Mean GH Research Articles

9318 Growth Response To Oral Growth Hormone Secretagogue LUM-201 In Children With Moderate GH Deficiency (GHD) Is Dependent On The Pattern Of Pulsatile GH Secretion Induced By LUM-201

Abstract Disclosure: A. Roslan: None. R. Roman: None. A. Avila: None. D. Said: None. I. Baier: None. E. Brincks: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. A. Bruchey: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. J. McKew: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. P. Pitukcheewanont: Employee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc.. M. Johnson: None. T. Garner: Consulting Fee; Self; Lumos Pharma, Inc.. Grant Recipient; Self; Novo Nordisk. M.O. Thorner: Consulting Fee; Self; Lumos Pharma, Inc.. Stock Owner; Self; Lumos Pharma, Inc. P.E. Clayton: Advisory Board Member; Self; Lumos Pharma, Inc.. Consulting Fee; Self; Lumos Pharma, Inc.. Grant Recipient; Self; Novo Nordisk. A. Stevens: Consulting Fee; Self; Lumos Pharma, Inc. F. Cassorla: Consulting Fee; Self; Lumos Pharma, Inc.. Background: Oral GH secretagogue, LUM-201, increases growth rates in children with moderate GHD in Phase 2 trials (OraGrowtH210 and 212) [ENDO 2023, OR21-06]. GH pulse profiles at baseline (D1) and 6 months (6M) were assessed in OraGrowtH212. This study aims to understand relationships between pulse profiles and growth response to LUM-201. Methods: The OraGrowtH212 trial is being conducted at a single site (Chile). 22 prepubertal children (M 14: F 8) with moderate GHD (peak GH level on two stimulation tests >3 and <10ng/ml), who had basal IGF-I >30ng/ml and an acute GH response to 0.8mg/kg LUM-201 of ≥5ng/ml, were randomised to receive LUM-201 1.6 or 3.2 mg/kg/day. 10min samples over 12hrs (08.00-20.00) were collected at D1 and M6 for measurement of GH concentration (ng/ml), with GH secretion rates (ng/ml/min) derived by deconvolution analysis. A univariate Spearman’s rank correlation matrix was used to screen for relationships (significant at p<0.05) between D1 characteristics, D1 height velocity, 6M annualised height velocity (AHV) and interpulse, pulsatile and total GH secretion at D1 and M6.The pattern of pulsatile GH secretion in the 12hr profile was characterised using Functional Principal Component Analysis (FPCA) - used to explore the dominant modes of variation in functional data, in this case the GH time series. Subjects were grouped into tertiles based on 6M AHV (High [mean 8.9cm/yr], Medium [7.7], and Low [6.7]), and the 12hr profiles were divided into three 4hr intervals. The interquartile range (IQR) for mean GH secretion (representing variation in amount) and principal components [PCs] (variation in pattern) for all subjects in each AHV tertile at D1 and M6 were generated. Results: All GH secretion parameters increased significantly from D1 to M6 (p<0.01). Age was negatively associated with 6m AHV (rs= -0.46), and D1 pulsatile GH secretion was positively associated with D1 AHV (rs = +0.51). However, GH secretion at D1 and M6 was not correlated with 6m AHV. In the FPCA, the difference in IQR for mean GH secretion from D1 to 6M was highest over 0-4hrs for subjects in the high and medium AHV tertiles (5- and 3.3-fold greater respectively compared to the other time intervals), while subjects with low AHV had the highest difference over 8-12hrs (42-fold greater). Using the first PC (which accounts for ∼50% of total variation), the change in IQR was highest over 0-4 and 4-8hrs in the high AHV tertile (3-fold greater compared to other time intervals), over 0-4hrs in the medium tertile (46-fold greater) and over 8-12hrs in the low tertile (3.4-fold greater). Conclusions: Oral LUM-201 stimulates significant increases in GH secretion over 6 months in children with moderate GH deficiency. Complex relationships exist between growth response and both the amount and pattern of GH secretion, with the highest growth responses to LUM-201 associated with the greatest pulsatile activity early in the profile. Presentation: 6/3/2024

Identifying patient-related predictors of permanent growth hormone deficiency.

Isolated childhood growth hormone deficiency (GHD) can persist into adulthood, and re-testing at the transition period is needed to determine whether continued growth hormone therapy is indicated. Here, our objective was to identify predictors of permanent GHD. Retrospective single-centre study of patients with childhood-onset GHD who were re-tested after adult height attainment. Auxological, clinical, laboratory, and MRI data throughout follow-up were collected. We included 101 patients. At GH treatment initiation, age was 8.1 ± 0.4 years, height -2.25 ± 0.8, and BMI -0.27 ± 0.1 SDS. The 29 (28.7%) patients with persistent GHD had lower height SDS (-2.57 ± 0.1 vs. -2.11 ± 0.1, p<0.001) and mean GH peaks (8.4 ± 1.0 vs.13.2 ± 0.5 mIU/L, p<0.001) at GHD diagnosis; at adult height, they had lower IGF1 (232 ± 19.9 vs. 331 ± 9.1 ng/mL, p<0.001) and higher BMI SDS (-0.15 ± 0.27 vs. -0.73 ± 0.13, p<0.005). By multivariate analysis, the best predictive model included height and BMI SDS, both GH peaks, and MRI findings at diagnosis. Patients with height at diagnosis <-3 SDS had a 7.7 (95% IC 1.4-43.1, p=0.02) fold higher risk of persistent GHD after adjustment on BMI SDS. An abnormal pituitary region by MRI was the strongest single predictor (7.2 times, 95% CI 2.7-19.8) and after multivariate analysis adjustment for GH peaks and height SDS at diagnosis, the risk increased to 10.6 (1.8 - 61.3) times. Height <-3 SDS at GHD diagnosis and pituitary MRI abnormalities should lead to a high index of suspicion for persistent GHD.

Long-term Effectiveness and Safety of GH Replacement Therapy in Adults ≥60 Years: Data From NordiNet® IOS and ANSWER.

Effectiveness and safety data on GH replacement therapy (GHRT) in older adults with adult GH deficiency (AGHD) are limited. To compare GHRT safety and clinical outcomes in older (≥60 years and, for some outcomes, ≥75 years) and middle-aged (35-<60 years) patients with AGHD. Ten-year follow-up, real-world data from 2 large noninterventional studies-NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program-were analyzed. GH-naïve and non-naïve patients with AGHD. Norditropin® (somatropin). Outcomes included GH exposure, IGF-I standard deviation scores (SDS), body mass index (BMI), glycated hemoglobin (HbA1c), serious and nonserious adverse reactions (SARs and NSARs, respectively), and serious adverse events (SAEs). Adverse reactions were events with possible/probable causal relationship to GHRT. The effectiveness analysis set comprised 545 middle-aged and 214 older patients (19 aged ≥75 years) from NordiNet® IOS. The full analysis set comprised 1696 middle-aged and 652 older patients (59 aged ≥75 years) from both studies. Mean GH doses were higher in middle-aged vs older patients. For both age groups and sexes, mean IGF-I SDS increased following GHRT, while BMI and HbA1c changes were similar and small.Incidence rate ratios (IRRs) did not differ statistically between older and middle-aged patients for NSARs [IRR (mean, 95% confidence interval) 1.05 (.60; 1.83)] or SARs [.40 (.12; 1.32)]. SAEs were more frequent in older than middle-aged patients [IRR 1.84 (1.29; 2.62)]. Clinical outcomes of GHRT in AGHD were similar in middle-aged and older patients, with no significantly increased risk of GHRT-related adverse reactions in older patients.

Native-tissue pelvic organ prolapse (POP) repair with perineorrhaphy for level III support results in reduced genital hiatus size and improved quality of life in sexually active and inactive patients

Introduction and hypothesisRecent findings address the importance of Level III defects with increased genital hiatus being associated with pelvic organ prolapse (POP), correlated with Level I defects and strongly related to POP recurrence. We hypothesised that concomitant perineorrhaphy in POP repair reduces genital hiatus (gh) and increases perineal body (pb), that gh would be larger with number of vaginal deliveries and that patients’ QOL was not different comparing sexually active vs inactive patients with overall judgement of cure comparable to the literature at evaluation. MethodsRetrospective observational study including consecutive patients with indications for posterior repair and Level III support between 2016 and 2018. Concomitant perineorrhaphy was indicated due to complaints of wide introitus or genital hiatus of ≥ 3.5 cm. Primary objective was to compare pre- and postoperative gh and pb according to POP-Q. Secondary objectives were preoperative gh and pb values by parity, POMs obtained with P-QOL/D comparing sexually active vs inactive patients, and subjective judgement of cure according to EGGS system. ResultsIn n = 121 patients, mean gh value was reduced postoperatively by 29.5 % (31 ± 6 vs 44 ± 10 mm, p < 0.001), mean pb value increased by 25.5 % (47 ± 8 vs 35 ± 8 mm, p < 0.001). Influence of parity on preoperative gh (p = 0.020), but not pb values (p = 0.119) was observed. All P-QOL/D domain scores improved significantly postoperatively without differences seen in sexually active vs inactive patients. EGGS responses indicated partial/full goal achievement in 90 % and cure in 87 %. ConclusionsIn the study cohort, perineorrhaphy as concomitant in POP repair led to Level III support reflected by decreased genital hiatus size. Functional QOL was improved regardless of sexual activity status and the majority of patients reported partial or full cure.

Increased GH Secretion and Body Growth in Mice Carrying Ablation of IGF-1 Receptor in GH-releasing Hormone Cells

Growth hormone (GH) secretion is controlled by short and long negative feedback loops. In this regard, both GH (short-loop feedback) and insulin-like growth factor 1 (IGF-1; long-loop feedback) can target somatotropic cells of the pituitary gland and neuroendocrine hypothalamic neurons to regulate the GH/IGF-1 axis. GH-releasing hormone (GHRH)-expressing neurons play a fundamental role in stimulating pituitary GH secretion. However, it is currently unknown whether IGF-1 action on GHRH-expressing cells is required for the control of the GH/IGF-1/growth axis. In the present study, we investigated the phenotype of male and female mice carrying ablation of IGF-1 receptor (IGF1R) exclusively in GHRH cells. After weaning, both male and female GHRHΔIGF1R mice exhibited increases in body weight, lean body mass, linear growth, and length of long bones (tibia, femur, humerus, and radius). In contrast, the percentage of body fat was similar between control and GHRHΔIGF1R mice. The higher body growth of GHRHΔIGF1R mice can be explained by increases in mean GH levels, GH pulse amplitude, and pulse frequency, calculated from 36 blood samples collected from each animal at 10-minute intervals. GHRHΔIGF1R mice also showed increased hypothalamic Ghrh mRNA levels, pituitary Gh mRNA expression, hepatic Igf1 expression, and serum IGF-1 levels compared with control animals. Furthermore, GHRHΔIGF1R mice displayed significant alterations in the sexually dimorphic hepatic gene expression profile, with a prevailing feminization in most genes analyzed. In conclusion, our findings indicate that GHRH neurons represent a key and necessary site for the long-loop negative feedback that controls the GH/IGF-1 axis and body growth.

Mean GH profile is more accurate than single fasting GH in the evaluation of acromegaly disease control during somatostatin receptor ligands therapy

PurposeThis study aims to compare the accuracy of mean GH profile (GHP) < 2.5 ng/ml and single fasting GH (SGH) < 1 ng/ml in the evaluation of disease control in acromegaly patients during somatostatin receptor ligands (SRLs) therapy.MethodsWe retrospectively enrolled 100 acromegaly patients, 68 responder, and 32 partial responder to SRLs. Controlled disease has been defined as IGF-I levels within age-related normal limits, while partial response as pathological IGF-I values despite a reduction ≥ 50%. In all patients, GHP, SGH, IGF-I, and IGFBP-3 were evaluated.ResultsMedian GHP levels (1.2 ng/ml, IQR 0.5–2.3 ng/ml) were lower (p = 0.001) than SGH (1.9 ng/ml, IQR 1.0–3.6 ng/ml). Accuracy of GHP was 81%, whereas that of SGH was 55%, with a Kappa index of 0.520 and 0.237, respectively. In multivariable analysis GHP (p = 0.002) and IGFBP-3 (p = 0.004), but not SGH, were independently associated with normal IGF-I levels. At receiver–operator characteristic curve (ROC) analysis GHP cut-off sensitivity and specificity were 94.1% and 50.0%, respectively, while SGH sensitivity and specificity were 35.3% and 93.7%, respectively. Finally, in obese patients the GH cut-off level (both as SGH and GHP) associated to good disease control was significantly different with respect to not obese ones.ConclusionsGHP associates with IGF-I (and therefore with appropriate control of disease) with higher accuracy than SGH. When GH evaluation is needed, the measurement of mean GHP should be preferred and use of BMI-related cut-offs is suggested.

Effects of Long-Acting Somatostatin Analogues on Lipid Metabolism in Patients with Newly Diagnosed Acromegaly: A Retrospective Study of 120 Cases.

The short-term effects of long-acting somatostatin analogues (SSAs) on lipid profiles in patients with acromegaly are not well studied. We retrospectively analyzed the effects of SSAs on lipid profiles and associated cardiovascular risk factors in a cohort of 120 newly diagnosed acromegaly patients. In this study, 69 females and 51 males were included. These patients were treated with either octreotide LAR (OCT) or lanreotide SR (LAN) for 3 months. After SSAs treatment, both GH and IGF-1 significantly decreased (p<0.001). Triglyceride (TG), total to high-density lipoprotein cholesterol (HDL-C) ratio, and lipoprotein (a) [Lp(a)] levels were significantly decreased, while HDL-C levels were increased (p<0.05). The reduction of mean serum GH (GHm) was positively associated with the decrease of TG (r=0.305, p=0.001) and Lp(a) (r=0.257, p=0.005), as well as the increase of HDL-C (r=-0.355, p<0.001). The changes of lipid profiles were observed only in OCT group, but not in LAN group. In addition, systolic blood pressure (SBP) had significantly declined after SSAs treatment, with an average reduction of 4.4 mmHg (126.7±1.28 vs. 122.3±1.44 mmHg, p=0.003), while no change was observed regarding diastolic blood pressure (DBP) (p>0.05). Fasting insulin, fasting C-peptide, and HOMA-IR were significantly decreased after SSAs treatment. In conclusion, our current study revealed that short-term SSAs treatment improves lipid profiles and other cardiovascular risk factors in patients with acromegaly.

Real-world experience with pasireotide-LAR in resistant acromegaly: a single center 1-year observation

ContextPasireotide-LAR, a second-generation somatostatin receptor ligand (SRL), is recommended for patients with acromegaly as second-line treatment. Its efficacy and safety were assessed in clinical trials; however, the real-world evidence is still scarce.ObjectiveThe aim of this study was to evaluate the impact of 1-year treatment with pasireotide-LAR on disease control and glucose metabolism in acromegaly patients resistant to first-generation SRLs.DesignA single-center prospective study.MethodsTwenty-eight patients with active acromegaly or acrogigantism on first-generation SRLs following ineffective pituitary surgery were switched to treatment with pasireotide-LAR 40 or 60 mg i.m. every 28 days. To assess the efficacy of the treatment GH and IGF-1 levels were measured every 3 months. Safety of treatment was carefully evaluated, especially its impact on glucose metabolism.ResultsComplete biochemical control (GH ≤ 1 ng/mL and IGF-1 ≤ 1 × ULN) was achieved in 26.9% of patients and partial + complete response (GH ≤ 2.5 ng/mL and IGF-1 ≤ 1.3 × ULN) in 50.0% of patients. Mean GH level decrease was the largest within first 6 months (P = 0.0001) and mean IGF-1 level decreased rapidly within the first 3 months (P < 0.0001) and they remained reduced during the study. Blood glucose and HbA1c levels increased significantly within 3 months (P = 0.0001) and stayed on stable level thereafter. Otherwise, the treatment was well tolerated and clinical improvement was noticed in majority of patients.ConclusionsThis real-life study confirmed good effectiveness of pasireotide-LAR in patients resistant to first-generation SRLs. Pasireotide-LAR was overall safe and well tolerated, however significant glucose metabolism worsening was noted.

Real-World Experience With Pasireotide Lar in Acromegaly Resistant to First-Generation Somatostatin Analogs: A Single Center 1-Year Observation

Introduction: First generation somatostatin analogs (SSAs) are the treatment of choice in persistent acromegaly after transsphenoidal surgery. However, they are effective in 25% to 45 % of patients and a second generation SSA - pasireotide LAR may be a more effective alternative. Aim Our aim was to evaluate the impact of 1-year treatment with pasireotide LAR on disease control and on glucose metabolism in patients with acromegaly after debulking surgery resistant to first-generation SSAs. Material and methods In this single-center prospective study 29 consecutive patients with resistant acromegaly were treated with pasireotide LAR. The initial drug dose was 40 mg i.m. every 28 days. If patient did not achieve biochemical control (GH <2.5 ng/mL and IGF-1 ≤ULN for age and sex) at month 3, the dose was increased to 60 mg i.m. every 28 days. Assessment (GH, IGF-1, glucose, HbA1c) was performed at month 3, 6, 9 and 12. Results: In total, 22 patients (10 females, 12 males) completed a 1-year treatment. Mean age was 41.8±13.8 years. Twelve patients (54.5%) were ≤ 40 years old (including 6 (27.3%) patients of age ≤30 years). At baseline, mean IGF-1 level was 2.3 (SD 0.7) x ULN (age- and sex-specific) (583.9 ng/mL; SD 182.2) and mean GH concentration was 3.9 (SD 2.8) ng/mL. Both values decreased significantly after 1 year of treatment (P<0.001). Pasireotide LAR dose was increased to 60 mg in 16 (72.7%) patients and decreased to 20 mg in one patient patient due to worsening of diabetes control. The magnitude of mean GH level decrease was the largest within first 6 months (mean change from baseline: -1.75 ng/mL, 95% CI: -2.64, -0.85, P=0.0006). Mean IGF-1 level decreased rapidly within the first 3 months (mean change from baseline: -153.20 ng/mL, 95% CI: -203.20, -103.19, P<0.0001) and remained low during 12-month follow-up. GH level ≤ 1 ng/mL and ≤2.5 ng/mL was achieved by 7 (31.8%) and 17 (77.3%) patients, respectively. Six patients (27.3%) achieved normal IGF-1 level (IGF-1 ≤1 x ULN) (P=0.0275). IGF-1 ≤1.3 x ULN was observed in 11 (50.0%) of patients. Full biochemical control (GH ≤1 ng/mL and IGF-1 ≤1 x ULN) was achieved in 3 (13.6%) patients. Pasireotide LAR treatment resulted in significant increase of mean fasting glucose level: 119.2 (SD 17.3) vs. 107.5 (SD 13.9) mg/dL, P<0.001. The largest change was observed in first 3 months, and it remained stable until month 12. HbA1c level also increased significantly during first 3 months and stayed on similar level during follow-up (mean for month 12: 6.3 (SD 0.6) vs. 5.9 (SD 0.5) % at baseline, P<0.001). Conclusions: Pasireotide LAR is an effective treatment in most patients with persistent acromegaly after surgical debulking resistant to first generation SSAs. The largest increase of glycemia occurs during first 3 months of treatment and it remains stable afterwards.

Addition of Cabergoline to Oral Octreotide Capsules May Improve Biochemical Control in Patients With Acromegaly Who Are Inadequately Controlled With Monotherapy

Background: Oral octreotide capsules (OOC; MYCAPSSA®) are approved in the US for individuals with acromegaly who responded to and tolerated treatment with injectable somatostatin receptor ligands (iSRLs). Add-on cabergoline therapy has shown effectiveness in patients previously inadequately controlled with iSRLS.1 The phase 3 MPOWERED trial assessed maintenance of response with OOC compared to iSRLs. Patients receiving OOC and ineligible for randomized controlled treatment (RCT) phase were eligible for a sub-study evaluating combination therapy with cabergoline, a dopamine agonist. Methods: Patients who fail to respond to 80 mg/d OOC for ≥2 weeks during the 26-week Run-in phase, or ineligible to enter the RCT on 80 mg/d OOC, due to inadequate biochemical control (insulin-like growth factor I [IGF-I] ≥1.3 × upper limit of normal [ULN] to <2 × ULN or IGF-I <1.3 × ULN and mean integrated growth hormone [GH] ≥2.5 ng/mL) were eligible for sub-study combination OOC 80 mg/d and cabergoline ≤3.5 mg/wk (fixed algorithm) for 36 weeks. End points included categorical changes in IGF-I and mean GH levels at sub-study end and adverse event (AE) incidence and severity. Echocardiogram was performed at sub-study start and every 12 weeks after. Results: Of 146 patients enrolled in MPOWERED, 14 entered the combination sub-study, 9 having IGF-I ≥1.3 × ULN at sub-study start. Final cabergoline doses were 1 (n=5), 2 (n=3), 3 (n=1), and 3.5 mg (n=5) with 25.4-week (SD, 14.1) mean treatment duration. Week 36 IGF-I improved in most patients (n=12; 85.7%). Of 9 patients with IGF-I ≥1.3 × ULN at sub-study start, 5 (55.6%; 95% CI, 21.2%-86.3%) exhibited IGF-I decreased to predefined responder range (<1.3 × ULN) by week 36. AE incidence and nature with combined treatment were similar to known octreotide safety profile and acromegaly disease burden. There were no serious AEs or AEs leading to discontinuation of either sub-study drug. Conclusion: We have shown for the first time the benefit of an all-oral combination treatment for acromegaly and avoidance of injection-related burdens. Addition of cabergoline to OOC yielded biochemical control improvement (IGF-I reduction) in patients inadequately controlled with OOC monotherapy. As both combination and OOC monotherapy safety profiles were similar, adjunctive cabergoline may be helpful in patients with acromegaly who do not achieve adequate biochemical control on OOC alone. 1Giustina A, et al. Nat Rev Endocrinol. 2014;10(4):243-248.

Sodium glucose cotransporter 2 inhibitors treatment in acromegalic patients with diabetes-a case series and literature review.

Diabetes mellitus (DM) represents one of the most frequent comorbidities in patients with acromegaly. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) represent an important class for diabetes management. However, limited data is reported regarding the use of this class in patients with acromegaly and diabetes. Reporting data regarding patients with acromegaly and diabetes under treatment with SGLT2i. 29 acromegalic patients with diabetes were identified. Treatment with SGLT-2i was documented in nine patients, out of them 5 females and 4 males with a mean age (SD) of 61 ± 12 yr. The mean (SD) duration of treatment with SGLT2i was 27.5 ± 7.3 months. Mean HbA1c before and after SGLT-2i initiation was 8.1 ± 1.1 and 7.0 ± 0.9% respectively. Mean IGF-1 level (SD) before SGLT-2i initiation was 177 ± 68 ng/mL and the mean GH level (SD) was 0.7 ± 0.5 µg/L. All nine patients are still under treatment with SGLT2i and none of them had reported any adverse reaction related to SGLT2i. The present article provides us for the first time with new data regarding the use of SGLT2i among acromegalic patients with diabetes.

Adherence to growth hormone therapy guidelines in a real-world French cohort of adult patients with growth hormone deficiency

ObjectiveUsing real-world data from patients with growth hormone deficiency (GHD), we evaluated whether clinical practice in France adheres to international guidelines regarding somatropin dose adjustment, and assessed the long-term effectiveness and safety of somatropin. MethodsData were obtained from a national prospective systematic longitudinal routine follow-up programme of naive/non-naive adults with childhood-onset (CO) or adult-onset (AO) GHD treated with Norditropin® (Novo Nordisk A/S). ResultsBetween 2003 and 2006, 331 treatment-naive and non-naive adults with severe GHD were enrolled and followed for a median duration of approximately 5 years; 328 patients were available for analysis. At baseline, mean patient age was 39.2 years; median standard deviation score (SDS) for insulin-like growth factor−1 (IGF-1) level was −2.2 in naive patients, subsequently fluctuating between −0.1 and +0.3 SDS during the study period. Mean GH doses ranged between 0.25 and 0.51mg/day (naive patients) and 0.39 and 0.46mg/day (non-naive patients). Despite generally receiving a higher somatropin dose, women (naive/non-naive) tended to have lower IGF-1 levels than men. Median somatropin dose was consistently higher in patients with CO-GHD than patients with AO-GHD. Extreme IGF-1 values (<–2 or >+2 SDS) were not systematically accompanied by somatropin dose adjustments. Waist circumference improved in approximately one third of patients, at a mean 3.5 years. Somatropin was well tolerated; there were no cardiovascular or cerebrovascular events during the 5-year analysis period. ConclusionCurrent clinical practice of physicians in France follows international guidelines regarding somatropin dose adjustment in adults with GHD. However, dose adjustments are not always sufficient, notably in women, and treatment effects may have been delayed due to low somatropin dose (Clinical trial registration NCT01580605).

Hornbill abundance and breeding incidence in relation to habitat modification and fig fruit availability

Asian hornbills are known to forage and breed in fragmented rainforests and agroforestry plantations in human‐modified landscapes adjoining contiguous protected forests. However, the factors influencing year‐round hornbill abundance, demography and tracking of key food resources such as wild fig Ficus fruits in modified habitats and protected forests remain poorly understood. We carried out monthly surveys of two species of high conservation concern, the Vulnerable Great Hornbill (GH, Buceros bicornis) and the endemic Malabar Grey Hornbill (MGH, Ocyceros griseus) for 15 months and monitored ripe fig fruit availability for 12 months along 11 line transects (total length 24 km) in shade‐coffee plantations and adjoining continuous rainforests in a protected area (PA) in the Anamalai Hills, Western Ghats, India. Both hornbill species used plantations and the PA year‐round but distance sampling density estimates were higher in the PA in both nesting (GH by 57%; MGH by 50%) and non‐nesting (GH by 53%; MGH by 144%) seasons. Relative to estimates from 2004 to 2005, mean GH density appeared stable or increasing, whereas MGH had declined by 39% in the PA and by 56% in plantations. Monthly encounter rate of both hornbills tended to be higher in the PA and that of MGH was also positively related to the density of fig trees with ripe fruit. Sex ratios of observed adult birds in the non‐nesting season were relatively even (GH) or slightly female‐biased (MGH), but became male‐biased in both species during the nesting season when females were confined in tree‐cavity nests. We used change in the adult sex ratio of observed birds from the non‐nesting to nesting season to estimate an index of the proportion of adult pairs breeding at any point within the season, providing the first such estimates for any hornbill species. The proportion of breeding pairs was higher in the PA (GH – 56%, MGH – 64%) than in the plantations (GH – 33%, MGH – 30%). Although hornbills use shade‐coffee plantations year‐round, partly due to fig fruit availability, differences in hornbill density and breeding incidence, as assessed from the sex ratios of observed adult birds, indicate that plantations are a sub‐optimal habitat for both species.

Outcomes in children treated with growth hormone for Prader-Willi syndrome: data from the ANSWER Program\xae and NordiNet\xae International Outcome Study

BackgroundGrowth hormone (GH) deficiency is common in patients with Prader-Willi syndrome (PWS) and leads to short adult stature. The current study assessed clinical outcomes based on real-world observational data in pediatric patients with PWS who were treated with GH.MethodsData from patients previously naïve to treatment with GH who began therapy with somatropin were collected from 2006 to 2016 in the observational American Norditropin® Studies: Web-Enabled Research (ANSWER) Program® and NordiNet® International Outcome Study. Variables affecting change from baseline in height standard deviation scores (HSDS; n = 129) and body mass index standard deviation scores (BMI SDS; n = 98) were determined.ResultsPatients included in both HSDS and BMI SDS analyses were treated with a mean GH dose of 0.03 mg/kg/d (SD, 0.01 mg/kg/d). Results from the HSDS analysis revealed that baseline age and years on treatment had a significant impact on the change in HSDS. In the BMI SDS analysis, longer GH treatment time led to a greater change in BMI SDS from baseline, and patients with a higher BMI at the start of treatment had a greater decrease in BMI over time.ConclusionsGH is effective in the management of children with PWS. Earlier treatment resulted in a greater gain in height, and a longer treatment period resulted in better outcomes for both height and BMI.Trial registrationThis study was registered with ClinicalTrials.gov (NCT01009905) on November 9, 2009.

Best implant choice for coracoid graft fixation during the Latarjet procedure depends on patients\u2019 morphometric considerations

PurposeTo assess the anthropometric dimensions of the coracoid process and the glenoid articular surface and to determine possible implications with the different commercially available Latarjet fixation techniques.MethodsIn a total of 101 skeletal scapulae the glenoid length (GL), the glenoid width (GW), the coracoid length (CL), the coracoid width (CW) and the coracoid thickness (CTh) were measured. In order to assess the ability of the transferred coracoid to restore the glenoid anatomy we created a hypothetical model of 10%, 15%, 20%, 25% and 30% glenoid bone loss. We analyzed four common surgical fixation techniques for the Latarjet procedure (4.5 mm screws, 3.75 mm screws, 3.5 mm screws, and 2.8 mm button). The distances from the superior-inferior and medio-lateral limits of the coracoid using the four different fixation methods were calculated. We hypothesized that the “safe distance” between the implant and the coracoid osteotomy should be at least equal to the diameter of the implant.ResultsThe intra and inter-observer reliability tests were almost perfect for all measurements. The mean GH was 36.8 ± 2.5 mm, the GW 26.4 ± 2.2 mm, the CL 23.9 ± 3 mm, the CW 13.6 ± 2.mm, and the mean CTh was 8.7 ± 1.3 mm. The CL was < 25 mm in 46% of the cases. In cases with 25% and 30% bone loss, the coracoid graft restored the glenoid anatomy in 96% and 79.2% of the cases. With the use of the 4.5 mm screws the “safe distance” was present in 56% of the cases, with the 3.75 mm screws in 85%, with the 3.5 mm screws in 87%, and with the 2.8 mm button in 98% of the cases. The distance from the medio-lateral limit of the coracoid could be significantly increased (up to 9 mm) when smaller-button implants are used.ConclusionsThe coracoid graft could not always restore glenoid defects of 30%. Larger implants could be positioned too close to the osteotomy and the “medio-lateral offset” of the coracoid could be increased with smaller implants.

Is MRI follow-up relevant in patients with GH-secreting pituitary adenomas primarily treated and responsive to long-acting somatostatin analogues (SMSa)?

Primary SMSa treatment can be associated with hormonal control and tumor shrinkage in patients with GH-secreting pituitary adenomas. The aim of this study was to evaluate whether regular MRI follow-up was necessary in patients with acromegaly-treated and responsive to first-generation long-acting SMSa. In this retrospective monocentric study we included patients with GH/IGF-1 hypersecretion and pituitary adenomas with normal visual field, primarily treated with first-generation long-acting SMSa between 1995 and 2015 and regularly monitored (clinical evaluation, GH/IGF-1 levels and pituitary MRI) for at least 3 years. We included 83 patients (32 men and 51 women, mean age at diagnosis 50 ± 12 years) with mean GH = 19.3 ± 25.6 ng/mL, IGF-1 = 284 ± 110% ULN and pituitary adenoma height = 12.9 ± 4.7 mm. Mean follow-up was 8.9 ± 4.9 years in 36 controlled patients and 2.0 ± 1.6 years in 47 partial responders to SMSa alone. No significant increase in pituitary adenoma height was observed. Pituitary adenoma height decreased significantly in controlled patients (diagnosis: 11.9 ± 4.8 mm, SMSa: 9.6 ± 3.3 mm, P < 0.001), and in partially responders (diagnosis: 13.6 ± 4.5 mm, SMSa: 11.5 ± 4.5 mm, P < 0.001). During SMSa treatment, no significant increase in GH-secreting adenoma size was observed. Primary SMSa treatment was associated with a significantly decrease in adenoma height in our population. Our cohort data suggest that regular MRI follow-up does not seem relevant in patients with acromegaly who are responsive to SMSa treatment.

MON-474 Dipeptidyl Peptidase-4 (DPP4) Inhibition Decreases Visceral Fat and Improves Glucose Metabolism in Overweight Women with Polycystic Ovarian Syndrome

Background: Women with PCOS have decreased GH secretion.1 Diminished GH is associated with increased visceral adiposity and impaired vascular function. GH releasing hormone is the primary stimulus for GH secretion and a substrate of dipeptidyl peptidase-4 (DPP4).2 We tested the hypothesis that one month of DPP4 inhibition with sitagliptin increases GH secretion and improves glucose metabolism and vascular function in women with PCOS. Methods: Eighteen women with PCOS (BMI ≥ 25 kg/m2) participated in a randomized, double-blinded, cross-over study during which they received sitagliptin 100 mg p.o. vs. placebo daily for one month separated by a minimum eight-week wash-out. At two weeks, women underwent a 75 g oral glucose tolerance test (OGTT). At one month, women were admitted for fasting laboratories, assessment of conduit artery vascular function, and measurement of body composition via DEXA. Overnight GH secretion was assessed using an automated deconvolution algorithm (AutoDecon) previously validated for the analysis of endogenous pulsatile GH secretion from time-series data obtained via frequent venous sampling from an indwelling catheter every ten minutes for twelve hours. Results: Sitagliptin 100 mg daily decreased DPP4 activity (p<0.001 vs. placebo) and increased GLP-1 levels (p<0.001 vs. placebo) during OGTT. Glucose metabolism improved during sitagliptin, as demonstrated by mean decrease in blood glucose of 15.4 mg/dL (95% CI 8.7, 22.1; p<0.001) at 100 minutes as compared to placebo. Sitagliptin enhanced early insulin secretion (from mean insulinogenic index 1.9 ± SD 1.2 to 3.2 ± 3.1; p=0.01). At one month, sitagliptin decreased visceral adipose tissue (VAT) (from 1141.9 g ± 700.7 to 1055.1 ± 710.1; p=0.02) and total cholesterol (from 168.8 mg/dL ± 26.3 to 162.5 ± 22.2; p=0.02) but did not affect vascular function. Sitagliptin did not increase overnight GH secretion, as summarized by area over the curve (AUC) or mean GH, but did increase GH half-life (from 13.9 min ± 3.6 to 16.8 ± 6.2, N=16; p=0.04) and the interpulse interval (from 53.2 min ± 20.0 to 77.3 ± 38.4, N=16; p<0.05). DPP4 activity levels during sitagliptin were associated with overnight GH secretion (GH AUC: rs= -0.60, p=0.01; mean GH: rs= -0.57, p=0.02), VAT mass (rs= 0.66; p<0.01), and insulin resistance (HOMA-IR rs=0.54; p=0.04). Conclusions: Sitagliptin improved blood glucoses following 75 g OGTT in overweight women with PCOS and decreased VAT but did not enhance vascular function. While sitagliptin did not increase overnight GH secretion, it did enhance GH half-life and the interpulse interval. Moreover, the response to sitagliptin was directly related to overnight GH secretion and inversely to VAT and insulin resistance. In this pilot study, sitagliptin improved glucose metabolism and body composition in accordance with GH secretion. 1 deBoer et al., Hum. Reprod. 2004 19: 504. 2 Frohman et al., J Clin Invest. 1986 78:906.

MON-LB047 GH Values in Serum and Blood Spots on Filter Paper Samples in Infants until 60 Days of Life by Electrochemiluminescence (ECLIA)

Congenital Growth Hormone Deficiency (GHD) in newborn is an infrequent condition, which can cause threat to life due mainly to hypoglycemia that begins in the first week of life. Severe neonatal GHD needs a fast diagnosis and the substitution with recombinant human GH because of the risk the morbi-mortality. A GH basal level (whether random or associated with spontaneous hypoglycemia) that distinguishes infants with GHD from those with GH sufficiency in the neonatal period is not conclusive. Few data have been reported about the GH measurements in serum and dried blood spots on filter paper samples in healthy neonates born appropriate for gestational age (AGA). Aims: To compare and correlate the GH values in serum and blood spots on filter paper samples in infants until 60 days of life. To establish GH reference values in healthy newborn until 15 days of life. To analyzed the correlation between GH concentrations in serum and blood spot and with hormones of the hypothalamic-pituitary-gonadal and adrenal axis. Subjects and methods: We analyzed 301 serum and whole blood spots samples obtained from AGA neonates between 2-60 days of life (2-15 days n=216, 16-30 days n=65 and 31-60 days n=20 (F: 154, M: 147). GH concentrations were measured by ECLIA Roche C600, which is calibrated against the 2nd International Standard Code 98/574 in serum as well as eluted from filter paper samples. The mean and SD GH value, P 5.0 and P 95.0 were calculated. The statistical analysis was performed by Spearman correlation coefficient. Results: 2-5 days: serum GH (ng/mL) mean value (SD): 20.81(15.8); P5: 6.30, P95: 42.30; 6-15 days: mean GH value 8.78 (4.34); P5: 3.29, P95: 15.19; 16-30 days: mean GH value: F: 10.55 (4.58), M: 7.72 (3.75) and 31-60 days: mean GH value: F: 4.67 (2.75), M 6.82 (4.57). Blood spots GH (ng/mL) mean value (SD): 2-5 days: 17.58 (9.95); P5: 5.68, P95: 33.60; 6-15 days: mean GH value: 10.31 (5.88), P5: 3.0, P95: 21.02; 16-30 days: mean GH value: F: 10.41 (6.01), M: 10.99 (7.78) and 31-60 days: mean GH value: 7.02 (5.25), M 9.12 (8.08). The Spearman correlation obtained between both techniques in parallel measurements was r2=0.85 (p< 0.0001). Conclusions: In agreement with different reports, our results showed high average GH levels in the first few days of life. Human GH secretion is pulsatile from the very beginning, however, newborn screening card spotted with blood during the first week of life, when neonatal hypersomatotropism is present, provides such high levels that, even at the nadir of GH pulsatility a basal value could contribute to detect GHD accurately. The good correlation obtained between both type of samples would indicate that the measurement of GH in dried blood spot samples is an appropriate and reliable method which can be incorporated in the diagnosis of neonatal GHD. The newborn screening samples may be a valuable resource for retrospectively assessing GH sufficiency if this neonatal window has passed. 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.

SUN-085 Assessing the Impact of Disease Activity on Clot Formation and Lysis in Patients with Acromegaly

Introduction: Data from previous studies suggest increased thrombogenic potential in patients with acromegaly, with higher levels of fibrinogen and a degree of impaired fibrinolysis, which may be contributing to the increased cardiovascular risk associated with acromegaly. However, it remains unclear whether these hemostatic abnormalities reverse in patients with disease remission. Patients and Methods: We conducted a cross-sectional study in 40 patients with acromegaly. The patients were divided into two groups based on the Endocrine Society criteria for disease remission (GH<1mcg/L and IGF-1 within the reference range) at the time of the study. We measured fibrinogen using the Clauss method and also analyzed clot formation and lysis using a validated turbidimetric assay. Results: Twenty-two patients with active acromegaly (Group 1; mean age 51±13 years) and 18 with disease remission (Group 2; mean age 55±13 years) were assessed. There was no difference in the two groups with regards to age, gender distribution, BMI, fat mass (as measured by bioimpedance), skinfold thickness, total cholesterol and HbA1c. Mean GH and IGF-1 values were significantly higher in the group with active acromegaly (2.6±2.4 vs. 0.5±0.5 mcg/L, p<0.001 and 163±105% vs. 73±23% of upper limit of normal, p<0.001 respectively). Mean duration of disease remission in Group 2 was 9.4±6 years. Patients in remission had more prolonged lag time for the initiation of clot formation (571±68 vs. 514±72 sec, p=0.02), however maximum clot optic density was similar in the two groups (Group 1: 0.40±0.12 vs. Group 2: 0.35±0.14 arbitrary units, p=0.26). Additionally, no statistical difference was found in the lysis times in the two groups (mean time from maximum clot formation to 50% lysis was 24.5±18.7 min in Group 1, compared with 34.4±25.3 min in Group 2; p=0.16). Fibrinogen levels were also similar (Group 1: 3.9±1.6 mg/ml vs. Group 2: 3.2±1.5 mg/ml; p=0.2). Duration of active disease was associated with higher fibrinogen levels (coefficient 0.06, p=0.03), while duration of disease remission was associated with longer lag time for clot formation (coefficient 5.0, p=0.015). Disease status was another predictor of lag time for clot formation, with active acromegaly being associated with shorter lag time (coefficient -56.5, p=0.016). Conclusions: We were not able to demonstrate any significant differences in the clot structure properties between patients with active acromegaly and those with disease remission. This may be due to a type II statistical error due to the relatively small sample size or suggest that hemostatic abnormalities described in other studies persist, despite biochemical control of acromegaly. The presence of active disease and the overall duration of this, appear to be associated with increased potential for clot formation in patients with acromegaly.

SAT-433 Long-Acting Pasireotide Provides Clinical Benefit to Patients with Uncontrolled Acromegaly over Continued Treatment with First‑Generation Somatostatin Analogues (SSAs): Results from Phase 3b, Open-Label Study

Background: In a 24-week, Phase 3 study (PAOLA), long-acting pasireotide demonstrated superior efficacy (GH <2.5 µg/L and IGF-1 <ULN) over continued treatment with long-acting octreotide/lanreotide in pts with uncontrolled acromegaly (Gadelha MR, et al. Lancet Diabetes Endocrinol. 2014;2:875-884). An earlier (3 months) switch to long-acting pasireotide and the current criteria for biochemical control, i.e. GH <1 μg/L and IGF-1 <ULN, are considered in the present phase 3b study. This study (clinicaltrials.gov: NCT02354508) evaluated the efficacy (GH <1 μg/L and IGF-1 <ULN) and safety of long‑acting pasireotide in pts with uncontrolled acromegaly despite ≥3 months of treatment with maximal approved doses of first-generation SSAs. Methods: Adults with uncontrolled acromegaly (mean GH [mGH] ≥1 µg/L and IGF-1 >1.3xULN) despite ≥3 months of treatment with maximal approved doses of long-acting octreotide/lanreotide received open-label long-acting pasireotide 40 mg/28 days. Pasireotide dose could be up titrated to 60 mg/28 days after week 12 if the biochemical control was not achieved or down titrated to 20 mg/28 days or 10 mg/28 days for tolerability. Primary endpoint: proportion of pts with mGH <1 μg/L and IGF-1 <ULN at week 36 overall and by screening mGH (1.0-2.5 μg/L and >2.5 μg/L). Results: 123 pts received long-acting pasireotide: median age, 43.0 years (range, 22-76); female, 50.4%; baseline median (range) mGH, 5.4 µg/L (1.2-195.5) and IGF-1, 2.3xULN (1.4-7.9); prediabetic/diabetic at baseline, n=112 (91.1%). The median duration of exposure to pasireotide was 36.0 weeks (median dose intensity, 53.3 mg/month). Overall, 18 pts (14.6% [95%CI, 8.9-22.1]) achieved biochemical control at week 36 (primary endpoint); 12 (42.9% [95%CI, 24.5-62.8]) and 6 pts (6.4% [95%CI, 2.4-13.4]) by screening mGH levels of 1.0 to 2.5 µg/L (n=28) and >2.5 µg/L (n=94), respectively. At week 36, 23 (18.7%), 16 (57.1%) and 7 pts (7.4%) had GH <1 µg/L; and 38 (30.9%), 14 (50.0%) and 24 pts (25.5%) had IGF-1 <ULN overall and by screening mGH levels of 1.0 to 2.5 µg/L and >2.5 µg/L, respectively. The median percentage decreases in mGH and standardized IGF-1 from baseline to week 36 were 56.8% and 42.8%. The most common AEs (>15%) regardless of study drug relationship were hyperglycemia (43.1%), diabetes mellitus (22.0%), and diarrhea (15.4%). Hyperglycemia-related AEs suspected to be drug related occurred in 81 pts (66%) overall and 4 of 11 pts (36.4%) who were nondiabetic at baseline. A total of 10 pts (8.1%) discontinued treatment either because of AEs (n=4; 3.3%) or unsatisfactory therapeutic effect (n=3; 2.4%), or consent withdrawal (n=3; 2.4%). Conclusions: In pts with uncontrolled acromegaly, switching to long-acting pasireotide after ≥3 months of treatment with first-generation SSAs provided biochemical control (mGH <1.0 μg/L and IGF-1 <ULN) in 15% of all pts and 43% of pts with lower screening mGH (1.0-2.5 µg/L).