Metabolic health of young adults who were born small for gestational age and treated with growth hormone, after cessation of growth hormone treatment: a 5-year longitudinal study

Background Growth hormone treatment reduces fat mass and insulin sensitivity and increases lean body mass. Data are only available for short-term longitudinal changes after cessation of growth hormone treatment in young adults born small for gestational age. We aimed to assess long-term changes over a 5-year period following cessation of growth hormone treatment. Methods We did a longitudinal study of young adults born small for gestational age and previously treated with growth hormone. Individuals were followed up for 5 years after attainment of adult height, when growth hormone treatment was discontinued: assessments were done at cessation of growth hormone treatment and at 6 months, 2 years, and 5 years thereafter. Data 5 years after cessation of growth hormone were compared with untreated age-matched controls. We used dual-energy x-ray absorptiometry to assess body composition, and did frequently sampled intravenous glucose tolerance tests to assess insulin sensitivity, acute insulin response, and the disposition index (a measure of β-cell function). This study is registered with ISRCTN, numbers ISRCTN96883876 and ISRCTN65230311. Findings Between April, 2004, and April, 2016, we followed up 199 young adults born small for gestational age and previously treated with growth hormone, during the 5 years after cessation of growth hormone treatment. Data at 5 years for these individuals were compared with those for 51 untreated adults born small for gestational age with short stature, 92 untreated adults born small for gestational age with spontaneous catch-up growth, and 142 adults born appropriate for gestational age and unexposed to growth hormone treatment. In young adults born small for gestational age and previously treated with growth hormone, 5 years after cessation of growth hormone treatment, there were increases in fat mass (estimated marginal mean 10·73 kg [95% CI 9·95–11·50] at cessation of treatment vs 16·12 kg [14·77–17·46] at 5 years; p<0·0001), trunk fat (5·34 kg [4·94–5·73] vs 7·86 kg [7·12–8·60]; p<0·0001), and limb fat (4·87 kg [4·49–5·25] vs 7·41 kg [6·78–8·05]; p<0·0001); furthermore, lean body mass had decreased (42·41 kg [95% CI 41·09–43·73] at cessation of treatment vs 41·42 kg [40·17–42·66] at 5 years; p=0·0013). Insulin sensitivity increased within 6 months of cessation and was sustained 5 years after treatment cessation (estimated marginal mean 4·14 mU/L [95% CI 3·79–4·53] at cessation of treatment vs 6·15 mU/L [5·21–7·24] at 5 years; p<0·0001), and acute insulin response was diminished at 6 months, which persisted at 5 year follow-up (597·63 mU/L [539·62–661·86] vs 393·69 mU/L [337·56–459·15]; p<0·0001). The disposition index was increased 6 months after treatment but values at 5 years were similar to those at cessation of treatment (2483·94 [95% CI 2233·43–2762·54] at cessation of treatment vs 2367·83 [2033·43–2757·22] at 5 years; p=0·49). 5 years after cessation of growth hormone treatment, adults born small for gestational age and previously treated with growth hormone had fat mass, insulin sensitivity, and disposition index similar to those of untreated adults born small for gestational age with short stature, but lean body mass (adjusted for sex and height) was lower (46·47 kg [44·95–48·00] in those born small for gestational age with short stature vs 44·32 kg [43·35–45·30] in those born small for gestational age and treated with growth hormone; p=0·007). In adults previously treated with growth hormone born small for gestational age, at 5 years after cessation of growth hormone treatment, compared with adults born small for gestational age with spontaneous catch-up growth and adults born appropriate for gestational age, lean body mass was lower and results from frequently sampled intravenous glucose tolerance tests were similar. Interpretation Significant changes in body composition and insulin sensitivity were recorded 5 years after cessation of growth hormone treatment in adults born small for gestational age, reflecting a loss of pharmacological effects of growth hormone. 5 years after cessation of treatment, fat mass, insulin sensitivity, and β-cell function of previously treated adults were similar to untreated adults born small for gestational age with short stature, indicating that long-term growth hormone treatment in children born small for gestational age has no unfavourable effects on metabolic health in early adulthood. Funding Novo Nordisk Farma BV (Netherlands).