Basal Growth Hormone Research Articles

5162 Oral LUM-201 Restores Pulsatile Growth Hormone Secretion and Growth Response in Moderate Pediatric Growth Hormone Deficiency (PGHD): Key Discoveries from Phase 2 of OraGrowtH212 Trial

Abstract Disclosure: F. Cassorla: Consulting Fee; Self; Lumos Pharma, Inc. Research Investigator; Self; Lumos Pharma, Inc. R. Roman: Research Investigator; Self; Lumos Pharma, Inc. M.L. Johnson: Consulting Fee; Self; Lumos Pharma, Inc. A. Avila: Research Investigator; Self; Lumos Pharma, Inc. G. Iñiguez: Research Investigator; Self; Lumos Pharma, Inc. I. Baier: Research Investigator; Self; Lumos Pharma, Inc. D. Said: Research Investigator; Self; Lumos Pharma, Inc. A. Bruchey: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. C. Smith: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. E. Brincks: Employee; Self; Lumos Pharma. Stock Owner; Self; Lumos Pharma, Inc. J. McKew: Employee; Self; Lumos Pharma. Stock Owner; Self; Lumos Pharma. M.O. Thorner: Consulting Fee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Ammonett Pharma LLC. P. Pitukcheewanont: Employee; Self; Lumos Pharma. Stock Owner; Self; Lumos Pharma. Objectives: The primary objective was to examine the pharmacokinetic/pharmacodynamic (PK/PD) aspects of oral LUM-201 at doses of 1.6 and 3.2 mg/kg/d with moderate PGHD, involving frequent GH sampling for 12 hours post-administration. Using deconvolutional analysis, the study compared the GH secretion patterns before & after 6 months (m) daily administration of LUM-201. LUM-201, an investigational agonist of the growth hormone (GH) Secretagogue Receptor 1a (GHSR1a), was employed as part of a predictive enrichment marker (PEM) test to identify moderate PGHD subjects likely to respond, based on baseline insulin-like growth factor-1 (IGF-1) level >30 ng/mL & a peak GH of ≥5 ng/mL post a single 0.8 mg/kg dose of LUM-201. Methods: The OraGrowtH212 Trial, conducted at Santiago, Chile, monitors subjects until they approach their near final height. The current report focuses on data analysis at 6 and 12m, with ongoing subject follow-ups extending to 24m. This trial randomized 22 PEM+ moderate PGHD subjects into two LUM-201 dosage groups: 1.6 or 3.2 mg/kg/d. To assess GH secretion, each child was sampled every 10 min from 0800-2000h at baseline & 6m. Safety was assessed throughout the study and growth evaluated at 6 & 12m intervals. Results: At start of the study, basal GH secretion in the LUM-201 1.6mg/kg/d group (all values expressed as mean ± SD µg/kg body weight) was 0.19 ±0.09, pulsatile GH was 1.17 ± 0.66, and total GH was 1.35 ± 0.66. At 6m, each of these parameters had significantly increased to 0.36 ± 0.21, 1.8 ±0.74 and 2.2 ±0.89 respectively (p values from 0.02-0.04). Similar significant increases were seen for LUM-201 3.2mg/kg/d. Combining the data from both LUM-201 doses demonstrated that GH secretion determined by deconvolution analysis was 3.3-4.0 µg/kg/24hrs compared to 5 µg/kg/24hrs derived from published data on normal children (Zadik et al, Horm Res 1992), indicating restoration of GH secretion by LUM-201. These values are considerably less than 25-34µg/kg/d of recombinant human GH used in the treatment of PGHD. At 6m, the annualized height velocity (AHV) was 7.2cm/yr for the LUM-201 1.6mg/kg/d and 8.1cm/yr for the 3.2 mg/kg/d dose. At 12m, AHV for a subset was 6.9cm/yr for the 1.6 dose and 7.2cm/yr for the 3.2 dose. Baseline IGF-1 SDS (mean ±SD) were -1±0.63 in 1.6mg/kg/d group & -0.85±0.47 in 3.2mg/kg/d group. The change over 12m was +0.9 on 1.6 dose and +1.1 on 3.2 dose, indicating similar efficacy for IGF-1 generation. LUM-201 showed good tolerability in this study, with no observed safety concerns in adverse events (AEs), labs, and ECGs. Conclusions: At 6m LUM-201 was able to restore endogenous GH pulsatile secretion to a similar level to that seen in normal children, while normalizing serum IGF-1 concentrations. These results indicate that by restoring endogenous GH secretion, LUM-201 facilitates growth utilizing a much lower amount of GH than that provided by daily exogenous rhGH administration. Presentation: 6/3/2024

VITAMIN D AND SOME GROWTH PARAMETERS IN CHILDREN WITH DIFFERENT FORMS OF SHORTISH STATURE

The aim of study – to analyze the level of 25(OH)D in the blood plasma of children withdifferent forms of shortish stature according to the state of the growth hormone (GH)/insulin-like growth factor (IGF-1) system.Materials and methods. In the Department of Pediatric Endocrine Pathology of the StateInstitution «V. P. Komisarenko Institute of Endocrinology and Metabolism of the NationalAcademy of Medical Sciences of Ukraine» 129 children with shortish stature werestudied. The following data were considered: sex and age of the patient, anthropometricdata, vitamin D level in blood (excluding summer months of recruitment), bone age, GHlevel before and after stimulation tests (clonidine, insulin), and IGF-1 level.The results of the study were statistically analyzed in Excel.Results. All groups of subjects had growth retardation ranging from minus 2.19±0.49 tominus 2.83±0.12 SDS. In children with biologically inactive growth hormone syndromeand idiopathic shortish stature (ISS), bone age retardation was within 1.84 years.In patients with intrauterine development delay (IDD), the bone age was practically thesame as the passport age, and children with growth hormone delete (GHD) had a delayin bone age of 2.44 years.The basal level of GH was low in all patients, but the lowest level was observed in childrenwith GHD and the highest in patients with syndrome of biologically inactive growthhormone (BIGHS). During the stimulation tests with clofelin and insulin, the maximumrelease of GH in the blood of the subjects was obtained. At the same time, in children withGHD it was low, indicating this pathology, in all other groups the level of GH increasedto normal values (more than 10 ng/ml). Conclusions. Basal GH levels were the lowest in children with GHD and the highest in patientswith BIGHS. The lowest IGF-1 levels were observed in children with IDD. The majority(60.87 %) of children with BIGHS were vitamin D deficient. Vitamin D deficiency was found inpatients with IDD: vit. D insufficiency in 52.94 % and vit. D deficiency in 47.06 %. The largestgroup of children with ISS and GHD had vit. D deficiency (48.57 % and 47.22 %, respectively).

The Preoperative Paradoxical GH Response to Oral Glucose Load Predicts a low Risk of Recurrence in Acromegaly.

a paradoxical growth hormone (GH) response to oral glucose load (OGTT) in acromegaly is associated with a milder phenotype. To study whether the GH response to OGTT predicts the risk of recurrence after initial surgical cure. Retrospective, observational study. Two tertiary care centers. We investigated 254 patients with acromegaly who were cured by surgery. All patients underwent OGTT at diagnosis before pituitary surgery. A peak-to-basal GH ratio ≥ 120% within 90 minutes was used to distinguish paradoxical (GH-Par) from non-paradoxical acromegalic patients (GH-NPar). Cox analysis was used to investigate whether the paradoxical GH response to OGTT was associated with the risk of disease recurrence. A paradoxical GH response to OGTT occurred in 87 patients (34.3%, termed GH-Par group). Recurrence of acromegaly occurred in three patients of the GH-Par group (3.4%) and in 20 patients in the GH-NPar group (12.0%). In the multivariate analysis, the paradoxical GH response to OGTT was significantly associated with the risk of recurrence (HR 0.18, 95% CI, 0.05-0.63; P = 0.007). Basal GH level at diagnosis was the only other variable associated with the risk of disease recurrence (HR 1.58, 95% CI, 1.01-2.47; P = 0.04). our study demonstrates that a paradoxical GH response to OGTT in the preoperative setting predicts a lower risk of disease recurrence after initial surgical cure. The pattern of GH responsiveness to OGTT is, therefore, useful to predict the long-term outcome of patients with acromegaly.

Predictors For TESE Outcomes and Fertility Potentials Among Infertile Adult Men

Background: Spermatogenesis is an essential process for human reproduction. Gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone play vital roles in the development and maturation of sperm. Growth hormone (GH) is thought to play a role in the reproductive system of both males and females. Growth Hormone deficiency can lead to reproductive problems. 
 Aim: to assess predictors of fertility potentials and TESE outcomes among adult males.
 Methods: we enrolled 162 males and assessed FSH, LH, basal GH, clonidine (GH) stimulation test one time and insulin stimulation test in another time. We designed a predictive model to identify the fertility potentials, Fertility Score= 4.442 + (Basal GH*0.074) + (GH_CLON*0.035) - (FSH*0.021) (BMI*0.062)- (Smoker*0.429). The net result of this equation should be approximated to the nearest integer to predict the fertility status where, 1=TESE Negative, 2= TESE Positive, 3=Oligozoospermia, and 4= Fertile control. 
 Results: multivariate analysis showed smoking status, testicular volume, BMI, Serum FSH, basal GH are not predictors for fertility potentials. GH after clonidine and after insulin stimulation GH after clonidine stimulation correlates positively with total motile count. Other semen parameters do not correlate with basal GH or GH after insulin or clonidine stimulation. Receiver Operator Characteristic (ROC) curve analysis is used to detect the cut off levels at which sperm recovery yield change. For the GH assessment only, the basal GH could be applied to predict the SRR in men with azoospermia, AUC=0.672 (95% CI: 0.499 to 0.844). Growth hormone after clonidine (AUC= 0.510) or Insulin stimulation (AUC=0.556) and therefore, cannot differentiate between TESE positive and TESE negative cases.
 Conclusion: Basal, post clonidine GH levels, has BMI and smoking are predictive factors for fertility potentials, our model have high sensitivity in predicting fertility potentials among positive TESE males. Basal GH can significantly predict TESE negative males.

Endocrine Outcomes and Associated Predictive Factors for Somatotrophin Pituitary Adenoma after Endoscopic Endonasal Transsphenoidal Surgery: 10 Years of Experience in a Single Institute.

Objective Biochemical remission rates of endoscopic endonasal transsphenoidal surgery (EETS) and its associated predictive factors were evaluated in patients with somatotrophin pituitary adenomas. Methods The patients who underwent EETS in Jinling Hospital were identified between 2011 and 2020. The surgeons' experience, preoperative insulin-like growth factor 1 (IGF-1), basal growth hormone (GH) levels, nadir GH levels, and the tumor characteristics were analyzed for their relationships with endocrine outcomes. Total 98 patients were included for single factor analysis and regression analysis. They were divided into three groups according to the admission chronologic order. Results The overall remission rate of the patients was 57% (56/98) for all the patients over 10 years. In the single factor analysis, we found that the tumor size, cavernous invasion, and sellar invasion were valuable to predict the endocrine outcome after surgery. As for the suprasellar invasion, no significant difference was found between the noninvasive group and the invasive group. The preoperative IGF-1 level ( p = 0.166), basal GH level ( p = 0.001), and nadir GH level ( p = 0.004) were also different between the remission group and the nonremission group in the single factor analysis. The logistic regression analysis indicated that the preoperative nadir GH (odds ratio = 0.930, 95% confidence interval = 0.891-0.972, p = 0.001) was a significant predictor for the endocrine outcomes after surgery. Conclusion The surgeons' experience is an important factor that can affect the patients' endocrine outcomes after surgery. The macroadenomas with lateral invasion are more difficult to cure. Patients with higher preoperative nadir GH levels are less likely to achieve remission.

Laron syndrome in South Indian children – A descriptive study

Objectives: The objectives of this study were to describe the clinical and biochemical features of five children with Laron syndrome (LS) from South India. Material and Methods: This is a prospective descriptive case series of five children with clinical and biochemical features of LS managed over 5 years. Results: Five children (two girls and three boys) with LS with the mean age group of 5.9 ± 1.7 years and the mean age at diagnosis of 2.7 ± 0.8 years are described. All children were born out of consanguinity and all had typical phenotypic facies of LS. The mean Z-scores of height, weight, and body mass index on follow-up for the cohort were −7.0 ± 1.6, −5.9 ± 2.8, and −0.1 ± 0.7, respectively, and they were within ± 2 SD of the mean for children in LS chart. The median basal growth hormone level for age was 13 ng/mL and the median growth hormone levels at 30 min, 60 min, 90 min, and 120 min post-stimulation test were 35 ng/mL, 35 ng/mL, 44 ng/mL, and 50 ng/mL, respectively. All of them had insulin-like growth factor-1 (IGF-1) levels less than the 3rd percentile and no increment during the IGF-1 generation test. The prevalence of micropenis was 100% and one child had symptomatic hypoglycemic episodes. Genetic analysis was performed in two boys and both harbored variants in the growth hormone receptor gene. Conclusion: LS should be suspected in children with clinical features of growth hormone deficiency along with elevated growth hormone levels and low IGF-1 levels with no increment of IGF-1 in the IGF-1 generation test.

Fasting and prolonged food restriction differentially affect GH secretion independently of GH receptor signaling in AgRP neurons.

Growth hormone (GH) receptor (GHR) is abundantly expressed in neurons that co-release the agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARH). Since ARHAgRP/NPY neurons regulate several hypothalamic-pituitary-endocrine axes, this neuronal population possibly modulates GH secretion via a negative feedback loop, particularly during food restriction, when ARHAgRP/NPY neurons are highly active. The present study aims to determine the importance of GHR signaling in ARHAgRP/NPY neurons on the pattern of GH secretion in fed and food-deprived male mice. Additionally, we compared the effect of two distinct situations of food deprivation: 16 h of fasting or four days of food restriction (40% of usual food intake). Overnight fasting strongly suppressed both basal and pulsatile GH secretion. Animals lacking GHR in ARHAgRP/NPY neurons (AgRP∆GHR mice) did not exhibit differences in GH secretion either in the fed or fasted state, compared to control mice. In contrast, four days of food restriction increased GH pulse frequency, basal GH secretion, and pulse irregularity/complexity (measured by sample entropy), whereas pulsatile GH secretion was not affected in both control and AgRP∆GHR mice. Hypothalamic Ghrh mRNA levels were unaffected by fasting or food restriction, but Sst expression increased in acutely fasted mice, but decreased after prolonged food restriction in both control and AgRP∆GHR mice. Our findings indicate that short-term fasting and prolonged food restriction differentially affect the pattern of GH secretion, independently of GHR signaling in ARHAgRP/NPY neurons.

Clinical profile of Laron dwarfism – experience from a tertiary care institute in Chennai

Laron dwarfism is a rare genetic disorder first reported among Israeli jewish children, subsequently about 350 cases cases have been reported worldwide. We aim to describe the clinical profile of nine children with Laron dwarfism from Institute of Child Health, Chennai. Analysis of case records from 2010 to 2018. Male:female ratio is 6:3. Mean age of the children at the time of diagnosis was 3 years. All children were extremely short, and mean height Z score (SD) was-7.7(0.8). All children had characteristic facies with no hypoglycaemic episodes. Microcephaly was present in four children out of which two had developmental delay. Three out of six boys had micropenis. All children had low insulin like growth factor-1 (IGF-1) and high basal growth hormone (GH) with a mean (SD) of 39.6 (11.2) ng/mL. Suspicion of Laron syndrome should be high when child presents with features of Growth Hormone Deficiency (GHD) with extreme stunting.

In Search of the Hyperglycemic Threshold Required to Induce Growth Hormone (GH) Suppression.

Introduction According to the 2014 Endocrine Society Clinical Practice Guideline on acromegaly, the confirmation of acromegaly diagnosis is established by finding a lack of suppression of growth hormone (GH) to < 1 ug/L following documented hyperglycemia during an oral glucose tolerance test. However, in this setting, the concept of hyperglycemia has never been clearly defined. Objective This study aimed to define the hyperglycemic threshold required to induce GH suppression. Methods We retrieved the glycemia profile of 44 individuals after a standard 2-h 75g oral glucose tolerance test prescribed to assess GH suppression and performed a comprehensive analysis of two subgroups of individuals (28 reaching GH suppression and 16 in whom GH suppression was not observed). All of the data were analyzed with the program Graph Pad Prism. Differences between means were assessed by Student's unpaired t-test or Mann-Whitney U test as deemed appropriate. Fisher's exact test was used for categorical variables. Results Individuals in G1 and G2 were different only for the median basal GH and median IGF-1. No significant differences in terms of the prevalence of diabetes and prediabetes were found. The glucose peak was achieved earlier in the group that reached GH suppression. The median of the highest glucose values of both subgroups was not different. A correlation between peak and baseline glucose value was found only among those in whom GH suppression was reached. Among these, the median glucose peak (P50) was 177 mg/dl, whereas the 75th percentile (P75) and 25th percentile (P25) were 199 mg/dl and 120 mg/dl, respectively. Conclusion Considering that 75% of those in whom GH suppression was observed after an oral glucose overload test reached blood glucose values above 120 mg/dl, we propose to use this value as the blood glucose threshold for inducing GH suppression. In light of our results, whenever GH suppression is not observed; and the highest glycemic value is below 120 mg/dl, it might be useful to repeat the test prior to any conclusion.

Difficulties in diagnosing acromegaly, acromegaly with apparently normal GH: Micromegaly

Abstract Introduction Acromegaly results from pathologically increased secretion of growth hormone (GH) from the pituitary somatotroph adenoma. If left untreated, it is associated with increased morbidity and mortality. We present a case of micromegaly, whose diagnosis is challenging for clinicians. Clinical Case A 40-year-old woman presented with complaints of enlarged facial features, hands and feet, and separation between teeth. She was using a salbutamol inhaler with the diagnosis of asthma. Her physical examination was unremarkable except for a body mass index of 28.7 kg/m2 and malocclusion. Insulin-like growth factor (IGF)-1 250 ng/mL (101–234) and GH 2.1 ng/mL was detected. 0, 1. and 2nd hour in oral glucose tolerance test (OGTT)-GH; hour GH/glucose values were 6.7/70, 1.5/98, 0.35 ng/ml /95 mg/dl, respectively. Sella magnetic resonance imaging (MRI) revealed an 8×5mm adenoma in the pituitary gland (Figure). Pseudoacromegaly causes such pachydermoperiostitis, severe insulin resistance, familial mandibular prognathism, use of phenytoin and minoxidil, and causes of false IGF-1 elevation such as pregnancy, puberty/adolescent period, thyrotoxicosis, glucocorticoid use were excluded. It was decided that the patient should be operated on. No adenoma was detected in the pathology tissue of the operated patient, but IGF-1 was detected at 201 ng/ml (101–234) and GH was 1,1 ng/ml in the 3rd postoperative month. The nadir GH was found to be 0.3 ng/ml in the OGTT-GH suppression test. Medical treatment was not started. The case has been followed for 2 years in remission. Conclusion Micromegaly describes a subset of patients with clinically evident acromegaly and elevated IGF-1 with apparently normal basal GH and often &amp;lt;0.4 ng/mL glucose suppressed GH. This condition is relatively rare in patients with acromegaly. As in our case, micromegaly should be considered in diagnosing patients with “normal” GH but with clinical signs, or even patients without clinical signs but with pituitary tumors and elevated IGF-1.

GENETIC FEATURES OF CHILDREN WITH IDIOPATHIC SHORT STATURE.

The aim: To investigate the clinical and genetic characteristics of children with idiopathic short stature, taking into account the polymorphism of the vitamin D receptor (VDR) BsmI gene. Materials and methods: Eighteen children diagnosed with of idiopathic short stature who were treated at the State Institution «V.P. Komisarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Sciences of Ukraine» were examined. The following values were taken into account: the patient's sex and age, anthropometric data, vitamin D level in the blood (excluding summer months of patient recruitment), bone age, basal growth hormone (GH) level and its level after stimulation tests (clonidine, insulin), IGF-1 levels, blood levels of total and ionized calcium and VDR gene polymorphism. Results: The A allele carriers of the polymorphic locus BsmI (rs1544410) of the VDR gene are significantly associated with the risk of developing idiopathic short stature OR = 4.47 (95% CI 2.11-9.48; p <0.05). The risk of idiopathic short stature is significantly higher OR = 9.33 (95% CI 3.09-28.16; p <0.05) in children with the presence of the G/A genotype. Vitamin D deficiency (43.83 ± 6.47 nmol/l) was found in children with the BsmI polymorphic variant G/G VDR, and vitamin D insufficiency was found in children with BsmI polymorphic variants G/A and A/A VDR (58.14 ± 20.05 and 51.58 ± 22.84 nmol/l, respectively). Conclusions: The data obtained regarding the polymorphic locus BsmI (rs1544410) of the of VDR gene cannot exclude it's the involvement in the pathogenesis of idiopathic short stature.

Understanding the role of growth hormone in situations of metabolic stress.

Growth hormone (GH) is secreted by the anterior pituitary gland and plays a key role in controlling tissue and body growth. While basal GH secretion is considerably reduced along adulthood and aging, several situations of metabolic stress can lead to robust increases in circulating GH levels. The objective of the present review is to summarize and discuss the importance of GH regulating different physiological functions in situations of metabolic stress, including prolonged food restriction, hypoglycemia, exercise, pregnancy, and obesity. The presented data indicate that GH increases hunger perception/food intake, fat mobilization, blood glucose levels and insulin resistance, as well as produces changes in energy expenditure and neuroendocrine responses during metabolic challenges. When all these effects are considered in the context of situations of metabolic stress, they contribute to restore homeostasis by 1) helping the organism to use appropriate energy substrates; 2) preventing hypoglycemia or increasing the availability of glucose; 3) stimulating feeding to provide nutrients in response to energy-demanding activities or to accelerate the recovery of energy stores; and 4) affecting the activity of neuronal populations involved in the control of metabolism and stress response. Thus, the central and peripheral effects of GH coordinate multiple adaptations during situations of metabolic stress that ultimately help the organism restore homeostasis, increasing the chances of survival.

Short-term and long-term remission after endoscopic transnasal adenomectomy in patients with acromegaly

Neurosurgery is the most effective treatment for acromegaly. As most of the patients present with macroadenomas, surgical treatment is not always successful, even with the expert level of a neurosurgeon. Assessment of the postoperative remission rates in acromegaly preoperative predictors of treatment efficacy is an urgent task of modern research. To assess the short-term and long-term remission of acromegaly after endoscopic transnasal adenomectomy in a tertiary medical center and assess preoperative predictors of the treatment effectiveness. A single-center, prospective, uncontrolled study was conducted. We included patients with active acromegaly who did not receive medical therapy with somatostatin analogues and were referred for endoscopic transsphenoidal adenomectomy. Plasma miRNA expression was assessed by quantitative reverse transcription PCR. Postoperative samples of adenomas were sent for study, with the determination of the immunohistochemical staining for somatostatin receptors 2 and 5 subtypes and morphology was performed on postoperative adenoma samples. The study included 44 patients: 32.8% men, median age 47.0 [34.0; 55.0], IGF-1 744.75 ng/ml [548.83;889.85], growth hormone 9.5 ng/ml [4.94; 17.07]. Tumor volume 832 mm3 [419.25; 2532.38]. Early postoperative remission was achieved in 35 patients (79.5%). Patients who achieved short-term remission had higher IGF-1 and basal growth hormone levels. Median follow-up was 19.0 months [12.5;29.0]. Long-term remission was achieved in 61.4% (27 patients), no remission in 9 (20.5%), recurrency in 2 patients (4.5%), 6 patients were to follow-up (13.6%). In patients with long-term remission, we observed lower growth hormone and IGF-1 levels. No differences in miRNA expression was observesd. The predictive value of basal GH before surgery for long-term remission was assessed: area under the curve 0.811 (95% CI: 0.649; 0.973). A cut-off value of 15.55 ng/mL corresponded to a sensitivity of 70.0% (34.8%; 93.3%), a specificity of 85.7% (67.3%; 96.0%), an accuracy of 81.6% (65 .7%; 92.3%), PPV 63.6% (39.3%; 82.5%), NPV 88.9% (75.4%; 95.4%). Rates of short-term and long-term remission after endoscopic transsphenoidal adenomectomy in our cohort is 79,5% и 61,4%, respectively, and is comparable with literature data for expert pituitary centers. Preoperative GH shows potential value in predicting the long-term remission of acromegaly, but further studies in a larger sample are needed to obtain more accurate cut-off values.

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.

Frequency of hyperostosis frontalis interna in patients with active acromegaly: is there a possible role of GH excess or hyperprolactinemia in its etiopathogenesis?

Acromegaly is characterized by bone changes due to excessive growth hormone (GH) secretion. Hyperostosis frontalis interna (HFI) is described as an overgrowth in the inner plate of the frontal bone. An increased incidence of HFI has been reported in patients with acromegaly. Since the etiology of HFI is poorly understood, we have analyzed whether there is a relationship between the hormonal and metabolic status of patients with acromegaly (with or without hyperprolactinemia) and the pathogenesis of HFI. Forty-five patients with acromegaly and two control groups consisting of 25 patients with prolactinoma (group 1) and 47 healthy subjects (group 2) were included in this retrospective study. Baseline hormonal data and cranial imaging were obtained from medical records and analyzed. Mean frontal bone thickness was 6.75mm in acromegaly, 4.85mm in group 1, and 5.1mm in group 2 of controls (p < 0.001). The frequency of HFI was higher in acromegalic patients than in the controls (22%, 0%, and 2.2%, respectively). There was no difference between the HFI positive and negative acromegalic patients in basal GH, IGF-1, and PRL levels, IGF-1 index, diagnosis lag time, and insulin resistance. There was no difference between groups regarding parietal and occipital bone thickness. Although the frequency of HFI is 22% in patients with acromegaly, neither excess GH nor hyperprolactinemia plays a role in its etiopathogenesis. Various genetic or epigenetic factors may contribute to its etiology.

Factors associated with therapeutic response in acromegaly diagnosed in the elderly in Spain.

ContextSome reports suggest that acromegaly in elderly patients has a more benign clinical behavior and could have a better response to first-generation long-acting somatostatin receptor ligands (SRL). However, there is no specific therapeutic protocol for this special subgroup of patients.ObjectiveThis study aimed at identifying predictors of response to SRL in elderly patients.DesignMulticentric retrospective nationwide study of patients diagnosed with acromegaly at or over the age of 65 years.ResultsOne-hundred and eighteen patients (34 men, 84 women, mean age at diagnosis 71.7 ± 5.4 years old) were included. Basal insulin-like growth factor type 1 (IGF-1) above the upper limit of normal (ULN) and growth hormone (GH) levels (mean ± SD) were 2.7 ± 1.4 and 11.0 ± 11.9 ng/ml, respectively. The mean maximal tumor diameter was 12.3 ± 6.4 mm, and up to 68.6% were macroadenoma. Seventy-two out of 118 patients (61.0%) underwent surgery as primary treatment. One-third of patients required first-line medical treatment due to a rejection of surgical treatment or non-suitability because of high surgical risk. After first-line surgery, 45/72 (63.9%) were in disease remission, and 16/34 (46.7%) of those treated with SRL had controlled disease. Patients with basal GH at diagnosis ≤6 ng/ml had lower IGF-1 levels and had smaller tumors, and more patients in this group reached control with SRL (72.7% vs. 33.3%; p < 0.04) [OR: 21.3, IC: 95% (2.4–91.1)], while male patients had a worse response [OR: 0.09, IC 95% (0.01–0.75)]. The predictive model curve obtained for SRL response showed an AUC of 0.82 CI (0.71–0.94).ConclusionsThe most frequent phenotype in newly diagnosed acromegaly in the elderly includes small adenomas and moderately high IGF-1 levels. GH at diagnosis ≤6 ng/ml and female gender, but not age per se, were associated with a greater chance of response to SRL.

Acute Sleep Disruption Does Not Diminish Pulsatile Growth Hormone Secretion in Pubertal Children.

In children, growth hormone (GH) pulses occur after sleep onset in association with slow-wave sleep (SWS). There have been no studies in children to quantify the effect of disrupted sleep on GH secretion. This study aimed to investigate the effect of acute sleep disruption on GH secretion in pubertal children. Fourteen healthy individuals (aged 11.3-14.1 years) were randomly assigned to 2 overnight polysomnographic studies, 1 with and 1 without SWS disruption via auditory stimuli, with frequent blood sampling to measure GH. Auditory stimuli delivered during the disrupted sleep night caused a 40.0 ± 7.8% decrease in SWS. On SWS-disrupted sleep nights, the rate of GH pulses during N2 sleep was significantly lower than during SWS (IRR = 0.56; 95% CI, 0.32-0.97). There were no differences in GH pulse rates during the various sleep stages or wakefulness in disrupted compared with undisrupted sleep nights. SWS disruption had no effect on GH pulse amplitude and frequency or basal GH secretion. In pubertal children, GH pulses were temporally associated with episodes of SWS. Acute disruption of sleep via auditory tones during SWS did not alter GH secretion. These results indicate that SWS may not be a direct stimulus of GH secretion.

Characteristics and treatment outcomes of micromegaly - acromegaly with apparently normal basal GH: A retrospective study and literature review.

Objective. Micromegaly describes a subgroup of patients with clinically evident acromegaly and elevated insulin-like growth factor I (IGF-I) with apparently normal basal growth hormone (bGH) and often a glucose-suppressed growth hormone (GH) of <1 ng/mL at diagnosis. It is controversial whether this condition is a distinct clinical entity or a classic acromegaly in early stages. The aim of the present article was to characterize the prevalence, clinical and biochemical characteristics, and therapeutic outcomes of micromegaly. Methods. A retrospective study of patients with an acromegaly followed ≥1 year at a tertiary center from 1995 to 2019. Patients without IGF-I or GH measurements at diagnosis were excluded. At diagnosis, bGH was considered normal if <2 ng/mL. Results. From 74 patients with acromegaly, 6 (8.1%) had normal bGH levels. There was no difference in the gender distribution, median diagnostic delay, and follow-up time between patients with normal bGH and elevated bGH. Patients with normal bGH were significantly older at time of the first acromegalic manifestation and diagnosis they had significantly lower nadir post-glucose GH and IGF-I levels, and tended to have a higher prevalence of obesity than patients with the elevated bGH. The frequency of acromegalic symptoms, signs, and other comorbidities than obesity was similar between groups. Five patients (83.3%) with normal bGH presented microadenomas. Post-operative remission and outcomes at last visit were comparable between patients with or without normal bGH. Conclusions. Normal bGH acromegaly is relatively uncommon in our patients. These patients showed differentiating characteristics from the classical acromegaly with elevated bGH. Further studies are needed to extend the knowledge about its clinical behavior, therapeutic outcomes, morbidity, and mortality.

Sex and age differences among patients with acromegaly.

Acromegaly is a chronic, slowly progressive disorder caused mostly by growth hormone (GH)-producing pituitary neuroendocrine tumors (PitNETs). Recently, the associations between sex and age at the time of diagnosis and the course of acromegaly have been a focus of debate. The aim of our study was to evaluate the association between sex and age at the time of diagnosis of acromegaly and the clinical features, biochemical status, severity of the disease, and comorbidities. This was a single‑center study conducted in a group of consecutive patients with acromegaly and no family history of PitNETs. The participants were divded into 2 subgroups according to sex (male, female) and 3 subgroups according to age at the time of diagnosis: i) younger (≤40 years), ii) middle‑aged (41-59 years), and iii) elderly patients (≥60 years). Our study included 101 patients (41 men, 60 women) who met the eligibility criteria. The mean (SD) age at the time of diagnosis was 47.3 (14.1) years and the median diagnostic delay was 5 years (interquartile range, 3-10). Age at the time of diagnosis and diagnostic delay were not statistically different in men and women. Levels of insulin‑like growth factor 1 (IGF‑1) above the upper limit of age‑adjusted normal range (%ULN IGF‑1) were greater in men than in women (mean [SD], 174.8% [98.9%] vs 109.4% [66.6%]; P = 0.002), while there was no significant difference in terms of %ULN IGF‑1 between the age groups. Median basal and nadir GH levels did not differ between the sexes. Men presented with hypogonadism more frequently than women (54% vs 26%; P = 0.005). Hyperprolactinemia, hypogonadism, and macroadenoma were more frequently observed in the younger patients than in the middle‑aged and elderly individuals (all P <0.05). According to our results, hypogonadism and greater IGF‑1 values were more frequently observed in men with acromegaly. Hyperprolactinemia, hypogonadism, and macroadenoma were more frequent in patients with acromegaly aged 40 years or younger.

Investigation of pituitary functions after acute coronavirus disease 2019.

Although coronavirus disease 2019 (COVID-19) mainly involves the lungs, it also affects many systems. The hypothalamic/pituitary axis is vulnerable to hypoxia, hypercoagulation, endothelial dysfunction and autoimmune changes induced by COVID-19 infection. Given that there is no extensive investigation on this issue, we investigated the pituitary functions three to seven months after acute COVID-19 infection. Forty-three patients after diagnosis of COVID-19 infection and 11 healthy volunteers were included in the study. In addition to the basal pituitary hormone levels, growth hormone (GH) and hypothalamo-pituitary adrenal (HPA) axes were evaluated by glucagon stimulation test (GST) and low-dose adrenocorticotropic hormone (ACTH) stimulation test, respectively. The peak cortisol responses to low-dose ACTH test were insufficient in seven (16.2%) patients. Twenty (46.5%) and four (9.3%) patients had inadequate GH and cortisol responses to GST, respectively. Serum insulin-like growth factor-1 (IGF-1) values were also lower than age and sex-matched references in four (9.3%) patients. The peak GH responses to GST were lower in the patient group when compared to the control group. Other abnormalities were mild thyroid-stimulating hormone elevation in four (9.3%) patients, mild prolactin elevation in two (4.6%) patients and central hypogonadism in four (9.3%) patients. Mean total testosterone values were lower in male patients when compared to male controls; however, the difference was not significant. These findings suggest that COVID-19 infection may affect pituitary functions, particularly the HPA and GH axes. These insufficiencies should be kept in mind in post-COVID follow-up. Long-term data are needed to determine whether these deficiencies are permanent or not.