Normal Growth Hormone Secretion Research Articles

6877 Withdrawing Growth Hormone Treatment at Mid-Puberty in Idiopathic Isolated Growth Hormone Deficiency: Baseline Characteristics in Patient-Preference Design Study

Abstract Disclosure: J. Vliegenthart: None. J. Wit: None. B. Bakker: None. A. Boot: None. C. de Bruin: None. M. Finken: None. J.V. Heyden: None. M. Houdijk: None. H. van der Kamp: None. E. Van Mil: None. A. Reedijk: None. T. Sas: None. D.A. Schott: None. P. van Setten: None. S. Straetemans: None. V. van Tellingen: None. B. Touwslager: None. A.V. Trotsenburg: None. P. voorhoeve: None. A.C. Hokken-Koelega: None. D.C. van der Kaay: None. Background: The majority of children diagnosed with idiopathic isolated growth hormone deficiency (IIGHD) show a normal growth hormone (GH) secretion (assessed by GH stimulation tests) when retested at near adult height (NAH). It appears plausible that, if normal stimulated GH secretion is observed in mid-puberty, continuing recombinant human GH (rhGH) treatment may only have a minor effect on NAH. The effect on NAH has never been investigated in a prospective study. Aim: To evaluate patient preference in the choice to (dis-)continue GH treatment from mid-puberty, and to study whether patients who discontinued treatment differed in baseline characteristics from those who continued treatment. Methods: The study population consisted of adolescents who were diagnosed in childhood with IIGHD (GH peak at diagnosis between 1.7 ug/L and 10 ug/L) and who had started rhGH therapy between 2005-2018. According to the national treatment protocol, GH secretion was retested in mid-puberty (males: Tanner stage G3/4, testicular volume >12 ml and bone age (BA) 13-16 years; females: Tanner stage B3/4 and BA 11-14 years). In this multicentre prospective patient-preference design study, adolescents who tested GH sufficient at mid-puberty (GH peak >6.7 ug/L) had the choice to discontinue or continue rhGH treatment until NAH (height velocity <2cm/year). Results: In total 127 patients (95 male, 75%) participated in this study. Forty-four patients (35%) chose to continue GH treatment until NAH (group 1), and 83 patients (65%) chose to discontinue GH treatment (group 2). Mean height at inclusion (group 1: -0.76±0.69 SDS vs group 2: -0.47±0.85 SDS; P=0.055), target height SDS (group 1: -0.73±0.54 SDS and -0.58±0.53 SDS, P=0.15) and age at inclusion (group 1: 14.0±1.1y and 13.9±1.1y, P=0.69) did not significantly differ between groups. Males and females did not differ in these characteristics. Currently, 109 patients (86%) have reached NAH. Conclusions: The majority of patients (65%) preferred to discontinue rhGH treatment after sufficient GH retesting in mid-puberty. An anticipated difference in baseline data between the groups (adolescents who choose to discontinue treatment may be taller and older) could not be confirmed. Data are being collected until all patients reach near adult height. Presentation: 6/3/2024

9262 Withdrawing Growth Hormone Treatment at Mid-Puberty in Idiopathic Isolated Growth Hormone Deficiency: Baseline Characteristics in Patient-Preference Design Study

Abstract Disclosure: J. Vliegenthart: None. J. Wit: None. B. Bakker: None. A. Boot: None. C. de Bruin: None. M. Finken: None. J.V. Heyden: None. M. Houdijk: None. H. van der Kamp: None. E. Van Mil: None. A. Reedijk: None. T. Sas: None. D.A. Schott: None. P. van Setten: None. S. Straetemans: None. V. van Tellingen: None. B. Touwslager: None. A.V. Trotsenburg: None. P. voorhoeve: None. A.C. Hokken-Koelega: None. D.C. van der Kaay: None. Background: The majority of children diagnosed with idiopathic isolated growth hormone deficiency (IIGHD) show a normal growth hormone (GH) secretion (assessed by GH stimulation tests) when retested at near adult height (NAH). It appears plausible that, if normal stimulated GH secretion is observed in mid-puberty, continuing recombinant human GH (rhGH) treatment may only have a minor effect on NAH. The effect on NAH has never been investigated in a prospective study. Aim: To evaluate patient preference in the choice to (dis-)continue GH treatment from mid-puberty, and to study whether patients who discontinued treatment differed in baseline characteristics from those who continued treatment. Methods: The study population consisted of adolescents who were diagnosed in childhood with IIGHD (GH peak at diagnosis between 1.7 ug/L and 10 ug/L) and who had started rhGH therapy between 2005-2018. According to the national treatment protocol, GH secretion was retested in mid-puberty (males: Tanner stage G3/4, testicular volume >12 ml and bone age (BA) 13-16 years; females: Tanner stage B3/4 and BA 11-14 years). In this multicentre prospective patient-preference design study, adolescents who tested GH sufficient at mid-puberty (GH peak >6.7 ug/L) had the choice to discontinue or continue rhGH treatment until NAH (height velocity <2cm/year). Results: In total 127 patients (95 male, 75%) participated in this study. Forty-four patients (35%) chose to continue GH treatment until NAH (group 1), and 83 patients (65%) chose to discontinue GH treatment (group 2). Mean height at inclusion (group 1: -0.76±0.69 SDS vs group 2: -0.47±0.85 SDS; P=0.055), target height SDS (group 1: -0.73±0.54 SDS and -0.58±0.53 SDS, P=0.15) and age at inclusion (group 1: 14.0±1.1y and 13.9±1.1y, P=0.69) did not significantly differ between groups. Males and females did not differ in these characteristics. Currently, 109 patients (86%) have reached NAH. Conclusions: The majority of patients (65%) preferred to discontinue rhGH treatment after sufficient GH retesting in mid-puberty. An anticipated difference in baseline data between the groups (adolescents who choose to discontinue treatment may be taller and older) could not be confirmed. Data are being collected until all patients reach near adult height. Presentation: 6/3/2024

Bone Quality Indices Correlate with Growth Hormone Secretory Capacity in Women Affected by Weight Excess: A Cross-Sectional Study.

Background/Objectives: Obesity can be associated with impaired growth hormone (GH) secretion, with possible negative repercussions on bone health. We aimed to investigate the relationships between GH secretory capacity, evaluated with GHRH + arginine stimulation test, and bone parameters, assessed with a dual-energy X-ray absorptiometer, in a population of adult female patients affected by overweight and obesity. Methods: We assessed 276 women affected by overweight or obesity referred to the High-Specialization Center for the Care of Obesity, Umberto I Polyclinic, between 2014 and 2019 with signs or symptoms of growth hormone deficiency (GHD). Results: A total of 97 patients were diagnosed with GHD, and 179 patients with normal GH secretion were considered our control group. GHD patients showed a significantly reduced trabecular bone score (TBS) (p = 0.01). Bone quality parameters corrected for body mass index (BMI) had a positive and significant linear correlation with stimulated GH secretory capacity. Conclusions: In conclusion, bone quality, evaluated by TBS and hip structural analysis, correlates with GH-stimulated secretory capacity. GHD may act as an additive factor in the alteration of bone microarchitecture in patients affected by obesity, who are already at a higher risk of fractures.

Deficient or Normal Growth Hormone Secretion in Polish Children with Short Stature: Searching for Clinical Differences.

Short stature affects approximately 2.5% of children. Some of them, when diagnosed with growth hormone deficiency (GHD), benefit from recombinant human growth hormone (rhGH) therapy; in others, this treatment is controversial. We aimed to present the clinical characteristics of Polish short stature children in the context of current GHD diagnostic standards, as obtaining more data gives a broader foundation for the potential modifications of diagnostic and therapeutic recommendations. This retrospective analysis was based on a cohort of 277 short stature children divided into two subgroups depending on their peak growth hormone (GH) cutoff level, set at 10 ng/mL: 138 had growth hormone deficiency (GHD) and 137 had normal growth hormone secretion (GHN). These subgroups were then compared based on the extracted clinical data. In the obtained result, no significant differences between the GHD and GHN subgroups were found in any of the variables, including the following: gender distribution, birth weight, bone age delay, height SDS, IGF-1 SDS, vitamin D levels, celiac disease indices, prevalence of hypothyroidism or anemia. As our results point to major clinical similarities between the GHD and GHN children, it seems that distinguishing patients with normal GH secretion from those with deficient GH secretion based on a 10 ng/mL cutoff value might not be clinically relevant.

Transient Isolated, Idiopathic Growth Hormone Deficiency-A Self-Limiting Pediatric Disease with Male Predominance or a Diagnosis Based on Uncertain Criteria? Lesson from 20 Years' Real-World Experience with Retesting at One Center.

In the majority of children with growth hormone (GH) deficiency (GHD), normal GH secretion may occur before the attainment of final height. The aim of the study was to assess the incidence of persistent and transient GHD and the effectiveness of recombined human GH (rhGH) therapy in children with isolated, idiopathic GHD with respect to the moment of therapy withdrawal and according to different diagnostic criteria of GHD. The analysis included 260 patients (173 boys, 87 girls) with isolated, idiopathic GHD who had completed rhGH therapy and who had been reassessed for GH and IGF-1 secretion. The incidence of transient GHD with respect to different pre- and post-treatment criteria was compared together with the assessment of GH therapy effectiveness. The incidence of transient GHD, even with respect to pediatric criteria, was very high. Normal GH secretion occurred before the attainment of near-final height. Application of more restricted criteria decreased the number of children diagnosed with GHD but not the incidence of transient GHD among them. Poor response to GH therapy was observed mainly in the patients with normal IGF-1 before treatment, suggesting that their diagnosis of GHD may have been a false positive. Further efforts should be made to avoid the overdiagnosis GHD and the overtreatment of patients.

Optimal final adult height achieved by low-dose recombinant human growth hormone therapy.

Thailand has been administering the recombinant human growth hormone (rhGH) treatment for >20 years. Due to limited resources being available, efforts have been directed toward utilizing rhGH at the lowest feasible dose. However, there is currently a lack of evidence in terms of the efficacy and outcomes. To evaluate the auxological outcomes of growth hormone (GH) treatment and the GH secretion ability after reaching final adult height (FAH) and discontinuing rhGH. Data of 40 patients were retrospectively reviewed. The clinical characteristics, auxological data, and results of biochemical and endocrine investigations before and during rhGH treatment were evaluated. In addition, GH retesting was performed in 24 patients using the insulin tolerance test. Twenty patients (50%) had complete growth hormone deficiency (GHD), defined as peak stimulated GH level <5 ng/mL, and the remaining patients had partial GHD. Most patients were male (n = 25, 62.5%). The mean age at which rhGH was initiated was 8.9 years. Patients with partial GHD received a higher dose of rhGH than those with complete GHD (30.9 µg/kg/d vs. 26.2 µg/kg/d, P = 0.02). Patients with complete and partial GHD reached FAH at height standard deviation scores (SDSs) of -0.65 and -1.47, respectively. The factors associated with obtaining a good clinical response in terms of height gain included peak-stimulated GH level, age of puberty, and age of discontinuing rhGH. After completing the rhGH treatment, 13 of the 24 patients showed normal GH secretion. Patients with multiple pituitary hormone deficiency (MPHD) were likely to have persistent GHD through adulthood (n = 8, 88.9%). This study has demonstrated that the use of low-dose rhGH could result in healthy populations achieving optimal FAHs. Patients with MPHD might not require retesting as they were likely to have persistent GHD. The results obtained in this research highlight the benefits of the treatment. This treatment can be applied in resource-limited countries.

Idiopathic Short Stature - A Case Report

Short stature in childhood is the most common reason for referral to pediatric endocrinologists. Idiopathic short stature is defined as ³2 SD below the corresponding mean height for a given age, sex, and population in a child with a normal birth size and normal body proportions and without evidence of any systemic, endocrine, nutritional, or chromosomal abnormalities. ISS children have normal GH responses to stimulation test and GH therapy has approved for the treatment of children with ISS. A six-year-old girl presented with not growing well in comparison to other peers since 6 months of her age. Her WAZ was -4.5 SD, HAZ was -7.7 SD, and projected height is far below parental target height. Bone age was 2-3 year and growth hormone stimulation showed normal growth hormone secretion. Here we reported a six-yearold girl diagnosed as a case of non-familial ISS and treated with growth hormone. Diagnosis of Idiopathic short stature was done by exclusion of other causes of short stature and growth hormone therapy was indicated.&#x0D; BANGLADESH J CHILD HEALTH 2022; VOL 46 (1) : 28-29

Early GH Treatment Is Effective and Well Tolerated in Children With Turner Syndrome: NordiNet® IOS and Answer Program.

Despite having normal growth hormone (GH) secretion, individuals with Turner syndrome (TS) have short stature. Treatment with recombinant human GH is recommended for TS girls with short stature. This work aimed to evaluate the effectiveness and safety of Norditropin (somatropin, Novo Nordisk) with up to 10 years of follow-up in children with TS. Secondary analysis was conducted of Norditropin data from 2 non-interventional studies: NordiNet® IOS (NCT00960128) and the ANSWER program (NCT01009905). A total of 2377 girls with TS were included in the safety analysis set (SAS), with 1513 in the treatment-naive effectiveness analysis set (EAS). At the start of treatment, 1273 (84%) participants were prepubertal (EAS); mean (SD) age was 8.8 (3.9) years. Mean (SD) dose received at the start of GH treatment was 0.045 (0.011) mg/kg/day (EAS). Mean (SD) baseline insulin-like growth factor-1 (IGF-I) SD score (SDS) was -0.86 (1.52), and mean (SD) duration of GH treatment (SAS) was 3.8 (2.8) years.Height SDS (HSDS) increased throughout follow-up, with near-adult HSDS reached by 264 (17%) participants (mean [SD] -1.99 [0.94]; change from baseline +0.90 [0.85]). During the study, 695 (46%) participants (EAS) entered puberty at a mean (SD) age of 12.7 (1.9) years (whether puberty was spontaneous or induced was unknown). Within the SAS, mean IGF-I SDS (SD) at year 10 was 0.91 (1.69); change from baseline +1.48 (1.70). Serious adverse reactions were reported in 10 participants (epiphysiolysis [n = 3]). GH-treated participants with TS responded well, without new safety concerns. Our real-world data are in agreement with previous studies.

OR14-4 Acute sleep disruption does not diminish pulsatile growth hormone secretion in pubertal children

Abstract Context: Growth hormone (GH) plays a critical role in glucose homeostasis and linear growth during childhood. GH secretion is controlled by multiple neurotransmitters and hormones. Sleep is also a powerful stimulus for GH secretion. In children, GH pulses occur after sleep onset in association with slow-wave sleep (SWS), but it is unclear if undisrupted sleep is required for normal GH secretion. Given the rising incidence of pediatric sleep disorders such as obstructive sleep apnea (OSA) that cause sleep fragmentation, it is critical to determine whether sleep fragmentation during childhood may dysregulate the somatotropic axis. Objective To quantify how undisrupted vs fragmented sleep affects GH secretion in children. Methods Pubertal subjects (10 M, 9 F; 9.1-14.4 yrs) were randomized to two overnight polysomnographic studies with frequent blood sampling (q10min) to measure GH: fourteen were healthy subjects studied with or without SWS disruption via auditory stimuli (3 sec, 1500 Hz tones, 40-100 dB followed by 18 sec of a 75 dB noise simulating a knock on the door) and five were subjects with OSA studied with or without prescribed continuous positive airway pressure (CPAP); the latter condition was expected to have sleep fragmentation due to untreated OSA. GH pulses were identified using sparse deconvolution. Studies without auditory stimuli or when using CPAP were combined and analyzed as 'undisrupted sleep'. The relationship between GH pulse rate per hour and sleep stage was evaluated using Poisson generalized estimating equations. Results In SWS disruption studies, an average of 77.51 ± 13.61 (range 23-190) auditory stimuli were delivered, causing a 40.02 ± 7.78% decrease in SWS in favor of lighter sleep stages. In subjects with OSA, CPAP withdrawal caused a slight increase in the apnea hypopnea index (1.08 ± 0.10 vs. 2.20 ± 1.70 events/hour of sleep, p=0.07) with no change in sleep stage durations. During undisrupted sleep, subjects had an average of 0.91 ± 0.067 GH pulses/hour with a mean pulse amplitude of 10.03 ± 1.00 ng/mL and mean basal secretion rate of 0.26 ± 0.10 ng/ml per min. GH pulses occurred more frequently during SWS (2.3 pulses/hour SWS, amplitude 9.92 ± 2.59 ng/mL) than during any other sleep stage (P &amp;lt; 0.001). Neither form of sleep disruption affected the distribution of GH pulses across sleep stages, GH pulse amplitude and frequency, nor basal GH secretion. Conclusion In children, nocturnal GH pulses are temporally associated with SWS. However, neither acute fragmentation of SWS nor nocturnal arousals from OSA altered basal or pulsatile GH secretion, indicating that somatotrophic axis activity is preserved in the face of acute sleep disruption in children. Presentation: Sunday, June 12, 2022 11:45 a.m. - 12:00 p.m.

Growth Hormone Secretory Capacity Is Associated with Cardiac Morphology and Function in Overweight and Obese Patients: A Controlled, Cross-Sectional Study.

Obesity is associated with increased cardiovascular morbidity. Adult patients with growth hormone deficiency (GHD) show morpho-functional cardiological alterations. A total of 353 overweight/obese patients are enrolled in the period between 2009 and 2019 to assess the relationships between GH secretory capacity and the metabolic phenotype, cardiovascular risk factors, body composition and cardiac echocardiographic parameters. All patients underwent GHRH + arginine test to evaluate GH secretory capacity, DEXA for body composition assessment and transthoracic echocardiography. Blood samples are also collected for the evaluation of metabolic parameters. In total, 144 patients had GH deficiency and 209 patients had normal GH secretion. In comparing the two groups, we found significant differences in body fat distribution with predominantly visceral adipose tissue accumulation in GHD patients. Metabolic syndrome is more prevalent in the GHD group. In particular, fasting glycemia, triglycerides and systolic and diastolic blood pressure are found to be linearly correlated with GH secretory capacity. Epicardial fat thickness, E/A ratio and indexed ventricular mass are worse in the GHD group. In the population studied, metabolic phenotype, body composition, cardiovascular risk factors and cardiac morphology are found to be related to the GH secretory capacity. GH secretion in the obese patient seems to be an important determinant of metabolic health.

Ablation of Growth Hormone Receptor in GABAergic Neurons Leads to Increased Pulsatile Growth Hormone Secretion.

Growth hormone (GH) acts in several hypothalamic neuronal populations to modulate metabolism and the autoregulation of GH secretion via negative-feedback loops. However, few studies have investigated whether GH receptor (GHR) expression in specific neuronal populations is required for the homeostatic control of GH secretion and energy homeostasis. In the present study, we investigated the consequences of the specific GHR ablation in GABAergic (VGAT-expressing) or glutamatergic (VGLUT2-expressing) cells. GHR ablation in GABAergic neurons led to increased GH secretion, lean mass, and body growth in male and female mice. VGAT-specific GHR knockout (KO) male mice also showed increased serum insulin-like growth factor-1, hypothalamic Ghrh, and hepatic Igf1 messenger RNA levels. In contrast, normal GH secretion, but reduced lean body mass, was observed in mice carrying GHR ablation in glutamatergic neurons. GHR ablation in GABAergic cells increased weight loss and led to decreased blood glucose levels during food restriction, whereas VGLUT2-specific GHR KO mice showed blunted feeding response to 2-deoxy-D-glucose both in males and females, and increased relative food intake, oxygen consumption, and serum leptin levels in male mice. Of note, VGLUT2-cre female mice, independently of GHR ablation, exhibited a previously unreported phenotype of mild reduction in body weight without further metabolic alterations. The autoregulation of GH secretion via negative-feedback loops requires GHR expression in GABAergic cells. Furthermore, GHR ablation in GABAergic and glutamatergic neuronal populations leads to distinct metabolic alterations. These findings contribute to the understanding of the neuronal populations responsible for mediating the neuroendocrine and metabolic effects of GH.

Evaluation of the growth response to growth hormone therapy in short children with normal growth hormone secretion

Introduction The availability of biosynthetic growth hormone (GH) ensures that children who are deficient can have replacement therapy, but it has also created the opportunity to treat children who are short but do not have a deficiency. The target height of children with short stature who have normal GH secretion, idiopathic short stature (ISS), without treatment, fails to reach their midparental potential. GH therapy for these children has resulted in variable height outcomes. While some children reached or exceeded genetic target height, others did not have a favorable response. Aim The aim of this study was to report the outcome of the children with ISS who had initial height standard deviation score (HtSDS) (Z score) less than −2, with normal stimulated GH levels (&gt;10 μg/l), after treatment with biosynthetic GH for at least 1 year. Patients and methods This retrospective study included 20 children with ISS, with initial HTSDS less than −2, normal stimulated GH levels (&gt;10 μg/l), who were treated with rhGH (0.04 mg/kg/day) for at least 1 year. None had any other systemic or endocrine disorder. All had normal complete blood count, liver, and renal functions. Results Twenty children (15 males and five females) with ISS, aged between 4.3 and 13.8 years (mean=9.88±2.62 years), who had mean peak GH=15.58±6.95 μg, were studied. All received GH treatment (average GH dose was 0.04 mg/kg/day) for a mean duration=2.49±1.61 years. The mean midparental HtSDS (MPHSDS) was −1.23±0.57. Their bone age did not differ significantly compared with their chronological age (the mean difference=−0.13±0.67 years). The mean HSDS before treatment was −2.34±0.41 and after 1 year of GH treatment was −1.83±0.48. This gave a gain of an average of 0.5 SD. At the last visit (after a mean of 2.5 years), the HtSDS −1.57±0.55 SD with a gain of 0.77±0.14 SD versus before treatment. The difference between children HtSDS compared with their MPHSDS was −1.08 SD before treatment that was changed to −0.3 SD at the last visit. The increment in HSDS was positively correlated with the duration of rhGH therapy (r=0.82, P=0.01) and negatively correlated with age at the start of treatment (r=−0.54, P=0.01). Conclusion Growth hormone therapy that benefits short children with normal growth hormone secretion achieves near-normal HSDS and approaches MPHSDS.

Inclusion and Withdrawal Criteria for Growth Hormone (GH) Therapy in Children with Idiopathic GH Deficiency—Towards Following the Evidence but Still with Unresolved Problems

According to current guidelines, growth hormone (GH) therapy is strongly recommended in children and adolescents with GH deficiency (GHD) in order to accelerate growth rate and attain normal adult height. The diagnosis of GHD requires demonstration of decreased GH secretion in stimulation tests, below the established threshold value. Currently, GHD in children is classified as secondary insulin-like growth factor-1 (IGF-1) deficiency. Most children diagnosed with isolated GHD present with normal GH secretion at the attainment of near-final height or even in mid-puberty. The most important clinical problems, related to the diagnosis of isolated GHD in children and to optimal duration of rhGH therapy include: arbitrary definition of subnormal GH peak in stimulation tests, disregarding factors influencing GH secretion, insufficient diagnostic accuracy and poor reproducibility of GH stimulation tests, discrepancies between spontaneous and stimulated GH secretion, clinical entity of neurosecretory dysfunction, discrepancies between IGF-1 concentrations and results of GH stimulation tests, significance of IGF-1 deficiency for the diagnosis of GHD, and a need for validation IGF-1 reference ranges. Many of these issues have remained unresolved for 25 years or even longer. It seems that finding solutions to them should optimize diagnostics and therapy of children with short stature.

Linear growth response to growth hormone therapy in underweight versus normal weight short children

Introduction Physiologically, growth hormone (GH) increases lean body mass and has a lipolytic function. However, long-term changes in weight status during GH treatment, as a function of pretreatment weight status have not previously been reported in large data sets. Aim To identify the growth response to GH therapy in those who were before treatment underweight versus normal weight short children. Patients and methods A retrospective study, we studied the auxologic data of 78 short, prepubertal children [height standard deviation score (HtSDS) less than −2 SDS below the mean for age and sex] with normal GH secretion [idiopathic short stature (ISS)]. Two groups were identified according to their pretreatment body mass index standard deviation score (BMISDS). Nineteen children were underweight (BMISDS &lt; −2) and 59 children had normal BMISDS (&gt;−2). All children received daily subcutaneous dose of GH (0.03–0.05 mg/kg/day) to keep their insulin-like growth factor-1 (IGF-1) level between 0 and 2 SD for 2 years. Results Before GH treatment, the underweight ISS group had significantly lower IGF-1 level versus the normal weight group with IGF-1 SD −1.633±0.766 SD versus −0.749±1.197 SD, respectively. Age and HtSDS did not differ among the two underweight and normal weight groups. Treatment with GH for 2 years was associated with a significant increase in the BMISDS in the underweight group (BMISDS increased by 0.45 SD) from −2.063±0.344 before treatment with GH versus −1.633±0.766 after treatment but not in the normal weight group. The HtSDS increased significantly in both groups after GH therapy, but the increase was greater in children with normal weight versus those with underweight as the increment in HtSDS was 0.42 and 0.374 SD, respectively. The difference of HtSDS from mid-parental HtSDS in low BMI versus normal BMI groups was −0.91 and −1.212 SD, respectively Conclusions GH therapy for 2 years significantly increased the IGF-1 level and improved BMISDS and HtSDS in underweight children with ISS. The BMISDS was better in the underweight group, but their HtSDS was less compared with the normal weight group.

Spine Bone Texture Assessed by Trabecular Bone Score in Active and Controlled Acromegaly: A Prospective Study.

ContextAcromegalic patients have an increased vertebral fracture (VFx) risk due to bone quality reduction, independently of bone mineral density (BMD).ObjectiveThe aim of the study is to describe bone quality in acromegaly, measured by trabecular bone score (TBS), a noninvasive index for assessing bone microarchitecture.MethodsWe collected data from 18 patients (13 female, age 56.2 ± 15 years) newly diagnosed with acromegaly. Thirty-six age- and sex-matched healthy controls were also recruited. Pituitary function, bone and calcium-phosphorous metabolism, and BMD at spine and femur and TBS (by dual-energy x-ray absorptiometry) were assessed in acromegalic patients at diagnosis and 12 months after the achievement of insulin-like growth factor 1 (IGF-1) normalization.ResultsAt diagnosis, BMD and the VFx prevalence were comparable between patients and controls (28.3 ± 5.9 vs 27.6 ± 3.7 and 11% vs 8.3%), whereas TBS was significantly lower in acromegalic patients (1.20 ± 0.13 vs 1.30 ± 0.06; P < .001) and carboxyterminal telopeptide (CTX) and osteocalcin were significantly higher compared to controls (707 ± 365.7 vs 371 ± 104.1 pg/mL; P = .001 and 31.6 ± 15.4 vs 17.0 ± 5.7 ng/mL; P = .001, respectively). One year after IGF-1 normalization, a significant reduction of bone turnover indexes was observed in the group of acromegalic patients surgically cured (osteocalcin decrease of 61.2%, CTX decrease of 60.3%) compared to the ones controlled by medical therapy (osteocalcin decrease of 39%, CTX decrease of 40.7%; P = .01 and P = .001, respectively). Despite these findings, no TBS or BMD variations were observed.ConclusionAcromegalic patients have impaired bone quality despite normal density. Achieving normal growth hormone secretion rapidly leads to the normalization of bone turnover.

The Effect of Growth Hormone Treatment on Physical Performance Indices in Children With Idiopathic Short Stature.

To examine the effect of growth hormone (GH) treatment on physical performance in children with idiopathic short stature and normal GH secretion. A total of 24 children participated in the study (13 GH-treated, 11 non-treated, aged 8-13y, 11 males and 13 females, Tanner stage 1-2). Participants performed a battery of motor skill performance tests (Eurofit), as well as the Wingate anaerobic test. No statistically significant differences in any of the Eurofit physical fitness test results (eg,20-m shuttle run 33.0 [15.1] vs 25.1 [21.0] laps in treated and nontreated participants, respectively, P = .25) or the Wingate anaerobic test were found between the groups (eg,peak power 5.0 [2.9] vs 3.9 [2.6]watts/kg in treated and nontreated participants, respectively, P = .2). Therapeutic usage of exogenous GH for pre and early pubertal children with idiopathic short stature and normal GH secretion was not associated with beneficial effects on physical performance indices. This suggests that the use of GH as a potential performance enhancing agent, in this age group, at least at commonly used doses, is not advantageous.

High-intensity interval exercise test stimulates growth hormone secretion in children

Backgroundexercise stimulates growth hormone (GH) secretion and may serve as a promising physiological test for the diagnosis of GH deficiency. However, exercise standardization for a feasible GH test is still lacking. The aim of the present study was to examine the GH secretion to high intensity interval exercise. MethodsSeventeen children (12.4 ± 2.6 years) with impaired growth rate performed high-intensity interval exercise test (HIIE) that included 10 intervals of 15 s all out pedaling against resistance determined by age, sex and weight on a cycle ergometer with 1-min active rest between each interval. Power output measurements were collected during the test. Blood samples were collected before, immediately after, 30, 45, and 60min after the beginning of the exercise test. GH response was compered to pharmacological provocation test (clonidine or glucagon). ResultsHIIE led to a significant increase in GH levels (p < 0.001), with high correlation to GH response following pharmacological stimulation (r = 0.82, r = 0.80 for clonidine and glucagon respectively, p < 0.001) A significant correlation was found between mean peak power to body weight and the GH response (r = 0.50, p = 0.04). 83% of the participants who reached peak power > 10 watts/kg had normal GH secretion. ConclusionsHIIE is a brief and individualized exercise protocol that may be used as a physiological provocation test for GH secretion. There might be a minimum of anaerobic power needed to induce adequate GH response during HIIE.

Prvi prikaz učinka terapije hormonom rasta kod pacijenta sa spondilodisplastičnim tipom Ehlers-Danlosovog sindroma i normalnom sekrecijom hormona rasta

Introduction/Aim: Spondylodysplastic Ehlers-Danlos Syndrome (sdEDS) is a rare genetic disorder of collagen synthesis, caused by a mutation in the B4GALT7, B3GALT6, or SLC39A13 gene. Features of this very rare disorder are short stature, hypotonia, hyperflexible joints, soft, thin, and overly stretchable skin, sparse hair and eyebrows, elderly face, wide forehead and prolonged wound healing. Molecular genetic analysis is needed for definite confirmation of the diagnosis. So far, only three case reports describing growth hormone treatment response in patients with sdEDS have been published. All of these patients had growth hormone (GH) deficiency. We present the first case report regarding growth hormone treatment response in a patient with sdEDS and normal GH secretion (without GH deficiency). Case report: Patient was a girl with short stature and normal GH secretion. Having in mind that the girl was born small for the gestational age, due to her short stature, she started using HR, before the diagnosis of sdEDS was made. Based on the lack of improvement in growth velocity as well as the girl's phenotype, genetic analyses were performed and the diagnosis of sdEDS due to biallelic mutations of the B4GALT7 gene was established. After the diagnosis of sdEDS was made and due to suboptimal response in growth velocity to the GH treatment, the GH therapy was stopped at the age of 11 years. Conclusion: This is a first case report regarding GH treatment in a child with sdEDS and normal GH secretion, demonstrating a very limited therapeutic effect of GH on linear growth in the presented patient.

Use of the Growth Hormone Stimulation Test Result in the Management of Patients With a Short Stature.

IntroductionA proportionate short stature (SS) assessment involves the documentation of normal growth hormone secretion via a growth hormone (GH) stimulation test. All available GH stimulation tests have some disadvantages. The decision to initiate GH therapy is dependent on multiple factors, including the GH stimulation test result. However, many patients receive GH therapy, even if they have a normal GH stimulation test result, with the indication of a presumed idiopathic SS.ObjectiveIn this study, we investigated the use of the GH stimulation test result in initiating GH therapy.MethodA cross-sectional study was conducted with patients diagnosed with proportionate SS. Age, gender, insulin-like growth factor 1 (IGF-1) level, and GH stimulation test results were collected retrospectively from the electronic medical records. The main outcome variable was the decision related to prescribing GH therapy.ResultsA total of 286 patient charts were reviewed, and the majority (n = 201, 64.6%) were male. For just less than half (n = 136, 47.6%), the result of the GH stimulation test was ≥ 10 ng/mL, in a small proportion (n = 53, 18.5%) the result was < 5 ng/mL, and for the rest of the cohort, the result was 5.0 - 9.9 ng/mL. The majority (n = 219, 70.4%) received GH therapy, irrespective of the GH stimulation test result. The odds ratio (OR) for GH treatment was 3.9 (CI: 1.79 - 8.49) and 3.0 (CI: 1.21 - 7.42) for patients with a result < 5 ng/mL and 5.0 - 9.9 ng/mL, respectively, compared to the group with a result of ≥ 10 ng/mL.ConclusionGH therapy is frequently prescribed for patients with SS, irrespective of the GH stimulation test result. However, the group with SS with a result of < 9.9 ng/mL was more likely to receive GH therapy. The question of whether a GH stimulation test is required, in the context of SS, is debatable.

Digenic Variants in the FGF21 Signaling Pathway Associated with Severe Insulin Resistance and Pseudoacromegaly.

Insulin-mediated pseudoacromegaly (IMPA) is a rare disease of unknown etiology. Here we report a 12-year-old female with acanthosis nigricans, hirsutism, and acromegalic features characteristic of IMPA. The subject was noted to have normal growth hormone secretion, with extremely elevated insulin levels. Studies were undertaken to determine a potential genetic etiology for IMPA. The proband and her family members underwent whole exome sequencing. Functional studies were undertaken to validate the pathogenicity of candidate variant alleles. Whole exome sequencing identified monoallelic, predicted deleterious variants in genes that mediate fibroblast growth factor 21 (FGF21) signaling, FGFR1 and KLB, which were inherited in trans from each parent. FGF21 has multiple metabolic functions but no known role in human insulin resistance syndromes. Analysis of the function of the FGFR1 and KLB variants in vitro showed greatly attenuated ERK phosphorylation in response to FGF21, but not FGF2, suggesting that these variants act synergistically to inhibit endocrine FGF21 signaling but not canonical FGF2 signaling. Therefore, digenic variants in FGFR1 and KLB provide a potential explanation for the subject’s severe insulin resistance and may represent a novel category of insulin resistance syndromes related to FGF21.