Moving to lower doses – oral contraceptives
Moving to Lower Doses Today’s low-dose combined OCs contain less than 50 [mu]g estrogen, down from 150 [mu]g in the first OC and 50 to 100 [mu]g in the OCs of the late 1960s and the 1970s. Estrogen doses of 30 or 35 [mu]g ethinyl estradiol are the most common. Some low-dose pills use 50 [mu]g mestranol, which is roughly as potent as 35 [mu]g ethinyl estradiol.
Progestin doses also have dropped substantially. For example, doses of norethindrone have dropped from 10 mg to 1.0 or 0.5 mg. Because progestins vary in potency by weight, doses of other progestins range from 0.05 mg to 2.0 mg.
Low-estrogen OCs are now the most widely used. Data from 37 areas in 1987 suggest that low-estrogen pills accounted for nearly 85 percent of pharmacy purchases of OCs in the developed areas and almost 60 percent in the developing areas (see Figure 1). In 1988 they comprised almost 80 percent of OCs donated to family planning programs in developing countries.
Pills With Less Estrogen
The reduction of estrogen doses followed research suggesting that lower doses would reduce circulatory system side effects. One of the first indications came in 1970, with a report to the UK Committee on Safety of Drugs that thromboembolic disorders were more likely with higher estrogen doses (227). Subsequent clinical trials in the US found that estrogen doses as low as 20 [mu]g were effective at preventing pregnancy. They also found that side effects such as nausea, vomiting, and headache occurred less often with less estrogen. Menstrual bleeding irregularities were more frequent, however (387).
Trials of low-estrogen OCs conducted in the early and mid-1970s usually reported pregnancy rates of less than one per 100 women per year. These rates are not significantly different from rates for higher-dose OCs (see p. 12). Most of the pregnancies were attributed to users’ failures to take pills on schedule (18, 21, 24, 39, 40, 48, 51, 60, 146, 147, 219, 265, 332, 390, 423, 427, 431, 481, 515, 550).
Studies that looked at hormone doses, pregnancy rates, and pill-taking practices suggest that a woman using low-dose OCs needs to be especially careful to take her pill every day (86, 153, 388). Women who miss low-dose pills on the last days of the pill cycle or start the next cycle late may face particular risk of pregnancy. These errors lengthen the hormone-free interval between cycles (183, 184) (see box, p. 12).
Breakthrough bleeding (intermenstrual bleeding requiring some external protection or pads) and amenorrhea (lack of bleeding at the end of the pill cycle) are common side effects of OCs with low estrogen doses. Some clinical trials involving women using OCs with 30 or 37.5 [mu]g estrogen for at least a year found that 25 to 50 percent of users experienced such effects. Less than 10 percent stopped using OCs because of them, however (18, 60, 187, 265, 481, 515, 550). One trial found that significant increases in discontinuation due to bleeding problems occurred only when the estrogen dose was lowered to 20 [mu]g (48).
Bleeding irregularities are most common in the early months of OC use and then diminish (18, 40, 60, 249, 265, 332, 360, 515, 558). A 1974 comparison of 30 [mu]g and 50 [mu]g estrogen doses–one of the few direct comparisons–found that in the first pill cycle users of the low-dose formulation were twice as likely to experience breakthrough bleeding. By the third cycle, however, the incidence had decreased in both groups, and there was no longer any significant difference between the two. Spotting (light bleeding) was more common in the users of low-dose OCs for somewhat longer, but the difference disappeared by the sixth cycle. The menstrual cycles of the low-dose users were shorter, with a longer period of bleeding. The incidence of amenorrhea was similar in the two groups (112).
Missing pills increases bleeding irregularities as well as pregnancy risks. A US study found that breakthrough bleeding was 13 to 16 times more likely in cycles when women missed a pill, even if they made it up the next day (476). An unfortunate pattern may develop in some women’s pill-taking habits: they miss a pill, causing bleeding. Because of the bleeding, they skip more pills, and more bleeding results. Eventually they may stop OCs entirely. To avoid this, as well as to ensure contraceptive protection, family planning programs are focusing attention on helping women to take pills regularly (see Population Reports, Counseling Guide to Oral Contraceptives, forthcoming).
Other side effects are less common with low-estrogen doses than with doses of 50 [mu]g or more. The 1974 comparison found significantly less cramping, nausea, and breast discomfort among the low-dose users (112). Similarly, studies that compared formulations with estrogen doses ranging from 15 to 40 [mu]g noted that headaches, gastrointestinal disturbances, cramps, and breast discomfort decreased with the estrogen amount (24, 277, 387).
The progestin doses in OCs vary widely because progestins differ greatly in potency by weight. Doses of progestins in the norethindrone family–norethindrone, norethindrone acetate, ethynodiol diacetate, and lynestrenol–range from 0.4 to 2 mg. Pills containing the more potent progestins levonorgestrel, desogestrel, and the recently developed gestogene use doses of 0.05 to 0.15 mg. The different progestins also have different physiological effects and interact with estrogen differently, possibly modifying its effects (56, 483).
Along with estrogens, progestin doses influence bleeding patterns. Recent studies by Family Health International (FHI) in Brazil, Panama, and Sri Lanka observed that higher progestin doses reduced intermenstrual bleeding. In all three countries women using pills containing 35 [mu]g estrogen and 1.0 mg norethindrone had significantly less breakthrough bleeding than women using pills with 35 [mu]g estrogen and 0.5 mg norethindrone (17, 34, 331).
At equal levels of contraceptive effectiveness, progestins of the norgestrel family seem to control bleeding irregularities better than those in the norethindrone family (26, 38, 120, 182, 193, 326, 394, 549). A combination of 0.15 mg levonorgestrel and 30 [mu]g ethinyl estradiol is now the world’s most widely used OC, sold under such brand names as Microgynon 30, Minigynon 30, and Nordette. Studies in a number of countries, including large World Health Organization (WHO) multinational clinical trials, have suggested that this combination controls bleeding patterns as well as levonorgestrel-containing pills with 50 [mu]g ethinyl estradiol and better than low-estrogen pills using other progestins (158, 315, 541, 545). The WHO studies and others suggest, although not conclusively, that nonmenstrual side effects such as nausea, vomiting, and headache may be more common with levonorgestrel than with other progestins (21, 159, 182, 326, 427, 541, 545, 549).
Less Risk with Low Doses?
It has been difficult to ascertain whether lower doses pose less risk of the uncommon, more severe side effects of OCs. Extensive use of low-dose OCs is fairly recent. Thus long-term studies have not yet been possible. A 4-year case-control study of low-dose OCs and risks of circulatory system diseases is planned in the US (9), but in the UK planning for a 5-to-10 year study of OC risks and benefits in 120,000 current OC users has been interrupted by funding difficulties (4).
The major cohort studies of OCs in the 1960s and 1970s–the Royal College of General Practitioners (RCGP) Oral Contraception Study and the Oxford University/Family Planning Association (Oxford/FPA) contraceptive study in the United Kingdom and, in the US, the Walnut Creek Contraceptive Drug Study–observed mainly women using pills with 50 [mu]g estrogen or more. Thus their findings may not apply to OC users today. The two British studies have continued into the 1980s, however, and have begun to generate data on lower-dose pills. In the US in the 1980s the Nurses’ Health Study, the Puget Sound Group Health Cooperative study, and the Cancer and Steroid Hormone (CASH) case-control study also have sometimes been able to compare higher and lower doses.
Available data, although limited, suggest that lower doses mean lower risks for some conditions. For example, as pills with less estrogen have come into wider use, OC-related risks of venous thrombosis and stroke appear to have declined (see pp. 17-19). Changing progestin doses and types in order to minimize metabolic effects may also be important to reducing health risks. While the consensus is that lower doses mean lower risks, some researchers still challenge this conclusion (424).
If the health risks of OCs diminish with dose, will the benefits diminish, too? OC use lowers the risk of benign breast disease, for example. This effect is associated with progestin dose. Lower doses provide less protection (55, 418). Also, women who use OCs have lower incidences of ovarian and uterine cancer. The research demonstrating these protective benefits, however, has involved mainly users of pills with 50 [mu]g estrogen or more. It is not yet clear whether these and other secondary health benefits of OCs are dose-related and, if so, to what extent (see pp. 15-17).
Progestin-Only and Multiphasic Pills
Progestin-only and multiphasic pills are special types of low-dose OCs. The progestin-only “minipill” was developed in the early 1970s in response to reports that estrogen was responsible for thromboembolic side effects of OCs. Each minipill tablet contains 0.3 to 0.6 mg of the norethindrone progestins or 0.03 to 0.0375 mg levonorgestrel. Minipills are taken continuously, with no hormone-free intervals between cycles.
Despite the concern about the side effects of estrogen, minipills have never become popular. They are somewhat less effective than combined OCs (see p. 13). Bleeding irregularities also are more common with minipills (363, 401, 541). An advantage of minipills is their safety for breastfeeding women (see box, p. 16).
The newest OCs are the multiphasics, which in the 1980s have become the most widely used pills in some developed countries. The doses in these OCs change during the pill cycle in order to provide menstrual cycle control, keep hormone doses low, and still prevent ovulation (90). In one type the daily progestin dose increases at mid-cycle, around the time when ovulation would occur, and then decreases again. In others the progestin amount increases in two steps. One variety also increases the estrogen dose from the seventh to the eleventh days.
Like other low-dose OCs, multiphasics appear to provide highly effective contraception when taken correctly. Some trials have observed that they provide good cycle control, with minimal breakthrough bleeding, spotting, or amenorrhea (22, 126, 156, 359). There is little evidence to date that risks of serious health problems are less with multiphasics than with other low-dose OCs (109, 453, 454).
A possible disadvantage of multiphasics is that taking pills out of order will result in an incorrect dose. This might reduce both contraceptive effectiveness and bleeding control (299, 323). Some family planning program managers think that the need to distinguish between two or three sets of pills in one cycle might lead to more incorrect use with multiphasics than with other low-dose pills (5, 495).
COPYRIGHT 1988 Department of Health
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