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A review of the pharmacology of oral contraceptives is presented with emphasis on selection and management for primary care physicians. The paper is introduced with illustrations and diagrams of the menstrual cycle. Orals are 97-99.9% effective in the 1st year of use, which puts them between injectables and IUDs in efficacy, although failure rates are about 4.7% in women 21 years or less. The estrogens and progestins in current pills are described, and their biological effects defined. The actual estrogenic or androgenic effects of combined pills on different organs is complex, but often useful. All pills marketed in the U.S. from 1960-1987 are tabulated with their composition. Triphasic pills are currently popular, primarily because of marketing: they probably do have fewer systemic effects due to lower overall steroid doses. The generic pills now available are Norethin, NII and Genora, with norethindrone and ethinyl estradiol in 1.35 or 1.50 dosages. Contraindications are listed. Specific pills must be started according to packaging, usually with back-up contraception for the 1st cycle. Women must be taught the serious adverse effects to watch for: a mnemonic "ACHES" is suggested. Mortal risks of cardiovascular disease primarily affect women over 35 who smoke. Risks for older nonsmokers are similar to those of pregnancy. Pills present no known cancer risks; may uncover existing susceptibility to to diabetes; and reduce risk of pelvic infection. Management of spotting and of other minor side effects is described. Noncontraceptive benefits of oral contraceptives prevent estimates 50,000 hospitalizations and 1210 deaths per year in the U.S.
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PMID:Oral contraceptives. 223 39

The relationship among postmenopausal estrogen use, coronary stenosis, and survival was examined retrospectively in 2268 women undergoing coronary angiography. The patients were selected for study if their age was 55 years or older at the time of angiography or if they had previously undergone bilateral oophorectomy. Postmenopausal estrogen use in 1178 patients with coronary artery disease (greater than 70% stenosis) and 644 patients with mild to moderate coronary artery disease (5% to 69% stenosis) was compared with 446 control subjects (0% stenosis) using life-table analysis. Over 10 years of follow-up, there was no significant difference in survival among patients initially free of coronary lesions on arteriography who had either never used (377) or ever used (69) estrogens. Among patients with mild to moderate coronary stenosis, 10-year survival of those who had never used estrogens was 85.0% and it was 95.6% among 99 "ever users." Survival was 60.0% among those with more than 70% coronary stenosis who had never used estrogen and it was 97.0% among 70 ever users. The "never users" group were older (65 vs 59 years), had a lower proportion of cigarette smokers (40% vs 57.1%), a higher proportion of subjects with diabetes (21.7% vs 12.9%) and hyperlipidemia (58% vs 44%), and approximately equal numbers of hypertensives (56.0% vs 54.3%). Cox's proportional hazards model was used to estimate survival as a function of multiple covariables. Estrogen use was found to have a significant, independent effect on survival in women. We conclude that estrogen replacement after menopause prolongs survival when coronary artery disease is present, but it has less effect in the absence of coronary artery disease.
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PMID:Estrogen replacement and coronary artery disease. Effect on survival in postmenopausal women. 224 72

Women with recent gestational diabetes mellitus were randomly assigned to one of two low-dose oral contraceptives to evaluate the effect of low-dose oral contraceptives on carbohydrate and lipid metabolism. A cohort of similar women requesting a non-oral-contraceptive method served as controls. The two oral contraceptives studied were ethinyl estradiol (0.035 mg)-norethindrone (0.40 mg) and ethinyl estradiol (0.030 to 0.040 mg)-levonorgestrel (0.050 to 0.125 mg). A 75 gm, 2-hour oral glucose tolerance test and a fasting lipid profile (total cholesterol, triglyceride, high- and low-density lipoprotein cholesterols) were performed at entry, after 3 months, and after 6 to 13 months of treatment. The prevalence of diabetes at 6 to 13 months (27/156 patients) was not significantly different between groups (non-oral-contraceptive group, 17%; ethinyl estradiol-norethindrone, 15%; ethinyl estradiol-levonorgestrel, 20%). When examined by prior gestational diabetes mellitus class, diabetes mellitus was present in 7% of prior class A1 and 29% of women with prior class A2 disease (p less than 0.001). Mean cholesterol and low-density lipoprotein cholesterol levels were significantly improved in all three groups at 3 months and at 6 to 13 months, whereas triglycerides remained unchanged. There were no differences in cholesterol, low-density lipoprotein cholesterol, or triglycerides levels between the groups. After 6 to 13 months, there was a significant increase in high-density lipoprotein cholesterol in the ethinyl estradiol-norethindrone group compared with the ethinyl estradiol-levonorgestrel and non-oral-contraceptive groups.
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PMID:Effect of low-dose oral contraceptives on carbohydrate and lipid metabolism in women with recent gestational diabetes: results of a controlled, randomized, prospective study. 225 89

Vascular risk, mainly thromboembolitic risk, attributed to oral contraceptives (OCs) since 1962, has been primarily linked to ethinyl estradiol (EE). OCs which combine estrogen and have been associated with cerebral vascular accidents. A 1977 study showed a 40% increase of mortality due to cardiovascular complications in women taking OCs. There were of both an arterial and a venous character. The risk of myocardial infarction was 3 times more frequent among OC users. Deep venous thrombosis and pulmonary embolism were more numerous. Some other risk factors include smoking, hypertension, diabetes, and age 35. The risk of heart attack vanishes a few years after stopping OC use. The reduction of EE (and similarly progesterone) dosage from 100-50 mcg also lower the risk of hypertension, cerebral vascular accidents, and venous thrombosis. Prolonged use of OCs causes disorders of hemostasis affecting the walls of blood vessels, modifying the viscosity of blood flow (increase of hematocrits, reduction of venous tonus), modifying plasmatic coagulation (increase of platelets, increase of factors VII and X and plasma fibrinogen, and decrease of antithrombin III activity), and increased fibrinolysis. These anomalies are exclusively associated with high doses of estrogens. 5% of women using OCs develop moderate hypertension of 5-10 mm Hg of systolic pressure 5 years later, but after cessation it is reversed. OCs stimulate the renin-angiotensin-aldosterone system causing accelerated production of angiotensin II with the resultant forceful vasotension. 3 months after quitting OC use, high blood pressure returns to normal. EE can provoke diabetes; it increases very low density lipoprotein (VLDL) and high density lipoprotein (HDL) production, but total cholesterol is hardly affected. The androgenic property of progestogens reduces HDL. Combined OCs are contraindicated for women with hypertension, hyperlipidemia, diabetes, and a family history of vascular accidents.
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PMID:[Oral contraception and the vascular risk]. 251 20

The sudden drop of circulating estrogen in the premenopausal phase causes somatic and psychosomatic symptoms in women around the age of 40, which necessitates hormonal substitution and also reliable contraception because of the risk of pregnancy owing to irregular cycles. At this age the risks of pregnancy-related thrombosis, hypertension, and diabetes, perinatal mortality congenital anomalies, and maternal mortality are higher. Only 6.3-7.3% of women giving birth are over 35 years of age in Austria, but still 26% of women having an abortion are 36 years old or older. The rate of conception ranges between 2% and 5%, and when it falls below 1%, contraception is no longer necessary (around age 45-49). The IUD is acceptable and safe, and pelvic inflammatory disease does not play a significant role at this age. The most frequent side effects are spotting, hypermenorrhea, lower abdominal pain, and difficulties with intercourse. The introduction of micropills with an ethinyl estradiol dose of under 50 mcg and several agents, such as desogestrel, gestoden, and norgestimate, has made it possible to use them over the age of 40, provided no risk factors, such as metabolic disorders or smoking, are present. However, prior determination of lipid status is required. Sterilization is a final form of contraception when an increase of family size is no longer desired; whether the husband or the wife should be sterilized also poses a question. For female sterilization laparoscopy is used almost exclusively with bipolar diathermy, thermocoagulation, or binding with clips or rings. Hysterectomy is recommended in the case of myomatous uterus with cycle irregularities and hypermenorrhea. The condom, the diaphragm, or the natural temperature, Billings, or symptothermal methods have much higher failure rates. The physician has to advise women about the most suitable method.
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PMID:[Contraception and the climacteric]. 262 31

Health care practitioners are often faced with the dilemma of whether or not to provide oral contraceptives (OCs) to women who have certain chronic medical conditions. Oral contraceptive use among gestational diabetics who use OCs may be at increased risk for developing insulin- dependent diabetes. It appears that progestins are primarily responsible because they decrease the number of insulin receptors on cell membranes. Norgestrel has a more marked effect on carbohydrate metabolism than norethindrone. Estrogen may also play a role by slowing the uptake of glucose. Findings of available studies show that progestin only OCs, combined, low-dose OCs (35 mcg of ethinyl estradiol), or preparations with norethindrone are relatively safe for gestational diabetics. In mitral valve prolapse (MVP) abnormal hemodynamics at the prolapsed valve may promote formation of thrombi and lead to cerebrovascular accidents (CVAs). Oral contraceptives are also known to increase the incidence of thrombi, especially in the lower extremities. A 1986 study of 11 OC users who had had CVAS found that a specific subject of women with MVP are at risk for CVA, perhaps due to persistent clotting abnormalities, however most could safely use a combined, low-dose pill unless headaches, smoking, and MVP symptoms. Oral contraceptive use has usually been avoided in women with sickle cell disease. The major concern has been the possibility of an additive or synergistic effect of OCs on the blood-clotting mechanism. However sickle cell disease is a relative contraindication. Several studies showed that OC use, even up to 54 months, did not increase sickle cell crises, and only 5 cases of thromboses have been reported. The increase of fetal and maternal mortality, however, is a definite risk, therefore a similar low-dose pill may be safe for women with the sickle cell trait.
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PMID:Oral contraceptive use in women with chronic medical conditions. 267 89

This third paper from the Persantine Aspirin Trial examines the data to identify risk factors for stroke in persons with a history of carotid territory transient ischemic attacks (TIAs) Fifteen centers in the United States and Canada participated, and 890 subjects were admitted and randomly allocated to either aspirin plus placebo or aspirin plus dipyridamole (Persantine). Persons with the following characteristics were in greater jeopardy for stroke, retinal infarction, or death: older age, history of heart disease, history of peripheral vascular disease, and persisting neurologic deficit from a recent event. Elevated diastolic blood pressure, diabetes, use of estrogen, and smoking were not found to be risk factors. Elevated systolic blood pressure was a risk factor primarily in subjects with a history of heart disease. Estrogen use may actually have had a protective effect for women. This cannot be considered as a report of the natural history of TIA patients; it does identify risk factors in a specific cohort of subjects under treatment.
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PMID:Persantine aspirin trial in cerebral ischemia--Part III: Risk factors for stroke. The American-Canadian Co-Operative Study Group. 286 49

Patients with a history of recurrent candidiasis and who were using Depo-Provera (medroxyprogesterone acetate, DMPA) for contraception were reviewed in order to determine the time relationship between episodes of proven candidiasis, episodes of pruritus vulvae suggestive of this infection (but unproven), and injection of DMPA. Recently, patients were included in the study who had been given DMPA specifically to prevent recurrences of candidiasis even when the drug's contraceptive action was unnecessary, such as after sterilization. In all cases, the infection was initially treated with a vaginal candidacide, most commonly 1 week of an imidazole. The patients ranged in age from 19-37 years at the time of the 1st injection. Diabetes had been eliminated in all the cases. DMPA was given intramuscularly at a dose of 150 mg every 12 weeks. Prior to 1983, an estrogen supplement was prescribed in most cases in an effort to produce monthly menstrual periods. Estrogen supplementation is no longer used routinely, with amenorrhea the aim, although it is occasionally given to women who experience breakthrough bleeding. Candidal infection was considered proven when the branching filaments of the species were seen on a stained vaginal smear or when the species were cultured in a laboratory from a vaginal swab taken a symptomatic patient. With the exception of 2 patients, clinical candidiasis did not occur within the time in which 150 mg of intramuscular DMPA is known to suppress ovulation in all women, i.e., 12 weeks -- except in the presence of exogenous estrogen (cases 1, 2, and 14) and in one case (15) in which the patient had an unplanned conception prior to the injection. Both patients who experienced clinical despite the use of DMPA alone (cases 8 and 13) asked remain on the drug because believe it was responsible for their longest remissions in the past few years. The study seemed to provide evidence that DMPA will prevent a recurrence of clinical candidiasis in many women who are prone to this condition. The study further indicated that estrogens may predispose women to this infection.
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PMID:Depo-Provera in the treatment of recurrent vulvovaginal candidiasis. 294 26

Oral hormonal contraception is a low risk and safe form of contraception for women between the ages of 15-35 without risk factors such as smoking, obesity, diabetes mellitus, hypertension, or hypercholesteremia. Women over 35 years of age should take the pill only when risk factors can be excluded. In general, low dose pills with less than 50 mcg ethinyl estradiol should be used since they have the lowest impact on the metabolism. Use of the pill could in fact have positive effects on health. For example, benign mamma tumors occur less frequently, dysmenorrhea generally improves, anemia and inflammatory adnexal diseases are less common occurrences, and there appears to be a clearly protective effect against morbidity of the endometrium and ovarian cancer. (author's modified)
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PMID:[Risk-benefit analysis of contraception with steroids]. 333 Mar 69

In Finland, the combinations of ethinyl estradiol (EE) and levonorgestrel (LNG) or desogestrel are most used for oral contraception (OC) and LNG, linestrol or nethisterone are employed in the pills containing only progestogen. Their effect is reduced by antiepileptics primarily phenytoin, carbamazepine, barbiturates, and primidone, however, clonazepam and sodium valproate do not exert any influence. The cause is the effect of the drugs on the liver as they accelerate the metabolism of steroids by enzyme induction. Phenytoin induces sex hormones binding globulin (SHGB) synthesized by the liver. In addition to natural hormones also LNG and norethisterone are bound to SHGB. The decrease of the effect of progestogens has not been documented, in fact, some research data indicate that progesterone exerts a beneficial effect in the treatment of epilepsy. Thus, combination OC tablets that contain at least 50 mcg of EE can be used for hormonal contraception of epileptics. Rifampicin applied in chemotherapy of tuberculosis (TB) also exhibits an effect inducing liver enzymes, and that is the reason why rifampicin treatment resulted in undesired pregnancy and bleeding disorders during contraception by combination tablets. Therefore, the concomitant use of both agents is contraindicated. In Finland data are scarce on this effect, as TB is very rare there. In the case of other antibiotics the incompatibility with OCs is proven. It must be noted, however, that as a secondary effect, diarrhea and gastroenteritis treated by antibiotics can produce an unwanted pregnancy. The treatment of diabetes and hypertension can also be contraindication to the use of hormonal contraception, although it may be permitted under medical supervision and control of diabetes.
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PMID:[Hormonal contraception and other drug treatments]. 333 Nov 52


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