A Pilot Randomized Clinical Trial of Intranasal Oxytocin to Promote Weight Loss in Individuals With Hypothalamic Obesity

Abstract

Context Hypothalamic obesity is a rare, treatment-resistant form of obesity. In preliminary studies, the hypothalamic hormone oxytocin (OXT) has shown promise as a potential weight loss therapy. Objective To determine whether 8 weeks of intranasal OXT (vs. 8 weeks of placebo) promotes weight loss in children, adolescents, and young adults with hypothalamic obesity. Design Randomized, double-blind, placebo-controlled, cross-over pilot trial (NCT02849743). Setting Outpatient academic medical center. Participants Aged 10y to 35y, hypothalamic obesity from hypothalamic/pituitary tumors. Intervention Intranasal OXT (Syntocinon, 40 USP units/mL, 4 IU/spray) vs. excipient-matched placebo, 16-24 IU three times daily at mealtimes. Main outcome measure(s) Weight loss attributable to OXT vs. placebo, safety (adverse events). Results Of 13 individuals randomized (54% female, 31% pre-pubertal, median age 15.3y, IQR 13.3-20.6), 10 completed the entire study. We observed a non-significant within-subject weight change of -0.6 kg (95% CI: -2.7, 1.5) attributable to OXT vs. placebo. A subset (2/18 screened, 5/13 randomized) had prolonged QTc interval on electrocardiography (ECG) prior to screening and/or in both treatment conditions. Overall, OXT was well-tolerated, and adverse events (epistaxis and nasal irritation, headache, nausea/vomiting, and changes in heart rate, blood pressure, and QTc interval) were similar between OXT and placebo. In exploratory analyses, benefits of OXT for anxiety and impulsivity were observed. Conclusions In this pilot study in hypothalamic obesity, we did not detect a significant impact of intranasal OXT on body weight. OXT was well-tolerated, so future larger studies could examine different dosing, combination therapies, as well as potential psychosocial benefits.

The neurohypophyseal hormone oxytocin and eating behaviors: a narrative review

“…These positive results could be attributable to the numerous metabolic effects of the neurohormone, including direct reduction of food intake by decreasing appetite in homeostatic and reward-driven conditions (hence, properly insisting on hypothalamic regions involved in the regulation of hunger and satiation), enhancement of lipolysis and energy expenditure, positive affection of body composition due to improvement of peripheral insulin sensitivity, ultimately favoring lean over fat mass building [ 78 ]. Nevertheless, a recently published randomized, double-blind, placebo-controlled, crossover pilot study (13 patients randomized; 10 concluded) did not find any relevant changes in body weight between the OT arm 16–24 IU at the three main mealtimes and placebo after 8 weeks of treatment [ 79 ]. This finding lays the basis for better-designed multicentric trials to assess the role of OT treatment (alone or in combination) in patients with hypothalamic injuries/dysfunction.…”

Acquired hypothalamic obesity: A clinical overview and update

“…Since OXT also acts outside the hypothalamus, particularly in the brainstem, pharmacological replacement of OXT has been proposed to address features of HO, in particular hyperphagia, as well as some of the psychosocial features of hypothalamic syndrome. In a pilot randomized, placebo‐controlled, crossover study of intranasal OXT (NCT02849743), no significant change in body weight was detected after 8 weeks of OXT, although a modest benefit for anxiety and impulsivity was found 115 . Multiple experimental considerations, including choice of OXT formulation, route of delivery, and technique for OXT measurement in relevant tissues add complexity to the study of this potential treatment.…”

“…In a pilot randomized, placebo-controlled, crossover study of intranasal OXT (NCT02849743), no significant change in body weight was detected after 8 weeks of OXT, although a modest benefit for anxiety and impulsivity was found. 115 Multiple experimental considerations, including choice of OXT formulation, route of delivery, and technique for OXT measurement in relevant tissues add complexity to the study of this potential treatment.…”

Treatment of hypothalamic obesity in people with hypothalamic injury: new drugs are on the horizon

“…In this small pilot study with 10 completers, there was no significant effect of intranasal OXT on body weight change. However, OXT was well tolerated, and in exploratory analyses, benefits of OXT for anxiety and impulsivity were noted ( 79 ). Preclinical research using labeled OXT administered intranasally to rhesus macaques or rabbits reached the cerebrospinal fluid and brain ( 80 , 81 ).…”