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H. M. Thomas
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I. C. Green
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M. Wallis
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R. Aston
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ABSTRACT

Male hypophysectomized rats treated with bovine (b)GH–monoclonal antibody complexes showed enhanced weight gain compared with animals treated with bGH alone over a 12-day treatment period. Liver microsomes prepared from animals showing enhanced weight gain exhibited increased specific binding of human (h)GH. Studies on the specificity of these binding sites showed that they were lactogenic, 125I-labelled hGH being displaced by ovine prolactin, but not by non-mammalian growth hormones. In this respect they were similar to lactogenic binding sites in the liver of pregnant rats. Monoclonal antibodies to hGH blocked binding to lactogenic receptors to different extents. The pattern of such inhibition was similar, but not identical, for the receptors induced in hypophysectomized rats and those from pregnant rat liver. The evidence available suggests that the lactogenic receptors induced by bGH–monoclonal antibody complexes are not directly involved in the enhancement of growth.

Journal of Endocrinology (1990) 124, 469–474

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C. Sernia
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R. T. Gemmell
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W. G. Thomas
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ABSTRACT

There is inconclusive evidence that oxytocin acts directly on the corpus luteum and affects steroidogenesis. Since any such action would probably be mediated by oxytocin receptors, these should be present in luteal tissue. In this study, homogenates of corpora lutea from both pregnant and non-pregnant ewes were examined for oxytocin receptors by radio-receptor assay. Specific oxytocin binding was not observed in luteal tissue during the oestrous cycle. However specific binding was found in the corpora lutea of pregnant ewes; appearing at a fetal head length of approximately 0·65 cm (about 30 days of pregnancy) and persisting to a head size of 11 cm, the largest size examined in this study. The affinity (K d) of the receptor was calculated as 2·9 ± 0·3 nmol/l (s.e.m.; n = 9), a value similar to that obtained for the uterus. The receptor number ranged from a low of 8·7± 3·2 fmol/mg protein (n = 6) at a head size of <0·65 cm, to a maximum of 40·1 ± 6·5 fmol/mg protein (n = 25) at a head size of 2·5–3·75 cm. These values were lower than our estimate of 588 ± 39 fmol/mg protein (n = 5) for the uterus. It is concluded that a direct action of oxytocin on the corpus luteum is possible but only after the first month of pregnancy and not in the corpus luteum of the oestrous cycle.

Journal of Endocrinology (1989) 121, 117–123

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STUART HANDWERGER
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R. E. FELLOWS
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M. C. CRENSHAW
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THOMAS HURLEY
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JANET BARRETT
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W. F. MAURER
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SUMMARY

The intravenous administration of ovine placental lactogen to pregnant and non-pregnant sheep produced significant acute decreases in plasma free fatty acid, glucose and amino nitrogen concentrations. Plasma insulin concentrations decreased 1 h after administration of ovine placental lactogen and then increased significantly above baseline concentrations. The results suggest that, like human placental lactogen, ovine placental lactogen is important in the modulation of intermediary metabolism during pregnancy. The sheep is an excellent animal model for the investigation of the physiology of placental lactogen.

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Samira Fargali Departments of, Neuroscience, Medicine, Geriatrics, Box 1065, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA

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Thomas Scherer Departments of, Neuroscience, Medicine, Geriatrics, Box 1065, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA

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Andrew C Shin Departments of, Neuroscience, Medicine, Geriatrics, Box 1065, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA

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Masato Sadahiro Departments of, Neuroscience, Medicine, Geriatrics, Box 1065, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA

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Christoph Buettner Departments of, Neuroscience, Medicine, Geriatrics, Box 1065, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA
Departments of, Neuroscience, Medicine, Geriatrics, Box 1065, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA

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Stephen R Salton Departments of, Neuroscience, Medicine, Geriatrics, Box 1065, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA
Departments of, Neuroscience, Medicine, Geriatrics, Box 1065, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029, USA

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Targeted deletion of VGF, a neuronal and endocrine secreted protein and neuropeptide precursor, produces a lean, hypermetabolic mouse that is resistant to diet-, lesion-, and genetically induced obesity and diabetes. We hypothesized that increased sympathetic nervous system activity in Vgf−/Vgf− knockout mice is responsible for increased energy expenditure and decreased fat storage and that increased β-adrenergic receptor stimulation induces lipolysis in white adipose tissue (WAT) of Vgf−/Vgf− mice. We found that fat mass was markedly reduced in Vgf−/Vgf− mice. Within knockout WAT, phosphorylation of protein kinase A substrate increased in males and females, phosphorylation of hormone-sensitive lipase (HSL) (ser563) increased in females, and levels of adipose triglyceride lipase, comparative gene identification-58, and phospho-perilipin were higher in male Vgf−/Vgf− WAT compared with wild-type, consistent with increased lipolysis. The phosphorylation of AMP-activated protein kinase (AMPK) (Thr172) and levels of the AMPK kinase, transforming growth factor β-activated kinase 1, were decreased. This was associated with a decrease in HSL ser565 phosphorylation, the site phosphorylated by AMPK, in both male and female Vgf−/Vgf− WAT. No significant differences in phosphorylation of CREB or the p42/44 MAPK were noted. Despite this evidence supporting increased cAMP signaling and lipolysis, lipogenesis as assessed by fatty acid synthase protein expression and phosphorylated acetyl-CoA carboxylase was not decreased. Our data suggest that the VGF precursor or selected VGF-derived peptides dampen sympathetic outflow pathway activity to WAT to regulate fat storage and lipolysis.

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G P Risbridger
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T Thomas
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C J Gurusinghe
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J R McFarlane
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Abstract

Inhibin and activin are members of the transforming growth factor β (TGFβ) family which can regulate cell proliferation in a number of tissues. The presence of inhibins and the related proteins, activins, in the prostate has been implicated by the detection of activin type II receptors. The aim of this study was to determine whether or not immunoactive (ir) inhibin and ir-activin are present in the rat prostate and to study the acute regulation by androgens. The results showed that mRNAs for the α and β inhibin subunits were detected in rat prostate by reverse transcription-PCR together with ir-inhibin and ir-activin in prostate cytosols. The levels of ir-activin in the prostate (223 ± 44 ng/gland) were greater than the levels of ir-inhibin (6·89 ng/gland), and activin immunoreactivity was localised to the epithelial cells. The presence of these proteins and the subunit mRNAs suggests that these proteins are produced in the prostate and may have a role in prostate function. The study of the effect of androgen withdrawal on the levels of ir-activin and ir-inhibin in these tissues showed no change in the content of ir-inhibin or ir-activin (ng/g tissue) after 3 days of castration or following the administration of the cytotoxic drug ethane dimethane sulphonate (EDS), although there was a significant (P<0·01) decline in prostate weight. Fourteen days after EDS treatment, as the prostate weight fell significantly lower, the amount of ir-inhibin and ir-activin per prostate gland was significantly (P<0·01) reduced although the concentration was unaffected. These data demonstrate, for the first time, that inhibin α and β subunit mRNA and ir-inhibin and ir-activin are present in the prostate; the role of these proteins in prostate function remains to be established.

Journal of Endocrinology (1996) 149, 93–99

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T. J. HAYDEN
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C. R. THOMAS
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SUSAN V. SMITH
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ISABEL A. FORSYTH
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Placental lactogen has been measured in goats throughout pregnancy by radioreceptor assay of prolactin-like activity. Lactogenic activity, which is not prolactin, increased from less than 5 nmol/l in week 8 to 27 nmol/l by week 16. There was no further change until term. Plateau concentrations (week 16 to term) were highest in animals carrying triplets, 49·5 nmol/l. There were marked fluctuations in placental lactogen over a 24 h period. These short-term fluctuations were not related to changes in glucose, non-esterified fatty acids or, in two animals, progesterone. However, there was a negative correlation between mean concentrations of placental lactogen and glucose in plasma of 20 goats sampled over a 24 h period between weeks 15 and 20 of gestation. There was no difference in placental lactogen concentration from week 16 to term between goats in their first and second pregnancies although the normal period of increase in placental lactogen was delayed by some 3 weeks in goats in their second pregnancy. In hemimastectomized goats, hypophysectomy on day 60 did not affect placental lactogen but daily treatment with bromocriptine (5 mg/day) from day 60 to day 120 blocked the normal rise in concentration.

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M. J. P. G. van Kroonenburgh
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J. L. Beck
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H. M. Vemer
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R. Rolland
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C. M. G. Thomas
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C. J. Herman
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ABSTRACT

Adult male Wistar rats were treated with a single injection (500 μg s.c.) of a new biodegradable depot formulation of the LH-releasing hormone (LHRH) analogue [d-Ser(But)6]AzGly10-LH-RH (Zoladex; ICI 118 630) to evaluate its potential for inhibiting spermatogenesis. The drug produced a marked (P≤0·05) decrease in serum concentrations of FSH, LH and testosterone with a maximum effect 14 days after treatment. Since striking focal histological changes were seen in the testis after only 1 week, at a time when changes in serum gonadotrophins were minimal, there may be a direct effect of the LHRH analogue on spermatogenesis. Degenerative changes in germ cells as well as Sertoli cells could be observed. Flow-cytometric analysis of testicular cell suspensions showed a significant decline in the absolute numbers of haploid cells (spermatids), tetraploid cells (mainly pachytene spermatocytes) and of the numbers of cells in the S-phase of the cell cycle. This suggests that the drug also inhibits proliferation of spermatogonia and/or primary spermatocytes. Testis weight, serum hormone concentrations, and histological and cytological parameters returned to essentially normal values 52 days after the injection. It is concluded that this new method of administration may have practical and pharmacokinetic advantages for the purpose of reversible inhibition of spermatogenesis.

J. Endocr. (1986) 111, 449–454

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G. B. Thomas
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J. T. Cummins
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G. A. Smythe
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R. M. Gleeson
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R. C. Dow
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G. Fink
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I. J. Clarke
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ABSTRACT

The concentrations of dopamine, noradrenaline and their respective primary neuronal metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethyleneglycol (DHPG) were measured in the hypophysial portal and peripheral plasma of sheep and rats by combined gas chromatography–mass spectrometry. Hypophysial portal and jugular blood samples were taken at 5- to 10-min intervals for 3–7 h from six conscious ovariectomized ewes. Blood was also collected for 30 min under urethane anaesthesia from the cut pituitary stalk from 16 pro-oestrous female and five intact male rats.

In ovariectomized ewes, noradrenaline concentrations were higher in hypophysial portal plasma than in peripheral plasma (6·6 ± 0·8 vs 2·2 ± 0·4 nmol/l). In contrast, dopamine was undetectable (<1 nmol/l) in the portal and peripheral plasma of all ewes. Plasma levels of DOPAC and DHPG in portal and jugular samples were similar. In all pro-oestrous female rats, plasma concentrations of dopamine were higher in portal blood than in jugular blood (8·0±1·4 vs 4·8± 0·6 nmol/l). Detectable concentrations of dopamine were measured in the portal plasma of two out of five male rats. Noradrenaline concentrations were higher in portal plasma than in peripheral plasma of both female (8·3 ± 1·7 vs 3·7 ± 0·6 nmol/l) and male (14·8± 2·7 vs 6·1± 1·2 nmol/l) rats.

These data show that noradrenaline, but not dopamine, is secreted into the long portal vessels in sheep. The results suggest that there are species differences in the secretion of hypothalamic dopamine into hypophysial portal blood.

Journal of Endocrinology (1989) 121, 141–147

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Cássio M Villicev Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 2415 Sao Paulo 05508-900, Brazil
School of Arts, Sciences & Humanities, University of Sao Paulo, Sao Paulo, Brazil
Department of Biosciences, Mackenzie Presbyterian University, Sao Paulo, Brazil
Departments of Pharmaceutical Chemistry & Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, SP, Brazil
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

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Fatima R S Freitas Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 2415 Sao Paulo 05508-900, Brazil
School of Arts, Sciences & Humanities, University of Sao Paulo, Sao Paulo, Brazil
Department of Biosciences, Mackenzie Presbyterian University, Sao Paulo, Brazil
Departments of Pharmaceutical Chemistry & Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, SP, Brazil
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

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Marcelo S Aoki Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 2415 Sao Paulo 05508-900, Brazil
School of Arts, Sciences & Humanities, University of Sao Paulo, Sao Paulo, Brazil
Department of Biosciences, Mackenzie Presbyterian University, Sao Paulo, Brazil
Departments of Pharmaceutical Chemistry & Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, SP, Brazil
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

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Cássio Taffarel Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 2415 Sao Paulo 05508-900, Brazil
School of Arts, Sciences & Humanities, University of Sao Paulo, Sao Paulo, Brazil
Department of Biosciences, Mackenzie Presbyterian University, Sao Paulo, Brazil
Departments of Pharmaceutical Chemistry & Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, SP, Brazil
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

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Thomas S Scanlan Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 2415 Sao Paulo 05508-900, Brazil
School of Arts, Sciences & Humanities, University of Sao Paulo, Sao Paulo, Brazil
Department of Biosciences, Mackenzie Presbyterian University, Sao Paulo, Brazil
Departments of Pharmaceutical Chemistry & Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, SP, Brazil
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

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Anselmo S Moriscot Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 2415 Sao Paulo 05508-900, Brazil
School of Arts, Sciences & Humanities, University of Sao Paulo, Sao Paulo, Brazil
Department of Biosciences, Mackenzie Presbyterian University, Sao Paulo, Brazil
Departments of Pharmaceutical Chemistry & Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, SP, Brazil
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

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Miriam O Ribeiro Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 2415 Sao Paulo 05508-900, Brazil
School of Arts, Sciences & Humanities, University of Sao Paulo, Sao Paulo, Brazil
Department of Biosciences, Mackenzie Presbyterian University, Sao Paulo, Brazil
Departments of Pharmaceutical Chemistry & Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, SP, Brazil
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

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Antonio C Bianco Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 2415 Sao Paulo 05508-900, Brazil
School of Arts, Sciences & Humanities, University of Sao Paulo, Sao Paulo, Brazil
Department of Biosciences, Mackenzie Presbyterian University, Sao Paulo, Brazil
Departments of Pharmaceutical Chemistry & Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, SP, Brazil
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

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Cecília H A Gouveia Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof Lineu Prestes, 2415 Sao Paulo 05508-900, Brazil
School of Arts, Sciences & Humanities, University of Sao Paulo, Sao Paulo, Brazil
Department of Biosciences, Mackenzie Presbyterian University, Sao Paulo, Brazil
Departments of Pharmaceutical Chemistry & Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, SP, Brazil
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

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It is well known that thyroid hormone affects body composition; however, the effect of the thyroid hormone receptor β (TRβ)-selective thyromimetic GC-1 on this biological feature had not been demonstrated. In the current study, we compared the effects of a 6-week treatment with triiodothyronine (T3; daily injections of 3 or 6 μg/100 g body weight) or GC-1 (equimolar doses) on different metabolic parameters in adult female rats. Whereas all animals gained weight (17–25 g) in a way not basically affected by T3 or GC-1 treatment, only T3 treatment selectively increased food intake (50–70%). Oxygen consumption was significantly and equally increased (50–70%) by T3 and GC-1. Analysis of body composition by dual-energy X-ray absorptiometry (DEXA) revealed that, whereas control animals gained about 80% of fat mass, T3- or GC-1-treated animals lost 70–90 and ~20% respectively. Direct analysis of the carcass showed that T3 treatment promoted a 14–74% decrease in fat content but GC-1 treatment promoted only a 15–23% reduction. The gain in lean mass by DEXA and the carcass protein content were not affected by T3 or GC-1 treatment. However, the mass of individual skeletal muscles was negatively affected by T3 but only barely by GC-1. These findings highlight the potential use of GC-1 for the treatment of obesity and the metabolic syndrome.

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V K Turan
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R I Sanchez
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J J Li
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S A Li
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K R Reuhl
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P E Thomas
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A H Conney
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M A Gallo
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F C Kauffman
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S Mesia-Vela
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Several investigators have suggested that certain hydroxylated metabolites of 17β-estradiol (E2) are the proximate carcinogens that induce mammary carcinomas in estrogen-sensitive rodent models. The studies reported here were designed to examine the carcinogenic potential of different levels of E2 and the effects of genotoxic metabolites of E2 in an in vivo model sensitive to E2-induced mammary cancer. The potential induction of mammary tumors was determined in female ACI rats subcutaneously implanted with cholesterol pellets containing E2 (1, 2, or 3 mg), or 2-hydroxyestradiol (2-OH E2), 4-hydroxyestradiol (4-OH E2), 16α-hydroxyestradiol (16α-OH E2), or 4-hydoxyestrone (4-OH E1) (equimolar to 2 mg E2). Treatment with 1, 2, or 3 mg E2 resulted in the first appearance of a mammary tumor between 12 and 17 weeks, and a 50% incidence of mammary tumors was observed at 36, 19, and 18 weeks respectively. The final cumulative mammary tumor incidence in rats treated with 1, 2, or 3 mg E2 for 36 weeks was 50%, 73%, and 100% respectively. Treatment of rats with pellets containing 2-OH E2, 4-OH E2, 16α-OH E2, or 4-OH E1 did not induce any detectable mammary tumors. The serum levels of E2 in rats treated with a 1 or 3 mg E2 pellet for 12 weeks was increased 2- to 6-fold above control values (~30 pg/ml). Treatment of rats with E2 enhanced the hepatic microsomal metabolism of E2 to E1, but did not influence the 2- or 4-hydroxylation of E2. In summary, we observed a dose-dependent induction of mammary tumors in female ACI rats treated continuously with E2; however, under these conditions 2-OH E2, 4-OH E2, 16α-OH E2, and 4-OH E1 were inactive in inducing mammary tumors.

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