A systematic review of hormone treatment for children with gender dysphoria and recommendations for research.

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.

Ten years with biosimilar rhGH in clinical practice in Sweden - experience from the prospective PATRO children and adult studies.

BACKGROUND: In 2007, Omnitrope® was the first biosimilar recombinant human growth hormone (rhGH) to be approved in Sweden for treatment in adults and children. Over 10 years' safety and effectiveness data for biosimilar rhGH can now be presented. METHODS: PATRO Children and PATRO Adults are multicenter, longitudinal, observational, post-marketing surveillance studies. Eligible patients include children 0-18 years and adults receiving biosimilar rhGH treatment. Adverse events (AEs) are monitored for safety evaluation. Growth variables in children and metabolic data in adults are recorded for effectiveness evaluation. RESULTS: As of January 2019, data from 136 children (48% male) were reported from Swedish centers. Mean age in rhGH treatment-naïve patients at study entry (n = 114) was 7.5 years, with mean 3.6 years treatment duration. No severe AEs of diabetes, impaired glucose tolerance, or malignancy were reported. The most frequently reported AE was nasopharyngitis (n = 16 patients). No clinically relevant anti-hGH or neutralizing antibodies were observed. The mean change from baseline in height standard deviation score (SDS) in naïve prepubertal GH deficiency patients was + 0.79 at 1 year, + 1.27 at 2 years, and + 1.55 at 3 years. Data from 293 adults (44% rhGH-naïve, 51% male) were included. Fatigue was the most frequently reported AE (n = 26 patients). The incidence of new neoplasms or existing neoplasm progression was 23.8 patients per 1000 patient-years. Type 2 diabetes mellitus was reported in four patients. At baseline in rhGH-naïve adults, mean (SD) body mass index (BMI) was 29.1 (5.6) kg/m2 and mean (SD) insulin-like growth factor (IGF)-I SDS was - 3.0 (1.4). Mean daily dose increased from 0.1 mg at baseline to 0.3 mg after 4 years. IGF-I SDS normalized during the first year of treatment. Mean BMI and glucose were unchanged over 4 years, while low-/high-density lipoprotein cholesterol ratio decreased. CONCLUSIONS: For the first time, Swedish data from the PATRO Children and Adults studies are presented. The 10-year data suggest that biosimilar rhGH is well tolerated across pediatric and adult indications. Safety and effectiveness were similar to previous reports for other rhGH preparations. These results need to be confirmed in larger cohorts, highlighting the importance of long-term post-marketing studies.

Using a spontaneous profile rather than stimulation test makes the KIGS idiopathic growth hormone deficiency model more accessible for clinicians.

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 (GHmax stim). We tested the hypothesis that using a 12-hour spontaneous profile (GHmax 12h) 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 GHmax stim (-0.16 SDS) and GHmax 12h (-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.

Marginally low birthweight increases the risk of underweight and short stature at three and a half years of age.

AIM: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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) dose-dependent IGF-I response relates to pubertal height gain.

BACKGROUND: Responsiveness to GH treatment can be estimated by both growth and ∆IGF-I. The primary aim of the present study was to investigate if mimicking the physiological increase during puberty in GH secretion, by using a higher GH dose could lead to pubertal IGFs in short children with low GH secretion. The secondary aim was to explore the relationship between IGF-I, IGFBP-3 and the IGF-I/IGFBP-3 ratio and gain in height. METHODS: A multicentre, randomized, clinical trial (TRN88-177) in 104 children (90 boys), who had received GH 33 µg/kg/day during at least 1 prepubertal year. They were followed from GH start to adult height (mean, 7.5 years; range, 4.6-10.7). At onset of puberty, children were randomized into three groups, to receive 67 µg/kg/day (GH(67)) given once (GH(67x1); n = 30) or divided into two daily injection (GH(33x2); n = 36), or to remain on a single 33 µg/kg/day dose (GH(33x1); n = 38). The outcome measures were change and obtained mean on-treatment IGF-I(SDS), IGFBP3(SDS) and IGF-I/IGFBP3 ratio(SDS) during prepuberty and puberty. These variables were assessed in relation to prepubertal, pubertal and total gain in heightSDS. RESULTS: Mean prepubertal increases 1 year after GH start were: 2.1 IGF-I(SDS), 0.6 IGFBP3(SDS) and 1.5 IGF-I/IGFBP3ratio(SDS). A significant positive correlation was found between prepubertal ∆IGFs and both prepubertal and total gain in height(SDS). During puberty changes in IGFs were GH dose-dependent: mean pubertal level of IGF-I(SDS) was higher in GH(67) vs GH(33) (p = 0.031). First year pubertal ∆IGF-I(SDS) was significantly higher in the GH(67)vs GH(33) group (0.5 vs -0.1, respectively, p = 0.007), as well as ∆IGF-I(SDS) to the pubertal mean level (0.2 vs -0.2, p = 0.028). In multivariate analyses, the prepubertal increase in '∆IGF-I(SDS) from GH start' and the 'GH dose-dependent pubertal ∆IGF-I(SDS)' were the most important variables for explaining variation in prepubertal (21 %), pubertal (26 %) and total (28 %) gain in height(SDS). TRIAL REGISTRATION: TRN 88-177, not applicable 1988. CONCLUSION: The dose-dependent change in IGFs was related to a dose-dependent pubertal gain in height(SDS). The attempt to mimic normal physiology by giving a higher GH dose during puberty was associated with both an increase in IGF-I and a dose-dependent gain in height(SDS).

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

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

Growth hormone treatment in children with Prader-Willi syndrome: safety and effectiveness data from the PATRO Children study.

Background: Recombinant human growth hormone (rhGH, somatropin) therapy is approved in children with Prader-Willi syndrome (PWS). Objectives: To report safety and effectiveness data for children with PWS treated with biosimilar rhGH (Omnitrope®, Sandoz) in the PAtients TReated with Omnitrope (PATRO) Children study. Design: PATRO Children was a multicenter, non-interventional, postmarketing surveillance study. Methods: Children with PWS received Omnitrope according to standard clinical practice. Adverse events (AEs) were monitored for the duration of Omnitrope treatment. Effectiveness outcomes were also assessed, including height standard deviation (SD) scores (HSDS). Results: As of July 2020 (study completion), 235 patients with PWS had been enrolled. At baseline, 95.7% (n = 225) of patients were prepubertal and 86.4% (n = 203) were rhGH treatment-naïve. At analysis, the median (range) treatment duration in the study was 56.8 (2.9-155.8) months. AEs were reported in 192 patients (81.7%) and were suspected as treatment-related in 39 patients (16.6%). Serious AEs (SAEs) were reported in 96 patients (40.9%) and were suspected as treatment-related in 22 patients (9.4%). The most frequent treatment-related SAEs were sleep apnea syndrome (n = 11; 4.7%), tonsillar hypertrophy (n = 4; 1.7%), and adenoidal hypertrophy (n = 4; 1.7%). Development of scoliosis was considered treatment-related in two patients; development of impaired glucose tolerance in one patient and type 2 diabetes mellitus in another patient were considered treatment-related. Effectiveness outcomes were primarily assessed in 153 patients who completed 3 years of treatment. Among the 151 prepubertal patients (135 treatment-naïve), mean (SD) change from baseline in HSDS after 3 years was +1.50 (1.07) across all patients and +1.57 (1.07) for treatment-naïve patients. Conclusion: These data suggest that biosimilar rhGH is well tolerated and effective in patients with PWS managed in real-life clinical practice. Patients with PWS should continue to be closely monitored for well-known safety issues (including respiratory, sleep, and glucose metabolism disorders, and scoliosis) during rhGH treatment.

Availability, Usage, and Preferences of Estradiol and Progestogen Preparations for Puberty Induction from a Multicentral Perspective.

INTRODUCTION: Natural oestrogen administration as oral or transdermal 17ß-estradiol is recommended for pubertal induction in girls with hypogonadism. However, suitable low-dose formulations are not consistently available globally. This questionnaire study aimed to identify the current availability of oestrogen and progesterone preparations worldwide. METHODS: Endorsed by the ESPE Turner Syndrome Working Group, the questionnaire targeted paediatric endocrinologists. Questions focused on accessibility of oral/transdermal 17ß-estradiol and progestogen preparations. Responses were collected through a SurveyMonkey survey disseminated via ESPE channels, direct outreach, and conferences from June 2020 to December 2022. RESULTS: Participation included 229 healthcare professionals from 45 countries. Oral and transdermal 17ß-estradiol in adult dosage was highly accessible (86.5% and 84.3%), with transdermal administration the preferred form (62.8%). Most commonly available estradiol preparations included 50 µg patches (32 countries) and 1 or 2 mg tablets (65.8% and 71.1% countries). However, 0.5 mg 17ß-estradiol tablets were available in only 20% of respondents from 8 countries. Patches delivering 14 or 25 µg/day of 17ß-estradiol were available in 3 and 20 countries, respectively. Oral progestogen had widespread availability (96.0%) and preference (87.0%), while transdermal usage was limited to 15.2% of respondents. CONCLUSION: This study highlights global challenges in accessing suitable hormone preparations for female pubertal induction. In most countries, the lowest dose of the estradiol is 50 µg for patches and 2 mg for tablets. Appropriate low-dose 17ß-estradiol tablets are much less available than low-dose patches. Our survey underscores the importance of adapting guidelines to local availability, and the need for improved accessibility to address these global disparities.

Ovarian failure in HAX1-deficient patients: is there a gender-specific difference in pubertal development in severe congenital neutropenia or Kostmann disease?

AIM: Severe congenital neutropenia (SCN) is a rare disorder of myelopoiesis characterized by neutropenia, recurrent bacterial infections and a maturation arrest of the myelopoiesis in the bone marrow. Homozygous mutations in the HAX1 gene were described in patients with autosomal recessive SCN or Kostmann disease. Some of these patients display neurological disease. We noted, during the course of clinical management of patients with Kostmann disease, insufficient pubertal development in female patients, but not in our male patients. The study objective was to provide a detailed account of this phenotype and its possible relation to HAX1 mutations. METHODS: Detailed clinical histories and laboratory investigations of three patients with Kostmann disease belonging to the original kindred in northern Sweden described by Rolf Kostmann are reported. RESULTS: We report one male patient with normal puberty and two female patients with insufficient pubertal development. Elevated levels of LH and FSH were recorded in both patients. All three patients harbour the same p.Glu190X mutation in the HAX1 gene. CONCLUSIONS: We show for the first time that female patients with Kostmann disease display primary gonadal insufficiency. This suggests a possible role for HAX1 in the development and/or function of the human ovary.

Normalization of puberty and adult height in girls with Turner syndrome: results of the Swedish Growth Hormone trials initiating transition into adulthood.

Objective: To study the impact of GH dose and age at GH start in girls with Turner syndrome (TS), aiming for normal height and age at pubertal onset (PO) and at adult height (AH). However, age at diagnosis will limit treatment possibilities. Methods: National multicenter investigator-initiated studies (TNR 87-052-01 and TNR 88-072) in girls with TS, age 3-16 years at GH start during year 1987-1998, with AH in 2003-2011. Of the 144 prepubertal girls with TS, 132 girls were followed to AH (intention to treat), while 43 girls reduced dose or stopped treatment prematurely, making n=89 for Per Protocol population. Age at GH start was 3-9 years (young; n=79) or 9-16 years (old; n=53). Treatment given were recombinant human (rh)GH (Genotropin® Kabi Peptide Hormones, Sweden) 33 or 67 µg/kg/day, oral ethinyl-estradiol (2/3) or transdermal 17ß-estradiol (1/3), and, after age 11 years, mostly oxandrolone. Gain in heightSDS, AHSDS, and age at PO and at AH were evaluated. Results: At GH start, heightSDS was -2.8 (versus non-TS girls) for all subgroups and mean age for young was 5.7 years and that of old was 11.6 years. There was a clear dose-response in both young and old TS girls; the mean difference was (95%CI) 0.66 (-0.91 to -0.26) and 0.57 (-1.0 to -0.13), respectively. The prepubertal gainSDS (1.3-2.1) was partly lost during puberty (-0.4 to -2.1). Age/heightSDS at PO ranged from 13 years/-0.42 for GH67young to 15.2 years/-1.47 for GH33old. At AH, GH67old group became tallest (17.2 years; 159.9 cm; -1.27 SDS; total gainSDS, 1.55) compared to GH67young group being least delayed (16.1 years; 157.1 cm; -1.73 SDS; total, 1.08). The shortest was the GH33young group (17.3 years; 153.7 cm: -2.28 SDS; total gainSDS, 0.53), and the most delayed was the GH33old group, (18.5 years; 156.5 cm; -1.82 SDS; total gainSDS, 0.98). Conclusion: For both young and old TS girls, there was a GH-dose growth response, and for the young, there was less delayed age at PO and at AH. All four groups reached an AH within normal range, despite partly losing the prepubertal gain during puberty. Depending on age at diagnosis, low age at start with higher GH dose resulted in greater prepubertal height gain, permitting estrogen to start earlier at normal age and attaining normal AH at normal age, favoring physiological treatment and possibly also bone health, hearing, uterine growth and fertility, psychosocial wellbeing during adolescence, and the transition to adulthood.

Decreased GH dose after the catch-up growth period maintains metabolic outcome in short prepubertal children with and without classic GH deficiency.

OBJECTIVE: Few studies have evaluated metabolic outcomes following growth hormone (GH) treatment in short prepubertal children during different periods of growth. Previously, we found that individualized GH dosing in the catch-up period reduced the variation in fasting insulin levels by 34% compared with those receiving a standard GH dose. We hypothesized that the GH dose required to maintain beneficial metabolic effects is lower during the prepubertal growth phase after an earlier catch-up growth period. DESIGN: Short prepubertal children with isolated GH deficiency or idiopathic short stature were randomized to individualized GH treatment (range, 17-100 µg/kg/day) or a standard dose in a preceding 2-year study. After achieving near mid-parental height(SDS) , children receiving an individualized dose were randomized to either a 50% reduced individualized dose (RID, n = 28) or an unchanged individualized dose (UID, n = 37) for 2 years. The dose remained unchanged in 33 children initially randomized to receive a standard dose (FIX, 43 µg/kg/day).We evaluated whether the variations in metabolic parameters measured during maintenance growth diminished in RID compared with UID or FIX. RESULTS: We observed less variation in fasting insulin levels (-50%), insulin sensitivity as assessed by homoeostasis model assessment (-55·1%), lean soft tissue (-27·8%) and bone mineral content (-31·3%) in RID compared with UID (all P < 0·05), but no differences compared with FIX. CONCLUSIONS: Continued reduced individualized GH treatment after the catch-up growth period is safe and reduces hyperinsulinism. Individualized GH dose can be reduced once the desired height(SDS) is achieved to avoid overtreatment in terms of metabolic outcome.

Rapid cardiovascular effects of growth hormone treatment in short prepubertal children: impact of treatment duration.

OBJECTIVE: Previous studies show that growth hormone (GH) treatment increases cardiac dimensions in short children with GH deficiency (GHD) and has diverse cardiac effects in children with idiopathic short stature (ISS). This study was performed to assess the effect of GH on the cardiovascular system in short children with a broad range of GH secretion and GH sensitivity/responsiveness. DESIGN AND PATIENTS: In this prospective, multicentre study, short prepubertal children diagnosed with isolated GHD (89) or ISS (38) were followed during 2 years of GH treatment. They were randomized to receive either a standard (43 µg/kg/day) or an individualized GH dose (range 17-100 µg/kg/day) based on GH responsiveness estimated by a prediction model and distance to target height. Echocardiography, blood pressure and electrocardiography were performed at baseline, 3, 12 and 24 months. RESULTS: Left ventricular mass (LVM) indexed to body surface area increased significantly during 2 years of GH treatment in both GHD and ISS irrespective of randomized dose. This change was already apparent at 3 months, when standard deviation scores (SDS) of wall thickness and diameter were increased. At 24 months, left ventricular diameter SDS remained increased, whereas myocardial thickness SDS returned to baseline values. There was no impairment of systolic or diastolic function. There was no correlation with treatment dose and LVM SDS at 24 months. CONCLUSIONS: Irrespective of GH status, there was a rapid increase in LVM during GH treatment in short children. At 3 months, wall thickness and diameter were increased, whereas only diameter remained increased at 24 months.

Different thresholds of tissue-specific dose-responses to growth hormone in short prepubertal children.

BACKGROUND: In addition to stimulating linear growth in children, growth hormone (GH) influences metabolism and body composition. These effects should be considered when individualizing GH treatment as dose-dependent changes in metabolic markers have been reported. HYPOTHESIS: There are different dose-dependent thresholds for metabolic effects in response to GH treatment. METHOD: A randomized, prospective, multicentre trial TRN 98-0198-003 was performed for a 2-year catch-up growth period, with two treatment regimens (a) individualized GH dose including six different dose groups ranging from 17-100 µg/kg/day (n=87) and (b) fixed GH dose of 43 µg/kg/day (n=41). The individualized GH dose group was used for finding dose-response effects, where the effective GH dose (ED 50%) required to achieve 50% Δ effect was calculated with piecewise linear regressions. RESULTS: Different thresholds for the GH dose were found for the metabolic effects. The GH dose to achieve half of a given effect (ED 50%, with 90% confidence interval) was calculated as 33(±24.4) µg/kg/day for Δ left ventricular diastolic diameter (cm), 39(±24.5) µg/kg/day for Δ alkaline phosphatase (µkat/L), 47(±43.5) µg/kg/day for Δ lean soft tissue (SDS), 48(±35.7) µg/kg/day for Δ insulin (mU/L), 51(±47.6) µg/kg/day for Δ height (SDS), and 57(±52.7) µg/kg/day for Δ insulin-like growth factor I (IGF-I) SDS. Even though lipolysis was seen in all subjects, there was no dose-response effect for Δ fat mass (SDS) or Δ leptin ng/ml in the dose range studied. None of the metabolic effects presented here were related to the dose selection procedure in the trial. CONCLUSIONS: Dose-dependent thresholds were observed for different GH effects, with cardiac tissue being the most responsive and level of IGF-I the least responsive. The level of insulin was more responsive than that of IGF-I, with the threshold effect for height in the interval between.

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

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

Safety and Effectiveness of Recombinant Human Growth Hormone in Children with Turner Syndrome: Data from the PATRO Children Study.

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.

Metabolic outcome of GH treatment in prepubertal short children with and without classical GH deficiency.

CONTEXT: Few studies have evaluated the metabolic outcomes of growth hormone (GH) treatment in idiopathic short stature (ISS). Moreover, children with ISS appear to need higher GH doses than children with GH deficiency (GHD) to achieve the same amount of growth and may therefore be at increased risk of adverse events during treatment. The individualized approach using prediction models for estimation of GH responsiveness, on the other hand, has the advantage of narrowing the range of growth response, avoiding too low or high GH doses. DESIGN: Short prepubertal children with either isolated GHD (39) or ISS (89) participated in a 2-year randomized trial of either individualized GH treatment with six different GH doses (range, 17-100 microg/kg/day) or a standard dose (43 microg/kg/day). OBJECTIVE: To evaluate if individualized GH treatment reduced the variance of the metabolic measures as shown for growth response and to compare changes in metabolic variables in children with ISS and GHD. HYPOTHESIS: Individualized GH dose reduces the range of metabolic outcomes, and metabolic outcomes are similar in children with ISS and GHD. RESULTS: We observed a narrower variation for fasting insulin (-34.2%) and for homoeostasis model assessment (HOMA) (-38.9%) after 2 years of individualized GH treatment in comparison with standard GH dose treatment. Similar metabolic changes were seen in ISS and GHD. Delta (Delta) height SDS correlated with Deltainsulin-like growth factor I (IGF-I), Deltaleptin and Deltabody composition. Principal component analysis identified an anabolic and a lipolytic component. Anabolic variables [Deltalean body mass (LBM) SDS and DeltaIGF-I SDS] clustered together and correlated strongly with Deltaheight SDS and GH dose, whereas lipolytic variables [Deltafat mass (FM) SDS and Deltaleptin] were clustered separately from anabolic variables. Regression analysis showed GH dose dependency in ISS, and to a lesser degree in GHD, for DeltaLBM SDS and Deltaheight SDS, but not for changes in FM. CONCLUSIONS: Individualized GH dosing during catch-up growth reduces the variance in insulin and HOMA and results in equal metabolic responses irrespective of the diagnosis of GHD or ISS.

Growth hormone (GH) dosing during catch-up growth guided by individual responsiveness decreases growth response variability in prepubertal children with GH deficiency or idiopathic short stature.

CONTEXT: Weight-based GH dosing results in a wide variation in growth response in children with GH deficiency (GHD) or idiopathic short stature (ISS). OBJECTIVE: The hypothesis tested was whether individualized GH doses, based on variation in GH responsiveness estimated by a prediction model, reduced variability in growth response around a set height target compared with a standardized weight-based dose. SETTING: A total of 153 short prepubertal children diagnosed with isolated GHD or ISS (n = 43) and at least 1 SD score (SDS) below midparental height SDS (MPH(SDS)) were included in this 2-yr multicenter study. INTERVENTION: The children were randomized to either a standard (43 microg/kg.d) or individualized (17-100 microg/kg.d) GH dose. MAIN OUTCOME MEASURE: We measured the deviation of height(SDS) from individual MPH(SDS) (diffMPH(SDS)). The primary endpoint was the difference in the range of diffMPH(SDS) between the two groups. RESULTS: The diffMPH(SDS) range was reduced by 32% in the individualized-dose group relative to the standard-dose group (P < 0.003), whereas the mean diffMPH(SDS) was equal: -0.42 +/- 0.46 and -0.48 +/- 0.67, respectively. Gain in height(SDS) 0-2 yr was equal for the GH-deficient and ISS groups: 1.31 +/- 0.47 and 1.36 +/- 0.47, respectively, when ISS was classified on the basis of maximum GH peak on the arginine-insulin tolerance test or 24-h profile. CONCLUSION: Individualized GH doses during catch-up growth significantly reduce the proportion of unexpectedly good and poor responders around a predefined individual growth target and result in equal growth responses in children with GHD and ISS.

The first-year growth response to growth hormone treatment predicts the long-term prepubertal growth response in children.

BACKGROUND: Pretreatment auxological variables, such as birth size and parental heights, are important predictors of the growth response to GH treatment. For children with missing pretreatment data, published prediction models cannot be used. The objective was to construct and validate a prediction model for children with missing background data based on the observed first-year growth response to GH. The accuracy and reliability of the model should be comparable with our previously published prediction model relying on pretreatment data. The design used was mathematical curve fitting on observed growth response data from children treated with a GH dose of 33 microg/kg/d. METHODS: Growth response data from 162 prepubertal children born at term were used to construct the model; the group comprised of 19% girls, 80% GH-deficient and 23% born SGA. For validation, data from 205 other children fulfilling the same inclusion and treatment criteria as the model group were used. The model was also tested on data from children born prematurely, children from other continents and children receiving a GH dose of 67 microg/kg/d. RESULTS: The GH response curve was similar for all children, but with an individual amplitude. The curve SD score depends on an individual factor combining the effect of dose and growth, the 'Response Score', and time on treatment, making prediction possible when the first-year growth response is known. The prediction interval (+/- 2 SD res) was +/- 0.34 SDS for the second treatment year growth response, corresponding to +/- 1.2 cm for a 3-year-old child and +/- 1.8 cm for a 7-year-old child. For the 1-4-year prediction, the SD res was 0.13 SDS/year and for the 1-7-year prediction it was 0.57 SDS (i.e. < 0.1 SDS/year). CONCLUSION: The model based on the observed first-year growth response on GH is valid worldwide for the prediction of up to 7 years of prepubertal growth in children with GHD/ISS, born AGA/SGA and born preterm/term, and can be used as an aid in medical decision making.

GH Dose Reduction Maintains Normal Prepubertal Height Velocity After Initial Catch-Up Growth in Short Children.

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.

Estradiol matrix patches for pubertal induction: stability of cut pieces at different temperatures.

OBJECTIVE: Transdermal estradiol patches are primarily designed for adult women. No low-dose patches are licensed for pubertal induction in hypogonadal girls. Low doses can be achieved by cutting a matrix patch into smaller pieces. However, the manufacturers do not guarantee stability or utility of cut estradiol patches. The aim of the study was to assess 1-month stability of cut estradiol patches from four different manufacturers in the laboratory at room temperature (+21°C) and at an elevated temperature (+35°C). DESIGN AND METHODS: Estraderm MX 50 µg, Systen 50 µg and Oesclim 25 µg matrix patches were cut into eight pieces while Estradot 50 µg small patches were cut in half. The cut patches were stored in their respective pouches at +21°C or at +35°C for up to 1 month. The estradiol drug was extracted from the patch by ethyl acetate n-hexane and determined by radioimmunoassay. RESULTS: Storage at +21°C or +35°C up to 1 month did not reduce the estradiol concentration in Estraderm MX, Systen and Oesclim patches. However, although the estradiol in Estradot patches was not affected by storage at +21°C, at +35°C, estradiol decreased by 57% (±1%) in cut pieces. CONCLUSIONS: Unused Estraderm MX, Systen and Oesclim patch pieces may be stored for at least 1 month at ≤+35°C. Where estradiol patches for children are not available, cut pieces of these or similar patches can be used for pubertal induction. The Estradot patch was too small to properly cut into low doses and not stable in elevated temperatures.