CRH-stimulated oxytocin in patients with hypopituitarism and hypothalamic damage: A randomized, single-blind, crossover, placebo-controlled trial

Roca Queralt Asla; Sanchez Maite Garrido; Rull Eulalia Urgell; Molina Silvia Terzan; Vives Alicia Santos; Miro Merce Fernandez; Nimmy Varghese; Cihan Atila; Anna Calabrese; Betina Biagetti; Mirjam Christ-Crain; Anne Eckert; Susan M Webb; Elizabeth A Lawson; Maso Ana Aulinas

doi:10.1530/endoabs.99.RC5.5

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Endocrine Abstracts (2024) 99 RC5.5 | DOI: 10.1530/endoabs.99.RC5.5

ECE2024 Rapid Communications Rapid Communications 5: Pituitary and Neuroendocrinology | Part I (8 abstracts)

CRH-stimulated oxytocin in patients with hypopituitarism and hypothalamic damage: A randomized, single-blind, crossover, placebo-controlled trial

Queralt Asla Roca ^1,2,3 , Maite Garrido Sánchez ⁴ , Eulàlia Urgell Rull ^2,5 , Silvia Terzan Molina ⁵ , Alicia Santos Vives ^2,6 , Mercè Fernández Miró ⁷ , Nimmy Varghese ^8,9 , Cihan Atila ^10,11 , Anna Calabrese ¹² , Betina Biagetti ¹³ , Mirjam Christ-Crain ^10,11 , Anne Eckert ^8,9 , Susan M Webb ^2,6,14 , Elizabeth A Lawson ^15,16 & Ana Aulinas Maso ^1,2,3,6

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¹Hospital de la Santa Creu i Sant Pau, Endocrinology and Nutrition, Barcelona, Spain; ²Institut de Recerca - Hospital Santa Creu i Sant Pau, Barcelona, Spain; ³University of Vic, Department of Medicine, Vic, Spain; ⁴Institut de Recerca Sant Pau (IR-SANTPAU), CIM, Barcelona, Spain; ⁵Hospital de la Santa Creu i Sant Pau, Biochemistry, Barcelona, Spain; ⁶ISCIII, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unit 747), Majadahonda, Spain; ⁷Hospital Dos de Maig, Endocrinology and Nutrition, Barcelona, Spain; ⁸Universität Basel, Research Cluster Molecular and Cognitive Neurosciences, Basel, Switzerland; ⁹University Psychiatric Clinics Basel, Neurobiology Lab for Brain Aging and Mental Health, Basel, Switzerland, ¹⁰Universitätsspital Basel, Endocrinology, Diabetology and Metabolism, Basel, Switzerland, ¹¹Universität Basel, Department of Clinical Research, Basel, Switzerland, ¹²University of Turin, Internal Medicine, Department of Clinical and Biological Sciences, S. Luigi Hospital, Torino, Italy, ¹³Vall d’Hebron University Hospital, Endocrinology and Nutrition, Barcelona, Spain, ¹⁴Universitat Autònoma de Barcelona, Department of Medicine, Bellaterra, Spain, ¹⁵Massachusetts General Hospital, Neuroendocrine Unit, Boston, United States, ¹⁶Harvard Medical School, Department of Medicine, Boston, United States

Introduction: Disruption of the hypothalamic/pituitary axes may lead to hypopituitarism. Anterior pituitary deficiencies (APD) and arginine-vasopressin deficiency (AVP-D) are well established and are treated with hormone replacement. Over the last decade, preliminary studies support the presence of an oxytocin (OXT)-deficient state that might be clinically relevant in patients with hypopituitarism and hypothalamic damage (HHD). Therefore, identifying a provocative test to diagnose an OXT deficiency will be important. The corticotropin-releasing hormone (CRH) – commonly used for the differential diagnosis of ACTH-dependent Cushing’s syndrome – is a promising candidate for such a test as it increases peripheral OXT secretion in animal models. This study aimed at examining the effects of CRH on endogenous OXT release in patients with HHD compared to healthy controls (HC). We hypothesized that OXT release after CRH would be lower in patients with HHD compared to HC.

Methods: This single-blind, randomized, placebo-controlled proof-of-concept study (NCT 04902235) with crossover assignment (CRH:placebo) was conducted at an academic medical center. Nineteen patients with HHD (10 females) and 20 HC (11 females) completed two main visits. We randomly assigned participants to receive either CRH (1.0 µg/kg) or placebo (0.9% normal saline) in the first visit. After a washout of ≥48 h participants received the alternative treatment. Fasting AM samples were collected over 120 minutes (T0, T15, T30, T45, T60, T90, T120) to assess OXT levels. The primary outcome was the change in OXT levels over time in response to CRH vs placebo in patients with HHD and HC. We used three-way ANOVA (factors treatment*participant*time) to evaluate the effects of CRH on OXT levels.

Results: Participants were balanced by age (median (IQR) 50.3 (22.8) years) and body mass index (27.5(5.6) kg/m²). HHD had more depression symptoms, alexithymia and impulsivity (all P<0.05), as well as worse quality of life (P<0.001) and sexual function (P<0.025) compared to HC; 80% of patients with HHD presented with ≥3 APD and 75% had AVP-D. Baseline OXT concentrations were similar across groups (P=0.822). CRH administration did not impact OXT levels across groups over time, three-way interaction was not significant (P=0.524). No significant differences in OXT levels overtime were observed in the subgroup of patients with HHD and AVP-D compared to those without AVP-D.

Conclusion: The response of OXT after CRH administration does not seem sufficient for CRH to be pursued as a provocative test to diagnose an OXT-deficient state in HHD. The identification of a safe and feasible provocative test is required.