scholarly journals Dose-Response Effects of 2-Methoxyestradiol on Estrogen Target Tissues in the Ovariectomized Rat

Endocrinology ◽  
2003 ◽  
Vol 144 (3) ◽  
pp. 785-792 ◽  
Author(s):  
J. D. Sibonga ◽  
S. Lotinun ◽  
G. L. Evans ◽  
V. S. Pribluda ◽  
S. J. Green ◽  
...  
Keyword(s):  
Body Weight ◽  
Bone Loss ◽  
Cancellous Bone ◽  
Dose Response ◽  
Bone Growth ◽  
Body Weight Gain ◽  
Hormone Replacement ◽  
Adult Rats ◽  
Cell Height ◽  
Ovx Rats

In three experiments, we evaluated the pharmacological effects of 2-methoxyestradiol (2ME2) on several estrogen target tissues. Experiment 1: we gavaged recently ovariectomized (OVX) 9.5-wk-old rats with 2ME2 at doses of 0, 0.1, 1, 4, 20, and 75 mg/kg in a 21-d dose-response study. 2ME2 reduced body weight and serum cholesterol, increased uterine weight and epithelial cell height, and inhibited longitudinal and radial bone growth compared with values in the untreated OVX rat. All doses of 2ME2 maintained cancellous bone mass at the baseline level, the lowest effective dose being 20-fold less than a uterotrophic dose. Experiment 2: in an 8-wk experiment in adult OVX rats, a nonuterotrophic dose of 2ME2 (4 mg/kg·d) suppressed body weight gain, inhibited bone formation in cancellous bone and partially prevented bone loss in the tibial metaphysis. Experiment 3: in weanling rats, ICI 182,780 did not antagonize the effect of 2ME2. We conclude that 2ME2 antagonizes the skeletal changes that follow OVX at doses that have minimal or no effects in the uterus in both young and adult rats; 2ME2 does not appear to act via estrogen receptors and is active on bone at doses well below those required for tumor suppression in mice. 2ME2, through a novel pathway, may be a useful alternative to conventional hormone replacement therapy for prevention of postmenopausal bone loss.

scholarly journals Tissue-selective effects of continuous release of 2-hydroxyestrone and 16alpha-hydroxyestrone on bone, uterus and mammary gland in ovariectomized growing rats

2001 ◽  
Vol 170 (1) ◽  
pp. 165-174 ◽  
Author(s):  
S Lotinun ◽  
KC Westerlind ◽  
RT Turner ◽  
RT Turner
Keyword(s):  
Body Weight ◽  
Mammary Gland ◽  
Weight Gain ◽  
Cancellous Bone ◽  
Bone Growth ◽  
Body Weight Gain ◽  
Biological Activities ◽  
Growing Rats ◽  
Cell Height ◽  
Wet Weight

2-Hydroxyestrone (2-OHE(1)) and 16alpha-hydroxyestrone (16alpha-OHE(1)) have been reported to be risk factors for negative bone balance and breast cancer, respectively. The roles of these two metabolites of estrone as estrogen agonists or antagonists with respect to estrogen target tissues, or both, are poorly defined. The purpose of this study was to characterize metabolite and tissue-specific differences between the actions of hydroxylated estrones on selected reproductive and non-reproductive estrogen target tissues in growing rats. First, the effects of ovariectomy were determined. Ovariectomy had the expected effects, including increases in all dynamic bone measurements at the proximal tibial epiphysis, without induction of bone loss. Second, ovariectomized growing rats were continuously treated for 3 weeks with 2-OHE(1), 16alpha-OHE(1), 17beta-estradiol (E(2)), a combination of E(2) and 2-OHE(1) (E(2)+2-OHE(1)), or a combination of E(2) and 16alpha-OHE(1) (E(2)+16alpha-OHE(1)), using controlled release subcutaneous implanted pellets containing 5 mg 2-OHE(1), 5 mg 16alpha-OHE(1), 0.05 mg E(2) or placebo. E(2) reduced body weight gain and radial and longitudinal bone growth as well as indices of cancellous bone turnover, and increased serum cholesterol, uterine wet weight and epithelial cell height, and proliferative cell nuclear antigen labeling in mammary gland. The hydroxylated estrones did not alter uterine wet weight and 16alpha-OHE(1) antagonized the E(2)-stimulated increase in epithelial cell height. 2-OHE(1) had no effect on cortical bone, whereas 16alpha-OHE(1) was an estrogen agonist with respect to all cortical bone measurements. 16alpha-OHE(1) also behaved as an estrogen agonist with respect to serum cholesterol and cancellous bone measurements. 2-OHE(1) had no effect on most E(2)-regulated indices of cancellous bone growth and turnover, but was a weak estrogen agonist with respect to mineral apposition rate and bone formation rate. Neither estrogen metabolite influenced body weight gain. Third, weanling rats were treated for 1 week with vehicle, E(2) (200 microg/kg per day) or 16alpha-OHE(1) (30, 100, 300, 1000 and 3000 microg/kg per day) to confirm uterotropic effects of daily subcutaneous (s.c.) administration of 16alpha-OHE(1). 16alpha-OHE(1) increased uterine weight in a dose-response manner to values that did not differ from rats treated with E(2). We conclude that the estrogen metabolites 2-OHE(1) and 16alpha-OHE(1) have target tissue-specific biological activities which differ from one another as well as from E(2). These findings add further support to the concept that there are several classes of estrogens with distinct biological activities. Furthermore, differences in the route of administration could influence the tissue specificity of estrogen metabolites.

Physiological plasma levels of androgens reduce bone loss in the ovariectomized rat

1998 ◽  
Vol 274 (2) ◽  
pp. E328-E335 ◽  
Author(s):  
C. K. Lea ◽  
A. M. Flanagan
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Protective Effect ◽  
Cancellous Bone ◽  
Plasma Levels ◽  
Slow Release ◽  
Bone Volume ◽  
Ovariectomized Rat ◽  
Ovx Rats ◽  
Reduce Bone Loss

The effect of androstenedione (ADIONE) slow-release pellets on cancellous bone volume (BV/TV) at the tibial metaphysis was investigated in ovariectomized (OVX) rats at various times from 21 to 180 days. Plasma levels of ADIONE and testosterone (T) in OVX rats were significantly reduced at 21 days and were restored close to levels in the sham rats with the 1.5-mg ADIONE pellet. OVX animals with and without ADIONE pellets resulted in close to a 50% reduction in BV/TV by day 21. By day 180, OVX rats had only ∼5% BV/TV, whereas that in ADIONE-treated OVX rats was significantly greater at ∼12%. The reduced BV/TV was associated with increased bone resorption and formation. In a separate 90-day experiment, we found that the antiandrogen, Casodex, abrogated the ADIONE-induced skeletal-protective effect in OVX rats, whereas the antiaromatase, Arimidex, had no effect. This provides evidence that ADIONE protects against the development of osteopenia in the estrogen-deficient rat and mediates its effect through androgens and not estrogens.

scholarly journals Hypothalamic leptin gene therapy reduces body weight without accelerating age-related bone loss

2015 ◽  
Vol 227 (3) ◽  
pp. 129-141 ◽  
Author(s):  
Russell T Turner ◽  
Michael Dube ◽  
Adam J Branscum ◽  
Carmen P Wong ◽  
Dawn A Olson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Body Weight ◽  
Bone Loss ◽  
Bone Mass ◽  
Bone Turnover ◽  
Cancellous Bone ◽  
Mass Density ◽  
Female Rats ◽  
Bone Mass Density ◽  
Age Related

Excessive weight gain in adults is associated with a variety of negative health outcomes. Unfortunately, dieting, exercise, and pharmacological interventions have had limited long-term success in weight control and can result in detrimental side effects, including accelerating age-related cancellous bone loss. We investigated the efficacy of using hypothalamic leptin gene therapy as an alternative method for reducing weight in skeletally-mature (9 months old) female rats and determined the impact of leptin-induced weight loss on bone mass, density, and microarchitecture, and serum biomarkers of bone turnover (CTx and osteocalcin). Rats were implanted with cannulae in the 3rd ventricle of the hypothalamus and injected with either recombinant adeno-associated virus encoding the gene for rat leptin (rAAV-Leptin,n=7) or a control vector encoding green fluorescent protein (rAAV-GFP,n=10) and sacrificed 18 weeks later. A baseline control group (n=7) was sacrificed at vector administration. rAAV-Leptin-treated rats lost weight (−4±2%) while rAAV-GFP-treated rats gained weight (14±2%) during the study. At study termination, rAAV-Leptin-treated rats weighed 17% less than rAAV-GFP-treated rats and had lower abdominal white adipose tissue weight (−80%), serum leptin (−77%), and serum IGF1 (−34%). Cancellous bone volume fraction in distal femur metaphysis and epiphysis, and in lumbar vertebra tended to be lower (P<0.1) in rAAV-GFP-treated rats (13.5 months old) compared to baseline control rats (9 months old). Significant differences in cancellous bone or biomarkers of bone turnover were not detected between rAAV-Leptin and rAAV-GFP rats. In summary, rAAV-Leptin-treated rats maintained a lower body weight compared to baseline and rAAV-GFP-treated rats with minimal effects on bone mass, density, microarchitecture, or biochemical markers of bone turnover.

Comparative effects of tamoxifen and angiotensin II type-1 receptor antagonist therapy on the hemodynamic profile of the ovariectomized female rat

2003 ◽  
Vol 81 (9) ◽  
pp. 915-919 ◽  
Author(s):  
My-Lan Pham-Dang ◽  
Robert Clement ◽  
Isabelle Mercier ◽  
Angelino Calderone
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Body Weight Gain ◽  
Left Ventricular ◽  
Female Rat ◽  
Ovx Rats ◽  
Hemodynamic Profile

Hormonal replacement therapy (HRT) has failed to provide a cardioprotective action in postmenopausal women, and thus alternative pharmacological approaches are required. The present study examined the therapeutic potential of the partial estrogen receptor agonist tamoxifen and the angiotensin II type-1 receptor antagonist irbesartan on the hemodynamic profile of ovariectomized (OVX) female Sprague–Dawley rats (9–11 weeks). Three weeks following ovariectomy, uterine atrophy was evident and body weight was increased as compared with sham-operated animals. Left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and mean arterial pressure (MAP) were significantly increased in the OVX rats as compared with sham rats. One week following ovariectomy, rats were treated with either tamoxifen (10 mg kg–1 day–1) or irbesartan (40 mg kg–1 day–1) for a period of 2 weeks. The administration of tamoxifen to OVX rats partially reversed uterine atrophy and prevented body weight gain, albeit body weight remained significantly lower than in sham-operated animals. LVSP and LVEDP were normalized in the tamoxifen-treated OVX rats, whereas MAP remained elevated. Irbesartan partially reduced the body weight gain of the OVX rats and did not influence uterine atrophy. LVSP and MAP were normalized in irbesartan-treated OVX rats, whereas LVEDP remained elevated. These data demonstrate that irbesartan rather than tamoxifen was efficacious in normalizing MAP in the OVX rats without a secondary effect on the uterus.Key words: ovariectomy, hemodynamics, tamoxifen, AT1 receptor antagonists.

Early nutritional changes induce sexually dimorphic long-term effects on body weight gain and the response to sucrose intake in adult rats

Metabolism ◽  
2012 ◽  
Vol 61 (6) ◽  
pp. 812-822 ◽  
Author(s):  
Esther Fuente-Martín ◽  
Miriam Granado ◽  
Cristina García-Cáceres ◽  
Miguel A. Sanchez-Garrido ◽  
Laura M. Frago ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Body Weight Gain ◽  
Sexually Dimorphic ◽  
Sucrose Intake ◽  
Long Term Effects ◽  
Adult Rats ◽  
Nutritional Changes

Postnatal intracerebroventricular exposure to neuropeptide Y causes weight loss in female adult rats

2003 ◽  
Vol 284 (6) ◽  
pp. R1560-R1566 ◽  
Author(s):  
Amit Varma ◽  
Jing He ◽  
Lisa Weissfeld ◽  
Sherin U. Devaskar
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Body Weight Gain ◽  
Sprague Dawley ◽  
Adult Rats ◽  
Sprague Dawley Rats ◽  
Old Adult ◽  
Arcuate Nuclei

We investigated the effect of repetitive postnatal (2–7 days) intracerebroventricular administration of neuropeptide Y (NPY) on food intake and body weight gain in the 3- to 120-day-old Sprague-Dawley rats. NPY caused a 32% transient increase in body weight gain with elevated circulating insulin concentrations within 24 h. This early intervention led to the persistence of hyperinsulinemia and relative hyperleptinemia with euglycemia in the 120-day-old female alone. This perturbation was associated with 50% suppression in adult female hypothalamic NPY concentrations and a 50–85% decline in NPY immunoreactivity in the paraventricular and arcuate nuclei. This change was paralleled by a ∼20% decline in food intake and body weight gain at 60 and 120 days. However, when exogenous NPY was stereotaxically reinjected into the paraventricular nucleus of the ∼120-day-old adult females who were pretreated with NPY postnatally, an increase in food intake and body weight gain was noted, attesting to no disruption in the NPY end-organ responsivity. We conclude that postnatal intracerebroventricular NPY has long-lasting effects that predetermine the resultant adult phenotype in a sex-specific manner.

Adverse effects of strenuous exercise: a densitometric and histomorphometric study in the rat

1994 ◽  
Vol 76 (5) ◽  
pp. 1999-2005 ◽  
Author(s):  
S. Bourrin ◽  
C. Genty ◽  
S. Palle ◽  
C. Gharib ◽  
C. Alexandre
Keyword(s):  
Bone Mineral Density ◽  
Bone Loss ◽  
Bone Mineral ◽  
Cancellous Bone ◽  
Bone Growth ◽  
Proximal Tibia ◽  
Bone Volume ◽  
Mineral Density ◽  
Osteoblastic Activity ◽  
Tibia Length

To investigate the manner in which cancellous bone in different skeletal sites and within a bone site adapts to strenuous training, 5-wk-old male rats were subjected to intensive treadmill running [80% of maximal O2 consumption (VO2max)] for 11 wk. VO2max, tibia length, and bone mineral density were measured. Histomorphometric analysis was performed in the epiphysis, primary spongiosa (1 zero sp) and secondary spongiosa (2 zero sp) of the contralateral proximal tibia, and the 2 zero sp of thoracic and lumbar vertebrae. VO2max was increased by 39%. No changes were observed in vertebrae. Tibia length, 1 zero sp bone volume, and number of trabeculae were significantly decreased, indicating a retarded longitudinal bone growth. Bone mineral density in the proximal tibia was significantly decreased. In the epiphysis, a trabecular thinning and an increase of trabecular number were shown. In the 2 zero sp, bone volume and number of trabeculae were significantly decreased. The increased total eroded surfaces could indicate an early but transient increase in bone resorption activity. Osteoid thickness was reduced, whereas osteoclast number and osteoid surfaces were unchanged, suggesting that the observed bone loss was mostly due to an impaired osteoblastic activity. In conclusion, 1) strenuous training in young rats reduces longitudinal bone growth and induces bone loss, 2) the cancellous bone adaptation is site specific, and 3) the bone loss is mainly due to decreased osteoblastic activity rather than a global adaptation of bone remodeling.

5 alpha-Dihydrotestosterone partially restores cancellous bone volume in osteopenic ovariectomized rats

1994 ◽  
Vol 267 (6) ◽  
pp. E853-E859 ◽  
Author(s):  
J. H. Tobias ◽  
A. Gallagher ◽  
T. J. Chambers
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Cancellous Bone ◽  
Bone Growth ◽  
Bone Volume ◽  
Ovariectomized Rats ◽  
Trabecular Thickness ◽  
Longitudinal Bone Growth ◽  
Periosteal Bone Formation

Although androgens are thought to be important for skeletal maintenance in females and males, little is known about the mechanisms involved. To investigate this question further, we examined the effects of administering 0.01, 0.1, or 1.0 mg/kg 5 alpha-dihydrotestosterone (DHT) for 60 days on the skeleton of ovariectomized rats. Treatment was delayed until 90 days after ovariectomy to enable bone loss to stabilize. We found that ovariectomy markedly reduced cancellous bone volume of the proximal tibial metaphysis due to a combination of loss and thinning of trabeculae. Cancellous bone volume was partially restored by all doses of DHT, with trabecular thickness, but not number, returning to that of sham-operated animals. DHT also stimulated longitudinal bone growth and endosteal and periosteal bone formation and suppressed histomorphometric indexes of cancellous bone resorption. This suggests that DHT influences skeletal metabolism in osteopenic ovariectomized rats both by stimulating bone formation and suppressing resorption, although it is unclear which, if any, of these actions predominate at cancellous sites.

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