The effect of growth hormone treatment on bone mineral density in prepubertal girls with Turner syndrome: a multicentre prospective clinical trial

Background Patients with Turner syndrome (TS) are treated with GH to increase adult height. Although it is well established that GH promotes longitudinal bone growth, the effects of GH treatment on bone density are less clear. Objective To determine how GH treatment affects trabecular bone mineral density (BMD) in girls with TS at prepubertal ages in a prospective multicentre study. Patients and method Twenty‐two patients with TS in the prepubertal period with a mean age of 9·8 ± 2·5 (range 3·6–12·8) years were included in the study. All girls with TS underwent measurement of areal BMD using dual‐energy X‐ray absorptiometry (DXA) to obtain pretreatment anteroposterior (AP) lumbar spine values at L1–L4. Patients received GH (Genotropin) subcutaneously for 1 year at a dose of 0·05 mg/kg/day. Height and weight were measured at 3‐monthly intervals. The AP lumbar spine areal BMD was remeasured using the same technique after 1 year of treatment. Lumbar spine BMD Z‐scores and volumetric BMD (vBMD) Z‐scores were calculated using national standards. Results The height SDS of our cases showed a significant increase with GH therapy. The pretreatment lumbar spine (L1–L4) BMD Z‐score was –1·2 ± 1·2 SD and the vBMD Z‐score was –0·8 ± 1·6 SD. There were no significant changes in these values after 1 year of GH treatment. Prepubertal TS girls more than 11 years of age had lower vBMD Z‐scores (–1·7 ± 1·7 SD) than the girls aged less than 11 (–0·1 ± 1·0 SD) (P < 0·05) at the onset of therapy. No significant changes were observed in these values after 1 year of GH therapy. Conclusions Osteopaenia becomes apparent in prepubertal TS patients as they reach pubertal age. BMD evaluation may be necessary in these prepubertal TS girls at diagnosis. Short‐term GH therapy in these TS patients does not have a significant effect on bone density when measured at a site with a predominance of trabecular bone.     

Glucocorticoid replacement is associated with hypertriglyceridaemia, elevated glucose and higher non-HDL cholesterol and may diminish the association of HDL cholesterol with the -629C>A CETP promoter polymorphism in GH-receiving hypopituitary patients

Objectives The effect of glucocorticoid substitution on the prevalence of metabolic syndrome components (NCEP ATP III criteria) and serum lipid levels was determined in GH‐replaced hypopituitary patients. As glucocorticoid replacement is associated with a pronounced decrease in plasma cholesteryl ester transfer protein (CETP) activity, we also tested associations of HDL cholesterol with the –629C>A CETP promoter polymorphism in subjects with and without ACTH deficiency. Design and patients In a university setting, we retrieved protocolized clinical and laboratory data from 165 adult hypopituitary patients, who had received GH for 1 year. Results After adjustment for age, sex and smoking, non‐HDL cholesterol (P = 0·05) and triglycerides (P = 0·004) were higher, but HDL cholesterol was not decreased in 117 glucocorticoid (mainly cortisone acetate in two divided doses) receiving subjects compared to 48 ACTH‐sufficient subjects. The prevalence of elevated plasma glucose and/or diabetes (P = 0·04) and hypertriglyceridaemia (P = 0·005), but not of other metabolic syndrome components, was higher in glucocorticoid‐replaced subjects. HDL cholesterol was higher in –629 A allele carriers compared to –629CC homozygotes in ACTH‐sufficient subjects (P = 0·04), but not in glucocorticoid‐treated subjects (P = 0·13). Multiple linear regression analysis demonstrated that only in ACTH‐sufficient subjects, HDL cholesterol was independently related to this CETP gene variation (P = 0·03). Conclusions In GH‐ and glucocorticoid‐replaced hypopituitary patients, serum non‐HDL cholesterol and triglycerides are higher and the prevalence of hyperglycaemia is increased, but HDL cholesterol is not decreased. Conventional glucocorticoid replacement appears to diminish the association of HDL cholesterol with a common CETP gene variation.     

Gene conversion events between GYPB and GYPE abolish expression of the S and s blood group antigens

Apheresis donation using citrate causes acute decrease in serum calcium and increase in serum parathyroid hormone. Long‐term consequences, such as decrease in bone mineral density (BMD), are not known. In this study, we compared the BMD of 20 postmenopausal apheresis donors (mean donation number 115 times in up to 15 years) with that of 20 whole blood donors (for 15 years or more) aged 55–70. BMD in the lumbar spine was not lower in apheresis donors than in blood donors (mean ± SD 1·00 ± 0·18 vs. 0·92 ± 0·12, P = 0·09). In the hip, BMD was not different between the groups.     

Eugonadal male patients with adrenal incidentalomas and subclinical hypercortisolism have increased rate of vertebral fractures

Objective Subclinical hypercortisolism (SH) is suggested to exert a deleterious effect on bone. This effect and the role of gonadal status in male subjects are not fully elucidated. We evaluated bone mineral density (BMD) and prevalence of vertebral fractures in eugonadal male subjects with adrenal incidentalomas (AI) and without SH. Design This 12‐month observational multicentre study was performed between January and December 2006 on inpatient basis in three referral Italian centres. Patients Eighty‐eight consecutive eugonadal male patients with AI and 90 matched control subjects were studied. Measurements All subjects underwent the determination of BMD by dual‐energy X‐ray absorptiometry at lumbar spine (LS) and femoral neck (FN), and spinal radiograph. In AI patients SH was diagnosed in the presence of two of the following: urinary free cortisol > 193·1 nmol/l, cortisol after 1 mg dexamethasone suppression test > 82·8 nmol/l, ACTH levels < 2·2 pmol/l. Results As compared to patients without SH (SH–, n = 66) and controls, patients with SH (SH+, n = 22) had lower BMD at LS (Z‐score: SH+, –1·04 ± 1·84; SH–, 0·19 ± 1·34, Controls 0·20 ± 1·28, P = 0·001 and FN (Z‐score: SH+, –0·63 ± 1·01; SH–, 0·01 ± 1·01, Controls 0·26 ± 1·06, P = 0·002) and higher prevalence of fractures (SH+, 72·7%; SH–, 21·2%, Controls 20·0%, P = 0·0001). Multivariable analyses showed that SH was associated to BMD at LS (β = –0·378, P = 0·0001) and vertebral fractures (OR = 7·81, 95% CI 1·96–31·17, P = 0·004). Conclusion In eugonadal male patients with AI, SH is associated with low BMD and high prevalence of vertebral fractures.     

Serum fasting cortisol in relation to bone, and the role of genetic variations in the glucocorticoid receptor

Objective To examine the relationship between endogenous cortisol and bone, and the role of genetic variations in the glucocorticoid receptor (GR). Design and patients The Longitudinal Ageing Study Amsterdam (LASA), a population‐based cohort study in older men and women. Measurements Serum fasting cortisol was assessed by competitive immunoassay (n = 1214); bone mineral density (BMD) by dual X‐ray absorptiometry (DXA) (n = 502); broadband ultrasound attenuation (BUA) by ultrasound (n = 1209); fractures by self‐report (n = 1211); and GR gene polymorphisms (ER22/23EK, N363S, 9beta, BclI) were genotyped by Taqman (n = 858). Results Higher serum fasting cortisol was significantly associated with lower BMD at all sites and BUA at the heel in women, although most relationships were attenuated by age and body mass index (BMI). The effect on femoral neck BMD remained statistically significant in the fully adjusted model (r = –0·135, P = 0·04). No significant associations in men were found. Female 9beta G‐allele carriers had 50·2 nmol/l lower cortisol and 1·2 lower free cortisol levels than AA homozygotes [P = 0·01 for (free) cortisol]. Furthermore, female BclI GG homozygotes had 54·8 nmol/l higher cortisol levels than C‐carriers (P = 0·03). In the total population, BclI GG homozygotes had 0·05 g/cm² lower trochanteric region BMD (P = 0·03). For the other GR gene polymorphisms, no significant associations were found. Conclusions Higher cortisol levels are associated with lower femoral neck BMD in elderly women. The G allele of the 9beta polymorphism was associated with lower serum cortisol levels in women. Female BclI GG homozygotes had higher serum cortisol levels, and BclI GG homozygotes had lower trochanteric region BMD in the total population.     

Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness

Background Critical illness results in activation of the hypothalamic–pituitary–adrenal (HPA) axis, which might be accompanied by a peripheral adaptation in glucocorticoid sensitivity. Tissue sensitivity is determined by the active glucocorticoid receptor GRα, of which two splice variants involving the hormone‐binding domain exist, GRβ and GR‐P. Objective To study tissue mRNA expression of the GR and its splice variants in fatal critical illness. Design and methods We assessed mRNA expression of the GRα, GRβ and GR‐P variants in liver (n = 58) and muscle (n = 65) of patients who had died after intensive care, and had been randomized for insulin treatment. We analysed whether GR mRNA expression was associated with insulin treatment, cortisol levels and glucocorticoid treatment. Results GRα and GR‐P mRNA constituted 87 ± 8% and 13 ± 2%, respectively, of total GR mRNA in liver. GRβ mRNA could only be amplified in five liver samples. All variants were present in most muscle samples (α = 96 ± 11%, P = 3·9 ± 0·4%, β = 0·010 ± 0·002%). GR expression was not associated with insulin therapy. A strong positive relationship was observed between the different GR variants in both liver and muscle (P < 0·001 for all). Serum cortisol levels were negatively associated with liver GRα and muscle GR‐P expression (P < 0·05). mRNA expression of both liver GRα and GR‐P, but not muscle GR, was substantially lower in patients who had received exogenous glucocorticoids (P < 0·01). Conclusion We demonstrate the presence of GRα and GR‐P mRNA in liver and of GRα, GRβ and GR‐P mRNA in muscle, with no evidence for altered splicing in critical illness. In contrast to muscle GR, liver GR expression was substantially lower in patients receiving exogenous glucocorticoids.     

Influence of ethnicity on IGF-I and procollagen III peptide (P-III-P) in elite athletes and its effect on the ability to detect GH abuse

Context A method based on the two GH dependent markers, IGF‐I and procollagen III peptide (P‐III‐P) has been proposed to detect exogenously administered GH. As previous studies involved predominantly white European elite athletes, it is necessary to validate the method in other ethnic groups. Objective To examine serum IGF‐I and P‐III‐P in elite athletes of different ethnicities within 2 h of competing at national or international events. Design Cross‐sectional observational study. Setting National and International sporting events. Subjects 1085 elite athletes of different ethnicities. Intervention Serum IGF‐I and P‐III‐P were measured and GH‐2000 discriminant function score was calculated. Effect of ethnicity was assessed. Results In men, IGF‐I was 21·7 ± 2·6% lower in Afro‐Caribbeans than white Europeans (P < 0·0001) but there were no differences between other ethnic groups. In women, IGF‐I was 14·2 ± 5·1% lower in Afro‐Caribbeans (P = 0·005) and 15·6 ± 7·0% higher in Orientals (P = 0·02) compared with white Europeans. P‐III‐P was 15·2 ± 3·5%, 26·6 ± 6·6% and 19·3 ± 5·8% lower in Afro‐Caribbean (P < 0·0001), Indo‐Asian (P < 0·0001) and Oriental men (P = 0·001), respectively, compared with white European men. In women, P‐III‐P was 15·7 ± 4·7% lower in Afro‐Caribbeans compared to white Europeans (P =0·0009) but there were no differences between other ethnicities. Despite these differences, most observations were below the upper 99% prediction limits derived from white European athletes. All GH‐2000 scores lay below the cut‐off limit proposed for doping. Conclusions The GH‐2000 detection method based on IGF‐I and P‐III‐P would be valid in all ethnic groups.     

BclI polymorphism of the glucocorticoid receptor gene is associated with decreased bone mineral density in patients with endogenous hypercortisolism

Objective The hypothalamic–pituitary–adrenal axis setpoint and the glucocorticoid sensitivity of various tissues are at least partially genetically determined. We investigated the impact of glucocorticoid receptor (GR) gene polymorphisms, including the BclI, N363S, ER22/23EK and A3669G variants on bone turnover and/or mineral density (BMD) in patients with endogenous glucocorticoid excess. Design Sixty patients including 35 patients with ACTH producing pituitary adenoma (CD) and 25 patients with adrenal Cushing's syndrome (ACS) as well as 129 healthy subjects were genotyped. Analysis of the GR gene polymorphisms were determined using allele specific PCR, PCR‐RFLP and Taqman allelic discrimination assays. Hormonal evaluation, BMD and bone marker measurements were carried out. Results No significant differences were found in allelic frequencies of the four polymorphisms between patients with ACS, CD and healthy controls. Patients with endogenous hypercortisolism carrying the BclI polymorphism in a homozygous form had reduced BMD at femoral subregions compared to patients with the wild‐type variant; femoral neck Z‐score (–1·44 ± 0·73 vs. –0·39 ± 0·91; P < 0·05), trochanteric Z‐score (–1·89 ± 0·47 vs.–0·54 ± 0·98; P < 0·05). Patients with homozygous BclI polymorphism had significantly higher β‐CrossLaps Z‐scores compared to those with the heterozygous and wild‐type variants (+4·42 ± 2·37 vs. +0·79 ± 1·67 and +0·11 ± 1·47; P < 0·01). Conclusions The BclI, N363S, ER22/23EK and A3669G polymorphisms of the GR gene probably do not modify the risk for the development of CD or ACS. Contrary to healthy subjects, however, the BclI polymorphism may modify the skeletal sensitivity to glucocorticoids in patients with endogenous glucocorticoid excess.     

Effect of progestins with different glucocorticoid activity on bone metabolism

Objective Progestins are commonly prescribed for hormone replacement therapy (HRT) and contraception. However, the effects of progestins on bone metabolism remain unclear and are often controversial. Design and patients This study was conducted to test the hypothesis that progestins with no significant glucocorticoid activity may be a better choice for HRT to achieve increased beneficial effects on bone metabolism than progestins with strong glucocorticoid activity. A total of 104 postmenopausal women aged 50–75 years with osteoporosis were allocated randomly to three groups: (1) conjugated oestrogen plus medroxyprogesterone acetate (HRT‐MPA, with significant glucocorticoid activity); (2) conjugated oestrogen plus norethisterone (HRT‐NET, with no significant glucocorticoid activity); and (3) control (no treatment). Measurements Vertebral X‐rays and bone mineral density (BMD) at distal 1/3 radius were assessed at baseline and every 6 months during the 2‐year study period, along with markers of bone turnover. The occurrence of new nonvertebral fractures was identified by X‐ray. Results After the 2‐year treatment, mean BMD changes relative to baseline in the HRT‐MPA, HRT‐NET and control groups were 1·6%, 2·3% and –1·9%, respectively. In addition, the rate of increase in HRT‐NET was significantly greater than that in HRT‐MPA (P = 0·019). The incidence of new fractures during the 2‐year treatment in the control group was 26% (9/34). HRT‐NET treatment significantly inhibited the occurrence of new fractures (RR 0·14, 95% CI 0·02–0·93, P = 0·04), while HRT‐MPA treatment failed to show a statistically significant reduction (RR 0·41, 95% CI 0·14–1·24, P = 0·11). Both HRT‐MPA and HRT‐NET treatments significantly decreased serum osteocalcin levels by 29·4% and 23·5%, respectively, after 6 months of treatment, with the decrease in HRT‐MPA being significantly greater than that in HRT‐NET (P = 0·042). Conclusions These findings suggest that progestins with no significant glucocorticoid activity may be a better choice for HRT, resulting in increased beneficial effects on bone metabolism compared with progestins with strong glucocorticoid activity.     

Substance P is increased in patients with sickle cell disease and associated with haemolysis and hydroxycarbamide use

Sickle cell disease (SCD) pain transitions from acute to chronic for unknown reasons. Chronic elevation of the pain neurotransmitter substance P (SP) sensitizes pain nociceptors. We evaluated SP levels in controls and SCD patients during baseline and acute pain and investigated associations between SP and age, gender, pain history, haemolysis and hydroxycarbamide (also termed hydroxyurea) use. Plasma SP levels were measured using enzyme‐linked immunosorbent assay. Independent samples t‐test compared SP levels between: (i) SCD baseline and controls, and (ii) SCD baseline and acute pain. Multivariate linear regression determined associations between SP and age, gender, pain history and hydroxycarbamide use. Spearman correlation determined an association between SP and haemolysis. We enrolled 35 African American controls, 25 SCD baseline and 12 SCD pain patients. SCD patients were 7‐19 years old. Mean ± standard deviation SP level (pg/ml) in SCD baseline was higher than controls (32·4 ± 11·6 vs. 22·9 ± 7·6, P = 0·0009). SP in SCD pain was higher than baseline (78·1 ± 43·4 vs. 32·4 ± 11·6, P = 0·004). Haemolysis correlated with increased SP: Hb (r = ?0·7, P = 0·0002), reticulocyte count (r = 0·61, P = 0·0016), bilirubin (r = 0·68, P = 0·0216), lactate dehydrogenase (r = 0·62, P = 0·0332), aspartate aminotransferase (r = 0·68, P = 0·003). Patients taking hydroxycarbamide had increased SP (β = 29·2, P = 0·007). SP could be a mediator of or marker for pain sensitization in SCD and a biomarker and/or target for novel pain treatment.     

Adiponectin, skeletal muscle adiponectin receptor expression and insulin resistance following dexamethasone

Objective Skeletal muscle is a major site of adiponectin action and of glucocorticoid‐induced insulin resistance. Little human data exist however, regarding the impact of exogenous glucocorticoids on adiponectin receptors in skeletal muscle. Design and patients Twelve subjects with type 2 diabetes and 12 controls underwent blood sampling and muscle biopsy of vastus lateralis before and after 4 days of 4 mg dexamethasone. Measurements (i) Total and high molecular weight (HMW) plasma adiponectin, glucose and insulin; (ii) Skeletal muscle adiponectin receptor AdipoR1 and AdipoR2 mRNA levels by quantitative real time RT‐PCR. Results Baseline total adiponectin (8·0 ± 0·89 vs. 12·5 ± 1·46 µg/ml, P = 0·013), HMW adiponectin (2·8 ± 0·44 vs. 5·9 ± 1·04 µg/ml, P = 0·014) and AdipoR2 mRNA levels (mean ΔC_T 14·71 ± 0·35 vs. 13·37 ± 0·28, P = 0·017) were significantly lower in diabetic subjects. After dexamethasone, AdipoR2 mRNA fell in the controls but there was no change in the diabetic group, while there was a significant increase in total (P = 0·002) and HMW adiponectin (P < 0·001) across both groups. Total and HMW plasma adiponectin correlated with clinical and biochemical measures of insulin sensitivity. However following dexamethasone which increased insulin resistance, the relationship between adiponectin and the biochemical measures was lost. Conclusions Plasma adiponectin and skeletal muscle AdipoR2 mRNA expression are reduced in subjects with diabetes; both are likely to contribute to the observed insulin resistance. Dexamethasone inhibits AdipoR2 mRNA expression in nondiabetic subjects, while there is a small rise in plasma adiponectin levels. The close relationship between plasma adiponectin and biochemical measures of insulin sensitivity is lost in the setting of glucocorticoid‐induced insulin resistance.     

Does partial surgical tumour removal influence the response to octreotide‐LAR in acromegalic patients previously resistant to the somatostatin analogue?

Objective To compare the intrapatient response to the same dose of slow‐release octreotide (OCT‐LAR) before and after noncurative surgery in acromegalic patients who did not attain disease control after primary treatment with OCT‐LAR. Design Prospective clinical study. Patients Eleven acromegalic patients (eight men, aged 42·45 ± 11·15 years, 10 macroadenomas) received OCT‐LAR (20 mg, n = 1; 30 mg, n = 10) every 28 days as the primary treatment (1stOCT‐LAR) for 11·3 ± 4·2 months, without IGF‐I normalization. They were subsequently submitted to surgery without cure and were then treated with the same dose of OCT‐LAR for 8·0 ± 6·5 months (2ndOCT‐LAR). Measurements GH and IGF‐I serum concentrations were obtained under basal conditions as well as during treatment. Pituitary tumour volume was assessed by magnetic resonance imaging (MRI) of the sella. IGF‐I was also expressed as a percentage of the upper limit of the normal age‐ and sex‐matched range (%ULNR IGF‐I). Results After 1stOCT‐LAR, there was a decrease in GH levels (P = 0·003) and %ULNR IGF‐I (P = 0·009) compared to baseline (B), but no IGF‐I normalization. Tumour shrinkage was observed in eight of 10 patients with macroadenomas (median 63·7%, range 24·5–75·5%). After surgery, mean levels of GH and %ULNR IGF‐I were lower than those at baseline (P = 0·0004 and P = 0·003, respectively), but not when compared to values during 1stOCT‐LAR (P = 1·000 and P = 0·957, respectively). MRI confirmed surgical tumour removal (median 64%, range 4·9–96·6%) in eight of the 10 patients. Comparing the 2ndOCT‐LAR results with postsurgical results, there were no significant decrease in %ULNR IGF‐I (P = 0·061) and GH levels (P = 0·414). Nine patients (82%) achieved IGF‐I normalization. The degree of surgical tumour reduction did not correlate with IGF‐I normalization (P = 0·794). When comparing the results between 1stOCT‐LAR and 2ndOCT‐LAR, there was a decrease, albeit not statistically significant, in serum GH levels (P = 0·059) and a significant decrease in %ULNR IGF‐I (P = 0·011). Conclusions Using strict criteria (same patient, same drug, same dose) our results strongly suggest that the surgical reduction of tumour mass can improve the outcome of OCT‐LAR treatment in acromegalic patients resistant to primary therapy with SA.     

Relation between plasma fibroblast growth factor-23, serum fetuin-A levels and coronary artery calcification evaluated by multislice computed tomography in patients with normal kidney function

Objective To examine the correlation of plasma fibroblast growth factor (FGF)‐23 and serum fetuin A levels with the coronary artery calcification score (CACS) in patients with normal kidney function. Background Vascular calcification is an active process that may be aggravated by hyperphosphataemia and hypercalcaemia. FGF‐23 and human fetuin‐A have been associated with calcifying arteriosclerosis in renal failure. Plasma FGF‐23 was identified as an independent factor negatively associated with peripheral vascular calcification. Fetuin‐A acts as a systemic inhibitor of ectopic calcification in dialysis patients and can be correlated to the survival of these patients. Very few data exists on the role of FGF‐23 and fetuin‐A in coronary calcification of patients without impaired kidney function. Materials and methods Sixty‐four patients, 21 females and 43 males, were subjected to 64‐slice coronary computed tomography (CT) to evaluate coronary artery calcification (CAC). Plasma intact FGF‐23 was determined by ELISA. Serum fetuin‐A concentration were evaluated nephelometrically. Results Mean plasma FGF‐23 level was 20·4 ± 9·1 pg/ml and serum fetuin‐A was 0·46 ± 0·09 g/l. There was no correlation between FGF‐23 (P = 0·777) and fetuin‐A (P = 0·767) levels and the CACS. No correlation was found between the presence of noncalcified plaques and coronary artery stenosis (CAS) ≥  50%, and FGF‐23 (P = 0·313 and P = 0·775) and fetuin‐A levels (P = 0·601 and P = 0·659). Conclusion Plasma intact FGF‐23 and serum fetuin‐A concentration do not correlate with the CACS, the grade of stenosis or presence of noncalcified plaques of the coronary arteries in patients with normal kidney function.     

The relationship between gonadotrophins, gonadal hormones and bone mass in men

Objective Inhibin A and B (Inh A and B), activin A (Act A) as well as FSH may play an important role in bone turnover in perimenopausal women. Data in men are lacking. The aim was to investigate the relationship between circulating concentrations of Inh B and Act A and FSH/LH/testosterone (T) and their contribution to bone mineral density (BMD) in a male population. Design and subjects Cross‐sectional case‐control study of 156 men, 63 with osteoporosis and 93 controls, aged (mean [SD]) 57·7 [13·7] years. Measurements Areal (aBMD) was measured at the femoral neck, total hip and lumbar spine. Volumetric BMD (vBMD) was calculated at the femoral neck and lumbar spine. Risk factors were assessed including the measurement of LH/FSH/T, Inh B and Act A. Results After correction for age and body mass index (BMI), associations were found between Inh B and FSH (beta regression coefficient β = ?0·326; P < 0·0001), T (β = ?0·36; P = 0·019) and Act A (β = ?0·4; P = 0·007) and between Inh B and LH (β = 0·23; P < 0·0001) in all patients. The controls had higher Inh B concentrations compared to the cases (Inh B: controls: 139 [86] pg/ml vs. cases 88 [51] pg/ml; P = 0·005). Act A tended to be lower in the controls (Act A: controls 0·63 [0·24] ng/ml vs. cases 0·75 [0·4] ng/ml; P = 0·056). Univariate regression analyses showed a positive association between Inh B and BMD (P < 0·01) at the lumbar spine and total hip. In contrast a negative association was seen between FSH and BMD at the lumbar spine and femoral neck (P < 0·01). In a partial multivariate regression model that included the gonadal factors only, a positive association was seen between Inh B and BMD at the hip (β = 0·088; P = 0·04). When all hormones including the gonadotrophins were entered in a full multivariate model, FSH and LH were found to be better predictors of BMD than Inh B or Act A in the controls and cases. Conclusions These data suggest that the gonadal peptides and gonadotrophins may play a role in the maintenance of bone mass in men. Future confirmatory longitudinal studies are needed.     

Complex karyotype predicts for inferior outcomes following reduced-intensity conditioning allogeneic transplant for chronic lymphocytic leukaemia

Complex karyotype (CK) on metaphase cytogenetics discriminates poor outcome in chronic lymphocytic leukaemia (CLL) patients undergoing salvage treatment; we hypothesized that it might provide prognostic information for patients undergoing allogeneic stem cell transplant. Fifty‐one CLL patients were analysed following transplant; 18‐month overall survival (OS), event‐free survival (EFS) and cumulative incidence of progression estimates were 35%, 14% and 63%, respectively, in patients with CK (n = 19) versus 83%, 68% and 29% in patients without (n = 32) (P ≤ 0·0001, P ≤ 0·0001, and P = 0·02). In patients with high‐risk interphase cytogenetics, CK remained predictive of worse OS (P = 0·02) and EFS (P = 0·009). These findings support further evaluation of metaphase karyotype in transplant risk assessment.     

Serum resistin is positively correlated with the accumulation of metabolic syndrome factors in type 2 diabetes

Objective Resistin, secreted from adipocytes, causes insulin resistance in rodents. We reported that the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at ?420 increases type 2 diabetes (T2DM) susceptibility by enhancing promoter activity. We also showed that serum resistin was positively correlated with G at SNP‐420, the duration of T2DM, and HbA1c in T2DM. The aim of this study was to determine the relation between serum resistin and factors related to the metabolic syndrome (MetS) in T2DM. Design, patients and measurements We analysed 238 Japanese T2DM subjects (124 males and 114 females, age 60·2 ± 11·3 years, body mass index (BMI) 24·1 ± 3·9) whose overnight fasting sera were available. Serum resistin was measured using ELISA. Results Serum resistin was higher in subjects with either obesity (P = 0·041), low HDL (P = 0·004), high triglycerides (TG) (P = 0·019), hypertension (HT) (P = 0·001) or atherosclerosis (P = 0·012). Simple regression analysis revealed that serum resistin was correlated with lower HDL, TG and high‐sensitivity C‐reactive protein (hsCRP). Multiple regression analysis (or logistic regression analysis for HT), adjusted for age, gender, BMI and the duration of T2DM, revealed that serum resistin was correlated with lower HDL (P = 0·008), TG (P = 0·041), HT (P = 0·031) and hsCRP (P = 0·004). Serum resistin was positively correlated with the number of MetS factors, independent of age, gender and the duration of T2DM (P < 0·001). Adjustment by either thiazolidinedione (TZD) treatment or hsCRP had no effects on these findings. Conclusions Serum resistin was positively correlated with the accumulation of MetS factors in T2DM.     

Inflammatory markers and visceral fat are inversely associated with maximal oxygen consumption in women with polycystic ovary syndrome (PCOS)

Background We investigated whether several different inflammatory markers including C‐reactive protein (CRP) and fibrinogen and white blood cells (WBCs) count, are associated with maximal oxygen consumption (VO_2max) in women with polycystic ovary syndrome (PCOS). Methods In PCOS women (n = 124, 24·1 ± 4·5 year‐old) VO_2max was measured during symptom‐limited cardiopulmonary exercise test. Abdominal fat distribution was determined by ultrasound. Physical activity level was assessed by a standardized questionnaire. CRP was measured by immunoassays, fibrinogen by the Clauss method, and WBCs count with a Coulter counter. Results Pearson's analysis showed a significant correlation between VO_2max and logCRP (r = –0·437, P < 0·001), fibrinogen (r = –0·479, P < 0·001), and WBCs count (r = –0·438, P < 0·001). Multivariable logistic regression model showed that age (β = –0·127, P = 0·005), AUC_INS (β = –0·335, P < 0·001), HDL‐C (β = 0·390, P < 0·001), physical activity score (β = 0·238, P = 0·002), visceral fat (β =–0·184), P = 0·023), FAI (β = –0·291, P = 0·028); CRP (β = –0·216, P = 0·011), fibrinogen (β = –0·113, P = 0·008) and WBCs count (β = –0·177, P < 0·001) were significantly associated with VO_2max. Conclusions Acute‐phase reactants, such as CRP and fibrinogen, and WBCs count were independently and inversely associated with a direct measure of cardiorespiratory fitness (VO_2max) in women with PCOS, even after adjustment for physical activity level and other potential confounding factors. These findings add to the growing body of evidence linking inflammation to cardiorespiratory fitness in PCOS women.     

Intravenous zoledronate improves bone density in adults with cystic fibrosis (CF)

Objective Reduced bone mineral density (BMD) and increased rates of atraumatic fracture are observed in cystic fibrosis (CF) patients, causing increasing morbidity as this population ages. The study aimed to assess the safety, tolerability and effect on BMD of intravenous zoledronate in adults with CF and osteopaenia. Design Randomized, double‐blind, placebo‐controlled clinical trial. Setting Adult CF outpatient clinics at two hospitals. Patients Twenty‐two non‐transplanted CF patients aged ≥ 18 years with a bone densitometry T‐score of < –1·5 at one of three sites (lumbar spine, femoral neck, distal forearm) were studied. Participants were randomized to receive either 2 mg zoledronate IV (n = 10) or normal saline (placebo, n = 12) every 3 months for 2 years (8 infusions). All participants received calcium and vitamin D supplements twice daily. Measurements Percentage change in areal BMD from baseline. Results Lumbar spine BMD increased from baseline more with zoledronate than placebo at 6 months (5·35 ± 0·76 vs. 1·19 ± 1·20%, P = 0·012), 12 months (6·6 ± 1·5 vs. 0·35 ± 1·55%, P = 0·011) and 24 months (6·14 ± 1·86 vs. 0·44 ± 0·10, P = 0·021). Femoral neck BMD increased more after zoledronate than placebo at 6 months (3·2 ± 1·6 vs.–1·43 ± 0·43%, P = 0·019), 12 months (4·12 ± 1·8 vs.–1·59 ± 1·4%, P = 0·024) and 24 months (4·23 ± 1·3 vs.–2·5 ± 1·41%, P = 0·0028). Forearm BMD did not change. Zoledronate was associated with flu‐like and musculoskeletal side effects, particularly after the first infusion. There were no fractures in either group. Conclusion Intravenous zoledronate was significantly more effective than placebo for increasing BMD in adults with CF and osteopaenia, but side effects limited its tolerability.     

Significant inverse relationship between serum free T4 concentration and body mass index in euthyroid subjects: differences between smokers and nonsmokers

Objective There are conflicting data regarding the relationship between thyroid function and body mass index (BMI) in euthyroid subjects, and it is uncertain whether tobacco smoking modifies this relationship. The objective of this study was to examine the relationships between thyroid function, BMI and smoking in euthyroid subjects. Design Linear regression models were used to examine the relationships between serum free T4, serum TSH, BMI and smoking in a cross‐sectional, community‐based sample of 1853 euthyroid subjects in Busselton, Western Australia. Results There was a significant negative relationship between free T4 and BMI: after adjustment for age and sex, each 1 pmol/l increase in free T4 was associated with a decrease in BMI of 0·12 kg/m² (95% CI 0·06, 0·18; P < 0·001). The mean BMI ± SD of subjects in the highest quintile of free T4 concentration was 24·4 ± 3·5 kg/m², compared with 26·1 ± 3·8 kg/m² for the lowest quintile. The relationship between free T4 and BMI was statistically significant (adjusted for age and sex) in subjects who had never smoked (P = 0·001) and former smokers (P = 0·011), but not in current smokers (P = 0·77). There was no significant relationship between TSH and BMI: after adjustment for age and sex, each 1 mU/l increase in TSH was associated with an increase in BMI of 0·08 kg/m² (95% CI –0·16, 0·32; P = 0·53). Conclusions In euthyroid subjects, small differences in free T4 are associated with differences in BMI. This relationship is not present in current smokers. We speculate that this may be relevant to weight changes associated with smoking cessation.