Reduced levels of GH during GnRH analogue treatment in pubertal short girls born small for gestational age (SGA).

CONTEXT: Several studies showed a decrease in height velocity during GnRH analogue (GnRHa) treatment. No information is available on GH levels during GnRHa treatment in short SGA girls. OBJECTIVE: To study overnight GH profiles and IGF-I and IGFBP-3 levels in girls with Tanner stage 2 and stage 3, before and after 3 months of GnRHa treatment, and to compare levels with those found in prepubertal short SGA girls. PATIENTS: Twenty-four pubertal and 16 prepubertal short SGA girls. INTERVENTION: After baseline overnight GH profiles, pubertal girls received leuprorelide acetate depots of 3.75 mg subcutaneously every 4 weeks. OUTCOME MEASURES: GH, IGF-I and IGFBP-3 levels. RESULTS: At baseline, GH levels were comparable to levels found in prepubertal short SGA girls and IGF-I and IGFBP-3 SDS were significantly below the population mean. After 3 months of GnRHa treatment, AUC(0) (P = 0.02), mean (P = 0.02) and maximum GH levels (P = 0.008) had significantly decreased. Mean GH levels were significantly lower than in prepubertal short SGA girls (P = 0.03). Eight girls with more than 40% decrease in mean GH levels also had a significantly greater decrease in IGF-I and IGFBP-3 levels. Mean and maximum GH levels at baseline correlated significantly with those after 3 months of GnRHa treatment. CONCLUSION: Short SGA girls lack the normal increase in GH levels seen in puberty and have reduced IGF-I and IGFBP-3 levels, which might explain their reduced pubertal growth spurt. GnRHa treatment led to a significant reduction in GH levels. Therefore, combining GnRHa treatment with GH treatment might improve adult height of short SGA girls.

Cardiovascular risk factors in parents of short children born small for gestational age.

Small for gestational age (SGA) children have a higher prevalence of cardiovascular risk factors at a young age. It is not known whether this increased risk is caused by their size at birth, a familial predisposition for cardiovascular disease or smallness at birth or a combination of these factors. The cardiovascular risk profile of parents of SGA children is unknown. We compared anthropometry, blood pressure, fasting serum lipid, glucose, and insulin levels of 482 parents (mean age 41 y) and 286 short SGA children with age- and sex-matched references. We also investigated whether these parameters correlated between parents and their offspring. Mothers had higher systolic blood pressure, fathers had a higher body mass index and parents had more frequently high fasting glucose levels than age- and sex-matched references. Children had significantly higher systolic and diastolic blood pressure than sex- and height-matched references. Twenty-four percent (mothers) and 10% (fathers) were born SGA but they did not have more cardiovascular risk factors than those born appropriate for gestational age. Cardiovascular risk factors did not correlate between parents and children. In conclusion, parents of short SGA children have a modest increase in some cardiovascular risk factors but risk factors did not correlate between parents and children.

Plasma matrix metalloproteinase-9 levels and blood pressure in short children born small for gestational age and effects of growth hormone treatment.

CONTEXT: Short small-for-gestational-age (SGA) children have an increased systolic blood pressure (BP) that decreases during long-term GH treatment. The underlying mechanism is still unknown. Matrix metalloproteinases (MMPs) are zinc-dependent endoproteinases that are involved in the remodelling of the extracellular matrix (ECM) and are thought to play a role in atherosclerosis. High MMP-9 levels are found in hypertensive patients and predict cardiovascular mortality. OBJECTIVES: To investigate whether GH treatment affects plasma MMP-9 levels in short SGA children and whether these are related to BP. DESIGN: Case-control study. INTERVENTION: GH treatment vs. no treatment during 36 months. Patients Thirty-eight short SGA children receiving GH treatment vs. 17 sex- and age-matched untreated short SGA controls. OUTCOME MEASURE: Plasma MMP-9 levels and BP were measured at baseline, and after 6, 12 and 36 months of study. RESULTS: MMP-9 decreased significantly during 3 years of GH treatment but remained similar in untreated SGA controls. After 3 years of GH treatment, MMP-9 levels were significantly lower in the GH group than in the untreated SGA controls. Systolic BP SDS significantly decreased in the GH group but remained unaltered in the untreated SGA controls. MMP-9 levels did not correlate with systolic or diastolic BP. CONCLUSIONS: Plasma MMP-9 levels and systolic BP SDS decreased to almost 50% of baseline values in the GH group but remained unchanged in untreated SGA controls. Our data indicate that GH has a positive effect on both MMP-9 levels and systolic BP SDS.

Subclassification of small for gestational age children with persistent short stature: growth patterns and response to GH treatment.

AIM: We determined whether subclassification of short small for gestational age (SGA) children according to birth anthropometrics could delineate different patterns in gestation, delivery, postnatal growth, response to growth hormone (GH) treatment and parental height. METHODS: 201 short SGA children were divided into three groups, SGA(L), SGA(L+W) and SGA(L+W+HC), according to birth length (L), weight (W) and head circumference (HC) < or =-2.00 standard deviation score (SDS). RESULTS: SGA(L+W+HC) children were born after the shortest gestational age and more often by caesarean section than SGA(L) children (36.3 vs. 38.1 weeks, 68.4 vs. 24.4%). SGA(L+W) children had an intermediate pattern and experienced most gestational hypertension (p = 0.01). At birth, SGA(L+W+HC) children were shorter than SGA(L) or SGA(L+W) (-4.12 vs. -2.67 and -3.72 SDS, p < or = 0.001). During the first 3 years of life, SGA(L+W+HC) children exhibited an increased growth in height (0.98 SDS) and HC (1.28 SDS) than SGA(L) (height, -0.06 SDS; HC, -0.30 SDS) and SGA(L+W) (height, 0.62 SDS; HC, -0.31 SDS). However, HC SDS remained smaller for SGA(L+W+HC) than the other groups at age 3. The groups did not differ in growth response during GH treatment. SGA(L) children tended to have shorter parents and target height than SGA(L+W+HC) children. CONCLUSIONS: Our study shows that subclassification of short SGA children might be a useful method for investigating SGA children as the subgroups revealed a different gestation, delivery and postnatal growth pattern. Response to GH treatment was not different between the groups.

Effect of growth hormone therapy on serum adiponectin and resistin levels in short, small-for-gestational-age children and associations with cardiovascular risk parameters.

BACKGROUND: Adiponectin and resistin are fat cell-derived hormones, which are thought to be respectively protective and disadvantageous with regard to the development of cardiovascular disease and diabetes mellitus type 2. Low birth weight has been associated with increased risks for the development of these diseases. In short, small-for-gestational-age (SGA) children, GH therapy has several positive effects regarding cardiovascular risk factors. On the other hand, concern has been expressed about the effects of GH therapy on insulin sensitivity. METHODS: We measured adiponectin and resistin levels in 136 short prepubertal children born SGA and their association with cardiovascular risk parameters and growth factors. Also, we compared the levels with normal-statured controls. The effect of GH treatment was evaluated in 50 short SGA children vs. baseline and vs. an untreated sex- and age-matched SGA control group. RESULTS: Short SGA children had similar adiponectin and lower resistin levels, compared with normal-statured controls. In GH-treated SGA children, neither adiponectin nor resistin levels changed significantly during 2 yr of GH treatment. Compared with untreated sex- and age-matched SGA controls, GH-treated SGA children had similar adiponectin and lower resistin levels. Adiponectin correlated inversely with age but not any cardiovascular risk parameter or growth factor. Higher IGF-I levels in GH-treated children were associated with lower resistin levels. CONCLUSIONS: Compared with normal-statured controls, short prepubertal SGA children had similar adiponectin and lower resistin levels. Two years of GH treatment had no effect on their adiponectin and resistin levels.

Risk factors for diabetes mellitus type 2 and metabolic syndrome are comparable for previously growth hormone-treated young adults born small for gestational age (sga) and untreated short SGA controls.

CONTEXT: Low birth weight might increase risk of diabetes mellitus type 2 and metabolic syndrome (MS). GH has insulin-antagonistic properties. Therefore, long-term follow-up of GH-treated children born small for gestational age (SGA) is important. OBJECTIVE AND PATIENTS: The objective of the study was to evaluate insulin sensitivity (Si) and disposition index (DI), all components of the MS and IGF-I and IGF binding protein (IGFBP)-3 levels in 37 previously GH-treated young SGA adults in comparison with 25 untreated short SGA controls. RESULTS: GH-treated subjects were 22.3 (1.7) yr old. Mean duration of GH treatment had been 7.3 (1.3) yr. Mean period after discontinuation was 6.5 (1.4) yr. Si and DI were comparable for GH-treated and untreated SGA subjects. Fasting glucose and insulin levels increased during GH treatment but recovered after discontinuation. Body mass index, waist circumference, high-density lipoprotein cholesterol levels, and triglycerides were equivalent. Systolic and diastolic blood pressure and cholesterol were significantly lower in GH-treated subjects. Thirty-two percent of untreated controls vs. none of the GH-treated subjects had an increased blood pressure. GH-induced rises in IGF-I and IGFBP-3 levels had completely recovered after GH stop. CONCLUSION: At 6.5 yr after discontinuation of long-term GH treatment, Si, DI, fasting levels of glucose and insulin, body mass index, waist circumference, and IGF-I and IGFBP-3 levels were equivalent for GH-treated and untreated young SGA adults. Systolic and diastolic blood pressure and serum cholesterol were even lower in GH-treated subjects. These data are reassuring because they suggest that long-term GH treatment does not increase the risk for diabetes mellitus type 2 and MS in young adults.

High serum levels of growth hormone (GH) and insulin-like growth factor-I (IGF-I) during high-dose GH treatment in short children born small for gestational age.

CONTEXT: Epidemiological studies have indicated that high serum levels of GH and IGF-I are associated with long-term risks. OBJECTIVE: The objective of the study was to evaluate the changes in serum levels of GH during overnight profiles, IGF-I, and IGF binding protein 3 (IGFBP-3) in short small for gestational age (SGA) children during GH treatment with two doses. PATIENTS: Thirty-six prepubertal short SGA children were the subjects of this study. INTERVENTION: Subjects received 1 (group A) or 2 (group B) mg GH/m(2).d. MAIN OUTCOME MEASURES: At baseline and after 6 months of GH treatment, overnight GH profiles were performed, and serum IGF-I and IGFBP-3 levels were measured. RESULTS: After 6 months, group B had significantly higher GH levels during the profile (mean, maximum, and area under the curve above zero line) than group A (P < 0.009). In group B, maximum GH levels increased from 43.9-161 mU/liter (P < 0.0002), and in group A, from 57.2-104 mU/liter (P = 0.002). During the profile (i.e. 12 h per day), children of group B had mean GH levels of 64.4 vs. 34.8 mU/liter in group A (P = 0.001). The IGF-I and IGF-I to IGFBP-3 ratio sd scores increased significantly in both groups, but were higher in group B than A [1.5 vs. 0.2 (P = 0.002) and 1.4 vs. 0.3 (P = 0.007), respectively]. In group B, 74% of the children had IGF-I levels in the highest quintile during GH treatment compared with 19% in group A. CONCLUSION: Our study shows that high-dose GH treatment in short SGA children results in high serum GH and IGF-I levels in most children. We recommend monitoring IGF-I levels during GH therapy to ensure that these remain within the normal range.

Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality.

CONTEXT: Adequate adrenal function is pivotal to survive meningococcal sepsis. OBJECTIVES: The objective of the study was to evaluate adrenocortical function in meningococcal disease. DESIGN: This was an observational cohort study. SETTING: The study was conducted at a university-affiliated pediatric intensive care unit. PATIENTS: Sixty children with meningococcal sepsis or septic shock participated in the study. MAIN OUTCOME MEASURES: The differences in adrenal function between nonsurvivors (n = 8), shock survivors (n = 43), and sepsis survivors (n = 9) on pediatric intensive care unit admission were measured. RESULTS: Nonsurvivors had significantly lower median cortisol to ACTH ratio than shock survivors and sepsis survivors. Because cortisol binding globulin and albumin levels did not significantly differ among the groups, bioavailable cortisol levels were also significantly lower in nonsurvivors than sepsis survivors. Nonsurvivors had significantly lower cortisol to 11-deoxycortisol ratios but not lower 11-deoxycortisol to 17-hydroxyprogesterone ratios than survivors. Using multiple regression analysis, decreased cortisol to ACTH ratio was significantly related to higher IL-6 levels and intubation with etomidate (one single bolus), whereas decreased cortisol to 11-deoxycortisol ratio was significantly related only to intubation with etomidate. Aldosterone levels tended to be higher in nonsurvivors than shock survivors, whereas plasma renin activity did not significantly differ. CONCLUSIONS: Our study shows that the most severely ill children with septic shock had signs of adrenal insufficiency. Bioavailable cortisol levels were not more informative on adrenal function than total cortisol levels. Besides disease severity, one single bolus of etomidate during intubation was related to decreased adrenal function and 11beta-hydroxylase activity. Decreased adrenal function was not related to decreased 21-hydroxylase activity. Based on our results, it seems of vital importance to take considerable caution using etomidate and consider combining its administration with glucocorticoids during intubation of children with septic shock.