Growth Hormone Replacement Research Articles

Ectopic lipid deposition and insulin resistance in patients with GH disorders before and after treatment.

Insulin resistance is associated with ectopic lipid deposition. Growth hormone (GH) status also modulates ectopic lipid accumulation, but how this associates with insulin resistance in patients with GH disorders is not well established. Twenty-one patients diagnosed with acromegaly and 12 patients with adult GH deficiency (GHD) were studied at diagnosis and after treatment. A reference group of 12 subjects was included. Each study day comprised assessment of body composition with dual-energy X-ray absorptiometry, ectopic lipid deposition in the liver by MR spectroscopy, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Disease control of acromegaly decreased lean body mass (LBM) (P < .000) and increased the percentage of total body fat (TBF) (P < .000). GH replacement increased LBM in the GHD patients (P = .007) and decreased the percentage of TBF (P = .010). The intrahepatic lipid (IHL) content increased after disease control in acromegaly (P = .004), whereas IHL did not change significantly after GH replacement in GHD (P = .34). Insulin resistance (HOMA-IR) improved after disease control of acromegaly (P < .000) and remained unaltered after GH replacement in the GHD patients (P = .829). GH status is a significant modulator of body composition and insulin sensitivity.GH excess reduces total fat mass and intrahepatic lipid content together with induction of insulin resistance.The data support the notion that GH-induced insulin resistance is unassociated with hepatic lipid accumulation.

Reduced CV risk with long-term GH replacement in AGHD: data from two large observational studies.

Adult growth hormone deficiency (AGHD) is associated with an increased risk of cardiovascular (CV) disease. Long-term growth hormone (GH) treatment could improve CV outcomes. The objective of this study was to evaluate CV disease risk in patients with AGHD who received GH replacement therapy for up to 10 years as part of NordiNet® IOS (NCT00960128) and the ANSWER Program (NCT01009905). The studies were observational, non-interventional and multicentre, monitoring long-term effectiveness and safety of GH treatment. NordiNet® IOS involved 23 countries (469 sites) across Europe and the Middle East. The ANSWER Program was conducted in the USA (207 sites). This analysis included patients aged 18-75 years who were GH naïve at study entry, who had ≤10 years of GH treatment data and who could be assessed for CV risk for at least 1 follow-up year. The main outcome measure was risk of CV disease by age 75 years, as calculated with the Multinational Cardiovascular Risk Consortium model (Brunner score) using non-high-density lipoprotein cholesterol adjusted for age, sex and CV risk factors. The results of this analysis showed that CV risk decreased gradually over the 10-year period for GH-treated patients. The risk was lower for patients treated for 2 and 7 years vs age- and sex-matched control groups (not yet started treatment) (14.51% vs 16.15%; P = 0.0105 and 13.53% vs 16.81%; P = 0.0001, respectively). This suggests that GH treatment in people with AGHD may reduce the risk of CV disease by age 75 years compared with matched controls.

A new insight into GH regulation and its disturbance from nutrition and autoimmune perspectives.

GH activates GH receptors, which activates IGF-1 in the liver through a cascade of processes. The GH/IGF-1 axis plays an important role in the regulation of metabolism. Insufficient GH secretion results in short stature in childhood, while adult GH deficiency (AGHD) is observed in adulthood. The early diagnosis of AGHD is important for early initiation of GH replacement therapy. This review described the regulatory mechanisms of GH signaling based on nutritional status and a novel disease concept pathogenesis that causes AGHD. GH-dependent IGF-1 production in the liver is regulated by a complex interplay between nutritional status, hormones, and growth factors. GH resistance is an adaptive response that enhances survival during starvation and malnutrition. Sirtuin 1 (SIRT1) negatively regulates GH-induced IGF-I production in the liver by directly inhibiting STAT5 activation, which causes GH resistance under starvation and malnutrition. The presence of autoantibodies is strongly associated with the disruption of immune tolerance in pituitary cells. Pituitary-specific transcription factors (PIT-1) are essential for the development, differentiation, and maintenance of GH, PRL, and TSH producing cells. However, the underlying mechanism that causes immune intolerance to PIT-1 remain unclear. The GH-IGF-1 system plays a pivotal role in growth, and the involvement of SIRT1 in this regulatory mechanism presents an intriguing perspective on the interplay between nutrient metabolism and lifespan. The discovery of the anti-PIT-1 pituitary antibody, a novel disease concept associated with AGHD, has provided valuable insights, which serves as a significant milestone towards unraveling the complete pathogenesis of the disease.

Guidance for the treatment of adult growth hormone deficiency with somapacitan, a long-acting growth hormone preparation.

Adult growth hormone deficiency (AGHD) is a rare endocrine disorder characterized by an abnormal body composition, metabolic abnormalities associated with increased cardiovascular diseases, bone loss, and impaired quality of life. Daily subcutaneous injections with recombinant growth hormone (GH) can alleviate the abnormalities associated with AGHD. Several long-acting GH (LAGH) preparations are currently in development that aim to reduce treatment burden for patients receiving daily GH injections. Somapacitan (Sogroya®; Novo Nordisk, Denmark) is the first LAGH preparation that has been approved for treatment of AGHD in the United States, Europe, and Japan. The recent approval of somapacitan and anticipated approval of other LAGH molecules presents new questions for physicians planning to treat AGHD with LAGH in the future. Differences in the technologies used to prolong the half-life of recombinant GH are expected to result in variations in pharmacokinetic and pharmacodynamic profiles between preparations. Therefore, it is essential that physicians understand and consider such variations when treating patients with these novel GH replacement therapies. Here, we present a set of treatment recommendations that have been created to guide physicians initiating therapy with somapacitan in patients with AGHD who are eligible for GH replacement. Furthermore, we will review the published data that underlie these recommendations to explain the rationale for the treatment and monitoring advice provided.

Growth Hormone Replacement Therapy Seems to Be Safe in Children with Low-Grade Midline Glioma: A Series of 124 Cases with Review of the Literature

to compare the recurrence rate in children with midline LGG, depending on whether or not they have received GHRT, in order to assess its impact on the risk of tumor recurrence. This bicentric retrospective study included 124 patients under the age of 18 who were diagnosed with a midline low-grade glial tumor between 1998 and 2016. We also reviewed literature on this subject. The main outcome measure was tumor relapse, demonstrated by brain MRI. There were 17 patients in the GH-supplemented group (14%) and 107 patients in the non-supplemented group (86%). Relapse occurred in 65 patients (45.5%); 7 patients died (4.9%); no deaths occurred in patients receiving GHRT. Two patients developed a second tumor (1.4%), none of which had received GHRT. Relapse concerned 36.4% of patients without GHRT and 52.9% of patients with GHRT. The difference was not statistically significant between the two groups (p = 0.3). GHRT does not lead to a statistically significant increase in risk of relapse for pediatric midline low-grade pediatric glioma in our cohort. Although these results appear reassuring, future natural history or prospective studies should be done to ascertain these findings. Nevertheless, these reassuring data regarding GHRT are in agreement with the data in the current literature.

Role of growth hormone in orthodontics

Human growth hormone (Somatotropin) is produced by acidophilic growth hormone cells in the anterior pituitary gland, stimulated by hypothalamus. Its production is regulated by several complex feedback mechanisms in response to stress, exercise, diet, sleep and growth hormone itself. Growth hormone plays a major role in linear body growth and craniofacial growth. In Orthodontics, it induces orthodontic tooth movement by activating specific cytokines to regulate osteoclast &amp; osteoblast activity. It mediates STAT signalling in liver &amp; pancreas to produce JAK-IGF-1. IGF-1 has stimulatory effects on osteoblasts and chondrocytes for endochondral ossification to promote bone growth. Growth hormone mediates mitogenic stimulus to odontoblast lineage cells by epidermal growth factor (EGF) to differentiate into odontoblasts. It also stimulates production of alkaline phosphatase and osteocalcin in osteoblasts to improve osteoblast proliferation and differentiation. It also induces osteoclastic activity indirectly by production of IGF-1 and IL- 6 thereby activating RANK-RANKL/OPG phenomenon. It also promotes myofibrillar diameter expansion so it increases muscle mass with strength. Growth Hormone Replacement therapy reduces facial convexity and its main effect appears to be on condylar growth. Since deficiencies of growth hormone can adversely affect orthodontic treatment, effects of growth hormone treatment on craniofacial structures should be considered in order to maximize the effectiveness of orthodontic treatment with appliances and it is more important to understand.

Childhood-Onset GH Deficiency versus Adult-Onset GH Deficiency: Relevant Differences Regarding Insulin Sensitivity.

The results of the studies on the pattern of insulin sensitivity (IS) are contradictory in patients with GH deficiency (GHD); however, the interference of the GHD onset stage, childhood or adulthood in the IS has not been assessed by euglycemic hyperinsulinemic clamp (EHC), a gold-standard method for the assessment of insulin sensitivity. In a prospective cross-sectional study, we assessed IS and body composition in 17 adults with hypopituitarism without GH replacement, ten with childhood-onset (COGHD) and seven with adulthood-onset (AOGHD) and compared them to paired control groups. COGHD presented higher IS (p = 0.0395) and a similar percentage of fat mass (PFM) to AOGHD. COGHD showed higher IS than the control group (0.0235), despite a higher PFM (0.0022). No differences were found between AODGH and the control group. In AOGHD and the control group, IS was negatively correlated with PFM (rs: −0.8214, p = 0.0234 and rs: −0.3639, p < 0.0344), while this correlation was not observed with COGHD (rs: −0.1152, p = 0.7514). Despite the higher PFM, patients with COGHD were more sensitive to insulin than paired healthy individuals, while patients with AOGHD showed similar IS compared to controls. The lack of GH early in life could modify the metabolic characteristics of tissues related to the glucose metabolism, inducing beneficial effects on IS that persist into adulthood. Thus, the glycometabolic findings in patients with COGHD seems to be not applicable to AOGHD.

Dynamic regulation of excitatory and inhibitory synaptic transmission by growth hormone in the developing mouse brain.

Normal sensory and cognitive function of the brain relies on its intricate and complex neural network. Synaptogenesis and synaptic plasticity are critical to neural circuit formation and maintenance, which are regulated by coordinated intracellular and extracellular signaling. Growth hormone (GH) is the most abundant anterior pituitary hormone. Its deficiencies could alter brain development and impair learning and memory, while GH replacement therapy in human patients and animal models has been shown to ameliorate cognitive deficits caused by GH deficiency. However, the underlying mechanism remains largely unknown. In this study, we investigated the neuromodulatory function of GH in young (pre-weaning) mice at two developmental time points and in two different brain regions. Neonatal mice were subcutaneously injected with recombinant human growth hormone (rhGH) on postnatal day (P) 14 or 21. Excitatory and inhibitory synaptic transmission was measured using whole-cell recordings in acute cortical slices 2 h after the injection. We showed that injection of rhGH (2 mg/kg) in P14 mice significantly increased the frequency of mEPSCs, but not that of mIPSCs, in both hippocampal CA1 pyramidal neurons and L2/3 pyramidal neurons of the barrel field of the primary somatosensory cortex (S1BF). Injection of rhGH (2 mg/kg) in P21 mice significantly increased the frequency of mEPSCs and mIPSCs in both brain regions. Perfusion of rhGH (1 μM) onto acute brain slices in P14 mice had similar effects. Consistent with the electrophysiological results, the dendritic spine density of CA1 pyramidal neurons and S1BF L2/3 pyramidal neurons increased following in vivo injection of rhGH. Furthermore, NMDA receptors and postsynaptic calcium-dependent signaling contributed to rhGH-dependent regulation of both excitatory and inhibitory synaptic transmission. Together, these results demonstrate that regulation of excitatory and inhibitory synaptic transmission by rhGH occurs in a developmentally dynamic manner, and have important implication for identifying GH treatment strategies without disturbing excitation/inhibition balance.

Evaluation of cardiac structure, exercise capacity and electrocardiography parameters in children with partial and complete growth hormone deficiency and their changes with short term growth hormone replacement therapy.

To evaluate cardiac structure, exercise capacity and electrocardiography (ECG) parameters of children with complete and partial growth hormone (GH) deficiency (GHD) and the effect of 12 months GH treatment on these. M-mode echocardiography, ECG and exercise test expressed as metabolic equivalent (MET) were performed in children with GHD, aged 9-14 years, divided into those with a peak GH response < 7µg/L (complete GHD; n = 30) and 7-10µg/L (partial GHD; n = 17) after two GH stimulation tests, at baseline and 12 months after GH initiation. Forty-eight healthy peers underwent the same tests once. Left ventricular mass (LVM) was significantly lower before treatment in both groups with GHD compared to healthy peers (p = 0.015 and p = 0.032) but LVM in the GHD groups was similar to controls after 12 months of treatment. The increase in LVM in the complete GHD group was significant (p = 0.044). LVM index was significantly reduced with treatment in children with partial GHD (p = 0.035). Max METs, VO2max and exercise duration were significantly increased in children with complete GHD after treatment (p = 0.022, p = 0.015 and p = 0.002, respectively). Significant changes in P wave and QTc dispersion on ECG between groups were within physiological limits. This study showed that children with both partial and complete GHD had smaller cardiac structures and less exercise capacity compared to their healthy peers prior to GH treatment but this improved with 12 months of treatment. The cardiac trophic effect of GH, as well as the effect of increasing exercise capacity, is greater in those with complete GHD than in those with partial GHD.

Normal-high IGF-1 level improves pregnancy rate after ovarian stimulation in women treated with growth hormone replacement therapy.

Growth hormone (GH) and insulin-like growth factors (IGFs) are not mandatory for reproductive life, but data suggest their synergistic action with follicle-stimulating hormone throughout ovarian folliculogenesis. We aimed to evaluate the association of IGF-1 level on clinical pregnancy rate after ovarian stimulation, with or without intrauterine insemination, in women with GH deficiency (GHD) treated with GH replacement therapy (GHRT) at conception. Data from 19 women with both GHD and hypogonadotropic hypogonadism referred to our reproductive medicine department were retrospectively collected. IGF-1 levels were assessed in a single laboratory, and values were expressed in s.d. from the mean. Amongst the seven patients receiving GHRT during ovarian stimulation, higher IGF-1 levels were significantly associated with clinical pregnancy (+0.4 s.d. vs-1.6 s.d., P = 0.03). Amongst the 24 pregnancies obtained by the 19 infertile patients, pregnancy loss was less frequent with the addition of GHRT than without (1 miscarriage out of 8 total pregnancies vs 4 miscarriages out of 16 total pregnancies). This is the first study evaluating the association of IGF-1 level on clinical pregnancy rate in GH-treated women at conception. When taking care of female infertility due to hypogonadotropic hypogonadism, practitioners should enquire about the associated GHD and IGF-1 levels. To ensure higher clinical pregnancy chances, practitioners should aim for IGF-1 values at conception, ranging from 0 s.d. to +2 s.d., and, if necessary, could discuss initiation or increase GH treatment. Prospective studies should help strengthen our results.

The Association between Somatotropin Therapy and the Risk of SARS-CoV-2 Infection in Children with Short Stature: A Population-Based Cross-Sectional Study.

COVID-19 is a worldwide pandemic caused by SARS-CoV-2, to which adults are usually more susceptible than children. Growth hormone (GH) levels differ between children and adults and decrease with age. There is bidirectional crosstalk between the GH/insulin-like growth factor-1 (IGF-1) pathway and the immune system that plays a significant role in SARS-CoV-2 infection. We evaluated the association between somatotropin treatment (GH replacement therapy) and the risk for SARS-CoV-2 positivity (a marker for COVID-19 infection) in children with growth hormone issues (GHI): growth hormone deficiency (GHD) and idiopathic short stature (ISS). A population-based cross-sectional study in Leumit Health Services (LHS) was performed using the electronic health record (EHR) database. The rates of SARS-CoV-2 positivity were evaluated among children with GHI, treated or untreated with somatotropin. Higher rates of SARS-CoV-2 positivity were found in GHI children, influenced by the same confounders reported in the pediatric population. A lower prevalence of SARS-CoV-2 PCR positivity was found among the somatotropin-treated children. A multivariate analysis documented that somatotropin treatment was associated with a reduced risk of SARS-CoV-2 positivity (Odds Ratio (OR) = 0.47, Confidence Interval (CI) 0.24-0.94, p = 0.032). Thus, somatotropin might be a protective factor against SARS-CoV-2 infections, possibly related to its immunomodulatory activity.

ODP643 Metabolic Effects of Growth Hormone Replacement in Craniopharyngioma and Pituitary Adenoma Patients: Analysis of the Hypopituitary Control and Complications Study (HypoCCS) Database

Abstract Introduction Craniopharyngioma (CP) is a rare, parasellar tumor associated with metabolic dysfunction and panhypopituitarism. We investigated the impact of growth hormone (GH) replacement on metabolic complications in patients with adult-onset CP or pituitary adenoma (PA) using data collected between 1996 and 2012 in HypoCCS, an open-label, global prospective surveillance study of GH replacement in GH deficiency. Methods GH-treated (≥6 months) vs untreated groups in CP and PA patients were compared using ANOVA or Wilcoxon rank-sum test for continuous variables and chi-square test or Fisher's exact test for categorical variables. Multivariable analysis adjusted for GH use prior to enrollment, IGF-1 level, adrenal insufficiency, androgen replacement, and BMI. Results Of 8418 GH-treated and 1268 untreated patients in HypoCCS, 592 had CP, with 544 on GH and 48 untreated. Mean (±SD) follow-up was 5.39 (±4. 07) and 3.91 (±3. 07) years, respectively. Adverse hepatic outcomes (primary endpoint) were slightly improved with GH (19% vs 27%; p=NS). Mean lean BMI increased 0.93 (±1.56) kg/m2 with GH vs decreased 1.57 (±1.4) without GH (p=0. 022). Median (IQR) waist-hip ratio decreased -0. 01 (-0. 03-0. 03) with GH and increased 0. 03 (0-0. 06) without GH, significant on univariable (p=0. 01) and multivariable analysis (parameter estimate -0. 03 [-0. 05, -0. 004]; p=0. 02). Median blood pressure (BP) was unchanged with GH (-10-10) but increased 5.5 (0-17) mmHg without GH, significant on univariable (-5.99 [-11.44, -0.54], p=0. 032). Mortality was slightly lower with GH (3.5% vs 5.9%; p=NS). Of 3972 PA patients, there were 3346 on GH and 626 untreated; mean (±SD) follow-up was 5.38 (±3.97) and 3.93 (±3.22) years, respectively. GH did not impact hepatic outcomes (17%). Median (IQR) fasting glucose increased 6 (0-13) mg/dL with GH vs 1 (-10-7) without (p=0. 04), mean HbA1C decreased -0.12% (±1.94) with GH vs -1.95% (±1.84) without (p=0. 037), and rate of lipid medication use was in 46% on GH vs 56% without (p&amp;lt;0. 001). BMI increased 0.23 (-0.99-1.56) kg/m2 with GH vs 0 (-1.4-1.12) without (p=0. 002), and GH was associated with increased BMI (0.32 [0. 04-0.59]; p=0. 024). Median mean arterial pressure was 94.67 (87.33-101.67) mmHg with GH vs 93.33 (86.67-100) without (p=0. 007) and median diastolic BP was 80 (70-84) mmHg with GH vs 76 (70-82) without (p&amp;lt;0. 001); GH was associated with higher diastolic BP (1.43 [0.43, 2.44]; p=0. 005). Mortality was lower with GH than without (2.9% vs 5.1%), significant on univariable (p=0. 017) and multivariable analysis (0.60 [0.35-1. 03]; p=0. 066). Conclusion HypoCCS data show GH replacement in adult-onset CP lowers waist-hip ratio and slightly improves hepatic outcomes and mortality while untreated patients had increased BP. In PA patients, BMI and hypertension worsened with GH and mortality decreased, while hepatic outcomes were unchanged. The results suggest a favorable impact for GH on metabolic complications and a potential benefit for GH replacement in adult-onset CP. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON61 Evaluation of elevated IGF-1 in patients without clinical evidence of acromegaly

Abstract Introduction Insulin-like growth factor-1 (IGF-1) acts downstream of growth hormone mediating many of its effects. It is the recommended screening test for acromegaly, in evaluating pituitary incidentalomas and possible hypopituitarism. Case-based observations suggest that elevated IGF-1 may occur in patients without acromegaly. The aims were to 1) identify the frequency of elevated IGF-1 without evidence of GH excess, and 2) to examine potential differences in relevant medications and comorbidities between people with an elevated IGF-1 compared to a control group matched for age, sex, gonadal and pituitary status. Methods All people whose IGF-1 was measured at a single reference laboratory between Dec 1st 2018 – Dec 1st 2020 were identified. The electronic records of those with at least one IGF1 &amp;gt;1.1x the upper limit of the age-matched reference range were appraised to determine; 1) documentation of acromegalic features, 2) presence of relevant comorbidities and medication use, and 3) further investigation to exclude pathological GH excess. Results There were 2759 IGF-1 levels measured in 1963 people over the specified period. Out of these, 204 were in patients over 18 years of age and were &amp;gt;1.1 times the upper limit of the age-matched reference range. We excluded 48 with diagnosed acromegaly, 4 who had further workup for acromegaly planned, 9 on GH substitution for proven GH deficiency, 3 with Cushing's syndrome and 5 who were pregnant. A further 33 were excluded based on insufficient data available. A total of 102 cases (61M, 41F) were included in the analysis. Of these 102 people, 67 had pituitary MRI scans, 24 had a 75g oral glucose tolerance test, 28 had a subsequent repeat IGF-1 that had normalised and 13 had random GH &amp;lt;1ug/L. The characteristics of these 102 cases were compared to those of the matched control group (n=102) with normal IGF-1 assayed in the same period. There was no significant difference between the elevated and normal IGF-1 groups in age (mean 46.7 vs 47.0 years, P=0.90), sex (P&amp;gt;0.99), gonadal status (P=0.87) or pituitary status (P=0.15). Variables that were significantly different between cases and controls included dopamine agonist therapy (19/102 cases vs 6/102 controls, OR=3.66, 95% CI: 1.45-9.29, P=0.009) and chronic kidney disease (14/102 cases vs 4/102 controls, OR = 3.90, 95% CI: 1.28-11.14, P=0.024). Conclusion Out of 1963 patients having IGF-1 measured at a reference laboratory, a significantly elevated IGF-1 occurred in 204. In 102 (50%) of these patients, there was no known acromegaly, GH replacement or glucocorticoid excess, and no documented definitive acromegalic features. There were significant associations with dopamine agonist use and CKD. While assay-related issues and accuracy of the age-matched reference ranges probably represent the main influences on the prevalence of elevated IGF-1, we have identified two additional factors which should be considered. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON60 Growth Hormone (GH) Replacement Therapy (GHRT) in Patients with Adult GH Deficiency (AGHD) Aged ≥60 Years: Data from NordiNet® IOS and the ANSWER Program

Abstract There are limited data on the effectiveness and safety of GHRT in older patients with AGHD. We compared real-world GHRT outcomes in older (aged ≥60 years) versus middle-aged (35–&amp;lt;60 years) adults. NordiNet® IOS (NCT00960128) and ANSWER (NCT01009905) were non-interventional studies investigating long-term effectiveness and safety of GHRT with Norditropin® (somatropin, Novo Nordisk). Safety was assessed in the Full Analysis Set (FAS) from both studies (non-GH-naïve patients included). The Effectiveness Analysis Set (EAS) was from NordiNet® IOS only (GH-naïve patients; ANSWER-EAS included patients previously treated for ≤6 months). Serious adverse reactions (SARs) and non-serious ARs (NSARs) with a suspected causal relationship to GHRT, and serious adverse events (SAEs) not considered related to GHRT are presented as incidence rates per 1000 patient-years and as incidence rate ratios (IRRs) for older versus middle-aged adults. Of the 759 patients in the EAS, 545 were middle-aged and 214 older adults, mean (standard deviation) age 48.5 (7.0) and 67.2 (4.9) years, with 45.9% and 39.3% females, respectively. At baseline, GH dose was 0.24 (0.16) and 0.20 (0.10) mg/day, insulin-like growth factor-I standard deviation score (IGF-I SDS) was -0.94 (1.40) and -0.82 (1.36) and BMI was 29.29 (6.09) and 28.95 (4.58) kg/m2, respectively. Mean follow-up was 5.4 (4.3) and 5.3 (3.9) years, respectively. Of the 2348 patients in the FAS, 1696 were middle-aged and 652 older adults, aged 48.4 (7.1) and 67.1 (5.1) years, of which 52.4% and 43.3% were female, respectively. Baseline GH dose was 0.32 (0.24) and 0.26 (0.18) mg/day, IGF-I SDS was -0.58 (1.53) and -0.27 (1.54) and BMI was 30.50 (7.26) and 29.42 (5.39) kg/m2, respectively. Mean follow-up was 5.2 (4.5) and 4.7 (3.9) years, respectively. Mean GH exposure was greater in women than men, and in middle-aged than older women (FAS); it increased slightly over time in all groups. Baseline IGF-I SDS was slightly higher in older versus middle-aged women, but not men (EAS). Mean IGF-I SDS increased from below 0 to values ≤1.24 with GHRT. Mean changes in BMI (EAS) and HbA1c (EAS and FAS) were small and similar between age groups in both sexes. No statistically significant differences were observed between older and middle-aged adults regarding incidence rates for NSARs (5.66 vs 5.38; IRR [mean; 95%CI] 1.051 [0.604;1.831]) and SARs (1.00 vs 2.52; IRR 0.396 [0.119;1.324]). As expected, SAE incidence rate (considered unrelated to GHRT) was higher in the older group (16.64 vs 9.04, IRR 1.840 [1.291;2.622]). Similarly, the IRRs of patients ≥75 (n=59) years versus the middle-aged group were only significant for SAEs (23.09 vs 9.04; IRR 2.553 [1.113;5.855]). These data suggest similar clinical outcomes with GHRT in patients with AGHD aged ≥60 compared with 35–&amp;lt;60 years without additional risk of adverse drug reactions in older patients. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON190 Characterization Of Lymphedema With Respect To Phenotype and Karyotype in Patients With Turner Syndrome

Abstract We characterize karyotypic and phenotypic features of a cohort of patients with Turner syndrome (TS) and lymphedema (LD). Medical records from two large TS specialized pediatric clinics were reviewed retrospectively. Seventy-one patients with TS and history of LD were identified, mean age 15.9 ± 7.71 years. Reported LD onset was in infancy in 72% of patients, with 56% (40/71) reporting LD present at birth. LD affected hands in 29% of patients, feet in 57%, and both hands and feet in 25%. 46% reported LD was a current problem, with 11% stating it was present but not a problem. 73% (52/71) of children in this cohort had the 45,X karyotype. The remainder had mosaic/complex karyotypes. 55% of children had congenital heart disease and 10% had renal anomalies. 76% were on growth hormone treatment, 52% had a history of estrogen replacement. Lymphedema is a frequently under-documented comorbidity in Turner syndrome, with limited data currently available. Analysis of a larger cohort comparing patients with TS with and without LD is underway including the role of growth hormone and estrogen replacement in LD. Given that new therapies are being developed for LD in other genetic conditions, a better understanding of LD in Turner syndrome is important for management considerations. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

OR17-4 Hormone Replacement Promotes Sexual Maturation and Fertility Restoration in Mice With Congenital Hypopituitarism Harboring Prop1 Mutation

Abstract Introduction The Ames strain, a spontaneous mutant mouse of the Prop1 gene, is deficient in GH, TSH, PRL and gonadotropins. In recent years, it has been the focus of studies on aging and there is a growing interest in elucidating the role of hormone replacement (HR) in the hypothalamic-pituitary-gonadal (HPG) axis. Aim The present study aimed to characterize sexual maturation and fertility restoration in isogenic strain under or not HR. Material and methods Five homozygous male animals were treated via intraperitoneal injections, starting 30 days postnatally, with levothyroxine 3x/week and recombinant human GH 5x/week for 40 days, followed by maintenance applications of both hormones once a week until they complete 90 days post natal. The sexual maturity was evaluated looking for balanoprepucial opening and descendent testis comparing untreated homozygous (n=5) with their wild type siblings (n=5). Fertility was evaluated by mating known fertile wild type animals with treated and untreated animals for 8 times. Reproductive parameters were evaluated between groups using histological sections of the testes (HE) and classified according to johnsen score where 1-2 was classified as absent germline cells and 8-10 normal development. At the sacrifice, testicular weight was measured using scale and spermogram was done looking for motility and viability in the sperm collected in the seminiferous tube. Gata2 transcription factor and pituitary hormones Lh, Fsh, Tsh, Prl and Gh transcriptional analysis were performed by RT-qPCR. Results The homozygous treated animals presented a 2 weeks delay in the age of sexual maturation compared to wild animals. Their fertility and reproductive parameters were restored noticed by increased testicular weight, improved spermatogenesis, similar morphology of seminiferous tubules (johnsen score 8.7) and spermogram compared to the wild type, besides presenting offspring when mated to their wild siblings. Sexual maturity was absent in most of the untreated homozygous animals presenting no offspring. The reproductive parameters in the untreated homozygous animals presented reduced testicular weight, size of seminiferous tubes leading to johnsen score as 5 and an azospermic spermogram in all animals. Interestingly 2 untreated homozugous animal had spontaneous maturation. Gata2 was significant decreased in the untreated animal (0,49 ± 0,19) compared to wild type (1 ± 0,15) (p≤ 0.019). LH transcriptional pattern was significant increase in the animals under treatment (1.56 ± 0.68) compared to homozygotes without hormonal intervention (0.36 ± 0.34) (p≤ 0.048). Conclusion Ames mutant mice under treatment with GH and levothyroxine replacement reached sexual maturation and restored fertility and the mechanics behind this phenomenon will be explored using RNA seq in the future. Presentation: Sunday, June 12, 2022 11:45 a.m. - 12:00 p.m.

ODP329 Long-term Effect of Daily Growth Hormone Replacement Therapy on Glucose Tolerance in Adult growth Hormone Deficiency

Abstract Background Growth hormone replacement therapy (GHRT) in adults with growth hormone deficiency (AGHD) has shown to improve body composition, lipid and bone metabolism, and quality of life (QOL), but its effect on glucose tolerance can be bidirectional. Objective To investigate the long-term effect of GHRT on glucose tolerance in AGHD patients. Patients and Methods We conducted a retrospective single-center study at Kobe University Hospital. One hundred twenty-five AGHD patients who had visited our department since January 2011 to September 2021 were enrolled. The exclusion criteria was as follows: Patients 1) who never received GHRT 2) whose HbA1c was 6.5% or higher, or under antidiabetic drugs before GHRT, 3) not available data on HbA1c at baseline or after GHRT 4) with functional pituitary adenomas, 5) who had initiated GHRT at childhood and had discontinued GH for less than 1year due to transition, 6) who receiving supraphysiological doses of steroid therapy, 7) GHRT interruption period for more than 1 year or its initiation from less than 2 months. Fifty-three AGHD patients eventually met the inclusion criteria. We collected data at baseline, 3, 6, 12 months after treatment, and at each patients’ last visit. The influence of GHRT on glucose metabolism and its associated factors were analyzed. All data were presented as median [interquartile range]. Results Fifty-three patients (27 female (51. 0%), 14 childhood onset (26.4%), age at GH initiation was 45 [32 - 60] years, the duration of GHRT was 4 [2 - 6] years) were analyzed. Both IGF-I levels and IGF-I SDS increased at the last visit compared to baseline: 56 [38 - 88] to 119 [84.5 - 181] ng/mL (P&amp;lt;0. 01), and -3.4 [-5.1 - -2.4] to -0.2 [-1.8 - 1.1] (P&amp;lt;0. 01), respectively. Waist circumference and BMI remained unchanged: 85 [78 - 90.5]cm to 78.5 [72.1 - 86. 0]cm (P=0.18), 23.1 [21.3 - 26.3] kg/m 2 to 22.9 [21.9 - 26.8] kg/m 2 (P=0.53), respectively. HbA1c at baseline, 3, 6, 12 months after treatment, and the last visit were unchanged: 5.7[5.4 - 5.9]%, 5.7 [5.5 - 5.9]%, 5.8 [5.5 - 6. 0]%, 5.7 [5.5 - 6. 0]%, and 5.7 [5.5 - 6. 0]% (P=0.27). Based on the amount of change in HbA1c (ΔHbA1c) between baseline and at the last visit, we divided into two groups; Elevated/ Unchanged (E/U), and Reduced (R). Interestingly, the amount of change in BMI increased in E/U group but decreased in R group (0.9[-0.1–1.8] vs. -1.2[-1.4 - -0.1], P=0. 02). Conclusions Overall, GHRT was safely used in regard with impaired glucose tolerance at least non-diabetes mellitus patients with AGHD. Among them, cases with impaired glucose tolerance during GHRT were associated with increased BMI. Presentation: No date and time listed

Metabolic Profile and Echocardiographic Evaluation in Adults with Growth Hormone Deficiency.

Adult growth hormone deficiency (AGHD) is associated with increased cardiovascular risks. The primary endpoint of this retrospective cohort study was to compare metabolic profile and echocardiographic parameters in childhood-onset (CO) and adulthood-onset (AO) AGHD patients. 26 patients with CO AGHD (19 males, 26.8±8.5 years) and 41 patients with AO AGHD (23 males, 35.1±6.8 years) were included. The standard deviation score of insulin-like growth factor-1 (IGF-1 SDS), metabolic profile, liver sonography and echocardiographic parameters were compared. The IGF-1 SDS were significantly lower in CO AGHD patients (p<0.05). AO AGHD patients showed much profound glycolipid aberrations, elevated C-reactive protein levels (p=0.012), and proportionally higher prevalence of non-alcoholic fatty liver disease (95.2% vs.8.3%, p<0.001). In all subjects, IGF-1 SDS was negatively related to low-density lipoprotein cholesterol, and positively related to total cholesterol and lipoprotein a (Lpa). There were significant differences between the two group with regard to the correlations between IGF-1 SDS and high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, LPa, uric acid and creatinine (all p for interaction<0.05). CO AGHD patients exhibited smaller heart, but similar ventricular ejection fraction compared to AO AGHD patients. AGHD may be a group of heterogenous entity based on the onset ages of disease. AO patients had prominent metabolic disorders, while CO patients had smaller heart but similar cardiac performance. Whether growth hormone replacement therapy will equally benefit both CO and AO AGHD patients needs further investigations.

Somapacitan: a long-acting growth hormone derivative for treatment of growth hormone deficiency

Growth hormone deficiency (GHD) is characterized by inadequate HG production from the anterior pituitary gland. Adult patients with GHD have increased fat mass, an abnormal lipid profile, decreased lean body mass and bone mineral density, decreased muscle strength and exercise endurance, and a diminished quality of life. Adult GHD (AGHD) has been treated with GH replacement therapy by daily subcutaneous injections. However, the administration of daily injections can be burdensome for some patients and affect treatment adherence. Somapacitan is a new long-acting human GH (hGH) analogue that is administered once a week by subcutaneous injection. It was first approved by the U.S. Food and Drug Administration (FDA) as GH replacement therapy for adults with GHD, becoming the first hGH therapy for AGHD administered by once-weekly injection, compared with other approved hGH therapies for AGHD administered by daily injection. This article reviews the pharmacokinetic, clinical and safety data that led to the approval of somapacitan as the first long-acting GH therapy for adults with GHD.

Effects of 18 months of GH replacement on cardiovascular risk factors and quality of life in GH deficient adults; a randomized controlled trial using a fixed very low and a standard dose of GH

ObjectiveLittle is known of the effects of a fixed very low dose of growth hormone (GH) replacement on cardiovascular risk factors, bone mass, muscle strength and quality of life (QoL) in hypopituitary patients. Design/patients/methodsThis was an open-label randomized study performed at a single center. Consecutive hypopituitary patients with adult onset GH deficiency (GHD) and BMI ≥ 27 kg/m2 were randomized to receive a very low fixed dose of GH (LG, n = 9) or a standard dose of GH (SG, n = 9). Body composition, glucose and lipid metabolism, bone mineral content (BMC) and density (BMD), muscle strength, and QoL were measured at baseline and after 6, 12 and 18 months. ResultsThe fixed GH dose in LG was 0.1 mg/day. In SG, the mean baseline GH dose of 0.13 mg/day was gradually increased to 0.31 mg/day at study end. Lean body mass (LBM) as measured using DEXA as well as total body water (TBW) and extracellular water (ECW) were increased only in SG (P < 0.01, P < 0.05, and P < 0.01 vs. LG, respectively). There were no between-groups differences in BMD, BMC, insulin sensitivity, lipids, or muscle strength. Finally, although not significant compared with SG, a sustained improvement in QoL was seen in LG according to the QoL-AGHDA questionnaire. ConclusionIn this pilot study, a fixed very low GH dose improved QoL in GHD adults without any induction of fluid retention. Other effects were comparable to those produced by the standard GH dose. Replacement with a very low GH dose could therefore be a treatment option in hypopituitary patients, especially in patients who do not tolerate higher GH dosage.Trial registrationThis study is registered at ClinicalTrials.gov, EU-nr 2009–016783-37.