Health-related quality of life in boys with constitutional delay of growth and puberty.

Introduction: Constitutional delay of growth and puberty (CDGP) is the most common reason for delayed puberty in healthy male adolescents. The main indication for medical treatment for this condition is psychosocial burden. However, to the best of our knowledge, no previous study has addressed the impact of puberty-promoting treatment on health-related quality of life (HRQoL) among boys with CDGP. Methods: We investigated HRQoL in 22 boys with CDGP, who participated in a randomized controlled trial in four Finnish pediatric endocrinology outpatient clinics between 2013 and 2017. The boys were randomized to receive either aromatase inhibitor letrozole (2.5mg/day; n=11) or intramuscular testosterone (1mg/kg/every 4 weeks; n=11) for 6 months and followed up to 12 months. HRQoL was assessed with a generic self-assessment 16D© instrument developed and validated for adolescents aged 12 to 15 years. The 16D includes 16 dimensions (vitality, sight, breathing, distress, hearing, sleeping, eating, discomfort and symptoms, speech, physical appearance, school and hobbies, mobility, friends, mental function, excretion and depression). The results were compared with an age-matched reference population that included 163 boys from the Finnish capital-city area. The study protocol is registered to ClinicalTrials.gov (registration number: NCT01797718). Results: At baseline, the mean 16D score of the CDGP boys was similar to the age-matched reference population (0.95 vs 0.96, p=0.838). However, the physical appearance score (satisfaction with general appearance, height and weight) was significantly lower in the CDGP boys (0.75 vs 0.92, p=0.004) than their peers. Twelve months after treatment, Appearance had improved significantly (0.75 vs 0.87, p=0.004) and no HRQoL dimension was inferior compared to the age-matched reference population. Discussion: In terms of HRQoL, the main impact of delayed puberty was dissatisfaction with physical appearance. Puberty promoting therapy was associated with a positive change in perceived appearance, with no clear difference between low-dose testosterone and letrozole treatments.

Circulating Liver-enriched Antimicrobial Peptide-2 Decreases During Male Puberty.

CONTEXT: Circulating levels of liver-enriched antimicrobial peptide 2 (LEAP2), a ghrelin receptor antagonist, decrease under caloric restriction and increase in obesity. The role of LEAP2 in male puberty, a phase with accelerated energy demand, is unclear. OBJECTIVE: This work aimed to investigate whether circulating LEAP2 levels are downregulated in boys following the onset of puberty to respond to the energy need required for growth. METHODS: We determined circulating LEAP2 levels in 28 boys with constitutional delay of growth and puberty (CDGP) who participated in a randomized controlled trial (NCT01797718), and were treated with letrozole (n = 15) or intramuscular low-dose testosterone (T) (n = 13) for 6 months. Blood sampling and dual-energy x-ray absorptiometry-measured body composition were performed at 0-, 6-, and 12-month visits. RESULTS: Serum LEAP2 levels decreased statistically significantly during pubertal progression (0-6 months: mean decrease -4.3 [10.3] ng/mL, P = .036 and 0-12 months: -3.9 [9.3] ng/mL, P = .033). Between 0 and 6 months, the changes in serum LEAP2 levels correlated positively with changes in percentage of body fat (rs = 0.48, P = .011), and negatively with growth velocity and estradiol levels (rs = -0.43, P = .022, rs = -0.55, P = .003, respectively). In the T group only, the changes in serum LEAP2 correlated negatively with changes in T and estradiol levels. Between 0 and 12 months, the change in LEAP2 levels correlated negatively with the change in high-density lipoprotein levels (rs = -0.44, P = .022) and positively with the change in insulin (rs = 0.50, P = .009) and HOMA-IR (rs = 0.51, P = .007) levels. CONCLUSION: Circulating LEAP2 levels decreased after induction of puberty reciprocally with increased growth rate and energy demand, reflecting the metabolic state of the adolescent. Further, the results suggest that estradiol levels may have a permissive role in downregulating circulating LEAP2 levels.

Serum testosterone and oestradiol predict the growth response during puberty promoting treatment.

OBJECTIVE: The influence of androgens and oestrogens on growth is complex, and understanding their relative roles is important for optimising the treatment of children with various disorders of growth and puberty. DESIGN: We examined the proportional roles of androgens and oestrogens in the regulation of pubertal growth in boys with constitutional delay of growth and puberty (CDGP). The study compared 6-month low-dose intramuscular testosterone treatment (1 mg/kg/month; n = 14) with per oral letrozole treatment (2.5 mg/day; n = 14) which inhibits conversion of androgens to oestrogen. PATIENTS: Boys with CDGP were recruited to a randomized, controlled, open-label trial between 2013 and 2017 (NCT01797718). MEASUREMENTS: The patients were evaluated at 0-, 3- and 6-month visits, and morning blood samples were drawn. Linear regression models were used for data analyses. RESULTS: In the testosterone group (T-group), serum testosterone concentration correlated with serum oestradiol concentration at the beginning of the study and at 3 months, whereas in the letrozole group (Lz-group) these sex steroids correlated only at baseline. Association between serum testosterone level and growth velocity differed between the T and Lz groups, as each nmol/L increase in serum testosterone increased growth velocity 2.7 times more in the former group. Serum testosterone was the best predictor of growth velocity in both treatment groups. In the Lz-group, adding serum oestradiol to the model significantly improved the growth estimate. Only the boys with serum oestradiol above 10 pmol/L had a growth velocity above 8 cm/year. CONCLUSIONS: During puberty promoting treatment with testosterone or aromatase inhibitor letrozole, growth response is tightly correlated with serum testosterone level. A threshold level of oestrogen appears to be needed for an optimal growth rate that corresponds to normal male peak height velocity of puberty. Serum testosterone 1 week after the injection and serum testosterone and oestradiol 3 months after the onset of aromatase inhibitor treatment can be used as biomarkers for treatment response in terms of growth.

Bone structure assessed with pQCT in prepubertal males with delayed puberty or congenital hypogonadotropic hypogonadism.

OBJECTIVE: Congenital hypogonadotropic hypogonadism (CHH) is associated with impaired bone mineral density in adulthood, whereas the estimates on bone structure in adolescents with CHH has not been previously evaluated. This study describes bone structure in CHH patients and compares it to that in boys with constitutional delay of growth and puberty (CDGP). DESIGN: A cross-sectional study. METHODS: Peripheral quantitative computed tomography (pQCT) of non-dominant arm and left leg were performed. Volumetric bone mineral density (BMD), bone mineral content, and area in trabecular and cortical bone compartments were evaluated, and bone age-adjusted Z-scores for the bone parameters were determined. RESULTS: The participants with CHH had more advanced bone age and were older, taller and heavier than the CDGP boys, yet they had lower trabecular BMD in distal radius (147.7 mg/mm3 [95% CI, 128-168 mg/mm3 ] vs. 181.2 mg/mm3 [172-192 mg/mm3 ], p = .002) and distal tibia (167.6 mg/mm3 [145-190 mg/mm3 ] vs. 207.2 mg/mm3 [187-227 mg/mm3 ], p = .012), respectively. CHH males had lower cortical thickness at diaphyseal tibia than the participants with CDGP (p = .001). These between-group differences remained significant in corresponding Z-scores adjusted for bone age and height (p = .001). In CDGP group, serum testosterone correlated positively with trabecular BMD (r = 0.51, p = .013) at distal radius, and estradiol levels correlated positively with trabecular BMD at the distal site of tibia (r = 0.58, p = .004). CONCLUSIONS: Five treatment-naïve male patients with CHH exhibited poorer trabecular BMD than untreated males with CDGP. We speculate that timely low-dose sex steroid replacement in CHH males may benefit skeletal health in adulthood.

Association of Serum Total Osteocalcin Concentrations With Endogenous Glucocorticoids and Insulin Sensitivity Markers in 12-Year-Old Children: A Cross-Sectional Study.

Background: Osteocalcin (OC) is an osteoblast-derived marker of bone turnover that has recently been linked to glucose metabolism, glucocorticoid action, and cardiovascular risk. Objective: We determined whether serum total OC (tOC) is associated with cardiometabolic factors, such as insulin sensitivity (IS) markers and endogenous glucocorticoids in 12-year-old children. In addition, we assessed whether low birth weight or exposure to maternal preeclampsia affect tOC concentrations. Methods: In this cross-sectional study, 192 children (109 girls) were studied at 12 years of age. Seventy of them had been born small (SGA), 78 appropriate for gestational age (AGA), and 44 from preeclamptic pregnancies (PRE) as AGA. Blood pressure was measured, and fasting blood samples were collected for markers of glucose metabolism, osteoblast, adipocyte, and adrenocortical function. IS was estimated by Quantitative Insulin Sensitivity Check Index (QUICKI). Free cortisol index (FCI) was calculated as serum cortisol/corticosteroid binding globulin. Results: The highest tOC concentrations were detected in midpubertal children (Tanner B/G stage 3). The children in the highest tOC quartile (n = 48) had lower body mass index (BMI), waist-to-height ratio, diastolic blood pressure, leptin, cortisol/cortisone ratio and FCI, and higher insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), IGFBP-3, and alkaline phosphatase (ALP) than those in the lower tOC quartiles (p < 0.02 for all). QUICKI was similar in these subgroups. In logistic regression analysis, pubertal developmental stages 2 and 3, high ALP, IGF-I, and low FCI and BMI (p < 0.02 for all) were associated independently with higher tOC. The means of serum tOC and IS markers were similar in the SGA, AGA, and PRE subgroups. Conclusions: In both sexes, the highest tOC levels were detected in midpubertal children reflecting the fast pubertal growth phase. Higher tOC levels were associated with lower BMI and FCI, whereas no association was found with IS. Birth weight or exposure to preeclampsia had no effect on tOC concentrations.

Fibroblast Growth Factor 21, Adiponectin, and Irisin as Markers of Unfavorable Metabolic Features in 12-Year-Old Children.

CONTEXT: Among cytokines, fibroblast growth factor 21 (FGF21), adiponectin (Adn), and irisin have been considered potential biomarkers for insulin sensitivity (IS). OBJECTIVE: We evaluated whether serum FGF21, Adn, and irisin associate with markers of IS and serum lipids in 12-year-old children. DESIGN PARTICIPANTS AND MAIN OUTCOME MEASURES: This cohort study included 192 12-year-old children (109 girls). Seventy-eight of them had been born appropriate for gestational age (AGA), 70 small for gestational age (SGA), and 44 from preeclamptic pregnancies (PREs) as AGA. Fasting serum FGF21, Adn, irisin, lipids, inflammatory markers, and IS markers were measured. Quantitative insulin sensitivity check index (QUICKI) was calculated. RESULTS: The means of serum FGF21, high molecular weight (HMW) Adn, and irisin did not differ between the sexes or between the SGA, AGA, and PRE children. In the whole study population, FGF21 associated positively with irisin and uric acid and negatively with leptin and high-density lipoprotein cholesterol (HDL-C). HMW Adn associated positively with total Adn, HDL-C, leptin, and SHBG. Apart from FGF21, irisin associated positively with insulin, high-sensitivity C-reactive protein, γ-glutamyltransferase, and triglycerides, and negatively with QUICKI, SHBG, and IGF binding protein-1. In multivariate regression analyses, irisin predicted lower IS and HMW Adn predicted higher HDL-C body mass index-independently, whereas FGF21 had no independent contribution to IS or lipid variables. CONCLUSION: In 12-year-old children, serum irisin was associated with markers reflecting reduced IS. HMW Adn predicted HDL-C, whereas FGF21 did not contribute to IS or lipid parameters in multivariate regression analyses.

Letrozole versus testosterone for promotion of endogenous puberty in boys with constitutional delay of growth and puberty: a randomised controlled phase 3 trial.

BACKGROUND: The treatment of constitutional delay of growth and puberty (CDGP) is an underinvestigated area in adolescent medicine. We tested the hypothesis that peroral aromatase inhibition with letrozole is more efficacious than intramuscular injection of low-dose testosterone in inducing puberty in boys with CDGP. METHODS: We did a randomised, controlled, open-label trial at four paediatric centres in Finland. Boys aged at least 14 years with CDGP who wanted medical intervention and exhibited the first signs of puberty were randomly assigned in blocks of ten to receive either six intramuscular injections of low-dose testosterone (about 1 mg/kg bodyweight) every 4 weeks for 6 months or peroral letrozole 2·5 mg once daily for 6 months. All boys were followed up for 6 months after the end of treatment. The primary outcomes were changes in testicular volume and hormonal markers of puberty at 6 months after treatment initiation, which were assessed in all participants who received the assigned treatment. All patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01797718. FINDINGS: Between Aug 1, 2013, and Jan 30, 2017, 30 boys were randomly assigned to receive testosterone (n=15) or letrozole (n=15). One boy in the testosterone group was excluded from the primary analyses because of a protocol deviation. During treatment, boys in the letrozole group had higher serum concentrations of luteinising hormone, follicle-stimulating hormone, testosterone, and inhibin B than did boys in the testosterone group. Testicular growth from baseline to 6 months was greater in the letrozole group than in the testosterone group (7·2 mL [95% CI 5·2-9·3] vs 2·2 mL [1·4-2·9]; between-group difference per month 0·9 mL [95% CI 0·6-1·2], p<0·0001). Most adverse events were mild. One boy in the testosterone group had aggressive behaviour for 1 week after each injection, and one boy in the letrozole group had increased irritability at 6 months. INTERPRETATION: Letrozole might be a feasible alternative treatment to low-dose testosterone for boys with CDGP who opt for medical intervention. However, the risks and benefits of manipulating the reproductive axis during early puberty should be weighed carefully. FUNDING: Helsinki University Hospital, Academy of Finland, and Finnish Foundation for Pediatric Research.

Serum IL-1 Receptor Antagonist Concentrations Associate With Unfavorable Metabolic Features in 12-Year-Old Children.

CONTEXT: Elevated IL-1 receptor antagonist (IL-1Ra) concentrations are associated with obesity, insulin resistance, and cardiovascular disease (CVD) risk in adults. OBJECTIVE: To determine if serum IL-1Ra and high-sensitivity C-reactive protein (hs-CRP) levels are associated with markers of reduced insulin sensitivity (IS) and serum lipids in 12-year-old children. DESIGN AND PARTICIPANTS: Of 191 children (n = 109 girls), 78 were categorized as having had birth weight and length appropriate for gestational age (AGA), 69 were small for gestational age, and 44 were AGA and from preeclamptic pregnancies. Serum markers of low-grade inflammation, IS, and lipids were measured. Quantitative Insulin Sensitivity Check Index (QUICKI) was calculated. RESULTS: Mean serum IL-1Ra levels did not differ between the sexes or among the gestational categories. Children in the highest IL-1Ra tertile had lower QUICKI, IGF-binding protein-1, SHBG, and high-density lipoprotein cholesterol values; and higher body mass index (BMI), waist circumference to height ratio (WHtR), and serum insulin, hs-CRP, leptin, and triglyceride concentrations than those in the lowest IL-1Ra tertile. Logistic regression analysis showed higher serum hs-CRP and leptin levels, and WHtR were associated with high serum IL-1Ra levels. IL-1Ra concentration could be used to discriminate the children with lowest IS (area under the curve, 0.68; P < 0.001); hs-CRP level could not. CONCLUSION: Children with the highest IL-1Ra levels had lower IS, higher hs-CRP levels and BMI, and a less favorable lipid profile than those with the lowest IL-1Ra levels, suggesting that high IL-1Ra concentrations may be associated with increased CVD risk in 12-year-old children.

Impaired growth and intracranial calcifications in autosomal dominant hypocalcemia caused by a GNA11 mutation.

OBJECTIVE: Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and inappropriately low PTH concentrations. ADH type 1 is caused by activating mutations in the calcium-sensing receptor (CASR), a G-protein-coupled receptor signaling through α11 (Gα11) and αq (Gαq) subunits. Heterozygous activating mutations in GNA11, the gene encoding Gα11, underlie ADH type 2. This study describes disease characteristics in a family with ADH caused by a gain-of-function mutation in GNA11. DESIGN: A three-generation family with seven members (3 adults, 4 children) presenting with ADH. METHODS: Biochemical parameters of calcium metabolism, clinical, genetic and brain imaging findings were analyzed. RESULTS: Sanger sequencing revealed a heterozygous GNA11 missense mutation (c.1018G>A, p.V340M) in all seven hypocalcemic subjects, but not in the healthy family members (n=4). The adult patients showed clinical symptoms of hypocalcemia, while the children were asymptomatic. Plasma ionized calcium ranged from 0.95 to 1.14mmol/L, yet plasma PTH was inappropriately low for the degree of hypocalcemia. Serum 25OHD was normal. Despite hypocalcemia 1,25(OH)2D and urinary calcium excretion were inappropriately in the reference range. None of the patients had nephrocalcinosis. Two adults and one child (of the two MRI scanned children) had distinct intracranial calcifications. All affected subjects had short stature (height s.d. scores ranging from -3.4 to -2.3 vs -0.5 in the unaffected children). CONCLUSIONS: The identified GNA11 mutation results in biochemical abnormalities typical for ADH. Additional features, including short stature and early intracranial calcifications, cosegregated with the mutation. These findings may indicate a wider role for Gα11 signaling besides calcium regulation.

Markers of Insulin Sensitivity in 12-Year-Old Children Born from Preeclamptic Pregnancies.

OBJECTIVE: To determine whether maternal preeclampsia influences insulin sensitivity (IS) or its biochemical markers in offspring. STUDY DESIGN: Sixty children born from a preeclamptic pregnancy (PRE) and 60 matched control subjects born from a normotensive pregnancy (non-PRE) were studied at age 12 years. IS was estimated using the Quantitative Insulin Sensitivity Check Index (QUICKI), and serum concentrations of adiponectin, leptin, insulin-like growth factor (IGF)-1, IGF-2, IGF-binding protein-1 (IGFBP-1), sex hormone-binding globulin, lipids, and casual blood pressure (BP) were measured. RESULTS: The mean values of QUICKI, serum adiponectin, leptin, IGF-1, IGF-2, IGFBP-1, and sex hormone-binding globulin did not differ between the PRE group and non-PRE group (P > .05 for all). The PRE subjects with the lowest IS (the lowest QUICKI tertile; n = 20) had significantly higher mean serum leptin (P = .007), triglyceride (P = .008), and IGF-1 (P = .005) levels and systolic BP (P = .019), and lower serum IGFBP-1 level (P = .007) compared with PRE subjects with higher QUICKI values (n = 40). Similarly, in logistic regression analysis, higher serum leptin (OR, 1.2; P = .009), triglyceride (OR, 1.2; P = .040), and IGF-1 (OR, 1.1; P = .031) levels and systolic BP (OR, 5.8; P = .024) were associated with low QUICKI in the PRE group. CONCLUSION: Maternal preeclampsia did not produce decreased IS in offspring by age of 12 years. However, the offspring with the lowest IS had higher mean serum triglyceride level and systolic BP, suggesting that components of the metabolic syndrome may cluster in this subgroup.

Cinacalcet Treatment in an Adolescent With Concurrent 22q11.2 Deletion Syndrome and Familial Hypocalciuric Hypercalcemia Type 3 Caused by AP2S1 Mutation.

CONTEXT: The 22q11.2 deletion syndrome (DS) is a common multiple anomaly syndrome in which typical features include congenital heart defects, facial dysmorphism, and palatal anomalies. Hypocalcemia due to hypoparathyroidism is a common endocrine manifestation resulting from variable parathyroid hypoplasia, but hypercalcemia has not previously been reported in 22q11.2 DS. CASE DESCRIPTION: Our patient is a 16-year-old adolescent male with dysmorphic facial features and delayed motor and speech development. At 2 years of age, 22q11.2 DS was confirmed by fluorescence in situ hybridization. In contrast to hypoparathyroidism that is usually seen in 22q11.2 DS, this patient had early childhood-onset hypercalcemia with inappropriately high PTH levels and hypocalciuria. Genomic DNA was obtained from the proband and screened for calcium-sensing receptor (CASR) mutations with negative results. No parathyroid tissue could be localized by imaging or surgical exploration. As a result of symptomatic hypercalcemia, the patient was treated with a calcimimetic (cinacalcet). During the treatment, plasma calcium normalized with mild symptoms of hypocalcemia. After discontinuation of cinacalcet, calcium returned to high pretreatment levels. Further DNA analysis of adaptor protein-2 σ subunit (AP2S1) showed a heterozygous missense mutation c.44 G>T, resulting in a p.R15L substitution; the mutation was absent in the healthy parents and two siblings. CONCLUSIONS: Hypercalcemia in our patient with 22q11.2 DS could be explained by the de novo mutation in AP2S1. Identification of a genetic cause for hypercalcemia is helpful in guiding management and avoiding unnecessary treatment.

Adrenocortical hormonal activity in 20-year-old subjects born small or appropriate for gestational age.

BACKGROUND: Altered adrenocortical activity is one suggested mechanism relating small birth size with the metabolic syndrome in adulthood. Adrenal androgen concentrations are higher in children born small (SGA) than appropriate for gestational age (AGA). AIM: To compare adrenocortical hormonal activity between 20-year-old subjects born SGA or AGA. METHODS: Seventy 20-year-old subjects (35 SGA and 35 age- and gender-matched AGA controls) were studied. Serum cortisol, cortisone, corticosteroid-binding globulin (CBG), glucocorticoid bioactivity (GBA), aldosterone, dehydroepiandrosterone sulfate (DHEAS) and androstenedione were measured, and the free cortisol index (FCI) was calculated. RESULTS: The mean levels of glucocorticoid parameters, aldosterone, DHEAS or androstenedione did not differ between the SGA and AGA groups. In both groups, the males had lower cortisol (p < 0.05) and CBG levels (p < 0.01) and higher DHEAS (p < 0.01) concentrations than the females. Females who used hormonal contraceptives had higher cortisol and CBG levels (p < 0.01) but similar FCI, GBA and DHEAS levels than females who did not use contraceptives. CONCLUSION: No differences in adrenocortical activity were found between 20-year-old SGA and AGA subjects. Enhanced peripubertal adrenal androgen secretion seems to disappear by early adulthood in full-term born SGA subjects. FCI and GBA are useful parameters in the evaluation of the glucocorticoid milieu during hormonal contraceptive use.

Tracking serum lipid levels and the association of cholesterol concentrations, blood pressure and cigarette smoking with carotid artery intima-media thickness in young adults born small for gestational age.

BACKGROUND: Small birth size is associated with increased cardiovascular disease risk, but the mediating factors are poorly understood. METHODS AND RESULTS: Serum lipids, blood pressure (BP), carotid artery intima-media thickness (CA-IMT), and brachial artery flow-mediated dilatation (BA-FMD) were studied in 70 20-year-old subjects [35 sex- and age-matched pairs born small (SGA) and appropriate for gestational age (AGA)]. The SGA subjects had higher serum levels of low-density lipoprotein (LDL) cholesterol, total/high-density lipoprotein (HDL) and LDL/HDL cholesterol ratios, and lower HDL cholesterol levels than the AGA subjects (2.71 vs 2.37 mmol/L, P<0.05; 3.12 vs 2.80, P<0.01; 1.98 vs 1.61, P=0.002; 1.43 vs 1.56 mmol/L, P<0.05, respectively). In the SGA group, total and LDL cholesterol levels correlated inversely with adult height SD score (r=0.463, P=0.006 and r=0.413, P=0.015, respectively). CA-IMT or BA-FMD did not differ between the groups, but cigarette smoking, higher diastolic BP, and shorter birth length associated with higher CA-IMT in the whole study population. A clear tracking of cholesterol levels was found from 12 to 20 years. CONCLUSIONS: SGA subjects had more unfavorable lipid profiles than the controls, the shortest having the highest LDL cholesterol. Cigarette smoking, higher diastolic BP, and shorter birth length associated with higher CA-IMT in the whole study population. A clear tracking of cholesterol levels through adolescence enables early targeting of lifestyle counseling for reducing cardiovascular disease risk.

Maternal preeclampsia predicts elevated blood pressure in 12-year-old children: evaluation by ambulatory blood pressure monitoring.

Ambulatory blood pressure (ABP) monitoring offers a reliable method for determining blood pressure (BP) in children. The aim of this cohort study was to examine whether maternal preeclampsia is associated with elevated BP in an offspring. The study population consisted of 57 children born to preeclamptic mothers (PRE) and their 57 age- and sex-matched control subjects born to normotensive mothers (non-PRE). We examined the 24-h ABP at 12 y of age in the PRE and non-PRE children. Within the two groups, the association of anthropometric measures, plasma catecholamine (epinephrine [E], norepinephrine [NE]) concentrations, and ABP was examined. The PRE children had significantly higher mean 24-h systolic and diastolic ABPs than the non-PRE children. The same was true for the mean daytime and nighttime systolic and diastolic ABPs. The PRE boys had higher 24-h systolic ABP than the PRE girls. In the PRE children, high plasma E concentration and being born small for gestational age (SGA) predicted high systolic 24-h ABP in logistic regression analysis. In the non-PRE children, high current body mass index (BMI) and high plasma E concentration was associated with high systolic 24-h ABP. In conclusion, systolic and diastolic ABP values were elevated in the PRE children. High plasma E concentration and being born SGA were associated with high systolic 24-h ABP in the PRE children. Presumably maternal preeclampsia affects offspring via several mechanisms, including genetic ones and metabolic consequences of restricted intrauterine growth.

Preeclampsia and androgen receptor gene CAG repeat length: results from both children and women.

PURPOSE: We studied whether the CAG (encoding glutamine) repeat length polymorphism in the first exon of the androgen receptor (AR) gene is predictive of preeclampsia. METHODS: Fifty-nine children born after preeclamptic pregnancy (PRE) and 58 control subjects born after normotensive pregnancy (non-PRE) were genotyped for the CAG repeat length of the AR gene. Secondly, the ARCAG repeat lengths of 133 unrelated preeclamptic women and 112 healthy controls were studied. The mean AR gene CAG lengths were compared between the preeclampsia and the control groups. RESULTS: The mean length of the CAG repeat segment among children was significantly shorter in the PRE group compared with the non-PRE group (p = 0.02). Interestingly, the difference between the PRE and the non-PRE boys was even more significant (p = 0.008). Also the distribution of allele frequencies was different, short repeat lengths being overrepresented in the PRE children. However, there were no significant differences in the mean CAG repeat lengths between the unrelated preeclamptic women and their controls, but the shortest CAG repeat lengths were found only in the preeclamptic women. CONCLUSIONS: The AR gene CAG repeat length is not a major determinant in the development of preeclampsia. The association of the shortest CAG repeats with preeclampsia is possible, but a larger study group is needed to confirm this finding.

Association of serum lipid concentrations, insulin resistance index and catch-up growth with serum cortisol/cortisone ratio by liquid chromatography tandem mass spectrometry in children born small for gestational age.

Intrauterine growth restriction (IUGR) may influence adrenocortical function, lipid metabolism and glucose tolerance in later life. Both cortisol (F) synthesis and metabolism contribute to serum F concentrations. 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) enzyme converts F to biologically inactive cortisone (E). Decreased 11beta-HSD2 activity has been suggested for a reason to IUGR and to its metabolic consequences. Our aim was to develop a specific liquid chromatography - tandem mass spectrometry (LC-MS/MS) method for analysing serum F and E concentrations, to determine the F/E ratios, and to correlate them with serum lipid concentrations, insulin resistance index (HOMA-IR), and catch-up growth in children born small for gestational age (SGA). The mean serum F and E concentrations, and F/E ratios did not differ between the SGA and their control children at 12 y age. The SGA children in the highest F/E ratio quartile had poorer gain in height between 0-12 y, and higher serum total and LDL cholesterol levels than those with lower F/E ratios. In logistic regression analysis, high LDL cholesterol, high HOMA-IR, and early pubertal stage associated with high F/E ratio in the SGA children. In conclusion, our LC-MS/MS method enables a reliable measurement of both F and E concentrations from a single serum sample. High serum F/E ratio may be associated with IUGR, its metabolic consequences, and poor catch-up growth in a subset of SGA children.

Serum markers of GH and insulin action in 12-year-old children born small for gestational age.

OBJECTIVES: Our aim was to determine whether markers of growth hormone and insulin action differ between children born small for gestational age (SGA) and those born of an appropriate size for gestational age (AGA). DESIGN: Fifty-five SGA children and their 55 age- and sex-matched AGA control subjects were studied in a case-control setting at 12 years of age. METHODS: We examined serum concentrations of insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein (IGFBP)-1 and IGFBP-3, sex hormone binding globulin (SHBG), leptin, fasting insulin, and blood glucose. Insulin sensitivity was evaluated by the homeostasis model assessment for insulin resistance (HOMA-IR). RESULTS: The body mass index (BMI), sex, and puberty-adjusted mean serum IGF-I concentration was higher in the SGA than in the AGA children (303.4 vs 282.3 microg/l, P = 0.006). The mean serum concentrations of IGF-II, IGFBP-I, IGFBP-3, SHBG, fasting insulin, blood glucose and HOMA-IR did not differ between the SGA and the AGA group. The BMI, sex, and puberty-adjusted mean serum leptin concentration was lower in the SGA than in the AGA children (7.9 vs 10.1 microg/l, P = 0.037). In multiple logistic regression analysis, high HOMA-IR predicted high serum IGF-I levels in the SGA children (odds ratio 8.3; 95% confidence interval 1.7-41; P = 0.010), whereas in the AGA group HOMA-IR did not associate with the serum IGF-I level. CONCLUSIONS: The BMI, sex, and puberty-adjusted mean serum IGF-I concentration was significantly higher and the leptin concentration was lower in the SGA than in the AGA children. No differences were found in the indices of insulin action or sensitivity between the SGA and AGA children at 12 years of age. However, HOMA-IR strongly associated with serum IGF-I levels in the SGA children.

Blood pressure, serum lipids, fasting insulin, and adrenal hormones in 12-year-old children born with maternal preeclampsia.

Women with prior preeclamptic pregnancies have an increased risk for metabolic syndrome and cardiovascular diseases. Maternal preeclampsia has been associated with elevated blood pressure (BP) in offspring during childhood. The aim of our study was to determine whether elevated BP pressure and metabolic changes, such as dyslipidemia, insulin resistance, and increased adrenal hormonal activity, are found in 12-yr-old children of preeclamptic mothers. Sixty children born after preeclamptic pregnancy (PRE) and 60 matched control subjects born after normotensive pregnancy (non-PRE) were studied at the age of 12 yr. The case-control pairs were matched for sex, gestational age (+/-1 wk), and size at birth. We measured BP and concentrations of blood glucose, serum fasting insulin, total and high density lipoprotein cholesterol, triglycerides, cortisol, dehydroepiandrosterone sulfate, and plasma epinephrine (E) and norepinephrine (NE). Low density lipoprotein cholesterol was calculated according to the Friedewald-Fredrickson formula. The PRE children had significantly higher mean systolic (116.4 vs. 113.2 mm Hg; P = 0.021) and diastolic (73.9 vs. 70.3 mm Hg; P = 0.022) BP than the non-PRE children, even when adjusted by current weight and height. At 12 yr of age, systolic BP values correlated inversely with birth weight (r = -0.459; P < 0.001) and length SD scores (r = -0.429; P = 0.001) in the PRE children. The mean concentrations of serum total, low density lipoprotein, and high density lipoprotein cholesterol; triglycerides; fasting insulin; blood glucose; serum cortisol; and dehydroepiandrosterone sulfate did not differ between the PRE and non-PRE groups. However, the mean plasma E concentration was higher in the PRE than in the non-PRE children (0.32 vs. 0.28 nmol/liter; P = 0.042), whereas the mean NE concentration did not differ between these two groups. In conclusion, 12-yr-old children born with maternal preeclampsia had elevated systolic and diastolic BPs and slightly increased E levels in the circulation. It is not known whether these changes are caused by genetic factors or by preeclampsia itself.

Increased adrenocortical and adrenomedullary hormonal activity in 12-year-old children born small for gestational age.

OBJECTIVES: To determine whether adrenal hormonal activity is altered in children born small for gestational age (SGA), and whether concentrations of adrenal hormones relate to those of serum lipids or to anthropometric measures. STUDY DESIGN: We studied 55 SGA children and 55 appropriate for gestational age (AGA) children at the age of 12 years in a case-control setting. The concentrations of fasting serum cortisol, dehydroepiandrosterone sulfate (DHEAS), plasma epinephrine (E), and norepinephrine (NE) were analyzed. RESULTS: The SGA children had significantly higher mean concentrations of serum DHEAS (3.53 vs 2.89 micromol/L, P =.009) and plasma E (0.33 vs 0.25 nmol/L, P =.005) than their age- and sex-matched control subjects. The mean serum cortisol and plasma NE concentrations did not differ significantly between the groups. However, the SGA children in the highest quartile for serum cortisol had significantly higher concentrations of plasma E (0.50 vs 0.28 nmol/L, P <.001), serum LDL (3.21 vs 2.73 mmol/L, P =.025) and total cholesterol (5.06 vs 4.42 mmol/L, P =.021) than the SGA children in the lower cortisol quartiles. The factors associating with high levels of plasma E in the SGA children were high level of serum cortisol [odds ratio (OR) = 3.8, 95% confidence interval (95% CI) = 1.5-10], LDL cholesterol (OR = 3.9, 95% CI = 1.3-12), male sex (OR = 8.3, 95% CI = 1.0-68) and low birth weight (OR = 1.4, 95% CI = 1.0-1.8) in multiple logistic regression analysis. CONCLUSIONS: Twelve-year-old children born SGA had increased DHEAS and epinephrine levels in circulation. High serum cortisol concentrations are associated with high epinephrine, LDL, and total cholesterol levels.

Ambulatory blood pressure in 12-year-old children born small for gestational age.

An association between low birth weight and subsequent elevated blood pressure has been demonstrated in a large number of studies, but the number of subjects born small for gestational age in these studies has been negligible. The inverse relationship between birth weight and blood pressure in children has been evaluated previously with an ambulatory blood pressure device, but only in children with normal birth weights. In this prospective case-control study from birth to the age of 12, we evaluated the ambulatory blood pressures in 50 children born at term but small for gestational age and in 50 full-term children born appropriate for gestational age. Children born small for gestational age had similar mean+/-SD systolic (117.5+/-8.5 mm Hg versus 115.3+/-7.4 mm Hg, P=0.221), and diastolic (69.2+/-5.3 mm Hg versus 67.3+/-4.4 mm Hg, P=0.075) 24-hour ambulatory blood pressure compared with the values of the children born appropriate for gestational age. However, 24-hour systolic blood pressure in the small-for-gestational-age children was higher (3.90 mm Hg; 95% confidence interval, 0.65 to 7.15) after adjusting for current body mass index. The difference in current body mass index was the only determinant for the difference in systolic blood pressure between the groups. Birth weight had no direct association with the blood pressure values. Impaired fetal growth may have a relationship with higher later blood pressure, but in 12-year-old children, blood pressure differences between small for gestational age and appropriate for gestational age children are much more dependent on current body size.