bluuebunny/crossref_metadata_2025_split huggingface dataset:
Free α-Subunit Is Superior to Luteinizing Hormone as a Marker of Gonadotropin-Releasing Hormone Despite Desensitization at Fast Pulse Frequencies1
Authors: Hayes Frances J. , McNicholl Dennis J. , Schoenfeld David , Marsh Erica E. , Hall Janet E. 
Published: January 2014

A pulsatile pattern of GnRH stimulation is essential for normal secretion of luteinizing hormone (LH), while both continuous and fast-frequency GnRH stimulation result in a paradoxical decrease in gonadotrope responsiveness known as desensitization. Under physiological conditions there is striking concordance between the pulsatile secretion of LH and the glycoprotein free α-subunit (FAS). The aims of this study were to determine whether the FAS response to GnRH is also decreased at fast frequencies of GnRH stimulation and whether FAS is superior to LH as a marker of GnRH secretory activity at fast-pulse frequencies. The model of GnRH-deficient men was chosen to permit precise control of the dose and frequency of GnRH stimulation of the gonadotrope. The frequency of iv administration of GnRH to 5 GnRH-deficient men was progressively increased from every 120 to every 60 min, from 60 to 30 min, and from 30 to 15 min during three 12-h admissions, 1 week apart. The bolus dose of GnRH remained constant and was set at that dose previously shown to produce physiological concentrations and amplitudes of LH secretion and normal testosterone levels.
As the frequency of GnRH stimulation was increased, a progressive rise in mean FAS levels was noted (353 ± 13, 448 ± 42, 466± 50, and 698 ± 85 ng/L [mean ± sem] for 120, 60, 30, and 15 min intervals; P &lt; 0.005). However, normalization of mean FAS levels to account for the increase in total GnRH delivered with increasing frequencies revealed a progressive decrease in pituitary responsiveness to each GnRH bolus with increasing frequency of stimulation (353 ± 13, 224 ± 21, 117 ± 13, 87 ± 11 ng/L; P &lt; 0.001). The decrease in normalized mean levels was supported by a decrease in the FAS pulse amplitude with increasing frequency (517± 53, 365 ± 50, 176 ± 29 ng/L for 120, 60, and 30 min intervals, respectively; P &lt; 0.005).
At interpulse intervals of 120 and 60 min, there was complete concordance of LH and FAS pulses in response to GnRH. However, at the 30-min frequency FAS proved to be a better marker of GnRH with a higher true positive rate and lower number of false positives than LH (P &lt; 0.05). At all frequencies, the number of false positive pulses detected tended to be lower for FAS than for LH (P = 0.06).
From these data we conclude that FAS is subject to desensitization in response to increasing frequencies of GnRH administration in GnRH-deficient men, but is superior to LH as a surrogate marker of GnRH pulse generator activity at fast pulse frequencies.
Reactivation of Pituitary Hormone Release and Metabolic Improvement by Infusion of Growth Hormone-Releasing Peptide and Thyrotropin-Releasing Hormone in Patients with Protracted Critical Illness1
Authors: Van den Berghe Greet , Wouters Pieter , Weekers Frank , Mohan Subburaman , Baxter Robert C. , Veldhuis Johannes D. , Bowers Cyril Y. , Bouillon Roger 
Published: January 2014

Protracted critical illness is marked by protein wasting resistant to feeding, by accumulation of fat stores, and by suppressed pulsatile release of GH and TSH. We previously showed that the latter can be reactivated by brief infusion of GH-releasing peptide (GHRP-2) and TRH. Here, we studied combined GHRP-2 and TRH infusion for 5 days, which allowed a limited evaluation of the metabolic effectiveness of this novel trophic endocrine strategy.
Fourteen patients (mean ± sd age, 68 ± 11 yr), critically ill for 40 ± 28 days, were compared to a matched group of community-living control subjects at baseline and subsequently received 5 days of placebo and 5 days of GHRP-2 plus TRH (1+1μ g/kg·h) infusion in random order.
At baseline, impaired anabolism, as indicated by biochemical markers (osteocalcin and leptin), was linked to hyposomatotropism [reduced pulsatile GH secretion, as determined by deconvolution analysis, and low GH-dependent insulin-like growth factor and binding protein (IGFBP) levels]. Biochemical markers of accelerated catabolism (increased protein degradation and bone resorption) were related to tertiary hypothyroidism and the serum concentration of IGFBP-1, but not to hyposomatotropism. Metabolic markers were independent of elevated serum cortisol.
After 5 days of GHRP-2 plus TRH infusion, osteocalcin concentrations increased 19% vs. −6% with placebo, and leptin had rose 32% vs. -15% with placebo. These anabolic effects were linked to increased IGF-I and GH-dependent IGFBP, which reached near-normal levels from day 2 onward. In addition, protein degradation was reduced, as indicated by a drop in the urea/creatinine ratio, an effect that was related to the correction of tertiary hypothyroidism, with near-normal thyroid hormone levels reached and maintained from day 2 onward. Concomitantly, a spontaneous tendency of IGFBP-1 to rise and of insulin to decrease was reversed. Cortisol concentrations were not detectably altered.
In conclusion, 5-day infusion of GHRP-2 plus TRH in protracted critical illness reactivates blunted GH and TSH secretion, with preserved pulsatility, peripheral responsiveness, and feedback inhibition and without affecting serum cortisol, and induces a shift toward anabolic metabolism. This provides the first evidence of the metabolic effectiveness of short term GHRP-2 plus TRH agonism in this particular wasting condition.
Hormone Replacement Therapy Causes a Respiratory Alkalosis in Normal Postmenopausal Women1
Authors: Orr-Walker Brandon J. , Horne Anne M. , Evans Margaret C. , Grey Andrew B. , Murray M. A. F. , McNeil Alan R. , Reid Ian R. 
Published: January 2014

Menopause is associated with an increase in venous bicarbonate concentrations that is reversible with hormone replacement therapy (HRT). However, the mechanism underlying this effect is not known. To address this question, we studied the changes in acid-base indexes in the arterialized venous blood of normal postmenopausal women commencing conjugated equine estrogen (0.625 mg/day), medroxyprogesterone acetate (MPA; 5 mg/day), their combination, or placebo, in a double blind randomized controlled study over 3 months.
Serum bicarbonate concentrations decreased significantly in the groups receiving either MPA or estrogen plus MPA (P = 0.008). This trend was apparent as early as 2 days and reached 2.7 and 2.3 mmol/L in the respective groups by 3 months. Similar changes were seen with partial pressure of carbon dioxide (P = 0.04); a change of −0.7 kPa occurred in the estrogen plus MPA group at 3 months. There were no changes in bicarbonate concentrations or partial pressure of carbon dioxide in those receiving estrogen alone or placebo. Accompanying changes in blood pH were apparent in the estrogen plus MPA group, where there was an upward trend at 1 week (P = 0.056) and a significant change from baseline (+0.013) at 3 months (P = 0.03). In the whole group, the changes in pH were inversely correlated with those in urinary excretion of hydroxyproline (r = −0.44; P = 0.01).
We conclude that HRT using conjugated estrogens and MPA produces small, but sustained, changes in acid-base status. These may contribute to the effects of HRT and menopause on many tissues and disease processes, including the development of osteoporosis.
The Relation between Bone Mineral Density, Insulin-Like Growth Factor I, Lipoprotein (a), Body Composition, and Muscle Strength in Adolescent Males
Authors: Thorsen Kim , Nordström Peter , Lorentzon Ronny , Dahlén Gösta H. 
Published: January 2014

Osteoporosis is the most common metabolic bone disease. A low peak bone mass is regarded a risk factor for osteoporosis. Heredity, physical activity, and nutrition are regarded important measures for the observed variance in peak bone mass. Lp(a) lipoprotein is a well-known risk factor for atherosclerosis. Serum insulin-like growth factor I (IGF-I) has been found to be increased in males with early cardiovascular disease. In this study, we evaluated the association between bone mass, body constitution, muscle strength, Lp(a), and IGF-I in 47 Caucasian male adolescents (mean age, 16.9 yr). Bone mineral density (BMD) and body composition were measured by dual x-ray absorptiometry, muscle strength of thigh using an isokinetic dynamometer, IGF-I by RIA, and Lp(a) by enzyme-linked immunosorbent assay. IGF-I was only associated with Lp(a) (r = 0.38, P &lt; 0.01). Lp(a) was related to total body (r= 0.40, P &lt; 0.01), skull (r = 0.45, P &lt; 0.01), and femoral neck BMD (r = 0.44, P &lt; 0.01). Lp(a) was also related to fat mass (r = 0.34, P &lt; 0.05) and muscle strength (r = 0.30–0.42, P &lt; 0.05). After multiple regression and principal component (PC) analysis, the so-called PC body size (weight, fat mass, lean body mass, and muscle strength) was the most significant predictor of BMD (β = 0.28–0.51, P &lt; 0.05–0.01), followed by the so-called PC physical activity (β = 0.28–0.38, P &lt; 0.05–0.01, weight-bearing locations). However, the PC analysis confirmed that Lp(a) was an independent predictor of total body, skull, and femoral neck BMD (β = 0.33–0.36, P &lt; 0.01).The present investigation confirms that BMD, body size, and muscle strength are closely related and that the level of physical activity is a major determinant of BMD. However, the positive relation of Lp(a), a major risk factor for cardiovascular disease, to BMD has not previously been described. The importance of this observation has to be further investigated.
High Prevalence of Antineutrophil Cytoplasmic Antibody Positivity in Childhood Onset Graves’ Disease Treated with Propylthiouracil
Authors: Sato Hirokazu , Hattori Motoshi , Fujieda Mikiya , Sugihara Shigetaka , Inomata Hiroaki , Hoshi Mari , Miyamoto Shigeki 
Published: January 2014

Propylthiouracil (PTU)-induced antineutrophil cytoplasmic antibody (ANCA)-related vasculitis and nephritis were recently reported in about 30 patients with hyperthyroidism. The objective of this study was to clarify the prevalence of ANCA and the relationship between ANCA and thyroid antibodies in children with Graves’ disease.
Titers of myeloperoxidase (MPO)-ANCA in sera of 51 patients with childhood onset Graves’ disease (16 before treatment, 25 and 10 treated with PTU and methimazole, respectively) were measured by enzyme-linked immunosolvent assay. Antithyroglobulin antibodies (TGAbs) and antithyroperoxidase antibodies (TPOAbs) were also measured by RIA in 25 PTU-treated patients. No patients had clinical manifestations of vasculitis and nephritis. MPO-ANCA was positive in 6.7% of patients before treatment and in 64.0% of those treated with PTU and in none of those treated with methimazole. MPO-ANCA had a significantly positive correlation with TGAbs (P &lt; 0.05) and no significant correlation with TPOAbs.
These findings show the high prevalence of the MPO-ANCA positivity in PTU-treated childhood onset Graves’ disease, suggesting that PTU may not be preferred as the first line for the treatment of children with Graves’ disease. The significant correlation between MPO-ANCA and TGAbs indicates that the severity of Graves’ disease may be a factor responsible for the MPO-ANCA positivity. The cross-reactivity between MPO-ANCA and TPOAbs may not play a role in the high prevalence of MPO-ANCA in the patients exposed to PTU.
Adrenocorticotropin and Corticotropin-Releasing Hormone Tests in Preterm Infants1
Authors: Karlsson Riikka , Kallio Jaana , Irjala Kerttu , Ekblad Satu , Toppari Jorma , Kero Pentti 
Published: January 2014

The short ACTH test is used in evaluating the hypothalamo-pituitary-adrenal axis (HPA-axis) in preterm neonates after dexamethasone treatment. This test mainly examines primary adrenal suppression but is also used as a method to test secondary adrenal insufficiency because long-term deprivation of ACTH causes atrophy of the adrenal cortex. The CRH test, on the other hand, directly examines the function of the pituitary. We tested 18 infants in the neonatal intensive care unit with both the ACTH test and the CRH test to determine which of these two tests more reliably demonstrates HPA-axis suppression.One patient had normal responses both in the ACTH test and in the CRH test when the limit of 360 nmol/L was used as a sign of proper cortisol secretion. In four cases the patients’ cortisol secretion would have been regarded as normal by the low-dose ACTH test, whereas the CRH test did not show an adequate cortisol response.In conclusion, the ACTH test did not reliably indicate HPA-axis suppression after a short (&lt;2 weeks) course of dexamethasone therapy in this study. Therefore, whether the infant is or will be under acute stress after short glucocorticoid treatment, ensuring adequate cortisol secretion with the CRH test should be considered.
Synergistic Effects of Nateglinide and Meal Administration on Insulin Secretion in Patients with Type 2 Diabetes Mellitus
Authors: Keilson Leonard , Mather Sergio , Walter Yulia H. , Subramanian Siva , McLeod James F. 
Published: January 2014

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

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

We have recently reported a patient with a homozygous partial deletion of the insulin-like growth factor-I (IGF-I) gene, resulting in IGF-I deficiency, insulin resistance, and short stature. Recombinant human IGF-I (rhIGF-I) therapy has been shown to improve insulin sensitivity (Si) and growth in other causes of IGF-I deficiency. We now report results of 1 yr of rhIGF-I therapy on body composition, bone mineral density (BMD), insulin sensitivity, and linear growth in this patient. rhIGF-I therapy was initiated at age 16.07 yr (bone age, 14.2 yr), at a starting dose of 40 μg/kg daily, increasing after 3 months to 80μ g/kg daily. Body composition, BMD, markers of bone mineralization, and auxological parameters (height, weight) were measured at 0, 6, and 12 months after start of therapy. Si, acute insulin response to glucose, and glucose effectiveness were determined at baseline, 3 months, and 12 months into therapy. On IGF-I therapy, body mass index increased from 17 kg/m2 to 18.6 kg/m2. Body composition studies (dual-energy x-ray absorbtiometry) revealed an initial decrease in total body fat, from 19.9% at baseline to 15.1% at 6 months; but by 12 months of therapy, this had reversed, with an increase to 21.8%. Si, calculated using Bergman’s minimal model, was substantially reduced at baseline at 1.45 × 10−4 min−1 (μU/mL) [normal value, 5.1 × 10−4 min−1 (lean adult male)]. rhIGF-I therapy resulted in a dose-related improvement of Si into the normal range (NR) (rhIGF-I dose: 40 μg/kg·day, Si = 2.06 × 10−4 min−1; rhIGF-I dose: 80 μg/kg·day, Si = 4.39 × 10−4 min−1). Baseline reduction in Si was accompanied by elevated acute insulin response to glucose, which also fell in a dose-dependent manner. Baseline BMD was severely reduced when compared with age-matched controls (−4.88 sd); however, calculation of bone mineral apparent density indicated that the true reduction in BMD was minimal. rhIGF-I therapy increased BMD by 17% and bone mineral apparent density by 7%, indicating that IGF-I has a greater effect on bone growth than bone mineralization. Bone turnover markers also increased on rhIGF-I; mean serum osteocalcin: 8.3 ng/mL pretreatment, 21.7 ng/mL after 6 months of rhIGF-I (NR for adult male, 3.4–9.1 ng/mL); mean bone specific alkaline phosphatase: 36.5 U/L pretreatment, 82.2 U/L after 6 months of therapy (NR for adult male, 15–41). Height velocity increased from 3.8 cm/yr pretreatment to 7.3 cm/yr on 80 μg/kg·day of rhIGF-I.
In this patient with severe insulin resistance, therapy with rhIGF-I resulted in beneficial effects on Si, body composition, bone size, and linear growth. These results have implications for IGF-I therapy in a variety insulin resistant states.
Leptin and Aging: Correlation with Endocrine Changes in Male and Female Healthy Adult Populations of Different Body Weights
Authors: Isidori Andrea M. , Strollo Felice , Morè Michele , Caprio Massimiliano , Aversa Antonio , Moretti Costanzo , Frajese Gaetano , Riondino Giuseppe , Fabbri Andrea 
Published: January 2014

Abstract
Aging is associated with changes in plasma levels of several hormones. There are conflicting reports on whether circulating leptin levels change during aging, the possible explanation for which is that alterations in adiposity and body mass index (BMI) also occur. In this study we measured plasma leptin and other hormonal parameters known to influence leptin in 150 men and 320 women of a wide age (18–77 yr) and BMI (18.5–61.1 kg/m2) range. Subjects of each gender were separated into 2 groups of similar BMI, i.e. nonobese (BMI, &lt;30) and obese (BMI, &gt;30), and treated separately. Statistical analysis was performed, treating each group of subjects as a whole population or divided into age groups (&lt;30, 30–50, and &gt;50 yr). BMI-adjusted leptin levels were progressively lower with increasing age in women, with a consistent fall after menopause (−21%; P &lt; 0.001); in men, leptin levels also tended to be lower in subjects more than 50 yr of age, but the reduction was not significant. Multiple linear regression analysis, performed on subjects treated either as a whole population or divided into obese and nonobese, showed that in both genders BMI and age were independent contributors of leptin levels, and there was an inverse relationship between leptin and age in both obese (standardized coefficient β = −0.25 in women and −0.23 in men; P &lt; 0.01) and nonobese (−0.22 in women and −0.20 in men; P &lt; 0.05) subjects. The correlation of leptin and age with plasma levels of sex and thyroid hormones, GH, insulin-like growth factor I, PRL, and insulin was also evaluated. The variables that correlated with leptin were included in a multiple regression model that included BMI and age. Testosterone in men (−0.43 in nonobese and −0.19 in obese; P &lt; 0.05) and estradiol in women (0.22 in nonobese and 0.24 in obese; P &lt; 0.05) were important contributors to leptin levels; also, dehydroepiandrosterone sulfate in obese women (−0.16) and sex hormone-binding globulin in obese subjects of both genders (0.15 in women and 0.19 in men) were significant determinants in the model. However, none of the hormonal parameters abolished the negative correlation between leptin and age or the gender difference in leptin levels. In conclusion, our data show that in adult humans of different body weight, serum leptin gradually declines during aging; leptin reduction is higher in women than in men, but it is independent from BMI and other age-related endocrine changes.
LMNA R482Q Mutation in Partial Lipodystrophy Associated with Reduced Plasma Leptin Concentration*
Authors: Hegele Robert A. , Cao Henian , Huff Murray W. , Anderson Carol M. 
Published: January 2014

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