Effects of estradiol, estrogen receptor subtype-selective agonists and genistein on glucose metabolism in leptin resistant female Zucker diabetic fatty (ZDF) rats.

The leptin resistant Zucker diabetic fatty (ZDF) rats are hyperphagic and become obese, but whereas the males develop type 2 diabetes mellitus (T2DM), the females remain euglycaemic. As estrogen deficiency is known to increase the risk of developing T2DM, we evaluated the role of ER subtypes alpha and beta in the development of glucose tolerance in leptin resistant ovariectomized (OVX) ZDF rats. At least six rats per group were treated with either vehicle (OVX), 17β-estradiol (E2), ER subtype-selective agonists (Alpha and Beta), or genistein (Gen) for 17 weeks.

Estrogen receptor beta is involved in skeletal muscle hypertrophy induced by the phytoecdysteroid ecdysterone.

Scope: The phytoectysteroid ecdysterone (Ecdy) was reported to stimulate protein synthesis and enhance physical performance. The aim of this study was to investigate underlying molecular mechanisms particularly the role of ER beta (ERβ).

Results: In male rats, Ecdy treatment increased muscle fiber size, serum IGF-1 increased, and corticosteron and 17β-estradiol (E2) decreased.

A prostaglandin E2 receptor antagonist prevents pregnancies during a preclinical contraceptive trial with female macaques.

Study Question: Can administration of a prostaglandin (PG) E2 receptor 2 (PTGER2) antagonist prevent pregnancy in adult female monkeys by blocking periovulatory events in the follicle without altering menstrual cyclicity or general health?

Summary Answer: This is the first study to demonstrate that a PTGER2 antagonist can serve as an effective non-hormonal contraceptive in primates.

What Is Known Already: The requirement for PGE2 in ovulation and the release of an oocyte surrounded by expanded cumulus cells (cumulus-oocyte expansion; C-OE) was established through the generation of PTGS2 and PTGER2 null-mutant mice. A critical role for PGE2 in primate ovulation is supported by evidence that intrafollicular injection of indomethacin in rhesus monkeys suppressed follicle rupture, whereas co-injection of PGE2 with indomethacin resulted in ovulation.

Molecular effects of ER alpha- and beta-selective agonists on regulation of energy homeostasis in obese female Wistar rats.

The molecular mechanisms underlying the effects of selective ER subtype activation on lipogenesis, adipogenesis, lipid utilization and storage as well as glucose metabolism are currently largely unknown and were analyzed in female OVX Wistar rats on a high-fat diet. Rats received estradiol (E2), ER subtype-selective agonists (Alpha and Beta), and genistein (Gen) for 10 weeks. In adipose tissue, treatment with E2, Alpha, and Beta significantly decreased lipogenic (SREBP-1c, FAS) and adipogenic genes (LPL, PPAR gamma).

Pharmacology and clinical use of sex steroid hormone receptor modulators.

Sex steroid receptors are ligand-triggered transcription factors. Oestrogen, progesterone and androgen receptors form, together with the glucocorticoid and mineralocorticoid receptors, a subgroup of the superfamily of nuclear receptors. They share a common mode of action, namely translating a hormone-i.

The estrogen receptor-α is required and sufficient to maintain physiological glucose uptake in the mouse heart.

Estrogens attenuate cardiac hypertrophy and increase cardiac contractility via their cognate estrogen receptors (ERs) ERα and ERβ. Because female sex hormones enhance global glucose use and because myocardial function and mass are tightly linked to cardiac glucose metabolism, we tested the hypothesis that expression and activation of the ERα might be required and sufficient to maintain physiological cardiac glucose uptake in the murine heart. Cardiac glucose uptake quantified in vivo by 18F-fluorodeoxyglucose positron emission tomography was strongly impaired in ovariectomized compared with gonadal intact female C57BL/6JO mice.

Granulocytes and vascularization regulate uterine bleeding and tissue remodeling in a mouse menstruation model.

Menstruation-associated disorders negatively interfere with the quality of life of many women. However, mechanisms underlying pathogenesis of menstrual disorders remain poorly investigated up to date. Among others, this is based on a lack of appropriate pre-clinical animal models.

Both estrogen receptor subtypes, ERα and ERβ, prevent aldosterone-induced oxidative stress in VSMC via increased NADPH bioavailability.

Activation of vascular mineralocorticoid (MR) or estrogen receptors (ER) exerts opposing effects on vascular remodeling. As we have previously shown, activation of either estrogen receptor subtype, ERα or ERβ, is fully sufficient to attenuate vascular remodeling in aldosterone salt-treated rats. To further elucidate the underlying mechanism(s) we tested the hypothesis that ER and MR activation might differentially modulate vascular reactive oxygen species (ROS) generation.

Estradiol release kinetics determine tissue response in ovariectomized rats.

Estrogen replacement is an effective therapy of postmenopausal symptoms such as hot flushes, bone loss, and vaginal dryness. Undesired estrogen effects are the stimulation of uterine and mammary gland epithelial cell proliferation as well as hepatic estrogenicity. In this study, we examined the influence of different estradiol release kinetics on tissue responsivity in ovariectomized (OVX) rats.

Selective estrogen receptor-β activation stimulates skeletal muscle growth and regeneration.

There is increasing evidence suggesting that estrogens augment skeletal muscle regeneration processes after injury. To study the contribution of estrogen receptors α and β (ERα and ERβ) during muscle regeneration, skeletal muscles of ovariectomized (OVX) rats, as well as ERα- and ERβ-knockout (αErko and βErko) mice, were injured with a myotoxin (notexin). OVX rats were simultaneously treated with the ER-selective ligands genistein, ERα agonist 16α-LE2 (alpha), ERβ agonist 8β-VE2 (beta), or 17β-estradiol (E(2)).

Impact of estradiol, ER subtype specific agonists and genistein on energy homeostasis in a rat model of nutrition induced obesity.

Estrogens are known to be involved in the control of energy homeostasis. Here we investigated the role of ER alpha and ER beta in a model of nutrition induced obesity. Ovariectomized Wistar rats were fed a high fat diet and received either vehicle, E2, ER subtype selective agonists (Alpha and Beta) or genistein.

ERβ-specific agonists and genistein inhibit proliferation and induce apoptosis in the large and small intestine.

Epidemiological data indicate that intake of estrogens and isoflavones may be beneficial for the prevention of colorectal cancer (CRC). Based on this data, the aim of the study was to investigate estrogen receptor (ER) subtype-specific effects on intestinal homeostasis. Ovariectomized (OVX) female Wistar rats were either treated with 17β-estradiol (4 μg/kg body wt/day) (E2), an ERα-specific agonist (ALPHA) (10 μg/kg body wt/day), an ERβ-specific agonist (BETA) (100 μg/kg body wt/day) or genistein (GEN) (10 mg/kg body wt/day) for three weeks.

Estradiol and genistein antagonize the ovariectomy effects on skeletal muscle myosin heavy chain expression via ER-beta mediated pathways.

The age-related decline in ovarian sex hormone production following the onset of menopause alters skeletal muscle metabolic, structural and functional characteristics. The myosin heavy chain (MHC) expression pattern defines skeletal muscle contraction velocity and is therefore an important factor in skeletal muscle function. The present study was designed to examine the effects of 17beta estradiol (E2), estrogen receptor (ER) subtype selective agonists (ERalpha, ERbeta) or genistein (Gen) following ovary removal (OVX) in female Wistar rats in combination with a high intensity treadmill-based exercise protocol (Ex) or normal cage-based activity (NoEx) on MHC protein expression patterns in the slow fiber type m.

Endogenous estrogen regulation of inflammatory arthritis and cytokine expression in male mice, predominantly via estrogen receptor alpha.

Objective: A number of experimental observations have associated elevated estrogen levels with amelioration of inflammation. The involvement of estrogen and estrogen receptor (ER) isotypes in the regulation of inflammation in males is not well understood. In this study, we used specific ERalpha and ERbeta agonists in male mice deficient in estrogen because of a deletion of aromatase (aromatase-knockout [ArKO] mice) to investigate ER isotype utilization in estrogen regulation of inflammation.

Comparative analysis of the uterine and mammary gland effects of progesterone and medroxyprogesterone acetate.

Objectives: In combined hormone replacement therapy (HRT) progestins are used to inhibit estradiol-activated uterine epithelial cell proliferation. In comparison to estradiol-only therapy, combined HRT leads to enhanced proliferation of mammary epithelial cells. In a quantitative mouse model, we assessed the balance between uterine and undesired mammary gland effects for two progestins that are widely used in HRT, progesterone and medroxyprogesterone acetate.

Differential effects of 17beta-estradiol and of synthetic progestins on aldosterone-salt-induced kidney disease.

Unlabelled: Elevated mineralocorticoid levels and female sex hormones have been shown to confer opposing effects on renal injury, but their combined effects are still unknown.

Objective: Identify the function of estrogens and of different synthetic progestins on aldosterone salt-mediated renal disease.

Methods: The role of 17beta-estradiol, medroxyprogesterone acetate (MPA), and drospirenone during renal injury was studied in Wistar rats subjected to uni-nephrectomy plus aldosterone salt treatment.

GPR30 does not mediate estrogenic responses in reproductive organs in mice.

The G protein-coupled receptor Gpr30 (Gper) was recently claimed to bind to estradiol and to activate cytoplasmic signal transduction pathways in response to estradiol. However, there are conflicting data regarding the role of Gpr30 as an estrogen receptor (ER): several laboratories were unable to demonstrate estradiol binding to GPR30 or estradiol-activated signal transduction in Gpr30-expressing cells. To clarify the potential role of Gpr30 as an ER, we generated Gpr30-deficient mice.

Effects of estrogen receptor alpha- and beta-selective substances in the metaphysis of the tibia and on serum parameters of bone and fat tissue metabolism of ovariectomized rats.

The functions of estrogen receptors (ER) alpha and beta (ER-alpha and beta) in bone and fat tissue are not precisely described. Therefore we studied the effects of a specific ERalpha and ERbeta agonist in bone and fat of ovariectomized (ovx) rats and compared them with the effects of estradiol (E2). Animals were s.

Neurotrophic estrogens: essential profile and endpoints for drug discovery.

Criteria for the early recognition of selective neurotrophic action are crucial for the discovery of estrogens for supplementation therapy. The comparative characterization of 'tool' compounds in different paradigms demonstrates that estrogen-mediated CNS effects are discernible before the manifestation of changes in primary target organs. Agonist activity at, and recruitment of the coactivator SRC-1 by, the estrogen receptor alpha accurately reflect peripheral, but not neurotrophic, efficacy.

In vivo characterization of estrogen receptor modulators with reduced genomic versus nongenomic activity in vitro.

Estrogen receptor (ER) ligands that are able to prevent postmenopausal bone loss, but have reduced activity in the uterus and the mammary gland might be of great value for hormone therapy. It is well established that the classical ER can activate genomic as well as nongenomic signal transduction pathways. In this study, we analyse the in vivo behaviour of ER ligands that stimulate nongenomic ER effects to the same extent as estradiol, but show clearly reduced activation of genomic ER effects in vitro.

G protein-coupled receptor 30 localizes to the endoplasmic reticulum and is not activated by estradiol.

The classical estrogen receptor (ER) mediates genomic as well as rapid nongenomic estradiol responses. In case of genomic responses, the ER acts as a ligand-dependent transcription factor that regulates gene expression in estrogen target tissues. In contrast, nongenomic effects are initiated at the plasma membrane and lead to rapid activation of cytoplasmic signal transduction pathways.

In vivo characterization of progestins with reduced non-genomic activity in vitro.

Postmenopausal women that still have an uterus and suffer from hot flushes are treated with combinations of estrogens and progestins. Whereas estrogens are indispensable for treating postmenopausal symptoms, progestins are added to counteract the proliferative activity of estrogens on uterine epithelial cells. However, in the mammary gland, progestins, given together with estrogens, stimulate the proliferation of mammary epithelial cells.

Estrogen receptor subtype-specific effects on markers of bone homeostasis.

To further elucidate the processes involved in the physiology of bone-protection by estrogens, ovariectomized (OVX) rats were treated subcutaneously with 17beta-estradiol (E(2)), the ERalpha-specific agonist (16alpha-LE2) and the ERbeta-specific agonist (8beta-VE2). OVX and intact animals served as controls. Biomarkers of bone-formation (osteocalcin (OC), osteopontin (OPN)) and bone-resorption (telopeptides of collagen type I (CTx), pyridinoline cross-links (Pyd)) were quantified.

Comparative analysis of the uterine and mammary gland effects of drospirenone and medroxyprogesterone acetate.

The role of progestins in combined hormone therapy is the inhibition of uterine epithelial cell proliferation. The Women's Health Initiative study provided evidence for an increased risk of breast cancer in women treated with conjugated equine estrogens plus the synthetic progestin medroxyprogesterone acetate (MPA), compared with conjugated equine estrogens-only treatment. These findings continue to be discussed, and it remains to be clarified whether the results obtained for MPA in the Women's Health Initiative study are directly applicable to other progestins used in hormone therapy.