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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| estradiol valerate | Experimental |
| |
| esthinylestradiol | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| estradiol valerate | Drug | estradiol valerate |
| |
| esthinylestradiol |
| 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. |
| 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. | |
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Inclusion Criteria:
Part 1
Part 2
Exclusion Criteria:
Part 1
Part 2
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Andi Nikaj, MD | Contact | +41 61 328 57 43 | andi.nikaj@usb.ch | |
| Ursula Gobrecht-Keller, MD | Contact | +41 61 32 86028 | ursula.gobrecht@usb.ch |
| Name | Affiliation | Role |
|---|---|---|
| Mirjam Christ-Crain, Prof. Dr. | University Hospital of Basel | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Basel | Recruiting | Basel | 4031 | Switzerland |
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| ID | Term |
|---|---|
| D020790 | Diabetes Insipidus, Neurogenic |
| D003919 | Diabetes Insipidus |
| ID | Term |
|---|---|
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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| ID | Term |
|---|---|
| D004958 | Estradiol |
| ID | Term |
|---|---|
| D004963 | Estrenes |
| D004962 | Estranes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
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This study will be conducted in two parts. Part 1 is a double-blinded, randomized cross-over proof-of-concept trial in healthy adults. Part 2 is an open-labeled single arm pilot study in adults with an established diagnosis of AVP-Deficiency. Study parts 1 and 2 will be conducted consecutively.
For part 1 16 participants will be enrolled and for part 2 12 patients will be enrolled.
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| Drug |
estradiol valerate |
|
| 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. |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D010900 | Pituitary Diseases |
| D004700 | Endocrine System Diseases |
| D011083 |
| Polycyclic Compounds |
| D045166 | Estradiol Congeners |
| D012739 | Gonadal Steroid Hormones |
| D042341 | Gonadal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |