Oxytocin in Young Children With Prader-Willi Syndrome

Results of a Randomized, Double-Blind, Placebo-Controlled, Crossover Trial Investigating 3 Months of Oxytocin

Layla Damen; Lionne N. Grootjen; Alicia F. Juriaans; Stephany H. Donze; T. Martin Huisman; Jenny A. Visser; Patric J.D. Delhanty; Anita C.S. Hokken-Koelega


Clin Endocrinol. 2021;94(5):774-785. 

In This Article

Abstract and Introduction


Context: Prader-Willi syndrome (PWS) is characterized by hypothalamic dysfunction, hyperphagia and a typical behavioural phenotype, with characteristics of autism spectrum disorder (ASD) like stubbornness, temper tantrums and compulsivity. It has been suggested that the oxytocin system in patients with PWS is dysfunctional. In ASD, intranasal oxytocin treatment has favourable effects on behaviour.

Objective: To evaluate the effects of 3 months of twice daily intranasal oxytocin (dose range 16–40 IU/day), compared to placebo, on behaviour and hyperphagia in children with PWS.

Design: Randomized, double-blind, placebo-controlled, crossover study in the Dutch PWS Reference Center.

Patients: Twenty-six children with PWS aged 3–11 years.

Main Outcome Measures: (Change in) behaviour and hyperphagia measured by Oxytocin Questionnaire and Dykens hyperphagia questionnaire.

Results: In the total group, no significant effects of oxytocin on social behaviour or hyperphagia were found. However, in boys, the Oxytocin Questionnaire scores improved significantly during oxytocin treatment, compared to a deterioration during placebo (4.5 (−0.8 to 15.3) vs. −4.0 (−11.3 to 0.8), P = .025). The Dykens hyperphagia questionnaire scores remained similar during oxytocin treatment, while there was a deterioration during placebo (0.0 (−0.8 to 4.3) vs. −3.5 (−6.0 to 0.0), P = .046). Patients with a deletion had significant improvements in both questionnaire scores during oxytocin treatment, but deteriorations during placebo. Oxytocin treatment was well tolerated, and there were no serious adverse events.

Conclusions: Intranasal oxytocin treatment has positive effects on social and eating behaviour in 3–11 years aged boys with PWS and in children with a deletion without safety concerns. Intranasal oxytocin in children with PWS might be considered, but individual effects should be carefully evaluated and treatment discontinued if no effects are found.


Prader-Willi syndrome (PWS) is a rare, neurodevelopmental disorder caused by the lack of expression of the Prader-Willi region of the paternally derived chromosome 15, mostly caused by a paternal deletion or maternal uniparental disomy (mUPD). PWS is characterized by a distinctive phenotype with neonatal hypotonia with suckling problems often requiring tube feeding, endocrine disturbances, developmental delay, hyperphagia and reduced energy expenditure resulting in obesity when uncontrolled and a typical behavioural phenotype.[1–3] Behaviour of children with PWS is characterized by stubbornness, temper tantrums, compulsivity and difficulties in changing routines.[2,4,5] Children thereby show symptoms of autism spectrum disorder (ASD), and 36% fulfil the criteria of ASD.[6] Growth hormone (GH) therapy results in significant improvements in body composition and mental and motor development in children with PWS.[7,8] However, effects of GH on behaviour and hyperphagia are limited.[9]

One of the genes in the Prader-Willi region is Magel2. Magel2-deficient mice have been shown to reproduce some of the phenotype of PWS.[10,11] Magel2-deficient mice have a major reduction of hypothalamic oxytocin secretion and a 50% neonatal mortality due to suckling defects.[10] A single oxytocin injection in mouse pups at 3–5 hours after birth normalized suckling and feeding behaviour, resulting in survival of all pups.[10] Furthermore, in the 50% surviving adult mice, deficiencies in learning abilities and social behaviours were found.[11] In these mice, oxytocin given 1 hour before behavioural testing reversed social recognition deficits.[11] This might suggest that oxytocin could potentially influence at least some of the behavioural phenotypes of PWS. Furthermore, the number of oxytocin-expressing neurons in the hypothalamus of patients with PWS is significantly decreased[12] and both higher and lower plasma oxytocin levels were found in PWS compared with healthy controls.[13,14] Altogether, findings suggest that the oxytocin system in patients with PWS is dysfunctional and oxytocin might be involved in the hyperphagia seen in PWS.

Oxytocin is known to be involved in social skills,[15] food intake,[16–18] energy expenditure[19] and body weight,[20] all of which are seriously affected in PWS. Currently, there are no pharmacotherapeutic options to effectively reduce symptoms of hyperphagia. Most psychotropic options to alleviate severe behavioural problems have undesirable side effects. Studies of oxytocin in autism have shown favourable effects on behaviour.[21–23] There are a few studies investigating short-term oxytocin, most for a maximum of 4 weeks and one investigated 8 weeks of oxytocin, in both children and adults with PWS.[24–29]These studies show varying effects. Our previous randomized, double-blind, placebo-controlled, crossover trial investigating 4 weeks of oxytocin vs. placebo showed positive effects on social behaviour in children aged 6–11 years, but not in older children,[28] indicating that younger children might benefit more from oxytocin treatment. However, there are currently no studies investigating effects of longer-term oxytocin treatment in young children with PWS.

Given the dysfunctional oxytocin system in PWS and involvement of oxytocin in social skills, food intake and body weight, we hypothesized that intranasal oxytocin in young children with PWS would improve social behaviour and hyperphagia. We, therefore, conducted a randomized, double-blind, placebo-controlled crossover study on the effects of 3 months of oxytocin versus 3 months of placebo. The primary endpoints were changes in social behaviour and hyperphagia. Furthermore, we investigated if there was a difference in effects between boys or girls or between the genetic subtypes.