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Anthropometric birth measurements analysed for 51 boys with hypospadias identified in a prospective cohort study showed significant reductions in mean values for birth weight, length, and head circumference compared with controls. The absence of the usual sex dimorphism for these variables suggests that the results represent a marker of fetal androgen dysfunction in this subgroup of infants. [ABSTRACT FROM AUTHOR]

Congenital adrenal hyperplasia has been reported to manifest with white matter aberrations. However, many previous studies included only small samples, restricted their analyses to females, lacked a control group and/or did not correct for brain size. Here, we examined the largest sample to date, comprising 53 male and female participants with congenital adrenal hyperplasia, who were matched with 53 male and female controls in terms of sex, age, education, and verbal intelligence. The four groups were compared with respect to their total white matter as well as white matter hyperintensities while applying brain size corrections. For both measures, total white matter and white matter hyperintensities, there were no significant sex differences or group-by-sex interactions. However, individuals with congenital adrenal hyperplasia had significantly smaller total white matter volumes compared to controls. Our findings align with previous reports of white matter variations in congenital adrenal hyperplasia. The absence of a group-by-sex interaction suggests that white matter variations in congenital adrenal hyperplasia may not be attributable to prenatal androgens. Instead, they may be a result of the condition itself and/or its treatment with glucocorticoids. The latter aspect warrants follow-up, particularly given that glucocorticoids are employed not only in congenital adrenal hyperplasia but also in other medical conditions., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Partial androgen insensitivity syndrome (PAIS) is a rare condition that is reported to be commonly associated with gynecomastia in males., Objectives: To assess the management of gynecomastia in male PAIS., Materials and Methods: Retrospective review of males with PAIS over the age of 10 years in the I-DSD registry., Results: Of the 205 eligible cases, information was available for 57 from 13 centers. An androgen receptor gene variant was confirmed in 45 (79%) with a median age at first presentation of 1.0 year (range 0.1, 26.0). Of the 45 genetically confirmed cases, gynecomastia was present in 41 (91%) with a median age at the time of gynecomastia development of 13.5 years (11.0, 29.0). In the other 4 (9%) with no gynecomastia, the median age at last assessment was 15.7 years (10.6, 17.0). In 30 cases with information available, micropenis was present at the time of gynecomastia development in 23 (77%). Of the 35 with information available, 2 (6%) exhibited spontaneous resolution between the ages of 15 and 21 years and 25 (71%) had breast surgery at a median age of 15.7 years (14.0, 23.0). Of these 25, 9 (26%) had previously received medical therapy. The median clinician score of effectiveness for medical therapy was 3 (1, 8) compared to 10 (3, 10) for surgery (P < .0001). In 31 with information available, 13 (42%) had received psychology support., Conclusion: Gynecomastia is common in PAIS but not universal. Surgical management may be more effective than medical therapy, but there is a need for further standardized and systematic studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking 1-4 . Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with β-thalassaemia, a condition in which GDF15 levels are chronically high 5 , report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG., (© 2023. The Author(s).)

Context: Vitamin D has been variably implicated in risk of developing type 1 diabetes based on cohorts of at-risk individuals. Emergent type 1 diabetes in childhood is putatively preceded by altered growth., Objective: We explored whether polymorphisms in vitamin D metabolism genes modify risk of type 1 diabetes via effects on growth in a prospective, population-based cohort of infants., Methods: The Cambridge Baby Growth Study enrolled newborns from Cambridgeshire, UK, for follow-up in infancy. In 612 infants, we genotyped single nucleotide polymorphisms in vitamin D metabolism genes that relate with type 1 diabetes: rs10741657 and rs12794714 in CYP2R1, rs12785878 in DHCR7, and rs10877012 in CYP27B1. Multivariate linear regression analyses tested associations between genotypes and anthropometric indices (weight, length, and skinfold thickness) or growth-related hormones (C-peptide, IGF-1, and leptin) in infancy., Results: Birth weight showed borderline associations with the diabetes risk-increasing alleles in CYP2R1, rs10741657 (β = -.11, P = .02) and rs12794714 (β = -.09, P = .04). The risk-increasing allele rs12794714 was also associated with higher IGF-1 levels at age 24 months (β = .30, P = .01). At age 3 months, the risk-increasing allele rs12785878 in DHCR7, known to negatively associate with 25-hydroxyvitamin D levels, showed a positive association with leptin levels (β = .23, P = .009), which was pronounced in girls (P = .004) vs boys (P = .7)., Conclusion: The vitamin D metabolism genes DHCR7 and CYP2R1 might influence infancy leptin and IGF-1 levels respectively. These findings open the possibility for a developmental role of vitamin D that is mediated by growth-related hormones with implications for the onset of type 1 diabetes autoimmunity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Several studies have reported associations between appetitive traits and weight gain during infancy or childhood, but none have directly compared these associations across both age periods. Here, we tested the associations between appetitive traits and growth velocities from birth to childhood. Appetitive trait data were collected using the Children's Eating Behaviour Questionnaire (CEBQ) in 149 children from the Cambridge Baby Growth Study at age 9-17 years. These participants also provided anthropometric measurements during infancy (birth, 3, 12, 18, and 24 months) and childhood (5 to 11 years). Standardized growth velocities (in weight, length/height, BMI, and body fat percentage) for 0-3 months, 3-24 months, and 24 months to childhood were estimated using individual linear-spline models. Associations between each of the eight CEBQ traits and each growth velocity were tested in separate multilevel linear regression models, adjusted for sex, age at CEBQ completion, and the corresponding birth measurement (weight, length, BMI, or body fat percentage). The three food-approach traits (food responsiveness, enjoyment of food and emotional overeating) were positively associated with infancy and childhood growth velocities in weight, BMI, and body fat percentage. By contrast, only one of the food-avoidant traits, satiety responsiveness, was negatively associated with all growth velocities. Significant associations were mostly of similar magnitude across all age periods. These findings reveal a broadly consistent relationship between appetitive traits with gains in weight and adiposity throughout infancy and childhood. Future interventions and strategies to prevent obesity may benefit from measuring appetitive traits in infants and children and targeting these as part of their programs., (© 2023. Springer Nature Limited.)

Growth patterns of breastfed infants show substantial inter-individual differences, partly influenced by breast milk (BM) nutritional composition. However, BM nutritional composition does not accurately indicate BM nutrient intakes. This study aimed to examine the associations between both BM intake volumes and macronutrient intakes with infant growth. Mother-infant dyads ( n 94) were recruited into the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) from a single maternity hospital at birth; all infants received exclusive breast-feeding (EBF) for at least 6 weeks. Infant weight, length and skinfolds thicknesses (adiposity) were repeatedly measured from birth to 12 months. Post-feed BM samples were collected at 6 weeks to measure TAG (fat), lactose (carbohydrate) (both by 1 H-NMR) and protein concentrations (Dumas method). BM intake volume was estimated from seventy infants between 4 and 6 weeks using dose-to-the-mother deuterium oxide ( 2 H 2 O) turnover. In the full cohort and among sixty infants who received EBF for 3+ months, higher BM intake at 6 weeks was associated with initial faster growth between 0 and 6 weeks ( β + se 3·58 + 0·47 for weight and 4·53 + 0·6 for adiposity gains, both P < 0·0001) but subsequent slower growth between 3 and 12 months ( β + se - 2·27 + 0·7 for weight and -2·65 + 0·69 for adiposity gains, both P < 0·005). BM carbohydrate and protein intakes at 4-6 weeks were positively associated with early (0-6 weeks) but tended to be negatively related with later (3-12 months) adiposity gains, while BM fat intake showed no association, suggesting that carbohydrate and protein intakes may have more functional relevance to later infant growth and adiposity.

Human males and females show average gender/sex differences for certain psychological phenomena. Multiple factors may contribute to these differences, including sex chromosomes, exposure to gonadal hormones, and socialization or learning. This study investigated potential hormonal and socialization/learning influences on gender/sex differences in childhood preferences for color, specifically pink and red vs. blues, and for toys. Children (aged 4 to 11 years) with congenital adrenal hyperplasia (CAH, n = 43 girls and 37 boys), marked by elevated prenatal adrenal androgen exposure, and without CAH (n = 41 girls and 31 boys) were studied. Prior research indicates girls with CAH are masculinized for certain behaviors, such as toy choices, while boys with CAH generally do not differ from boys without CAH. In the current study, children indicated preferences for stereotyped hues of pink vs. blue as well as two control color pairs. They also indicated their preference between gender/sex-typed toys (doll vs. car) presented in black and white, in gender/sex-congruent colors (pink doll vs. blue car) and in gender/sex-incongruent colors (pink car vs. blue doll). Color findings: Control girls preferred stereotyped pink over blue more than boys or girls with CAH did; the latter two groups did not differ in their color preferences. No preference differences occurred for other color pairs. Toy findings: In black/white or gender/sex-congruent colors, boys preferred the car more than control girls or girls with CAH did, while girls with CAH preferred the car more than control girls did. In gender/sex-incongruent colors (pink car vs. blue doll), boys still preferred the car, while girls with CAH showed reduced and control girls showed increased preferences for the pink car compared to the car preferences in black/white. Results support learning theories of color preferences, perhaps also influenced by pre-existing toy preferences which may occur for other reasons, including early androgen exposure. Specifically, girls with CAH may have learned they do not enjoy stereotypical toys for girls, often colored pink, and pink coloring may subsequently diminish their preference for a car. Our results highlight the importance of gonadal hormones and learning in the development of childhood toy and color preferences., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Although it was common in the 1970s-1990s to assign female gender of rearing to 46,XY infants with limited virilization of varying etiologies, including those with partial androgen insensitivity syndrome (PAIS), long-term data on outcomes for these individuals are sparse. Therefore, our goal was to use the power of an international registry to evaluate clinical features, surgical management, and pubertal data in patients with a molecularly confirmed diagnosis of PAIS who were born before 2008 and were raised as girls., Methods: The current study interrogated the International Disorders of Sex Development Registry for available data on management and pubertal outcomes in individuals with genetically confirmed PAIS who were raised as girls., Results: Among the 11 individuals who fulfilled the key criteria for inclusion, the external masculinization score (EMS) at presentation ranged from 2 to 6 (median 5); 7 girls underwent gonadectomy before the age of 9 years, whereas 4 underwent gonadectomy in the teenage years (≥ age 13). Clitoral enlargement at puberty was reported for 3 girls (27%) who presented initially at the time of puberty with intact gonads. In the 9 individuals (82%) for whom gonadal pathology data were provided, there was no evidence of germ cell tumor at median age of 8.1 years. All girls received estrogen replacement, and 8/11 had attained Tanner stage 4-5 breast development at the last assessment., Conclusion: In general, although it appears that female assignment in PAIS is becoming uncommon, our data provide no evidence to support the practice of prophylactic prepubertal gonadectomy with respect to the risk of a germ cell tumor., (© 2023 S. Karger AG, Basel.)

Context: Differences of sex development (DSD) represent a wide range of conditions presenting at different ages to various health professionals. Establishing a diagnosis, supporting the family, and developing a management plan are important., Objective: We aimed to better understand the presentation and prevalence of pediatric DSD., Methods: A retrospective, observational cohort study was undertaken in a single tertiary pediatric center of all children and young people (CYP) referred to a DSD multidisciplinary team over 25 years (1995-2019). In total, 607 CYP (520 regional referrals) were included. Data were analyzed for diagnosis, sex-assignment, age and mode of presentation, additional phenotypic features, mortality, and approximate point prevalence., Results: Among the 3 major DSD categories, sex chromosome DSD was diagnosed in 11.2% (68/607) (most commonly 45,X/46,XY mosaicism), 46,XY DSD in 61.1% (371/607) (multiple diagnoses often with associated features), while 46,XX DSD occurred in 27.7% (168/607) (often 21-hydroxylase deficiency). Most children (80.1%) presented as neonates, usually with atypical genitalia, adrenal insufficiency, undescended testes or hernias. Those presenting later had diverse features. Rarely, the diagnosis was made antenatally (3.8%, n = 23) or following incidental karyotyping/family history (n = 14). Mortality was surprisingly high in 46,XY children, usually due to complex associated features (46,XY girls, 8.3%; 46,XY boys, 2.7%). The approximate point prevalence of neonatal referrals for investigation of DSD was 1 in 6347 births, and 1 in 5101 overall throughout childhood., Conclusion: DSD represent a diverse range of conditions that can present at different ages. Pathways for expert diagnosis and management are important to optimize care., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

It was previously observed that maternal iron supplementation in pregnancy was associated with increased offspring size and adiposity at birth, possibly mediated through increased risk of gestational diabetes. In this study we investigated potential long-term associations of maternal iron supplementation in pregnancy with offspring growth in infancy, and growth and cardiometabolic risk factors in mid-childhood to seek evidence of nutritional programming. Using a nested case-control format, markers of growth and adiposity were measured at 3, 12 and 24 months of age in 341 infants from the Cambridge Baby Growth Study whose mothers supplemented with iron in pregnancy and 222 infants whose mothers did not. Measures of growth, glucose tolerance (using a 30 minute 1.75 g glucose/kg body weight oral glucose tolerance test), insulin sensitivity (HOMA IR) and blood pressure were collected in 122 and 79 of these children, respectively, at around 9.5 years of age. In infancy adiposity-promoting associations with maternal iron supplementation in pregnancy were evident at 3 months of age (e.g. mean difference in skinfold thickness: β = +0.15 mm, p = 0.02, in n = 341 whose mothers supplemented versus 222 that did not; waist circumference: β = +0.7 cm, p = 0.04, in n = 159 and 78, respectively) but differences lessened after this time (e.g. 3-12 month change in mean difference in skinfold thickness: β = -0.2 mm, p = 0.03, in n = 272 and 178, respectively). At ~9.5 years of age children whose mothers supplemented with iron in pregnancy had lower mean arterial blood pressures (β = -1.0 mmHg, p = 0.03, in n = 119 and 78, respectively). There were no apparent differences in markers of growth or other cardiometabolic factors. These results suggest that most of the associations of maternal iron supplementation in pregnancy on growth and adiposity evident at birth disappear during infancy, but there may be some evidence of long-term nutritional programming of blood pressure in mid-childhood., Competing Interests: The authors state that they have no relevant conflicts of interest to disclaim.

Background: It has been suggested that fetal sex may be able to modify maternal metabolism and physiology during pregnancy. Recently pregnant women carrying a male fetus were reported to be more insulin sensitive than those carrying females, although related evidence is inconsistent., Methods: In this study we administered a 75 g oral glucose tolerance test at around week 28 of pregnancy in 813 pregnant women from a contemporary birth cohort (the Cambridge Baby Growth Study), derived surrogate indices of insulin secretion and sensitivity, and related them to the fetal sex., Results: Carrying a male fetus was associated with lower fasting glucose (difference in mean concentrations ≈ 0.1 mmol/L; β' = 0.063; p = 0.02) and insulin (≈ 1.1 pmol/L; β' = 0.075; p = 0.01) concentrations but not with post-load glucose or insulin concentrations. Male fetal sex was also associated with lower HOMA IR (≈ 1.08 units; β' = 0.071; p = 0.02) and higher QUICKI (≈ 1.06 units; β' = 0.080; p = 0.007) values suggesting increased basal insulin sensitivity. There were no differences in indices of insulin secretion, except for the insulin disposition index which was higher in women carrying a male fetus (≈ 1.15 units; β' = 0.090; p = 0.007). Birth weights were higher in male offspring., Conclusions: Women carrying a male fetus were relatively more insulin sensitive in the fasting state and secreted more insulin relative to this degree of insulin sensitivity. These results are consistent with the idea that the fetal sex may be able to modify the maternal glucose-insulin axis., (© 2022. The Author(s).)

Paracetamol (acetaminophen) is the preferred antipyretic/analgesic for pregnant women as it is believed there are no adverse fetal effects at the recommended dose. However, emerging evidence suggests that intrauterine paracetamol exposure may be associated with certain urogenital/reproductive disorders in the offspring. In this mini-review, we describe human fetal sex development and possible pharmacological mechanisms by which paracetamol may disrupt this process, including reduced testicular production of testosterone and/or insulin-like peptide 3. We then review the available epidemiological literature on associations between maternal paracetamol exposure and offspring sexual development. Three epidemiological studies have reported associations between maternal paracetamol intake and increased risk of cryptorchidism, although five others have not. None have found associations with hypospadias or penile length. Two out of three studies have reported a shorter anogenital distance (a marker of androgen action during the masculinisation programming window, ∼8-14 weeks of gestation) in male infants antenatally exposed to paracetamol. One study has described a dose-dependent relationship between maternal paracetamol consumption and earlier female (but not male) attainment of puberty. Such epidemiological analyses are complicated by various factors, including method of paracetamol exposure assessment (usually retrospective self-report), variation in diagnostic accuracy, selection bias, confounding by clinical indication, and demographic/genetic differences between geographically separated populations. There is an urgent need for stronger evidence in this area, from both relevant experimental studies and large, carefully-designed prospective studies. In the meantime, a precautionary attitude to gestational paracetamol usage should be considered as the evidence for clinically significant reproductive effects in humans is limited., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tadokoro-Cuccaro, Fisher, Thankamony, Ong and Hughes.)

It is paramount that any child or adolescent with a suspected difference or disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD and is discussed with the regional DSD service. In most cases, the paediatric endocrinologist within this service acts as the first point of contact but involvement of the regional multidisciplinary service will also ensure prompt access to specialist psychology and nursing care. The underlying pathophysiology of DSD and the process of delineating this should be discussed with the parents and affected young person with all diagnostic tests undertaken in a timely fashion. Finally, for rare conditions such as these, it is imperative that clinical experience is shared through national and international clinical and research collaborations., (© 2021 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Background: Anthropometry-based equations are commonly used to estimate infant body composition. However, existing equations were designed for newborns or adolescents. We aimed to (a) derive new prediction equations in infancy against air-displacement plethysmography (ADP-PEA Pod) as the criterion, (b) validate the newly developed equations in an independent infant cohort and (c) compare them with published equations (Slaughter-1988, Aris-2013, Catalano-1995)., Methods: Cambridge Baby Growth Study (CBGS), UK, had anthropometry data at 6 weeks (N = 55) and 3 months (N = 64), including skinfold thicknesses (SFT) at four sites (triceps, subscapular, quadriceps and flank) and ADP-derived total body fat mass (FM) and fat-free mass (FFM). Prediction equations for FM and FFM were developed in CBGS using linear regression models and were validated in Sophia Pluto cohort, the Netherlands, (N = 571 and N = 447 aged 3 and 6 months, respectively) using Bland-Altman analyses to assess bias and 95% limits of agreement (LOA)., Results: CBGS equations consisted of sex, age, weight, length and SFT from three sites and explained 65% of the variance in FM and 79% in FFM. In Sophia Pluto, these equations showed smaller mean bias than the three published equations in estimating FM: mean bias (LOA) 0.008 (-0.489, 0.505) kg at 3 months and 0.084 (-0.545, 0.713) kg at 6 months. Mean bias in estimating FFM was 0.099 (-0.394, 0.592) kg at 3 months and -0.021 (-0.663, 0.621) kg at 6 months., Conclusions: CBGS prediction equations for infant FM and FFM showed better validity in an independent cohort at ages 3 and 6 months than existing equations., (© 2021 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Growth and nutrition during early life have been strongly linked to future health and metabolic risks. The Cambridge Baby Growth Study (CBGS), a longitudinal birth cohort of 2229 mother-infant pairs, was set up in 2001 to investigate early life determinant factors of infant growth and body composition in the UK setting. To carry out extensive profiling of breastmilk intakes and composition in relation to infancy growth, the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) was established upon the original CBGS. The strict inclusion criteria were applied, focusing on a normal birth weight vaginally delivered infant cohort born of healthy and non-obese mothers. Crucially, only infants who were exclusively breastfed for the first 6 weeks of life were retained in the analysed study sample. At each visit from birth, 2 weeks, 6 weeks, and then at 3, 6, 12, 24, and 36 months, longitudinal anthropometric measurements and blood spot collections were conducted. Infant body composition was assessed using air displacement plethysmography (ADP) at 6 weeks and 3 months of age. Breast milk was collected for macronutrients and human milk oligosaccharides (HMO) measurements. Breast milk intake volume was also estimated, as well as sterile breastmilk and infant stool collection for microbiome study.

Objective: This study explored the link between HLA polymorphisms that predispose to type 1 diabetes and birth size, infancy growth, and/or circulating IGF-I in a general population-based birth cohort., Research Design and Methods: The Cambridge Baby Growth Study is a prospective observational birth cohort study that recruited 2,229 newborns for follow-up in infancy. Of these, 612 children had DNA available for genotyping single nucleotide polymorphisms in the HLA region that capture the highest risk of type 1 diabetes: rs17426593 for DR4 , rs2187668 for DR3 , and rs7454108 for DQ8 . Multivariate linear regression models at critical ages (cross-sectional) and mixed-effects models (longitudinal) were performed under additive genetic effects to test for associations between HLA polymorphisms and infancy weight, length, skinfold thickness (indicator of adiposity), and concentrations of IGF-I and IGF-binding protein-3 (IGFBP-3)., Results: In longitudinal models, the minor allele of rs2187668 tagging DR3 was associated with faster linear growth ( P = 0.007), which was more pronounced in boys ( P = 3 × 10 -7 ) than girls ( P = 0.07), and was also associated with increasing IGF-I ( P = 0.002) and IGFBP-3 ( P = 0.003) concentrations in infancy. Cross-sectionally, the minor alleles of rs7454108 tagging DQ8 and rs17426593 tagging DR4 were associated with lower IGF-I concentrations at age 12 months ( P = 0.003) and greater skinfold thickness at age 24 months ( P = 0.003), respectively., Conclusions: The variable associations of DR4 , DR3 , and DQ8 alleles with growth measures and IGF-I levels in infants from the general population could explain the heterogeneous growth trajectories observed in genetically at-risk cohorts. These findings could suggest distinct mechanisms involving endocrine pathways related to the HLA-conferred type 1 diabetes risk., (© 2021 by the American Diabetes Association.)