Differential Effects of Raloxifene and Estrogen on Insulin Sensitivity in Postmenopausal Women

Lee, Cathy C.; Kasa-Vubu, Joséphine Z.; Supiano, Mark A.

doi:10.1034/j.1600-0579.2003.00214.x

Cited by 31 publications

(18 citation statements)

References 45 publications

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“…Menopause increases adiposity independent of aging (336,429,535,550,714,739,741), and some data indicate that high-estrogen hormone-replacement treatment (HRT) prevents this (297,312,419,628,686). Whether ovariectomy (or oophorectomy), menopause, or exogenous estrogens affect eating in women, however, remains in doubt, perhaps due to the inadequacies in the designs used so far.…”

Section: R1226 Sex Differences In the Physiology Of Eatingmentioning

confidence: 99%

Sex differences in the physiology of eating

Asarian

Geary²

2013

American Journal of Physiology-Regulatory, Integrative and Comp

414

349

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(HPG) axis function fundamentally affects the physiology of eating. We review sex differences in the physiological and pathophysiological controls of amounts eaten in rats, mice, monkeys, and humans. These controls result from interactions among genetic effects, organizational effects of reproductive hormones (i.e., permanent early developmental effects), and activational effects of these hormones (i.e., effects dependent on hormone levels). Male-female sex differences in the physiology of eating involve both organizational and activational effects of androgens and estrogens. An activational effect of estrogens decreases eating 1) during the periovulatory period of the ovarian cycle in rats, mice, monkeys, and women and 2) tonically between puberty and reproductive senescence or ovariectomy in rats and monkeys, sometimes in mice, and possibly in women. Estrogens acting on estrogen receptor-␣ (ER␣) in the caudal medial nucleus of the solitary tract appear to mediate these effects in rats. Androgens, prolactin, and other reproductive hormones also affect eating in rats. Sex differences in eating are mediated by alterations in orosensory capacity and hedonics, gastric mechanoreception, ghrelin, CCK, glucagon-like peptide-1 (GLP-1), glucagon, insulin, amylin, apolipoprotein A-IV, fatty-acid oxidation, and leptin. The control of eating by central neurochemical signaling via serotonin, MSH, neuropeptide Y, Agouti-related peptide (AgRP), melanin-concentrating hormone, and dopamine is modulated by HPG function. Finally, sex differences in the physiology of eating may contribute to human obesity, anorexia nervosa, and binge eating. The variety and physiological importance of what has been learned so far warrant intensifying basic, translational, and clinical research on sex differences in eating.neuroendocrinology; estrogens; testosterone; eating disorders; obesity SEX DIFFERENCES ARE PERVASIVE in physiology and medicine (51,64,73,109,110,466,797,826). The controls of eating and energy homeostasis are no exceptions. It was observed approximately 100 years ago that removal of the ovaries leads to marked accretion of adipose tissue in rats (697), that daily food intake expressed as kilocalories per gram body weight differs between male and female rats (778), and that food intake varies regularly through the ovarian cycle in intact female rats (674, 779). Sex differences in eating have been the subject of physiological research ever since. The clinical relevance of this work is increasingly evident. In the United States, women are approximately threefold more vulnerable than men to psychiatric eating disorders (346,351) and approximately twofold more vulnerable to severe and morbid obesity (BMI Ն 35 and 40 kg/m 2 , respectively, mass/height 2 ) (226). Women also appear to suffer more from these disorders in terms of physical and psychological functioning and quality of life (24,84,273,292,465,531,762). The increased obesity burden suffered by women is reflected in the fact that Ͼ80% of bariatric surgery patients in the U...

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Section: R1226 Sex Differences In the Physiology Of Eatingmentioning

confidence: 99%

Sex differences in the physiology of eating

Asarian

Geary²

2013

American Journal of Physiology-Regulatory, Integrative and Comp

414

349

View full text Add to dashboard Cite

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“…Raloxifene acts as an estrogen agonist on the arterial vasculature, bone, and lipid metabolism and as an estrogen antagonist on the breast and uterus (17,18). To our knowledge, few studies have investigated the effect of raloxifene on body composition (19,20), and none has investigated the effect of raloxifene on muscle strength. We conducted a randomized, double-blind, placebo-controlled trial to assess the effects of raloxifene on body composition and muscle strength and power in elderly women.…”

Section: Introductionmentioning

confidence: 99%

Raloxifene and body composition and muscle strength in postmenopausal women: a randomized, double-blind, placebo-controlled trial

Jacobsen

Samson

Emmelot-Vonk

et al. 2010

European Journal of Endocrinology

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Objective: To compare the effects of raloxifene and placebo on body composition and muscle strength. Design: Randomized, double-blind, placebo-controlled trial involving 198 healthy women aged 70 years or older conducted between July 2003 and January 2008 at the University Medical Centre, Utrecht, The Netherlands. Methods: Participants were randomly assigned to receive raloxifene 60 mg or placebo daily for 12 months. Measurements were taken at baseline, 3, 6, and 12 months, and change from baseline was calculated. Main outcome measures were body composition (bioelectrical impedance analysis), muscle strength, and muscle power (maximum voluntary isometric knee extension strength, explosive leg extensor power, and handgrip strength). Results: At 12 months, the body composition of women taking raloxifene was significantly different from that of women taking placebo: fat-free mass (FFM) had increased by a mean of 0.83 (2.4) kg in the raloxifene group versus 0.03 (1.5) kg in the placebo group (PZ0.05), and total body water had increased by a mean of 0.6 (1.8) litres in the raloxifene group versus a decrease of 0.06 (1.1) litres in the placebo group (PZ0.02). Muscle strength and power were not significantly different. Conclusion: Raloxifene significantly changed body composition (increased FFM; increased water content) compared with placebo in postmenopausal women.

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“…Several lines of investigation in humans and rodents clearly show that inactivation of these stress kinases by pharmacological or genetic means leads to improved insulin action and reversal of diabetic complications (3,41,84). Similarly, 17␤-estradiol supplementation has been shown to diminish inflammatory signaling (26 -27, 34, 72) and improve insulin action (10,46), but the link between these two pathways and whole body substrate metabolism is poorly defined.…”

mentioning

confidence: 99%

Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERα-deficient mice

Ribas

Nguyen

Henstridge

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

271

249

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Ribas V, Nguyen MT, Henstridge DC, Nguyen A, Beaven SW, Watt MJ, Hevener AL. Impaired oxidative metabolism and inflammation are associated with insulin resistance in ER␣-deficient mice. Am J Physiol Endocrinol Metab 298: E304 -E319, 2010. First published November 17, 2009 doi:10.1152/ajpendo.00504.2009.-Impaired estrogen action is associated with the metabolic syndrome in humans. We sought to determine whether impaired estrogen action in female C57Bl6 mice, produced by whole body Esr1 ablation, could recapitulate aspects of this syndrome, including inflammation, insulin resistance, and obesity. Indeed, we found that global knockout (KO) of the estrogen receptor (ER)␣ leads to reduced oxygen uptake and caloric expenditure compared with wild-type (WT) mice. In addition, fasting insulin, leptin, and PAI-1 levels were markedly elevated, whereas adiponectin levels were reduced in normal chow-fed KO. Furthermore, ER␣-KO mice exhibited impaired glucose tolerance and marked skeletal muscle insulin resistance that was accompanied by the accumulation of bioactive lipid intermediates, inflammation, and diminished PPAR␣, PPAR␦, and UCP2 transcript levels. Although the relative glucose intolerance and insulin resistance phenotype in KO mice became more severe with high-fat feeding, WT mice were refractory to these dietary-induced effects, and this protection coincided with a marked increase in circulating adiponectin and heat shock protein 72 levels in muscle, liver, and fat. These data indicate that ER␣ is critical for the maintenance of whole body insulin action and protection against tissue inflammation during both normal chow and high-fat feeding.estrogen receptor-␣; estrogen action; fatty acid metabolism; insulin action INSULIN RESISTANCE IS A CENTRAL FACTOR in the pathogenesis of type 2 diabetes and a defining feature of the metabolic syndrome, a constellation of abnormalities that includes obesity, hypertension, glucose intolerance, and dyslipidemia (21, 50). Prior to menopause, the incidence of type 2 diabetes is lower in women compared with men (50, 57). However, following menopause or ovariectomy this protection is lost, and a precipitous decline in insulin sensitivity coincides with increased fat mass and elevated circulating inflammatory markers [TNF␣, IL-6, and plasminogen activator inhibitor-1 (PAI-1)], LDL, triglycerides, and fatty acids (13,58,66). Similarly, alterations in estrogen receptor (ER) expression in both sexes have been linked with increased prevalence of certain aspects of the metabolic syndrome (22,(53)(54)67). We hypothesize that ER␣ is important in the regulation of tissue substrate metabolism and inflammatory signaling and thus is critical in modulating insulin action and adiposity.It is now widely accepted that impaired fatty acid metabolism and/or fatty acid oversupply cause heightened inflammatory signaling, and these are central contributors to whole body insulin resistance (3,41,84). Accumulation of lipid intermediates in insulin-responsive tissues can activate a host of "stress" kinases,...

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Differential Effects of Raloxifene and Estrogen on Insulin Sensitivity in Postmenopausal Women

Cited by 31 publications

References 45 publications

Sex differences in the physiology of eating

Sex differences in the physiology of eating

Raloxifene and body composition and muscle strength in postmenopausal women: a randomized, double-blind, placebo-controlled trial

Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERα-deficient mice

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