Primary tumour diameter as a risk factor for advanced disease features of differentiated thyroid carcinoma

Objective  To study the relationship between primary tumour size and the risk of advanced disease features (multifocal or locally invasive disease, lymph-node or distant metastases) in differentiated thyroid carcinoma (DTC).
Design  A retrospective chart review study.
Patients  The study sample comprised 935 papillary (PTC) and 291 follicular thyroid carcinoma (FTC) patients treated in our hospital from 1978 to 2007.
Measurements  Kaplan–Meier analyses and log-rank tests were performed to calculate tumour size-adjusted cumulative risk of advanced disease features.
Results  Accounting for primary tumour diameter, there were no significant differences in cumulative risks of multifocal carcinoma ( P =  0·12) or distant metastases ( P =  0·49) between PTC and FTC. PTC showed higher cumulative risks of local invasion ( P <  0·0001) or lymph-node metastases ( P <  0·0001). The cumulative risk of tumour multifocality increased 5%/cm of primary tumour diameter. The cumulative risk of local invasion or lymph-node metastases in PTC and of distant metastases in DTC increased exponentially at a threshold tumour diameter of 10 mm. In FTC, lymph-node metastases are associated almost exclusively with primary tumours showing extrathyroidal growth.
Conclusions  Starting with a 1 cm primary tumour diameter, increasing tumour size is associated with an exponentially increasing risk of local invasion or lymph-node or distant metastases of DTC. The current classification of carcinomas < 2 cm as T1 is therefore questionable.     

Higher serum TSH in thyroid cancer patients occurs independent of age and correlates with extrathyroidal extension

Background  It has previously been shown that higher serum TSH is associated with increased thyroid cancer incidence and advanced-stage disease. In the healthy adult population, mean TSH increases with age. As age over 45 years is a known prognostic indicator for thyroid cancer, it is important to know whether higher TSH in patients with thyroid cancer occurs independent of age.
Objective  To determine the relationship between higher TSH, cancer and age.
Design  A retrospective cohort study.
Patients and methods  A total of 1361 patients underwent thyroid surgery between May 1994 and December 2007 at a single institution. Of these patients, 954 had pathological data, preoperative TSH and complete surgical history available. Data were analysed in relation to age and TSH.
Results  Mean TSH was significantly higher in cancer patients regardless of age < 45 years or ≥ 45 years ( P =  0·046 and P  = 0·027, respectively). When examining age groups < 20, 20–44, 45–59 and ≥ 60 years, there was a trend of rising mean TSH with age. Despite the rise in the benign subgroups, mean TSH was consistently higher in those with cancer vs. those without. On multivariate analysis, higher TSH was independently associated with cancer ( P =  0·039) and pathological features of Hashimoto's thyroiditis ( P =  0·001) but not with age ( P =  0·557). On multivariate analysis of high-risk features associated with poor prognosis, there was a significant association between higher TSH and extrathyroidal extension ( P =  0·002), whereas there was no clear relationship with age, tumour size > 4 cm, and distant metastases.
Conclusion  Independent of age, thyroid cancer incidence correlates with higher TSH. Higher TSH is associated with extrathyroidal extension of disease.     

Characterization of the anaemia associated with Graves' disease

Background  Graves' disease (GD) is associated with hyperthyroidism. Thyrotoxicosis adversely affects multiple organ systems including haematopoiesis. Anaemia occurring specifically in GD has not been systematically studied previously.
Objective  To define the prevalence and characteristics of the anaemia associated with GD.
Design  Eighty-seven newly diagnosed patients with GD were recruited. Haematological indices, thyroid function and inflammatory parameters were examined at presentation and following successful treatment of hyperthyroidism.
Setting  Tertiary care academic referral centre.
Results  Thirty-three per cent of subjects presented with anaemia. The prevalence of anaemia not attributable to other causes (GD anaemia) was 22%. GD anaemia affected 41·6% (10/24) of men compared to 17·5% of women (11/63). Mean erythropoietin (EPO) levels (15·5 ± 5·3 mIU/ml) were within normal reference limits but significantly higher ( P =  0·004) than those of the non-anaemic controls. Hgb correlated inversely with EPO ( P =  0·05) and CRP ( P =  0·04) levels, a relationship that persisted after multivariate adjustment for TT3 or TT4. With antithyroid therapy for 16 ± 6·3 weeks, Hgb levels normalized in 8 out of 9 subjects with GD anaemia (10·7 ± 0·8 to 13·5 ± 1·3 g/dl, P  = 0·0001). After normalization of Hgb, mean MCV and TIBC were significantly increased, and median ferritin and mean EPO were significantly decreased.
Conclusions  GD anaemia is common, resembles the anaemia of chronic disease, and is associated with markers of inflammation. It corrects promptly with return to the euthyroid state following treatment.     

Does the RET variant G691S influence the features of sporadic medullary thyroid carcinoma?

Objective  The RET (rearranged during transfection) proto-oncogene G691S variant is over-represented in the germline of patients with sporadic medullary thyroid carcinoma (sMTC) vs. normal controls but so far is not associated with any medical or pathological features of the tumour. The aim of our study was to assess the influence of this variant on the age of onset, clinical, biological and pathological features of sMTC.
Design and patients  One hundred patients with histologically proven MTC, for whom the germline genetic analysis of RET was negative and medical records were available, were included in the study.
Results  Patients with the heterozygous GS variant or the homozygous SS variant ( n  = 36) were on average 8·0 years younger than patients with the wild-type GG variant ( n  = 64, mean age 43·9 vs. 51·9 years, P  < 0·01). The former group did not differ from the wild-type group in terms of MTC size, prevalence of C-cell hyperplasia (CCH) or papillary thyroid carcinoma (PTC). However, the prevalence of an increased preoperative basal calcitonin (bCT) level (> 1000 pg/ml) was 2·75-fold higher in the patients with the GS or SS variant than in those with the wild-type variant ( P <  0·001). The proportion of patients with lymph node metastases was also higher in the former group ( P <  0·05). Multivariate analysis confirmed that the presence of the RET variant is independently associated with higher preoperative bCT values ( P =  0·011).
Conclusions  Our data demonstrate that the RET G691S variant could modulate the age of onset of sMTC as demonstrated previously for familial tumours. Moreover, this variant is an independent predictor of a higher basal calcitonin synthesis rate in patients with sMTC.     

Effect of metformin, orlistat and pioglitazone treatment on mean insulin resistance and its biological variability in polycystic ovary syndrome

Context  Mean insulin resistance (IR) is greater and it is also more variable in overweight women with polycystic ovarian syndrome (PCOS) compared to weight matched controls. Whilst treatment will reduce the mean IR, it is not known if the IR variability is also reduced.
Objective  To compare the change in IR and its variability before and after treatment with insulin sensitization through metformin and pioglitazone, compared to that induced by weight loss with orlistat.
Design  Randomized, open labelled parallel study.
Setting  Endocrinology outpatient clinic at a referral centre.
Patients  Thirty obese PCOS patients [BMI 36·0 ± 1·2 kg/m² (mean ± SEM)] participated in the study.
Intervention  The change in biological variability (BV) was assessed by measuring IR (homeostasis model assessment method) at 4-day intervals on 10 consecutive occasions before and 12 weeks after randomization to metformin, pioglitazone or orlistat.
Outcome measured  The primary end point of the study was a change in BV of IR.
Results  Treatment with pioglitazone, orlistat and metformin reduced the overall IR by 41·0 ± 4·1%, 19·7 ± 6·4% and 16·1 ± 6·8% ( P =  0·005, P  = 0·013, P  = 0·17, respectively) and IR variability by 28·5 ± 18·0%, 41·8 ± 11·6% and 23·7 ± 17·0 ( P =  0·20, P  = 0·015 and P  = 0·28, respectively). Free androgen index reduced significantly with all treatments.
Conclusion  Only orlistat reduced both IR and its variability significantly, though all three drugs were effective in reducing hyperandrogenism within the 12-week period of the study.     

Peroxisome proliferator-activated receptor γ (PPAR) agonism reduces the insulin-stimulated increase in circulating interleukin-6 in GH replaced GH-deficient adults

Context  Peroxisome proliferator-activated receptor γ (PPARγ) agonists modify cardiovascular risk factors and inflammatory markers in patients with type 2 diabetes. GH treatment in GH-deficient (GHD) patients may cause insulin resistance and exerts ambiguous effects on inflammatory markers.
Objective  To investigate circulating markers of inflammation and endothelial function in GH replaced GHD patients before and after 12 weeks administration of either pioglitazone 30 mg/day ( N  = 10) or placebo ( N  = 10) in a randomized double-blind parallel design.
Methods  Circulating levels of interleukins (ILs)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, high sensitivity C-reactive protein, vascular cell adhesion molecule-I, and osteoprotegerin (OPG) were measured in the basal state and after a 2·5 h hyperinsulinaemic euglycaemic clamp.
Results  Insulin sensitivity improved in the group receiving PPARγ agonist ( P =  0·03). Serum IL-6 levels increased by 114 ± 31% (mean ± SE) in the entire group ( N  = 20) following the hyperinsulinaemic euglycaemic clamp ( P =  0·01) performed at study start. Twelve weeks of PPARγ agonist treatment significantly abrogated this insulin-stimulated increment in IL-6 levels compared to placebo ( P =  0·01). Furthermore PPARγ agonist treatment significantly lowered basal IL-4 levels ( P <  0·05).
Conclusions  (i) IL-6 levels increase during a hyperinsulinaemic clamp in GH replaced patients (ii) This increase in IL-6 is abrogated by PPARγ agonist treatment (iii) we hypothesize that PPARγ agonist-induced improvement of insulin sensitivity may obviate a compensatory rise in IL-6.     

Decreased hepatic RBP4 secretion is correlated with reduced hepatic glucose production but is not associated with insulin resistance in patients with liver cirrhosis

Objective  Patients with liver cirrhosis have a high incidence of insulin resistance and diabetes. This study was designed to determine circulating levels and hepatic production of retinol-binding protein 4 (RBP4) in relation to parameters of hepatic and systemic metabolism in patients with liver cirrhosis.
Design and method  Circulating RBP4 levels were measured in 19 patients with liver cirrhosis at different clinical stages of the disease and in 20 age-, sex- and body mass index (BMI)-matched controls. Hepatic production rates of RBP4 and glucose were assessed by measuring the arterial hepatic venous concentration difference together with hepatic blood flow. Insulin resistance was determined by the Quantitative Insulin Sensitivity Check Index (QUICKI) and the homeostasis model assessment of insulin resistance (HOMA-IR), energy expenditure by indirect calorimetry and body composition by bioelectrical impedance analysis (BIA).
Results  Compared with controls, RBP4 levels in cirrhosis were decreased (8·1 ± 1·8 vs. 22·6 ± 2·4 mg/l, P  < 0·001) due to decreased hepatic production ( P <  0·05). RBP4 correlated with hepatic protein synthesis capacity ( P <  0·01), but not with insulin resistance, energy expenditure, BMI or body fat mass. Plasma RBP4 correlated with hepatic glucose production ( P <  0·05).
Conclusions  These data demonstrate that RBP4 in cirrhosis (i) is decreased due to reduced hepatic production, (ii) is not associated with insulin resistance, and (iii) might have a beneficial role by decreasing hepatic glucose production and could thus also be regarded as a hepatokine.     

Anaemia and marrow fibrosis in patients with primary hyperparathyroidism before and after curative parathyroidectomy

Objective  To determine the relationship between anaemia and myelofibrosis in patients with symptomatic primary hyperparathyroidism (PHPT) and to assess the effect of curative parathyroidectomy on anaemia and marrow fibrosis.
Design and methods  In this prospective follow-up study of 28 consecutive patients with symptomatic PHPT from January 2005 to June 2006, 15 patients were diagnosed with anaemia (haemoglobin < 130 g/l in males and < 120 g/l in females), eight (53%) of whom were finally recruited for the study. Complete blood cell count, serum calcium, phosphorus, alkaline phosphatase, intact PTH and 25-hydroxyvitamin D and bone marrow examination were performed both before and after parathyroidectomy in all ( n  = 8) patients, but bone marrow examination after surgery was performed only in those who had marrow fibrosis at baseline ( n  = 6).
Results  Anaemia was observed in 15 (53·3%) of the 28 patients with symptomatic PHPT. Normocytic normochromic anaemia that is characteristic of PHPT was found in 14 (50%) patients. Eight of the 15 patients with anaemia had a bone marrow examination and marrow fibrosis was observed in six (75%). Both anaemia and marrow fibrosis improved after successful parathyroidectomy, but improvement in anaemia was significant ( P =  0·02) only in those with marrow fibrosis at baseline. Marrow fibrosis did not correlate with duration of the disease ( P =  0·17), degree of hypercalcaemia ( P =  0·53) or serum levels of intact PTH ( P =  0·60).
Conclusions  Anaemia is common in patients with symptomatic PHPT, and was associated with marrow fibrosis in the majority of the patients who underwent bone biopsy. Both anaemia and marrow fibrosis improved after curative parathyroidectomy, but improvement in anaemia was noticeable only in those who had marrow fibrosis at presentation.     

Multiple endocrine neoplasia type 1 (MEN1): its manifestations and effect of genetic screening on clinical outcome

Objective  Effect of genetic screening on outcome in multiple endocrine neoplasia type 1 (MEN1) remains unclear. Expression of MEN1 is described using currently available diagnostic techniques. Manifestations and outcome are compared in patients diagnosed because of clinical expression with those diagnosed by genetic screening.
Design  Retrospective cohort study. Patients are divided into two groups: patients with a (i) clinical MEN1 diagnosis and (ii) MEN1 diagnosis by genetic screening.
Patients and measurements  Demographic and clinical data were collected on MEN1 patients treated in the UMCU up to 1 January 2008. Results of mutation analysis were obtained from the Department of Medical Genetics.
Results  A total of 74 patients was included (median follow-up 5·5 year); 78% had hyperparathyroidism, 46% a pancreatic neuro-endocrine tumour (NET), 38% a pituitary abnormality, 8% a NET of other origin and 16% an adrenal adenoma at the end of follow-up. Of the patients 18% had no manifestation. All five MEN1-related tumours were seen as first manifestation. Compared with patients identified by genetic screening, patients with a clinical MEN1 diagnosis had significantly more manifestations at diagnosis ( P <  0·001) and at end of follow-up ( P =  0·002). Eleven of 30 patients with a genetic MEN1 diagnosis (mean age at diagnosis 30·0 years) already had manifestations at diagnosis. No malignancy or death was seen in genetically diagnosed patients.
Conclusions  MEN1 is a syndrome with high morbidity. Genetic diagnosis is associated with less morbidity at diagnosis and at follow-up. Early genetic diagnosis might therefore lead to improvement of long-term outcome.     

Occurrence of impaired fasting glucose in GH-deficient adults receiving GH replacement compared with untreated subjects

Objective  The effects of GH replacement on glucose metabolism in GH-deficient (GHD) adults in clinical practice are not well defined. Therefore, we assessed GH treatment effects on fasting plasma glucose (FPG) and haemoglobin A1c (A1c) concentrations in GHD adults in a clinical setting.
Design  Post-hoc analysis of the observational Hypopituitary Control and Complications Study conducted at 157 US centres (1997–2002).
Patients  GH-deficient adults who were GH-naïve at study entry and had at least two FPG measurements.
Measurements  Effect of GH treatment on the frequency and time course of abnormal FPG (≥5·6 mmol/l) development, FPG normalization, progression of increased FPG and abnormal follow-up A1c (>6%) values in GHD patients treated with GH ( n  = 403) or untreated ( n  = 169) at their physician's discretion.
Results  In subjects without pre-existing diabetes mellitus, development of an abnormal FPG tended to occur in a greater percentage of GH-treated than untreated subjects (35·3% versus 24·5, P  =   0·06). Additionally, GH treatment was associated with a mild, transient increase in FPG and shorter time to development of an abnormal FPG in these subjects ( P  <   0·01). Most (∼80%) abnormal FPG values were below 7 mmol/l and normalized in 69% of GH-treated subjects without diabetes. Treatment with GH had no effect on the rate of FPG normalization, progression of increased FPG or abnormal follow-up A1c values.
Conclusions  Initiation of GH replacement in GHD adults was associated with a mild increase in FPG that often normalized spontaneously. Nevertheless, clinicians should monitor FPG in patients receiving GH treatment.     

Application of the intravenous glucose tolerance test and the minimal model to patients with insulinoma: insulin sensitivity (Si) and glucose effectiveness (Sg) before and after surgical excision

Background  The unmodified frequently sampled intravenous glucose tolerance test (FSIGT) has not previously been used to assess insulin/glucose kinetics in patients with insulinoma.
Objective  To measure insulin sensitivity (Si) and glucose effectiveness (Sg) by means of the FSIGT in patients with insulinoma, before and after surgical removal of the tumour.
Subjects and methods  FSIGTs were performed in five patients, before and approximately 3 months post-surgery, and in 11 controls. Si and Sg were estimated using Minimal Model computer analysis of dynamic glucose and insulin data.
Results  Si was lower in insulinoma patients before, compared with after surgery (3·37 ± 0·62 vs. 6·24 ± 1·09 SE [×10⁻⁴] min⁻¹µU⁻¹ ml, P  < 0·05). Sg was similar in patients pre- and post-surgery (3·0 ± 0·67 vs. 2·4 ± 0·6 [×10⁻²] min⁻¹, NS).
Conclusions  Insulin sensitivity improves after excision of an insulinoma. Glucose effectiveness is not influenced by chronic hyperinsulinaemia and hypoglycaemia.     

A randomized study of buffy coat platelets in platelet additive solution stored 1–5 versus 6–7 days prior to prophylactic transfusion of allogeneic haematopoietic progenitor cell transplant recipients

Background and Objective  Storage of platelets > 5 days provides improved availability, logistical management and decreased outdating. Promising results on in vitro parameters and on in vivo post-transfusion recovery and survival of autologous platelets in healthy volunteers have earlier been shown. To provide additional verification, randomized patient transfusion studies are needed.
Materials and Methods  Sixty allogeneic haematopoietic progenitor cell transplant recipients were randomized to receive buffy-coat (BC) platelets stored in platelet additive solution (PAS) for 1–5 days the first time a prophylactic transfusion was needed after transplantation, followed the second time by platelets stored for 6–7 days or vice versa. The corrected count increment (CCI) for 1 and 24 h were calculated.
Results  CCI 1 h and CCI 24 h were higher for platelets stored 1–5 days as compared to 6–7 days, 10·4 ± 5·1 vs. 7·4 ± 3·8 ( P <  0·001) and 5·4 ± 4·1 vs. 2·6 ± 2·6 ( P <  0·001), respectively. Time to next platelet transfusion was significantly longer after a transfusion of platelets stored for 1–5 days as compared to platelets stored for 6–7 days: 2·2 ± 1·1 vs. 1·6 ± 0·8 days, respectively ( P <  0·005). No differences in bleeding events and no transfusion reaction were recorded.
Conclusion  The advantage of an extension of platelet storage time beyond day 5 should be balanced against the increased need for platelet transfusions that may occur and the conceivable risk of transfusion failure.     

Antiphospholipid antibodies in adults with immune thrombocytopenic purpura

To determine the clinical significance of antiphospholipid antibodies (aPL) in patients with immune thrombocytopenic purpura (ITP), anticardiolipin (aCL) (IgG and IgM) and lupus anticoagulant (LA) were sought at diagnosis in 215 ITP adults with platelets <50 × 10⁹/l. aPL (aCL and/or LA) were detected in 55 patients (26%): aCL alone in 39 (18%), aCL and LA in 15 (7%) and LA alone in one (0·5%). LA was significantly associated with high IgG-aCL levels ( P  =   0·001). Among age, sex, initial platelet count, bleeding score, acute or chronic ITP outcome, only younger age was significantly associated with LA-positivity (mean age 29 ± 14 years vs. 45 ± 20 years, P  =   0·002). After a median follow-up of 31 months, 14/215 (7%) patients developed thrombosis (four arterial, 10 venous and/or pulmonary embolism); four of them (29%) had high aCL levels and LA. Multivariate analysis significantly associated thrombosis events only with age [hazard ratio (HR)   =   1·6; 95% confidence interval (CI): 1·2–2·4], LA (HR: 9·9; 95% CI: 2·3–43·4) or high IgG-aCL level (HR: 7·5; 95% CI; 1·8–31·5). Although the thrombosis rate was low, the significant associations between thrombosis and LA or high aCL level suggest that aPL should be tested at ITP diagnosis.     

Levels of non-transferrin-bound iron as an index of iron overload in patients with thalassaemia intermedia

Non-transferrin-bound iron (NTBI) was evaluated as an index of iron overload in a cross-sectional randomised study in 74 non-transfused patients with thalassaemia intermedia (TI). Mean NTBI (2·92 ± 3·43 μmol/l), serum ferritin (1023 ± 780 ng/ml) and liver iron concentration (LIC; 9·0 ± 7·4 mg Fe/g dry weight) were increased above reference-range levels. Significant positive correlations occurred between mean NTBI and LIC (Pearson correlation 0·36; P  = 0·002) and serum ferritin (Pearson correlation 0·421; P  < 0·0001); with higher levels observed in splenectomised patients. NTBI assessment has potential as a simple reliable approach to determining iron status in TI.     

Augmentation index in resistance to thyroid hormone (RTH)

Objective  Resistance to thyroid hormone (RTH) is associated with a varied clinical presentation. The cardiac effects of RTH have been described but vascular function has yet to be fully evaluated in this condition. We have measured the arterial function of those with RTH to assess any vascular changes.
Design  An observational study.
Patients  Twelve RTH patients were recruited from the thyroid clinic (mean value ± SD), age 40·8 ± 18·7 years; BMI 27·2 ± 4·2 kg/m² and compared with 12 healthy, euthyroid, age-matched controls (age 41·4 ± 19·3; BMI 24·8 ± 4·4 kg/m²) with no history of cardiovascular disease. No interventional measures were instituted.
Measurements  Arterial stiffness was measured using pulse wave analysis at the radial artery. Thyroid function, fasting lipids and glucose were also measured on the same occasion in both patients and controls.
Results  The corrected augmentation index, a surrogate marker of arterial stiffness was significantly higher in patients compared with controls (21·0% ± 14·1% vs. 5·4% ± 18·2%, P  < 0·03). Low density lipoprotein cholesterol (LDL-cholesterol) levels were also significantly elevated in patients compared with controls (3·0 ± 0·6 vs. 2·1 ± 0·5 mmol/l; P  < 0·002).
Conclusion  RTH patients show evidence in this study of increased augmentation index consistent with an increase in arterial stiffness compared with euthyroid controls. They also demonstrate elevated LDL-cholesterol levels. Both these measures may lead to increased cardiovascular risk.     

Pulmonary vein isolation for atrial fibrillation in patients with symptomatic sinus bradycardia or pauses

Introduction: Sick sinus syndrome is commonly associated with tachyarrhythmias and bradyarrhythmias that often are symptomatic. The aim of this study was to assess the effect of pulmonary vein isolation in patients with sick sinus syndrome and atrial fibrillation (AF).
Methods and Results: Three hundred fourteen consecutive patients who underwent pulmonary vein isolation between December 2000 and January 2002 were included in the study. Thirty-one patients had sick sinus syndrome, which was defined as a preprocedural history of symptomatic sinus bradycardia or pauses. Endpoints included AF recurrence, change in the frequency of sinus pauses, and symptoms of presyncope or syncope, as well as mean heart rate and percentage of atrial pacing in patients with pacemakers implanted prior to the pulmonary vein isolation. Patients had AF for an average of 6 ± 3 years. Patients were 58 ±8 years old and had ejection fractions of 55 ± 4%. Sixty-one percent had implanted pacemakers. AF recurred within 6 months in 4 patients. Two had a successful second pulmonary vein isolation procedure. There were no recurrences of presyncopal events (P < 0.05) or documented sinus pauses (P < 0.05) after successful pulmonary vein isolation in the patients without permanent pacemakers. Patients with pacemakers had a 13-fold reduction in the percentage of atrial pacing (P < 0.05). Both groups showed a significant increase in average heart rates at 6-month follow-up.
Conclusion: Cure of AF by pulmonary vein isolation helped resolve the clinical manifestations of sick sinus syndrome, suggesting that the occurrence of AF and/or the associated treatment could be partially responsible for sick sinus syndrome. (J Cardiovasc Electrophysiol, Vol. 15, pp. 784-789, July 2004)     

Spinal volumetric trabecular bone mass in acromegalic patients: a longitudinal study

Objective  Data on trabecular bone mass in acromegaly are controversial. All the studies are cross-sectional and bone mineral density (BMD) has been evaluated largely by dual X-ray absorptiometry (DXA), which is influenced by bone enlargement. In this study we assessed in acromegalic patients the effects overtime of GH excess on trabecular bone mass measured by single-energy quantitative computed tomography (QCT) which is not influenced by bone size.
Design  Longitudinal retrospective study.
Patients  A total of 46 acromegalic patients followed-up for 48 months (median), subdivided into four groups: group A (eugonadal patients with active disease: n  = 13), group B (hypogonadal patients with active disease; n  = 9), group C (eugonadal patients with controlled disease; n  = 10), group D (hypogonadal patients with controlled disease; n  = 14).
Measurements  Serum GH and IGF-I levels, spinal trabecular BMD, and vertebral fractures were evaluated in all patients. BMD variations were reported as change (Δ) in Z -values (Z-QCT) measured at baseline and end of follow-up per year (Δ Z-QCT).
Results  Δ Z-QCT was greater in group A vs. group B and D ( P = 0·002 and P  = 0·0001, respectively) and in group C vs. group D ( P = 0·009). Multivariate regression analysis showed that hypogonadal status (β = –0·69; P  = 0·001) and baseline duration of hypogonadism (β = 0·44; P  = 0·02) but not baseline duration of acromegaly, length of follow-up and disease activity, were significantly associated with Δ Z-QCT.
Conclusions  This longitudinal study suggests that the effect of chronic GH excess on spinal trabecular bone mass seems to be anabolic in active eugonadal patients but not in hypogonadal ones.     

Ultrasound of peripheral nerves in acromegaly: changes at 1-year follow-up

Context  We have previously demonstrated peripheral nerve enlargement in acromegaly.
Objective  The aim of this study was to use ultrasound (US) to assess any changes in the peripheral nerves of patients with acromegaly 1 year after the first evaluation.
Patients  We prospectively examined the median and ulnar nerve cross-sectional area (CSA) in 34 non-diabetic, patients with acromegaly (18 females and 16 males; 18–79 years) and 34 age-, sex-, BMI-matched controls, using a 17–5 MHz US probe.
Intervention  The median nerve was examined at the mid-forearm (MN-f) and at the carpal tunnel (MN-Ct) levels; the ulnar nerve at mid-forearm (UN-f) and at distal arm (UN-a). Patients were grouped according to the clinical control of the disease: 'improved'; 'always controlled'; 'always uncontrolled'; and 'worsened'.
Results  The median nerve at mid-forearm (MN-f), the ulnar nerve at mid-forearm (UN-f) and at distal arm (UN-a) were significantly reduced after 1-year follow-up in all patients ( P <  0·001, P  < 0·008, P  < 0·012, respectively). In the 'improved' group, there was a significant reduction of median nerve CSA examined at mid-forearm (MN-f) ( P =  0·02), and distal arm ulnar nerve CSA (UN-a) ( P =  0·002). In the other groups no statistically significant differences in ultrasound parameters were recorded. However, UN-a, UN-f, MN-f, MN-ct were still significantly higher in all groups compared with controls ( P <  0·001).
Conclusion  These data demonstrate that median and ulnar nerves CSA are reduced after 1 year follow-up, in line with the reduction of GH/IGF-I levels. However, as the control of the disease incompletely reverts nerve enlargement, this phenomenon could be only partially reversible.     

Peroxisome proliferator-activated receptor gamma agonism modifies the effects of growth hormone on lipolysis and insulin sensitivity

Context  Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists such as thiazolidinediones (TZDs) improve insulin sensitivity in type 2 diabetes mellitus (T2DM) through effects on fat metabolism whereas GH stimulates lipolysis and induces insulin resistance.
Objective  To evaluate the impact of TZDs on fat metabolism and insulin sensitivity in subjects exposed to stable GH levels.
Design  A randomized, placebo-controlled, double-blind parallel-group study including 20 GH-deficient patients on continued GH replacement therapy. The patients were studied before and after 12 weeks.
Intervention  Patients received either pioglitazone 30 mg ( N  = 10) or placebo ( N  = 10) once daily for 12 weeks.
Results  Adiponectin levels almost doubled during pioglitazone treatment ( P =  0·0001). Pioglitazone significantly decreased basal free fatty acid (FFA) levels ( P =  0·02) and lipid oxidation ( P =  0·02). Basal glucose oxidation rate ( P =  0·004) and insulin sensitivity ( P =  0·03) improved in the patients who received pioglitazone treatment. The change in insulin-stimulated adiponectin level after pioglitazone treatment was positively correlated to the change in insulin-stimulated total glucose disposal ( R  = 0·69, P  = 0·04).
Conclusion  The impact of GH on lipolysis and insulin sensitivity can be modified by administration of TZDs.     

Recombinant LH (lutropin alfa) for the treatment of hypogonadotrophic women with profound LH deficiency: a randomized, double-blind, placebo-controlled, proof-of-efficacy study

Objective  To confirm the safety and efficacy of 75 IU lutropin alfa with concomitant follitropin alfa in inducing follicular development in women with profound gonadotrophin deficiency.
Design  Double-blind, randomized, placebo-controlled trial conducted in 25 medical centres in four countries.
Patients  Thirty-nine patients with LH < 1·2 IU/l and FSH < 5·0 IU/l were treated with concomitant 75 IU lutropin alfa and 150 IU follitropin alfa or concomitant placebo and 150 IU follitropin alfa.
Measurements  Primary efficacy end-point (intent-to-treat): follicular development defined by (i) at least one follicle ≥ 17 mm; (ii) serum E₂ level ≥ 400 pmol/l on day of hCG administration (DhCG); and (iii) mid-luteal phase progesterone level ≥ 25 nmol/l.
Results  In the analysis of evaluable patients, 66·7% (16 of 24) of patients given lutropin alfa achieved follicular development compared with 20·0% (2 of 10) of patients receiving placebo ( P =  0·023). In the intent-to-treat analysis, follicular development was achieved in 65·4% (17 of 26) of patients receiving lutropin alfa and 15·4% (2 of 13) of patients receiving placebo ( P =  0·006). The statistical difference between treatment groups was preserved when over-response leading to cycle cancellation was analysed as a failed response ( P =  0·034). Lutropin alfa was well tolerated.
Conclusion  Subcutaneous co-administration of 75 IU lutropin alfa with follitropin alfa is safe and effective in inducing follicular development in women with profound gonadotrophin deficiency.