The validity of automatic methods for estimating skeletal age in young athletes: a comparison of the BAUSport ultrasound system and BoneXpert with the radiographic method of Fels.

This study examined the validity of two automated methods (BAUSport, BoneXpert software using Fels, Greulich-Pyle, Tanner-Whithouse III protocols) for estimating skeletal age (SA) in young athletes in comparison to a reference standard (Fels). 85 male and female athletes, nine to seventeen years of age, from multiple sports were assessed for SA as part of an annual medical and health screening programme. Intra-class correlations demonstrated high degrees of association between the automatic methods for estimating SA (BAUSport r = .98; BoneXpert r = .96-.99) and the discrepancy between SA and chronological age (SA-CA) (BAUSport r = .93; BoneXpert r = .88-.97), with the reference standard. Concordance analyses for the categorisation of participants as early, on-time and late maturing also demonstrated substantial levels of agreement for both methods (BAUSport Kappa = .71; BoneXpert Fels Kappa = .63) with the reference standard. Bland-Altman plots comparing the automatic methods with the reference standard identified statistically significant fixed biases, ranging in magnitude from small to large. Collectively, these results suggest that BoneXpert and BAUSport can provide comparable estimates of SA and SA-CA in young athletes relative to the Fels method. Biases in the estimation of SA should, however, be considered and the automatic methods should be implemented as part of a comprehensive growth and maturity screening protocol. The non-invasive nature of the BAUSport method affords particular advantages (no radiation exposure, portability) in contexts where the regular estimation of SA is recommended.

Functional hypogonadism in adolescence: an overlooked cause of secondary hypogonadism.

Hypogonadism is a clinical syndrome resulting from failure to produce physiological concentrations of sex steroid hormones with accompanying symptoms, such as slowed growth and delayed pubertal maturation. Hypogonadism may arise from gonadal disease (primary hypogonadism), dysfunction of the hypothalamic-pituitary axis (secondary hypogonadism) or functional hypogonadism. Disrupted puberty (delayed or absent) leading to hypogonadism can have a significant impact on both the physical and psychosocial well-being of adolescents with lasting effects. The diagnosis of hypogonadism in teenagers can be challenging as the most common cause of delayed puberty in both sexes is self-limited, also known as constitutional delay of growth and puberty (CDGP). Although an underlying congenital cause should always be considered in a teenager with hypogonadism, acquired conditions such as obesity, diabetes mellitus, other chronic diseases and medications have all been associated with low sex steroid hormone levels. In this review, we highlight some forms of functional hypogonadism in adolescents and the clinical challenges to differentiate normal variants from pathological states.

Sex chromosome aneuploidies and fertility: 47,XXY, 47,XYY, 47,XXX and 45,X/47,XXX.

The overall incidence of sex chromosome aneuploidies is approximately 1 per 500 live-born infants, but far more common at conception. I shall review the fertility aspects of the sex chromosome trisomies, XXY, XYY, and XXX, with special reference to the karyotype 45,X/47,XXX. Each has a 'specific' (but variable) phenotype but may be modified by mosaicism. Although the alterations in the hypothalamic-pituitary-gonadal axis are important (and discussed), the emphasis here is on potential fertility and if one might predict that at various epochs within an individual's life span: fetal, 'mini'-puberty, childhood, puberty, and adulthood. The reproductive axis is often affected in females with the 47,XXX karyotype with diminished ovarian reserve and accelerated loss of ovarian function. Fewer than 5% of females with Turner syndrome have the 45,X/47,XXX karyotype. They have taller stature and less severe fertility issues compared to females with the 45,X or other forms of Turner syndrome mosaicism. For the 47,XXY karyotype, non-obstructive azoospermia is almost universal with sperm retrieval by micro-testicular sperm extraction possible in slightly fewer than half of the men. Men with the 47,XYY karyotype have normal to large testes and much less testicular dysfunction than those with the 47,XXY karyotype. They do have a slight increase in infertility compared to the reference population but not nearly as severe as those with the 47,XXY karyotype. Assisted reproductive technology, especially micro-testicular sperm extraction, has an important role, especially for those with 47,XXY; however, more recent data show promising techniques for the in vitro maturation of spermatogonial stem cells and 3D organoids in culture. Assisted reproductive technology is more complex for the female, but vitrification of oocytes has shown promising advances.

Allometric Scaling of Testosterone Enanthate Pharmacokinetics to Adolescent Hypogonadal Males (IM and SC Administration).

Context: Intramuscular (IM) testosterone enanthate (TE) and testosterone pellets were US Food and Drug Administration approved before 1962 for pediatric use but not studied in controlled trials in adolescents. Objective: An analysis using nonlinear mixed effect (NLME) modeling was designed to evaluate the adult pharmacokinetics (PK) of subcutaneous (SC) and IM TE. This model was used to simulate SC and IM TE administration in adolescents of different weight groups. Methods: Data from adult male patients in a phase 2 trial were used to characterize the PK of TE using population PK modeling for SC and IM administration: Allometry was used to scale PK parameters from the adult model to simulate adolescent (aged 12 to < 18 years) serum testosterone levels at body weights of 30, 40, 50, and 60 kg after weekly, every-other-week (EOW), and monthly SC and IM administration of 12.5, 25, 50, 75, and 100 mg TE regimens. Results: The final data set included 714 samples from 15 patients receiving 100 mg SC TE and 123 samples from 10 patients receiving 200 mg IM TE. In simulated populations, average serum concentration SC:IM ratios were 0.783, 0.776, and 0.757 at steady state for weekly, EOW, and monthly dosing groups, respectively. Simulated regimens of 12.5 mg SC TE monthly produced serum testosterone levels representative of early puberty and simulated pubertal stage progression following multiple subsequent testosterone dose increases. Conclusion: SC TE administration achieved a testosterone exposure-response relationship similar to IM TE in simulated adolescent hypogonadal males, which may reduce size of fluctuations in serum T and related symptoms.

Diagnosis and testing for growth hormone deficiency across the ages: a global view of the accuracy, caveats, and cut-offs for diagnosis.

Growth hormone deficiency (GHD) is a clinical syndrome that can manifest either as isolated or associated with additional pituitary hormone deficiencies. Although diminished height velocity and short stature are useful and important clinical markers to consider testing for GHD in children, the signs and symptoms of GHD are not always so apparent in adults. Quality of life and metabolic health are often impacted in patients with GHD; thus, making an accurate diagnosis is important so that appropriate growth hormone (GH) replacement therapy can be offered to these patients. Screening and testing for GHD require sound clinical judgment that follows after obtaining a complete medical history of patients with a hypothalamic-pituitary disorder and a thorough physical examination with specific features for each period of life, while targeted biochemical testing and imaging are required to confirm the diagnosis. Random measurements of serum GH levels are not recommended to screen for GHD (except in neonates) as endogenous GH secretion is episodic and pulsatile throughout the lifespan. One or more GH stimulation tests may be required, but existing methods of testing might be inaccurate, difficult to perform, and can be imprecise. Furthermore, there are multiple caveats when interpreting test results including individual patient factors, differences in peak GH cut-offs (by age and test), testing time points, and heterogeneity of GH and insulin-like growth factor 1 assays. In this article, we provide a global overview of the accuracy and cut-offs for diagnosis of GHD in children and adults and discuss the caveats in conducting and interpreting these tests.

New developments and future trajectories in supernumerary sex chromosome abnormalities: a summary of the 2022 3rd International Workshop on Klinefelter Syndrome, Trisomy X, and XYY.

The 3rd International Workshop on Klinefelter Syndrome, Trisomy X, and 47,XYY syndrome was held in Leiden, the Netherlands, on September 12-14, 2022. Here, we review new data presented at the workshop and discuss scientific and clinical trajectories. We focus on shortcomings in knowledge and therefore point out future areas for research. We focus on the genetics and genomics of supernumerary sex chromosome syndromes with new data being presented. Most knowledge centre specifically on Klinefelter syndrome, where aspects on testosterone deficiency and the relation to bone, muscle and fat were discussed, as was infertility and the treatment thereof. Both trisomy X and 47,XYY syndrome are frequently affected by infertility. Transitioning of males with Klinefelter syndrome was addressed, as this seemingly simple process in practise is often difficult. It is now realized that neurocognitive changes are pervasive in all supernumerary sex chromosome syndromes, which were extensively discussed. New intervention projects were also described, and exciting new data concerning these were presented. Advocacy organizations were present, describing the enormous burden carried by parents when having to explain their child's specific syndrome to most professionals whenever in contact with health care and education systems. It was also pointed out that most countries do not have health care systems that diagnose patients with supernumerary sex chromosome syndromes, thus pinpointing a clear deficiency in the current genetic testing and care models. At the end of the workshop, a roadmap towards the development of new international clinical care guidelines for Klinefelter syndrome was decided.

Celebration of a century of insulin therapy in children with type 1 diabetes.

Insulin is the key anabolic hormone of metabolism, with clear effects on glycaemia. Near-complete insulin deficiency occurs in type 1 diabetes (T1D), the predominant form affecting children, and uniformly fatal until the discovery of insulin. By the early 20th century, it was known that T1D was caused by the lack of a factor from pancreatic islets, but isolation of this substance proved elusive. In 1921, an unusual team in Toronto comprising a surgeon, a medical student, a physiologist and a biochemist successfully isolated a glucose-lowering pancreatic endocrine secretion. They treated an emaciated 14-year-old boy in 1922, restoring his health and allowing him to live for another 13 years. Thus began an era of remarkable progress and partnership between academia and the pharmaceutical industry to produce drugs that benefit sick people. The Toronto team received the 1923 Nobel Prize, and more Nobel Prizes for work with insulin followed: for elucidation of its amino acid sequence and crystalline structure, and for its role in the development of radioimmunoassays to measure circulating hormone concentrations. Human insulin was the first hormone synthesised by recombinant methods, permitting modifications to enable improved absorption rates and alterations in duration of action. Coupled with delivery via insulin pens, programmable pumps and continuous glucose monitors, metabolic control and quality of life vastly improved and T1D in children was converted from uniformly fatal to a manageable chronic condition. We describe this remarkable ongoing story as insulin remains a paradigm for human ingenuity to heal nature's maladies.

A Brief History of the Pediatric Endocrine Society (PES).

The Pediatric Endocrine Society (PES) was initially established in 1972 as the Lawson Wilkins Pediatric Endocrine Society (LWPES), by some of Wilkins' former fellows. As the society grew from its 37 founding members and Dr. Wilkins' influence faded, the name of the society was changed in 2010 and now counts about 1,500 members, mostly from the US and Canada. Pediatric endocrine training programs headed by (LW)PES members have welcomed fellows from throughout the world, many of whom have gone on to leadership positions in their home countries. Starting in 1981, the (LW)PES has collaborated with pediatric endocrine societies around the world in quadrennial meetings, fostering collaborations, transfer of ideas, devising joint practice guidelines, and enjoying one another's fellowship and counsel. The PES presently has committees and special interest groups concerned with all aspects of pediatric endocrinology, assuring that our clinical and academic resources reflect both breadth and depth. To celebrate our 50th anniversary, selected members have written the historical manuscripts featured in this special issue of Hormone Research in Pediatrics. These historical reviews delve into the origins of our specialty, sometimes deep into antiquity, provide useful background information, and illustrate the kinds of intellectual struggles that have led to the development of contemporary pediatric endocrinology, worldwide.

Growth and Growth Hormone through the Ages: Art and Science.

BACKGROUND: People have long been fascinated with the size and growth of living things, from the giants of classic mythology and art to the little people who also have appeared in classical art, as well as the courts of European monarchs, and were exploited in "shows." Serious medical evaluation began in the late 19th century with the description of acromegaly and its association with pituitary tumors. In the early 20th century, multiple investigators attempted to extract a growth-promoting factor from the anterior pituitary and then, over the decades, to purify it and distinguish it from other anterior pituitary hormones. With relatively pure growth hormone (GH), its biological activity in growth promotion and as a metabolic hormone were studied, and species specificity became apparent: primate GH was the only GH active in man. Human GH was prepared from cadaveric pituitaries and distributed by the NIH to treat children with GH deficiency, but there was never enough pituitary hGH for all of the children who required it. When Creutzfeldt-Jakob disease was found in some patients who received pituitary GH, the production and FDA approval of biosynthetic hGH dramatically accelerated. With a large supply, one could treat those who were GH deficient and test its efficacy in other causes of short stature; longer acting versions of hGH have now been developed, tested, and in a few instances received FDA approval. SUMMARY: It has been a long journey from the description of over- and underproduction of GH in animals to the production and clinical use of the biosynthetic hormones. KEY MESSAGES: The efforts of basic scientists led to the extraction and purification of GH. Clinical scientists have expanded the appropriate use of hGH for short children with conditions in addition to GH deficiency.

The History of the Insulin-Like Growth Factor System.

The growth hormone (GH)-insulin-like growth factor (IGF) cascade is central to the regulation of growth and metabolism. This article focuses on the history of the components of the IGF system, with an emphasis on the peptide hormones, IGF-I and -II, their cell surface receptors, and the IGF binding proteins (IGFBPs) and IGFBP proteases that regulate the availability of the peptide hormones for interaction with their receptors in relevant target tissues. We describe landmark events in the evolution of the somatomedin hypothesis, including evidence that has become available from experiments at the molecular and cellular levels, whole animal and tissue-specific gene knockouts, studies of cancer epidemiology, identification of prismatic human cases, and short- and long-term clinical trials of IGF-I therapy in humans. In addition, this new evidence has expanded our clinical definition of GH insensitivity (GHI) beyond growth hormone receptor mutations (classic Laron syndrome) to include conditions that cause primary IGF deficiency by impacting post-receptor signal transduction, IGF production, IGF availability to interact with the IGF-I receptor (IGF-1R), and defects in the IGF-1R, itself. We also discuss the clinical aspects of IGFs, from their description as insulin-like activity, to the use of IGF-I in the diagnosis and treatment of GH deficiency, and to the use of recombinant human IGF-I for therapy of children with GHI.

Gonadotropin-releasing hormone analog therapies for children with central precocious puberty in the United States.

Gonadotropin-releasing hormone agonists (GnRHa's) are the standard treatment for children with central precocious puberty (CPP). We aim to present data on available GnRHa options with an easy-to-review table and discuss factors that influence treatment selection. Five GnRHa's are currently FDA-approved and prescribed in the US and published data suggest similar safety and efficacy profiles over the first year of treatment. One- and 3-month intramuscular (IM) leuprolide acetate (LA) have long-term safety and efficacy data and allow for flexible dosing. Six-month IM triptorelin pamoate offers a longer duration of treatment, but without long-term efficacy and outcome data. Six-month subcutaneous (SQ) LA combines a SQ route of injection and long duration of action but lacks long-term efficacy and outcome data. The 12-month SQ histrelin acetate implant avoids injections and offers the longest duration of action, but requires a minor surgical procedure with local or general anesthesia. Factors in treatment selection include route of administration, needle size, injection volume, duration of action, and cost. The current GnRHa landscape provides options with varying benefits and risks, allowing physicians and caregivers to select the most appropriate therapy based on the specific needs and concerns of the child and the caregiver. Agents have different advantages and disadvantages for use, with no one agent displaying superiority.

Trends in Growth and Maturation in Children with Cystic Fibrosis Throughout Nine Decades.

Since cystic fibrosis (CF) was first described in 1938, there have been many discoveries and innovations in the field, each having a profound impact on survival, growth and quality of life. For example, the introduction of enteric-coated pancreatic enzyme microspheres increased fat absorption and improved nutritional status. Early detection of CF through newborn screening facilitated prompt nutritional intervention for infants at high risk of malnutrition. Use of anti-pseudomonal therapy, such as inhaled tobramycin, increased weight gain and pulmonary function in addition to reducing pulmonary exacerbations. Similarly, DNAse and hypertonic saline improved pulmonary function and reduced exacerbations. The identification of the CFTR gene and its protein product were fundamental in understanding the pathophysiology of CF and paved the way for advances in both diagnosis and management. In fact, CFTR modulator therapies have revolutionized the care for individuals with CF. Here, we examine the impact of these interventions on the nutritional status, growth and pubertal maturation of children and adolescents with CF.

Average IGF-1 Prediction for Once-Weekly Lonapegsomatropin in Children With Growth Hormone Deficiency.

CONTEXT: Serum insulin-like growth factor 1 (IGF-1) levels are relatively constant in somatropin-treated children with growth hormone deficiency (GHD), and guide dose adjustments for clinical efficacy and long-term safety. IGF-1 levels following treatment with long-acting growth hormones such as lonapegsomatropin (lonapegsomatropin-tcgd, TransCon hGH), a once-weekly somatropin prodrug, exhibit a characteristic profile over the dosing interval. OBJECTIVE: This study aimed to develop a method to predict average IGF-1 in lonapegsomatropin-treated GHD children to interpret IGF-1 data based on a single sample obtained any time at steady state. METHODS: A population nonlinear mixed-effect pharmacodynamic model for IGF-1 was developed based on 2 randomized, open-label trials of TransCon hGh in GHD children and used to develop a linear mixed model with Taylor series to fit simulated IGF-1 profiles of lonapegsomatropin-treated children. A TOTAL OF: 49 896 IGF-1 sample data simulated from 105 lonapegsomatropin-treated GHD children were utilized for the final prediction model. The dosage range of TransCon hGh was 0.14 to 0.30 hGH mg/kg/week, and weekly average IGF-1 was calculated using IGF-1 profiles simulated from the nonlinear pharmacodynamic model. Predicted average IGF-1 was obtained by linear mixed model with Taylor series. RESULTS: The nonlinear mixed-effect model provided satisfactory model fit. The linear mixed model with Taylor series fit simulated IGF-1 data well, with a relatively straightforward prediction formula. IGF-1 values sampled at ~4.5 days post-dose coincided with weekly average IGF-1 at steady state. CONCLUSION: A formula to predict average IGF-1 from a single sample of IGF-1 at steady state was established to aid clinicians in interpreting IGF-1 levels in GHD children administered lonapegsomatropin.

Human Growth and Growth Hormone: From Antiquity to the Recominant Age to the Future.

Since antiquity Man has been fascinated by the variations in human (and animal) growth. Stories and art abound about giants and little people. Modern genetics have solved some of etiologies at both extremes of growth. Serious study began with the pathophysiology of acromegaly followed by early attempts at treatment culminating in modern endoscopic surgery and multiple pharmacologic agents. Virtually at the same time experiments with the removal of the pituitary from laboratory animals noted the slowing or stopping of linear growth and then over a few decades the extraction and purification of a protein within the anterior pituitary that restored, partially or in full, the animal's growth. Human growth hormone was purified decades after those from large animals and it was noted that it was species specific, that is, only primate growth hormone was metabolically active in primates. That was quite unlike the beef and pork insulins which revolutionized the care of children with diabetes mellitus. A number of studies included mild enzymatic digestion of beef growth hormone to determine if those "cores" had biologic activity in primates and man. Tantalizing data showed minimal but variable metabolic efficacy leading to the "active core" hypothesis, for these smaller peptides would be amenable to peptide synthesis in the time before recombinant DNA. Recombinant DNA changed the landscape remarkably promising nearly unlimited quantities of metabolically active hormone. Eight indications for therapeutic use have been approved by the Food and Drug Administration and a large number of clinical trials have been undertaken in multiple other conditions for which short stature in childhood is a sign. The future predicts other clinical indications for growth hormone therapy (and perhaps other components of the GH?IGF-1 axis), longer-acting analogues and perhaps a more physiologic method of administration as virtually all methods at present are far from physiologic.

Growth response to growth hormone (GH) treatment in children with GH deficiency (GHD) and those with idiopathic short stature (ISS) based on their pretreatment insulin-like growth factor 1 (IGFI) levels and at diagnosis and IGFI increment on treatment.

OBJECTIVES: Some idiopathic short stature (ISS) patients may have varying degrees of insulin-like growth factor 1 (IGFI) deficiency. Others with growth hormone deficiency (GHD) (peak GH < 7 ng/dL after provocation) have normal IGFI levels. Do children with ISS or those with GHD with variable pretreatment IGFI standard deviation score (IGFISDS) have different IGFI and growth responses to recombinant human growth hormone (rhGH) therapy? METHODS: We studied the effect of GH therapy (0.035-0.06 mg/kg/day) on linear growth and weight gain per day (WGPD) in children with ISS (n=13) and those with GHD (n=10) who have low pretreatment IGFISDS (IGF SDS < -1.5) and compared them with age-matched prepubertal children with ISS (n=10) and GHD (n=17) who had normal pretreatment IGFISDS. An untreated group of children with ISS (n=12) served as a control group. RESULTS: At presentation, the height standard deviation score (HtSDS) of children with ISS who had low pretreatment IGFISDS was significantly lower compared to the normal IGFI group. The age, body mass index (BMI), BMISDS, peak GH response to clonidine provocation and bone age did not differ between the two study groups. After 1 year of treatment with rhGH (0.035-0.06 mg/kg/day) IGFISDS increased significantly in both groups (p<0.05). Both had significantly increased HtSDS (catch-up growth). The increase in the HtSDS and WGPD were significantly greater in the lower pretreatment IGFISDS group. The IGFSDS, BMISDS, HtSDS and difference between HtSDS and mid-parental HtSDS were significantly greater in the rhGH treated groups vs. the not treated group. In the GHD groups (normal and low IGFISDS), after 1 year of GH therapy (0.03-0.05 mg/kg/day), the HtSDS increased significantly in both, (p<0.01). The WGPD and increment in BMI were significantly greater in children who had low pretreatment IGFISDS. There was a significant increase in the IGFSDS in the two treated groups (p<0.05), however, the WGPD was greater in the pretreatment low IGFISDS. CONCLUSIONS: IGFI deficiency represents a low anabolic state. Correction of IGFI level (through rhGH and/or improved nutrition) in short children (ISS and GHD) was associated with increased linear growth and WGPD denoting significant effect on bone growth and muscle protein accretion.

Long-term GH Therapy Does Not Advance Skeletal Maturation in Children and Adolescents.

CONTEXT: There is no consensus on the effect of recombinant human GH (rhGH) therapy on skeletal maturation in children despite the current practice of annual monitoring of skeletal maturation with bone age in children on rhGH therapy. AIMS: To investigate the effects of long-term rhGH therapy on skeletal age in children and explore the accuracy of bone age-predicted adult height (BAPAH) at different ages based on 13 years of longitudinal data. METHODS: A retrospective longitudinal study of 71 subjects aged 2 to 16 years, mean 9.9 ±â€…3.8 years, treated with rhGH for nonsyndromic short stature for a duration of 2 to 14 years, mean, 5.5 ±â€…2.6 years. Subjects with syndromic short stature and systemic illnesses such as renal failure were excluded. RESULTS: Bone age minus chronological age (BA-CA) did not differ significantly between baseline and the end of rhGH therapy (-1.05 ±â€…1.42 vs -0.69 ±â€…1.63, P = 0.09). Piecewise regression, however, showed a quantifiable catch-up phenomenon in BA of 1.5 months per year of rhGH therapy in the first 6.5 years (P = 0.017) that plateaued thereafter (P = 0.88). BAPAH overestimated near-adult height in younger subjects but became more accurate in older subjects (P < 0.0001). IGF-I levels correlated significantly with increases in child's height and BA-CA. CONCLUSION: Long-term rhGH therapy demonstrated an initial catch-up phenomenon in skeletal maturation in the first 6.5 years that plateaued thereafter with no overall significant advancement in bone age. These findings are reassuring and support strategic, but not the insurance company mandated reflexive annual monitoring of skeletal maturation with bone age in children receiving rhGH therapy.