bluuebunny/crossref_metadata_2025 huggingface dataset:
Growth Hormone (GH) Deficiency (GHD) of Childhood Onset: Reassessment of GH Status and Evaluation of the Predictive Criteria for Permanent GHD in Young Adults
Authors: Maghnie Mohamad , Strigazzi Carolina , Tinelli Carmine , Autelli Michele , Cisternino Mariangela , Loche Sandro , Severi Francesca
Published: January 2014

GH secretion was reevaluated after completion of GH treatment at a mean age of 19.2 ± 3.2 yr in 35 young adults with childhood-onset GH deficiency (GHD). The patients were subdivided into 4 groups according to their first pituitary magnetic resonance imaging (MRI) findings: group I, 11 patients with isolated GHD (IGHD) and normal pituitary volume (280 ± 59.4 mm3); group II, 7 patients with IGHD and small pituitary gland (163.1 ± 24.4 mm3; P = 0.0009 vs. group I); group III, 13 patients (5 with IGHD and 8 with multiple pituitary hormone deficiency) with congenital hypothalamic-pituitary abnormalities such as pituitary hypoplasia (95.8 ± 39.3 mm3; P < 0.00001 vs. group I and P = 0.003 vs. group II), pituitary stalk agenesis, and posterior pituitary ectopia; and group IV, 4 patients with multiple pituitary hormone deficiency secondary to craniopharyngioma. Pituitary MRI and GH secretory status were reevaluated after GH withdrawal using arginine, insulin induced-hypoglycemia, and sequential arginine-insulin tests. Serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were determined at the time of retesting and 6, 12, and 24 months after discontinuation of treatment in the patients with permanent GHD and after 6 months in those with normal GH responses to stimulation. The patients in groups I and II showed a normal response to stimulation after completion of GH treatment regardless of pituitary size, whereas all patients in groups III and IV still had a GH response of less than 3 μg/L to any of the tests. Pituitary volume normalized in 6 of 7 patients in group II, whereas in all patients in group III MRI studies confirmed the initial findings. Mean IGF-I and IGFBP-3 concentrations at the time of retesting were significantly higher in groups I and II than in groups III and IV. In patients of groups III and IV, mean IGF-I was significantly decreased after 6 and 12 months, whereas IGFBP-3 was significantly decreased 12 months after treatment withdrawal. Our results confirm that a high proportion of children with IGHD and normal or small pituitary show normalization of GH secretion at the completion of GH treatment, whereas GHD is permanent in all patients with pituitary hypoplasia, pituitary stalk agenesis, and posterior pituitary ectopia. IGF-I and IGFBP-3 determinations shortly after GH withdrawal had limited value in the diagnosis of GHD of childhood onset associated with congenital hypothalamic-pituitary abnormalities, but became accurate after 6–12 months. We suggest that patients with GHD and congenital hypothalamic-pituitary abnormalities do not require further investigation of GH secretion, whereas patients with IGHD and normal or small pituitary gland should be retested well before the attainment of adult height.
Predictors of Chances to Conceive in Ovulatory Patients during Clomiphene Citrate Induction of Ovulation in Normogonadotropic Oligoamenorrheic Infertility1
Authors: Imani Babek , Eijkemans Marinus J. C. , te Velde Egbert R. , Habbema J. Dik F. , Fauser Bart C. J. M.
Published: January 2014

The present prospective follow-up study was designed to identify whether clinical, endocrine, or ultrasound characteristics assessed by standardized initial screening of normogonadotropic oligo/amenorrheic infertile patients could predict conception in 160 women who reached ovulation after clomiphene citrate (CC) medication. Additional inclusion criteria were total motile sperm count of the partner above 1 million and a negative history for any tubal disease. Daily CC doses of 50 mg (increasing up to 150 mg in case of absent ovarian response) from cycle days 3–7 were used. First conception (defined as a positive urinary pregnancy test) was the end point for this study. A cumulative conception rate of 73% was reached within 9 CC-induced ovulatory cycles. Patients who did conceive presented more frequently with lower age (P < 0.0001) and amenorrhea (P < 0.05) upon initial screening. In a univariate analysis, patients with elevated initial serum LH concentrations (>7.0 IU/L) had a higher probability of conceiving (P < 0.01). In a multivariate analysis, age and cycle history (oligomenorrhea vs. amenorrhea) were identified as the only significant parameters for prediction of conception.

These observations suggest that there is more to be gained from CC ovulation induction in younger women presenting with profound oligomenorrhea or amenorrhea. Screening characteristics involved in the prediction of ovulation after CC medication in normogonadotropic oligo/amenorrheic patients (body weight and hyperandrogenemia, as shown previously) are distinctly different from predictors of conception in ovulatory CC patients (age and the severity of cycle abnormality). This disparity suggests that the FSH threshold (magnitude of FSH required for stimulation of ongoing follicle growth and ovulation) and oocyte quality (chances for conception in ovulatory cycles) may be differentially regulated.
Severity of Osteopenia in Estrogen-Deficient Women with Anorexia Nervosa and Hypothalamic Amenorrhea1
Authors: Grinspoon Steven , Miller Karen , Coyle Caryn , Krempin Judy , Armstrong Catharina , Pitts Sarah , Herzog David , Klibanski Anne
Published: January 2014

Reduced bone density is observed in over half of women with anorexia nervosa (AN), in whom the risk of fracture is significantly increased even at a young age. It is unknown to what extent low bone density in AN differs from other conditions of premenopausal osteoporosis and is related to estrogen deficiency and/or other factors, such as nutritional status. We therefore investigated bone loss in nutritionally replete and nutritionally deplete amenorrheic women by comparing patients with AN (n = 30) to age-matched subjects with hypothalamic amenorrhea (HA; n = 19) in whom duration of amenorrhea, prior estrogen use, and age of menarche were comparable. Healthy, age-matched, eumenorrheic women were studied as a control group (NL; n = 30). Weight and nutritionally dependent factors including (body mass index, 20.7 ± 0.3 vs. 16.7 ± 0.3 kg/m2; P < 0.0001), insulin-like growth factor I (270 ± 18 vs. 203 ± 17 ng/mL; P < 0.01), percent body fat (26% vs. 19%; P < 0.0001), and lean body mass (38.7 ± 1.1 vs. 34.3 ± 0.8, P < 0.01) were significantly different between the HA and AN groups, respectively. The bone densities of the anterior-posterior (AP) spine, total hip, and total body measured by dual energy x-ray absortiometry were reduced in both amenorrheic groups compared to those in control subjects, but were significantly lower in women with AN than in those with HA. The t scores for AP spine and hip were −1.80 ± 0.15 (AN), −0.80 ± 0.22 (HA), and 0.28 ± 0.19 sd (NL) for the AP spine and −1.62 ± 0.17 (AN), −0.51 ± 0.21 (HA), and 0.25 ± 0.16 (NL) for the total hip, respectively (P < 0.01 for all comparisons). Among the amenorrheic subjects, duration of amenorrhea, age of menarche, and N-telopeptide were inversely correlated with bone density at all sites, whereas body mass index, insulin-like growth factor I, lean body mass, and fat intake were positively correlated with bone density at all sites measured. In multivariate regression analyses, bone density was most significantly related to lean body mass (P= 0.05 and P = 0.03 for the spine and hip, respectively), but not to the duration of amenorrhea or other indexes of estrogen status among patients with AN. In contrast, bone density of the lumbar spine was significantly related to weight and duration of amenorrhea among patients with HA. These data demonstrate that the severity of osteopenia in AN is greater than that in patients with HA and is critically dependent upon nutritional factors in addition to the degree or duration of estrogen deficiency itself. Lean body mass, independent of the duration or severity of estrogen deficiency, is an important predictor of bone loss among women with AN.
Sulfate Transport Is Not Impaired in Pendred Syndrome Thyrocytes
Authors: Kraiem Z. , Heinrich R. , Sadeh O. , Shiloni E. , Nassir E. , Hazani E. , Glaser B.
Published: January 2014

Pendred syndrome is the most common form of syndromic deafness, characterized by dyshormonogenic goiter associated with sensory-neural deafness. The gene responsible for the disease (PDS) has been cloned, but its function is as yet unknown and the connection between thyroid goiter and sensory-neural deafness remains an enigma. PDS codes for a novel protein, pendrin, which is closely related to a number of sulfate transporters. Mechanisms by which abnormal sulfate transport could deleteriously affect iodide organification have been proposed. We tested sulfate transport in thyrocytes obtained from Pendred syndrome patients and found that it was not defective. This suggests that pendrin in fact may not be a sulfate transporter, and emphasizes the importance of functional studies on this novel protein.
Neuroendocrine Processes Underlying Ultradian Sleep Regulation in Man
Authors: Gronfier Claude , Simon Chantal , Piquard François , Ehrhart Jean , Brandenberger Gabrielle
Published: January 2014

Sleep is not a uniform state but is characterized by the cyclic alternation between rapid eye movement (REM) and non-REM sleep with a periodicity of 90–110 min. This cycle length corresponds to one of the oscillations in electroencephalographic (EEG) activity in the delta frequency band (0.5–3.5 Hz), which reflect the depth of sleep. To demonstrate the intimate link between EEG and neuroendocrine rhythmic activities in man, we adopted a procedure permitting simultaneous analysis of sleep EEG activity in the delta band and of two activating systems: the adrenocorticotropic system and the autonomic nervous system. Adrenocorticotropic activity was evaluated by calculating the cortisol secretory rate in blood samples taken at 10-min intervals. Autonomic activity was estimated by two measures of heart rate variability: 1) by the ratio of low-frequency (LF) to high-frequency (HF) power from spectral analysis of R-R intervals; and 2) by the interbeat autocorrelation coefficient of R-R intervals (rRR intervals between two successive cardiac beats).

The results revealed that oscillations in delta wave activity, adrenocorticotropic activity, and autonomic activity are linked in a well-defined manner. Delta wave activity developed when cortisol secretory rates had returned to low levels and sympathetic tone was low or decreasing, as reflected by a low LF/HF ratio and by low levels in rRR. Conversely, the decrease in delta wave activity occurred together with an increase in the LF/HF ratio and in rRR. REM sleep was associated with a decrease in cortisol secretory rates preceding REM sleep onset, whereas the LF/HF ratio and rRR remained high.

These results demonstrate a close coupling of adrenocorticotropic, autonomic, and EEG ultradian rhythms during sleep in man. They suggest that low neuroendocrine activity is a prerequisite for the increase in slow wave activity.
Short-Term Oxandrolone Administration Stimulates Net Muscle Protein Synthesis in Young Men1
Authors: Sheffield-Moore Melinda , Urban Randall J. , Wolf Steven E. , Jiang J. , Catlin Don H. , Herndon David N. , Wolfe Robert R. , Ferrando Arny A.
Published: January 2014

Short term administration of testosterone stimulates net protein synthesis in healthy men. We investigated whether oxandrolone[ Oxandrin (OX)], a synthetic analog of testosterone, would improve net muscle protein synthesis and transport of amino acids across the leg. Six healthy men [22 ± 1 (±se) yr] were studied in the postabsorptive state before and after 5 days of oral OX (15 mg/day). Muscle protein synthesis and breakdown were determined by a three-compartment model using stable isotopic data obtained from femoral arterio-venous sampling and muscle biopsy. The precursor-product method was used to determine muscle protein fractional synthetic rates. Fractional breakdown rates were also directly calculated. Total messenger ribonucleic acid (mRNA) concentrations of skeletal muscle insulin-like growth factor I and androgen receptor (AR) were determined using RT-PCR. Model-derived muscle protein synthesis increased from 53.5 ± 3 to 68.3 ± 5 (mean ± se) nmol/min·100 mL/leg (P < 0.05), whereas protein breakdown was unchanged. Inward transport of amino acids remained unchanged with OX, whereas outward transport decreased (P < 0.05). The fractional synthetic rate increased 44% (P < 0.05) after OX administration, with no change in fractional breakdown rate. Therefore, the net balance between synthesis and breakdown became more positive with both methodologies (P < 0.05) and was not different from zero. Further, RT-PCR showed that OX administration significantly increased mRNA concentrations of skeletal muscle AR without changing insulin-like growth factor I mRNA concentrations. We conclude that short term OX administration stimulated an increase in skeletal muscle protein synthesis and improved intracellular reutilization of amino acids. The mechanism for this stimulation may be related to an OX-induced increase in AR expression in skeletal muscle.
Asynchronous Development of Bilateral Nodular Adrenal Hyperplasia in Gastric Inhibitory Polypeptide-Dependent Cushing’s Syndrome1
Authors: N’Diaye Nina , Hamet Pavel , Tremblay Johanne , Boutin Jean-Marie , Gaboury Louis , Lacroix André
Published: January 2014

Gastric inhibitory polypeptide (GIP)-dependent Cushing’s syndrome has been reported to occur either in unilateral adrenal adenoma or in bilateral macronodular adrenal hyperplasia. A 33-yr-old woman with Cushing’s syndrome was found to have two 2.5- to 3-cm nodules in the right adrenal on computed tomography scan; the left adrenal appeared normal except for the presence of a small 0.8 × 0.6-cm nodule. Uptake of iodocholesterol was limited to the right adrenal. Plasma morning cortisol was 279 nmol/L fasting and 991 nmol/L postprandially, and ACTH remained suppressed. Plasma cortisol increased after oral glucose (202%) or a lipid-rich meal (183%), but not after a protein-rich meal (95%) or iv glucose (93%); the response to oral glucose was blunted by pretreatment with 100 μg octreotide, sc. Plasma cortisol and GIP levels were positively correlated (r = 0.95; P = 0.0001); cortisol was stimulated by the administration of human GIP iv (225%), but not by GLP-1, insulin, TRH, GnRH, glucagon, arginine vasopressin, upright posture, or cisapride orally. A right adrenalectomy was performed; GIP receptor messenger ribonucleic acid was overexpressed in both adrenal nodules and in the adjacent cortex. Histopathology revealed diffuse macronodular adrenal hyperplasia without internodular atrophy. Three months after surgery, fasting plasma ACTH and cortisol were suppressed, but cortisol increased 3.6-fold after oral glucose, whereas ACTH remained suppressed; this was inhibited by octreotide pretreatment, suggesting that cortisol secretion by the left adrenal is also GIP dependent. We conclude that GIP-dependent nodular hyperplasia can progress in an asynchronous manner and that GIPR overexpression is an early event in this syndrome.
Low- Versus High-Dose Radiotherapy for Graves’ Ophthalmopathy: A Randomized, Single Blind Trial
Authors: Kahaly George J. , Rösler Hans-Peter , Pitz Susanne , Hommel Gerhard
Published: January 2014

Orbital radiotherapy (Rx) is a commonly used treatment for Graves’ ophthalmopathy (GO), but controlled clinical trials evaluating different Rx doses and application forms have not been performed. In euthyroid patients with moderately severe GO, we randomly compared the efficacy and tolerability of three Rx protocols. Orbital Rx (telecobalt) was administered either in 20 divided fractions of 1 Gray (Gy) weekly over 20 weeks (group A) or in 10 fractions of 1 Gy (B) and 2 Gy (C) daily over 2 weeks. Before and 24 weeks after starting Rx, ophthalmic investigation and magnetic resonance imaging were performed. Response to therapy, defined as a significant amelioration of three objective parameters, was noted in 12 A (67%), 13 B (59%), and 12 C (55%) subjects (C vs. A, P = 0.007). Ophthalmic symptoms and signs regressed most in group A; changes in lid fissure width were −1.5, −0.5, and 0 mm in the A, B, and C groups, respectively (A vs. C, P = 0.005), whereas changes in intraocular pressure (upgaze) were −3, +1, and −1.5 mm Hg, respectively (A vs. B, P = 0.002). The median decreases in proptosis were −2 mm (A, P = 0.0001),− 1.5 mm (B, P = 0.02), and −1 mm (C, P = 0.007; A vs. C, P = 0.0380. Visual acuity (+0.15; P = 0.02) and eye muscle motility (bulbar elevation, 30° vs. 37°, P = 0.03, A vs. C, P = 0.0020; abduction, 45 vs. 49°, P = 0.02; A vs. C, P = 0.017) improved in group A only. A significant change in all rectus muscle areas was noted in 14 A (78%), 12 B (55%), and 9 C (41%) subjects (C vs. A, P = 0.002). A decrease in the NOSPECS classes was observed in 12 A (67%), 13 B (59%), and 13 C (59%) patients (A vs. B/C, P = 0.01). Rx-induced conjunctivitis was not observed in group A, but was seen in 4 B (18%) and 8 C (36%) subjects (C vs. A, P= 0.003). At 24 weeks, satisfaction rates were 67%, 59%, and 55% in the A, B, and C groups, respectively (C vs. A, P = 0.008). Thus, in patients with moderately severe GO, similar response rates were observed for low and high Rx doses, but the 1 Gy/week protocol was more effective and better tolerated than the short arm regimens.
Antifracture Efficacy of Antiresorptive Agents Are Related to Changes in Bone Density
Authors: Wasnich Richard D. , Miller Paul D.
Published: January 2014

There is a current debate about the extent to which antifracture efficacy of antiresorptive drugs are related to changes in bone mineral density (BMD). In vitro studies show that most of the variability in bone strength is related to BMD, and prospective studies have shown that low BMD is an important predictor of fracture risk. It seems that higher levels of bone turnover are also associated with increased fracture risk. Over the short term, a reduction in activation frequency or resorption depth would lead to fewer (and/or shallower) resorption sites and refilling of existing sites initially. There is also evidence that inhibiting resorption allows bone to respond to mechanical demands, preferentially thickening critical trabeculae, and this may help compensate for reduced connectivity. Each of these mechanisms would increase BMD and would disproportionately improve bone strength. Over the long term, maintaining bone mass and preventing loss of structural elements would result in progressively greater differences in BMD and fracture risk over time, relative to untreated women. The conceptual model predicts that both the short- and long-term antifracture efficacy of antiresorptive drugs will depend on the extent to which treatment can increase and maintain BMD. To examine this issue, we compiled data from clinical trials of antiresorptive agents and plotted the relative risk of vertebral fractures against the average change in BMD for each trial. The confidence intervals are large for individual trials, and there was substantial variability in antifracture efficacy at any given level of change in BMD. Overall, however, trials that reported larger increases in BMD tended to observe greater reductions in vertebral fracture risk. Poisson regression was used to quantify this relationship. The model predicts that treatments that increase spine BMD by 8% would reduce risk by 54%; most of the total effect of treatment was explained by the 8% increase in BMD (41% risk reduction). These findings are consistent with the short-term predictions of the conceptual model and with reports from randomized trials. The small but significant reductions in risk that were not explained by measurable changes in BMD might be related to publication bias, measurement errors, or limitations of current BMD technology.
The Desmopressin Test in the Differential Diagnosis between Cushing’s Disease and Pseudo-Cushing States
Authors: Moro Mirella , Putignano Pietro , Losa Marco , Invitti Cecilia , Maraschini Caterina , Cavagnini Francesco
Published: January 2014

Differentiating Cushing’s disease (CD) from pseudo-Cushing (PC) states may still be difficult in current practice. Because desmopressin (1-deamino-8D-arginine vasopressin, DDAVP), a vasopressin analogue, stimulates ACTH release in patients with CD but not in the majority of normal, obese, and depressed subjects, we investigated its ability to discriminate CD from PC states. One hundred seventy-three subjects (76 with active CD, 30 with PC, 36 with simple obesity, and 31 healthy volunteers) were tested with an iv bolus of 10 μg DDAVP. Sixty-one of these subjects also underwent a control study with saline. DDAVP induced marked ACTH and cortisol rises in CD (P < 0.005 vs. saline, for both ACTH and cortisol) but not in PC. A significant ACTH elevation occurred upon DDAVP administration also in normal and obese subjects, but it was much smaller than that observed in patients with CD (P < 0.0001). A peak absolute ACTH increase (≥6 pmol/L), after DDAVP, allowed us to recognize 66 of 76 patients with CD and 88 of 97 subjects of the other groups. The same criterion correctly identified 18 of 20 patients with mild CD (24-h urinary free cortisol ≤ 690 nmol/day) and 29 of 30 PC, resulting in a diagnostic accuracy of 94%, which was definitely higher than that displayed by urinary free cortisol, overnight 1-mg dexamethasone suppression test, and midnight plasma cortisol. In conclusion, the DDAVP test seems to be a useful adjunctive tool for the evaluation of hypercortisolemic patients chiefly because of its ability to differentiate mild CD from PC states.
Circulating Thyrotropin Bioactivity in Sporadic Central Hypothyroidism1
Authors: Persani Luca , Ferretti Elisabetta , Borgato Stefano , Faglia Giovanni , Beck-Peccoz Paolo
Published: January 2014

The etiopathogenesis of sporadic central hypothyroidism (CH) involves pituitary and hypothalamic lesions. Pituitary CH (pCH) implies a diminished number of functioning thyrotropes, accounting for the quantitative impairment of TSH secretion. Hypothalamic CH (hCH) is characterized by normal or even increased TSH concentrations and qualitative abnormalities of TSH secretion, including a decreased bioactivity of circulating TSH. However, controversy still exists about the actual occurrence of bioinactive TSH among CH patients, and no data are available in pCH. Therefore, we studied 41 CH patients with different hypothalamic-pituitary disorders. Immunoreactive TSH (TSH-I) ranged from 0.08–11.1 mU/L (normal, 0.24–4.0), free T4 (FT4) ranged from 0.6–8.8 pmol/L (normal, 9–18), and FT3 ranged from 1.2–5.4 pmol/L (normal, 4–8). A blunted TSH response to TRH (<4 mU/L), indicating prevalent pCH, was found in 56% of the patients, and a net TSH-I increment ≥4 mU/L, indicating prevalent hCH, was found in the remaining 44%. Net TSH-I increments showed significant correlation with basal FT4 (P < 0.02), indicating the relevance of pituitary TSH reserve in the pathogenesis of CH. Circulating TSH was immunoconcentrated and tested in bioassay and in ricin affinity chromatography. The ratio between biological (B) and immunological (I) activities of circulating TSH was reduced (n = 25; TSH B/I, 0.38 ± 0.19) compared to the values recorded in normal subjects (n = 26; TSH B/I, 1.53 ± 0.54; P < 0.001) and primary hypothyroid patients (n = 24; TSH B/I, 0.74 ± 0.31; P < 0.001), but no difference between pCH (n = 9; 0.36 ± 0.16) and hCH (n = 16; 0.39 ± 0.20) was seen. TSH B/I values in CH patients showed a limited overlap with normal values (20%) and a highly significant correlation with the FT3 response to endogenous TRH-stimulated TSH (P < 0.005). The elevated sialylation degree of TSH molecules may explain part of these findings.

In conclusion, the secretion of TSH molecules with reduced bioactivity is a common alteration in the patients with hypothalamic-pituitary lesions, contributing along with the impairment of pituitary TSH reserve to the pathogenesis of CH.
The Effect of Droloxifene and Estrogen on Thyroid Function in Postmenopausal Women1
Authors: Marqusee Ellen , Braverman Lewis E. , Lawrence Jennifer E. , Carroll Judith S. , Seely Ellen W.
Published: January 2014

Estrogen is known to increase serum T4-binding globulin (TBG) concentrations, thereby increasing serum total T4 concentrations. Serum free T4 concentrations, however, remain normal. Tamoxifen, a selective estrogen receptor modifier (SERM), also raises serum TBG concentrations, but whether newer SERMs with less stimulatory action on the endometrium do so is not known. We, therefore, compared the effect of droloxifene, a SERM, and conjugated equine estrogen on pituitary-thyroid function in normal postmenopausal women.

Ten women were treated for 6 weeks with conjugated estrogen (Premarin), 0.625 mg/day, and droloxifene, 60 mg/day, in a double-blind crossover study with an intervening 4-week no-treatment period. We measured serum T4, T3, TBG, free T4 index, and TSH at baseline and at the end of each 6-week period. The baseline values were compared with the 6-week values using paired t tests.

The mean (±sd) serum TBG concentrations increased significantly during both treatment periods (baseline, 1.5 ± 0.4 mg/dL; conjugated estrogens, 2.7 ± 0.6 mg/dL; droloxifene, 2.1 ± 0.6 mg/dL; P < 0.001 and P= 0.001, respectively). There were no significant changes in the serum free T4 index. Serum T4 and T3 concentrations increased during both treatment periods, however, the increase was significant only for T4 during the conjugated estrogen treatment period. The serum TSH concentrations increased significantly during both treatment periods (18% during conjugated estrogen and 11% during droloxifene), and the values remained within the normal range in all women.

Administration of both conjugated estrogen and droloxifene for 6 weeks increases serum TSH and TBG concentrations, but does not alter free T4 index values in postmenopausal women.
Formation of Proinflammatory Cytokines in Human Term Myometrium Is Stimulated by Lipopolysaccharide But Not by Corticotropin-Releasing Hormone1
Authors: Sehringer Bernd , Schäfer Wolfgang R. , Wetzka Birgit , Deppert Wolfgang R. , Brunner-Spahr Ralph , Benedek Eszter , Zahradnik Hans Peter
Published: January 2014

Human term myometrium is poorly characterized as a source of proinflammatory mediators involved in parturition. We have investigated the basal expression of cytokines in myometrium, as well as the effects of CRH and lipopolysaccharide (LPS) on cytokine release.

Explants from term myometrium were challenged with CRH or LPS (1μ g/mL each) in short-term tissue culture. Interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)α concentrations in the medium were quantified by enzyme immunoassay. The major cytokines released after 24 h were IL-6 and IL-8. All cytokines investigated were stimulated significantly by LPS (P < 0.05) but not by CRH. Messenger RNA levels of these cytokines were investigated by RT-PCR. IL-1β and IL-6 messenger RNA were present in preterm and term myometrium before and during labor, whereas IL-8 and TNFα were expressed only by myometrium in active labor. Furthermore, myometrial CRH receptors and macrophages were characterized immunohistochemically.

We conclude that human term myometrium is a site of production of proinflammatory cytokines and is involved in the inflammation-like reactions mediating the birth process. Cytokine release in term myometrium seems not to be under control of CRH.
The Transforming Growth Factor-β Superfamily Cytokine Macrophage Inhibitory Cytokine-1 Is Present in High Concentrations in the Serum of Pregnant Women1
Authors: Moore A. G. , Brown D. A. , Fairlie W. D. , Bauskin A. R. , Brown P. K. , Munier M. L. C. , Russell P. K. , Salamonsen L. A. , Wallace E. M. , Breit S. N.
Published: January 2014

Macrophage inhibitory cytokine-1 (MIC-1) is a recently described divergent member of the transforming growth factor-β superfamily. MIC-1 transcription up-regulation is associated with macrophage activation, and this observation led to its cloning. Northern blots indicate that MIC-1 is also present in human placenta. A sensitive sandwich enzyme-linked immunosorbent assay for the quantification of MIC-1 was developed and used to examine the role of this cytokine in pregnancy. High levels of MIC-1 are present in the sera of pregnant women. The level rises substantially with progress of gestation. MIC-1 can also be detected, in large amounts, in amniotic fluid and placental extracts. In addition, the BeWo placental trophoblastic cell line was found to constitutively express the MIC-1 transcript and secrete large amounts of MIC-1. These findings suggest that the placental trophoblast is a major source of the MIC-1 present in maternal serum and amniotic fluid. We suggest that MIC-1 may promote fetal survival by suppressing the production of maternally derived proinflammatory cytokines within the uterus.
Insulin Regulation of Human Hepatic Growth Hormone Receptors: Divergent Effects on Biosynthesis and Surface Translocation1
Authors: Leung Kin-Chuen , Doyle Nathan , Ballesteros Mercedes , Waters Michael J. , Ho Ken K. Y.
Published: January 2014

Insulin modulates the biological actions of GH, but little is known about its effect on human hepatic GH receptors (GHRs). Using the human hepatoma cell line HuH7 as a model, we investigated insulin regulation of total, intracellular, and cell surface GHRs and receptor biosynthesis and turnover. Insulin up-regulated total and intracellular GHRs in a concentration-dependent manner. It increased surface GHRs in a biphasic manner, with a peak response at 10 nmol/L, and modulated GH-induced Janus kinase-2 phosphorylation in parallel with expression of surface GHRs. The abundance of GHR messenger ribonucleic acid and protein, as assessed by RT-PCR and Western analysis, respectively, markedly increased with insulin treatment. To examine whether insulin regulates GHRs at the posttranslational level, its effects on receptor surface translocation and internalization were investigated. Insulin suppressed surface translocation in a concentration-dependent manner, whereas internalization was unaffected. Moreover, insulin actions on total GHRs and surface translocation were inhibited by PD98059 and wortmannin, respectively. In conclusion, insulin regulates hepatic GHR biosynthesis and surface translocation in a reciprocal manner, with surface receptor availability the net result of the divergent effects. The divergent actions of insulin appear to be mediated by the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways, respectively.
Decreased Prorenin Processing Develops before Autonomic Dysfunction in Type 1 Diabetes1
Authors: Hoeldtke Robert D. , Bryner Kimberly D. , Komanduri Padma , Christie Ian , Ganser Gary , Hobbs Gerald R.
Published: January 2014

It is well documented that diabetic patients with chronic complications have decreased renin secretion and elevations in the renin precursor prorenin. It is uncertain, however, whether the abnormal processing of prorenin is reflective of microvascular disease, hypertension, or autonomic neuropathy. Dechaux et al. (Transplant Proc. 18:1598–1599, 1986) observed abnormalities in prorenin processing in uncomplicated diabetes and suggested that it was the result of subclinical autonomic neuropathy. To test this hypothesis, we measured renin, prorenin, and autonomic function in early type 1 diabetes at a time when there is little or no microvascular disease or hypervolemia. Thirty-seven patients (10 males, 27 females) enrolled 2–22 months after diagnosis in a longitudinal study in which renin, prorenin, and autonomic function were measured annually for 3 years. Forty-one age-matched control subjects were also studied.

PRA in the diabetic patients at the time of the second and third evaluations was 1.71 ± 0.24 ng angiotensin I/mL·h and 1.67± 0.24 ng angiotensin I/mL·h, respectively, significantly lower (P < 0.05) than that of the control subjects in whom PRA was 2.96 ± 0.38 ng angiotensin I/mL·h. Prorenin was not different in the diabetic patients in comparison with controls. The renin to prorenin ratio in the diabetic patients at the time of the first, second, and third evaluations was 0.260 ± 0.03, 0.235± 0.05, and 0.227 ± 0.05, respectively, significantly lower (P < 0.01) than in control subjects in whom the renin to prorenin ratio was 0.475 ± 0.08. Despite this, at the time of the first and second evaluations, there was no evidence of autonomic dysfunction and no correlation between any test of autonomic function and the renin to prorenin ratio. At the time of the third evaluation, however, the intermediate frequency (0.04–0.15 Hz) power spectra while patients were supine (an index of sympathetic modulation of heart rate variability) showed a highly significant (P < .001) correlation with the renin to prorenin ratio. High frequency (0.15–0.40 Hz) spectra from supine patients at the third evaluation also correlated with the renin to prorenin ratio (P < 0.01).

We conclude abnormal processing of prorenin develops in diabetic patients prior to microvascular disease, even before the first evidence of autonomic dysfunction. Although the latter may play a contributory role, additional as yet unidentified mechanisms seem to interrupt the processing of prorenin in early diabetes.
Tissue Iodine Content and Serum-Mediated 125I Uptake-Blocking Activity in Breast Cancer*
Authors: Kilbane M. T. , Ajjan R. A. , Weetman A. P. , Dwyer R. , McDermott E. W. M. , O’Higgins N. J. , Smyth P. P. A.
Published: January 2014

In the thyroid, active transport of iodide is under control of the TSH-dependent Na+/I− symporter (NIS), whereas in the breast such control is less well understood. In this study, NIS expression was demonstrated by RT-PCR in 2 of 2 fibroadenomata and 6 of 7 breast carcinoma messenger ribonucleic acid isolates. In addition, mean total tissue iodine levels of 80.9 ± 9.5 ng I/mg protein in 23 benign tumors (fibroadenomata) were significantly higher than those in 19 breast cancers taken from either the tumor (18.2 ± 4.6 ng I/mg) or morphologically normal tissue taken from within the tumor-bearing breast (31.8 ± 4.9 ng I/mg; P< 0.05 in each case). Inhibition of 125I uptake into NIS-transfected CHO cells was observed in serum from 20 of 105 (19.0%) breast carcinoma, 8 of 49 (16.3%) benign breast disease, and 27 of 86 (31.4%) Graves’ patients, but in only 1 of 33 (3.0%) age-matched female controls. IgG purified from serum of patients showing positive 125I uptake inhibition also inhibited iodide uptake, suggesting that such inhibition was antibody mediated. 125I uptake inhibition was significantly associated with thyroid peroxidase antibody positivity (P < 0.05) in sera from breast cancer patients, but not in those with benign breast disease, once again suggesting an association between thyroid autoimmunity and breast carcinoma.
Glucose Metabolism Rather Than Insulin Is a Main Determinant of Leptin Secretion in Humans
Authors: Wellhoener Peter , Fruehwald-Schultes Bernd , Kern Werner , Dantz Dorle , Kerner Wolfgang , Born Jan , Fehm Horst L. , Peters Achim
Published: January 2014

Circulating plasma insulin and glucose levels are thought to be major regulators of leptin secretion. There is evidence from in vitro and animal experiments that glucose metabolism rather than insulin alone is a main determinant of leptin expression. Here, we tested the hypothesis that in humans also leptin secretion is primarily regulated by glucose uptake and only secondarily by plasma insulin and glucose. In 30 lean and healthy men we induced 4 experimental conditions by using the blood glucose clamp technique. A total of 60 hypoglycemic and euglycemic clamps, lasting 6 h each, were performed. During these clamps insulin was infused at either high (15.0 mU/min·kg) or low (1.5 mU/min·kg) rates, resulting in low-insulin-hypo, high-insulin-hypo, low-insulin-eu, and high-insulin-eu conditions. Serum leptin increased from 0–360 min by 20.5 ± 4.1% in the low-insulin-hypo, 33.6 ± 7.6% in the high-insulin-hypo, 39.6 ± 6.0% in the low-insulin-eu, and 60.4 ± 7.6% in the high-insulin-eu condition. Multiple regression analysis revealed a significant effect of circulating insulin (low vs. high insulin; P = 0.001) and blood glucose (hypoglycemia vs. euglycemia; P = 0.001) on the rise of serum leptin. However, when the total amount of dextrose infused during the clamp (grams of dextrose per kg BW) was included into the regression model, this variable was significantly related to the changes in serum leptin (P = 0.001), whereas circulating insulin and glucose had no additional effect. These findings in humans support previous in vitro data that leptin secretion is mainly related to glucose metabolism.
Progesterone Exposure Prevents Matrix Metalloproteinase-3 (MMP-3) Stimulation by Interleukin-1α in Human Endometrial Stromal Cells1
Authors: Keller Nancy R. , Sierra-Rivera Elaine , Eisenberg Esther , Osteen Kevin G.
Published: January 2014

Suppression of endometrial matrix metalloproteinases (MMPs) is necessary to maintain tissue stability during the invasive events of implantation and placental development. Several laboratories have shown that inflammatory cytokines, including interleukin-1α (IL-1α), can oppose progesterone suppression of MMPs in the human endometrium. Furthermore, we have recently demonstrated colocalization of epithelial cell IL-1α and MMP-7 expression at sites of ectopic pregnancy. The current study extends these findings, revealing a previously unrecognized interrelationship between progesterone and IL-1α in regulation of MMP-3. Although IL-1α is a potent stimulator of MMP-3 in proliferative phase endometrium in organ culture, we demonstrate that progesterone exposure in vivo reduces IL-1α stimulation of MMP-3 in secretory phase tissue. This loss of sensitivity to IL-1α was duplicated in isolated stromal cells treated with progesterone in vitro, and IL-1α stimulation of MMP-3 returned in a dose-dependent manner with progesterone withdrawal. The antiprogestin, onapristone, partially blocked the ability of progesterone to prevent stimulation of MMP-3 by IL-1α. These data suggest a novel mechanism by which progesterone may preserve tissue integrity during the establishment and maintenance of pregnancy by limiting stimulation of MMPs by inflammatory cytokines such as IL-1α.
The Severity of Chronic Heart Failure due to Coronary Artery Disease Predicts the Endocrine Effects of Short- Term Growth Hormone Administration1
Authors: Osterziel Karl Josef , Blum Werner F. , Strohm Oliver , Dietz Rainer
Published: January 2014

Treatment with human recombinant GH has yielded conflicting results in patients with heart failure. As GH sensitivity may be important for treatment effects, the present study evaluated GH secretion and sensitivity in noncachectic patients with ischemic heart failure. Twenty clinically stable, male patients with moderate heart failure (mean New York Heart Association class, 2.0 ± 0.8; mean ejection fraction, 30.0 ± 8.4%) due to coronary artery disease were randomly assigned single blind to a low dose (group A; n = 10) and a high dose (group B; n = 10) group, receiving either 5μ g/kg·day recombinant human GH for 4 days followed by 10μ g/kg·day GH for another 4 days or 10 and 20 μg/kg·day GH, respectively. Cardiac function was assessed by echocardiography. Serum insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), and 24-h urinary GH excretion as a measure of pituitary GH secretion were determined at baseline and on days 5 and 9. Baseline IGF-I and IGFBP-3 levels and GH excretion were significantly diminished compared to those in age-matched controls. There was a dose-dependent increase in IGF-I and IGFBP-3 during GH treatment. The increase in IGF-I induced by 10 μg/kg·day GH correlated positively to left ventricular ejection fraction (r = 0.59; P = 0.006) and inversely to left ventricular end-diastolic and end-systolic dimensions (r < –0.6 and P < 0.01 for both). In conclusion, GH secretion and serum levels of IGF-I and IGFBP-3 are diminished in patients with moderate ischemic heart failure. Left ventricular function determines the sensitivity of the GH/IGF-I system, measured as the IGF-I response to GH application. This finding suggests that individual dose adjustments may be an indispensable prerequisite for successful GH therapy in heart failure.
Expression of Leptin Receptor in Human Endometrium and Fluctuation during the Menstrual Cycle
Authors: Kitawaki Jo , Koshiba Hisato , Ishihara Hiroaki , Kusuki Izumi , Tsukamoto Katsumi , Honjo Hideo
Published: January 2014

Leptin is secreted by adipocytes and regulates appetite through interaction with hypothalamic leptin receptors (OB-R). Accumulated evidence shows that leptin is involved in the stimulation of reproductive functions and that local expression of leptin and OB-R in the ovary, oocyte, embryo, and placenta plays a role in early development. To investigate the role of leptin in implantation, we examined the expression of OB-R and leptin in the human endometrium. Northern and Western blot analyses and RT-PCR showed that the long form of OB-R (OB-RL) messenger ribonucleic acid (mRNA) and protein were expressed. In contrast, leptin mRNA or protein was not detected. All of the splice variants of OB-R (OB-RT) and OB-RL transcripts were expressed in 90% and 84% of the cases, respectively. OB-R mRNA expression peaked in the early secretory phase. Decidual tissue of early gestation also expressed OB-RT and OB-RL. Their incidence and abundance were comparable among endometria with benign uterine diseases and disease-free endometria and were not related to a body mass index within the normal range. The present results indicate that OB-R, but not leptin, is expressed in the human endometrium.
The Plasma Levels of Dehydroepiandrosterone Sulfate Are Decreased in Patients with Chronic Heart Failure in Proportion to the Severity*
Authors: Moriyama Yasushi , Yasue Hirofumi , Yoshimura Michihiro , Mizuno Yuji , Nishiyama Koichi , Tsunoda Ryusuke , Kawano Hiroaki , Kugiyama Kiyotaka , Ogawa Hisao , Saito Yoshihiko , Nakao Kazuwa
Published: January 2014

Dehydroepiandrosterone sulfate (DHEAS) is the major secretory steroid of the human adrenal glands. The secretion of DHEAS decreases with aging. The incidence of heart failure also rises in the elderly population. We measured the plasma levels of DHEAS and cortisol in 49 patients with chronic heart failure (CHF) and 32 age-matched controls and assessed its relation to plasma levels of A-type natriuretic peptide and B-type natriuretic peptide, biochemical markers of heart failure. Plasma levels of DHEAS were significantly lower in patients with CHF than in controls, whereas there was no significant difference in plasma levels of cortisol between the two groups. In stepwise regression analysis, the plasma level of DHEAS was significantly and independently correlated with age (β = −0.451; P < 0.0001) and the plasma level of B-type natriuretic peptide (β = −0.338; P < 0.001), and the plasma cortisol/DHEAS ratio was significantly and independently correlated with the plasma levels of A-type natriuretic peptide (β = 0.598; P < 0.0001) and thiobarbituric acid-reactive substances (a marker of oxidative stress;β = 0.252; P < 0. 01) and age (β = 0.171; P < 0.05). These results indicate that the plasma levels of DHEAS are decreased in patients with CHF in proportion to its severity and that oxidative stress is associated with decreased levels of DHEAS in patients with CHF.
Cytokine Gene Polymorphisms in Autoimmune Thyroid Disease
Authors: Hunt P. J. , Marshall S. E. , Weetman A. P. , Bell J. I. , Wass J. A. H. , Welsh K. I.
Published: January 2014

Susceptibility to the autoimmune thyroid diseases, Graves’ disease (GD) and autoimmune hypothyroidism (AIH), depends on a complex interaction between environmental and genetic factors. The human leukocyte antigen and cytotoxic T lymphocyte-associated-4 regions appear to influence susceptibility to disease, but the effect is not major, and the other genes remain unknown. Cytokines are crucial in the regulation of immune and inflammatory responses and therefore are potential candidate genes for autoimmune thyroid disease. In a case-control study, using a unified method of genotyping, we have examined 15 polymorphisms in 9 cytokine genes in 215 patients with autoimmune thyroid disease (GD, 138; AIH, 77) and 101 normal controls.

Polymorphisms in the genes for interleukin-1α (IL-1α), IL-1β, IL-1 receptor antagonist, IL-1 receptor 1, IL-4, IL-4 receptor, IL-6, IL-10, and transforming growth factor-β were investigated. Genotyping was performed using the PCR and sequence-specific primers. Analysis showed a reduced frequency of the variant t allele in the IL-4 promoter polymorphism (position −590) in patients with GD and in the entire patient group (GD and AIH) compared with the control group [corrected P (Pc) = 0.00004 and Pc < 0.00001 for GD and all patients, respectively]. This was reflected in a reduction in the heterozygote genotype in the patient groups compared to the controls [c/t heterozygotes GD, 12%; Pc = 0.06, odds ratio, 0.4 (95% confidence interval, 0.2–0.7); all patients, 11%; Pc = 0.008; odds ratio, 0.4 (95% confidence interval, 0.2–0.7); control subjects, 23%]. There were no significant differences between the study groups for the other polymorphisms examined, and subgroup analysis revealed no association with clinical parameters of disease.

These results suggest that an IL-4 variant or a closely linked gene has a modest protective effect against the development of autoimmune thyroid disease, particularly GD. This variation in the IL-4 gene may provide further clues to the pathogenesis of autoimmune thyroid disease and other organ-specific autoimmune diseases. Furthermore, these results suggest that subtle variation in immunoregulatory genes may be associated with autoimmune disease states.
Effects of Recombinant Human Insulin-Like Growth Factor I Administration on Spontaneous and Growth Hormone (GH)-Releasing Hormone-Stimulated GH Secretion in Anorexia Nervosa1
Authors: Gianotti Laura , Pincelli Angela I. , Scacchi Massimo , Rolla Mimma , Bellitti Deanna , Arvat Emanuela , Lanfranco Fabio , Torsello Antonio , Ghigo Ezio , Cavagnini Franco , Müller Eugenio E.
Published: January 2014

Exaggerated GH and reduced insulin-like growth factor I (IGF-I) levels are common features in anorexia nervosa (AN). A reduction of the negative IGF-I feedback could account, in part, for GH hypersecretion. To ascertain this, we studied the effects of recombinant human (rh)IGF-I on spontaneous and GH-releasing hormone (GHRH)-stimulated GH secretion in nine women with AN [body mass index, 14.1 ± 0.6 kg/m2] and in weight matched controls (normal weight). Mean basal GH concentrations (mGHc) and GHRH (2.0μ g/kg, iv) stimulation were significantly higher in AN. rhIGF-I administration (20 μg/kg, sc) significantly reduced mGHc in AN (P < 0.01), but not normal weight, and inhibited peak GH response to GHRH in both groups; mGHc and peak GH, however, persisted at a significantly higher level in AN. Insulin, glucose, and IGFBP-1 basal levels were similar in both groups. rhIGF-I inhibited insulin in AN, whereas glucose remained unaffected in both groups. IGFBP-1 increased in both groups (P < 0.05), with significantly higher levels in AN. IGFBP-3 was under basal conditions at a lower level in AN (P < 0.05) and remained unaffected by rhIGF-I. This study demonstrates that a low rhIGF-I dose inhibits, but does not normalize, spontaneous and GHRH-stimulated GH secretion in AN, pointing also to the existence of a defective hypothalamic control of GH release. Moreover, the increased IGFBP-1 levels might curtail the negative IGF-I feedback in AN.