Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aromatase (CYP19) is a cytochrome P450 enzyme that catalyzes the formation of aromatic C18 estrogens from C19 androgens. It is expressed in various tissues and contributes to sex-specific differences in cellular metabolism. We have generated aromatase-knockout (ArKO) mice in order to study the role of estrogen in the regulation of glucose metabolism. The mean body weights of male ArKO (-/-) mice (n=7) and wild-type littermates (+/+) (n=7) at 10 and 12 weeks of age were 26.7+/-1.9 g vs 26.1+/-0.8 g and 28.8+/-1.4 g vs 26.9+/-1.0 g respectively. The body weights of the ArKO and wild-type mice diverged between 10 and 12 weeks of age with the ArKO males weighing significantly more than their wild-type littermates (P<0.05). The ArKO males showed significantly higher blood glucose levels during an intraperitoneal glucose tolerance test compared with wild-type littermates beginning at 18 weeks of age. By 24 weeks of age, they had higher fasting blood glucose levels compared with wild-type littermates (133.8+/-22.8 mg/dl vs 87.8+/-20.3 mg/dl respectively; P<0.01). An intraperitoneal injection of insulin (0.75 mU insulin/g) caused a continuous decline in blood glucose levels in wild-type mice whereas ArKO males at 18 weeks and older exhibited a rebound increase in glucose levels 30 min after insulin injection. Thus, ArKO male mice appear to develop glucose intolerance and insulin resistance in an age-dependent manner. There was no difference in fasting serum triglyceride and total cholesterol levels between ArKO male mice and wild-type littermates at 13 and 25 weeks of age. However, serum triglyceride and cholesterol levels were significantly elevated following a meal in ArKO mice at 36 weeks of age. Serum testosterone levels in ArKO male mice were continuously higher compared with wild-type littermates. Treatment of ArKO males with 17beta-estradiol improved the glucose response as measured by intraperitoneal glucose and insulin tolerance tests. Treatment with fibrates and thiazolidinediones also led to an improvement in insulin resistance and reduced androgen levels. As complete aromatase deficiency in man is associated with insulin resistance, obesity and hyperlipidemia, the ArKO mouse may be a useful animal model for examining the role of estrogens in the control of glucose and lipid homeostasis.
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PMID:Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency. 1255 72

Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Impaired hepatic FA beta-oxidation in peroxisomes, microsomes, and mitochondria results in progression of massive hepatic steatosis in estrogen deficiency. This impairment, although latent, is potentially serious: About 3% of the general population in the United States is now suffering from nonalcoholic steatohepatitis associated with obesity and hyperlipidemia. Therefore, in the present study we tried to restore impaired hepatic FA beta-oxidation by administering a novel statin, pitavastatin, to aromatase-deficient (Ar-/-) mice defective in intrinsic estrogen synthesis. Northern blot analysis of Ar-/- mice liver revealed a significant restoration of mRNA expression of essential enzymes involved in FA beta-oxidation such as very long fatty acyl-CoA synthetase in peroxisome, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase. Severe hepatic steatosis observed in Ar-/- mice substantially regressed. Consistent findings were obtained in the in vitro assays of FA beta-oxidation activity. These findings demonstrate that pitavastatin is capable of restoring impaired FA beta-oxidation in vivo via the peroxisome proliferator-activated receptor-alpha-mediated signaling pathway and is potent enough to ameliorate severe hepatic steatosis in mice deficient in intrinsic estrogen.
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PMID:Pitavastatin ameliorates severe hepatic steatosis in aromatase-deficient (Ar-/-) mice. 1288 Jan 7

Tamoxifen is a cheap and effective estrogen-receptor antagonist, used as the adjuvant hormonal treatment of choice in women with estrogen-receptor-positive breast cancer. Tamoxifen-induced non-alcoholic steatohepatitis (NASH) may increase the demand on oncologists, not only with regard to screening for diabetes, but also for the suggested link of NASH with high incidence of coronary heart disease. At present, there is no guideline for treatment of hyperlipidaemia associated with tamoxifen-induced NASH. However, exemstane (and other aromatase inhibitors) has been shown to lower triglyceride and have a neutral effect on low-denisty lipoprotein and cholesterol levels. These may be alternative agents if severe progressive liver disease or hyperlipidaemia were encountered with tamoxifen administration. Other lipid-lowering medications may have potential benefits in the treatment of tamoxifen-induced NASH and is discussed in this article.
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PMID:Tamoxifen-induced non-alcoholic steatohepatitis: where are we now and where are we going? 1718 45

Everolimus is an orally available inhibitor of the mammalian target of rapamycin (mTOR), which has been approved in combination with exemestane for hormone receptor-positive (HR) breast cancer after failure of treatment with non-steroidal aromatase inhibitors. Everolimus is generally very well tolerated with most common side effects including stomatitis, rash, fatigue, hyperglycemia, hyperlipidemia, and myelosuppression. Most of these side effects are mild and resolve with dose interruptions or dose reductions. Symptomatic non-infectious pneumonitis is a relatively uncommon class effect of mTOR inhibitors, which can be life threatening. Given the efficacy of everolimus in HR-positive metastatic breast cancer, it is crucial for physicians to recognize toxicities related to everolimus and start timely interventions. This review will focus on the adverse events reported with everolimus in breast cancer trials and will provide practical guidelines for the management of these adverse events.
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PMID:Everolimus: side effect profile and management of toxicities in breast cancer. 2390 51

Polycystic ovary syndrome (PCOS) is recognized as the most common endocrine disorder of reproductive-aged women around the world. This document, produced by the collaboration of the American Association of Clinical Endocrinologists and the Androgen Excess Society aims to highlight the most important clinical issues confronting physicians and their patients with PCOS. It is a summary of current best practices in 2014. Insulin resistance is believed to play an intrinsic role in the pathogenesis of PCOS. The mechanism by which insulin resistance or insulin give rise to oligomenorrhea and hyperandrogenemia, however, is unclear. Hyperinsulinemic-euglycemic clamp studies have shown that both obese and lean women with PCOS have some degree of insulin resistance. Insulin resistance is implicated in the ovulatory dysfunction of PCOS by disrupting the hypothalamic-pituitary-ovarian axis. Given the association with insulin resistance, all women with PCOS require evaluation for the risk of metabolic syndrome (MetS) and its components, including type 2 diabetes, hypertension, hyperlipidemia, and the possible risk of clinical events, including acute myocardial infarction and stroke. Obese women with PCOS are at increased risk for MetS with impaired glucose tolerance (IGT; 31 to 35%) and type 2 diabetes mellitus (T2DM; 7.5 to 10%). Rates of progression from normal glucose tolerance to IGT, and in turn to T2DM, may be as high as 5 to 15% within 3 years. Data suggest the need for baseline oral glucose tolerance test every 1 to 2 years based on family history of T2DM as well as body mass index (BMI) and yearly in women with IGT. Compared with BMI- and age-matched controls, young, lean PCOS women have lower high-density lipoprotein (HDL) size, higher very-low-density lipoprotein particle number, higher low-density lipoprotein (LDL) particle number, and borderline lower LDL size. Statins have been shown to lower testosterone levels either alone or in combination with oral contraceptives (OCPs) but have not shown improvement in menses, spontaneous ovulation, hirsutism, or acne. Statins reduce total and LDL cholesterol but have no effect on HDL, C-reactive protein, fasting insulin, or homeostasis model assessment of insulin resistance in PCOS women, in contrast to the general population. There have been no long-term studies of statins on clinical cardiac outcomes in women with PCOS. Coronary calcification is more prevalent and more severe in PCOS than in controls. In women under 60 years of age undergoing coronary angiography, the presence of polycystic ovaries on sonography has been associated with more arterial segments with >50% stenosis, but the relationship between PCOS and actual cardiovascular events remains unclear. Therapies for PCOS are varied in their effects and targets and include both nonpharmacologic as well as pharmacologic approaches. Weight loss is the primary therapy in PCOS--reduction in weight of as little as 5% can restore regular menses and improve response to ovulation- inducing and fertility medications. Metformin in premenopausal PCOS women has been associated with a reduction in features of MetS. Clamp studies using ethinyl estradiol/drosperinone combination failed to reveal evidence of an increase in either peripheral or hepatic insulin resistance. Subjects with PCOS have a 1.5-times higher baseline risk of venous thromboembolic disease and a 3.7-fold greater effect with OCP use compared with non-PCOS subjects. There is currently no genetic test to screen for or diagnose PCOS, and there is no test to assist in the choice of treatment strategies. Persistent bleeding should always be investigated for pregnancy and/or uterine pathology--including transvaginal ultrasound exam and endometrial biopsy--in women with PCOS. PCOS women can have difficulty conceiving. Those who become pregnant are at risk for gestational diabetes (which should be evaluated and managed appropriately) and the microvascular complications of diabetes. Assessment of a woman with PCOS for infertility involves evaluating for preconceptional issues that may affect response to therapy or lead to adverse pregnancy outcomes and evaluating the couple for other common infertility issues that may affect the choice of therapy, such as a semen analysis. Women with PCOS have multiple factors that may lead to an elevated risk of pregnancy, including a high prevalence of IGT--a clear risk factor for gestational diabetes--and MetS with hypertension, which increases the risk for pre-eclampsia and placental abruption. Women should be screened and treated for hypertension and diabetes prior to attempting conception. Women should be counseled about weight loss prior to attempting conception, although there are limited clinical trial data demonstrating a benefit to this recommendation. Treatment for women with PCOS and anovulatory infertility should begin with an oral agent such as clomiphene citrate or letrozole, an aromatase inhibitor.
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PMID:AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME - PART 2. 2664 2

Aromatase inhibitors represent an effective endocrine treatment for patients with hormone receptor-positive breast cancer, in early stage and in metastatic disease. However, by decreasing levels of serum estrogens they also potentially reduce the protective effect of estrogens on the cardiovascular system. Patients treated with aromatase inhibitors, in fact, compared with those who receive tamoxifen, more often develop hyperlipidemia, hypercholesterolemia, and hypertension, which are recognized risk factors for cardiovascular disease. This might raise some concerns especially in the adjuvant setting where the aim of treatment is the cure, and for postmenopausal patients who are already at risk for cardiovascular disease. However, whether the relative higher incidence of cardiac adverse events reported with aromatase inhibitors compared with tamoxifen is related to an actual cardiac toxicity of aromatase inhibitors rather than a cardioprotective effect of tamoxifen is still unclear. In this article we review the available literature on cardiotoxicity of aromatase inhibitors and provide some practical advice to improve the cardiovascular safety profile of these drugs.
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PMID:Cardiotoxicity of Aromatase Inhibitors in Breast Cancer Patients. 2756 3

Anastrozole is a selective non-steroidal aromatase inhibitor that blocks the conversion of androgens to estrogens in peripheral tissues. It is used as adjuvant therapy for early-stage hormone-sensitive breast cancer in postmenopausal women. Significant side effects of anastrozole include osteoporosis and increased levels of cholesterol. To date, seven case reports on anastrozole hepatotoxicity have been published. We report the case of an 81-year-old woman with a history of breast cancer, arterial hypertension, type 2 diabetes mellitus, hyperlipidemia, and chronic renal insufficiency. Four days after switching hormone therapy from tamoxifen to anastrozole, icterus developed along with a significant increase in liver enzymes (measured in the blood). The patient was admitted to hospital, where a differential diagnosis of jaundice was made and anastrozole was withdrawn. Subsequently, hepatic functions quickly normalized. The observed liver injury was attributed to anastrozole since other possible causes of jaundice were excluded. However, concomitant pharmacotherapy could have contributed to the development of jaundice and hepatotoxicity, after switching from tamoxifen to anastrozole since several the patient's medications were capable of inhibiting hepatobiliary transport of bilirubin, bile acids, and metabolized drugs through inhibition of ATP-binding cassette proteins. Telmisartan, tamoxifen, and metformin all block bile salt efflux pumps. The efflux function of multidrug resistance protein 2 is known to be reduced by telmisartan and tamoxifen and breast cancer resistance protein is known to be inhibited by telmisartan and amlodipine. Moreover, the activity of P-glycoprotein transporters are known to be decreased by telmisartan, amlodipine, gliquidone, as well as the previously administered tamoxifen. Finally, the role of genetic polymorphisms of cytochrome P450 enzymes and/or drug transporters cannot be ruled out since the patient was not tested for polymorphisms.
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PMID:Drug-induced liver injury after switching from tamoxifen to anastrozole in a patient with a history of breast cancer being treated for hypertension and diabetes. 3324 Apr 77