Plasma Oxytocin Response to Oral Estrogens in Healthy Controls and AVP-Deficiency

Official title

Plasma Oxytocin in Response to Oral Estradiol Valerate and Ethinylestradiol in Healthy Controls and Patients With AVP-Deficiency

Overview

The PHOENIX study aims to investigate whether oral estradiol valerate (EV) and ethinylestradiol (EE) can stimulate oxytocin (OXT) and neurophysin-1 (NP-1) release in humans. The goal is to assess their potential as a safe diagnostic stimulation test for oxytocin deficiency, particularly in patients with arginine vasopressin (AVP) deficiency.

Detailed description

Oxytocin (OXT) and arginine vasopressin (AVP) are hypothalamic peptides involved in water balance and emotional regulation. Patients with AVP-Deficiency (central diabetes insipidus) often experience psychological symptoms such as anxiety and depressed mood, possibly due to coexisting OXT deficiency. Previous research showed that 3,4-Methylenedioxy-N-methylamphetamine (MDMA) can increase plasma OXT in healthy individuals but not in AVP-deficient patients, suggesting a clinically relevant OXT deficiency. However, the side effects of MDMA limit its clinical use as a diagnostic tool. Estrogen is known to stimulate OXT release via estrogen receptor β in the hypothalamus. This study evaluates whether oral estradiol valerate (EV) and ethinylestradiol (EE) can safely and effectively provoke OXT and NP-1 release, offering a potential alternative to MDMA-based tests.

The study consists of two parts:

Part 1 (Proof of Concept): A randomized, double-blind, cross-over trial in healthy adults to compare the stimulatory effects of EV and EE on plasma OXT and NP-1.

Part 2 (Pilot Study): An open-label trial in patients with AVP-Deficiency using the estrogen compound identified as most effective in Part 1, to determine whether OXT and NP-1 responses are blunted compared to healthy controls.

Interventions

• Drug estradiol valerate
  estradiol valerate
• Drug esthinylestradiol
  estradiol valerate

Primary outcome measures

• Relative Change in Plasma Oxytocin [Time frame: From baseline (0 min) to 300 minutes post-dose.]
• Relative Change in Neurophysin-1 [Time frame: From baseline (0 min) to 300 minutes post-dose.]

Secondary outcome measures (12)

• Area Under the Curve (AUC) for Plasma OXT and NP-1 [Time frame: From baseline (0 min) to 300 minutes post-dose.]
• Peak change in plasma OXT/NP-1 levels [Time frame: From baseline (0 min) to 300 minutes post-dose.]
• Time course of plasma OXT/NP-1 levels [Time frame: From baseline (0 min) to 300 minutes post-dose.]
• Changes in Coagulation Parameters: time course (von Willebrand factor) [Time frame: From baseline (0 min) to 300 minutes post-dose.]
• Changes in Coagulation Parameters: time course (Protein S) [Time frame: From baseline (0 min) to 300 minutes post-dose.]
• Changes in Coagulation Parameters: time course (D-dimer) [Time frame: From baseline (0 min) to 300 minutes post-dose.]
• Changes in Coagulation Parameters: time course (Factor VIII) [Time frame: From baseline (0 min) to 300 minutes post-dose.]
• Changes in Coagulation Parameters: time course (Fibrinogen) [Time frame: From baseline (0 min) to 300 minutes post-dose.]
• Changes in Coagulation Parameters: peak (von Willebrand factor) [Time frame: From baseline (0 min) to 300 minutes post-dose.]
• Changes in Coagulation Parameters: peak (Protein S) [Time frame: From baseline (0 min) to 300 minutes post-dose.]
• Changes in Coagulation Parameters: peak (D-dimer) [Time frame: From baseline (0 min) to 300 minutes post-dose.]
• Changes in Coagulation Parameters: peak (Factor VIII) [Time frame: From baseline (0 min) to 300 minutes post-dose.]

Eligibility criteria

Inclusion criteria

Part 1

• Adult healthy controls
• No medication (including hormonal contraception)
• Female patients (except post-menopausal): regular cycle (21-35 days of duration) in the last 6 months

Part 2

• Confirmed diagnosis of AVP-Deficiency
• Age ≥ 18 years
• Female patients (except post-menopausal): regular cycle (21-35 days of duration) in the last 6 months or in the case of hormone replacement therapy, with a 1-week pause from the respective treatment

Exclusion criteria

Part 1

• Participation in a trial with investigational drugs within 30 days
• BMI >30
• Age >50
• Illicit substance use (except for cannabis) during the last 30 days
• Consumption of alcoholic beverages >15 drinks/week
• Tobacco smoking >10 cigarettes/day
• Pregnancy and breastfeeding
• Hormonal contraception
• Migraine with and without aura
• Any cardiometabolic, cardiovascular, and hematological diseases (including deep vein thrombosis/pulmonary embolism and thrombophilia (DVT/PE))
• Active liver dysfunction or alanine aminotransferase (ALAT) or aspartate aminotransferase (ASAT) levels 2.5 times above the normal range
• Diagnosed chronic kidney disease (CKD) > grade III (GRF < 30ml/min)

Part 2

• Participation in a trial with investigational drugs within 30 days
• BMI >30
• Age >50
• Illicit substance use (except for cannabis) during the last 30 days
• Consumption of alcoholic beverages >15 drinks/week
• Tobacco smoking >10 cigarettes/day
• Pregnancy and breastfeeding
• Hormonal contraception
• Migraine with and without aura
• Any cardiometabolic, cardiovascular, and hematological diseases (including DVT/PE and Thrombophilia)
• Active liver dysfunction or alanine aminotransferase (ALAT) or aspartate aminotransferase (ASAT) levels 2.5 times above the normal range
• Diagnosed CKD > grade III (GRF < 30ml/min)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Crossover

Masking

Triple blind

Primary purpose

Diagnostic

Study locations

Switzerland · 1 center

• University Hospital Basel — Basel

Identifiers

NCT: NCT07361263 · 2025-02197;kt25ChristCrain5

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗