Prospective study of GHD patients evaluated before and during short- (1 year, n=100) and long-term (5 years, n=50) rhGH therapy.

Effects of rhGH on IGF1 levels, body composition (body fat percentage, BF%), body mass index, lipid profile, and glucose homeostasis (fasting insulin and glucose, insulin sensitivity indexes) were evaluated according to the presence or the absence of the d3GHR variant.

The different genotype did not influence basal phenotype of GHD. Short-term rhGH determined normalization of IGF1 levels, decrease in BF%, and worsening of insulin sensitivity, independently from the presence of the d3GHR allele. A significant increase in high-density lipoprotein cholesterol occurred in the d3GHR group. Normalization of IGF1 levels and decrease in BF% were maintained after 5 years. Insulin sensitivity restored to basal values, though in d3GHR patients fasting glucose remained significantly higher than at baseline. After both 1 and 5 years, percentage of subjects with impaired glucose tolerance, similar in the two groups at baseline, decreased in fl/fl while doubled in d3GHR patients. In this last group, a long-term significant reduction in total and low-density lipoprotein cholesterol was also observed.

The functional difference of d3GHR may influence some metabolic effects of rhGH on GHD adults.

Germline DNA samples of 131 Italian sporadic acromegalic patients including 38 individuals with multiple tumors, and of six FIPA families (four homogeneous for prolactinomas and two heterogeneous with prolactin/nonfunctioning pituitary adenomas) were collected in a multicentric collaborative study. The prevalence of AIP and CDKN1B gene point mutations and copy number variations were evaluated.

Two novel (IVS3+1G>A and c.871G>A) and one previously described (c.911G>A) AIP mutations were detected in four apparently sporadic cases (3.1%) with relatively high age at diagnosis (49±18, range 30–67). No mutations/rearrangements were detected in FIPA families. The highly conserved c.871G>A substitution was detected in a patient who also carried a MEN1 mutation suggesting that she is a double heterozygote. The possible pathogenic effect on AIP splicing of the silent substitution c.144G>A found in another patient was ruled out using a minigene-based approach. CDKN1B mutations/rearrangements were neither identified in patients with multiple neoplasia nor in FIPA families.

AIP is mutated in about 3% of apparently sporadic acromegalic patients. The relatively high age at diagnosis, as well as its sporadic presentation, suggests that these patients are carriers of mutations with reduced pathogenicity. p27^KIP1 is unlikely to represent the common unifying nonendocrine etiology for acromegaly and cancer.

The study was prospectively designed and included 64 patients who underwent pituitary surgery for conditions other than Cushing's disease. An ITT was performed preoperatively, on the 6th postoperative day and at the 1st postoperative month. Basal serum cortisol levels were measured on the 2nd, 3rd, 4th, 5th, and 6th postoperative days.

Patients with a preoperative basal cortisol level of <165 nmol/l (6 µg/dl) showed insufficient cortisol response and those with levels higher than 500 nmol/l (18 µg/dl) had sufficient cortisol response to the preoperative ITT. The positive predictive value of the ITT performed on the 6th postoperative day was 69.7%, and the negative predictive value in predicting adrenal insufficiency at the 1st postoperative month was 58%. Patients were considered to have an insufficient cortisol response to ITT at the 1st postoperative month if their basal cortisol levels were <193 nmol/l (7 µg/dl) or 220 nmol/l (8 µg/dl) or 193 nmol/l (7 µg/dl) or 165 nmol/l (6 µg/dl) or 83 nmol/l (3 µg/dl) on the 2nd–6th postoperative days respectively.

Serum basal cortisol levels may be used as the first-line test in the assessment of the hypothalamic–pituitary–adrenal axis both preoperatively and postoperatively. Dynamic testing should be limited to the patients with indeterminate basal cortisol levels.

Seven healthy men (age, 22–32 years) participated in a night sleep condition (sleep 2300–0700 h) and a day sleep condition (0700–1500 h) with hourly blood samples taken for 25 h (starting at 1900 h) and isocaloric meals every 4th hour awake. The blood samples were analyzed for IGFBP1, insulin, GH, glucose, and cortisol.

The acute shift of sleep and meal timing (to 8 h) shifted the 24-h patterns of IGFBP1, glucose, insulin, and GH to a similar degree. However, the day sleep condition also resulted in elevated levels of IGFBP1 (area under curve (AUC)+22%, P<0.05), and reduced glucose levels (AUC–7%, P<0.05) compared with nocturnal sleep. Sleeping during the day resulted in elevated cortisol levels during early sleep and reduced levels in late sleep, but also in increased levels the subsequent evening (P's<0.05).

Sleep-fasting seems to be the primary cause for the elevation of IGFBP1, irrespective of sleep timing. However, sleeping during the day resulted in higher levels of IGFBP1 than nocturnal sleep, suggesting altered metabolism among healthy individuals, which may have implications for other groups with altered sleep/eating habits such as shift workers. Moreover, sleep and meal times should be accounted for while interpreting IGFBP1 samples.

Prospective observational follow-up study.

Totally 219 patients with type 1 diabetes (41% females, age 46±13 years (mean±s.d.), duration of diabetes 21±12 years, and HbAlc 8.5±1.1%) were followed in a 1-year observational study. Plasma EPO and serum VEGF levels were measured at baseline with ELISA. Events of severe hypoglycaemia defined by third party assistance were recorded and validated in telephone interviews within 24 h.

Totally 235 episodes of severe hypoglycaemia (1.1 episodes per patient-year) were reported by 82 patients (37%). At baseline, plasma EPO was 8.6 (3.1–34.3) U/l (median (range)), and serum VEGF was 52.2 (6.6–337) pg/ml. The levels of EPO and VEGF were not associated with frequency of severe and mild hypoglycaemia. The levels of EPO were not associated with age, sex, duration of diabetes, body mass index, HbAlc, C-peptide level or hypoglycaemia awareness status. The levels of VEGF were positively associated with age and female sex.

Although several studies suggest that VEGF and EPO may affect brain function during hypoglycaemia, this study does not support random VEGF or EPO levels to determine future risk of severe hypoglycaemia in people with type 1 diabetes.

Cross-sectional study involving 64 Chinese women with PCOS and 59 normal women. Circulating total adiponectin and its multimeric forms were determined by ELISA, and IR was estimated using the homeostasis model assessment IR index (HOMA-IR).

After controlling for BMI status, levels of both total and HMW adiponectin were significantly lower in women with PCOS compared with normal women (P<0.05). Furthermore, HMW adiponectin provided a stronger contribution to models predicting IR than total adiponectin. Lastly, decreased HMW adiponectin was associated with increased HOMA-IR in both normal and PCOS women, and this association was independent of both overall adiposity and visceral adiposity.

Levels of both total and HMW adiponectin were decreased in Chinese women with PCOS compared with normal control women, and the differences in HMW adiponectin persisted after controlling for BMI. Furthermore, HMW adiponectin is a stronger predictor of IR than total adiponectin in both women with PCOS and normal women.

The single nucleotide polymorphisms (SNPs) rs806381, rs10485179 and rs1049353 were genotyped, and body fat and fat distribution were assessed by the use of dual-energy X-ray absorptiometry and magnetic resonance imaging in a population-based study comprising of 783 Danish men, aged 20–29 years.

The rs806381 polymorphism was significantly associated with visceral fat mass (FM) only, whereas the rs1049353 was significantly and directly associated with visceral and intermuscular FM. None of the SNPs analysed were associated with total body FM or subcutaneous FM.

The results point towards a link between common variants of the CNR1 and fat distribution in young men.

We studied 21 adolescents (mean age 13.5 years, range 11.5–15.9 years) referred to secondary care due to severe obesity (relative weight for height >+60% or body mass index >98th percentile for age and sex, before the age of 10 years) and their eight non-obese siblings (mean age 14.4 years, range 11.8–16.7 years). All subjects underwent oral glucose tolerance tests, followed by magnetic resonance spectroscopy (MRS) to measure the intramyocellular fat content in mainly oxidative soleus and mainly glycolytic tibialis anterior muscles. MRS was also used to measure liver fat. Abdominal fat (subcutaneous, intraperitoneal and retroperitoneal) was measured using MR imaging.

Compared with their non-obese siblings, the obese adolescents had increased fat deposition in all anatomic locations studied. Eight obese adolescents had IGT, and they also had increased intramyocellular fat in the soleus (P=0.03) and increased intraperitoneal fat (P=0.04) compared with obese subjects with normal glucose tolerance (NGT). In contrast, no significant difference was seen between obese adolescents with NGT and IGT in liver fat (P=0.9) or intramyocellular fat in the tibialis anterior (P=0.13). In logistic regression analysis, increased soleus intramyocellular fat and intraperitoneal fat were significant predictors of IGT.

IGT in obese adolescents is associated with increased intramyocellular and intraperitoneal fat rather than liver fat.

To study the in vivo effect of a single dose of E₂ on VLDL–TG kinetics and oxidation in humans.

Eight healthy, postmenopausal women were given a single dose of either placebo or E₂ (4 mg) orally. VLDL–TG kinetics was assessed by a 240-min primed-continuous infusion of ex vivo labeled [1-¹⁴C]triolein-labeled VLDL. Fractional and absolute VLDL–TG oxidation was determined by hyamin trapping of exhaled ¹⁴C label. Indirect calorimetry provided measurements of lipid oxidation.

Administration of 4 mg of E₂ orally rapidly increased plasma E₂ concentrations from below detection threshold to premenopausal levels. Free fatty acids (FFA) and TG concentrations were unaltered. No immediate effect was observed on either VLDL–TG production (placebo versus E₂): 20.0±12.4 vs 24.1±10.7 µmol/min, P=0.33; VLDL–TG oxidation: 12.3±10.9 vs 12.6±5.6 µmol/min, P=0.93); or VLDL–TG clearance rates: 51.4±16.8 vs 64.9±28.8 ml/min, P=0.34).

Short-term E₂ elevation does not affect VLDL–TG production, oxidation, or clearance in humans. We therefore propose that HRT-associated dyslipidemia has a gradual rather than immediate onset.

A case–control study with 1057 DM2 and 516 nondiabetic subjects was performed. All participants underwent genotyping of the D2 Thr92Ala polymorphism. Additionally, systematic review and meta-analysis of the literature for genetic association studies of D2 Thr92Ala polymorphism and DM2 were performed in Medline, Embase, LiLacs, and SciELO, and major meeting databases using the terms ‘rs225014’ odds ratio (OR) ‘thr92ala’ OR ‘T92A’ OR ‘dio2 a/g’.

In the case–control study, the frequencies of D2 Ala92Ala homozygous were 16.4% (n=173) versus 12.0% (n=62) in DM2 versus controls respectively resulting in an adjusted OR of 1.41 (95% confidence intervals (CI) 1.03–1.94, P=0.03). The literature search identified three studies that analyzed the association of the D2 Thr92Ala polymorphism with DM2, with the following effect estimates: Mentuccia (OR 1.40 (95% CI 0.78–2.51)), Grarup (OR 1.09 (95% CI 0.92–1.29)), and Maia (OR 1.22 (95% CI 0.78–1.92)). The pooled effect of the four studies resulted in an OR 1.18 (95% CI 1.03–1.36, P=0.02).

Our results indicate that in a case–control study, the homozygosity for D2 Thr92Ala polymorphism is associated with increased risk for DM2. These results were confirmed by a meta-analysis including 11 033 individuals, and support a role for intracellular T₃ concentration in skeletal muscle on DM2 pathogenesis.

To investigate the myocardial effects of long-term exogenous subclinical hyperthyroidism using two-dimensional speckle tracking echocardiography imaging (2D-STE).

Prospective, single-blinded, placebo-controlled randomized trial of 6 months duration with two parallel groups.

Totally 25 patients with a history of differentiated thyroid carcinoma on long-term TSH-suppressive levothyroxine (l-T₄) substitution were randomized to persistent TSH-suppressive l-T₄ substitution (low-TSH group) or restoration of euthyroidism. Additionally 40 euthyroid controls were studied.

At baseline, the group of patients showed normal left ventricular (LV) systolic function but impaired diastolic function as assessed with conventional echocardiographic parameters. Importantly, 2D-STE analysis demonstrated the presence of subclinical LV systolic and diastolic dysfunction with impaired circumferential and longitudinal strain and strain rate at the isovolumic relaxation time. After restoration of euthyroidism, a significant improvement in LV systolic and diastolic function as assessed with 2D-STE strain was observed.

Prolonged subclinical hyperthyroidism leads to systolic and diastolic dysfunction, which is reversible after restoration of euthyroidism. 2D-STE is a more sensitive technique to evaluate subtle changes in LV performance of these patients.

We conducted a cross-sectional study within the Cooperative Health Research in the Region of Augsburg (KORA)-F3 study. A total of 1484 participants aged 50–69 years (52% women) had agreed to provide four saliva samples during a regular weekday.

We measured salivary cortisol concentrations at wake-up (F0), 1/2 h (F1/2), 8 h (F8), and 14 h (F14) after waking. We calculated cortisol awakening response (CAR), slope, and area under the curve (AUC_G) of the circadian cortisol secretion. Sociodemographic and clinical characteristics were evaluated by interview and questionnaires, sampling conditions by protocol. In total, 1208 participants returned saliva samples, exclusion criteria left 990 subjects for final analyses.

Salivary cortisol levels were (means±s.d.) F0=13.7±7.6, F1/2=20.5±9.8, F8=5.4±3.3, and F14=2.0±1.8 nmol/l. Earlier sampling times were associated with higher CAR and smaller slope. Cortisol secretion was also influenced by gender and smoking habits. Higher perceived social support was associated with lower AUC_G and smaller slope.

We provide data on salivary cortisol concentrations in a large middle-aged community sample. Gender, sampling time, smoking habits, and perceived social support appeared as determinants of cortisol secretion.

To identify all adult Norwegian patients with CAH and obtain population-based data on subjective and psychological health status, working ability and fertility.

Classical CAH patients were identified through search in electronic diagnosis registries at all the university hospitals in Norway. The diagnosis was verified by scrutiny of medical records. The patients were invited to a questionnaire survey including medical history, and the Short Form-36 (SF-36) and Quality of Life Scale questionnaires. The questionnaire responses and fertility data were compared with normative data.

We identified 104 adult patients (101 alive) with classical CAH (63% female), yielding overall incidence at 1/20 000 live births (1/16 000 in females). Seventy-two (72%) responded; median age 38 years (range 18–72). All the SF-36 scales were significantly impaired, most pronounced for general health and vitality perception. Working disability was reported by 19% of the patients, compared with 10% in the general population. The female patients were often single, and the CAH women had only 21% of the expected number of children compared with the general population.

In this population-based survey of patients with classical CAH, we found that subjective health status and working ability were impaired, and that fertility was reduced in females. There is a need for improvement of the medical treatment and the general care of this patient group.

In a prospective case–control design, we studied 51 PHPT patients without any cardiovascular risk factors/diseases and 51 healthy matched controls. Cardiac structure, and systolic and diastolic function were evaluated by echocardiography and Doppler tissue imaging (DTI). Blood pressure (BP) and heart rate were measured.

We observed no differences in systolic or diastolic function or in cardiac morphology between the PHPT patients and the age-matched healthy controls. The regional peak systolic myocardial velocities (S') measured with DTI decreased at all sites (P<0.05) after PTX (tricuspid annulus 14.23±1.85 to 13.48±1.79, septal 8.48±0.96 to 7.97±0.85, and lateral 9.61±2.05 to 8.87±1.63 cm/s, part of the mitral annulus). At baseline, systolic BP was higher in patients compared to controls (127.6±17.1 vs 119.6±12.6 mmHg, P<0.05). After PTX, both systolic (127.6±17.1 vs 124.6±16.6 mmHg, P<0.05) and diastolic (80.3±9.6 vs 78.4±8.6 mmHg, P<0.05) BP decreased.

Our results indicate that patients with PHPT without cardiovascular risk factors have a normal global systolic and diastolic function and cardiac morphology. BP and the systolic velocities were marginally reduced after PTX, but reflected the values of the control group. Our findings warrant further investigation of the clinical and prognostic significance of these possibly disease-related inotropic effects.

Cross-sectional study done in healthy blue-collar workers.

A medical history was taken, and FGF21 (measured using an ELISA commercial kit), glucose, uric acid, plasma lipids, total/high-molecular weight (HMW) adiponectin, and retinal-binding protein 4 (RBP4) were measured in 210 individuals with (n=81) and without (n=129) metabolic syndrome.

The median of serum FGF21 levels were higher in subjects with metabolic syndrome (339.5 vs 276.4 ng/l, P=0.01). Serum FGF21 levels correlated positively with body mass index (BMI; r=0.23, P=0.001) and age (r=0.17, P=0.01). After adjusting for age and BMI, a significant positive correlation persisted for fasting glucose, uric acid, and physical activity in both males (r=0.21, r=0.11, and r=0.19, all P<0.05) and females (r=0.20, r=0.19, and r=0.14, all P<0.05). In addition, FGF21 also correlates negatively with RBP4 (r=–0.27, P=0.02), total (r=–0.26, P=0.03), and HMW adiponectin (r=–0.30, P=0.01) in women. A multiple linear regression model analysis identified that BMI (standardized β (SB)=0.247; P=0.008), glucose (SB=0.226; P=0.003), uric acid (SB=0.191; P=0.04), and physical activity (SB=0.223; P=0.004) are independent factors influencing serum FGF21 levels (F=10.05, r²=0.19, P<0.001). In addition, fasting hyperglycemia ≥100 mg/dl, excess body weight with BMI ≥25 kg/m², and uric acid ≥5.5 mg/dl predicted higher serum FGF21 levels.

Serum FGF21 levels are influenced by BMI, fasting glycemia, uric acid, and physical activity.

A randomized controlled 1-year clinical trial on 30 prepubertal children (M:F=14:16) affected by OI (type I, IV, and III) being treated with neridronate.

Following an observational period of 12 months during ongoing neridronate treatment, the patients were randomly divided into two groups: 15 were treated for 12 months with rGH and neridronate (group Bp+rGH) and 15 continued neridronate alone (group Bp). We evaluated auxological parameters, number of fractures, bone age (BA), bone metabolic parameters, and bone mass measurements (at lumbar spine and radius by dual-energy X-ray absorptiometry).

The mean variation in percentage of BMD (%BMD) – at lumbar spine (L2–L4), at distal and ultradistal radius – and the projected area of lumbar spine increased significantly in group Bp+rGH (P<0.05). Growth velocity was significantly higher during rGH treatment in group Bp+rGH versus group Bp and versus pretreatment (P<0.05), with no difference in increase in BA or fracture risk rate. Patients with quantitative (-qt) collagen synthesis defects had a higher, although not significant, response to rGH in terms of growth velocity and BMD.

In OI patients, the combined rGH–Bp treatment may give better results than Bp treatment alone, in terms of BMD, lumbar spine projected area and growth velocity, particularly in patients with quantitative defects.