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Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany
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Objective
Patients with non-functioning pituitary adenomas exhibit high morbidity and mortality rates. Growth hormone deficiency and high doses of glucocorticoid substitution therapy have been identified as corresponding risk factors. Interestingly, high levels of endogenous cortisol in, e.g., patients with post-traumatic stress disorder or patients with Cushing’s disease have been linked to shorter telomere length. Telomeres are noncoding DNA regions located at the end of chromosomes consisting of repetitive DNA sequences which shorten with aging and hereby determine cell survival. Therefore, telomere length can serve as a predictor for the onset of disease and mortality in some endocrine disorders (e.g., Cushing’s disease).
Design/methods
Here, we examine telomere length from blood in patients (n = 115) with non-functioning pituitary adenomas (NFPA) in a cross-sectional case–control (n = 106, age-, gender-matched) study using qPCR. Linear regression models were used to identify independent predictors of telomere length.
Results
We show that patients with NFPA exhibited shorter telomeres than controls. No significant association of indices of growth hormone deficiency (IGF-1-level-SDS, years of unsubstituted growth hormone deficiency etc.) with telomere length was detected. Interestingly, linear regression analysis showed that hydrocortisone replacement dosage in patients with adrenal insufficiency (n = 52) was a significant predictor for shorter telomere length (β = 0.377; P = 0.018) independent of potential confounders (gender, age, BMI, arterial hypertension, systolic blood pressure, number of antihypertensive drugs, total leukocyte count, waist-to-hip ratio, waist circumference, diabetes mellitus type 2, HbA1c, current statin use). Median split analysis revealed that higher hydrocortisone intake (>20 mg) was associated with significantly shorter telomeres.
Conclusion
These observations strengthen the importance of adjusted glucocorticoid treatment in NFPA patients with respect to morbidity and mortality rates.
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Center for Healthy Aging Research, Oregon State University, Corvallis, Oregon, USA
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Center for Healthy Aging Research, Oregon State University, Corvallis, Oregon, USA
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Mice are a commonly used model to investigate aging-related bone loss but, in contrast to humans, mice exhibit cancellous bone loss prior to skeletal maturity. The mechanisms mediating premature bone loss are not well established. However, our previous work in female mice suggests housing temperature is a critical factor. Premature cancellous bone loss was prevented in female C57BL/6J mice by housing the animals at thermoneutral temperature (where basal rate of energy production is at equilibrium with heat loss). In the present study, we determined if the protective effects of thermoneutral housing extend to males. Male C57BL/6J mice were housed at standard room temperature (22°C) or thermoneutral (32°C) conditions from 5 (rapidly growing) to 16 (slowly growing) weeks of age. Mice housed at room temperature exhibited reductions in cancellous bone volume fraction in distal femur metaphysis and fifth lumbar vertebra; these effects were abolished at thermoneutral conditions. Mice housed at thermoneutral temperature had higher levels of bone formation in distal femur (based on histomorphometry) and globally (serum osteocalcin), and lower global levels of bone resorption (serum C-terminal telopeptide of type I collagen) compared to mice housed at room temperature. Thermoneutral housing had no impact on bone marrow adiposity but resulted in higher abdominal white adipose tissue and serum leptin. The overall magnitude of room temperature housing-induced cancellous bone loss did not differ between male (current study) and female (published data) mice. These findings highlight housing temperature as a critical experimental variable in studies using mice of either sex to investigate aging-related changes in bone metabolism.
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Objective
To investigate the impact of early exposure to androgen excess on gonadotropin-dependent puberty (GDP) and final height (FH) of patients with androgen-secreting adrenocortical tumors (ACT) in childhood.
Methods
Retrospective cohort study. Occurrence of GDP and achievement of FH were evaluated. Central precocious puberty (CPP) and early fast puberty (EFP) were considered pubertal disorders. Patients with normal puberty and pubertal disorders were compared.
Results
The study included 63 patients (44F), followed in a single institution from 1975 until 2017. At diagnosis of ACT, median age was 25.8 months; duration of signs, 6 months; stature SDS, 0.5 (−3.6 to 3.9) and bone age advancement, 14.7 months (−27.9 to 85.4). To date, 37 patients developed GDP: 26 had normal puberty; one, precocious thelarche; seven, CPP and three, EFP. GnRHa effectively treated CPP/EFP. Tall stature and older age at diagnosis of ACT were associated with risk of CPP alone (RR 4.17 (95% CI 1.17–14.80)) and CPP/EFP (RR 3.0 (95% CI 1.04–8.65)). Recurrence/metastasis during follow-up were associated with risk of CPP alone (RR 4.17 (95% CI 1.17–14.80)) and CPP/EFP (RR 3.0 (95% CI 1.12–8.02)). Among the 19 patients that reached FH, stature SDS dropped from 1.4 to −0.02 since diagnosis of ACT (P = 0.01). Seventeen achieved normal FH. There was no difference in FH SDS between patients with normal puberty and pubertal disorders (P = 0.75).
Conclusions
Gonadotropin-dependent pubertal disorders are common in patients with androgen-secreting ACT in childhood. FH is usually not impaired. The study reinforces the importance of close follow-up after surgery to identify and treat consequences of early exposure to androgen excess.
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Reference Center for Rare Disorders of Calcium and Phosphate Metabolism, Le Kremlin Bicêtre, France
Plateforme d’Expertise Paris Sud Maladies Rares and Filière OSCAR, Bicêtre Paris Sud, Le Kremlin Bicêtre, France
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Reference Center for Rare Disorders of Calcium and Phosphate Metabolism, Le Kremlin Bicêtre, France
Plateforme d’Expertise Paris Sud Maladies Rares and Filière OSCAR, Bicêtre Paris Sud, Le Kremlin Bicêtre, France
INSERM U1169, Hôpital Bicêtre, Le Kremlin Bicêtre, et Université Paris-Saclay, Le Kremlin Bicêtre, France
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APHP, Department of Pediatric Orthopedic Surgery, Necker Hospital, Paris, France
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Background
X-linked hypophosphatemic rickets (XLHR) is due to mutations in PHEX leading to unregulated production of FGF23 and hypophosphatemia. XLHR is characterized by leg bowing of variable severity. Phosphate supplements and oral vitamin analogs, partially or, in some cases, fully restore the limb straightness. Surgery is the alternative for severe or residual limb deformities.
Objective
To retrospectively assess the results of surgical limb correction in XLHR (osteotomies and bone alignment except for 3 transient hemiepiphysiodesis).
Methods
We analyzed the incidence of recurrence and post-surgical complications in 49 XLHR patients (29F, 20M) (mean age at diagnosis 6.0 years (± 7.1)).
Results
At first surgery, the mean age was 13.4 years (± 5.0). Recurrence was observed in 14/49 (29%) patients. The number of additional operations significantly decreased with age (2.0 (± 0.9), 1.7 (± 1.0) and 1.2 (± 0.4) in children <11 years, between 11 and 15, and >15 years; P < 0.001). Incidence of recurrence seemed to be lower in patients with good metabolic control of the rickets (25% vs 33%). Complications were observed in 57% of patients.
Conclusion
We report a large series of surgical procedures in XLHR. Our results confirm that phosphate supplements and vitamin D analog therapy is the first line of treatment to correct leg bowing. Surgery before puberty is associated with a high risk of recurrence of the limb deformity. Such procedures should only be recommended, following multidisciplinary discussions, in patients with severe distortion leading to mechanical joint and ligament complications, or for residual deformities once growth plates have fused.
Department of Internal Medicine, Department of Clinical Sciences Malmö, Social Medicine and Global Health, University of Gothenburg, PO Box 454, SE-405 30 Gothenburg, Sweden
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Department of Internal Medicine, Department of Clinical Sciences Malmö, Social Medicine and Global Health, University of Gothenburg, PO Box 454, SE-405 30 Gothenburg, Sweden
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Objectives
Obesity is associated with low levels of sex hormone-binding globulin (SHBG). While the reason is not fully understood, we aimed to study the association between serum insulin and levels of SHBG in a random population.
Design and methods
Between 2001 and 2005, a random sample of 2816 participants aged 30–74 years were enrolled in a cross-sectional survey in the South-west of Sweden. Fasting blood samples were collected and an oral glucose tolerance test (OGTT) was conducted in all subjects without known diabetes. Diabetes mellitus was defined according to criteria from WHO, and clinical characteristics were used to discriminate between type 1 (T1D) and type 2 diabetes (T2D). Analyses of SHBG were successful in 2782 participants (98%), who thus constituted the current study population.
Results
We found significant inverse association between levels of SHBG and fasting serum insulin in both genders (men: β=−0.090, P=0.001; women: β=−0.197, P<0.001), which was independent of differences in age and BMI. The associations remained when also differences in fasting plasma glucose were accounted for (men: β=−0.062, P=0.022; women: β=−0.176, P≤0.001). Subjects with T1D exhibited higher levels of SHBG than both T2D (men: δ=15.9 nmol/l, P<0.001; women: δ=71.1 nmol/l, P<0.001) and non-diabetic subjects (men: δ=15.1 nmol/l, P<0.001; women: δ=72.9 nmol/l, P<0.001) independent of age, BMI and fasting glucose levels.
Conclusion
These findings are consistent with high levels of SHBG in T1D, and correspondingly low levels in T2D subjects, suggesting an inhibitory effect of insulin on the SHBG production in the liver.
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Raphael Recanati Genetic Institute, Rabin Medical Center – Beilinson Hospital, Petach Tikva, Israel
Felsenstein Medical Research Center, Petach Tikva, Israel
Pediatric Genetics, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel
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Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel
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Shalom and VardaYoran Institute for Human Genome Research, Tel Aviv University, Tel Aviv, Israel
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Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel
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Mutation in the insulin-like growth factor-1 receptor (IGF1R) gene is a rare cause for intrauterine and postnatal growth disorders. Patients identified with IGF1R mutations present with either normal or impaired glucose tolerance. None of the cases described so far showed hypoglycemia. We aimed to identify the genetic basis for small for gestational age, short stature and hypoglycemia over three generations in one family. The proband, a 9-year-old male, presented in infancy with recurrent hypoglycemic episodes, symmetric intrauterine growth retardation and postnatal growth retardation. Blood DNA samples from the patient, his parents, a maternal sister and maternal grandmother underwent Sanger sequencing of the IGF1R gene. Primary skin fibroblast cultures of the patient, his mother and age- and sex-matched control donors were used for gene expression and receptor functional analyses. We found a novel heterozygous mutation (c.94 + 1g > a, D1105E) affecting the splicing site of the IGF1R mRNA in the patient, his mother and his grandmother. Primary fibroblast cultures derived from the patient and his mother showed reduced proliferation and impaired activation of the IGF1R, evident by reduced IGF1R and AKT phosphorylation upon ligand binding. In conclusion, the newly identified heterozygous missense mutation in exon 1 of IGF1R (D1105E) results in impaired IGF1R function and is associated with small for gestational age, microcephaly and abnormal glucose metabolism. Further studies are required to understand the mechanisms by which this mutation leads to hypoglycemia.
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To date, the value of fasting plasma acylated ghrelin (AG) and unacylated ghrelin (UAG) as potential novel biomarkers in patients with neuroendocrine tumors (NETs) is unknown. The aims of this study are to (i) compare fasting AG and UAG levels between nonobese, nondiabetic NET patients (N=28) and age- (±3 years) and sex-matched nonobese, nondiabetic controls (N=28); and (ii) study the relationship between AG, UAG, and AG/UAG ratios and biochemical (chromogranin-A (CgA) and neuron-specific enolase (NSE) levels) and clinical parameters (age at diagnosis, sex, primary tumor location, carcinoid syndrome, ENETS TNM classification, Ki-67 proliferation index, grading, prior incomplete surgery) in NET patients. Fasting venous blood samples (N=56) were collected and directly stabilized with 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride after withdrawal. Plasma AG and UAG levels were determined by ELISA. Expression of ghrelin was examined in tumor tissue by immunohistochemistry. There were no significant differences between NET patients and controls in AG (median: 62.5 pg/mL, IQR: 33.1–112.8 vs median: 57.2pg/mL, IQR: 26.7–128.3, P=0.66) and UAG in levels (median: 76.6pg/mL, IQR: 35.23–121.7 vs median: 64.9, IQR: 27.5–93.1, P=0.44). No significant correlations were found between AG, UAG, and AG/UAG ratios versus biochemical and clinical parameters in NET patients with the exception of age at diagnosis (AG: ρ= −0.47, P=0.012; AG/UAG ratio: ρ= −0.50, P=0.007) and baseline chromogranin-A levels (AG/UAG ratio: ρ= −0.44, P=0.019). In our view, fasting plasma acylated and unacylated ghrelin appear to have no value as diagnostic biomarkers in the clinical follow-up of patients with NETs.
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Circulating IGFs are important regulators of prenatal and postnatal growth, and of metabolism and pregnancy, and change with sex, age and pregnancy. Single-nucleotide polymorphisms (SNPs) in genes coding for these hormones associate with circulating abundance of IGF1 and IGF2 in non-pregnant adults and children, but whether this occurs in pregnancy is unknown. We therefore investigated associations of plasma IGF1 and IGF2 with age and genotype at candidate SNPs previously associated with circulating IGF1, IGF2 or methylation of the INS – IGF2 – H19 locus in men (n=134), non-pregnant women (n=74) and women at 15 weeks of gestation (n=98). Plasma IGF1 concentrations decreased with age (P<0.001) and plasma IGF1 and IGF2 concentrations were lower in pregnant women than in non-pregnant women or men (each P<0.001). SNP genotypes in the INS – IGF2 – H19 locus were associated with plasma IGF1 (IGF2 rs680, IGF2 rs1004446 and IGF2 rs3741204) and IGF2 (IGF2 rs1004446, IGF2 rs3741204 and H19 rs217727). In single SNP models, effects of IGF2 rs680 were similar between groups, with higher plasma IGF1 concentrations in individuals with the GG genotype when compared with GA (P=0.016), or combined GA and AA genotypes (P=0.003). SNPs in the IGF2 gene associated with IGF1 or IGF2 were in linkage disequilibrium, hence these associations could reflect other genotype variations within this region or be due to changes in INS – IGF2 – H19 methylation previously associated with some of these variants. As IGF1 in early pregnancy promotes placental differentiation and function, lower IGF1 concentrations in pregnant women carrying IGF2 rs680 A alleles may affect placental development and/or risk of pregnancy complications.
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Background
Polycystic ovary syndrome (PCOS) is a multi-symptom disorder linked with a range of metabolic and hormonal disturbances. Psychological and sexual aspects of PCOS also need to be considered.
Objective of the study
This study aimed to assess sexual satisfaction (SS) in PCOS patients and eumenorrheic controls (CON). The relationships between SS, depressive symptoms, health-related quality of life (HRQoL), and hormonal and metabolic profiles were evaluated.
Methods
In this study, 190 patients with PCOS (mean age 26.34 ± 5.47 years) and 197 age-matched CON (mean age 27.12 ± 4.97 years) were enrolled. All subjects completed Polish version of the Sexual Satisfaction Questionnaire (SSQ), WHO Quality of Life-BREF (WHOQOL-BREF), and the Center for Epidemiologic Studies Depression Scale-Revised (CESD-R) questionnaire. Fasting blood samples were collected to assess hormonal, lipid, and glucose profiles. Anthropometric measures were collected. Metabolic syndrome (MS) was evaluated according to the IDF-AHA/NHLBI criteria.
Results
Patients with PCOS and MS had lower SS vs non-MS-PCOS. There were no significant differences in the level of SS, presence of depressive symptoms, or HRQoL between PCOS and CON (P > 0.05). Negative correlations were found between the SS level and BMI, waist circumference, and waist-to-height ratio in PCOS women. However, overweight or obese PCOS women did not differ in SS levels vs normal-weight PCOS patients. The social dimension of WHOQOL-BREF was the only significant predictor of SS in PCOS patients.
Conclusions
SS in PCOS women appears to be undisturbed. However, MS in PCOS patients could negatively influence SS. The level of SS should be assessed in PCOS women, especially if MS is present.
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Objective
Radioactive iodine (RAI) therapy is effective for differentiated thyroid cancer (DTC) patients with lung metastasis. However, some patients have a poor prognosis despite the RAI accumulation. The utility of inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), has been reported as a prognostic factor for many carcinomas. This study aimed to investigate the risk factors related to DTC patient survival with RAI-avid lung metastasis and to attempt risk stratification.
Design and methods
This retrospective study included 123 patients with RAI-accumulating lung metastatic DTC. The cause-specific survival (CSS) rate from the time of detection of lung metastasis was tested using the Kaplan–Meier log-rank test, and the multivariate analysis was calculated using the Cox proportional hazards model. NLR was retrospectively calculated using the blood sample collected before initial RAI treatment. The NLR cutoff value was 2.6 on the ROC curve.
Results
Age ≥ 55 years at the time of operative treatment, follicular carcinoma, lung metastasis tumor ≥ 10 mm in diameter, age ≥ 55 years at the time of detection of lung metastasis, age ≥ 55 years at the time of RAI treatment, and NLR ≥ 2.6 at the initial RAI treatment were predictive of decreased CSS. Multivariate analysis identified that the independent prognostic factors were lung metastatic tumor ≥ 10 mm in diameter and NLR ≥ 2.6. Patients in the high-risk group with both factors had significantly lower CSS rates than those in the low- and intermediate-risk groups with one or none of these factors.
Conclusions
The high-risk group patients had significantly poorer survival, and these patients could be considered as future candidates for tyrosine kinase inhibitor therapy.
