Pulsed administration for physiological estrogen replacement in mice

Estrogens are important regulators of body physiology and have major effects on metabolism, bone, the immune- and central nervous systems. The specific mechanisms underlying the effects of estrogens on various cells, tissues and organs are unclear and mouse models constitute a powerful experimental tool to define the physiological and pathological properties of estrogens. Menopause can be mimicked in animal models by surgical removal of the ovaries and replacement therapy with 17β-estradiol in ovariectomized (OVX) mice is a common technique used to determine specific effects of the hormone. However, these studies are complicated by the non-monotonic dose-response of estradiol, when given as therapy. Increased knowledge of how to distribute estradiol in terms of solvent, dose, and administration frequency, is required in order to accurately mimic physiological conditions in studies where estradiol treatment is performed. In this study, mice were OVX and treated with physiological doses of 17β-estradiol-3-benzoate (E2) dissolved in miglyol or PBS. Subcutaneous injections were performed every 4 days to resemble the estrus cycle in mice. Results show that OVX induces an osteoporotic phenotype, fat accumulation and impairment of the locomotor ability, as expected. Pulsed administration of physiological doses of E2 dissolved in miglyol rescues the phenotypes induced by OVX. However, when E2 is dissolved in PBS the effects are less pronounced, possibly due to rapid wash out of the steroid.

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TRPA1 and TRPM8 Receptors May Promote Local Vasodilation that Aggravates Oxaliplatin-Induced Peripheral Neuropathy Amenable to 17β-Estradiol Treatment

Current Neurovascular Research ◽

10.2174/1567202613666160601144254 ◽

2016 ◽

Vol 13 (4) ◽

pp. 309-317 ◽

Cited By ~ 7

Author(s):

Yuwei Pan ◽

Fengguo Chen ◽

Si Huang ◽

Zejian Cai ◽

Hai Lan ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Estradiol Treatment ◽

17Β Estradiol

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In Vivo 17β-Estradiol Treatment Contributes to Podocyte Actin Stabilization in Female db/db Mice

Endocrinology ◽

10.1210/en.2012-1637 ◽

2012 ◽

Vol 153 (12) ◽

pp. 5888-5895 ◽

Cited By ~ 8

Author(s):

Paola Catanuto ◽

Alessia Fornoni ◽

Simone Pereira-Simon ◽

Fayi Wu ◽

Kerry L. Burnstein ◽

...

Keyword(s):

Actin Cytoskeleton ◽

Transcriptional Activation ◽

Cell Types ◽

Proper Function ◽

Estradiol Treatment ◽

Diabetic Glomerulosclerosis ◽

Podocyte Damage ◽

Rac1 Activity ◽

17Β Estradiol

Abstract We recently showed that 17β-estradiol (E2) treatment ameliorated type 2 diabetic glomerulosclerosis in mice in part by protecting podocyte structure and function. Progressive podocyte damage is characterized by foot process effacement, vacuolization, detachment of podocytes from the glomerular basement membrane, and apoptosis. In addition, podocytes are highly dependent on the preservation of their actin cytoskeleton to ensure proper function and survival. Because E2 administration prevented podocyte damage in our study on diabetic db/db mice and has been shown to regulate both actin cytoskeleton and apoptosis in other cell types and tissues, we investigated whether actin remodeling and apoptosis were prevented in podocytes isolated from E2-treated diabetic db/db mice. We performed G-actin/F-actin assays, Western analysis for Hsp25 expression, Ras-related C3 botulinum toxin substrate 1 (Rac1) activity, and apoptosis assays on previously characterized podocytes isolated from both in vivo-treated placebo and E2 female db/db mice. We found that in vivo E2 protects against a phenotype change in the cultured podocytes characterized by a percent increase of F-actin vs. G-actin, suppression of Hsp25 expression and transcriptional activation, increase of Rac1 activity, and decreased apoptotic intermediates. We conclude from these studies that E2 treatment protects against podocyte damage and may prevent/reduce diabetes-induced kidney disease.

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Tissue Swelling During Extended Material Testing of Ligaments

ASME 2007 Summer Bioengineering Conference ◽

10.1115/sbc2007-176660 ◽

2007 ◽

Cited By ~ 1

Author(s):

Trevor J. Lujan ◽

Clayton C. Underwood ◽

Nathan T. Jacobs ◽

Jeffrey A. Weiss

Keyword(s):

Mechanical Properties ◽

Mechanical Behavior ◽

Biological Tissue ◽

Material Testing ◽

Test Environment ◽

Physiological Conditions ◽

Specific Effects

Material testing is often used to characterize the mechanical properties of biological tissue and to understand the specific effects of treatments and pathologies on mechanical behavior. To have confidence in results from material testing, it is important that the test environment is repeatable between samples and that tests are performed in an environment that mimics physiological conditions.

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The Effect of 17β-Estradiol Administration on Cutaneous Wound Healing in 24-Week Ovariectomized Female Mice

Journal of Hormones ◽

10.1155/2014/234632 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Kanae Mukai ◽

Yukari Nakajima ◽

Tamae Urai ◽

Emi Komatsu ◽

Kana Takata ◽

...

Keyword(s):

Wound Healing ◽

Inflammatory Response ◽

Cutaneous Wound Healing ◽

Full Thickness ◽

Estrogen Replacement ◽

Wound Area ◽

Cutaneous Wound ◽

Female Mice ◽

Exogenous Estrogen ◽

17Β Estradiol

Estrogen replacement promotes cutaneous wound healing in 8–10-week young ovariectomized female mice. However, research using aged ovariectomized female mice has not been reported, to the best of our knowledge. Therefore, we investigated the effect of 17β-estradiol on cutaneous wound healing using 24-week middle-aged ovariectomized female mice. Twenty-week-old female mice were divided into three groups: medication with 17β-estradiol after ovariectomy (OVX + 17β-estradiol), ovariectomy (OVX), and sham (SHAM). After 4 weeks, the mice received two full-thickness wounds. Then, the OVX + 17β-estradiol group was administered 17β-estradiol at 0.01 g/day until healing. The ratio of wound area in the OVX + 17β-estradiol group was significantly decreased compared with that in the OVX group. The numbers of neutrophils and macrophages in the OVX + 17β-estradiol group were significantly smaller than those in the OVX group. In addition, the ratio of myofibroblasts in the OVX + 17β-estradiol group was significantly higher than that in the OVX group. These data suggested that exogenous continuous 17β-estradiol administration promotes cutaneous wound healing in 24-week OVX female mice by reducing wound area, shortening inflammatory response, and promoting wound contraction. However, it is unclear whether the effect of exogenous estrogen on wound healing outweighs the delay of wound healing due to advanced age.

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Essential role of Ca2+-dependent phospholipase A2in estradiol-induced lysosome activation

AJP Cell Physiology ◽

10.1152/ajpcell.00429.2001 ◽

2002 ◽

Vol 283 (5) ◽

pp. C1461-C1468 ◽

Cited By ~ 39

Author(s):

Bruno Burlando ◽

Barbara Marchi ◽

Isabella Panfoli ◽

Aldo Viarengo

Keyword(s):

Blood Cells ◽

Neutral Red ◽

Short Term ◽

Estradiol Treatment ◽

Lysosomal Membranes ◽

A 23187 ◽

17Β Estradiol ◽

Dependent Mechanism ◽

Sustained Increase

The mechanism of lysosome activation by 17β-estradiol has been studied in mussel blood cells. Cell treatment with estradiol induced a sustained increase of cytosolic free Ca2+that was completely prevented by preincubating the cells with the Ca2+chelator BAPTA-AM. Estradiol treatment was also followed by destabilization of the lysosomal membranes, as detected in terms of the lysosomes' increased permeability to neutral red. The effect of estradiol on lysosomes was almost completely prevented by preincubation with the inhibitor of cytosolic Ca2+-dependent PLA2(cPLA2), arachidonyl trifluoromethyl ketone (AACOCF3), and was significantly reduced by preincubation with BAPTA-AM. In contrast, it was virtually unaffected by preincubation with the inhibitor of Ca2+-independent PLA2, ( E)-6-(bromomethylene)tetrahydro-3-(1-naphtalenyl)-2 H-pyran-2-one (BEL). The Ca2+ionophore A-23187 yielded similar effects on [Ca2+]iand lysosomes. Exposure to estradiol also resulted in cPLA2translocation from cytosol to membranes, lysosome enlargement, and increased protein degradation. These results suggest that the destabilization of lysosomal membranes following cell exposure to estradiol occurs mainly through a Ca2+-dependent mechanism involving activation of Ca2+-dependent PLA2. This mechanism promotes lysosome fusion and catabolic activities and may mediate short-term estradiol effects.

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Fathead minnow vitellogenin: Complementary DNA sequence and messenger RNA and protein expression after 17β-estradiol treatment

Environmental Toxicology and Chemistry ◽

10.1002/etc.5620190426 ◽

2000 ◽

Vol 19 (4) ◽

pp. 972-981 ◽

Cited By ~ 98

Author(s):

Joseph J. Korte ◽

Michael D. Kahl ◽

Kathleen M. Jensen ◽

Mumtaz S. Pasha ◽

Louise G. Parks ◽

...

Keyword(s):

Protein Expression ◽

Dna Sequence ◽

Messenger Rna ◽

Fathead Minnow ◽

Estradiol Treatment ◽

Complementary Dna ◽

17Β Estradiol

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Altered phosphorylation and distribution status of vimentin in rat seminiferous epithelium following 17β-estradiol treatment

Histochemistry and Cell Biology ◽

10.1007/s00418-011-0856-5 ◽

2011 ◽

Vol 136 (5) ◽

pp. 543-555 ◽

Cited By ~ 16

Author(s):

Rahul Upadhyay ◽

Ryan D’Souza ◽

Shobha Sonawane ◽

Reshma Gaonkar ◽

Shilpa Pathak ◽

...

Keyword(s):

Seminiferous Epithelium ◽

Estradiol Treatment ◽

17Β Estradiol

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Neuroprotective and Neurotrophic Efficacy of Phytoestrogens in Cultured Hippocampal Neurons

Experimental Biology and Medicine ◽

10.1177/153537020222700716 ◽

2002 ◽

Vol 227 (7) ◽

pp. 509-519 ◽

Cited By ~ 111

Author(s):

Lixia Zhao ◽

Qi Chen ◽

Roberta Diaz Brinton

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuroprotective Effect ◽

Membrane Damage ◽

Glutamate Excitotoxicity ◽

Neuronal Membrane ◽

Estrogen Replacement ◽

17Β Estradiol ◽

Β Amyloid ◽

Ldh Release

Epidemiological data from retrospective and case-control studies have indicated that estrogen replacement therapy (ERT) can decrease the risk of developing Alzheimer's disease. In addition, ERT has been found to promote cellular correlates of memory and to promote neuronal survival both in vivo and in vitro. Phytoestrogens have been proposed as potential alternatives to ERT. To determine whether phytoestrogens exert estrogen agonist effect in neural tissue, investigations of neuroprotective and neurotrophic efficacy of phytoestrogens were conducted. Six phytoestrogens, genistein, genistin, daldzein, daidzin, formononetin, and equol, were tested for their neuroprotective efficacy against two toxic insults, glutamate excitotoxicity and β-amyloid25–35. Neuronal membrane damage was quantitatively measured by lactate dehydrogenase (LDH) release, and neuronal mitochondrial viability was determined by 3-[4,5-dimethylthiazoi-2-yl]-2,5-diphenyl tetrazolium bromld (MTT) assay. Results of these studies demonstrated that all phytoestrogens induced a modest but significant reduction in LDH release following exposure to glutamate and β-amyloid25–35. In contrast, none of phytoestrogens induced a significant increase in reduced MTT levels, which occurred in the presence of a full estrogen agonist, 17β-estradiol. Analysis of the neurotrophic potential of genistein and daidzein, two phytoestrogens that exerted a significant reduction in LDH release, demonstrated that neither of these molecules promoted hippocampal neuron process outgrowth. Results of these analyses indicate that although phytoestrogens exert a neuroprotective effect at the plasma membrane, they do not sustain neuron mitochondrial viability nor do they induce cellular correlates of memory as neurite outgrowth and synaptogenesis are putative mechanisms of memory. Data derived from these investigations would predict that phytoestrogens could exert some neuroprotective effects analogous to that of antioxidants, but that these molecules are not functional equivalents to endogenously active 17β-estradiol or to estrogen replacement formulations and, therefore, would raise the concern that they may not reduce the risk of Alzheimer's disease or sustain memory function in postmenopausal women.

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Testosterone Prevents Cutaneous Ischemia and Necrosis in Males Through Complementary Estrogenic and Androgenic Actions

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.117.309219 ◽

2017 ◽

Vol 37 (5) ◽

pp. 909-919 ◽

Cited By ~ 5

Author(s):

Caroline Chenu ◽

Marine Adlanmerini ◽

Frederic Boudou ◽

Elodie Chantalat ◽

Anne-Laure Guihot ◽

...

Keyword(s):

Estrogen Receptor ◽

Direct Action ◽

Skin Flap ◽

Treatment Strategies ◽

Estrogen Receptor Α ◽

Male Mice ◽

Resistance Arteries ◽

Estradiol Treatment ◽

Impaired Wound Healing ◽

17Β Estradiol

Objective— Chronic nonhealing wounds are a substantial medical concern and are associated with morbidity and mortality; thus, new treatment strategies are required. The first step toward personalized/precision medicine in this field is probably in taking sex differences into account. Impaired wound healing is augmented by ischemia, and we previously demonstrated that 17β-estradiol exerts a major preventive effect against ischemia-induced skin flap necrosis in female mice. However, the equivalent effects of testosterone in male mice have not yet been reported. We then investigated the role of steroid hormones in male mice using a skin flap ischemia model. Approach and Results— Castrated male mice developed skin necrosis after ischemia, whereas intact or castrated males treated with testosterone were equally protected. Testosterone can (1) activate the estrogen receptor after its aromatization into 17β-estradiol or (2) be reduced into dihydrotestosterone, a nonaromatizable androgen that activates the androgen receptor. We found that dihydrotestosterone protected castrated wild-type mice by promoting skin revascularization, probably through a direct action on resistance arteries, as evidenced using a complementary model of flow-mediated outward remodeling. 17β-estradiol treatment of castrated male mice also strongly protected them from ischemic necrosis through the activation of estrogen receptor-α by increasing skin revascularization and skin survival. Remarkably, 17β-estradiol improved skin survival with a greater efficiency than dihydrotestosterone. Conclusions— Testosterone provides males with a strong protection against cutaneous necrosis and acts through both its estrogenic and androgenic derivatives, which have complementary effects on skin survival and revascularization.

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