Median GH Research Articles

Robust growth hormone responses to GH-releasing peptide 2 in adolescents.

GH-releasing peptide-2 (GHRP2) can be used for provocative growth hormone testing (GHT). Since it acts as a powerful stimulus for GH secretion, cut-off peak GH level in GHRP2 loading test (GHRP2T) is higher than in other GHT. Nevertheless, data on response at adolescents are limited. This report aimed to investigate peak GH levels in GHRP2T in adolescents. Clinical data of adolescents after onset of puberty who underwent GHRP2T at our institution from May 2010 to March 2023 were collected retrospectively. Subjects were classified into three groups according to underlying diseases. A total of 23 patients were included: 12 in organic or genetic GHD (o/gGHD) group, three in idiopathic GHD (iGHD) group, and eight in short stature (SS) group. The median GH peak levels were 3.4 ng/mL in o/gGHD group, 88.9 ng/mL in iGHD group, and 90.1 ng/mL in SS group, indicating a robust response of GH peak levels in iGHD and SS groups. Two patients exceeded the cut-off for GHRP2T but below for other GHT, indicating the current cut-off for GHRP2T may miss some GHD patients. The GH response to GHRP2T in adolescents except the o/gGHD group may be robustly responsive. For the correct diagnosis of GHD, the cut-off peak GH levels in GHRP2T in adolescents may require revisiting.

Hypoventilation in patients with Prader-Willi syndrome across the pediatric age.

Few data on alveolar hypoventilation in Prader-Willi syndrome (PWS) are available and the respiratory follow-up of these patients is not standardized. The objectives of this study were to evaluate the prevalence of alveolar hypoventilation in children with PWS and identify potential risk factors. This retrospective study included children with PWS recorded by polysomnography (PSG) with transcutaneous carbon dioxide pressure (PtcCO2) or end-tidal CO2 (ETCO2) measurements, between 2007 and 2021, in a tertiary hospital center. The primary outcome was the presence of alveolar hypoventilation defined as partial pressure of carbon dioxide (pCO2) ≥ 50 mmHg during ≥2% of total sleep time (TST) or more than five consecutive minutes. Among the 57 included children (38 boys, median age 4.8 years, range 0.1-15.6, 60% treated with growth hormone [GH], 37% obese), 19 (33%) had moderate-to-severe obstructive sleep apnea syndrome (defined as obstructive apnea-hypopnea index ≥5/h) and 20 (35%) had hypoventilation. The median (range) pCO2 max was 49 mmHg (38-69). Among the children with hypoventilation, 25% were asymptomatic. Median age and GH treatment were significantly higher in children with hypoventilation compared to those without. There was no significant difference in terms of sex, BMI, obstructive or central apnea-hypopnea index between both groups. The frequency of alveolar hypoventilation in children and adolescents with PWS is of concern and may increase with age and GH treatment. A regular screening by oximetry-capnography appears to be indicated whatever the sex, BMI, and rate of obstructive or central apneas.

THU172 Accuracy Of The Glucagon Testing In The Diagnosis Of Growth Hormone Deficiency During Transition

Abstract Disclosure: N. Di Iorgi: None. D. Guglielmi: None. N. Flavia: None. A. Allegri: None. D. Fava: None. E. Casalini: None. G. Patti: None. M. Maghnie: None. Objectives: To evaluate the accuracy of the Glucagon test (GST) compared with the Insulin Tolerance test (ITT) as the gold standard in the diagnosis of Growth Hormone deficiency (GHD) in young adults with childhood-onset GHD (COGHD). Methods: Eighty-six subjects with COGHD (33F, 55M) were evaluated by ITT and GST stimulation tests and IGF-1 SDS at adult height achievement (median age of 17.5; IQR 13.9-18.4 years). Subjects were recruited from a single Center and based on the AACE 2019 Guidelines [1] classified as 1. idiopathic isolated GHD (I-GHD n=40 with normal brain MRI); 2. organic moderate GHD (omGHD with less than 3 pituitary deficiencies-PD and IGF-1<0 SDS, total n=40; n=12 midline defects, n=2 ALL, n=26 CNS tumors); 3. congenital/genetic defects/organic severe GHD (osGHD ≥3 PD and IGF-1 <-2 SDS, total n=6; n=1 midline defect, n=5 CNS tumors). ROC analyses were performed in order to analyze the Sensitivity (Se) and Specificity (Sp) of the GH peak after GST and of IGF-1 SDS compared to ITT. A peak GH value <6μg/L after ITT was suggestive of permanent GHD [2]. Results: Median GH peak to ITT (0.2; IQR 0.01-0.7 μg/L) and GST (0.1; IQR 0.01-1.4μg/L) were lower in osGHD compared to I-GHD subjects (15.0; IQR 8.6-21.9 to ITT and 12.6; IQR 10.5-18.8 μg/L to GST, P’s <0.0001); similarly, GH peak to ITT (2.1; IQR 1.1-6.8 μg/L) and GL (2.7; IQR 1.2-5.8) were lower in omGHD compared to I-GHD subjects (P’s <0.0001). Mean IGF-1 were also lower in osGHD (-3.2 SDS; IQR -7.4- -2.9, P<0.0001) and in omGHD (-2.0 SDS; IQR -2.8 - -0.7; P<0.0001) compared to I-GHD subjects (0,1; IQR -0.6-1.1SDS). A GH peak value to GST of 7.59 mcg/L (Se 92.3%, Sp of 87.2%; AUC=0.94; 95% CI, 0.89-0.99) correctly classified 89.5% of the entire cohort while an IGF-1 cut-off of -1.45 SDS (Se 73%; Sp 93.5%; AUC=0.84; 95% CI, 0.75 - 0.94) correctly classified 83,1%. A GH peak value to GST of 5.81 mcg/L (Se 96.6%, Sp of 81.8%; AUC=0.95; 95% CI, 0.88-1.02) correctly classified 92.5% of omGHD patients while an IGF-1 cut-off of -1.64 SDS (Se 72.3%, Sp of 90.9%; AUC=0.94; 95% CI, 0.89-0.99) correctly classified 77.5% omGHD patients. Median BMI SDS was higher in patients with osGHD (1.8; IQR 1,6- 2.2, P<0.001) and omGHD (0.6; IQR 0.1- 1.8, P<0.001) compared to I-GHD (0.2; IQR -0.7- 1.1). GH peak to GST correlated with BMI SDS only in the total cohort (r -0.313, P=0.0031). Conclusions: Our results suggest that a peak value <6 μg/L after GST is accurate in detecting permanent GHD during transition in a cohort of patients with organic GHD with less than 3 pituitary defects and IGF-1 values <0 SDS; the GH response to GST could be affected by BMI SDS, but further studies are needed. [1] Yuen KCJ et al. Endocr Pract 2019; 25 (11):1191-1232. [2] Maghnie M et al, EJE 2005; 152:589-596. Presentation: Thursday, June 15, 2023

Long-term effects of GH therapy in adult patients with Prader-Willi syndrome: a longitudinal study.

Prader-Willi syndrome (PWS) is a complex disorder resulting from the failure of expression of paternal alleles in the PWS region of chromosome 15. The PWS phenotype resembles that observed in the classic non-PWS GH deficiency (GHD), including short stature, excessive fat mass, and reduced muscle mass. To date, a small number of studies on the long-term effects of GH treatment are available in adult subjects with PWS. In this longitudinal study, 12 obese subjects with PWS (GHD/non-GHD 6/6) were treated for a median of 17 years, with a median GH dose of 0.35 mg/day. The median age was 27.1 years. Anthropometric, body composition, hormonal, biochemical, and blood pressure variables were analyzed in all subjects. Waist circumference was significantly lower at the end of the treatment period (p-value=0.0449), while body mass index (BMI) did not differ significantly. Compared to the baseline, a highly significant reduction of Fat Mass % (FM%) was observed (p-value=0.0005). IGF-I SDS values significantly increased during GH therapy (p-value=0.0005). A slight impairment of glucose homeostasis was observed after GH therapy, with an increase in the median fasting glucose levels, while insulin, HOMA-IR, and HbA1c values remained unchanged. Considering GH secretory status, both subjects with and without GHD showed a significant increase in IGF-I SDS and a reduction of FM% after GH therapy (p-value= 0.0313 for all). Our results indicate that long-term GH treatment has beneficial effects on body composition and body fat distribution in adults with PWS associated with obesity. However, the increase in glucose values during GH therapy should be considered, and continuous surveillance of glucose metabolism is mandatory during long-term GH therapy, especially in subjects with obesity.

Effects of acromegaly treatment on left ventricular systolic function assessed by speckle tracking echocardiography in relation to sex differences: results from a prospective single center study.

Despite the preserved LVEF, patients with acromegaly are characterized by subclinical systolic dysfunction i.e., abnormal global longitudinal strain (GLS) assessed by speckle tracking echocardiography (STE). The effect of acromegaly treatment on LV systolic function assessed by STE, has not been evaluated so far. Thirty-two naïve acromegalic patients without detectable heart disease were enrolled in a prospective, single-center study. 2D-Echocardiography and STE were performed at diagnosis, 3&6 months on preoperative somatostatin receptor ligand (SRL) treatment and 3 months after transsphenoidal surgery (TSS). Treatment with SRL resulted in reduction in median (IQR) GH&IGF-1 levels after 3 months, from 9.1(3.2-21.9) to 1.8(0.9-5.2) ng/mL (p<0.001) and from 3.2(2.3-4.3) to 1.5(1.1-2.5) xULN (p<0.001), respectively. Biochemical control on SRL was achieved in 25.8% of patients after 6 months and complete surgical remission was achieved in 41.7% of patients. TSS resulted in decrease in median (IQR) IGF-1 compared to IGF-1 levels on SRL treatment: from 1.5(1.2-2.5) to 1.3(1.0-1.6) xULN (p=0.003). Females had lower IGF-1 levels at baseline, on SRL and after TSS compared to males. The median end diastolic and end systolic left ventricle volumes were normal. Almost half of the patients (46.9%) had increased LVMi, however the median value of LVMi was normal in both sex groups: 99g/m2 in males and 94g/m2 in females. Most patients (78.1%) had increased LAVi and the median value was 41.8mL/m2. At baseline 50% of patients, mostly men (62.5% vs. 37.5%) had GLS values higher than -20%. There was a positive correlation between baseline GLS and BMI r=0.446 (p=0.011) and BSA r=0.411 (p=0.019). The median GLS significantly improved after 3 months of SRL treatment compared to baseline: -20.4% vs. -20.0% (p=0.045). The median GLS was lower in patients with surgical remission compared to patients with elevated GH&IGF-1 levels: -22.5% vs. -19.8% (p=0.029). There was a positive correlation between GLS and IGF-1 levels after TSS r=0.570 (p=0.007). The greatest beneficial effect of acromegaly treatment on LV systolic function is visible already after 3 months of preoperative SRL treatment, especially in women. Patients with surgical remission have better GLS compared to patients with persistent acromegaly.

Giant growth hormone-secreting pituitary adenomas from the endocrinologist's perspective.

Since giant (≥40 mm) GH-secreting pituitary adenomas are rarely encountered, data on their characteristics and treatment outcomes are limited. We aimed to investigate the characteristics of giant GH-secreting pituitary adenomas and to compare their clinical, biochemical, imaging and histopathological features with non-giant macroadenomas. We have evaluated 15 (six female/nine male) and 57 (29 female/28 male) patients with acromegaly in giant and <40 mm adenoma groups, respectively. Patients with <40 mm adenoma were further divided into subgroups with adenoma size 20-29 mm and 30-39 mm. In giant adenoma group, median (IQR) preoperative maximal diameter of adenoma was 40 mm (5 mm), median preoperative GH level was 40 (153.4) ng/mL and median baseline IGF-1 level was 2.19 (1.88) × ULN for age and sex. The number of surgeries was significantly higher in giant adenoma group (median 2, IQR 2) in which 66.7% of patients underwent repeated surgeries (p = 0.014). Residual tumor was detected after last operation in all patients with giant adenoma. Total number of treatment modalities administered postoperatively increased as adenoma size increased (p = 0.043). After a median follow-up duration of 10 years (IQR 10), hormonal remission was achieved in six patients (40%) of giant adenoma group, while the rate of hormonal remission in non-giant adenoma group was 37%. Although preoperative GH and IGF-1 levels and Ki-67 index tended to be higher with increasing adenoma size, there was no statistically significant difference between groups in terms of these variables, as well as age, sex and invasion status. Hormonal remission rates of acromegaly patients with ≥20 mm pituitary macroadenoma were comparable. However, giant GH-secreting pituitary adenomas require an aggressive multimodal treatment approach.

Clinical, hormonal and pathomorphological markers of somatotroph pituitary neuroendocrine tumors predicting the treatment outcome in acromegaly.

BackgroundTranssphenoidal adenomectomy (TSS) of somatotroph pituitary neuroendocrine tumor (PitNET) is the first-line treatment of acromegaly. Pharmacological treatment is recommended if surgery is contraindicated or did not lead to disease remission. The choice of treatment best fitting each patient should be based on thorough investigation of patients’ characteristics. The current analysis attempts to create a tool for personalized treatment planning.AimThis study aimed to assess whether clinical, biochemical, imaging and pathological characteristics can predict surgical remission and response to first-generation somatostatin receptor ligands (SRLs) and pasireotide-LAR in acromegaly.Patients and methodsA retrospective study of 153 acromegaly patients, treated in the Department of Endocrinology in Bielanski Hospital in Warsaw, Poland was performed. Data on demographics, hormonal and imaging results, pathological evaluation, and treatment outcome was extracted from the Polish Acromegaly Registry collecting information from 11 endocrinology centers in Poland and analyzed.ResultsPatients with surgical remission had lower GH and IGF-1 concentrations at diagnosis (median GH 5.5 µg/L [IQR: 3.1-16.0] vs. 19.9 µg/L [IQR: 9.8-42.4], p=<0.001 and mean IGF-1 3.1xULN ± SD=1.2 vs. 3.7xULN ± SD=1.2, p=0.007, respectively) and smaller tumors (median 12.5mm [IQR: 9-19] vs. 23mm [IQR: 18-30], p<0.001). These tumors were more often densely granulated (DG) (73.2% vs. 40.0%, p=0.001) with positive staining for alpha-subunit (α-SU) (58.3% vs. 35.5%, p=0.021) and lower Ki-67 index (p=0.002). Patients responding well to SRLs were more often male (55.6% vs 44.4%, p=0.026), presented lower GH concentration (median GH 17.2 µg/L [IQR: 6.2-29.0] vs. 23.8 µg/L [IQR: 11.2-49.5], p=0.048) and had more often DG tumors (63.0% vs. 14.3%, p<0.001). No significant differences between good and poor-response to pasireotide-LAR groups were found. In multivariate logistic regression analysis fasting GH concentration <8.63 µg/L, maximal tumor diameter <15.5mm, normoprolactinemia and DG tumor turned out to be independent predictors of surgical remission (OR=0.92, p=0.026; OR=0.87, p=0.069, OR=3.86, p=0.096 and OR=3.05, p=0.181, respectively). Fasting GH concentration <36.6 µg/L and DG tumor turned out to be independent predictors of good response to first-generation SRLs (OR=0.96, p=0.06 and OR=10.68, p=0.002, respectively).ConclusionsYounger age at diagnosis, male sex, lower GH, IGF-1 and PRL concentrations, smaller tumor size at diagnosis as well as positive α-SU staining, lower Ki-67 index and DG tumors predicted better treatment outcome in acromegaly patients.

"I would have to sell things in order to get the money": A qualitative exploration of willingness to pay for the RTS,S/AS01 malaria vaccine in the Volta region, Ghana.

BackgroundMalaria morbidity and mortality remain a challenge in Ghana. A promising childhood vaccine is being piloted in Ghana, however with the loss of its low-income status, Ghana is losing associated donor co-funding. User fees have been considered an alternative financing method, so this study utilised qualitative methods and explored caregivers’ willingness to pay for the malaria vaccine (RTS,S/AS01) to inform future service provision.MethodsThe study design was cross-sectional. Twenty in-depth interviews were conducted between February 2020 and March 2020 amongst a purposive sample of caregivers of RTS,S/AS01 eligible children, in the Volta region, Ghana. Interviews were audio-recorded and transcribed into English Language. Thematic analysis followed, using NVIVO12 to organise this data.ResultsCaregivers could distinguish between RTS,S/AS01 and routine vaccines and were willing to pay median GH₵5 (US$0.94), interquartile range GH₵3.75–5 (US$0.71–0.94) per dose of RTS,S/AS01. The maximum amount participants were willing to pay per dose was GH₵10 (US$1.88), interquartile range GH₵6–10 (US$1.13–1.88). Caregivers mentioned that they would work more to cover this cost because they were happy with services rendered to them during the RTS,S/AS01 pilot phase, and preferred vaccines over vector control measures. The results suggest that a willingness to pay was based on beliefs that the vaccine is fully effective. Although no participant declared that they would be unwilling to pay hypothetical user fees, there were still widespread concerns about affordability, with the majority feeling that the government should be responsible to pay for RTS,S/AS01.ConclusionsParticipants expressed a willingness to pay due to an appreciation of vaccines, shaped by personal experiences with immunisations and disease. Participants’ average income was lower than the national average, potentially affecting the perceived affordability of RTS,S/AS01. Because of the belief that RTS,S/AS01 is fully effective, caregivers may pay less attention to other preventative measures, thus unintentionally undermining malaria vector control.

Diagnosis of severe growth hormone deficiency in the newborn

OBJECTIVE Severe neonatal growth hormone deficiency (GHD) can cause recurrent hypoglycaemia. Early diagnosis is warranted. The aim of the study was to analyse the GH content in screening cards of 25 affected and 281 healthy newborns. PATIENTS AND MEASUREMENTS A total of 110 screening cards from ill newborns were sent to us for measuring GH content by a highly sensitive GH ELISA. Clinical information was obtainable in 61 cases. Severe GHD was defined by the presence of recurrent hypoglycaemia with a significant pituitary malformation or two additional pituitary hormone deficiencies. Screening cards from 281 healthy newborns (34.0-37.9 weeks) were prospectively analysed. RESULTS In 25 newborns (5 preterm), the definition of severe GHD was fulfilled based on recurrent hypoglycaemia in combination with malformation of the pituitary or midline structures in 21 cases and combined TSH and ACTH deficiency in four cases. The median GH concentration of those affected with severe GHD was 3.9 µg/L (range: 1.1-11.8), significantly below the previously reported reference range (P < .001). A GH concentration of 7 µg/L was confirmed as the cut-off for term newborns with the best accuracy (90.0% sensitivity and 98.7% specificity). The 95% reference range for healthy preterm newborns (n = 151) was 7.6-47.1 µg/L (median: 20.3 µg/L). CONCLUSIONS A GH content <7.0 µg/L in the newborn screening card confirms severe GHD with high accuracy. In preterm newborns, the lower limit of the reference interval was 0.6 µg/L higher than in term newborns. The newborn screening card is a valuable source for the very early diagnosis of GH deficiency.

The therapeutic response of somatotropinomas according to the T2-weighted signal intensity on the MRI.

Identifying the predictive factors of tumoral and hormonal answer of somatotropinomas to the medical treatment with somatostatin analogs represent an important element for treatment management. The aim of this study was to assess the therapeutic answer of the somatotropinomas according to the T2-weighted signal intensity on the MRI. We included 31 acromegalic patients, mean age 51.35 ± 10.37 years, who underwent surgery. The patients were divided according to the T2-weighted MRI signal intensity - hypointense, hyperintense and isointense - of the GH-secreting pituitary adenoma and were evaluated after surgery, 3, 6 and 12 months with somatostatin analogs therapy. 16 (51.61%) somatropinomas were hypointense, 9 (29.03%) were hyperintense and 6 (19.35%) were isointense. The median IGF-1 and GH level decreased significantly in macroadenomas (p<0.001, p<0.001, respectively), whereas GH decreased significantly only in microadenomas (p=0.010). A significant statistical correlation was found between IGF-1 or GH levels and tumor volume before surgery (Spearman=0.38, p<0.001; Spearman=0.64, p<0.001, respectively) and after surgery (Spearman=0.61, p=0.001; Spearman=0.74, p<0.001). The percentage of optimally controlled patients increased from 12.9% after surgery, to 28.57% after 12 months with somatostatin analogs. The highest percentage of optimally controlled patients with somatostatin analogs treatment was in hypointense somatotropinomas (50%). The T2-weighted MRI signal intensity classifies the somatotropinomas into groups with certain evolutive and medical treatment response particularities, of which we found that the hypointense somatotropinomas have a better therapeutic response after surgery and after long-term treatment with somatostatin analogs.

GH Receptor Exon 3 Genotype and Echocardiographic Abnormalities in Patients With Active Acromegaly

Background: The GH receptor (GHR) exon 3 polymorphism occurs at a genomic level. Approximately 50-60% of the population is homozygous for the exon-3 containing genotype (+3/+3), 30-40% are heterozygous (+3/-3) and 10-20% are homozygous for the exon-3 lacking genotype (-3/-3). Some studies suggest that children homo- and heterozygous for the GHR exon 3 lacking genotype (-more efficient 3/-3 and +3/-3, respectively) respond better to treatment with exogenous rhGH and there is also in vitro evidence showing a more efficient signal transduction through this exon 3 deleted isoform. Some studies have found that patients with acromegaly harboring the exon 3-deleted genotype may have a higher prevalence of diabetes and hypertension. Hypothesis and Objective: Patients with active acromegaly harboring the exon 3-lacking GHR genotype may have more echocardiographic abnormalities than those who are homozygous for the exon 3 containing genotype. Patients and Methods: This is a cross-sectional study of patients with active acromegaly, defined by an IGF-1 level > 1.3 times the upper limit of normal (x ULN), who underwent transthoracic echocardiography. Exon-3 GHR genotype was determined by PCR using previously described sense and antisense primers. Results: The cohort consisted of 28 patients, 54% female, with a mean age of 51 ± 12 years. Mean disease duration at the time of echocardiographic examination was 4.48 ± 4.7 years; median basal GH and IGF-1 were 12 ± 26 ng/mL and 2.4 ± 1.04 x ULN. The prevalence of hypertension and diabetes were 43% and 36%, respectively. Fifty three percent of the patients were homozygous for the exon 3-containaing genotype (+3/+3), 18% were homozygous for the exon 3-lacking genotype (-3/-3) and 29% were heterozygous (+3/-3). Clinical and biochemical features did not differ between patients with the different GHR genotypes, except for hypertension that was more prevalent in the +3/+3 genotype group (60% vs 23%, p= 0.04). The frequency of the different echocardiographic parameters was similar among groups (left ventricular hypertrophy 33% vs 15%, p= 0.27; diastolic dysfunction 47% vs 31%, p= 0.39; subclinical systolic dysfunction 42% vs 54%, p= 0.54; left ventricular ejection fraction 59±10% vs 60±16%, p= 0.83); aortic valve abnormalities 19% vs 15%, p=0.63; mitral valve abnormalities 46% vs 15%, p=0.07). Conclusions: Echocardiographic abnormalities in patients with active acromegaly do not differ among patients with the different GHR exon 3 genotypes. The clinical spectrum of acromegaly varies considerably. Although such variability is usually related to the severity of the hypersomatotropinemia, in many patients this is not the case.

Genetic spectrum and predictors of mutations in four known genes in Asian Indian patients with growth hormone deficiency and orthotopic posterior pituitary: an emphasis on regional genetic diversity.

Regional variation in prevalence of genetic mutations in growth hormone deficiency (GHD) is known. Study phenotype and prevalence of mutations in GH1, GHRHR, POU1F1, PROP1 genes in GHD cohort. One hundred and two patients {Isolated GHD (IGHD): 79; combined pituitary hormone deficiency (CPHD): 23} with orthotopic posterior pituitary were included. Auxologic, hormonal and radiological details were studied. All four genes were analysed in IGHD patients. POU1F1 and PROP1 were studied in CPHD patients. Of 102, 19.6% were familial cases. Height SDS, mean (SD) was - 5.14 (1.63). Peak GH, median (range) was 0.47ng/ml (0-6.59), 72.5% patients had anterior pituitary hypoplasia (APH). Twenty mutations (novel: 11) were found in 43.1% patients (n = 44, IGHD-36, CPHD-8). GHRHR mutations (n = 32, p.Glu72* = 24) were more common than GH1 mutations (n = 4) in IGHD cohort. POU1F1 mutations (n = 6) were more common than PROP1 mutations (n = 2) in CPHD cohort. With few exceptions, this prevalence pattern is contrary to most studies in world-literature. No patients with peak GH > 4ng/ml had mutations, signifying it as negative predictor. While many parameters were significant on univariate analysis, only positive family history and lower median peak GH levels were significant predictors of mutations on multivariate analysis in IGHD patients. At variance with world literature, we found reverse predominance of GHRHR over GH1 mutations, POU1F1 over PROP1 mutations and predominance of GHRHR p.Glu72* mutations thus re-affirming the regional diversity in GHD genetics. We report positive and negative predictors of mutations in GHD.

Diagnosis of severe growth hormone deficiency in the newborn.

Severe neonatal growth hormone deficiency (GHD) can cause recurrent hypoglycaemia. Early diagnosis is warranted. The aim of the study was to analyse the GH content in screening cards of 25 affected and 281 healthy newborns. A total of 110 screening cards from ill newborns were sent to us for measuring GH content by a highly sensitive GH ELISA. Clinical information was obtainable in 61 cases. Severe GHD was defined by the presence of recurrent hypoglycaemia with a significant pituitary malformation or two additional pituitary hormone deficiencies. Screening cards from 281 healthy newborns (34.0-37.9weeks) were prospectively analysed. In 25 newborns (5 preterm), the definition of severe GHD was fulfilled based on recurrent hypoglycaemia in combination with malformation of the pituitary or midline structures in 21 cases and combined TSH and ACTH deficiency in four cases. The median GH concentration of those affected with severe GHD was 3.9µg/L (range: 1.1-11.8), significantly below the previously reported reference range (P<.001). A GH concentration of 7µg/L was confirmed as the cut-off for term newborns with the best accuracy (90.0% sensitivity and 98.7% specificity). The 95% reference range for healthy preterm newborns (n=151) was 7.6-47.1µg/L (median: 20.3µg/L). A GH content <7.0µg/L in the newborn screening card confirms severe GHD with high accuracy. In preterm newborns, the lower limit of the reference interval was 0.6µg/L higher than in term newborns. The newborn screening card is a valuable source for the very early diagnosis of GH deficiency.

OR10-02 Diagnosis of Severe GH Deficiency in Newborns: New Reference Range for the Preterm and Confirmation of the GH Cut-Off

IntroductionInborn severe GHD is caused by rare disorders of pituitary morphogenesis or function and frequently associated with additional pituitary hormone deficiencies. Affected newborns commonly present with recurrent hypoglycemia; therefore early diagnosis and therapy is warranted. The GH content of the newborn screening card is a reliable indicator of severe neonatal GHD. Here, we studied the GH content in screening cards and the history of 25 newborns with severe GHD. In addition, we determined the reference range of the GH content in screening cards from 282 healthy preterm newborns.Patients and MethodsSince 2010, a total of 110 screening cards from hospitalized ill newborns were sent to our laboratory for measuring GH content. Using a questionnaire we obtained relevant clinical information from senders in 61 cases. Severe GHD was defined by the presence of recurrent neonatal hypoglycemia with either a significant cerebral MRI morphology or two additional pituitary hormone deficiencies. In addition, the GH content of screening cards from 282 healthy newborns born preterm with a gestational age at birth from 34.0 to 37.9 weeks was prospectively analyzed. The GH concentration of the eluate from the screening card was measured by a highly sensitive ELISA (Mediagnost, Germany); the GH serum concentration was calculated.ResultsIn 25 patients, the definition of severe GHD of the newborn was fulfilled; based on recurrent hypoglycemia in combination with ectopia of the neurohypophysis in 17, septum pellucidum agenesis plus opticus hypoplasia in two, severely hypoplastic pituitary gland in two, and combined TSH and ACTH deficiency with no cMRI findings in four newborns. Five newborns with severe GHD were preterm. The median GH concentration of the term newborns with severe GHD (n=20) was 3.9 µg/l (range; 1.1 to 11.8). This was significantly below the previously reported reference data from healthy term newborns (n=269) (median 16.4 µg/l; 95% reference range 7.0 to 39.4) (p<0.001). Using ROC plot analysis a GH serum concentration of 7.0 µg/l was identified as cut-off with the highest accuracy (90.0% sensitivity and 98.7% specificity). The median GH concentration of the 5 preterm newborns with severe GHD was 7.7 µg/l (range; 2.1 to 9.9). The newly determined 95% reference range for healthy newborns born preterm with a gestational age from 34.0 to 37.9 weeks (n=282) spanned from 7.9 to 41.1 µg/l with a median of 20.3 µg/l.ConclusionsA GH content below 7.0 ng/ml in the newborn screening card identified severe GHD with 90% sensitivity and 98.7% specificity. In preterm newborns, the lower limit of the 95% reference interval was by 0.9 µg/l higher than in term newborns. The newborn screening card is a valuable source for the diagnosis of GH deficiency in newborns and young infants.

Increased Serum Sclerostin Levels in Patients With Active Acromegaly.

Bone mineral density is normal in acromegalic patients and the cause of increased fracture risk that characterizes active acromegaly is unknown. This study compared serum sclerostin levels between patients with active acromegaly and healthy individuals. The serum sclerostin levels of patients with active acromegaly were compared with those of healthy volunteers in a cross-sectional study. The mean age of the 30 acromegaly patients (male/female: 14/16) was 47.26 ± 12.52 years (range, 18-64 years) and that of the healthy volunteers (male/female: 17/13) was 44.56 ± 10.74 years (range, 19-62 years). IGF-1 and GH levels were measured using an electrochemiluminescence method, and serum sclerostin levels using an ELISA. The Mann-Whitney U test was used to compare sclerostin levels between the 2 groups. The correlations of sclerostin level with IGF-1 and GH were determined using Spearman's test. The 2 groups did not differ in age or sex (P > 0.05). The median GH and IGF-1 levels in the patient group were 2.49 ng/mL (range, 0.22-70.00 ng/mL) (interquartile range [IQR], 1.3-4.52) and 338.5 ng/mL (range, 147-911 ng/mL) (IQR, 250-426), respectively. The median GH and IGF-1 levels in the control group were 0.95 ng/mL (range, 0.3-2.3) and 144 ng/mL (range, 98-198), respectively. The median sclerostin level was 29.95 ng/mL (range, 7.5-78.1 ng/mL) (IQR, 14.37-37.47) in the acromegaly group and 22.44 ng/mL (range, 8.45-36.44 ng/mL) (IQR, 13.71-27.52) in the control group (P < 0.05). There was a moderate positive correlation between the sclerostin and IGF-1 levels (rho = 0.54; P < 0.01), and between the sclerostin and GH levels (rho = 0.41; P < 0.05). High sclerostin levels may contribute to the increased fracture risk seen in patients with acromegaly.

Gender differences and temporal trends over two decades in acromegaly: a single center study in 112 patients.

To evaluate the impact of gender and year at surgery on clinical presentation and postoperative outcomes in acromegaly. Retrospective review of patients operated between 1994 and 2016 to compare presentation and outcomes in groups defined by gender and year of surgery. Kaplan-Meier survival analyses with a composite endpoint (recurrence, reoperation, and radiation) were used for gender comparison and Youden indices for biochemical remission rates changes during study period. Primary indications for evaluation were phenotype, neurological symptoms, incidentaloma, hypogonadism, and galactorrhea. At surgery, men (N = 54) were younger (43.6 ± 12.7 years) than women (N = 58, 48.7 ± 12.3, P = 0.04). Male:female ratios before and after age 50 were 1.4 and 0.6 respectively. Men had higher mean IGF-1 levels (874 ± 328 vs 716 ± 296, P < 0.01) and smaller tumors (1.8 ± 1.3 cm vs 2.3 ± 1.5, P = 0.04). Postoperative remission rates were comparable (51% men, 56% women) and inversely associated with cavernous sinus invasion and GH levels. Women had longer mean follow-up (5.2 ± 3.4 years vs 3.6 ± 3.6 men, P = 0.02) and longer endpoint-free survival (P < 0.01). At last follow-up, 89.6% women and 70% men had normal IGF-1 levels (P = 0.03). Postoperative remission rates were higher in patients operated after February 15, 2011 (67.35 vs 43.5% previously, P = 0.01). In late vs early surgery group, physical changes as main indication for screening decreased (54 vs 30%, P < 0.01), while incidentaloma and hypogonadism increased. Median GH levels were lower in late vs early surgery group (P = 0.03). We demonstrate gender-specific characteristics and an evolving spectrum of clinical presentation with implications for earlier diagnosis and personalized management of acromegaly.

IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction.

ContextThe X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition.ObjectiveWe aimed to evaluate the role of IGSF1 in human and murine somatotrope function.Patients, Design, and SettingWe evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting.Main Outcome MeasuresWe compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates.ResultsIGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels.ConclusionsWe demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.

SUN-LB074 Racial Distribution, Presentation and Outcome in Acromegaly and Cushing's Disease: A Tertiary Referral Center Study in 220 Patients

Background: Transsphenoidal surgery (TSS) is the primary therapy for acromegaly (ACM) and Cushing’s disease (CD) with superior outcomes at high-volume centers. According to the U.S. Central Brain Tumor Registry, African Americans (AA) have higher incidence of pituitary adenomas than non-Hispanic white (W) patients, but race-specific data in ACM and CD are not available. Our aims are to evaluate racial distribution, presentation, and long-term outcomes of adult patients who underwent TSS for these conditions at our pituitary center by a single dedicated neurosurgeon. Methods: We reviewed all cases of TSS operated between 1994-2016 and compared presentation and postoperative events (biochemical remission, recurrence, reoperation, radiation, and death) across racial demographic groups. For patients living in Metropolitan Atlanta, we used U.S. Census data to compare patient racial distribution to the demographics. Results The ACM group consisted of 112 patients (54 men and 58 women), of whom 87 were W and 13 AA. Age and gender were similar in AA and W. Main reasons for referral were physical changes (23% AA vs 44% W), headaches (38% AA vs 17% W), and pituitary incidentaloma (31% AA vs 14% W). AA had higher rates of diabetes (54% vs 16%, p 0.005) and hypertension (69% vs 42% p 0.08), lower mean IGF-1 levels (662±324 ng/ml vs 823±321 ng/ml, p 0.06), and lower median GH levels (8.6. vs 45 ng/ml p 0.002). Mean tumor diameter and cavernous sinus invasion were similar. Biochemical remission at 3 months (46% AA and 55% W) and event-free survival during follow-up (median 3.8 years) were similar in AA and W. Normal IGF-1 at last follow-up was achieved by 92% AA and 80%W after multimodality therapy. The CD group consisted of 108 patients (15 men and 93 women) of whom 70 were W and 24 AA. Age, gender, and prevalence of diabetes and hypertension were similar in AA and W. Mean urinary cortisol and ACTH levels were similar. Mean tumor diameter was similar but AA had more macroadenomas (33% AA vs 14% W). During follow-up (median 4.3 years), event-free survival was similar although AA had fewer recurrences (4.35% vs 22.0% W, p 0.06). Of the total 220 operated patients, 88% lived in Georgia and 59% in Metropolitan Atlanta. In the latter group, W represented 75% of ACM and 62% of CD patients; AA 16% ACM and 28% CD; Hispanics (H) 0% ACM and 6.5% CD; Asian 8.2% ACM and 3% CD. Census racial distribution during study period was 58-67% W, 33-34% AA, 7-10% H, and 3-5% Asians. Conclusions To our knowledge, this is the first report of race-specific patient characteristics in CD and ACM. Proportion of AA and H with ACM operated at our tertiary referral center was lower than expected, while such disparity was not seen in CD. In addition AA with ACM exhibited different clinical presentations and milder biochemical activity. Notably, the long-term outcomes of patients with ACM and CD treated at our center were similar in AA and W. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

SAT-436 Adjuvant Therapeutic Modalities in Acromegaly: Clinical Course and Factors Predicting Biochemical Controls

Background Although surgical resection is the first line therapy for acromegaly, many patients do not achieve biochemical remission after surgery and require the adjuvant therapy including medical treatment (somatostatin analogues; SSA, GH antagonist, and dopamine agonist), conventional radiotherapy, and gamma-knife surgery (GKS). Due to the limitations of rare disease, there are few studies evaluating the efficacy of each adjuvant treatment. In this study, we investigated clinical course and disease control after initiation of adjuvant treatment. Method We performed a single-center retrospective study including acromegalic patients treated with SSA at least for 6 months from January 1, 2005 to June 30, 2018. Age, gender, fasting GH, IGF-1 levels, 75 g oral glucose tolerance tests and tumor size were measured before/after operation, medical treatments, or radiotherapy. The patients were considered biochemically controlled/cured if fasting mean GH levels were less than 2.5ng/ml or nadir GH after oral glucose loading was less than 1 ng/ml together with age- and sex-matched normalized IGF-1. Result We analyzed 72 patients for median 62.9 months (40.0-111.5). The median age was 46 (37-53) years. The median duration of SSA use was 31.5 months (12.6-53.0). The median GH level was 30.5 (17.6-47.3) ng/ml, IGF-1 was 694.7 (600.0-862.8) ng/ml, initial tumor size was 24 (17.2-32.2) mm. Of 72 patients, 59 patients (81%) underwent surgical resection and 40 patients (55.6%) underwent GKS. Of the 40 patients who underwent GKS, 16 (40%) discontinued the medication after 26 (10.3-35.2) months. After treatment, 54 patients (75%) were biochemically controlled. Before initiation of SSA treatment, biochemically controlled group had significantly lower GH (3.63 vs 15.35ng/ml, p<0.001), IGF-1 (514.0 vs 641.9ng/ml, p=0.005), nadir GH after oral glucose loading (2.66 vs 7.9ng/ml, p<0.001) and basal glucose level (94.5 vs 104.5g/ml, p=0.098) than non-controlled group. There was no significant difference in tumor size and Hardy classification between biochemically controlled group and non-controlled group. Among the enrolled patients, 34 subjects (52.3%) had a size reduction of more than 10%. A group with a decrease in tumor size by more than 10% had a smaller initial tumor size (20.0 vs 29.5mm, p<0.001) and lower GH level (3.30 vs. 5.05 ng/ml, p=0.033). There was no significant difference in IGF-1, nadir GH, and basal glucose level. Conclusion In conclusion, basal GH level and presence of visible remnant tumor was correlated with biochemical response after adjuvant treatment. Appropriate adjuvant treatment should be decided according to the disease status of acromegalic patients.

Perineal Body and Genital Hiatus in the Third Trimester and Risk of Perineal Laceration.

We aimed to determine whether pelvic organ prolapse quantification measurements of genital hiatus (gh) or perineal body (pb) obtained in the late third trimester are predictors of obstetric perineal laceration in nulliparous women. Nulliparous women with singleton gestation were prospectively recruited after 35-week gestation, and gh and pb measurements were obtained. After delivery, determination of the presence and degree of perineal laceration were recorded. Correlation of gh and pb measurements with risk of perineal laceration (defined as second, third, or fourth degree) was assessed using the Wilcoxon rank sum test. We recruited 224 patients and 133 met inclusion criteria after delivery. The mean (SD) age was 27.2 (4.0) years and mean (SD) prepregnancy body mass index was 24.1 (4.6) kg/m. Seventy patients (52.6%) had either a second-degree (n = 64) or third-degree (n = 6) laceration. No fourth-degree lacerations were recorded. We found no significant difference in the median gh (3.5 vs 3.0 cm, P = 0.34) and pb (3.5 vs 3.5 cm, P = 0.54) measurements among women with and without perineal lacerations. Our data suggest that antenatal measurement of gh and pb does not correlate with the risk of obstetric perineal laceration in nulliparous patients undergoing spontaneous vaginal delivery.