Oxytocin Levels in Response to Pituitary Provocation Tests in Healthy Volunteers

Background: Oxytocin, secreted into the circulation through the posterior pituitary, regulates lactation, weight, and socio-behavioral functioning. Oxytocin deficiency has been suggested in patients with hypopituitarism, however, diagnostic testing for oxytocin deficiency has not been developed. Known stimuli used in the diagnosis of pituitary deficiencies - the hypertonic saline and arginine infusion tests stimulating copeptin levels, and the oral macimorelin test stimulating growth hormone levels - have also been shown to stimulate oxytocin secretion in animal models. We hypothesized that these provocation tests would stimulate plasma oxytocin levels in humans. Methods: Basal plasma oxytocin levels were measured for all three tests. Stimulated plasma oxytocin was measured once plasma sodium >150 mmol/l for the hypertonic saline and after 45 minutes for the arginine infusion and the oral macimorelin test, expected peak of copeptin and growth hormone levels, respectively. Primary outcome was change between basal and stimulated oxytocin levels using a paired t-test. Results: Median (IQR) age of all participants was 24 years (22, 28), 51% were female. As expected, copeptin increased in response to hypertonic saline from 4.0 pmol/L [3.3, 6.7] to 34.2 pmol/L [23.2, 45.4] (p-value <0.001) and in response to arginine infusion from 4.6 pmol/L [3.2, 6.2] to 8.3 pmol/L [6.4, 10.8] (p-value <0.001). Growth hormone increased in response to oral macimorelin from 1.6 ng/mL [0.3, 17.2] to 106.0 ng/mL [73.3, 127.2] (p-value <0.001). Oxytocin levels increased in response to hypertonic saline infusion from 0.3 pg/mL [0.3, 0.5] to 0.6 pg/mL [0.4, 0.7] (p-value 0.007), while there was no change in response to arginine infusion (basal 0.4 pg/mL [0.4, 0.6], stimulated 0.4 pg/mL [0.3, 0.6], p-value 0.6), nor to oral macimorelin (basal 38.7 pg/mL [31.1, 66.9], stimulated 34.2 pg/mL [31.2, 48.2], p-value 0.3). Conclusion: We found that hypertonic saline infusion results in doubling of oxytocin levels. Further research will be important to determine whether this test could be used diagnostically to identify patients with oxytocin deficiency. In contrast to animal data, arginine and macimorelin did not stimulate oxytocin.