Increased symptoms of anxiety and depression in prepubertal girls, but not boys, with premature adrenarche: associations with serum DHEAS and daily salivary cortisol concentrations.

Concerns over anxiety and depressive symptoms in children with premature adrenarche (PA) have been recently raised. However, to date, most relevant studies are on a small number of girls. In this cross-sectional study, 82 pre-pubertal children (66 girls and 16 boys) diagnosed with PA, were compared to 63 control children regarding their psychological characteristics and hypothalamic-pituitary-adrenal (HPA) axis function, as assessed by salivary cortisol measurement. Symptoms of anxiety and depression were assessed by child self-report (Spence Children's Anxiety Scale (SCAS) and Depression self-rating scale for Children (DSRS)) and parent-report (Child Behaviour Checklist (CBCL)) tests validated for the Greek population. Salivary cortisol levels were determined directly after awakening (approximately 7am) and evening (8pm) of the same day. Morning serum DHEAS levels were assessed in PA children. Girls with PA scored significantly higher on anxiety (p = .016) and depression (p =.039) scales than controls. No group differences were noted for parent reports and children's salivary cortisol concentrations. Boys with PA did not demonstrate significant differences in any of the aforementioned parameters. Our findings suggest that girls with PA may be at higher risk for reporting symptoms of anxiety and depression than their non-PA peers. HPA axis dysregulation in this population was not documented.

Early Adiposity Rebound and Premature Adrenarche.

OBJECTIVES: To examine differences in the growth pattern and the age at adiposity rebound (AR) between children with premature adrenarche (PA) and their healthy peers (controls). STUDY DESIGN: In this cross-sectional study of 82 prepubertal children with PA and 63 controls, the main outcome measures were height and body mass index SDS progression, from birth to presentation at the clinic, baseline biochemical and hormonal evaluation, bone age determination, and age at AR. RESULTS: Children with PA were significantly taller and more adipose than controls from the first years of life. 33% of children with PA presented the growth pattern of constitutional advancement of growth (ie, early growth acceleration) vs 19% of controls (P = .045). Children with PA had an earlier AR compared with controls; mean age at AR in girls with PA was 3.73 (1.03) years vs 4.93 (1.36) years for control girls (P = .001) and in boys with PA was 3.45 (0.73) vs 5.10 (1.50) years in control boys (P = .048). Both obese and nonobese girls with PA were taller and had earlier age at AR compared with nonobese controls. CONCLUSIONS: Early AR and constitutional advancement of growth may be triggering factors for adrenal androgen production and PA.

Evo-devo of Child Growth: The Role of Weaning in the Transition from Infancy to Childhood.

Homo sapiens are unique in having a life history phase of childhood, which follows infancy, as defined by breastfeeding. This review uses evolutionary life history theory in understanding child growth in a broad evolutionary perspective, using the data and theory of evolutionary predictive adaptive growth-related strategies for transition from infancy to childhood. We have previously shown that a delayed infancy-childhood transition has a lifelong impact on stature. Feeding practices during infancy are fundamental elements of nutrition as they program for future growth and body composition. A relationship between the duration of breastfeeding and the nature of weaning has been suggested as a possible cause for later obesity and growth patterns. This review highlights the role that breast milk feeding and variations in the weaning age have on transition to childhood, growth, and body composition.

Environmental rather than genetic factors determine the variation in the age of the infancy to childhood transition: a twins study.

OBJECTIVE: Using a twins study, we sought to assess the contribution of genetic against environmental factor as they affect the age at transition from infancy to childhood (ICT). STUDY DESIGN: The subjects were 56 pairs of monozygotic twins, 106 pairs of dizygotic twins, and 106 pairs of regular siblings (SBs), for a total of 536 children. Their ICT was determined, and a variance component analysis was implemented to estimate components of the familial variance, with simultaneous adjustment for potential covariates. RESULTS: We found substantial contribution of the common environment shared by all types of SBs that explained 27.7% of the total variance in ICT, whereas the common twin environment explained 9.2% of the variance, gestational age 3.5%, and birth weight 1.8%. In addition, 8.7% was attributable to sex difference, but we found no detectable contribution of genetic factors to inter-individual variation in ICT age. CONCLUSIONS: Developmental plasticity impacts much of human growth. Here we show that of the ∼50% of the variance provided to adult height by the ICT, 42.2% is attributable to adaptive cues represented by shared twin and SB environment, with no detectable genetic involvement.

Predicting pubertal development by infantile and childhood height, BMI, and adiposity rebound.

BACKGROUND: Despite substantial heritability in pubertal development, children differ in maturational tempo. HYPOTHESES: (i) puberty and its duration are influenced by early changes in height and adiposity. (ii) Adiposity rebound (AR) is a marker for pubertal tempo. METHODS: We utilized published prospective data from 659 girls and 706 boys of the Study of Early Child Care and Youth Development. We investigated the age of pubarche-thelarche-gonadarche-menarche as a function of early height, BMI, and AR. RESULTS: In girls, height standard deviation scores correlated negatively with thelarche and pubarche from 15 mo of age and with menarche from 54 mo. BMI correlated negatively with thelarche from 36 mo of age and menarche from 54 mo. In boys, age at gonadarche correlated negatively with height from 36 mo of age. An AR was detected in 47% of girls and 55% of boys, who became heavier and had earlier and faster puberty than those with no AR. CONCLUSION: The onset and tempo of puberty are influenced by a two-hit program. The first is exerted during the infancy-childhood transition (ICT; 6-12 mo) and includes height, as an early predictor of maturational tempo. The second hit occurs at the childhood-juvenility transition (5-7 y) and is based on adiposity and its rebound.

Role of growth hormone in enchondroplasia and chondral osteogenesis: evaluation by X-ray of the hand.

BACKGROUND: The process of growth and maturation of long (radius and ulna) and short (metacarpals and phalanges) bones of the hand (enchondroplasia) differs from that of the carpal cuboid bones (chondral osteogenesis). This study aimed to assess the impact of growth hormone (GH) on these two processes of bone maturation. METHODS: Subjects of the study were 95 prepubertal children: 30 children with GH deficiency and 65 children with idiopathic short stature, aged 7.4 ± 1.9 y (mean ± SD) (trial registration number 98-0198-033). Bone maturation was assessed by the Greulich and Pyle method from X-rays obtained at the start and at 1 and 2 y of GH treatment, separately for carpals, long bones, and short bones, and was expressed as years of delay relative to chronological age. RESULTS: At GH start, the delay in bone maturation in the GH-deficient group was significantly greater for carpals (3.6 ± 1.3 y) than for long (3.0 ± 1.3 y) and short (1.7 ± 1.1 y) bones. The delay was nonsignificantly greater for carpal bones in GH-deficient subjects than in subjects with idiopathic short stature (3.6 ± 1.3 vs. 3.1 ± 1.1 y, respectively) and was normalized after 2 y of GH treatment. CONCLUSION: The dominant effect of GH was on chondral osteogenesis, with milder effect on enchondroplasia. A distinct delay in carpal and long-bone maturation, which normalizes during 2 y of GH treatment, was typical in GH-deficient children. Therefore, separate carpal bone assessment in bone age reading is needed.

Age at menarche in relation to nutritional status and critical life events among rural and urban secondary school girls in post-conflict northern Uganda.

BACKGROUND: Menarche age is an important indicator of reproductive health of a woman or a community. In industrial societies, age at menarche has been declining over the last 150 years with a secular trend, and similar trends have been reported in some developing countries. Menarche age is affected by genetic and environmental cues, including nutrition. The study was designed to determine the age at menarche and its relation to childhood critical life events and nutritional status in post-conflict northern Uganda. METHODS: This was a comparative cross-sectional study of rural and urban secondary school girls in northern Uganda. Structured questionnaires were administered to 274 secondary school girls, aged 12 - 18 years to determine the age at menarche in relation to home location, nutritional status, body composition and critical life events. RESULTS: The mean age at menarche was 13.6 ± 1.3 for rural and 13.3 ± 1.4 years for urban dwelling girls (t = -1.996, p = 0.047). Among the body composition measures, hip circumference was negatively correlated with the age at menarche (r = -0.109, p = 0.036), whereas height, BMI and waist circumference did not correlate with menarche. Paternal (but not maternal) education was associated with earlier menarche (F = 2.959, p = 0.033). Childhood critical life events were not associated with age at menarche. CONCLUSIONS: Age at menarche differed among urban and rural dwelling school girls and dependent on current nutritional status, as manifested by the hip circumference. It was not associated with extreme stressful childhood critical life events.

[Evolutionary perspective in precocious puberty].

Pubertal development is subject to substantial heritability, but much variation remains to be explained, including fast changes over the last 150 years, that cannot be explained by changes of gene frequency in the population. This article discusses the influence of environmental factors to adjust maturational tempo in the service of fitness goals. Utilizing evolutionary development thinking (evo-devo), the author examines adolescence as an evolutionary life-history stage in its developmental context. The transition from the preceding stage of juvenility entails adaptive plasticity in response to energy resources, social needs of adolescence and maturation toward youth and adulthood. Using Belsky's evolutionary theory of socialization, I show that familial psychosocial environment during the infancy-childhood and childhood-juvenility transitions foster a fast life-history and reproductive strategy rather than early maturation being just a risk factor for aggression and delinquency. The implications of the evo-devo framework for theory building, illuminates new directions in the understanding of precocious puberty other than a diagnosis of a disease.

Evolutionary medicine--the quest for a better understanding of health, disease and prevention.

Clinical medicine has neglected the fact that the make-up of organs and body functions, as well as the human-specific repertoire of behaviors and defenses against pathogens or other potential dangers are the product of adaptation by natural and sexual selection. Even more, for many clinicians it does not seem straightforward to accept a role of evolution in the understanding of disease, let alone, treatment and prevention.Accordingly, this Editorial seeks to set the stage for an article collection that aims at dealing precisely with the question of why evolutionary aspects of health and disease are not only interesting, but necessary to improve clinical medicine.

Evo-devo of human adolescence: beyond disease models of early puberty.

Despite substantial heritability in pubertal development, much variation remains to be explained, leaving room for the influence of environmental factors to adjust its phenotypic trajectory in the service of fitness goals. Utilizing evolutionary development biology (evo-devo), we examine adolescence as an evolutionary life-history stage in its developmental context. We show that the transition from the preceding stage of juvenility entails adaptive plasticity in response to energy resources, other environmental cues, social needs of adolescence and maturation toward youth and adulthood. Using the evolutionary theory of socialization, we show that familial psychosocial stress fosters a fast life history and reproductive strategy rather than early maturation being just a risk factor for aggression and delinquency. Here we explore implications of an evolutionary-developmental-endocrinological-anthropological framework for theory building, while illuminating new directions for research.

Secular trends in new childhood epidemics: insights from evolutionary medicine.

In the last few decades, pediatric medicine has observed a dramatic increase in the prevalence of hitherto rare illnesses, among which obesity, diabetes, allergies and other autoimmune diseases stand out. In addition, secular trends towards earlier onset of puberty and sexual activity contribute to the psychological problems of youth and adolescents. All this has occurred in spite of the improved health care provision for children, yet traditional concepts of medicine have failed to explain these new "epidemics". A recent conference and science school of the European Society of Paediatric Endocrinology (ESPE) in Acre, Israel, has taken up this challenge. Experts across disciplines including medicine, anthropology and developmental psychology discussed potential causes of childhood ill-health from an evolutionary point-of-view. Seen from an evolutionary vantage point, the "epidemics" of childhood obesity, diabetes and psychological dysfunction appear, in part, to be related to a mismatch between ancestral adaptations and novel environmental contingencies. These include changing exposures to pathogens, which impact on the function of the immune system, as well as changing patterns of parenting, which influence the timing of puberty and the risk for developing psychopathology.

Effects of breastfeeding on body composition and maturational tempo in the rat.

BACKGROUND: Features of life history are subject to environmental regulation in the service of reproductive fitness goals. We have previously shown that the infant-to-childhood transition reflects the adaptive adjustment of an individual's size to the prevailing and anticipated environment. METHODS: To evaluate effects of weaning age on life-history traits in rats, we repeatedly measured length and body mass index (BMI), as well as physiological development and sexual maturation in pups weaned early (d16), normally (d21) or late (d26). Males were bred to females of the same weaning age group for four generations. RESULTS: Here, we show that the age at weaning from lactation regulates a rat's life history, growth, body composition and maturational tempo. We show that early-weaned rats developed faster than normal- or late-weaned rats; they are leaner and longer than late-weaned ones who are heavier and shorter. Early-weaned progeny develop more rapidly (that is, fur budding, pinnae detachment, eye opening); females show earlier vaginal opening and estrous and males show earlier onset of testicular growth. In generations 3 and 4, early-weaned rats bear larger litter sizes and heavier newborn pups. The entire traits complex is transmitted to subsequent generations from the paternal side. CONCLUSIONS: The findings presented here lend support to the proposition that the duration of infancy, as indexed by weaning age, predicts and perhaps programs growth, body composition, and the tempo of physiological development and maturation, as well as litter size and parity and, thereby, reproductive strategy.

Energy Trade-off and 4 Extreme Human Body Types.

BACKGROUND: Resource trade-off theory suggests that increased performance on a given trait comes at the cost of decreased performance on other traits. METHODS: Growth data from 1889 subjects (996 girls) were used from the GrowUp1974 Gothenburg study. Energy Trade-Off (ETO) between height and weight for individuals with extreme body types was characterized using a novel ETO-Score (ETOS). Four extreme body types were defined based on height and ETOI at early adulthood: tall-slender, short-stout, short-slender, and tall-stout; their growth trajectories assessed from ages 0.5-17.5 years.A GWAS using UK BioBank data was conducted to identify gene variants associated with height, BMI, and for the first time with ETOS. RESULTS: Height and ETOS trajectories show a two-hit pattern with profound changes during early infancy and at puberty for tall-slender and short-stout body types. Several loci (including FTO, ADCY3, GDF5, ) and pathways were identified by GWAS as being highly associated with ETOS. The most strongly associated pathways were related to "extracellular matrix," "signal transduction," "chromatin organization," and "energy metabolism." CONCLUSIONS: ETOS represents a novel anthropometric trait with utility in describing body types. We discovered the multiple genomic loci and pathways probably involved in energy trade-off.

Post-term birth is associated with greater risk of obesity in adolescent males.

OBJECTIVE: To test the hypothesise that post-term birth (>42 weeks gestation) adversely affects longitudinal growth and weight gain throughout childhood. STUDY DESIGN: A total of 525 children (including 17 boys and 20 girls born post-term) were followed from birth to age 16 years. Weight and height were recorded prospectively throughout childhood, and respective velocities from birth to end of puberty were calculated using a mathematical model. RESULTS: At birth, post-term girls were slimmer than term girls (ponderal index, 27.7 ± 2.6 kg/m(3) vs 26.3 ± 2.8 kg/m(3); P<.05). At age 16 years, post-term boys were 11.8 kg heavier than term subjects (body mass index [BMI], 25.4 ± 5.5 kg/m(2) vs 21.7 ± 3.1 kg/m(2); P<.01). The rate of obesity was 29% in post-term boys and 7% in term boys (P<.01), and the combined rate of overweight and obesity was 47% in post-term boys and 13% in term boys (P<.01). Weight velocity, but not height velocity, was higher in post-term boys at age 1.5-7 years (P<.05) and again at age 11.5-16 years (P<.05). BMI was higher in post-term boys at age 3 years, with the difference increasing thereafter. BMI and growth were similar in post-term and term girls. CONCLUSION: In this post-term birth cohort, boys, but not girls, demonstrated accelerated weight gain during childhood, leading to greater risk of obesity in adolescence.

Growth of the Kalahari Desert's bushman--the Ju/'hoansi San.

AIM: The Ju/'hoansi San (JHS) of the Kalahari Desert are the archetype of a hunter-gatherer society that practices natural fertility, living on a rich diet in a harsh environs. METHODS: To explore the evolutionary adaptation of child growth under such conditions, the present study takes a life history approach and compares the growth data of 140 JHS females and 126 JHS males age 1-25 to those in 3rd percentile American and Swedish references. The data are based on observations of the JHS that were made in 1967-1969. RESULTS: During infancy, the JHS boys lose 1.5 SDS and girls - 0.3 SDS in terms of Swedish reference. The height SDS of the JHS did not change significantly during their childhood, but growth deceleration during the juvenile period (middle childhood) was substantially greater and longer, amounting to a loss of 1.6 SDS for both girls and boys. Adolescent spurt was substantially later and smaller than that of the short-statured Americans. CONCLUSIONS: The results suggest that the short stature of the JHS is mostly established during juvenility, in adaptation to their unique living conditions.

Family Size and the Age at Infancy-Childhood Transition Determine a Child's Compromised Growth in Large Families.

Background: Data on growth of Israeli school children show that children from Jewish ultra-orthodox Haredi and Bedouin Arab families have a higher prevalence of stature below the 3rd percentile. While these populations are usually from lower socioeconomic strata, they also have larger families. This study aimed to evaluate if family structure and the timing of a child's infancy-childhood transition (ICT) are central to variations in stature. Study Design: We analyzed the association between family size, birth order and inter-birth interval with child growth and the age at ICT in 3 groups of children, 148 high birth order children from large families (LF ≥ 6), 118 low birth order children from large families (LF ≤ 3) and 150 children from small families (SF). Results: High birth order children from large families were shorter in childhood than children from small families with a difference of 0.5 SDS in length. We found that birth length and birth order explained 35% of the total variance in infancy length whereas ICT age and infancy length explained 72% of the total variance in childhood length. Conclusion: Infancy and childhood length are compromised in children from large families. As the family grows larger the younger children tend to be shorter. Reduced length gain in the period between infancy to childhood is when growth is most affected.

Long-term response to GH therapy in short children with a delayed infancy-childhood transition (DICT).

Transition of growth from infancy to childhood is associated with activation of the GH-IGF-I axis. Children with a delayed infancy-childhood transition (DICT) are short as adults. Thus, age at ICT may impact on growth response to GH. The objective was to investigate associations between growth response to GH treatment and ICT timing in children with idiopathic short stature (ISS) in a randomized, controlled, multicenter trial, TRN 88-080. A total of 147 prepubertal children (mean age, 11.5 ± 1.4 y) were randomized to receive GH 33 µg/kg/d (GH33, n = 43), GH 67 µg/kg/d (GH67, n = 61), or no treatment (n = 43). Data on growth to final height (FH) were analyzed after categorization into those with normal (n = 76) or delayed ICT (n = 71). Within the GH33 group, significant height gain at FH was only observed in children with a DICT (p < 0.001), with each month of delay corresponding to gain of 0.13 SD score (SDS). For the GH67 group, the timing of the onset of the ICT had no impact on growth response. In conclusion, ISS children with a DICT responded to standard GH dose (better responsiveness), whereas those with a normal ICT required higher doses to attain a significant height gain to FH.

11ß-Hydroxysteroid dehydrogenase type 1 activity in short small-for-GA children and in response to GH therapy.

Small for GA (SGA) children are at risk for developing the metabolic syndrome. Those who do not catch up, and remain short (SSGA), may benefit from GH therapy. 11ß Hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) is expressed in visceral fat and is implicated in metabolic morbidity. We hypothesized that SSGA children will have increased basal and glucocorticoid (GC)-stimulated 11ß-HSD-1 activity. Twenty SSGA children, aged 7.1 ± 1 y (mean ± SD), were studied before and while on GH therapy and compared with 12 normal age-matched controls. 11ß-HSD-1 activity was evaluated by gas chromatography mass spectrometry (GCMS) of urinary steroid product/substrate ratios. GC-stimulated 11ß-HSD-1 activity was assessed after overnight dexamethazone (DEX), by oral cortisone conversion to cortisol. In SSGA children, 11ß-HSD-1 activity was lower (p < 0.05) and GC-stimulated activity enhanced. SSGA children had maximal cortisol generation of 883 ± 108 compared with 690 ± 63 nmol/L in controls (p < 0.04). GH treatment suppressed 11ß-HSD-1 activity. GC-stimulated enzyme activity correlated negatively with GA (r = -0.53, p < 0.01) and birth weight (r = -0.55, p < 0.01). SSGA is associated with enhanced GC-stimulated 11ß-HSD-1 activity. This may be programmed in utero, as it is not a function of body composition or secondary metabolic derangement. GH therapy normalizes GC-stimulated 11ß-HSD-1 activity.

Impact of infancy duration on adult size in 22 subsistence-based societies.

AIM: Humans evolved to withstand harsh environments by adaptively decreasing their body size. Thus, adaptation to a hostile environment defers the infancy-childhood transition age (ICT), culminating in short stature. In natural-fertility human societies, this transition is associated with weaning from breastfeeding and the mother's new pregnancy. We therefore used the interbirth interval (IBI) as a surrogate for the ICT. METHODS: We hypothesized that long IBI will be associated with smaller body size. The sample used is 22 subsistence-based societies of foragers, horticulturalists and pastorals from Africa, South America, Australia and Southeast Asia. RESULTS: The IBI correlated negatively with the average adult bodyweight but not height. After correction for 'pubertal spurt takeoff' and 'weight at age 5', the IBI explains 81% of 'average adult weight' variability. CONCLUSIONS: This inter-population study confirms that body weight is adaptively smaller in hostile environments and suggests that the selected trait for this adaptation is the ICT age.

Uncoupling of the Infancy Life History Stage.

BACKGROUND: The life history of Homo sapiens is unique in having a comparatively short stage of infancy which lasts for 2-3 years. Infancy is characterized by suckling of breast milk, the development of sensorimotor cognition, the acquisition of language, mini-puberty, deciduous dentition, and almost complete skull growth. Infancy ends with the infancy-childhood growth transition (ICT) and separation from the mother. In modern-day affluent societies, breastfeeding depends on the mother's decision and may happen at any age, and the characteristic traits of infancy have uncoupled. The data and theory for this contention are presented. SUMMARY: The biological traits of mini-puberty and ICT characteristic of infancy occur before age 1 along with language acquisition. The cognitive (sensorimotor) component occurs by age 2, and the social component of separation from the mother by any age from 1 to 3 years. Key Messages: Human life history is based on a coherent stage of infancy which assumes coupling between the biological, cognitive, and social maturation of a baby. This is no longer the case in industrial societies and might never be so again. The upbringing of an infant needs to consider the new biology of this dissociated infancy and a new timetable of the infant's life-history events.