bluuebunny/crossref_metadata_2025 huggingface dataset:
Failure of Cortisone Acetate Treatment in Congenital Adrenal Hyperplasia because of Defective 11β-Hydroxysteroid Dehydrogenase Reductase Activity*
Authors: Nordenström Anna , Marcus Claude , Axelson Magnus , Wedell Anna , Ritzén E. Martin
Published: January 2014

Congenital adrenal hyperplasia in children is often treated with cortisone acetate and fludrocortisone. It is known that certain patients with congenital adrenal hyperplasia require very high substitution doses of cortisone acetate, and a few patients do not respond to this treatment at all.

A patient with 21-hydroxylase deficiency, for whom elevated pregnanetriol (P3) levels in urine were not suppressed during treatment with cortisone acetate (65 mg/m2·day), was examined. The activation of cortisone to cortisol was assessed by measuring urinary metabolites of cortisone and cortisol.

The patient’s inability to respond to treatment with cortisone acetate was found to be caused by a low conversion of cortisone to cortisol, assumed to be secondary to low 11β-hydroxysteroid dehydrogenase activity (11-oxoreductase deficiency). All exons and exon/intron junctions of the 11β-hydroxysteroid dehydrogenase type1 gene (HSD11L) were sequenced without finding any mutations, but a genetic lesion in the promoter or other regulatory regions cannot be ruled out. The deficient 11-oxoreductase activity seems to have been congenital, in this case, but can possibly be attributable to a down-regulation of the enzyme activity. The results support the use of hydrocortisone, rather than cortisone acetate, for substitution therapy in adrenal insufficiency.
Plasma Leptin Levels after Biliopancreatic Diversion: Dissociation with Body Mass Index
Authors: De Marinis L. , Mancini A. , Valle D. , Bianchi A. , Milardi D. , Proto A. , Lanzone A. , Tacchino R.
Published: January 2014

Human obesity is associated with increased leptin levels, related to body composition and fat mass (FM). Insulin has been suggested to be a regulator of in vivo leptin secretion. To further investigate the relationships between insulin and leptin levels in human obesity, we have studied 10 obese females, aged 26–57 yr [body mass index (BMI), 42.9 ± 6.3], successfully treated by biliopancreatic (BPD) diversion, in an early postoperative period (2 months after surgery, post-BPD I; BMI, 37.2 ± 7.5) and a late postoperative period (16–24 months after surgery; BMI, 27.6 ± 3.96). Fourteen normal female subjects (18–59 yr; BMI, 27.9 ± 1.4 kg/m2) were studied as controls. In pre-BPD obese subjects, leptin levels were higher than those in controls (60.5± 18.8 vs. 28.7 ± 4.8 ng/mL; P < 0.001). BMI and insulin levels were also significantly greater (P < 0.0001 and P < 0.03, respectively). After surgery, the three parameters considered significantly decreased (P = 0.0007 for BMI, P < 0.0001 for leptin, and P = 0.038 for insulin, using Friedman’s test for repeated data). Concerning the correlation between leptin and FM in our patients, control subjects and pre-BPD subjects confirmed the correlation found in the general population (r = 0.78; P < 0.01). On the contrary, post-BPD patients at 2 months lay outside the general correlation between FM and leptin; in fact, patients with low leptin levels still had a high FM. Moreover, in the post-BPD patients there was no longer a significant correlation between FM and leptin. Concerning the correlation between insulin and leptin levels, a significant correlation was present in control subjects and pre-BPD patients (r = 0.46; P < 0.05). Using correlation analysis for repeated measures in surgically treated obese patients, a significant correlation within the subjects was present (r = 0.91; P < 0.0001). After operation, BMI and leptin levels had a different pattern of decrease; leptin decreased rapidly, without correlation with BMI, indicating that body composition is not the only factor regulating leptin levels. The consistent correlation with insulin levels suggests an important interaction between these two hormones in post-BPD obese subjects.
The Effects of 10 Years of Recombinant Human Growth Hormone (GH) in Adult GH-Deficient Patients
Authors: Gibney J. , Wallace J. D. , Spinks T. , Schnorr L. , Ranicar A. , Cuneo R. C. , Lockhart S. , Burnand K. G. , Salomon F. , Sonksen P. H. , Russell-Jones D.
Published: January 2014

The long term effects of GH replacement in adult GH-deficient (GHD) patients have not yet been clarified. We studied 21 GHD adults who originally took part in a randomized, double blind, placebo-controlled trial of GH treatment in 1987. After completion of that trial, 10 patients received continuous GH replacement for the subsequent 10 yr, whereas 11 did not. A group of 11 age- and sex-matched normal controls were also studied in 1987 and 1997. Lean body mass, as assessed by total body potassium measurement and computed tomography scanning of the dominant thigh, increased in the GH-treated group (P < 0.01 for both) only (P < 0.05 between groups for total body potassium). Low density lipoprotein cholesterol decreased in the GH-treated group (P < 0.05) only. Carotid intima media thickness was significantly greater (P < 0.05) in the untreated group than in the GH-treated group. Assessment of psychological well-being using the Nottingham Health Profile revealed improvement in overall score, energy levels, and emotional reaction in the GH-treated group compared with those in the untreated group (P < 0.02). In conclusion, GH treatment for 10 yr in GHD adults resulted in increased lean body and muscle mass, a less atherogenic lipid profile, reduced carotid intima media thickness, and improved psychological well-being.
Low Levels of Estradiol Are Associated with Vertebral Fractures in Older Men, But Not Women: The Rancho Bernardo Study1
Authors: Barrett-Connor Elizabeth , Mueller Judith E. , von Mühlen Denise G. , Laughlin Gail A. , Schneider Diane L. , Sartoris David J.
Published: January 2014

This longitudinal study included 288 postmenopausal women without estrogen use (median age, 72 yr) and 352 men (median age, 66 yr). All were community-dwelling, ambulatory, and Caucasian. Blood for hormone assays (total and bioavailable estradiol and testosterone, estrone, androstenedione, dihydrotestosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate) was obtained in 1984–1987, and vertebral fractures were diagnosed from lateral spine radiographs obtained in 1992–1996. At least one vertebral fracture was found in 21% of women and 8% of men. Among men, age-adjusted hormone levels differed by fracture status only for total (64.1 vs. 75.4 pmol/L, P = 0.012) and bioavailable (43.0 vs. 51.4 pmol/L, P = 0.008) estradiol. There was a graded association between higher concentrations of total and bioavailable estradiol and lower fracture prevalence (trend P < 0.01 for both hormones). Men with total testosterone levels compatible with hypogonadism (<7 nmol/L) were not more likely to have vertebral fractures. In women, none of the measured sex hormones was associated with vertebral fractures. There was also no increased prevalence of fractures in women with estradiol levels below the assay sensitivity (<11 pmol/L). These data suggest that estrogen plays a critical role in the skeletal health of older men and confirm other studies showing no association of postmenopausal endogenous estrogen levels with vertebral fractures in older women.
Retesting Young Adults with Childhood-Onset Growth Hormone (GH) Deficiency with GH-Releasing-Hormone-Plus-Arginine Test1
Authors: Aimaretti G. , Baffoni C. , Bellone S. , Di Vito L. , Corneli G. , Arvat E. , Benso L. , Camanni F. , Ghigo E.
Published: January 2014

Within an appropriate clinical context, severe GH deficiency (GHD) in adults has to be defined biochemically by provocative testing of GH secretion. Patients with childhood-onset GHD need retesting in late adolescence or young adulthood to verify whether they have to continue recombinant human GH treatment. GHRH + arginine (GHRH+ARG) is the most reliable alternative to the insulin-induced hypoglycemia test (ITT) as a provocative test for the diagnosis of GHD in adulthood, provided that appropriate cut-off limits are assumed (normal limits, 16.5 μg/L as 3rd and 9.0 μg/L as 1st centile). We studied the GH response to a single GHRH (1 μg/kg iv) + ARG (0.5 g/kg iv) test in 62 young patients who had undergone GH replacement in childhood, based on the following diagnosis: 1) organic hypopituitarism with GHD (oGHD)[ n = 18: 15 male (M), 3 female (F); age, 26.8 ± 2.2 yr; GH peak < 10 μg/L after two classical tests]; 2) idiopathic isolated GHD (iGHD) [n = 23 (15 M, 8 F); age, 23.0 ± 1.5 yr; GH peak < 10 μg/L after two classical tests]; and 3) GH neurosecretory dysfunction (GHNSD) [n = 21 (10 M, 11 F); age, 25.1 ± 1.6 yr; GH peak > 10 μg/L after classical test but mGHc < 3 μg/L]. The GH responses to GHRH+ARG in these groups were also compared with that recorded in a group of age-matched normal subjects (NS) [n = 48 (20 M, 28 F); age, 27.7 ± 0.8 yr]. Insulin-like growth factor I levels in oGHD subjects (61.5 ± 13.7μ g/L) were lower (P < 0.001) than those in iGHD subjects (117.2 ± 13.1 μg/L); the latter were lower than those in GHNSD subjects (210.2 ± 12.9 μg/L), which, in turn, were similar to those in NS (220.9 ± 7.1 μg/L). The mean GH peak after GHRH+ARG in oGHD (2.8 ± 0.8 μg/L) was lower (P < 0.001) than that in iGHD (18.6 ± 4.7μ g/L), which, in turn, was clearly lower (P < 0.001) than that in GHNSD (31.3 ± 1.6 μg/L). The GH response in GHNSD was lower than that in NS (65.9 ± 5.5 μg/L), but this difference did not attain statistical significance. With respect to the 3rd centile limit of GH response in young adults (i.e. 16.5 μg/L), retesting confirmed GHD in all oGHD, in 65.2% of iGHD, and in none of the GHNSD subjects. With respect to the 1st centile limit of GH response (i.e. 9.0 μg/L), retesting demonstrated severe GHD in 94% oGHD and in 52.1% of iGHD. All oGHD and iGHD with GH peak after GHRH+ARG lower than 9 μg/L had also GH peak lower than 3 μg/L after ITT. In the patients in whom GHD was confirmed by retesting, the mean GH peak after GHRH+ARG was higher than that after ITT (3.4 ± 0.5 vs. 1.9 ± 0.4). In conclusion, given appropriate cut-off limits, GHRH+ARG is as reliable as ITT for retesting patients who had undergone GH treatment in childhood. Among these patients, severe GHD in adulthood is generally confirmed in oGHD, is frequent in iGHD, but never occurs in GHNSD.
Bilateral Laparoscopic Adrenalectomy for Congenital Adrenal Hyperplasia with Severe Hypertension, Resulting from Two Novel Mutations in Splice Donor Sites of CYP11B1
Authors: Chabre Olivier , Portrat-Doyen Stéphanie , Chaffanjon Philippe , Vivier Josiane , Liakos Panagiotis , Labat-Moleur Françoise , Chambaz Edmond , Morel Yves , Defaye Geneviève
Published: January 2014

We present an in vivo and in vitro study of congenital adrenal hyperplasia in a patient with 11β-hydroxylase deficiency. Sequencing of the CYP11B1 gene showed two new base substitutions, a conservative 954 G→C transversion at the last base of exon 5 (T318T), and a IVS8 + 4A→G transition in intron 8. In addition, two polymorphisms were found in exons 1 and 2. The genetically female patient was raised as a male because of severe pseudohermaphroditism. Glucocorticoid-suppressive treatment encountered difficulties in equilibration and compliance, resulting in uncontrolled hypertension with pronounced hypertrophic cardiomyopathy. At 42 yr of age the occurrence of central retinal vein occlusion with permanent loss of left eye vision led to the decision to perform bilateral laparoscopic adrenalectomy. Surgery was followed by normalization of blood pressure and good compliance with glucocorticoid and androgen substitutive therapies. In vitro, adrenal cells in culture and isolated mitochondria showed extremely low 11β-hydroxylase activity. Analysis of adrenal CYP11B1 messenger ribonucleic acid (mRNA) by RT-PCR and sequencing showed the expression of a shorter mRNA that lacked exon 8 and did not contain either the exon 5 mutation or the exon 1 and 2 polymorphisms. This suggested that one CYP11B1 allele carried the intron 8 mutation, responsible for skipping exon 8. The other allele carried the exon 5 mutation, and its mRNA was not detectable. Western blot analysis showed weak expression of a shorter CYP11B immunoreactive band of 43 kDa, consistent with truncation of exon 8. Thus, bilateral adrenalectomy in this patient allowed effective treatment of severe hypertension and helped in understanding the mechanisms and physiopathological consequences of two novel mutations of CYP11B1.
Parity as a Thyroid Size-Determining Factor in Areas with Moderate Iodine Deficiency
Authors: Rotondi Mario , Amato Giovanni , Biondi Bernadette , Mazziotti Gherardo , Del Buono Andrea , Rotonda Nicchio Maria , Balzano Simona , Bellastella Antonio , Glinoer Daniel , Carella Carlo
Published: January 2014

Among the factors that may influence thyroid size, pregnancy and its goitrogenic effect have been widely investigated, but thyroid volume and pregnancy have never been compared retrospectively, and there are no data on the possible relationship between thyroid size and parity. The purpose of this work was to evaluate the effects of pregnancy on thyroid volume in a moderate iodine deficiency area, to assess the possibility of a relationship between thyroid size and parity status in healthy females. A group of 208 nongoitrous healthy women underwent thyroid volume estimation by ultrasound examination. All subjects were euthyroid and negative for thyroid autoantibodies. They were assigned to different groups, according to the number of completed pregnancies. Five groups were formed (0, 1, 2, 3, 4 or more term pregnancies). Mean thyroid volume increased progressively among the groups: group 0 (14.8 ± 0.7 mL); group I (16.0 ± 0.9 mL); group II (17.1 ± 0.6 mL); group III (18.2 ± 0.6 mL); group IV (20.3 ± 0.9 mL). The increment in thyroid volume was statistically significant between group 0 and groups III (P < 0.01) and IV (P < 0.001), and also between group I and group IV (P < 0.05). No independent effect of body weight and age on thyroid volume was seen. Our results indicate that, in an area with moderate iodine deficiency, the goitrogenic effect of pregnancy is not fully reversible. Moreover, the statistically significant increase in thyroid volume, observed in relation to parity, is the first clinical demonstration of a cumulative goitrogenic effect of successive pregnancies, providing a strong argument to increase the iodine supply during pregnancy, even in conditions with moderate iodine deficiency.
Angiogenesis in Pituitary Adenomas and the Normal Pituitary Gland
Authors: Turner Helen E. , Nagy Zsusha , Gatter Kevin C. , Esiri Margaret M. , Harris Adrian L. , Wass John A. H.
Published: January 2014

Angiogenesis is essential for tumor growth beyond a few millimeters in diameter, and the intratumoral microvessel count that represents a measure of angiogenesis has been correlated with tumor behavior in a variety of different tumor types. To date no systematic study has assessed pituitary tumors of different secretory types, correlating vascular count with tumor size. The vascular densities of pituitary tumors and normal anterior pituitary were therefore assessed by counting vessels labeled using the vascular markers CD31 and ulex europaeus agglutinin I. One hundred and twelve surgically removed pituitary adenomas (30 GH-secreting, 25 prolactinomas, 15 ACTH-secreting, and 42 nonfunctioning tumors) were compared with 13 specimens of normal anterior pituitary gland. The vascular counts in the normal anterior pituitary gland were significantly higher (P < 0.05) than those in the tumors using both CD31 and ulex europaeus agglutinin I. In addition, microprolactinomas were significantly less vascular (P < 0.05) than macroprolactinomas, although there was no such difference between vascular densities of microadenomas and macroadenomas producing GH. ACTH-secreting tumors were, like microprolactinomas, of much lower vascular density than the normal pituitary and other secreting and nonsecreting tumor types. In marked contrast to other tumors, pituitary adenomas are less vascular than the normal pituitary gland, suggesting that there may be inhibitors of angiogenesis that play an important role in the behavior of these tumors.
Familial Hypercalcemia and Hypercalciuria Caused by a Novel Mutation in the Cytoplasmic Tail of the Calcium Receptor*
Authors: Carling Tobias , Szabo Eva , Bai Mei , Ridefelt Peter , Westin Gunnar , Gustavsson Peter , Trivedi Sunita , Hellman Per , Brown Edward M. , Dahl Niklas , Rastad Jonas
Published: January 2014

Familial hyperparathyroidism (HPT), characterized by hypercalcemia and hypercalciuria, and familial benign hypocalciuric hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. The calcium-sensing receptor (CaR) regulates PTH secretion and renal calcium excretion. Heterozygous inactivating mutations of the gene cause FHH, whereas CaR gene mutations have not been demonstrated in HPT. In a kindred with 20 affected individuals, the hypercalcemic disorder segregated with inappropriately higher serum PTH and magnesium levels and urinary calcium levels than in unaffected members. Subtotal parathyroidectomy revealed parathyroid gland hyperplasia/adenoma and corrected the biochemical signs of the disorder in seven of nine individuals. Linkage analysis mapped the condition to markers flanking the CaR gene on chromosome 3q. Sequence analysis revealed a mutation changing phenylalanine to leucine at codon 881 of the CaR gene, representing the first identified point mutation located within the cytoplasmic tail of the CaR. A construct of the mutant receptor (F881L) was expressed in human embryonic kidney cells (HEK 293), and demonstrated a right-shifted dose-response relationship between the extracellular and intracellular calcium concentrations. The hypercalcemic disorder of the present family is caused by an inactivating point mutation in the cytoplasmic tail of the CaR and displays clinical characteristics atypical of FHH and primary HPT.
Variations in Vitamin D-Binding Protein (Group-Specific Component Protein) Are Associated with Fasting Plasma Insulin Levels in Japanese with Normal Glucose Tolerance*
Authors: Hirai Masashi , Suzuki Susumu , Hinokio Yoshinori , Hirai Aki , Chiba Masaki , Akai Hiroaki , Suzuki Chitose , Toyota Takayoshi
Published: January 2014

The locus of the vitamin D-binding protein (DBP; also known as group-specific component protein or Gc) gene, chromosome 4q12, has been reported to be associated with glucose metabolism in several ethnic groups, including Pima Indians. We have recently reported the association of the DBP genotype with type 2 diabetes mellitus in Japan. The aim of this study was to investigate whether genetic variations of DBP have any influence on glucose metabolism without secondary effects of hyperglycemia or diabetes mellitus using 82 Japanese with normal glucose tolerance. The variations of the DBP gene (Gc 1F, 1S, and 2) were determined by PCR-restriction fragment length polymorphism. Fasting plasma insulin concentration and homeostasis model assessment, an index of insulin resistance, were significantly different based on the DBP genotype (P < 0.01 and P < 0.05, respectively). The people with Gc 1S-2 (5.73 ± 2.57 μU/mL) and 1S-1S (5.30 ± 3.46 μU/mL) had significantly higher fasting plasma concentrations than those with 1F-1F (2.84 ± 1.67 μU/mL) (P < 0.01 and P < 0.03, respectively). There was no significant difference in plasma glucose concentration, body mass index, total cholesterol, triglyceride, and blood pressure. In conclusion, genetic variations of DBP are associated with insulin resistance in Japanese with normal glucose tolerance, which might contribute to the development of type 2 diabetes.
Pediatric Adrenocortical Tumors: Molecular Events Leading to Insulin-Like Growth Factor II Gene Overexpression*
Authors: Wilkin Françoise , Gagné Nancy , Paquette Jean , Oligny Luc L. , Deal Cheri
Published: January 2014

It has been previously shown that adrenocortical tumors (ACT) in adults exhibit structural abnormalities in tumor DNA in approximately 30% of cases. These abnormalities involve chromosome 11p15 and include loss of heterozygosity, paternal isodisomy, and overexpression of the gene for insulin-like growth factor II (IGF2), correlating with DNA demethylation at this locus. It has been hypothesized that these events occur late in the tumorigenic process in adults and seem to correlate with a worse prognosis. We present 4 pediatric cases of ACT diagnosed at 2.5 yr, 10 months, 12 yr, and 2.2 yr. All 4 patients presented with virilization, and 1 patient also showed signs and symptoms of glucocorticoid excess. The youngest patient’s maternal aunt had surgical excision of a more than 15-cm ACT 18 yr previously, but the aunt is doing well at age 23 yr. They all had surgical removal of their tumors. The 2.5-yr-old child also received chemotherapy and radiotherapy because of capsular rupture and, after 3 local recurrences, died 3.3 yr after initial presentation. We investigated all 4 tumors for chromosome 11 structural abnormalities (11p15.5 to 11q23), IGF2 and H19 expression by competitive RT-PCR analysis, and IGF2 methylation patterns by Southern analysis. All 4 tumors (100%) showed a combination of structural abnormalities at the 11p15 locus with mosaic loss of heterozygosity involving 11p. All tumors also had significantly increased IGF2 messenger ribonucleic acid levels relative to normal adrenal (up to 36-fold) and significant IGF2 demethylation (mean, 87%). H19 messenger ribonucleic acid levels were undetectable in 3 of 4 tumors, explained in part by mosaic loss of the actively expressed maternal allele for this imprinted gene. By immunohistochemistry we were able to confirm increased IGF-II peptide levels within the tumor tissue in 10 pediatric patients, including the 4 patients described above. Concomitantly, we also observed nuclear accumulation of p53, suggesting somatic mutations. For the 10-month-old patient, sequencing revealed a p53 germline mutation. We therefore conclude that in pediatric ACT, structural abnormalities of tumor DNA and IGF2 overexpression as well as p53 mutations are very common and are therefore less useful for prognosis than in adults. Our findings support the theory that pediatric ACT, whose IGF2 expression and steroidogenesis evoke the phenotype of the fetal adrenal cortex, may arise because of defective apoptosis.
Insulin Inhibits the Expression of Intercellular Adhesion Molecule-1 by Human Aortic Endothelial Cells through Stimulation of Nitric Oxide1
Authors: Aljada Ahmad , Saadeh Rana , Assian Ezzat , Ghanim Husam , Dandona Paresh
Published: January 2014

Intercellular adhesion molecule-1 (ICAM-1) is expressed by endothelial and other cell types and participates in inflammation and atherosclerosis. It serves as a ligand for leukocyte function-associated antigen-1 on leukocytes and is partially responsible for the adhesion of lymphocytes, granulocytes, and monocytes to cytokine-stimulated endothelial cells and the subsequent transendothelial migration. Its expression on endothelial cells is increased in inflammation and atherosclerosis. As it has been suggested that insulin and hyperinsulinemia may have a role in atherogenesis, we have now investigated whether insulin has an effect on the expression of ICAM-1 on human aortic endothelial cells (HAEC). HAEC were prepared from human aortas by collagenase digestion and were grown in culture. Insulin (100 and 1000 μU/mL) caused a decrease in the expression of ICAM-1 (messenger ribonucleic acid and protein) by these cells in a dose-dependent manner after incubation for 2 days. This decrease was associated with a concomitant increase in endothelial nitric oxide synthase (NOS) expression also induced by insulin. To examine whether the insulin-induced inhibition of ICAM-1 was mediated by nitric oxide (NO) from increased endothelial NOS, HAEC were treated with Nω-nitro-l-arginine, a NOS inhibitor. Nω-Nitro-l-arginine inhibited the insulin-induced decrease in ICAM-1 expression in HAEC at the messenger ribonucleic acid and protein levels. Thus, the inhibitory effect of insulin on ICAM-1 expression is mediated by NO. We conclude that insulin reduces the expression of the proinflammatory adhesion molecule ICAM-1 through an increase in the expression of NOS and NO generation and that insulin may have a potential antiinflammatory and antiatherosclerotic effect rather than a proatherosclerotic effect.
A Prospective Study of the Prevalence of the Polycystic Ovary Syndrome in Unselected Caucasian Women from Spain1
Authors: Asunción Miryam , Calvo Rosa M. , San Millán José L. , Sancho José , Avila Sergio , Escobar-Morreale Héctor F.
Published: January 2014

We prospectively estimated the prevalence of the polycystic ovary syndrome (PCOS), as defined by the NIH/NICHHD 1990 endocrine criteria, in a population of 154 Caucasian women of reproductive age reporting spontaneously for blood donation. Anthropometric data; the presence of hirsutism, acne, and androgenic alopecia; and the menstrual history were recorded by a single investigator. In 145 women, blood samples were also obtained for measurement of serum androgen levels. PCOS was defined by the presence of 1) oligomenorrhea, 2) clinical and/or biochemical hyperandrogenism, and 3) exclusion of hyperprolactinemia, thyroid disorders, and nonclassic 21-hydroxylase deficiency. Hirsutism was defined by a modified Ferriman- Gallwey score of 8 or more, acne was considered as a sign of hyperandrogenism when persistent after the second decade of life, and hyperandrogenemia was defined by an increase in circulating testosterone or dehydroepiandrosterone sulfate or an increase in the free androgen index above the 95th percentile of the control values derived from the nonhirsute, nonacneic women having regular menses who were not receiving hormonal therapy. PCOS was present in 10 (6.5%), hirsutism was present in 11 (7.1%), and acne was present in 19 (12.3%) of the 154 women. Our results demonstrate a 6.5% prevalence of PCOS, as defined, in a minimally biased population of Caucasian women from Spain. The polycystic ovary syndrome, hirsutism, and acne are common endocrine disorders in women.
Recombinant Human Insulin-Like Growth Factor I Has Significant Anabolic Effects in Adults with Growth Hormone Receptor Deficiency: Studies on Protein, Glucose, and Lipid Metabolism*
Authors: Mauras Nelly , Martinez Victor , Rini Annie , Guevara-Aguirre Jaime
Published: January 2014

The physiological effects of insulin-like growth factor I (IGF-I) on intermediate metabolism of substrates have been extensively studied in a variety of experimental situations in man, and its effects on linear growth of children with GH receptor mutations have proven beneficial. However, there is a paucity of data on the metabolic effects of IGF-I as replacement therapy in adults with GH receptor deficiency (Laron’s syndrome). We designed these studies to investigate the in vivo effects of 8 weeks of therapy with recombinant human IGF-I (rhIGF-I) in a unique group of 10 adult subjects with profound IGF-I deficiency due to a mutation in the GH receptor gene (mean ± sem age, 29.2 ± 2.0 yr; 4 males and 6 females). At baseline, patients had infusions of stable tracers, including l-[13C]leucine,[ 2H2]glucose, and d5-glycerol, as well as indirect calorimetry, assessment of body composition (dual energy x-ray absortiometry), and measurements of growth factor concentrations. Patients were then discharged to receive twice daily rhIGF-I (60μ g/kg, sc) for the next 8 weeks when the studies were repeated identically.

Plasma IGF-I concentrations increased during rhIGF-I treatment from 9.3 ± 1.5 μg/L to 153 ± 23 (P = 0.0001). There was no change in weight during these studies, but a significant change in body composition was observed, with a decrease in percent fat mass (P = 0.003) and an increase in lean body mass (P = 0.001). These were accompanied by increased rates of protein turnover, decreased protein oxidation, and increased rates of whole body protein synthesis, as measured by leucine tracer methods (P < 0.01). These results are similar to those observed in GH-deficient subjects treated with GH. All measures of lipolytic activity and fat oxidation increased during treatment, with an 18% increase in the glycerol turnover rate (P = 0.04), an increase in free fatty acid andβ -hydroxybutyrate concentrations, and a significant increase in fat oxidation, as measured by indirect calorimetry (P = 0.04). There were significant decreases in insulin concentrations (P = 0.01) and a reciprocal increase in glucose production rates (P = 0.04) during rhIGF-I, yet plasma glucose concentrations remained constant, suggestive of a significant insulin-like action of this peptide. RhIGF-I was well tolerated by all patients.

In conclusion, 8 weeks of treatment with rhIGF-I had significant positive effects on body composition and measures of intermediate metabolism independent of GH. These results suggest that, similar to GH treatment of adults with GH deficiency, rhIGF-I may be beneficial as long term replacement therapy for the adult patient with Laron’s syndrome.
BIM-23244, a Somatostatin Receptor Subtype 2- and 5-Selective Analog with Enhanced Efficacy in Suppressing Growth Hormone (GH) from Octreotide-Resistant Human GH-Secreting Adenomas1
Authors: Saveanu A. , Gunz G. , Dufour H. , Caron P. , Fina F. , Ouafik L. , Culler M. D. , Moreau J. P. , Enjalbert A. , Jaquet P.
Published: January 2014

Although both somatostatin receptor subtype 2 (SSTR2) and SSTR5 messenger ribonucleic acid (mRNA) are consistently expressed in GH-secreting adenomas, SSTR2 has been believed to be the key modulator of somatostatin-mediated inhibition of GH release. The somatostatin agonists currently in clinical use, octreotide and lanreotide, are directed mainly to SSTR2 (IC50 12- to 18-fold higher than for SSTR5). Recently, however, it was demonstrated that an SSTR5 preferential agonist, BIM-23268, not only suppressed PRL release from prolactinomas and mixed GH-PRL adenomas, but also inhibited GH release in about half of GH adenomas. In addition, the SSTR5-preferring analog showed a slight additive effect when used in combination with SSTR2 preferential drugs at submaximal concentrations in octreotide partially sensitive adenomas. In the present study we quantified SSTR2 and SSTR5 mRNA expression and the GH-suppressive effects of somatostatin-14; octreotide; a SSTR2-preferential compound, BIM-23197; a SSTR5-preferential compound, BIM-23268; and a new SSTR2- and SSTR5-bispecific compound, BIM-23244, in GH-secreting tumors classified as either full responders to octreotide (n = 5) or partially sensitive to octreotide (n = 5). The octreotide-sensitive GH secretory adenomas presented with a high level of both SSTR2 and SSTR5 mRNA expression [222 ± 61 and 327 ± 136 pg/pg glyceraldehyde-3-phosphate dehydrogenase (GAPDH), respectively]. In these tumors the suppression of GH release was similarly achieved at picomolar ranges by octreotide, BIM-23197, and BIM-23244 (EC50 = 25 ± 15, 3 ± 2, and 3 ± 3 pmol/L, respectively). The compounds preferential for only SSTR5 were unable to inhibit GH release in such tumors. Among the octreotide partially responsive tumors, SSTR2 mRNA expression was 9-fold lower than in the octreotide-sensitive tumors (25 ± 12 vs. 222 ± 61 pg/pg GAPDH; P < 0.015), whereas SSTR5 mRNA expression was approximately 7-fold higher than in the octreotide-sensitive tumors (2271 ± 1197 pg/pg GAPDH). In these octreotide partially responsive tumors, the SSTR5-preferential compound, BIM-23268, and the SSTR2- and SSTR5-bispecific compound, BIM-23244, were quite effective in suppressing GH secretion (EC50 = 25 ± 13 and 50 ± 31 pmol/L, respectively). Similarly, BIM-23244, was able to suppress by 51 ± 5% PRL release from five mixed GH- and PRL-secreting adenomas. These data indicate that due to heterogeneous expression of SSTR2 and SSTR5 receptor subtypes, in GH-secreting tumors, a bispecific analog, such as BIM-23244, that can activate both receptors could achieve better control of GH hypersecretion in a larger number of acromegalic patients.
Six Months of Recombinant Human GH Therapy in Patients with Ischemic Cardiac Failure Does Not Influence Left Ventricular Function and Mass
Authors: Smit Jan W. A. , Janssen Yvonne J. H. , Lamb Hildo J. , van der Wall Ernst E. , Stokkel Marcel P. M. , Viergever Eric , Biermasz Nienke R. , Bax Jeroen J. , Vliegen Hubert W. , de Roos Albert , Romijn Johannes A. , Roelfsema Ferdinand
Published: January 2014

Beneficial effects of recombinant human GH on cardiac function have been reported in humans with GH deficiency and in patients with idiopathic dilated cardiomyopathy. No randomized controlled trial has been performed on the effects of recombinant human GH on cardiac function in patients with ischemic cardiac failure. We therefore randomly assigned 22 patients with ischemic cardiac failure (left ventricular ejection fraction, <40%; 19 men and 3 women; mean age, 64 yr) to receive 6 months of unblinded therapy with recombinant human GH (2.0 IU/d) or no treatment. Primary end points were left ventricular ejection fraction and left ventricular mass. Left ventricular end-diastolic volume, left ventricular end-systolic volume, and myocardial perfusion, both at rest and during exercise, were assessed as well. Cardiac imaging techniques were electrocardiographically gated single photon emission computer tomography and magnetic resonance imaging. In addition, biochemical and biometric measurements were performed. Nineteen patients completed the study (10 controls and 9 GH-treated subjects). IGF-I and IGF-binding protein-3 increased significantly after recombinant human GH treatment (+24% and +58%, respectively) compared with control values (−14% and +5%; P < 0.05). Left ventricular ejection fraction, left ventricular end-diastolic volume, left ventricular end-systolic volume, left ventricular mass, and myocardial perfusion were not influenced by recombinant human GH therapy. We conclude that 6 months of recombinant human GH treatment in patients with ischemic cardiac failure had no beneficial effect on left ventricular function and mass.
Anabolic-Androgenic Steroid Therapy in the Treatment of Chronic Diseases
Authors: Basaria Shehzad , Wahlstrom Justin T. , Dobs Adrian S.
Published: January 2014

The purpose of this study was to review the preclinical and clinical literature relevant to the efficacy and safety of anabolic androgen steroid therapy for palliative treatment of severe weight loss associated with chronic diseases. Data sources were published literature identified from the Medline database from January 1966 to December 2000, bibliographic references, and textbooks. Reports from preclinical and clinical trials were selected. Study designs and results were extracted from trial reports. Statistical evaluation or meta-analysis of combined results was not attempted.

Androgenic anabolic steroids (AAS) are widely prescribed for the treatment of male hypogonadism; however, they may play a significant role in the treatment of other conditions as well, such as cachexia associated with human immunodeficiency virus, cancer, burns, renal and hepatic failure, and anemia associated with leukemia or kidney failure. A review of the anabolic effects of androgens and their efficacy in the treatment of these conditions is provided. In addition, the numerous and sometimes serious side effects that have been known to occur with androgen use are reviewed.

Although the threat of various side effects is present, AAS therapy appears to have a favorable anabolic effect on patients with chronic diseases and muscle catabolism. We recommend that AAS can be used for the treatment of patients with acquired immunodeficiency syndrome wasting and in severely catabolic patients with severe burns. Preliminary data in renal failure-associated wasting are also positive. Advantages and disadvantages should be weighed carefully when comparing AAS therapy to other weight-gaining measures. Although a conservative approach to the use of AAS in patients with chronic diseases is still recommended, the utility of AAS therapy in the attenuation of severe weight loss associated with disease states such as cancer, postoperative recovery, and wasting due to pulmonary and hepatic disease should be more thoroughly investigated.
Ghrelin Enhances Appetite and Increases Food Intake in Humans
Authors: Wren A. M. , Seal L. J. , Cohen M. A. , Brynes A. E. , Frost G. S. , Murphy K. G. , Dhillo W. S. , Ghatei M. A. , Bloom S. R.
Published: January 2014

Ghrelin is a recently identified endogenous ligand for the growth hormone secretagogue receptor. It is synthesized predominantly in the stomach and found in the circulation of healthy humans. Ghrelin has been shown to promote increased food intake, weight gain and adiposity in rodents. The effect of ghrelin on appetite and food intake in man has not been determined. We investigated the effects of intravenous ghrelin (5.0 pmol/kg/min) or saline infusion on appetite and food intake in a randomised double-blind cross-over study in nine healthy volunteers. There was a clear-cut increase in energy consumed by every individual from a free-choice buffet (mean increase 28 ± 3.9%, p<0.001) during ghrelin compared with saline infusion. Visual analogue scores for appetite were greater during ghrelin compared to saline infusion. Ghrelin had no effect on gastric emptying as assessed by the paracetamol absorption test. Ghrelin is the first circulating hormone demonstrated to stimulate food intake in man. Endogenous ghrelin is a potentially important new regulator of the complex systems controlling food intake and body weight.
Elevated Leptin Levels Are Associated with Excess Gains in Fat Mass in Girls, But Not Boys, with Type 1 Diabetes: Longitudinal Study during Adolescence
Authors: Ahmed M. L. , Ong K. K. L. , Watts A. P. , Morrell D. J. , Preece M. A. , Dunger D. B.
Published: January 2014

Adolescents, in particular girls, with type 1 diabetes may gain excessive weight during puberty. We present the results of a longitudinal study aimed to determine the roles of leptin and insulin in changes in body composition in subjects with type 1 diabetes and controls. Forty-six children (23 boys) with type 1 diabetes and 40 controls (20 boys) were followed from 8–17 yr of age. Height, weight, and sc skinfolds were assessed every 6 months, and a blood sample taken for leptin determination. Throughout the age range, body mass index (mean ± sem) was greater by 1.45 ± 0.69 kg/m2 in girls and 1.46 ± 0.55 kg/m2 in boys with type 1 diabetes compared with control values. In girls with type 1 diabetes, this reflected greater percent body fat (3.2 ± 1.0%; P = 0.002), whereas in boys it related to differences in fat-free mass. Both boys and girls with type 1 diabetes had higher leptin levels adjusted for percent body fat than controls; in the girls this was related to insulin dose (regression coefficient B = 0.006 ± 0.003; P = 0.04) and greater gains in fat mass. Hyperinsulinemia and raised leptin levels are associated with gains in fat mass throughout puberty in girls, but not boys, with type 1 diabetes.
Analysis of ret/PTC Gene Rearrangements Refines the Fine Needle Aspiration Diagnosis of Thyroid Cancer
Authors: Cheung Carol C. , Carydis Bessie , Ezzat Shereen , Bedard Yvan C. , Asa Sylvia L.
Published: January 2014

Papillary carcinoma (PC) represents the most common malignancy of the thyroid gland. Therefore, the assessment of fine needle aspiration biopsies of thyroid nodules rests heavily on the identification of nuclear features of PC. The ret/PTC oncogene, formed by several gene rearrangements, is specific for PC among thyroid tumors. In this study we examined thyroid aspirates for the presence of ret/PTC gene rearrangements by RT-PCR and Southern hybridization. We prospectively collected thyroid aspirates in Cytolyt solution and prepared slides for cytological examination using the ThinPrep method. All remaining material was then used for nucleic acid extraction with subsequent RT-PCR for the housekeeping gene PGK-1 to ensure ribonucleic acid integrity, for thyroglobulin to ensure the presence of follicular epithelial cells, and for the three most common ret/PTC gene rearrangements (ret/PTC-1, -2, and -3). The results of the first 73 cases with surgical follow-up were correlated with the cytological diagnosis and final histopathology. ret/PTC gene rearrangements were detected in 17 of 33 samples (52%) that were PC on histopathology; the presence of gene rearrangements was confirmed by molecular analysis of corresponding surgically resected frozen tissue. There were no false positives. The identification of ret/PTC gene rearrangements refined the diagnosis of PC in 9 of 15 specimens (60%) that would otherwise have been considered indeterminate and in 2 of 6 that were considered insufficient for cytological diagnosis. The results indicate that RT-PCR for ret/PTC is a specific marker that can be applied to fine needle aspiration biopsies and improves the diagnosis of malignancy when used as an adjunct to traditional cytology.
Growth Hormone (GH) Secretion in Patients with an Inactivating Defect of the GH-Releasing Hormone (GHRH) Receptor Is Pulsatile: Evidence for a Role for Non-GHRH Inputs into the Generation of GH Pulses
Authors: Roelfsema Ferdinand , Biermasz Nienke R. , Veldman Ronald Groote , Veldhuis Johannes D. , Frölich Marijke , Stokvis-Brantsma W. Henriëtte , Wit Jan-Maarten
Published: January 2014

GH secretion is regulated by the interaction of GHRH and somatostatin and is released in 10–20 pulses in each 24-h cycle. The exact roles in pulse generation played by somatostatin, GHRH, and the recently isolated GH-releasing peptide, Ghrelin, are not fully elucidated. To investigate the GHRH-mediated GH secretion in human, we investigated pulsatile, entropic, and 24-h rhythmic GH secretion in two young adults (male, 24 yr; female, 23 yr) from a Moroccan family with a novel inactivating defect of the GHRH receptor gene. Data were compared with values in age- and gender-matched controls. Plasma GH concentration were measured by a sensitive immunofluorometric assay, with a detection limit of 0.01 mU/L. All plasma GH concentrations in the female patient were measurable; in the male patient 30 of 145 samples were at or below the detection limit. GH secretion was pulsatile, with 21 and 23 secretory episodes/24 h in the male and female patients, respectively. The fraction of basal to total GH secretion was raised in both patients by 0.18 and 0.15, respectively. The total 24-h GH production rate was greatly diminished; in the male patient it was 6.9 mU/L (normal values for his age, 26–63 mU/L), and in the female patient it was 4.2 mU/L (normal values for her age, 96–390 mU/L). The nyctohemeral plasma GH rhythm was preserved (P < 0.001), with normal acrophases (0430 and 0218 h in the male and female, respectively). Approximate entropy was greatly elevated in both subjects (0.82 in the male and 1.17 in the female; upper normal values for age and gender, 0.24 and 0.59, respectively). Intravenous injection of 50 μg GHRH failed to increase the plasma GH concentration in both patients, but 100 μg GH-releasing peptide-2 elicited a definite increase (male patient, 0.13 to 1.74 mU/L; female patient, 0.29 to 0.87 mU/L). Both patients had a partial empty sella on magnetic resonance imaging scanning.

In summary, the present studies in two patients with a profound loss of function mutation of the GHRH receptor favor the view that in the human the timing of GH pulses is primarily supervised by intermittent somatostatin withdrawal, and the amplitude of GH pulses is driven by GHRH. In addition, we infer that effectual GHRH input controls the GH cell mass and the orderliness of the secretory process.
TNF-α and Hyperandrogenism: A Clinical, Biochemical, and Molecular Genetic Study
Authors: Escobar-Morreale Héctor F. , Calvo Rosa M. , Sancho José , San Millán José L.
Published: January 2014

To evaluate the role of TNF-α in the pathogenesis of hyperandrogenism, we have evaluated the serum TNF-α levels, as well as several polymorphisms in the promoter region of the TNF-α gene, in a group of 60 hyperandrogenic patients and 27 healthy controls matched for body mass index.

Hyperandrogenic patients presented with mildly increased serum TNF-α levels as compared with controls (mean[median] ± sd: 7.2[7.0] ± 3.3 pg/ml vs. 5.6[4.4] ± 4.0 pg/ml, P < 0.02). Although no differences in body mass index and insulin resistance indexes were observed between patients and controls, when subjects were classified by body weight, serum TNF-α was increased only in lean patients as compared with lean controls, but this difference was not statistically significant when comparing obese patients with obese controls.

The TNF-α gene polymorphisms studied here (−1196C/T, −1125G/C,− 1031T/C, −863C/A, −857C/T, −316G/A, −308G/A, −238G/A, and− 163G/A) were equally distributed in hyperandrogenic patients and controls. However, carriers of the −308A variant presented with increased basal and leuprolide-stimulated serum androgens and 17-hydroxyprogesterone levels when considering patients and controls as a group. No differences were observed in serum TNF-α levels, body mass index, and insulin resistance indexes, depending on the presence or absence of these variants.

In conclusion, our present results suggest that the TNF-α system might contribute to the pathogenesis of hyperandrogenism, independent of obesity and insulin resistance. However, elucidation of the precise mechanisms underlying the relationship between the TNF-α system and androgen excess is needed before considering TNF-α as a significant contributing factor to the development of hyperandrogenism.
Somatic Mutations in MEN Type 1 Tumors, Consistent with the Knudson “Two-Hit” Hypothesis
Authors: Pannett Anna A. J. , Thakker Rajesh V.
Published: January 2014

MEN type 1 is an autosomal dominant disorder characterized by the combined occurrence of tumors of the parathyroids, anterior pituitary, and pancreatic islet cells. The MEN1 gene, which is located on chromosome 11q13, consists of 10 exons and encodes a 610-amino acid protein named MENIN. The observation of LOH involving 11q13 in MEN type 1 tumors and the inactivating germline mutations found in patients suggest that the MEN1 gene acts as a tumor suppressor, in keeping with the “two-hit” model of hereditary cancer. The second hit in MEN type 1 tumors typically involves large chromosomal deletions that include 11q13. However, this only represents one mechanism by which the second hit may occur, and the other mechanisms, such as intragenic deletions or point mutations that inactivate the gene, have not been reported in MEN type 1 tumors. We have therefore undertaken studies to search for such mutations in six MEN type 1 tumors (four parathyroid tumors, one insulinoma, and one lipoma) that did not have LOH at 11q13 as assessed using the flanking markers D11S480, D11S1883 and PYGM centromerically and D11S449 and D11S913 telomerically. This revealed four somatic mutations, which consisted of two missense mutations and two frameshift mutations in two parathyroid tumors, one insulinoma, and one lipoma. Thus, our results, which represent the first small intragenic somatic mutations reported in MEN type 1 tumors, provide further evidence that the role of the MEN1 gene is consistent with that of a tumor suppressor gene, as postulated by Knudson’s “two-hit” hypothesis.