Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluated whether our previous reports of increased postmenopausal breast cancer risk with higher body mass index (BMI) or of reduced premenopausal and postmenopausal breast cancer risk with higher physical activity levels varied according to the tumor's estrogen receptor (ER) and progesterone receptor (PR) status. Participants enrolled in either of two population-based case-control studies in Los Angeles County, California: one of premenopausal women (ages < or = 40 years), and one of postmenopausal women (ages 55-64 years). Case participants were diagnosed for the first time with in situ or invasive breast cancer from 7/1/83 through 12/31/88 (premenopausal women) or from 3/1/87 through 12/31/89 (postmenopausal women). Joint ER/PR status was collected for 424 premenopausal and 760 postmenopausal case participants. The analysis included 714 premenopausal and 1091 postmenopausal age-matched, race-matched (white or Hispanic), parity-matched (premenopausal women only), and residential neighborhood-matched control participants. Among the postmenopausal women, obesity was associated with an increased odds of ER+/PR+ breast cancer (odds ratio, 2.45 for women in the highest versus the lowest body mass index quartile; 95% confidence interval, 1.73-3.47). Body mass index was associated with neither ER-/PR- tumors among the postmenopausal women nor with any ER/PR subgroup among the premenopausal women. For both premenopausal and postmenopausal women, higher recreational physical activity levels (> or = 17.6 MET-hours/week versus no activity) were associated with a 30-60% reduction in risk of nearly all ER/PR subtypes, although the associations were generally of borderline statistical significance. Examining these potentially modifiable breast cancer risk factors by tumor ER and PR status may provide us with greater insight into breast cancer etiology and the mechanisms underlying the risk factor associations.
 ...
PMID:Body size, physical activity, and breast cancer hormone receptor status: results from two case-control studies. 1091 38

Targeted disruption of the receptor for glycoprotein hormone, FSH (FSH-R) causes a gene dose-related endocrine and gametogenic abnormality in female mice. The resulting FSH-R knockout (FORKO) mutants have disordered estrous cycles, ovulatory defects, and atrophic uterus. The heterozygous animals that initially show reduced fertility undergo early reproductive senescence and stop breeding altogether. Lack of FSH-R signaling in females causes severe ovarian underdevelopment producing chronic estrogen deficiency. This was accompanied by increases in serum testosterone levels. Ovarian aromatase gene transcription and translation are unaltered in the mutants. Early loss of estrogen in the null mutants leads to obesity and skeletal abnormalities that intensify with age producing (kyphosis), a hunchback appearance. Both these changes also become apparent in older heterozygous mice coincident with early reproductive senescence. The expression of nuclear estrogen receptor(s) alpha and beta genes and the corresponding proteins in the ovary and uterus of FORKO mice appear to be intact. The loss of ovarian estrogen creates an imbalance in A and B forms of the progesterone receptor in the uterus of both heterozygotes and null mutants. Some of the changes we have documented here in FORKO mice are reminiscent of the ovarian dysfunction and other major symptoms that are usually associated with estrogen deficiency. In null mutants, estradiol-17beta administration promptly induced uterine growth and reversed the accumulation of adipose tissue indicating that estrogen receptors are functional. Thus, the phenotypes evident in these genetically altered FSH-R mutants may provide an experimental system to explore the effects of estrogenic compounds on different targets including the ovary in a nonsurgical setting.
 ...
PMID:Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice. 1108 65

There have been inconsistent results on the association of postmenopausal obesity with breast cancer risk according to the estrogen (ER) and/or progesterone receptor (PR) status in the breast tissue, and this requires further evaluation. This study was designed to assess whether postmenopausal obesity differs according to receptor status. Information on risk factors was obtained from 1154 breast cancer cases and 21714 controls at Aichi Cancer Center Hospital, Nagoya, Japan between 1988 and 1992. The receptor status was known for 40% of cases. Obese postmenopausal women showed an increased risk of breast cancer (odds ratio (OR) for 5 kg of current weight=1.17, 95% confidence interval (CI)=1.10-1.25; OR for 1 kg/m(2) of body mass index (BMI)=1.07, 95% CI=1.04-1.10). The elevated OR was strongest for ER-positive, as well as with PR-positive, breast cancer among postmenopausal women who had a high BMI. The risk did not differ significantly according to ER status. However, obesity indices among postmenopausal women differed with borderline significance according to PR status. These results are consistent with the hypothesis that there is a gradient of risk for postmenopausal obesity according to hormonal receptor status, at least for PR status, although this was not statistically significant.
 ...
PMID:Postmenopausal obesity as a breast cancer risk factor according to estrogen and progesterone receptor status (Japan). 1132 99

Estrogen receptor (ER) and progesterone receptor (PgR) levels were determined in patients with a ductal infiltrating breast carcinoma. In premenopausal patients, the distribution of the PgR was higher than that of the ER. With increasing age of the patients, the concentration of the ER increased, whereas the PgR values showed an inverse relationship. According to the menstrual status, ER and PgR values were found to be higher in postmenopausal patients than in premenopausal ones. In relation to body fat distribution, in premenopausal patients the ER or PgR values were not found to be statistically significantly different (data no shown). In postmenopausal patients, the concentration of ER was diminished by 20% in patients with obesity of the upper body segment and by 40% in patients with obesity of the lower body segment as compared with the ER values of nonobese patients. While the PgR values diminished by 20% in patients with obesity of the lower body segment, in relation to PgR values of patients with obesity of the upper body segment, we found no statistically significant differences when compared with the PgR values of nonobese patients. With regard to the body mass index, this has remained constant in both types of body fat distribution. When body mass index values were compared with serum ER and PgR levels, no statistically significant differences were found.
 ...
PMID:Hormone-related factors associated with hormone receptor levels in breast cancer. 1172 42

The brown adipose tissue (BAT) thermogenic response to diet-induced obesity and cold has been found to be gender dependent. In the present work, we aimed to investigate the effects of the main physiological male and female sex hormones, i.e. testosterone, progesterone and 17-beta-estradiol, on the expression of uncoupling protein I (UCP1)--the main mediator of BAT thermogenesis--and on UCP2 and lipid accumulation in rodent brown adipocytes differentiated in culture. Testosterone-treated cells showed fewer and smaller lipid droplets than control cells and a dose-dependent inhibition of UCP1 mRNA expression, under adrenergic stimulation by norepinephrine (NE). These effects were reverted by the androgen receptor antagonist flutamide, suggesting they are dependent, at least in part, on the androgen receptor. Progesterone- and 17-beta-estradiol-treated cells showed more and larger lipid droplets and progesterone stimulated NE-induced UCP1 mRNA expression at the lower concentration tested, but not at higher concentrations, suggesting that for brown adipocytes, this hormone is dose dependent. 17-beta-Estradiol did not have any remarkable effect either on UCP1 or UCP2 mRNA expression. Interestingly, the specific progesterone receptor antagonist RU486 induced UCP1 and UCP2 mRNAs, including UCP1 mRNA expression in non-NE-treated brown adipocytes, suggesting a profound effect of this antiprogestagen on brown adipocyte thermogenic capacity. Thus, are conclude that testosterone, 17-beta-estradiol, progesterone and RU486 have distinct actions on brown adipocytes, thus modulating UCP1 and UCP2 mRNA expression and/or lipid accumulation, and that sex hormones are factors that may explain in part the gender-dependent BAT thermogenic response.
 ...
PMID:Opposite actions of testosterone and progesterone on UCP1 mRNA expression in cultured brown adipocytes. 1247 82

Glucocorticoids potentiate the early steps of preadipocyte differentiation and promote obesity in Cushing's syndrome and during prolonged steroid therapy. We show that glucocorticoids stimulate 3T3 L1 preadipocyte differentiation through a non-transcriptional mechanism mediated through the ligand-binding domain of the glucocorticoid receptor. This enhanced the onset of CCAAT/enhancer binding protein (C/EBPalpha) expression by potentiating its initial transcriptional activation by C/EBPbeta. In the absence of steroid, C/EBPbeta associated with a transcriptional corepressor complex containing mSin3A and histone deacetylase 1 (HDAC1), but lacking HDAC2 and RbAp46/48. HDAC1/mSin3A were recruited to the C/EBPalpha promoter with C/EBPbeta and promoted the deacetylation of histone H4. Steroid induced the specific depletion of this corepressor by targeting the HDAC1 within the complex for degradation through the 26S proteasome. Treatment with histone deacetylase inhibitors replaced the effects of steroid treatment on preadipocyte differentiation and C/EBPalpha expression, while overexpression of HDAC1 abrogated the stimulatory effects of steroid. Recapitulation of the glucocorticoid effect by progestin treatment in the presence of the progesterone receptor ligand-binding domain suggests a conserved mechanism relevant to many aspects of steroid-mediated differentiation.
 ...
PMID:Stimulation of preadipocyte differentiation by steroid through targeting of an HDAC1 complex. 1272 80

Sex steroid hormones are involved in the metabolism, accumulation and distribution of adipose tissues. It is now known that oestrogen receptor, progesterone receptor and androgen receptor exist in adipose tissues, so their actions could be direct. Sex steroid hormones carry out their function in adipose tissues by both genomic and nongenomic mechanisms. In the genomic mechanism, the sex steroid hormone binds to its receptor and the steroid-receptor complex regulates the transcription of given genes. Leptin and lipoprotein lipase are two key proteins in adipose tissues that are regulated by transcriptional control with sex steroid hormones. In the nongenomic mechanism, the sex steroid hormone binds to its receptor in the plasma membrane, and second messengers are formed. This involves both the cAMP cascade and the phosphoinositide cascade. Activation of the cAMP cascade by sex steroid hormones would activate hormone-sensitive lipase leading to lipolysis in adipose tissues. In the phosphoinositide cascade, diacylglycerol and inositol 1,4,5-trisphosphate are formed as second messengers ultimately causing the activation of protein kinase C. Their activation appears to be involved in the control of preadipocyte proliferation and differentiation. In the presence of sex steroid hormones, a normal distribution of body fat exists, but with a decrease in sex steroid hormones, as occurs with ageing or gonadectomy, there is a tendency to increase central obesity, a major risk for cardiovascular disease, type 2 diabetes and certain cancers. Because sex steroid hormones regulate the amount and distribution of adipose tissues, they or adipose tissue-specific selective receptor modulators might be used to ameliorate obesity. In fact, hormone replacement therapy in postmenopausal women and testosterone replacement therapy in older men appear to reduce the degree of central obesity. However, these therapies have numerous side effects limiting their use, and selective receptor modulators of sex steroid hormones are needed that are more specific for adipose tissues with fewer side effects.
 ...
PMID:Direct effects of sex steroid hormones on adipose tissues and obesity. 1545 95

Breast cancers classified by estrogen receptor (ER) and/or progesterone receptor (PR) expression have different clinical, pathologic, and molecular features. We examined existing evidence from the epidemiologic literature as to whether breast cancers stratified by hormone receptor status are also etiologically distinct diseases. Despite limited statistical power and nonstandardized receptor assays, in aggregate, the critically evaluated studies (n = 31) suggest that the etiology of hormone receptor-defined breast cancers may be heterogeneous. Reproduction-related exposures tended to be associated with increased risk of ER-positive but not ER-negative tumors. Nulliparity and delayed childbearing were more consistently associated with increased cancer risk for ER-positive than ER-negative tumors, and early menarche was more consistently associated with ER-positive/PR-positive than ER-negative/PR-negative tumors. Postmenopausal obesity was also more consistently associated with increased risk of hormone receptor-positive than hormone receptor-negative tumors, possibly reflecting increased estrogen synthesis in adipose stores and greater bioavailability. Published data are insufficient to suggest that exogenous estrogen use (oral contraceptives or hormone replacement therapy) increase risk of hormone-sensitive tumors. Risks associated with breast-feeding, alcohol consumption, cigarette smoking, family history of breast cancer, or premenopausal obesity did not differ by receptor status. Large population-based studies of determinants of hormone receptor-defined breast cancers defined using state-of-the-art quantitative immunostaining methods are needed to clarify the role of ER/PR expression in breast cancer etiology.
 ...
PMID:Etiology of hormone receptor-defined breast cancer: a systematic review of the literature. 1546 70

Medroxyprogesterone acetate (MPA), a widely used synthetic progestational contraceptive, occasionally leads to Cushingoid side effects such as hypertension, fluid retention, and centripetal obesity. We investigated the effect of MPA on classic mineralocorticoid target genes, alpha-epithelial Na channel (ENaC) and sgk1, in the collecting duct. In adrenalectomized mice, aldosterone, dexamethasone, and MPA increased alpha-ENaC mRNA levels in kidney cortex. MPA and dexamethasone, but not progesterone, dose dependently increased alpha-ENaC and sgk1 mRNA in M-1 and in Madin-Darby canine kidney-C7 cells, both collecting duct cell lines. The stimulatory effect of MPA and dexamethasone on alpha-ENaC expression was inhibited by RU-38486, a combined glucocorticoid receptor (GR) and progesterone receptor (PR) antagonist, but not by Org31710, a pure PR antagonist. MPA and dexamethasone dose dependently increased alpha-ENaC promoter-driven luciferase activity in M-1 cells, which was not inhibited by Org31710, indicating that MPA regulates alpha-ENaC in a PR-independent manner. When tested in HT29 cells, MPA could only stimulate alpha-ENaC-driven reporter activity when GR was coexpressed, confirming the requirement for functional GR in the transcriptional effect of MPA. The activation of steroid receptors such as GR can explain the apparent glucocorticoid effects of MPA, independent of PR activation.
 ...
PMID:Medroxyprogesterone acetate binds the glucocorticoid receptor to stimulate alpha-ENaC and sgk1 expression in renal collecting duct epithelia. 1618 95

There is scarce information about the factors associated with estrogen receptors (ER) at menopause. In 113 volunteers pre- and post-menopausal healthy women, grouped as with and without obesity, estrogen receptors-alpha and -beta, and progesterone receptor (PR) were measured by immunohistochemistry in skin punch biopsies obtained from the external gluteal area. In pre-menopausal women, biopsies and a blood sample were performed between days 7 and 14 of the cycle. Serum hormone levels were measured by immunoradiometric assay or radioimmunoassay. After menopause, ER and PR amounts decreased significantly. At pre-menopause, obese women had lower PR levels than non obese (P<.006). In the post-menopausal group, obese women showed higher ER-alpha (P<.03) and ER-beta (P<.02) levels than the non obese group. In the analysis of factors associated with the amount of steroid receptors for the total group, log[ER-alpha], log[ER-beta], and log[PR] were associated with age (P<.002, <.005, and <.004, respectively). The log[ER-alpha] was also associated with log[FSH] (P<.0008); meanwhile, the log[PR] showed a marginal correlation with log[FSH]. In pre-menopausal women no factor associated with any of the three receptors was found. In post-menopausal women log[ER-alpha] was associated with log[estrone] and log[DHEAS] (P<.003 and <.02, respectively). log[PR] was associated with BMI (P<.002), years since menopause (P<.05), and log[DHEAS] (P<.003). We concluded that ER and PR diminish sharply at post-menopause. At this stage the amount of receptors depends on several factors such as BMI, years since menopause, and androgen precursors.
 ...
PMID:Factors associated with estrogen receptors-alpha (ER-alpha) and -beta (ER-beta) and progesterone receptor abundance in obese and non obese pre- and post-menopausal women. 1656 54


<< Previous 1 2 3 4 5 6 7 Next >>