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Low dose estrogen tablets, containing less than 50 mcg of ethinyl estradiol, were formulated because of the recognized dose response relationship with the steroid content of the tablet and side effects. These new oral contraceptives (OCs) are as effective as the older high-dose OCs, and available evidence reports fewer side effects. This discussion reviews pharmacology of these new OCs, the mechanism of action, contraindications, side effects, and problems with the low-dose estrogen OC. Ethinyl estradiol is the only estrogen used in the low-dose combination OC. There are several synthetic progestins: norethindrone, norethindrone acetate, norgestrel, levonorgestrel, and ethynodiol diacetate. These progestins have different potencies so the pharmacologic activity cannot be accurately predicted based on the amount present in the tablet. The synthetic steroids in OCs are absorbed in the small intestine, metabolized in the liver, excreted in the bile and feces with a half-life of 24 hours. The low-dose estrogen combination preparation is taken 3 out of every 4 weeks. Its contraceptive effect is primarily a result of hypothalamic mediated gonadotropin suppression with subsequent inhibition of ovulation. Contraindications to taking the low-dose OC are the same as for the higher dose OC: thromboembolic or cardiovascular disease, estrogen dependent neoplasia, markedly impaired liver function, undiagnosed genital bleeding, congenital hyperlipidemia, pregnancy, and women over age 30 who smoke. Relative contraindications include hypertension, diabetes mellitus, migraine headaches, uterine myomas, and epilepsy. The often quoted 2-5-fold increased incidence of thromboembolic disease, myocardial infarction, and stroke is based on large epidemiologic studies involving patients taking the older higher dose OCs. Current data from patients taking the newer low-dose medication demonstrate minimal if any increased incidence of these problems in young women who do not smoke. The low-dose estrogen OCs have minimal effect on lipid levels. Early reports of patients using the low-dose OC have shown little if any increased incidence of hypertension. The low-dose contraceptives have little effect on glucose tolerance, and there is no evidence to show an increased incidence of overt diabetes in OC users. There is no evidence that use of the combination OC causes an increase in cancer of the cervix, uterus, or ovaries. Clinical complaints of nausea, breast discomfort, chloasma, weight changes, and depression are reduced with the low-dose estrogen preparation. Hypomenorrhea while taking the OC occasionally occurs because the lower dose of estrogen is insufficient to stimulate the endometrial growth in face of the predominant progestin-atrophy effect.
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PMID:Oral contraceptives in 1984. 649 Mar 38

The charts of patients between the ages of 15-40 years admitted to the Foothills or Calgary General Hospitals in Alberta, Canada between January 1, 1976 and December 31, 1981 and discharged with a diagnosis of reversible ischemic neurological deficits (RIND) or transient ischemic attacks (TIA) were reviewed. A basic work-up was done in almost every instance. 76 patients ranging in age from 16 to 40 years were identified -- 30 male and 46 female. 12 patients (16%) had angiographic evidence of atherosclerosis at a site appropriate to their symptoms, and atheroslerosis was therefore assumed to be the cause of the occlusive cerebrovascular event. 11 (14.5%) were believed to have cardiac sources for emboli and 4 (5%) were thought to have emoblized from intracranial aneurysms. 6 (8%) had a stroke or RIND associated with complicated migraine. 12 patients were pregnant or taking oral contraceptives (OCs) at the time of their illness and in 7 (15% of the female group) this was apparently the only significant coincident risk factor. 11 (14.5%) had other causes for their ischemic episodes, and in 25 instances (33%) no cause was identified. 56 patients (73.5%) had a cranial tomography (CT) scan, 55 (72.5%) had cerebral angiography, and 44 (58%) underwent echocardiography. Only 23 (30%) had all 3 tests. Of 12 patients with atherosclerosis, 7 were male and 5 female. These persons tended to be at the upper end of the age range for the study with a mean age of 36 years. Almost all had 1 or more risk factors for atherosclerosis, such as hypertension, diabetes mellitus, hyperlipidemia, obesity, or smoking. 11 patients had an identified cardiac source for an embolous. 55 patients (72.5%) in this series had cerebral angiograms and 4 of these demonstrated intracranial aneurysms. In 7 females with no direct discernible cause for an ischemic event, 6 were using OCs and 1 was pregnant. A variety of other causes were detected in 11 patients. A total of 25 individuals had no cause identified for their illness. Occlusive cerebrovascular disease is not uncommon in young adults. OCs are seldom implicated, and a high yield of identifiable treatable lesions justifies extending conventional screening investigations to include echocardiography and cerebral angiography.
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PMID:Occlusive cerebrovascular disease in young adults. 673 11

All contributory factors to the unusual occurrence of stroke in young people were evaluated in patients under age 40 admitted to the Stroke Unit of the Austin Hospital in Melbourne, Australia. Over the August 1977 to December 1980 period there were 700 admissions. Of these 14 patients were under the age of 40. There were 7 males and 7 females whose ages ranged from 17-38 years. Each patient was screened for factors which might contribute to premature vascular disease including hypertension, diabetes, smoking, obesity, and hyperlipidemia. In addition, the following tests were performed to exclude an arteritic process: full blood examination; ESR; protein electrophoresis; syphilis serology; and the presence of antinuclear factor. Each of the 14 patients suffered cerebral infarction. A summary of each case is presented in a table. In 9 patients, infarction occurred in the carotid territory of supply. Large cortical infarcts with or without subcortical involvement occurred in cases 1-8, of whom 5 had major vessel occlusion demonstrated angiographically and another had stenosing and ulcerative atheromatous disease at the extracranial carotid bifurcation. In a further 4 patients, infarction occurred within the vertebrobasilar territory and was either confined to the brain stem, the occiptal cortex, or involved both. Angiograms were performed in 2 of these patients and showed irregular narrowing of the vertebral artery which was interpreted as spasm and segmentally narrowing of the basilar artery. The final patient had several ischemic events which included right sided amaurosis fugax, and left frontal, right parieto-occipital and left occipital infarctions. Angiography was normal. All patients survived the stroke and were able to go home. There may be an interrelationship between the pathological findings of Irey et al. (1978) and the effect oral contraceptives (OCs) has on migraine. This is relevant to Case 13. Sustained exposure to OCs may produce the pathological changes described (visible as segmental narrowing angiographically). In 2 patients cerebral infarction was caused by atheromatous or hypertensive occlusive vascular disease. In Case 3 an embolus occluded the middle cerebral artery. Infarction complicating migraine was diagnosed confidently in 4 patients on the basis of typical migrainous symptomatology in the past and accompanying the stroke. Of the 12 patients fully evaluated, there were no cases of polycythemia or thrombocytosis. There were no abnormalities of the clotting factors. Almost every patient had some form of emotional upset, and there were 7 who had significant psychiatric illness and emotional problems of extreme magnitide.
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PMID:Stroke syndromes in young people. 692 82

OC (oral contraception) can cause hypertension in a small minority, about 5%, of users. There does not seem to be a relationship between estrogen dosage and hypertension, while a relationship between progesterone and hypertension seems more possible. Hypertensive reaction to OC has been primarily seen in patients over 30; length of use is another important factor; the incidence after the 5th year of use is reputed to be 2.5-3 times higher than for the first year. Almost all women who develop hypertension with OC use will return to normal levels after OC termination. Several studies indicate a 4-fold to 6-fold increase in the risk of thrombosis and of thrombophlebitis among OC users and especially among woman over 35. OCs containing 50 mcg or less of estrogen can decrease the incidence of thromboembolic diseases by as much as 25%. It has also been reported that OC use before a surgical procedure increases the risk of postsurgical thromboembolism. Frequency of cerebral thrombosis, however rare, also seems to be higher in OC users, especially smokers. Risk of myocardial infarction is also higher among OC users especially in relation to age and smoking. A British study found that mortality rates among smokers were 10.2/100,000 pill users, versus 2.6 in nonusers in the age group 30-39; rates were 62.0 and 15.9 respectively in women over 40; duration of OC use is also a relevant factor. Absolute contraindications to OC use include any precedent of history of cardiovascular or cerebrovascular disease, impaired liver functions, any known or suspected form of neoplasia, genital bleeding, congenital hyperlipidemia, and obviously pregnancy. Relative contraindications include hypertension, migraine, epilepsy, varicose veins, diabetes, uterine leiomyomas, age over 35, and elective surgery. Potential OC users should be carefully screened to minimize possible risks. Age, health history, and smoking are extremely important. Starting OC with a dose lower than 50 mcg of estrogen is also advisable. A woman on OC should be seen every 6 months. Despite side effects and complications, OCs are the most effective and safest method of contraception a physician can offer.
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PMID:Complications and contraindications of oral contraception. 702 10

It is stimulating to ascertain the comparative risk to the woman of hormonal contraceptives of the various kinds used today: combination preparations, which rely on blocking the secretion of gonadotropic hormones by the hypothesis; sequential preparations, which rearrange the physiological relationships of the menstrual cycle; gestagen preparations (minipills), which heighten the viscosity of the cervical mucus; longterm injectable preparations, which initially block ovulation and then act on the cervical mucus; postcoital preparations, which act by inducing abortion of the fertilized egg. Of these the most reliable are the fixed combinations, while sequential preparations are somewhat less so. The minipills are the least reliable. Interaction with other medications can reduce the reliability of these preparations; for instance, women on contraceptives have become pregnant after taking antiepileptic medications containing phenobarbitol and hydantoin. As far as risk is concerned, we must distinguish between those that merely harm the woman and those that pose a threat to life. Some of the former are: bleeding between cycles, failure of menses to appear after cessation of contraception, depression, breast-pains, hypertension, thrombophlebitis, and reduced libido. Hormonal contraceptives also have a series of beneficial effects, especially in women who ordinarily have menstrual difficulties. Among the more serious side effects are: risk of teratogenicity, carcinogenicity, liver problems, thromboses, and infarctions. To reduce the risks of these various side effects, the physician should observe carefully the contraindications: these are both absolute (cerebrovascular and retinal problems, thrombo-embolisms, hepatic disease, diabetes, porphyria, and sickle-cell anemia and relative (migraines, cardiac pains, hyperlipemia, epilepsy, and multiple sclerosis).
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PMID:[Safety and risks of hormonal contraceptives]. 712 52

From 123 hospital charts with a diagnosis of migraine, seen between the years 1974 and 1978, ten cases have been selected of complicated migraine and three cases of migraine with special features. A review, and a discussion of the clinical characteristics, and of the treatment of these unusual migraines has been made. The three cases with special features include migraine in association with hyperlipidemia, with Raynaud's disease and with meningioma.
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PMID:[Unusual migraines]. 744 46

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

Transient global amnesia (AGT) is a well-defined syndrome of unknown aetiology. It is generally believed to be of vascular origin. Other theories suggest epilepsy or migraine as the cause. We studied the clinical features and associated risk factors in 24 patients with AGT, comparing them with two control groups with 24 people in each group, paired for age and sex. The first control group contained healthy individuals (CN) and the second patients with transient ischaemic attacks (AIT). Of the patients with AGT, 70% were women and 30% men. Their average age was 60 (range 14-76). The attacks were abrupt in onset in 100%. In 8% there was a recognisable trigger factor (driving, physical exercise, etc). The average duration was 7 hours. On study of the cardiovascular risk factors, it was found that 36% were hypertensive, 24% had cardiopathy, 12% had diabetes mellitus, 8% were smokers, 4% had polycythaemia, 16% had hyperlipidaemia, 4% were alcoholics. There was a history of migraine in 29%. No patient had a past history of epilepsy. Further investigation showed ECG changes in 12%. In 24% there were non-specific changes in the EEG. On cerebral CT scan there were lesions compatible with ischaemia in 12.5% of the patients. Levels of arterial hypertension were significantly higher in the AGT group as compared to the normal control group (Odds ratio 7.86; CI. 1.29-11.38). A past history of migraine was seen to be a risk factor associated with AGT as compared with both groups of controls (AGT/CN Odds ratio 9.47; CI 1.01-444.92; AGT/AIT Odds ratio > 1.72).
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PMID:[Transient global amnesia. Case-control study of 24 cases]. 868 Nov 72

Unsafe and potentially safe herbal therapies are discussed. The use of herbal therapies is on the rise in the United States, but most pharmacists are not adequately prepared educationally to meet patients' requests for information on herbal products. Pharmacists must also cope with an environment in which there is relatively little regulation of herbal therapies by FDA. Many herbs have been identified as unsafe, including borage, calamus, coltsfoot, comfrey, life root, sassafras, chaparral, germander, licorice, and ma huang. Potentially safe herbs include feverfew, garlic, ginkgo, Asian ginseng, saw palmetto, St. John's wort, and valerian. Clinical trials have been used to evaluate feverfew for migraine prevention and rheumatoid arthritis; garlic for hypertension, hyperlipidemia, and infections; ginkgo for circulatory disturbances and dementia; ginseng for fatigue and cancer prevention; and saw palmetto for benign prostatic hyperplasia. Also studied in formal trials have been St. John's wort for depression and valerian for insomnia. The clinical trial results are suggestive of efficacy of some herbal therapies for some conditions. German Commission E, a regulatory body that evaluates the safety and efficacy of herbs on the basis of clinical trials, cases, and other scientific literature, has established indications and dosage recommendations for many herbal therapies. Pharmacists have a responsibility to educate themselves about herbal therapies in order to help patients discern the facts from the fiction, avoid harm, and gain what benefits may be available.
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PMID:Unsafe and potentially safe herbal therapies. 1003 May 29

In recent years, many genomewide screens have been performed, to identify novel loci predisposing to various complex diseases. Often, only a portion of the collected clinical data from the study subjects is used in the actual analysis of the trait, and much of the phenotypic data is ignored. With proper consent, these data could subsequently be used in studies of common quantitative traits influencing human biology, and such a reanalysis method would be further justified by the nonbiased ascertainment of study individuals. To make our point, we report here a quantitative-trait-locus (QTL) analysis of body-mass index (BMI) and stature (i.e., height), with genotypic data from genome scans of five Finnish study groups. The combined study group was composed of 614 individuals from 247 families. Five study groups were originally ascertained in genetic studies on hypertension, obesity, osteoarthritis, migraine, and familial combined hyperlipidemia. Most of the families are from the Finnish Twin Cohort, which represents a population-wide sample. In each of the five genome scans, approximately 350 evenly spaced markers were genotyped on 22 autosomes. In analyzing the genotype data by a variance-component method, we found, on chromosome 7pter (maximum multipoint LOD score of 2.91), evidence for QTLs affecting stature, and a second locus, with suggestive evidence for linkage to stature, was detected on chromosome 9q (maximum multipoint LOD score of 2.61). Encouragingly, the locus on chromosome 7 is supported by the data reported by Hirschhorn et al. (in this issue), who used a similar method. We found no evidence for QTLs affecting BMI.
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PMID:Quantitative-trait-locus analysis of body-mass index and of stature, by combined analysis of genome scans of five Finnish study groups. 1141 Aug 40


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