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Aim: The aim of this systematic review was to assess the effects on psychosocial and mental health, cognition, body composition, and metabolic markers of hormone treatment in children with gender dysphoria. Methods: Systematic review essentially follows PRISMA. We searched PubMed, EMBASE and thirteen other databases until 9 November 2021 for English-language studies of hormone therapy in children with gender dysphoria. Of 9934 potential studies identified with abstracts reviewed, 195 were assessed in full text, and 24 were relevant. Results: In 21 studies, adolescents were given gonadotropin-releasing hormone analogues (GnRHa) treatment. In three studies, cross-sex hormone treatment (CSHT) was given without previous GnRHa treatment. No randomised controlled trials were identified. The few longitudinal observational studies were hampered by small numbers and high attrition rates. Hence, the long-term effects of hormone therapy on psychosocial health could not be evaluated. Concerning bone health, GnRHa treatment delays bone maturation and bone mineral density gain, which, however, was found to partially recover during CSHT when studied at age 22 years. Conclusion: Evidence to assess the effects of hormone treatment on the above fields in children with gender dysphoria is insufficient. To improve future research, we present the GENDHOR checklist, a checklist for studies in gender dysphoria.

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Introduction: PATRO Children is an international, observational, postmarketing surveillance study for a biosimilar recombinant human growth hormone (rhGH; somatropin, Omnitrope®; Sandoz), approved by the European Medicines Agency in 2006. We report safety and effectiveness data for patients with Turner syndrome (TS). Methods: The study population included infants, children, and adolescents with TS who received Omnitrope® treatment according to standard clinical practice. Adverse events (AEs) were monitored for safety evaluation, and height velocity (HV), height standard deviation score (HSDS), and HVSDS were calculated to evaluate treatment effectiveness. Results: As of August 2019, 348 TS patients were enrolled from 130 centers. At baseline, 314 patients (90.2%) were prepubertal and 284 patients (81.6%) were rhGH treatment naïve. The mean (range) age at baseline was 9.0 (0.7–18.5) years, and mean (SD) treatment duration in the study was 38.5 (26.8) months. Overall, 170 patients (48.9%) reported AEs, which were considered treatment related in 25 patients (7.2%). One treatment-related serious AE was reported (intracranial hypertension). Mean ΔHSDS after 3 years of therapy was +1.17 in treatment-naïve prepubertal patients and +0.1 in pretreated prepubertal patients. In total, 51 patients (31.1%) reached adult height (AH), 35 of whom were rhGH treatment naïve; in these patients, mean (SD) HSDS was −2.97 (1.03) at the start of Omnitrope® treatment, and they achieved a mean (SD) AHSDS of −2.02 (0.9). Conclusion: These data suggest that biosimilar rhGH is well tolerated and effective in TS patients managed in real-life clinical practice. Optimization of rhGH dose may contribute to a higher AH.

Aim Children treated with a growth hormone (GH) for idiopathic growth hormone deficiency (IGHD) may be monitored with the first-year prediction model from the Pfizer International Growth Database (KIGS) using auxology, age, GH dose and the maximum GH concentration from a stimulation test (GHmaxstim). We tested the hypothesis that using a 12-hour spontaneous profile (GHmax12h) would be as accurate. Methods We studied 98 prepubertal Swedish children (78 boys) aged 2-12 years enrolled in KIGS. The first-year growth was predicted using the GHmax from the GH profile and a stimulation test and both of these were compared separately with the observed growth response. Results The increased height observed in the first year was 0.74 standard deviation scores (SDS) and the studentised residuals for the predicted and observed growth with GHmaxstim (-0.16 SDS) and GHmax12h (-0.22) were similar. Individual predictions calculated with stimulated or spontaneous GHmax showed a significant correlation (r=0.80). Conclusion We validated the KIGS IGHD prediction model and found that the stimulated GHmax peak can be reliably replaced by the GHmax 12h with similar accuracy. This makes the model more accessible for clinicians, who can then provide realistic expectations for the growth response during the first year of treatment. This article is protected by copyright. All rights reserved.

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

Objective: This study aimed to investigate whether reported high mortality in childhood recombinant human GH (rhGH)-treated patients was related to birth-characteristics and/or rhGH treatment. Design and Setting: We sought to develop a mortality model of the Swedish general population born between 1973 and 2010, using continuous-hazard functions adjusting for birth characteristics, sex, age intervals, and calendar year to estimate standardized mortality ratio (SMR) and to apply this model to assess expected deaths in Swedish rhGH-treated patients with idiopathic isolated GH deficiency (IGHD), idiopathic short stature (155) or born small for gestational age (SGA). Participants:The general population: Swedish Medical Birth Register (1973-2010: 1 880 668 males; 1 781 131 females) and Cause of Death Register (1985-2010). Intervention Population: Three thousand eight hundred forty-seven patients starting rhGH treatment between 1985 and 2010 and followed in the National GH Register and/or in rhGH trials diagnosed with IGHD (n = 1890), ISS (n = 975), or SGA (n=982). Main Outcome Measures: Death. Results: Using conventional models adjusting for age, sex, and calendar-year, the SMR was 1.43 (95% confidence interval, 0.89-2.19), P = .14, observed/expected deaths 21/14.68. The rhGH population differed (P < .001) from the general population regarding birth weight, birth length, and congenital malformations. Application of an Advanced Model: When applying the developed mortality model of the general population, the ratio of observed/expected deaths in rhGH-treated patients was 21/21.99; SMR = 0.955 (0.591-1.456)P = .95. Model Comparison: Expected number of deaths were 14.68 (14.35-14.96) using the conventional model, and 21.99 (21.24-22.81) using the advanced model, P < .001, which had at all ages a higher gradient of risk per SD of the model, 24% (range, 18-42%; P < .001). Conclusions: Compared with the general Swedish population, the ratio of observed/expected deaths (21/21.99) was not increased in childhood rhGH-treated IGHD, ISS, and SGA patients when applying an advanced sex-specific mortality model adjusting for birth characteristics.

Little is known about the long-term health of marginally low birthweight (LBW) children. This study characterised growth among infants weighing 2000 g-2500 g and explored the prevalence and predictors of sustained growth restriction.This prospective observational trial followed the weight and height of 281 Swedish marginally LBW children from birth to 3.5 years of age. Children with a standard deviation score (SDS) for body mass index or height below -2 were considered underweight and short, respectively.The mean SDS for weight and height showed a rapid increase before 12-19 weeks of age. The most rapid weight gain was in infants born small for gestational age. However, at 3.5 years of age, 9.5% of the children remained underweight and 6.5% had short stature. Regression models showed that slow weight gain before 19 weeks of age was the strongest predictor for lasting underweight, while slow height gain before 19 weeks of age and male sex were associated with short stature.Marginally LBW infants were more likely to be underweight and have a short stature at 3.5 years of age and the absence of catch-up growth during the first five months after birth identified those at highest risk.

Growth hormone (GH) is a highly dynamic hormone, influencing growth and metabolism. GH secretion varies with biological maturity and nutritional state, illness, stress, and physical activity. GH deficiency (GHD) may be observed in the neonatal period or later throughout life. Thus, knowledge on normal physiology is necessary. Before any GH investigation, other conditions interfering with GH secretion or action must be ruled out.

Context GH responsiveness guides GH dosing during the catch-up growth (CUG) period; however, little is known regarding GH dosing during the prepubertal maintenance treatment period. Objective To evaluate whether SD score (SDS) channel parallel growth with normal height velocity can be maintained after CUG by reducing the GH dose by 50% in children receiving doses individualized according to estimated GH responsiveness during the catch-up period. Design and Settings Prepubertal children (n = 98; 72 boys) receiving GH during CUG (GH deficient, n = 33; non-GH deficient, n = 65), were randomized after 2 to 3 years to either a 50% reduced individualized dose (GHRID; n = 27; 20 boys) or unchanged individualized dose (GHUID; n = 38; 27 boys). Another 33 children (25 boys) continued a standard weight-based dose [43 µg/kg/d (GHFIX)]. Main Outcome Measures The primary endpoint was the proportion of children with ΔheightSDS within ±0.3 at 1 year after GH dose reduction compared with two control groups: GHUID and GHFIX. The hypothesis was that heightSDS could be maintained within ±0.3 with a reduced individualized GH dose. Results For the intention-to-treat population at 1 year, 85% of the GHRIDgroup maintained ΔheightSDS within ±0.3 vs 41% in the GHUIDgroup (P = 0.0055) and 48% in the GHFIXgroup (P = 0.0047). The ΔIGF-ISDS in the GHRID group was -0.75 ± 1.0 at 3 months (P = 0.003) and -0.72 ± 1.2 at 1 year compared with the GHUID group (0.15 ± 1.2; P = 0.005) and GHFIX group (0.05 ± 1.0; P = 0.02). Conclusions Channel parallel growth (i.e., normal height velocity) and IGF-ISDS levels within ±2 were maintained after completed CUG using a 50% lower individualized dose than that used during the CUG period.

Daily subcutaneous self-injection of GH is used worldwide to treat short stature in childhood; longitudinal data on the impact of this regimen on GH-uptake are lacking.Children with/without GH-deficiency participating in clinical trials were followed prospectively (≤8 times). Blood was sampled pre-GH-injection (dose GHIn the Clinical-setting, median CVery broad intra-individual and inter-individual variability was found. A high GH-peak will optimize growth effects; the highest C

Safety concerns for recombinant human growth hormone (rhGH) treatments include impact on cancer risk, impact on glucose homeostasis, and the formation of antibodies to endogenous/exogenous GH. Omnitrope (R) (biosimilar rhGH) was approved by the European Medicines Agency in 2006, with approval granted on the basis of comparable quality, safety, and efficacy to the reference medicine (Genotropin (R)). Additional concerns that may exist in relation to biosimilar rhGH include safety in indications granted on the basis of extrapolation and the impact of changing to biosimilar rhGH from other rhGH treatments. A substantial data set is available to fully understand the safety profile of biosimilar rhGH, which includes data from its clinical development studies and 10 years of post-approval experience. As of June 2016, 106,941,419 patient days (292,790 patient-years) experience has been gathered for biosimilar rhGH. Based on the available data, there have been no unexpected or unique adverse events related to biosimilar rhGH treatment. There is no increased risk of cancer, adverse glucose homeostasis, or immunogenic response with biosimilar rhGH compared with the reference medicine and other rhGH products. The immunogenicity of biosimilar rhGH is also similar to that of the reference and other rhGH products. Physicians should be reassured that rhGH products have a good safety record when used for approved indications and at recommended doses, and that the safety profile of biosimilar rhGH is in keeping with that of other rhGH products.

The overall goal of pubertal sex hormone replacement therapy (HRT) in girls is not only about development of secondary sexual characteristics, but also to establish an adult endocrine and metabolic milieu, as well as adult cognitive function. Estradiol (E2) is the first choice for HRT compared to ethinyl estradiol (EE2). E2 is the most potent endogenous estrogen in the circulation, with established levels during spontaneous puberty. Transdermal E2, compared to oral administration, is the first choice to start pubertal HRT. Transdermal application avoids liver exposure to supraphysiologic estrogen concentrations and provides a more physiologic mechanism for hormone delivery. By cutting E2 matrix patches in doses of 0.05-0.07 µg/kg or administrate E2 gel in doses of 0.1 mg/day, serum concentrations of E2 seen in early spontaneous puberty can be obtained. Patches can be removed in the morning and thereby mimic the normal circadian rhythm. For those clinics with access to sensitive E2 determinations methods (extraction followed by radioimmunoassay or mass spectrometry) monitoring the attained E2 serum levels is recommended in order to optimally mimic the levels seen in early puberty as well as growth velocity, breast and uterus development. Mid- and late pubertal HRT is obtained by increased doses of E2, adding cyclic oral or transdermal progestin, as well as testosterone gel over the pubic area if indicated.

The overall goal of pubertal sex hormone replacement therapy (HRT) in girls is not only about development of secondary sexual characteristics, but also to establish an adult endocrine and metabolic milieu, as well as adult cognitive function. Estradiol (E2) is the first choice for HRT compared to ethinyl estradiol (EE2). E2 is the most potent endogenous estrogen in the circulation, with established levels during spontaneous puberty. Transdermal E2, compared to oral administration, is the first choice to start pubertal HRT. Transdermal application avoids liver exposure to supraphysiologic estrogen concentrations and provides a more physiologic mechanism for hormone delivery. By cutting E2 matrix patches in doses of 0.05-0.07 µg/kg or administrate E2 gel in doses of 0.1 mg/day, serum concentrations of E2 seen in early spontaneous puberty can be obtained. Patches can be removed in the morning and thereby mimic the normal circadian rhythm. For those clinics with access to sensitive E2 determinations methods (extraction followed by radioimmunoassay or mass spectrometry) monitoring the attained E2 serum levels is recommended in order to optimally mimic the levels seen in early puberty as well as growth velocity, breast and uterus development. Mid- and late pubertal HRT is obtained by increased doses of E2, adding cyclic oral or transdermal progestin, as well as testosterone gel over the pubic area if indicated.

This study investigated the relationship between seasonal variations in 25-hydroxyvitamin D (25(OH)D) levels and growth in prepubertal children during both the pretreatment year and the first year of GH treatment.The study included 249 short prepubertal children with a broad range of GH secretion, GH(max) during a 24 h profile median 23; range 1-127 mU/L, 191 boys (mean age ± SD, 8.6 ± 2.6 years), 58 girls (7.5 ± 1.9 years) receiving GH treatment (mean 43 µg/kg/day; range 17-99 µg/kg/day). Serum 25(OH)D was measured using an automated IDS-iSYS immunoassay.25(OH)D levels showed seasonal variation, and decreased significantly during GH treatment. 25(OH)D levels at start and first year reduction in 25(OH)D, correlated (-) with the first year growth response during treatment. The degree of GH secretion capacity within our study population of mainly non-GH deficient children and 25(OH)D sufficient (67 ± 29 nmol/L) had no influence on 25(OH)D levels. Growth during GH treatment were independent of seasonal variations in 25(OH)D. Multiple regression analysis showed that 25(OH)D levels at treatment start, together with auxological data and IGF-binding protein-(3)SDS, explained 61 % of the variation in first year gain in heightSDS.25(OH)D levels were associated with first year growth response to GH and may be a useful contribution to future growth prediction models.

CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality. OBJECTIVE: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors. DESIGN, SETTING AND PARTICIPANTS: Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls. MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined. RESULTS: Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p