Conclusion: Although surgery continues to be commonly recommended, strategies for such patients should increasingly seek to define treatment based on the estimation of an individual’s thyroid cancer risk in comparison with associated operative risk and morbidity. In doing so, the rate of unnecessary surgical procedures and associated complications can be reduced.

Participants: An open international multidisciplinary expert meeting was held in October 2006 in Toulouse, France, with 37 invited speakers and session chairs (see Acknowledgments) and 85 additional registered participants. The meeting was supported by an unrestricted educational grant from Pfizer.

Evidence: Invited participants with particular expertise reviewed the published evidence base for their specialist topic and unpublished data from personal experience, previous national and international PWS conferences, and PWS Association clinical advisory groups. Sessions covered epidemiology, psychiatric, and behavioral disorders; breathing and sleep abnormalities; genetics; endocrinology; and management in infancy, childhood, transition, and adulthood.

Consensus Process: This included group meetings including open discussion after each session. The guidelines were written by the Scientific Committee (authors), using the conclusions provided by the sessions chairs and summary provided by each speaker, including incorporation of changes suggested after review by selected meeting participants (see Acknowledgments).

Conclusions: The diagnosis and management of this complex disorder requires a multidisciplinary approach with particular emphasis on the importance of early diagnosis using accredited genetic testing, use and monitoring of GH therapy from early childhood, control of the food environment and regular exercise, appropriate management of transition, consideration of group home placement in adulthood, and distinction of behavioral problems from psychiatric illness.

Evidence Acquisition: A detailed literature search from 1985–2008 was performed using PubMed and subsequent reference searches of retrieved articles. Selection of included articles was based on rigor of scientific design, adequate sample size, quality of the data, statistical analysis, and hypothesis testing.

Evidence Synthesis: CVD risk factors in children predict pathological lesions of atherosclerosis in young adults, and their clinical manifestations, as judged by carotid intima medial thickness, coronary artery calcium, or brachial flow-mediated dilatation. About half the offspring of a parent with premature CVD have a primary dyslipidemia. However, use of family history to identify such youth will miss the majority of children with dyslipidemia. Treatment of dyslipidemia starts with a low-fat diet supplemented with water-soluble fiber, plant stanols, and plant sterols, weight control, and exercise. Drug therapy with inhibitors of hydroxymethylglutaryl coenzyme A reductase, bile acid sequestrants (BAS), and cholesterol absorption inhibitors can be considered in adolescents with a positive family history of premature CVD and a low-density lipoprotein cholesterol of more than 160 mg/dL. Such dietary and drug therapy appears safe and efficacious and is likely to retard atherosclerosis.

Conclusions: Early identification and treatment of youth at risk for early atherosclerosis will require an integrated assessment of predisposing CVD risk factors and a comprehensive universal screening and treatment program.

Participants: Participants were 32 invited leaders in the field.

Evidence: Evidence was obtained by extensive literature review and from clinical experience.

Consensus: Participants reviewed discussion summaries, voted, and reached a majority decision on each document section.

Conclusions: ISS is defined auxologically by a height below –2 sd score (SDS) without findings of disease as evident by a complete evaluation by a pediatric endocrinologist including stimulated GH levels. Magnetic resonance imaging is not necessary in patients with ISS. ISS may be a risk factor for psychosocial problems, but true psychopathology is rare. In the United States and seven other countries, the regulatory authorities approved GH treatment (at doses up to 53 µg/kg·d) for children shorter than –2.25 SDS, whereas in other countries, lower cutoffs are proposed. Aromatase inhibition increases predicted adult height in males with ISS, but adult-height data are not available. Psychological counseling is worthwhile to consider instead of or as an adjunct to hormone treatment. The predicted height may be inaccurate and is not an absolute criterion for GH treatment decisions. The shorter the child, the more consideration should be given to GH. Successful first-year response to GH treatment includes an increase in height SDS of more than 0.3–0.5. The mean increase in adult height in children with ISS attributable to GH therapy (average duration of 4–7 yr) is 3.5–7.5 cm. Responses are highly variable. IGF-I levels may be helpful in assessing compliance and GH sensitivity; levels that are consistently elevated (>2.5 SDS) should prompt consideration of GH dose reduction. GH therapy for children with ISS has a similar safety profile to other GH indications.

Design: Sixty overweight youth (8–17 yr old) completed two OGTTs (interval between tests 1–25 d). Insulin sensitivity was assessed by the surrogate measures of fasting glucose to insulin ratio, whole-body insulin sensitivity index, and homeostasis model assessment of insulin resistance, and insulin secretion by the insulinogenic index with calculation of the glucose disposition index (GDI).

Results: Of the 10 subjects with impaired glucose tolerance (IGT) during the first OGTT only three (30%) had IGT during the second OGTT. The percent positive agreement between the first and second OGTT was low for both impaired fasting glucose and IGT (22.2 and 27.3%, respectively). Fasting blood glucose had higher reproducibility, compared with the 2-h glucose. Youth with discordant OGTTs, compared with those with concordant results, were more insulin resistant (glucose/insulin 2.7 ± 1.4 vs. 4.1 ± 1.8, P = 0.006, whole-body insulin sensitivity index of 1.3 ± 0.6 vs. 2.2 ± 1.1, P = 0.003, and homeostasis model assessment of insulin resistance 10.6± 8.1 vs. 5.7 ± 2.8, P = 0.001), had a lower GDI (0.45 ± 0.58 vs. 1.02 ± 1.0, P = 0.03), and had higher low-density lipoprotein cholesterol (117.7 ± 36.6 vs. 89.9 ± 20.1, P = 0.0005) without differences in physical characteristics.

Conclusions: Our results show poor reproducibility of the OGTT in obese youth, in particular for the 2-h plasma glucose. Obese youth who have discordant OGTT results are more insulin resistant with higher risk of developing type 2 diabetes mellitus, as evidenced by a lower GDI. The implications of this remain to be determined in clinical and research settings.

Objective: Our objective was to determine the prevalence of unrecognized probable diabetes in this patient population determined by elevated hemoglobin A1c (HbA1c) level.

Design: We conducted a prospective observational cohort trial with retrospective follow-up of patients with elevated HbA1c levels and no diagnosis of diabetes. HbA1c levels were obtained for all patients.

Setting: The study was conducted at an acute care general hospital.

Patients: Patients included 695 adult, nonobstetric patients admitted on 11 d in 2006.

Main Outcome Measures: Outcome measures included rate of unrecognized probable diabetes, defined as admission HbA1c of more than 6.1% and no diagnosis of diabetes or treatment with antidiabetic medications before or during their admission and rate of unrecognized diabetes 1 yr after discharge.

Results: Eighteen percent of hospitalized patients had elevated HbA1c levels without a diagnosis of diabetes. Random glucose levels poorly predicted elevated HbA1c levels (area under receiver operating characteristic curve, 0.60). Neither diagnosed diabetes nor HbA1c level was associated with length of stay or costs (P > 0.1 for all comparisons). Only 15% of patients with elevated HbA1c levels who continued to receive care within the system studied had diabetes diagnosed in the year after the index admission.

Conclusions: Nearly one in five adult patients admitted to a large general hospital had unrecognized probable diabetes, based on elevated HbA1c levels. Random glucose levels during the hospital stay were poorly predictive of this condition. Few hospitalized patients with elevated HbA1c levels were diagnosed within the year after admission.

Objective: Our objective was to compare standard-dose and low-dose corticotropin tests for diagnosing HPAI.

Data Sources: We searched the PubMed database from 1966–2006 for studies reporting diagnostic value of standard-dose or low-dose corticotropin tests, with patient-level data obtained from original investigators.

Study Selection: Eligible studies had more than 10 patients. All subjects were evaluated because of suspicion for chronic HPAI, and patient-level data were available. We excluded studies with no accepted reference standard for HPAI (insulin hypoglycemia or metyrapone test) if test subjects were in the intensive care unit or if only normal healthy subjects were used as controls.

Data Extraction: We constructed receiver operator characteristic (ROC) curves using patient-level data from each study and then merged results to create summary ROC curves, adjusting for study size and cortisol assay method. Diagnostic value of tests was measured by calculating area under the ROC curve (AUC) and likelihood ratios.

Data Synthesis: Patient-level data from 13 of 23 studies (57%; 679 subjects) were included in the metaanalysis. The AUC were as follows: low-dose corticotropin test, 0.92 (95% confidence interval 0.89–0.94), and standard-dose corticotropin test, 0.79 (95% confidence interval 0.74–0.84). Among patients with paired data (seven studies, 254 subjects), diagnostic value of low-dose corticotropin test was superior to standard-dose test (AUC 0.94 and 0.85, respectively; P < 0.001).

Conclusions: Low-dose corticotropin test was superior to standard-dose test for diagnosing chronic HPAI, although it has technical limitations.

Objective: We aimed to assess the contribution of weight and specific measures of central and peripheral adiposity to GH response to GHRH-arginine testing in lean, overweight, and obese men.

Design: A total of 75 men [mean age, 44.3 ± 1.1 yr; body mass index (BMI), 28.8 ± 0.7 kg/m²] were investigated. Subjects were classified as lean (BMI < 25 kg/m²; n = 23), overweight (BMI ≥ 25 and <30 kg/m²; n = 28), or obese (BMI ≥ 30 kg/m²; n = 24). Subjects were also stratified by waist circumference (WC) (<102 cm, n = 47; ≥102 cm, n = 28). Body composition and regional adiposity were assessed by anthropometrics, dual-energy x-ray absorptiometry (DEXA), and abdominal computed tomography (CT) scans.

Results: Peak stimulated GH was 36.4 ± 5.4, 16.6 ± 2.9, and 7.6 ± 0.9 µg/liter among lean, overweight, and obese subjects, respectively (P < 0.001 for all comparisons). Peak stimulated GH was 26.9 ± 3.4 µg/liter among subjects with WC less than 102 cm compared to 7.9 ± 0.9 µg/liter among subjects with WC of 102 cm or greater (P < 0.0001). Separate multivariate models using anthropometric, DEXA, and CT-derived measures of central adiposity demonstrated strong associations between peak stimulated GH and measures of central adiposity including WC, trunk fat by DEXA, and visceral adiposity by CT, controlling for age, BMI, and more general measures of adiposity. WC was independently associated with peak GH response to GHRH-arginine in a model including age, BMI, and hip circumference. In this model, BMI was no longer significant, and peak GH was reduced 1.02 µg/liter for each 1 cm increase in WC (P = 0.02).

Conclusions: GH response to GHRH-arginine testing is reduced in both overweight and obese subjects and negatively associated with indices of central abdominal obesity including WC, trunk fat, and visceral adipose tissue. The use of waist circumference, as a surrogate for central adiposity, adds predictive information to the determination of GH response, independent of BMI.

Objective: To clarify the inheritance of hypothyroidism, we looked at the DUOX2 gene in patients with transient congenital hypothyroidism.

Design: DUOX2, thyroid peroxidase, Na⁺/I^– symporter and dual oxidase maturation factor 2 genes were analyzed in eight patients with transient congenital hypothyroidism, using the PCR-amplified direct sequencing method.

Patients: The eight patients were found by a neonatal screening program. Six of these patients belonged to two independent families; the other two were unrelated. Their serum TSH values varied from 24.8–233.0 mU/liter. Six of the eight patients had a low serum freeT₄ level (0.19–0.84 ng/dl). Seven of the eight patients were treated with thyroid hormone replacement therapy, which ceased to be necessary by 9 yr of age.

Results: Eight novel mutations were detected in the DUOX2 gene. Four patients in one family were compound heterozygous for p.L479SfsX2 and p.K628RfsX10. Two patients in a second family were compound heterozygous for p.K530X and p.[E876K;L1067S]. The two remaining unrelated patients were also compound heterozygous, for p.H678R/p.L1067S and p.A649E/p.R885Q, respectively.

Conclusion: All eight patients had biallelic mutations in the DUOX2 gene. We find that loss of DUOX2 activity results in transient congenital hypothyroidism and that transient congenital hypothyroidism caused by DUOX2 mutations is inherited as an autosomal recessive trait.

Objective: The objective of the study was to examine the interrelationships among testosterone (T), androstenedione, estradiol (E₂), estrone, and SHBG in postmenopausal women.

Design: This was a cross-sectional study of women participating in the National Heart, Blood, and Lung Institute-sponsored Women’s Ischemia Syndrome Evaluation study.

Setting: The study was conducted at four academic medical centers.

Patients: A total of 284 postmenopausal women with chest pain symptoms or suspected myocardial ischemia.

Main Outcome Measures: Post hoc analysis of the relationships among sex steroid hormones with insulin resistance, body mass index (BMI), and presence or absence of coronary artery disease as determined by coronary angiography.

Results: BMI was significantly associated with insulin resistance, total E₂, free E₂, bioavailable E₂, and free T. Highly significant correlations were found for total T, free T, and androstenedione with total E₂, free E₂, bioavailable E₂, and estrone and persisted after adjustment for BMI and insulin resistance. A significant relationship was present between total and free T and the presence of coronary artery disease after adjustment for the effect of E₂.

Conclusions: Serum levels of androgens and estrogens track closely in postmenopausal women referred for coronary angiography for suspected myocardial ischemia. Epidemiological studies that relate sex steroid hormones to physiological or pathological processes need to control for the independent effect of both estrogens and androgens.

Objectives: Our objectives were to analyze the relationship between weight and circulating VEGF-A in morbidly obese subjects before and after bariatric surgery, and investigate the relationship between circulating VEGF-A and certain adipocytokines and hormones regulating adipocytes.

Methods: A total of 45 morbidly obese women and nine lean females were included in the study. Patients underwent bariatric surgery: vertical banded gastroplasty (n = 17), gastric bypass (n = 17), and biliopancreatic diversion (n = 11). Serum samples for VEGF-A, adiponectin, leptin, ghrelin, and insulin were obtained preoperatively and 9–12 months after surgery.

Results: Obese patients showed significantly higher VEGF-A levels than controls (306.3 ± 170.3 vs. 187.6 ± 91.9 pg/ml; P = 0.04), decreasing to 246.1 ± 160.4 after surgery (P < 0.001), with no differences among surgical procedures. In controls there was an inverse correlation between VEGF-A and ghrelin (r = –0.85; P <.01), but not in obese patients. Leptin and insulin concentrations were increased in obese patients, with a significant decrease shown after weight loss with surgery. Conversely, adiponectin concentrations were lower in obese patients, with a significant increase shown after weight loss with surgery. Ghrelin was higher in controls than obese patients, decreasing after gastric bypass and biliopancreatic diversion, but not after vertical banded gastroplasty.

Conclusion: Serum VEGF-A levels are significantly higher in obese patients than in lean controls, decreasing after weight loss with bariatric surgery, behaving similarly to other hormones related to adipose mass like leptin and insulin.

Objective: The objective of the study was to examine the relationship between the concentrations of serum enzymatically and nonenzymatically generated oxysterols, measures of obesity, and metabolic components including insulin resistance and levels of blood pressure and serum lipids.

Design: This was a cross-sectional study.

Setting: All subjects were examined between 2003 and 2005 at a hospital, a part of a follow-up evaluation mother-daughter pairs representing pregnancies affected or unaffected by gestational diabetes that resulted in the deliveries in 1989–1991.

Subjects: Subjects included a subset (n = 89) of the total study population of 189 adolescent girls with a mean age of 15.32 ± 0.65 yr and body mass index of 22.54 ± 3.98 kg/m².

Main Outcome Measures: Measures included serum levels of the oxysterols 7-hydroxy-cholesterol, 7β-hydroxycholesterol, and 7-ketocholesterol; and body mass index, homeostasis model assessment insulin resistance index, fasting insulin, fasting glucose, blood pressure, total cholesterol, non-high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B (ApoB).

Results: Serum oxysterol concentrations in the adolescent cohort correlated positively with insulin (P < 0.05), total cholesterol (P < 0.05), non-high-density lipoprotein cholesterol (P < 0.05), low-density lipoprotein cholesterol (P < 0.05), and ApoB (P < 0.01). ApoB and fasting insulin were found to be the major determinants of serum oxysterols after adjustment for body mass index. Being a daughter of gestational diabetes pregnancy alone did not seem to be a predisposing factor to increased oxidative stress in our cohort.

Conclusion: Serum oxysterol concentrations increase with obesity, insulin, and ApoB, which are established derangements associated with the metabolic syndrome.

Objective: Because severe variants in HH-related genes cause a severe puberty phenotype, we hypothesized that common subtle variation in these genes could contribute to the population variation in pubertal timing.

Design: We assessed common genetic variation in 10 HH-related genes in 1801 women from the Hawaii and Los Angeles Multiethnic Cohort with either early (age < 11 yr) or late (age > 14 yr) menarche and in other replication samples. In addition to these common variants, we also studied the most frequently reported HH mutations to assess their role in the population variation in pubertal timing.

Setting and Patients/Other Participants: Within the general community, 1801 women from the Hawaii and Los Angeles Multiethnic Cohort participated.

Main Outcome Measures: We assessed the association of genetic variation with age at menarche.

Results: We found no significant association between any of the variants tested and age at menarche, although we cannot rule out modest effects of these variants or of other variants at long distances from the coding region. In several self-reported racial/ethnic groups represented in our study, we observed an association between estimated genetic ancestry and age at menarche.

Conclusions: Our results suggest that common variants near 10 HH-related loci do not play a substantial role in the regulation of age at menarche in the general population.

Objective: We investigated the effects of metformin, oral contraceptives (OCs), and/or lifestyle modification in obese adolescent women with PCOS.

Design: Two small, randomized, placebo-controlled clinical trials were performed.

Patients and Participants: A total of 79 obese adolescent women with PCOS participated.

Interventions: In the single treatment trial, subjects were randomized to metformin, placebo, a lifestyle modification program, or OC. In the combined treatment trial, all subjects received lifestyle modification and OC and were randomized to metformin or placebo.

Main Outcome Measures: Serum concentrations of androgens and lipids were measured.

Results: Lifestyle modification alone resulted in a 59% reduction in free androgen index with a 122% increase in SHBG. OC resulted in a significant decrease in total testosterone (44%) and free androgen index (86%) but also resulted in an increase in C-reactive protein (39.7%) and cholesterol (14%). The combination of lifestyle modification, OC, and metformin resulted in a 55% decrease in total testosterone, as compared to 33% with combined treatment and placebo, a 4% reduction in waist circumference, and a significant increase in HDL (46%).

Conclusions: In these preliminary trials, both lifestyle modification and OCs significantly reduce androgens and increase SHBG in obese adolescents with PCOS. Metformin, in combination with lifestyle modification and OC, reduces central adiposity, reduces total testosterone, and increases HDL, but does not enhance overall weight reduction.

Methods: In the PROgramming factors for GRowth And Metabolism study, a cohort of 297 young adults, aged 18–24 yr, the influence of clinical parameters on total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, lipoprotein a, and apolipoprotein (apo) A-1 and apoB was analyzed with multiple regression modeling. In addition, differences in these lipid levels and ApoE genotype prevalence were analyzed in four subgroups: young adults either born small for gestational age with short stature or with catch-up growth, or born appropriate for gestational age with idiopathic short stature or with normal stature (controls).

Results: Birth length sd score (SDS) and birth weight SDS were no significant determinants of the serum lipid levels, whereas gender, ApoE genotype, adult height SDS, adult weight SDS, and fat mass were. Comparison of the subgroups showed that small for gestational age with short stature subjects had a significantly higher apoB than controls. There were no other significant differences in lipid levels or ApoE genotype prevalence among the four subgroups.

Conclusions: ApoE genotype is an important genetic determinant of lipid levels in young adulthood. Furthermore, fat accumulation during childhood significantly determines serum lipid levels, whereas birth size has no significant contribution. For public health practice, this means that parents and their children need to be informed about the risks of fat accumulation during childhood.

Objective: We investigated adipose tissue gene expression from human obese women according to energy deficit and the fat and carbohydrate content of the diet.

Design and Setting: Obese subjects recruited among eight European clinical centers were followed up 10 wk of either a low-fat (high carbohydrate) or a moderate-fat (low carbohydrate) hypoenergetic diet.

Subjects: Two sets of 47 women in each dietary arm were selected among 648 subjects matched for anthropometric and biological parameters.

Main Outcome Measure: We measured adipose tissue gene expression changes in one set using a candidate gene approach. The other set was used to survey 24,469 transcripts using DNA microarrays. Results were analyzed using dedicated statistical methods. Diet-sensitive regulations were confirmed on the other set of subjects.

Results: The two diets induced similar weight loss and similar changes for most of the biological variables except for components of the blood lipid profile. One thousand genes were regulated by energy restriction. We validated an effect of the fat to carbohydrate ratio for five genes (FABP4, NR3C1, SIRT3, FNTA, and GABARAPL2) with increased expression during the moderate-fat diet.

Conclusions: Energy restriction had a more pronounced impact on variations in human adipose tissue gene expression than macronutrient composition. The macronutrient-sensitive regulation of a subset of genes may influence adipose tissue function and metabolic response.

Objective: The aim of the study was to determine the value of Dex-oCRH testing in the investigation of childhood CS.

Design: We conducted a retrospective analysis of data from children evaluated for CS vs. PCSS from 1998–2006; body mass index Z (BMIZ) and height-for-age Z (HAZ) scores were estimated.

Setting: A clinical research center was the setting for the study.

Main Outcome Measures: The main outcomes were confirmation of the diagnosis of CS by histology and response to Dex-oCRH.

Results: Thirty-two children (ages 3–17 yr) were studied: 11 had CS and 21 had PCSS; of the latter, 11 had a BMIZ score greater than 2. Children with CS had a mean HAZ score of –1.3 ± 0.51 vs. 0.31 ± 0.38 in nonobese and 0.71 ± 0.39 in obese children (P < 0.001). The previously established criterion of a cortisol of 1.4 µg/dl (38 nmol/liter) after Dex-oCRH identified all 10 normal children who were not very obese and those with CS; 5 of 11 normal children with more severe obesity had cortisol values greater than 1.4 µg/dl (38 nmol/liter) after Dex-oCRH, lowering the test specificity to 55%. Without consideration for obesity, an increase of the cutoff cortisol value after Dex-oCRH to 3.2 µg/dl (88 nmol/liter) will have 91% sensitivity and 95% specificity; the corresponding values for a cutoff of 2.2 µg/dl (61 nmol/liter) were 100 and 90.5%, respectively.

Conclusion: Our study showed that height gain is a simple way of distinguishing children with PCCS from those with CS; the interpretation of Dex-oCRH in children is confounded by severe obesity, which limits the utility of this test.

Objective: We evaluated 40 reported thyroid cancer-derived cell lines using short tandem repeat and single nucleotide polymorphism array analysis.

Results: Only 23 of 40 cell lines tested have unique genetic profiles. The following groups of cell lines are likely derivatives of the same cell line: BHP5-16, BHP17-10, BHP14-9, and NPA87; BHP2-7, BHP10-3, BHP7-13, and TPC1; KAT5, KAT10, KAT4, KAT7, KAT50, KAK1, ARO81-1, and MRO87-1; and K1 and K2. The unique cell lines include BCPAP, KTC1, TT2609-C02, FTC133, ML1, WRO82-1, 8505C, SW1736, Cal-62, T235, T238, Uhth-104, ACT-1, HTh74, KAT18, TTA1, FRO81-2, HTh7, C643, BHT101, and KTC-2. The misidentified cell lines included the DRO90-1, which matched the melanoma-derived cell line, A-375. The ARO81-1 and its derivatives matched the HT-29 colon cancer cell line, and the NPA87 and its derivatives matched the M14/MDA-MB-435S melanoma cell line. TTF-1 and Pax-8 mRNA levels were determined in the unique cell lines.

Conclusions: Many of these human cell lines have been widely used in the thyroid cancer field for the past 20 yr and are not only redundant, but not of thyroid origin. These results emphasize the importance of cell line integrity, and provide the short tandem repeat profiles for a panel of thyroid cancer cell lines that can be used as a reference for comparison of cell lines from other laboratories.

Objective: The aim of the study was to investigate the effect on growth to FH of two GH doses given to short children, mainly with ISS, compared with untreated controls.

Design and Setting: A randomized, controlled, long-term multicenter trial was conducted in Sweden.

Intervention: Two doses of GH (Genotropin) were administered, 33 or 67 µg/kg·d; control subjects were untreated.

Subjects: A total of 177 subjects with short stature were enrolled. Of these, 151 were included in the intent to treat (All_ITT) population, and 108 in the per protocol (All_PP) population. Analysis of ISS subjects included 126 children in the ITT (ISS_ITT) population and 68 subjects in the PP (ISS_PP) population.

Main Outcome Measures: We measured FH sd score (SDS), difference in SDS to midparenteral height (diff MPH_SDS), and gain in height_SDS.

Results: After 5.9 ± 1.1 yr on GH therapy, the FH_SDS in the All_PP population treated with GH vs. controls was –1.5 ± 0.81 (33 µg/kg·d, –1.7 ± 0.70; and 67 µg/kg·d, –1.4 ± 0.86; P < 0.032), vs. –2.4 ± 0.85 (P < 0.001); the diff MPH_SDS was –0.2 ± 1.0 vs. –1.0 ± 0.74 (P < 0.001); and the gain in height_SDS was 1.3 ± 0.78 vs. 0.2 ± 0.69 (P < 0.001). GH therapy was safe and had no impact on time to onset of puberty. A dose-response relationship identified after 1 yr remained to FH for all growth outcome variables in all four populations.

Conclusion: GH treatment significantly increased FH in ISS children in a dose-dependent manner, with a mean gain of 1.3 SDS (8 cm) and a broad range of response from no gain to 3 SDS compared to a mean gain of 0.2 SDS in the untreated controls.

Objective: The goal of this study was to identify and characterize novel mutations in pituitary specific transcription factors from CPHD patients.

Design: Genomic DNA was isolated from patients with hypopituitarism to amplify and sequence eight pituitary specific transcription factors (HESX1, LHX3, LHX4, OTX2, PITX2, POU1F1, PROP1, and SIX6). Characterization of novel mutations is based on structural and functional studies.

Results: We describe two unrelated children with CPHD who presented with neonatal hypoglycemia, and deficiencies of GH, TSH, LH, FSH, and ACTH. Magnetic resonance imaging revealed anterior pituitary hypoplasia with an ectopic posterior pituitary. A novel heterozygous OTX2 mutation (N233S) was identified. Wild-type and mutant OTX2 proteins bind equivalently to bicoid binding sites, whereas mutant OTX2 revealed decreased transactivation.

Conclusions: A novel mutation in OTX2 binds normally to target genes and acts as a dominant negative inhibitor of HESX1 gene expression. This suggests that the expression of HESX1, required for spaciotemporal development of anterior pituitary cell types, when disrupted, results in an absent or underdeveloped anterior pituitary with diminished hormonal expression. These results demonstrate a novel mechanism for CPHD and extend our knowledge of the spectrum of gene mutations causing CPHD.

Objective: The aim of this study was to investigate the association of estimated regional fat mass, measured with DEXA and CVD risk factors.

Design, Setting, and Participants: This was a cross-sectional study of 175 men and 417 women. DEXA measurements of regional fat mass were performed on all subjects, who subsequently participated in a community intervention program.

Main Outcome Measures: Outcome measures included impaired glucose tolerance, hypercholesterolemia, hypertriglyceridemia, and hypertension.

Results: We began by assessing the associations of the adipose measures with the cardiovascular outcomes. After adjustment for confounders, a sd unit increase in abdominal fat mass was the strongest predictor of most cardiovascular variables in men [odds ratio (OR) = 2.63–3.37; P < 0.05], whereas the ratio of abdominal to gynoid fat mass was the strongest predictor in women (OR = 1.48–2.19; P < 0.05). Gynoid fat mass was positively associated with impaired glucose tolerance, hypertriglyceridemia, and hypertension in men (OR = 2.07–2.15; P < 0.05), whereas the ratio of gynoid to total fat mass showed a negative association with hypertriglyceridemia and hypertension (OR = 0.42–0.62; P < 0.005).

Conclusions: Abdominal fat mass is strongly independently associated with CVD risk factors in the present study. In contrast, gynoid fat mass was positively associated, whereas the ratio of gynoid to total fat mass was negatively associated with risk factors for CVD.

Objective: Our objective was to define more precisely the chromosomal regions and uncover novel genes associated with MTC tumorigenesis.

Design and Setting: In this study, we used high resolution array-based comparative genomic hybridization to define tumor-associated copy number alterations (CNA) in 30 primary MTCs: 20 sporadic tumors (50% of which harbored RET mutation), and 10 hereditary.

Results: We identified 98 CNA, including 76 genomic allelic losses, two gains, and 20 copy number variations associated with MTC. Across sporadic and hereditary groups, there was a similar and overlapping pattern of predominant allelic loss. There were 29 regions containing at least 30% CNA in the 30 tumor samples. The most frequent allelic loss occurred in four loci, 7q36.1, 12p13.31, 13q12.11, and 19p13.3-11. No regions were found to be uniquely altered in the hereditary tumors. There were 21 CNA specific to sporadic MTC, with loss of 11q23.3 uniquely altered in RET negative tumors. Pathway analysis found cellular growth and proliferation as the most significant overall target, and cell death as the most significant pathway targeted in sporadic MTC.

Conclusions: Our findings underscore the importance of candidate tumor suppressor genes together with RET alterations in MTCs. Despite of RET status, all MTC might share similar oncogenetic mechanisms. Dysfunction of cell proliferation and cell death may both be involved in MTC tumorigenesis.

Objective: A woman of short adult stature (1.46 m, –3 sd score) born with severe intrauterine growth retardation (1.25 kg at term, –5.4 sd score) and atypical diabetes diagnosed at the age of 23 yr had a balanced chromosomal translocation t(1;11) (p36.22; p15.5). We hypothesized that her phenotype resulted from disruption of her paternally derived IGF2 gene because her daughter who inherited the identical translocation had normal birth weight.

Design: Both chromosomal break points were identified using fluorescent in situ hybridization. Sequence, methylation, and expression of the IGF2 gene was examined. Hyperinsulinemic, euglycemic clamp with glucose tracers and magnetic resonance imaging of the thorax, abdomen, and pelvis were performed.

Results: The 11p15.5 break point mapped 184 kb telomeric of the IGF2 gene. Microsatellite markers confirmed paternal origin of this chromosome. IGF2 gene sequence and methylation was normal. IGF2 gene expression was reduced in lymphoblasts. Clamp studies showed marked hepatic and total insulin resistance. Massive excess sc fat was seen on magnetic resonance imaging despite slim body mass index (21.1 kg/m²).

Conclusions: A break point 184 kb upstream of the paternally derived IGF2 gene, separating it from some telomeric enhancers, resulted in reduced expression in some mesoderm-derived adult tissues causing intrauterine growth retardation, short stature, lactation failure, and insulin resistance with altered fat distribution.

Objective: Our objective was to asses the impact of T₃/T₄ on human HF in vitro.

Methods: Human anagen HFs were isolated from skin obtained from females undergoing facelift surgery. HFs from euthyroid females between 40 and 69 yr (average, 56 yr) were cultured and treated with T₃/T₄.

Results: Studying microdissected, organ-cultured normal human scalp HFs, we show here that T₄ up-regulates the proliferation of hair matrix keratinocytes, whereas their apoptosis is down-regulated by T₃ and T₄. T₄ also prolongs the duration of the hair growth phase (anagen) in vitro, possibly due to the down-regulation of TGF-β2, the key anagen-inhibitory growth factor. Because we show here that human HFs transcribe deiodinase genes (D2 and D3), they may be capable of converting T₄ to T₃. Intrafollicular immunoreactivity for the recognized thyroid hormone-responsive keratins cytokeratin (CK) 6 and CK14 is significantly modulated by T₃ and T₄ (CK6 is enhanced, CK14 down-regulated). Both T₃ and T₄ also significantly stimulate intrafollicular melanin synthesis.

Conclusions: Thus, we present the first evidence that human HFs are direct targets of thyroid hormones and demonstrate that T₃ and/or T₄ modulate multiple hair biology parameters, ranging from HF cycling to pigmentation.

Objectives: Because variability in clinical features and age at onset in APS-I frequently results in unusual presentations, we prospectively checked the diagnostic potential of anti-interferon antibodies in additional APS-I panels with other truncations or rare missense mutations and in disease controls with chronic mucocutaneous candidiasis (CMC) but without either common AIRE mutation.

Design: The study was designed to detect autoantibodies against interferon-2 and interferon- in antiviral neutralization assays.

Setting and Patients: Patients included 14 British/Irish, 15 Sardinian, and 10 Southern Italian AIRE-mutant patients with APS-I; also 19 other patients with CMC, including four families with cosegregating thyroid autoimmunity.

Outcome: The diagnostic value of anti-interferon autoantibodies was assessed.

Results: We found antibodies against interferon-2 and/or interferon- in all 39 APS-I patients vs. zero of 48 unaffected relatives and zero of 19 British/Irish CMC patients. Especially against interferon-, titers were nearly always high, regardless of the exact APS-I phenotype/duration or AIRE genotype, including 12 different AIRE length variants or 10 point substitutions overall (n = 174 total). Strikingly, in one family with few typical APS-I features, these antibodies cosegregated over three generations with autoimmune hypothyroidism plus a dominant-negative G228W AIRE substitution.

Conclusions: Otherwise restricted to patients with thymoma and/or myasthenia gravis, these precocious persistent antibodies show 98% or higher sensitivity and APS-I specificity and are thus a simpler diagnostic option than detecting AIRE mutations.

Objective: We identified and functionally characterized a novel T599I-VKSR(600–603)del BRAF mutation in a FV-PTC patient. We analyzed in vitro the effects of this novel mutation in comparison with other thyroid cancer-associated mutations.

Design: Expression vectors for the BRAF mutants were generated and their in vitro kinase activity, signaling along the MAPK pathway, and capability of stimulating transcription from an AP1-responsive reporter evaluated.

Results: BRAF kinase and signaling were increased to a similar extent by the T599I-VKSR (600–603)del, V600E, and K601E mutations. Instead, the G474R, a mutation previously found in a FV-PTC, knocked down the BRAF kinase and its intracellular signaling. Some cancer-associated low-activity BRAF mutants stimulate the MAPK cascade via CRAF; however, the G474R protein lacked also this property.

Conclusion: The T599I-VKSR(600–603)del is a novel gain-of-function mutation that targets BRAF in FV-PTC. Moreover, G474R is the first example of a mutation knocking down enzymatic BRAF activity in a FV-PTC. These findings underscore the importance of functional studies to characterize the role of BRAF mutations associated with thyroid cancer.

Objective: A mutated, replication-competent, vaccinia virus (GLV-1h68) has oncolytic effects on human ATC cell lines in vitro. We assessed the utility of GLV-1h68 in treating anaplastic thyroid cancer in vivo.

Design: Athymic nude mice with xenograft flank tumors of human ATCs (8505C and DRO90–1) were treated with a single intratumoral injection of GLV-1h68 at low dose (5 x 10⁵ plaque-forming unit), high dose (5 x 10⁶ plaque-forming unit), or PBS. Virus-mediated marker gene expression (luciferase, green fluorescent protein, and β-galactosidase), viral biodistribution, and flank tumor volumes were measured.

Results: Luciferase expression was detected 2 d after injection. Continuous viral replication within tumors was reflected by increasing luciferase activity to d 9. At d 10, tumor viral recovery was increased more than 50-fold as compared with the injected dose, and minimal virus was recovered from the lung, liver, brain, heart, spleen, and kidneys. High-dose virus directly injected into normal tissues was undetectable at d 10. The mean volume of control 8505C tumors increased 50.8-fold by d 45, in contrast to 10.5-fold (low dose) and 2.1-fold (high dose; P = 0.028) increases for treated tumors. DRO90–1 tumors also showed significant growth inhibition by high-dose virus. No virus-related toxicity was observed throughout the study.

Conclusions: GLV-1h68 efficiently infects, expresses transgenes within, and inhibits the growth of ATC in vivo. These promising findings support future clinical trials for patients with ATC.

Objective: The objective of the study was to describe the precise ontogeny of androgen receptor expression in the human testis from fetal life through adulthood.

Design: This was an immunohistochemical study on testicular biopsies from fetal, neonatal, prepubertal, pubertal, and adult human testes.

Main Outcome Measures: Quantification of androgen receptor expression in Sertoli cells was measured. Evaluation of androgen receptor expression in peritubular and interstitial cells as well as anti-Müllerian hormone and inhibin- was also performed.

Results: Androgen receptor expression was first observed in the nuclei of few Sertoli cells at the age of 5 months. Labeling was weak in 2–15% of Sertoli cells until 4 yr of age and progressively increased thereafter. High levels of androgen receptor expression were observed in more than 90% from the age of 8 yr through adulthood. Androgen receptor was positive in peritubular cells and variable in interstitial cells. Anti-Müllerian hormone immunolabeling was strong in all Sertoli cells from fetal life throughout prepuberty and weakened progressively as spermatogenesis developed. Inhibin- expression was detected in all Sertoli cells from fetal life through adulthood.

Conclusions: A lack of androgen receptor expression could explain a physiological Sertoli cell androgen insensitivity during fetal and early postnatal life, which may serve to protect the testis from precocious Sertoli cell maturation, resulting in proliferation arrest and spermatogenic development.

Design/Methods: A Medline search and examination of reference lists of included studies and relevant review articles identified 11 studies with utilizable, robust data, involving a total of 268 patients. All included studies were randomized, double blind, placebo controlled, and of either parallel or crossover design. Information was retrieved in uniform format, with data pertaining to patient numbers, study design, GH dose, age, IGF-I levels, and the exercise variables maximal oxygen uptake and maximal power output recorded. The data were analyzed using a fixed-effects model, using continuous data measured on different scales. A summary effect measure (d_s) was derived for the individual exercise parameters, whereas an overall summary effect was derived from the sum of all studies across different variables; 95% confidence intervals were calculated from the weighted variances of individual study effects.

Results: GH replacement was associated with significant improvement with all studies combined (d_s = +0.32, 0.08–0.56), for maximal power output (d_s = +0.4, 0.06–0.74), and maximal oxygen uptake (d_s = +0.34, 0.07–0.62). There was no association between age or GH dose on the degree of improvement.

Conclusions: There is strong evidence that GH replacement improves exercise performance in GH-deficient patients. This evidence should be considered when decisions are made regarding prescription of GH.

Methods: In the present study, we measured circulating blood levels of obestatin and ghrelin and assessed their relationships with anthropometric and clinical measures in 20 AN patients, 21 BN patients, and 20 appropriate healthy controls.

Results: Compared with healthy women, patients with BN showed no significant differences in plasma obestatin and ghrelin concentrations and in the ghrelin/obestatin ratio, whereas underweight AN patients displayed significantly increased circulating levels of both obestatin (P < 0.009) and ghrelin (P < 0.002) and an increased ghrelin/obestatin ratio (P < 0.04). Moreover, in AN women, positive correlations emerged between the ghrelin/obestatin ratio and current body weight and body mass index.

Conclusions: Underweight AN patients are characterized by increased concentrations of ghrelin and obestatin and a higher ghrelin to obestatin ratio. No changes in circulating ghrelin or obestatin as well as in ghrelin to obestatin ratio seem to occur in acutely ill patients with BN. Although those changes likely reflect the physiological state of symptomatic AN individuals, they may also contribute to the pathophysiology of the disorder.

Objective/Subjects: The objective of the study was to examine the distribution of the timing of the onset of puberty in normal Greek girls.

Design: Onset of puberty, i.e. breast development (B2), was studied longitudinally in 311 prepubertal schoolgirls aged 6.4–8.2 yr until the onset of puberty. We also studied cross-sectionally 126 girls, 6–14 yr old.

Setting: Clinical examinations took place in the school setting.

Results: In the longitudinal study, median of the distribution of age at B2 was 10.0 yr (with the 25th and 75th centiles being 9.2 and 10.6 yr, respectively). Skewness was –0.45 (P = 0.001), suggesting a negatively skewed distribution. In the cross-sectional study, 126 subjects were found at B2. The median of the age distribution at B2 was 10.1 yr (with the 25th and 75th centiles being 9.7 and 11.2 years, respectively). Skewness was –0.44 (P = 0.03), suggesting a negatively skewed distribution.

Conclusions: A non-Gaussian distribution of the age at the onset of puberty in girls was documented. The currently used cutoff ages for precocious and delayed puberty may not be applicable to modern children; therefore, up-to-date studies on pubertal maturation are much needed.

Objective: Our objective was to map the gene predisposing to familial thyroid epithelial neoplasia in a large Portuguese family.

Methods and Results: The clinical screening of a Portuguese family identified 11 members affected with benign thyroid lesions and five affected with thyroid carcinomas. Linkage analysis excluded the involvement of the fPTC/PRN, NMTC1, MNG1, and TCO loci. To map the gene predisposing to thyroid epithelial neoplasia in this family, a genome-wide linkage analysis was conducted, using DNA samples from 17 family members and high-density single-nucleotide polymorphism arrays. A genome-wide significant evidence of linkage, to a single region on chromosome 8p23.1-p22 was obtained, with a maximum parametric haplotype-based LOD score of 4.41 ( = 0.00). Linkage analysis with microsatellite markers confirmed linkage to 8q23.1-p22, and recombination events delimited the minimal region to a 7.46-Mb span. Seventeen suggestive candidate genes located in the minimal region were excluded as susceptibility genes by mutational analysis. Allelic losses in the 8p23.1-p22 region were absent in seven thyroid tumors from family members, suggesting that the inactivation of a putative tumor suppressor gene may have occurred through other mechanisms.

Conclusions: Our results present evidence for the existence of a novel familial thyroid epithelial neoplasia susceptibility locus on chromosome 8p23.1-p22, providing the basis for the identification of a gene for this disease.

Design, Participants, and Setting: In a university hospital clinical research center setting, SCD1 gene expression was measured in sc adipose and vastus lateralis muscle of 86 nondiabetic subjects; 10 wk of pioglitazone (45 mg daily) and metformin (1000 mg twice daily) treatment were assessed in 36 impaired glucose-tolerant subjects. Adipocytes were treated with pioglitazone, and SCD1 expression was attenuated with small interfering RNA (siRNA) to examine other adipocyte genes.

Results: There was no significant relationship between adipose or muscle SCD1 mRNA and either body mass index or insulin sensitivity. After pioglitazone (but not metformin) treatment, there was a 2-fold increase in SCD1 mRNA and protein in adipose tissue. Pioglitazone also increased SCD1 in vitro. There were significant positive correlations between SCD1 and peroxisomal proliferator-activated receptor (PPAR) as well as other PPAR-responsive genes, including lipin-β, AGPAT2, RBP4, adiponectin receptors, CD68, and MCP1. When SCD1 expression was inhibited with a siRNA, lipin-β, AGPAT2, and the adiponectin R2 receptor expression were decreased, and adipocyte MCP-1 was increased.

Conclusions: SCD1 is closely linked to PPAR expression in humans, and is increased by PPAR agonists. The change in expression of some downstream PPAR targets after SCD1 knockdown suggests that PPAR up-regulation of SCD1 leads to increased lipogenesis and potentiation of adiponectin signaling.

Hypothesis: Estradiol (E₂) stimulates the synthesis rather than inhibits the metabolic clearance of acylated ghrelin.

Setting: The study took place at an academic medical center.

Subjects: Healthy postmenopausal women participated.

Interventions: Interventions included prospectively randomized, double-blind separate-day iv infusions of saline or five graded doses of ghrelin in estrogen-deficient (n = 12) and E₂-supplemented (n = 8) women.

Outcomes: Metabolic clearance rate (MCR), volume of distribution, half-life, and secretion rate of acylated ghrelin were assessed.

Results: In pilot iv bolus ghrelin infusions, the median half-lives of acylated and total ghrelin were 21 and 36 min (P < 0.01), MCRs 58 and 8.1 liters/kg·d (P < 0.01), and volumes of distribution of 1.0 and 0.32 liters/kg (P < 0.01), respectively. Transdermal E₂ supplementation for 3 wk increased peak nighttime acylated ghrelin concentrations from 99 ± 12 to 141 ± 34 pg/ml (P = 0.039). Exposure to E₂ did not alter the linear relationships between 1) plasma acylated ghrelin concentration and ghrelin infusion rate (638 ± 12 slope units), 2) MCR of acylated ghrelin and ghrelin infusion rate (10 ± 2.5 slope units), and 3) MCR and plasma concentration of acylated ghrelin (0.017 ± 0.004 slope units). These data predict peak nighttime production rates of acylated ghrelin of 3.8 ± 0.9 (E₂) and 1.9 ± 0.2 (no E₂) ng/kg·min (P = 0.039).

Conclusion: Acylated ghrelin has a multifold larger distribution volume and MCR than total ghrelin. An estrogenic milieu augments synthesis and/or acylation of ghrelin peptide without altering its MCR.

Objective: Our objective was to replicate and identify the novel candidate genes in the quantitative trait loci (QTL) at chromosome 14q QTL.

Subjects and Methods: Eighteen microsatellite markers were genotyped for a 117-cM interval in 306 Southern Chinese pedigrees with 1459 subjects. Successful replication of the QTL was confirmed within this region for trochanter and total hip BMD. Using a gene prioritization approach as implemented in the Endeavour program, we genotyped 65 single-nucleotide polymorphisms in the top five ranking candidate genes within the linkage peak in 706 and 760 case-control subject pairs with extremely high and low trochanter and total hip BMD, respectively.

Results: Single-marker and haplotype analyses revealed that ESR2 and latent TGF-β binding protein 2 (LTBP2) had significant associations with trochanter and total hip BMD. Multiple logistic regression revealed a strong genetic association between LTBP2 gene locus and total hip BMD variation (P = 0.0004) and prevalent fracture (P = 0.01). Preliminary in vitro study showed differential expression of LTBP2 gene in MC3T3-E1 mouse preosteoblastic cells in culture.

Conclusions: Apart from ESR2, LTBP2 is a novel positional candidate gene in chromosome 14q QTL for BMD variation and fracture.

Design: The aim of this prospective study was to analyze the expression of these genes at the last stages of follicular maturation in GCs from 17 patients with PCOS and 15 controls undergoing controlled ovarian hyperstimulation during a cycle with in vitro fertilization.

Materials and Methods: On the day of oocyte retrieval, follicular fluids were collected from small follicles (SF; 8–13 mm) and large follicles (17–22 mm) in separate tubes. Total RNAs and proteins were extracted from GCs. Reverse transcription was performed and quantification of gene expression levels was achieved by real-time quantitative PCR.

Results: AMH and FSHR mRNA levels were significantly higher in PCOS than in controls in GCs from both SF and large follicles. Likewise, AR and AMH receptor II mRNA levels in GCs from SF were significantly higher in PCOS compared with controls. In both PCOS patients and controls, AMH and AR mRNA levels correlated strongly, positively, and independently to FSHR mRNA levels.

Conclusion: Using quantitative RT-PCR, AMH, AMH receptor II, FSHR, and AR genes were shown to be overexpressed by GCs from stimulated follicles of women with PCOS undergoing controlled ovarian hyperstimulation. This could be the sign of a maturation defect or may reflect hyperandrogenism.

Objective: We hypothesized that in PPARG mutations, abnormal adipose tissue triglyceride storage causes insulin resistance.

Design, Patients, and Main Outcome Measures: Whole-body and adipose tissue-specific metabolic phenotyping through arteriovenous blood sampling was made before and after a mixed meal including ¹³C-palmitic acid. Studies were performed in a 32-yr-old male with partial lipodystrophy and type 2 diabetes, heterozygous for the PPARG P467L mutation and in an apparently phenotypically normal 32-yr-old male heterozygous for the PPARG n.AAA553T mutation. Comparator groups were age- and sex-matched healthy participants (n = 10) and type 2 diabetes sex-matched participants (n = 6).

Results: The P467L patient had elevated unmodulated fasting and postprandial plasma nonesterified fatty acid (NEFA) concentrations, despite a low adipose tissue NEFA output. Instead, NEFA appeared to originate directly from triglyceride-rich lipoproteins: ¹³C-palmitic acid accumulated rapidly in the NEFA fraction, as a sign of impaired fatty acid trapping in tissues. In contrast to the Pparg haploinsufficient mouse, the patient with n.AAA553T mutation did not exhibit paradoxically insulin sensitive and showed a mostly normal metabolic pattern.

Conclusions: The lipodystrophic PPARG P467L phenotype include excessive and uncontrolled generation of NEFA directly from triglyceride-rich lipoproteins, explaining high systemic NEFA concentrations, whereas the human PPARG haploinsufficiency is metabolically almost normal.

Site: The study took place at an academic medical center.

Subjects: Subjects were healthy postmenopausal women (n = 25).

Methods: The study included randomized assignment to estradiol (n = 13) or placebo (n = 12) administration for 16 d and randomly ordered administration of 0, 1.0, 1.5, and 2.0 mg/m² recombinant human IGF-I sc on separate days fasting.

Analysis: Deconvolution analysis of pulsatile and basal GH secretion and approximate entropy (pattern-regularity) analysis were done to quantify feedback effects of IGF-I.

Outcomes: Recombinant human IGF-I injections increased mean and peak serum IGF-I concentrations dose dependently (P < 0.001) and suppressed mean GH concentrations (P < 0.001), pulsatile GH secretion (P = 0.001), and approximate entropy (P < 0.001). Decreased GH secretion was due to reduced secretory-burst mass (P = 0.005) and frequency (P < 0.001) but not basal GH release (P = 0.52). Estradiol supplementation lowered endogenous, but did not alter infused, IGF-I concentrations while elevating mean GH concentrations (P = 0.012) and stimulating pulsatile (P = 0.008) and basal (P < 0.001) GH secretion. Estrogen attenuated IGF-I’s inhibition of pulsatile GH secretion (P = 0.042) but was unable to restore physiological GH pulse frequency or normalize approximate entropy.