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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 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.

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 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 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 IGF-I 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.

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 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.

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.

Malnutrition may be classified as acute or chronic and by severity into mild, moderate, and severe forms. Features of chronic malnutrition include diminished weight gain, stunted growth, mental apa...

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 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 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 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.

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.

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.

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.

Context We characterized linear growth in infants and children with X-linked hypophosphatemia (XLH). Objective Provide linear growth curves for children with XLH from birth to early adolescence. Design Data from 4 prior studies of XLH were pooled to construct growth curves. UX023-CL002 was an observational, retrospective chart review. Pretreatment data were collected from 3 interventional trials: two phase 2 trials (UX023-CL201, UX023-CL205) and a phase 3 trial (UX023-CL301). Setting Medical centers with expertise in treating XLH. Patients Children with XLH, 1-14 years of age. Intervention None. Main Outcome Measure Height-for-age linear growth curves, including values for the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles for children with XLH compared to population norms. Results A total of 228 patients (132 girls, 96 boys) with 2381 height measurements were included. Nearly all subjects (> 99%) reported prior management with supplementation therapy. Compared to the Center for Disease Control and Prevention growth curves, boys at age 3 months, 6 months, 9 months, 1 year, and 2 years had median height percentiles of 46%, 37%, 26%, 18%, and 5%, respectively; for girls the median height percentiles were 52%, 37%, 25%, 18%, and 7%, respectively. Annual growth in children with XLH fell below that of healthy children near 1 year of age and progressively declined during early childhood, with all median height percentiles < 8% between 2 and 12 years old. Conclusion Children with XLH show decreased height gain by 1 year of age and remain below population norms thereafter. These data will help evaluate therapeutic interventions on linear growth for pediatric XLH.

“Doping” is as old as the ancient Olympics (776 BC to 394 AD) when athletes used herbal medications, animal organs (organotherapy was common to cure diseases and to improve vitality), stimulants, and hallucinogenic mushrooms to improve athletic performance. We discuss the issues of proper medical use of prohibited drugs (therapeutic use exemption) and the concept of the athlete’s biological passport to highlight disordered physiology rather than necessarily the chemical iasdentification of a banned substance. The growth hormone/IGF-1 system is used as an example of both the detection of the drugs and the consequences upon multiple analytes with the ongoing validation of a peptides module, just as hematologic and steroid modules have been used.

Context Growth hormone (GH) treatment has a generally good safety profile; however, concerns about increased mortality risk in adulthood have been raised. Objective This work aims to assess the long-term safety of GH treatment in clinical practice. Methods Data were collected from 676 clinics participating in 2 multicenter longitudinal observational studies: the NordiNet International Outcome Study (2006-2016, Europe) and ANSWER Program (2002-2016, USA). Pediatric patients treated with GH were classified into 3 risk groups based on diagnosis. Intervention consisted of daily GH treatment, and main outcome measures included incidence rates (events/1000 patient-years) of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious ADRs, and their relationship to GH dose. Results The combined studies comprised 37 702 patients (68.4% in low-risk, 27.5% in intermediate-risk, and 4.1% in high-risk groups) and 130 476 patient-years of exposure. The low-risk group included children born small for gestational age (SGA; 20.7%) and non-SGA children (eg, with GH deficiency; 79.3%). Average GH dose up to the first adverse event (AE) decreased with increasing risk category. Patients without AEs received higher average GH doses than patients with more than one AE across all groups. A significant inverse relationship with GH dose was shown for ADR and SAE incidence rates in the low-risk group (P = .003 and P = .001, respectively) and the non-SGA subgroup (both P = .002), and for SAEs in the intermediate- and high-risk groups (P = .002 and P = .05, respectively). Conclusions We observed no indication of increased mortality risk nor AE incidence related to GH dose in any risk group. A short visual summary of our work is available (1).

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 ± 3.8 years, treated with rhGH for nonsyndromic short stature for a duration of 2 to 14 years, mean, 5.5 ± 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 ± 1.42 vs -0.69 ± 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 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.

Testosterone replacement therapy (TRT) is routinely prescribed in adolescent males with constitutional delay of growth and puberty (CDGP) or hypogonadism. With many new testosterone (T) formulations entering the market targeted for adults, we review current evidence and TRT options for adolescents and identify areas of unmet needs. We searched PubMed for articles (in English) on testosterone therapy, androgens, adolescence, and puberty in humans. The results indicate that short-term use of T enanthate (TE) or oral T undecanoate is safe and effective in inducing puberty and increasing growth in males with CDGP. Reassuring evidence is emerging on the use of transdermal T to induce and maintain puberty. The long-term safety and efficacy of TRT for puberty completion and maintenance have not been established. Current TRT regimens are based on consensus and expert opinion, but evidence-based guidelines are lacking. Limited guidance exists on when and how T should be administered and optimal strategies for monitoring therapy once it is initiated. Only TE and T pellets are US Food and Drug Administration approved for use in adolescent males in the United States. Despite the introduction of a wide variety of new T formulations, they are designed for adults, and their metered doses are difficult to titrate in adolescents. In conclusion, TRT in adolescent males is hindered by lack of long-term safety and efficacy data and limited options approved for use in this population. Additional research is needed to identify the route, dose, duration, and optimal timing for TRT in adolescents requiring androgen therapy.

Context Application of ultrasound (US) to evaluate attainment and morphology of glandular tissue provides a new rationale for evaluating onset and progression of female puberty, but currently no hormone references complement this method. Furthermore, previous studies have not explored the predictive value of endocrine profiling to determine female puberty onset. Objective To integrate US breast staging with hypothalamic-pituitary-gonadal hormone references and test the predictive value of an endocrine profile to determine thelarche. Design Setting and Participants Cross-sectional sample of 601 healthy Norwegian girls, ages 6 to 16 years. Main Outcome Measures Clinical and ultrasound breast evaluations were performed for all included girls. Blood samples were analyzed by immunoassay and ultrasensitive liquid chromatography–tandem mass spectrometry (LC-MS/MS) to quantify estradiol (E2) and estrone (E1) from the subpicomolar range. Results References for E2, E1, luteinizing hormone, follicle-stimulating hormone, and sex hormone–binding globulin were constructed in relation to chronological age, Tanner stages, and US breast stages. An endocrine profile index score derived from principal component analysis of these analytes was a better marker of puberty onset than age or any individual hormone, with receiver-operating characteristic area under the curve 0.91 (P

Emotional deprivation can lead to growth faltering of infants and children. The mechanism(s) involved differ in that for infants, the major metabolic problem is inadequate energy intake for growth. In young children, it is likely that the emotional deprivation causes a syndrome not only of growth faltering, but with bizarre behaviors, especially with regard to food: hoarding, gorging and vomiting, hyperphagia, drinking from the toilet, and eating from garbage pails. Other disturbed behaviors include, poor sleep, night wanderings, and pain agnosia. The pathophysiology appears to be reversible hypopituitarism, at least for the growth hormone and hypothalamic-pituitary- adrenal axes. The review begins with an historical perspective concerning stress, children and growth and then moves to the issue of hospitalism, where young infants failed to thrive (and died) due to inadequate stimulation and energy intake. Refeeding programs at the end of World Wars I and II noted that some children did not thrive despite an adequate energy intake. It appeared that in addition taking care of their emotional needs permitted super-physiologic (catch-up) growth. Next came the first notions from clinical investigation that hypopituitarism might be the mechanism of growth faltering. Studies that address this mechanism from a number of observational and clinical research studies are reviewed in depth to show that the hypopituitarism was relieved upon removal from the deprivational environment and occurred much too quickly to be due to adequate energy alone. These findings are then compared to those from malnourished children and adoptees from emerging countries, especially those from orphanages where their psychosocial needs were unmet despite adequate caloric intake. Together, these various conditions define one aspect of the field of psychoneuroendocrinology.

We provide an in-depth review of the role of androgens in male maturation and development, from the fetal stage through adolescence into emerging adulthood, and discuss the treatment of disorders of androgen production throughout these time periods. Testosterone, the primary androgen produced by males, has both anabolic and androgenic effects. Androgen exposure induces virilization and anabolic body composition changes during fetal development, influences growth and virilization during infancy, and stimulates development of secondary sexual characteristics, growth acceleration, bone mass accrual, and alterations of body composition during puberty. Disorders of androgen production may be subdivided into hypo- or hypergonadotropic hypogonadism. Hypogonadotropic hypogonadism may be either congenital or acquired (resulting from cranial radiation, trauma, or less common causes). Hypergonadotropic hypogonadism occurs in males with Klinefelter syndrome and may occur in response to pelvic radiation, certain chemotherapeutic agents, and less common causes. These disorders all require testosterone replacement therapy during pubertal maturation and many require lifelong replacement. Androgen (or gonadotropin) therapy is clearly beneficial in those with persistent hypogonadism and self-limited delayed puberty and is now widely used in transgender male adolescents. With more widespread use and newer formulations approved for adults, data from long-term randomized placebo-controlled trials are needed to enable pediatricians to identify the optimal age of initiation, route of administration, and dosing frequency to address the unique needs of their patients.

Background/Aims: A meta-analysis was performed to determine the likelihood of hypothalamic-pituitary-adrenal (HPA) axis suppression following short-term cutaneous treatment of atopic dermatitis with topical corticosteroids (TCS) in pediatric patients. Methods: All published pediatric clinical trials evaluating TCS use with pre- and post-treatment HPA axis assessment by cosyntropin stimulation testing were included. Results: Of 128 eligible trials, 12 were selected for meta-analysis with a total of 522 participants. There were 20 observed cases of HPA axis suppression (3.8%, 95% CI 2.4–5.8). The percentage of HPA axis suppression with low- (classes 6–7), medium- (classes 3–5) and high-potency (classes 1–2) TCS use was 2% (3 of 148 patients, 95% CI 0.7–5.8), 3.1% (7 of 223 patients, 95% CI 1.5–6.3), and 6.6% (10 of 151 patients, 95% CI 3.6–11.8), respectively. Conclusion: There is a low rate of reversible HPA axis suppression with the use of mid- to low-potency TCS compared to more potent formulations. In pediatric clinical practice, the limited use of mid- to low-potency TCS is rarely associated with clinically significant adrenal insufficiency or adrenal crisis. In the absence of signs and symptoms of adrenal insufficiency, there is little need to test the HPA axis of these patients.

This report illustrates the links between history, sport, endocrinology, and genetics to show the ways in which historical context is key to understanding the current conversations and controversies about who may compete in the female category in elite sport. The International Association of Athletics Federations (IAAF) introduced hyperandrogenemia regulations for women’s competitions in 2011, followed by the International Olympic Committee (IOC) for the 2012 Olympics. The policies concern female athletes who naturally produce higher-than-average levels of testosterone and want to compete in the women’s category. Hyperandrogenemia guidelines are the current effort in a long series of attempts to determine women’s eligibility scientifically. Scientific endeavors to control who may participate as a woman illustrate the impossibility of neatly classifying competitors by sex and discriminate against women with differences of sex development (also called intersex by some).

Background: In adolescents, testosterone may have several effects including promotion of secondary sexual characteristics and pubertal growth, attainment of optimal muscle mass and peak bone mass, optimization of the metabolic profile, and psychosocial maturation and well-being. Summary: Testosterone therapy is a cornerstone of the management of hypogonadism in boys. Since the initial report of the chemical synthesis of testosterone, several formulations have continued to develop, and although many of these have been used in boys, none of them have been studied in detail in this age group. Given the wide ranging effects of testosterone, the level of evidence for their effects in boys and the heterogeneity of conditions that lead to early-onset hypogonadism, a standardized protocol for monitoring testosterone replacement in this age group is needed. Key Messages: In this review, we focus on the perceived benefits of androgen replacement in boys affected by pubertal delay and highlight the need to improve the health monitoring of boys who receive androgen replacement therapy, proposing different approaches based on the underlying pathophysiology.

The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency. info:eu-repo/semantics/publishedVersion

Context Clomiphene is a performance-enhancing drug commonly abused by males in sport, but the extent to which testosterone increases in healthy males following its use is unknown. In addition, evidence suggests that clomiphene, a mixture of cis- and trans-isomers zuclomiphene and enclomiphene, is detectable in urine for months following use; the isomer-specific urinary detection window has yet to be characterized in a controlled study. Objective To determine the effect of once-daily, 30-day clomiphene treatment on serum testosterone and gonadotropin levels in the subject population studied and the urinary clearance and detection window of clomiphene isomers following administration for antidoping purposes. Participants and Design Twelve healthy males aged 25 to 38 years, representing a recreational athlete population, participated in this open-label, single-arm study. Intervention Oral clomiphene citrate (50 mg) was self-administered once daily for 30 days. Serum and urine samples were collected at baseline and at days 7, 14, 21, 28, 30, 32, 35, 37, 44, 51, and 58; urine collections continued periodically up to day 261. Results Mean testosterone, LH, and FSH levels increased 146% (SEM, ±23%), 177% (±34%), and 170% (±33%), respectively, during treatment compared with baseline. Serum drug concentrations and urinary excretion were nonuniform among individuals as isomeric concentrations varied. The zuclomiphene urinary detection window ranged from 121 to >261 days. Conclusions Clomiphene significantly raised serum testosterone and gonadotropin levels in healthy men and thus can be abused as a performance-enhancing drug. Such abuse is detectable in urine for ≥4 months following short-term use.

Advantages of testosterone nasal gel include ease of administration, low dose, and no risk of secondary transference. The efficacy and safety of testosterone nasal gel was evaluated in hypogonadal males. The ninety-day, randomized, open-label, dose-ranging study, included potential dose titration and sequential safety extensions to 1 year. At 39 US outpatient sites, 306 men (mean age 54.4 years) with two fasting morning total serum testosterone levels

Klinefelter syndrome (KS) is the leading genetic cause of primary hypogonadism and infertility in men. The clinical phenotype has expanded beyond the original description of infertility, small testes, and gynecomastia. Animal models, epidemiologic studies, and clinical research of male subjects with KS throughout the lifespan have allowed the better characterization of the variable phenotype of this condition. This review provides an overview on what is known of the epidemiology, clinical features, and pathophysiology of KS, followed by a more focused discussion of testicular development and the clinical management of hypogonadism and fertility in boys and men with KS.

We are writing this piece in the aftermath of the 2016 Olympic Games in Rio de Janeiro, Brazil. Each of the words in the title plays a role(s) in deciding who may compete, especially who may compete as a woman. Sex verification and anti-doping measures are not new in sport. The sex verification process has gone from inspection of genitalia, to Barr body (chromosome), to genes that determine testicular development, to measuring circulating levels of testosterone to now none of these. Genetic differences are clear among animals, whether single genes or the interactions among multiple genes—some of which may confer sport performance advantages, for example, the erythropoietin receptor, may be neutral, for example complete androgen insensitivity or may confer a disadvantage, for example, some of the genes coding for collagen structure. Those involving hormones are to be clearly distinguished from doping, which implies an exogenous source of drug or a prohibited method, such as blood transfusion. Some athletes with medical conditions have low levels of specific hormones and it is medically recognized that hormone replacement is appropriate. For these athletes a therapeutic use exemption (TUE) is available. It is within this context that pediatric and internal medicine endocrinologists become involved in the diagnosis, treatment and longitudinal care of these athletes.

Small-for-gestational age (SGA) infants are at risk for short and long term medical and metabolic complications. Most SGA infants (85-90%) demonstrate spontaneous catch-up growth, typically in the first year after birth. Although catch-up growth (CUG) is a desired goal, it is important to note if CUG is too rapid the infants are at increased risk for insulin resistance and type 2 diabetes mellitus as they become adults. On the flip side, infants who do not exhibit CUG are also at increased risk of adverse adult outcomes including those for cardiovascular disease, insulin resistance and type 2 diabetes mellitus, neurodevelopmental and cognitive impairments, in addition to adult short stature. Treatment with growth hormone is safe and effective not only in increasing adult height, but also in improving body composition and decreasing metabolic complications. The aims of this review are to summarize the current knowledge on what constitutes "healthy" catch-up growth in children born SGA as well as provide an update on the role of growth hormone treatment for short children born SGA.

SummaryContext and objective Titrating the dosage of growth hormone (GH) to serum levels of insulin-like growth factor-I (IGF-I) is a feasible treatment strategy in children with GH deficiency (GHD) and idiopathic short stature (ISS). The objective was to assess the dose-sparing effect and theoretical safety of IGF-I-based GH therapy. Design, setting and patients This was a post hoc analysis of a previously described 2-year, multicenter, open-label, randomized, outpatient, controlled clinical trial in 172 prepubertal short children [age 7·5 ± 2·4 years; height standard deviation score (HSDS) −2·64 ± 0·61] classified by baseline peak GH levels as GHD (

Despite the high prevalence of performance-enhancing drug (PED) use, media attention has focused almost entirely on PED use by elite athletes to illicitly gain a competitive advantage in sports, and not on the health risks of PEDs. There is a widespread misperception that PED use is safe or that adverse effects are manageable. In reality, the vast majority of PED users are not athletes but rather nonathlete weightlifters, and the adverse health effects of PED use are greatly underappreciated. This scientific statement synthesizes available information on the medical consequences of PED use, identifies gaps in knowledge, and aims to focus the attention of the medical community and policymakers on PED use as an important public health problem. PED users frequently consume highly supraphysiologic doses of PEDs, combine them with other PEDs and/or other classical drugs of abuse, and display additional associated risk factors. PED use has been linked to an increased risk of death and a wide variety of cardiovascular, psychiatric, metabolic, endocrine, neurologic, infectious, hepatic, renal, and musculoskeletal disorders. Because randomized trials cannot ethically duplicate the large doses of PEDs and the many factors associated with PED use, we need observational studies to collect valid outcome data on the health risks associated with PEDs. In addition, we need studies regarding the prevalence of PED use, the mechanisms by which PEDs exert their adverse health effects, and the interactive effects of PEDs with sports injuries and other high-risk behaviors. We also need randomized trials to assess therapeutic interventions for treating the adverse effects of PEDs, such as the anabolic-androgen steroid withdrawal syndrome. Finally, we need to raise public awareness of the serious health consequences of PEDs.

Traumatic brain injury (TBI) is a common cause of death and disability in young adults with consequences ranging from physical disabilities to long-term cognitive, behavioral, psychological and social defects. Recent data suggest that pituitary hormone deficiency is not infrequent among TBI survivors; the prevalence of reported hypopituitarism following TBI varies widely among published studies. The most common cause of TBI is motor vehicle accidents, including pedestrian-car and bicycle car encounters, falls, child abuse, violence and sports injuries. Prevalence of hypopituitarism, from total to isolated pituitary deficiency, ranges from 5 to 90 %. The time interval between TBI and pituitary function evaluation is one of the major factors responsible for variations in the prevalence of hypopituitarism reported. Endocrine dysfunction after TBI in children and adolescents is common. Adolescence is a time of growth, freedom and adjustment, consequently TBI is also common in this group. Sports-related TBI is an important public health concern, but many cases are unrecognized and unreported. Sports that are associated with an increased risk of TBI include those involving contact and/or collisions such as boxing, football, soccer, ice hockey, rugby, and the martial arts, as well as high velocity sports such as cycling, motor racing, equestrian sports, skiing and roller skating. The aim of this paper is to summarize the best evidence of TBI as a cause of pituitary deficiency in children and adults.

Background/Aims: Limited data exist on long-term dose response to recombinant human growth hormone (rhGH) in prepubertal GH-deficient (GHD) children. The effect of low, intermediate, and high-dose rhGH (25, 50, and 100 μg/kg/day, respectively) on growth and puberty in children with GHD was investigated for 48 months. Methods: A prospective, dose-response study in 111 patients (aged 3-16 years) evaluated growth velocity (cm/year), height standard deviation score (HSDS), corrected HSDS, bone age/chronologic age ratio, body mass index SDS, and the percentage starting puberty. Results: Dose-related increases were observed in growth velocity (p < 0.001), HSDS (p < 0.001), and corrected HSDS (p < 0.001) from baseline to 48 months. Increases in the bone age/chronologic age ratio (p = 0.043) and body mass index SDS (p = 0.018) occurred up to 36 months at intermediate and high doses versus low-dose rhGH; increases at 48 months were not significant. No significant differences in growth were found between intermediate and high doses of rhGH. Percentages of rhGH-treated patients starting puberty at each dose were equivalent (p = 0.607). Conclusions: rhGH, 50 and 100 μg/kg/day, induced greater growth than 25 μg/kg/day without altering the proportion of children starting puberty. The maximum approved dose for pubertal patients (100 μg/kg/day) is not required or recommended for prepubertal children with GHD.

Recombinant human growth hormone (rhGH) has been available since 1985. Before 1985 growth hormone (GH) was extracted from cadaveric pituitary glands, but this was stopped in most countries that year, following the recognition that it could transmit Creutzfeldt–Jacob disease. The primary goal of rhGH treatment in GHD patients is to normalize height during childhood and adolescence and attain an adult height within the normal range and within the target height range (genetic potential). Genome-wide association studies have been used increasingly to study the genetic influence on height. There is a wide response to rhGH therapy, likely due to compliance issues, severity of GH deficiency and patient's sensitivity to rhGH. While some pediatric endocrinologists will use a fixed dose of rhGH, most will use an auxology-based dosing approach. This will involve starting at the lower end of the dose range and then titrating upwards based on the patient's response to therapy with measurement of IGF-1 concentrations to ensure that the patient is not over treated or undertreated. Although treatment of children with GHD with rhGH has generally been safe, careful follow-up by a pediatric endocrinologist in partnership with the pediatrician or primary care physician is recommended. The aim of this paper is to review the strategies and recommendations for treatment of GHD in children and patients in the transition to adult care.

Short stature in children may be associated with low IGF-I despite normal stimulated GH levels and without other causes.Our objective was to assess the safety and efficacy of recombinant human IGF-I (rhIGF-I) in short children with low IGF-I levels.This was a 1-yr, randomized, open-label trial (MS301).The study was conducted at 30 U.S. pediatric endocrinology clinics.A total of 136 short, prepubertal subjects with low IGF-I (height and IGF-I sd scores-2, stimulated GHor =7 ng/ml); 124 completed the study, and six withdrew for adverse events and six for other reasons.rhIGF-I was administered sc, twice daily using weight-based dosing (40, 80, or 120 microg/kg; n = 111) or subjects were observed (n = 25).First-year height velocity (centimeters per year, cm/yr), height sd score, IGF-I, and adverse events were prespecified outcomes.First-year height velocities for subjects completing the trial were increased for the 80- and 120-microg/kg twice-daily vs. the untreated group (7.0 +/- 1.0, 7.9 +/- 1.4, and 5.2 +/- 1.0 cm/yr, respectively; all P0.0001) and for the 120- vs. 80-microg/kg group (P = 0.0002) and were inversely related to age. They were not predicted by GH stimulation or IGF-I generation test results and were not correlated with IGF-I antibody status. The most commonly reported adverse events of special interest during treatment were headache (38% of subjects), vomiting (25%), and hypoglycemia (14%).rhIGF-I treatment was associated with age- and dose-dependent increases in first-year height velocity. Adverse events during treatment were less common than in previous studies and were generally transient, easily managed, and without known sequelae.

Whether for the prepubertal or pubertal child, the goal of fertility preservation is to obtain cells or tissues to be used to produce future children. For the prepubertal child, preservation efforts involve germ cells, earlier forms of sperm, and immature follicles, rather than mature spermatozoa or follicles. Options for prepubertal children include for boys freezing testicular tissue and extracting testicular sperm or for girls obtaining ovarian cortical or follicular tissue for storage. These procedures involve extraction and storage of immature gametes for subsequent in vitro maturation, although attempts for sperm currently involve only animal studies. For adolescent subjects who have sufficient gonadal development and reserve, sperm, oocytes, and ovarian cortex can be retrieved as among adults.

Weight-based dosing of growth hormone (GH) is the standard of therapy in short children although insulin-like growth factor-I (IGF-I) is a major mediator of GH actions on growth. Objective: to test whether the IGF-I levels achieved during GH therapy are determinants of the growth responses to GH therapy. This was a two-year open-label, randomized IGF-I concentration-controlled trial. Prepubertal short children [n = 172; mean age 7.53 years; mean height SD score (HT-SDS - 2.64] with low IGF-I levels (mean IGF-I SDS - 3.56) were randomized to receive one of two GH dose-titration arms in which GH dosage was titrated to achieve an IGF-I SDS at the mean [IGF(low) group, n = 70) or the upper limit of the normal range [+2 SDS, IGF(high) group, n = 68] or to a comparison group of conventional GH dose of 40 mg/kg/day (n = 34). The multicenter study was performed in the outpatient centers. The primary outcome measure was to determine changes in HT-SDS during 2-year therapy. One hundred and forty-seven patients completed the trial. Target IGF-I levels were achieved in the dose-titration arms within 6-9 months. The changes in HT-SDS were +1.0, +1.1, and +1.6 for conventional, IGF(low), and IGF(high), respectively, with IGF(high) showing significantly greater linear growth response (p < 0.001), compared with the two other groups). The IGF-I(high) arm required higher doses ( > 2.5 times) than the IGF-I(low) arm, and these GH doses were highly variable (20-346 mg/kg/day). Multivariate analyses suggest that the rise in IGF-I SDS significantly impacted height outcome along with the GH dose and the pretreatment peak-stimulated GH level. IGF-I-based GH dosing is clinically feasible and allows maintaining serum IGF-I concentrations within the desired target range. Titrating the GH dose to achieve higher IGF-I target results in improved growth responses, although at higher average GH doses.

The foundation for the diagnosis of growth hormone (GH) deficiency in childhood must be auxology, that is, the comparison of the child's growth pattern to that of established norms for gender and ethnicity. It is only in those growing considerably more slowly than average that testing for GHD makes sense. Assessment of laboratory tests, whether static, for example, the measurement of growth factors or their binding proteins, or dynamic, for example, secretagogue-stimulated GH secretion is confirmatory. One must be cognizant of the assay used to determine GH, for there may be a 3-fold difference in the concentration of GH among commercially-available assays. Controversy still exists concerning the measurement of spontaneous GH release and whether sex-steroid priming is appropriate in prepubertal children. Imaging analysis may prove helpful in some children with congenital GHD or to detect a space-occupying lesion in the area of the hypothalamus and pituitary. The final diagnosis is based on multiple parameters and occasionally on a therapeutic trial of GH therapy to determine if there is a significant acceleration of growth velocity.

Idiopathic short stature is a condition in which the height of the individual is more than 2 SD below the corresponding mean height for a given age, sex and population, in whom no identifiable disorder is present. It can be subcategorized into familial and non-familial ISS, and according to pubertal delay. It should be differentiated from dysmorphic syndromes, skeletal dysplasias, short stature secondary to a small birth size (small for gestational age, SGA), and systemic and endocrine diseases. ISS is the diagnostic group that remains after excluding known conditions in short children.

In the management of ISS auxological, biochemical, psychosocial and ethical elements have to be considered. In boys with constitutional delay of growth and puberty androgens are effective in increasing height and sexual characteristics, but adult height is unchanged. GH therapy is efficacious in increasing height velocity and adult height, but the inter-individual variation is considerable. The effect on psychosocial status is uncertain. Factors affecting final height gain include GH dose, height deficit in comparison to midparental height, age and first year height velocity. In case of a low predicted adult height at the onset of puberty, addition of a GnRH analogue can be considered. Although GH therapy appears safe, long-term monitoring is recommended.

Context: Weight-based dosing of GH is the standard of care for short children, although IGF-I is thought to be the main mediator of GH actions on growth. Objective: The objective of the study was to test whether IGF-I levels achieved during GH therapy are determinants of the growth responses to GH treatment. Design: This was a 2-yr, open-label, randomized, IGF-I concentration-controlled trial. Prepubertal short children [n = 172, mean age 7.53 yr, mean height sd score (HT-SDS) −2.64] with low IGF-I levels (mean IGF-I SDS −3.56) were randomized to receive one of two GH dose-titration arms in which GH dosage was titrated to achieve an IGF-I SDS at the mean [IGF(low) group, n = 70] or the upper limit of the normal range [+2 SDS, IGF(high) group, n = 68] or to a comparison group of conventional GH dose of 40 μg/kg/d (n = 34). Setting: The study was conducted in a multicenter, outpatient setting. Primary Outcome Measure: Change in HT-SDS over 2 yr was measured. Results: One hundred forty-seven patients completed the trial. Target IGF-I levels were achieved in the dose-titration arms within 6–9 months. The changes in HT-SDS were +1.0, +1.1, and +1.6 for conventional, IGF(low), and IGF(high), respectively, with IGF(high) showing significantly greater linear growth response (P < 0.001, compared with the other two groups). The IGF(high) arm required higher doses (>2.5 times) than the IGF(low) arm, and these GH doses were highly variable (20–346 μg/kg/d). Multivariate analyses suggested that the rise in the IGF-I SDS significantly impacted height outcome along with the GH dose and the pretreatment peak-stimulated GH level. Conclusion: IGF-I-based GH dosing is clinically feasible and allows maintaining serum IGF-I concentrations within the desired target range. Titrating the GH dose to achieve higher IGF-I targets results in improved growth responses, although at higher average GH doses.

The use of human growth hormone to treat children with short stature resulting from growth hormone deficiency or insufficiency has now accrued over 40 years of clinical experience with a satisfactory safety and efficacy record. Growth hormone deficiency is the primary indication for growth hormone treatment in childhood. It is basically a clinical diagnosis, based upon auxologic features, and confirmed by biochemical testing. For assurance of compliance, dosing and, perhaps, safety considerations, a dosing algorithm based upon insulin-like growth factor-I response seems to be appropriate. Current data suggest that such algorithms reflect the true growth hormone needs of a patient, and allow optimization of growth hormone treatment. For patients who display a suboptimal growth response or in whom the insulin growth factor levels remain low with assurance of adherence to the injection schedule, it is reasonable to increase the growth hormone dose. The availability of recombinant human insulin-like growth factor-I treatment may provide an alternative for massively increasing the dose of growth hormone. Dose reductions should be considered for patients with serum insulin-like growth factor-I levels substantially above the normal range.

Administration of insulin-like growth factor-I to patients with diabetes enhances insulin action and reduces the degree of hyperglycemia but it is associated with a high rate of adverse events. Infusion of the combination of rhIGFBP-3 (the principal binding protein for IGF-I in plasma) with rhIGF-I to patients with type I diabetes improved insulin sensitivity and was associated with a low incidence in side effects. In this study, 52 patients with insulin-treated type 2 diabetes received recombinant human IGF-I plus rhIGFBP-3 in one of four dosage regimens for 14 days. The four groups were: (1) continuous subcutaneous infusion of 2 mg/kg/day; (2) the same 2 mg/kg dose infused subcutaneously over 6 h between 2000 and 0200 h; (3) 1 mg/kg twice a day by bolus subcutaneous injection; (4) a single bedtime subcutaneous injection of 1 mg/kg. Across these four groups rhIGF-I/rhIGFBP-3 decreased insulin requirements between 54% and 82%. Fasting glucose decreased by 32-37%. Mean daily blood glucose (4 determinations per day) declined in all 4 groups (range 9-23% decrease). Frequent sampling for total IGF-I, free IGF-I and IGFBP-3 was performed on days 0,1,7,14 and 15. The peak total IGF-I values were increased to 4.0-4.8-fold at 16-24 h. For free IGF-I the increase varied between 7.1 and 8.2-fold and peak values were attained at 16-20 h after administration. Both the time to maximum concentration (Tmax) and the maximum free IGF-I levels (Cmax) on day 1 for all groups were substantially less than previously published studies, wherein lower doses of rhIGF-I were given without IGFBP-3. The improvement in glucose values and the degree of reduction in insulin requirement were the greatest in groups 2 and 3 and the patients in those groups had the highest free IGF-I levels. The frequency of side effects such as edema, jaw pain and arthralgias was 4% which is less than that has been reported in previous studies wherein IGF-I was administered without IGFBP-3. We conclude that rhIGF-I/rhIGFBP-3 significantly lowers insulin requirements yet improves glucose values and these changes may reflect improvement in insulin sensitivity. Coadministration of IGFBP-3 with IGF-I produces lower free IGF-I (Tmax and Cmax) levels compared to administration of IGF-I alone and is associated with relatively low incidence of side effects during 2 weeks of administration.

In March 2004 a group of 65 physicians and other health professionals representing nine countries on four continents convened in Israel to discuss the widespread public health crisis in childhood obesity. Their aim was to explore the available evidence and develop a consensus on the way forward. The process was rigorous, although time and resources did not permit the development of formal evidence-based guidelines. In the months before meeting, participants were allocated to seven groups covering prevalence, causes, risks, prevention, diagnosis, treatment, and psychology. Through electronic communication each group selected the key issues for their area, searched the literature, and developed a draft document. Over the 3-d meeting, these papers were debated and finalized by each group before presenting to the full group for further discussion and agreement. In developing a consensus statement, this international group has presented the evidence, developed recommendations, and provided a platform aimed toward future corrective action and ongoing debate in the international community.