Effects of growth hormone on sleep patterns in Prader-Willi syndrome

Jennifer Miller¹, Janet Silverstein¹, Abby Wagner², and Daniel J Driscoll³

Department of Pediatrics, Divisions of ¹Endocrinology, ²Pulmonology, and ³Genetics, University of Florida College of Medicine, Gainesville, FL.

            Children with Prader-Willi syndrome (PWS) have significant sleep-related respiratory problems, including obstructive sleep apnea (OSA), central sleep apnea (CSA), abnormal arousal, and abnormal cardiorespiratory response to hypercapnia.  Polysomnographic studies (PSS) of PWS patients show that these respiratory problems are unrelated to weight, tonsillar/adenoid size, or evidence of airway obstruction.

Treatment of PWS patients with recombinant human growth hormone (rhGH) has been shown to improve CSA and increase the respiratory response to hypercarbia.  However, recent reports document that nine PWS patients have died suddenly during sleep soon after starting rhGH treatment.  Although it is uncertain whether the deaths were related to rhGH therapy, a postulated mechanism is increased OSA due to IGF-1 mediated hypertrophy of the tonsillar/adenoid tissue.  While increases in OSA have been seen in non-PWS rhGH-treated patients, no studies have documented the incidence of OSA in PWS patients before and after rhGH treatment.  This study was undertaken to evaluate the effect of rhGH on OSA and ventilatory drive in patients with PWS.

Methods:  PSS was performed in a standard sleep laboratory with 23 PWS patients.  Studies were evaluated for evidence of sleep-disordered breathing (SDB) including CSA, central hypopnea, OSA, obstructive hypopnea, hypoxemia, and hypercarbia.  All patients were either naïve to rhGH or had been off rhGH treatment for at least 12 weeks prior to the initial study.  Subsequently all patients started rhGH and had a follow-up study done after 6 weeks on rhGH.  IGF-1 levels were checked prior to beginning rhGH and at the time of the follow-up sleep study.

Results:  All PWS patients before or off rhGH had episodes of obstruction, either causing apnea or hypopnea during the sleep study, with worsening of SDB during REM sleep.  On rhGH all patients except one had improvement of SDB during REM sleep.  Two patients with high IGF-1 levels on rhGH had worsening of OSA and obstructive hypopnea, which improved when the rhGH dose was lowered and the IGF-1 levels were in the normal range.  Additionally, 6 patients had significant clinical improvement in episodes of OSA/hypopnea on rhGH.  The one patient who had worsening of OSA during REM had a history of an underlying pulmonary effusion and was a smoker.

            Discussion:  All patients with PWS studied had some degree of OSA and CSA as a baseline.  rhGH did not worsen obstructive events, central events, or duration of events in the majority of patients.  rhGH decreased the number and duration of obstructive events in several of our patients, with no significant effect on central events.  rhGH treatment improved SDB during REM in all but one of our patients when IGF-1 levels were normal.  Our results suggest that elevated IGF-1 levels may worsen obstructive sleep disturbances, necessitating close follow-up of sleep studies and rhGH dose.  It is unclear at this time which patients may have high IGF-1 levels on the recommended starting dose of rhGH, so is important to monitor IGF-1 levels routinely in this patient population.

June 2004