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

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.

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.

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)