Objectives. Klotho-deficient mice develop a syndrome resembling accelerated ageing, and genetic variants of Klotho have been associated with human ageing. In humans, serum levels of soluble Klotho decrease with age and with chronic renal failure. The aim of our study was to examine the relationship between excess growth hormone (GH) and serum levels of Klotho in patients with acromegaly, a disease usually caused by a pituitary adenoma, which is associated with high phosphate levels and reduced life expectancy.Patients and design. We determined the levels of soluble Klotho, GH and insulin-like growth factor 1 (IGF-1) in serum samples from 24 consecutive patients with acromegaly (nine women ⁄ 15 men, age 28-76 years) before and after transsphenoidal surgery.Results. Soluble Klotho levels were excessively high at baseline (mean ± SEM, 4.2 ± 0.7 ng mL )1 ) and correlated with GH (r = 0.64), IGF-1 (r = 0.57) and tumour size (r = 0.5). In multiple regression analysis, soluble Klotho was associated with GH after correction for age, gender and levels of creatinine and phosphate (P = 0.029). After surgery, GH and IGF-1 levels decreased in all patients (from 26.3 ± 5.2 to 2.6 ± 0.6 lg L )1 , P < 0.0001, and from 588 ± 35 to 193 ± 12 lg L )1 , P < 0.001, 0.0001, respectively). Creatinine increased from 71 ± 3 to 80 ± 3 lmol L )1 (P < 0.001), and phosphate decreased from 1.37 ± 0.04 to 1.06 ± 0.02 mmol L )1 (P < 0.001). The markedly increased preoperative levels of soluble Klotho returned towards normal after surgery (0.7 ± 0.1 ng mL )1 , P < 0.0001).Conclusions. This is the first study to show dramatically increased soluble Klotho levels in an acquired disease in humans. Reversal following tumour removal suggests a causal relation between the GH-producing adenoma and high serum Klotho concentration in acromegaly.

Objective: Klotho is a lifespan-influencing gene expressed mainly in the kidneys. Soluble a-Klotho (aKL) is released into the circulation. In this study, we present baseline aKL serum levels of patients with acromegaly compared with controls with other pituitary adenomas and assess changes following transsphenoidal surgery. Design: Prospective controlled study. Methods: We measured soluble aKL (sandwich ELISA) and IGF1 (RIA) in sera of 14 patients (eight females and six males) with active acromegaly and in 22 control patients (13 females and nine males) operated for non-GH-producing pituitary adenomas. Immunohistochemical staining for Klotho was performed in resected adenomas and in normal pituitary tissue samples. Results: Soluble aKL was high in the acromegaly group preoperatively (median 4217 pg/ml, interquartile range (IQR) 1812-6623 pg/ml) and declined after surgery during early follow-up (2-6 days; median 645 pg/ml, IQR 550-1303 pg/ml) (P!0.001) and during late follow-up (2-3 months post-operatively; median 902 pg/ml, IQR 497-1340 pg/ml; P!0.001). In controls, preoperative soluble aKL was significantly lower than in acromegalics, 532 pg/ml (400-677 pg/ml; P!0.001). Following surgery, soluble aKL remained low during early and late follow-up -changes over time within the control group were not statistically significant. These results were independent of age, sex and kidney function. Klotho staining was equal or slightly decreased in GH-positive adenomas compared with controls. Conclusion: High soluble aKL serum levels were specific to GH-producing adenomas and decreased rapidly following adenoma removal. Thus, soluble aKL appears to be a new specific and sensitive biomarker reflecting disease activity in acromegaly. Similar Klotho staining patterns in controls and acromegalics suggest that the rise in serum aKL is caused by systemic actions of pituitary GH rather than due to increased expression of Klotho by the pituitary (adenoma).

Background: A genomic deletion of exon 3 (d3-GHR) of the growth hormone (GH) receptor (GHR) has been linked to the effectiveness of GH therapy in children with GH deficiency. Carriers of the d3-GHR genotype had higher GH-induced growth rates than children homozygous for the full-length (fl)-GHR. The aim of this study was to test whether the relationship between GH and insulin-like growth factor-1 (IGF-1) concentrations is influenced by the GHR genotype in patients with acromegaly. Methods: Study participants were 44 adult patients with established diagnosis of acromegaly. The genotype of the GHR was determined in leukocyte DNA from peripheral blood. Clinical and biochemical findings at the time of diagnosis of acromegaly were obtained from the medical records of the patients. Results: fl-GHR homozygosity was found in 22 (50%) of patients, and 22 (50%) of patients had at least 1 d3 allele (d3-GHR). Demographic and clinical characteristics (age, height, weight, estimated duration of disease, and

Context: Nonpancreatic tumors may cause recurrent hypoglycemia known as nonislet cell tumor hypoglycemia. It is due to overproduction and secretion by the tumor of incompletely processed IGF-II, termed big IGF-II. We recently identified a patient with recurrent hypoglycemia and low insulin, but without elevated big IGF-II. Multiple small lung nodules were detected by computed tomography scan. An undifferentiated large-cell carcinoma was diagnosed from an axillary lymph node metastasis. Objective:The objective was to investigate whether the patient's hypoglycemia was due to excessive IGF-I production by the tumor.Methods: Serum IGF-I and IGF-II, insulin, and GH were measured by RIA; the distribution of IGFs between IGF binding protein complexes in serum was analyzed after neutral gel filtration. Tissue IGF-I was identified by immunohistochemistry and in situ hybridization, and by RT-PCR after RNA extraction.Results: Total and free serum IGF-I, but not total, free, and big IGF-II, was increased, and the IGF-I content of the two IGF binding protein complexes was elevated. Immunohistochemistry demonstrated IGF-I peptide in situ hybridization IGF-I mRNA in the lymph node metastasis. Combined GH/glucocorticoid treatment prevented hypoglycemia, but did not lower IGF-I. After chemotherapy with carboplatinum/etoposide, the lung nodules largely regressed, and serum IGF-I and the IGF-I content of the two binding protein complexes became normal. Hypoglycemia did not recur despite discontinuation of GH/glucocorticoid treatment. Conclusion