bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Adrenocorticotropin-Secreting Pituitary Adenomas Show Frequent Loss of Heterozygosity at the Glucocorticoid Receptor Gene Locus1
Authors: Huizenga Nannette A. T. M. , de Lange Pieter , Koper Jan W. , Clayton Richard N. , Farrell William E. , van der Lely Aart Jan , Brinkmann Albert O. , de Jong Frank H. , Lamberts Steven W. J. 
Published: January 2014

Corticotropinomas are characterized by a relative resistance to the negative feedback action of cortisol on ACTH secretion. In this respect there is a similarity with the clinical syndrome of cortisol resistance. As cortisol resistance can be caused by genetic abnormalities in the glucocorticoid receptor (GR) gene, we investigated whether the insensitivity of corticotropinomas to cortisol is also caused by de novo mutations in the GR gene.
We screened for the GR gene in leukocyte and tumor DNA from 22 patients with Cushing’s disease for mutations using PCR/single strand conformation polymorphism analysis. In a previous study, we identified 5 polymorphisms in the GR gene in a normal population. These polymorphisms were used as markers for the possible occurrence of loss of heterozygosity (LOH) at the GR gene locus.
Except for 1 silent point mutation, we did not identify novel mutations in the GR gene in leukocytes or corticotropinomas from these patients. Of the 22 patients, 18 were heterozygous for at least 1 of the polymorphisms. In 6 of these patients, LOH had occurred in the tumor DNA. Of 21 patients examined for LOH on chromosome 11q13, only 1, with a corticotroph carcinoma, showed allelic deletion. As controls we studied 28 pituitary tumors of other subtypes (11 clinically nonfunctioning, 8 prolactinomas, and 9 GH-producing adenomas) and found evidence for LOH in only 1 prolactinoma.
In six patients LOH was found at the GR gene locus (chromosome 5) in DNA derived from adenoma cells. Our observations indicate for the first time that LOH at the GR gene locus is a relatively frequent phenomenon in pituitary adenomas of patients with Cushing’s disease. This might explain the relative resistance of the adenoma cells to the inhibitory feedback action of cortisol on ACTH secretion. The specificity of the GR LOH to corticotropinomas supports this concept. Somatic mutations of the GR are not a frequent cause of relative cortisol resistance in these cells.
Sex Differences in Endocrine and Psychological Responses to Psychosocial Stress in Healthy Elderly Subjects and the Impact of a 2-Week Dehydroepiandrosterone Treatment1
Authors: Kudielka Brigitte M. , Hellhammer Juliane , Hellhammer Dirk H. , Wolf Oliver T. , Pirke Karl-Martin , Varadi Enikö , Pilz Jürgen , Kirschbaum Clemens 
Published: January 2014

Evidence from animal as well as human studies has suggested that significant sex differences exist in hypothalamus-pituitary-adrenal axis (HPA) activity. As gonadal steroids could be important modulators of HPA sex differences, stress responses were investigated in subjects of advanced age after dehydroepiandrosterone (DHEA) or placebo treatment.
After a 2-week treatment with 50 mg DHEA daily or placebo, 75 men and women (mean age, 67.6 yr) were exposed to the Trier Social Stress Test (TSST). The TSST is a brief psychosocial stress that consists of a free speech and mental arithmetic task in front of an audience. The results show that the TSST induced significant increases in ACTH, salivary free cortisol, total plasma cortisol, norepinephrine, and heart rates (all P &lt; 0.0001) as well as decreased positive affect in the elderly (P = 0.0009). Men showed larger stress responses in ACTH (P = 0.004), salivary free cortisol (P = 0.044), and plasma total cortisol (P = 0.076) compared to women. No sex differences were observed in norepinephrine, epinephrine, or heart rate responses. In contrast to ACTH and cortisol response differences, women reported that they were significantly more stressed by the TSST than men (P = 0.0051).
Women treated with DHEA showed ACTH stress responses similar to those of men, but significantly enhanced compared to those of women taking placebos (P &lt; 0.009). No other stress response differences emerged between DHEA and placebo groups. Finally, DHEA treatment did not result in an improvement of subjective well-being.
We conclude that elderly men show larger HPA responses than women to psychosocial stress, as studied in the TSST. Estrogen effects on hypothalamic CRF-producing neurons might be responsible for these sex differences.
Involvement of Ovarian Steroids in the Opioid-Mediated Reduction of Insulin Secretion in Hyperinsulinemic Patients with Polycystic Ovary Syndrome
Authors: Guido Maurizio , Pavone Virginia , Ciampelli Mario , Murgia Francesca , Fulghesu Anna Maria , Apa Rosanna , Caruso Alessandro , Mancuso Salvatore , Lanzone Antonio 
Published: January 2014

To evaluate the possible involvement of ovarian steroids on the opioid-mediated disorders of insulin in patients affected by polycystic ovary syndrome (PCOS), we studied 40 PCOS women. All patients underwent an oral glucose tolerance test (OGTT; 75 g) and basal hormone assay; based on the insulin response to OGTT, 26 women were classified as hyperinsulinemic and continued the study protocol.
Patients were randomly divided into three groups characterized by different treatments: group A (nine patients) was treated with GnRH analog (one ampule every 28 days for 2 months), group B (eight patients) was treated with naltrexone (an oral opioid antagonist, 50 mg/day, orally) for 8 weeks, and group C (nine patients) was treated with GnRH analog plus naltrexone for 2 months. After continuation of treatment, all patients repeated the basal study in a second hospitalization.
Naltrexone treatment significantly reduced the insulin response to OGTT, whereas GnRH analogue administration did not significantly change the insulin secretion after the glucose load. The GnRH analog/naltrexone cotreatment was not able to influence the insulin secretory pattern; in fact, the insulin area under the curve was superimposable before and after therapy. These data could lead to the hypothesis that the opioidergic regulation of insulin secretion requires a normal steroidogenic pattern, thus suggesting that ovarian steroids modulate opioid activity also at peripheric districts.
Enhanced Slow Wave Sleep in Patients with Prolactinoma
Authors: Frieboes Ralf-Michael , Murck Harald , Stalla Günter Karl , Antonijevic Irina A. , Steiger Axel 
Published: January 2014

abstract
Bidirectional interactions between nocturnal hormone secretion and sleep regulation are well established. In particular, a link between PRL and rapid eye movement (REM) sleep has been hypothesized. Short-term administration of PRL and even long-term hyperprolactinemia in animals increases REM sleep. Furthermore, sleep disorders are frequent symptoms in patients with endocrine diseases. We compared the sleep electroencephalogram of seven drug-free patients with prolactinoma (mean PRL levels 1450 ± 1810 ng/mL; range between 146 and 5106 ng/mL) with that of matched controls. The patients had secondary hypogonadism but no other endocrine abnormalities. They spent more time in slow wave sleep than the controls (79.4 ± 54.4 min in patients vs. 36.6 ± 23.5 min in controls, P &lt; 0.05). REM sleep variables did not differ between the samples. Our data suggest that chronic excessive enhancement of PRL levels exerts influences on the sleep electroencephalogram in humans. Our result, which seems to be in contrast to the enhanced REM sleep under hyperprolactinemia in rats, leads to the hypothesis that both slow wave sleep and REM sleep can be stimulated by PRL. These findings are in accordance with reports of good sleep quality in patients with prolactinoma, which is in contrast to that of patients with other endocrine diseases.
Circulating Tumor Necrosis Factor-α Concentrations in a Native Canadian Population with High Rates of Type 2 Diabetes Mellitus1
Authors: Zinman Bernard , Hanley Anthony J. G. , Harris Stewart B. , Kwan Jeremy , Fantus I. George 
Published: January 2014

Recent research suggests that tumor necrosis factor-α (TNFα) may play an important role in obesity-associated insulin resistance and diabetes. We studied the relationship between TNFα and the anthropometric and physiological variables associated with insulin resistance and diabetes in an isolated Native Canadian population with very high rates of type 2 diabetes mellitus (DM).
A stratified random sample (n = 80) of participants was selected from a population-based survey designed to determine the prevalence of type 2 DM and its associated risk factors. Fasting blood samples for glucose, insulin, triglyceride, leptin, and TNFα were collected; a 75-g oral glucose tolerance test was administered, and a second blood sample was drawn after 120 min. Insulin resistance was estimated using the homeostasis assessment (HOMA) model. Systolic and diastolic blood pressure (BP), height, weight, and waist and hip circumferences were determined, and percent body fat was estimated using biological impedance analysis. The relationship between circulating concentrations of TNFα and the other variables was assessed using Spearman correlation coefficients, analysis of covariance, and multiple linear regression.
The mean TNFα concentration was 5.6 pg/mL (sd = 2.18) and ranged from 2.0–12.9 pg/mL, with no difference between men and women (P = 0.67). There were moderate, but statistically significant, correlations between TNFα and fasting insulin, HOMA insulin resistance (HOMA IR) waist circumference, fasting triglyceride, and systolic BP (r = 0.23–0.34; all P &lt; 0.05); in all cases, coefficients for females were stronger than those for males. Individuals with normal glucose tolerance had lower log TNFα concentrations than those with impaired glucose tolerance or type 2 DM (both P = 0.03, adjusted for age and sex), although differences were not significant after adjustment for HOMA IR (both P &gt; 0.25). Regression analysis indicated that log HOMA IR and log systolic BP were significant independent contributors to variations in log TNFα concentration (model r2 = 0.32). We conclude that in this homogeneous Native Canadian population, circulating TNFα concentrations are positively correlated with insulin resistance across a spectrum of glucose tolerance. The data suggest a possible role for TNFα in the pathophysiology of insulin resistance.
Linkage of Familial Euthyroid Goiter to the Multinodular Goiter-1 Locus and Exclusion of the Candidate Genes Thyroglobulin, Thyroperoxidase, and Na+/I− Symporter*
Authors: Neumann Susanne , Willgerodt Helmut , Ackermann Frank , Reske Andreas , Jung Martin , Reis André , Paschke Ralf 
Published: January 2014

Abstract
Iodine deficiency is the most important etiological factor for euthyroid endemic goiter. However, family and twin pair studies also indicate a genetic predisposition for euthyroid simple goiter. In hypothyroid goiters several molecular defects in the thyroglobulin (TG), thyroperoxidase (TPO), and Na+/I− symporter (NIS) genes have been identified. The TSH receptor with its central role for thyroid function and growth is also a strong candidate gene. Therefore, we investigated a proposita with a relapsing euthyroid goiter and her family, in which several members underwent thyroidectomy for euthyroid goiter. Sequence analysis of the complementary DNA (cDNA) of the TPO and TSH receptor genes revealed several previously reported polymorphisms. As it is not possible to exclude a functional relevance for all polymorphisms, we opted for linkage analysis with microsatellite markers to investigate whether the candidate genes are involved in the pathogenesis of euthyroid goiter. The markers for the genes TG, TPO, and NIS gave two-point and multipoint logarithm of odds score analysis scores that were negative or below 1 for all assumed recombination fractions. As no significant evidence of linkage was found, we conclude that these candidate genes can be excluded as a major cause of the euthyroid goiters in this family. In contrast, we have found evidence for linkage of familial euthyroid goiter to the recently identified locus for familial multinodular nontoxic goiter (MNG-1) on chromosome 14q. The haplotype cosegregates clearly with familial euthyroid goiter. Our results provide the first confirmation for MNG-1 as a locus for nontoxic goiter.
Apparent Cortisone Reductase Deficiency: A Functional Defect in 11β-Hydroxysteroid Dehydrogenase Type 1*
Authors: Jamieson A. , Wallace A. M. , Andrew R. , Nunez B. S. , Walker B. R. , Fraser R. , White P. C. , Connell J. M. C. 
Published: January 2014

AbstractA 36-yr-old woman was referred to the endocrine clinic for investigation of oligomenorrhea, hirsutism, and acne. She was plethoric and overweight with central fat distribution. Plasma cortisol was normal, but her adrenal glands were enlarged (CT scan). Urinary tetrahydrocortisone excretion rate was consistently high, raising the possibility of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) deficiency. In addition, 5β- reduction of cortisol and cortisone was markedly enhanced. The levels of all cortisol metabolites were suppressed normally with dexamethasone, but conversion of oral cortisone acetate to plasma cortisol was delayed and subnormal compared with that of healthy volunteers. This was accompanied by a larger than normal increase in plasma cortisone concentration. Thus, the defect appears to be in 11β-HSD1 activity and not in 5β-reductase activity. Three close relatives of the subject showed no comparable abnormalities, and analysis of the coding region and exon/intron boundaries of the 11β-HSD1 gene of the case revealed no differences from the consensus sequence. The defect may lie outside the coding region. Alternatively, some other inherited or acquired defect may lead to inhibition of this enzyme system.
Daily Treatment with Human Recombinant Parathyroid Hormone-(1–34), LY333334, for 1 Year Increases Bone Mass in Ovariectomized Monkeys*
Authors: Brommage Robert , Hotchkiss Charlotte E. , Lees Cynthia J. , Stancill Melanie W. , Hock Janet M. , Jerome Christopher P. 
Published: January 2014

AbstractPTH stimulates bone formation to increase bone mass and strength in rats and humans. The aim of this study was to determine the skeletal effects of recombinant human PTH-(1–34) [rhPTH-(1–34)] in monkeys, as monkey bone remodeling and structure are similar to those in human bone.Adult female cynomolgus monkeys were divided into sham-vehicle (n= 21), ovariectomized (OVX)-vehicle (n = 20), and OVX groups given daily sc injections of rhPTH-(1–34) at 1 (n = 39) or 5 (n = 41) μg/kg for 12 months. Whole body bone mineral content was measured, as was bone mineral density (BMD) in the spine, proximal tibia, midshaft radius, and distal radius. Serum and urine samples were also analyzed. rhPTH-(1–34) treatment did not influence serum ionized Ca levels or urinary Ca excretion, but depressed endogenous PTH while increasing serum calcitriol levels. Compared to that in the OVX group, the higher dose of rhPTH-(1–34) increased spine BMD by 14.3%, whole body bone mineral content by 8.6%, and proximal tibia BMD by 10.8%. Subregion analyses suggested that the anabolic effect of rhPTH-(1–34) on the proximal tibia was primarily in cancellous bone. Similar, but less dramatic, effects on BMD were observed with the lower dose of rhPTH-(1–34). Daily sc rhPTH-(1–34) treatment for 1 yr increases BMD in ovariectomized monkeys without inducing sustained hypercalcemia or hypercalciuria.
Hormonal and Biochemical Parameters in the Determination of Osteoporosis in Elderly Men*
Authors: Center Jacqueline R. , Nguyen Tuan V. , Sambrook Philip N. , Eisman John A. 
Published: January 2014

Abstract
The extent to which changes in several hormonal and biochemical parameters are involved in the pathogenesis of osteoporosis in men remains controversial. This study examined the roles of free testosterone (T), estradiol (E2), sex hormone-binding globulin (SHBG), 25-hydroxyvitamin D, PTH, and insulin-like growth factor I in the determination of bone mineral density (BMD) in 437 community-dwelling elderly men. Age, height, weight, quadriceps strength, and femoral neck (FN) and lumbar spine (LS) BMD were also obtained. In multiple regression analysis, after adjusting for age and weight, low E2 (P = 0.01), and high SHBG (P = 0.0002) levels were common determinants of FN and LS BMD. In addition, high PTH (P = 0.03) was an independent predictor of FN BMD, and low free T (P = 0.02) was an independent predictor of LS BMD. Low free T was associated with FN BMD in univariate analysis only. The hormonal measurements collectively accounted for 5% and 7% of the age- and weight-adjusted variance of FN and LS BMD, respectively. The sex steroids, SHBG and insulin-like growth-I were found to be interrelated using a technique of path analysis that examines the intercorrelation between these variables. A subject with any one abnormal serum parameter had a 4-fold increase in the risk of osteoporosis, whereas three abnormal parameters were associated with an 11-fold increased risk, although the latter group only applied to 1% of the study population. Although the precise causal effects these biochemical parameters may have on the development of osteoporosis remains to be determined, the present findings support an important interrelated role for these hormonal and biochemical parameters on changes in bone density in elderly men.
Corticotropin-Releasing Hormone Stimulates P450 17α-Hydroxylase/17,20-Lyase in Human Fetal Adrenal Cells via Protein Kinase C*
Authors: Chakravorty Aruna , Mesiano Sam , Jaffe Robert B. 
Published: January 2014

AbstractCRH directly stimulates dehydroepiandrosterone sulfate (DHEAS) production in human fetal adrenal cells. In the human fetal and adult pituitary, CRH acts via protein kinase A (PKA). We determined the CRH signal transduction pathway in fetal adrenal cells, i.e. whether CRH modulates human fetal adrenal steroidogenesis via PKA and/or protein kinase C (PKC).In primary cultures, CRH increased inositol trisphosphate. After CRH treatment, inositol tris-, bis-, and monophosphates increased within 1 min, reaching maximal levels at 5 min. In contrast, PGF2α, known to act via PKC, induced a sustained response for up to 20 min. The response to CRH was dose dependent, maximal at 1μ mol/L at both 1 and 5 min. CRH increased DHEAS production, with a much lesser effect on cortisol. CRH did not stimulate inositol phospholipid in adult adrenal glands, suggesting that this pathway is unique to the fetal adrenal. CRH increased messenger ribonucleic acid encoding 17α-hydroxylase/17,20 lyase (P450c17), but not 3β-hydroxysteroid dehydrogenase/Δ4–5 isomerase. However, 3βHSD expression was stimulated by ACTH. PKC, but not PKA, inhibitors blocked CRH-stimulated P450c17 induction, whereas PKA inhibitors blocked ACTH-stimulated cortisol. Thus, CRH is coupled to the phospholipase C-inositol phosphate second messenger system and preferentially induces the expression of P450c17 and DHEAS, suggesting a unique role of CRH regulating human fetal adrenal function via PKC.
Effect of Severe Growth Hormone (GH) Deficiency due to a Mutation in the GH-Releasing Hormone Receptor on Insulin-Like Growth Factors (IGFs), IGF-Binding Proteins, and Ternary Complex Formation Throughout Life1
Authors: Aguiar-Oliveira Manuel H. , Gill Matthew S. , de Elenilde S. , Barretto A. , Alcântara Marta R. S. , Miraki-Moud Farideh , Menezes Carlos A. , Souza Anita H. O. , Martinelli Carlos E. , Pereira F. A. , Salvatori Roberto , Levine Michael A. , Shalet Stephen M. , Camacho-Hubner Cecilia , Clayton Peter E. 
Published: January 2014

Measurement of the insulin-like growth factors (IGFs) and their binding proteins has become commonplace in the indirect assessment of the integrity of the GH axis. However, the relative effect of GH deficiency (GHD) on each component of the IGF axis and the merit of any one parameter as a diagnostic test have not been defined in a homogeneous population across all ages. We therefore measured IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, IGFBP-3, and acid labile subunit (ALS) in 27 GHD subjects (aged 5–82 yr) from an extended kindred in Northeast Brazil with an identical GHRH receptor mutation and in 55 indigenous controls (aged 5–80 yr). The effect of GHD on the theoretical distribution of IGFs between the IGFBPs and the ternary complex was also examined.
All components of the IGF axis, measured and theoretical, showed complete separation between GHD and control subjects, except IGFBP-1 and IGFBP-2 concentrations, which did not differ. The most profound effects of GHD were on total IGF-I, IGF-I in the ternary complex, and ALS. The proportion of IGF-I associated with IGFBP-3 remained constant throughout life, but was significantly lower in GHD due to an increase in IGF-I/IGFBP-2 complexes. IGF-I in the ternary complex was determined principally by concentrations of ALS in GHD and IGFBP-3 in controls, implying that ALS has greater GH dependency. In the controls, IGF-II was associated primarily with IGFBP-3 and to a lesser extent with IGFBP-2, whereas in GHD the reverse was found. There was also a dramatic decline in the proportion of free ALS in GHD adults that was not evident in controls. As diagnostic tests, IGF-I in the ternary complex and total IGF-I provided the greatest separation between GHD and controls in childhood. Similarly, in older adults the best separation was achieved with IGF-I in the ternary complex, with free ALS being optimal in younger adults.
Severe GHD not only reduces the amounts of IGFs, IGFBP-3, and ALS, but also modifies the distribution of the IGFs bound to each IGFBP. Diagnostic tests used in the investigation of GHD should be tailored to the age of the individual. In particular, measurement of IGF-I in the ternary complex may prove useful in the diagnosis of GHD in children and older adults, whereas free ALS may be more relevant to younger adults.
Evaluation of the Adequacy of Levothyroxine Replacement Therapy in Patients with Central Hypothyroidism1
Authors: Ferretti Elisabetta , Persani Luca , Jaffrain-Rea Marie-Lise , Giambona Salvatore , Tamburrano Guido , Beck-Peccoz Paolo 
Published: January 2014

As there are few data on the evaluation of the adequacy of levothyroxine (l-T4) therapy in patients with central hypothyroidism (CH), a prospective study was performed to assess the accuracy of various parameters in the follow-up of 37 CH patients. Total and free thyroid hormones, TSH, and a series of clinical and biochemical indexes of peripheral thyroid hormone action have been evaluated off and on l-T4 therapy. Samples were taken before the daily administration of l-T4. In all patients off therapy, clinical hypothyroidism and low levels of free T4 (FT4) were observed, whereas values of FT3, total T4, and total T3 were below the normal range in 73%, 57%, and 19% of cases, respectively. Most of the indexes of thyroid hormone action were significantly modified after l-T4 withdrawal and exhibited significant correlation with free thyroid hormone levels. During l-T4 replacement therapy, 32 patients had circulating levels of FT4 and FT3 and indexes within the normal range with a mean l-T4 daily dose of 1.5 ± 0.3 μg/kg BW. Despite normal serum FT4, 3 patients had borderline high values of FT3 and a clear elevation of serum-soluble interleukin-2 receptor concentrations, suggesting overtreatment. Low or borderline low FT4/FT3 levels indicated undertreatment in 2 patients. The clinical parameters lack the required specificity for the diagnosis or follow-up of CH patients. The l-T4 daily dose should be established, taking into account the weight, the age, and the presence of other hormone deficiencies or pharmacological treatment of CH patients.
In conclusion, our results indicate that the diagnosis of CH is reached at best by measuring TSH and FT4 concentrations. In the evaluation of the adequacy of l-T4 replacement therapy, both FT4 and FT3 serum levels together with some biochemical indexes of thyroid hormone action are all necessary to a more accurate disclosure of over- or undertreated patients.