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Indications and complications of estrogen replacement therapy are discussed in this edited transcription of a conference held at the UCLA School of Medicine. Although many of the symptoms of loss of ovarian function can be corrected by estrogen replacement therapy, several potentially harmful side effects are associated with the administration of estrogen. Hot flashes, the most common menopausal symptom for which women seek treatment, may continue over extended periods of time and the loss of ovarian feedback signals. Several types of evidence indicate that hot flashes are centrally rather than peripherally mediated disturbances, and it now appears that the hypothalamic factors which stimulate pulsatile release of luteinizing hormone play an integral role in initiation of hot flashes. The fact that the extent of estrogen deficiency differs among postmenopausal women may explain why all women do not have hot flashes. The effects of body size on estrogen production and plasma protein binding appear to be significant variables modulating the extent of estrogen deficiency and hypothalamic function. Other studies suggest that calcitonin and gonadal steroids are linked in the pathogenesis and treatment of osteoporosis, but the mechanism of action of estrogen replacement therapy in the treatment of osteoporosis has not been elucidated. Most investigations have failed to show the presence of estrogen receptors in bone. It is likely that the term osteoporosis includes heterogeneous skeletal disorders and that both sex hormones and calcemic hormones are important in pathogenesis. Further research is required on the possible effect of estrogen replacement therapy in decreasing relative risk of arteriosclerotic heart disease. Vaginal atrophy is an accepted indication for estrogen replacement, but its use for skin indications should not be recommended until a beneficial cosmetic effect is shown. Complications of estrogen replacement include endometrial cancer, breast cancer, hypertension, hyperlipidemia, and gallbladder disease, the latter 3 apparently resulting from hepatic action of estrogen replacement therapy. Because of the enhanced hepatic action of orally administered estrogen, other routes of administration are being explored. Additional research is needed to define the risk-benefit ratio of estrogen replacement therapy.
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PMID:Estrogen replacement therapy: indications and complications. 682 55

The symptomatic postmenopausal woman with breast cancer presents the clinician with a difficult task with respect to hormone replacement therapy (HRT). All of the published meta-analyses have been consistent in showing that there is a slightly increased risk of developing breast cancer in those patients using postmenopausal estrogens for greater than 10 years. However, there have been no published placebo-controlled clinical trials on the effects of HRT in women with a history of breast cancer. Quality of life must be balanced against the theoretical risk of tumor promotion. Assessment of osteoporotic and cardiac risk factors (i.e., smoking, hypertension, family history, hyperlipidemia) should influence the decision. Valid alternatives to estrogen replacement include low-dose progesterones such as Bellergal or vitamin E for hot flashes, and biphosphonates, calcium, anabolic steroids, and calcitonin for osteoporosis.
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PMID:The management of menopausal symptoms in women with breast cancer. 761 Jun 43

Recent cohort and case control studies of low-dose combined oral contraceptives (COCs) containing the new generation of progestogens have allowed classification of adverse effects into those which are rare but serious and should be considered risks and those which are more frequent but are less of a threat to health. Low-dose COCs continue to affect coagulation in a complex way, but the risk is less than with the older preparations, and it can be minimized by screening women for a personal or familial history of early or unusual thrombosis and for levels of protein C, S, and antithrombin III. Women with true migraine with focal signs should also avoid using COCs. The relative risk of myocardial infarction (MI) may increase from 4:1 in women with one risk factor (age, smoking, hypertension, hyperlipidemia, and diabetes) to 20:1 with two risk factors and 128:1 with three or more risk factors. In the absence of all risk factors, a recent study indicated that the relative risk of MI with COC use was 1.9 for current and past use. COC use also causes a slight increase in hypertension in most women, especially those who are older or have a family history of hypertension. While the COC can affect carbohydrate and lipid metabolism, the new generation of progestogens has reduced these effects. The COC may accelerate presentation of gallbladder disease in predisposed women. The COC protects against benign breast disease but may increase the risk of breast cancer and cervical cancer slightly. There is a strong link between hepatocellular adenoma and COC use, but the incidence is low. Return to fertility after use has not been a problem. Both estrogenic adverse effects (nausea, dizziness, irritability, weight gain, bloating) and progestogenic adverse effects (vaginal dryness, acne, hirsutism, weight gain, depression, loss of libido) can occur in 50% of women, but these generally disappear after a few months of use. In conclusion, the low-dose, third generation COCs are associated with minimal risks in the absence of other risk factors and have many beneficial effects such as the prevention of ovarian and endometrial cancer; a decrease in pelvic inflammatory disease and ectopic pregnancies; and protection from anemia, primary dysmenorrhea, functional ovarian cysts, and benign breast disease as well as from the morbidity and mortality associated with pregnancy.
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PMID:The combined oral contraceptive. Risks and adverse effects in perspective. 776 40

In order to understand the determinants of oral contraceptive (OC) use in Italy, data were analyzed on 1577 women under age 60 (median age 50 years) admitted as controls in a case-control study of breast cancer. Women were included with acute, non-neoplastic, non-gynecologic, non-hormone-related diseases, admitted between 1991 and 1994 to a network of hospitals in 6 Italian centers. A total of 275 (17.4%) women reported ever use of OCs. OC use was strongly related to the level of education: the multivariate odds ratios (OR) of ever use were 2.2 and 3.5, respectively, in women reporting 7-11 and or= 12 years of schooling (p 0.001) compared to women reporting 7 years of schooling. OC use was inversely related to body mass index (BMI): the OR of ever use was 0.8 and 0.7, respectively, in women with BMI 25 - 30 and or= 30 (p = 0.07) compared to leaner women (BMI, Kg/m2, 25). Parous women more frequently tended to be OC users than nulliparous ones, the estimated OR being 2.4 and 2.3, respectively, in women reporting 1 or 2-3 or more births in comparison with nulliparae. Likewise, women with a history of induced abortions were more frequently ever users (OR for or= 1 induced abortions vs. no induced abortion, 1.8, (95% CI 1.2-2.6). However, no relationship emerged between OC use and history of spontaneous abortions. Finally, there was no relation between pill use and history of hypertension, cholelithiasis, thyroid diseases, hyperlipidemia, family history of breast cancer, uterine fibroids and benign breast disease. Women with a history of diabetes were less likely to be OC users (OR 0.6), but the finding was not significant. The results of this analysis are comparable with those of a study conducted in the same population in the early 1980's, and suggest that sociodemographic and reproductive factors, rather than medical history, are major determinants of OC use in this population.
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PMID:Correlates of oral contraceptive use in Italian women, 1991-93. 884 87

The concept of predictive medicine based on the detection of genetic markers for disease susceptibility stemmed from the finding that many diseases are associated with specific HLA alleles. This model suggested that similar associations probably existed with other genes located all along the human genome. The Human Specimen Study Center (HSSC) was created to assist in investigating this possibility and has contributed significantly to the knowledge contained in current genetic and physical human genome maps. Predictive medicine is intended not for patients but for healthy individuals, its goal being to determine whether their susceptibility to a specific disease is increased or not. Fetuses with evidence of disease are excluded from the province of predictive medicine, which can, however, determine whether a healthy fetus is at high risk for developing a disease in adolescence or adulthood. Predictive medicine is based on probabilities: it evaluates diseases susceptibility but cannot predict with 100% certainty that a specific disease will occur. Whereas many preventive interventions are directed at groups (e.g., immunization programs), predictive medicine is conducted on an individualized basis. For instance, glaucoma is a monogenic disease whose early detection can allow to prevent permanent loss of vision. The fruits of predictive medicine are expected to be greatest, however, in the polygenic multifactorial diseases that are prevalent in industrialized countries, such as diabetes mellitus, hypertension, myocardial infarction, hyperlipidemia, and arteriosclerosis. An ability to detect subjects who are susceptible to breast cancer would be extraordinarily useful, and may be a goal within reach since two breast cancer susceptibility genes have already been identified. Genes associated with increased susceptibility to colon cancer have also been reported. Predictive medicine raises a number of sensitive ethical issues. Individuals should be free to accept or decline disease susceptibility testing after having been fully informed. Confidentiality is vital. The results of susceptibility tests should not be made available to employers or insurance agencies. Susceptibility testing should be offered only if the disease requires a specific treatment or lifestyle modification. Unnecessary anxiety may be one of the main adverse effects of susceptibility testing. A large number of disease susceptibility or resistance genes will probably be identified in the near future, and this will inevitably have an impact on the way physicians approach their patients. Physicians in the XXIst century will spend an increasingly large proportion of their time counselling their patients on how to stay healthy. This trend can be expected to translate into a marked increase in life expectancy. Rather than seeking to add years to life, physicians will strive to add life to years.
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PMID:[Predictive medicine and its ethics]. 929 63

The effect of tamoxifen, an antiestrogenic agent, on lipid metabolism was studied in postmenopausal patients with breast cancer who received the drug for postoperative adjuvant treatment following mastectomy. To measure total cholesterol and triglyceride concentrations, fasting blood samples were collected before and 2 months after the initiation of tamoxifen therapy from 16 patients who satisfied the study criteria. All patients were normolipidemic before tamoxifen was administered. Control samples were obtained from hypertriglyceridemia patients who were free from breast cancer. Marked hypertriglyceridemia was observed in 3 of 16 patients after tamoxifen treatment. The activity of lipoprotein lipase and hepatic triglyceride lipase, the key enzymes of triglyceride metabolism, decreased significantly in all of 16 patients as a result of tamoxifen treatment (P = 0.008 and P = 0.007, respectively). However, the mean mass of lipoprotein lipase significantly increased (P = 0.011) after tamoxifen treatment. We therefore conclude that tamoxifen might increase inactive lipoprotein lipase. Because marked hyperlipidemia is a potent risk factor for life-threatening acute pancreatitis and arteriosclerosis, plasma lipid levels should be tested periodically during tamoxifen treatment, even if the patients are normolipidemic during the pretreatment stage.
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PMID:Effect of tamoxifen on serum lipid metabolism. 958 69

We recently reported three cases of severe hypertriglyceridemia caused by tamoxifen-treatment after breast cancer surgery. In that report we showed that one of the three patients had apo E3/3 and another had E4/2 phenotype. There are few data about the relationship between apoprotein E phenotype, one of modifiers of lipoprotein metabolism, and tamoxifen induced lipemia. In the present study, we studied apo E phenotype to clarify the relationship between apo E phenotype and the changes in lipids during tamoxifen treatment. Plasma triglyceride levels in apo E3/3 and apo E4/3 were 114 +/- 9 mg/dl and 87 +/- 12 mg/dl, respectively, before tamoxifen treatment, and increased significantly to 191 +/- 35 mg/dl in apo E3/3 and 167 +/- 35 mg/dl in apo E4/3 during tamoxifen treatment. There was no significant difference between apo E3/3 and apo E4/3 in triglyceride levels before and during tamoxifen treatment. Plasma levels of total cholesterol during tamoxifen treatment in both apo E3/3 and apo E4/3 were similar to those before treatment. Our data suggest that the increase in triglyceride during tamoxifen treatment may occur in every type of apo E phenotype.
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PMID:Relation between apolipoprotein e phenotype and the changes in lipids during tamoxifen treatment. 970 Apr 80

A patient who was given tamoxifen as adjuvant treatment for breast cancer developed very severe hypertriglyceridaemia, hypercholesterolaemia and acute pancreatitis after being treated for 4 months. The hyperlipidaemia was corrected after cessation of the tamoxifen and the institution of gemfibrozil treatment. This patient appears to have type IV hyperlipidaemia. It is suggested that, in such patients, tamoxifen should be used with extreme caution because the weakly oestrogenic effect of this agent can cause severe and life threatening hyperlipidaemia.
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PMID:Severe hypertriglyceridaemia and hypercholesterolaemia associated with tamoxifen use. 976 83

A 71-year-old woman was admitted to our hospital because of severe hypertriglyceridemia. The patient had a 26-year history of non-insulin-dependent diabetes mellitus and hyperlipidemia (T-chol 300 mg/dl, TG 300 mg/dl). She was treated with sulfonylurea and clofibrate. Seven years before admission, she had undergone a radical mastectomy for cancer of the left breast. After the operation, she had received tamoxifen and fluorouracil. One month before admission, she had marked hypertriglyceridemia (triglyceride 2,106 mg/dl). After discontinuation of tamoxifen and fluorouracil, her serum triglyceride level decreased to 372 mg/dl; when tamoxifen was given again, it increased to 581 mg/dl, and her hepatic triglyceride lipase activity decreased from 0.228 to 0.164 mumol FFA/ml/min. Apolipoprotein E phenotype was wild type E3/3. The concentration of sex-hormone-binding globulin increased from 110 to 130 nmol/l. These changes associated with tamoxifen treatment were similar to those seen after administration of estrogen. Tamoxifen, an anti-estrogen, has been used as adjuvant therapy in cases of estrogen-receptor-positive breast cancer. Tamoxifen has some weak estrogenic activity. The tamoxifen-induced hypertriglyceridemia seen in this case was an effect of its estrogenic action.
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PMID:[Severe hypertriglyceridemia induced by tamoxifen]. 1006 74

We report a case of non-alcoholic steatohepatitis with cirrhosis in a woman receiving tamoxifen as adjuvant treatment for breast cancer. Despite the presence of other risk factors for non-alcoholic steatohepatitis (such as diabetes, obesity and hyperlipidemia), the patient developed non-alcoholic steatohepatitis and cirrhosis only after tamoxifen was started. We suggest that patients receiving tamoxifen, especially patients with predisposing metabolic disorders, should be evaluated for non-alcoholic steatohepatitis, because progression to cirrhosis may occur.
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PMID:[Cirrhosis with non alcoholic steatohepatitis: role of tamoxifen]. 1113 82


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