin. Linear mixed-effects regression model evaluated the change in oxytocin after CRH/placebo in HHD vs. HC. CRH administration did not impact oxytocin concentrations across groups over time (p = 0.97). HHD had greater psychopathology (most ps < 0.05), sexual dysfunction (p < 0.03) and worse QoL (p < 0.001) compared to HC, nevertheless, baseline oxytocin concentrations and area under the curve of oxytocin were not significantly associated with psychopathology, sexual function or QoL, neither in HHD or HC. In conclusion, CRH administration does not appear to be a suitable provocative test for diagnosing OXT-D in HHD. Identifying a reliable diagnostic test for OXT-D remains crucial. Alternative provocative tests or biomarkers should be explored.

Keywords: Arginine-vasopressin deficiency; Corticotropin-releasing hormone; Hypopituitarism; Hypothalamic damage; Oxytocin; Pituitary disease.

Fig. 1

Scheme of main study visits and procedures. HC, healthy controls; HHD, patients with hypopituitarism and hypothalamic damage, CRH corticotropin-releasing hormone; T, timepoint.

Fig. 2

Study flow diagram. HC, healthy controls; HHD, patients with hypopituitarism and hypothalamic damage, CRH corticotropin-releasing hormone; V1, visit 1 and V2; visit 2.

Fig. 3

Response of OXT concentrations over time (from T0 to T120) after CRH across groups (HHD vs. HC) expressed as mean and standard error of the mean. OXT, oxytocin; T; timepoint; HC, healthy controls; HHD, patients with hypopituitarism and hypothalamic damage, CRH corticotropin-releasing hormone.