Identification and Clinical Relevance of an Oxytocin Deficient State (CRH 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, corticorelin hormone (CRH) has shown to increase OT release. This study is designed to evaluate oxytocin values after administration of CRH in adults (healthy volunteers and patients with hypopituitarism). The investigators hypothesize that OT response will be blunted following CRH 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 (CRH 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 (CRH 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: CRH 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 aminotransferase (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 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 CRH 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
Interventional Model Description: Single-blind, randomized, placebo-controlled proof-of-concept studies with a crossover assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CRH administration<br>Experimental: CRH administration | Drug: Experimental: CRH administration<br>* CRH at 1.0 µg/kg/body weight will be injected intravenously as a bolus over 30 seconds and samples will be collected over 2 hours (15 (T15), 30 (T30), 45 (T45), 60 (T60'), 90 (T90) and 120 (T120) minutes) after CRH:placebo administration to assess OT secretory patterns<br>|
| Placebo Comparator: Placebo administration<br>Control: Placebo administration | Drug: Control: Placebo administration<br>* Sodium Chloride 0.9% will be administered intravenously as a bolus over 30 seconds at equivalent volume than CRH administration (1.0 µg/kg/body weight)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in oxytocin concentration | Change in oxytocin concentration (pg/mL) after administration of 1.0 µg/kg/body weight of CRH 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) | Maximal change in oxytocin concentration (pg/mL) after administration of 1.0 µg/kg/body weight of CRH or 0.9% NaCl | Within the two hours after the injection | 
| Overall oxytocin secretion | Oxytocin area under the curve after administration of 1.0 µg/kg/body weight of CRH or 0.9% NaCl | Within the two hours after the injection | 
| Change in cortisol concentration (nmol/L) | Change in cortisol concentration (nmol/L) after administration of 1.0 µg/kg/body weight of CRH 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 adrenocorticotropic hormone (ACTH) values | Change in ACTH values (pmol/L) after administration of 1.0 µg/kg/body weight of CRH 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 | Correlation 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 | Correlation 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 | Correlation between Barratt Impulsiveness Scale (range from 30 to 120, higher scores indicate greater impulsivity) and baseline oxytocin concentration (pg/mL) | Baseline | 
| Alexithymia assessment | Correlation 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, panhypopituitarism, central diabetes insipidus, hypothalamus-pituitary diseases, cortisol, ACTH, corticorelin hormone