bluuebunny/crossref_metadata_2025 huggingface dataset:
Change in C-terminal cross-linking domain of type I collagen in urine, a new marker of bone resorption, during and after gonadotropin-releasing hormone agonist administration
Authors: Taga M , Minaguchi H
Published: January 2005

OBJECTIVE: The major side effect of GnRH agonist (GnRHa) therapy is the reduction of bone mass. To analyze bone resorption by GnRHa, we measured the urinary excretion of C-terminal telopeptides of type I collagen (CTX), a new marker of bone resorption. METHODS: We used a new ELISA for CTX (CrossLaps) in a sample of 18 premenopausal women with leiomyoma who were treated with daily administration of 400 micrograms nafarelin or 900 micrograms buserelin for 16 weeks. RESULTS: Urinary CTX excretion increased significantly during GnRHa treatment and then decreased at 12 and 24 weeks after the cessation of GnRHa therapy. Whereas the excretory profile of CTX during GnRHa therapy was almost similar to that of pyridinoline (Pyr) or deoxypyridinoline (D-Pyr), both biochemical markers of bone resorption, the magnitude of the change in CTX was significantly greater than that in Pyr or D-Pyr. CONCLUSIONS: These results indicate that CTX could be a more sensitive marker for bone resorption than the currently used biochemical markers, and that CrossLaps ELISA is useful for therapeutic monitoring during and after GnRHa treatment.
One microgram is the lowest ACTH dose to cause a maximal cortisol response. There is no diurnal variation of cortisol response to submaximal ACTH stimulation
Authors: Dickstein G , Spigel D , Arad E , Shechner C
Published: January 2005

There are many suggestions in the literature that the adrenal gland is more sensitive to ACTH in the evening than in the morning. However, all these studies in humans were conducted when the basal cortisol level was not suppressed, and were based on the observation that, after stimulation, the increases in cortisol differed, though the peak values were the same. To examine this, we established the lowest ACTH dose that caused a maximal cortisol stimulation even when the basal cortisol was suppressed, and used a smaller dose of ACTH for morning and evening stimulation. The lowest ACTH dose to achieve maximal stimulation was found to be 1.0 microgram, with which dose cortisol concentration increased to 607.2 +/- 182 nmol/l, compared with 612.7 +/- 140.8 nmol/l with the 250 micrograms test (P > 0.3). The use of smaller doses of ACTH (0.8 and 0.6 microgram) achieved significantly lower cortisol responses (312 +/- 179.4 and 323 +/- 157.3 nmol/l respectively; both P < 0.01 compared with the 1 microgram test). When a submaximal ACTH dose (0.6 microgram) was used to stimulate the adrenal at 0800 and 1600 h, after pretreatment with dexamethasone, no difference in response was noted at either 15 min (372.6 +/- 116 compared with 394.7 +/- 129.7 nmol/l) or 30 min (397.4 +/- 176.6 compared with 403 +/- 226.3 nmol/l; P > 0.3 for both times). These results show that 1.0 microgram ACTH, used latterly as a low-dose test, is very potent in stimulating the adrenal, even when baseline cortisol is suppressed; smaller doses cause reduction of this potency. Our data show that there is probably no diurnal variation in the response of the adrenal to ACTH, if one eliminates the influence of the basal cortisol level and uses physiologic rather than superphysiologic stimuli.
ACTH-producing carcinoma of the pituitary with haematogenic metastases
Authors: Garrao AF , Sobrinho LG ,   Pedro-Oliveira, Bugalho MJ , Boavida JM , Raposo JF , Loureiro M , Limbert E , Costa I , Antunes JL
Published: January 2005

The case report is presented of a 47-year-old white woman with Cushing's disease treated by bilateral adrenalectomy in June 1981. A first computed tomography (CT) scan in September 1984 showed a voluminous pituitary adenoma with invasion of the sphenoid sinus and left parasellar extension. The tumour increased progressively in size, a suprasellar extension developed and the optic chiasm was eventually affected. In March 1988 and June 1989 the patient underwent two surgeries for the pituitary tumour, the second followed by radiotherapy. During this period, the ACTH values varied between 100 pmol/l and 403 pmol/l (normal: < 13 pmol/l). After radiotherapy, a progressive shrinking of the tumour was observed and the ACTH concentrations decreased to a lowest value of 27.5 pmol/l. The patient was clinically well until September 1993 when, suddenly, the plasma ACTH concentration increased to very high levels (greater than 965 pmol/l). There was no evidence of tumour growth on the sellar CT scan. In January 1995, an ACTH-producing pituitary carcinoma was diagnosed, based on the presence of bone metastases. The patient died in May 1995.
Molecular structure of the human gonadotropin-releasing hormone receptor gene
Authors: Kakar SS
Published: January 2005

GnRH receptors belong to the family of G protein-coupled receptor proteins and have been localized to the anterior pituitary, brain and reproductive organs as well as many steroid-dependent tumor tissues. Recently, cDNAs for the GnRH receptors of several species including the human have been cloned. To determine the structure of the gene encoding the human GnRH receptor, we isolated the receptor gene clones from the human genomic libraries. Comparison of the genomic and cDNA sequences revealed that the human GnRH receptor gene is composed of three exons and two introns and spans over 20 kb in size. Exon 1 encodes the 5' untranslated sequence and nucleotide +1 to +522 in the open reading frame, exon 2 encodes nucleotide +523 to +742 and exon 3 encodes nucleotide +743 to +987 in the open reading frame as well as the 3' untranslated sequence. Southern blot analysis of genomic DNA and localization of the GnRH receptor gene to a single site on human chromosome 4 (4q13) indicate the presence of a single copy of the gene in the human genome. Several regulatory sequences for various hormones and other regulatory factors were identified, including PEA-3, AP-1, AP-2, and Pit-1 sites. In addition, glucocorticoid/progesterone response element thyroid hormone response element, and cAMP response element sequences were identified. Reverse transcriptase-primer extension and 5' RACE analysis of the human pituitary RNA demonstrated the presence of multiple transcriptional start sites upstream of the translational start site. Analysis of the 5' flanking region of the gene also revealed the presence of multiple TATA and CAAT sequences. The finding of multiple transcriptional start sites raises the possibility of tissue-specific regulation and the existence of variable size transcripts. Chimeras containing 1.26 kb (-534 to 728) of the 5' flanking region of the receptor gene and the luciferase (Luc) gene expressed a significant luciferase activity when transfected into a human endometrial tumor cell line (HEC-1A) and a breast tumor cell line (MCF-7) but not in a mouse pituitary gonadotrope cell line (alpha T3-1), suggesting the existence of multiple promoter elements in the gene. These findings indicate a multiplicity of regulation of expression of the GnRH receptor and provide the substrate for detailed investigation in the reproductive system.
Effect of the somatostatin analog, octreotide, and of other hormones on the release of the acid-labile subunit of the 150 kDa complex by rat hepatocyte in primary culture
Authors: Barreca AM , Voci A , Lee PD , Arvigo M , Ghigliotti V , Fugassa E , Giordano G , Minuto F
Published: January 2005

OBJECTIVE: In normal subjects, the major form of circulating IGF is the GH-dependent 150 kDa complex. The liver appears to be the main source of the three components of the 150 kDa complex and, in particular, hepatocytes synthesize the insulin-like growth factor (IGF) peptide and the acid-labile subunit (ALS), whereas Kupffer and sinusoidal endothelial cells produce IGF-binding protein-3 (IGFBG-3). We have studied the effects of the somatostatin analog octreotide, IGF-II des(1-3)IGF-I, transforming growth factor (TGF)-beta 1 and tri-iodothyronine (T3) on ALS secretion into the medium conditioned by rat hepatocytes in primary culture. METHODS: The regulation of ALS release was evaluated in the conditioned medium of adult rat hepatocytes exposed to increasing concentrations of test substances or to vehicle alone (control), after gel filtration in basic conditions, by immunoblot using an antiserum generated against the N-terminal 34 amino acids of human ALS. RESULTS: The results demonstrate that: 1) octreotide in vitro produces a dose-dependent inhibition of both basal and GH-stimulated ALS secretion into the hepatocyte conditioned medium; 2) the release of ALS by adult rat hepatocytes is not affected by the presence during the incubation of des(1-3)IGF-I or IGF-II; 3) an inhibitory effect, although only with very high doses, can be observed after treatment with TGF-beta 1; and 4) a small but significant increase of ALS released into the medium can be seen when hepatocytes are treated with T3. CONCLUSIONS: Evaluation of the effect of substances known to affect the production of IGF peptides, the IGFBPs, or both, on adult rat hepatocytes in primary culture revealed no powerful stimulator, but instead a potent inhibitor of ALS release/synthesis. Our data suggest that the effect of somatostatin on the 150 kDa complex is mediated not only by the reduction in GH concentration, but also by a direct inhibition of ALS release or synthesis.
Glucocorticoid osteoporosis--mechanisms and management
Authors: Reid IR
Published: January 2005

Glucocorticoids are potent osteopenic agents, producing negative calcium and bone balance via actions at many sites. The most significant adverse effects of glucocorticoid drugs on the skeleton are probably a direct inhibition of matrix synthesis by the osteoblast, reductions in calcium absorption in both the gut and the renal tubule, and the production of hypogonadism, particularly in men. Reductions in bone density of 10-40% result, the loss being more marked in trabecular bone and in patients receiving a high cumulative dose of the steroid. Fractures occur in about 30% of individuals who take these drugs for an average of 5 years. Bone loss is reversible when glucocorticoid treatment is withdrawn. Bone density can also be increased by sex hormone replacement in those with demonstrable deficiency, by bisphosphonates, and possibly by vitamin D metabolites. All patients treated with glucocorticoids for more than 6 months should be considered for bone densitometry and be offered appropriate drug treatment if values are towards the lower end of the young normal range or if there is already evidence of fractures occurring after minimal trauma. With this approach, the significant morbidity associated with steroid osteoporosis might be substantially avoided.
Effects of long-term total fasting and insulin on ob gene expression in obese patients
Authors: Andersen PH , Kristensen K , Pedersen SB , Hjollund E , Schmitz O , Richelsen B
Published: January 2005

In the present study the effect of long-term fasting (6 days) on obese (ob) gene expression was examined in nine severely obese females of 34 +/- 3 years and with a body mass index of 46.4 +/- 2.3 kg/m2. Six days of fasting induced a significant weight loss (126.8 +/- 5.3 vs 120.5 +/- 5.1 kg, P < 0.0001). Insulin-stimulated glucose uptake (hyperinsulinemic, euglycemic clamp, insulin infusion rate 1.5 mU/kg per min) was markedly reduced following fasting (M-value 5.96 +/- 0.74 vs 2.79 +/- 0.23 mg/kg per min, P < 0.0001). Ob mRNA/beta-actin concentration in fat biopsies from abdominal subcutaneous adipose tissue was unchanged after 6 days of fasting (1.50 +/- 0.40 vs 1.47 +/- 0.36 arbitrary units, not significant), whereas serum leptin levels decreased significantly from 53.8 +/- 4.7 to 30.7 +/- 2.0 ng/ml (P < 0.0001) during the same period. No significant correlations were found between insulin-stimulated glucose uptake and serum leptin concentration, either prior to the fast or after the fast. Serum leptin levels were unchanged by hyperinsulinemia for 3 h during the clamp prior to the fast, while hyperinsulinemia for 3 h after 6 days of fasting increased serum leptin by 25% (P < 0.01). In conclusion, 6 days of fasting reduced serum leptin by about 40%. In contrast, ob mRNA in abdominal subcutaneous adipose tissue was unchanged. Furthermore, after 6 days of fasting insulin was able to increase the serum level of leptin significantly, indicating that the effect of insulin on the level of leptin is dependent on the nutritional state.
Vitamin E and nicotinamide have similar effects in maintaining residual beta cell function in recent onset insulin-dependent diabetes (the IMDIAB IV study)
Authors: Pozzilli P , Visalli N , Cavallo MG , Signore A , Baroni MG , Buzzetti R , Fioriti E , Mesturino C , Fiori R , Romiti A , Giovannini C , Lucentini L , Matteoli MC , Crino A , Teodonio C , Paci F , Amoretti R , Pisano L , Suraci C , Multari G , Suppa M , Sulli N , De Mattia G , Faldetta MR
Published: January 2005

OBJECTIVE: Protection of residual beta cell function at the time of diagnosis of insulin-dependent diabetes mellitus (IDDM) by intensive insulin therapy and the addition of nicotinamide (NA) has been established. The objective of this study was to evaluate the effect of a free oxygen radical scavenger such as vitamin E (Vit E) on residual beta cell function and parameters of metabolic control in patients with recent onset IDDM undergoing intensive insulin therapy. DESIGN: The effect of Vit E was compared with that of NA (control group) in a randomized multicentre trial. METHODS: Eighty-four IDDM patients between 5 and 35 years of age (mean age 15.8 +/- 8.4 (s.d.) years) entered a one year prospective study. One group of patients (n = 42) was treated with Vit E (15 mg/kg body weight/day) for one year; the other group (n = 42) received NA for one year (25 mg/kg body weight/day). All patients were under intensive insulin therapy with three to four injections a day. Basal and stimulated (1 mg i.v. glucagon) C-peptide secretion, glycosylated haemoglobin and insulin dose were evaluated at diagnosis and at three-monthly intervals up to one year. RESULTS: Preservation and slight increase of C-peptide levels at one year compared with diagnosis were obtained in the two treated patient groups. No statistically significant differences were observed in basal or stimulated C-peptide levels between the two groups of patients for up to one year after diagnosis. Glycosylated haemoglobin and insulin dose were also similar between the two groups; however patients receiving Vit E under the age of 15 years required significantly more insulin than NA-treated patients one year after diagnosis (P < 0.04). CONCLUSIONS: Our data indicate that Vit E and NA possess similar effects in protecting residual beta cell function in patients with recent onset IDDM. Since their putative mechanism of protection on beta cell cytotoxicity is different, combination of these two vitamins may be envisaged for future trials of intervention at IDDM onset.
Increased fracture frequency in adult patients with hypopituitarism and GH deficiency
Authors: Rosen T , Wilhelmsen L , Landin-Wilhelmsen K , Lappas G , Bengtsson BA
Published: January 2005

Fracture frequency was studied in 107 hypopituitary patients with GH deficiency (GHD) (69 men, mean age 53 years, range 18-74 and 38 women, mean age 54 years, range 31-73). Routine hormonal replacement therapy was given, except GH. Five male patients and 15 female patients with untreated hypogonadism were allocated to a separate group. The mean duration of hypopituitarism was 13.4 years. The prevalence of a history of fractures was assessed using questionnaires. A subsample of the Goteborg WHO MONICA Project was used as a reference population (n = 323). The total fracture frequency was threefold higher (P < 0.001) in patients (24.1%) compared with controls (8.7%) (odds ratio 3.49) (1.85-6.56; 95% confidence intervals). In men (n = 64) the fracture frequency was 25.0%, compared with 7.8% among the controls (P < 0.001). In women (n = 23) the fracture frequency was 21.7%, compared with 9.5% among the controls (P = 0.08). The odds ratios for fracture frequency were 3.97 (1.81-8.40; 95% confidence intervals) and 2.64 (0.89-7.81; 95% confidence intervals) in men and women respectively. In conclusion, adult hypopituitary patients with GHD had a threefold increased fracture frequency compared with controls. Further studies are needed to ascertain whether long-term recombinant human GH treatment can reduce the fracture rate in hypopituitary patients with GHD.
Circulating non-22 kDa growth hormone isoforms in healthy children of normal stature: relation to height, body mass and pubertal development
Authors: Boguszewski CL , Jansson C , Boguszewski MC , Rosberg S , Wikland KA , Carlsson B , Carlsson LM
Published: January 2005

The proportion of non-22 kDa GH isoforms was evaluated in 93 healthy children (48 boys aged 6.8-18.4 years and 45 girls aged 3.9-18.4 years) of normal stature (height +/- 2 s.d. score) at different stages of puberty. In addition, correlations among the proportion of non-22 kDa GH isoforms, auxology, spontaneous GH secretion and biochemical measurements were investigated. Serum non-22 kDa GH levels, expressed as percentage of total GH concentration in the samples, were determined by the 22 kDa GH exclusion assay, in which monomeric and dimeric 22 kDa GH are removed from serum and the non-22 kDa GH isoforms are quantitated using a polyclonal antibody GH assay. Samples were selected from spontaneous GH peaks in 24-h GH profiles. For boys, the median proportion of non-22 kDa GH isoforms was 8.5% (range 3.2-26.6%) and for girls it was 9.6% (1.8-17.4%), with no influence of age and no sex-related difference in prepubertal (boys, 7.2%; girls, 8.8%) or pubertal children (boys, 9.1%; girls, 9.9%). However, the median proportion of non-22 kDa GH isoforms was significantly higher in pubertal boys (9.1%) than in prepubertal boys (7.2%; P = 0.03). In pubertal boys, height S.D. scores (SDS) were inversely correlated to the proportion of non-22 kDa GH isoforms (r = -0.38; P = 0.02), especially at mid-puberty (r = -0.7; P = 0.01), indicating that the presence of increased amounts of circulating non-22 kDa GH isoforms was associated with less growth. In prepubertal children, positive correlations between non-22 kDa GH and weight SDS (r = 0.46; P = 0.03), weight-for-height SDS (r = 0.51; P = 0.01) and body mass index (r = 0.42; P = 0.04) were observed. No significant correlations were seen with spontaneous GH secretion or measurements of IGF-1, IGF-binding protein-3, insulin and leptin. These findings in normal children indicate that the proportion of circulating non-22 kDa GH isoforms may have physiologic significance for growth and metabolism in different stages of development, and emphasize the importance of evaluating the circulating ratio of 22 kDa and non-22 kDa GH in children with growth disorders.
Evaluation and treatment of persistent thyroglobulinemia in patients with well-differentiated thyroid cancer
Authors: Pachucki J , Burmeister LA
Published: January 2005

Whereas in the past a negative diagnostic 131I whole body scan (WBS) was interpreted as the lack of significant residual or recurrent thyroid cancer, today the patient with negative WBS and measurable serum thyroglobulin (Tg) presents a diagnostic and therapeutic dilemma. Previous studies have shown a high rate of visualization of uptake and a decrease in Tg after one or more therapeutic doses of 131I. In order to further assess the significance of this finding, retrospective analysis of patients with persistent thyroglobulinemia and negative WBS was performed for evidence of surgically amenable disease. Seven out of seventeen patients had neck ultrasound and/or computerized tomography (neck +/- chest) showing the presence of pathologically confirmed malignant masses ranging from 1 to 4 cm in size. Their serum Tg while on L-thyroxine ranged between 2.4 and 1173 pmol/l. Removal of the identified masses resulted in a greater than 75% reduction in serum Tg in four out of five patients in the group. One patient achieved a serum Tg of < 1.5 pmol/l while hypothyroid. Empiric 131I treatment of eleven patients with persistent thyroglobulinemia resulted in demonstrated uptake on post-therapy scan in seven. Further study is needed to compare the efficacy, safety and cost of a diagnostic approach to radiologically identify and surgically resect identified disease versus empiric therapeutic 131I treatment and high-dose WBS in this group of patients. Patients with negative WBS and persistent thyroglobulinemia, even to levels < 4.5 pmol/l, may have significant foci of thyroid cancer in surgically accessible areas. This suggests the need for a redefinition or clarification of the term 'recurrence' in thyroid cancer.
Absence of angiotensin II type 1 receptor gene mutations in human adrenal tumors
Authors: Sachse R , Shao XJ , Rico A , Finckh U , Rolfs A , Reincke M , Hensen J
Published: January 2005

Regulatory actions of angiotensin II (AngII), which is involved in the pathophysiology of hypertension and also participates in cell proliferation and cell differentiation, are mainly mediated by AngII type 1 (AT1) receptor. Recently, activating mutations of receptors causing hyperfunctioning endocrine diseases have been described in the case of the TSH and LH receptors, implicating that such mutations might occur in other G-protein-coupled receptors. Furthermore it seems to be possible that genetic variations of AT1 receptor have an influence upon the action of AngII. Therefore, we searched by sequence analysis of the coding region of AT1 receptor gene for activating mutations and genetic polymorphisms in 56 human adrenal tumors (16 aldosterone-producing adenomas, 10 cortisol-producing adenomas, 1 aldosterone-producing carcinoma, and 29 incidentalomas). We were not able to identify any activating mutation in the coding region of AT1 receptor gene. We conclude that activating mutations of the AT1 receptor are not a major cause of the development of adrenal adenomas, if at all. In addition, polymorphic subtypes of AT1 receptor do not seem to play a major role in the pathogenesis of these tumors, even though a tendency towards a higher frequency of the polymorphic base substitution at position 573 (T573-->C) in cortisol-producing tumors needs to be further evaluated.
An unusual case of papillary carcinoma of the thyroid with cutaneous and breast metastases only
Authors: Loureiro MM , Leite VH , Boavida JM , Raposo JF , Henriques MM , Limbert ES , Sobrinho LG
Published: January 2005

Cutaneous metastases of thyroid carcinoma are infrequent and, when present, are usually located in the vicinity of a widespread primary tumor. Breast metastases from these tumors are even less common. We report the case of a 64-year-old female with a toxic multinodular goiter in whom a fine-needle biopsy, performed in 1985 at the age of 52, was suggestive of papillary carcinoma of the thyroid. Total thyroidectomy for a papillary carcinoma, follicular variant, was performed in 1988. Four months after surgery, a cutaneous metastasis was discovered in the right thigh. Surgical excision of the lesion followed by treatment with radioactive iodine decreased serum Tg levels from 7495 to 3.3 micrograms/l. Under suppressive therapy with L-thyroxine, serum Tg remained undetectable for the next 4 years. Then, serum Tg levels rose to 3.9-5.6 micrograms/l and a second cutaneous metastasis was removed from the abdominal wall. The patient was again treated with radioactive iodine and the post-treatment whole-body scan did not show any area of increased uptake of the radionuclide. However, serum Tg levels under suppression with L-thyroxine remained elevated at 4-20 micrograms/l for the next 2 years. In August 1995, a 1.5 cm nodule was found in the right breast. Cytological examination was suggestive of a breast metastasis from thyroid carcinoma and the lesion was removed by enucleation. This proved to be a metastasis from a papillary carcinoma of the thyroid. Elevated (19-44 micrograms/l) serum Tg levels persisted postoperatively. A third cutaneous metastasis was revealed by 131I scintigraphy in the right buttock and surgically removed in December 1996. Serum Tg levels have remained undetectable since then. To the best of our knowledge, this is a unique case of a papillary carcinoma of the thyroid with a propensity to metastasize only to the skin and breast during a follow-up of 11 years.
Starvation-induced increase in the parathyroid hormone/PTH-related protein receptor mRNA of bone and kidney in sham-operated and thyroparathyroidectomized rats
Authors: Kawane T , Saikatsu S , Akeno N , Abe M , Horiuchi N
Published: January 2005

Parathyroid hormone (PTH) acts on bone and kidneys by binding to PTH/PTH-related protein (PTHrP) receptors and regulating calcium (Ca) and phosphorus (P) homeostasis. PTH/PTHrP receptor mRNA was expressed at high levels in PTH target tissues such as the kidneys and bone including the calvaria, femur, and tibia. Because short-term starvation influences Ca and P ion homeostasis, we measured changes in PTH/PTHrP receptor mRNA expression in the bone and kidneys. Food deprivation for 3 days decreased the serum Ca and P concentrations, and reinstitution of feeding for 2 days normalized the serum Ca level and significantly increased the serum P level. Concomitantly, rat immunoreactive PTH (riPTH) was increased during starvation and returned to the control level after 2 days of subsequent feeding. Serum 1 alpha, 25-dihydroxyvitamin D3 (1,25(OH)2D3) concentrations did not significantly change during starvation and subsequent feeding. Starvation up-regulated PTH/PTHrP receptor mRNA expression in both bone and kidney. The effects of food deprivation on the receptor transcript abundance were greater in bone (threefold increase compared with control) than in the kidney (1.8-fold increase), whereas the mRNA level increase by food deprivation was more rapid in the kidneys than in bone. The PTH-induced adenylyl cyclase activity of renal membranes increased in starvation. Feeding after starvation normalized the mRNA levels in both tissues. Serum PTH depression, initiated by thyroparathyroidectomy, did not affect PTH/PTHrP receptor mRNA levels in bone and kidney in rats that were fed or starved for 3 days. The abundance of receptor mRNA in bone and kidney was significantly lower in fed rats given either corticosterone or vehicle than in starved rats. These data indicate that starvation induces PTH/PTHrP receptor mRNA expression in bone and kidney, independently of serum PTH and corticosterone concentrations. The factors leading to up-regulated receptor mRNA induced by starvation remain unknown.
The steroid antagonist RU486 given at pro-oestrus induces hypersecretion of follicle-stimulating hormone from oestrus afternoon to early metoestrus in the rat
Authors: Sanchez-Criado JE , Tebar M , Ruiz A , Padron L
Published: January 2005

Administration of the steroid antagonist RU486 to cyclic rats at pro-oestrus blunts the preovulatory surge of LH and suppresses the first and second surges of FSH. In addition, administration of oestradiol to RU486-treated rats reactivates the LH surge the following day. The present study explored the effects of RU486 (4 mg/0.2 ml oil), administered at 0800 h on the day of pro-oestrus, on serum FSH and LH concentrations through oestrus and early metoestrus. RU486 induced a hypersecretion of FSH, which started at 1400 h on the day of oestrus and was maintained until 0800 h on the day of metoestrus. Because the timing and magnitude of this secretion of FSH were similar to those of the periovulatory secretion of FSH during pro-oestrus and early oestrus in intact cyclic rats, we investigated the effects of: 1) LHRH antagonist (LHRHa) injected at either 0900 h or 2000 h on the day of oestrus, 2) oestradiol benzoate injected at 1600 h on the day of pro-oestrus and at 0900 h on the day of oestrus, 3) bovine follicular fluid (bFF) given either at 1100 h or at 2000 h on the day of oestrus, or 4) adrenalectomy (ADX) at 1100 h on the day of oestrus, on serum FSH and LH concentrations at 1800 h on the day of oestrus and at 0200 h on the day of metoestrus in rats injected with RU486 at pro-oestrus. The results showed that 1) both components (late oestrus and early metoestrus) of FSH hypersecretion in RU486-injected rats in pro-oestrus were inhibited by oestradiol benzoate and bFF, 2) the metoestrous component was not affected by LHRHa, whereas the oestrous component was partially reduced, and 3) ADX partially reduced serum FSH concentrations only on the day of metoestrus, possibly because, as the serum concentrations of corticosterone reflected, the antiglucocorticoid activity of 4 mg RU486 lasted only 24 h. The results support the hypothesis that blockade of progesterone actions at pro-oestrus results in the maintenance of the daily neural signal that activates the release of gonadotrophins. Whereas the expression of LH secretion requires high levels of oestradiol, FSH secretion is expressed against a background of low oestradiol levels. The results of this study also indicate that the release of FSH during oestrus and metoestrus in rats injected with RU486 at pro-oestrus is a consequence of the lack of ovarian negative feedback inhibition on the pituitary.
Effects of castration on early postnatal development of male accessory sex glands in the domestic pig
Authors: Raeside JI , Friendship RM , Vrablic OE
Published: January 2005

In the neonatal pig there is a remarkable production of steroids by the testes for the first few weeks after birth. Several androgens and estrogens reach a peak at about one month of age. In order to gain an understanding of the significance of this early steroid secretion we examined the effect on accessory sex glands of removal of the testes before the peak in these compounds would have occurred. Pigs were castrated (n = 38) at 2-3 weeks of age, with littermates serving as intact controls (n = 33). Animals were killed at ages ranging from 4-12 weeks. Blood samples were taken and both bulbourethral (BU) and vesicular glands (VG) were removed, as well as the testes of intact males. Organ pairs were weighted and samples fixed for histological examination. Plasma samples were stored at -20 degrees C until assayed, without extraction, for testosterone, dehydroepiandrosterone sulfate (DHEAS) and estrone sulfate (E1S) by radioimmunoassay. Of the hormones measured, plasma DHEAS concentrations were highest, but variable over the time period (304.2 and 75.6 nmol/l; 87.7 and 21.8 ng/ml at 5 and 12 weeks respectively). E1S declined steadily from 76.6 to 5.8 nmol/l (20.7 to 1.56 ng/ml). Testosterone levels were lowest but rose from 2.67 to 9.54 nmol/l (0.77 to 2.75 ng/ml). No steroids were clearly detectable in samples from castrated males. Testes weights (wt) increased fourfold, as did body wt for both intact and castrate males. Both BU and VG showed absolute increase in wt (3.5x and 5x respectively) in intact males, and each was about 2.8x greater than in castrates (mg/kg body wt). Histological sections were markedly distinctive for both BU and VG between intact and castrate animals, and a lack of developmental changes in both glands was noted in the castrates. Our findings provide clear evidence of an influence of the testes on accessory sex glands in the early postnatal life of the pig.
Interactions between interleukin-1 beta, nitric oxide and prostaglandin E2 in the rat ovary: effects on steroidogenesis
Authors: Ahsan S , Lacey M , Whitehead SA
Published: January 2005

It has been reported that interleukin (IL)-1 beta induces the synthesis of both nitric oxide (NO) and prostaglandin (PG)E2 in cultures of dispersed ovarian cells and exerts cytotoxic effects on these cells. Since PGE2, NO and IL-1 beta have been implicated as modulators of steroidogenesis, experiments have been undertaken to determine how IL-1 beta-induced NO and PGE2 production may affect steroidogenesis in cultures of ovarian dispersates obtained from untreated adult oestrous rats and to compare the action of IL-1 beta in cultures of granulosa/luteal (GL) cell-only cultures and GL cells co-cultured with peritoneal macrophages. IL-1 beta significantly increased the production of NO (assessed by nitrite measured in the culture medium) and PGE2 in cultures of ovarian dispersates but had no effect on cultures of GL cells in which NO production was typically very low and PGE2 production was undetectable. In contrast both NO and PGE2 were high in co-cultures and were not significantly altered by the addition of IL-1 beta. The NO donor sodium nitroprusside inhibited steroidogenesis in cultures of ovarian cells in a dose-dependent manner while PGE2 had a stimulatory effect. Concomitant inhibition of NO production with aminoguanidine and PG production with indomethacin resulted in a significant enhancement of basal progesterone production in these cultures. Finally, IL-1 beta inhibited progesterone responses to forskolin and PGE2 in ovarian dispersates: an effect not observed in GL cell-only cultures nor in co-cultures in which forskolin-induced progesterone production is always inhibited. No cytotoxic effects of IL-1 beta during the 48 h period of culture were observed. A comparison of the steroidogenic NO and PGE2 responses to IL-1 beta in the three culture models suggests that (i) the response to IL-1 beta observed in ovarian dispersates could be due to cytokine activation of resident and infiltrating macrophages or that the action of IL-1 beta requires some other heterologous cell-cell contact, and (ii) IL-1 beta acts indirectly on signal transduction pathways which stimulate steroidogenesis.
Role of the testis in the response of the pituitary-testicular axis to nitric oxide-related agents
Authors: Gaytan F , Bellido C , Aguilar R , Morales C , van Rooijen N , Aguilar E
Published: January 2005

Nitric oxide (NO) is generated from the guanidine group of L-arginine by NO synthases (NOS) in a wide variety of tissues, including endocrine organs. In order to discriminate between central and local effects of NO-related agents on the pituitary-testicular axis, adult rats were injected intraperitoneally with 1 g/kg body weight (bw) L-arginine methyl ester (L-AME, an exogenous substrate of NOS), 0.5 mg/kg bw sodium nitroprusside (SNP, an NO donor) or vehicle (0.9% NaCl) or intratesticularly with 2 mg/testis L-AME, 2 micrograms/testis SNP or 25 microliters vehicle, and killed at 60 or 120 min after treatment. Both intraperitoneal and intratesticular administration of L-AME had the same effects: a decrease in the serum concentrations of LH and testosterone and in those of testosterone in the testicular interstitial fluid. However, treatment with SNP was more effective when given intratesticularly, inducing a decrease in serum and interstitial fluid testosterone concentrations, without significant changes in LH concentrations. Furthermore, when rats were injected intraperitoneally with 4 mg L-AME (the same dose as that given intratesticularly), serum LH concentrations were not changed. In addition, L-AME administration was not effective in modifying serum LH concentrations in castrated rats. To test the possible role of Leydig cells, the effects of systemic administration of L-AME were studied in rats depleted of Leydig cells by treatment with ethylene dimethane sulphonate. In these animals L-AME significantly decreased serum LH concentrations. To study the role of macrophages in this system, rats depleted of testicular macrophages by the liposome-suicide approach were injected intraperitoneally (1 g/kg bw) or intratesticularly (2 mg/testis) with L-AME or vehicle, 10 days after macrophage depletion, and killed at 120 min after treatment. The effects of L-AME on serum LH concentrations were blocked when the drug was administered intratesticularly.
Insulin-like growth factor-I stimulates myofibrillar genes and modulates atrial natriuretic factor mRNA in rat heart
Authors: Donath MY , Gosteli-Peter MA , Hauri C , Froesch ER , Zapf J
Published: January 2005

We have investigated the effect of a 6-day infusion of recombinant human (rh) IGF-I (0.3-1.0 mg/day) or rhGH (200 mU/day) into normal and hypophysectomized rats on the ventricular expression of myofibrillar genes (alpha- and beta-myosin heavy chain (MHC), skeletal and cardiac alpha-actin) and of atrial natriuretic factor (ANF). In normal rats, beta-MHC was not detectable either before or after IGF-I or GH, but alpha-MHC mRNA increased significantly (twofold) with GH (not statistically significant for IGF-I). In contrast to normal rats, hypophysectomized rats did not express alpha-MHC either before or after IGF-I or GH, but beta-MHC was strongly expressed and significantly stimulated (1.8-fold) by IGF-I (not statistically significantly with GH). Skeletal alpha-actin expression remained unchanged during IGF-I or GH treatment of normal rats, but was enhanced by both IGF-I and GH (2.5- and 2.8-fold respectively) in hypophysectomized rats. Expression of cardiac alpha-actin in normal and hypophysectomized rats was not altered by either treatment. IGF-I and GH decreased ventricular expression of ANF in normal rats by 63% and 45% respectively, but did not influence ANF expression in hypophysectomized rats. Our results show that IGF-I and GH (possibly via IGF-I) stimulate expression of myofibrillar genes and modulate ANF mRNA concentrations in rat heart ventricles in vivo, depending on the hormonal status of the animals. However, neither IGF-I nor GH caused a shift from the beta- to the alpha-MHC isoform in hypophysectomized rats.
Endemic cretinism in Thailand: a multidisciplinary survey
Authors: Rajatanavin R , Chailurkit L , Winichakoon P , Mahachoklertwattana P , Soranasataporn S , Wacharasin R , Chaisongkram V , Amatyakul P , Wanarata L
Published: January 2005

Endemic cretinism has been classified into neurological and myxedematous types. Profound mental deficiency, deaf-mutism and cerebral diplegia are predominantly found in the former. The latter have been described as less mentally retarded but with severe growth retardation and myxedematous features. The pathogenesis of different clinical types of endemic cretinism is still unclear. Recently, a unifying hypothesis suggested that iodine deficiency, severe enough to cause maternal and fetal hypothyroxinemia, results in neurological defects in all cretins. We conducted the present study in northern Thailand to determine the validity of this hypothesis in another geographical area. The study consisted of a multidisciplinary survey on 112 endemic cretins aged 2-66 years in Nan. They were categorized clinically into three types of endemic cretins, neurological (n = 57), myxedematous (n = 19) and mixed form (n = 36). The subjects were generally short and the majority had severe mental retardation (mean intellectual quotient (I.Q.) 30.8 +/- 8.8), psychomotor defect and profound sensorineural hearing loss. The I.Q. score and proportion of cretins with sensorineural hearing loss and psychomotor defect were similar among the three types of cretins. The most frequent neurological abnormalities were spasticity, hyper-reflexia, the presence of primitive reflexes and gait disturbance. These abnormalities were distributed equally among the three types of endemic cretins. Delayed skeletal maturation and abnormal epiphysis were also present in all types of cretins. However, myxedematous cretins were shorter (P < 0.01), having more myxedematous features (P < 0.05 to P < 0.001) and less sexual maturation (P < 0.05). Thyroid volume was lower in cretins with hypothyroidism (P < 0.01). In conclusion, our findings support the hypothesis that neurological features are present in all types of cretins, and are the consequence of maternal and fetal hypothyroxinemia due to severe iodine deficiency. The clinical manifestations of the cretins were subsequently modified by the length and severity of postnatal iodine deficiency and hypothyroidism.
Effects of immigration on the incidence of congenital hypothyroidism
Authors: Kaiserman I , Maytal A , Siebner R , Sack J
Published: January 2005

OBJECTIVE: The incidence of congenital hypothyroidism (CH) has been shown to vary among different parts of the world. This could result from environmental or hereditary factors. Studies of other congenital diseases have shown that immigrants tend to retain the incidence of their country of origin while their children acquire the incidence of their new homeland, suggesting an environmental influence. This study aimed to assess the differences in the incidence of CH among immigrants from different parts of the world and to study the effects of immigration on its occurrence. METHODS: During the 9-year period between 1979 and 1987, 196 Jewish infants with primary CH were born in Israel; this constitutes an incidence of 1:3354 live births. We collected data from hospitals, endocrine pediatric clinics and the children's parents regarding the birth place of the parents and grandparents of those infants. These data were compared with the birth place of the parents and grandparents of all infants born in Israel during that period in order to learn about the incidence of CH among infants of different origins and to compare the incidence between children of parents born in Israel and those of immigrants of the same grandparental origin. RESULTS: CH incidence was lower among offspring of mothers and fathers of Israeli origin (1:4717 and 1:4255 live births respectively) and higher among those of African mothers (1:2950) and Asian fathers (1:2941). Parents of Asian or African origin, born in Israel have a lower incidence of CH-affected children compared with parents of the same origin born in their own continent. This trend is reversed for European and American parents, for whom being born in Israel is related to an increase in the CH incidence in their children. The difference in CH incidence between offspring of parents born in Israel and those of parents born in their original country was statistically significant (P < 0.05). In the different origin groups the gender of the parent did not influence significantly the incidence of CH. CONCLUSIONS: Environmental changes resulting from immigration can influence the incidence of congenital hypothyroidism.
Clinical and genetic analysis of an inherited case of thyroid adenoma/cancer
Authors: Asakawa H , Kobayashi T , Komoike Y , Nakano Y , Tamaki Y , Matsuzawa Y , Monden M
Published: January 2005

We studied a family in which thyroid neoplasms appeared to occur through genetic inheritance. Six blood relations, including the two probands, had thyroid carcinoma, and six others had benign thyroid tumors. When both parents had a thyroid neoplasm, their children frequently had thyroid neoplasms; this was confirmed through two generations of this family. To clarify the mechanism of inheritance, we performed chromosomal analysis, Southern blot analysis of three variable number of tandem repeats markers and HLA typing on two probands, and examined their RET proto-oncogenes, and p53 and RB tumor suppressor genes. We could not find any positive data on genetic analysis, although our data were limited. In conclusion, we studied a family in which thyroid neoplasms have occurred partly through genetic inheritance, although environmental factors may have influenced the occurrence of thyroid diseases. A search for a predisposing gene, using the microsatellite technique, is required to clarify the gentic factors involved.
Serum TSH and the response to radioiodine treatment of toxic multinodular goitre
Authors: Pedersen-Bjergaard U , Kirkegaard C
Published: January 2005

A retrospective analysis of data from 73 consecutive patients with toxic multinodular goitre treated with iodine-131 (131I) during a 2-year period was performed to investigate if serum TSH at the time of 131I treatment influences the outcome. The dose of 131I was calculated according to a model compensating for thyroid size estimated by palpation and 24-h 131I uptake. Serum TSH was determined by a third-generation assay with a functional sensitivity of 0.03 mU/l. A significantly more pronounced response to 131I treatment was observed in patients with TSH > 0.0 mU/l than in patients with TSH = 0.0 mU/l (P = 0.0006. This difference resulted in a threefold lower frequency of non-responders and a fivefold higher rate of early hypothyroidism in the group with detectable serum TSH. While the high frequency of hypothyroidism among patients with measurable serum TSH can be explained by destruction of normal thyroid tissue, the high frequency of treatment failure in the group with serum TSH = 0.0 mU/l suggests that autonomous thyroid tissue may also be sensitized to a deleterious effect of 131I through stimulation by TSH. We conclude that serum TSH has a significant influence on the outcome of 131I treatment of toxic multinodular goitre. The results of 131I treatment may be improved by adjustment of the dose of 131I according to the serum TSH level, in addition to adjustment for goitre size and 24-h 131I uptake.
Identification and characterization of a novel de novo mutation (L346V) in the thyroid hormone receptor beta gene in a family with generalized thyroid hormone resistance
Authors: Macchia E , Gurnell M , Agostini M , Giorgilli G , Marcocci C , Valenti TM , Martino E , Chatterjee KK , Pinchera A
Published: January 2005

We have investigated an Italian family with generalized resistance to thyroid hormone (RTH), consisting of two individuals with elevated serum thyroid hormones (TH) and a non-suppressed TSH, together with unaffected family members, for a mutation in the thyroid hormone receptor beta gene (hTR beta). We have identified a single nucleotide substitution (1321 CTT to GTT) corresponding to a leucine to valine substitution at codon 346 (L346V) in the predicted protein. The index case and her affected child are heterozygous for the receptor defect, with normal sequence in unaffected family members. Furthermore, both parents of the index case were unaffected, suggesting that the mutation had arisen de novo. When expressed in vitro, the L346V mutant receptor showed a marked reduction in its affinity for tri-iodothyronine (T3), impaired ligand-dependent transactivation and potent dominant negative activity. Its functional impairment could not be alleviated, even at supraphysiological concentrations of T3, suggesting that the mutation might interfere with the intrinsic ligand-dependent transactivation function (AF-2) located in the hormone binding domain of hTR beta. Finally, the presence of the L346V mutation in the son of the propositus, who died from complications associated with congenital heart disease, raises the possibility that RTH might have contributed to the pathogenesis or severity of the latter.