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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Insipidus; AVP Deficiency
• Intervention / Treatment: Drug: estradiol valerate; Drug: esthinylestradiol

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.

• Study Type: Interventional
• Enrollment (Estimated): 28
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Andi Nikaj, MD; Phone Number: +41 61 328 57 43; Email: andi.nikaj@usb.ch
• Study Contact Backup: Name: Ursula Gobrecht-Keller, MD; Phone Number: +41 61 32 86028; Email: ursula.gobrecht@usb.ch

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • Recruiting
    • University Hospital Basel
    • Contact: Andi Nikaj, MD; Phone Number: +41 61 328 57 43; Email: andi.nikaj@usb.ch
    • Contact: Michelle Müller, MD; Phone Number: +41 61 328 55 23; Email: michelle.mueller@usb.ch
    • Sub-Investigator: Ursula Gobrecht-Keller, MD
    • Principal Investigator: Mirjam Christ-Crain, MD
    • Sub-Investigator: Andi Nikaj, MD
    • Sub-Investigator: Michelle Müller, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Part 1

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

Part 2

1. Confirmed diagnosis of AVP-Deficiency
2. Age ≥ 18 years
3. 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

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

Part 2

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: estradiol valerate	Drug: estradiol valerate; estradiol valerate
Experimental: esthinylestradiol	Drug: esthinylestradiol; estradiol valerate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative Change in Plasma Oxytocin	The primary endpoint is the relative change in plasma oxytocin (OXT) concentrations (pg/mL respectively pM) from baseline to the maximum observed value within 300 minutes after administration of oral estradiol valerate (EV) or ethinylestradiol (EE). Baseline is defined as 100% of the initial pre-dose concentration.	From baseline (0 min) to 300 minutes post-dose.
Relative Change in Neurophysin-1	The primary endpoint is the relative change in neurophysin-1 (NP-1) concentrations (pg/mL respectively pM) from baseline to the maximum observed value within 300 minutes after administration of oral estradiol valerate (EV) or ethinylestradiol (EE). Baseline is defined as 100% of the initial pre-dose concentration.	From baseline (0 min) to 300 minutes post-dose.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve (AUC) for Plasma OXT and NP-1		From baseline (0 min) to 300 minutes post-dose.
Peak change in plasma OXT/NP-1 levels		From baseline (0 min) to 300 minutes post-dose.
Time course of plasma OXT/NP-1 levels		From baseline (0 min) to 300 minutes post-dose.
Changes in Coagulation Parameters: time course (von Willebrand factor)	Time course and peak of coagulation marker von Willebrand factor	From baseline (0 min) to 300 minutes post-dose.
Changes in Coagulation Parameters: time course (Protein S)	Time course and peak of coagulation marker Protein S	From baseline (0 min) to 300 minutes post-dose.
Changes in Coagulation Parameters: time course (D-dimer)	Time course and peak of coagulation marker D-dimer	From baseline (0 min) to 300 minutes post-dose.
Changes in Coagulation Parameters: time course (Factor VIII)	Time course and peak of coagulation marker Factor VIII	From baseline (0 min) to 300 minutes post-dose.
Changes in Coagulation Parameters: time course (Fibrinogen)	Time course and peak of coagulation marker Fibrinogen	From baseline (0 min) to 300 minutes post-dose.
Changes in Coagulation Parameters: peak (von Willebrand factor)	Peak of coagulation marker von Willebrand factor	From baseline (0 min) to 300 minutes post-dose.
Changes in Coagulation Parameters: peak (Protein S)	Peak of coagulation marker Protein S	From baseline (0 min) to 300 minutes post-dose.
Changes in Coagulation Parameters: peak (D-dimer)	Peak of coagulation marker D-dimer	From baseline (0 min) to 300 minutes post-dose.
Changes in Coagulation Parameters: peak (Factor VIII)	Peak of coagulation marker Factor VIII	From baseline (0 min) to 300 minutes post-dose.
Changes in Coagulation Parameters: peak (Fibrinogen)	Peak of coagulation marker Fibrinogen	From baseline (0 min) to 300 minutes post-dose.
Changes in Other Endocrine Hormones	Time course of plasma estrogen, testosterone, copeptin, cortisol,Luteinizing Hormone/Follicle-Stimulating Hormone (LH/FSH), and other pituitary hormones.	From baseline (0 min) to 300 minutes post-dose.
Subjective Emotional Effects	Changes in subjective feelings assessed by Numeric Rating Scale (NRS). NRS will be repeatedly used to assess subjective alterations in consciousness over time. NRS will be presented as a range from 0 to 10 marked with "not at all" on the left and "extremely" on the right. The following NRS will be used: "any effect", "good effect", "bad effect", "liking", "high", "happy", "fear", "stimulated", "feeling close to others", "concentration", "thinking", "open", and "trust".	At baseline (0 min), 30, 60, 90, 120, 150, 180, 210, 240, 270 and 300 minutes and 24 hours post-dose.
Adverse effects	Participants will be asked to report any adverse events that occur during the sessions or between sessions at the start of the next session. The test requires about 2 minutes.	300 minutes post-dose.
List of complaints (LC)	The LC consists of 66 items, yielding a global score measuring physical and general discomfort. The LC list is administered at the beginning and the end of the session with reference to complaints throughout the entire session.	300 minutes post-dose.
Changes in anxiety assessed by State-Trait Anxiety Inventory (STAI-State and Trait).	This is a questionnaire given to adults to determine the general anxiety levels. Based on responses to 20 items, with scores ranging from 1 ("almost never") to 4 ("almost always"), a total score is calculated. The total trait score (STAI-T) ranges from 20 to 80, with higher scores indicating more pronounced anxiety and scores. The STAI-T evaluates relatively stable aspects of "anxiety proneness," including general states of calmness, confidence, and security. A score above 45/80 indicating clinically significant anxiety symptoms. The state score (STAI-S) evaluates the current state of anxiety, asking how respondents feel "right now," using items that measure subjective feelings of apprehension, tension, nervousness, worry, and activation/arousal of the autonomic nervous system. We will use the STAI-T for the baseline visit and the STAI-S for the treatment visits. The test requires about 5 minutes.	Baseline, 90 and 270 minutes post-dose.
Emotion Recognition Performance - EmBody/EmFace Task	The EmBody and EmFace subtasks comprise each of 42 stimuli showing body or facial expressions of angry, happy, or neutral affect (14 clips per emotion, half in front view and half in half-profile side view from the left). Stimuli last 1.5 seconds at 24 frames per second and are geometrically and optically standardized to prevent biases induced by ethnic cues (e.g., hair or skin tone) or clothing. Item order is pseudorandom to prevent sequence effects and was determined using the following constraints: the same emotion is shown no more than twice in a row; the same view per emotion is not shown consecutively (i.e., no angry-front, angry-front). The test is performed twice during each treatment visit.	Baseline and 270 minutes post-dose.
Emotion Recognition Performance - Face Recognition Task (FERT)	The FERT is used to assess recognition of basic emotions. The task includes 10 neutral faces and 160 faces that express one of four basic emotions (i.e., happiness, sadness, anger, and fear), with pictures morphed between 0% (neutral) and 100% in 10% steps. Two female and two male pictures are used for each of the four emotions. Stimuli are shown in random order for 500 ms and are then replaced by the rating screen where participants have to indicate the correct emotion. The outcome measure is accuracy (proportion correct). The test data is recorded on a computer and processed into scores for each emotion using an established matlab routine according to standard operating procedures (SOP) (clinical pharmacology, Orca DKF). The test is performed once during each treatment visit, exactly 270min after EV/EE administration.	At 270 minutes post-dose.
Vital parameters: blood pressure	Blood pressure (systolic and diastolic) will be measured at several timepoints during the treatment visit	30 minutes pre-dose; 0, 30, 60, 120, 150, 180, 210, 240, 270, 300minutes, 24hours post-dose.
Vital parameters: heart rate	Heart rate will be measured at several timepoints during the treatment visit	30 minutes pre-dose; 0, 30, 60, 120, 150, 180, 210, 240, 270, 300minutes, 24hours post-dose.
Vital parameters: body temperature	body temperature will be measured at several timepoints during the treatment visit	30 minutes pre-dose; 0, 30, 60, 120, 150, 180, 210, 240, 270, 300minutes, 24hours post-dose.
Concentration of Plasma Sodium	Sodium concentration (mmol/l) will be assessed in plasma.	At 0, 180 and 300 minutes post-dose.
Concentration of Plasma Potassium	Sodium concentration (mmol/l) will be assessed in plasma.	At 0, 180 and 300 minutes post-dose.
Concentration of Saliva Oxytocin		At 0, 60, 90, 120, 180, 270, 300 minutes and 24 hours post-dose.

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Study Chair: Mirjam Christ-Crain, Prof. Dr., University Hospital of Basel

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2026
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2027

Study Registration Dates

• First Submitted: January 5, 2026
• First Submitted That Met QC Criteria: January 14, 2026
• First Posted (Actual): January 22, 2026

Study Record Updates

• Last Update Posted (Actual): January 23, 2026
• Last Update Submitted That Met QC Criteria: January 22, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Oxytocin; ethinylestradiol; estradiol valerate
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Pituitary Diseases; Diabetes Insipidus; Diabetes Insipidus, Neurogenic; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Estradiol
• Other Study ID Numbers: 2025-02197;kt25ChristCrain5

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No