Objective: Our objective was to examine the association of endogenous sex hormones with incident T2DM in postmenopausal women and possible explanatory factors.

Design, Setting, and Participants: The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective study that included 1612 postmenopausal women aged 45–84 yr, followed between the years 2000–2006, who were not taking hormone replacement therapy, had no prevalent cardiovascular disease or diabetes, and had complete ascertainment of sex hormones.

Main Outcome Measures: T2DM was defined based on fasting glucose and/or treatment for diabetes.

Results: There were 116 incident cases of diabetes during follow-up. Across higher quartiles of bioavailable T and E2 and lower quartiles of SHBG, we found significantly greater hazards of developing incident T2DM (all P for trend ≤0.001). After adjustment for body mass index and insulin resistance estimated by homeostasis model assessment of insulin resistance, bioavailable T was no longer associated with incident T2DM. The associations of E2 and SHBG with incident T2DM were partially explained by body mass index and insulin resistance but persisted in fully adjusted models (both P for trend <0.02). Dehydroepiandrosterone had no relationship with incident T2DM.

Conclusions: Adiposity and insulin resistance explained most of the association of bioavailable T but only partially explained the associations of E2 and SHBG with incident T2DM among postmenopausal women.

Method: We measured serum levels of estrone, total and free estradiol, and SHBG in 180 postmenopausal women participating in the Estrogen in the Prevention of Atherosclerosis Trial (EPAT), 91 receiving estradiol therapy (ET) and 89 taking placebo, every 6 months over 2 yr. Mean on-trial levels of estrogens and SHBG were compared across age, body mass index (BMI), and waist to hip ratio categories among ET users and placebo separately.

Results: Among the ET users, total (P = 0.01) and free estradiol (P = 0.002) were significantly directly associated with BMI adjusted for age. SHBG was inversely related to waist to hip ratio adjusted for age (P = 0.005). Age was not associated with any of the estrogen or SHBG concentrations in ET or placebo groups. BMI was positively associated with estrone concentrations among older but not younger ET users (P for interaction = 0.03).

Conclusion: Overweight and obese women using ET attain greater concentrations of estrogen compared to women with normal BMI, whereas ET users with abdominal obesity attain lower SHBG levels. Obese older women using ET have the highest concentration of estrone. It may be useful to consider age and obesity when prescribing HT to minimize the risk of venous thrombosis or stroke in postmenopausal women. Further research regarding relationships among circulating hormone levels and risk for these conditions is required to substantiate this conclusion.

Objective: The objective of the study was to test whether body composition and bone mineral density (BMD) are altered in PA and study whether genetic variation in low-density lipoprotein receptor-related protein 5 (LRP5) affects BMD in PA.

Design: This was a cross-sectional study.

Setting: The study was conducted at a university hospital.

Subjects and Measures: The study included 126 prepubertal children (64 with PA, 10 boys; 62 non-PA controls, 10 boys). Femoral neck and lumbar spine areal and calculated volumetric BMD (dual energy X-ray absorptiometry), body composition (bioimpedance), serum 25-hydroxyvitamin D, and markers of bone turnover and calcium homeostasis were compared between the PA and control groups. Single-nucleotide polymorphisms of LRP5 were determined and associated with BMD.

Results: Children with PA had higher femoral neck and lumbar spine BMD_areal than the controls (Z-score 0.56 vs. –0.09, P < 0.001, and 0.20 vs. –0.31, P = 0.009, respectively). However, the mean BMDs did not differ significantly between the groups when adjusted for height or bone size. BMD_areal correlated strongly with height sd score in both groups. Among the PA children, LRP5 single-nucleotide polymorphism E644E minor variant was associated with lower and F549F minor variant with higher BMD. Total body fat mass, fat percent, serum PTH, and alkaline phosphatase concentrations were higher and 25-hydroxyvitamin D lower in the PA group.

Conclusions: Prepubertal children with PA had higher BMD_areal compared with healthy controls. This was mainly explained by their increased height. LRP5 polymorphisms may contribute to bone mass accrual in prepubertal PA children.

Objective: The objective of the study was to determine the effects of unopposed CEE on changes in domain-specific cognitive function and affect in older postmenopausal women with prior hysterectomy.

Design: This was a randomized, double blind, placebo-controlled clinical trial.

Setting: The study was conducted at 14 of 40 Women’s Health Initiative (WHI) clinical centers.

Participants: Participants were 886 postmenopausal women with prior hysterectomy, aged 65 yr and older (mean 74 yr), free of probable dementia, and enrolled in the WHI and WHI Memory Study (WHIMS) CEE-Alone trial for a mean of 3 yr and followed up for a mean of 2.70 yr.

Intervention: Intervention was 0.625 mg of CEE daily or placebo.

Main Outcome Measures: Annual rates of change in specific cognitive functions and affect, adjusted for time since randomization, were measured.

Results: Compared with placebo, unopposed CEE was associated with lower spatial rotational ability (P < 0.01) at initial assessment (after 3 yr of treatment), a difference that diminished over 2.7 yr of continued treatment. CEE did not significantly influence change in other cognitive functions and affect.

Conclusions: CEE did not improve cognitive functioning in postmenopausal women with prior hysterectomy. CEE was associated with lower spatial rotational performance after an average of 3 yr of treatment. Overall, CEE does not appear to have enduring effects on rates of domain-specific cognitive change in older postmenopausal women.

Research Design and Methods: The coding regions of EIF2AK3 were sequenced in 34 probands with infancy-onset diabetes with a clinical phenotype suggestive of WRS (n = 28) or homozygosity at the WRS locus (n = 6).

Results: Twenty-five probands (73.5%) were homozygous or compound heterozygous for mutations in EIF2AK3. Twenty of the 26 mutations identified were novel. Whereas a diagnosis of WRS was suspected before genetic testing in 22 probands, three patients with apparently isolated diabetes were diagnosed after identifying a large homozygous region encompassing EIF2AK3. In contrast to nonconsanguineous pedigrees, mutations in EIF2AK3 are the most common known genetic cause of diabetes among patients born to consanguineous parents (24 vs. < 2%). Age at diabetes onset and birth weight might be used to prioritize genetic testing in the latter group.

Conclusions: WRS is the most common cause of permanent neonatal diabetes mellitus in consanguineous pedigrees. In addition to testing patients with a definite clinical diagnosis, EIF2AK3 should be tested in patients with isolated neonatal diabetes diagnosed after 3 wk of age from known consanguineous families, isolated populations, or countries in which inbreeding is frequent.

Patients and Methods: Fifty-one of the 63 original patients (28 euthyroid, 23 hypothyroid) participated. Forty-eight received rhTSH and serum thyroglobulin (Tg) sampling. A ¹³¹I whole-body scan was performed in 43 patients, and successful ablation was defined by criteria from the previous study. Based on the criterion of uptake less than 0.1% in thyroid bed, 100% (43 of 43) remained ablated. When no visible uptake instead was used, five patients (four euthyroid, one hypothyroid) had minimal visible activity. When the TSH-stimulated Tg criterion was used, only two of 45 (one euthyroid, one hypothyroid) had a stimulated Tg level greater than 2 ng/ml.

Results: No patient in either group died, and no patient declared disease free had sustained tumor recurrence. Nine (four euthyroid, five hypothyroid) had received additional ¹³¹I between the original and current studies due to detectable Tg or imaging evidence of disease; with follow-up, all now had a negative rhTSH-stimulated whole-body scan and seven (three euthyroid, four hypothyroid) had a stimulated serum Tg less than 2 ng/ml.

Conclusions: In conclusion, after a median 3.7 yr, low-risk thyroid cancer patients prepared for postoperative remnant ablation either with rhTSH or after L-T4 withdrawal were confirmed to have had their thyroid remnants ablated and to have comparable rates of tumor recurrence and persistence.

Objective: The aim of this study was to assess diagnosis- and treatment-dependent risk of hypogonadism in male childhood cancer survivors (CCS).

Design: Male CCS who were treated during the period 1970–2002 and who in 2004 were 18–45 yr of age were eligible.

Setting: The study was conducted in a university hospital clinic.

Patients: A consecutive group of CCS treated at Lund University Hospital was selected for the study, of whom 151 (38%) agreed to participate. Furthermore, 141 healthy fertile men served as controls.

Interventions: We measured serum levels of free and total testosterone, SHBG, and LH.

Main Outcome Measures: Odds ratios (OR) for biochemical hypogonadism, defined as total testosterone less than 10 nmol/liter and/or LH above 10 IU/liter, were calculated and related to type of cancer, treatment received, as well as testicular volume.

Results: Hypogonadism was more commonly detected in CCS than in controls (OR, 6.7; 95% CI, 2.7, 17). The increased presence of hypogonadism was noted in the following treatment groups: brain surgery, chemotherapy (with and without radiotherapy), and testicular irradiation. Low total testicular volume (≤24 ml) was associated with a high risk of hypogonadism (OR, 31; 95% CI, 11, 92).

Conclusion: Adult male survivors of childhood cancer are at risk of hypogonadism, which should be acknowledged in the long-term follow-up of these men.

Objective: The genetic analysis of the TSHR gene was performed to determine the prevalence of TSHR gene mutations in non-autoimmune subclinical hypothyroidism during the pediatric age. The new mutations were studied for genotypic-phenotypic correlation.

Patients: Thirty-eight children (ages 0.5–18.0 yr) affected by non-autoimmune subclinical hypothyroidism diagnosed in our center (follow-up from 1 to 11.5 yr) and normal at neonatal screening were enrolled in the genetic study. In 11 cases, the relatives were included in the genetic analysis.

Results: Eleven different mutations of the TSHR gene were identified in 11 of the 38 patients. Two are new: the nonsense mutation C31X and the missense mutation P68S, which shows a decrease in TSH binding capacity but not in biological activity. In all cases the carrier parent was identified.

Conclusions: To date, this study demonstrates the highest prevalence (29%) of TSHR gene mutations in children and adolescents with non-autoimmune subclinical hypothyroidism not selected by neonatal screening. Functional studies show that some mutations cause a slight inactivation of the TSHR. This reveals a possible limit of the in vitro study or of the knowledge of mechanisms involving TSHR, or that other candidate genes must be considered.

Objective: The aim of the study was to evaluate the accuracy of ITT, mean 12-h spontaneous nocturnal GH (SNGH), and IGF-I in the definition of permanent GHD.

Design and Setting: The study was conducted in two Pediatric Endocrinology Centers.

Patients and Methods: ITT, 12-h SNGH, and IGF-I were evaluated as single or combined tests in 79 subjects with COGHD (median age, 18.0 yr). The cohort consisted of 48 subjects with isolated GHD or one additional pituitary defect and normal MRI or anterior pituitary hypoplasia (group LLGHD, low likelihood GHD), and 31 subjects with structural hypothalamic-pituitary abnormalities or multiple pituitary hormone deficiencies (group HLGHD, high likelihood GHD).

Results: Receiver operating characteristic analysis showed the best diagnostic accuracy for peak GH cutoffs to ITT of 5.62 µg/liter or less [sensitivity, 77.4%; specificity, 93.8%; area under the curve (AUC) = 0.92], mean 12-h SNGH of 1.20 µg/liter or less (sensitivity, 90.3%; specificity, 89.6%; AUC = 0.93), and IGF-I of –2.83 sd score or less (sensitivity, 80.7%; specificity, 95.7%; AUC = 0.93). Seven patients in group HLGHD showed a peak GH to ITT above 5.62 µg/liter, but a median IGF-I that was significantly lower than that of group LLGHD (–3.30 vs. –0.73 sd score; P = 0.0001). Peak GH to ITT of 3.6 µg/liter or less and arginine of 3.1 µg/liter or less at childhood diagnosis can predict a future permanent GHD condition.

Conclusions: The adopted peak GH to ITT below 5.62 µg/liter is an accurate diagnostic cutoff point for HLGHD in young adults with COGHD. In addition, IGF-I is a reliable marker providing information about the severity of GHD. Careful follow-up is required for subjects with discordant ITT and IGF-I results.

Objectives: The aim of the study was to investigate effects of long-term continuous GH treatment on body composition, growth, bone maturation, and safety parameters.

Setting: We conducted a multicenter prospective trial.

Design: Fifty-five children with a mean ± sd age of 5.9 ± 3.2 yr were followed during 4 yr of continuous GH treatment (1 mg/m² · d). Data were annually obtained in one center: fat percentage (fat%) and lean body mass (LBM) by dual-energy x-ray absorptiometry, height, weight, head circumference, bone age, blood pressure, and fasting IGF-I, IGF binding protein-3, glucose, insulin, glycosylated hemoglobin, total cholesterol, high-density lipoprotein, and low-density lipoprotein. sd scores (SDS) were calculated according to Dutch and PWS reference values (SDS and SDS_PWS).

Results: Fat%SDS was significantly lower after 4 yr of GH treatment (P < 0.0001). LBMSDS significantly increased during the first year (P = 0.02) but returned to baseline values the second year and remained unchanged thereafter. Mean ± sd height normalized from –2.27 ± 1.2 SDS to –0.24 ± 1.2 SDS (P < 0.0001). Head circumference SDS increased from –0.79 ± 1.0 at start to 0.07 ± 1.1 SDS after 4 yr. BMISDS_PWS significantly decreased. Mean ± sd IGF-I and the IGF-I/IGF binding protein-3 ratio significantly increased to 2.08 ± 1.1 and 2.32 ± 0.9 SDS, respectively. GH treatment had no adverse effects on bone maturation, blood pressure, glucose homeostasis, and serum lipids.

Conclusions: Our study in children with PWS shows that 4 yr of continuous GH treatment (1 mg/m² · d) improves body composition by decreasing fat%SDS and stabilizing LBMSDS and head circumference SDS and normalizes heightSDS without adverse effects. Thus, long-term continuous GH treatment is an effective and safe therapy for children with PWS.

Methods: Using the West Midlands Acromegaly database (n = 501; 275 female), we assessed the influence of prior radiotherapy and hypopituitarism (and replacement therapy) on mortality in patients with acromegaly. Median duration of follow-up was 14.0 yr (interquartile range, 7.9–21 yr).

Results: All-cause mortality was elevated [SMR, 1.7 (1.4, 2.0); P < 0.001]. On external analysis, prior radiotherapy, ACTH, and gonadotropin deficiency were associated with an elevated SMR [radiotherapy SMR, 2.1 (1.7–2.6); P = 0.006; ACTH deficiency SMR, 2.5 (1.9–3.2); P < 0.0005; and gonadotropin deficiency SMR, 2.1 (1.6–2.7); P = 0.037].

On internal analysis, the relative risk (RR) of mortality was increased in the radiotherapy [RR, 1.8 (1.2–2.8); P = 0.008] and ACTH-deficiency groups [RR, 1.7 (1.2–2.5); P = 0.004], but not in the gonadotropin- or TSH-deficiency groups. In the ACTH-deficient group, increased replacement doses of hydrocortisone greater than 25 mg/d were associated with increased mortality compared to lower doses.

Conclusions: Radiotherapy and ACTH deficiency are significantly associated with increased mortality in patients with acromegaly. In ACTH-deficient patients, a daily dose of more than 25 mg hydrocortisone is associated with increased mortality compared to lower doses. These results have important implications for the treatment of patients with acromegaly and also raise issues as to the optimum hydrocortisone treatment regimens for ACTH-deficient patients.

Design: Community-dwelling older men received GnRH agonist plus 5 or 10 g testosterone gel plus 0, 3, or 5 µg recombinant human GH daily. P3NP levels were measured at baseline and wk 4, 8, 12, and 16. LBM and appendicular skeletal muscle mass (ASM) were measured by dual-energy x-ray absorptiometry.

Results: One hundred twelve men completed treatment; 106 underwent serum P3NP measurements. P3NP levels were higher at wk 4 than baseline (6.61 ± 2.14 vs. 4.51 ± 1.05, P < 0.0001) and reached plateau by wk 4 in men receiving testosterone alone. However, wk 8 P3NP levels were higher than wk 4 levels in men receiving testosterone plus recombinant human GH. Increases in P3NP from baseline to wk 4 and 16 were significantly associated with gains in LBM (r = 0.26, P = 0.007; r = 0.53, P < 0.001) and ASM (r = 0.17, P = 0.07; r = 0.40, P < 0.0001). Importantly, for participants receiving only testosterone, P3NP increases at wk 4 and 16 were related to muscle strength gains (r = 0.20, P = 0.056 and r = 0.36, P = 0.04). In stepwise regression, change in P3NP explained 28 and 30% of the change in ASM and LBM, respectively, whereas change in testosterone but not IGF-I and age provided only small improvements in the models.

Conclusion: Early changes in serum P3NP levels are associated with subsequent changes in LBM and ASM during testosterone and GH administration. Serum P3NP may be a useful early predictive biomarker of anabolic response to GH and testosterone.

Objective: The aim of the study was to investigate ACTH and cortisol ultradian patterns using an automated, repetitive blood sampling technique.

Design: Samples for ACTH and cortisol were collected from 10 patients with moderate to severe OSA under basal conditions, at 10-min intervals over 24 h, at diagnosis and 3 months after compliant continuous positive airway pressure (CPAP) therapy. Multiple-parameter deconvolution estimated specific measures of ACTH and cortisol pulsatile secretion from blood hormone concentrations.

Results: Mean total ACTH and cortisol production were elevated pre-CPAP compared to post-CPAP (ACTH, 1459.8 ± 123.0 vs. 808.1 ± 97.9 pg/ml, P < 0.001; cortisol, 5748.9 ± 364.9 vs. 3817.7 ± 351.7 nmol/liter, P < 0.001) as were mean total pulsatile production (ACTH, 764.1 ± 86.3 vs. 383.5 ± 50.0 pg/ml, P = 0.002; cortisol, 4715.9 ± 253.3 vs. 3227.7 ± 258.8 nmol/liter, P < 0.001). ACTH and cortisol secretory burst mean half-duration were higher at diagnosis (12.3 ± 0.7 and 13.5 ± 0.7 vs. 7.8 ± 0.4 and 8.4 ± 0.6 min, respectively, P < 0.001); thus, 95% of each ACTH secretion occurred in 21.0 ± 1.2 vs. 12.9 ± 0.8 min post-CPAP (P < 0.001) and for cortisol in 23.0 ± 1.2 vs. 14.2 ± 1.1 min post-CPAP (P < 0.001). Approximate entropy (ApEn) revealed greater disorderliness in both ACTH (P = 0.03) and cortisol (P = 0.001) time series pre-CPAP. Forward and reverse cross-ApEn suggested nodal disruption at central and adrenal levels pre-CPAP (P = 0.01). Significantly elevated cortisol responses to a single breath of 35% CO₂ occurred pre-CPAP (P = 0.006).

Conclusions: Untreated compared to treated OSA is associated with marked disturbances in ACTH and cortisol secretory dynamics, resulting in prolonged tissue exposure to disordered, elevated hormone levels.

Methods: In 207 young men of the PROGRAM/PREMS cohort study, aged 18–24 yr, the influence of preterm birth, birth length, and birth weight on serum levels of anti-Mullerian hormone, inhibin B, testosterone, SHBG, non-SHBG-bound testosterone, LH, and FSH was analyzed with multiple regression modeling. In addition, markers of male gonadal function were analyzed in four subgroups: men born SGA with either short stature or catch-up growth, or men born appropriate for gestational age with idiopathic short stature or with normal stature (control).

Results: Preterm birth and SGA did not affect gonadal function. After adjustment for age, birth size, adult height, fat mass, and socioeconomic status (SES), preterm birth even showed a positive relation with inhibin B. Higher SES was associated with higher inhibin B levels. Higher fat mass was associated with decreased testosterone and SHBG levels and maternal smoking with increased LH and non-SHBG-bound testosterone levels. After adjustment for confounders, there were no significant differences in gonadal function between the subgroups.

Conclusion: Preterm birth and SGA did not affect gonadal function in young men. Factors that affected gonadal function were: lower SES, a higher fat mass, and maternal smoking during pregnancy.

Objective: The objective of the study was to investigate the diagnostic value of the glucagon test as an alternative test to insulin tolerance test (ITT) and arginine in GHD children younger than 6 yr.

Design and Setting: This study was conducted in two pediatric endocrinology centers.

Patients and Methods: Forty-eight children (median age 4.2 yr, median height –3.0 sd score) with GHD confirmed by a peak GH to ITT and arginine less than 10 µg/liter (median 4.7 and 3.4 µg/liter, respectively) underwent a glucagon stimulation test. Magnetic resonance imaging showed normal hypothalamic-pituitary anatomy in 24 children, isolated anterior pituitary hypoplasia in seven, and structural hypothalamic-pituitary abnormalities in 17.

Results: Median GH peak response to glucagon (13.5 µg/liter) was significantly higher than that observed after ITT and arginine (P < 0.0001). GH peak after glucagon was less than 10 µg/liter in 20 subjects (group 1) and greater than 10 µg/liter in 28 subjects (group 2) without significant clinical or biochemical differences between the two groups. Median GH peak after glucagon was similar between patients with multiple pituitary hormone deficiency and those with isolated GHD and between subjects with and without structural hypothalamic-pituitary abnormalities. The magnitude of the GH peak after glucagon was negatively correlated to age at diagnosis ( = –0.636, P < 0.0001).

Conclusions: This study shows that glucagon has an effective GH-releasing activity and can be used to evaluate somatotroph function in young children with short stature. Normative data for this test in young children need to be established before its use in clinical practice.

Objective: Utilizing metabolic feeding and supervised exercise training, we examined the influence of caloric restriction vs. exercise training with and without weight loss on hepatic and peripheral insulin resistance.

Design, Participants, and Intervention: Thirty-four obese, older subjects were randomized to: caloric restriction with weight loss (CR), exercise training with weight loss (EWL), exercise training without weight loss (EX), or controls. Based on an equivalent caloric deficit in EWL and CR, we induced matched weight loss. Subjects in the EX group received caloric compensation. Combined with [6,6²H₂]glucose, an octreotide, glucagon, multistage insulin infusion was performed to determine suppression of glucose production (SGP) and insulin-stimulated glucose disposal (ISGD). Computed tomography scans were performed to assess changes in fat distribution.

Results: Body weight decreased similarly in EWL and CR, and did not change in EX and controls. The reduction in visceral fat was significantly greater in EWL (–71 ± 15 cm²) compared to CR and EX. The increase in SGP was also almost 3-fold greater (27 ± 2%) in EWL. EWL and CR promoted similar improvements in ISGD [+2.5 ± 0.4 and 2.4 ± 0.9 mg · kg fat-free mass (FFM)^–1 · min^–1], respectively.

Conclusions: EWL promoted the most significant reduction in visceral fat and the greatest improvement in SGP. Equivalent increases in ISGD were noted in EWL and CR, whereas EX provided a modest improvement. Based on our results, EWL promoted the optimal intervention-based changes in body fat distribution and systemic insulin resistance.

Methods: We here report a novel homozygous mutation, c.385T>C in FGF23 exon 2, which changes codon 129 from serine to proline (S129P) in a previously described individual affected by HFTC. The S129P mutation as well as two known FGF23 mutations, S71G and S129F, were introduced into an expression vector encoding wild-type (wt) human (h) FGF23 to yield [P129]hFGF23, [F129]hFGF23, and [G71]hFGF23; whole lysates, glycoprotein fractions, and conditioned media from HEK293 and COS-7 cells expressing these constructs were subjected to Western blot analysis using affinity-purified goat anti-hFGF23(51-69) and anti-hFGF23(206-222) antibodies.

Results: We detected 25- and 32-kDa protein species in total lysates of HEK293 cells expressing wt-hFGF23. The 32-kDa band, representing O-glycosylated hFGF23, was not detectable in the glycoprotein fraction of lysates from HEK293 cells expressing [P129]hFGF23, and in comparison with wt-FGF23 only small amounts of [P129]hFGF23 were secreted into the medium. Similar results were obtained for cells expressing [G71]hFGF23 and [F129]hFGF23.

Conclusion: Our data for the first time directly show that FGF23 mutations associated with HFTC impair O-glycosylation in vitro resulting in poor secretion of the mutant hormone thereby explaining the characteristic hyperphosphatemic phenotype of homozygous carriers in vivo.

Design: Anthropometry and fasting blood levels were studied in 49 mothers who had lost 36 ± 1.8% body weight sustained for 12 ± 0.8 yr and their 111 children (54 BMS and 57 AMS) aged 2.5–26 yr.

Results: AMS children had lower birth weight (2.9 ± 0.1 AMS vs. 3.3 ± 0.1 kg BMS, P = 0.003) associated with a reduced prevalence of macrosomia (1.8 AMS vs. 14.8% BMS, P = 0.03) with no difference in underweight. At the time of follow-up, AMS children exhibited 3-fold lower prevalence of severe obesity (11 vs. 35%, P = 0.004), greater insulin sensitivity (homeostasis model assessment of insulin resistance index 3.4 ± 0.3 vs. 4.8 ± 0.5, P = 0.02), improved lipid profile (cholesterol/high-density lipoprotein cholesterol 2.96 ± 0.11 vs 3.40 ± 0.18, P = 0.03; high-density lipoprotein cholesterol 1.50 ± 0.05 vs. 1.35 ± 0.05 mmol/liter, P = 0.04), lower C-reactive protein (0.88 ± 0.17 vs. 2.00 ± 0.34 µg/ml, P = 0.004), and leptin (11.5 ± 1.5 vs.19.7 ± 2.5 ng/ml, P = 0.005) and increased ghrelin (1.28 ± 0.06 vs.1.03 ± 0.06 ng/ml, P = 0.005) than BMS offspring (AMS vs. BMS, respectively, for all).

Conclusions: This unique study of children aged 2.5–26 yr born before and after maternal antiobesity surgery demonstrated improvements in cardiometabolic markers sustained into adolescence, attributable to an improved intrauterine environment.

Objective: Our objective was to review maternal and fetal outcomes in pregnant women with type 2 vs. type 1 DM.

Study Selection: We conducted a systematic review of papers providing original data on pregnancy outcomes in both type 2 and type 1 DM (Medline search of the period January 1, 1987, to June 30, 2008). Two independent investigators considered papers for eligibility, and a third one solved discrepancies.

Data Extraction: Metaanalysis tools were used to compare four main outcomes (major congenital malformations, stillbirth, and neonatal and perinatal mortality) and 15 secondary ones (five maternal, 10 fetal). Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were used to assess quality.

Data Synthesis: Thirty-three studies qualified for inclusion of 3743 citations retrieved. Women with type 2 DM had lower glycated hemoglobin (HbA1c) at booking and throughout pregnancy but a higher risk of perinatal mortality [odds ratio (OR) 1.50, 95% confidence interval (CI) 1.15–1.96] without significant differences in the rates of major congenital malformations, stillbirth, and neonatal mortality. As to secondary outcomes, women with type 2 DM had less diabetic ketoacidosis (OR 0.09, 95% CI 0.02–0.34) and cesarean section (OR 0.80, 95% CI 0.59–0.94) without differences in other outcomes.

Conclusions: Despite a milder glycemic disturbance, women with type 2 DM had no better perinatal outcomes than those with type 1, indicating that type 2 DM in pregnancy is a serious condition.

Objective: To determine whether a controlled aerobic exercise program (without weight loss) improves peripheral and hepatic insulin sensitivity and affects glucose production (GPR), gluconeogenesis and glycogenolysis in sedentary lean and obese Hispanic adolescents.

Patients and Design: Twenty-nine post-pubertal adolescents (14 lean: 15.1 ± 0.3y; 20.6 ± 0.8kg/m²; 18.9±1.5% body fat and 15 obese: 15.6 ± 0.4y; 33.2 ± 0.9kg/m²; 38.4 ± 1.4% body fat) (mean ± SE), completed a 12 wk aerobic exercise program (4 x 30 min/week at ≥70% of VO₂ peak). Peripheral and hepatic insulin sensitivity and glucose kinetics were quantified using GCMS pre- and post-exercise.

Results: No weight loss occurred. Lean and obese participants complied well with the program (~90% of the exercise sessions attended, resulting in ~15% increase in fitness in both groups). Peripheral and hepatic insulin sensitivity were higher in lean than obese adolescents but increased in both groups; peripheral insulin sensitivity by 35 ± 14% (lean) (p < 0.05) and 59 ± 19% (obese) (p < 0.01) and hepatic insulin sensitivity by 19 ± 7% (lean) (p < 0.05) and 23 ± 4% (obese) (p < 0.01). GPR, gluconeogenesis and glycogenolysis did not differ between the groups. GPR decreased slightly, 3 ± 1% (lean) (p < 0.05) and 4 ± 1% (obese) (p < 0.01). Gluconeogenesis remained unchanged, while glycogenolysis decreased slightly in the obese group (p < 0.01).

Conclusion: This well accepted aerobic exercise program, without weight loss, is a promising strategy to improve peripheral and hepatic insulin sensitivity in lean and obese sedentary adolescents. The small decrease in GPR is probably of limited clinical relevance.

Objective: Our objective was to investigate volumetric and geometric parameters of the appendicular skeleton, biochemical markers, and anthropometrics in men with IO.

Design, Setting, and Participants: Our cross-sectional study included 107 men diagnosed with idiopathic low bone mass, 23 of their adult sons, and 130 age-matched controls.

Main Outcome Measures: Body composition and areal bone parameters (dual-energy x-ray absorptiometry) and volumetric and geometric parameters of radius and tibia (peripheral quantitative computed tomography) were assessed. Serum levels of testosterone, estradiol (E₂), and SHBG, and bone turnover markers were measured using immunoassays. Free hormone fractions were calculated.

Results: Men with idiopathic low bone mass had lower weight (–9.6%), truncal height (–3.3%), and upper/lower body segment ratio (–2.7%; all P < 0.001) and presented at the radius and tibia lower trabecular (–19.0 and –23.6%, respectively; both P < 0.001) and cortical volumetric bone mineral density (vBMD) (–2.4 and –1.7%; both P < 0.001) and smaller cortical areas (–9.7 and –13.6%; both P < 0.001) and thicknesses (–13.5 and –14.5%, both P < 0.001) due to larger endosteal circumferences (+11.8 and +7.4%, both P < 0.001) than controls. Furthermore, (free) E₂ was lower and SHBG higher (both P < 0.01). Their sons had lower trabecular vBMD (–10.3%, P = 0.036) and a thinner cortex (–8.3%, P = 0.024) at the radius.

Conclusion: Bone mass deficits in men with idiopathic low bone mass involve trabecular and cortical bone, resulting from lower vBMD and smaller cortical bone cross-sectional areas and thicknesses. A similar bone phenotype is present in at least part of their sons. The lower E₂, together with characteristics as lower upper/lower body segment ratio, larger endosteal circumferences and lower vBMD, may indicate an estrogen-related factor in the pathogenesis of male IO.

Objective: To explore the cause of organification defect in one child with CH and a eutopic thyroid gland, genetic analyses of TPO, DUOX2, and DUOXA2 genes were performed.

Patient: One child with CH, a eutopic thyroid gland, and a partial organification defect was shown after ¹²³I scintigraphy and perchlorate test.

Methods: In the child with the organification defect, TPO, DUOX2, and DUOXA2 genes were analyzed. The functional activity of the DUOX2 mutants was studied after expression in eukaryotic cells.

Results: No TPO or DUOXA2 gene mutations were identified. Direct sequencing of the DUOX2 gene revealed a compound heterozygous genotype for S911L and C1052Y substitutions. S911L and C1052Y caused a partial defect in H₂O₂ production after transient expression in HeLa cells.

Conclusions: We performed a genetic analysis in one child with CH and a eutopic thyroid gland. Two new mutations in DUOX2 gene responsible for the partial deficit in the organification process were identified.

Aim: The aim of this study was to determine the effects of acute and chronic kisspeptin administration on gonadotropin release in women with HA.

Methods: We performed a prospective, randomized, double-blinded, parallel design study. Women with HA received twice-daily sc injections of kisspeptin (6.4 nmol/kg) or 0.9% saline (n = 5 per group) for 2 wk. Changes in serum gonadotropin and estradiol levels, LH pulsatility, and ultrasound measurements of reproductive activity were assessed.

Results: On the first injection day, potent increases in serum LH and FSH were observed after sc kisspeptin injection in women with HA (mean maximal increment from baseline within 4 h after injection: LH, 24.0 ± 3.5 IU/liter; FSH, 9.1 ± 2.5 IU/liter). These responses were significantly reduced on the 14th injection day (mean maximal increment from baseline within 4 h postinjection: LH, 2.5 ± 2.2 IU/liter, P < 0.05; FSH, 0.5 ± 0.5 IU/liter, P < 0.05). Subjects remained responsive to GnRH after kisspeptin treatment. No significant changes in LH pulsatility or ultrasound measurements of reproductive activity were observed.

Conclusion: Acute administration of kisspeptin to women with infertility due to HA potently stimulates gonadotropin release, but chronic administration of kisspeptin results in desensitization to its effects on gonadotropin release. These data have important implications for the development of kisspeptin as a novel therapy for reproductive disorders in humans.

Objective: We estimated the distribution and heritability of the ARR and tested for associations between ARR and blood pressure (BP) with 11 polymorphisms at the CYP11B1/CYP11B2 locus.

Design and Setting: A total of 1172 individuals from 248 Caucasian families ascertained via a hypertensive proband were evaluated.

Main Outcome Measure: Plasma aldosterone was measured by RIA, and plasma renin concentration was measured by the LIAISON Direct Renin chemiluminescent immunoassay.

Results: Unadjusted and adjusted ARR were continuously distributed in normotensives and hypertensives, with no evidence of a cutoff that would identify a separate population with PA. Median ARR was 4.19 ng/liter per mIU/liter (range, 0.04–253.16). ARR levels were higher in females and associated with age, body mass index, and potassium. Antihypertensive agents had significant predictable effects on the ARR. Renin was negatively associated, and ARR was positively associated with ambulatory BP readings (P < 0.001) in subjects not taking antihypertensives. The heritability of the ARR was 38.1% (P < 10^–8). Plasma aldosterone, but not ARR, was influenced by the intron 2 conversion variation in the CYP11B2 gene (β = –0.07; P = 0.04).

Conclusions: The ARR is continuously distributed, is influenced by genetic and environmental factors, and is not a marker of a distinct pathological abnormality but possibly reflects the long-term influence of aldosterone on cardiovascular homeostasis.

Objective: The objective of the study was to describe the phenotype associated with partial isolated GH deficiency of a young patient born to unrelated parents and identify the molecular basis of his disease.

Results: The growth delay (–3.0 sd) was associated with recurrent episodes of abdominal pain, vomiting, ketosis, hypoglycemia, and a low body mass index. GHSR sequencing revealed that the patient was compound heterozygous for two new defects: 1) an early occurring transition predicting a premature stop codon (c.6G>A, p.W2X) inherited from his unaffected father, therefore strongly arguing against haploinsufficiency as a disease mechanism, and 2) a missense mutation (c.709A>T, p.R237W) inherited from his healthy mother, involving an evolutionary invariant residue from the third intracellular loop. In vitro experiments showed that the p.R237W mutation would result in a partial loss of constitutive activity of the receptor, whereas both its ability to respond to ghrelin and its cell surface expression are preserved.

Conclusion: These data, which describe the first case of recessive partial isolated GH deficiency due to GHSR mutations and emphasize the physiological importance of the GHSR in somatic growth, are discussed in light of the dominantly expressed p.A204E mutation.

Results: We used AtT20 mouse pituitary corticotroph tumor cells stably overexpressing SST2 or SST5 and TtT/GF mouse pituitary folliculostellate cells stably or transiently expressing SST receptors to examine ligand-receptor activation by SST2- and SST5-selective agonists. We show that pasireotide was more potent than either octreotide or somatostatin-14 in mouse corticotroph cells. Pasireotide potency is not affected by SST2 abundance, SST2 antagonist treatment, or octreotide cotreatment in SST2-overexpressing cells. Pasireotide also does not induce SST2 internalization and attenuates octreotide or SRIF14-induced SST2 internalization only at superphysiological dose ranges. In contrast, octreotide attenuates pasireotide potency in SST5-overexpressing cells. Moreover, short exposure to pasireotide causes prolonged inhibition of forskolin or CRH-induced cAMP accumulation, in contrast to somatostatin-14- and SST2-selective agonists that induced postwithdrawal cAMP rebound. Long-term pasireotide signaling effects are enhanced by SST5 overexpression.

Conclusion: The results indicate that SST5 determines short- and long-term enhanced pasireotide action in corticotroph cells, whereas the ligand action on SST2 is negligible.

Objectives: Our objectives were to characterize bone mass, microarchitecture, and trabecular bone stiffness in premenopausal IOP and to determine whether women with low aBMD who have never fractured have abnormal microarchitecture and stiffness.

Design, Setting, and Patients: We conducted a prospective cohort study of 27 normal controls and 31 women with IOP defined by low trauma fracture (n = 21) or low BMD (Z score ≤–2.0; n = 10).

Main Outcome Measures: We assessed aBMD by dual-energy x-ray absorptiometry; volumetric BMD and cortical and trabecular microarchitecture of the radius and tibia by high-resolution (82 µm) peripheral quantitative computed tomography; and trabecular bone stiffness (elastic moduli), estimated by micro-finite element analysis.

Results: Fracture subjects did not differ from controls by age or body mass index, which was lower in low-BMD subjects than controls. Fracture subjects also had lower aBMD than controls at all sites (P < 0.05–0.0001). Bone size was similar in controls and fracture subjects but 10.6% smaller in low-BMD subjects (P < 0.05). Every trabecular parameter in both fracture and low-BMD groups was markedly worse than controls (P < 0.01–0.0001). Cortical thickness was significantly lower in both fracture and low-BMD groups at the tibia but not radius. Bone stiffness estimated by micro-finite element analysis was comparably reduced in low-BMD and fracture groups.

Conclusion: Premenopausal women with IOP had marked trabecular microarchitectural deterioration at the radius and tibia. Cortical parameters were affected only at the tibia. Although they had not fractured, microarchitectural deterioration was similar in IOP women with low BMD and those with fractures.

Objective: The aim of the study was to determine the prevalence of MetS in fathers and brothers of women with PCOS compared to men from the general population.

Design and Setting: We conducted a cross-sectional observational study at academic medical centers.

Participants: A total of 211 fathers and 58 brothers of women with PCOS were studied and compared to 1153 and 582 Third National Health and Nutrition Survey (NHANES III) men of similar age and race/ethnicity, respectively.

Main Outcome Measure: We measured MetS prevalence.

Results: The prevalence of MetS was increased in fathers (42 vs. 32%; P = 0.006) and brothers (22 vs. 9%; P = 0.001) compared to NHANES III men. Fathers and brothers had higher body mass index (BMI) than NHANES III men (P < 0.0001). MetS rates were similar in fathers and brothers compared to NHANES III groups after adjusting for BMI. Total testosterone was inversely related to MetS in both fathers and brothers, but this relationship was also accounted for by the higher BMI in male relatives.

Conclusion: Male relatives of women with PCOS had increased prevalence rates of MetS and obesity compared to the general U.S. male population from NHANES III. In contrast to women with PCOS and their female relatives, the higher prevalence of MetS in male relatives was accounted for by elevated BMI. These findings suggest that the high rates of MetS in male relatives of women with PCOS are related to higher rates of obesity than the general population.

Design: The head and neck paragangliomas of two VHL patients were analyzed for mutations by direct sequencing of the VHL gene. In addition loss of heterozygosity analysis was performed for three microsatellite loci near the VHL gene. To rule out other underlying genetic causes of the parasympathetic paragangliomas, mutation analysis of the SDHB, SDHC, and SDHD genes was also performed.

Results: Apart from germline VHL mutations, no additional mutations were found in the paraganglioma-related tumor suppressor genes SDHB, SDHC, and SDHD. Analysis of paraganglioma tissue revealed loss of the VHL wild-type allele in both tumors, indicating that in these tumors biallelic VHL gene inactivation occurred.

Conclusions: These findings indicate that parasympathetic paragangliomas in VHL disease, although rare, are part of the syndrome and related to VHL gene inactivation. Clinicians should be aware of the potential occurrence of parasympathetic paragangliomas in VHL disease.

Objective: We describe the identification and biochemical characterization of a novel CASR gene mutation that caused apparent autosomal recessive FHH in an extended consanguineous kindred.

Design: The study design involved direct sequence analysis of the CaSR gene, clinical and biochemical analyses of patients, and in vitro immunobiochemical studies of the mutant CaSR.

Results: A novel inactivating mutation (Q459R) was identified in exon 4 of both alleles of the CASR in the proband, who presented with asymptomatic hypercalcemia and hypocalciuria at age 2 yr. The proband’s parents were heterozygous for the Q459R mutation consistent with autosomal recessive inheritance of FHH. Among 13 family members that were studied, eight subjects were heterozygous for the Q459R mutation and five had normal genotypes. All heterozygous subjects were asymptomatic and normocalcemic apart from one subject who was mildly hypercalcemic. The Q459R mutant CaSR was normally expressed at the cell membrane but retained only 30–50% of the calcium-dependent activity of the wild-type CaSR.

Conclusion: We identified a novel loss-of-function Q459R mutation in the CASR gene that exhibits mildly reduced sensitivity to calcium and that is associated with apparent autosomal recessive transmission of FHH. This study demonstrates the importance of genetic testing in FHH to distinguish between de novo and inherited mutations of the CASR gene and assist in management decisions.

Aims: The objective of the study was to define the frequency of FGFR1 mutations in a large cohort of nIHH, delineate the spectrum of reproductive phenotypes, assess functionality of the FGFR1 mutant alleles in vitro, and investigate genotype-phenotype relationships.

Design: FGFR1 sequencing of 134 well-characterized nIHH patients (112 men and 22 women) and 270 healthy controls was performed. The impact of the identified mutations on FGFR1 function was assessed using structural prediction and in vitro studies.

Results: Nine nIHH subjects (five males and four females; 7%) harbor a heterozygous mutation in FGFR1 and exhibit a wide spectrum of pubertal development, ranging from absent puberty to reversal of IHH in both sexes. All mutations impair receptor function. The Y99C, Y228D, and I239T mutants impair the tertiary folding, resulting in incomplete glycosylation and reduced cell surface expression. The R250Q mutant reduces receptor affinity for FGF. The K618N, A671P, and Q680X mutants impair tyrosine kinase activity. However, the degree of functional impairment of the mutant receptors did not always correlate with the reproductive phenotype, and variable expressivity of the disease was noted within family members carrying the same FGFR1 mutation. These discrepancies were partially explained by additional mutations in known IHH loci.

Conclusions: Loss-of-function mutations in FGFR1 underlie 7% of nIHH with different degrees of impairment in vitro. These mutations act in concert with other gene defects in several cases, consistent with oligogenicity.

Objective: The aim of the study was to analyze whether HFE mutations causing hereditary hemochromatosis (HH) are associated with primary HTG.

Design: Genetic predisposition to HH was analyzed in a case-control study.

Setting: The study was conducted at University Hospital Lipid Clinic.

Participants: We studied two groups: 1) the HTG group, composed of 208 patients; and 2) the control group, composed of 215 normolipemic subjects and 161 familial hypercholesterolemia patients.

Intervention: Two HFE mutations (C282Y and H63D) were analyzed.

Main Outcome Measure: We measured HH genetic predisposition difference between groups.

Results: HH genetic predisposition was 5.9 and 4.4 times higher in the HTG group than in the normolipemic (P = 0.02) and FH (P = 0.05) subjects, respectively. There were 35 cases (16.8%) of iron overload in the primary HTG group, 14 (6.5%) and nine (5.6%) in the normolipidemic and FH groups, respectively. A higher HH genetic predisposition and a different prevalence of iron overload in subjects with HH genetic predisposition among groups contributed to this higher prevalence. None of the four cases with the HFE genotype associated with high risk of HH in the control groups presented iron overload; however, in eight of 11 subjects (72.7%) with primary HTG and HH genetic predisposition, the iron overload was present.

Conclusion: Mutations in HFE gene, favoring iron overload and causing HH, could play an important role in the development of several phenotypes of primary HTG.

Objective: The objective of the study was to test the 111In-labeled GLP-1R agonist 111In-DOTA-exendin-4 in localizing insulinomas using single photon emission computed tomography in combination with computed tomography images.

Design: This was a prospective open-label investigation.

Setting: The study was conducted at three tertiary referral centers in Switzerland.

Patients: Patients included six consecutive patients with proven clinical and biochemical endogenous hyperinsulinemic hypoglycemia.

Intervention: ¹¹¹In-DOTA-exendin-4 was administered iv at a dose of about 90 MBq (30 µg peptide) over 5 min. Whole-body planar images of the abdomen were performed at 20 min, 4 h, 23 h, 96 h, and up to 168 h after injection. After surgical removal of the insulinomas, GLP-1R expression was assessed in the tumor tissue in vitro by GLP-1R autoradiography.

Main Outcome Measure: The detection rate of insulinomas was measured.

Results: In all six cases, the GLP-1R scans successfully detected the insulinomas identified using conventional methods in four cases. By using a -probe intraoperatively, GLP-1R detection permitted a successful surgical removal of the tumors in all patients, diagnosed histopathologically as five pancreatic and one extrapancreatic insulinomas. In vitro GLP-1R autoradiography showed a high density of GLP-1R in all tested insulinomas.

Conclusion: In vivo GLP-1R imaging is an innovative, noninvasive diagnostic approach that successfully localizes small insulinomas pre- and intraoperatively and that may in the future affect the strategy of insulinoma localization.

Objective: A tissue array block was made using tissue from 35 cases of nonfunctioning pituitary adenomas (16 cases with early recurrence ≤4 yr after surgery, 10 cases with late recurrence >4 yr after surgery, and nine cases without recurrence). Levels of tumor tissue cellular markers associated with cell proliferation or apoptosis were analyzed, and immunohistochemical study of cellular markers was conducted using sectioned slides from the tissue array block.

Results: High Ki-67 and TUNEL labeling indexes were associated with recurrent nonfunctioning pituitary adenomas. Tumors with a high level of expression of phospho-Akt, phospho-p44/42 MAPK, and PTTG1 were associated with early recurrence. However, high levels of expression of phospho-CREB and ZAC1 were inversely associated with recurrence.

Conclusions: Tumors with high levels of expression of phospho-Akt and phospho-p44/42 MAPK and low levels of expression of phospho-CREB and ZAC1 should be followed closely and may require adjunctive therapy to prevent tumor recurrence.

Outcome Measures: GH peak after GHRH+ARG and IGF-I levels reported as sd score.

Subjects: Subjects included 408 controls (218 women, 190 men, aged 15–80 yr) and 374 patients with hypopituitarism (167 women, 207 men, aged 16–83 yr).

Results: In the (elderly) healthy subjects 15–25 yr old (young), 26–65 yr old (adults) and older than 65 yr, GH cutoffs were 15.6, 11.7, and 8.5 µg/liter, 11.8, 8.1, and 5.5 µg/liter, and 9.2, 6.1, and 4.0 µg/liter, respectively, in the lean, overweight, and obese subjects. Waist circumference was the best predictor of GH peak (t = –7.6, P < 0.0001) followed by BMI (t = –6.7, P < 0.0001) and age (t = –5.7, P < 0.0001). Based on the old (<9.1 µg/liter) and new GH cutoff, 286 (76.5%) and 276 (73.8%) of 374 hypopituitary patients had severe GHD. The receiving-operator characteristic analysis showed GH cutoffs in line with the third percentile or slightly higher results so that the prevalence of GHD increased to 90.1%.

Conclusions: The results of the current study show that waist circumference and BMI are the strongest predictors of GH peak after GHRH+ARG followed by age. However, the old cutoff value of 9.0 µg/liter was in line with the new cutoffs in 95% of patients.

Patients and Methods: We reviewed the records of consecutive patients with metastatic thyroid cancer referred to the Phase I Clinical Trials Program from March 2006 to April 2008. Best response was assessed by Response Evaluation Criteria in Solid Tumors.

Results: Fifty-six patients were identified. The median age was 55 yr (range 35–79 yr). Of 49 patients evaluable for response, nine (18.4%) had a partial response, and 16 (32.7%) had stable disease for 6 months or longer. The median progression-free survival was 1.12 yr. With a median follow-up of 15.6 months, the 1-yr survival rate was 81%. In univariate analysis, factors predicting shorter survival were anaplastic histology (P = 0.0002) and albumin levels less than 3.5 g/dl (P = 0.05). Among 26 patients with tumor decreases, none died (median follow-up 1.3 yr), whereas 52% of patients with any tumor increase died by 1 yr (P = 0.0001). The median time to failure in our phase I clinical trials was 11.5 months vs. 4.1 months for the previous treatment (P = 0.04).

Conclusion: Patients with advanced thyroid cancer treated on phase I clinical trials had high rates of partial response and prolonged stable disease. Time to failure was significantly longer on the first phase I trial compared with the prior conventional treatment. Patients with any tumor decrease had significantly longer survival than those with any tumor increase.

Objective: We sought to determine the genetic basis for severe hypercalciuria and nephrolithiasis/nephrocalcinosis in an adolescent male with elevated serum levels of calcitriol but normal serum levels of calcium and phosphorus.

Design and Setting: We used PCR to analyze the SLC34A3 gene in the proband and members of his family.

Results: The proband was a compound heterozygote for two SLC34A3 missense mutations, a novel c.544C->T in exon 6 that results in replacement of arginine at position 182 by tryptophan (R182W) and c.575C->T in exon 7 that results in replacement of serine at position 192 by leucine (S192L). The R182W and S192L alleles were inherited from the mother and father, respectively, both of whom had hypercalciuria. A clinically unaffected brother was heterozygous for S192L.

Conclusion: We report a novel mutation in the SLC34A3 gene in a patient with an unusual presentation of HHRH. This report emphasizes that moderate and severe hypercalciuria can be manifestations of heterozygous or homozygous loss-of-function mutations in the SLC34A3 gene, respectively, providing further evidence for a gene dosage effect in determining the phenotype. HHRH may be an underdiagnosed condition that can masquerade as idiopathic hypercalciuria or osteopenia.

Aim: The aim of the study was to compare the frequency of TA in twin individuals from OS and monozygotic (MZ) twin pairs.

Design: This was a case-control study of 240 individuals (120 females and 120 males) from OS twin pairs (cases) and 568 control individuals from MZ pairs (284 females and 284 males).

Methods: Antibodies toward thyroid peroxidase (TPOAb), thyroglobulin (TgAb), and the TSH receptor (TSHRAb) were measured and considered positive if greater than 60 U/ml, greater than 60 U/ml, and greater than 1.0 U/liter, respectively.

Results: The frequency of TPOAb, TgAb, and TSHRAb among female cases was 15.0, 5.0, and 4.2%, respectively, which was higher than the corresponding prevalences in the female control population: 7.4% (P = 0.018), 1.1% (P = 0.023), and 0.7% (P = 0.026), respectively. However, when corrected for the number of phenotypes studied (TPOAb, TgAb, TSHRAb, and any thyroid antibody), the association remained significant only in the combined group, P_corrected = 0.012. Essentially similar results were obtained in males.

Conclusion: Both female and male twins from OS pairs, as opposed to MZ pairs, have an increased frequency of TA, indicating a potential role of microchimerism in developing TA.

Objectives: The aim of this study was to assess iodine balance and to determine its relationship with thyroid function in preterm infants.

Design: Thyroid functions of preterm infants born at 34 wk gestation or less were evaluated in the first (n = 31) and third (n = 19) weeks. Mothers’ breast milk (BM) and random urine samples of infants were taken on the same days for thyroid function tests.

Results: Iodine concentrations in BM were very high (198–8484 µg/liter), and one third of the infants had an iodine intake of more than 100 µg/kg per day at the third week after birth (excessive iodine intake group). At that time, the levels of TSH were positively correlated with urinary iodine (r = 0.622; P = 0.004). The frequencies of subclinical hypothyroidism were high in the excessive iodine intake group at the third and sixth weeks. The estimated daily iodine intake at the third week (51.2 ± 45.5 vs. 149.0 ± 103.8 µg/kg per day; P = 0.033), urinary iodine at the third week (913.2 ± 1179.7 vs. 1651.3 ± 1135.2 µg/liter; P = 0.051), and estimated daily iodine intake at the sixth week (32.8 ± 35.5 vs. 92.1 ± 51.2 µg/kg per day; P = 0.032) were significantly higher in infants with subclinical hypothyroidism than in controls.

Conclusions: Excessive iodine intake from BM contributed to subclinical hypothyroidism in these preterm Korean infants.

Subjects and Methods: A total of 257 obese/overweight children (mean body mass index-sd score, 2.2 ± 0.3), aged 11.6 ± 2.3 yr were divided into three groups according to birth weight percentile: 44 were small for gestational age (SGA), 161 were appropriate for gestational age (AGA), and 52 were large for gestational age (LGA). Participants underwent a 3-h oral glucose tolerance test with glucose, insulin, and C-peptide measurements. Homeostasis model of assessment for insulin resistance, insulinogenic index, and disposition index were calculated to evaluate insulin sensitivity and β-cell function. Glucose and insulin area under the curve (AUC) were also considered. One-way ANOVA was used to compare the three groups.

Results: SGA and LGA subjects had higher homeostasis model of assessment for insulin resistance than AGA subjects, but they diverged when oral glucose tolerance test response was considered. Indeed, SGA subjects showed higher glucose AUC and lower insulinogenic and disposition indexes. Insulin AUC was not different between groups, but when singular time points were considered, SGA subjects had lower insulin levels at 30 min and higher insulin levels at 180 min.

Conclusions: SGA obese children fail to adequately compensate for their reduced insulin sensitivity, manifesting deficit in early insulin response and reduced disposition index that results in higher glucose AUC. Thus, SGA obese children show adverse metabolic outcomes compared to AGAs and LGAs.

Objective: The objective of the study was to study the effects of treatment with the TZD pioglitazone on sc adipose tissue morphology and function in insulin-resistant subjects.

Design: This was a placebo-controlled, randomized crossover study.

Setting: The study was conducted at a university medical center.

Patients: Twelve adult patients with congenital adrenal hyperplasia (CAH) characterized by insulin resistance were included in this study.

Intervention: After a 4-wk run-in phase, patients were treated with pioglitazone (45 mg/d) followed by placebo, each for 16 wk or vice versa.

Main Outcome Measures: After both placebo and pioglitazone treatment, insulin sensitivity was determined by hyperinsulinemic euglycemic clamp and abdominal sc adipose tissue was obtained to measure adipocyte cell surface and expression of genes involved in glucose uptake and inflammation.

Results: Pioglitazone treatment significantly improved the insulin sensitivity index (placebo: 0.35 ± 0.16 µmol/kg · min per milliunit per liter; pioglitazone 0.53 ± 0.16 µmol/kg · min per milliunit per liter, P < 0.001) and increased mRNA expression levels of adiponectin and glucose transporter-4 in adipose tissue. The increase in insulin sensitivity was accompanied by a significant enlargement of the sc adipocyte cell surface (placebo: 2323 ± 725 µm²; pioglitazone 2821 ± 885 µm², P = 0.03).

Conclusions: In the human situation, treatment of insulin-resistant subjects with pioglitazone improves insulin sensitivity, whereas at the same time, sc adipocyte cell surface increases.

Objective: The aim of the study was to investigate the relationship between different stages of renal insufficiency and PTH levels in PHPT patients.

Design: We conducted a cross-sectional study.

Patients and Methods: We studied 294 consecutive PHPT patients. Biochemical evaluation included total and ionized serum calcium, phosphate, creatinine, immunoreactive intact PTH, and 25-hydroxyvitamin D3 levels in the fasting state. GFR was assessed with the Modification of Diet in Renal Disease Study formula.

Results: The mean GFR of the whole group of PHPT patients was 92.3 ± 31.6 ml/min · 1.73 m². The patients were divided into four groups according to National Kidney Foundation Disease Outcomes Quality Initiative (K/DOQI) guidelines: group 1 with normal or increased GRF (>90 ml/min · 1.73 m²; n = 153); group 2 with mild decreased GFR (60–89 ml/min · 1.73 m²; n = 90); group 3 with moderately decreased GFR (30–59 ml/min · 1.73 m²; n = 45); and group 4 with severely decreased GFR (<30 ml/min · 1.73 m²; n = 6). PTH levels were comparable across groups 1–3, whereas group 4 showed significantly higher PTH levels (P < 0.0001).

Conclusion: In our series of PHPT patients, only a severe impairment of GFR was characterized by a further PTH increase. These findings challenge the concept of a PTH elevation below the threshold of 60 ml/min of GFR.

Objective: We sought to understand how meals high in carbohydrate, protein, and fat affect serum concentrations of total ghrelin and total PYY, hypothesizing that these macronutrients would exert differential effects on their secretion.

Design and Setting: This was a cross-sectional study at one tertiary care center.

Subjects: Subjects were 7- to 11-yr-old healthy normal-weight (NW) and obese (OB) volunteers recruited from local advertisements.

Interventions: After an overnight fast, the subjects were given a breakfast high in carbohydrate, protein, or fat at 0800 h. Blood samples for total ghrelin and total PYY were taken at baseline, 30 min, and hourly from 0900 to 1200 h.

Main Outcome Measure: We assessed postprandial ghrelin suppression and PYY elevation, as well as changes in reported hunger and satiety, after the three test meals.

Results: After the high-protein meal, ghrelin declined gradually in both groups over the study period without subsequent increase, whereas ghrelin suppressed more rapidly to a nadir at 60 min after the high-carbohydrate meal in both NW and OB children, followed by rebound in ghrelin levels. Similarly, after the high-protein meal, PYY concentrations increased steadily over the course of the morning in both groups without decline, whereas PYY levels peaked 30 min after the high-carbohydrate meal in both NW and OB subjects with significant decline thereafter. Ghrelin and PYY responses to the high-fat meal were somewhat intermediate between that observed with high carbohydrate and high protein. The OB children reported higher hunger and lower satiety after the high-carbohydrate meal compared to the NW subjects, whereas appetite ratings were similar between the groups after the high-protein and high-fat meals. Additionally, within the OB group, area under the curve (AUC) analysis revealed significantly greater PYY response, as well as lower AUC hunger and higher AUC satiety, to the high-protein meal than the high-carbohydrate and high-fat meals.

Conclusions: The patterns of secretion of ghrelin and PYY in our study of prepubertal children suggest that they may play a role in the effectiveness of high-protein/low-carbohydrate diets in promoting weight loss.

Methods: Magnetic resonance imaging and spectroscopy were used to measure left ventricular (LV) function and abdominal sc and visceral fat areas to estimate respective masses, pericardial fat depots, and myocardial triglyceride content in 53 subjects (10 lean ND, 25 obese ND, six impaired-glucose-tolerance, and 12 type 2 diabetic patients with macrovascular disease); gender effects and adiponectin levels were evaluated in the available subset of subjects.

Results: Myocardial and pericardial fat increased progressively across study groups. They were lower in obese women than men (P = 0.002), but cardiac steatosis caught up in hyperglycemic women (+81% vs. ND, P = 0.01). Adiponectin was inversely related with both fat depots (P < 0.01) and LV mass (P = 0.003) and positively with LV function (P = 0.03). In multiple regression analysis, myocardial and pericardial fat were independently related with plasma glucose levels, only pericardial fat mass was associated with visceral adiposity and myocardial fat with cardiac output and work.

Conclusions: We conclude that glycemia, gender, adiponectin, and cardiac workload are associated with, and hyperglycemia and male gender are independent positive predictors of, heart adiposity. Once glucose tolerance becomes impaired, the evolution of cardiac steatosis is more pronounced in women.

Objective: The objectives of the study were to determine whether AGER1 correlates with AGEs and OS/infl and a reduction of dietary AGEs (dAGEs) lowers OS/infl in healthy adults and chronic kidney disease (CKD-3) patients.

Design: This study was cross-sectional with 2-yr follow-up studies of healthy adults and CKD-3 patients, a subset of which received a reduced AGE or regular diet.

Setting: The study was conducted at general community and renal clinics.

Participants: Participants included 325 healthy adults (18–45 and >60 yr old) and 66 CKD-3 patients.

Intervention: An isocaloric low-AGE (30–50% reduction) or regular diet was given to 40 healthy subjects for 4 months and to nine CKD-3 patients for 4 wk.

Main Outcome: Relationships between age, dAGEs, serum AGEs, peripheral mononuclear cell AGE-receptors, and OS/Infl before and after reduction of dAGE intake were measured.

Results: AGEs, oxidant stress, receptor for AGE, and TNF were reduced in normal and CKD-3 patients after the low-AGE diet, independently of age. AGER1 levels in CKD-3 patients on the low-AGE diet resembled 18- to 45-yr-old normal subjects. Dietary, serum, and urine AGEs correlated positively with peripheral mononuclear cell AGER1 levels in healthy participants. AGER1 was suppressed in CKD-3 subjects, whereas receptor for AGE and TNF were increased.

Conclusions: Reduction of AGEs in normal diets may lower oxidant stress/inflammation and restore levels of AGER1, an antioxidant, in healthy and aging subjects and CKD-3 patients. AGE intake has implications for health outcomes and costs and warrants further testing.

Objective: To determine the association of fetuin-A levels with changes in body composition over 5 yr.

Study Design: Observational cohort study nested in the Health Aging and Body Composition Study.

Predictor: Serum fetuin-A levels.

Outcomes: Visceral adipose tissue (VAT), abdominal sc adipose tissue, and thigh muscle area by computed tomography, and waist circumference and body mass index were measured at baseline and again after 5 yr. Percent change and extreme change (>1.5 sds) in each measure were calculated.

Results: Over 5 yr, subjects lost body mass in each measure, including 6% decline in VAT. Yet each sd (0.42 g/liter) higher fetuin-A concentration was associated with a 5.5% increase in VAT over 5 yr (95% confidence interval 1.9–9.2%; P = 0.003) in models adjusted for age, sex, race, clinical site, diabetes, physical activity, triglycerides, kidney function, and the baseline VAT score. Similarly, higher fetuin-A concentrations were associated with extreme VAT gain (relative risk 1.70, 95% confidence interval 1.12–2.60, P = 0.01). Fetuin-A concentrations were not statistically significant associated with change in any other measures of body composition (P > 0.20).

Conclusions: Higher fetuin-A concentrations are associated with the accumulation of VAT in well-functioning, community-living older persons. The mechanisms linking fetuin-A, VAT, and insulin resistance remain to be determined.

Objective: The main aim of the study was to compare serum levels of ZAG and its expression (mRNA levels and protein) in adipose tissue and the liver between obese and nonobese subjects. The relationship between ZAG and insulin resistance was also explored.

Design: This was a case-control study.

Setting: The study was conducted at a university referral center.

Patients and Methods: Samples of serum, sc adipose tissue (SAT), visceral adipose tissue (VAT), and liver were obtained from 20 obese subjects during bariatric surgery. Samples from 10 nonobese patients matched by age and gender were used as a control group. Serum ZAG levels were determined by ELISA. ZAG mRNA levels were measured by real-time PCR and protein content by Western blot. The effect of insulin on liver production of ZAG was assessed using HepG2 cultures.

Results: Serum concentration of ZAG (micrograms per milliliter) was significantly lower in obese subjects (40.87 ± 10.45 vs. 63.26 ± 16.40; P = 0.002). ZAG expression was significantly lower in the adipose tissue (SAT and VAT) and liver of obese patients than in control subjects. Significant negative correlations between body mass index and circulating ZAG (r = –0.65, P < 0.001) as well as between body mass index and mRNA ZAG levels in SAT (r = –0.68, P < 0.001) and VAT were detected (r = –0.64, P < 0.001). No relationship was found between ZAG and homeostasis model assessment for insulin resistance and insulin had no effect on ZAG production in vitro.

Conclusion: A down-regulation of ZAG in SAT, VAT, and liver exists in obese patients but seems unrelated to insulin resistance.

Objectives: Here we asked whether, in vivo, acute hyperinsulinemia regulates adiponectin formation and oligomeric complex distribution at the transcriptional or posttranslational level.

Design: Nine lean and nine uncomplicated obese males were studied in the postabsorptive state and during a euglycemic-hyperinsulinemic clamp combined with the microdialysis technique. Subcutaneous abdominal adipose tissue biopsies and interstitial and serum samples were taken at baseline and after the hyperinsulinemia. Adiponectin complexes were characterized by nonheating/nonreducing SDS-PAGE.

Results: At baseline, serum and interstitial total adiponectin levels were lower (P < 0.01) in obese than in lean subjects primarily due to a reduction of the high-molecular-weight isoforms. After hyperinsulinemia, serum and interstitial total adiponectin was reduced in both groups. The degree of adiponectin reduction was more prominent in interstitial fluid than in serum. Lean individuals showed an equal suppression of the high-, low-, and middle-molecular-weight adiponectin complexes both in serum and in situ (P < 0.01 vs. basal). In obese subjects, despite the lower interstitial adiponectin subfractions, insulin challenge reduced significantly the circulating middle-molecular-weight forms only. At the mRNA level, adiponectin and its receptors 1 and 2, as well as the abundance of the endoplasmic reticulum chaperone proteins ERp44 and Ero1-L were similar within the groups, before and after the clamp.

Conclusions: In human obesity, the impaired adiponectin oligomeric pattern in the circulation is mimicked at the tissue level, and hyperinsulinemia may differentially affect the compartmental distribution of the adiponectin complexes.

Objective: The objective of the study was to examine the effect of the MICA5.1 allele in subjects with 21OH autoantibodies on progression to AD.

Design: Two components were used: 1) a cross-sectional study with subjects with AD identified and enrolled from September 1993 to November 2008 and 2) a cohort study prospectively following up patients with T1D who screened positive for 21OH autoantibodies.

Setting: Subjects were identified from the Barbara Davis Center and through the National Adrenal Diseases Foundation.

Patients: Sixty-three subjects with AD were referred through the National Adrenal Diseases Foundation (AD referrals). Sixty-three subjects with positive 21OH antibodies from the Barbara Davis Center were followed up for progression to AD, and 11 were diagnosed with AD (progressors).

Results: Seventy-three percent of progressors (eight of 11) and 57% of AD referrals (36 of 63) were MICA5.1 homozygous (P = ns). Overall, 59% of patients with AD (44 of 74) were MICA5.1/5.1 compared with 17% of nonprogressors (nine of 52) (P < 0.0001) and 19% of normal DR3/4-DQB1*0302 controls (64 of 336) (P < 0.0001).

Conclusions: Identifying extreme risk should facilitate monitoring of progression from 21OH antibody positivity to overt AD. The HLA-DR3/0404 genotype defines high-risk subjects for adrenal autoimmunity. MICA5.1/5.1 may define those at highest risk for progression to overt AD, a feature unique to AD and distinct from T1D.

Objective: The aim of this study was to investigate the impact of GHR blockade on substrate metabolism and insulin sensitivity during fasting.

Design: We conducted a randomized, placebo-controlled, crossover study in 10 healthy young men.

Intervention: After 36 h of fasting with saline or pegvisomant (GHR blockade), the subjects were studied during a 4-h basal period and 2.5-h hyperinsulinemic euglycemic clamp.

Main Outcome: We measured whole-body and forearm glucose, lipid, and protein metabolism, peripheral insulin sensitivity, and acyl and desacyl ghrelin.

Results: GHR blockade significantly suppressed circulating free fatty acids (1226 ± 83 vs. 1074 ± 65 µmol/liter; P = 0.03) and ketone bodies (3080 ± 271 vs. 2015 ± 235 µmol/liter; P ≤ 0.01), as well as forearm uptake of free fatty acids (0.341 ± 0.150 vs. 0.004 ± 0.119 µmol/100 ml · min; P < 0.01) and lipid oxidation (1.3 ± 0.1 vs. 1.2 ± 0.1 mg/kg · min; P = 0.03) in the basal period. By contrast, IGF-I levels in either serum or peripheral tissues were not impacted by GHR blockade, and protein metabolism was also unaffected. Basal glucose levels were elevated by GHR blockade, but insulin sensitivity was similar; this was associated with an increased acyl/desacyl ghrelin ratio.

Conclusion: GHR blockade, without changes in circulating or tissue IGF-I levels, selectively suppresses lipid mobilization and oxidation after short-term fasting. This supports the notion that stimulation of lipolysis is a primary and important effect of GH.

Objective: The aim of the study is to investigate the regulation of LAT2 and 4F2hc by progesterone and the antiprogestin mifepristone and their functions in primary human uterine leiomyoma smooth muscle (LSM) cells and tissues from 39 premenopausal women.

Results: In primary LSM cells, progesterone significantly induced LAT2 mRNA levels, and this was blocked by cotreatment with mifepristone. Progesterone did not alter 4F2hc mRNA levels, whereas mifepristone significantly induced 4F2hc mRNA expression. Small interfering RNA knockdown of LAT2 or 4F2hc markedly increased LSM cell proliferation. LAT2, PR-B, and PR-A levels were significantly higher in freshly isolated LSM cells vs. adjacent myometrial cells. In vivo, mRNA levels of LAT2 and PR but not 4F2hc were significantly higher in leiomyoma tissues compared with matched myometrial tissues.

Conclusion: We present evidence that progesterone and its antagonist mifepristone regulate the amino acid transporter system LAT2/4F2hc in leiomyoma tissues and cells. Our findings suggest that products of the LAT2/4F2hc genes may play important roles in leiomyoma cell proliferation. We speculate that critical ratios of LAT2 to 4F2hc regulate leiomyoma growth.

Patients and Methods: We prospectively included 99 women. Our study included a conventional karyotype and DNA microarrays comprising 4500 bacterial artificial chromosome clones spread on the entire genome.

Results: Thirty-one CNVs have been observed, three on the X chromosome and 28 on autosomal chromosomes. Data have been compared to control populations obtained from the Database of Genomic Variants (http://projects.tcag.ca/variation). Eight statistically significantly different CNVs have been identified in chromosomal regions 1p21.1, 5p14.3, 5q13.2, 6p25.3, 14q32.33, 16p11.2, 17q12, and Xq28.

Conclusion: We report the first study of CNV analysis in a large cohort of Caucasian POF patients. In the eight statistically significant CNVs we report, we found five genes involved in reproduction, thus representing potential candidate genes in POF. The current study along with emerging information regarding CNVs, as well as data on their potential association with human diseases, emphasizes the importance of assessing CNVs in cohorts of POF women.

Design and Participants: Insulin action was investigated in a matched cohort of lean healthy, obese nondiabetic, and obese type 2 diabetic subjects by the euglycemic-hyperinsulinemic clamp technique combined with muscle biopsies. Activity, site-specific phosphorylation, and upstream signaling of GS were evaluated in skeletal muscle.

Results: GS activity correlated inversely with phosphorylation of GS site 2+2a and 3a. Insulin significantly decreased 2+2a phosphorylation in lean subjects only and induced a larger dephosphorylation at site 3 in lean compared with obese subjects. The exaggerated insulin resistance in T2DM compared with obese subjects was not reflected by differences in site 3 phosphorylation but was accompanied by a significantly higher site 1b phosphorylation during insulin stimulation. Hyperphosphorylation of another Ca²⁺/calmodulin-dependent kinase-II target, phospholamban-Thr17, was also evident in T2DM. Dephosphorylation of GS by phosphatase treatment fully restored GS activity in all groups.

Conclusions: Dysregulation of GS phosphorylation plays a major role in impaired insulin regulation of GS in obesity and T2DM. In obesity, independent of T2DM, this is associated with impaired regulation of site 2+2a and likely site 3, whereas the exaggerated insulin resistance to activate GS in T2DM is linked to hyperphosphorylation of at least site 1b. Thus, T2DM per se seems unrelated to defects in the glycogen synthase kinase-3 regulation of GS.

Design: To explore whether common genetic variation at the human PYY locus influences plasma PYY or metabolic traits, we systematically resequenced the gene for polymorphism discovery and then genotyped common single-nucleotide polymorphisms across the locus in an extensively phenotyped twin sample to determine associations. Finally, we experimentally validated the marker-on-trait associations using PYY 3'-untranslated region (UTR)/reporter and promoter/reporter analyses in neuroendocrine cells.

Results: Four common genetic variants were discovered across the locus, and three were typed in phenotyped twins. Plasma PYY was highly heritable (P < 0.0001), and genetic pleiotropy was noted between plasma PYY and body mass index (BMI) (P = 0.03). A PYY haplotype extending from the proximal promoter (A-23G, rs2070592) to the 3'-UTR (C+1134A, rs162431) predicted not only plasma PYY (P = 0.009) but also other metabolic syndrome traits. Functional studies with transfected luciferase reporters confirmed regulatory roles in altering gene expression for both 3'-UTR C+1134A (P < 0.001) and promoter A-23G (P = 0.0016).

Conclusions: Functional genetic variation at the PYY locus influences multiple heritable metabolic syndrome traits, likely conferring susceptibility to obesity and subsequent cardiorenal disease.

Objective: In this study, hCG was proposed as an arteriogenic factor that could promote perivascular cell recruitment and vessel stabilization.

Design: The aortic ring assay, a three-dimensional ex vivo angiogenesis system mimicking all the steps of the angiogenesis process was used to study the impact of hCG on pericyte recruitment and vessel maturation.

Setting: The study was conducted at a university hospital laboratory.

Main Outcome Measures: Perivascular cell proliferation, migration, and apposition were quantified by computerized image analysis.

Results: Physiological concentrations of hCG (10–400 IU/ml) significantly enhanced pericyte sprouting and migration and gave rise to the maturation and coverage of endothelial capillaries. In a three-dimensional coculture model of endothelial and perivascular cells, hCG enhanced vessel tube formation and endothelial/mural cell adhesion. In addition, hCG stimulated the proliferation of human umbilical vein endothelial cells and smooth muscle cells. The specificity of these effects was determined by using an anti-hCG blocking antibody. Signaling pathways implicated on this hCG effect is protein kinase A and phospholipase C/protein kinase C dependent for the proliferative effect but only phospholipase C/protein kinase C for the migrative process.

Conclusions: Our findings highlight a novel paracrine role of this early embryonic signal in vessel maturation by stimulating perivascular cell recruitment, migration, and proliferation.

Design and Outcome Measures: Fifteen haplotype-tagging single-nucleotide polymorphisms in the IL-1, IL-1β, and IL-1 receptor antagonist genes were determined in a Finnish population survey (n = 6771). Glucose and insulin concentrations were measured, and indices of insulin resistance and β-cell function were calculated using the homeostasis model assessment. Two-hour oral glucose tolerance tests were carried out on a subsample of 1390 participants. Associations with prevalent diabetes were tested for replication in a sample of European myocardial infarction survivors (n = 972).

Results: The minor allele of the IL-1β rs1143634(G->A) was associated with higher blood glucose than the major allele: 5.37, 5.41, and 5.48 mmol/liter for the GG, AG, and AA genotypes, respectively (multivariate adjusted P for trend <0.0001; Bonferroni corrected P = 0.00096). The 2-h glucose was also higher (6.45 and 7.20 mmol/liter for the GG vs. AA; P = 0.003, Bonferroni corrected P = 0.045). The haplotype ACG of rs1143634, rs3917356, and rs16944 associated with higher glucose, higher homeostasis model assessment for insulin resistance index, higher 2-h insulin, and prevalent diabetes (adjusted rate ratio = 1.54; 95% confidence interval = 1.03–2.30; P = 0.037). The association with prevalent diabetes was replicated among European myocardial infarction survivors (rate ratio = 2.09; 95% confidence interval = 1.17–3.76; P = 0.013).

Conclusions: These results suggest that genetic variation in the IL-1 gene family is associated with measures of glucose homeostasis and prevalent diabetes.

Objective: The objective of the study was to investigate LMF1 gene in hypertriglyceridemic patients in whom mutations in LPL, APOC2, and APOA5 genes had been excluded.

Results: The resequencing of LMF1 gene led to the discovery of a novel homozygous nonsense mutation in one patient with severe hypertriglyceridemia and recurrent episodes of pancreatitis. The mutation causes a G>A substitution in exon 9 (c.1395G>A), leading to a premature stop codon (W464X). LPL activity and mass were reduced by 76 and 50%, respectively, compared with normolipidemic controls. The proband over the years has shown a good response to treatment. The proband’s son, heterozygous for the W464X, shows normal plasma triglyceride levels.

Conclusions: We identified the second novel pathogenic mutation in LMF1 gene in a patient with severe hypertriglyceridemia. LPL deficiency in our patient was milder than in the carrier of the Y439X previously described.

Objective: Our objective was to study GR expression in adrenocortical tumors (ACTs) and to assess its utility as an adjunct to the Weiss score.

Design: Microarray analysis, real-time quantitative RT-PCR (qPCR), immunohistochemistry, Western blot, and direct sequencing were performed.

Results: Analysis of 28 ACTs by microarray and 49 ACTs by qPCR found NR3C1 expression to be up-regulated in ACCs compared with ACAs (P < 0.001). Western blotting and RT-PCR confirmed the presence of the GR isoform in ACCs, and no mutations were detected on direct sequencing. Immunohistochemistry for GR in an overlapping cohort of ACTs demonstrated strongly positive nuclear staining in 31 of 33 ACCs (94%), with negative staining in 40 of 41 ACAs (98%) (P < 0.001). This finding was validated in an external cohort of ACTs, such that 14 of 18 ACCs (78%) demonstrated positive nuclear staining whereas 32 of 33 ACAs (94%) were negative (P < 0.001).

Conclusions: The immunohistochemical finding of nuclear GR staining identified ACCs with high diagnostic accuracy. We propose that GR immunohistochemistry may complement the Weiss score in the diagnosis of ACC in cases that display borderline histology. The possibility that GR is transcriptionally active in these tumors, and may therefore be a therapeutic target, requires further study.

Objective: The present study aims to define metabolic signals associated with the suppression of the cerebrocortical response in obese humans.

Design and Setting: We determined insulin-mediated modulation of spontaneous cerebrocortical activity by magnetoencephalography during a hyperinsulinemic euglycemic clamp and related it to measures of ectopic fat deposition and mediators of peripheral insulin resistance. Visceral fat mass and intrahepatic lipid content were quantified by magnetic resonance imaging and spectroscopy. Multiple regression analysis was used to analyze associations of cerebrocortical insulin sensitivity and metabolic markers related to obesity.

Participants: Forty-nine healthy, nondiabetic humans participated in the study.

Results: In a multiple regression, insulin-mediated stimulation of theta activity was negatively correlated to body mass index, visceral fat mass, and intrahepatic lipid content. Although fasting saturated nonesterified fatty acids mediated the correlations of theta activity with abdominal and intrahepatic lipid stores, adipocytokines displayed no independent correlation with insulin-mediated cortical activity in the theta frequency band.

Conclusions: Thus, insulin action at the level of cerebrocortical activity in the brain is diminished in the presence of elevated levels of saturated nonesterified fatty acids.

Methods: Serum TSH, FT4, FT3, and thyroid peroxidase antibodies (TPOAbs) were measured in 970 pregnant women at 28 wk gestation. rs4704397 genotype was available on 877 subjects. Reference range calculations were based on the TPOAb-negative women.

Results: TSH, but not FT4, FT3, or TPOAbs, varied with genotype and was highest in those with the AA genotype (median, 2.16, 1.84, and 1.73 mIU/liter for AA, AG, and GG genotypes, respectively; P = 0.0004). A greater proportion of women with the AA genotype had TSH concentrations above 4.21 mIU/liter, the upper limit of the reference range, compared with the AG and GG genotypes (9.6 vs. 3.5%, respectively; P = 0.004). Maternal PDE8B genotype was not associated with offspring birthweight or gestational age at delivery.

Conclusion: Genetic variation in TSH levels in pregnancy associated with the PDE8B rs4704397 genotype has implications for the number of women treated for subclinical hypothyroidism under current guidelines. Consideration should be made to individualization of normal ranges, potential effects on pregnancy outcome, and intention to treat for subclinical hypothyroidism in pregnancy.

Objective: Our objective was to investigate the clinical relevance of cancer-testis antigen sperm-associated antigen 9 (SPAG9) as early diagnostic and therapeutic target in thyroid cancer.

Design, Setting, and Subjects: SPAG9 gene and protein expression was determined in thyroid cancer cell lines in 138 thyroid tumor specimens, 60 adjacent noncancerous tissues (ANCT), 22 multinodular goiters (nonneoplastic hyperplasia), and 20 follicular adenoma tissue samples by RT-PCR, in situ RNA hybridization, and immunohistochemistry. Gene silencing approach was used to examine the effects of suppression of SPAG9 protein on cellular growth and colony formation. Humoral immune response against SPAG9 in thyroid cancer patients was analyzed using ELISA.

Results: SPAG9 mRNA and protein expression was detected in 78% of the thyroid cancer patients but not multiple goiters and follicular adenoma disease patients. It is interesting to note that majority of early-stage (T1) thyroid cancer patients exhibited higher antibody response against SPAG9. Small interfering RNA-mediated knockdown of SPAG9 expression in thyroid cancer cell significantly reduced cellular growth and colony formation.

Conclusions: SPAG9 expression may play a role in cellular growth and thyroid carcinogenesis. These findings support a potential role for SPAG9 as diagnostic biomarker as well as a possible therapeutic target in thyroid cancer treatment.

Objective: The objective of the study was to characterize the activation state of adipose tissue macrophages in human obesity.

Design/Setting: We performed a single-center prospective study.

Participants/Interventions: Paired biopsies of sc and omental adipose tissue were obtained during gastric surgery in 16 premenopausal obese women (aged 41.1 ± 8.6 yr; body mass index 43.8 ± 3.4 kg/m²). Subcutaneous adipose tissue biopsies were obtained 3 months later in obese subjects and in 10 nonobese women (aged 43.3 ± 3.5 yr; body mass index 22.5 ± 0.75 kg/m²). The number of macrophages stained with CD40, CD206, and CD163 surface markers was determined by immunochemistry.

Main Outcomes: The number of CD40⁺ macrophages significantly increased with obesity and in omental vs. sc adipose tissue in obese women. No significant changes in CD163⁺ and CD206⁺ macrophage counts was found with obesity and fat pad anatomical location. Three months after gastric surgery, the ratio of CD40⁺ to CD206⁺ macrophages was 2-fold lower than before surgery in the sc adipose tissue of obese subjects (P < 0.001) due to a concomitant decrease of CD40⁺ and increase of CD206⁺ macrophages counts.

Conclusion: We suggest that the activation state of adipose tissue macrophages is weighted toward M1 over M2 status in obese subjects and switch to a less proinflammatory profile 3 months after gastric bypass.

Patients and Methods: We sequenced the TACR3 gene in a family in which three siblings had nIHH. The novel mutant receptor thus identified was studied in a heterologous expression system using calcium flux as the functional readout.

Results: All affected siblings were homozygous for the His148Leu mutation, in the first extracellular loop of the NKB receptor. The His148Leu mutant receptor exhibited profoundly impaired signaling in response to NKB (EC₅₀ = 3 ± 0.1 nm and >5 µm for wild-type and His148Leu, respectively). The location of the mutation in an extracellular part of the receptor led us also to test whether senktide, a synthetic NKB analog, may retain ability to stimulate the mutant receptor. However, the signaling activity of the His148Leu receptor in response to senktide was also severely impaired (EC₅₀ = 1 ± 1 nm for wild-type and no significant response of His148Leu to 10 µm).

Conclusions: Homozygosity for the TACR3 His148Leu mutation leads to failure of sexual maturation in humans, whereas signaling by the mutant receptor in vitro in response to either NKB or senktide is severely impaired. These observations further strengthen the link between NKB, the NKB receptor, and regulation of human reproductive function.

Objective: The aim of the study was to evaluate the occurrence of nonfunctioning pancreatic neuroendocrine tumors in asymptomatic children with MEN1.

Patients: Twelve asymptomatic Northern European children, aged 6 to 16 yr, who were known to have MEN1 mutations were studied.

Results: Two asymptomatic children, who were aged 12 and 14 yr, had normal plasma fasting gastrointestinal hormones and were found to have nonfunctioning pancreatic neuroendocrine tumors that were more than 2 cm in size. Surgery and immunostaining revealed that the tumors did not have significant expression of gastrointestinal hormones but did contain chromogranin A and synaptophysin, features consistent with those of nonfunctioning pancreatic neuroendocrine tumors. The tumors had a loss of menin expression. The 14 yr old also had primary hyperparathyroidism and a microprolactinoma, and the 12 yr old had a nonfunctioning pituitary microadenoma. Three other children had primary hyperparathyroidism and a microprolactinoma.

Conclusion: Nonfunctioning pancreatic neuroendocrine tumors may occur in asymptomatic children with MEN1 mutations, and screening for such enteropancreatic tumors in MEN1 children should be considered earlier than the age of 20 yr, as is currently recommended by the international guidelines.

Evidence Acquisition: Ovid Medline and PubMed from 1950 to present were searched using the following strategies: [<saliva or salivary>and<cortisol or hydrocortisone>and<Cushing or Cushing’s>] and [<saliva or salivary>and<cortisol or hydrocortisone>and<adrenal insufficiency or hypoadrenalism or hypopituitarism or Addison’s disease>]. The bibliographies of all relevant citations were evaluated for any additional appropriate citations.

Evidence Synthesis: Measurement of an elevated late-night (2300 to 2400 h) salivary cortisol has a greater than 90% sensitivity and specificity for the diagnosis of endogenous Cushing’s syndrome. Late-night salivary cortisol measurements are also useful to monitor patients for remission and/or recurrence after pituitary surgery for Cushing’s disease. Because it is a surrogate for plasma free cortisol, the measurement of salivary cortisol may be useful during an ACTH stimulation test in patients with increased plasma binding protein concentrations due to increased estrogen, or decreased plasma binding protein concentrations during critical illness. Most reference laboratories now offer salivary cortisol testing.

Conclusions: It is expected that the use of the measurement of salivary cortisol will become routine in the evaluation of patients with disorders of the HPA axis.

Objective: To test the hypothesis that the combination of tumors might represent a rare syndrome, similar cases were searched for. Five additional patients with gastric stromal tumor, paraganglioma, and pulmonary chondroma were found, and all were young women. None had a family history of the tumors. The combination of the three tumors was later referred to as the Carney triad.

Features of the Syndrome: Among 77 patients with the syndrome, 85% were women and 15% were men. Onset ranged from 7 to 48 yr (mean, 20 yr). The gastric lesion was usually the presenting tumor (75%), followed by the lung lesion (15%) and the paraganglionic tumor (10%). Twenty percent of the patients had adrenocortical adenoma(s), and 10% had esophageal leiomyoma(s). All the tumors were multifocal. The gastric and paraganglionic tumors metastasized in one third and one tenth of the patients, respectively. The pulmonary tumors were asymptomatic and benign.

Follow-up: At follow-up, 80% of the patients were alive, two thirds with pulmonary chondroma, 25% with metastatic or residual gastric stromal tumor, and 5% with primary or metastatic paraganglioma. Twenty percent of the patients were dead, usually from metastatic gastric stromal tumor, less frequently from metastatic paraganglioma.

Conclusion: The Carney triad is a chronic, persistent, indolent but sometimes fatal disorder of unknown etiology.

Objective: The aim of this study was to conduct a systematic review evaluating effectiveness and risks of T₃ and/or T₄ therapy in these populations.

Data Sources: Electronic databases and reference lists were searched.

Study Selection: Studies with comparable control groups comparing T₃ and/or T₄ therapy to placebo in randomized controlled trials (RCTs) or prospective observational studies were selected.

Data Extraction: Three reviewers performed serial abstraction.

Data Synthesis: During caloric deprivation of obese subjects, T₃ therapy decreased serum TSH and T₄ concentrations. Consistent effects of T₃ or T₄ on weight loss, protein breakdown, metabolic rate, and heart rate could not be established. In euthyroid cardiac patients, T₃ decreased TSH and free T₄ levels, without consistent effects of T₃ or T₄ on heart rate, cardiac output, or systemic vascular resistance. Mortality increased 3.3-fold with T₄ therapy in acute renal failure patients, whereas an effect in cardiac, critically ill, and burn patients could not be established. Equivalence testing indicated that larger RCTs are required to determine whether thyroid hormone therapy alters end-points in obesity or nonthyroidal illnesses.

Limitations: Numbers of usable unique studies were small, numbers of patients in each study were inadequate, end-points were variable, few RCTs were performed, and study quality of non-RCTs was poor.

Conclusions: Available data are inconclusive regarding effectiveness of thyroid hormone therapy in treating obesity or nonthyroidal illnesses, whereas data support that such therapy induces subclinical hyperthyroidism.

Objective: We sought to conduct a systematic review and meta-analysis of randomized controlled trials of DHEA effects on HRQOL in women with adrenal insufficiency.

Data Sources: We searched electronic databases (MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science, CINAHL, and PsycInfo) and reference lists of eligible studies through July 2008.

Study Selection: Eligible trials randomly assigned women with primary or secondary adrenal insufficiency to either DHEA or control and measured the effect of treatment on HRQOL.

Data Extraction: Reviewers working independently and in duplicate assessed the methodological quality of trials and collected data on patient characteristics, interventions, and outcomes.

Data Synthesis: We found 10 eligible trials that measured HRQOL and depression, anxiety, and sexual function. Random-effects meta-analysis showed a small improvement in HRQOL in women treated with DHEA compared with placebo [effect size of 0.21; 95% confidence interval, 0.08 to 0.33; inconsistency (I²) = 32%]. There was a small beneficial effect of DHEA on depression; effects on anxiety and sexual well-being were also small and not statistically significant.

Conclusions: DHEA may improve, in a small and perhaps trivial manner, HRQOL and depression in women with adrenal insufficiency. There was no significant effect of DHEA on anxiety and sexual well-being. The evidence appears insufficient to support the routine use of DHEA in women with adrenal insufficiency.

Objective: We hypothesized that cardiopulmonary fitness would be reduced in youth with T2D in association with insulin resistance (IR) and cardiovascular dysfunction.

Design, Setting, and Participants: We conducted a cross-sectional study at an academic hospital that included 14 adolescents (age range, 12–19 yr) with T2D, 13 equally obese adolescents and 12 lean adolescents similar in age, pubertal stage, and activity level.

Main Outcome Measures: Cardiopulmonary fitness was measured by peak oxygen consumption (VO₂peak) and oxygen uptake kinetics (VO₂kinetics), IR by hyperinsulinemic clamp, cardiac function by echocardiography, vascular function by venous occlusion plethysmography, body composition by dual-energy x-ray absorptiometry, intramyocellular lipid by magnetic resonance spectroscopy, and inflammation by serum markers.

Results: Adolescents with T2D had significantly decreased VO₂peak and insulin sensitivity, and increased soleus intramyocellular lipid, C-reactive protein, and IL-6 compared to obese or lean adolescents. Adolescents with T2D also had significantly prolonged VO₂kinetics, decreased work rate, vascular reactivity, and adiponectin, and increased left ventricular mass and fatty acids compared to lean adolescents. In multivariate linear regression analysis, IR primarily, and fasting free fatty acids and forearm blood flow secondarily, were significant independent predictors of VO₂peak.

Conclusions: Given the strong relationship between decreased cardiopulmonary fitness and increased mortality, these findings in children are especially concerning and represent early signs of impaired cardiac function.

Study Design and Population: Longitudinal study over 2 yr comparing data from 32 AGA vs. 32 SGA children, matched for gender, height, weight, and body mass index at the age of 6 yr.

Main Outcomes: Fasting insulin, dehydroepiandrosterone sulfate (DHEAS), SHBG, high-molecular-weight (HMW) adiponectin, leptin, IGF-I; body composition by absorptiometry; and abdominal fat partitioning by magnetic resonance imaging.

Results: Between 6 and 8 yr, novel AGA-vs.-SGA divergences emerged (higher DHEAS and lower SHBG in SGA; P < 0.001), and some earlier divergences widened further (HMW adiponectin, visceral fat; P < 0.001), whereas others stabilized (fasting insulin, IGF-I). At age 8 yr, the most discerning features of SGA children were a high ratio of visceral over sc fat in the abdominal region (69% of SGA children), HMW hypoadiponectinemia (41%), fasting hyperinsulinemia (34%), and elevated circulating IGF-I levels (31%).

Conclusion: SGA children with spontaneous catch-up growth develop relatively high DHEAS and low SHBG levels and become more often HMW hypoadiponectinemic and viscerally adipose between 6 and 8 yr of age.

Objectives: The aim of the study was to compare the occurrence of worsening or development of TAO in patients who were treated with radioiodine or antithyroid drugs.

Design: We conducted a randomized trial (TT 96) with a follow-up of 4 yr.

Patients, Setting, and Intervention: Patients with a recent diagnosis of Graves’ hyperthyroidism were randomized to treatment with iodine-131 (163 patients) or 18 months of medical treatment (150 patients). Early substitution with T₄ was given in both groups.

Main Outcome Measure: Worsening or development of TAO was significantly more common in the iodine-131 treatment group (63 patients; 38.7%) compared with the medical treatment group (32 patients; 21.3%) (P < 0.001).

Results: The risk for de novo development of TAO was greater in patients treated with iodine-131 (53 patients) than with medical treatment (23 patients). However, worsening of TAO in the 41 patients who had ophthalmopathy already before the start of treatment was not more common in the radioiodine group (10 patients) than in the medical group (nine patients). Smoking was shown to influence the risk of worsening or development of TAO, and smokers treated with radioiodine had the overall highest risk for TAO. However, in the group of smokers, worsening or development of TAO was not significantly associated with the choice of treatment for hyperthyroidism.

Conclusions: Radioiodine treatment is a significant risk factor for development of TAO in Graves’ hyperthyroidism. Smokers run the highest risk for worsening or development of TAO irrespective of treatment modality.

Methods: One hundred pairs of healthy twins aged 8.9 yr (range, 7.2–10.9 yr) had fasting blood samples collected, blood pressure (BP) measured, and anthropometry assessed. All measurements were converted to sd scores (SDS) to adjust for age and sex.

Results: Mean birth weights in both monozygotic and dizygotic twins were –0.90 SDS lower than the UK reference. In postnatal life, 58% of monozygotic twins and 59% of dizygotic twins showed rapid weight gain (a change of more than +0.67 in weight SDS) from birth. Postnatal weight gain was positively associated with sum of skinfolds (r = 0.51; P < 0.0005), fasting insulin levels (r = 0.35; P < 0.0005), systolic BP (r = 0.30; P < 0.0005), and diastolic BP (r = 0.15; P < 0.05) at follow-up. Heritability estimates (additive genetic components) were calculated using variance components models for: birth weight, 44%; postnatal weight gain, 80%; childhood height, 89%; body mass index, 72%; sum of skinfolds, 89%; waist circumference, 74%; fasting insulin, 65%; systolic BP, 33%; and diastolic BP, 29%.

Conclusions: Postnatal weight gain from birth, rather than birth weight, was associated with childhood risk markers for adult metabolic disease. Childhood weight gain was highly heritable, and genetic factors associated with postnatal weight gain are likely to also contribute to risks for adult disease.

Objective: The aim of the study was to establish the prospective relationship between early life androgen exposure and PCOS in adolescence.

Design and Setting: A prospective cohort study was conducted in the general community.

Patients or Other Participants: A total of 2900 pregnant women were recruited at 18 wk gestation. Prenatal androgen exposure was measured from maternal blood samples (at 18 and 34–36 wk) and umbilical cord blood. Timed (d 2–5 menstrual cycle) blood samples were collected, clinical hyperandrogenism was assessed, and transabdominal ultrasound examination of ovarian morphology was performed in 244 unselected girls from the Raine cohort aged 14–17 yr.

Main Outcome Measure(s): We examined the relationship between early life androgen exposure and PCOS in adolescence.

Results: We did not observe a statistically significant relationship between early life androgen exposure and PCOS in adolescence.

Conclusions: This is the first prospective study to evaluate the relationship between prenatal androgen exposure and PCOS in adolescence in normal pregnancy. Our findings do not support the hypothesis that maternal androgens, within the normal range for pregnancy, directly program PCOS in the offspring.

Objective: The aim of the study was to assess the effects of GHR_d3 on baseline height and the first year’s growth response to rhGH treatment in prepubertal GHD and non-GHD children with short stature.

Design: We conducted a systematic review and meta-analysis.

Methods: Fifteen studies reporting the effect of GHR_d3 on growth parameters were included. Principal outcomes were baseline height sd score (SDS) and the weighted average of change in growth velocity ( cm/yr) and height gain ( height SDS) after 1 yr of rhGH.

Results: In GHD, not in non-GHD, baseline height SDS was 0.159 sd higher [95% confidence interval (CI), 0.020, 0.298] in GHR_d3 compared with GHR_wt-wt. In GHR_d3, rhGH therapy resulted in a higher increase in growth velocity (0.521 cm/yr; 95% CI, 0.196, 1.015) and height gain (0.075 sd; 95% CI, 0.007, 0.143) compared with GHR_wt-wt. Meta-regression demonstrated a larger difference between GHR_d3 and GHR_wt-wt in studies using lower rhGH doses and carried out at a higher age, independently of the cause of short stature.

Conclusions: This meta-analysis in prepubertal children with short stature indicates that GHR_d3 is associated with increased baseline height in GHD, but not in non-GHD. Furthermore, GHR_d3 stimulates growth velocity by an additional effect of approximately 0.5 cm during the first year of rhGH treatment, and this effect is more pronounced at lower doses of rhGH and higher age.

Objective: The objective of the study was to evaluate the feasibility, safety, and effectiveness of intrauterine l-thyroxine treatment in a large cohort with nonimmune fetal goitrous hypothyroidism.

Design: This was a retrospective study of 12 prenatally treated fetuses diagnosed between 1991 and 2005 in France.

Methods: During pregnancy, goiter size and thyroid hormone levels were compared before and after prenatal treatment. At birth, clinical, laboratory, and ultrasound data were evaluated.

Results: Prenatal treatment varied widely in terms of l-thyroxine dosage (200–800 µg/injection), number of injections (one to six), and frequency (every 1–4 wk). No adverse events were recorded. During pregnancy, thyroid size decreased in eight of nine cases and amniotic-fluid TSH levels decreased in the six investigated cases, returning to normal in four. However, at birth, all babies had hypothyroidism, indicating that intraamniotic TSH levels did not reliably reflect fetal thyroid function.

Conclusion: Our data confirm the feasibility and safety of intraamniotic l-thyroxine treatment for nonimmune fetal goitrous hypothyroidism. Although goiter size reduction is usually obtained, thyroid hormone status remains deficient at birth. Amniocentesis seems inadequate for monitoring fetal thyroid function. Further studies are needed to determine the optimal management of this disorder.

Objective: We sought to determine the factors that contribute to early changes in carotid IMT in youth with type 2 diabetes mellitus and to identify any predictors of increased carotid IMT.

Methods: Demographic, anthropometric, laboratory data and carotid imaging were obtained in 129 youth of mixed ethnicity, ages 10–23 yr. Associations of carotid IMT outcomes and risk variables were analyzed by regression analysis. Logistic regression was performed to elucidate independent determinants that predict a worse carotid IMT.

Results: Carotid IMT increased with higher glycosylated hemoglobin (HbA1c) levels and longer duration of diabetes. Regression modeling showed that HbA1c and duration of diabetes in the presence of traditional cardiovascular risk factors (male sex, LDL cholesterol, and blood pressure) were independent determinants of carotid IMT. Logistic regression analysis demonstrated that each 1% increase in HbA1c or each year increase in duration of type 2 diabetes mellitus is associated with approximately 30% increased odds of a thicker carotid IMT.

Conclusions: Poorer glycemic control and longer disease duration have independent adverse effects on carotid IMT in youth with type 2 diabetes mellitus. These adverse effects appear to be more prominent in males. Developing effective strategies to improve blood glucose control in youth with type 2 diabetes mellitus is essential to prevent or limit the development and progression of atherosclerotic cardiovascular disease.

Outcome Measures: Primary measures were fasting GH 2.5 µg/liter or less and IGF-I normalized for age and tumor shrinkage. Secondary measures were control of hypertension, arrhythmias, left ventricular hypertrophy, diastolic and systolic dysfunction, and change in lipid and glucose profile.

Patients: Patients included 45 de novo patients (18 women and 27 men, aged 20–82 yr); 28 were treated with octreotide-long-acting release and 17 with lanreotide.

Results: GH was controlled in 100% and IGF-I levels in 97.8%, tumor shrinkage was 74.9 ± 22.1 and 78.2±14.5%, in the octreotide-long-acting release and lanreotide groups, respectively. There was a significant improvement in the prevalence of hypertension (from 46.7 to 22.2%, P = 0.027), arrhythmias (from 17.8% to zero, P = 0.01), left ventricular hypertrophy (from 82.2 to 42.2%, P < 0.0001), diastolic dysfunction (from 60.0 to 15.6%, P < 0.0001), systolic dysfunction (from 40.0 to 4.4%, P < 0.0001), and hypertriglyceridemia (from 40.0 to 4.4%, P < 0.0001). The prevalence of impaired glucose tolerance (IGT; from 28.9 to 20.0%. P = 0.46) and diabetes mellitus (from 22.4 to 31.1%, P = 0.64) did not change.

Conclusions: In patients with severe comorbidities and those who refuse surgery, 5 yr of exclusive SSA therapy induce successful control of GH and IGF-I; tumor shrinkage (by median 80%), and improvement of hypertension, cardiac performance; and dyslipidemia. No patient was withdrawn from treatment because of side effects, and glucose tolerance was stable. We suggest that first-line SSA treatment may be safely continued in patients with acromegaly, according to an individual patient’s indications and preferences.

Objective: The objective of the study was to compare the effectiveness of methimazole (MMI) or prednisone (GLU) in type 2 AIT patients who had a short cure time according to a published predictive model.

Design: This was a matched retrospective cohort study.

Setting: The study was conducted at a university center.

Patients: Forty-two untreated type 2 AIT patients with a predicted cure time ≤40 d were divided into two groups (MMI and GLU groups). After matching for the predicted cure time, patients in the GLU group were selected in a 1:1 ratio to patients in the MMI group.

Intervention: Patients were treated with GLU or MMI for 40 d. Patients still thyrotoxic after 40 d continued glucocorticoids if in the GLU group or were switched to prednisone (MMI-GLU group) if in the MMI group.

Main Outcome Measure: Time and rate of cure (healing) at 40 d were measured.

Results: Patients still thyrotoxic after 40 d were 23.8 ± 9.3% in the GLU group and 85.7 ± 7.6% in the MMI group (P = 0.000). The GLU and MMI-GLU groups did not significantly differ in the nonhealing rate at 40 d (P = 0.730). When patients in the MMI group were treated with glucocorticoids, 94.1% patients achieved euthyroidism within 40 d. However, the global median cure time (MMI period + prednisone period) was longer (60 d, 95% confidence interval 53.5–66.5 d) in the MMI-GLU group than the GLU group (21 d, 95% confidence interval 15.1–26.9 d).

Conclusions: Glucocorticoids are the first-line treatment in type 2 AIT, whereas thionamides play no role in this destructive thyroiditis.

Objectives: The aim of the study was to evaluate BMD in children with PWS and to study the effects of GH treatment.

Design: We conducted a randomized controlled GH trial. Forty-six prepubertal children were randomized into either a GH-treated group (1.0 mg/m² · d) or a control group for 2 yr. At start, 6, 12, and 24 months of study, total body and lumbar spine BMD were measured by dual-energy x-ray absorptiometry, and lumbar spine bone mineral apparent density (BMAD) was calculated.

Results: Baseline total body and lumbar spine BMD sd score (SDS) were normal [mean (sd), –0.2 SDS (1.1) and –0.4 SDS (1.2), respectively]. BMADSDS, which corrects for short stature, was also normal [mean (sd), 0.40 SDS (1.1)]. Total body BMDSDS decreased during the first 6 months of GH (P < 0.0001), but increased during the second year of treatment. After 24 months of study, total body and lumbar spine BMDSDS, and the BMADSDS did not significantly differ between GH-treated children and randomized controls (P = 0.30, P = 0.44, and P = 0.47, respectively). Results were similar when corrected for body mass index SDS. Repeated measurements analysis showed a significant positive association between IGF-I SDS and total body and lumbar spine BMDSDS, but not with BMADSDS.

Conclusions: Our results show that prepubertal children with PWS have a normal BMD. GH treatment had no effect on BMD, except for a temporary decrease of total body BMDSDS in the first 6 months.

Design: We conducted a randomized, open-label trial.

Patients and Interventions: Postmenopausal women with osteoporosis on alendronate or raloxifene for at least 18 months added teriparatide (Add groups) or switched to teriparatide (Switch groups) for 18 months.

Main Outcome Measures: We measured bone turnover markers (BTM) and bone mineral density (BMD).

Results: In the alendronate stratum, increases in BTM were smaller in the Add vs. Switch group [6-month PINP (64 vs. 401%); bone ALP (15 vs. 71%); βCTX (27 vs. 250%); all P < 0.001]. However, at 6 months, total hip BMD increased more in the Add vs. Switch group (1.4 vs. –0.8%; P = 0.002). In the Add vs. Switch group, 18-month BMD increments were higher in lumbar spine (8.4 vs. 4.8%; P = 0.003) and total hip (3.2 vs. 0.9%; P = 0.02), but not in femoral neck (2.7 vs. 2.3%; P = 0.75). In the raloxifene stratum, increases in BTM were also smaller in the Add vs. Switch group [6-month PINP (131 vs. 259%; P < 0.001), bone ALP (31 vs. 44%; P = 0.035), and βCTX (67 vs. 144%; P = 0.001)]. At 6 months, total hip BMD increase was greater in the Add vs. Switch group (1.8 vs. 0.5%; P = 0.028). At 18 months, increases in lumbar spine (9.2 vs. 8.1%), total hip (2.8 vs. 1.8%), and femoral neck (3.8 vs. 2.2%) were not significantly different between groups.

Conclusions: In women with osteoporosis treated with antiresorptives, greater bone turnover increases were achieved by switching to teriparatide, whereas greater BMD increases were achieved by adding teriparatide.

Objective: The aim of the study was to evaluate the differential effects of obesity and body fat distribution on glomerular filtration.

Design and Setting: We conducted a cross-sectional study of the Japanese-American community in Seattle, Washington.

Participants: We studied a representative sample of second-generation Japanese-American men and women with normal glucose tolerance (n = 124) and impaired glucose metabolism (impaired fasting glucose and/or impaired glucose tolerance) (n = 144) residing in King County, Washington.

Main Outcome Measures: Glomerular filtration rate was estimated by 24-h urinary creatinine clearance, body size by body mass index (BMI), and intra-abdominal fat (IAF), sc fat (SCF), and lean thigh areas by CT scan.

Results: Creatinine clearance was positively correlated with BMI (r = 0.429; P < 0.001), fasting glucose (r = 0.198; P = 0.001), and insulin levels (r = 0.125; P = 0.042), as well as IAF (r = 0.239; P < 0.001), SCF (r = 0.281; P < 0.001), and lean thigh (r = 0.353; P < 0.001) areas. The association between creatinine clearance and BMI remained significant after adjustments for IAF, SCF areas, and fasting insulin levels (r = 0.337; P < 0.001); whereas IAF and SCF areas were not independently associated with creatinine clearance after adjusting for BMI. Creatinine clearance increased with increasing BMI after adjusting for fasting insulin, fasting glucose, IAF and SCF areas in subjects with normal glucose tolerance (r = 0.432; P < 0.001) and impaired glucose metabolism (r = 0.471; P < 0.001).

Conclusions: BMI rather than body fat distribution is an independent determinant of creatinine clearance in nondiabetic subjects. Lean body mass, rather than adiposity, may explain this association.

Objective: The aim of the study was to assess declarative memory in overt and subclinical (SCH) hypothyroid patients before and after l-T₄ (LT4) replacement and in matched normal subjects.

Design and Setting: A prospective, open-labeled interventional study was conducted at a teaching hospital.

Participants and Intervention: Hypothyroid (n = 21) and SCH (n = 17) patients underwent neuropsychological tests at baseline and 3 and 6 months after LT4 replacement. Normal subjects were studied at the same time-points.

Main Outcome: Tests of spatial, verbal, associative, and working memory; attention; and response inhibition and the Hospital Anxiety and Depression Scale were administered.

Results: Baseline deficits in spatial, associative, and verbal memory, which rely upon the integrity of the hippocampal and frontal areas, were identified in patients with overt hypothyroidism. Spatial and verbal memory were impaired in SCH patients (P < 0.05). TSH levels correlated negatively (P < 0.05) with these deficits. After LT4 replacement, verbal memory normalized. Spatial memory normalized in the SCH group but remained impaired in the hypothyroid group. Associative memory deficits persisted in the overt hypothyroid group. Hospital Anxiety and Depression Scale scores did not correlate with cognitive function. Measures of attention and response inhibition did not differ from control subjects.

Conclusion: Cognitive impairment occurs in SCH and more markedly in overt hypothyroidism. These impairments appear predominantly mnemonic in nature, suggesting that the etiology is not indicative of general cognitive slowing. We propose that these deficits may reflect an underlying disruption of normal hippocampal function and/or connectivity.

Methods: In this randomized-order, crossover, blinded trial in 11 healthy postmenopausal women, we compared four commercial sources of isoflavones from soy cotyledon, soy germ, kudzu, and red clover and a positive control of oral 1 mg estradiol combined with 2.5 mg medroxyprogesterone or 5 mg/d oral risedronate (Actonel®) for their antiresorptive effects on bone using novel ⁴¹Ca methodology.

Results: Risedronate and estrogen plus progesterone decreased net bone resorption measured by urinary ⁴¹Ca by 22 and 24%, respectively (P < 0.0001). Despite serum isoflavone profiles indicating bioavailability of the phytoestrogens, only soy isoflavones from the cotyledon and germ significantly decreased net bone resorption by 9% (P = 0.0002) and 5% (P = 0.03), respectively. Calcium absorption and biochemical markers of bone turnover were not influenced by interventions.

Conclusions: Dietary supplements containing genistein-like isoflavones demonstrated a significant but modest ability to suppress net bone resorption in postmenopausal women at the doses supplied in this study over a 50-d intervention period.

Objective: The aim of this study was to assess cross-sectional and longitudinal associations of estradiol, bioavailable estradiol, testosterone, bioavailable testosterone (bioT), and SHBG with frailty status.

Design and Setting: The Osteoporotic Fractures in Men (MrOS) study was conducted at six U.S. clinical centers.

Participants: A total of 1469 community-dwelling men at least 65 yr old with baseline data participated; 1245 men had frailty status reassessed 4.1 yr later.

Main Outcome Measure: Proportional odds models estimated the likelihood of greater frailty status. Frail men had at least three of the following: weakness, slowness, low activity, exhaustion, and shrinking/sarcopenia; intermediate men had one or two criteria; and robust men had none. At follow-up, death was included as an additional ordinal outcome. Sex hormones were assayed by spectrometry/chromatographic methods.

Results: In cross-sectional analyses, men in the lowest quartile of bioT had 1.39-fold (95% confidence interval, 1.02, 1.91) increased odds of greater frailty status compared to men in the highest quartile after adjustment for covariates including age, body size, health status, and medical conditions. In age-adjusted longitudinal analyses, men in the lowest quartile of bioT had 1.51-fold (95% confidence interval, 1.10, 2.07) increased odds of greater frailty status 4.1 yr later. This association was largely attenuated by adjustment for covariates. No other hormones were associated in a cross-sectional or longitudinal manner with frailty status after adjustment.

Conclusions: Low levels of bioT were independently associated with worse baseline frailty status. Frailty status should be considered as an outcome in trials of testosterone supplementation.

Design: Serum concentrations of antimüllerian hormone (AMH) have been determined in 26 women with POI due to steroidogenic cell autoimmunity (SCA-POI), 66 with nonautoimmune idiopathic POI (iPOI), 40 postmenopausal women (PMW), and 44 healthy fertile women (HW). SCA-POI was diagnosed according to presence of steroidogenic enzyme autoantibodies (17-hydroxylase, side chain cleavage, and 21-hydroxylase autoantibodies).

Results: AMH concentrations were significantly higher in women with SCA-POI than women with iPOI (P = 0.018) or PMW (P = 0.03) but significantly lower than HW (P < 0.0001). AMH was detected in 11 of 26 women with SCA-POI (42%) and seven of 66 with iPOI (11%) (P = 0.002). Serum concentrations above the fifth percentile of the normal range (0.6 ng/ml) were detected in nine of 26 women with SCA-POI (35%) and four of 66 with iPOI (6%) (P = 0.001). Eight of 12 women with SCA-POI with less than 5 yr (67%) and one of 14 with longer disease duration (7%) had AMH concentrations within the normal range (P = 0.003). AMH concentrations correlated inversely with disease duration in women with SCA-POI (rho = –0.563, P = 0.003) but not women with iPOI. AMH correlated inversely with FSH serum concentrations in HW (rho = –0.584, P < 0.001) but not PMW or women with POI.

Conclusions: Two thirds of women with recent-onset SCA-POI had normal AMH concentrations. Women with SCA-POI, differently from those with iPOI, present a preserved ovarian follicle pool for several years after diagnosis of ovarian insufficiency.

Methods: Nondiabetic subjects (n = 712) were recruited in Toronto and London, Ontario, Canada, between 2004 and 2006, based on the presence of one or more risk factors for type 2 diabetes mellitus including obesity, hypertension, a family history of diabetes, and/or a history of gestational diabetes. Fasting blood samples were collected and oral glucose tolerance tests administered, with additional samples for glucose and insulin drawn at 30 and 120 min. Measures of IR included the homeostasis model assessment (HOMA-IR) and Matsuda’s insulin sensitivity index, whereas measures of β-cell dysfunction included the insulinogenic index divided by HOMA-IR as well as the insulin secretion-sensitivity index-2. Associations of hematological parameters with IR and β-cell dysfunction were assessed using multiple linear regression and analysis of covariance with adjustments for age, gender, ethnicity, smoking, cardiovascular disease, systolic and diastolic blood pressure, and waist circumference.

Results: HOMA-IR increased across quartiles of HCT, Hgb, RBC, and white blood cell count after adjustment for age, gender, ethnicity, and smoking (all P (trend) <0.0001). Similarly, there was a strong stepwise decrease in the Matsuda’s insulin sensitivity index across increasing quartiles of these hematological measures (all P (trend) <0.0001). The associations remained significant after further adjustment for previous cardiovascular disease, blood pressure, and waist circumference (all P (trend) <0.0001). Similarly, there was a strong pattern of decreasing β-cell function across increasing quartiles of all hematological patterns (all P (trend) <0.0001). The findings for HCT, Hgb, and RBC were attenuated slightly after full multivariate adjustment, although the trend across quartiles remained highly significant.

Conclusion: These findings suggest that standard, clinically relevant hematological variables may be related to the underlying pathophysiological changes associated with type 2 diabetes mellitus.

Objective: The aim of the study was to assess GH and/or sex steroid administration effects on serum glucose, insulin, insulin sensitivity, and lipids in older individuals.

Design: A double-masked, 2 x 2 factorial, placebo-controlled, double-dummy design was used for the study.

Intervention: GH and/or sex steroid [transdermal estradiol plus oral medroxyprogesterone acetate in women (HRT); testosterone enanthate (T) in men] were administered for 6 months.

Participants: Healthy, community-dwelling women (n = 57) and men (n = 74) ages 65–88 yr (mean, 72 yr) participated in the study.

Main Outcome Measures: We measured serum glucose, insulin, and insulin sensitivity [quantitative insulin sensitivity check index (QUICKI) and insulin sensitivity index (ISI)] before and during an oral glucose tolerance test and lipid profiles.

Results: In women, GH did not alter oral glucose tolerance test 120 min or 2-h area under the curve (AUC) glucose values, but it increased 120 min insulin and AUC insulin. There were no significant effects of HRT or GH+HRT. ISI and QUICKI decreased after GH. In men, GH increased 120 min and AUC glucose and insulin AUC. GH+T increased 120 min glucose and glucose and insulin AUCs. T alone did not affect glucose or insulin. ISI decreased after GH and GH+T, whereas QUICKI decreased after GH. GH in women and men and GH+T in men decreased QUICKI by 4 wk. In women, HRT decreased total cholesterol and low-density lipoprotein (LDL)-cholesterol, and GH decreased LDL-cholesterol. In men, total cholesterol decreased after T and GH+T. LDL-cholesterol decreased after GH and GH+T. GH increased serum triglycerides.

Conclusions: GH administration to healthy older individuals for 6 months increased insulin resistance with moderately beneficial effects on lipids.

Objective: The primary aim of this study was to examine the effects of omega-3 fatty acids on liver fat in PCOS. The secondary aim was to assess their effects on traditional cardiovascular risk factors.

Design and Setting: We conducted a randomized, crossover study at a tertiary cardiovascular research center.

Subjects: Twenty-five women with PCOS (mean age, 32.7 yr; mean body mass index, 34.8 kg/m²) participated in the study.

Intervention: We compared 4g/d of omega-3 fatty acids with placebo over 8 wk.

Main Outcome Measures: The primary outcome measure was hepatic fat content quantified using proton magnetic resonance spectroscopy. Secondary outcome measures included fasting lipids and blood pressure.

Results: Omega-3 fatty acids significantly decreased liver fat content compared with placebo [10.2 (1.1) vs. 8.4 (0.9)%; P = 0.022]. There was also a reduction in triglycerides [1.19 (1.03–1.47) vs. 1.02 (0.93–1.18) mmol/liter; P = 0.002], systolic blood pressure [124.1 (12.1) vs. 122.3 (14.5) mm Hg; P = 0.018], and diastolic blood pressure [73.2 (8.4) vs. 69.7 (8.3) mm Hg; P = 0.005] with omega-3 fatty acids compared with placebo. Omega-3 fatty acids particularly decreased hepatic fat in women with hepatic steatosis, defined as liver fat percentage greater than 5% [18.2 (11.1) vs. 14.8 (9.3)%; P = 0.03].

Conclusions: Omega-3 fatty acid supplementation has a beneficial effect on liver fat content and other cardiovascular risk factors in women with PCOS, including those with hepatic steatosis. Whether this translates into a reduction in cardiometabolic events warrants further study.

Objective: This study evaluated carotid structure and function in PHPT patients compared with population-based controls.

Design: This is a case-control study.

Setting: The study was conducted in a university hospital metabolic bone disease unit.

Participants: Forty-nine men and women with PHPT and 991 controls without PHPT were studied.

Outcome Measures: We measured carotid intima-media thickness (IMT), carotid plaque presence and thickness, and carotid stiffness, strain, and distensibility.

Results: IMT, carotid plaque thickness, carotid stiffness, and distensibility were abnormal in PHPT patients, and IMT was higher in patients than controls (0.959 vs. 0.907 mm, P < 0.0001). In PHPT, PTH levels, but not calcium concentration, predicted carotid stiffness (P = 0.04), strain (P = 0.06), and distensibility (P = 0.07). Patients with increased carotid stiffness had significantly higher PTH levels than did those with normal stiffness (141 ± 48 vs. 94.9 ± 44 pg/ml, P = 0.002), and odds of abnormal stiffness increased 1.91 (confidence interval = 1.09–3.35; P = 0.024) for every 10 pg/ml increase in PTH, adjusted for age, creatinine, and albumin-corrected calcium.

Conclusions: Mild PHPT is associated with subclinical carotid vascular manifestations. IMT, a predictor of cardiovascular outcomes, is increased. Measures of carotid stiffness are associated with extent of PTH elevation, suggesting that those with more severe PHPT may have impaired vascular compliance and that PTH, rather than calcium, is the mediator.

Objective: The aim of the study was to evaluate the diagnostic performance of screening tests for Cushing’s syndrome in overweight and obese subjects with at least two other features of the disorder.

Design and Setting: We conducted a cross-sectional prospective study.

Subjects and Methods: A total of 369 subjects (73% female) completed two or three tests: a 24-h urine cortisol, and/or late-night salivary cortisol, and/or 1 mg dexamethasone suppression test (DST). If any result was abnormal [based on laboratory reference range or cortisol after DST ≥1.8 µg/dl (50 nmol/liter)], tests were repeated and/or a dexamethasone-CRH test was performed. Subjects with abnormal DST results and a low dexamethasone level were asked to repeat the test with 2 mg of dexamethasone.

Results: In addition to obesity, subjects had a mean of five to six features of Cushing’s syndrome. None was found to have Cushing’s syndrome. Test specificities to exclude Cushing’s syndrome for subjects who completed three tests were: urine cortisol, 96% [95% confidence interval (CI), 93–98%]; DST, 90% (95% CI, 87–93%); salivary cortisol, 84% by RIA (95% CI, 79–89%) and 92% by liquid chromatography-tandem mass spectrometry (95% CI, 88–95%). The combined specificity (both tests normal) for all combinations of two tests was 84 to 90%, with overlapping CIs.

Conclusion: These data do not support widespread screening of overweight and obese subjects for Cushing’s syndrome; test results for such patients may be falsely abnormal.

Objective: A locus on chromosome 8 has previously been linked to the disease in three families, but no underlying gene defect has to date been identified.

Design: The study design comprised single-nucleotide polymorphism genotyping and mutation detection.

Setting: The study was conducted at secondary and tertiary referral centers.

Patients: Eighty probands from families referred for investigation of the genetic cause of FGD participated in the study.

Interventions: There were no interventions.

Results: Analysis by single-nucleotide polymorphism array of the genotype of one individual with FGD previously linked to chromosome 8 revealed a large region of homozygosity encompassing the steroidogenic acute regulatory protein gene, STAR. We identified homozygous STAR mutations in this patient and his affected siblings. Screening of our total FGD patient cohort revealed homozygous STAR mutations in a further nine individuals from four other families.

Conclusions: Mutations in STAR usually cause lipoid congenital adrenal hyperplasia, a disorder characterized by both gonadal and adrenal steroid deficiency. Our results demonstrate that certain mutations in STAR (R192C and the previously reported R188C) can present with a phenotype indistinguishable from that seen in FGD.

Objective: The aim of the study was to examine the prevalence pattern and to identify clinical and laboratory markers associated with the risk for NAFLD.

Design: This was a cross-sectional study.

Setting: The study setting was a rehabilitation clinic.

Study Participants: A total of 532 obese subjects (291 girls) aged 8–19 yr participated in the study.

Main Measurements: Steatosis hepatis and visceral fat mass were determined by ultrasound. Laboratory tests included serum lipids, adiponectin, high-sensitivity C-reactive protein, sex steroids, and an oral glucose tolerance test.

Results: Prevalence of hepatic steatosis was significantly higher in boys (41.1%) than in girls (17.2%) and was highest in postpubertal boys (51.2%) and lowest in postpubertal girls (12.2%). Severity of steatosis was associated with increased visceral fat mass, insulin resistance, lower adiponectin levels, and higher blood pressure. Three factors were extracted from the panel of investigated parameters by principal component analysis. Logistic regression analysis revealed significant associations of simple steatosis with the "insulin resistance and visceral fat" factor and the "body fat distribution and inflammation" factor in both genders and additionally with the "steroid hormones" factor in girls. Risk for steatosis hepatis with concomitantly elevated ALT was associated only with "insulin resistance and visceral fat" in girls and with all three factors in boys.

Conclusion: Our results suggest significant associations of NAFLD with markers of visceral obesity and insulin resistance in both genders and gender-specific associations with parameters of body fat distribution and sex steroids.

Objective: The aim of the study was to determine an optimal range for hydrocortisone dosing during puberty in children with classical CAH who were exclusively treated with hydrocortisone.

Methods: The effects of glucocorticoid treatment for classical CAH were retrospectively analyzed in 92 patients (57 females). Growth pattern, final height (FH), and mean daily hydrocortisone dose were recorded.

Results: Pubertal growth was significantly reduced in all patients: salt-wasting (SW) females, 13.8 ± 7.4 cm; simple virilizing (SV) females, 13.1 ± 6.2 cm; vs. reference, 20.3 ± 6.8 cm (P < 0.05); and SW males, 17.7 ± 6.7 cm; SV males, 16.2 ± 5.7 cm; vs. reference, 28.2 ± 8.2 cm (P < 0.05). Decreased pubertal growth resulted in FH at the lower limit of genetic potential (corrected FH in SW females, –0.6 ± 0.9; SV females, –0.3 ± 0.9; SW males, –0.8 ± 0.8; and SV males, –1.0 ± 1.0). During puberty, mean daily hydrocortisone dose was 17.2 ± 3.4 mg/m² in females (SW, 17.0 ± 3.3; SV, 17.4 ± 3.5) and 17.9 ± 2.5 mg/m² in males (SW, 17.4 ± 2.0; SV, 18.7 ± 3.1). In a logistic regression model, a significant correlation between hydrocortisone dose and FH was found (P < 0.01), and the positive predictive value for short stature rose from below 30% to above 60% when hydrocortisone dose exceeded 17 mg/m².

Conclusion: With conventional hydrocortisone treatment, pubertal growth is significantly reduced in both sexes, resulting in a FH at the lower limit of genetic potential. These deleterious effects on pubertal growth can be reduced if hydrocortisone does not exceed 17 mg/m².

Objectives: The aim of the study was to evaluate adiponectin and visfatin in acromegaly, compared to control subjects, and to analyze their relationship with body composition and bone markers.

Methods: Bone markers [osteocalcin, total amino-terminal propeptide of type 1 procollagen (total P1NP), carboxy-terminal telopeptide (β-Crosslaps)], body composition (by dual-energy x-ray absorptiometry), adiponectin (by ELISA), and visfatin (by immunoanalysis)] were evaluated in 60 acromegalic patients (24 males and 36 females) and in 105 age- and gender-matched healthy controls (33 males and 72 females). Acromegalic patients were classified as controlled, with normal IGF-I and nadir GH no greater than 1 µg/liter (n = 41), or active (n = 19).

Results: Acromegalic patients had lower adiponectin (P < 0.01), more lean body mass (P < 0.01), more total body mass (P < 0.01), higher bone formation markers (osteocalcin and total P1NP, P < 0.05 and P < 0.01, respectively), but less bone resorption markers (β-Crosslaps, P < 0.001) than controls. No differences in visfatin and BMD were found between patients and controls. Adiponectin correlated negatively with BMD (r = –0.374; P < 0.05) and lean mass (r = –0.301; P < 0.05) and positively with age (r = 0.341; P < 0.001) in acromegaly. Visfatin correlated negatively with BMD (r = –0.359; P < 0.05). BMD was the predictor for adiponectin and visfatin.

Conclusions: Acromegalic patients present hypoadiponectinemia and a favorable bone marker profile. Adiponectin and visfatin could be a link between fat mass and bone in acromegaly.

Objective: The aim of the study was to identify the GATA3 mutation in a HDR patient and determine its functional consequences.

Patient and Design: A patient with HDR was studied after approval from the local ethical committee. Leukocyte DNA was used with GATA3-specific primers for PCR amplification, and the DNA sequences of the PCR products were determined. Wild-type and mutant GATA3 constructs were transfected into COS-7 cell, and their functions were assessed by Western blot analysis, immunocytochemistry, EMSAs, luciferase reporter assays, and three-dimensional modeling.

Results: A novel missense mutation, Thr272Ile, in zinc finger 1 (ZnF1) of GATA3 was identified. Western blot analysis and immunofluorescence revealed that the mutation did not affect nuclear localization of GATA3. However, EMSAs showed it to reduce DNA binding affinity, but not stability, and yeast two-hybrid assays demonstrated that the mutant GATA3 resulted in a loss of interaction with ZnF1 and ZnF6 of the cofactor FOG2. The mutant GATA3 significantly reduced luciferase reporter activity by more than 65% (P < 0.001), and three-dimensional modeling indicated that the functional abnormalities may be due to a loss of Thr272 polar side chain interaction with Leu268.

Conclusions: A novel missense HDR-associated GATA3 mutation, Thr272Ile, has been identified and shown to result in reduced DNA binding, a partial loss of FOG2 interaction, and a decrease in gene transcription.

Objective: The study objective was to determine the effect of the timing of levothyroxine administration in relationship to food on serum thyrotropin levels.

Design: Participants were randomized to one of six sequences, each consisting of three 8-wk regimens in a three-period crossover design. These regimens were in a fasting state, at bedtime, and with breakfast. The concentrations of TSH, free T₄, and total T₃ during each of the three timing regimens were documented. The primary outcome was the difference between serum TSH concentrations under fasting conditions compared with concentrations during the other 8-wk regimens.

Setting: The study was conducted in an academic medical center.

Participants: Study participants were receiving levothyroxine for treatment of hypothyroidism or thyroid cancer.

Results: Sixty-five patients completed the study. The mean thyrotropin concentration was 1.06 ± 1.23 mIU/liter when levothyroxine was administered in the fasting state. When levothyroxine was taken with breakfast, the serum thyrotropin concentration was significantly higher (2.93 ± 3.29 mIU/liter). When levothyroxine was taken at bedtime, the serum TSH concentration was also significantly higher (2.19 ± 2.66 mIU/liter).

Conclusion: Nonfasting regimens of levothyroxine administration are associated with higher and more variable serum TSH concentrations. If a specific serum TSH goal is desired, thereby avoiding iatrogenic subclinical thyroid disease, then fasting ingestion of levothyroxine ensures that TSH concentrations remain within the narrowest target range.

Patient: We describe a very lean boy who has intrauterine growth restriction and progressive postnatal growth failure associated with normal hearing, microcephaly, and mild intellectual impairment. He had markedly reduced concentrations of IGF-I, with IGFBP-3 and ALS serum levels in the upper normal range or above. IGF-I serum concentrations differed according to the immunoassay used. A higher than average GH dose was required for catch-up growth. Given the mismatch between IGF-I and IGFBP-3 levels, we sequenced his IGF1 gene.

Result: We identified a homozygous missense IGF1 mutation. This causes the replacement of a highly conserved amino acid (arginine 36) by a glutamine (R36Q) in the C domain of the predicted peptide. We showed that the abnormal IGF-I peptide has reduced mitogenic activity and partial loss of binding to its receptor IGF-1R. The patient’s IGF-I level was undetectable in a highly specific monoclonal assay but elevated in a polyclonal assay.

Conclusion: This first report of mild deficiency of IGF-I activity demonstrates that the integrity of IGF-I signaling is important for normal growth and brain development. Molecular defects leading to partial loss of IGF-I activity may not be uncommon in patients born small for gestational age. The characterization of this complex phenotype and identification of such molecular defects have therapeutic implications, particularly now that, in addition to GH, recombinant IGF-I is available for clinical use.

Objective: The objective of the study was to investigate the sensitivity of 6-[F-18]fluoro-l-dihydroxyphenylalanine positron emission tomography (¹⁸F-DOPA PET), compared with ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG) scintigraphy and computer tomography (CT)/magnetic resonance imaging (MRI) for tumor localization in patients with catecholamine excess.

Design and Setting: All consecutive patients with catecholamine excess visiting the University Medical Center Groningen, Groningen, The Netherlands, between March 2003 and January 2008 were eligible.

Patients: Forty-eight patients were included. The final diagnosis was pheochromocytoma in 40, adrenal hyperplasia in two, paraganglioma in two, ganglioneuroma in one, and unknown in three.

Main Outcome Measures: Sensitivities and discordancy between ¹⁸F-DOPA PET, ¹²³I-MIBG, and CT or MRI were analyzed for individual patients and lesions. Metanephrines and 3-methoxytyramine in plasma and urine and uptake of ¹⁸F-DOPA with PET were measured to determine the whole-body metabolic burden and correlated with biochemical tumor activity. The gold standard was a composite reference standard.

Results: ¹⁸F-DOPA PET showed lesions in 43 patients, ¹²³I-MIBG in 31, and CT/MRI in 32. Patient-based sensitivity for ¹⁸F-DOPA PET, ¹²³I-MIBG, and CT/MRI was 90, 65, and 67% (P < 0.01 for ¹⁸F-DOPA PET vs. both ¹²³I-MIBG and CT/MRI, P = 1.0 ¹²³I-MIBG vs. CT/MRI). Lesion-based sensitivities were 73, 48, and 44% (P < 0.001 for ¹⁸F-DOPA PET vs. both ¹²³I-MIBG and CT/MRI, P = 0.51 ¹²³I-MIBG vs. CT/MRI). The combination of ¹⁸F-DOPA PET with CT/MRI was superior to ¹²³I-MIBG with CT/MRI (93 vs. 76%, P < 0.001). Whole-body metabolic burden measured with ¹⁸F-DOPA PET correlated with plasma normetanephrine (r = 0.82), urinary normetanephrine (r = 0.84), and metanephrine (r = 0.57).

Conclusion: To localize tumors causing catecholamine excess, ¹⁸F-DOPA PET is superior to ¹²³I-MIBG scintigraphy and CT/MRI.

Objective: The objective of the study was to evaluate whether GH/IGF-I excess might influence BC response to chemotherapy.

Design: We evaluated GH and IGF-I effects on cell proliferation of a BC cell line, MCF7 cells, in the presence of doxorubicin (Doxo), frequently used in BC chemotherapy, and the possible mechanisms involved.

Results: GH and IGF-I induce MCF7 cell growth in serum-free conditions and protect the cells from the cytotoxic effects of Doxo. GH effects are direct and not mediated by IGF-I because they are apparent also in the presence of an IGF-I receptor blocking antibody and disappear in the presence of the GH antagonist pegvisomant. The expression of the MDR1 gene, involved in resistance to chemotherapeutic drugs, was not induced by GH. In addition, c-fos transduction was reduced by Doxo, which prevented GH stimulatory effects. Pegvisomant inhibited basal and GH-induced c-fos promoter transcriptional activity. Autocrine GH action is ruled out by the lack of endogenous GH expression in this MCF7 cell strain.

Conclusions: These data indicate that GH can directly induce resistance to chemotherapeutic drugs with a mechanism that might involve GH-induced early gene transcription and support the hypothesis that GH excess can hamper BC treatment, possibly resulting in an increased mortality.

Objective: The aim of our study was the identification of mutations in sporadic patients with a IGHD-IB phenotype.

Subjects and Methods: The GHRHR gene was systematically screened by DHPLC in 134 IGHD patients with no family history of the disorder or declared parental consanguinity.

Results: We identified a novel variation, Val10Gly, within the signal peptide at the heterozygous state in three patients and in one of 1084 controls (P = 0.004), suggesting that it might contribute to IGHD. The functional analysis showed that the signal peptide is not cleaved from the mutant GHRHR, which in turn is not translocated to the cellular surface, demonstrating that 10Gly drastically affects the receptor correct processing. Because 10Gly was also present in normal-stature relatives of the patients as well as in a control, it is likely that it exerts its effects in the context of other genetic and environmental susceptibility factors.

Conclusion: At difference from previous papers reporting GHRHR mutations in familial cases with a clear recessive mode of inheritance, our study was conducted on a large sample of sporadic patients and allowed to discover a novel mechanism of the disease caused by a recurrent dominant mutation in the GHRHR signal peptide associated with incomplete penetrance.

Objective: The aim of this study was to characterize rhTSH clinical safety and peak TSH response in DTC patients 18 yr old or younger.

Design and Setting: We conducted a retrospective study involving 23 tertiary referral centers in 12 European, Asian, and Oceanian countries.

Patients: One hundred DTC patients (69% female, 31% male, 84% papillary, 61% N1, 18% M1) ages 4.9–18 yr at first rhTSH administration were studied.

Interventions: A total of 181 rhTSH courses were administered (range, one to eight per patient; 42% of patients received two or more courses), 92% using the approved adult regimen (one 0.9 mg im injection daily on two consecutive days), 34% including thyroid hormone withdrawal for less than 7 d ("mini-THW").

Main Outcome Measures: Clinical adverse event (AE) incidence, type, and severity, and peak post-rhTSH serum TSH concentrations were assessed.

Results: No clinical AEs occurred in 88% of rhTSH courses. Most common clinical AEs were nausea (5% of courses) and vomiting (3%). Multiple or severe AEs were rare (0.6% and 2.8% of courses, respectively); serious AEs were absent. Peak TSH concentration post-rhTSH exceeded 25 mU/liter in approximately 98% of courses. In logistic regression analyses, the rhTSH regimen, "mini-THW," peak TSH concentration, body mass index (BMI), or peak TSH concentration/unit of BMI were not associated with clinical AE occurrence. In analyses of covariance, higher BMI was associated with lower peak TSH concentrations.

Conclusions: rhTSH was clinically well tolerated in pediatric DTC patients although courses preponderantly comprised the adult regimen, and repeated courses were frequent. Both the adult and reduced-dose regimens almost always sufficiently elevate TSH in children and adolescents.

Subjects and Methods: Human leukocyte antigen (HLA) typing has been performed in 38 unrelated individuals and in 11 family members detected to carry a Q318X mutation in the course of CYP21 genotyping using sequence, multiplex ligation-dependent probe amplification, and Southern blot analyses.

Results: The majority (n = 32, 84.2%) of the 38 unrelated individuals carrying the Q318X mutation had the trimodular RCCX haplotype, carrying the Q318X mutation on a duplicated CYP21A2 gene. Twenty-two individuals of these 32 (68.8%) were of the rare HLA-B*50-Cw*06 haplotype, suggesting a common ancestry of this haplotype. In five (13.2%) of the 38 subjects, the Q318X mutation was not associated with a duplicated CYP21A2 gene and thus represents a CAH allele. None of these five patients had the above mentioned HLA haplotype.

Conclusion: The majority of individuals in whom Q318X mutations are detected carry a duplicated functional CYP21A2 gene and the rare HLA-B*50-Cw*06 haplotype.

Methods and Results: We compared the results of a 1.75 g/kg oral glucose tolerance test performed in patients with ACH/HCH and AN with age-, sex-, and puberty-matched short children. Three of the patients were treated with recombinant human GH (dose range, 45–50 µg/kg/d), one patient had discontinued treatment 6 months before presentation, and one had never been treated. All patients had a fasting plasma glucose of less than 6 mmol/liter, and no patient had a plasma glucose greater than 7.8 mmol/liter at 2 h after ingestion of a glucose load. Although body mass index was higher in patients with skeletal dysplasia (28.9 ± 7.3 vs. 20 ± 0.6 kg/m²; P = 0.01), mean fasting plasma insulin concentration was greater in controls (14.4 ± 4.8 vs. 6.0 ± 4.5 mU/liter; P = 0.03), as was homeostasis assessment index for insulin resistance (2.5 ± 0.9 vs. 1.17 ± 0.8; P = 0.05).

Conclusion: Our findings suggest that the development of AN in patients with ACH/HCH is not due to insulin insensitivity either on its own or secondary to treatment with recombinant human GH. Whether the AN is due to altered melanocyte function in these individuals remains to be established.

Objective: We analyzed TSH profiles in healthy men and women to delineate differences in the hypothalamo-pituitary-thyroid system.

Subjects and Intervention: The subjects, 24 men (mean age 44 ± 3 yr) and 22 women (mean age 42 ± 3 yr) underwent a 24-h study with blood sampling intervals of 10 min. Premenopausal women were investigated in the early follicular phase of the cycle.

Methods: Serum TSH concentration profiles were analyzed with a newly developed automated deconvolution program, approximate entropy, and cosinor regression.

Results: Basal and pulsatile TSH secretion, and also pulse frequency, hormone half-lives, and secretory mode were indistinguishable in the two genders. There were no differences in diurnal variation, and the times of maximal secretion coincided. Approximate entropy, reflecting secretory regularity, was not different between men and women. In women but not men, TSH secretion was dependent linearly on age.

Conclusions: TSH secretion is gender invariant and depends on age in women only.

Objective: We explored the potential causal role of CRP on measures of adiposity.

Design: We used a Mendelian randomization approach with the CRP and LEPR genes as instrumental variables in a cross-sectional Caucasian population-based study comprising 2526 men and 2836 women. Adiposity was measured using body mass index (BMI), fat and lean mass estimated by bioelectrical impedance, and waist circumference.

Results: Log-transformed CRP explained by the rs7553007 single-nucleotide polymorphism tagging the CRP gene was significantly associated with BMI [regression coefficient: 1.22 (0.18; 2.25), P = 0.02] and fat mass [2.67 (0.65; 4.68), P = 0.01] but not with lean mass in women, whereas no association was found in men. Log-transformed CRP explained by the rs1805096 LEPR single-nucleotide polymorphism was also positively associated, although not significantly, with BMI or fat mass. The combined CRP-LEPR instrument explained 2.24 and 0.77% of CRP variance in women and men, respectively. Log-transformed CRP explained by this combined instrument was significantly associated with BMI [0.98 (0.32; 1.63), P = 0.004], fat mass [2.07 (0.79; 3.34), P = 0.001], and waist [2.09 (0.39; 3.78), P = 0.01] in women but not men.

Conclusion: Our data suggest that CRP is causally and positively related to BMI in women and that this is mainly due to fat mass. Results on the combined CRP-LEPR instrument suggest that leptin may play a role in the causal association between CRP and adiposity in women. Results in men were not significant.

Rationale: Small frequent LH pulses in middle-aged men could reflect impaired feedback by systemic T.

Hypothesis: Middle age disrupts negative feedback by T on selected facets of LH secretion.

Subjects and Setting: Healthy men were studied at an academic medical center.

Methods: The protocol comprised blockade of gonadal steroidogenesis and graded transdermal addback of T doses of 0, 2.5, 5, or 7.5 mg/d designed to span the castrate to physiological range of T concentrations in each of 23 healthy men ages 19–71 yr (interquartile range, 28–53 yr). We quantified 12-h basal and pulsatile LH secretion (92 time series) using a mathematically justified deconvolution method.

Results: Stepwise T supplementation from the hypogonadal through the eugonadal range repressed mean (12-h) LH concentrations (P = 0.001). By regression analysis, age attenuated the capabilities of increasing T concentrations to 1) increase LH secretory-burst mass (P < 0.0001); and 2) decrease LH secretory-burst frequency (P = 0.025). Age did not alter T’s feedback on basal LH secretion, interpulse regularity, the waveform of LH secretory bursts, or the slow half-life of LH.

Conclusion: Middle age impairs both the positive and negative actions of systemic T on pulsatile LH secretion in healthy men, thus potentially explaining earlier inconsistencies in feedback studies based upon single-sample mean LH concentrations. Longitudinal studies will be required to elucidate the precise age dependence of inferred dual feedback failure.

Objective: The aim of this study was to investigate TNMD tissue distribution and TNMD gene expression in human adipose tissue in relation to obesity and metabolic disease.

Design, Patients, and Interventions: TNMD gene expression, tissue distribution, and TNMD gene expression in adipose tissue from different depots, from lean and obese subjects, and during diet-induced weight reduction were analyzed by DNA microarray and real-time PCR.

Main Outcome Measure: We primarily measured TNMD gene expression.

Results: The TNMD gene was predominantly expressed in sc adipose tissue. TNMD gene expression was higher in sc than omental adipose tissue both in lean (P = 0.002) and obese subjects (P = 0.014). In both women and men, TNMD gene expression was significantly higher in the obese subjects compared to the lean subjects (P = 1.1 x 10^–26 and P = 0.010, respectively). In a multiple linear regression analysis, BMI was a significant independent predictor of TNMD gene expression. TNMD gene expression was down-regulated during diet-induced weight loss, with a 65% decrease after 18 wk of diet (P < 0.0001).

Conclusions: We conclude that human adipose tissue TNMD gene expression is highly affected by obesity, adipose tissue location, and weight loss, indicating that TNMD may play a role in adipose tissue function.

Objective: To investigate the relationship between intramyocellular lipids (IMCL), intrahepatic lipids, and peak-stimulated GH in premenopausal women with obesity.

Design and Setting: We conducted a cross-sectional study at a clinical translational research center.

Patients: Patients included 21 premenopausal women with obesity (mean body mass index, 34.0 ± 4.5 kg/m²) and 17 normal-weight controls (mean body mass index, 21.9 ± 2.0 kg/m²) of comparable mean age.

Main Outcomes Measures: IMCL and intrahepatic lipids were measured with proton magnetic resonance spectroscopy (¹H-MRS). Body composition was measured with magnetic resonance imaging. Peak GH was measured after stimulation with GHRH-arginine.

Results: Obese subjects had higher IMCL, intrahepatic lipids, abdominal and thigh fat, and thigh muscle mass compared with normal-weight controls. There were strong inverse associations between peak GH and both IMCL and intrahepatic lipids independent of age and visceral adiposity. There were positive associations between IMCL and intrahepatic lipids with measures of insulin resistance and serum triglycerides.

Conclusion: In premenopausal women with obesity, peak GH is inversely associated with IMCL and intrahepatic lipids independent of age and visceral adiposity. This suggests that low GH may contribute to insulin resistance in obesity through effects on muscle and intrahepatic lipids.

Objective: We report the study of a novel selenocysteine insertion sequence-binding protein 2 (SBP2) gene mutation (R128X) and its clinical and molecular characterization.

Subjects and Methods: A family of African origin was studied. The proband presented with growth retardation, low serum selenium level, and thyroid test abnormalities consisting of high serum total and free T₄ concentrations associated with low T₃, high rT₃, and normal TSH. The entire coding region of the SBP2 gene was sequenced and minigenes constructed to explain the nature of the defect.

Results: The proband was homozygous for a nonsense gene mutation that produces an early stop codon (R128X). Both parents and a sister were heterozygous but showed no growth or thyroid test abnormalities. Despite the severity of the defect, the patient had a relatively mild phenotype, similar to that associated with partial SBP2 deficiency. In vitro analysis showed that the mutant minigene synthesized SBP2 from at least three downstream ATGs capable of generating molecules containing the essential functional domains. Treatment with l-T₃ accelerated the growth velocity and advanced the bone age.

Conclusions: We identified a novel SBP2 gene mutation producing an early arrest in the synthesis of a full-length molecule. The demonstration that SBP2 isoforms containing all functional domains could be synthesized from three downstream ATGs explains the relatively mild phenotype caused by this defect.

Aim: Our aim was to evaluate the impact of body composition on adiponectin and IR determined by homeostasis model assessment (HOMA) in a population-based study on relatively healthy young men, minimizing the possible effects of age, obesity, and severe comorbidity.

Design, Methods, and Subjects: A population-based, cross-sectional study of 783 men aged 20–29 yr, randomly drawn from the Danish Central Personal Registry. Adiponectin was assessed using an in-house assay, and IR was determined using HOMA. Central fat mass (CFM) and lower extremity fat mass (LEFM) was measured by dual-energy x-ray absorptiometry, and visceral adipose tissue (VAT), sc adipose tissue (SAT), and thigh fat area (TFA) were assessed by magnetic resonance imaging.

Results: Using multiple linear regression analysis, adiponectin correlated negatively with CFM (r = –0.27; P < 0.001) and SAT (r = –0.20; P < 0.001) and positively with LEFM (r = 0.19; P < 0.001) and TFA (r = 0.18; P < 0.001), whereas VAT did not associate significantly. In multiple linear regression analysis, HOMA-IR (dependent variable), correlated significantly with CFM (r = 0.27; P < 0.001) and SAT (r = 0.15; P < 0.001), whereas LEFM, VAT, or TFA did not correlate. Adiponectin was an independent predictor of HOMA-IR in both analyses (r = –0.14; P < 0.001).

Conclusion: SAT rather than VAT was inversely associated with adiponectin levels, and, interestingly, fat on the lower extremities was positively associated with adiponectin. Focusing on insulin resistance, SAT rather than VAT and TFA independently predicted a higher HOMA-IR. The observation that adiponectin was independently associated with lower HOMA-IR must be repeated in other populations.

Objectives: We sought to define: 1) the extent of TSPY1 copy number variation within and among Y chromosome haplogroups; and 2) the role of TSPY1 dosage in spermatogenic efficiency.

Materials and Methods: A total of 154 idiopathic infertile men and 130 normozoospermic controls from Central Italy were analyzed. We used a quantitative PCR assay to measure TSPY1 copy number and also defined Y haplogroups in all subjects.

Results: We provide evidence that TSPY1 copy number shows substantial variation among Y haplogroups and thus that population stratification does represent a potential bias in case-control association studies. We also found: 1) a significant positive correlation between TSPY1 copy number and sperm count (P < 0.001); 2) a significant difference in mean TSPY1 copy number between patients and controls (28.4 ± 8.3 vs. 33.9 ± 10.7; P < 0.001); and 3) a 1.5-fold increased risk of abnormal sperm parameters in men with less than 33 copies (P < 0.001).

Conclusions: TSPY copy number variation significantly influences spermatogenic efficiency. Low TSPY1 copy number is a new risk factor for male infertility with potential clinical consequences.

Objective: This study explores the effects of vitamin D replacement on insulin sensitivity, endothelial function, inflammation, oxidative stress, and leptin in vitamin D-deficient subjects.

Design, Setting, and Patients: Twenty-three asymptomatic vitamin D-deficient subjects with 25-hydroxyvitamin D [25(OH)D] levels below 25 nmol/liter were compared with a control group that had a mean 25(OH)D level of 75 nmol/liter. The vitamin D-deficient group received 300,000 IU im monthly for 3 months. The following parameters were evaluated before and after treatment: vitamin D metabolites, leptin, endothelial function by brachial artery flow mediated dilatation (FMD), insulin sensitivity index based on oral glucose tolerance test, and lipid peroxidation as measures of thiobarbituric acid reactive substances (TBARS).

Results: FMD measurements were significantly lower in 25(OH)D-deficient subjects than controls (P = 0.001) and improved after replacement therapy (P = 0.002). Posttreatment values of TBARS were significantly lower than pretreatment levels (P < 0.001). A positive correlation between FMD and 25(OH)D (r = 0.45; P = 0.001) and a negative correlation between FMD and TBARS (r = –0.28; P < 0.05) were observed. There was a significant increase in leptin levels after therapy, and the leptin levels were positively correlated with 25(OH)D levels (r = 0.45; P < 0.05).

Conclusions: This study shows that 25(OH)D deficiency is associated with endothelial dysfunction and increased lipid peroxidation. Replacement of vitamin D has favorable effects on endothelial function. Vitamin D deficiency can be seen as an independent risk factor of atherosclerosis. Hypovitaminosis D-associated endothelial dysfunction may predispose to higher rates of cardiovascular disease in the winter.

Design and Participants: A total of 859 prepubertal euthyroid Danish children aged 4–9 yr underwent a thorough clinical investigation, including anthropometrical measurements and determination of TSH, thyroid hormones, autoantibodies, urinary iodine excretion, and thyroid volume (TV) by ultrasound. Longitudinal growth data from birth were available.

Results: TV increased significantly with age (r = 0.487; P < 0.001). Mean TV ± sd for different age groups were as follows: 4 yr, 2.2 ± 1.4 ml; 5 yr, 2.5 ± 1.3 ml; 6 yr, 2.8 ± 1.3 ml; 7 yr, 3.2 ± 1.3 ml; 8 yr, 3.5 ± 1.3 ml; 9 yr, 3.7 ± 1.3 ml. We found a significant positive association between IGF-I and TV (P < 0.001). Furthermore, in multiple regression analyses, TSH (P < 0.013), free T₄ (P < 0.001), lean body mass (P < 0.001), and body surface area (P < 0.001) as well as other anthropometrical measurements were identified as factors significantly associated with TV. Family history of thyroid disease and presence of incidental abnormal ultrasound findings were also positively associated with TV (P = 0.025 and 0.022, respectively).

Conclusions: In our cohort of prepubertal Danish children, the GH/IGF-I-axis was positively correlated with thyroid size, suggesting a role in the regulation of thyroid growth. Moreover, anthropometric measurements, in particular body surface area, were the best predictors of TV.

Objective: To gain insight in the interaction between innate immune system and metabolic disturbances (obesity and insulin resistance), we investigated the relationship between circulating lactoferrin and chronic inflammation-associated insulin resistance according glucose tolerance status in Caucasian population.

Design, Setting, Participants, and Main Outcome Measures: Circulating nonstressed lactoferrin (ELISA), metabolic variables, and inflammatory markers were measured in 229 men, 94 with normal (NGT) and 135 with altered glucose tolerance (AGT). Lactoferrin secretion by neutrophil was investigated in whole-blood culture (four young NGT subjects, four older NGT subjects, and four patients with type 2 diabetes) under microbial lipopolysaccharide (LPS) with IL-6 and rosiglitazone treatment. We also tested the lactoferrin action in THP-1 cells under LPS stimulus.

Results: Circulating lactoferrin was significantly decreased in patients with AGT (431.5 ± 187.5 vs. 493.5 ± 238.9 ng/ml, P = 0.02). In addition, circulating lactoferrin was negatively associated with hyperglycemia and obesity measures and positively with insulin sensitivity. Lactoferrin was negatively related to inflammatory markers, especially in AGT subjects. In ex vivo experiments, we found a significant decrease in LPS-induced lactoferrin release from neutrophils in subjects with type 2 diabetes. IL-6 coincubation decreased LPS-induced lactoferrin release in NGT subjects (P < 0.001). Finally, rosiglitazone treatment led to increased lactoferrin secretion (398 ± 193 vs. 280.1 ± 104.9 ng/ml, P < 0.0001). Lactoferrin decreased nuclear factor-β activation and IL-6, IL-8, and macrophage chemoattractant protein-1 expression under LPS challenge.

Conclusions: Decreased circulating lactoferrin levels may play a role in chronic low level inflammation-associated insulin resistance.

Setting: The study was conducted at a tertiary medical center.

Subjects: We studied normal women (n = 22) and men (n = 26) [ages, 23–77 yr; body mass index (BMI), 21–32 kg/m²].

Methods: Volunteers underwent 10-min blood sampling to create 24-h ACTH concentration profiles.

Outcomes: Dynamic measures of ACTH secretion were studied.

Results: Mean ACTH concentrations (R² = 0.15; P = 0.006) and both pulsatile (R² = 0.12; P = 0.018) and basal (nonpulsatile) (R² = 0.16; P = 0.005) ACTH secretion correlated directly with BMI (n = 48). Men had greater basal (P = 0.047), pulsatile (P = 0.031), and total (P = 0.010) 24-h ACTH secretion than women, including when total secretion was normalized for BMI (P = 0.019). In men, both ACTH-cortisol feedforward and cortisol-ACTH feedback asynchrony (cross-ApEn) increased with age (R² = 0.20 and 0.22; P = 0.021 and 0.018). ACTH spikiness rose with age (P = 0.046), principally in women. Irregularity of cortisol secretion (ApEn) increased with age (n = 48; P = 0.010), especially in men. In both sexes, percentage pulsatile ACTH secretion predicted 24-h mean cortisol concentrations (R² = 0.14; P = 0.009).

Conclusion: Valid comparisons of ultradian ACTH dynamics will require cohorts matched for age, gender, and BMI, conditions hitherto not satisfied in most physiological studies of this axis.

Objective: The aim of the study was to investigate a possible role for prostaglandin (PG) E₂ in human fetal ovary development.

Design: In vitro analysis of ovarian development between 8 and 20 wk gestation was performed.

Main Outcome Measure(s): The expression patterns of PG synthesis enzymes and the PGE₂ receptors EP2 and EP4 in the ovary were assessed, and downstream effects of PGE₂ on gene expression were analyzed.

Results: Ovarian germ cells express the PG synthetic enzymes COX2 and PTGES as well as the EP2 and EP4 receptors, whereas COX1 is expressed by ovarian somatic cells. Treatment in vitro with PGE₂ increased the expression of BDNF mRNA 1.7 ± 0.16-fold (P = 0.004); INHBA mRNA, 2.1 ± 0.51-fold (P = 0.04); and MCL1 mRNA, 1.15 ± 0.06-fold (P = 0.04), but not that of OCT4, DAZL, VASA, NTF5, or SMAD3.

Conclusions: These data indicate novel roles for PGE₂ in the regulation of germ cell development in the human ovary and show that these effects may be mediated by the regulation of factors including BDNF, activin A, and MCL1.

Objective: The objective of the study was to study the antiproliferative effects of 8-Cl-ADO on growth and proliferation in B-lymphocytes of Carney complex patients that have PKA defects and to determine whether 8-CL-ADO could be used as a therapeutic agent in the treatment of Carney complex-associated tumors.

Design: We used a multiparametric approach (i.e. growth and proliferation assays, PKA, and PKA subunit assays, cAMP and ³H-cAMP binding assays, and apoptosis assays) to understand the growth and proliferative effects of 8-Cl-ADO on human B-lymphocytes.

Results: 8-Cl-ADO inhibited proliferation, mainly through its intracellular transport and metabolism, which induced apoptosis. PKA activity, cAMP levels, and ³H-cAMP binding were increased or decreased, respectively, by 8-Cl-ADO, whereas PKA subunit levels were differentially affected. 8-Cl-ADO also inhibited proliferation induced by G protein-coupled receptors for isoproterenol and adenosine, as well as proliferation induced by tyrosine kinase receptors.

Conclusions: 8-Cl-ADO in addition to unambiguously inhibiting proliferation and inducing apoptosis in a PKA-independent manner also has PKA-dependent effects that are unmasked by a mutant PRKAR1A. Thus, 8-Cl-ADO could serve as a therapeutic agent in patients with Carney complex-related tumors.

Methods: To validate the MRS method, we measured TG content in the pancreatic tissue of 12 lean and 12 fatty ZDF rats (ages 5–14 weeks) both by MRS and the gold standard biochemical assay. We used MRS to measure pancreatic TG content in vivo in 79 human volunteers. Additionally, to assess the reproducibility of the method, in 33 volunteers we obtained duplicate MRS measurements 1–2 weeks apart.

Results: MRS quantifies pancreatic TG content with high reproducibility and concordance to the biochemical measurement (Spearman’s rank correlation coefficient = 0.91). In humans, median pancreatic TG content was as follows: (1) normal weight and normoglycemic group 0.46 f/w%, (2) overweight or obese but normoglycemic group 3.16 f/w%, (3) impaired fasting glucose or impaired glucose tolerance group (BMI matched with group 2) 5.64 f/w%, and (4) untreated type 2 diabetes group (BMI matched with group 2) 5.54 f/w% (Jonckheere-Terpstra trend test across groups p < 0.001).

Conclusions: Human pancreatic steatosis, as measured by MRS, increases with BMI and with impaired glycemia. MRS is a quantitative and reproducible non-invasive clinical research tool which will enable systematic studies of the relationship between ectopic fat accumulation in the pancreas and development of type 2 diabetes.

Objective: This study aimed to explore the role of the PAT proteins OXPAT and ADRP in skeletal muscle lipid metabolism and their putative role in modulating insulin sensitivity.

Design: Muscle OXPAT and ADRP protein content was examined during the development of insulin resistance in Zucker diabetic fatty (ZDF) rats and in type 2 diabetes patients and BMI-matched control subjects. Furthermore, we examined the effect of 8 wk of insulin sensitizing by rosiglitazone on muscle OXPAT and ADRP content.

Results: OXPAT and ADRP protein expression is muscle fiber type specific in humans and rats, with highest protein content in fibers containing most intramyocellular lipids (IMCL). Muscle OXPAT and ADRP protein content was 2- to 3-fold higher in ZDF rats during the progression of type 2 diabetes than in lean normoglycemic control rats, which was paralleled by high IMCL levels. Muscle OXPAT and ADRP content, as well as IMCL level, was not different between type 2 diabetes patients and control subjects. ADRP content was negatively associated with insulin-stimulated glucose uptake (r = –0.50; P = 0.017). Interestingly, rosiglitazone treatment decreased muscle OXPAT (–29%) and ADRP (–28%) content in diabetes patients, without affecting IMCL.

Conclusions: These results indicate involvement of OXPAT and ADRP in muscular lipid accumulation and type 2 diabetes.

Objective/Patients: Four males in a family were affected by AHCH. Our aim was to locate the genetic cause of their disease, knowing that they had no mutation in the obvious candidate gene, NR0B1.

Design: Linkage analysis of the X chromosome and mutational screening of conserved noncoding regions upstream of NR0B1 were performed. To functionally characterize the genetic defect, studies of transcription and expression of DAX1 and steroidogenic factor 1 (SF-1) were done.

Results: A 60 Mb inversion on the X chromosome with one of the inversion breakpoints located in a conserved noncoding region 4 kb upstream of NR0B1 was detected. The inversion causes relocation of a putative SF-1 binding site implicated in murine gonadal development. A reporter construct lacking this enhancer element upstream of NR0B1 was unresponsive to SF-1 transcriptional activation. Immunohistochemistry suggested that the inversion leads to SF-1 silencing in the patients’ testes both in childhood and in adult life.

Conclusion: We report a noncoding mutation causing AHCH, an inversion resulting in a phenotype similar to what is caused by intragenic NR0B1 null mutations. The inversion seems to disrupt and/or relocate regulatory sites crucial in DAX1 expression.

Objective: We tested whether variation in ACP1 is associated with type 2 diabetes-related traits in 1035 individuals in 339 Mexican-American families of probands with or without a previous diagnosis of gestational diabetes mellitus (GDM).

Design: Study participants were phenotyped by oral glucose tolerance test (for glucose and insulin level) and iv glucose tolerance test (for insulin sensitivity and acute insulin response) and had dual-energy x-ray absorptiometry scans to assess body composition. Six tag single nucleotide polymorphisms (SNPs) were identified from among 15 SNPs genotyped across the ACP1 region. SNPs were tested for association with phenotypes using a likelihood ratio test under a variance components framework.

Results: After Bonferroni correction, none of the SNPs were associated with type 2 diabetes mellitus-related phenotypes. However, we observed a significant sex-specific effect of rs3828329. Among males, rs3828329 was significantly associated with fasting insulin (Bonferroni P = 0.007) and insulin sensitivity (Bonferroni P = 0.019) and marginally associated with 2-h insulin (Bonferroni P = 0.058) and percentage body fat (Bonferroni P = 0.09).

Conclusions: There were no significant associations in females. We conclude that variation in ACP1 is associated with fasting insulin and insulin sensitivity in a sex-specific manner.

Research Design and Methods: A total of 101 patients with type 2 diabetes mellitus were included in this study. Liver fat (1H-magnetic resonance spectroscopy) and carotid intima media thickness (IMT) were measured.

Results: Sixty-one (60.3%) patients had steatosis (hepatic triglyceride content greater than 5.5%). Liver fat content was correlated with fasting serum triglycerides (r = 0.22; P = 0.02) and alanine aminotransferase (r = 0.42; P = 0.0001). Sixty-eight percent of subjects with severe steatosis (hepatic triglyceride content greater than 15%) had aspartate aminotransferase in the normal range. Age was strongly correlated with IMT (r = 0.37; P = 0.0002). Steatosis did not correlate with IMT (r = –0.03; P = 0.75). There was no significant difference between the two groups (with and without hepatic steatosis) for IMT values.

Conclusions: this study suggests that in people with type 2 diabetes, fatty liver is not associated with cardiovascular disease. In a diabetic population, it seems that fatty liver is not a determinant factor associated with carotid IMT.

Objective: The objective of the study was to investigate the efficacy of MEK and mTOR inhibitors in preclinical thyroid cancer treatment models with defined mutation status.

Experimental Design: The MEK inhibitor AZD6244 (ARRY-142886) and mTOR inhibitor rapamycin were tested separately and in combination in 10 differentiated thyroid cancer and anaplastic thyroid cancer cell lines and in a xenograft model for evidence of pathway inhibition, growth inhibition, apoptosis, and long-range adaptation and resistance.

Results: Seven of 10 tested lines had evidence of significant basal activity of the PI-3K/AKT/mTOR pathway, with elevated phosphorylated AKT and phosphorylated p70 S6 kinase. Activation of ras/RAF/MEK/ERK was equally common in this panel. All 10 lines exhibited better than 60% growth inhibition with combined MEK and mTOR inhibition, including lines with BRAF, Ret-PTC, ras, and PTEN mutations. Rapamycin or AZD6244 alone achieved this threshold in six and two lines, respectively. Dual-pathway inhibition in the Ret-PTC mutant cell line TPC1 caused an intense G₁ arrest in cell culture and reversible cytostatic inhibition in a xenograft model. We did not observe significant feedback up-regulation of AKT activation in either acute or prolonged exposures.

Conclusion: These preclinical results support the inclusion of thyroid cancer patients in early-phase clinical trials combining ras/RAF/MEK/ERK and PI-3K/AKT/mTOR pathway inhibition.

Objective: Here, we examined the relationship between type 2 diabetes risk alleles and birth weight in a diabetic environment presented in children of mothers with type 1 diabetes.

Research Design and Methods: Birth weight and genotyping of single nucleotide polymorphisms (SNPs) at the CDKAL1, HHEX-IDE, and SLC30A8 loci was obtained and analyzed in 729 singleton full-term children of mothers with type 1 diabetes born in Germany.

Results: The fetal risk alleles of HHEX-IDE SNP rs5015480 and SNP rs10882102 were associated with reduced birth weight: 81g (95% confidence interval, 20–140 g; P = 0.009) and 85 g (95% confidence interval, 25–145 g; P = 0.005) lower birth weight per risk allele, respectively. The association remained significant after adjusting for maternal pregnancy-glycosylated hemoglobin. Fetal genotypes at the CDKAL1 and SLC30A8 loci were not associated with birth weight in this cohort.

Conclusions: The association of low birth weight and type 2 diabetes risk alleles of the HHEX-IDE locus is confirmed in children of mothers with type 1 diabetes.

Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence, which was low or very low.

Consensus Process: Committees and members of The Endocrine Society, European Society of Endocrinology, European Society for Paediatric Endocrinology, Lawson Wilkins Pediatric Endocrine Society, and World Professional Association for Transgender Health commented on preliminary drafts of these guidelines.

Conclusions: Transsexual persons seeking to develop the physical characteristics of the desired gender require a safe, effective hormone regimen that will 1) suppress endogenous hormone secretion determined by the person’s genetic/biologic sex and 2) maintain sex hormone levels within the normal range for the person’s desired gender. A mental health professional (MHP) must recommend endocrine treatment and participate in ongoing care throughout the endocrine transition and decision for surgical sex reassignment. The endocrinologist must confirm the diagnostic criteria the MHP used to make these recommendations. Because a diagnosis of transsexualism in a prepubertal child cannot be made with certainty, we do not recommend endocrine treatment of prepubertal children. We recommend treating transsexual adolescents (Tanner stage 2) by suppressing puberty with GnRH analogues until age 16 years old, after which cross-sex hormones may be given. We suggest suppressing endogenous sex hormones, maintaining physiologic levels of gender-appropriate sex hormones and monitoring for known risks in adult transsexual persons.

Setting and Patient: This report describes a case of an elderly gentleman with a metastatic pancreatic insulinoma and severe hypoglycemia. A continuous infusion of octreotide lowered the blood glucose levels further. He required diazoxide, a thiazide diuretic, phenytoin, and a constant infusion of glucose to control the hypoglycemia and elevated insulin levels.

Intervention: Rapamycin was administered at an oral dose of 2 mg/d.

Results: On the mTOR (mammalian target of rapamycin) agent rapamycin, he was weaned off all drugs except for the thiazide diuretic and maintained euglycemia with a reduction of circulating insulin levels. He remained euglycemic for the past year with no evidence of tumor progression based on Octreoscan. His quality of life is excellent, and he remains active having recently completed a triathlon.

Conclusions: Rapamycin may provide a useful means of abrogating tumor growth and controlling hypoglycemia in malignant insulinomas by reducing the malignant β-cell growth and proliferation as well as inhibiting insulin production.

Evidence Acquisition: All published randomized controlled studies on glucose control in ICU were reviewed. The methodological differences between the repeat studies, most specifically NICE-SUGAR, and the original proof-of-concept studies, were systematically analyzed.

Evidence Synthesis: There were important methodological differences, possibly explaining different outcomes. These comprised different target ranges for blood glucose in control and intervention groups, different routes for insulin administration and types of infusion-pumps, different sampling sites, and different accuracies of glucometers, as well as different nutritional strategies and varying levels of expertise.

Conclusions: These differences do not permit confident recommendations for a single optimal glucose target in variable ICU settings. Respecting the "primum non nocere" principle, it appears safe not to embark on targeting age-normal levels in ICUs that are not equipped to accurately and frequently measure blood glucose and have not acquired extensive experience with iv insulin administration using a customized guideline. A simple overall fall-back position could be to maintain blood glucose levels as close to normal as possible without evoking unacceptable fluctuations, hypoglycemia, and hypokalemia.

Evidence: Circulating biomarkers of these pathways such as TNF, IL-6, C-reactive protein (CRP) (inflammation), vascular cellular adhesion molecule-1, interstitial cellular adhesion molecule-1, E-selectin, von Willebrand factor (endothelial dysfunction), plasminogen activator inhibitor-1, fibrinogen, P-selectin (procoagulant state), and adiponectin (antiinflammation) may be associated with development of both type 1 and type 2 diabetes and some studies, particularly in type 2 diabetes, have demonstrated that certain biomarkers may have independent predictive value. Similarly studies have shown that these biomarkers may be associated with development of diabetic nephropathy and retinopathy, and again, particularly in type 2 diabetes, with cardiovascular events as well. Finally, the comorbidites of diabetes, namely obesity, insulin resistance, hyperglycemia, hypertension and dyslipidemia collectively aggravate these processes while antihyperglycemic interventions tend to ameliorate them.

Conclusions: Increased CRP, IL-6, and TNF, and especially interstitial cellular adhesion molecule-1, vascular cellular adhesion molecule-1, and E-selectin are associated with nephropathy, retinopathy, and cardiovascular disease in both type 1 and type 2 diabetes. Whereas further work is needed, it seems clear that these biomarkers are predictors of increasing morbidity in prediabetic and diabetic subjects and should be the focus of work testing their clinical utility to identify high-risk individuals as well as perhaps to target interventions.

Patients and Methods: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees).

Results: Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, –4.7 ± 1.6 SDS vs. –3.4 ± 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR.

Conclusions: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.

Objective: The aim of the study was to determine the prevalence of vitamin D deficiency in obese African-American (AA) adolescent females in a southeastern latitude and to determine the relationship of 25-hydroxyvitamin D [25(OH)D] with insulin and glucose dynamics.

Design: We conducted a cross-sectional study in a University Children’s Hospital.

Methods: Serum 25(OH)D, fasting glucose, PTH, serum calcium, serum lipids, serum transaminases, and C-reactive protein were assessed. Indices of insulin sensitivity and resistance were determined from an oral glucose tolerance test. Subjects were classified as vitamin D deficient or sufficient, based on the traditional vitamin D deficiency definition [serum 25(OH)D <20 ng/ml] and also by a lower 25(OH)D cut-point of 15 ng/ml or less.

Results: A total of 51 AA adolescent females (body mass index, 43.3 ± 9.9 kg/m²; age, 14 ± 2 yr) were studied. Serum 25(OH)D concentrations were 20 ng/ml or less in 78.4% and 15 ng/ml or less in 60.8% of subjects. There were no significant group differences in the metabolic outcomes when subjects were classified using the traditional vitamin D deficiency definition. The Matsuda index of insulin sensitivity was significantly lower (P = 0.02), and insulin area under the curve was significantly higher (P = 0.04) in subjects with 25(OH)D concentrations of 15 ng/ml or less vs. those with higher concentrations.

Conclusions: Vitamin D deficiency is highly prevalent in obese, AA female adolescents and may promote insulin resistance. Our data suggest that a 25(OH)D concentration of 15 ng/ml or less may be the threshold by which vitamin D deficiency confers negative effects on insulin sensitivity.

Objective: The objective of the study was to investigate in these patients SDI and factors influencing the prevalence of fractures.

Design: This was a retrospective, multicenter study.

Setting: The study was conducted on an in- and outpatient basis.

Patients: Patients included 287 adrenal incidentaloma patients (111 eugonadal males, 31 premenopausal, 145 postmenopausal females) and 194 controls (90 eugonadal males, 29 premenopausal, 75 postmenopausal females).

Main Outcome Measure: Bone mineral density (BMD) was measured by dual X-ray absorptiometry at lumbar spine and femoral neck. By radiograph each vertebra was assessed as intact (grade 0) or grade 1 (20–25%), 2 (25–40%), or 3 (>40%) deformity; SDI was calculated by summing the grade of deformity for each vertebra. SH was diagnosed in the presence of at least two of the following: urinary free cortisol greater than 70 µg per 24 h (193.1 nmol/liter), cortisol after 1-mg dexamethasone test greater than 3.0 µg/dl (>82.8 nmol/liter), ACTH less than 10 pg/ml (<2.2 pmol/liter).

Results: BMD was significantly lower in SH+ than SH– patients and controls (lumbar spine –0.73 ± 1.43, 0.17 ± 1.33, 0.12 ± 1.21, respectively; femoral neck –0.37 ± 1.06, 0.07 ± 1.09, 0.17 ± 1.02). Patients with SH had higher fracture prevalence and SDI than those without SH and controls (70.6, 22.2, 21.8%, respectively, P < 0.0001; 0.31 ± 0.68, 0.39 ± 0.93, 1.35 ± 1.27, respectively, P < 0.0001). Fractures and SDI were associated with SH (odds ratio 7.27, 95% confidence interval 3.94–13.41, P = 0.0001; β = 0.352, t = 6.241, P = 0.0001, respectively) regardless of age, BMD, menopause, and gender.

Conclusion: SH is associated with low BMD, high fracture prevalence, and reduced bone quality as measured by SDI.

Objective: The aim of the study was to identify factors associated with greater efficacy during ZOL 5 mg treatment.

Design, Setting, and Patients: We conducted a subgroup analysis (preplanned and post hoc) of a multicenter, double-blind, placebo-controlled, 36-month trial in 7765 women with postmenopausal osteoporosis.

Intervention: A single infusion of ZOL 5 mg or placebo was administered at baseline, 12, and 24 months.

Main Outcome Measures: Primary endpoints were new vertebral fracture and hip fracture. Secondary endpoints were nonvertebral fracture and change in femoral neck bone mineral density (BMD). Baseline risk factor subgroups were age, BMD T-score and vertebral fracture status, total hip BMD, race, weight, geographical region, smoking, height loss, history of falls, physical activity, prior bisphosphonates, creatinine clearance, body mass index, and concomitant osteoporosis medications.

Results: Greater ZOL induced effects on vertebral fracture risk were seen with younger age (treatment-by-subgroup interaction, P = 0.05), normal creatinine clearance (P = 0.04), and body mass index ≥ 25 kg/m² (P = 0.02). There were no significant treatment–factor interactions for hip or nonvertebral fracture or for change in BMD.

Conclusions: ZOL appeared more effective in preventing vertebral fracture in younger women, overweight/obese women, and women with normal renal function. ZOL had similar effects irrespective of fracture risk factors or femoral neck BMD.

Objective: The objective of the study was to determine whether RT adds to CR in improving body composition and the metabolic profile.

Design and Setting: This was a 6-month, randomized, clinical trial.

Patients: Patients included 107 postmenopausal women (body mass index >27 kg/m²).

Intervention: The intervention was a 6-month CR alone or in combination with a RT program.

Main Outcome Measures: Fat mass (FM), lean body mass (LBM), abdominal sc fat and visceral fat, fasting lipids, insulin sensitivity, resting blood pressure, and inflammation markers were measured.

Results: Both groups were similar at baseline and significantly decreased body weight, body mass index, FM, percent FM, abdominal sc fat, and visceral fat after the study (P < 0.001), with greater losses of percent FM and trunk FM in the CR + RT group (P < 0.05). LMB significantly decreased in the CR (–0.9 ± 2.4 kg) and the CR+RT (–0.4 ± 2.2 kg) groups (P < 0.005), with no difference between them. Both groups significantly improved plasma triglycerides, fasting insulin level, glucose disposal, and markers of the inflammation profile after weight loss (P < 0.05), with no difference between groups. No improvements were observed for the other variables of interest in both groups.

Conclusions: CR+RT was associated with greater losses in percent FM and trunk FM compared with CR alone. However, CR+RT was not associated with additional improvements in the metabolic profile compared with CR alone.

Objective: The aim of the study was to evaluate the psychological development of infants aged 3 to 18 months whose mothers had received 300 µg of potassium iodide during the first trimester of their pregnancy and compare with infants whose mothers had received no iodine supplements.

Design and Study Subjects: The study included 133 women who had received 300 µg of potassium iodine and 61 women who had received no iodine supplements.

Main Outcome Measures: The neuropsychological status of the children was evaluated with the Bayley Scales of Infant Development, and measurements were made of TSH, free T₃, free T₄, and urinary iodine.

Results: Those children whose mothers had received an iodine supplement of 300 µg had a more favorable psychometric assessment than those of the other group of mothers. They had higher scores on the Psychomotor Development Index (P = 0.02) and the Behavior Rating Scale.

Conclusions: Dietary iodine supplements not only have no harmful effect on the neurodevelopment of the children, they may even be beneficial. Given the possible presence of confounding variables not controlled for in this study, these findings should be considered as preliminary.

Objective: The aim of the study was to test the hypothesis that, when part of a Western-like lifestyle, recurrent bedtime restriction may result in decreased glucose tolerance and reduced insulin secretion and action.

Design and Setting: We conducted a randomized crossover study at a university clinical research center and sleep research laboratory.

Participants: Eleven healthy volunteers (five females and six males) with a mean (±sd) age of 39 ± 5 yr and body mass index of 26.5 ± 1.5 kg/m² participated in the study.

Intervention: The study included two 14-d periods of controlled exposure to sedentary living with ad libitum food intake and 5.5- or 8.5-h bedtimes.

Main Outcome Measures: Oral and iv glucose challenges were used to obtain measures of glucose tolerance, glucose effectiveness, insulin secretion, and insulin sensitivity at the end of each intervention. Secondary measures included circulating concentrations of the glucose counter-regulatory hormones, cortisol, GH, epinephrine, and norepinephrine.

Results: Bedtime restriction reduced daily sleep by 122 ± 25 min. Both study periods were associated with comparable weight gain; however, recurrent sleep restriction resulted in reduced oral glucose tolerance (2-h glucose value, 144 ± 25 vs. 132 ± 36 mg/dl; P < 0.01) and insulin sensitivity [3.3 ± 1.1 vs. 4.0 ± 1.6 (mU/liter)^–1 · min^–1; P < 0.03], and increased glucose effectiveness (0.023 ± 0.005 vs. 0.020 ± 0.005 min^–1; P < 0.04). Although 24-h cortisol and GH concentrations did not change, there was a modest increase in 24-h epinephrine and nighttime norepinephrine levels during the 5.5-h bedtime condition.

Conclusions: Experimental bedtime restriction, designed to approximate the short sleep times experienced by many individuals in Westernized societies, may facilitate the development of insulin resistance and reduced glucose tolerance.

Methods: We measured CRP and body fat parameters in 1166 men and 1413 women ages 30–65 in the population-based Dallas Heart Study. Total fat mass (TFM) was measured using dual-energy x-ray absorptiometry scanning and was subdivided into truncal fat (TrF) and lower body fat (LBF). The TrF/LBF ratio was used to measure fat distribution. Abdominal fat compartments (ip and sc) were measured using magnetic resonance imaging. Log-transformed CRP was used as the outcome variable in sex-combined models with interaction tests.

Results: Median body mass index was higher in women than in men (29.9 vs. 28.2 kg/m²), as was TFM (29.7 vs. 20.5 kg) (P < 0.001 each). TFM was linearly associated with log CRP in both sexes, with a steeper slope of association in women (P interaction = 0.003). CRP increased to a greater degree with increasing TrF (P interaction = 0.0004) in women compared with men, even after adjustment for TFM; values were similar across sexes for LBF. Fat distribution (TrF/LBF ratio) was more strongly associated with CRP levels in women vs. men (R² adjusted for TFM = 0.04 vs. 0.008). Greater increases in CRP were also observed with increasing ip and sc fat in women compared with men.

Conclusions: The quantity and distribution of body fat influence CRP to a greater extent in women compared with men. Adiposity as a contributor to subclinical inflammation may be particularly relevant in women.

Objective: The aim of the study was to determine whether pituitary responsiveness to GnRH is attenuated with aging.

Design and Setting: A GnRH antagonist and graded doses of GnRH were used to isolate pituitary responsiveness in Clinical Research Center studies at an academic medical center.

Subjects: Subjects were healthy postmenopausal women (PMW) aged 48–57 yr (n = 10) or 70–77 yr (n= 9).

Interventions: A suppressive dose of the NAL-GLU GnRH antagonist (150 µg/kg sc) was administered and was followed by GnRH doses of 25, 75, 250, or 750 ng/kg iv every 4 h.

Results: The LH response to GnRH was attenuated with aging (P = 0.05) with an interaction between age and dose (P = 0.01) such that the LH amplitude was less in older PMW at the higher doses (250 ng/kg, 50 ± 9 vs. 29 ± 4.9 IU/liter, for young and old PMW, respectively, P = 0.02; and 750 ng/kg, 97.7 ± 11 vs. 70.2 ± 9.3 IU/liter, P = 0.002), but not the lower doses of GnRH. The FSH response to GnRH was also attenuated with aging in PMW (P = 0.005).

Conclusions: In studies that isolated the pituitary from endogenous GnRH stimulation, aging attenuated the LH and FSH responses to exogenous GnRH in PMW. These studies indicate that the pituitary plays a role in the decline in gonadotropin levels with aging, further supporting the potential contribution of age-associated changes in both hypothalamic and pituitary function to reproductive senescence.

Objective: The aim of the study was to examine the effects of GH receptor (GHR) antagonist treatment on exercise performance.

Design: Subjects were treated with the GHR antagonist pegvisomant or placebo for 16 d. After the treatment period, they exercised to determine exercise performance and hormonal and metabolic responses.

Participants: Twenty healthy males participated in the study.

Intervention: Subjects were treated with the GHR antagonist (n = 10; 10 mg/d) or placebo (n = 10). After the treatment period, they performed a maximal oxygen uptake (O_2max) test and a prolonged exercise test, consisting of 60 min of submaximal cycling followed by exercise to fatigue at 90% of O_2max.

Main Outcome Measures: O_2max was measured before and after the treatment period. Hormonal and metabolic responses and time to exhaustion during prolonged exercise were determined.

Results: Resting serum IGF-I concentration decreased by 20% in the GHR antagonist-treated group (P < 0.05), whereas no change was observed in the placebo group. Conversely, resting serum GH concentration was significantly higher in the treatment group compared with the placebo group (P < 0.01). O_2max did not change significantly in either group after the treatment period. Time to exhaustion at 90% of O_2max was significantly shorter in the treatment group (P < 0.05). No significant differences were observed between the groups in terms of changes in serum free fatty acids, glycerol, O₂, or relative fat oxidation.

Conclusion: GH might be an important determinant of exercise capacity during prolonged exercise, but GHR antagonist did not alter fat metabolism during exercise.

Objectives: The aim of the study was to examine important environmental or sociodemographic factors influencing 25-hydroxyvitamin D [25(OH)D] levels and estimate its heritability.

Design: A sample of 226 male and female adolescent twins aged 13–20 yr from a large prospective twin cohort of rural Chinese children and adolescents that has been followed for 6 yr were evaluated.

Main Outcome Measure(s): Blood level of 25(OH)D was measured using tandem mass spectrometry methodology.

Results: The overall mean (sd) 25(OH)D level was 18.0 (9.4) ng/ml, with wide variation by gender and season. In males (47.4% of subjects), the mean (sd) 25(OH)D level was 12.1 (4.2) ng/ml in non-summer and 27.4 (8.8) ng/ml in summer; in females, it was 10.1 (4.1) ng/ml in non-summer and 19.5 (6.3) ng/ml in summer. A multivariate model that included gender, age, season, physical activity, and student status demonstrated that male gender, summer season, and high physical activity significantly increased 25(OH)D levels. Summer season and male gender also significantly decreased the risk of being in the lowest 25(OH)D tertile. Overall, 68.9% of the variability in 25(OH)D level was attributable to additive genetic influence. Stratification by gender found that in males, 85.9% of the variability in 25(OH)D level was attributable to such influence, but in females, it was only 17%.

Conclusion: In this sample of rural Chinese adolescents, 25(OH)D level was influenced by gender, season, and physical activity level. There was a strong genetic influence on 25(OH)D level in males only.

Objective: The aim of the study was to assess adrenal function during childhood and pubertal development in daughters of women with PCOS (PCOSd).

Design: We included 98 PCOSd [64 during childhood (ages 4–8 yr) and 34 during the peripubertal period (ages 9–13 yr)] and 51 daughters of control women (Cd) [30 during childhood and 21 during the peripubertal period]. In both groups, an acute ACTH-(1–24) stimulation test (0.25 mg) and an oral glucose tolerance test were performed. Bone age and serum concentrations of cortisol, androstenedione, 17-hydroxyprogesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), glucose, and insulin were determined.

Results: PCOSd and Cd were similar in age and body mass index. During the peripubertal period, basal and poststimulated DHEAS concentrations were higher in PCOSd compared to Cd. Among PCOSd, 12.5% of girls in childhood and 32.4% in peripuberty presented biochemical evidence of exaggerated adrenarche. Stimulated insulin was higher in PCOSd compared to Cd during childhood (P = 0.03) and peripuberty (P = 0.03). An advancement of 8 months between bone and chronological age was observed in peripubertal PCOSd compared to Cd.

Conclusions: In PCOSd, basal and stimulated DHEAS concentrations were higher during the onset of puberty. Around 30% of the PCOSd demonstrated an exacerbated adrenarche, which may reflect increased P450c17 activity. In addition, a modest advance in bone age was observed, probably secondary to the hyperinsulinemia and/or adrenal hyperandrogenism.

Methods: In a prospective study, we examined the prevalence of DM in adult participants in an intramural National Institutes of Health (NIH) TS study. Results were analyzed with respect to karyotype, age, body mass index (BMI), and autoimmune indices. Insulin sensitivity and secretion were compared in age- and BMI-matched euglycemic women with TS and healthy female controls. We compared gene expression profiles in lymphocytes from differentially affected TS groups.

Results: Type 2 DM was present in 56 of 224 (25%) of the women with TS; type 1 DM was found in only one woman (<0.5%). DM was more prevalent among women with an isoXq chromosome compared to X monosomy (40.0 vs. 17.3%; P = 0.004). Euglycemic women with TS (n = 72; age, 33 ± 12 yr; BMI, 23 ± 3 kg/m²) had significantly higher glycemic and lower insulin responses to OGTT, with insulin sensitivity similar to controls. Gene expression profiles comparing 46,X,i(X)q vs. 45,X groups showed a significant increase in Xq transcripts and in potentially diabetogenic autosomal transcripts in the isoXq group.

Conclusion: Type 2 DM associated with deficient insulin release is significantly increased among women with monosomy for the X-chromosome but is increased even more among women with monosomy for Xp coupled with trisomy for Xq. These data suggest that haploinsufficiency for unknown Xp genes increases risk for DM and that excess dosage of Xq genes compounds the risk.

Patients: Seven (four females, three males) nonobese patients with T1D aged 21–30 yr were studied on four occasions in random order. On each visit, overnight endogenous GH production was suppressed by octreotide. Three 1-h pulses of recombinant human GH (rhGH) or placebo were administered on two visits each. Acipimox, an antilipolytic drug, or a placebo were ingested every 4 h on two visits each. Stable glucose and glycerol isotopes were used to assess glucose and glycerol turnover. The overnight protocol was concluded by a two-step hyperinsulinemic euglycemic clamp on each visit.

Main Outcome: rhGH administration led to increases in the insulin infusion rate required to maintain euglycemia overnight (P = 0.008), elevated basal endogenous glucose production (P = 0.007), decreased basal peripheral glucose uptake (P = 0.03), and reduced glucose uptake during step 1 of the clamp (P < 0.0001). Coadministration of rhGH and acipimox reversed these effects and suppression of lipolysis in the absence of GH replacement led to further increases in insulin sensitivity.

Results: GH pulses were associated with an increase in endogenous glucose production and decreased rates of peripheral glucose uptake, which was entirely reversed by acipimox. Therefore, GH-driven decreases in insulin sensitivity are mainly determined by the effect of GH on lipolysis.

Objective: The objective of the study was to examine the relationship between levels of 25[OH]D and 1,25[OH]₂D and measures of adiposity in Hispanic and African-Americans at baseline and on change in these measures over time.

Design and Setting: The Insulin Resistance Atherosclerosis (IRAS) Family Study examined 917 Hispanics and 439 African-Americans at baseline and again 5.3 yr later (n = 1081 at follow-up).

Main Outcome Measure: 25[OH]D (nanograms per milliliter) and 1,25[OH]₂D (picograms per milliliter) were measured at baseline. Abdominal sc adipose tissue (SAT), visceral adipose tissue (VAT; both determined by computed tomography scan), and body mass index (BMI) were measured at baseline and follow-up.

Results: 25[OH]D was inversely associated with BMI, VAT, and SAT in both populations at baseline (P < 0.001). 25[OH]D was marginally inversely associated with baseline visceral fat to sc fat ratio in African-Americans (P = 0.049) but not Hispanics. 1,25[OH]₂D was inversely associated with BMI (P < 0.0001, P = 0.002) and VAT (P = 0.0005, P = 0.012) in Hispanics and African-Americans, respectively, whereas 1,25[OH]₂D was inversely associated with SAT in Hispanics (P < 0.0001) and with visceral fat to sc fat ratio in African-Americans (P = 0.02). Adjusting for 25[OH]D attenuated these associations; 1,25[OH]₂D remained associated with BMI in both populations (P < 0.05) and with SAT (P = 0.004) in Hispanics. No significant associations between 5-yr change in adiposity and 25[OH]D or 1,25[OH]₂D were seen.

Conclusions: Vitamin D levels were inversely associated with baseline BMI, SAT, and VAT in Hispanic and African-Americans but were not associated with 5-yr change in adiposity.

Objective: The objective of the study was to determine whether vitamin D increased calcium absorption.

Design: This was an experimental study.

Setting: The study was conducted at a teaching hospital.

Participants: Participants included 17 children with nutritional rickets.

Intervention: The participants were randomized to 1.25 mg oral vitamin D₃ (n = 8) or vitamin D₂ (n = 9).

Main Outcome Measure: Fractional calcium absorption 3 da after vitamin D administration was measured.

Results: Mean baseline 25-hydroxyvitamin D concentrations were 20 ng/ml (range 5–31 ng/ml). The increase in 25-hydroxyvitamin D was equivalent after vitamin D₃ (29 ± 10 ng/ml) or vitamin D₂ (29 ± 17 ng/ml). Mean 1,25-dihydroxyvitamin D values increased from 143 ± 76 pg/ml to 243 ± 102 pg/ml (P = 0.001), and the increase in 1,25-dihydroxyvitamin D did not differ between vitamin D₂ and vitamin D₃ (107 ± 110 and 91 ± 102 ng/ml, respectively). The increment in 1,25-dihydroxyvitamin D was explained almost entirely by the baseline 25-hydroxyvitamin D concentration (r² = 0.72; P < 0.001). Mean fractional calcium absorption did not differ before (52.6 ± 21.4%) or after (53.2 ± 23.5%) vitamin D, and effects of vitamin D₂ and vitamin D₃ on calcium absorption were not significantly different. Fractional calcium absorption was not closely related to concentrations of 25-hydroxyvitamin D (r = 0.01, P = 0.93) or 1,25-dihydroxyvitamin D (r = 0.21, P = 0.24). The effect of vitamin D on calcium absorption did not vary with baseline 25-hydroxyvitamin D values or with the absolute increase in 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D values.

Conclusions: Despite similar increases in 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D with vitamin D₂ or vitamin D₃, fractional calcium absorption did not increase, indicating that rickets in Nigerian children is not primarily due to vitamin D-deficient calcium malabsorption.

Objective: We tested whether persistence of a positive response to DDAVP after successful surgery identifies patients at risk of CD recurrence.

Design: We prospectively included all CD patients who had a positive response to DDAVP before successful surgery from 1995 through 2007.

Setting: The study was performed at a university hospital.

Patients: One hundred seventy-four patients with CD, 148 women and 26 men, mean age 36.1 ± 0.8 yr, were studied. The median follow-up after surgery was 58 months (interquartile range 22–93 months).

Intervention: DDAVP test was performed immediately before and after surgery.

Main Outcome Measure: An ACTH and cortisol increment of at least 30 and 20% above baseline, respectively, were considered as a positive response to DDAVP. The risk of CD recurrence was analyzed according to the postoperative hormonal response to DDAVP.

Results: Recurrence of CD occurred in 19 patients (10.9%). The recurrence-free survival at 5 yr was 89.8% [95% confidence interval (CI) 84.2–95.4]. Patients with a positive ACTH response had a 5-yr recurrence-free survival of 82.6% (95% CI 70.6–94.6%) as compared with 94.0% (95% CI 88.2–99.8%; P < 0.01) in patients without it. Multivariate analysis showed that persistence of a positive ACTH response to DDAVP was significantly associated with CD recurrence.

Conclusion: Positive ACTH response to DDAVP after surgery is associated with an increased risk of CD recurrence. However, the specificity and predictive value of this finding are low.

Objective: The aim of the current study was to investigate the prevalence of GH deficiency in a patient population with CHF and evaluate the cardiovascular effects of GH replacement therapy.

Design and Setting: The randomized, single-blind, controlled trial was conducted at the Federico II University.

Participants: One hundred fifty-eight patients with CHF, New York Heart Association class II-IV, underwent a GH stimulation test. Sixty-three patients satisfied the criteria for GH deficiency, and 56 of them were enrolled in the trial.

Intervention: The treated group (n = 28) received GH at a replacement dose of 0.012 mg/kg every second day (~2.5 IU).

Main Outcomes Measures: Changes in physical performance and various cardiovascular indexes were measured.

Results: GH replacement therapy improved quality of life score (from 46 ± 5 to 38 ± 4; P < 0.01), increased peak oxygen uptake and exercise duration (from 12.9 ± .9 to 14.5 ± 1 ml/kg · min and from 520 ± 36 to 586 ± 43 sec, respectively; P < 0.01), and flow-mediated vasodilation (from 8.8 ± 1.3 to 12.7 ± 1.2%; P < 0.01). GH increased left ventricular ejection fraction (from 34 ± 2 to 36 ± 2%; P < 0.01) and reduced circulating N-terminal pro-brain natriuretic peptide levels (from 3201 ± 900 to 2177 ± 720 pg/ml; P = 0.006). No significant changes from baseline were observed in controls.

Conclusions: As many as 40% of patients with CHF are GH deficient. GH replacement therapy in these patients improves exercise capacity, vascular reactivity, left ventricular function, and indices of quality of life.

Objective: The objective of the study was to examine associations between nonvertebral fracture risk and bioavailable estradiol (bioE2), bioavailable testosterone (bioT), and SHBG.

Design: This was a case-cohort study.

Setting: The Osteoporotic Fractures in Men Study (MrOS) was conducted in a prospective U.S. cohort in 5995 community-dwelling men 65 yr old or older.

Participants: Participants included a subcohort of 1436 randomly chosen white men plus all 446 minorities and all those with incident hip and other nonvertebral fractures.

Main Outcome Measures: Baseline testosterone and estradiol were measured by mass spectrometry (MS) and SHBG by RIA.

Results: Men with the lowest bioE2 (<11.4 pg/ml) or highest SHBG (>59.1 nm) had greater risk of all nonvertebral fractures [adjusted hazard ratio (HR) [95% confidence interval]: 1.5 (1.2–1.9) and 1.4 (1.1–21.8), respectively]. Men with the lowest bioT (<163.5 ng/dl) had no increased fracture risk after adjustment for bioE2 [adjusted HR 1.16 (0.90–1.49)]. A significant interaction between SHBG and bioT (P = 0.03) resulted in men with low bioT and high SHBG having higher fracture risk [HR 2.1 (1.4–3.2)]. Men with low bioE2, low bioT, and high SHBG were at highest risk [HR 3.4 (2.2–5.3)].

Conclusions: Older men with low bioE2 or high SHBG levels are at increased risk of nonvertebral fracture. When SHBG levels are high, men with low bioT levels have higher risk. The strongest association occurred when all measures were considered in combination.

Aim: The aim of the study was to evaluate effects of GHD and GH therapy on cardiac function using load-dependent and load-independent indices of myocardial contractility.

Patients and Methods: Echocardiography was performed in 24 GHD children at baseline and 1 and 2 yr after GH therapy and in 24 controls.

Results: Compared with controls, GHD children at baseline had lower LV mass (LV mass/BSA 50.6 ± 1.8 vs. 60.5 ± 2.4 g/m²; P < 0.002, and LV mass/H^2.7 28.7 ± 1.2 vs. 33.6 ± 1.3 g/m^2.7; P < 0.009). Global systolic function was normal, with only a trend toward slight impairment of the fractional shortening (34.9 ± 1.5 vs. 37.6 ± 1.1%). However, subtle LV dysfunction was revealed by load-dependent and load-independent indices of myocardial contractility. In fact, GHD patients compared with controls showed lower rate-corrected mean velocity of circumferential fiber shortening (1.0 ± 0.03 vs. 1.18 ± 0.03 circ/sec; P = 0.0001) and stress shortening index (0.10 ± 0.02 vs. 0.18 ± 0.02; P < 0.007) and higher end-systolic stress (49.2 ± 1.4 vs. 45.7 ± 1.0 g/cm²; P < 0.05). One year of G