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Potencies of oral contraceptives.

Oral contraceptives are combinations of estrogens and progestogens or, in the case of the mini-pills, progestogens alone. With specific test procedures in laboratory animals or human subjects, it is possible to assign potency evaluations to the components relative to the progestational, estrogenic, or antiestrogenic activities of the progestogen or to the estrogenic potencies of the estrogenic component. It might even be possible to quantify the synergistic effects of the estrogen on the progestational agent. Unfortunately, however, it is impossible now to amalgamate such assay results into single estimates of the potencies of the combinations (either the combination products per se or the combination tablets of sequential products). For example, an over-all estrogenic potency of a combination preparation would involve the integration of contributions form the estrogen itself plus the estrogenic products of metabolism of the progestogen minus the antagonistic effect of the progestational agent, if any. These factors cannot now be quantified independently, much less merged into a single figure of clinical significance. Further, even if it were possible to produce such an estimate, it is unlikely that the evaluation would be meaningful in relation to any putative side effect or adverse reaction, i.e., the alleged thrombogenic effects of oral contraceptives cannot currently be related directly to any measure of potency that will allow prediction of these clinical conditions from laboratory models. Any evaluation of the potential of a given contraceptive to produce a specific side effect will depend upon data generated with specific regard to that adverse reaction and the individual product in question.

Contraceptives, Oral

Serum bile acids and the bile acid tolerance test under oral contraception.

Oral contraceptives (OC) have lithogenic properties as shown by a rise in biliary cholesterol secretion and cholesterol saturation index. Since we noted not only a rise in saturation index, but also a reduction in chenodeoxycholate (CDC) pool size and an increase in cholate (C) pool size during oral contraception (30 micrograms ethinylestradiol + 150 micrograms desogestrel), we investigated the endogenous bile acid tolerance test as a potential predictor of this effect on bile acid pool sizes using a cholecystokinin infusion of 55 min duration (1.2 U.kg-1.hr-1) as stimulus of the enterohepatic bile acid circulation in 12 healthy females before and during oral contraception for 3-5 months. Serum C and CDC conjugates were measured at 5-10 min intervals over a period of 150 min and analysed by two specific RIA's. Although no significant correlations between the serum CDC and C measurements and CDC and C pool sizes were found, a significant reduction of nearly 40% for both serum peak levels and the integrated area under the serum curve of CDC conjugates during oral contraception, but not of C conjugates was found. The reduction in serum levels of CDC conjugates during OC using the present model is best explained by both a reduction in CDC pool size and more efficient hepatic uptake of CDC conjugates (consisting of considerably more taurine conjugates during OC use), as well as by an intestinal effect on bile acid absorption under OC.

Adult

A current appraisal of side effects of oral contraceptives.

Oral contraception, although offering almost 100 per cent protection against pregnancy, is associated with many side effects which have resulted in much unnecessary adverse publicity. Such side effects, the majority of which are of annoying nature only, are due to the synthetic hormones used, and have resulted in many changes in formulation and in the withdrawal of several preparations. The types of preparations available are discussed and the side effects appraised from both the patient's and the physician's viewpoint.

Abnormalities, Drug-Induced

Response to short-duration signals, pre- and postmenses, in subjects using oral contraceptives and subjects not using oral contraceptives.

Sixteen female subjects were studied to determine threshold change occurring during and postmenses at thresholds of 1 and 4 kHz for signal durations of 500, 20, and 2 msec. The results indicated that there was no significant difference (p less than 0.05) for the thresholds of 1 and 4 kHz at any duration over the three test times. However, there was a significant second degree trend present at 1 kHz for the 20-msec signal. A comparison was made between the thresholds obtained by nine subjects who were using an oral contraceptive and seven subjects who were not. A significant difference (p less than 0.05) between the groups was found at 4 kHz for the 2-msec signal duration in that the group using oral contraceptives obtained threshold at a lower intensity than did the group not using oral contraceptives.

Acoustic Stimulation

Reduction in incidence of rheumatoid arthritis associated with oral contraceptives. Royal College of General Practitioners' Oral Contraception Study.

Analyses of the frequency of reporting of rheumatoid arthritis have been undertaken as part of the continuing major prospective survey of oral contraceptives. The rate of reporting in oral-contraceptive users (takers) is half of the rate in non-users (controls). The rates for ex-takers and controls are not materially different. The expected rise in the rate of reporting in women over 35 is apparent in controls but suppressed in takers. In the absence of any accountable bias, it is concluded that oral contraceptives protect against the development of rheumatoid arthritis. Although the effect is small, the observation may be valuable in understanding the aetiology of the disease and the mechanism of action of oral contraceptives.

Adult

Mortality among oral-contraceptive users. Royal College of General Practitioners' Oral Contraception Study.

In a large prospective study carried out in the United Kingdom, the death-rate from diseases of the circulatory system in women who had used oral contraceptives was five times that of controls who had never used them; and the death-rate in those who had taken the pill continuously for 5 years or more was ten times that of the controls. The excess deaths in oral-contraceptive users were due to a wide range of vascular conditions. The total mortality-rate in women who had ever used the pill was increased by 40%, and this was due to an increase in deaths from circulatory diseases of 1 per 5000 ever-users per year. The excess was substantially greater than the death-rate from complications of pregnancy in the controls, and was double the death-rate from accidents. The excess mortality-rate increased with age, cigarette smoking, and duration of oral contraceptive use.

Adolescent

Update on oral contraceptive pills and postcoital contraception.

Modern oral contraceptive pills are safe for the majority of American women. The most important contraindications to oral contraceptive pill use are a history of thrombophlebitis or thromboembolism while on the pill or during pregnancy, smoking over 15 cigarettes daily if over 35 years of age, active liver disease, hypertension, diabetes, a lipid disorder, or breast cancer. A history of gestational diabetes is not an absolute contraindication to oral contraceptive pill use, but women with such a history must be encouraged to exercise and eat properly to reduce the high risk of developing overt diabetes. Couples should be encouraged to use condoms to reduce the risk of sexually transmitted diseases. Most antibiotics do not decrease the effectiveness of the pill. Nonuse of contraception among adolescents and older couples is the most common reason for failure. Postcoital contraceptive pills are available but are not completely effective. The use of modern contraceptives is almost always safer than nonuse.

Anti-Bacterial Agents

Noncontraceptive benefits of modern low-dose oral contraceptives.

Most oral contraceptive formulations in current use contain 50 micrograms or less of ethinyl estradiol and 1 mg or less of the various progestins: norethindrone (0.5-1 mg), norgestrel (0.3-0.5 mg), or levonorgestrel (0.05-0.25 mg) [1]. The new generation of progestins--norgestimate, desogestrel and gestodene--are derived from levonorgestrel, the biologically active enantiomer of norgestrel. These steroids have specific metabolic and pharmacologic activity that allow oral contraception at lower doses than previous progestins. Desogestrel and norgestimate are both prodrugs and must undergo hepatic and gastrointestinal metabolism to become biologically active compounds. Gestodene is immediately and completely bioavailable [2]. For the new formulations containing less than 50 micrograms of ethinyl estradiol, the incidence of complications has decreased. With most of the early medical problems identified, current research can now focus on other aspects of oral contraception such as compliance and OC use failure. Prominent noncontraceptive health benefits have been observed in OC users and represent new directions for future research. When the risk-benefit ratio of OC use is evaluated in healthy women today, it clearly favors the benefits. However, these will not be fully realized without an increase in method compliance.

Blood Coagulation

Medical aspects of oral contraceptive discontinuation.

Oral contraceptive (OC) compliance is adversely affected by three medical factors: side effects, poor cycle control, and patients' fears of serious diseases. Most physicians recognize these factors but fail to understand their true impact on continuation rates. In one study, half of current OC users who changed brands and half of former OC users cited unwanted side effects as their reason for discontinuation. Moreover, a substantial number of women discontinue OCs without consulting their physicians. Among the so-called nuisance side effects cited by patients, the most prominent are bleeding irregularities. In new patients just beginning OC therapy, bleeding irregularities such as breakthrough bleeding and amenorrhea can lead to a very high discontinuation rate; as many as 50% of new users discontinue OCs before the end of the first year because of such side effects. OC discontinuation rates among other patient populations vary. The problem has not been studied extensively, but existing data show the problem is a large one. One study involving 550 women of various ages and years of OC use confirmed that cycle control problems led many women to discontinue OC use--often resulting in an unplanned pregnancy. Six percent of the women in this study discontinued OC use because of poor cycle control, and 23% of this group experienced subsequent unwanted pregnancies. In contrast, clinical tolerance with the new progestins such as gestodene is good; in one study 86% of patients had normal bleeding patterns. The principal consequences of poor cycle control are loss of confidence in the OC and the physician, increased anxiety, disruption of sexual relations, additional physician calls and visits, pregnancy tests, discontinuation, and noncompliance. The perception that European women have regarding the pill is that it is a reliable method that does not interfere with sexual activities. However, doubts about the safety of OCs influence compliance with the method. While concerns regarding blood clots have diminished, the fear of cancer is still a concern for many women. The androgenic side effects of weight gain, acne,and breast tenderness are particularly troubling for adolescents, who are sensitive to changes in body image. In one recent study, 20% to 25% of women stopped taking OCs because of weight gain or acne, and another 25% stopped because of fear of cancer. The medical component of improving compliance is the physician's choice of OC. Formulations with low, effective doses of hormones and the fewest side effects should be selected. Cycle control and the side-effect profile are improved with the new progestins.(ABSTRACT TRUNCATED AT 400 WORDS)

Contraceptives, Oral, Combined

Oral contraceptive use and breast cancer risk: a meta-analysis of variations with age at diagnosis, parity and total duration of oral contraceptive use.

OBJECTIVE: To review published reports of risk of breast cancer with oral contraceptive use. DESIGN: Meta-analysis of study results, using regression techniques to explore the inter-study heterogeneity. SETTING: Twenty-seven epidemiological studies of breast cancer risk and oral contraceptive use published 1980-1989. MAIN OUTCOME MEASURES: Relative risk of breast cancer with oral contraceptive use; variations by age at diagnosis, parity, and total duration of use, and with study design characteristics. RESULTS: The overall relative risk estimate was 1.16 (95% CI 1.07-1.25) for the less than 45 years group, 1.21 (95% CI 0.99-1.47) for the nulliparous subgroup, and 1.27 (95% CI 1.12-1.44) for durations of use of more than 8 years. Source of subjects, their marital status, the type of study, data collection methods, matching for geographical area, the number of adjustment factors used in the study analysis, the country of study and the calendar period in which the study ended were all important explanatory factors for inter-study variation, but a substantial proportion of inter-study variation remained unexplained. CONCLUSIONS: These meta-analyses suggest that risk of breast cancer may be raised by around 20% in younger, nulliparous and long use duration subgroups of oral contraceptive users. Risk estimates appear to be influenced by several study design factors, which should be considered carefully in designing and reviewing future studies.

Age Factors

Hormone levels and anogenital swelling of female chimpanzees as a function of estrogen dosage in a combined oral contraceptive.

A combined oral contraceptive consisting of ethinyl estradiol (EE2) in three dosages (50, 100, and 400 micrograms) and norethindrone (0.5 mg) was given to female chimpanzees to determine the effect on endogenous sex hormone levels and anogenital swelling. Serum levels of EE2 increased with increasing dosages of EE2, estradiol decreased, and luteinizing hormone, progesterone and testosterone were maintained at approximately midfollicular phase levels. Urinary levels of EE2 glucuronide increased with the increasing dosages of EE2, whereas estrone and pregnanediol glucuronide were essentially undetectable. The cyclic increase in female anogenital swelling was abolished when the norethindrone was combined with 50 micrograms of EE2 and relatively constant and low levels of swelling were recorded. Relatively constant but successively higher levels of swelling were recorded when the norethindrone was combined with the higher dosages of EE2. These effects of oral contraceptives on female genital tissues are relevant to our laboratory studies of sexual behavior in chimpanzees given oral contraceptives and could also have implications for women taking oral contraceptives.

Anal Canal