The Journal of Clinical Endocrinology & Metabolism

Terui, Ken; Sakihara, Satoru; Kageyama, Kazunori; Nigawara, Takeshi; Takayasu, Shinobu; Matsuhashi, Yuki; Kon, Akihito; Yamamoto, Hayato; Ohyama, Chikara; Sasano, Hironobu; Suda, Toshihiro

doi: 10.1210/jc.2009-2787pmid: 20685888

Kim, Sun Wook; Lee, Ji In; Kim, Jong-Won; Ki, Chang-Seok; Oh, Young Lyun; Choi, Yoon-La; Shin, Jung Hee; Kim, Hee Kyung; Jang, Hye Won; Chung, Jae Hoon

doi: 10.1210/jc.2009-2795pmid: 20501689

Catov, Janet M.; Ness, Roberta B.; Wellons, Melissa F.; Jacobs, David R.; Roberts, James M.; Gunderson, Erica P.

doi: 10.1210/jc.2009-2028pmid: 20501685

Context: Preterm birth is associated with maternal cardiovascular risk, but mechanisms are unknown.Objective: We considered that dyslipidemia may predispose women to both conditions and that prepregnancy lipids may be related to preterm birth risk. We hypothesized that low or high prepregnancy plasma lipids would be associated with preterm birth.Design, Setting, and Participants: A total of 1010 women (49% black) enrolled in the multicenter, prospective Coronary Artery Risk Development in Young Adults study with at least one singleton birth during 20 yr of follow-up were evaluated.Main Outcome Measure: Postbaseline preterm births less than 34 wk or 34 to less than 37 wk vs. greater than 37 wk gestation.Results: We detected a U-shaped relationship between prepregnancy cholesterol concentrations and preterm birth risk. Women with prepregnancy cholesterol in the lowest quartile compared with the second quartile (<156 vs. 156–171 mg/dl) had an increased risk for preterm birth 34 to less than 37 wk (odds ratio 1.86; 95% confidence interval 1.10, 3.15) and less than 34 wk (odds ratio 3.04; 1.35, 6.81) independent of race, age, parity, body mass index, hypertension during pregnancy, physical activity, and years from measurement to birth. Prepregnancy cholesterol in the highest quartile (>195 mg/dl) was also associated with preterm birth less than 34 wk among women with normotensive pregnancies (odds ratio 3.80; 95% confidence interval 1.07, 7.57). There were no associations between prepregnancy triglycerides, low-density lipoprotein cholesterol, or high-density lipoprotein cholesterol and preterm birth.Conclusions: Both low and high prepregnancy cholesterol were related to preterm birth risk. These may represent distinct pathways to the heterogeneous outcome of preterm birth. Additional studies are needed to elucidate mechanisms that link low or high cholesterol to preterm birth and later-life sequelae.

Fast, Søren; Hegedüs, Laszlo; Grupe, Peter; Nielsen, Viveque Egsgaard; Bluhme, Christa; Bastholt, Lars; Bonnema, Steen Joop

doi: 10.1210/jc.2010-0634pmid: 20519346

Context and Objective: Stimulation with recombinant human TSH (rhTSH) before radioiodine (131I) therapy augments goiter volume reduction (GVR). Observations indicate that rhTSH has a preconditioning effect beyond increasing thyroid 131I uptake. We test the hypothesis that an equivalent GVR might be obtained by an absorbed thyroid dose well below what has been used previously.Patients and Design: In a double-blinded setup, 90 patients (78 women; median age, 52 yr; range, 22–83) with a nontoxic nodular goiter (median size, 63 ml; range, 25–379 ml) were randomized to either 0.1 mg rhTSH (n = 60) followed by a thyroid dose of 50 Gy or placebo followed by 100 Gy (n = 30).Results: At 12 months, the mean relative GVR in the placebo and the rhTSH group was identical (35 ± 3%; P = 0.81). The median administered 131I-activity was 170 MBq (45–1269) in the rhTSH group and 559 MBq (245–3530) in the placebo group (70% reduction, P < 0.0001). According to the official radiation regulation, hospitalization was required in 14 patients in the placebo group vs. one patient in the rhTSH group (P < 0.0001). In both groups, goiter-related symptoms were effectively relieved in the majority of patients. The prevalence of myxedema (10%) did not differ among groups.Conclusions: This is the first study to demonstrate that rhTSH not only increases the thyroid 131I uptake, but per se potentiates the effect of 131I-therapy, allowing a major reduction of the 131I-activity without compromising efficacy. This approach is attractive in terms of minimizing posttherapeutic restrictions and in reducing the potential risk of radiation-induced malignancy.

Abdulrahman, Randa M.; Verloop, Herman; Hoftijzer, Hendrieke; Verburg, Erik; Hovens, Guido C.; Corssmit, Eleonora P.; Reiners, Christoph; Gelderblom, Hans; Pereira, Alberto M.; Kapiteijn, Ellen; Romijn, Johannes A.; Visser, Theo J.; Smit, Johannes W.

Fitter, Stephen; Vandyke, Kate; Schultz, Christopher G.; White, Deborah; Hughes, Timothy P.; Zannettino, Andrew C. W.

doi: 10.1210/jc.2010-0086pmid: 20466781

Context: The mechanism(s) by which imatinib improves glycemic control in chronic myeloid leukemia (CML) patients with type 2 diabetes remains unclear.Objective: Adiponectin is an important regulator of insulin sensitivity that is secreted exclusively by adipocytes. We previously reported that imatinib promotes adipocytic differentiation of mesenchymal stromal cells. We therefore hypothesized that imatinib therapy would be associated with an increase in peripheral and intramedullary adiposity and elevated plasma adiponectin levels.Research Design and Methods: Adiponectin levels in CML patient plasma, at diagnosis and then during imatinib mesylate therapy, was measured using an ELISA. Adiponectin multimers in plasma were analyzed using nondenaturing PAGE and immunoblotting. Intramedullary adiposity and adipose tissue mass was determined using histomorphometry and dual-energy X-ray absorptiometry, respectively.Results: In CML patients, an increase in intramedullary and peripheral adiposity was observed after 6 months of imatinib therapy and plasma adiponectin levels, in the form of high- and low-molecular-weight complexes, were elevated 3-fold, compared with pretreatment levels, after 3, 6, and 12 months of therapy.Conclusions: Elevated adiponectin levels in imatinib-treated CML patients provide a possible mechanism for improved glucose and lipid metabolism reported for some imatinib-treated patients.

Rothenbuhler, Anya; Marchand, Isis; Bougnères, Pierre; Linglart, Agnès

doi: 10.1210/jc.2009-2814pmid: 20501688

Background: Hypocalcemia carries a risk of cardiac conduction incidents and death. Hypocalcemia is a frequent adverse effect of pamidronate.Objective: The objective of this study was to investigate whether pamidronate infusion lengthens the ventricular repolarization in children.Design and Methods: Thirty-four children with cerebral palsy and severe osteoporosis were treated for approximately 1 yr with pamidronate (three times per year). Calcemia and corrected QT interval (QTc) (in which the QT interval is a measure between the Q and T waves in the electrical cycle of the heart) were measured before and after each cycle of intravenous infusions.Results: Pamidronate decreased calcemia in all patients from 2.40 to 2.21 mm (P < 0.0001) and increased QTc from 390 to 403 ms (P < 0.0001), with 7.4% of postinfusion QTc becoming longer than 440 ms. QTc at baseline was significantly correlated to final QTc (P < 0.0001; r2 = 0.27).Conclusions: Because we observed a lengthening in QTc after bisphosphonate infusion, we recommend that children treated with pamidronate should receive attention as to other possible risk factors of prolonged QT and have a preinfusion and postinfusion measurement of their QTc.

Birzniece, Vita; Sata, Akira; Sutanto, Surya; Ho, Ken K. Y.

doi: 10.1210/jc.2010-0476pmid: 20444909

Context: Paracrine regulation is emerging as a discrete control mechanism in the endocrine system. In hypogonadal men, stimulation of GH secretion by testosterone requires prior aromatization to estradiol, a paracrine effect unmasked by central estrogen receptor blockade with tamoxifen. In hypogonadal women, estrogen replacement via a physiological non-oral route fails to enhance GH secretion, indicating an absence of an endocrine effect. The aim was to investigate whether local estrogens produced from aromatization regulate GH secretion.Design: We conducted an open-label, two-phase, crossover study.Patients and Intervention: We compared the effects on GH secretion of tamoxifen with estradiol valerate in postmenopausal women. Ten women were treated with tamoxifen (10 and 20 mg/d) and estradiol valerate (2 mg/d) via oral route for 2 wk each, with a washout period of at least 6 wk.Main Outcome Measures: We measured the GH response to arginine and circulating levels of IGF-I and SHBG, markers of hepatic estrogen effect.Results: The GH response to arginine was reduced by 10- and 20-mg tamoxifen in a dose-dependent manner and potentiated significantly (P < 0.05) by estradiol valerate. Mean IGF-I concentration was reduced significantly with high-dose tamoxifen (P < 0.01) and estradiol valerate treatment (P < 0.05), whereas mean SHBG levels rose with both (P < 0.01).Conclusions: Blunted GH response to stimulation occurring in the face of reduced IGF-I feedback inhibition with tamoxifen indicates that GH secretion was suppressed by estrogen receptor antagonism. Because circulating estradiol was unaffected, these data indicate a significant role of local estrogen in the central control of GH secretion. We conclude that aromatase mediates the paracrine control of GH secretion in women.

Lima, Marcelo M. O.; Pareja, José C.; Alegre, Sarah M.; Geloneze, Sylka R.; Kahn, Steven E.; Astiarraga, Brenno D.; Chaim, Élinton A.; Geloneze, Bruno

doi: 10.1210/jc.2010-0085pmid: 20484482

Context: Insulin resistance ameliorates after bariatric surgery, yet there is still a need for data on the acute effect of Roux-en-Y gastric bypass (RYGBP) on insulin sensitivity.Objective: The objective of the study was to describe the acute effect of RYGBP on insulin sensitivity, measured by both the euglycemic-hyperinsulinemic clamp and homeostasis model assessment insulin resistance index (HOMA-IR).Design and Setting: Evaluations were conducted before and 1 month after RYGBP at State University of Campinas (São Paulo, Brazil).Patients: Patients included 19 premenopausal women with metabolic syndrome aged 35.3 (6.7) yr, body mass index 45.50 (3.74) kg/m2 [mean (sd)]. Six had mild type 2 diabetes, seven impaired glucose tolerance, and six normal glucose tolerance.Interventions and Main Outcome Measures: The volunteers underwent RYGBP either alone or combined with omentectomy. Euglycemic-hyperinsulinemic clamp, HOMA-IR, nonesterified fatty acids, leptin, ultrasensitive C-reactive protein, adiponectin, and IL-6 were assessed at baseline and 4.5 (0.9) wk postoperatively.Results: Fasting glucose decreased [99.2 (13.1) to 83.6 (8.1) mg/dl, P < 0.01] along with a reduction in fasting insulin [30.4 (17.0) to 11.4 (6.3) mU/liter, P < 0.01]. M value did not improve postoperatively [25.82 (6.30) to 22.02 (6.05) μmol/kgFFM · min] despite of a decrease in body weight [114.8 (14.5) to 102.3 (14.5) kg, P < 0.001]. This finding was discordant to the observation of an improvement in HOMA-IR [3.85 (2.10) to 1.42 (0.76), P < 0.01]. Nonesterified fatty acids increased. Leptin and C-reactive protein decreased. IL-6 and adiponectin remained unchanged.Conclusions: A month after RYGBP, fasting glucose metabolism improves independent of a change in peripheral insulin sensitivity.

Sayers, Adrian; Marcus, Michele; Rubin, Carol; McGeehin, Michael A.; Tobias, Jonathan H.

doi: 10.1210/jc.2009-2446pmid: 20484488

Context: There is evidence that sex differences in hip structure are increased during puberty, possibly as a consequence of associated changes in body composition.Objectives: The objective of the study was to explore relationships between sex, puberty, hip structure, and body composition.Design/Setting: The design was a longitudinal birth cohort study: The Avon Longitudinal Study of Parents and Children.Participants: Participants included 3914 boys and girls (mean age 13.8 yr).Outcome Measures: Measures included dual-energy x-ray absorptiometry-derived femoral neck width (FNW), cortical thickness (CT), bending strength [cross-sectional moment of inertia (CSMI)], section modulus, buckling ratio (BR), and femoral neck and total hip bone mineral density.Results: FNW, CT, and CSMI were higher in boys, whereas BR was lower in girls (P < 0.001). Differences in hip structure were studied according to puberty (self-completion Tanner stage questionnaires). FNW, CT, and CSMI were higher in Tanner stage IV/V vs. I/II, particularly in boys (P < 0.001, puberty-sex interaction). BR was lower in Tanner stage IV/V, particularly in girls (P = 0.008, puberty-sex interaction). Adjusting for height, fat mass, and lean mass resulted in differential attenuation in the sexes, such that CT attenuated by about 80% and about 40% in boys and girls, respectively (P = 0.004, puberty-sex interaction for adjusted CT, Tanner stages I/II vs. IV/V). The difference in BR showed little attenuation after adjustment.Conclusion: During puberty, hip-bending strength increases, particularly in boys, due to their greater FNW, reflecting changes in height, fat mass, and lean mass. In contrast, BR falls during puberty, particularly in girls, reflecting their smaller FNW relative to CT, involving mechanisms partly independent of height and body composition.