The ongoing challenge of discrepant growth hormone and insulin-like growth factor I results in the evaluation of treated acromegalic patients: a systematic review and meta-analysis.

OBJECTIVE: Growth hormone (GH) and insulin-like growth factor I (IGF-I) are the principal biomarkers used to assess disease activity in acromegaly, and any discrepancy between them renders interpretation of results inconclusive. Purpose of this study was to assess the frequency of this discrepancy and identify parameters that might affect its occurrence. DESIGN: A systematic review of MEDLINE and Scopus was performed (1987-2013) followed by a meta-analysis to address the frequency of discrepant results between GH and IGF-I levels. Meta-regression and subgroup analyses were performed assessing the effects of the year of publication, the different types of GH testing and GH assays used, as well as the impact of treatment with somatostatin analogues (SSAs) on the occurrence of this discrepancy. RESULTS: The analysis retrieved 39 eligible studies totalling 7071 patients. The pooled discordance rate between GH and IGF-I was 25·7% (95% CI: 22·3-29·4), and the predominant format was that of elevated IGF-I with normal GH levels (15·3%, 95% CI: 12·5-18·7). No significant correlation between the discordance rate and the year of publication was shown; whereas, the use of ultrasensitive GH assays resulted in higher discordance rates (30·7%, 95% CI: 25·9-35·9 vs 19·8%, 95% CI: 14·1-27·2, P = 0·04) as did treatment with SSAs (32·5%, 95% CI: 27·8-37·4) vs (21·6%, 95% CI: 17·8-25·6, P = 0·001). CONCLUSIONS: Discrepancy between GH and IGF-I results is encountered in a quarter of treated patients with acromegaly, especially when using ultrasensitive GH assays or in patients receiving SSAs, a fact that the clinician should take into consideration when making clinical decisions.

Impact of gsp mutations in somatotroph pituitary adenomas on growth hormone response to somatostatin analogs: a meta-analysis.

OBJECTIVE: Somatic mutations in the GNAS1 gene, which encodes the alpha-subunit of G stimulatory proteins (gsp), are frequently detected in somatotroph pituitary tumors and have been associated to specific clinical and histopathological characteristics. However, the question whether the presence of a somatic gsp mutation affects the response to somatostatin analog treatment remains unresolved. DESIGN: Following a literature search, we performed a meta-analysis, including 8 eligible studies, in order to estimate the effect of gsp mutation on the percent reduction of growth hormone (GH) levels during an acute octreotide suppression test (OST). A total of 310 patients with acromegaly [126 gsp (+) and 184 gsp (-)] were included in the analysis. RESULTS: The presence of the gsp mutation was related with a greater reduction in GH levels on OST [Weighted Mean Difference (WMD): 9.08 % (95 % CI, 2.73, 15.42); p = 0.005; random effects model]. There was significant heterogeneity for this effect estimate (I(2) = 58 %, p value for heterogeneity = 0.02). A sensitivity analysis after exclusion of a study with different methodology of OST provided similar estimates [WMD: 6.93 % (95 % CI, 1.40, 12.46); p = 0.01], albeit with no significant heterogeneity (I(2) = 35 %, p value for heterogeneity = 0.16). CONCLUSIONS: The present meta-analysis suggests a role for gsp mutation as a prognostic factor of treatment response to somatostatin analogs.

The effect of L-thyroxine substitution on lipid profile, glucose homeostasis, inflammation and coagulation in patients with subclinical hypothyroidism.

AIMS: Subclinical hypothyroidism (SH) is associated with increased risk for atherosclerosis, mainly attributable to dyslipidaemia and hypercoagulability. However, conflicting data exist regarding the effect of L-thyroxine substitution on these parameters. The purpose of this study was to assess the effect of L-thyroxine therapy on lipidaemic profile, coagulation markers, high-sensitivity C-reactive protein (hsCRP) and glucose homoeostasis in SH patients. METHODS: It was a prospective open-label study. The following parameters were measured before and 6 months after intervention: anthropometric data, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoproteins B (apoB) and A1 (apoA1), lipoprotein (a) [Lp(a)], fasting plasma glucose and insulin, homoeostasis model assessment-insulin resistance (HOMA-IR), hsCRP, antithrombin III (AT-III), protein C (PC), protein S (PS), fibrinogen and homocysteine. RESULTS: Thirty-two patients (30 women) aged 52.1 ± 13.9 years with SH completed the study. Baseline mean TSH levels were 6.79 ± 2.58 mIU/ml. Achievement of euthyroidism significantly reduced systolic blood pressure (BP) in patients with SH (from 135.2 ± 18.5 to 129.7 ± 15.8 mmHg, p = 0.03) and diastolic BP only in those with baseline TSH levels > 7 mIU/ml (from 79.5 ± 9.8 to 72.1 ± 7.3 mmHg, p = 0.03). No significant changes in body weight, TC, LDL-C, HDL-C, TG, apoB, glucose, insulin, HOMA-IR, hsCRP, AT-III, PC, PS, fibrinogen or homocysteine levels were noticed after restoration of euthyroidism, except for a decrease in apoA1 (p = 0.04) and an increase in Lp(a) levels (p = 0.02). CONCLUSIONS: Except for a reduction in systolic and diastolic BP, thyroid substitution therapy does not affect lipidaemic profile, systematic inflammation, glucose homoeostasis or coagulation in patients with SH.

Oxidative stress and reduced antioxidative status, along with endothelial dysfunction in acromegaly.

Acromegaly is characterized by high cardiovascular morbidity and mortality. Oxidative stress and endothelial dysfunction are underlying mechanisms of atherosclerosis.The aim of this study was to evaluate the blood redox status and endothelial function by means of nitric oxide (NO) levels in patients with acromegaly. Total antioxidant capacity (TAC), catalase activity and glutathione concentration (GSH), as measures of antioxidative capacity, total oxidized glutathione (GSSG) and thiobarbituric acid reactive substances (TBARS), as indices of oxidative stress, and NO levels were assessed in 15 patients with acromegaly (age 55.4±10.5 years; 6 males) and 15 age- and sex-matched controls (age 58.4±8.1 years; 7 males). Active disease was present in 12 patients: 11 on current pharmacotherapy and 1 newly diagnosed. Three acromegalics were in remission after successful treatment. Acromegalics as compared with controls had significantly lower levels of catalase activity (8.2±5.8 vs. 51.3±29.1 mmol/ml/min, p<0.001), GSH (0.97±0.54 vs. 1.41±0.35 mmol/l, p=0.006), GSSG (0.27±0.19 vs. 2.04±1.32 mmol/l, p=0.002) and NO levels (6.0±3.1 vs. 43.0±29.8 mmol/l, p<0.001), but higher TBARS (16.3±8.9 vs. 10.1±10.8, nmol/ml, p=0.019). After adjustment for confounders, differences in catalase activity, NO levels and TBARS remained significant (p=0.004, p<0.001 and p=0.025, respectively). No association between IGF-I/GH and oxidative stress markers was noticed, except for a positive correlation between nadir GH and GSSG (r²=0.563, p=0.036). Acromegaly is associated with increased levels of oxidative stress coupled by diminished antioxidant capacity and endothelial dysfunction indicated by the presence of decreased NO levels.

Associations of estrogen receptor alpha and beta gene polymorphisms with sex steroid levels and body fat content in men.

OBJECTIVE: Estrogens play an important role in male physiology. We investigated the possible association of four single nucleotide polymorphisms in Estrogen Receptor α ( ESR1) and Estrogen Receptor ß ( ESR2) genes with circulating levels of sex steroids and Sex Hormone Binding Globulin (SHBG) in men. DESIGN AND METHODS: SHBG, total and calculated free testosterone (TT and cal FT), estradiol (E2) and free Estradiol (FE2) were determined in a population-based cohort of 170 apparently healthy Greek men. Body mass index (BMI), waist circumference (WC) and percentage of body fat (%fat) content were measured in all participants. Genotyping for the PVU II and XBA I polymorphisms of the ESR1 gene and for the RSA I and ALU I polymorphisms of the ESR2 gene was performed. RESULTS: PVU II showed an association with E2 levels [median (IQR) pp 58.5 (42.1-73.4) pg/ml vs. Pp 48.8 (42.9-60.1) and PP 57.7 (44-70.5), p=0.032], and with %fat [mean±SD pp 24.6±5.3 vs. Pp 22.4±5.2 and PP 21.2±6.7, p=0.044], after adjustment for age and WC. Furthermore, the effect of PVU II on E2 was independent of %fat (p=0.038). A synergistic effect of the two ESR1 polymorphisms on E2 (p=0.023), FE2 (p=0.03) and %fat (p=0.004) was present. Finally, a synergistic effect of the ESR1 and ESR2 genes on TT (p=0.009), independent of age, WC and %fat also emerged. CONCLUSIONS: Genetic variation in ESR1 is associated with serum estradiol levels and body fat content regulation in men. Furthermore, a synergistic effect of ESR1 and ESR2 genes is exerted on serum testosterone levels.

De novo autoimmune hepatitis associated with PTH(1-34) and PTH(1-84) administration for severe osteoporosis in a liver transplant patient.

De novo autoimmune hepatitis (AIH) is a rare graft dysfunction occurring in patients having undergone liver transplantation (LT) for causes other than AIH. We describe for the first time a case of de novo AIH associated with the administration of parathyroid hormone 1-34 [PTH(1-34)] and PTH(1-84) for severe osteoporosis. A 61-year-old woman was referred to our metabolic bone clinic due to severe osteoporosis, 3 years after LT for primary biliary cirrhosis. Initial treatment with PTH(1-34) led to asymptomatic hypertransaminasemia (two-fold the upper limit of normal), which normalized after drug discontinuation. A new flare of transaminases (three-fold the upper limit of normal) along with elevated alkaline phosphatase was observed after administration of PTH(1-84), which did not resolve after PTH(1-84) withdrawal. Subsequently, after exclusion of common causes of liver enzyme elevation, a liver biopsy was performed. Histological findings showed de novo AIH, which responded rapidly to treatment with methylprednisolone.

Acromegaly: presentation, morbidity and treatment outcomes at a single centre.

OBJECTIVE: Analysis of patients with acromegaly followed-up at a single centre, focusing on baseline characteristics, morbidity and efficacy of treatment. DESIGN AND METHODS: Retrospective review of electronic medical records of acromegalics from 1987 to 2009. RESULTS: One hundred and fifteen patients (45 men), aged 47 ± 14 years, with a mean follow-up of 8.8 ± 0.8 years were studied. Twenty-five per cent had micro- and 75% macroadenomas. Forty-three per cent presented with visual field defects, 49% had hypertension, 25% diabetes mellitus and 35% dyslipidaemia. At follow-up, 50% had myocardial hypertrophy, 55% colon polypodiasis, 74% nodular thyroid disease and 18% adrenal masses. Surgery was performed in 79% (8% twice), followed by conventional radiotherapy in 27%. Fifty-two per cent of the patients achieved remission. Disease control was reported in 65% of microadenomas and 41% of macroadenomas. Remission rates with surgery alone were 41%. Improvement of remission rates was achieved with subsequent treatment with somatostatin analogues (SSA) (53%), or conventional radiotherapy (63%). Nevertheless, pituitary reserve was compromised with the latter. SSA significantly improved outcomes in microadenomas, even as a monotherapy (remission in 89%), in contrast to macroadenomas (0%), although these agents were associated with impaired glucose metabolism and cholelithiasis in half of the patients. CONCLUSIONS: Acromegaly is associated with an increased morbidity. About half of the treated patients achieved remission (2/3 of microadenomas). The best outcomes were reported for the combination of surgery with radiotherapy, in spite of a higher risk of hypopituitarism. SSA led to remission in a significant percentage of microadenomas, but was associated with increased rates of cholelithiasis and impaired glucose homeostasis.

Non-functioning pituitary adenomas: a single center experience.

INTRODUCTION: To describe the clinical imaging and hormonal characteristics and the natural course of patients with clinically non-functioning pituitary adenomas (NFPAs) presenting at our department from 1984 to 2009. MATERIALS AND METHODS: Retrospective review of electronic medical records of patients with NFPAs. The patients underwent basal and dynamic evaluation of the hypothalamic-pituitary axis. Size and functional alterations were estimated at yearly intervals. RESULTS: 114 patients (55 men and 59 women, aged 47±2) were studied. The mean follow-up time was 55±6 months (range 0-240). 45% of the adenomas were incidentally discovered and 75% were macroadenomas (73% with extrasellar extension). At diagnosis, 53% had headache and 76% of those with macroadenomas had visual field defects. Disruption of ≥1 pituitary axes was identified in 31% of patients at diagnosis. Surgery was performed in 59% and radiotherapy in 9% of the cases. 88% of surgically treated patients reported improvement in headache and 59% in visual fields. However, the prevalence of permanent diabetes insipidus increased from 2% at diagnosis to 15% postoperatively. The prevalence of ≥1 pituitary deficiencies and panhypopituitarism increased significantly postoperatively. 58% of the adenomas relapsed in size. 29% of the patients were managed conservatively and tumor size remained stable in 83% of them. CONCLUSIONS: The majority of NFPAs not selected for surgery at diagnosis remained stable in size. Pituitary dysfunction and visual defects at diagnosis were common. Surgical debulking led to clinical improvement, but relapse occurred in 2/3 of the cases.

Pituitary incidentalomas: a single-centre experience.

AIM: Pituitary incidentalomas (PIs) are diagnosed in about 10% of the patients undergoing radiological investigation for non-pituitary disorders. The aim of this study was to describe the morphological and hormonal characteristics of PIs in a cohort of patients, followed up in a single centre from 1982-2009. METHODS: Retrospective analysis of electronic medical records of patients with PIs was carried out. All patients underwent basal and dynamic evaluation of the hypothalamus-pituitary axis. Mass size was assessed at yearly intervals. RESULTS: Sixty-one patients (38 men/23 women, aged 53±2 years) were studied. The mean follow-up time was 48±8 months, and mean size of PIs was 20±2 mm. Twelve PIs (20%) were microadenomas, 48 (78%) were macroadenomas and one (2%) was a Rathke's cyst. The most common reasons that led to their discovery were headaches, dizziness, syncope, stroke and head injury. Forty-seven of the 61 PIs (77%) were non-functioning, 11 (18%) prolactinomas, and two (3%) GH-secreting adenomas. Hypopituitarism was present in 12% at diagnosis. Forty-eight per cent of the patients were submitted to surgery with conventional radiotherapy in 8%. Relapse in size was observed in 48% of the surgically treated patients. Of the PIs followed conservatively, 78% remained stable, 11% showed decrease and 11% increase in size during follow up. Hypopituitarism rose to 57% postoperatively. CONCLUSIONS: Majority of PIs are non-functioning adenomas that remain stable in size. Relapse in size and hypopituitarism postoperatively are common. PIs, for which conservative management was initially considered appropriate, did not progress in size.

Long term follow-up of patients with adrenal incidentalomas--a single center experience and review of the literature.

INTRODUCTION: Adrenal incidentalomas (AIs) constitute an emerging clinical entity due to the increased use of abdominal imaging for diagnostic purposes. Most often it consists of benign-nonfunctioning lesions and an increase in size during follow-up is reported in about 9% (0-26%), whereas their functional evolution is rare. MATERIALS AND METHODS: Sixty-four patients (22 males and 42 females; mean age 61.6 ± 1.2 years), with AIs and follow-up of 3.1 ± 0.4 years (range 0-19) were retrospectively evaluated. The patients underwent basal and dynamic evaluation of the hypothalamic-pituitary-adrenal axis, renin-angiotensin-aldosterone system and adrenomedullary function. Mass enlargement and adrenal hyperfunction were estimated at yearly intervals. RESULTS: Adrenalectomy was performed in 5 patients (4 benign cortical adenomas and 1 pheochromocytoma). Abnormal manifestation, based on clinical, laboratory and histological evaluation, was observed in 4 patients [1 (1.56%) with SCS, 2 (3.12%) with pheochromocytoma and 1 (1.56%) with aldosteronoma], 3 of which were diagnosed at their initial evaluation and 1 at the 3 (rd) year of follow-up. The remainders [60 patients (93.75%)] were harbouring a non-secretory mass (8 potential myelolipomas, 8 nodular hyperplasias, 3 cystic lesions). Eleven patients (17.2%) had bilateral AIs. Mass enlargement (5-13 mm) was observed in 9 patients (14%), ≥10 mm 4 (6.25%), while mass shrinkage (5-19 mm) in 3 (4.7%) during follow-up. No hormonal evolution was noticed. CONCLUSIONS: AIs present usually as benign, non-secretory lesions. Criteria for surgical intervention were met at initial assessment for the majority of AIs. Size alterations during follow-up are uncommon and functional evolution is rare.

The effect of zoledronic acid on serum dickkopf-1, osteoprotegerin, and RANKL in patients with Paget's disease of bone.

Overexpression of dickkopf (DKK)-1 in pagetic osteoblast cultures resulted in stimulation of osteoclast proliferation and inhibition of osteoblast growth. The aim of this study was to evaluate for the first time in Paget's disease of bone (PDB): 1) the serum levels of DKK1; 2) the association of DKK-1 with receptor activator of nuclear factor kappa B (RANKL) and osteoprotegerin (OPG); and 3) the effect of zoledronic acid (ZOL) on serum DKK-1, RANKL, and OPG. The study was conducted as a prospective open-label cohort study. Eleven patients with PDB (median age 60 years) were recruited. Twelve age- gender- and body mass index (BMI)-matched healthy individuals were used as controls at baseline. Blood samples were obtained before treatment (baseline) and after 3, 6, 12, and 18 months following ZOL infusion in patients with PDB. Patients with PDB had significantly higher RANKL (p=0.002), OPG (p=0.001), and bone markers (total alkaline phosphatase and C-terminal cross-linking telopeptide of type I collagen) compared with controls at baseline. There was no difference between groups in DKK-1 at baseline. Bone markers were both significantly decreased after therapy. Serum OPG, RANKL, RANKL:OPG ratio, and DKK-1 remained unaffected throughout the study. No correlations were found between OPG, RANKL, RANKL:OPG ratio, and DKK-1 at baseline nor between their changes during the study. Although both OPG and RANKL were increased in patients with PDB, ZOL had no effect on their serum levels. Serum DKK-1 was neither increased in patients with PDB nor related to OPG and RANKL, and was unaffected by ZOL.

The use of demographic, ultrasonographic and scintigraphic data in the diagnostic approach of thyroid nodules.

INTRODUCTION: Thyroid nodules are a common diagnostic challenge mainly because of the need to exclude thyroid malignancy. The aim of this study was to evaluate the usefulness of demographic, ultrasonographic and scintigraphic findings in differentiating benign from malignant thyroid lesions in patients presenting with thyroid nodules. MATERIALS AND METHODS: 941 patients, who presented with palpable thyroid nodules and underwent at least one fine-needle aspiration biopsy (FNAB), were retrospectively evaluated. RESULTS: The thyroid was assessed by ultrasonography (US) in 796 patients and by scintigraphy (SC) in 774 patients. The final diagnostic outcome was established after surgery (n=183) or after a minimum of one-year clinical follow-up period. Higher rates of malignancy were observed in male gender (p<0.001), in patients presenting with a solitary nodule in US (p<0.001), in nodules with maximum diameter > or =4.5 cm in US (p=0.024) and in nodules detectable by SC (p=0.006). There were no statistical differences in the rates of malignancy among cystic, solid or mixed nodules in US or among "hot", "warm" or "cold" nodules in SC. CONCLUSIONS: Male gender, solitary nodule and nodule diameter > or =4.5 cm can serve as adjuncts to FNAB in predicting the risk of thyroid malignancy in patients presenting with thyroid nodules.

Primary adrenal lymphoma presenting as Addison's disease. Case report and review of the literature.

Primary Adrenal Lymphoma (PAL) is a very rare clinical entity. Adrenal insufficiency is a common complication of this pathology. Most patients present with clinical and laboratory findings of adrenal insufficiency and bilateral enlargement of the adrenal glands. We present a 78-year-old woman admitted to our institution with typical clinical and laboratory findings of adrenal insufficiency. Computerized tomography (CT) of the abdomen revealed bilateral enlargement of the adrenal glands. The patient was eventually diagnosed with a diffuse large B-cell lymphoma after a CT-guided needle adrenal biopsy and treated with combined immuno-chemotherapy (R-LPD-COP). Twenty months after the initial evaluation, she is in good condition, with no signs of adrenal insufficiency.

Effect of exogenous intermittent recombinant human PTH 1-34 administration and chronic endogenous parathyroid hormone excess on glucose homeostasis and insulin sensitivity.

We aimed to evaluate the effects of exogenous intermittent teriparatide (rhPTH 1-34) administration versus the chronic exposure to excess endogenous parathyroid hormone (PTH), as in pHPT, on glucose homeostasis. Two patient groups were studied: Group 1 included 25 normocalcemic women with postmenopausal osteoporosis (age 65.2+/-1.6 years) studied before and six months after teriparatide initiation; Group 2 included 19 postmenopausal women with pHPT (age 55.2+/-2.5 years) studied before and six months after successful parathyroidectomy. Calcium - total (Ca) and corrected (CCa) - ALP, PTH, as well as glucose and insulin concentrations during an oral glucose tolerance test (OGTT) were determined before and six months after either intervention. Area under the curve for glucose (AUCglu) and insulin (AUCins) were calculated. DeltaIns30'/DeltaGlu30' was applied as an index of insulin secretion. The HOmeostasis Model of Assessment (HOMA) and Matsuda ISI (Insulin Sensitivity Index) were used to calculate insulin resistance (IR) and whole body insulin sensitivity, respectively. In Group 1 no difference was found in any OGTT-derived parameter. In Group 2 significant reductions in AUCins and DeltaIns30'/DeltaGlu30' were observed. No correlation between the change in DeltaCCa or DeltaPTH and DeltaAUCglu or DeltaAUCins was found in either group. Our data suggest that while subtle transient alterations of Ca and PTH within the normal range as in exogenous rhPTH 1-34 administration do not affect glucose homeostasis, the continuously elevated Ca and endogenous PTH levels as in pHPT affect insulin sensitivity and result in increased insulin secretion.

Head-to-head comparison of risedronate vs. teriparatide on bone turnover markers in women with postmenopausal osteoporosis: a randomised trial.

AIMS: We aimed to compare the effect of risedronate (RIS) and teriparatide (TPTD) (recombinant human parathyroid hormone 1-34) on bone turnover markers in women with postmenopausal osteoporosis. METHODS: Forty-four Caucasian women (age 65.1 +/- 1.6 years) with postmenopausal osteoporosis were randomly assigned to receive either RIS 35 mg once weekly (n = 22) or TPTD 20 microg once daily (n = 22) for 12 months. Serum N-terminal propeptide of type 1 collagen (P1NP), C-terminal telopeptide of type 1 collagen (CTx), total alkaline phosphatase (ALP) and intact parathyroid hormone (iPTH) were obtained from all women before, 3 and 6 months after treatment initiation. Lumbar spine bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry before and 12 months after treatment initiation. RESULTS: P1NP, CTx and total ALP levels decreased in RIS group (p < 0.001) and increased in TPTD group (p < 0.001) throughout the treatment. iPTH increased significantly in RIS group (p < 0.05) and decreased in TPTD group (p < 0.001). Finally, lumbar spine BMD increased significantly in both RIS (p = 0.003) and TPTD groups (p < 0.001) without significant differences between them. CONCLUSIONS: Our data suggest that both serum P1NP and CTx are reliable markers of RIS and TPTD action in women with postmenopausal osteoporosis. In a similar way, serum total ALP can be used as an alternative marker for monitoring both RIS and TPTD action, while iPTH can be used only for TPTD-treated women. The increase in P1NP and CTx after 3 months of treatment with RIS or TPTD can predict the increase in BMD after 12 months of treatment.

Long-term changes and variability in diabetes risk factors prior to the development of impaired glucose homeostasis.

AIMS: To determine whether rate of change and variability in risk factors provides insight into the development of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or Type 2 diabetes (DM). METHODS: In a nested case-control study, repeated risk factor measurements (mean number 4.3, duration 11.4 years) culminated in 59 men developing IFG (n = 37), IGT (n = 14) and/or DM (n = 11). For each case, two control subjects were matched for age and equivalence of follow-up. Rates of change and variability in diabetes risk factors prior to diagnosis were quantified by regression analysis. Changes between penultimate and diagnostic visits were also analysed. RESULTS: The age-related rise in body mass index (BMI) was attenuated prior to IFG compared with control subjects (+0.102 vs. +0.772 kg/m2/decade, P = 0.02). There was also some evidence for this prior to IGT and DM (IGT: -1.530 vs. +0.158 kg/m2/decade, P = 0.09; DM: -1.146 vs. +0.332 kg/m2/decade, non-significant). Prior to onset, IGT cases were distinguished by higher inflammatory marker levels, a decline in insulinogenic index and greater variability in oral glucose tolerance test (OGTT) insulin, and DM cases by lower insulin sensitivity and higher liver enzyme activities. Fasting and OGTT glucose levels changed little during the mean 8.9 years prior to onset of IFG, IGT or DM. The transition to IGT or DM was accompanied by a fall in insulin sensitivity. CONCLUSIONS: Except for BMI, change or variability in risk factor levels appears relatively unimportant in the development of clinically elevated glucose levels. Deterioration in glucose levels to IGT or DM occurs as a rapid, incremental increase accompanied by a decline in insulin sensitivity.

Correlation of estrogen receptor beta gene polymorphisms with spinal bone mineral density in peri- and post-menopausal Greek women.

Estrogens play a significant role in bone physiology. Their action is mainly exerted through their receptors. Estrogen receptor alpha (ERalpha) plays a major role in bone homeostasis and there is evidence suggesting that estrogen receptor beta (ERbeta) has also an effect on BMD. We investigated the possible effect of two ERbeta gene polymorphisms on spinal bone mineral density (BMD) and metabolic bone markers in Greek women. Spine BMD as well as biochemical bone markers were measured in 147 healthy peri- and post-menopausal women [mean age (S.D.) 54 (7.9) years]. Genotyping was performed for two restriction fragment length polymorphisms (RFLPs) of ERbeta gene, RsaI in exon 5 and AluI in exon 8. For each polymorphism studied the cohort was divided into two groups: the "wild-type" group (RR and AA, respectively) and the "carrier" group including subjects with at least one allele with the restriction site (Rr&rr and Aa&aa, respectively). The distribution of RsaI genotypes was RR: 91.2% (n = 134), Rr: 8.2% (n = 12), and rr: 0.6% (n = 1) and of AluI genotypes AA: 36.7% (n = 54), Aa: 57.2% (n = 84), and aa: 6.1% (n = 9). No linkage disequilibrium was found between the two polymorphic sites studied. Spine BMD did not differ significantly in the two groups of either polymorphism, after adjusting for age, weight, height, and years since menopause [mean BMD (S.D.) for RR 0.841 (0.17) g/cm(2) versus Rr&rr 0.798 (0.13) g/cm(2), p = 0.25, and mean BMD (S.D.) for AA 0.828 (0.16)g/cm(2) versus Aa&aa 0.848 (0.17) g/cm(2), p = 0.32]. No significant differences were noted in metabolic bone markers except for a marginal difference of RR versus Rr/rr in urinary hydroxyproline/creatinine ratio [median (IQR) 3.88 (6.04) micromol/mmol in RR versus 8.2 (4.32) micromol/mmol in Rr/rr, p = 0.05]. Furthermore, no interaction between the two polymorphisms on BMD was found. In conclusion, in a Greek female post-menopausal population, the two ERbeta gene polymorphisms were not associated with BMD, or metabolic bone markers.

The impact of ethnicity on glucose regulation and the metabolic syndrome following gestational diabetes.

AIMS/HYPOTHESIS: We assessed the impact of ethnic origin on metabolism in women following gestational diabetes mellitus (GDM). MATERIALS AND METHODS: Glucose regulation and other features of the metabolic syndrome were studied at 20.0 (18.2-22.1) months (geometric mean [95% CI]) post-partum in women with previous GDM (185 European, 103 Asian-Indian, 80 African-Caribbean). They were compared with the same features in 482 normal control subjects who had normal glucose regulation during and following pregnancy. RESULTS: Impaired glucose regulation or diabetes by WHO criteria were present in 37% of women with previous GDM (diabetes in 17%), especially in those of African-Caribbean and Asian-Indian origin (50 and 44%, respectively vs 28% in European, p=0.009). BMI, waist circumference, diastolic blood pressure, fasting triglyceride and insulin levels, and insulin resistance by homeostatic model assessment (HOMA), were increased following GDM (p<0.001 for all, vs control subjects). Where glucose regulation was normal following GDM, basal insulin secretion (by HOMA) was high (p<0.001 vs control subjects). Irrespective of glucose regulation in pregnancy, Asian-Indian origin was associated with high triglyceride and low HDL cholesterol levels, and African-Caribbean with increased waist circumference, blood pressure, and insulin levels, together with insulin resistance and low triglyceride concentrations. Nonetheless, the GDM-associated features were consistent within each ethnic group. The metabolic syndrome by International Diabetes Federation criteria was present in 37% of women with previous GDM, especially in non-Europeans (Asian-Indian 49%, African-Caribbean 43%, European 28%, p=0.001), and in 10% of controls. CONCLUSIONS/INTERPRETATION: Following GDM, abnormal glucose regulation and the metabolic syndrome are common, especially in non-European women, indicating a need for diabetes and cardiovascular disease prevention strategies.

Apolipoprotein E polymorphism is not associated with spinal bone mineral density in peri- and postmenopausal Greek women.

OBJECTIVES: A number of studies have shown a positive relation between ApoE gene and osteoporosis or fracture risk but this finding has not been uniform in all populations studied. The aim of the present study was to determine the possible effect of ApoE gene polymorphism on spinal bone mineral density and metabolic bone markers in Greek women. METHODS: One hundred and forty-seven healthy peri- and postmenopausal women (mean age 54.3 +/- 7.8 years) participated in the study. In all participants, ApoE gene genotype was determined and spinal bone mineral density (BMD) as well as biochemical bone markers were measured. The ApoE genotypes distribution was 0.7% (n = 1) for E2/2, 5.4% (n = 8) for E2/3, 2% (n = 3) for E2/4, 73.5% (n = 108) for E3/3, 16.3% (n = 24) for E3/4 and 2% (n = 3) for E4/4. Participants were divided in two groups according to the presence of the E4 haplotype: E4 carriers (n = 30) and E4 non-carriers (n = 117). RESULTS: Spinal BMD was similar in the two groups, after adjusting for age, weight, height and years since menopause (mean +/- S.D., 0.835 +/- 0.16 g/cm2 in E4 non-carriers versus 0.831 +/- 0.16 g/cm2 in E4 carriers, P = 0.99). Serum osteocalcin levels did not differ significantly in the two groups (median (interquartile range, IQR), 0.55 (0.58) nmol/l in E4 non-carriers versus 0.51 (0.43) nmol/l in E4 carriers), whereas urinary hydroxyproline/creatinine ratio was significantly higher in the E4 non-carriers group (median (IQR), 5.18 (6.04) micromol/mmol in E4 non-carriers versus 1.73 (3.45) micromol/mmol in E4 carriers, P < 0.01). Urinary pyridinoline/creatinine and deoxypyridinoline/creatinine ratios, measured in a subgroup of 51 women, were similar between ApoE carriers and non-carriers, respectively (median (IQR), 25.1 (9.3) nmol/mmol in E4 non-carriers versus 21.8 (7) nmol/mmol in E4 carriers and 6.7 (3.1) nmol/mmol in E4 non-carriers versus 7 (2.2) nmol/mmol in E4 carriers). CONCLUSION: In conclusion, in a Greek female postmenopausal population, ApoE gene does not seem to play an important role in determining BMD and neither does it affect the majority of metabolic bone markers.