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Long-acting hormonal contraceptives for women.

Following the development and widespread use of oral hormonal contraceptives, it became evident that alternative long-acting delivery systems would be required to improve contraceptive practice in some cultural settings where injectable or subdermal routes of administration are preferred. Nowadays, long-acting contraceptives constitute an important option in family planning services in many parts of the world. Indeed, two long-acting injectable contraceptives containing just a synthetic progestogen (depot-medroxyprogesterone acetate (DMPA) and norethisterone enantate (NET-EN)) have been in clinical practice for more than 20 years. The World Health Organization's (WHO) Special Programme of Research in Human Reproduction, in collaboration with the U.S. National Institute of Child Health and Human Development (NICHD) and universities primarily in developing countries undertook a synthesis programme aimed at producing an improved injectable preparation by developing new derivatives of known steroids. One such compound (levonorgestrel 17-butanoate) is now at the stage of Phase II clinical testing. In addition, the Special Programme has developed and improved once-a-month injectable formulations and assessed their safety and efficacy in different countries worldwide. After large scale clinical testing, at least two progestogen-estrogen combinations have reached the point of introductory trials.

Aniline Compounds↗

Benefits and risks of oral contraceptives.

The major benefits of modern low-dose oral contraceptives include relative safety and a high degree of efficacy, decreasing the need for abortion or surgical sterilization; reduced risks of bacterial (but not viral) pelvic inflammatory disease and of endometrial and ovarian cancer; improved menstrual regularity, with less dysmenorrhea and blood flow; and, when low-dose combination (not progestogen-only) oral contraceptives are used, reduced acne and hirsutism. Major risks are cardiovascular. Preliminary data from nonrandomized studies suggest that oral contraceptives containing third-generation progestogens are associated with increased risk of venous thromboembolism, particularly in carriers of the coagulation factor V Leiden mutation. The risk of arterial thrombosis, such as myocardial infarction or stroke, may be directly related to estrogen dose, particularly in women who have hypertension, smoke, or are >35 years old. Considering that only users aged >/=30 years who smoke >/=25 cigarettes/d have a higher estimated mortality rate than that of pregnant women, the benefits of oral contraceptives appear to outweigh their risks.

Cardiovascular Diseases↗

Incidence of endometrial cancer in relation to the use of oral contraceptives.

Female residents of King and Ierce Counties in the state of Washington in whom endometrial cancer was diagnosed during 1975--77 were interviewed concerning prior use of oral contraceptives. Their responses were compared with those of a random sample of women from the same population. Women who had taken Oracon (0.1 mg of ethinyl estradiol and 25 mg of dimethisterone) were estimated to have a risk of endometrial cancer 7.3 times that of other women (P = 0.007). This elevation in risk was not seen in users of other sequential preparations. Women who had used combined oral contraceptives had only 50 per cent of the incidence of endometrial cancer of nonusers (P = 0.05), although the protective effect was not evident among those who subsequently took menopausal estrogens for more than two years. These associations suggest that development of neoplasia in the endometrium can be extremely sensitive to hormonal factors: if an oral contraceptive, like Oracon, emphasizes the estrogenic component, promotion of cancer can result; if like combined preparations, the contraceptive emphasizes the progestational component, protection against cancer can result.

Adult↗

Combined oral contraceptives: acceptability and effective use.

With over 60 million users of 'the pill' worldwide, safety and efficacy remain the two most relevant issues to both the consumer and the research scientist. Safety of combined oral contraception (COC) has advanced appreciably. Lessons learned from cohort and case-control studies have been applied to the practical management of oral contraception use, based on screening, selection and regular monitoring of users. Most health risks of COCs appear to be dependent on the dose and potency (or biological impact) of the constituent steroids. While many of the non-contraceptive benefits of COCs are maintained when modern low dose preparations are used, most, if not all, of the adverse effects have been reduced progressively. Moreover the range of modern hormonal contraceptives has widened with the introduction of a new generation of 'selective' progestogens (Desogestrel, Norgestimate and Gestodene), which have minimal androgenicity. User failure of COCs is still high in many countries. The cause is a combination of poor compliance and anxiety about perceived adverse effects. Compliance can be enhanced by improving the quality of instruction in pill use. Fears of adverse effects of COCs may be allayed through education of users and providers, and sympathetic management of side effects.

Adult↗

A contraceptive subdermal implant releasing the progestin ST-1435: ovarian function, bleeding patterns, and side effects.

OBJECTIVE: To study ovarian function, bleeding patterns, and side effects during the 1-year use of a new modified contraceptive subdermal implant releasing the progestin ST-1435 with a lifetime of 2 years. DESIGN, PATIENTS: The effect on ovarian function and bleeding patterns of one contraceptive implant releasing the progestin ST-1435 was studied in 26 healthy women who volunteered. Side effects were recorded. SETTING: The outpatient clinic of the City Maternity Hospital, Helsinki, Finland. INTERVENTION: One ST-1435 contraceptive implant was inserted subcutaneously into the ventral aspect of left upper arm. MAIN OUTCOME MEASURES: The women attended the clinic at half-year intervals. Records of bleeding were kept. Blood samples were collected from 5 women before insertion of an implant, from 12 women during the first 5 to 6 weeks of use, and from 10 women during the 6th and 12th month of use. Serum concentrations of ST-1435, progesterone, and estradiol were determined. Side effects were reported. RESULTS: The study covered 302 woman-months. The implant gave serum concentrations of ST-1435 high enough to inhibit ovulation in all of the 37 analyzed cycles. No pregnancies occurred. Irregular bleeding or spotting was the main event observed, especially during the 1st year of use. One half of the users had irregular cycles. None of the women's implants was removed during 1 year of use because of irregular bleeding. The implant was well accepted and tolerated by the women; no hormonal side effects were reported. CONCLUSIONS: One single 4-cm subdermal ST-1435 implant with a lifetime of 2 years showed good contraceptive efficacy and led to suppression of ovulation. No hormonal side effects were reported. Irregular bleeding patterns were common but well-tolerated, and the implant had a high continuation rate.

Adult↗

Characteristics of women who stop using contraceptives.

A relatively new multivariate life-table technique has permitted the effect of socioeconomic characteristics on first-year contraceptive failure rates to be determined to a greater degree of precision than was possible in the past. This technique is employed in this article to determine the one-year rates of contraceptive discontinuation among currently married U.S. women, using data from the 1973 and 1976 National Surveys of Family Growth (NSFG). The results indicate that poor women, black women and younger women are all relatively more likely to stop using contraceptives for reasons other than method-switching or the desire to become pregnant, as are women who have not completed high school, Catholic women and those who have never had a birth. Of all methods, the IUD is associated with the lowest rate of discontinuation. Pill users over age 30 are more likely to stop using their method than are comparable women using the IUD, diaphragm or condom. Women relying on spermicides are generally most likely to cease using a method. Finally, the subgroups of women who are most likely to stop using a particular method also are generally the groups that are most likely to experience contraceptive failures, while those that are least likely to discontinue use are also least likely to fail. Two exceptions are women who rely on rhythm and those who use the pill. The former experience relatively high rates of failure but are relatively less likely to stop using the method, and the latter have relatively high rates of discontinuation despite a low rate of failure.

Adolescent↗

A two-year clinical study of the effects of two triphasic oral contraceptives on plasma lipids.

OBJECTIVE: Oral contraceptive formulations can alter plasma lipid and lipoprotein levels; however, lower-dose triphasic tablets show only minimal metabolic effects during 6 or 12 cycles of use. Involvement of lipids in chronic cardiovascular conditions, plus long-term use of oral contraceptive tablets, prompted this first 24-cycle study of the effect of triphasic formulations on young women. METHODS: 69 women assigned randomly to an ethinyl estradiol/levonorgestrel formulation (Triphasil) or an ethinyl estradiol/norethindrone formulation (Ortho 7/7/7) and 25 control women (no hormonal contraception) had blood sampled for lipids and lipoproteins pre-trial, and at 3- or 6-cycle intervals for 24 cycles. RESULTS: At cycle 24, control women experienced no significant change from baseline in any variable except apolipoprotein B (apo B). Plasma apo B increased 42% (P < .01), reflecting the LDL apo B increase (42%, P < .01). Both combination formulations significantly increased apo B (plasma, VLDL, IDL and LDL); the increases ranged between 47% and 84%. Plasma apo A1 rose (15%, P < .001) in the Ortho 7/7/7 group only. Plasma and LDL triglycerides were increased significantly (P < .001) by the norethindrone product, 43% and 81%, respectively, and plasma and LDL cholesterol, 14% and 28%, respectively. Cholesterol decreased in all other subfractions, including HDL (11%, P < .01). HDL cholesterol decreased significantly in the Triphasil group (8%, P < .05); no other cholesterol subfractions changed significantly. All cycle-24 lipid and lipoprotein values remained well within respective normal ranges. CONCLUSION: Although 2-year exposure to the triphasic oral contraceptive formulations changed the lipid risk factors for cardiovascular disease only within normal ranges, there remains potential for long-term health effects when compounded with other risk factors.

Adolescent↗

Long-acting injectable contraception with depot medroxyprogesterone acetate.

Depot medroxyprogesterone acetate (DMPA) is the only injectable contraceptive available in the United States. After more than 20 years of regulatory review, the Food and Drug Administration approved DMPA for contraceptive use in 1992 after the publication of reassuring data about its possible association with breast cancer. It has been used by 30 million women in more than 90 countries. The recommended dosage, 150 mg intramuscularly every 3 months, has a contraceptive efficacy exceeding 99%. After a 150 mg dose, ovulation is inhibited for at least 14 weeks. Almost all users experience menstrual changes, typically episodes of unpredictable irregular spotting and bleeding, particularly during the first year of use. With continued use, spotting and bleeding decrease, and amenorrhea becomes common. Although ovulation suppression may rarely persist for as long as 18 months after the last injection, DMPA does not permanently affect fertility. Long-term DMPA use reduces menstrual blood loss, has been associated with a decreased incidence of candidal vulvovaginitis and pelvic inflammatory disease, and dramatically lowers the risk of endometrial cancer. Prolonged DMPA use may be associated with reversible reduction in bone density, probably related to suppression of endogenous production of estrogen. The most recently published data suggest that long-term use of DMPA induces moderate changes in lipid metabolism that are unfavorable in terms of risk of atherosclerosis. DMPA should be considered a highly effective, safe, convenient, and reversible contraceptive option for appropriately selected patients.

Delayed-Action Preparations↗

Dysmenorrhea and use of oral contraceptives in adolescent women attending a family planning clinic.

OBJECTIVES: This study examined the prevalance of dysmenorrhea in female adolescents and the effect of experiencing a reduction in dysmenorrhea on oral contraceptive use. STUDY DESIGN: This was a prospective panel study in which 308 adolescent women at an inner-city family planning clinic were interviewed about their experiences with dysmenorrhea and their oral contraceptive use at three points in time over a 6-month period. A chi 2 test and multiple logistic regression analysis were done. RESULTS: The overall prevalence of dysmenorrhea in this population was 79.6%; 18.2% reported severe dysmenorrhea. Those who had severe dysmenorrhea and also experienced the reduction of dysmenorrhea as a result of oral contraceptives were eight times more likely to be consistent oral contraceptive users (p less than or equal to 0.02). CONCLUSIONS: It is important to screen female adolescents for dysmenorrhea, provide them with information about the beneficial side effects of oral contraceptives, and follow up these young women to make sure they are experiencing the alleviation of their symptoms.

Adolescent↗

Contraception in Sweden.

In 1987, a survey of contraceptive use, knowledge and attitudes was conducted in Sweden by the International Health Foundation (IHF) as part of a multi-country study that has so far involved six other countries in Europe. The women involved, who were aged 15-44, completed a standard questionnaire. The overall percentage use of contraceptive methods, especially the reliable ones, was found to be high (95%). Oral contraception was the most frequently used method, followed by barrier methods and the intrauterine device (IUD). Contraceptive methods were chosen or abandoned mainly because of health reasons and better reliability. Knowledge of fertility proved to be generally good. Medical methods such as oral contraceptives and IUDs were associated with health hazards. In the case of the pill, fears of cardiovascular risks, thrombosis and cancer were widespread, while infection risk and menorrhagia were the most frequently quoted perceived disadvantages of the IUD. Indeed, these two methods suffer from a very negative image among Swedish users.

Adolescent↗

Reduced serum cholecystokinin and increase in body fat during oral contraception.

This investigation was undertaken to explore a possible role of the "satiety peptide" cholecystokinin and some other gastrointestinal hormones for changes in appetite and weight during oral contraception. Ten young healthy women attending a youth health care center for contraceptive counseling volunteered for the study. A standardized meal test was used for recordings of appetite and gastrointestinal hormone response before and after 5 months of treatment with a monophasic combined oral contraceptive. Body fat was calculated from measurements of skin-fold thickness. Oral contraceptives caused a suppression of basal levels of serum cholecystokinin, which was correlated to an increase in body fat. Meal-related response of cholecystokinin and appetite were not affected. Serum levels of gastrin and insulin were also unchanged, whereas triglycerides and postprandial glucose levels were elevated. The results suggest a role of cholecystokinin in regulation of body composition. Cholecystokinin stimulates the release of insulin and stimulates lipolysis in adipose tissue. Reduced cholecystokinin levels may, therefore, be related to mild impairment of glucose tolerance and promote body fat storage during oral contraception.

Adipose Tissue↗

Contraception and dyslipidemia.

The risks of cardiovascular disease associated with dyslipidemia differ in women and men, being more strongly associated with triglyceride/high-density lipoprotein in middle-aged women than in men. Although the incidence of heart disease is lower in women because they live longer, over a lifetime, cardiovascular disease in women is equal to that in men, with the greatest incidence after age 65 years. Major coronary events are rare among reproductive-age women who use oral contraceptives and are related to the concomitant effects of age, smoking, diabetes, hypertension, and obesity. Low estrogen-progestin dose oral contraceptives appear not to promote cardiovascular disease and can be used in women with controlled cholesterol elevations. Alternative contraceptive measures should be considered for patients with severe uncontrolled hypercholesterolemia or a lipid disorder that carries a high risk of coronary heart disease. In these conditions, thrombotic propensity associated with supraphysiologic doses of estrogen in oral contraceptives might accelerate coronary thrombosis should an arteriosclerotic plaque rupture. Treatment of hypercholesterolemia should follow the guidelines of the National Cholesterol Education Program and emphasize hygienic measures. Contraceptive selection in hyperlipidemic patients should reflect a balance between the risks--and their management--of developing cardiovascular disease versus the risks of pregnancy.

Cardiovascular Diseases↗

Contraceptive choices for women with endocrine complications.

Previous confusion regarding the interference by oral contraceptives in measurements of endocrine function have been largely eliminated by the advent of improved, more sensitive assays. There are few if any contraindications to oral contraceptive use in patients with thyroid disease. Patients with prolactinoma can be treated with bromocriptine to restore fertility and prevent mineral loss. However, as a less expensive alternative, oral contraceptives can be prescribed to correct mineral loss, because there is no convincing evidence of an adverse effect on prolactinomas by the steroidal content of the pill. Oral contraceptives comprise a near ideal treatment modality for women with polycystic ovary disease because, among other effects, oral contraceptives reduce synthesis of androgen by inhibiting pituitary gonadotropin secretion.

Contraception↗

Oral contraceptives and blood coagulation: a critical review.

Based on epidemiologic data, women who take oral contraceptives seem to have an increased risk of developing thromboembolic disease. In order to explain this association, some studies have been undertaken to find abnormalities in the hemostasis system. Many conflicting test results have been reported, probably reflecting in part the technical difficulties in use of reliable, reproducible, and specific assay systems. None of the data obtained seems to be specific for users of oral contraceptive drugs, and none was found uniformly in all takers of the drugs. Many findings are probably unimportant from the overall point of view of the physiology of hemostasis. Unfortunately, there seems to be no test procedure or even combination of tests that will reliably predict which patient might develop a thromboembolic episode in association with oral contraceptives or in association with any other condition recognized as being a risk factor. Even in most patients who do have a thrombosis, the test procedures fail to signal this event with reliability and predictability. At this time, it is not known whether oral contraceptives do or do not trigger the hemostasis system to develop a thrombosis or by which mechanism they could trigger the event. Fortunately, only a very small number of women develop thrombosis in association with oral contraceptives.

Adult↗

The effects of contraceptive hormones on the replication of Chlamydia trachomatis in human endometrial cells.

Several recent reports have documented a lower incidence of pelvic inflammatory disease (PID) among oral contraceptive users. The interpretation of this observation is difficult because the action of the contraceptive hormones may be directly by action on a specific host cell-parasite relationship, or indirectly via their action on other systems. In the present study we investigated the susceptibility of cultured human epithelial cells of the endometrium to infection by chlamydia and the influence of contraceptive steroids (ethinyl estradiol, mestranol and medroxyprogesterone acetate) upon replication of chlamydia in these cells. Forty-eight hours post-infection, elementary and reticulate bodies were observed in vacuoles of the infected endometrial cells by electron microscopy. Treatment of chlamydial-infected cells with contraceptive steroids in three different concentrations (10(-5)M, 10(-6)M and 10(-7)M) resulted in no effect on chlamydial replication, as examined by one-step growth curve. These results indicate that contraceptive hormones do not prevent chlamydial infection by direct effect on the replication of the agent.

Chlamydia Infections↗

Contraceptives for lactating women: a comparative trial of a progesterone-releasing vaginal ring and the copper T 380A IUD.

From approximately one week before normal ovulation resumes, lactating women require protection against pregnancy by a contraceptive that is safe for both infant and mother in a multicenter one-year study, the natural hormone, progesterone, delivered vaginally by a sequence of four contraceptive rings designed for continuous use, was evaluated as a contraceptive for nursing mothers in comparison with the Copper T 380A IUD. Individual rings release in effective average dose of 10 mg day for a 3 month period. Evaluation included measures of lactational performance as well as of contraceptive efficacy and safety to mother and child. Nine participating clinics enrolled 802 ring users and 734 IUD acceptors between postpartum days 29 and 63. Life table analyses were performed with parallel decrements for ring and IUD subjects. Continuation in the study and analysis required that subjects not stop breastfeeding. The ring, with a one-year pregnancy rate of 1.5 per 100, did not differ significantly from the IUD with respect to contraceptive effectiveness (p > 0.05). More than half of the ring subjects were continuing at 6 months post admission and a quarter (23.5 per hundred) were still using the ring and breastfeeding one year after admission. Women with the IUD, however, had higher continuation rates (p < 0.001) at both time points. The largest single decrement for each method was that for weaning. Ring users had more complaints of vaginal problems but had fewer vaginal disorders on examination. At 12 months postpartum, 46 per 100 continuing ring users remained in amenorrhea. Lactation performance and the health and weight gain of the infants were similar among users of either regimen.

Administration, Intravaginal↗

Modification of oral contraceptive relationships on breast cancer risk by selected factors among younger women.

In a case-control study of 1647 breast cancer cases and 1501 population controls under 45 years of age, potential modifying effects of other risk factors on the relationship of oral contraceptives to breast cancer were examined. Among the total series of study subjects, the relationship of extended pill usage was greater in non-white than white women. Oral contraceptive associations, however, did not appear to be substantially modified by other risk factors, including parity, body size, or family history of breast cancer (apart from a somewhat enhanced relationship among subjects who reported a sister with breast cancer. Further, oral contraceptive relationships did not vary by a history of benign breast disease, although the majority of subjects began pill usage prior to the development of benign breast disease. Among the women under the age of 35, in whom oral contraceptive relationships were heightened (over a twofold excess risk for use of 5 years or longer), pill relationships were less modified by race than in the total series. Although among these younger subjects there was no effect of pill usage in heavy women, and an enhanced relationship among heavier consumers of alcoholic beverages, these interactive effects were not statistically significant. The findings of this study generally support no substantial variation in oral contraceptive relationships by other breast cancer risk factors, although some further attention might be warranted regarding possible modifying effects of race, body size, type of relative with breast cancer, and alcohol consumption.

Adult↗

Contraceptive status and sexual function of climacteric Chinese women.

The objective of the present survey was to assess the contraceptive status and sexual function of climacteric Chinese women. One cross-sectional study randomly recruited 742 premenopausal, perimenopausal, and naturally menopausal women aged 45-55 years from Beijing. Contraceptive methods were used by 75.6% of premenopausal and 54.2% of perimenopausal women. The primary methods were the IUD and barrier method. The women's choices of methods were related to parity and frequency of sexual activities. Sexual activity was related to the satisfaction of contraceptive methods. Perimenopausal and postmenopausal women were about half as likely to enjoy sexual activity and to experience orgasms than premenopausal women. Women of higher socioeconomic status had a lower risk for decreased sexual functioning. The IUD was the most popular and the most appropriate contraceptive method for perimenopausal women. Sexual function was associated with the women's satisfaction with the contraceptive method used, their menopausal status, and their socioeconomic class.

China↗