Childhood growth hormone treatment and metabolic and cardiovascular risk in adults born small for gestational age after growth hormone cessation in the Netherlands: a 12-year follow-up study.

BACKGROUND: Childhood growth hormone treatment has been associated with increased cardiovascular mortality and morbidity in adults born small for gestational age (SGA) compared with the general population, but these risks have not been compared with untreated control groups. We aimed to investigate longitundinal metabolic and cardiovascular health in adults born SGA after cessation of growth hormone treatment. METHODS: We longitudinally investigated the metabolic and cardiovascular health profile of 167 adults born SGA and previously treated with growth hormone during the 12 years after growth hormone cessation. Metabolic and cardiovascular parameters were assessed with the frequently sampled intravenous glucose tolerance test, serum lipids and blood pressure were measured, body composition was determined by dual-energy x-ray absorptiometry, and visceral fat was measured by MRI. At approximately age 30 years, we compared the metabolic and cardiovascular health profile of adults born SGA and previously treated with growth hormone (SGA-GH) with 219 untreated adults: 127 born SGA with either persistent short stature (SGA-S) or spontaneous catch-up to typical adult stature (SGA-CU), and 92 born appropriate for gestational age. FINDINGS: During 12 years of follow-up, SGA-GH adults maintained normal ß-cell function (p=0·157 for the difference from growth hormone cessation to 12-year follow-up) and showed an increase in insulin sensitivity (p=0·002), fat mass (p<0·001), total cholesterol (p<0·001), and blood pressure (p<0·001). By around age 30 years, these parameters reached similar levels to those in SGA-S adults (insulin sensitivity p=0·242; fat mass p=0·449; total cholesterol p=0·616; systolic blood pressure p=0·523; diastolic blood pressure p=0·538). By around age 30 years, SGA-GH adults also had similar metabolic and cardiovascular health parameters to adults born appropriate for gestational age, with the exception of lower lean body mass (estimated marginal mean 44·67 kg [95% CI 43·54-45·80] in SGA-GH adults vs 47·65 kg [46·39-48·92] in adults born appropriate for gestational age) and higher concentrations of adverse serum lipids, such as cholesterol (4·75 mmol/L [4·55-4·95] vs 4·33 mmol/L [4·13-4·5]), which were present in all groups born SGA. Abdominal adiposity (visceral adipose tissue p=0·107; subcutaneous adipose tissue: p=0·244), liver fat fraction (p=0·104), and blood pressure (systolic blood pressure 0·927; diastolic blood pressure: 0·737) were similar between SGA-GH adults and all control groups. INTERPRETATION: At approximately age 30 years, SGA-GH adults had a similar metabolic and cardiovascular health profile to untreated adults born SGA or appropriate for gestational age, indicating long-term metabolic and cardiovascular safety of growth hormone treatment for children born SGA with short stature. FUNDING: Novo Nordisk.

Children Born Small for Gestational Age: Differential Diagnosis, Molecular Genetic Evaluation, and Implications.

Children born small for gestational age (SGA), defined as a birth weight and/or length below -2 SD score (SDS), comprise a heterogeneous group. The causes of SGA are multifactorial and include maternal lifestyle and obstetric factors, placental dysfunction, and numerous fetal (epi)genetic abnormalities. Short-term consequences of SGA include increased risks of hypothermia, polycythemia, and hypoglycemia. Although most SGA infants show catch-up growth by 2 years of age, ∼10% remain short. Short children born SGA are amenable to GH treatment, which increases their adult height by on average 1.25 SD. Add-on treatment with a gonadotropin-releasing hormone agonist may be considered in early pubertal children with an expected adult height below -2.5 SDS. A small birth size increases the risk of later neurodevelopmental problems and cardiometabolic diseases. GH treatment does not pose an additional risk.

Cardiovascular risk factors and carotid intima media thickness in young adults born small for gestational age after cessation of growth hormone treatment: a 5-year longitudinal study.

BACKGROUND: Growth hormone treatment reduces blood pressure and lipid concentrations. We assessed long-term changes in blood pressure, lipid concentrations, and carotid intima media thickness over a 5-year period after cessation of growth hormone treatment in adults born small for gestational age. METHODS: We did a longitudinal observational study at a medical centre in the Netherlands between April 1, 2004, and April 1, 2016. We included adults born small for gestational age who were treated with growth hormone (1 mg/m2 per day); treatment started during childhood until adult height. Participants were evaluated at cessation of treatment, and 6 months, 2 years, and 5 years later. We compared cardiovascular risk factors with untreated controls from the PROGRAM study. FINDINGS: We included 199 participants born small for gestational age and treated with growth hormone along with 285 controls: 51 untreated short adults born small for gestational age, 92 untreated adults born small for gestational age with spontaneous catch-up growth, and 142 adults born appropriate for gestational age. In the 6 months after treatment cessation, systolic blood pressure increased temporarily from 113·00 mm Hg (95% CI 111·18-114·82) to 116·92 mm Hg (115·07 to 118·77; p<0·001) and diastolic blood pressure increased temporarily from 62·19 mm Hg (60·99-63·38) to 66·51 mm Hg (65·14-67·89; p<0·001). At 5 years after treatment cessation, mean systolic blood pressure was 109·2 mm Hg (105·5-113·0) and mean diastolic blood pressure was 63·4 mm Hg (60·9-65·9), similar to the values at cessation. Lipid concentrations were non-significantly higher 5 years after treatment cessation (p values 0·09-0·21) than at treatment cessation. Cessation of growth hormone had no effect on carotid intima media thickness. At 5 years after cessation, total cholesterol was lower in adults treated with growth hormone (mean 4·21 mmol/L, 95% CI 4·04-4·38) than in untreated short adults born small for gestational age (4·66 mmol/L, 4·42-4·92; p=0·0030), as was mean LDL cholesterol (2·28 mmol/L, 2·14-2·43 vs 2·85 mmol/L, 2·62-3·10; p<0·0001); blood pressure and carotid intima media thickness did not differ between these two groups (p values >0·12). At 5 years after cessation, systolic blood pressure, diastolic blood pressure, lipid concentrations, and carotid intima media thickness of adults treated with growth hormone were not different to those in adults born small for gestational age who had spontaneous catch-up growth or adults born appropriate for gestational age. INTERPRETATION: Long-term growth hormone treatment in children born small for gestational age has no unfavourable effects on cardiovascular health in early adulthood and improves lipid profiles. FUNDING: Novo Nordisk (Netherlands).

Bone Mineral Density After Cessation of GH Treatment in Young Adults Born SGA: A 5-Year Longitudinal Study.

Context: Short children born small for gestational age (SGA) have below-average bone mineral density (BMD). Growth hormone (GH) treatment improves height and BMD in short SGA children. Longitudinal data on BMD in adults born SGA, after GH cessation (GH-stop), are lacking. Objective: To determine BMD in young adults born SGA during 5 years after GH-stop. Methods: In 173 GH-treated adults born SGA (SGA-GH), BMD of total body (BMDTB) and bone mineral apparent density of lumbar spine (BMADLS) were measured longitudinally at adult height (AH) and 6 months, 2 years, and 5 years thereafter. At 5 years after GH-stop (age 21 years), data were compared with 45 untreated short SGA adults (SGA-S), 59 SGA adults with spontaneous catch-up (SGA-CU), and 81 adults born appropriate for gestational age (AGA). Results: At GH-stop (mean age 16.4 years), estimated mean (standard error) BMDTB standard deviation score (SDS) was -0.40 (0.1) in males and -0.51 (0.1) in females, followed by a trend toward a decrease of BMDTB in males to -0.59 (0.1) at 5 years after GH-stop (P = 0.06), whereas it remained stable in females [-0.57 (0.1); P = 0.33]. At GH-stop, BMADLS SDS was -0.01 (0.1) in males and -0.29 (0.1) in females, followed by a decrease in males and females to -0.38 and -0.55, respectively, at 5 years after GH-stop (P < 0.001). At 5 years after GH-stop, BMDTB and BMADLS in SGA-GH were similar compared with SGA-S, SGA-CU, and AGA. Conclusion: After GH-stop, there is a gradual decline of BMADLS, but at the age of 21 years, BMDTB and BMADLS are similar as in untreated short SGA adults.

Effects of size at birth, childhood growth patterns and growth hormone treatment on leukocyte telomere length.

BACKGROUND: Small size at birth and rapid growth in early life are associated with increased risk of cardiovascular disease in later life. Short children born small for gestational age (SGA) are treated with growth hormone (GH), inducing catch-up in length. Leukocyte telomere length (LTL) is a marker of biological age and shorter LTL is associated with increased risk of cardiovascular disease. OBJECTIVES: To investigate whether LTL is influenced by birth size, childhood growth and long-term GH treatment. METHODS: We analyzed LTL in 545 young adults with differences in birth size and childhood growth patterns. Previously GH-treated young adults born SGA (SGA-GH) were compared to untreated short SGA (SGA-S), SGA with spontaneous catch-up to a normal body size (SGA-CU), and appropriate for gestational age with a normal body size (AGA-NS). LTL was measured using a quantitative PCR assay. RESULTS: We found a positive association between birth length and LTL (p = 0.04), and a trend towards a positive association between birth weight and LTL (p = 0.08), after adjustments for gender, age, gestational age and adult body size. Weight gain during infancy and childhood and fat mass percentage were not associated with LTL. Female gender and gestational age were positively associated with LTL, and smoking negatively. After adjustments for gender, age and gestational age, SGA-GH had a similar LTL as SGA-S (p = 0.11), SGA-CU (p = 0.80), and AGA-NS (p = 0.30). CONCLUSIONS: Larger size at birth is positively associated with LTL in young adulthood. Growth patterns during infancy and childhood are not associated with LTL. Previously GH-treated young adults born SGA have similar LTL as untreated short SGA, SGA with spontaneous catch-up and AGA born controls, indicating no adverse effects of GH-induced catch-up in height on LTL.

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 ß-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 ß-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).

Metabolic Health and Long-Term Safety of Growth Hormone Treatment in Silver-Russell Syndrome.

Context: Children with Silver-Russell syndrome (SRS) are born small for gestational age (SGA) and remain short. Growth hormone (GH) treatment improves height in short SGA children, including those with SRS. Data on metabolic health and long-term safety of GH treatment in SRS are lacking. Objective: To investigate metabolic health in SRS patients during and until 2 years after discontinuation of GH treatment. Design: Metabolic health was assessed longitudinally at GH-start, GH-stop, 6 months, and 2 years thereafter. Patients: Twenty-nine SRS patients vs 171 non-SRS subjects born SGA. Main Outcome Measures: Lean body mass (LBM), fat mass percentage (FM%), insulin sensitivity (Si), ß-cell function, blood pressure, and serum lipids. Results: At GH-start [mean age (standard deviation) 5.4 (2.1) years in SRS and 6.7 (2.0) years in non-SRS (P = 0.003)], blood pressure, serum lipids, glucose, and insulin levels were similar and within normal ranges in SRS and non-SRS. LBM standard deviation score (SDS) and FM% SDS were lower than average in both groups. During treatment, LBM SDS remained stable whereas FM% SDS increased in both groups. During the 2 years after GH-stop, LBM decreased and FM% increased, whereas Si and ß-cell function improved. At 2 years after GH-stop (mean age 18 years), all parameters were similar and within normal ranges in SRS and non-SRS. None of the SRS patients developed metabolic syndrome, diabetes mellitus type 2, or adverse events. Conclusion: GH-treated SRS patients have a similar metabolic health and safety profile as non-SRS subjects born SGA, both during and until 2 years after GH-stop.

Leukocyte Telomere Length in Young Adults Born Preterm: Support for Accelerated Biological Ageing.

BACKGROUND: Subjects born preterm have an increased risk for age-associated diseases, such as cardiovascular disease in later life, but the underlying causes are largely unknown. Shorter leukocyte telomere length (LTL), a marker of biological age, is associated with increased risk of cardiovascular disease. OBJECTIVES: To compare LTL between subjects born preterm and at term and to assess if LTL is associated with other putative cardiovascular risk factors at young adult age. METHODS: We measured mean LTL in 470 young adults. LTL was measured using a quantitative PCR assay and expressed as T/S ratio. We analyzed the influence of gestational age on LTL and compared LTL between subjects born preterm (n = 186) and at term (n = 284). Additionally, we analyzed the correlation between LTL and potential risk factors of cardiovascular disease. RESULTS: Gestational age was positively associated with LTL (r = 0.11, p = 0.02). Subjects born preterm had shorter LTL (mean (SD) T/S ratio = 3.12 (0.44)) than subjects born at term (mean (SD) T/S ratio = 3.25 (0.46)), p = 0.003). The difference remained significant after adjustment for gender and size at birth (p = 0.001). There was no association of LTL with any one of the putative risk factors analyzed. CONCLUSIONS: Young adults born preterm have shorter LTL than young adults born at term. Although we found no correlation between LTL and risk for CVD at this young adult age, this biological ageing indicator may contribute to CVD and other adult onset diseases at a later age in those born preterm.