Quality of life and socioeconomic and educational status in patients with congenital hypothyroidism.

BACKGROUND: The aim of this study was to investigate the influence of primary congenital hypothyroidism (CH) on quality of life, level of education and socioeconomic status (SES). METHODS: Two independent study cohorts, a national and a regional, were collected from Finnish national registers and patient records. Data on social security benefits, SES, marital status, and education were collected from Statistics Finland. Health-related quality of life (HRQoL) was studied in the regional patient cohort with the standardized 15D and 16D instruments. RESULTS: There were no statistically significant differences in education level, marital status, or SES between CH patients (n = 40) and their matched controls at the age of 25 years. The mean 15D score was both statistically significantly and clinically importantly lower in CH patients (n = 29) than controls (0.904 vs. 0.953, p = 0.008). CH patients reported significantly lower scores across various dimensions of physical and mental HRQoL, including breathing, sleeping, speech, excretion, mental function, distress, and vitality. The mean 16D score was lower in CH patients compared to controls (0.917, vs. 0.947), but without statistical significance. CONCLUSION: SES of CH patients did not differ from matched controls. Thus, most CH patients integrate well into society, but their HRQoL is impaired. IMPACT: Most patients with primary congenital hypothyroidism integrate well into society. In the current study, their socioeconomic and marital status did not differ from matched controls at the age of 25 years. However, health-related quality of life measured using 15D instrument was impaired. Every fourth patient reported that congenital hypothyroidism influenced everyday life.

Health-related quality of life of young adult women with a history of premature adrenarche.

INTRODUCTION: Children with premature adrenarche (PA) have increased adrenal androgen concentrations and earlier pubertal development than their peers. Early sexual maturation and exposure to androgens have both been associated with an increased risk for neuropsychological adversities in adulthood. Such adversities would presumably influence the experienced health-related quality of life (HRQoL) of those affected. METHODS: A longitudinal case-control cohort study, in which 30 PA girls and 40 age-matched controls were followed from childhood to young adult age. The main outcome measure was the total 15D HRQoL score. In addition, we assessed specific dimensions of the questionnaire, the subjects' relationship statuses and living arrangements. RESULTS: There were no differences between the groups in the overall 15D scores (PA, 0.956 (0.052); control, 0.947 (0.055); p 0.482), or on any dimension of this instrument. CONCLUSION: The study suggests that a history of PA does not lead to impaired HRQoL in adult age.

Accelerated Early Childhood Growth Is Associated With the Development of Earlier Adrenarche and Puberty.

Context: Small birth size and increased postnatal growth have been associated with earlier timing of adrenarche and puberty, but it is not well known whether these factors alone or together lead to earlier maturation. Objective: This work aimed to search for different growth trajectories using a clustering approach to analyze the effects of birth size and postnatal growth on adrenarchal and pubertal development. Methods: Altogether 351 children (48% girls) were examined prospectively at ages 6 to 9 and 9 to 11 years. Birth and early-growth data were collected retrospectively. Main outcome measures included clinical signs of adrenarche and puberty, and serum androgen concentrations (dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, testosterone). Results: We detected 4 clusters with different birth sizes and postnatal growth trajectories: 1) children with average birth size and increased postnatal growth (AI), 2) children with small birth size and increased postnatal growth (SI), 3) children with average birth size and postnatal growth (AA), and 4) children with small birth size and average postnatal growth (SA). Thelarche at age 9 to 11 was most common and serum androgens at ages 6 to 9 and 9 to 11 years were highest in girls belonging to the AI and SI groups. Similar patterns in the onset of puberty and in androgen levels were not seen in the SA group. Conclusion: Increased early growth and weight gain predict higher serum androgen concentrations and earlier onset of puberty in girls. Adrenarche and puberty do not appear to be shifted earlier in children with small birth size who do not have catch-up growth.

Mechanisms of thyrotropin receptor-mediated phenotype variability deciphered by gene mutations and M453T-knockin model.

The clinical spectrum of thyrotropin receptor-mediated (TSHR-mediated) diseases varies from loss-of-function mutations causing congenital hypothyroidism to constitutively active mutations (CAMs) leading to nonautoimmune hyperthyroidism (NAH). Variation at the TSHR locus has also been associated with altered lipid and bone metabolism and autoimmune thyroid diseases. However, the extrathyroidal roles of TSHR and the mechanisms underlying phenotypic variability among TSHR-mediated diseases remain unclear. Here we identified and characterized TSHR variants and factors involved in phenotypic variability in different patient cohorts, the FinnGen database, and a mouse model. TSHR CAMs were found in all 16 patients with NAH, with 1 CAM in an unexpected location in the extracellular leucine-rich repeat domain (p.S237N) and another in the transmembrane domain (p.I640V) in 2 families with distinct hyperthyroid phenotypes. In addition, screening of the FinnGen database revealed rare functional variants as well as distinct common noncoding TSHR SNPs significantly associated with thyroid phenotypes, but there was no other significant association between TSHR variants and more than 2,000 nonthyroid disease endpoints. Finally, our TSHR M453T-knockin model revealed that the phenotype was dependent on the mutation's signaling properties and was ameliorated by increased iodine intake. In summary, our data show that TSHR-mediated disease risk can be modified by variants at the TSHR locus both inside and outside the coding region as well as by altered TSHR-signaling and dietary iodine, supporting the need for personalized treatment strategies.

Effects of 2-Year Physical Activity and Dietary Intervention on Adrenarchal and Pubertal Development: The PANIC Study.

CONTEXT: Childhood overweight has been linked to earlier development of adrenarche and puberty, but it remains unknown if lifestyle interventions influence sexual maturation in general populations. OBJECTIVE: To investigate if a 2-year lifestyle intervention influences circulating androgen concentrations and sexual maturation in a general population of children. METHODS: We conducted a 2-year physical activity and dietary intervention study in which 421 prepubertal and mostly normal-weight 6- to 9-year-old children were allocated either to a lifestyle intervention group (119 girls, 132 boys) or a control group (84 girls, 86 boys). The main outcome measures were serum dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione (A4), and testosterone concentrations, and clinical adrenarchal and pubertal signs. RESULTS: The intervention and control groups had no differences in body size and composition, clinical signs of androgen action, and serum androgens at baseline. The intervention attenuated the increase of DHEA (P = .032), DHEAS (P = .001), A4 (P = .003), and testosterone (P = .007) and delayed pubarche (P = .038) in boys but it only attenuated the increase of DHEA (P = .013) and DHEAS (P = .003) in girls. These effects of lifestyle intervention on androgens and the development of pubarche were independent of changes in body size and composition, but the effects of intervention on androgens were partly explained by changes in fasting serum insulin. CONCLUSION: A combined physical activity and dietary intervention attenuates the increase of serum androgen concentrations and sexual maturation in a general population of prepubertal and mostly normal-weight children, independently of changes in body size and composition.

Comorbidity in Congenital Hypothyroidism-A Nationwide, Population-based Cohort Study.

CONTEXT: Patients with congenital hypothyroidism (CH) are affected more often than the general population by other chronic diseases and neurological difficulties. OBJECTIVE: The aim of this nationwide population-based register study was to investigate the incidence of congenital malformations, comorbidities, and the use of prescribed drugs in patients with primary CH. METHODS: The study cohort and matched controls were identified from national population-based registers in Finland. All diagnoses from birth until the end of 2018 were collected from the Care Register, and subject-specific prescription drug purchases were identified from The Prescription Register from birth until the end of 2017. RESULTS: Diagnoses of neonatal and chronic diseases were collected for 438 full-term patients and 835 controls (median follow-up time 11.6 years; range, 0-23 years). Newborns with CH were more often found to have neonatal jaundice (11.2% and 2.0%; P < .001), hypoglycemia (8.9% and 2.8%; P < .001), metabolic acidemia (3.2% and 1.1%; P = .007), and respiratory distress (3.9% and 1.3%; P < .003) as compared to their matched controls.Congenital malformations were diagnosed in 66 of 438 (15.1%) CH patients and in 62 of 835 (7.4%) controls (P < .001). The most commonly affected extrathyroidal systems were the circulatory and musculoskeletal systems. The cumulative incidence of hearing loss and specific developmental disorders was higher among CH patients than controls. The use of antidepressant and antipsychotic drugs was similar in CH patients and their controls. CONCLUSION: CH patients have more neonatal morbidity and congenital malformations than their matched controls. The cumulative incidence of neurological disorders is higher in CH patients. However, our results do not support the existence of severe psychiatric comorbidity.

Cardiorespiratory Fitness in Young Adult Women With a History of Premature Adrenarche.

Context: Premature adrenarche (PA) may predispose to some adverse long-term health outcomes. Cardiorespiratory fitness (CRF) is one of the strongest factors known to predict overall health, but no data exist on the CRF of women with a history of PA. Objective: To study if hyperandrogenism in childhood resulting from PA leads to a measurable difference in CRF between young adult PA and control women. Methods: A total of 25 women with PA and 36 age-matched controls were followed from prepubertal age until adulthood. Anthropometric measurements, body composition, biochemical, and lifestyle factors were assessed. The main outcome measure was maximal cycle ergometer test result at the mean age of 18.5 years. We also assessed prepubertal predicting factors for CRF with different linear regression models. Results: Though prepubertal children with PA were taller and heavier than their non-PA peers, there were no significant differences in height, body mass index, body composition, or physical activity in young adulthood. We observed no significant differences in any of the parameters of the maximal cycle ergometer test, including maximal load (P = .194) or peak oxygen consumption (P = .340). Hemodynamic responses of the groups were similar. None of the examined models or prepubertal factors significantly predicted CRF at adult age. Conclusion: This study suggests that hyperandrogenism in childhood/adolescence resulting from PA does not have a significant impact on adulthood CRF.

Treatment of Congenital Hypothyroidism: Impact of Secular Changes in Levothyroxine Initial Dose on Early Growth.

INTRODUCTION: Newborn screening of congenital hypothyroidism (CH) has enabled early treatment with levothyroxine (LT4), ensuring normal growth and development. The initial LT4 dose recommendation has increased over decades. We evaluated whether the increased LT4 dosing influenced thyroid-stimulating hormone (TSH) and thyroxine (fT4) concentrations, growth, or treatment-related symptoms. METHODS: LT4 doses, TSH, fT4, anthropometrics, and treatment-related symptoms until age 2 years were evaluated in 172 Finnish CH patients born between 1980 and 2018. The patients were grouped according to birth decade: 1980s (n = 19, mean LT4 starting dose 6.8 µg/kg/day), 1990s (n = 50, 7.4 µg/kg/day), 2000s (n = 59, 9.7 µg/kg/day), and 2010s (n = 44, 10.8 µg/kg/day). RESULTS: TSH concentrations were higher during the first 2 years of life in children born in the 1980s compared to children born later. TSH concentrations were often subnormal in children receiving higher LT4 doses (children born in the 2000s and 2010s). However, symptoms of overtreatment were uncommon. Linear or head growth showed no differences between the groups during the first 2 years of life. Although growth was within the normal spectrum, children in all groups were shorter than their target length at 2 years and their weight-for-length was above the mean through the first 2 years of life. DISCUSSION: Current treatment practice with higher LT4 dose normalizes TSH rapidly without significant increase in side effects. However, irrespective of initial LT4 dose, children were shorter than expected at 2 years of age. Effects of different initial LT4 dose on cognitive development urges further investigation.

Incidence of primary congenital hypothyroidism over 24 years in Finland.

BACKGROUND: A rise in the incidence of congenital hypothyroidism (CH) has been reported worldwide. This nationwide study aimed to describe the secular trends and current incidence of CH in Finland. METHODS: Two independent study cohorts, a national and a regional, were collected from national registers and patient records. The national cohort represents all CH cases born in Finland between 1994 and 2017. Birth data, results of the screening test, and the incidence of CH were reviewed. RESULTS: Between 1994 and 2017, 1,400,028 children were born in Finland. Of these children, 503 were diagnosed with primary CH (incidence 1:2783). Male-to-female sex ratio was 1:2.0. The nationwide incidence was 33 cases per 100,000 live births between 1994 and 1999, 38 cases per 100,000 live births between 2000 and 2005, 40 cases per 100,000 live births between 2006 and 2011, and 33 cases per 100,000 live births between 2012 and 2017. In the regional cohort (n = 139), the incidence of transient CH was 3.6%. The incidence of mild, moderate, and severe CH remained constant. CONCLUSIONS: In Finland, the incidence of CH has not changed during the 24-year study period. IMPACT: As opposed to recent reports worldwide, the incidence of congenital hypothyroidism has not changed between 1994 and 2017 in Finland. The proportions of mild, moderate, and severe congenital hypothyroidism did not change significantly over the study period. Lowering the TSH cut-off limit or increasing immigration did not affect the incidence rate of primary congenital hypothyroidism in Finland.

Recurrent Hypokalemia and Adrenal Steroids in Patients With APECED.

Context: Hypokalemia is a common finding in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) but its exact cause often remains unknown. Objective: To explore the prevalence and etiology of hypokalemia and the role of adrenal steroids therein in a cohort of patients with APECED. Methods: We performed a cross-sectional assessment and retrospective data collection on 44 Finnish patients with APECED to identify subjects with episodes of hypokalemia. Also 68 healthy matched controls attended the cross-sectional evaluation. Factors associating with a tendency for hypokalemia were analyzed by reviewing medical records during 1960-2021 and performing a cross-sectional analysis of serum adrenal steroids. Results: In total 14 of the 44 APECED patients (32%) had episodes of hypokalemia; 2 presented with hypokalemia at cross-sectional evaluation and 12 had a history of hypokalemia before the cross-sectional evaluation. Hypokalemic episodes started at the median age of 14.1 years; 12/14 (86%) had primary adrenal insufficiency (PAI). The median number of hypokalemic periods per year was 0.3 (range 0.04-2.2); the frequency correlated positively with the number of clinical APECED manifestations at the time of cross-sectional evaluation (r=0.811, p<0.001). Etiologies of hypokalemia varied but episodes often occurred when new clinical manifestations developed and during hospitalizations. Three patients had kidney defects, also associated with electrolyte imbalances. Severity of hypokalemia varied (range 2.2-3.2 mmol/L), but no severe complications were observed. At cross-sectional evaluation, patients with PAI (n = 30) had significantly lower median plasma potassium and higher sodium concentration than controls, suggesting that fludrocortisone treatment contributed to hypokalemia. Detailed analysis of adrenal steroids provided no conclusive differences between patients with and without episodes of hypokalemia. Conclusions: In APECED, hypokalemia is common and varies in terms of frequency, etiology, and severity. PAI and kidney disease predispose to hypokalemia. In addition, hypokalemic periods seem to be more common in patients with more severe phenotype of APECED.

The Mediating Role of Endocrine Factors in the Positive Relationship Between Fat Mass and Bone Mineral Content in Children Aged 9-11 Years: The Physical Activity and Nutrition in Children Study.

Introduction: We aimed to investigate whether the relationship between fat mass and bone mineral content (BMC) is mediated by insulin, leptin, adiponectin, dehydroepiandrosterone sulphate, testosterone and estradiol in children aged 9-11 years. Materials and Methods: We utilised cross-sectional data from the Physical Activity and Nutrition in Children study (n = 230 to 396; 112 to 203 girls). Fat mass and BMC were assessed with dual-energy X-ray absorptiometry. Endocrine factors were assessed from fasted blood samples. We applied the novel 4-way decomposition method to analyse associations between fat mass, endocrine factors, and BMC. Results: Fat mass was positively associated with BMC in girls (ß = 0.007 to 0.015, 95% confidence interval (CI) 0.005 to 0.020) and boys (ß = 0.009 to 0.015, 95% CI 0.005 to 0.019). The relationship between fat mass and BMC was mediated by free leptin index in girls (ß = -0.025, 95% CI -0.039 to -0.010) and boys (ß = -0.014, 95% CI -0.027 to -0.001). The relationship between fat mass and BMC was partially explained by mediated interaction between fat mass and free leptin index in boys (ß = -0.009, 95% CI -0.013 to -0.004) and by interaction between fat mass and adiponectin in girls (ß = -0.003, 95% CI -0.006 to -0.000). Conclusion: At greater levels of adiponectin and free leptin index, the fat mass and BMC relationship becomes less positive in girls and boys respectively. The positive association between fat mass with BMC was largely not explained by the endocrine factors we assessed. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT01803776], identifier NCT01803776.

Congenital Hypothyroidism and Hyperthyroidism Alters Adrenal Gene Expression, Development, and Function.

Background: The human adrenal cortex undergoes several rapid remodeling steps during its lifetime. In rodents, similar remodeling occurs postnatally in the "X-zone" layer through unknown mechanisms. Furthermore, little is known regarding the impact of thyroid hormone (TH) on adrenal glands in humans. Methods: To investigate the impact of TH on adrenal pathophysiology, we created two genetic murine models mimicking human nonautoimmune hypothyroidism and hyperthyroidism. Moreover, we analyzed serum thyrotropin (TSH) and steroid hormone concentrations in patients diagnosed with congenital hypothyroidism and premature adrenarche (PA). Results: We found that TH receptor beta-mediated hypertrophy of the X-zone significantly elevated the adrenal weights of hyperthyroid women. In the hypothyroid model, the X-zone was poorly developed in both sexes. Moreover, large reciprocal changes in the expression levels of genes that regulate adrenal cortical function were observed with both models. Unexpectedly, up- and downregulation of several genes involved in catecholamine synthesis were detected in the adrenal glands of the hypothyroid and hyperthyroid models, respectively. Furthermore, TSH and adrenal steroid concentrations correlated positively in pediatric patients with congenital hypothyroidism and PA. Conclusions: Our results revealed that congenital hypothyroidism and hyperthyroidism functionally affect adrenal gland development and related steroidogenic activity, as well as the adrenal medulla.

Boys but Not Girls Exposed to Maternal Gestational Diabetes Mellitus Have Unfavorable Fat Distribution.

BACKGROUND: Maternal gestational diabetes mellitus (GDM) and overweight are associated with an increased risk of obesity and the metabolic syndrome in the adult offspring. We studied the influence of maternal GDM on prepubertal children's body composition and bone mineral biochemistry. METHODS: A total of 134 prepubertal Caucasian children (age range 4.4-9.7 years) were studied in a controlled cross-sectional study. Seventy-six children had been exposed to maternal GDM and 58 children born after a normal pregnancy served as controls. The outcome variables were body fat %, android fat %, gynoid fat %, android/gynoid fat ratio, bone mineral density (BMD), bone mineral content (BMC), muscle mass, lean mass (LM) and serum 25-hydroxyvitamin D, ionized calcium, phosphate, and alkaline phosphatase concentrations. RESULTS: There were no differences in body fat %, android fat %, BMD, BMC, muscle mass, or LM between the study groups. Gynoid fat % was higher in the GDM than control children (p = 0.03). Android fat %, gynoid fat %, and android/gynoid fat ratio were higher in the GDM boys than control boys (p = 0.046, 0.037, and 0.038) respectively, but no differences were found between the GDM and control girls. CONCLUSIONS: Boys exposed to maternal GDM presented with more unfavorable fat distribution than their controls, whereas no difference was found between the girls. Otherwise, the differences in body composition were minimal between prepubertal GDM and control children.

PCOS Features and Steroid Profiles Among Young Adult Women with a History of Premature Adrenarche.

CONTEXT: Premature adrenarche (PA) may increase the risk for polycystic ovary syndrome (PCOS). OBJECTIVE: To study features of PCOS in young adult women with a history of PA. METHODS: Thirty PA and 42 control females were followed from prepuberty to young adulthood (median age 18.1 years). The main outcome measures were ovarian function, the use of contraceptives, and clinical and biochemical indicators of hyperandrogenism. RESULTS: We found no differences in the use of hormonal contraceptives (50 vs 50%, PA vs controls, respectively; P > .999), indication for using contraceptives (P = .193), or in the history of oligo- (17 vs 26%, P = .392) and amenorrhea (0 vs 0%, P > .999). Among women not using hormonal contraceptives, those with a history of PA had a higher prevalence of hirsutism (27 vs 0%, P = .023) but not acne (87 vs 67%, P = .252). Steroid profiles were broadly comparable between the groups, but PA women had lower sex hormone-binding globulin (SHBG) concentrations (30.1 vs 62.4 nmol/L, P < .001) resulting in higher free androgen index (3.94 vs 2.14, P < .001). The difference in SHBG levels persisted through body mass index adjustment. SHBG correlated negatively with the homeostasis model assessment for insulin resistance (r -0.498, P = .003). Anti-Müllerian hormone concentrations were comparable between the groups (39.3 vs 32.1 pmol/L, P = .619). CONCLUSION: PA was not associated with evident ovarian dysfunction in young adult women. However, women with a history of PA had decreased SHBG levels and thus, increased bioavailability of circulating androgens.

Long-Term Outcome and Treatment in Persistent and Transient Congenital Hyperinsulinism: A Finnish Population-Based Study.

CONTEXT: The management of congenital hyperinsulinism (CHI) has improved. OBJECTIVE: To examine the treatment and long-term outcome of Finnish patients with persistent and transient CHI (P-CHI and T-CHI). DESIGN: A population-based retrospective study of CHI patients treated from 1972 to 2015. PATIENTS: 106 patients with P-CHI and 132 patients with T-CHI (in total, 42 diagnosed before and 196 after year 2000) with median follow-up durations of 12.5 and 6.2 years, respectively. MAIN OUTCOME MEASURES: Recovery, diabetes, pancreatic exocrine dysfunction, neurodevelopment. RESULTS: The overall incidence of CHI (n = 238) was 1:11 300 live births (1972-2015). From 2000 to 2015, the incidence of P-CHI (n = 69) was 1:13 500 and of T-CHI (n = 127) 1:7400 live births. In the 21st century P-CHI group, hyperinsulinemic medication was initiated and normoglycemia achieved faster relative to earlier. Of the 74 medically treated P-CHI patients, 68% had discontinued medication. Thirteen (12%) P-CHI patients had partial pancreatic resection and 19 (18%) underwent near-total pancreatectomy. Of these, 0% and 84% developed diabetes and 23% and 58% had clinical pancreatic exocrine dysfunction, respectively. Mild neurological difficulties (21% vs 16%, respectively) and intellectual disability (9% vs 5%, respectively) were as common in the P-CHI and T-CHI groups. However, the 21st century P-CHI patients had significantly more frequent normal neurodevelopment and significantly more infrequent diabetes and pancreatic exocrine dysfunction compared with those diagnosed earlier. CONCLUSIONS: Our results demonstrated improved treatment and long-term outcome in the 21st century P-CHI patients relative to earlier.

The effects of a 2-year physical activity and dietary intervention on plasma lipid concentrations in children: the PANIC Study.

PURPOSE: We studied the effects of a physical activity and dietary intervention on plasma lipids in a general population of children. We also investigated how lifestyle changes contributed to the intervention effects. METHODS: We carried out a 2-year controlled, non-randomized lifestyle intervention study among 504 mainly prepubertal children aged 6-9 years at baseline. We assigned 306 children to the intervention group and 198 children to the control group. We assessed plasma concentrations of total, LDL, HDL, and VLDL cholesterol, triglycerides, HDL triglycerides, and VLDL triglycerides. We evaluated the consumption of foods using 4-day food records and physical activity using a movement and heart rate sensor. We analyzed data using linear mixed-effect models adjusted for age at baseline, sex, and pubertal stage at both time points. Furthermore, specific lifestyle variables were entered in these models. RESULTS: Plasma LDL cholesterol decreased in the intervention group but did not change in the control group ( - 0.05 vs. 0.00 mmol/L, regression coefficient (ß) = - 0.0385, p = 0.040 for group*time interaction). This effect was mainly explained by the changes in the consumption of high-fat vegetable oil-based spreads (ß = - 0.0203, + 47% change in ß) and butter-based spreads (ß = - 0.0294, + 30% change in ß), moderate-to-vigorous physical activity (ß = - 0.0268, + 30% change in ß), light physical activity (ß = - 0.0274, + 29% change in ß) and sedentary time (ß = - 0.0270, + 30% change in ß). The intervention had no effect on other plasma lipids. CONCLUSION: Lifestyle intervention resulted a small decrease in plasma LDL cholesterol concentration in children. The effect was explained by changes in quality and quantity of dietary fat and physical activity. CLINICAL TRIAL REGISTRY NUMBER: NCT01803776, ClinicalTrials.gov.

Birth Size as a Determinant of Cardiometabolic Risk Factors in Children.

The association between birth size and cardiometabolic disease risk may be U-shaped. Being born small for gestational age (SGA) has a definitive association with later cardiovascular risk, but the impact of being born large for gestational age (LGA) on cardiometabolic health is more controversial. In addition to birth size, early postnatal growth pattern and later weight gain affect cardiometabolic risk in adulthood. Most SGA-born children have catch-up and LGA-born children have catch-down growth during the first years of life. The extent of this early compensatory growth may contribute to the adverse health outcomes. Both SGA- and LGA-born children are at an increased risk for overweight and obesity. This may have a long-term impact on cardiometabolic health as overweight tends to track to adulthood. Other cardiometabolic risk factors, including alterations in glucose metabolism, dyslipidemia, hypertension, and low-grade inflammation are associated with birth weight. Many of these risk factors are related to overweight or adverse fat distribution. Since later cardiometabolic risk is often mediated by early growth pattern and later overweight in SGA and LGA children, it is important to focus on staying normal weight throughout life. Hence, effective interventions to reduce cardiometabolic risk in LGA and SGA children should be developed.

A 2 year physical activity and dietary intervention attenuates the increase in insulin resistance in a general population of children: the PANIC study.

AIMS/HYPOTHESIS: We studied for the first time the long-term effects of a combined physical activity and dietary intervention on insulin resistance and fasting plasma glucose in a general population of predominantly normal-weight children. METHODS: We carried out a 2 year non-randomised controlled trial in a population sample of 504 children aged 6-9 years at baseline. The children were allocated to a combined physical activity and dietary intervention group (306 children at baseline, 261 children at 2-year follow-up) or a control group (198 children, 177 children) without blinding. We measured fasting insulin and fasting glucose, calculated HOMA-IR, assessed physical activity and sedentary time by combined heart rate and body movement monitoring, assessed dietary factors by a 4 day food record, used the Finnish Children Healthy Eating Index (FCHEI) as a measure of overall diet quality, and measured body fat percentage (BF%) and lean body mass by dual-energy x-ray absorptiometry. The intervention effects on insulin, glucose and HOMA-IR were analysed using the intention-to-treat principle and linear mixed-effects models after adjustment for sex, age at baseline, and pubertal status at baseline and 2 year follow-up. The measures of physical activity, sedentary time, diet and body composition at baseline and 2 year follow-up were entered one-by-one as covariates into the models to study whether changes in these variables might partly explain the observed intervention effects. RESULTS: Compared with the control group, fasting insulin increased 4.65 pmol/l less (absolute change +8.96 vs +13.61 pmol/l) and HOMA-IR increased 0.18 units less (+0.31 vs +0.49 units) over 2 years in the combined physical activity and dietary intervention group. The intervention effects on fasting insulin (regression coefficient ß for intervention effect -0.33 [95% CI -0.62, -0.04], p = 0.026) and HOMA-IR (ß for intervention effect -0.084 [95% CI -0.156, -0.012], p = 0.023) were statistically significant after adjustment for sex, age at baseline, and pubertal status at baseline and 2 year follow-up. The intervention had no effect on fasting glucose, BF% or lean body mass. Changes in total physical activity energy expenditure, light physical activity, moderate-to-vigorous physical activity, total sedentary time, the reported consumption of high-fat (≥60%) vegetable oil-based spreads, and FCHEI, but not a change in BF% or lean body mass, partly explained the intervention effects on fasting insulin and HOMA-IR. CONCLUSIONS/INTERPRETATION: The combined physical activity and dietary intervention attenuated the increase in insulin resistance over 2 years in a general population of predominantly normal-weight children. This beneficial effect was partly mediated by changes in physical activity, sedentary time and diet but not changes in body composition. TRIAL REGISTRATION: ClinicalTrials.gov NCT01803776 Graphical abstract.

Tracking of Serum DHEAS Concentrations from Age 1 to 6 Years: A Prospective Cohort Study.

CONTEXT: Adrenarche is a gradual process, but its programming is unknown. OBJECTIVE: The objective of this article is to examine the trajectory of dehydroepiandrosterone sulfate (DHEAS) from age 1 to 6 years and the associations of early growth with DHEAS concentration by age 6 years. DESIGN AND PARTICIPANTS: Longitudinal data from a population sample of 78 children (43 girls) with serum samples for DHEAS and insulin-like growth factor 1 (IGF-1) measurements available at ages 1 and 6 years. MAIN OUTCOME MEASURE: Serum DHEAS concentration at age 6 years. RESULTS: DHEAS concentration at age 1 year correlated with DHEAS concentration at age 6 years (r = 0.594, P < .001). DHEAS levels at age 6 years increased with tertiles of DHEAS at age 1 year (medians (µg/dL); 4.2, 14.4, 22.6; P < .001) and with those of greater increase in length by age 1 year (6.0, 11.7, 16.4; P = .047), and decreased with tertiles of birth length (17.7, 13.3, 7.1; P = .042). In a regression model including birth size, biochemical covariates at age 1 year, and growth measures by age 6 years, higher DHEAS concentration at age 1 year was an independent determinant of falling into the highest DHEAS tertile at age 6 years. CONCLUSIONS: Higher serum DHEAS concentrations already at age 1 year are associated with those at age 6 years. Also, shorter birth length and rapid catch-up growth in length by age 1 year are associated with higher DHEAS concentrations at age 6 years. These results corroborate the early origin of adrenarche and strongly suggest that part of adrenarchal programming already takes place by the end of infancy.

Child-related and parental predictors for thelarche in a general population of girls: the PANIC study.

BACKGROUND: Obesity has been associated with earlier thelarche, whereas other predictors for it remain unclear. METHODS: We studied child-related and parental predictors for earlier thelarche in 195 girls aged 6-8 years followed up for 2 years. A physician evaluated breast development by inspection and palpation. Body fat percentage (BF%) was measured by dual-energy X-ray absorptiometry, diet by food records, and physical activity and sedentary time by body movement and heart rate monitors. Parental education, smoking, and alcohol consumption and household income were assessed by questionnaires. Gestational age, birth weight, and maternal prepregnancy BMI were obtained from hospital registers. Predictors for thelarche were examined using logistic regression analysis adjusted for age and follow-up time. RESULTS: The incidence of thelarche during 2 years increased by 11% (OR 1.11, CI 1.06-1.17, p < 0.001) for 1 unit increase in baseline BF%. Girls with a smoking parent had a 2.64 (95% CI 1.21-5.77, p = 0.015) times higher incidence of thelarche than other girls. The associations of lower parental education and higher maternal prepregnancy BMI with the higher incidence of thelarche were largely explained by BF%. Other possible predictors were not associated with thelarche. CONCLUSIONS: Higher BF% and exposure to tobacco smoke are independent predictors for earlier thelarche.