bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum Levels of 20-Kilodalton Human Growth Hormone (GH) Are Parallel Those of 22-Kilodalton Human GH in Normal and Short Children
Authors: Ishikawa Mayumi , Yokoya Susumu , Tachibana Katsuhiko , Hasegawa Yukihiro , Yasuda Toshiaki , Tokuhiro Etsurou , Hashimoto Yoshihide , Tanaka Toshiaki
Published: January 2014

Twenty-kilodalton human GH (20K), which is one of the human GH (hGH) variants, is thought to be produced by alternative premessenger ribonucleic acid splicing. However, its physiological role is still unclear due to the lack of a specific assay. We have measured serum 20K and 22-kDa hGH (22K) by specific ELISAs to investigate the physiological role of 20K in children.

The subjects were 162 normal children, aged 1 month to 20 yr; 12 patients with GH deficiency (GHD), aged 11 months to 13 yr; 57 children with non-GHD short stature, aged 2–17 yr; and 13 girls with Turner’s syndrome, aged 5 months to 15 yr. Samples were collected at random from normal children and were collected after hGH provocative tests and 3-h nocturnal sleep from GHD, non-GHD short stature, and Turner’s syndrome children. The mean basal serum concentrations of 22K and 20K were 2.4 ± 2.8 ng/mL and 152.3 ± 184.0 pg/mL in normal boys and 2.5 ± 3.1 ng/mL and 130.6 ± 171.5 pg/mL in normal girls, respectively. The percentages of 20K (%20K) were 5.8 ± 2.1% and 6.0 ± 3.2% in 83 normal boys and 79 normal girls, respectively. There was no significant difference in %20K either among ages or between the prepubertal stage and the pubertal stage in normal boys and girls. The mean %20K values in basal samples of provocative tests in 12 patients with GHD, non-GHD short stature, and Turner’s syndrome were 6.5 ± 2.4%, 6.5 ± 3.8%, and 5.9 ± 3.2%, respectively. There was no significant difference in %20K among normal children and these growth disorders, and there was no significant difference in %20K throughout the hGH provocative tests and 3-h nocturnal sleep in these growth disorders. There was also no significant correlation between the percentage of 20K and the height sd score or body mass index in either normal children or subjects with these growth disorders.

In conclusion, the %20K is constant, regardless of age, sex, puberty, height sd score, body mass index, and GH secretion status. The regulation of serum 20K levels remains to be established.
Testosterone Administration Preserves Protein Balance But Not Muscle Strength during 28 Days of Bed Rest1
Authors: Zachwieja Jeffrey J. , Smith Steven R. , Lovejoy Jennifer C. , Rood Jennifer C. , Windhauser Marlene M. , Bray George A.
Published: January 2014

Decrements in muscle strength as a result of prolonged bed rest are well defined, but little is known about potential countermeasures for preventing loss of strength under this condition. The purpose of this study was to determine whether testosterone administration would preserve protein balance and muscle strength during prolonged bed rest. Ten healthy men (age, 36 ± 2 yr; height, 177.2 ± 3.4 cm; weight, 80.5 ± 3.9 kg; mean ± se) were admitted to our in-patient metabolic unit. After a 1-week ambulatory run-in period, each subject was confined to bed for 28 days at 6° head-down tilt while receiving a daily oral dose of T3 (50 μg/day). During the bed rest/T3 period, six of the men were randomized to receive testosterone enanthate by im injection (T; 200 mg/week) while four received placebo in a double blind fashion. Nitrogen balance was determined throughout, and whole body[ 13C]leucine kinetics were assessed at baseline and on day 26 of bed rest. Before bed rest and on the third day of reambulation, the muscle strength of the knee extensors and flexors and shoulder extensors and flexors was determined at 60°/s on a Cybex isokinetic dynamometer. Despite improved [13C]leucine kinetics and maintenance of nitrogen balance and lean body mass in T-treated subjects, little preservation of muscle strength, particularly in the knee extensors, was noted. Muscle strength[ reported as the best work repetition in foot-pounds (FtLb)] for right knee extensors declined (P = 0.011) similarly in both groups; from 165 ± 15 to 126 ± 18 FtLb in T-treated men and from 179 ± 22 to 149 ± 13 FtLb in placebo-treated men. Overall, there was less of a decline in extension and flexion strength of the shoulder compared to the knee, with no benefit from T. These results suggest that in the absence of daily ambulatory activity, T administration will not increase or, in the case of this bed rest model, preserve muscle strength.
β-Adrenergically Stimulated Fat Oxidation Is Diminished in Middle-Aged Compared to Young Subjects*
Authors: Blaak E. E. , van Baak M. A. , Saris W. H. M.
Published: January 2014

The effect of aging on β-adrenergically mediated substrate utilization was investigated in nine young (25.2 ± 1.7 yr old) and eight older males (52.9 ± 2.1 yr old), matched for body weight and body composition. In a first experiment, the nonselectiveβ -agonist isoprenaline (ISO) was infused in increasing standardized doses, and during each infusion period energy expenditure and substrate utilization were determined by indirect calorimetry. In a second experiment, forearm skeletal muscle metabolism was studied during a standardized infusion dose of ISO (19 ng/kg fat-free mass·min). During β-adrenergic stimulation there was an increased carbohydrate oxidation (at an ISO infusion dose of 24 ng/kg fat-free mass·min, 31% vs. 21% of total energy expenditure; P < 0.05) and a decreased fat oxidation (51 vs. 62 of total energy expenditure; P < 0.05) in older compared to young subjects. Skeletal muscle lactate release significantly increased in the older subjects (from −175 ± 32 to −366 ± 66 nmol/100 mL forearm tissue·min), whereas there was no change in young subjects (from− 32 ± 21 to 23 ± 57 nmol/100 mL forearm tissue·min; interaction group × ISO, P < 0.01). Additionally, there was a tendency toward a blunted ISO-induced increase in nonesterified fatty acid uptake in the older subjects (interaction group × ISO, P = 0.062). Thus, middle-aged subjects have a blunted ability to oxidize fat during β-adrenergic stimulation compared to young subjects. This diminished fat oxidation may be an important etiological factor in the age-related increase in body fatness and obesity by favoring fat storage above oxidation.
Molecular Basis of Human Salt Sensitivity: The Role of the 11β-Hydroxysteroid Dehydrogenase Type 2*
Authors: Lovati Emanuela , Ferrari Paolo , Dick Bernhard , Jostarndt Kristin , Frey Brigitte M. , Frey Felix J. , Schorr Ulrike , Sharma Arya M.
Published: January 2014

Salt-sensitive subjects (SS) increase their blood pressure with increasing salt intake. Because steroid hormones modulate renal sodium retention, we hypothesize that the activity of the 11β-hydroxy-steroid dehydrogenase type 2 (11βHSD2) enzyme is impaired in SS subjects as compared with salt-resistant (SR) subjects. The 11βHSD2 enzyme inactivates 11-hydroxy steroids in the kidney, thus protecting the nonselective mineralocorticoid receptor from occupation by glucocorticoids. We performed an association study using a recently identified single AluI polymorphism in exon 3 and a polymorphic microsatellite marker of the HSD11B2 gene in 149 normotensive white males (37 SS and 112 SR). The activity of the enzyme 11βHSD2 was assessed by determining the urinary ratio of cortisol (THF+5αTHF) to cortisone (THE) metabolites by gas chromatography in all the 37 SS subjects and in 37 age- and body habitus-matched SR volunteers. Mean (THF+5αTHF)/THE ratio was markedly elevated in SS subjects compared with SR subjects (1.51 ± 0.34 vs. 1.08 ± 0.26, P < 0.00001), indicating enhanced access of glucocorticoids to the mineralocorticoid receptor in SS subjects. In 58% of SS subjects this ratio was higher than the maximum levels in SR subjects. The salt-induced elevation in arterial pressure increased with increasing (THF+5αTHF)/THE ratio (r2 = 0.51, P < 0.0001). A total of 12 alleles of the polymorphic microsatellite marker were detected. Homozygosity for the allele A7 was higher in SS subjects than in SR subjects (41 vs. 28%, P < 0.005), whereas the occurrence of the allele A7 with allele A8 was lower in SS subjects than in SR subjects (8 vs. 15%, P< 0.03). The prevalence of salt sensitivity was 35% in subjects with allele A7/A7, whereas salt sensitivity was present in only 9% of the subjects with allele A7/A8. The (THF+5αTHF)/THE ratio was higher in subjects homozygous for the A7 microsatellite allele as compared with the corresponding control subjects. The prevalence of the AluI allele was 8.0% in SR subjects and 5.4% in SS subjects and did not correlate with blood pressure. The decreased activity of the 11βHSD2 in SS subjects indicates that this enzyme is involved in salt-sensitive blood pressure response in humans. The association of a polymorphic microsatellite marker of the gene with a reduced 11βHSD2 activity suggests that variants of the HSD11B2 gene contribute to enhanced blood pressure response to salt in humans.
Hepatocyte Growth Factor Stimulates Trophoblast Invasion: A Potential Mechanism for Abnormal Placentation in Preeclampsia1
Authors: Kauma Scott W. , Bae-Jump Vicki , Walsh Scott W.
Published: January 2014

Hepatocyte growth factor (HGF) is a cytokine that is produced in the placental villous core and acts in a paracrine manner on trophoblasts that express the HGF receptor Met. Because HGF stimulates the invasion of many epithelial cell types, villous core HGF could regulate placental trophoblast invasion. As preeclampsia is characterized by inadequate trophoblast invasion, we investigated the hypothesis that decreased placental HGF production is a mechanism for inadequate trophoblast invasion in this disease. Placental villous explant HGF production over 24 h was 25% lower in patients with preeclampsia (n = 5; 7.29 ± 0.8 ng/mL) than in normal patients (n = 5; 9.76 ± 0.5 ng/mL; P < 0.05). The human first trimester trophoblast cell line (ED27) used in subsequent invasion studies was found to express c-met messenger ribonucleic acid by RT-PCR and Met protein by Western analysis, and underwent phosphorylation of tyrosine residues on Met with HGF exposure. A Boyden chamber invasion assay using collagen type I showed that HGF caused a specific dose-response increase in trophoblast invasion first seen at 10 ng/mL (2.2-fold increase; P < 0.05). The stimulation of trophoblast invasion by HGF may in part be due to the 2-fold induction of 92-kDa collagenase as determined by zymogram analysis of the trophoblast-conditioned medium. These studies suggest that HGF has an important role in placental trophoblast invasion through the activation of Met and the subsequent induction of 92-kDa collagenase in these cells. In addition, decreased placental production of HGF in preeclampsia provides a potential mechanism for the lack of trophoblast invasion that is seen in this pregnancy disorder.
Corticotropin-Releasing Hormone: A Potent Androgen Secretagogue in Girls with Hyperandrogenism after Precocious Pubarche1
Authors: Ibáñez Lourdes , Potau Neus , Marcos Maria Victoria , de Zegher Francis
Published: January 2014

CRH is an adrenal androgen secretagogue in men and has been proposed as a candidate regulator of adrenarche. CRH also affects androgen production by theca cells and may be involved in the pathogenesis of ovarian hyperandrogenism (OH). Precocious pubarche (PP) in girls can precede adolescent OH, a condition characterized by a high ovarian 17-hydroxyprogesterone (17-OHP) response 24 h after GnRH agonist challenge.

In adolescent girls with a history of PP, we assessed the early androgen response to CRH, as well as the CRH effect on the late ovarian response to GnRH agonist.

Within a randomized cross-over design, saline or CRH (human CRH 1μ g/kg·h in saline) was infused over 3-h (1100–1400 h) into 12 adolescent girls (age 17 ± 2 yr; body mass index 21.4 ± 0.9 Kg/m2) who had been pretreated with dexamethasone (1 mg at 0 h) and GnRH agonist (leuprolide acetate 500 μg sc at 0800 h = time 0). All adolescents had hirsutism, irregular menses, hyperandrogenemia, and hyperinsulinemia after PP. Serum LH, FSH, androstenedione, dehydroepiandrosterone (DHEA), and DHEA-sulfate (DHEAS) were measured at time 0, 3, 6, and 24 h, and ACTH and 17-OHP were measured at time 0, 6, and 24 h.

ACTH concentrations at the end of saline or CRH infusions were less than 45 pg/mL; neither saline nor CRH infusions evoked early changes in 17-OHP levels. Within 3 h of CRH infusion, DHEAS increased by 46%, on average; androstenedione increased 2.5-fold and DHEA increased 5-fold during CRH infusion (all P < 0.0001 compared with saline). There was no detectable CRH effect on the responses of LH, FSH, DHEA, DHEAS, 17-OHP, androstenedione, testosterone, and estradiol 24 h after GnRH agonist administration; five of 12 girls had elevated 17-OHP responses suggestive of OH.

In conclusion, CRH was found to be a potent adrenal androgen secretagogue in adolescent girls with hyperandrogenism after PP. In this study, CRH failed to detectably affect the ovarian androgen response to gonadotropins.
Genotyping of Adrenocortical Tumors: Very Frequent Deletions of the MEN1 Locus in 11q13 and of a 1-Centimorgan Region in 2p161
Authors: Kjellman Magnus , Roshani Leyla , Teh Bin Tean , Kallioniemi Olli-Pekka , Höög Anders , Gray Steven , Farnebo Lars-Ove , Holst Mikael , Bäckdahl Martin , Larsson Catharina
Published: January 2014

To identify chromosomal regions that may contain loci for tumor suppressor genes involved in adrenocortical tumor development, a panel of 60 tumors (39 carcinomas and 21 adenomas) were screened for loss of heterozygosity. Although the vast majority of loss of heterozygosity (LOH) were detected in the carcinomas and involved chromosomes 2, 4, 11, and 18, only few were found in the adenomas. Therefore, 2 loci that harbor the familial cancer syndromes Carney complex in 2p16 and the multiple endocrine neoplasia type 1 gene in 11q13 were further studied in 27 (13 carcinomas and 14 adenomas) of the 60 tumors. Detailed analysis of the 2p16 region mapped a minimal area of overlapping deletions to a 1-centimorgan region, which is separate from the Carney complex locus. LOH for a microsatellite marker (PYGM), very close to the MEN1 gene, was detected in all 8 informative carcinomas (100%) and in 2 of 14 adenomas. Of the 27 cases analyzed in detail, 13 cases (11 carcinomas and 2 adenomas) showed LOH on chromosome 11 and was therefore selected for MEN1 gene mutation analysis. In 6 cases a common polymorphism (Asp418Asp) was found, but no mutation was detected. In conclusion, our data indicate the existence of tumor suppressor genes at multiple chromosomal locations, whose inactivations are involved in the development of adrenocortical carcinomas. Loss of genetic material from 2p16 was strongly associated with the malignant phenotype, as it was seen in almost all carcinomas but not in any of the adenomas. LOH in 11q13 also occurred frequently in the carcinomas, but was not associated with a MEN1 mutation, suggesting the involvement of a different tumor suppressor gene on this chromosome.
Two Different Mutations in the Thyroid Peroxidase Gene of a Large Inbred Amish Kindred: Power and Limits of Homozygosity Mapping1
Authors: Pannain Silvana , Weiss Roy E. , Jackson Charles E. , Dian Donald , Beck John C. , Sheffield Val C. , Cox Nancy , Refetoff Samuel
Published: January 2014

Approximately 10% of newborns with congenital hypothyroidism are unable to convert iodide into organic iodine. This iodide organification defect has a prevalence of 1 in 40,000 newborns and may be caused by defects in the thyroid peroxidase enzyme (TPO), the hydrogen peroxide-generating system, the TPO substrate thyroglobulin, or inhibitors of TPO.

We identified a high incidence of severe hypothyroidism due to a complete iodide organification defect in the youngest generation of five nuclear families belonging to an inbred Amish kindred. Genealogical records permitted us to trace their origin to an ancestral couple 7–8 generations back and to identify an autosomal recessive pattern of inheritance. Initial studies of homozygosity by descent using two polymorphic markers within the TPO gene showed no linkage to the phenotype. In fact, 4 of 15 affected siblings from 2 of the nuclear families were heterozygous, resulting in homozygosity values of 73% and 53% in affected and unaffected family members, respectively. A genome-wide homozygosity screen using DNA pools from affected and unaffected family members localized the defect to a locus close to the TPO gene. Linkage analysis using 4 additional polymorphic markers within the TPO gene reduced the number of homozygous unaffected siblings to zero without altering the percent homozygosity initially found in the affected. Sequencing of the TPO gene revealed 2 missense mutations, E799K and R648Q. TPO 779K was found in both alleles of the 11 affected homozygotes, both mutations were present in each of the 3 affected compound heterozygotes, and there were no TPO mutations in 1 subject with hypothyroidism of different etiology. These results demonstrate the power of the DNA pooling strategy in the localization of a defective gene and the pitfalls of linkage analysis when 2 relatively rare mutations coexist in an inbred population.
Pharmacokinetic Profiles of Repaglinide in Elderly Subjects With Type 2 Diabetes
Authors: Hatorp Vibeke , Huang Won-Chin , Strange Poul
Published: January 2014

Pharmacokinetic profiles of single- and multiple-dose regimens of repaglinide were evaluated in 12 elderly subjects with type 2 diabetes. On day 1, following a 1-hour fast, subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, each subject received a 2-mg dose of repaglinide 15 minutes before each of the three main meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve (AUC), log(AUC), maximal concentration (Cmax), log(Cmax), time to maximal concentration (Tmax), and half-life (T1/2), were determined at completion of the single- and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7. The mean log(AUC) values after multiple dosing were significantly higher than the values obtained after a single dose. The mean values for log(Cmax), and Tmax were comparable after each dosing regimen. The T1/2 of repaglinide after multiple dosing was 1.7 hours. The trough values for repaglinide were low. No hypoglycemic events were reported. The pharmacokinetic profiles of repaglinide after single- and multiple-dose regimens were similar, and repaglinide was well tolerated by elderly subjects with type 2 diabetes.
Trp64Arg Polymorphism of theβ 3-Adrenergic Receptor Gene in Pregnancy: Association with Mild Gestational Diabetes Mellitus
Authors: Festa Andreas , Krugluger Walter , Shnawa Nadja , Hopmeier Pierre , Haffner Steven M. , Schernthaner Guntram
Published: January 2014

A missense mutation of the β3-adrenergic receptor gene (Trp64Arg) has been associated with obesity and increased capacity to gain weight in nonpregnant populations. Furthermore, the mutation is a potential modifying factor in the etiology of impaired glucose tolerance and type 2 diabetes. We studied the relation of theβ 3-adrenergic receptor genotype to glucose tolerance during pregnancy, a state of physiological insulin resistance. In 179 pregnant women (mean age, 28.5 ± 0.4 yr), a 2-h oral glucose tolerance test was performed between gestational weeks 20 and 31. Theβ 3-adrenergic receptor genotype was assessed using restriction fragment length polymorphism.

The frequency of the Arg64 allele was 9.15%. In women with mild gestational diabetes (n = 70), as defined by 60 min postload glucose values, the Trp64Arg genotype was more frequent than in women with normal glucose tolerance (n = 109; 26% vs. 11%; P = 0.01). Furthermore, the Trp64Arg polymorphism was associated with increased weight gain during pregnancy (baseline to gestational weeks 20–31) and increased postload glucose, insulin, and C peptide values during the oral glucose tolerance test.

The results of the present study extend current knowledge about the association of the Trp64Arg β3-adrenergic receptor polymorphism with glucose tolerance to a pregnant population. The association with mild gestational diabetes suggests that the impact of the polymorphism may be clinically important during pregnancy, a state of physiological insulin resistance.
Treatment of Obese Subjects with the Oral Growth Hormone Secretagogue MK-677 Affects Serum Concentrations of Several Lipoproteins, But Not Lipoprotein(a)1
Authors: Svensson J. , Jansson J.-O. , Ottosson M. , Johannsson G. , Taskinen M.-R. , Wiklund O. , Bengtsson B.-Å.
Published: January 2014

Obesity is associated with blunted GH secretion and an unfavorable lipoprotein pattern. The objective of this study was to investigate the effects of treatment with the oral GH secretagogue MK-677 on lipoproteins in otherwise healthy obese males. The study was randomized, double blind, and parallel. Twenty-four obese males, aged 18–50 yr, with body mass index greater than 30 kg/m2 and waist/hip ratio above 0.95 were treated with 25 mg MK-677 (n = 12) or placebo (n = 12) daily for 8 weeks.

MK-677 treatment did not significantly change serum lipoprotein(a) [Lp(a)] levels. Serum apolipoprotein A-I and E (apoA-I and apoE) were increased at 2 weeks (P < 0.001 and P < 0.01 vs. placebo, respectively), but were not changed at study end. Serum total cholesterol and low density lipoprotein (LDL) cholesterol (LDL-C) levels were not significantly changed by MK-677 treatment. Serum high density lipoprotein (HDL) cholesterol (HDL-C) was increased at 2 weeks of MK-677 treatment (P < 0.01 vs. placebo), but not at 8 weeks. The LDL-C/HDL-C ratio was reduced after 8 weeks of MK-677 treatment (P < 0.05 vs. placebo). Mean LDL particle diameter was decreased at 2 weeks (P < 0.05 vs. placebo), but was unchanged compared with baseline values at 8 weeks (P = NS vs. placebo). The level of serum triglycerides was increased at 2 (P < 0.05 vs. placebo), but not at 8, weeks. Lipoprotein lipase activity in abdominal and gluteal sc adipose tissue was not affected by active treatment.

In conclusion, treatment with the oral GH secretagogue MK-677 affected circulating lipoproteins. The effects on serum apoA-1, apoE, triglycerides, and mean LDL particle diameter were transient. At study end, the LDL-C/HDL-C ratio was decreased. MK-677 treatment did not significantly affect serum Lp(a) concentrations at the present dose and administration protocol.
High Prevalence of the Polycystic Ovary Syndrome and Hirsutism in Women with Type 1 Diabetes Mellitus1
Authors: Escobar-Morreale Héctor F. , Roldán Belén , Barrio Raquel , Alonso Milagros , Sancho José , de la Calle Hermenegildo , GarcÍa-Robles Rafael
Published: January 2014

The current recommendation for strict metabolic control of type 1 diabetes mellitus requires the administration of supraphysiological doses of insulin, which might result in insulin-mediated stimulation of androgen synthesis, as occurs in insulin-resistant states. At present, the prevalence of hyperandrogenic disorders in women with type 1 diabetes mellitus is unknown.

Eighty-five women with type 1 diabetes mellitus were evaluated for symptoms and signs of hyperandrogenism. In 68 of the patients, several serum androgen and hormone concentrations were measured. The polycystic ovary syndrome (PCOS) was defined by the presence of menstrual dysfunction, together with clinical and/or biochemical evidence of hyperandrogenism, and exclusion of other etiologies. Eighteen healthy women, menstruating regularly, served as controls for the androgenic profiles.

Thirty-three patients (38.8%) presented hyperandrogenic disorders (16 had PCOS, and 17 had hirsutism without menstrual dysfunction). Type 1 diabetic patients with PCOS presented increased serum total and free testosterone concentrations, and serum androstenedione levels, but had normal serum sex hormone-binding globulin and dehydroepiandrosterone-sulfate levels. Hirsute type 1 diabetic women without menstrual dysfunction presented normal serum androgen levels. There were no significant differences between hyperandrogenic and nonhyperandrogenic type 1 diabetes mellitus women in clinical variables such as the duration of diabetes, age at diagnosis of diabetes, conventional or intensive insulin therapy, mean daily insulin dosage, or metabolic control.

In conclusion, women with type 1 diabetes mellitus have a high prevalence of hyperandrogenic disorders, including PCOS and hirsutism.
Growth Hormone Replacement Therapy Improves Body Composition and Increases Bone Metabolism in Elderly Patients with Pituitary Disease1
Authors: Fernholm Rita , Bramnert Margareta , Hägg Erik , Hilding Agneta , Baylink David J. , Mohan Subburaman , Thorén Marja
Published: January 2014

Although a specific GH deficiency (GHD) syndrome in the adult and the response to GH replacement therapy are well recognized, there are few data available on the effect of GH replacement therapy in elderly GH-deficient patients. We studied the effect of GH therapy on body composition and bone mineral density measured by dual energy x-ray absorptiometry, markers for bone metabolism, insulin-like growth factors (IGFs), and IGF-binding proteins (IGFBPs) in 31 patients (6 women and 25 men; aged 60–79 yr; mean, 68 yr) with multiple pituitary hormone deficiencies. The GH response to arginine or insulin was below 3 μg/L (9 mU/L) in all subjects. They were randomized to GH (Humatrope, Eli Lilly & Co.) or placebo for 6 months, followed by 12 months of open treatment. The dose was 0.05 IU/kg·week for 1 month, and after that it was 0.1 IU/kg·week divided into daily sc injections (0.75–1.25 IU/day).

There were no changes in any of the measured variables during placebo treatment. GH treatment normalized serum IGF-I in a majority of the patients and increased IGFBP-3 and -5 as well as IGFBP-4 and IGF-II to values within normal range. Lean body mass was increased, and the increase at 6 and 12 months correlated with the increase in IGF-I (r = 0.46; P = 0.010 and r = 0.54, respectively; P = 0.003). GH treatment caused a modest, but highly significant, reduction of total body fat. Mean bone mineral density was not different from that in healthy subjects of the same age and did not change during the observation period. Markers for bone formation (bone-specific alkaline phosphatase activity, osteocalcin, and procollagen I carboxyl-terminal peptide in serum) increased within the normal range, and levels were sustained throughout the study. The bone resorption marker (pyridinoline in urine) was significantly elevated for 12 months. Side-effects were mild, mostly attributed to fluid retention. In two patients with normal glucose tolerance at the start of the study, pathological glucose tolerance occurred in one patient and was impaired in one.

In conclusion, elderly patients with GHD respond to replacement therapy in a similar manner as younger subjects, with an improvement in body composition and an increase in markers for bone metabolism. Side-effects are few, and elderly GHD patients can be offered treatment. As long-term risks are unknown, GH doses should be titrated to keep IGF-I within the age-related physiological range.
Progesterone Enhances Interleukin-15 Production in Human Endometrial Stromal Cells in Vitro1
Authors: Okada Hidetaka , Nakajima Tatsuya , Sanezumi Mayumi , Ikuta Akiko , Yasuda Katsuhiko , Kanzaki Hideharu
Published: January 2014

Interleukin-15 (IL-15) is a novel cytokine that stimulates lymphocyte proliferation and migration via a trimeric receptor sharing the β andγ signal-transducing chains with the IL-2 receptor. It is suggested that IL-15 is involved in regulating the proliferation and differentiation of uterine natural killer cells. In the human endometrium, we have recently reported that IL-15 messenger ribonucleic acid (mRNA) levels significantly increased during the secretory phase compared with those during the proliferative phase. In this study we investigated whether the female sex steroids progesterone (P) and estradiol (E2) regulate IL-15 messenger RNA (mRNA) and the secretion in human endometrial stromal cells (ESC) in vitro. Northern blot analyses revealed a significant increase in IL-15 mRNA levels in ESC treated with P alone or E2 plus P compared with vehicle. Furthermore, P is a potent inducer of IL-15 mRNA expression in ESC in a dose-dependent manner. On the other hand, E2 alone did not increase IL-15 mRNA expression. By enzyme-linked immunosorbent assay, IL-15 protein secretion was stimulated by P and further enhanced by combined treatment with E2 and P, whereas E2 alone was ineffective. It is suggested that IL-15 is deeply involved in the hormonal control of the human endometrium by P and E2.
Prognostic Factors for the Course of β Cell Function in Autoimmune Diabetes1
Authors: Törn C. , Landin-Olsson M. , Lernmark Å. , Palmer J. P. , Arnqvist H. J. , Blohmé G. , Lithner F. , Littorin B. , Nyström L. , Scherstén B. , Sundkvist G. , Wibell L. , Östman J.
Published: January 2014

This study presents a 2-yr follow-up of 281 patients, aged 15–34 yr, diagnosed with diabetes between 1992 and 1993. At diagnosis, 224 (80%) patients were positive for at least one of the following autoantibodies: islet cell antibodies (ICAs), glutamic acid decarboxylase antibodies (GADAs), or tyrosine phosphatase antibodies (IA-2As); the remaining 57 (20%) patients were negative for all three autoantibodies. At diagnosis, C-peptide levels were lower (0.27; 0.16–0.40 nmol/L) in autoantibody-positive patients compared with autoantibody-negative patients (0.51; 0.28–0.78 nmol/L; P < 0.001). After 2 yr, C-peptide levels had decreased significantly in patients with autoimmune diabetes (0.20; 0.10–0.37 nmol/L; P = 0.0018), but not in autoantibody-negative patients. In patients with autoimmune diabetes, a low initial level of C-peptide (odds ratio, 2.6; 95% confidence interval, 1.7–4.0) and a high level of GADAs (odds ratio, 2.5; 95% confidence interval, 1.1–5.7) were risk factors for a C-peptide level below the reference level of 0.25 nmol/L 2 yr after diagnosis. Body mass index had a significant effect in the multivariate analysis only when initial C-peptide was not considered. Factors such as age, gender, levels of ICA or IA-2A or insulin autoantibodies (analyzed in a subset of 180 patients) had no effect on the decrease in β-cell function.

It is concluded that the absence of pancreatic islet autoantibodies at diagnosis were highly predictive for a maintained β-cell function during the 2 yr after diagnosis, whereas high levels of GADA indicated a course of decreased β-cell function with low levels of C-peptide. In autoimmune diabetes, an initial low level of C-peptide was a strong risk factor for a decrease in β-cell function and conversely high C-peptide levels were protective. Other factors such as age, gender, body mass index, levels of ICA, IA-2A or IAA had no prognostic importance.
Carrier Analysis and Prenatal Diagnosis of Congenital Adrenal Hyperplasia Caused by 21-Hydroxylase Deficiency in Chinese1
Authors: Lee Hsien-Hsiung , Kuo Jing-Mei , Chao Hsiang-Tai , Lee Yann-Jinn , Chang Jan-Gowth , Tsai Chang-Hai , Chung Bon-chu
Published: January 2014

Congenital adrenal hyperplasia (CAH) is a common autosomal recessive disorder mainly caused by defects in the steroid 21-hydroxylase (CYP21) gene. We screened 1,000 healthy people, using a previously developed differential PCR method combined with single-strand conformation polymorphism and amplification-created restriction site methods for the carrier detection of the CYP21 gene deficiency. Our results indicated that the rate of occurrence of the heterozygous CAH carrier was about 12 in 1,000, with a gene frequency of 0.0060 and an incidence frequency of 1 in 28,000 in the Chinese population. In addition, 9 cases of CAH families were performed with prenatal diagnosis. Among them, 3 cases were diagnosed as the severe form, 4 cases carried the heterozygous mutation, and 2 were normal. This is the first report of carrier frequency analysis and prenatal diagnosis of 21-hydroxylase deficiency in Chinese.
Insulin-Like Growth Factor I and Growth Hormone (GH) Treatment in GH-Deficient Humans: Differential Effects on Protein, Glucose, Lipid, and Calcium Metabolism1
Authors: Mauras Nelly , O’Brien Kimberly O. , Welch Susan , Rini Annie , Helgeson Kevin , Vieira Nancy E. , Yergey Alfred L.
Published: January 2014

We examined the effects of recombinant human (rh) insulin-like growth factor I (IGF-I) vs. rhGH in a variety of metabolic paths in a group of eight severely GH-deficient young adults using an array of contemporary tools. Protein, glucose, and calcium metabolism were studied using stable labeled tracer infusions of l-[1-13C]leucine,[ 6,6-2H2]glucose, and 42Ca and 44Ca; substrate oxidation rates were assessed using indirect calorimetry; muscle strength was determined by isokinetic and isometric dynamometry of the anterior quadriceps, as well as growth factors, hormones, glucose, and lipid concentrations in plasma before and after 8 weeks of rhIGF-I (60 μg/kg, sc, twice daily), followed by 4 weeks of washout, then 8 weeks of rhGH (12.5 μg/kg·day, sc); the treatment order was randomized.

In the doses administered, rhIGF-I and rhGH both increased fat-free mass and decreased the percent fat mass, with a more robust decrease in the percent fat mass after rhGH; both were associated with an increase in whole body protein synthesis rates and a decrease in protein oxidation. Neither hormone affected isokinetic or isometric measures of skeletal muscle strength. However, rhGH was more potent than rhIGF-I at increasing lipid oxidation rates and improving plasma lipid profiles. Both hormones increased hepatic glucose output, but rhGH treatment was also associated with decreased carbohydrate oxidation and increased glucose and insulin concentrations, indicating subtle insulin resistance. Neither hormone significantly affected bone calcium fluxes, supporting the concept that these hormones, by themselves, are not pivotal in bone calcium metabolism. In conclusion, rhIGF-I and rhGH share common effects on protein, muscle, and calcium metabolism, yet have divergent effects on lipid and carbohydrate metabolism in the GH-deficient state. These differences may allow for better selection of treatment modalities depending on the choice of desired effects in hypopituitarism.
Vitamin D Receptor Gene Polymorphism Is Associated with Birth Height, Growth to Adolescence, and Adult Stature in Healthy Caucasian Men: A Cross-Sectional and Longitudinal Study1
Authors: Lorentzon Mattias , Lorentzon Ronny , Nordström Peter
Published: January 2014

Vitamin D receptor (VDR) polymorphism has been associated with bone mineral density (BMD), but recent data indicate association to parameters of body constitution and growth. We investigated VDR gene polymorphism, defined by BsmI and TaqI, in 90 healthy Caucasian males and any relation with parameters of body constitution at birth, and to parameters of body constitution, BMD and bone area, at age 16.9 ± 0.3 yr (mean ± sd) and at age 19.2 ± 0.7. Using PCR and the restriction enzyme BsmI and TaqI, the allelic variants BB, Bb, and bb, and TT, Tt, and tt were identified. Height (cm) and weight (kg) were measured using standardized equipment, and BMD of the total body, lumbar spine, and femoral neck, and bone area (cm2) of the total body, humerus, femur was measured using dual-energy x-ray absorptiometry. BsmI and TaqI genotypes were related in 89 of the 90 cases; hence, the same associations were found for both genotypes. Boys with the BB genotype were shorter at birth (P = 0.01) and grew less from birth to age 16.9 ± 0.3 (P = 0.01) than their Bb and bb counterparts. Both during puberty (age 16.9 ± 0.3) and after puberty (age 19.3 ± 0.7), the BB boys were shorter (P = 0.005–0.008) and had lower bone area of the humerus, femur, and total body (P < 0.05) than the Bb and bb boys. The allelic variants were not related to BMD at any site. A prediction model including parental height, birth height, birth weight, and VDR alleles could predict up to 39% of the total variation in adult height in our population. The VDR allelic variants alone contributed to 8% of the total variation.
Increased Leptin Levels in Serum and Peritoneal Fluid of Patients with Pelvic Endometriosis1
Authors: Matarese Giuseppe , Alviggi Carlo , Sanna Veronica , Howard Jane K. , Lord Graham M. , Carravetta Carlo , Fontana Silvia , Lechler Robert I. , Bloom Stephen R. , De Placido Giuseppe
Published: January 2014

Pelvic endometriosis is an immune-related chronic inflammatory disease, characterized by ectopic implants of endometrium in the peritoneal cavity and associated with increased secretion of proinflammatory cytokines and neoangiogenesis. Leptin, the adipocyte-derived hormone, has been shown to have a role in food intake, basal metabolism, and reproductive function. Leptin levels are dynamically regulated, being elevated by inflammatory mediators and reduced by starvation. Leptin itself can influence the proinflammatory immune responses of CD4+ T lymphocytes, and reports have also shown this hormone to be an angiogenic factor in vitro and in vivo. We investigated whether leptin concentrations in serum and peritoneal fluid (PF) differed between 13 patients with different stages of endometriosis and 15 age- and body mass index-matched controls. We found a statistically significant (P < 0.05) increase in leptin levels in serum (30.3 ± 14.8 ng/mL) and PF (35.9 ± 17.4 ng/mL) of patients with endometriosis, compared with our control population (serum, 15.6 ± 8.4; PF, 17.5 ± 7.2 ng/mL). Regression equations, relating leptin to body mass index, were also significantly different in endometriosis patients, compared with controls. Higher levels of leptin were observed in the earlier stages of endometriosis than advanced-stage disease.

These data suggest that the proinflammatory and neoangiogenic actions of leptin may contribute to the pathogenesis of endometriosis.
Abnormal Cytokine and Adrenocortical Hormone Regulation in Myotonic Dystrophy*
Authors: Johansson Åsa , Carlström Kjell , Ahrén Bo , Cederquist Kristina , Krylborg Eva , Forsberg Håkan , Olsson Tommy
Published: January 2014

Metabolic-endocrine dysfunctions, including hyperinsulinemia, hypertriglyceridemia, increased fat mass, and dysregulation of the hypothalamic-pituitary-adrenal axis, are common in myotonic dystrophy (MD). We hypothesized that increased production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) may be important underlying mechanisms.

We studied the diurnal rhythmicity of cytokines and cortisol, ACTH, and dehydroepiandrosterone in 18 men with adult onset MD and 18 controls. Morning levels of androstenedione, 17-hydroxyprogesterone, testosterone, and insulin were also determined. Genetic analyses were performed, including calculation of allele sizes.

Median circulating 24-h levels of IL-6 (P < 0.001), TNF-α (P = 0.05), ACTH (P < 0.05), and cortisol (P < 0.05) were all significantly increased in MD, whereas dehydroepiandrosterone levels were decreased (P< 0.001). The diurnal rhythms of these cytokines/hormones were disturbed in patients. Morning testosterone levels were decreased and insulin levels increased (P < 0.01 for both). Patients with high body fat mass had significantly increased insulin levels and decreased morning levels of cortisol, ACTH, and testosterone.

IL-6 and TNF-α levels are increased and adrenocortical hormone regulation is disturbed in MD. Adiposity may contribute to these disturbances, which may be of importance for decreased adrenal androgen hormone production and metabolic, muscular, and neuropsychiatric dysfunction in MD.
Expression of Cyclooxygenase-2 and Prostanoid Receptors by Human Myometrium*
Authors: Erkinheimo Tiina-Liisa , Saukkonen Kirsi , Narko Kirsi , Jalkanen Jyrki , Ylikorkala Olavi , Ristimäki Ari
Published: January 2014

Prostanoids play an important role in the regulation of parturition. All reproductive tissues, including fetal membranes, decidua, and myometrium, have the capacity to synthesize prostanoids, and fetal membranes have been shown to express elevated levels of cyclooxygenase-2 (Cox-2) at the onset of labor. We have now investigated the expression of Cox-2 in human myometrium. Myometrial samples collected from women in labor during lower segment cesarean section expressed 15-fold higher levels of Cox-2 messenger ribonucleic acid (mRNA) compared to myometrial specimens collected from women not in labor, as detected by Northern blot analysis. Immunohistochemical detection of Cox-2 protein showed cytoplasmic staining in the smooth muscle cells of the myometrium. Cultured myometrial cells expressed low levels of Cox-2 mRNA under baseline conditions, but interleukin-1β (IL-1β) caused a 17-fold induction of expression of the Cox-2 transcript after incubation for 6 h. IL-1β also induced expression of biologically active Cox-2 protein, as detected by immunofluorescence, Western blot analysis, and measuring the conversion of arachidonic acid to prostanoids in the presence and absence of a Cox-2-selective inhibitor, NS-398. PGE2 receptor subtype EP2 mRNA was expressed in cultured myometrial smooth muscle cells, whereas transcripts for EP1, EP3, EP4, FP, and IP were low or below the detection limit as measured by Northern blot analysis. However, IL-1β stimulated expression of EP4 receptor mRNA. Our data suggest that expression of Cox-2 transcript is elevated at the onset of labor in myometrial smooth muscle cells, which may depend on induction by cytokines. As, in addition to Cox-2, the expression of prostanoid receptors is regulated, not only the production of prostanoids, but also responsiveness to them, may be modulated.
Linear Growth and Final Height after Treatment for Cushing’s Disease in Childhood
Authors: Lebrethon Marie-Christine , Grossman Ashley B. , Afshar Farhad , Plowman P. Nicholas , Besser G. Michael , Savage Martin O.
Published: January 2014

Cushing’s disease is associated with growth failure in childhood and adolescence. Growth and final height were analyzed in 10 patients who were cured or in remission after treatment of Cushing’s disease. Seven males and 3 females, aged 6.8–17.6 yr (bone age, 3.3- 15.4 yr), had transsphenoidal surgery, which was combined with pituitary irradiation (4500 cGy in 25 fractions) in 5 patients. At presentation, 5 patients were prepubertal (males), and 5 were pubertal (2 males and 3 females). The mean height sd score was −2.15 ± 1.26 (range, −0.21 to −4.32) compared with mean target height sd score of −0.43 ± 0.58. Height velocity in 6 patients was subnormal (0.9–3.8 cm/yr). After treatment, short-term height velocity, over a mean interval of 0.57 yr, in 8 patients not receiving human GH (hGH) therapy, was variable (range, 0.8–7.6 cm/yr). GH stimulation tests (insulin tolerance test/glucagon) in 9 subjects showed peak GH levels of 0.5–20.9 mU/L. Eight were treated with hGH (14 IU/m2·wk), combined in 2 girls and 1 boy with a GnRH analog. After 1 yr of hGH, the mean height sd score had increased from −2.45 ± 1.0 at initiation of hGH to −2.07± 1.2 (P = 0.01). GH therapy was continued until final height or latest assessment. The mean final height sd score (n = 6) was −1.24 ± 1.38, and at the latest assessment the mean height sd score (n = 4) was− 1.52 ± 1.33. Combining these 2 groups, the mean height sd score was −1.36 ± 1.29. The difference between final or latest height sd score and target height sd score was 0.93 ± 1.13, i.e. less (P = 0.005) than the difference between height and target height sd score of 1.72 ± 1.26 at presentation. In conclusion, catch-up and favorable long-term growth was seen after treatment for Cushing’s disease. Posttreatment GH deficiency was frequent, and early hGH replacement may have contributed to the encouraging outcome.
Alterations in Serum Protein Levels in Patients with Cushing’s Syndrome before and after Successful Treatment
Authors: Putignano P. , Kaltsas G. A. , Korbonits M. , Jenkins P. J. , Monson J. P. , Besser G. M. , Grossman A. B.
Published: January 2014

Alteration in serum protein concentration is used commonly in clinical practice as a nonspecific indicator of underlying disease or to monitor disease activity. Although hypercortisolemia may affect protein metabolism directly or indirectly, data regarding alterations of levels of serum protein in a large series of patients with Cushing’s syndrome (CS) have been lacking. We have now evaluated, retrospectively, the levels of circulating serum albumin, globulins, total proteins, and the albumin to globulin ratio in 99 patients with endogenous CS before, immediately after, and 3, 6, and 12 months following successful treatment. Subjects with concomitant infections or other chronic diseases were excluded from the analysis.

Although mean serum albumin and total protein levels were within the normal reference ranges, in general, they gradually increased after treatment with maximal values being reached at 12 months after normalization of hypercortisolemia (P < 0.0001 for both); there were no significant changes in serum globulin levels or in the albumin to globulin ratio. Patients with CS as a whole showed a weak but significant negative correlation between serum albumin and 0900 h cortisol level (r = −0.303; P = 0.0035).

In conclusion, our data suggest that CS is associated with a small but significant reduction in circulating serum protein levels, which are restored following treatment of hypercortisolemia, although these changes occur within the reference range. Thus, extreme alterations in serum total protein or albumin levels in patients with CS should alert physicians to the presence of concomitant pathology, and additional specific investigation should be undertaken to elucidate the cause.
Growth and Adult Height in GH-Treated Children with Nonacquired GH Deficiency and Idiopathic Short Stature: The Influence of Pituitary Magnetic Resonance Imaging Findings
Authors: Coutant Régis , Rouleau Stéphanie , Despert François , Magontier Nathalie , Loisel Didier , Limal Jean-Marie
Published: January 2014

We analyzed the final height of 146 short children with either nonacquired GH deficiency or idiopathic short stature. Our purpose was 1) to assess growth according to the pituitary magnetic resonance imaging findings in the 63 GH-treated children with GH deficiency and 2) to compare the growth of the GH-deficient patients with normal magnetic resonance imaging (n = 48) to that of 32 treated and 51 untreated children with idiopathic short stature (GH peak to provocative tests >10 μg/liter). The mean GH dose was 0.44 IU/kg·wk (0.15 mg/kg·wk), given for a mean duration of 4.6 yr.

Among the GH-deficient children, 15 had hypothalamic-pituitary abnormalities (stalk agenesis), all with total GH deficiency (GH peak<5 μg/liter). They were significantly shorter and younger at the time of diagnosis than those with normal magnetic resonance imaging, had better catch-up growth (+2.7 ± 0.9 vs.+ 1.3 ± 0.8 sd score; P < 0.01), and reached greater final height (−1.1 ± 1.0 vs.− 1.7 ± 1.0 sd score; P < 0.05). Among patients with normal magnetic resonance imaging, there was no difference in catch-up growth and final height between partial and total GH deficiencies.

GH-deficient subjects with normal magnetic resonance imaging and treated and untreated patients with idiopathic short stature had comparable auxological characteristics, age at evaluation, and target height. Although they had different catch-up growth (+1.3 ± 0.8,+ 0.9 ± 0.6, and +0.7 ± 0.9 sd score, respectively; P < 0.01, by ANOVA), these patients reached a similar final height (−1.7 ± 1.0, −2.1 ± 0.8, and −2.1 ± 1.0 sd score, respectively; P = 0.13).

Pituitary magnetic resonance imaging findings show the heterogeneity within the group of nonacquired GH deficiency and help to predict the response to GH treatment in these patients. The similarities in growth between the GH-deficient children with normal magnetic resonance imaging and those with idiopathic short stature suggest that the short stature in the former subjects is at least partly due to factors other than GH deficiency.