Identification and Clinical Relevance of an Oxytocin Deficient State (GLP1 Study)

Study Overview
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Brief Summary
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Oxytocin (OT) is a hypothalamic peptide that enters the peripheral circulation via the posterior pituitary gland. OT plays a key role in regulating appetite, psychopathology, prosocial behavior and sexual function. Hypopituitarism is associated with increased obesity, increased psychopathology, sexual and prosocial dysfunction despite appropriate hormone replacement. A few studies suggest the existence of a possible OT deficient state in hypopituitarism. In animal models, glucagon-like peptide 1 (GLP1) has shown to increase OT release. This study is designed to evaluate OT values after administration of GLP1 in adults (healthy volunteers and patients with hypopituitarism). The investigators hypothesize that OT response will be blunted following GLP1 receptor agonist (GLP1-RA) in patients with hypopituitarism compared to healthy controls.

Detailed Description
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This research is focused on two groups of participants: healthy controls (HC) and hypopituitary patients (HYPO) with at least one symptom of hypothalamic damage, presumably at highest risk for OT deficiency. The aim is to improve knowledge on the physiology and patho-physiology of endogenous OT secretion in hypopituitary patients compared to healthy controls using a randomized, single-blind, crossover assignment (GLP1-RA vs placebo), placebo-control design. Clinical implications of secretory OT dynamics and release under different stimuli using validated questionnaires to evaluate psychopathology, socio-emotional functioning, disordered eating behavior, impaired quality of life and sexual dysfunction, will be also evaluated.

Official Title
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Identification and Clinical Relevance of an Oxytocin Deficient State: a Randomized, Crossover, Placebo-controlled, Proof-of-concept, Physiopathological Study (GLP1 Study)

Conditions
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Hypopituitarism, Central Diabetes Insipidus, Panhypopituitarism, Psychological Disorder, Social Isolation, Hypothalamic Diseases, Pituitary Diseases, Oxytocin Deficiency

Intervention / Treatment
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* Drug: Experimental: GLP1-RA (exenatide) administration
* Drug: Control: Placebo administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with hypopituitarism (HYPO) (>1 pituitary hormone deficiency) and stable hormone replacement for the prior three months At least one clinical sign of hypothalamic damage Female participants will be done in the early to midfollicular phase Exclusion Criteria: uncorrected hormone deficiency creatinine >1.5mg/dL alanine aminotransferase (ALT) or aspartate amino transferase (AST) >2.5x upper limit of normal hematocrit less than 30% suicidality or active psychosis participation in a trial with investigational drugs within 30 days using a high glucocorticoid dose Any type of diabetes mellitus Obese patients on GLP1-RA therapies vigorous physical exercise alcohol intake within 24 hours before the study participation evidence of any acute illness or any illness that the Investigator determines could interfere with study participation or safety pregnancy or breastfeeding for last 8 weeks known allergies towards GLP1-RA patients refusing or unable to give written informed consent Additionally for healthy controls: the presence of brain or pituitary tumor, radiation involving the hypothalamus or pituitary, history of hypopituitarism or receiving testosterone or glucocorticoids esters.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: GLP1-RA administration<br>A single dose of 10 mcg of GLP1-RA (exenatide) will be injected subcutaneously and samples will be collected over 2 hours (15 (T15), 30 (T30), 45 (T45), 60 (T60'), 90 (T90) and 120 (T120) minutes) after GLP1-RA:placebo administration to assess OT secretory patterns | Drug: Experimental: GLP1-RA (exenatide) administration<br>* a single dose of 10 mcg of GLP-RA (exenatide) will be administered subcutaneously and samples to assess OT secretory patterns will be collected over 2 hours<br>|
| Placebo Comparator: Control: Placebo administration<br>Sodium Chloride 0.9% will be administered subcutaneously at equivalent volume than GLP1-RA (exenatide) administration | Drug: Control: Placebo administration<br>* Sodium Chloride 0.9% will be administered subcutaneously at equivalent volume than 10 mcg of exenatide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in oxytocin concentration (pg/mL) | Change in oxytocin concentration (pg/mL) after administration of 10 µg of GLP1-RA (exenatide) or 0.9% sodium chloride (NaCl) | Baseline blood exam (timepoint 0) and further blood collections after 15, 30, 45, 60, 90 and 120 minutes after baseline blood collection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal change in oxytocin concentration (pg/mL) | Change in oxytocin concentration (pg/mL) after administration of 10 µg of GLP1-RA (exenatide) or 0.9% NaCl | Within the two hours after the injection | 
| Overall oxytocin secretion (pg/mL) | Oxytocin area under the curve after administration of 10 µg of GLP1-RA (exenatide) or 0.9% NaCl | Within the two hours after the injection | 
| Change in glucose concentration (mg/dL) | Change in glucose concentration (mg/dL) after administration of 10 µg of GLP1-RA (exenatide) or 0.9% NaCl | Baseline blood exam (timepoint 0) and further blood collections after 15, 30, 45, 60, 90 and 120 minutes after baseline blood collection | 
| Change in insulin concentration (pmol/L) | Change in insulin concentration (pmol/L) after administration of 10 µg of GLP1-RA (exenatide) or 0.9% NaCl | Baseline blood exam (timepoint 0) and further blood collections after 15, 30, 45, 60, 90 and 120 minutes after baseline blood collection | 
| Mood assessment | Association between Beck Depression Inventory-2 score (range from 0 to 63, higher scores mean a worse outcome) and baseline oxytocin concentration (pg/mL) | Baseline | 
| Quality of life assessment | Association between 36-item Short Form Health Survey score (range from 0 to 100, the higher scores indicate better health status) and baseline oxytocin concentration (pg/mL) | Baseline | 
| Impulsivity assessment | Association between Barratt Impulsiveness Scale (range from 30 to 120, higher scores indicate greater impulsivity) and baseline oxytocin concentration (pg/mL) | Baseline | 
| Alexithymia assessment | Association between Toronto Alexithymia scales-20 score (range from 20 to 100, higher scores mean a worse outcome) and baseline oxytocin concentration (pg/mL) | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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oxytocin, hypopituitarism, diabetes insipidus, hypothalamic-pituitary diseases, psychopathology, exenatide