Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Circulating levels of adiponectin, a hormone with insulin-sensitizing properties, are decreased in conditions related to obesity and hyperinsulinemia, which are recognized risk factors for endometrial cancer. Eighty-seven cases with incident, histologically confirmed endometrial cancer and 132 controls admitted for acute, nonneoplastic diseases were interviewed in northeastern Italy between 1999 and 2002, and blood samples were collected. Levels of adiponectin were evaluated in samples by means of a RIA. An inverse association with endometrial cancer risk emerged for plasma adiponectin levels [odds ratio (OR), 0.42; 95% confidence interval, 0.19-0.94] when comparing the highest vs. the lowest tertiles. Similar results emerged for serum adiponectin (OR, 0.30; 95% confidence interval, 0.14-0.68). The association was stronger in pre- than in postmenopausal women, but no significant heterogeneity was observed across strata of body mass index (BMI) or parity. BMI and adiponectin showed independent effects on the risk of endometrial cancer according to a multiplicative model (OR, 6.45 in the highest level of BMI and in the lowest one of adiponectin).
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PMID:Circulating adiponectin and endometrial cancer risk. 1500 2

Polycystic ovary syndrome [PCOS] is the most common endocrinopathy of women in reproductive age. An association between PCOS and type-1 endometrial cancer has often been reported in the literature. The prolonged anovulation with consequent continued secretion of estrogen unopposed by progesterone may enhance the development and growth of this malignancy, particularly in young women. Hypersecretion of luteinizing hormone [LH], chronic hyperinsulinemia and increased serum insulin-like growth factor [IGF]-I levels may represent risk factors for endometrial cancer. However, data available in the literature do not allow a meta-analysis to be carried out to calculate an estimate of the relative risk of endometrial cancer in women with PCOS. Anecdotal cases of low-grade endometrial stromal sarcoma and carcinosarcoma have been reported in association with prolonged unopposed estrogen stimulation, and in particular with PCOS. A few studies have addressed the possibility of an association between PCOS and epithelial ovarian cancer risk, and the results are conflicting but generally reassuring, and similarly the few available data appear to exclude a strong association between PCOS and breast cancer.
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PMID:Polycystic ovary syndrome and gynecological cancers: is there a link? 1601 62

Polycystic ovarian syndrome is a common disorder associated with a significant long-term risk of developing type 2 diabetes and cardiovascular diseases. Insulin resistance and hyperinsulinemia play an important role in its pathophysiology and therefore insulin sensitizers have been proposed as a possible treatment option for this condition. In this review, pertinent literature is described that supports the use of insulin sensitizers for the management of short-term (fertility and hyperandrogenism) as well as long-term (type 2 diabetes, cardiovascular diseases and endometrial cancer) clinical issues of the syndrome. There is sufficient evidence in the literature to support the initial use of insulin sensitizers for fertility and the chronic treatment of hyperandrogenism. Furthermore, insulin sensitizers may prevent type 2 diabetes or cardiovascular diseases, whereas some evidence suggests that oral contraceptives could increase these risks. Therefore, although oral contraceptives may provide a more reliable control of menstrual disorders, insulin sensitizers should be considered as a preferential treatment option in women with polycystic ovarian syndrome at an increased risk of developing type 2 diabetes or cardiovascular disease, especially if they do not need contraception.
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PMID:Use of insulin sensitizers in polycystic ovarian syndrome. 1625 22

Polycystic ovary is characterized by anovulation, hyperandrogenemia and insulin resistance. Hyperinsulinemia is known to be associated with an increase in cardiovascular risk and the development of diabetes mellitus. The finding that insulin resistance has important implications in the pathogenesis of polycystic ovarian disease has elicit the concept of a therapeutic approach of insulin-sensitizing drugs. Last decade multiple clinical trials about these drugs and upon genesis of polycystic ovary were designed; hence there is now sufficient evidence in the literature to support its clinical use. The management of polycystic ovary includes short-term objectives, such as treatment of infertility and control of androgen excess, as well as long-term considerations, such as prevention of endometrial cancer and management of dysmetabolic syndrome with its associated risk for developing type 2 diabetes and cardiovascular disease. The present review justifies the rationale use of insulin-sensitizing drugs in order to treat both short-term and long-term issues regarding polycystic ovarian disease.
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PMID:[Insulin sensitizers in the treatment of polycystic ovary]. 1630 38

Atypical endometrial hyperplasia has been associated with progression to endometrial cancer, the most common genital malignancy. There are multiple risk factors for endometrial cancer, such as early menarche, exogenous estrogen exposure, obesity and diabetes. Diabetics have a 3-4 fold relative risk of endometrial cancer. Also, several studies have demonstrated an association between insulin resistance and endometrial cancer. There is known the first description of atypical endometrial hyperplasia resistant to progestogen therapy, which was subsequently treated with an insulin-sensitizng agent, metformin. Metformin is a biguanide antihyperglycemic agent used in the treatment of adult-onset diabetes. Unlike the sulfonylureas, metformin does not act primarily by increasing insulin secretion. In contrast, metformin lowers the rate of gluconeogenesis in the presence of insulin. Therefore, it is considered an insulin-sensitizer. Increased insulin sensitivity may improve the metabolic effect of insulin and decrease its mitogenic effect by tissue-specific mechanisms. One explanation for tissue specific differences in insulin binding and action may be through the relative expression of the insulin receptor (IR) isoforms. The IR isoforms IR-A and IR-D differ by 12 amino acid residues, owing to the alternative splicing of exon. The IR-A is predominantly expressed in malignant tissues and may lead to mitogenic effects within the cell. The relative expressions of IR-A and IR-B in normal and malignant endometrial tissue is not known. Besides direct effects on the IR, several additional mechanisms have been proposed for the mitogenic effect of insulin in endometrial cancer. In addition to the possible direct mitogenic effects of insulin through the IR-A, insulin resistance may be associated with alterations in expression of insulin-like growth factors (IGFs) and the IGF binding proteins (IGFBPs) or may inhibit the protective effect of progestagens. Binding sites for IGF-1 and IGF-2 have been confirmed in both normal and malignant endometrium. Binding of IGF-1 is significantly higher in endometrial cancer compared to normal endometrium. In the Ishikawa human endometrial cancer cell line IGF-1 was a more potent mitogen than insulin or IGF-2. Insulin may increase mitogenicity by regulating the expression of IGFBPs. The IGFBPs are a family of proteins that have both proliferative and anti-proliferative effects. While all six high-affinity IGFBPs are expressed in the endometrium, IGFBP-1 is the best characterized. Hyperinsulinemia can decrease IGFBP-1 even in the presence of progesterone, perhaps inhibiting progesterone's protective effects. Interestingly, IGFBP-1 was undetectable or minimally expressed in endometrial cancers. Nestler discussed results of a 6-month treatment of 100 nonebese women with PCOS, which showed a somewhat greater effect of metformin than rosiglitazone and no benefit of administering both agents in combination. Long-term treatment with oral contraceptives decreases endometrial cancer, with a reduction in serum androgens and a decreases in hirsutism and acne, but may worsen insulin resistance and lead to deteriration in glucose tolerance. Insulin sensitizers, on the other hand, should decrease endometrial hyperplasia by inducing regular menses, but may not be as beneficial in improving androgen - related symptoms. Note that the Nurses Health Study (NHS) showed increased risk of diabetes in oral contraceptive users. These considerations may be related to the finding that women who used oral contraceptives have increased risk of myocardial infarction. Thus, in view of the particular increase in CVD risk among women with PCOS, one might be less likely to recommend oral contraceptives, while insulin sensitizers may be of particular benefit, decreasing androgens, improving ovulation and fertility, and reducing the risk of diabetes and CVD. Theoretically, metformin, a treatment which is now widely used to treat infertile women with PCOS, may have a role in preventing endometrial hyperstimulation by lowering insulin concentrations and restoring ovulation. However, the long-term effects of this drug in women with PCOS are not known and more studies are required before suggesting its use for preventing endometrial cancer.
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PMID:[Molecular action of insulin-sensitizing agents]. 1635 Jul 24

Studies in our laboratory and elsewhere have demonstrated numerous abnormalities of steroid and polypeptide hormone secretion in obesity: hyperestrogenemia and hypogonadotropic hypogonadism in obese men; diminished SHBG levels in both sexes; elevated free testosterone and free estradiol in obese women; PCOS-like gonadotropin and sex-hormone abnormalities in obese women; elevated serum insulin in both sexes; blunted stimulability of prolactin, growth hormone, and vasopressin in both sexes; and elevated basal levels and blunted stimulability and suppressibility of beta-endorphin in both sexes. All of these abnormalities have been clearly shown to be partly or completely reversible with weight loss, with the exception of the endorphin abnormalities. In that area, four out of the five studies reported show no reversibility with weight loss. Reversibility of nearly all the hormonal abnormalities of obesity (i.e., all but the hyperendorphinemia) by weight loss suggests that none of them is causative of obesity. Nevertheless, some of the reversible abnormalities may secondarily amplify the morbidity associated with obesity: the hyperinsulinemia may be related to the increased risk of hypertension, hyperlipidemia, coronary disease, and Type II diabetes; the elevated levels of free estradiol in obese women may be related to their increased risk of breast and endometrial cancer. The role of hyperendorphinemia in obesity clearly requires further investigation, since it is the only observed hormonal abnormality that appears to be non-reversible by weight loss, and also since there seems to be increased sensitivity to beta-endorphin in obesity. The possibility that endorphin abnormalities may be causal in obesity cannot be ruled out.
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PMID:A perspective on the hormonal abnormalities of obesity: are they cause or effect? 1635 9

Polycystic ovarian syndrome (PCOS) is a common endocrinopathy characterized by oligo/anovulatiaon and elevated circulating androgens or evidence of hyperandrogenism after all known potential causes have been excluded. In addition, insulin resistance and accompanying hyperinsulinemia commonly occur in women with PCOS. There is increasing evidence that the endocrinologic and metabolic abnormalities in PCOS may have complex effects on the endometrium, contributing to the infertility and endometrial disorders observed in women with this syndrome. Androgen receptors and steroid receptor co-activators are over-expressed in the endometrium of women with PCOS. Also, biomarkers of endometrial receptivity to embryonic implantation-such as alpha(v)beta3-integrin and glycodelin-are decreased, and epithelial expression of estrogen receptor alpha (ERalpha) abnormally persists in the window of implantation in endometrium in women with PCOS. In addition to being responsive to the steroid hormones estradiol, progesterone, and androgens, the endometrium is also a target for insulin, the receptor for which is cyclically regulated in normo-ovulatory women. In vitro, insulin inhibits the normal process of endometrial stromal differentiation (decidualization). In addition, insulin-like growth factors (IGFs) and their binding proteins are regulated in and act on endometrial cellular constituents, and hyperinsulinemia down-regulates hepatic IGFBP-1, resulting in elevated free IGF-I in the circulation. Thus, elevated estrogen (without the opposing effects of progesterone in the absence of ovulation), hyperinsulinemia, elevated free IGF-I and androgens, and obesity all likely contribute to endometrial dysfunction, infertility, increased miscarriage rate, endometrial hyperplasia, and endometrial cancer common in women with PCOS. The potential mechanisms underlying these disorders, specifically in women with PCOS, are complex and await additional transdisciplinary research for their complete elucidation.
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PMID:Endometrium in PCOS: Implantation and predisposition to endocrine CA. 1677 54

Although there is accumulating evidence that hyperinsulinemia in the context of insulin resistance is associated with carcinogenesis, only one prospective study of endometrial cancer incidence, in relation to diabetes, addressed this issue and showed no significant positive association. No previous study has investigated whether physical activity can modify the association between diabetes and endometrial cancer. We examined the association between diabetes and incidence of endometrial cancer and the potential effect modification by obesity and physical activity in the Swedish Mammography Cohort, a prospective cohort of 36,773 women, including 225 incident endometrial adenocarcinoma cases. After adjustments, the relative risk (RR) for endometrial cancer among women with diabetes comparing with nondiabetic women was 1.94 [95% confidence interval (95% CI), 1.23-3.08]. Among obese diabetics, the RR was 6.39 (95% CI, 3.28-12.06) compared with nonobese nondiabetic women. Among diabetics with low physical activity, the RR for endometrial cancer was 2.80 (95% CI, 1.62-4.85) compared with physically active nondiabetic women. Obese diabetics with low physical activity had a RR of 9.61 (95% CI, 4.66-19.83) compared with normal weight nondiabetic women with high physical activity. Diabetes was associated with a 2-fold increased risk, and combination of diabetes with obesity and low physical activity was associated with a further increased risk for endometrial cancer. Interventions to reduce body weight and increase physical activity may have important implications in terms of prevention of endometrial cancer and future management of diabetic subjects.
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PMID:Diabetes and risk of endometrial cancer: a population-based prospective cohort study. 1730 Dec 60

An association between polycystic ovary syndrome (PCOS) and endometrial carcinoma was first suggested in 1949. Since then, several studies have been published that appear to support this association, and it is common practice among gynecologists and physicians to prescribe hormonal treatment to reduce this perceived risk, although there is no consensus as to the subgroup of PCOS in whom this is required. The mechanism(s) underlying any association are also unclear, but it is again widely assumed that chronic anovulation, which results in continuous estrogen stimulation of the endometrium unopposed by progesterone, is a major factor. However, obesity, hyperinsulinemia, and hyperandrogenism, which are also features of PCOS, are risk factors for endometrial carcinoma, but it does not necessarily follow that the incidence or mortality from endometrial cancer is increased in women with the syndrome. Potential strategies to prevent endometrial cancer in PCOS women are discussed.
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PMID:Polycystic ovary syndrome and endometrial cancer. 1818 Oct 84

Obesity is a major risk factor for endometrial cancer, a relationship thought to be largely explained by the prevalence of high estrogen levels in obese women. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed whether insulin and/or insulin-like growth factor-I (IGF-I), a related hormone, are associated with endometrial cancer while accounting for estrogen levels. We therefore conducted a case-cohort study of incident endometrial cancer in the Women's Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. The study involved all 250 incident cases and a random subcohort of 465 subjects for comparison. Insulin, total IGF-I, free IGF-I, IGF-binding protein-3, glucose, and estradiol levels were measured in fasting baseline serum specimens. Cox models were used to estimate associations with endometrial cancer, particularly endometrioid adenocarcinomas, the main histologic type (n = 205). Our data showed that insulin levels were positively associated with endometrioid adenocarcinoma [hazard ratio contrasting highest versus lowest quartile (HR(q4-q1)), 2.33; 95% confidence interval (95% CI), 1.13-4.82] among women not using hormone therapy after adjustment for age and estradiol. Free IGF-I was inversely associated with endometrioid adenocarcinoma (HR(q4-q1), 0.53; 95% CI, 0.31-0.90) after adjustment for age, hormone therapy use, and estradiol. Both of these associations were stronger among overweight/obese women, especially the association between insulin and endometrioid adenocarcinoma (HR(q4-q1), 4.30; 95% CI, 1.62-11.43). These data indicate that hyperinsulinemia may represent a risk factor for endometrioid adenocarcinoma that is independent of estradiol. Free IGF-I levels were inversely associated with endometrioid adenocarcinoma, consistent with prior cross-sectional data.
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PMID:A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. 1839 32


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