Normal GH Levels Research Articles

THU182 Widening The Spectrum Of ABCC8-related Disease: Insulin-mediated Pseudoacromegaly

Abstract Disclosure: I.F. Machado: None. B.B. Mendonca: None. A. Latronico: None. M.Y. Nishi: None. L.G. Gomes: None. Introduction: Insulin-mediated pseudoacromegaly is a rare condition characterized by acromegaloid phenotype without excessive GH secretion in the context of severe hyperinsulinemia. Case report: A 10.5 years old girl with tall stature, obesity, acanthosis nigricans, neurosensorial hearing deficiency and acromegaloid features was referred for clinical investigation. She was born of non-consanguineous parents, full-term, with normal birth weight and stature. She had no history of neonatal hypoglycemia or in infancy. At six years of age, she presented marked accelerated growth velocity and weight gain resulting in bilateral slipped femoral epiphysis. She developed thelarche at 7 years old, and was treated with gonadotropin releasing hormone agonist (GnRHa) from 8-10.5 years. Hearing deficiency was diagnosed at 7 years of age. Her family history was remarkable for paternal sudden cardiac death at age 35. At physical examination, she had an acromegaloid facial appearance with a prominent forehead and jaw, large hands and feet, and severe acanthosis nigricans in neck and axillae. Her weight and height were 99.5 kgs (Z 8.8) and 170 cm (Z 4.6), respectively; target height was 1.66 m (Z 0,72) and BMI was 34.4 (Z 3.5). Her breast and pubic hair development were Tanner stage IV. Laboratory exams showed normal IGF-1 and random GH levels. There was an abnormal response of GH (2.63 ng/mL) following an oral glucose tolerance test (OGTT), considered as false positive in the context of obesity and puberty. Her brain magnetic resonance was normal. She had a hemoglobin glycated of 6.1% and very high basal insulin levels of 98 µUI/mL with a normal glucose value of 81 mg/dL and OGTT-120 minutes insulin levels > 1000 µUI/mL with glucose of 113 mg/dL. Exome sequencing analysis showed a heterozygous missense ABCC8 variant c.622G>A p.(Glu208Lys), located in an exonic hotspot, and allele frequency absent from gnomAD databases. The ACMG classified this variant as pathogenic. Pseudoacromegaly, a heterogeneous condition, is caused by multiple genetic and pathophysiological backgrounds. In insulin-mediated pseudoacromegaly, the defects are mainly associated with postreceptor insulin signaling and action. We described a new type of hyperinsulinemic pseudoacromegaly caused by a mutation in the ABCC8 gene, which encodes the sulfonylurea receptor, a member of the K(ATP) channel superfamily. This gene is associated with congenital hyperinsulinemia causing hypoglycemia, generally when in homozygous state. This clinical report illustrates a new phenotype associated with ABCC8 mutation, and identifies a new genetic cause of hyperinsulinemic pseudoacromegaly. Conclusion: We described a patient with insulin-mediated pseudoacromegaly associated with neurosensorial hearing deficiency caused by a dominant variant in the ABCC8 gene, defining a new genetic cause of this intriguing disorder. Presentation: Thursday, June 15, 2023

Short stature related to Growth Hormone Insensitivity (GHI) in childhood.

Linear growth during childhood is the result of the synergic contribution of different factors. The best growth determinant system during each period of life is represented by the growth hormone-insulin-like growth factor axis (GH-IGF), even if several other factors are involved in normal growth. Within the broad spectrum of growth disorders, an increased importance has been placed on growth hormone insensitivity (GHI). GHI was reported for the first time by Laron as a syndrome characterized by short stature due to GH receptor (GHR) mutation. To date, it is recognized that GHI represents a wide diagnostic category, including a broad spectrum of defects. The peculiar characteristic of GHI is the low IGF-1 levels associated with normal or elevated GH levels and the lack of IGF-1 response after GH administration. Recombinant IGF-1 preparations may be used in the treatment of these patients.

Relationship between hemoglobin and insulin-like growth factor-1 in children and adolescents with idiopathic short stature

BackgroundThe growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis is critical for the regulation of children’s growth and development. Serum IGF-1 concentrations are usually low in individuals with idiopathic short stature (ISS) despite normal endogenous GH levels, and the associated underlying factors are unknown. This study aimed to explore the relationship between IGF-1 and hemoglobin (Hb) in children with ISS.MethodsA cross-sectional analysis was performed including 178 children and adolescents with ISS who were enrolled from March 2013 to February 2019. The related clinical and biochemical parameters were evaluated for each patient. Univariate analysis, smooth curve fitting and multivariate piecewise linear regression were performed.ResultThe mean levels of IGF-1 standard deviation scores (SDS) and Hb were − 0.99 (− 1.60 - -0.09) and 131.81 ± 9.36 g/L, respectively. Univariate analysis displayed a significant positive association between Hb and IGF-1 SDS (P < 0.001). After adjusting for potential confounding factors, the positive relationship between Hb and IGF-1 SDS remained (P = 0.001). Furthermore, there was an inflection point for Hb in the curve. In a multivariate piecewise linear regression model, IGF-1 SDS was significantly positively associated with Hb when Hb concentrations were lower than 145 g/L (B 0.05; 95% CI 0.02, 0.07; P < 0.001). However, IGF-1 SDS decreased with increasing Hb levels when Hb concentrations were greater than 145 g/L (B -0.15; 95% CI -0.23, − 0.06; P = 0.001).ConclusionThis study demonstrated that Hb is associated with IGF-1 in Chinese children and adolescents with ISS. The levels of IGF-1 increased with the elevation of Hb, but when the concentration of Hb exceeded a certain range, with the increase of Hb, IGF-1 decreased instead.

SAT-LB54 Acute Sterile Meningitis as a Primary Manifestation of Pituitary Apoplexy

Background: Pituitary apoplexy (PA) is a rare endocrinopathy that requires prompt diagnosis and treatment. Presentation with acute neutrophilic meningitis is uncommon.Clinical Case: A 67-year-old man presented to our hospital with a 2-week history of worsening bilateral frontal headache, nausea, and dry heaving. On admission, the patient was somnolent with a score of 13 on the GCS assessment (E2, V5, M6). The neurological exam was overall normal with normal ocular motion and intact cranial nerves, except for a left eye peripheral vision defect. Plain head CT revealed a well-circumscribed ovoid pituitary mass with suprasellar enlargement, consistent with a pituitary macroadenoma. Sellar MRI showed a pituitary mass, roughly 20 x 19 x 24 mm, bulging into the suprasellar cistern with optic chiasm elevation. Analysis of pituitary function revealed low ACTH concentration of 2.8 pg/mL (n = 7.2 - 63.3 pg/mL), a low random cortisol level of 1.7 ug/dL (n = 2.9 - 19.4 ug/dL), a low TSH of < 0.1 uIU/mL (n = 0.35 - 4.9 uIU/mL), a low free T4 level of 0.72 ng/dL (n = 0.77 - 1.48 ng/dL), a low LH of 0.8 IU/L (n = 1.7 - 8.6 IU/L) with a very low total testosterone level of < 3 ng/dL (n = 300 - 720 ng/dL) and normal prolactin, IGF-1 and GH levels. On hospital day 2, the patient had worsening encephalopathy with left eye ptosis and decreased vision. Repeat CT and MRI showed no interval change in the pituitary adenoma or evidence of bleeding. An immediate lumbar puncture was performed and CSF analysis revealed an increased leukocyte count of (1106/mm3) with 89% neutrophilic granulocytes, and increased total protein level of 138 mg/dL (n = 15 - 40 mg/dL), red blood cell count of 2040 without xanthochromia and glucose of 130 mg/dL (n = 40 - 70 mg/dL). Based on the laboratory results and new symptoms, empirical antibiotic (vancomycin, ceftriaxone, and ampicillin) therapy was started for suspected bacterial meningitis before the confirmation of the CSF culture study. CSF culture did not grow any organisms. Given the sudden visual impairment and neurological deterioration, the patient underwent transsphenoidal resection of the tumor with free nasal mucosal graft reconstruction. Histological examination revealed a necrotic pituitary adenoma with apoplexy and no evidence of hemorrhage. Postoperatively, his neurological exam greatly improved. His left pupil was reactive to light and the third palsy was improving.Conclusion: This case reinforces the importance of including PA in the differential diagnosis of acute headache, particularly in patients presenting with visual disturbances. Patients with PA often present with sterile meningitis due to increased debris and blood in the subarachnoid space which closely mimics acute bacterial meningitis. While MRI remains a sensitive imaging modality for the detection of PA, the latter remains a clinical diagnosis. Timely diagnosis with high clinical suspicion and treatment is essential.

SAT-078 Griscelli Syndrome and Late Endocrine Effects After Stem Cell Transplant

BACKGROUND: This a unique case of late-onset endocrinopathies after stem cell transplant in a girl with Griscelli syndrome. Griscelli syndrome is a rare disorder characterized by partial albinism, silver hair and immune failure with alteration in genes necessary for melanin transport, which is curative by stem cell transplant. Although late endocrinopathies are quite common in other disorders after stem cell transplant, these complications have not been reported in Griscelli syndrome. CLINICAL CASE: A 7-year old female who received a stem cell transplant as a toddler and subsequently developed graft-versus-host-disease (GvHD) at 2 years of age presented for evaluation of growth failure. Patient had severe short stature along with mild hyperthyroxinemia with subsequent diagnosis of Graves’ disease which was treated with methimazole. Although hypothyroidism is more commonly seen after stem cell transplant, rare cases of hyperthyroidism have been reported. Despite normal GH and IGF-1 levels, GH therapy was commenced due to persistent growth failure. She showed a robust increase in growth parameter from -6 to -2 SD below the mean. She started spontaneous puberty, however, biochemical evaluation showed hypergonadotropic hypogonadism with undetectable anti-mullerian hormone (AMH) which is consistent with low ovarian reserve most likely related to total body irradiation prior to stem cell transplant. CONCLUSION: Our patient demonstrates that growth failure, thyroid disease and ovarian dysfunction can be complications of stem cell transplants in young children with Griscelli syndrome. This can be a result of the underlying disease leading to transplant, conditioning regimen prior to transplant or complications thereafter. GvHD may also be a risk factor for future autoimmune endocrine complications in this syndrome and in other syndromes treated with stem cell transplant. REFERENCES: (1) Griscelli C, Prunieras M. Pigment dilution and immunodeficiency: a new syndrome. Int J Dermatol. 1978;10:788–91.(2) Sağ E, Gönç N, Alikaşifoğlu A, et al. Hyperthyroidism after allogeneic hematopoietic stem cell transplantation: A Report of Four Cases. J Clin Res Pediatr Endocrinol. 2015;4:349–54.

Abstract TP167: Prevalence of Growth Hormone Deficiency in the Chronic Phase of Recovery From Stroke

Introduction: The objective of the current retrospective study was to determine the prevalence of growth hormone deficiency (GHD) in middle-aged patients with ischemic and hemorrhagic stroke who were at least 3 months post-stroke. It was hypothesized a large percentage of patients with stroke would exhibit growth hormone deficiency, as well as, other hormone deficiencies. A secondary objective was to determine if chronic health conditions often associated with stroke were associated with neuroendocrine dysfunction. Methods: Clinical records from 139 adult patients (from 2009-2017), who were in the post-acute phase of their recovery, were obtained to analyze findings from standard endocrine blood tests. Patients with a pre-stroke history of endocrine anomalies were excluded from the study. Growth hormone was assessed by the glucagon stimulation test (GST). Results: GHD was identified in 54% of the patients with stroke during the chronic phase of recovery. Patients with GHD took longer to be admitted to post-acute rehabilitation compared to patients with normal GH levels. Patients with GHD also had lower levels of follicle stimulating hormone (FSH), triiodothyronine (T3), luteinizing hormone (LH) and sex hormone binding globulin. Body mass index was higher in patients with GHD. Conclusions: There is a considerable risk of developing hypopituitarism, particularly GHD, following ischemic or hemorrhagic stroke. In this relatively large sample of middle-aged stroke patients, GHD was associated with decreased levels of T3 and gonadotrophic hormones. Co-morbidities for stroke and neuroendocrine dysfunction overlap and may have implications for recovery following stroke and warrant further investigation.

Growth Hormone's Links to Cancer.

Several components of the GH axis are involved in tumor progression, and GH-induced intracellular signaling has been strongly associated with breast cancer susceptibility in genome-wide association studies. In the general population, high IGF-I levels and low IGF-binding protein-3 levels within the normal range are associated with the development of common malignancies, and components of the GH-IGF signaling system exhibit correlations with clinical, histopathological, and therapeutic parameters in cancer patients. Despite promising findings in preclinical studies, anticancer therapies targeting the GH-IGF signaling system have led to disappointing results in clinical trials. There is substantial evidence for some degree of protection against tumor development in several animal models and in patients with genetic defects associated with GH deficiency or resistance. In contrast, the link between GH excess and cancer risk in acromegaly patients is much less clear, and cancer screening in acromegaly has been a highly controversial issue. Recent studies have shown that increased life expectancy in acromegaly patients who attain normal GH and IGF-I levels is associated with more deaths due to age-related cancers. Replacement GH therapy in GH deficiency hypopituitary adults and short children has been shown to be safe when no other risk factors for malignancy are present. Nevertheless, the use of GH in cancer survivors and in short children with RASopathies, chromosomal breakage syndromes, or DNA-repair disorders should be carefully evaluated owing to an increased risk of recurrence, primary cancer, or second neoplasia in these individuals.

Treatment escape reduces the effectiveness of cabergoline during long-term treatment of acromegaly in monotherapy or in association with first-generation somatostatin receptor ligands.

Few studies evaluated the use of cabergoline (CAB) for acromegaly treatment in monotherapy or in combination with first-generation somatostatin receptor ligands (SRLs). To evaluate the efficacy, predictors of response and safety of CAB treatment in acromegaly both in monotherapy and in combination with SRLs. We retrospectively collected demographic, biochemical, tumour and treatment data. Short-term disease control was defined as random GH level < 1.0μg/L and normal age-matched IGF-I level after 3-6months of treatment with the higher dose used. Long-term disease control was defined as maintenance of normal GH and IGF-I levels at the last visit (at least 9months of treatment). Eighty-two patients were studied. The median total time of treatment in monotherapy or in combination with SRLs was 14months (3-124) and 34months (3-88), respectively. Short-term disease control was observed in 6 (21%) patients in the monotherapy group and in 20 (32%) in the combination group. Treatment escape was observed in 1 patient after 16months of CAB monotherapy and in 6 (30%) patients with combination therapy (after a median of 38months), resulting in long-term disease control of 18% and 23%, respectively. Hyperprolactinemia was a predictor of response to monotherapy and pretreatment GH level to combination treatment. We presented the results of the largest single-centre study with CAB in monotherapy and in combination with SRL. The efficacy of CAB in acromegaly seems to be lower than that of other drugs, and treatment escape may occur after a long-term follow-up.

Genetic disorders of GH action pathway

While insensitivity to GH (GHI) is characterized by low IGF-I levels, normal or elevated GH levels, and lack of IGF-I response to GH treatment, IGF-I resistance is characterized by elevated IGF-I levels with normal/high GH levels. Several genetic defects are responsible for impairment of GH and IGF-I actions resulting in short stature that could affect intrauterine growth or be present in the postnatal period. The genetic defects affecting GH and/or IGF-I action can be divided into five different groups: GH insensitivity by defects affecting the GH receptor (GHR), the intracellular GH signaling pathway (STAT5B, STAT3, IKBKB, IL2RG, PIK3R1), the synthesis of insulin-like growth factors (IGF1, IGF2), the transport/bioavailability of IGFs (IGFALS, PAPPA2), and defects affecting IGF-I sensitivity (IGF1R).Complete GH insensitivity (GHI) was first reported by Zvi Laron and his colleagues in patients with classical appearance of GH deficiency, but presenting elevated levels of GH. The association of GH insensitivity with several clinical sings of immune-dysfunction and autoimmune dysregulation are characteristic of molecular defects in the intracellular GH signaling pathway (STAT5B, STAT3, IKBKB, IL2RG, PIK3R1). Gene mutations in the IGF1 and IGF2 genes have been described in patients presenting intrauterine growth retardation and postnatal short stature. Molecular defects have also been reported in the IGFALS gene, that encodes the acid-labile subunit (ALS), responsible to stabilize circulating IGF-I in ternary complexes, and more recently in the PAPPA2 gen that encodes the pregnancy-associated plasma protein-A2, a protease that specifically cleaves IGFBP-3 and IGFBP-5 regulating the accessibility of IGFs to their target tissues.Mutations in the IGF1R gene resulted in IGF-I insensitivity in patients with impaired intrauterine and postnatal growth.These studies have revealed novel molecular mechanisms of GH insensitivity/primary IGF-I deficiency beyond the GH receptor gene. In addition, they have also underlined the importance of several players of the GH-IGF axis in the complex system that promotes human growth.

Compound heterozygosity for two GHR missense mutations in a patient affected by Laron Syndrome: a case report

BackgroundMutations localized in the Growth Hormone Receptor (GHR) gene are often associated with the pathogenesis of Laron Syndrome, an autosomal recessive hereditary disorder characterized by severe growth retardation. Biochemically, patients present normal to high circulating GH levels, in presence of very low or undetectable IGF-I levels, which do not rise after rhGH treatment.Case presentationWe describe the case of a 3.8 years old girl with symmetrical short stature (−3.76 SDS), low IGF-1 and IGFBP-3, in presence of normal GH levels. Parents were not relatives and there was no family history of short stature. During the second day of birth, she developed severe hypoglycaemia that required glucose infusion. She presented frontal bossing and depressed nasal bridge. IGF-1 generation test showed no response, suggesting a GH resistance evidence. In the hypothesis of Laron Syndrome, we decided to perform a molecular analysis of Growth Hormone Receptor (GHR) gene. This analysis demonstrated that the patient was compound heterozygote for two missense mutations.ConclusionsGHR gene mutations are a well demonstrated cause of GH insensitivity. In heterozygous patients, probably the normal stature may be achieved by a compensatory mechanism of GH secretion or signalling. On the contrary, in homozygous or compound heterozygous patients these compensatory mechanisms are inadequate, and short stature may be the consequence.

Utility of baseline serum phosphorus levels for predicting remission in acromegaly patients.

High GH and IGF I levels increase tubular phosphate reabsorption in patients with acromegaly. We aimed to investigate the utility of serum phosphorus levels as an indicator for predicting chance of remission in acromegaly patients. Fifty-one patients (n: 51; F: 24, M: 27) with diagnosis of acromegaly were included in the study. Plasma IGF-1, Phosphorus (P) and nadir GH levels on oral glucose tolerance test (OGTT) at the time of diagnosis were analysed retrospectively. Patients were classified into two groups according to their plasma P levels; P ≤ 4.5mg/dl (Group-1, n: 23, 45.1%), P>4.5mg/dl (Group-2, n: 28, 54.9%). Two groups were compared according to remission status; remission (n: 27) and non-remission (n: 24). Remission was defined with absence of clinical symptoms, normal plasma IGF-1 (adjusted for age and gender) and GH levels (<1 mcg/dl) at least 3 months after initial treatment. Serum P levels decreased significantly after treatment in both groups (p < 0.001). There was a significant correlation between baseline phosphorus levels and remission rates, nadir GH in OGTT, pituitary adenoma size and Ki-67 scores (p = 0.001, r: -0.51; p = 0.01, r: 0.44; p = 0.001, r: 0.52; p = 0.02, r: 0.71, respectively). Mean baseline P levels were significantly higher in patients with non-remission (4.8 vs 4.2, P < 0.001). Logistic regression analysis did not reveal an independent effect on remission with any of these risk factors. High serum P levels may be an indicator for a low likelihood of onset of remission in acromegaly patients. Further studies with wider spectrum are needed to make specific suggestions.

Pituitary gigantism: a retrospective case series.

Pituitary gigantism (PG) is a rare pediatric disease with poorly defined long-term outcomes. Our aim is to describe the longitudinal clinical course in PG patients using a single-center, retrospective cohort study. Patients younger than 19 years diagnosed with PG were identified. Thirteen cases were confirmed based on histopathology of a GH secreting adenoma or hyperplasia and a height >2 SD for age and gender. Laboratory studies, initial pathology, and imaging were abstracted. Average age at diagnosis was 13 years with an average initial tumor size of 7.4×3.8 mm. Initial transsphenoidal surgery was curative in 3/12 patients. Four of the nine patients who failed the initial surgery required a repeat procedure. Octreotide successfully normalized GH levels in 1/6 patients with disease refractory to surgery (1/6). Two out of five patients received pegvisomant after failing octreotide but only one patient responded to treatment. Five patients were ultimately treated with radiosurgery or radiation patients were followed for an average of 10 years. PG is difficult to treat. In most patients, the initial transsphenoidal surgery failed to normalize GH levels. If the initial surgery was unsuccessful, repeat surgery was unlikely to control GH secretion. Treatment with octreotide or pegvisomant was successful in less than half the patients failing surgery. Radiosurgery was curative, but is not an optimal treatment for pediatric patients. Despite the small sample, our study suggests that the treatment outcome of pediatric PG may be different than adults.

Growth hormone - insulin-like growth factor-I axis and bone mineral density in adults with thalassemia major

Introduction:Bone disease and short stature are frequent clinical features of patients with beta-thalassaemia major. Dysfunction of the GH-IGF-1 axis has been described in many thalassemics children and adolescents with short stature and reduced growth velocity. Assessment of the GH-IGF-1 axis in short adults with TM after attainment of final height may be required to select those who are candidates for replacement therapy and to prevent the development of bone disease. The aim of our study was to investigate GH secretion in adult thalassemic patients in relation to their bone mineral density (BMD) and serum ferritin concentrations.Materials and Methods:We performed clonidine stimulation test in 30 thalassemic patients (18 males, 12 females) with a mean age of 31.5± 7.2 years. The cut-off level for GH response was set at 7ug/l, according to the literature. Serum ferritin, IGF-I, liver enzymes, alkaline phosphatase (ALP) and type 1 Collagen Carboxy Telopeptide (CCT1) were also determined.Results:We diagnosed GH deficiency (GHD) in 12 patients (40%) and IGF-I deficiency (IGF-I SDS <-2) was diagnosed in 20 patients (67%). Adult patients with TM had significantly decreased IGF-I concentrations and bone mineral density (BMD) at the femur neck and lumbar spine compared to normal controls. Thalassemic patients with GHD and IGF-I deficiency had significantly lower BMD T score at the lumbar spine compared to patients with normal GH and IGF-I levels. Thalassemic patients had higher serum CCT1 concentrations compared to normal controls. Peak GH levels were correlated significantly with IGF- I concentrations and IGF-I levels were correlated significantly with the height SDS (HtSDS) of thalassemic patients. Neither GH peak nor IGF-I concentrations were correlated to serum ferritin concentrations.Conclusions:We conclude that GH status should be tested in adult thalassemic patients especially those with short stature and/or decreased BMD. Clonidine test appears to be effective and safe in adults with TM. If the diagnosis of adult GHD is established, GH treatment may be considered for possible improvement of bone mineral density and heart function in patients with TM.

Growth Hormone – Insulin-Like Growth Factor –I (IGF-I) Axis and Bone Mineral Density In Adults With Thalassemia Major (TM)

Bone disease and short stature are frequent clinical features of patients with beta-thalassaemia major. Dysfunction of the GH-IGF-1 axis has been described in many thalassaemic children and adolescents with short stature and reduced growth velocity.Assessment of the GH-IGF-1 axis in short adults with TM after attainment of final height may be required to select those who are candidates for replacement therapy and to prevent the development of bone disease. The aim of our study was to investigate GH secretion in adult thalassaemic patients in relation to their bone mineral density (BMD) and serum ferritin concentrations. Patients and methodsWe performed clonidine stimulation test in 30 thalassaemic patients (18 males, 12 females) with a mean age of 31.5 +/- 7.2 years. The cut-off level for GH response was set at 7 microg/l, according to the literature. Serum ferritin, IGF-1, liver enzymes, alkaline phosphatase (ALP) and and type1 Collagen CarboxyTelopeptide (CCT1) were also determined. ResultsWe diagnosed GH deficiency (GHD) in 12 patients (40 %) and IGF-I deficiency (IGF-I SDS < -2) was diagnosed in 20 patients (67 %). Adult patients with TM had significantly decreased IGF-I concentrations and bone mineral density (BMD) at the femur neck and lumbar spine compared to normal controls. Thalassemic patients with GHD and IGF-I deficiency had significantly lower BMD T score at the lumbar spine compared to patients with normal GH and IGF-I levels. Thalassemic patients had higher serum CCT1 concentrations compared to normal controls. Peak GH levels were correlated significantly with IGF- I concentrations and IGF-I levels were correlated significantly with the height SDS (HtSDS) of thalassemic patients. Neither GH peak nor IGF-I concentrations were correlated to serum ferritin concentrations. ConclusionsWe conclude that GH status should be tested in adult thalassaemic patients especially those with short stature and/or decreased BMD. If the diagnosis of adult GHD is established, GH treatment may be considered for possible improvement of bone mineral density and heart function in thalassaemic patients. Disclosures:No relevant conflicts of interest to declare.

AIP expression in sporadic somatotropinomas is a predictor of the response to octreotide LAR therapy independent of SSTR2 expression

mutation and/or a history of medical treatment with SRL before surgery. Biochemical assessment was performed 3 months after surgery by oral glucose tolerance test (OGTT) and evaluations of IGF1 levels. Patients were considered non-cured based on nonsuppressible GH levels on OGTT and plasma IGF1 levels higher than those of age-matched normal subjects. Medical therapy with OCT-LAR was started at a dose of 20 mg every 4 weeks, and the dose was increased to 30 mg in patients with non-controlled disease after 3 months of therapy. The efficacy of medical therapy was evaluated during the last patient visit. Patients were considered to have non-controlled disease if they had plasma IGF1 levels greater than those of age-matched normal subjects or basal GH levels O1.0 ng/ml after at least 6 months of treatment with OCT-LAR at a dosage of 30 mg. The AIP and SSTR2 expressions were analyzed through immunohistochemistry in paraffin-embedded

Identification of the first PAR1 deletion encompassing upstream SHOX enhancers in a family with idiopathic short stature

Short stature homeobox-containing gene, MIM 312865 (SHOX) is located within the pseudoautosomal region 1 (PAR1) of the sex chromosomes. Mutations in SHOX or its downstream transcriptional regulatory elements represent the underlying molecular defect in ~60% of Léri-Weill dyschondrosteosis (LWD) and ~5-15% of idiopathic short stature (ISS) patients. Recently, three novel enhancer elements have been identified upstream of SHOX but to date, no PAR1 deletions upstream of SHOX have been observed that only encompass these enhancers in LWD or ISS patients. We set out to search for genetic alterations of the upstream SHOX regulatory elements in 63 LWD and 100 ISS patients with no known alteration in SHOX or the downstream enhancer regions using a specifically designed MLPA assay, which covers the PAR1 upstream of SHOX. An upstream SHOX deletion was identified in an ISS proband and her affected father. The deletion was confirmed and delimited by array-CGH, to extend ~286 kb. The deletion included two of the upstream SHOX enhancers without affecting SHOX. The 13.3-year-old proband had proportionate short stature with normal GH and IGF-I levels. In conclusion, we have identified the first PAR1 deletion encompassing only the upstream SHOX transcription regulatory elements in a family with ISS. The loss of these elements may result in SHOX haploinsufficiency because of decreased SHOX transcription. Therefore, this upstream region should be included in the routine analysis of PAR1 in patients with LWD, LMD and ISS.

Medical therapy of acromegaly in Turkey

Acromegaly is associated with multiple co-morbidities and risk of premature mortality. Mortality rate of acromegalic patients is similar to that of the general population when normal GH levels are achieved. Surgery is the mainstay of acromegaly but when surgery fails to achieve disease control, or when surgery is impossible or contraindicated, patients are offered medical therapy and/or radiotherapy. Current medical therapy modalities were revised in this short review.

Growth hormone status predicts left ventricular mass in patients after cure of acromegaly

Context Growth hormone excess and growth hormone deficiency (GHD) are both associated with increased cardiovascular morbidity. A specific acromegaly-related cardiomyopathy has been described, characterized in part by increased left ventricular mass (LVM). Growth hormone deficiency is associated with reduced LVM. Following cure of acromegaly with surgery or radiation therapy, GHD may develop; however, its effects on cardiac morphology and function in this population are not established. Objective We hypothesized that the development of GHD in patients with prior acromegaly would be associated with cardiac morphologic and functional changes that differ from those in patients who are GH sufficient following cure of acromegaly. Design A cross-sectional study was conducted in a Clinical Research Center. Study participants consisted of three groups of subjects ( n = 34): I. Cured acromegaly with GHD ( n = 15), II. Cured acromegaly with GH sufficiency ( n = 8), and III. Active acromegaly ( n = 11). Main outcome measures included cardiac morphology and function, using echocardiography parameters. Results Mean age and BMI, 44.6 ± 2.3 years (SEM) and 30.7 ± 1.3 kg/m 2, respectively, were not different among the three groups. Mean peak GH values were: I. 2.8 ± 0.4 ng/ml; II. 30.1 ± 9.1 ng/ml ( p = 0.0002.) In group I, left ventricular mass, indexed to body surface area (LVMi), was within the normal range in all patients; moreover, left ventricular (LV) geometry was normal. At least 50% of patients in groups II and III had elevated LVMi, and in 50% of patients, LV geometry was abnormal, indicating pathologic hypertrophy. Ejection fraction was similar between all three groups. There were no significant differences in diastolic function. Conclusions Patients who develop GHD following cure of acromegaly do not demonstrate elevated LV mass, in contrast to patients with a history of acromegaly but normal GH levels or to patients with active acromegaly. This suggests that GH status after treatment of acromegaly correlates with LV mass, and that, in GH sufficient patients, reversal of remodeling may be slower than previously thought. These data suggest that it will be important to determine whether GH replacement alters left ventricular morphology over time.

Growth Hormone Increases mRNA Levels of PPAR.DELTA. and Foxo1 in Skeletal Muscle of Growth Hormone Deficient lit/lit Mice

GH plays an important role in lipid metabolism as a partitioning hormone. PPARdelta regulates lipid oxidation in skeletal muscle and is activated by several physiological ligands including fatty acids. To investigate whether GH has an effect on the regulation of transcription of PPARdelta and other genes involved in energy metabolism in skeletal muscle, mRNA levels were studied by real-time RT-PCR in lit/lit mice (isolated GH deficiency) and lit/+ mice controls (normal GH levels). Mice received either a single bolus (120 ng/g) of rat GH or vehicle, and skeletal muscle was collected 4h later. PPARdelta mRNA was increased in vehicle-treated lit/lit mice compared to vehicle-treated lit/+ mice (1.67 fold, P<0.05). lit/lit mice treated with GH showed a further increase in PPARdelta mRNA levels (2.83 fold vs. vehicle-treated lit/+ mice, P<0.001). mRNA levels of Foxo1 were increased in vehicle-treated lit/lit mice compared to vehicle-treated lit/+ mice (1.74 fold, P<0.05). lit/lit mice treated with GH showed a further increase in Foxo1 mRNA levels (6.30 fold vs. vehicle-treated lit/+ mice, P<0.001). mRNA levels of acyl CoA-oxidase showed a trend to be higher in vehicle-treated lit/lit mice compared to vehicle-treated lit/+ mice. This reached statistical significance in GH-treated lit/lit mice compared to vehicle-treated lit/+ mice (2.11 fold, P<0.05). In summary, mRNA levels of PPARdelta and Foxo1 were increased in skeletal muscle of GH-deficient mice, and further acutely increased by GH administration. These results suggest that GH plays a relevant role in the lipid catabolism in skeletal muscle.

Control of IGF‐I levels with titrated dosing of lanreotide Autogel over 48 weeks in patients with acromegaly

BackgroundAn essential criterion for control of acromegaly is normalization of IGF-I levels. Somatostatin analogues act to suppress IGF-I and GH levels.ObjectiveTo assess the efficacy and safety of 48 weeks titrated dosing of lanreotide Autogel.DesignOpen-label, multicentre, phase III, 48-week trial.MethodsPatients with active acromegaly (IGF-I levels > 1·3 times upper limit of age-adjusted normal range) were recruited. Twelve injections of lanreotide Autogel were given at 28-day intervals: during the 16-week fixed-dose phase, patients received 90 mg; in the 32-week dose-titration phase, patients received 60, 90 or 120 mg according to GH and IGF-I levels. Intention-to-treat analysis was performed to determine the proportion of patients with normalized age-adjusted IGF-I levels at study end. Secondary evaluations included GH levels, clinical acromegaly signs and safety.ResultsFifty-seven of 63 patients completed the study. Lanreotide Autogel resulted in normalized age-adjusted IGF-I levels in 27 patients (43%, 95% CI 31–55). Mean GH levels decreased from 6·2 to 1·5 µg/l at study end, with 53 of 62 patients (85%) having GH levels ≤ 2·5 µg/l (95% CI 76·7–94·3) and 28 of 62 patients (45%) with levels < 1 µg/l (95% CI 32·8–57·6). Twenty-four (38%) had both normal IGF-I levels and GH levels ≤ 2·5 µg/l. Acromegaly symptoms reduced significantly in most patients throughout the study. The most common adverse events were gastrointestinal, as expected for somatostatin analogues.ConclusionsUsing IGF-I as primary end-point, 48 weeks lanreotide Autogel treatment, titrated for optimal hormonal control, controlled IGF-I and GH levels effectively, reduced acromegaly symptoms and was well tolerated.