bluuebunny/crossref_metadata_2025 huggingface dataset:
Muscle Sympathetic Nerve Activity in Patients with Acromegaly
Authors: Capaldo Brunella , Lembo Giuseppe , Rendina Virgilio , Guida Raffaele , Marzullo Paolo , Colao Annamaria , Lombardi Gaetano , Saccà Luigi
Published: January 2014

Muscle sympathetic nerve activity was measured in nine acromegalic patients (age, 35 ± 4 yr; body mass index, 28 ± 2 kg/m2) and eight healthy subjects (age, 32 ± 3 yr; body mass index, 25 ± 2 kg/m2) by combining the forearm arterial-venous difference technique with the tracer method[ infusion of tritiated norepinephrine (NE)]. Muscle NE release was quantified both at rest and during physiological hyperinsulinemia while maintaining euglycemia (∼90 mg/dL) by means of the euglycemic clamp.

Arterial plasma NE was similar in the two groups at rest (197 ± 28 and 200 ± 27 pg/mL−1) and slightly increased during insulin infusion. Forearm NE release was 2.33 ± 0.55 ng·liter−1·min−1 in healthy subjects and 2.67 ± 0.61 ng·liter−1·min−1 in acromegalic subjects in the basal state and increased to a similar extent during insulin infusion in both groups (3.13 ± 0.71 and 3.32 ± 0.75 ng·L−1· min−1, P < 0.05 vs. basal), indicating a normal stimulatory effect of insulin on muscle sympathetic activity. In contrast, insulin-stimulated forearm glucose uptake was markedly lower in acromegalic patients (2.3 ± 0.4 mg·L−1·min−1) than in control subjects (7.9 ± 1.3 mg·L−1·min−1, P < 0.001), indicating the presence of severe insulin resistance involving glucose metabolism.

Our data demonstrate that patients with long-term acromegaly have normal sympathetic activity in the skeletal muscle in the basal, postabsorptive state and normal increments in NE spillover in response to the sympatho-excitatory effect of insulin. Thus, the presence of severe insulin resistance in acromegaly is not accounted for by adrenergic mechanisms.
Effects of Human Recombinant Luteinizing Hormone and Follicle-Stimulating Hormone in Patients with Acquired Hypogonadotropic Hypogonadism: Study of Sertoli and Leydig Cell Secretions and Interactions
Authors: Young Jacques , Couzinet Beatrice , Chanson Philippe , Brailly Sylvie , Loumaye Ernest , Schaison Gilbert
Published: January 2014

Experimental data suggest that FSH-stimulated Sertoli cells can enhance LH-induced Leydig cell testosterone (T) production. The function of Leydig and Sertoli cells can be selectively studied by using recombinant human LH (rhLH) and recombinant human FSH (rhFSH) in patients with complete gonadotropin deficiency. The aim of the present study was to assess the secretion of testicular T, estradiol (E2), and inhibin B and the physiological relevance of the Sertoli-Leydig cell interaction in man. For that purpose, six patients with acquired complete hypogonadotropic hypogonadism received the following treatments for three periods of 1 month in a random order: 1) rhLH, 900 IU/day sc; 2) rhFSH, 150 IU/day sc; and 3) combined rhLH/rhFSH treatments. Each treatment period was separated by a washout period of 15 days. Plasma LH, FSH, T, E2, and inhibin B were measured before and every 10 days during each treatment. During rhLH administration, mean plasma LH levels rose significantly from 0.4 ± 0.2 IU/L to 11.7 ± 1.2 IU/L (P < 0.01) and plasma FSH levels did not change. rhFSH administration induced a significant increase in plasma FSH levels (from 0.5 ± 0.4 to 12.1 ± 1.4 IU/L; P < 0.01), whereas mean plasma LH levels remained low. Mean plasma E2 levels were unchanged during rhFSH treatment, but they increased significantly during rhLH from 22 ± 4 to 54 ± 8 pmol/L (P < 0.01) and during rhLH plus rhFSH administration. rhFSH treatment induced a sustained elevation of mean plasma inhibin B levels from 58 ± 13 to 175 ± 25 pg/mL (P < 0.01), similar to the increase occurring during rhFSH plus rhLH administration. In contrast, mean plasma inhibin B levels did not increase during rhLH administration. Finally, a similar and significant increase in mean plasma T levels occurred during both rhLH and rhLH plus rhFSH treatment from 0.9 ± 0.3 to 5.4 ± 0.7 nmol/L (P < 0.01) and from 1.0 ± 0.4 to 6.0 ± 0.9 nmol/L (P < 0.01), respectively. In contrast, during rhFSH treatment mean plasma T levels remained unchanged when compared with baseline. In conclusion: 1) the increase of plasma E2 induced by rhLH and the absence of effect of rhFSH confirm that Leydig cells are the major site of testicular E2 production in man; 2) the secretion of inhibin B is increased by rhFSH and not by rhLH, and, thus, Sertoli cells seem to be the main source of inhibin B production; and 3) the increase of plasma T induced by rhLH is not enhanced by rhFSH. These results suggest that the stimulatory effect of FSH on Leydig cell steroidogenesis by a Sertoli cell paracrine factor does not seem to play a major physiologic role in man.
Tumor Necrosis Factor Microsatellite Polymorphism Influences the Development of Insulin Dependency in Adult-Onset Diabetes Patients with the DRB1∗1502-DQB1∗0601 Allele and Anti-Glutamic Acid Decarboxylase Antibodies
Authors: Obayashi Hiroshi , Hasegawa Goji , Fukui Michiaki , Kamiuchi Kenji , Kitamura Akane , Ogata Masakazu , Kanaitsuka Toshihiro , Shigeta Hirofumi , Kitagawa Yoshihiro , Nakano Koji , Nishimura Masataka , Ohta Mitsuhiro , Nakamura Naoto
Published: January 2014

Recently, several studies have demonstrated that tumor necrosis factor microsatellite polymorphism (TNFa) contributes to the susceptibility of type 1 diabetes. This study investigates the influence of TNFa on the predisposition to insulin dependency in adult-onset diabetic patients with type 1 diabetes-protective human leukocyte antigen haplotypes. The TNFa of three groups of DRB1∗1502-DQB1∗0601-positive diabetic patients who had initially been nonketotic and noninsulin dependent for more than 1 yr was analyzed. Group A included 11 antibodies to glutamic acid decarboxylase (GADab)-positive patients who developed insulin dependency within 4 yr of diabetes onset. Group B included 11 GADab-positive patients who remained noninsulin dependent for more than 12 yr. Group C included 12 GADab-negative type 2 diabetes, and a control group included 18 nondiabetic subjects. In the group C and control subjects, DRB1∗1502-DQB1∗0601 was strongly associated with the TNFa13 allele. DRB1∗1502-DQB1∗0601 was strongly associated with the TNFa12 allele among the group A patients, but not among the group B patients. Interestingly, sera from all patients with non-TNFa12 and non-TNFa13 in group B reacted with GAD65 protein by Western blot. These results suggest that TNFa is associated with a predisposition to progression to insulin dependency in GADab/DRB1∗1502-DQB1∗0601-positive diabetic patients initially diagnosed with type 2 diabetes and that determination of these patients’ TNFa genotype may allow for better prediction of their clinical course.
Increased Risk for Nonmedullary Thyroid Cancer in the First Degree Relatives of Prevalent Cases of Nonmedullary Thyroid Cancer: A Hospital-Based Study
Authors: Pal Tuya , Vogl Florian D. , Chappuis Pierre O. , Tsang Richard , Brierley James , Renard Helene , Sanders Kevin , Kantemiroff Tania , Bagha Sabira , Goldgar David E. , Narod Steven A. , Foulkes William D.
Published: January 2014

The genetic basis for nonmedullary forms of thyroid cancer (NMTC) is less well established than that of medullary thyroid cancer. However, epidemiological and family studies suggest that a proportion of NMTC may be due to inherited predisposition. To estimate the familial risk of thyroid cancer, we conducted a hospital-based case-control study at the Princess Margaret Hospital in Toronto, Ontario, Canada, and at 2 university hospitals in Montréal, Québec, Canada. We obtained pedigrees from 339 unselected patients diagnosed with NMTC and from 319 unaffected ethnically matched controls. Family histories of cancer were obtained from the cases and controls for 3292 first degree relatives of cases and controls. Seventeen cases (5.0%) and 2 controls (0.6%) reported at least one first degree relative with thyroid cancer.

In relatives of patients with thyroid cancer, the incidence of any type of cancer (including NMTC) was 38% higher than in relatives of controls (incidence rate ratio, 1.4; 95% confidence interval, 1.1–1.7). The relative risk for thyroid cancer was 10-fold higher in relatives of cancer patients than in controls (incidence rate ratio, 10.3; 95% confidence interval, 2.2–47.6).

Our findings suggest that hereditary or other familial factors are important in a small proportion of NMTC. Molecular studies are needed to determine the genetic basis of cancer susceptibility in these families.
Prospective Study of the Natural History of Gastrinoma in Patients with MEN1: Definition of an Aggressive and a Nonaggressive Form
Authors: Gibril Fathia , Venzon David J. , Ojeaburu Jeremiah V. , Bashir Showkat , Jensen Robert T.
Published: January 2014

The natural history of pancreatic endocrine tumors (PETs) in patients with MEN1 is largely unknown. Recent studies in patients with sporadic PETs show that in a subset, tumor growth is aggressive. To determine whether PETs in patients with MEN1 show similar growth behavior, we report results from a long-term prospective study of 57 patients with MEN1 and Zollinger-Ellison syndrome. All patients had tumor imaging studies yearly, and the mean follow-up was 8 yr. Only patients with PETs 2.5 cm or larger underwent abdominal surgical exploration. Hepatic metastases occurred in 23%, and in 14% tumors demonstrated aggressive growth. Three tumor-related deaths occurred, each due to liver metastases, and in each, aggressive tumor growth was present. Overall, 4% of the study group, 23% with liver metastases and 38% with aggressive disease, died. Aggressive growth was associated with higher gastrins and larger tumors. Patients with liver metastases with aggressive growth differed from those with liver metastases without aggressive growth in age at MEN1 onset or diagnosis and primary tumor size. Survival was decreased (P = 0.0012) in patients with aggressive tumor growth compared with those with liver metastases without aggressive growth or with no liver metastases without aggressive growth. Based on these results a number of factors were identified that may be clinically useful in determining in which patients aggressive tumor growth may occur. These results demonstrate in a significant subset of patients with MEN1 and Zollinger-Ellison syndrome, aggressive tumor growth occurs and can lead to decreased survival. The identification of prognostic factors that identify this group will be important clinically in allowing more aggressive treatment options to be instituted earlier.
Atrial Natriuretic Hormone, Vessel Dilator, Long-Acting Natriuretic Hormone, and Kaliuretic Hormone Decrease the Circulating Concentrations of Total and Free T4 and Free T3 with Reciprocal Increase in TSH
Authors: Vesely David L. , San Miguel Gloria I. , Hassan Imran , Gower William R. , Schocken Douglas D.
Published: January 2014

The present investigation was designed to determine whether atrial natriuretic peptides (ANPs) consisting of amino acids 1–30[ i.e. long-acting natriuretic hormone (LANH)], 31–67 (vessel dilator), 79–98 (kaliuretic hormone), and 99–126 (atrial natriuretic hormone [ANH]) of the 126-amino acid ANH prohormone decrease the circulating concentrations of total and free T4 and/or free T3 in healthy humans (n = 30). Vessel dilator, kaliuretic hormone, LANH, and ANH decreased the circulating concentrations of total T4 by 61%, 58%, 47%, and 55% and of free T4 by 60%, 67%, 79%, and 79%, whereas free T3 decreased 72%, 67%, 71%, and 67% (P < 0.05 for each), respectively, when infused at 100 ng/kg BW·min for 60 min. Vessel dilator, kaliuretic hormone, LANH, and ANH simultaneously increased circulating TSH concentrations 4- to 12.5-fold (P < 0.004). The decreases in T4 and T3 with reciprocal increases in TSH lasted 2–3 h after cessation of the respective ANP infusions. The reciprocal increase in TSH with the decreases in T4 and T3 suggests that their modulation of T4 and T3 concentrations occurs in the thyroid rather than in the pituitary or hypothalamus, because TSH would be decreased in the circulation if their inhibitory effects were in either the hypothalamus or pituitary.
The Effects on Insulin Action in Adult Hypopituitarism of Recombinant Human GH Therapy Individually Titrated for Six Months
Authors: McConnell E. M. , Atkinson A. B. , Ennis C. , Hadden D. R. , McCance D. R. , Sheridan B. , Bell P. M.
Published: January 2014

There is controversy about the effect of replacement GH on insulin action in adult hypopituitary patients. GH replacement calculated from weight leads to unacceptable side effects in some patients. Recent studies suggest it should be individually titrated in adults using serum IGF-I levels. We have assessed the effect of titrated GH replacement on peripheral and hepatic insulin action in 13 adult-onset hypopituitary patients (8 males and 5 females; ages 47 ± 10 yr, mean duration of hypopituitarism 6 yr) with confirmed GH deficiency (GHD; maximum GH <5 mU/liter during insulin induced hypoglycemia), ACTH deficiency, and normal glucose tolerance. All patients were on stable hydrocortisone replacement (15 mg with breakfast, 5 mg with evening meal) for at least 2 months before the trial. Insulin action was assessed by the euglycemic hyperinsulinemic glucose clamp technique (1 mU/kg·min) before and after 6 months of GH therapy. GH was started at 0.8 IU sc daily and titrated monthly until the serum IGF-I increased to within 1–2 sd of the mean of normal age-matched controls. Body mass index did not change significantly during the 6 months of GH therapy. Fasting plasma glucose and HbA1c increased significantly after 6 months (5.2 ± 0.0 vs. 5.5 ± 0.0 mmol/liter, P < 0.0001, and 4.5 ± 0.1 vs. 4.7 ± 0.1%, P < 0.0005, respectively). There was no increase in fasting serum insulin (51.6 ± 10.2 vs. 60.0 ± 10.2 pmol/liter, P= 0.12). Exogenous glucose infusion rates required to maintain euglycemia were similar after GH (23.0 ± 0.4 vs. 21.1 ± 0.3 μmol/kg·min, P = 0.6). Endogenous glucose production in the fasting state was also unchanged following GH (11.8 ± 0.7 vs.12.3 ± 0.9μ mol/kg·min, P = 0.5) and suppressed to a similar extent following insulin (4.4 ± 0.8 vs. 5.5 ± 0.8 μmol/kg·min, P = 0.3). In summary, GH therapy for 6 months, with serum IGF-I maintained in the upper physiological range, increased fasting plasma glucose and HbA1c. There was no effect on peripheral or hepatic insulin sensitivity. Patients receiving GH therapy require long-term monitoring of glucose tolerance.
Follow-Up Examination at the Age of 15 Months of Extremely Preterm Infants after Postnatal Estradiol and Progesterone Replacement
Authors: Trotter Andreas , Bokelmann Birgit , Sorgo Wolfgang , Bechinger-Kornhuber Doris , Heinemann Hilde , Schmücker Gesine , Oesterle Margarethe , Köhntop Brigitte , Brisch Karl-Heinz , Pohlandt Frank
Published: January 2014

A randomized controlled pilot study was performed with a sample of extremely preterm infants to evaluate the impact of postnatal estradiol and progesterone replacement on postnatal bone mineral accretion. Twenty-five of 30 infants in the pilot study survived, and of these, 24 infants were available for the follow-up examination at a median chronological age of 18.1 months (minimum-maximum, 17.0–20.6) corresponding to a corrected age of 14.8 months (minimum-maximum, 12.9–17.4). Somatic growth data and bone mineralization showed no differences between the hormone-treated and control group infants. The deviation of the skeletal age from the corrected age was 0.0 months (minimum-maximum, −7.7 to 7.4) for hormone-treated infants compared with −1.7 months (minimum-maximum, −7.5 to 5.9) for the control group. The Bayley scales mental and psychomotor developmental indexes were 89 (minimum-maximum, 71–107) and 101 (minimum-maximum, 49–121) for the hormone-treated infants and 93 (minimum-maximum, 49–111) and 71 (minimum-maximum, 49–121) for the control group infants, respectively (mental developmental index, P = 1.0; psychomotor developmental index, P = 0.14). The normal psychomotor development in the hormone-treated infants compared with the below average development in the control group infants is encouraging and indicates the potentially important integrative role of sex steroids for the developing brain. Larger studies on the effects of the postnatal replacement of estradiol and progesterone in extremely preterm infants are warranted.
Frequency of Macroprolactinemia Due to Autoantibodies against Prolactin in Pregnant Women
Authors: Pascoe-Lira Dalila , Duran-Reyes Genoveva , Contreras-Hernández Iris , Manuel-Apolinar Leticia , Blanco-Favela Francisco , Leaños-Miranda Alfredo
Published: January 2014

The frequency of macroprolactinemia related to the presence of anti-PRL autoantibodies in the serum of 209 healthy women at different stages of pregnancy was studied. Measurements were taken of serum PRL concentrations before and after chromatographic separation (gel filtration and affinity with proteins A and G) and extraction of free PRL with polyethylene glycol (PEG). Sera from 8 of the 209 women (3.8%) were found to have a significantly high proportion of precipitated PRL by PEG (macroprolactinemia); in these patients, gel filtration showed that a substantial amount of big big PRL (molecular mass >100 kDa) was present (19.0–78.2% vs. 3.8–4.9%, P = 0.009 in normal pregnant women with a normal proportion of precipitated PRL by PEG). The presence of macroprolactinemia was attributable to anti-PRL autoantibodies in 5 of the 8 women. Comparison of serum levels of direct and free PRL between women with macroprolactinemia related to anti-PRL autoantibodies and women without macroprolactinemia showed significant differences (direct PRL: 270.2 ± 86.9 vs. 203.4 ± 69.0 μg/L, P = 0.04; and free PRL: 107.0 ± 75.9 vs. 173.3 ± 67.6 μg/L, P = 0.002). On the other hand, there was no difference between women with macroprolactinemia not related to anti-PRL autoantibodies and women with macroprolactinemia caused by anti-PRL autoantibodies, nor was there a difference between women with macroprolactinemia not related to anti-PRL autoantibodies and women without macroprolactinemia. There was a positive correlation between titers of the anti-PRL autoantibody and serum PRL levels (r = 0.82, P = 0.09). The presence of the anti-PRL autoantibody had no relation to the patient’s age, stage of gestation, or number of previous pregnancies. We concluded that the frequency of macroprolactinemia was 3.8% among healthy, pregnant women, which was caused by a anti-PRL autoantibodies in 62.5% of the cases. The autoantibodies were found in the bloodstream, forming a PRL-IgG complex, in accordance with the following observations: 1) immunoreactive PRL on gel filtration was eluted in the fractions corresponding to the molecular mass of IgG (150 kDa); 2) a significantly high proportion of immunoreactive PRL was retained on an affinity gel for IgG (proteins A and G); and 3) a significantly high proportion of serum PRL bound to IgG was precipitated by protein A. There was a positive correlation between titers of anti-PRL autoantibodies and serum PRL levels. Serum levels of total PRL were higher, and serum levels of free PRL were lower, in pregnant women with anti-PRL autoantibodies than in pregnant women without macroprolactinemia.
The N363S Polymorphism of the Glucocorticoid Receptor: Potential Contribution to Central Obesity in Men and Lack of Association with Other Risk Factors for Coronary Heart Disease and Diabetes Mellitus1
Authors: Dobson Mark G. , Redfern Christopher P. F. , Unwin Nigel , Weaver Jolanta U.
Published: January 2014

Considerable evidence suggests that diabetes mellitus and hypertension are influenced by genetic factors. Studies in humans have associated glucocorticoid receptor (GR) polymorphisms with high blood pressure, insulin sensitivity, body mass index, increased visceral fat, and variations in tissue-specific steroid sensitivity. The N363S polymorphism of the GR results in an asparagine to serine amino acid substitution in a modulatory region of the receptor. Phosphorylation of serine residues in this region has been shown to enhance transactivation of GR responsive genes. The aim of this study was to investigate the association between the 363S allele and risk factors for coronary heart disease and diabetes mellitus in a population of European origin living in the northeast of the United Kingdom. Blood samples from 135 males and 240 females were characterized for 363 allele status. The overall frequency of the 363S allele was 3.0%, 23 heterozygotes (7 males and 16 females) but no 363S homozygotes were identified. The data show a significant association of the 363S allele with increased waist to hip ratio in males but not females. This allele was not associated with blood pressure, body mass index, serum cholesterol, triglycerides, low-density lipoprotein and high-density lipoprotein cholesterol levels, and glucose tolerance status. The results of this study suggest that this GR polymorphism may contribute to central obesity in men. Further studies are required to elucidate the properties of GR363S at a molecular level.
Blood-Brain Barrier Transport and Brain Metabolism of Glucose during Acute Hyperglycemia in Humans1
Authors: Hasselbalch Steen G. , Knudsen Gitte M. , Capaldo Brunella , Postiglione Alfredo , Paulson Olaf B.
Published: January 2014

It is controversial whether transport adaptation takes place in chronic or acute hyperglycemia. Blood-brain barrier glucose permeability and regional brain glucose metabolism (CMRglc) was studied in acute hyperglycemia in six normal human subjects (mean age, 23 yr) using the double indicator method and positron emission tomography and[ 18F]fluorodeoxyglucose as tracer. The Kety-Schmidt technique was used for measurement of cerebral blood flow (CBF). After 2 h of hyperglycemia (15.7 ± 0.7 mmol/L), the glucose permeability-surface area product from blood to brain remained unchanged (0.050 ± 0.008 vs. 0.059 ± 0.031 mL/100 g·min). The unidirectional clearance of[ 18F]fluorodeoxyglucose (K1*) was reduced from 0.108 ± 0.011 to 0.061 ± 0.005 mL/100 g·min (P < 0.0004). During hyperglycemia, global CMRglc remained constant (21.4 ± 1.2 vs. 23.1 ± 2.2 μmol/100 g·min, normo- and hyperglycemia, respectively). Except for a significant increase in white matter CMRglc, no regional difference in CMRglc was found. Likewise, CBF remained unchanged.

The reduction in K1* was compatible with Michaelis-Menten kinetics for facilitated transport. Our findings indicate no major adaptational changes in the maximal transport velocity or affinity to the blood-brain barrier glucose transporter. Finally, hyperglycemia did not change global CBF or CMRglc.
Dyslipemia in Familial Partial Lipodystrophy Caused by an R482W Mutation in the LMNA Gene
Authors: Schmidt Hartmut H.-J. , Genschel Janine , Baier Peter , Schmidt Martina , Ockenga Johann , Tietge Uwe J. F. , Pröpsting Marcus , Büttner Carsten , Manns Michael P. , Lochs Herbert , Brabant Georg
Published: January 2014

Lipatrophic diabetes, also referred to as familial partial lipodystrophy, is a rare disease that is metabolically characterized by hypertriglyceridemia and insulin resistance. Affected patients typically present with regional loss of body fat and muscular hypertrophic appearance. Variable symptoms may comprise pancreatitis and/or eruptive xanthomas due to severe hypertriglyceridemia, acanthosis nigricans, polycystic ovaria, and carpal tunnel syndrome. Mutations within the LMNA gene on chromosome 1q21.2 were recently reported to result in the phenotype of familial partial lipodystrophy. The genetic trait is autosomal dominant. We identified a family with partial lipodystrophy carrying the R482W (Arg482Trp) missense mutation within LMNA. Here we present the lipoprotein characteristics in this family in detail. Clinically, the loss of sc fat and muscular hypertrophy especially of the lower extremities started as early as in childhood. Acanthosis and severe hypertriglyceridemia developed later in life, followed by diabetes. The characterization of the lipoprotein subfractions revealed that affected children present with hyperlipidemia. The presence and severity of hyperlipidemia seem to be influenced by age, apolipoprotein E genotype, and the coexistence of diabetes mellitus. In conclusion, dyslipemia is an early and prominent feature in the presented lipodystrophic family carrying the R482W mutation within LMNA.
The Relationship between Steroidogenic Factor 1 and DAX-1 Expression and in Vitro Gonadotropin Secretion in Human Pituitary Adenomas1
Authors: Aylwin S. J. B. , Welch J. P. , Davey C. L. , Geddes J. F. , Wood D. F. , Besser G. M. , Grossman A. B. , Monson J. P. , Burrin J. M.
Published: January 2014

The orphan nuclear receptors, steroidogenic factor 1 (SF-1) and DAX-1, are involved in gonadotroph differentiation, and SF-1 has been shown to activate the LH-β and glycoprotein hormone α-subunit (αGSU) gene promoters. Pituitary adenomas from 34 patients [13 somatotroph tumors, 4 prolactinomas, and 17 clinically nonfunctioning pituitary adenomas (NFPAs)] were enzymatically dispersed and cultured in vitro for 48 h. Tissue culture medium was collected and assayed for LH, FSH, and αGSU; messenger RNA was extracted from adherent cells, and expression of SF-1 and DAX-1 messenger RNA was determined by RT-PCR and verified by direct DNA sequencing. The presence of DAX-1 protein in tumor tissue was confirmed by immunocytochemistry.

DAX-1 was demonstrated in all NFPAs, 7 of 13 somatotroph tumors and 0 of 4 prolactinomas. SF-1 expression occurred in 8 of 16 NFPAs, 4 of 12 somatotroph tumors, and 1 of 4 prolactinomas. LH secretion in vitro was greater in NFPAs that were SF-1 positive (P < 0.05). Neither FSH secretion nor αGSU secretion in vitro were significantly related to the expression of SF-1 or DAX-1. SF-1-positive somatotroph tumors immunostained positively for LH-β and/or FSH-β and secreted gonadotropins in vitro.

SF-1 expression is associated with the in vitro secretion of LH by NFPAs. A proportion of somatotroph tumors also express SF-1 and DAX-1 and secrete gonadotropin hormones in vitro.
Specific Factors Predict the Response to Pulsatile Gonadotropin-Releasing Hormone Therapy in Polycystic Ovarian Syndrome1
Authors: Gill Sabrina , Taylor Ann E. , Martin Kathryn A. , Welt Corrine K. , Adams Judith M. , Hall Janet E.
Published: January 2014

Ovulation induction is particularly challenging in patients with polycystic ovarian syndrome (PCOS) and may be complicated by multifollicular development. Pulsatile GnRH stimulates monofollicular development in women with anovulatory infertility; however, ovulation rates are considerably lower in the subgroup of patients with PCOS. The aim of this retrospective study was to determine specific hormonal, metabolic, and ovarian morphological characteristics that predict an ovulatory response to pulsatile GnRH therapy in patients with PCOS.

Subjects with PCOS were defined by chronic amenorrhea or oligomenorrhea and clinical and/or biochemical hyperandrogenism in the absence of an adrenal or pituitary disorder. At baseline, gonadotropin dynamics were assessed by 10-min blood sampling, insulin resistance by fasting insulin levels, ovarian morphology by transvaginal ultrasound, and androgen production by total testosterone levels. Intravenous pulsatile GnRH was then administered. During GnRH stimulation, daily blood samples were analyzed for gonadotropins, estradiol (E2), progesterone, inhibin B, and androgen levels, and serial ultrasounds were performed.

Forty-one women with PCOS underwent a total of 144 ovulation induction cycles with pulsatile GnRH. Fifty-six percent of patients ovulated with 40% of ovulatory patients achieving pregnancy. Among the baseline characteristics, ovulatory cycles were associated with lower body mass index (P < 0.05), lower fasting insulin (P = 0.02), lower 17-hydroxyprogesterone and testosterone responses to hCG (P < 0.03) and higher FSH (P < 0.05). In the first week of pulsatile GnRH treatment, E2 and the size of the largest follicle were higher (P < 0.03), whereas androstenedione was lower (P < 0.01) in ovulatory compared with anovulatory patients. Estradiol levels of 230 pg/mL (844 pmol/L) or more and androstenedione levels of 2.5 ng/mL (8.7 nmol/L) or less on day 4 and follicle diameter of 11 mm or more by day 7 of pulsatile GnRH treatment had positive predictive values for ovulation of 86.4%, 88.4%, and 99.6%, respectively. Ovulatory patients who conceived had lower free testosterone levels at baseline (P < 0.04).

In conclusion, pulsatile GnRH is an effective and safe method of ovulation induction in a subset of patients with PCOS. Patient characteristics associated with successful ovulation in response to pulsatile GnRH include lower body mass index and fasting insulin levels, lower androgen response to hCG, and higher baseline FSH. In ovulatory patients, high free testosterone is negatively associated with pregnancy. A trial of pulsatile GnRH therapy may be useful in all PCOS patients, as E2 and androstenedione levels on day 4 or follicle diameter on day 7 of therapy are highly predictive of the ovulatory response in this group of patients.
Modulation of Cortisol Metabolism by the Growth Hormone Receptor Antagonist Pegvisomant in Patients with Acromegaly1
Authors: Trainer P. J. , Drake W. M. , Perry L. A. , Taylor N. F. , Besser G. M. , Monson J. P.
Published: January 2014

Pegvisomant is a GH receptor antagonist and highly efficacious new treatment for acromegaly. The two isoenzymes of 11β-hydroxysteroid dehydrogenase are responsible for the interconversion of cortisol and its inactive metabolite cortisone. We demonstrated previously that the type I isoform, which is principally responsible for conversion of cortisone to cortisol, is partially inhibited by GH. The net activity of the enzyme can be measured by analysis of the urinary ratio of 11-hydroxy/11-oxo cortisol metabolites or of the urinary ratio of tetrahydrocortisol/tetrahydrocortisone [(tetrahydrocortisol + 5α-tetrahydrocortisol)/tetrahydrocortisone]. We studied the influence of pegvisomant on cortisol metabolism in patients with active acromegaly. Seven patients (four women and three men; median age, 58 yr; range, 39–72) were studied at baseline and again after a mean of 46 weeks of treatment. The mean insulin-like growth factor I (IGF-I) level at baseline fell from 939.7 ± 271.1 to 346.9 ± 379.0 ng/mL on 20 mg/day pegvisomant. The 11-hydroxy/11-oxo ratio increased from a pretreatment mean value of 0.61 ± 0.18 to 0.88 ± 0.20 (P < 0.02) and when the six patients in whom serum IGF-I normalized were considered separately, the change was from 0.62 ± 0.19 to 0.90 ± 0.21 (P < 0.04). The tetrahydrocortisols/tetrahydrocortisone ratio increased from a pretreatment mean value of 0.64 ± 0.21 to 0.98 ± 0.26 (P < 0.02) and in the six patients in whom serum IGF-I normalized, the ratio rose from 0.66 ± 0.23 to 1.01 ± 0.26 (P < 0.04). These data 1) indicate that blockade of GH action with pegvisomant in patients with acromegaly is associated with reversal of the inhibition of 11β-hydroxysteroid dehydrogenase and correction of cortisol metabolism, and 2) suggest that in active acromegaly, cortisol clearance is accelerated and that this is reversed by successful treatment. This is further evidence of the efficacy of pegvisomant in the management of acromegaly and has important implications for determining optimum glucocorticoid replacement.
Effects of GH and/or Sex Steroid Administration on Abdominal Subcutaneous and Visceral Fat in Healthy Aged Women and Men
Authors: Münzer Thomas , Harman S. Mitchell , Hees Paul , Shapiro Ed , Christmas Colleen , Bellantoni Michele F. , Stevens Thomas E. , O’Connor Kieran G. , Pabst Katherine M. , St. Clair Carol , Sorkin John D. , Blackman Marc R.
Published: January 2014

Aging is associated with reduced GH, IGF-I, and sex steroid axis activity and with increased abdominal fat. We employed a randomized, double-masked, placebo-controlled, noncross-over design to study the effects of 6 months of administration of GH alone (20 μg/kg BW), sex hormone alone (hormone replacement therapy in women, testosterone enanthate in men), or GH + sex hormone on total abdominal area, abdominal sc fat, and visceral fat in 110 healthy women (n= 46) and men (n = 64), 65–88 yr old (mean, 72 yr). GH administration increased IGF-I levels in women (P = 0.05) and men (P = 0.0001), with the increment in IGF-I levels being higher in men (P = 0.05). Sex steroid administration increased levels of estrogen and testosterone in women and men, respectively (P = 0.05). In women, neither GH, hormone replacement therapy, nor GH + hormone replacement therapy altered total abdominal area, sc fat, or visceral fat significantly. In contrast, in men, administration of GH and GH + testosterone enanthate decreased total abdominal area by 3.9% and 3.8%, respectively, within group and vs. placebo (P = 0.05). Within-group comparisons revealed that sc fat decreased by 10% (P = 0.01) after GH, and by 14% (P = 0.0005) after GH + testosterone enanthate. Compared with placebo, sc fat decreased by 14% (P = 0.05) after GH, by 7% (P= 0.05) after testosterone enanthate, and by 16% (P = 0.0005) after GH + testosterone enanthate. Compared with placebo, visceral fat did not decrease significantly after administration of GH, testosterone enanthate, or GH + testosterone enanthate. These data suggest that in healthy older individuals, GH and/or sex hormone administration elicits a sexually dimorphic response on sc abdominal fat. The generally proportionate reductions we observed in sc and visceral fat, after 6 months of GH administration in healthy aged men, contrast with the disproportionate reduction of visceral fat reported after a similar period of GH treatment of nonelderly GH deficient men and women. Whether longer term administration of GH or testosterone enanthate, alone or in combination, will reduce abdominal fat distribution-related cardiovascular risk in healthy older men remains to be elucidated.
The Acute Leptin Response to GH
Authors: Lissett Catherine A. , Clayton Peter E. , Shalet Stephen M.
Published: January 2014

The effect of an acute bolus of GH on serum leptin in normal individuals and the factors affecting this response have not previously been studied. Seventeen healthy volunteers with normal body mass index, with ages ranging from 20.5–78.2 yr were studied. Each subject received three single doses of GH in random order at least 4 wk apart. Bioimpedence analysis was performed to provide estimates of fat and lean masses. Serum samples for leptin, insulin, and IGF-I were taken 0, 18, 24, 48, 72, and 120 h after each dose of GH.

Leptin levels changed significantly after the 0.67- and 7-mg doses of GH, but not after the 0.27-mg dose. Compared with baseline, there was a significant elevation (P < 0.001) in serum leptin levels at 24 h, followed by a significant decrease (P < 0.01) at 72 h.

Baseline and peak leptin levels were significantly determined by gender, fat mass, and log10 insulin. Nadir leptin levels were significantly determined by gender and fat mass. In contrast, the increment in leptin levels was significantly determined by age, although this only accounted for 24% of the variability in the increment in leptin levels.

We have demonstrated that administration of a single bolus dose of GH significantly increases serum leptin levels, followed by a significant nadir. This occurs not only after a supraphysiological dose of GH, but also after 0.67 mg, a dose within the physiological replacement range. The increment in leptin increases with advancing age, suggesting that at the level of the adipocyte, aging increases responsiveness to GH. However, this only partially explains the changes seen, and it is likely that another factor(s) is involved in the acute impact of GH on circulating leptin levels. The presence of a significant nadir after the peak in leptin levels supports the existence of a negative feedback loop, linking circulating leptin to its own biosynthesis in adipose tissue, mediated by peripheral leptin receptors.

These data provide unequivocal evidence that GH can affect serum leptin levels in the absence of a change in body composition.
Regulation of GH Secretion in Acromegaly: Reproducibility of Daily GH Profiles and Attenuated Negative Feedback by IGF-I
Authors: Jaffe Craig A. , Pan Wenqin , Brown Morton B. , DeMott-Friberg Roberta , Barkan Ariel L.
Published: January 2014

GH hypersecretion is a hallmark of acromegaly. It is unknown whether the secretory activity of somatotroph adenoma is autonomous or is still governed by central or peripheral mechanisms. In this study we investigated whether GH secretion in acromegaly 1) has a reproducible circadian pattern and 2) is inhibited by exogenous IGF-I. Eleven patients with newly diagnosed acromegaly were studied in 2 protocols. In protocol 1, peripheral blood was sampled every 10 min for 48 h in 6 patients for the determination of concordance between 24-h GH profiles. There was no significant day to day variability in mean 24-h output. There was, however, a significant time effect, and the 24-h GH secretion pattern was maintained between days. In protocol 2, 5 patients were sampled for GH every 10 min twice, once during infusion of normal saline and once during iv infusion of recombinant human IGF-I (10 μg/kg·h). The recombinant human IGF-I infusion increased plasma IGF-I to approximately 230% of the baseline concentration. This resulted in GH suppression (4220 ± 1950 vs. 3223 ± 1472 μg/liter·min; P = 0.001), but did not alter GH secretion pattern. There were highly significant cross-correlations for 10 of the 11 of the subjects in the two protocols when the lag was 0 min. By harmonic analysis, nocturnal augmentation of GH was maintained, and maximum daily GH occurred at approximately 2300 h. These data demonstrate that the pattern of GH secretion in acromegaly is not random, but is highly preserved with 24-h periodicity. In addition, negative feedback regulation by IGF-I is preserved, although the degree of negative feedback is grossly attenuated. Thus, secretory activity of somatotroph adenomas is not autonomous or haphazard, but is still subject to both feedback and feedforward regulatory mechanisms.
The Cardiovascular Risk of Adult GH Deficiency (GHD) Improved after GH Replacement and Worsened in Untreated GHD: A 12-Month Prospective Study
Authors: Colao Annamaria , di Somma Carolina , Pivonello Rosario , Cuocolo Alberto , Spinelli Letizia , Bonaduce Domenico , Salvatore Marco , Lombardi Gaetano
Published: January 2014

Increased cardiovascular morbidity and mortality were reported in GH deficiency (GHD), and GH replacement can ameliorate cardiac abnormalities of adult GHD patients. To test the potential progression of untreated GHD on the cardiovascular risk and cardiac function, cardiovascular risk factors, cardiac size, and performance were prospectively evaluated in 15 GHD patients (age, 18–56 yr) who were treated with recombinant GH at the dose of 0.15–1.0 mg/d, 15 GHD patients (age, 18–56 yr) who refused GH replacement, and 30 healthy subjects (age, 18–53 yr).

Electrocardiogram, systolic and diastolic blood pressure, and heart rate measurement, serum IGF-I, total cholesterol, low- and high-density lipoprotein (LDL, HDL) cholesterol, triglycerides, and fibrinogen level assay, echocardiography, and equilibrium radionuclide angiography were performed basally and after 12 months.

At study entry, low IGF-I levels, unfavorable lipid profile, and inadequate cardiac and physical performance were found in GHD patients compared with controls. After 12 months of GH treatment, IGF-I levels normalized; HDL-cholesterol levels, left ventricular (LV) mass index (LVMi), left ventricular ejection fraction (LVEF) at peak exercise, peak filling rate, exercise duration and capacity significantly increased; total- and LDL-cholesterol levels significantly decreased. After 12 months in GH-untreated GHD patients, IGF-I levels remained stable, and HDL-cholesterol levels, LVEF both at rest and at peak exercise, and exercise capacity were further reduced; total- and LDL-cholesterol levels increased slightly. LVEF at rest and its response at peak exercise normalized in 60 and 53.3%, respectively, of GH-treated patients and in none of the GH-untreated patients.

In conclusion, 12 months of GH replacement normalized IGF-I and improved lipid profile and cardiac performance in adult GHD patients. A similar period of GH deprivation induced a further impairment of lipid profile and cardiac performance. This finding strongly supports the need of GH replacement in adult GHD patients.
Twenty-One Day Administration of Dienogest Reversibly Suppresses Gonadotropins and Testosterone in Normal Men
Authors: Meriggiola M. Cristina , Bremner William J. , Costantino Antonietta , Bertaccini Alessandro , Morselli-Labate Antonio Maria , Huebler Doris , Kaufmann Guenter , Oettel Michael , Flamigni Carlo
Published: January 2014

Androgen-progestin combinations are promising male contraceptive regimens. Optimization of these regimens includes the development of new progestins with more favorable biological properties. In this context we tested the effects of the progestin dienogest (DNG) on reproductive hormones and metabolic parameters in men.

After a 3-wk control period, 25 men were randomly assigned to receive daily doses of 2, 5, or 10 mg DNG or placebo and 10 mg cyproterone acetate for 21 d (n = 5 subjects/group). Subjects were followed for 2 wk after cessation of hormone administration. Weekly blood samples, physical examinations, hormone and chemistry measurements, semen analysis, and sexual/behavioral assessments were performed. These parameters were compared among study groups and within each group at different time points throughout the study periods.

DNG and cyproterone acetate administration resulted in profound suppression of gonadotropins and T with no change in SHBG levels. No adverse effects were detected in any subject. Hormone levels returned to baseline after stopping hormone intake.

DNG is a potent suppressor of gonadotropins and T in men and does not induce adverse effects over a 21-d administration. DNG is a promising progestin to be used in clinical trials for male contraception.
A Novel, C-Terminal Dominant Negative Mutation of the GR Causes Familial Glucocorticoid Resistance through Abnormal Interactions with p160 Steroid Receptor Coactivators
Authors: Vottero Alessandra , Kino Tomoshige , Combe Herve , Lecomte Pierre , Chrousos George P.
Published: January 2014

Primary cortisol resistance is a rare, inherited or sporadic form of generalized end-organ insensitivity to glucocorticoids. Here, we report a kindred in which affected members had a heterozygous T to G base substitution at nucleotide 2373 of exon 9α of the GR gene, causing substitution of Ile by Met at position 747. This mutation was located close to helix 12, at the C terminus of the ligand-binding domain, which has a pivotal role in the formation of activation function (AF)-2, a subdomain that interacts with p160 coactivators. The affinity of the mutant GR for dexamethasone was decreased by about 2-fold, and its transcriptional activity on the glucocorticoid-responsive mouse mammary tumor virus promoter was compromised by 20- to 30-fold. In addition, the mutant GR functioned as a dominant negative inhibitor of wild-type receptor-induced transactivation. The mutant GR through its intact AF-1 domain bound to a p160 coactivator, but failed to do so through its AF-2 domain. Overexpression of a p160 coactivator restored the transcriptional activity and reversed the negative transdominant activity of the mutant GR. Interestingly, green fluorescent protein (GFP)-fused GRαI747M had a slight delay in its translocation from the cytoplasm into the nucleus and formed coarser nuclear speckles than GFP-fused wild-type GRα. Similarly, a GFP-fused p160 coactivator had a distinctly different distribution in the nucleus in the presence of mutant vs. wild-type receptor, presenting also as coarser speckling. We conclude that the mutation at amino acid 747 of the GR causes familial, autosomal dominant glucocorticoid resistance by decreasing ligand binding affinity and transcriptional activity, and by exerting a negative transdominant effect on the wild-type receptor. The mutant receptor has an ineffective AF-2 domain, which leads to an abnormal interaction with p160 coactivators and a distinct nuclear distribution of both.
Marked Disproportionality in Bone Size and Mineral, and Distinct Abnormalities in Bone Markers and Calcitropic Hormones in Adult Turner Syndrome: A Cross-Sectional Study
Authors: Gravholt Claus Højbjerg , Lauridsen Anna Lis , Brixen Kim , Mosekilde Leif , Heickendorff Lene , Christiansen Jens Sandahl
Published: January 2014

Most women with Turner syndrome (TS) have no gonadal activity and thus lack estrogen. Bone mineral density (BMD) is often reduced, leading to an increased risk of osteoporosis and fractures. However, growth retardation with reduced final height and other endocrine disturbances may compromise interpretation of skeletal measurements. The aim of the present study was to explore skeletal findings, bone metabolism, and calcium homeostasis in TS. Sixty women with TS (age, 37 ± 9 yr) and 181 normal age-matched female controls were studied. Bone area (A; square centimeters), bone mineral content (BMC; grams), area-adjusted BMD (aBMD; grams/square centimeter), and volumetric BMD (vBMD; grams/cubic centimeter) were measured at lumbar spine, femoral neck, and forearm using dual energy x-ray absorptiometry. Twenty-eight percent had osteopenia, and 23% had osteoporosis, according to World Health Organization criteria. At the lumbar spine, A, BMC, aBMD, and vBMD were reduced by 18, 27, 11, and 6%, respectively; at the femoral neck, A, BMC, and aBMD were reduced by 2, 10, and 8%, respectively, whereas the 9% reduction in vBMD was insignificant (P = 0.07); and in the forearm, A, BMC, and aBMD were reduced by 53, 55, and 9%, respectively. Bone markers indicated an enhanced bone resorption (21 and 23% increase in C-terminal and N-terminal cross-linking telopeptides of type I collagen/creatinine, respectively) with unchanged (osteocalcin, procollagen I N-terminal propeptide) or reduced (54% reduction in bone alkaline phosphatase) bone formation. Plasma levels of calcium and 25-hydroxyvitamin D (26%) were reduced, and PTH levels increased (74%) in TS. IGF-I (30%), IGF binding protein 3 (18%), testosterone (50%), and SHBG (40%) were reduced in TS.

In summary, A, BMC, and aBMD were found to be universally reduced in TS, whereas vBMD was slightly reduced in the spine. Increased resorption of bone was present, with normal or blunted bone formation, suggesting uncoupling or imbalance in bone remodeling. Skeletal changes may be induced by chromosome abnormalities or by secondary endocrine or metabolic changes related to a relative estrogen deficiency, testosterone deficiency, reduced IGF-I, low vitamin D status, and secondary hyperparathyroidism.