Consensus of the Polish Society of Endocrinology. Presurgical somatostatin analogs therapy in acromegaly

Consensus statement of the Polish Society of Endocrinology, regarding presurgical somatostatin analogs in acromegaly has been presented. It is suggested to administer depot somatostatin analog (Octreotide LAR at the dose 20 mg and then 30 mg or equivalent doses of Lanreotide Autogel 90/120 mg every 4 weeks) in order to normalize or suppress to a maximal extent GH and IGF-1 concentrations. The period of therapy in case of microadenoma would be at least 3 months (targets: biochemical improvement, reduced risk of disease's complications, perioperative risk reduction, inhibition of tumor growth). The period of therapy in case of macroadenoma would be at least 6 months, until maximal possible reduction of GH and IGF-1 concentrations (targets: tumor shrinkage, biochemical improvement, reduced risk of disease's complications, perioperative risk reduction). Using an uniform approach in a group, as numerous as possible, of treated patients would allow objective evaluation of long-term efficacy of the treatment.     

Consensus statement of the Polish Society for Endocrinology: presurgical somatostatin analogs therapy in acromegaly

Consensus statement of the Polish Society for Endocrinology, regarding presurgical somatostatin analogs in acromegaly has been presented. It is suggested to administer depot somatostatin analog (Octreotide LAR at the dose 20 mg and then 30 mg or equivalent doses of Lanreotide Autogel 90/120 mg every 4 weeks) in order to normalize or suppress to a maximal extent GH and IGF-1 concentrations. The period of therapy in case of microadenoma would be at least 3 months (targets: biochemical improvement, reduced risk of disease's complications, perioperative risk reduction, inhibition of tumor growth). The period of therapy in case of macroadenoma would be at least 6 months, until maximal possible reduction of GH and IGF-1 concentrations (targets: tumor shrinkage, biochemical improvement, reduced risk of disease's complications, perioperative risk reduction). Using an uniform approach in a group, as numerous as possible, of treated patients would allow objective evaluation of long-term efficacy of the treatment.     

Pegvisomant--growth hormone receptor antagonist in the treatment of acromegaly

INTRODUCTION: Pegvisomant, growth hormone (GH) antagonist is a new perspective in the treatment of acromegaly. Pegvisomant interferes with GH action by competitive binding to receptor and blocking signal transduction. We present first experiences with treatment acromegaly with pegvisomant in Poland. Aim of the study was to assess pegvisomant efficacy in treatment patients with persistent acromegaly after transspheno-ideal surgery and unsatisfactory disease control with somatostatin analogue octreotide (OCTR). MATERIAL AND METHODS: Material consisted of 10 patients (6 M, 4 F) aged 24-48 with active acromegaly, after neurosurgery, in which OCTR was ineffective in disease control. Patients with glucose metabolism disturbances were assigned to group receiving PEG. Controls were matched for age, sex, disease history, GH and IGF-1 levels. Patients received pegvisomant throughout 12 weeks, then combined therapy with PEG and OCTR-LAR was started for 8 weeks and then OCTR-LAR alone was given for next 8 weeks. Controls were medicated with OCTR-LAR 30 mg each 4 weeks during study. Clinical symptoms and IGF-1 level, fasting glucose and HbA(1c) was measured to assess treatment efficacy. RESULTS: Pegvisomant reduced IGF-1 after first week of therapy from 1270+/-229 to 759+/-223 (40%, p<0.04). Prolonged therapy led to further IGF-1 decrease. After 12 weeks of treatment IGF-1 was significantly lower in comparison to initial as well as to controls (604 mg/l vs. 1270 and 1330, respectively, p<0.02). Combined therapy with PEG and OCTR-LAR was not superior to PEG alone. During treatment with pegvisomant improvement of glucose metabolism was seen, as well as decrease in insulin doses required. No adverse events was recorded. CONCLUSIONS: Pegvisomant--GH receptor antagonist--effectively lowers IGF-1 concentration and improves disease control in patients with acromegaly after unsuccessful surgery and with octreotide unresponsiveness. Significantly improves glucose metabolism. Pegvisomant is indicated in patients with active acromegaly after standard treatment failure, especially in cases of coexistent diabetes mellitus.     

The Prevalence of Cancer and Its Relation to Disease Activity in Patients With Acromegaly: Two Centers' Experience

ObjectiveAcromegaly is characterized by increased serum concentrations of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). Although animal studies have demonstrated a relationship between these hormones and cancer risk, the results of human studies evaluating cancer prevalence in acromegaly are inconsistent. We aimed to investigate the prevalence of malignant neoplasms in patients with acromegaly.MethodsCancer risk was evaluated in a cohort of 280 patients (male/female: 120/160; mean age: 50.93 ± 12.07 years) with acromegaly. Patients were categorized into 2 groups according to the presence or absence of cancer. Standard incidence ratios were calculated as compared to the general population.ResultsFrom 280 patients, cancer was diagnosed in 19 (6.8%) patients; 9 (47%) of them had thyroid cancer, which was the most common cancer type. Standard incidence ratios of all cancers were 0.8 (95% CI, 0.5-1.1) and 1.0 (95% CI, 0.8-1.3) in men and women, respectively. Compared to patients without cancer, the current age was higher in patients with cancer (59 [49-65] to 51 [42-59], P = .027). In contrast, the age at diagnosis was similar in both groups. Not only was the time to diagnosis and disease duration similar in both groups but also the basal and current GH and IGF-1 levels. The prevalence of active disease was also similar between the groups (32% to 23%, P = .394).ConclusionOur findings were not consistent with the studies suggesting that patients with acromegaly encounter an increased cancer risk. Furthermore, there were similar basal and current GH and IGF-1 levels in patients with acromegaly, both with and without cancer.     

Acromegaly induced by growth hormone replacement therapy

Recombinant human growth hormone (GH) has been shown to be efficacious and safe in the treatment of various growth disorders and GH deficiency. We here report a 61-year-old man with idiopathic hypopituitarism in whom clinically active acromegaly developed. Complete GH deficiency had been diagnosed earlier by arginine stimulation testing, and therapy with recombinant human GH (maintenance dose 2 IU/day) was implemented at the age of 54 years. At presentation, the patient's insulin-like growth factor 1 (IGF-1; 439 ng/ml) and insulin-like growth factor binding protein 3 (4.3 mg/l) levels were highly elevated. Endogenous GH production and pituitary adenoma were excluded. Retrospectively, IGF-1 levels up to 621 ng/ml had been documented (but not appreciated) in the preceding 7 years. Upon GH dose reduction, the IGF-1 serum levels returned to normal, and the patient's clinical status stabilized. No GH receptor polymorphisms were identified in the patient's genomic DNA. This observation demonstrates that the indiscriminate use of recombinant GH bears the risk of active acromegaly, emphasizing the need for long-term patient monitoring programs as integral part of GH therapy.     

Limitations of Current Approaches For The Treatment of Acromegaly

Objective: Acromegaly is a rare disease characterized by hypersecretion of growth hormone (GH), typically from a benign pituitary somatotroph adenoma, that leads to subsequent hypersecretion of insulin-like growth factor 1 (IGF-1). Patients with acromegaly have an increased risk of mortality and progressive worsening of comorbidities. Surgery, medical therapy, and radiotherapy are currently available treatment approaches for patients with acromegaly, with overall therapeutic goals of lowering GH levels and achieving normal IGF-1 levels, reducing tumor size, improving comorbidities, and minimizing mortality risk. Although surgery can lead to biochemical remission in some patients with acromegaly, many patients will continue to have uncontrolled disease and require additional treatment.Methods: We reviewed recently published reports and present a summary of the safety and efficacy of current treatment modalities for patients with acromegaly.Results: A substantial proportion of patients who receive medical therapy or radiotherapy will have persistently elevated GH and/or IGF-1. Because of the serious health consequences of continued elevation of GH and IGF-1, there is a need to improve therapeutic approaches to optimize biochemical control, particularly in high-need patient populations for whom current treatment options provide limited benefit.Conclusion: This review discusses current treatment options for patients with acromegaly, limitations associated with each treatment approach, and areas within the current treatment algorithm, as well as patient populations for which improved therapeutic options are needed. Novel agents in development were also highlighted, which have the potential to improve management of patients with uncontrolled or persistent acromegaly.Abbreviations:AACE = American Association of Clinical EndocrinologistsAE = adverse eventATG = AutogelCFRT = conventional fractionated radiotherapyDA = dopamine agonistENDO = Endocrine SocietyGH = growth hormoneGHRA = growth hormone receptor antagonistIGF-1 = insulin-like growth factor 1LAR = long-acting releaseLFT = liver function testSC = subcutaneousSRS = stereotactic radiosurgerySSA = somatostatin analoguesst = somatostatin receptorsst₂ = somatostatin receptor subtype 2sst₅ = somatostatin receptor subtype 5TSS = transsphenoidal surgery     

Acromegaly in a patient with normal pituitary gland and somatotropic adenoma located in the sphenoid sinus

Ectopic acromegaly is a very rare clinical entity occurring in less than 1% of acromegalic patients. In most cases it is caused by GHRH or rarely GH-secreting neoplasms. Even rarer are ectopic pituitary adenomas located in the sphenoid sinus or nasopharynx that originate from pituitary remnants in the craniopharyngeal duct. This dissertation presents the difficulties in visualizing GH-secreting adenoma located in the sphenoid sinus. A 55-year-old man had somatic features of acromegaly for several years. MRI imaging revealed a slightly asymmetric pituitary gland (14 yen 4 mm) without focal lesions. Simultaneously, a spherical mass, 10 mm in diameter, corresponding with ectopic microadenoma was demonstrated on the upper wall of the sphenoid sinus. The serum GH level was 4.3 mg/l, IGF-1 = 615 mg/l, and a lack of GH suppression with oral glucose was proven. After preliminary treatment with a long-acting somatostatin analogue, transsphenoidal pituitary tumour removal was performed. Histopathological, electron microscopical and immunohistochemical analysis revealed densely granulated somatotropic pituitary adenoma: GH(+), PRL(-), ACTH(-), TSH(-), FSH(-), LH(-), MIB1 < 1%, SSTR3(+) and SSTR5(+). Post-surgical evaluation showed normal pituitary MRI scans, GH and IGF-1 levels 0.18 mug/l and 140 mg/l, respectively, as well as normal GH suppression with oral glucose. The careful analysis of possible pituitary embryonic malformations points out their significance for proper localization of extrapituitary adenomas.     

Relationship of liver and skeletal muscle IGF-1 mRNA to plasma GH profile, production of IGF-1 by liver, plasma IGF-1 concentrations, and growth rates of cattle

Growth hormone (GH), insulin-like growth factor-1 (IGF-1), and thyroid hormone (T3 and T4) concentrations in blood plasma of 18 crossbred cattle (six bulls, six steers, and six heifers) were measured over an 8-hr period. One week later at slaughter, IGF-1 production by liver slices and IGF-1 mRNA concentrations in skeletal muscle and liver were measured. Bulls had higher (P less than 0.05) mean plasma GH and GH peak amplitudes (P less than 0.01) than heifers, and values for steers were intermediate between bulls and heifers. Baseline GH concentrations and number of GH peaks were not significantly different for the three groups. Bulls had 1.6-fold (P less than 0.01) and 3.0-fold (P less than 0.01) greater liver IGF-1 mRNA concentrations than steers or heifers, respectively, whereas the steers had 1.8-fold (P less than 0.05) greater IGF-1 mRNA in liver than heifers. Production of IGF-1 by liver slices was greater (P less than 0.05) in bulls than steers or heifers. Bulls had 1.3-fold greater plasma IGF-1 than steers (P less than 0.01), whereas steers had 1.8-fold greater plasma IGF-1 than heifers (P less than 0.01). There were no significant differences in concentrations of skeletal muscle IGF-1 mRNA between the three groups of animals. Liver IGF-1 mRNA, liver IGF-1 production, and plasma IGF-1 were all significantly correlated with gain and mean GH peak amplitude, but not with GH baseline, GH peak frequency, or concentrations of T3 and T4. Concentrations if IGF-1 mRNA in skeletal muscle were not correlated to gain or any parameter of the GH profile. Plasma concentrations of T3 were significantly (P less than 0.05) negatively correlated to plasma GH baseline concentrations. Muscle IGF-1 mRNA concentration was negatively related to plasma T4 and T3. The results of this study suggest that the cascade of events starting with secretion of GH from the pituitary, expression of liver IGF-1 mRNA, and secretion of IGF-1 by the liver are important phenomena for growth of cattle.     

Distribution of growth hormone and prolactin in secretory granules of the normal and neoplastic human adenohypophysis

Growth hormone [GH] and prolactin [PRL] can be demonstrated simultaneously in electron micrographs by means of the double immunocytochemical labeling technique using colloidal gold particles of two different sizes. This method was used to study biopsy specimens obtained from 15 patients suffering from acromegaly, 11 patients suffering from prolactinomas, and eight biopsy specimens obtained during adenomectomy from the normal, paraadenomatous pituitary tissue. Four granule populations with different immunoreactions were found: (1) granules containing GH only, (2) granules containing PRL only, (3) mixed granules containing GH and PRL, and (4) granules displaying no immunoreactivity. The existence of mixed granules indicated that the two hormones are synthesized by the same cell and in communicating compartments of the cells; i.e., the rough-surfaced endoplasmic reticulum. The number of GH-containing granules (pure GH granules and mixed GH-PRL granules) was greater than that of PRL-containing granules (pure PRL granules and mixed PRL-GH granules) in adenomas causing acromegaly and in the normal pituitary tissue, whereas the opposite was true for prolactinomas. The number of PRL-containing granules was larger in biopsy specimens from patients who had acromegaly and hyperprolactinemia than in patients with acromegaly and normal serum PRL levels.     

Mode of growth hormone action in osteoblasts

Growth hormone (GH) affects bone size and mass in part through stimulating insulin-like growth factor type 1 (IGF-1) production in liver and bone. Whether GH acts independent of IGF-1 in bone remains unclear. To define the mode of GH action in bone, we have used a Cre/loxP system in which the type 1 IGF-1 receptor (Igf1r) has been disrupted specifically in osteoblasts in vitro and in vivo. Calvarial osteoblasts from mice homozygous for the floxed IGF-1R allele (IGF-1R(flox/flox)) were infected with adenoviral vectors expressing Cre. Disruption of IGF-1R mRNA (>90%) was accompanied by near elimination of IGF-1R protein but retention of GHR protein. GH-induced STAT5 activation was consistently greater in osteoblasts with an intact IGF-1R. Osteoblasts lacking IGF-1R retained GH-induced ERK and Akt phosphorylation and GH-stimulated IGF-1 and IGFBP-3 mRNA expression. GH-induced osteoblast proliferation was abolished by Cre-mediated disruption of the IGF-1R or co-incubation of cells with an IGF-1-neutralizing antibody. By contrast, GH inhibited apoptosis in osteoblasts lacking the IGF-1R. To examine the effects of GH on osteoblasts in vivo, mice wild type for the IGF-1R treated with GH subcutaneously for 7 days showed a doubling in the number of osteoblasts lining trabecular bone, whereas osteoblast numbers in similarly treated mice lacking the IGF-1R in osteoblasts were not significantly affected. These results indicate that although direct IGF-1R-independent actions of GH on osteoblast apoptosis can be demonstrated in vitro, IGF-1R is required for anabolic effects of GH in osteoblasts in vivo.     

Serum IGF-1 In the Diagnosis of Acromegaly and the Profile of Patients with Elevated IGF-1 but Normal Glucose-Suppressed Growth Hormone

ObjectiveTo report the utility of insulin-like growth factor-1 (IGF-1) as a single biomarker for establishing the diagnosis of acromegaly and to examine the clinical and biochemical profile of patients with an elevated IGF-1 in whom a diagnosis of acromegaly could not be confirmed by means of the oral glucose tolerance test (OGTT).MethodsBetween the years 1999 and 2010, we identified 101 patients who underwent pituitary surgery and had histologically proven somatotroph adenomas (Group 1, Gr 1). We selected 149 patients with non- growth hormone (GH) secreting pituitary macroadenomas (Gr 2, n = 97) and microadenomas (Gr 3, n = 52) to serve as control subjects. In addition, we identified 34 patients with elevated IGF-1values in whom acromegaly could not subsequently be proven by the OGTT (Gr 4).ResultsIGF-1 was elevated in all patients with acromegaly prior to therapy with a median (range) standard deviation score (SDS) of + 9.52 (+ 2.34 to + 9.2), compared to SDS − 1.46 (− 2.91 to + 2.17) and − 1.22 (− 2.8 to + 1.58) in Gr 2 and 3, respectively (P < 0.001). IGF- 1 SDS values were + 3.28 (+ 2.05 to + 6.1), and IGF-1 was less than twice the upper limit of normal in all patients in Gr 4. OGTT was performed in 51 of the 101 acromegalic patients. The nadir GH in these patients was 4.01 (0.2 to 46.7) in comparison with 0.2 (< 0.05 to 0.6) in Gr 4 (P < 0.001).ConclusionElevated IGF-1 levels, alone, are sufficient to establish a diagnosis of acromegaly in the majority of clinically suspected cases. The OGTT may be useful to obtain corroborative evidence when there is modest elevation of IGF-1 with absent or equivocal clinical features. (Endocr Pract. 2012;18:817-825)     

Oral Octreotide: A Review of Recent Clinical Trials and Practical Recommendations for Its Use in the Treatment of Patients With Acromegaly

ObjectiveAcromegaly is characterized by chronic growth hormone (GH) and insulin-like growth factor 1 (IGF-1) hypersecretion, often caused by a GH-secreting pituitary adenoma. Even though surgery remains the first line of treatment, medical therapy is essential if surgery is contraindicated, does not achieve remission, or does not prevent recurrence despite apparent surgical remission. Oral octreotide capsules (OOCs) that combine octreotide with a transient permeability enhancer technology are the first oral somatostatin receptor ligands (SRLs) approved in the United States for acromegaly.MethodsWe review the literature and clinical trial data on OOC therapy in patients with acromegaly and discuss the clinical assessment of OOC use, potential drug–drug interactions, drug initiation, dose titration, and monitoring of drug efficacy and tolerability.ResultsIn 4 pivotal clinical trials involving 238 patients with acromegaly treated with OOC, effective suppression of serum GH and IGF-1 levels, maintenance of disease control, decreased breakthrough symptoms and symptomatic improvement with non-inferiority of OOCs to injectable SRLs in maintaining biochemical response was seen. Additionally, the safety profile of OOC therapy is comparable to that of injectable SRLs. Most patients who completed the clinical trials of OOCs have also expressed preference for oral compared with injectable SRL administration.ConclusionOOCs are an effective treatment option for patients with acromegaly who previously responded to injectable SRLs, with the benefits of avoiding injection-related side effects. This article provides a review of the pharmacology, safety, and efficacy and offers practical recommendations on the use of OOCs to treat injectable SRL-responsive patients with acromegaly.     

Goiter and impairment of thyroid function in acromegalic patients: basal evaluation and follow-up.

AIMS: We evaluated morphological, biochemical and cytological thyroid parameters in acromegalic patients, investigated before and after treatment for acromegaly. PATIENTS: 28 acromegalics were investigated before and, in 18 cases, after 2-7 years of therapy. Fourteen patients were from areas of moderate iodine deficiency in Southern Italy. One patient underwent thyroidectomy before entering this study. RESULTS: 19 patients were euthyroid (FT4: 17.7 +/- 0.8 pmol/l and FT3 4.6 +/- 0.2 pmol/l), but TSH was undetectable in 5/19. Among them, TRH-stimulated TSH increase was absent/impaired or exaggerated/delayed in 9 and one cases, respectively. Decreased FT3 and/or FT4 values with low/normal TSH values were detected in 7 cases; TRH-stimulated TSH response was absent/impaired in 2 patients and exaggerated/delayed in another two. Increased free T4 and free T3 concentrations with undetectable TSH levels were found in one. Two euthyroid patients had high TPOAb levels. Goiter was diagnosed in 21 cases and nodules were found in 14/21. 99Tc scintiscan showed "cold" areas in 13/14 cases and a "hot" nodule in the hyperthyroid patient. Acromegalics from iodine deficient areas showed a not significant increase of prevalence of goiter (86 vs. 71 %) and of mean thyroid volume (35 +/- 7 vs. 28 +/- 4 ml, NS), compared to others. Thyroid volume (TV) did not correlate with GH, IGF-1 and TSH levels, the area under the curve of insulin-increase during OGTT, the age of patients or the duration of acromegaly. Fine needle aspiration biopsy (FNAB), performed in 11/14 patients with nodular goiter, showed colloid nodules in 8 cases, hyperplastic nodules in 2 and an adenomatous nodule in one. Neurosurgery, radiotherapy or medical treatment for acromegaly induced a significant decrease of mean GH and IGF-1 levels (21.5 +/- 8.5 vs. 12.9 +/- 9.6 ng/ml, p< 0.005 and 747 +/- 94 vs. 503 +/- 88 ng/ml, p < 0.02, respectively), but both GH and IGF-1 values normalized only in 3 cases. No significant variation of mean TSH levels was found. Although TV normalized in 3 patients, ultrasound evaluation showed a not significant decrease of mean TV and no changes in the diameter and number of nodules. FNAB was unchanged. CONCLUSIONS: Our results suggest that, despite no correlation between serum GH and IGF-1 levels and thyroid volume being found, a decrease in serum GH and IGF-1 levels has favourable effects on thyroid status.     

Modulation of cortisol metabolism during treatment of acromegaly is independent of body composition and insulin sensitivity

OBJECTIVES: The set point of cortisol-cortisone conversion is shifted in the direction of cortisone by the inhibition of the activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) during adult GH replacement and in active acromegaly. Additionally, both fat mass and insulin may modulate 11beta-HSD1 and are both influenced by changes in GH status. This study examined the relative direct contribution of GH/IGF1 in modulating cortisol metabolism. METHODS: Overall cortisol/cortisone conversion (ratio of urine 11-hydroxy-/11-oxo-cortisol metabolites; Fm/Em), insulin sensitivity (homeostatic model assessment; HOMA %S) and fat mass (DXA) were examined in parallel in 6 patients (mean age 53 years, range 42-76; 4 males, 2 females) with previously untreated active acromegaly during 6 months of therapy with Sandostatin LAR (20-30 mg i.m. 4 weekly). All but 1 patient had normal ACTH reserve. RESULTS: At baseline, Pearson correlation demonstrated an inverse relationship between serum GH (mean of a 5-point day curve) and Fm/Em (r = -0.83, p = 0.04) and a trend towards an inverse relationship between HOMA %S and Fm/Em (r = -0.79, p = 0.06) but no other patterns were evident. During the course of treatment, serum GH decreased from 9.9 +/- 6.4 (mean +/- SD) to 3.5 +/- 3.1 ng/ml (p < 0.01) and serum IGF-1 from 785 +/- 268 to 431 +/- 156 ng/ml (p < 0.005). Fm/Em increased from 0.52 +/- 0.1 to 0.75 +/- 0.08 (p < 0.03) consistent with increased 11beta-HSD1 activity. There were no significant changes in truncal fat percentage (33.0 +/- 9.0 vs. 33.0 +/- 8.2) or insulin sensitivity (HOMA %S: 37.1 +/- 8.6 vs. 52.8 +/- 33.7). CONCLUSIONS: Modulation of cortisol metabolism during treatment of active acromegaly is dependent on changes in GH/IGF-1 status and is not influenced by any individual change in body composition or insulin sensitivity.     

A critical analysis of the role of growth hormone and IGF-1 in aging and lifespan

Studies in Caenorhabditis elegans demonstrate that disruption of the daf-2 signaling pathways extends lifespan. Similarities among the daf-2 pathway, insulin-like signaling in flies and yeast, and the mammalian insulin-like growth factor 1 (IGF-1) signaling cascade raise the possibility that modifications to IGF-1 signaling could also extend lifespan in mammals. In fact, growth hormone (GH)/IGF-1-deficient dwarf mice do live significantly longer than their wild-type counterparts. However, multiple endocrine deficiencies and developmental anomalies inherent in these models confound this interpretation. Here, we critique the current mammalian models of GH/IGF-1 deficiency and discuss the actions of GH/IGF-1 on biological aging and lifespan.     

Discordance Between Gh and Igf-1 Levels in Turkish Acromegalic Patients

Objective: Discordance between insulin-like growth factor-1 (IGF-1) and growth hormone (GH) levels is an important problem in the follow-up of patients diagnosed with acromegaly. Our aims were to evaluate the discordance between IGF-1 and GH levels and compare the performance of different cut-off levels for the nadir in GH (GHn) in acromegalic patients.Methods: The study included 63 acromegalic patients in a follow-up at a tertiary care university hospital facility. Levels of IGF-1, IGF binding protein-3 (IGFBP-3), and GH were investigated. The baseline GH and GHn levels were evaluated after an oral glucose tolerance test (cut-offs of 0.4 and 1 ng/mL, respectively). The discordance rates between GHn and IGF-1 levels, and IGF-1/IGFBP-3 ratios were determined.Results: We first adopted a GHn cut-off value of 1 ng/mL and found that 27 patients (42.9%) exhibited biochemical remission (BR) (IGF-1 <95^th percentile, GH <1), and 25 patients (39.7%) had no BR (NBR) (IGF-1 ≥95^th percentile, GH >1).Discordance in the presence of normal IGF-1 and nonsuppressed GH (DC1) occurred in 2 of 63 (3.2%) patients; discordance in the presence of high IGF-1 and suppressed GH (DC2) occurred in 9 of 63 (14.3%) patients. If the GHn cut-off value adopted was 0.4 ng/mL, the distributions were 17 of 63 (27.0%) patients in BR, 29 of 63 (46.0%) patients in NBR, 12 of 63 (19.0%) in DC1, and 5 of 63 (7.9%) patients in DC2. If only the baseline GH values were considered, the distributions were very similar to those with a GHn cut-off value of 0.4 ng/mL. The IGF-1/IGFBP-3 ratio was lowest in the BR group.Conclusion: Adopting a GHn cut-off value of 0.4 ng/mL did not increase the test performance compared with baseline GH only. In contrast, in the follow-up of acromegalic patients, the IGF-1/IGFBP-3 ratio might be a useful measurement when discordance between IGF-1 and GH levels occurs. We propose that these values be considered in clinical practice.Abbreviations:BR = biochemical remissionDC1 = discordance group 1DC2 = discordance group 2DM = diabetes mellitusGH = growth hormoneGHn = nadir in GHIGF-1 = insulin-like growth factor-1IGFBP-3 = IGF binding protein-3LAR = long-acting releaseNBR = not in biochemical remissionOGTT = oral glucose tolerance test     

Role of the growth hormone-insulin-like growth factor-1-insulin system signaling in aging and longevity: evolutional aspect

Growth hormone (GH)/ insulin-like growth factor 1 (IGF-1)/ insulin signaling molecules linked to longevity include DAF-2 and insulin-receptor and their homologues in mammals, and to inactivation of corresponding genes followed by increased life span in nematodes, fruit flies, and mice. It is possible that the life-prolonging effect of calorie restriction is due to decreasing IGF-1 levels. A search of pharmacological modulators of life-span-extending mutations in the GH/IGF-1/insulin signaling pathway and mimetic effects of caloric restriction is a priority directions in the regulation of longevity. Some literature and our own observations suggest that antidiabetic drugs could be promising candidates for both life span extension and prevention of cancer.