bluuebunny/crossref_metadata_2025 huggingface dataset:
Decrease in Carotid Intima-Media Thickness after One Year Growth Hormone (GH) Treatment in Adults with GH Deficiency1
Authors: Borson-Chazot Françoise , Serusclat André , Kalfallah Yadh , Ducottet Xavier , Sassolas Geneviève , Bernard Sophie , Labrousse Florence , Pastene Jorge , Sassolas Agnès , Roux Yves , Berthezène François
Published: January 2014

An increased carotid arterial intima-media thickness (IMT) has been reported in hypopituitary adults untreated for GH deficiency. In the present study, the effect of GH replacement on IMT and cardiovascular risk factors was prospectively investigated, in GH deficiency patients treated at a mean dose of 1 UI/day during 1 yr (n = 22) and 2 yr (n = 11). The IMT measurements were performed by the same experienced physician, and the coefficient of variation (calculated in two control groups) was below 6.5%. IMT at baseline was related to conventional risk factors. After 1 yr GH treatment, IMT decreased from 0.78 ± 0.03 mm to 0.70 ± 0.03 mm (P < 0.001). The decrement was observed in 21 of 22 patients. After 2 yr GH treatment, IMT had stabilized at 0.70 ± 0.04 mm and remained significantly different from baseline values (P < 0.003). GH treatment resulted in a moderate decrease in waist circumference and body fat mass and an increase in VO2 max. Conventional cardiovascular risk factors were unmodified except for a transient 10% decrease in low-density lipoprotein cholesterol at 6 months. The contrast between the limited metabolic effect of treatment and the importance and precocity of the changes in IMT suggests that the decrease in IMT was not exclusively attributable to a reversal in the atherosclerotic process. A direct parietal effect of GH replacement on the arterial wall might also be involved. The consequences, in terms of cardiovascular risk, should be established by randomized prospective trials.
Reactivation of Pituitary Hormone Release and Metabolic Improvement by Infusion of Growth Hormone-Releasing Peptide and Thyrotropin-Releasing Hormone in Patients with Protracted Critical Illness1
Authors: Van den Berghe Greet , Wouters Pieter , Weekers Frank , Mohan Subburaman , Baxter Robert C. , Veldhuis Johannes D. , Bowers Cyril Y. , Bouillon Roger
Published: January 2014

Protracted critical illness is marked by protein wasting resistant to feeding, by accumulation of fat stores, and by suppressed pulsatile release of GH and TSH. We previously showed that the latter can be reactivated by brief infusion of GH-releasing peptide (GHRP-2) and TRH. Here, we studied combined GHRP-2 and TRH infusion for 5 days, which allowed a limited evaluation of the metabolic effectiveness of this novel trophic endocrine strategy.

Fourteen patients (mean ± sd age, 68 ± 11 yr), critically ill for 40 ± 28 days, were compared to a matched group of community-living control subjects at baseline and subsequently received 5 days of placebo and 5 days of GHRP-2 plus TRH (1+1μ g/kg·h) infusion in random order.

At baseline, impaired anabolism, as indicated by biochemical markers (osteocalcin and leptin), was linked to hyposomatotropism [reduced pulsatile GH secretion, as determined by deconvolution analysis, and low GH-dependent insulin-like growth factor and binding protein (IGFBP) levels]. Biochemical markers of accelerated catabolism (increased protein degradation and bone resorption) were related to tertiary hypothyroidism and the serum concentration of IGFBP-1, but not to hyposomatotropism. Metabolic markers were independent of elevated serum cortisol.

After 5 days of GHRP-2 plus TRH infusion, osteocalcin concentrations increased 19% vs. −6% with placebo, and leptin had rose 32% vs. -15% with placebo. These anabolic effects were linked to increased IGF-I and GH-dependent IGFBP, which reached near-normal levels from day 2 onward. In addition, protein degradation was reduced, as indicated by a drop in the urea/creatinine ratio, an effect that was related to the correction of tertiary hypothyroidism, with near-normal thyroid hormone levels reached and maintained from day 2 onward. Concomitantly, a spontaneous tendency of IGFBP-1 to rise and of insulin to decrease was reversed. Cortisol concentrations were not detectably altered.

In conclusion, 5-day infusion of GHRP-2 plus TRH in protracted critical illness reactivates blunted GH and TSH secretion, with preserved pulsatility, peripheral responsiveness, and feedback inhibition and without affecting serum cortisol, and induces a shift toward anabolic metabolism. This provides the first evidence of the metabolic effectiveness of short term GHRP-2 plus TRH agonism in this particular wasting condition.
Polymorphism in the 5′-Leader Cistron of theβ 2-Adrenergic Receptor Gene Associated with Obesity and Type 2 Diabetes
Authors: Yamada Kentaro , Ishiyama-Shigemoto Satomi , Ichikawa Fumi , Yuan Xiaohong , Koyanagi Atsuko , Koyama Wasaku , Nonaka Kyohei
Published: January 2014

We screened the 5′-untranslated region of theβ 2-adrenergic receptor gene from 40 obese subjects by the PCR-direct sequencing technique. Two polymorphic sites were identified; a T → C substitution at −47 and a T → C substitution at −20. We further analyzed the association of the polymorphisms with obesity in 574 subjects by PCR and restriction digestion. The substituion at −47 was in tight linkage disequilibrium with that at −20. The polymorphisms were also in linkage disequilibrium with codon 16 and codon 27 polymorphisms. Subjects carrying the −47C/−20C allele had greater body mass index (25.5 ± 4.5 vs. 24.2 ± 4.1 kg/m2, P = 0.007) and higher serum triglyceride levels (166 ± 160 vs. 139 ± 95 mg/dl, P= 0.015) than −47T/−20T homozygotes. The variant allele frequency was significantly higher in obese subjects than in non-obese subjects (0.18 vs. 0.11, P = 0.0026). Furthermore, an increased frequency of the variant allele was shown in diabetic patients compared with non-diabetic subjects (0.19 vs.0.11, P = 0.0005). The association may be attributable to the greater proportion of diabetic patients in the obese group. The exchange at −47 may alter the expression level of the β2-adrenergic receptor gene, because the nucleotide substitution at −47 results in a Cys → Arg exchange at the C terminal of the leader peptide. The −47C/−20C allele may be associated with genetic predisposition to obesity and obesity-related metabolic disorders.
Hormone Replacement Therapy Causes a Respiratory Alkalosis in Normal Postmenopausal Women1
Authors: Orr-Walker Brandon J. , Horne Anne M. , Evans Margaret C. , Grey Andrew B. , Murray M. A. F. , McNeil Alan R. , Reid Ian R.
Published: January 2014

Menopause is associated with an increase in venous bicarbonate concentrations that is reversible with hormone replacement therapy (HRT). However, the mechanism underlying this effect is not known. To address this question, we studied the changes in acid-base indexes in the arterialized venous blood of normal postmenopausal women commencing conjugated equine estrogen (0.625 mg/day), medroxyprogesterone acetate (MPA; 5 mg/day), their combination, or placebo, in a double blind randomized controlled study over 3 months.

Serum bicarbonate concentrations decreased significantly in the groups receiving either MPA or estrogen plus MPA (P = 0.008). This trend was apparent as early as 2 days and reached 2.7 and 2.3 mmol/L in the respective groups by 3 months. Similar changes were seen with partial pressure of carbon dioxide (P = 0.04); a change of −0.7 kPa occurred in the estrogen plus MPA group at 3 months. There were no changes in bicarbonate concentrations or partial pressure of carbon dioxide in those receiving estrogen alone or placebo. Accompanying changes in blood pH were apparent in the estrogen plus MPA group, where there was an upward trend at 1 week (P = 0.056) and a significant change from baseline (+0.013) at 3 months (P = 0.03). In the whole group, the changes in pH were inversely correlated with those in urinary excretion of hydroxyproline (r = −0.44; P = 0.01).

We conclude that HRT using conjugated estrogens and MPA produces small, but sustained, changes in acid-base status. These may contribute to the effects of HRT and menopause on many tissues and disease processes, including the development of osteoporosis.
Identification of a Three-Amino Acid Deletion in theα 2B-Adrenergic Receptor That Is Associated with Reduced Basal Metabolic Rate in Obese Subjects
Authors: Heinonen Paula , Koulu Markku , Pesonen Ullamari , Karvonen Matti K. , Rissanen Aila , Laakso Markku , Valve Raisa , Uusitupa Matti , Scheinin Mika
Published: January 2014

The α2-adrenergic receptors mediate part of the actions of the catecholamines noradrenaline and adrenaline on the regulation of energy balance. As part of an ongoing study on the genetics of obesity, the entire coding sequence of the α2B-adrenoceptor gene was screened in 58 obese, nondiabetic Finns by PCR-single stranded conformational analysis (PCR-SSCA). A polymorphism that leads to a deletion of 3 glutamic acids from a glutamic acid repeat element (Glu × 12, amino acids 297–309) present in the third intracellular loop of the receptor protein was identified. This repeat element has previously been shown to be important for agonist-dependent receptor desensitization. Of 166 genotyped subjects, 47 (28%) had 2 normal (long) alleles (Glu12/Glu12), 90 (54%) were heterozygous (Glu12/Glu9), and 29 (17%) were homozygous for the short (Glu9/Glu9) form. The basal metabolic rate, determined by indirect calorimetry and adjusted for fat-free body mass, fat mass, sex, and age, was 94 Cal/day (5.6%) lower (95% confidence interval for difference, 32, 156) in subjects homozygous for the short allele than in subjects with two long alleles (F = 4.84; P = 0.009, by ANOVA). Thus, a genetic polymorphism of the α2B-adrenoceptor subtype can partly explain the variation in basal metabolic rate in an obese population and may therefore contribute to the pathogenesis of obesity.
Reduced Growth Hormone Receptor Messenger Ribonucleic Acid in an Aged Man with Chronic Malnutrition and Growth Hormone Resistance
Authors: Shuto Yujin , Nakano Tadasumi , Sanno Naoko , Domoto Hideharu , Sugihara Hitoshi , Wakabayashi Ichiji
Published: January 2014

A severely malnourished 87-yr-old man presented with hypoglycemia. Serum GH levels were elevated, and serum levels of insulin-like growth factor I (IGF-I), IGF-binding protein-3, and GH-binding protein were extremely reduced. The patient’s GH was biologically active. Administration of GH for 4 consecutive days resulted in a slight increment in serum IGF-I levels, but no elevation of serum IGF-binding protein-3. The expression of GH receptor messenger ribonucleic acid in the liver was greatly reduced. An autopsy revealed a Rathke’s cleft cyst confined to the sella turcica. Immunohistochemical studies for GH showed that there was nothing to suggest a tumor overproducing GH. In addition, TSH levels were elevated in the presence of normal thyroid hormone levels, and there was a cluster of cells showing strong immunohistochemical staining for the TSH β-subunit in the pituitary. In this patient, the decreased expression of GH receptor messenger ribonucleic acid in the liver may have been responsible for the GH resistance, which was probably caused by malnutrition.
Leptin Responses to Overfeeding: Relationship with Body Fat and Nonexercise Activity Thermogenesis1
Authors: Levine James A. , Eberhardt Norman L. , Jensen Michael D.
Published: January 2014

Administration of leptin to rodents results in weight loss through decreased food intake and increased energy expenditure that occurs in part through increased spontaneous activity. In humans, low levels of spontaneous physical activity and below normal plasma leptin concentrations predict subsequent excess weight gain. We recently found that failure to increase nonexercise activity thermogenesis (NEAT) with overfeeding results in greater fat gain in humans, and subsequently evaluated whether changes in leptin are related to NEAT activation. We measured plasma leptin concentrations and adipose tissue leptin messenger ribonucleic acid together with the components of energy expenditure in 16 nonobese humans before and after overfeeding to assess the relationship between leptin responses to overfeeding and the changes in NEAT. Adipocyte leptin expression was up-regulated with overfeeding, and leptin concentrations increased. Leptin concentrations correlated with body fat before and after overfeeding. Changes in leptin with overfeeding were strongly related to changes in body fat, but not to changes in NEAT. Changes in NEAT correlated inversely with fat gain. It is, therefore, unlikely that leptin mediates activation of NEAT with overfeeding in nonobese humans; rather, leptin directly reflects body fat mass and fat mass gain.
The Relation between Bone Mineral Density, Insulin-Like Growth Factor I, Lipoprotein (a), Body Composition, and Muscle Strength in Adolescent Males
Authors: Thorsen Kim , Nordström Peter , Lorentzon Ronny , Dahlén Gösta H.
Published: January 2014

Osteoporosis is the most common metabolic bone disease. A low peak bone mass is regarded a risk factor for osteoporosis. Heredity, physical activity, and nutrition are regarded important measures for the observed variance in peak bone mass. Lp(a) lipoprotein is a well-known risk factor for atherosclerosis. Serum insulin-like growth factor I (IGF-I) has been found to be increased in males with early cardiovascular disease. In this study, we evaluated the association between bone mass, body constitution, muscle strength, Lp(a), and IGF-I in 47 Caucasian male adolescents (mean age, 16.9 yr). Bone mineral density (BMD) and body composition were measured by dual x-ray absorptiometry, muscle strength of thigh using an isokinetic dynamometer, IGF-I by RIA, and Lp(a) by enzyme-linked immunosorbent assay. IGF-I was only associated with Lp(a) (r = 0.38, P < 0.01). Lp(a) was related to total body (r= 0.40, P < 0.01), skull (r = 0.45, P < 0.01), and femoral neck BMD (r = 0.44, P < 0.01). Lp(a) was also related to fat mass (r = 0.34, P < 0.05) and muscle strength (r = 0.30–0.42, P < 0.05). After multiple regression and principal component (PC) analysis, the so-called PC body size (weight, fat mass, lean body mass, and muscle strength) was the most significant predictor of BMD (β = 0.28–0.51, P < 0.05–0.01), followed by the so-called PC physical activity (β = 0.28–0.38, P < 0.05–0.01, weight-bearing locations). However, the PC analysis confirmed that Lp(a) was an independent predictor of total body, skull, and femoral neck BMD (β = 0.33–0.36, P < 0.01).

The present investigation confirms that BMD, body size, and muscle strength are closely related and that the level of physical activity is a major determinant of BMD. However, the positive relation of Lp(a), a major risk factor for cardiovascular disease, to BMD has not previously been described. The importance of this observation has to be further investigated.
Breast Tissues in Transsexual Women–A Nonprostatic Source of Androgen Up-Regulated Production of Prostate-Specific Antigen
Authors: Goh Victor H. H.
Published: January 2014

The present study made use of the female transsexual model and sought to evaluate the contributions of the ovarian, endometrial, and breast tissues to the androgen up-regulated production of prostate specific antigen (PSA). Serum levels of PSA were significantly raised in female transsexuals before surgery, after long-term androgen therapy (mean ± se = 35.3 ± 6.2 pg/mL) when compared with female transsexuals before surgery, but with no androgen therapy (mean ± se = 1.53 ± 0.25 pg/mL). In addition, in androngenized female transsexuals, after surgery, concentrations of PSA (mean ± se = 14.5 ± 2.8 pg/mL) were significantly lowered compared with androngenized female transsexuals after surgery, but the levels were, nevertheless, significantly higher than in normal females. Monthly im injection of 250 mg Sustanon-250 to female transsexuals had raised serum testosterone levels to within the male range. In five subjects, in whom serial measurements were taken, serum testosterone levels were greatly raised 24 h after the testosterone therapy; the mean level (±se) was 19.5 ± 2.1 ng/mL. But in spite of these high testosterone levels, serum PSA levels (mean ± se= 2.2 ± 0.9 pg/mL) were not significantly raised. However, after 12 months of androgen therapy, the mean (±se) PSA level in these five subjects was 47 ± 11.6 pg/mL and was significantly higher than the mean level in nonandrogenized female transsexuals. The present study confirmed that high levels of testosterone were able to up-regulate PSA production in women. This up-regulation of PSA production is both a dose- and time-dependent process. Furthermore, the evidence indicates that breast tissues are possibly a nonprostatic source of androgen up-regulated production of PSA women.
Expression of the Calcium-Sensing Receptor in Gastrinomas
Authors: Goebel Stephan U. , Peghini Paolo L. , Goldsmith Paul K. , Spiegel Allen M. , Gibril Fathia , Raffeld Mark , Jensen Robert T. , Serrano Jose
Published: January 2014

Extracellular calcium levels are able to influence the secretion of gastrin by gastrinomas and possibly affect the growth pattern. The molecular mechanisms of these functions are not known. The purpose of the present study was to investigate the presence of the calcium-sensing receptor (CaR) in 10 gastrinomas and determine the extent of expression in the tumors. The amounts of CaR messenger ribonucleic acid in eight tumors were determined by quantitative RT-PCR. Protein expression was analyzed by Western blot and immunohistochemistry using a monoclonal antibody (ADD). CaR messenger ribonucleic acid was detected in all gastrinomas with levels ranging from 0.04–3.16 times the amount of β-actin transcripts. The Western blot showed a major immunoreactive band at 250 kDa and a minor at 140 kDa, corresponding to the receptor dimer and monomer, respectively. Immunohistochemistry demonstrated variable membranous staining in all gastrinomas and normal pancreatic islets. No staining was observed in the normal liver, lymph node, or exocrine pancreas. We conclude that the CaR is present in all gastrinomas, with expression varying by 80-fold. It probably contributes to the calcium-stimulated gastrin release by gastrinomas. Whether the density of the CaR is a determining factor of the magnitude of this gastrin release or plays a role in regulating the growth pattern of the gastrinoma, as it does in other cells, remains unclear at present.
High Prevalence of Antineutrophil Cytoplasmic Antibody Positivity in Childhood Onset Graves’ Disease Treated with Propylthiouracil
Authors: Sato Hirokazu , Hattori Motoshi , Fujieda Mikiya , Sugihara Shigetaka , Inomata Hiroaki , Hoshi Mari , Miyamoto Shigeki
Published: January 2014

Propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA)-related vasculitis and nephritis were recently reported in about 30 patients with hyperthyroidism. The objective of this study was to clarify the prevalence of ANCA and the relationship between ANCA and thyroid antibodies in children with Graves’ disease.

Titers of myeloperoxidase (MPO)-ANCA in sera of 51 patients with childhood onset Graves’ disease (16 before treatment, 25 and 10 treated with PTU and methimazole, respectively) were measured by enzyme-linked immunosolvent assay. Antithyroglobulin antibodies (TGAbs) and antithyroperoxidase antibodies (TPOAbs) were also measured by RIA in 25 PTU-treated patients. No patients had clinical manifestations of vasculitis and nephritis. MPO-ANCA was positive in 6.7% of patients before treatment and in 64.0% of those treated with PTU and in none of those treated with methimazole. MPO-ANCA had a significantly positive correlation with TGAbs (P < 0.05) and no significant correlation with TPOAbs.

These findings show the high prevalence of the MPO-ANCA positivity in PTU-treated childhood onset Graves’ disease, suggesting that PTU may not be preferred as the first line for the treatment of children with Graves’ disease. The significant correlation between MPO-ANCA and TGAbs indicates that the severity of Graves’ disease may be a factor responsible for the MPO-ANCA positivity. The cross-reactivity between MPO-ANCA and TPOAbs may not play a role in the high prevalence of MPO-ANCA in the patients exposed to PTU.
Associations among Oral Estrogen Use, Free Testosterone Concentration, and Lean Body Mass among Postmenopausal Women1
Authors: Gower Barbara A. , Nyman Lara
Published: January 2014

Circulating concentrations of sex hormone-binding globulin (SHBG) are increased by use of oral estrogen. The objective of this study was to determine whether postmenopausal women who used oral estrogen had higher serum concentrations of SHBG and lower serum concentrations of free testosterone (T) than nonusers, and whether free T was associated with lean body mass, particularly skeletal muscle mass. Subjects were 70 postmenopausal women, 46–55 yr old, 46 of whom used oral estrogen. Total and regional body composition were determined by dual-energy x-ray absorptiometry. Serum concentrations of SHBG, total T, and estradiol (E2) were determined by RIA. Free T was calculated from concentrations of total T and SHBG. Hormone users had higher serum concentrations of E2 and SHBG (182.0 ± 58.5 vs. 82.9 ± 41.1 nmol/L, mean ± sd, P < 0.001) and lower concentrations of free T (3.7 ± 2.2 vs. 7.9± 4.1 pmol/L, mean ± sd, P < 0.001); total T did not differ. Total lean mass and leg lean mass were significantly correlated with free, but not total T [r values of 0.29 (P < 0.05) and 0.31 (P < 0.01) for total and leg lean mass, respectively, vs. free T]; arm lean mass was not correlated with either measure of T. Serum E2 was significantly correlated with SHBG (r = 0.50, P < 0.001) and free T (r = −0.33, P < 0.01). These observations imply that, by reducing the concentration of bioavailable T, oral estrogen therapy may accelerate or augment lean mass loss among postmenopausal women. This conclusion awaits confirmation by longitudinal observation.
Adrenocorticotropin and Corticotropin-Releasing Hormone Tests in Preterm Infants1
Authors: Karlsson Riikka , Kallio Jaana , Irjala Kerttu , Ekblad Satu , Toppari Jorma , Kero Pentti
Published: January 2014

The short ACTH test is used in evaluating the hypothalamo-pituitary-adrenal axis (HPA-axis) in preterm neonates after dexamethasone treatment. This test mainly examines primary adrenal suppression but is also used as a method to test secondary adrenal insufficiency because long-term deprivation of ACTH causes atrophy of the adrenal cortex. The CRH test, on the other hand, directly examines the function of the pituitary. We tested 18 infants in the neonatal intensive care unit with both the ACTH test and the CRH test to determine which of these two tests more reliably demonstrates HPA-axis suppression.

One patient had normal responses both in the ACTH test and in the CRH test when the limit of 360 nmol/L was used as a sign of proper cortisol secretion. In four cases the patients’ cortisol secretion would have been regarded as normal by the low-dose ACTH test, whereas the CRH test did not show an adequate cortisol response.

In conclusion, the ACTH test did not reliably indicate HPA-axis suppression after a short (<2 weeks) course of dexamethasone therapy in this study. Therefore, whether the infant is or will be under acute stress after short glucocorticoid treatment, ensuring adequate cortisol secretion with the CRH test should be considered.
Synergistic Effects of Nateglinide and Meal Administration on Insulin Secretion in Patients with Type 2 Diabetes Mellitus
Authors: Keilson Leonard , Mather Sergio , Walter Yulia H. , Subramanian Siva , McLeod James F.
Published: January 2014

This study assessed the synergistic effects of nateglinide (a nonsulfonylurea d-phenylalanine derivative) and meals on insulin secretion in 24 patients with type 2 diabetes. Oral doses of 60 and 180 mg or 120 and 240 mg were administered to two cohorts of subjects 10 min before meals (or fasting) three times daily for 7 days, with washout intervals between treatment periods. Dose-dependent increases in plasma insulin occurred, with the peak effect within 2 h after treatment. Significantly greater insulin secretion was observed when nateglinide was taken before a meal compared to nateglinide given in the fasted state or in response to just the meal. Nateglinide lowered plasma glucose concentrations significantly vs. placebo at all doses, and doses of 120 and 240 mg were more effective than 60 mg (P < 0.05). Adverse event rates were similar for nateglinide and placebo, and no hypoglycemic episodes or serious adverse events were reported during the study. Nateglinide (120 mg) was the maximum effective dose in this study and was shown to be a safe and well tolerated therapy for control of mealtime glucose excursions in patients with type 2 diabetes. Results indicate that a synergistic interaction occurs between nateglinide and elevated mealtime plasma glucose concentrations to stimulate insulin secretion.
Close Correlation between Estrogen Treatment and Renal Phosphate Reabsorption Capacity
Authors: Uemura Hirokazu , Irahara Minoru , Yoneda Naoto , Yasui Toshiyuki , Genjida Kaori , Miyamoto Ken-ichi , Aono Toshihiro , Takeda Eiji
Published: January 2014

To determine the influence of estrogen on the activity of renal proximal tubular reabsorption of inorganic phosphate (Pi) in women, we examined the changes of the renal threshold phosphate concentration (also denoted as TmP/GFR), as well as the changes in the concentrations of mineral components in the circulation in two groups of women—one receiving hormone replacement therapy (HRT) and one receiving gonadotropin-releasing hormone agonists (GnRH-a) therapy. We also examined the changes in the concentrations of serum PTH in the GnRH-a group. The patients in the HRT group were continuously treated with 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate per day. The patients in the GnRH-a group were treated with a monthly injection of 3.75 mg leuprolide acetate depot for 6 months. The values of TmP/GFR decreased in all of the patients who received HRT. The mean percentage change in TmP/GFR was− 14.5% (range, −24.3% to −9.6%). In contrast, in all of the patients treated with GnRH-a, the values of TmP/GFR increased after 6 months of treatment (the mean percentage change was 28.5%; range, 18.2–78.3%) and returned to the preadministration level at 12 weeks after stopping therapy. In these patients, both the values of TmP/GFR and the concentrations of serum Pi correlated significantly with circulating estradiol levels (r = −0.767, P< 0.01 and r = −0.797, P < 0.01, respectively), but the concentrations of serum corrected calcium did not correlate. Moreover, in the same patients, the levels of serum intact PTH decreased significantly (P < 0.05) after 6 months of treatment, but at 12 weeks after stopping therapy the trends of these levels varied among individual patients. These results suggest that estrogen could act directly to suppress sodium-dependent Pi reabsorption in the renal proximal tubules.
Effects of Insulin-Like Growth Factor I (IGF-I) Therapy on Body Composition and Insulin Resistance in IGF-I Gene Deletion
Authors: Woods K. A. , Camacho-Hübner C. , Bergman R. N. , Barter D. , Clark A. J. L. , Savage M. O.
Published: January 2014

We have recently reported a patient with a homozygous partial deletion of the insulin-like growth factor-I (IGF-I) gene, resulting in IGF-I deficiency, insulin resistance, and short stature. Recombinant human IGF-I (rhIGF-I) therapy has been shown to improve insulin sensitivity (Si) and growth in other causes of IGF-I deficiency. We now report results of 1 yr of rhIGF-I therapy on body composition, bone mineral density (BMD), insulin sensitivity, and linear growth in this patient. rhIGF-I therapy was initiated at age 16.07 yr (bone age, 14.2 yr), at a starting dose of 40 μg/kg daily, increasing after 3 months to 80μ g/kg daily. Body composition, BMD, markers of bone mineralization, and auxological parameters (height, weight) were measured at 0, 6, and 12 months after start of therapy. Si, acute insulin response to glucose, and glucose effectiveness were determined at baseline, 3 months, and 12 months into therapy. On IGF-I therapy, body mass index increased from 17 kg/m2 to 18.6 kg/m2. Body composition studies (dual-energy x-ray absorbtiometry) revealed an initial decrease in total body fat, from 19.9% at baseline to 15.1% at 6 months; but by 12 months of therapy, this had reversed, with an increase to 21.8%. Si, calculated using Bergman’s minimal model, was substantially reduced at baseline at 1.45 × 10−4 min−1 (μU/mL) [normal value, 5.1 × 10−4 min−1 (lean adult male)]. rhIGF-I therapy resulted in a dose-related improvement of Si into the normal range (NR) (rhIGF-I dose: 40 μg/kg·day, Si = 2.06 × 10−4 min−1; rhIGF-I dose: 80 μg/kg·day, Si = 4.39 × 10−4 min−1). Baseline reduction in Si was accompanied by elevated acute insulin response to glucose, which also fell in a dose-dependent manner. Baseline BMD was severely reduced when compared with age-matched controls (−4.88 sd); however, calculation of bone mineral apparent density indicated that the true reduction in BMD was minimal. rhIGF-I therapy increased BMD by 17% and bone mineral apparent density by 7%, indicating that IGF-I has a greater effect on bone growth than bone mineralization. Bone turnover markers also increased on rhIGF-I; mean serum osteocalcin: 8.3 ng/mL pretreatment, 21.7 ng/mL after 6 months of rhIGF-I (NR for adult male, 3.4–9.1 ng/mL); mean bone specific alkaline phosphatase: 36.5 U/L pretreatment, 82.2 U/L after 6 months of therapy (NR for adult male, 15–41). Height velocity increased from 3.8 cm/yr pretreatment to 7.3 cm/yr on 80 μg/kg·day of rhIGF-I.

In this patient with severe insulin resistance, therapy with rhIGF-I resulted in beneficial effects on Si, body composition, bone size, and linear growth. These results have implications for IGF-I therapy in a variety insulin resistant states.
Impaired Insulin-Stimulated Expression of the Glycogen Synthase Gene in Skeletal Muscle of Type 2 Diabetic Patients Is Acquired Rather Than Inherited1
Authors: Huang Xudong , Vaag Allan , Hansson Mona , Weng Jianping , Laurila Esa , Groop Leif
Published: January 2014

To examine whether defective muscle glycogen synthase (GYS1) expression is associated with impaired glycogen synthesis in type 2 diabetes and whether the defect is inherited or acquired, we measured GYS1 gene expression and enzyme activity in muscle biopsies taken before and after an insulin clamp in 12 monozygotic twin pairs discordant for type 2 diabetes and in 12 matched control subjects. The effect of insulin on GYS1 fractional activity, when expressed as the increment over the basal values, was significantly impaired in diabetic (15.7 ± 3.3%; P < 0.01), but not in nondiabetic (23.7 ± 1.8%; P = NS) twins compared with that in control subjects (28.1 ± 2.3%). Insulin increased GYS1 messenger ribonucleic acid (mRNA) expression in control subjects (from 0.14 ± 0.02 to 1.74 ± 0.10 relative units; P < 0.01) and in nondiabetic (from 0.24 ± 0.05 to 1.81 ± 0.16 relative units; P < 0.01) and diabetic (from 0.20 ± 0.07 to 1.08 ± 0.14 relative units; P < 0.01) twins. The effect of insulin on GYS1 expression was, however, significantly reduced in the diabetic (P < 0.003), but not in the nondiabetic, twins compared with that in control subjects. The postclamp GYS1 mRNA levels correlated strongly with the hemoglobin A1c levels (r = −0.61; P < 0.001). Despite the decrease in postclamp GYS1 mRNA levels, the GYS1 protein levels were not decreased in the diabetic twins compared with those in the control subjects (2.10 ± 0.46 vs. 2.10 ± 0.34 relative units; P = NS). We conclude that 1) insulin stimulates GYS1 mRNA expression; and 2) impaired stimulation of GYS1 gene expression by insulin in patients with type 2 diabetes is acquired and most likely is secondary to chronic hyperglycemia.
Evaluation of the Treatment of Thyrotropin-Secreting Pituitary Adenomas with a Slow Release Formulation of the Somatostatin Analog Lanreotide
Authors: Kuhn J. M. , Arlot S. , Lefebvre H. , Caron P. , Cortet-Rudelli C. , Archambaud F. , Chanson P. , Tabarin A. , Goth Mi , Blumberg J. , Catus F. , Ispas S. , Beck-Peccoz P.
Published: January 2014

Somatostatin analogs have been shown to be effective for the treatment of TSH-secreting pituitary adenomas. However, their use in this indication is limited by the fact that available analogs require several daily sc injections. The present study was performed to evaluate the effects of a slow release formulation of the somatostatin analog lanreotide (SR-L) on both hormone secretion and tumor size and to assess the tolerance in a series of thyrotropinomas treated for 6 months. Eighteen patients with hyperthyroidism related to a TSH-secreting pituitary adenoma, evidenced by pituitary magnetic resonance imaging, were studied. After a basal assessment, each patient received 30 mg SR-L, im, every 14 days for 1 month. Then, according to the free T3 (fT3) plasma level measured, 9 of 18 patients were injected twice monthly, and 7 of 18 patients received SR-L every 10 days for 5 additional months. One patient was dismissed from the study in month 1 of the study for side-effects and another in month 3 for noncompliance to the protocol. Clinical and biological evaluations (plasma TSH, free α-subunit, fT4, fT3, and lanreotide levels) were performed before and in months 1, 3, and 6 of treatment. Pituitary magnetic resonance imaging and gallbladder ultrasonography were performed both at entry and at the end of the study. Clinical signs of hyperthyroidism improved within 1 month in all 16 evaluable patients. Mean (±sem) plasma lanreotide levels reached 1.11 ± 0.43 and 1.69 ± 0.65 ng/mL in month 3 using 2 and 3 injections/month, respectively, then remained stable until the end of the study. During therapy, the plasma TSH level decreased from 2.72 ± 0.32 to 1.89 ± 0.27 mU/L (P < 0.01), with parallel significant changes in free α-subunit. During the same period, plasma fT4 and fT3 levels decreased from 37.9 ± 2.9 to 19.7 ± 2.3 pmol/L (P < 0.01) and from 14.6 ± 1.1 to 8.3 ± 0.8 pmol/L (P < 0.01), respectively. No statistically significant change in mean adenoma size was observed after 6 months of treatment. Side-effects, including pain at the injection point, abdominal cramps, and diarrhea, were mild and transient and did not lead to interruption of the treatment. No gallstones occurred during the study. SR-L appears to be able to suppress clinical signs of hyperthyroidism in our series of patients with TSH-secreting pituitary adenomas. The analog also reduces plasma TSH and thyroid hormone levels, which were normalized in 13 of 16 cases. The effect was maintained throughout the treatment using 2 or 3 SR-L injections monthly without any problem of tolerance. We conclude that SR-L is a safe and effective treatment of thyrotropinomas and avoids the drawbacks of the modes of administration of other somatostatin analogs, given three times daily.
Expression and Regulation of P2U-Purinergic Receptor in Human Granulosa-Luteal Cells1
Authors: Tai Chen-Jei , Kang Sung Keun , Cheng Kwai Wa , Choi Kyung-Chul , Nathwani Parimal S. , Leung Peter C. K.
Published: January 2014

The P2U purinoceptor (P2UR) has been identified pharmacologically in the ovary. However, the expression and regulation of the P2UR messenger RNA (mRNA) in human ovarian cells are still poorly characterized. The present study was designed to examine the expression and regulation of the P2UR in human granulosa-luteal cells (hGLCs) by RT-PCR and Northern blot analysis. A PCR product corresponding to the expected 599-bp P2UR complementary DNA was obtained from hGLCs. Molecular cloning and sequencing of the PCR product revealed an identical sequence to the reported P2UR complementary DNA. Two mRNA transcripts of 2.0 kb and 4.6 kb were identified in hGLCs using Northern blot analysis. The expression of the P2UR mRNA was down-regulated by human CG in a dose- and time-dependent manner. Treatment with 8-bromo-cAMP and forskolin also attenuated P2UR mRNA levels. Calcium signaling following the activation of the P2UR in single hGLCs was studied using microspectrofluorimetry. It revealed that, like ATP, uridine triphosphate (UTP) also induced cytosolic calcium mobilization in a dose-dependent manner. These results demonstrate for the first time that the P2UR mRNA is expressed in hGLCs and that P2UR mRNA is regulated by human CG, cAMP, and forskolin. The P2UR expressed in hGLCs functional because activation of the P2UR by ATP or UTP resulted in rapid and transient mobilization of cytosolic calcium at the single cell level. These findings further support a potential role of this neurotransmitter receptor in the human ovary.
Leptin and Aging: Correlation with Endocrine Changes in Male and Female Healthy Adult Populations of Different Body Weights
Authors: Isidori Andrea M. , Strollo Felice , Morè Michele , Caprio Massimiliano , Aversa Antonio , Moretti Costanzo , Frajese Gaetano , Riondino Giuseppe , Fabbri Andrea
Published: January 2014

Aging is associated with changes in plasma levels of several hormones. There are conflicting reports on whether circulating leptin levels change during aging, the possible explanation for which is that alterations in adiposity and body mass index (BMI) also occur. In this study we measured plasma leptin and other hormonal parameters known to influence leptin in 150 men and 320 women of a wide age (18–77 yr) and BMI (18.5–61.1 kg/m2) range. Subjects of each gender were separated into 2 groups of similar BMI, i.e. nonobese (BMI, <30) and obese (BMI, >30), and treated separately. Statistical analysis was performed, treating each group of subjects as a whole population or divided into age groups (<30, 30–50, and >50 yr). BMI-adjusted leptin levels were progressively lower with increasing age in women, with a consistent fall after menopause (−21%; P < 0.001); in men, leptin levels also tended to be lower in subjects more than 50 yr of age, but the reduction was not significant. Multiple linear regression analysis, performed on subjects treated either as a whole population or divided into obese and nonobese, showed that in both genders BMI and age were independent contributors of leptin levels, and there was an inverse relationship between leptin and age in both obese (standardized coefficient β = −0.25 in women and −0.23 in men; P < 0.01) and nonobese (−0.22 in women and −0.20 in men; P < 0.05) subjects. The correlation of leptin and age with plasma levels of sex and thyroid hormones, GH, insulin-like growth factor I, PRL, and insulin was also evaluated. The variables that correlated with leptin were included in a multiple regression model that included BMI and age. Testosterone in men (−0.43 in nonobese and −0.19 in obese; P < 0.05) and estradiol in women (0.22 in nonobese and 0.24 in obese; P < 0.05) were important contributors to leptin levels; also, dehydroepiandrosterone sulfate in obese women (−0.16) and sex hormone-binding globulin in obese subjects of both genders (0.15 in women and 0.19 in men) were significant determinants in the model. However, none of the hormonal parameters abolished the negative correlation between leptin and age or the gender difference in leptin levels. In conclusion, our data show that in adult humans of different body weight, serum leptin gradually declines during aging; leptin reduction is higher in women than in men, but it is independent from BMI and other age-related endocrine changes.
Corticotropin-Independent Cushing’s Syndrome Caused by an Ectopic Adrenal Adenoma
Authors: Ayala Alejandro R. , Basaria Shehzad , Udelsman Robert , Westra William H. , Wand Gary S.
Published: January 2014

Although nonsecreting suprarenal embryonic remnants are frequently found in the urogenital tract, adenomatous transformation resulting in glucocorticoid excess is a rare phenomenon. We report a case of a 63-yr-old woman that presented with new-onset hirsutism, facial plethora, hypertension, centripetal obesity, and a proximal myopathy. The 24-h urinary free cortisol excretion rate was elevated, and the serum ACTH level was suppressed. The patient failed an overnight and low dose dexamethasone suppression test and did not respond to CRH stimulation. In light of the undetectable baseline morning ACTH levels and the blunt response to CRH, the diagnosis of corticotropin-independent Cushing’s syndrome was made. Imaging studies revealed normal adrenal glands and enlargement of a left pararenal nodule incidentally observed 4 yr before the onset of symptoms. Dramatic resolution of symptoms was observed after surgical removal of the 3.5-cm mass. Pathological exam confirmed adrenocortical adenoma in ectopic adrenal tissue. The case reported here represents the unusual circumstance in which the development of adenomatous transformation of ectopic adrenal tissue has been prospectively observed with imaging studies. It illustrates the importance of considering ectopic corticosteroid-secreting tumors in the context of corticotropin-independent Cushing’s syndrome.
LMNA R482Q Mutation in Partial Lipodystrophy Associated with Reduced Plasma Leptin Concentration*
Authors: Hegele Robert A. , Cao Henian , Huff Murray W. , Anderson Carol M.
Published: January 2014

Mutations in LMNA, which encodes lamins A and C, have been found in patients with autosomal dominant Dunnigan-type familial partial lipodystrophy (FPLD). We analyzed the relationship between plasma leptin and the rare LMNA R482Q mutation in 23 adult FPLD subjects compared with 25 adult family controls with normal LMNA in an extended Canadian FPLD kindred. We found that the LMNA Q482/R482 genotype was a significant determinant of plasma leptin, the ratio of plasma leptin to body mass index (BMI), plasma insulin, and plasma C peptide (P = 0.015, P = 0.0007, P = 0.0004, and P < 0.0001, respectively), but not BMI (P = 0.67). Family members who were heterozygous for LMNA Q482/R482 had significantly lower plasma leptin and leptin:BMI ratio than unaffected R482/R482 homozygotes. Fasting plasma concentrations of insulin and C peptide were both significantly higher in LMNA Q482/R482 heterozygotes than in R482/R482 homozygotes. Multivariate regression analysis revealed that the LMNA R482Q genotype accounted for 40.9%, 48.2%, 86.9%, and 81.0%, respectively, of the attributable variation in log leptin, leptin:BMI ratio, log insulin, and log C peptide (P = 0.013, P= 0.0007, P = 0.0002 and P < 0.0001, respectively). The results indicate that a rare FPLD mutation in LMNA determines the plasma leptin concentration. It remains to be established whether the reduction in leptin results from the reduced adipose tissue mass in FPLD or from another subcellular effect of mutant LMNA. It also remains to be established whether the insulin resistance in FPLD is a consequence of the reduced plasma leptin or of another functional change resulting from mutant LMNA.
Activation of L-Type Calcium Channels Induces Corticotropin-Releasing Factor Secretion from Human Placental Trophoblasts*
Authors: Robidoux Jacques , Simoneau Lucie , Masse André , Lafond Julie
Published: January 2014

The ultimate outcome of pregnancy, parturition, is a well orchestrated process in which placental corticotropin-releasing factor (CRF) seems to play an important role. The objective of the present study was to investigate the involvement of L-type calcium channels and calcium-dependent signaling in the depolarization-induced CRF release from human syncytiotrophoblast. The basal secretion of CRF by trophoblastic cells, isolated from human term placenta, was maximal after their functional differentiation, which was monitored by hCG measurements. On the fourth day of culture, the basal CRF secretion of the cells in serum-free medium was linear between 2 and 8 h. Incubation of the trophoblasts with KCl, a depolarizing stimulus, or with Bay K8644, an L-type calcium channel agonist, for 3 or 8 h led to an increase in CRF secretion, but was without effect on its synthesis. This stimulated CRF release was calcium dependent, as it could be prevented by loading cells with 1,2-bis(0-Aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (acetoxymethyl) ester. Furthermore, the KCl-induced CRF secretion involved L-type calcium channels activation, as 2 μmol/L nitrendipine, an L-type specific blocker, abolished the stimulation. In trophoblasts, where we have previously shown calcium-dependent protein kinase C (cPKCs) activity, incubation with Bay K8644 also stimulated calcium calmodulin kinase II (CaMKII) and extracellular regulated kinase activities. In the present study we observed that CaMKII and cPKCs were linked to the Bay K8644-induced secretion of CRF, as only the autocamtide-2 related inhibitory peptide, a CaMKII inhibitor, and Gö6976, an inhibitor of μ and cPKCs partially prevented (30–78%) the activation of CRF release by Bay K8644. The use of PD 098056, an inhibitor of the ERKs kinases, showed no effect on CRF release. Taken together, these results support a depolarization-induced and calcium-dependent exocytotic-like secretion of CRF from human placental trophoblasts. In addition, CaMKII and cPKCs seem to be potential modulators or mediators of these calcium effects on CRF secretion.
Occurrence of Gonadoblastoma in Females with Turner Syndrome and Y Chromosome Material: A Population Study*
Authors: Gravholt Claus Højbjerg , Fedder Jens , Naeraa Rune Weis , Müller Jørn
Published: January 2014

The presence of Y chromosome material in patients with Turner syndrome is a risk factor for the development of gonadoblastoma. However, no cases with gonadoblastoma or other ovarian malignancies have been found in epidemiological studies of cancer, morbidity, or mortality in Turner syndrome. We examined 114 females with Turner syndrome for the presence of Y chromosome material by PCR. Initially, five different primer sets were used. Y Chromosome-positive individuals were further examined with an additional four primer sets. We found 14 (12.2%; 95% confidence interval, 6.9–19.7%) patients who had Y chromosome material. The karyotype in 7 of these patients did not suggest the presence of Y chromosome material. Seven of the patients had been ovariectomized before entering the study due to verified Y chromosome material, whereas three patients were operated upon after the DNA analysis. The histopathological evaluations showed that 1 of the 10 ovariectomized patients actually had a gonadoblastoma. The rest of the patients did not have gonadoblastoma or carcinoma in situ on histopathological evaluation. Three patients (age, >50 yr) positive for Y chromosome material chose not to have ovariectomy performed, and detailed ultrasonographies did not suggest the presence of gonadoblastoma. The frequency of Y chromosome material is high in Turner syndrome (12.2%), but the occurrence of gonadoblastoma among Y-positive patients seems to be low (7–10%), and the risk may have been overestimated in previous studies, perhaps due to problems with selection bias. This study emphasizes the need for prospective unbiased studies.