Targeted deletion of the Vgf gene indicates that the encoded secretory peptide precursor plays a novel role in the regulation of energy balance.
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To determine the function of VGF, a secreted polypeptide that is synthesized by neurons, is abundant in the hypothalamus, and is regulated in the brain by electrical activity, injury, and the circadian clock, we generated knockout mice lacking Vgf. Homozygous mutants are small, hypermetabolic, hyperactive, and infertile, with markedly reduced leptin levels and fat stores and altered hypothalamic proopiomelanocortin (POMC), neuropeptide Y (NPY), and agouti-related peptide (AGRP) expression. Furthermore, VGF mRNA synthesis is induced in the hypothalamic arcuate nuclei of fasted normal mice. VGF therefore plays a critical role in the regulation of energy homeostasis, suggesting that the study of lean VGF mutant mice may provide insight into wasting disorders and, moreover, that pharmacological antagonism of VGF action(s) might constitute the basis for treatment of obesity. (+info)
Reproductive and endocrine function in rams exposed to the organochlorine pesticides lindane and pentachlorophenol from conception.
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There is controversy over the potential endocrine modulating influence of pesticides, particularly during sensitive phases of development. In this study, ram lambs were exposed to lindane and pentachlorophenol from conception to necropsy at 28 weeks of age. The rams (and their mothers) were given untreated feed (n = 7) or feed treated with 1 mg kg-1 body weight per day of lindane (n = 12) or pentachlorophenol (n = 5). Semen was collected from 19 weeks onwards and reproductive behaviour was tested at 26 weeks. Serum was collected every 2 weeks and at 27 weeks every 15 min for 6 h during both day and night, and for 1 h before and 5 h after stimulation with GnRH, adrenocorticotrophic hormone and thyroid-stimulating hormone. The pesticides did not affect body weight and ejaculate characteristics, or cause overt toxicity. In pentachlorophenol-treated rams, scrotal circumference was increased. However, seminiferous tubule atrophy was more severe and epididymal sperm density was reduced in comparison with untreated rams at necropsy (P < 0.05). Thyroxine concentrations were lower in pentachlorophenol-treated rams than in untreated rams (P < 0.05). However, after thyroid-stimulating hormone treatment, the thyroxine response was unaltered. Reproductive behaviour was reduced in lindane-treated rams compared with control rams (P < 0.05). Serum LH and oestradiol concentrations during reproductive development, LH pulse frequency at 27 weeks and testosterone secretion after GnRH treatment were lower in lindane-treated rams than in untreated rams (P < 0.05). In summary, the effects of pentachlorophenol on the testis may be linked to a decrease in thyroxine concentrations, and reduced reproductive behaviour in lindane-treated rams may be related to decreased LH, oestradiol and testosterone concentrations. (+info)
Inhibitory effects of cyproheptadine on pituitary-thyroid axis and pancreatic beta cells in rats.
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AIM: To study the influences of cyproheptadine (Cyp) on the endocrine functions of pituitary-thyroid axis and pancreatic beta cells in rats. METHODS: The effects of Cyp on functions of pituitary-thyroid axis and pancreatic beta cells were observed by radioimmunoassay, biochemical analysis, and electron microscope. RESULTS: Cyp 2.3 mg.kg-1 ig for 10 d decreased serum thyroid stimulating hormone (TSH) from control groups (5.3 +/- 0.9) to (4.2 +/- 0.9) mU.L-1 and insulin levels from (64 +/- 8) to (50 +/- 9) kIU.L-1 (P < 0.05 and 0.01). Cyp 4.6 mg.kg-1 decreased serum TSH (3.8 +/- 0.5) mU.L-1, T3 (1.2 +/- 0.2) mmol.L-1, T4 (62 +/- 7) mmol.L-1, and insulin levels (42 +/- 8) kIU.L-1 decreased (P < 0.05 or 0.01). The retrograde changes of ultrastructure of pituitary TSH cells and pancreatic beta cells. CONCLUSION: Cyp has an inhibiting action on endocrine functions of pituitary-thyroid axis and pancreatic beta cells in rats. (+info)
Effects of phenobarbital, pregnenolone-16alpha-carbonitrile, and propylthiouracil on thyroid follicular cell proliferation.
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Reduced thyroid hormone concentrations (T4 and/or T3) and increased thyroid-stimulating hormone (TSH) have been proposed to mediate the thyroid tumor promoting effects of hepatic microsomal enzyme inducers (MEI) and antithyroid drugs. TSH is known to stimulate thyroid gland function and growth, as well as neoplasia. Thyroid weight has been used as an indicator of thyroid gland growth in MEI studies, but little is known about the effects of these inducers on thyroid cell proliferation. Therefore, we determined the time-course of thyroid cell proliferation of rats treated with MEI, and with the antithyroid drug propylthiouracil (PTU). Male Sprague-Dawley rats were fed either a basal diet or a diet containing phenobarbitol (PB) (1200 ppm), PCN (500 ppm), or PTU (30 ppm) for 3, 7, 14, 21, 30, 45, 60, or 90 days. PB and PCN treatments did not affect T3, but PTU reduced T3 60%. PB and PCN treatments reduced T4 25%, whereas PTU treatment reduced T4 90%. PB and PCN treatments increased thyroid weight 80%, and PTU increased thyroid weight 500%. TSH was not appreciably altered in PB-treated rats, but was increased 75% and 830% in PCN- and PTU-treated rats, respectively. Thyroid cell proliferation was increased 260, 330, and 850% in rats treated with PB, PCN, or PTU, respectively, for 7 days, but returned to control levels by the 45th treatment day. In conclusion, treatment with MEI that produced mild increases in TSH resulted in dramatic increases in thyroid cell proliferation, which peaked after 7 days of treatment and then returned to control values. This result is similar to that of antithyroid drugs, which produce large increases in TSH. These findings may have important implications for the role thyroid follicular cell proliferation has in mediating the thyroid tumor promoting effects of MEI. (+info)
Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study.
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BACKGROUND: Administration of protease inhibitors (PIs) to HIV-infected individuals has been associated with hyperlipidemia. In this study, we characterized the lipoprotein profile in subjects receiving ritonavir, indinavir, or nelfinavir, alone or in combination with saquinavir. METHODS AND RESULTS: Plasma lipoprotein levels were quantified in 93 HIV-infected adults receiving PIs. Comparison was done with pretreatment values and with 28 nonPI-treated HIV-infected subjects. An elevation in plasma cholesterol levels was observed in all PI-treated groups but was more pronounced for ritonavir (2.0+/-0.3 mmol/L [mean+/-SEM], n=46, versus 0.1+/-0.2 mmol/L in nonPI treated group, P<0.001) than for indinavir (0.8+/-0.2 mmol/L, n=26, P=0.03) or nelfinavir (1.2+/-0.2 mmol/L, n=21, P=0.01). Administration of ritonavir, but not indinavir or nelfinavir, was associated with a marked elevation in plasma triglyceride levels (1.83+/-0.46 mmol/L, P=0.002). Plasma HDL-cholesterol levels remained unchanged. Combination of ritonavir or nelfinavir with saquinavir did not further elevate plasma lipid levels. A 48% increase in plasma levels of lipoprotein(a) was detected in PI-treated subjects with pretreatment Lp(a) values >20 mg/dL. Similar changes in plasma lipid levels were observed in 6 children receiving ritonavir. CONCLUSIONS: Administration of PIs to HIV-infected individuals is associated with a marked, compound-specific dyslipidemia. The risk of pancreatitis and premature atherosclerosis due to PI-associated dyslipidemia remains to be established. (+info)
Somatostatin receptor scintigraphy in pituitary adenomas: a somatostatin receptor density index can predict hormonal and tumoral efficacy of octreotide in vivo.
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Previous studies have failed to predict somatostatin analog response with somatostatin receptor scintigraphy in pituitary adenomas. In vitro studies have shown that the density of somatostatin receptors in pituitary tumors might be critical for octreotide response. METHODS: The density of somatostatin receptors was calculated in vivo combining the uptake index obtained from somatostatin receptor scintigraphy and the tumor volume obtained by MRI. The ratio of these two values, called density index (DI), was established in 32 of 37 consecutive patients with pituitary adenomas (11 had growth hormone-secreting adenomas, 4 thyroid-stimulating hormone-secreting and 17 nonfunctioning). It was compared with hormonal response, assessed in 15 secreting adenomas on growth hormone or thyroid stimulating hormone suppression (which was considered significant when it reached at least 50% of basal level), and with tumor shrinkage (which was considered significant when > or =20% of pretherapeutic value) in 12 secreting and 14 nonfunctioning adenomas. RESULTS: In agreement with previous reports, uptake index is not predictive of octreotide response. In contrast, DI predicts both hormonal suppression and tumor shrinkage (P = 0.009 and P = 0.0002, respectively) obtained with octreotide therapy. DI sensitivity, specificity and accuracy were 92% each, and a positive correlation was found between DI and the percentage of tumor shrinkage (r = 0.54, P = 0.004). CONCLUSION: The combination of scintigraphic and MRI data allows the computation of a DI for somatostatin receptors that points out patients who can profit from somatostatin analog treatment. (+info)
Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child.
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BACKGROUND: When thyroid deficiency occurs simultaneously in a pregnant woman and her fetus, the child's neuropsychological development is adversely affected. Whether developmental problems occur when only the mother has hypothyroidism during pregnancy is not known. METHODS: In 1996 and 1997, we measured thyrotropin in stored serum samples collected from 25,216 pregnant women between January 1987 and March 1990. We then located 47 women with serum thyrotropin concentrations at or above the 99.7th percentile of the values for all the pregnant women, 15 women with values between the 98th and 99.6th percentiles, inclusive, in combination with low thyroxine levels, and 124 matched women with normal values. Their seven-to-nine-year-old children, none of whom had hypothyroidism as newborns, underwent 15 tests relating to intelligence, attention, language, reading ability, school performance, and visual-motor performance. RESULTS: The children of the 62 women with high serum thyrotropin concentrations performed slightly less well on all 15 tests. Their full-scale IQ scores on the Wechsler Intelligence Scale for Children, third edition, averaged 4 points lower than those of the children of the 124 matched control women (P= 0.06); 15 percent had scores of 85 or less, as compared with 5 percent of the matched control children. Of the 62 women with thyroid deficiency, 48 were not treated for the condition during the pregnancy under study. The full-scale IQ scores of their children averaged 7 points lower than those of the 124 matched control children (P=0.005); 19 percent had scores of 85 or less. Eleven years after the pregnancy under study, 64 percent of the untreated women and 4 percent of the matched control women had confirmed hypothyroidism. CONCLUSIONS: Undiagnosed hypothyroidism in pregnant women may adversely affect their fetuses; therefore, screening for thyroid deficiency during pregnancy may be warranted. (+info)
Protirelin (thyrotropin-releasing hormone) in thyroid gland: possible involvement in regulation of thyroid status.
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AIM: To establish the presence of the hypothalamic hormone protirelin (thyrotropin-releasing hormone, TRH) in human thyroid and to investigate whether the concentration of this peptide in the thyroid gland is sensitive to thyroid status. METHODS: A procedure has been developed for the determination of TRH in the thyroid gland, distinct from TRH-like peptides which also react with TRH-antibody. RESULTS: Human thyroid was shown to contain both authentic TRH and TRH-like peptides, a similar pattern was seen in a range of animal thyroids. The concentrations of TRH in non-active goiter thyroids were substantial (41.6-248 pmol.g-1); in contrast the thyroids from hyperthyroid patients contained very little TRH (0.01-2.52 pmol.g-1). CONCLUSION: The physiologic role of TRH in the thyroid is not known but the large difference between the concentrations of this hormone in non-active and hyperactive thyroids suggests that thyroidal TRH may be involved in the regulation of thyroid status. (+info)