CĂĄncer de mama
11 de septiembre
2008 EtiologĂa y manifestaciones
Contenido CapĂtulo 1 ............................................................................................................................................ 3 HORMONAL CONTRACEPTIVES ........................................................................................................... 3 Estrogen Plus Progestin Contraceptives ............................................................................................. 3 Mechanisms of Action......................................................................................................................... 4
HORMONAL CONTRACEPTIVES These types of contraceptives are currently available in a wide variety of forms: pill, injection, transdermal patch, implant, and a transvaginal ring. Combination oral contraceptives—"The Pill"—consist of a combination of estrogen and progestin, or a progestin only pill—the minipill. Other forms contain progestins alone or a combination of estrogen and progestin. Unfortunately, no reliable reversible male hormonal contraceptives have been developed (Kamischke, 2004).
Estrogen Plus Progestin Contraceptives
Combination oral contraceptives (COCs) are the most frequently used method of hormonal contraception, and an 3
almost bewildering variety are marketed (Table 5-3). Although generic formulations accounted for only 3.6 percent of prescriptions in 1990, they accounted for 18 percent by 2001 (Keith, 2001). These oral contraceptives typically consist of a combination of an estrogen and a progestational agent taken daily for 3 weeks and then stopped for 1 week, during which time there is withdrawal uterine bleeding. Longer durations of active hormone administration, designed to minimize withdrawal bleeding, have been investigated (Edelman, 2006; Miller, 2003). Such extended-cycle products are now available: Seasonale and Seasonique (Barr Pharmaceuticals, Pomona, NY).
Mechanisms of Action
The contraceptive actions of COCs are multiple. The most important effect is to prevent ovulation by suppression of hypothalamic gonadotropin-releasing factors, which in turn 4
prevents pituitary secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Estrogen suppresses FSH release and stabilizes the endometrium to prevent metrorrhagia, which is often called breakthrough bleeding in this setting. Progestins inhibit ovulation by suppressing LH, they thicken cervical mucus to retard sperm passage, and they render the endometrium unfavorable for implantation. The net effect is extremely effective ovulation suppression, inhibition of sperm migration, and creation of an unfavorable endometrium for implantation. Thus, combined oral contraceptives, if taken daily for 3 out of every 4 weeks, provide virtually absolute protection against conception.
PHARMACOLOGY In the United States, the only estrogens available are ethinyl estradiol, and less commonly its 3-methyl ether, mestranol. Almost all currently available progestins are 19nortestosterone derivatives, but one is an aldosterone derivative. Although individual progestins were initially chosen because of their progestational potency, they are often compared and prescribed based on their presumed estrogenic, antiestrogenic, and especially their androgenic effects. Despite this, a scientific basis for such selective prescribing is lacking (Wallach, 2000). For example, all progestins lower serum free testosterone levels and inhibit 6
5 -reductase and thus conversion of testosterone to the active dihydrotestosterone. Because of this, all progestins are expected to have salutary effects on androgen-related conditions such as acne (see Chap. 17, Acne). DOSAGE Since their initial development, COCs now contain markedly reduced amounts of estrogen and progestin. As a result, because most adverse effects are dose related, side effects have similarly decreased with modern pill dosages. For most, the lowest acceptable dose is governed by the ability to prevent unacceptable breakthrough bleeding. Although daily estrogen content varies from 20 to 50 g of ethinyl estradiol, most pills contain 35 g or less (see Table 5-3). The amount of progestin can be varied in two ways: (1) progestin dose remains constant during the cycle— monophasic pills, and (2) progestin—and in some, estrogen—dosage varies during the cycle—biphasic and triphasic pills. Ideally, women should start COCs on the first day of a menstrual cycle, in which case an additional contraceptive method is unnecessary. A more traditional schedule—the Sunday start—requires pill initiation on the first Sunday following menstruation onset. This schedule necessitates use of an additional method for 1 week to ensure that conception does not occur. Alternatively, immediate initiation of COCs, regardless of menses, has been shown to be safe and to improve short-term continuation rates (Westhoff, 2007). To obtain maximum protection and promote regular use, most suppliers offer dispensers that provide 21 sequential 7
color-coded tablets containing hormones, followed by seven inert tablets of another color. It is important for maximum contraceptive efficacy that each woman adopt an effective scheme for assuring dailyâ€”or nightlyâ€”self-administration. If one dose is missed, conception is unlikely with higherdose monophasic estrogen and progestin pills. When this is recognized, a woman may choose to double that day's dose to minimize breakthrough bleeding. The remainder of the pill pack is completed with one pill taken daily. If several doses are missed or lower-dose pills are used, the next dose is doubled and an effective barrier technique is added for the subsequent 7 days. The remainder of the pill pack is completed with one pill taken daily. Alternatively, a new pack can be started with a barrier method as additional contraception for a week. If withdrawal bleeding does not follow during the week of placebo pills, a woman should continue the pills but seek medical attention to exclude pregnancy. PHASIC PILLS These preparations were developed in an effort to reduce the amount of total progestin per cycle without sacrificing contraceptive efficacy or cycle control. The reduction is achieved by beginning with a low dose of progestin, and increasing it later in the contraceptive cycle. Theoretically, the lower total dose should result in a reduction in progestin-attributable metabolic changes and adverse side effects. The estrogen dose may be kept constant, or it also may be increased later in the cycle. In all such preparations, however, estrogens are kept between 20 and 40 g of ethinyl estradiol (see Table 5-3). Despite the cited advantages, both theoretical and actual, 8
there are distinct disadvantages to triphasic formulations. These include confusion due to multicolored pills and breakthrough bleeding or spotting, which likely is increased compared with monophasic pills (Woods, 1992). DRUG INTERACTIONS Oral contraceptives interfere with the actions of some drugs (Table 5-4). Conversely, some drugs decrease the contraceptive effectiveness of COCs (Table 5-5). Phenytoin and rifampin are believed to increase breakthrough bleeding and reduce contraceptive effectiveness of pills containing less than 50 g of ethinyl estradiol (Hatcher, 1998). Many antiretrovirals decrease contraceptive efficacy, therefore barrier contraceptive methods are recommended (University of California at San Francisco, 2005). Although package inserts for some broad-spectrum antibiotics such as ampicillin and tetracycline warn that they may reduce the efficacy of oral contraceptives, this likely is not true. Any decreased efficacy is related to underlying associated gastrointestinal symptoms, such as vomiting or diarrhea, which can decrease absorption. Another agent, vitamin C, competes for active sulfate in the intestinal wall and increases the bioavailability of ethinyl estradiol. Thus, erratic use of vitamin C can result in breakthrough bleeding (Kubba, 1993).
SAFETY In general, oral contraceptives have proven to be safe for most women. The possibility of adverse effects from COCs has received so much attention for so long that clinicians as well as the public are frequently confused by the often 9
conflicting reports. BENEFICIAL EFFECTS As shown in Table 5-6, there are many beneficial effects from use of the combined estrogen plus progestin contraceptives. POSSIBLE ADVERSE EFFECTS A number of metabolic changes, often qualitatively similar to those of pregnancy, have been identified in women taking oral contraceptives. For example, total plasma thyroxine and thyroid-binding proteins are elevated. Plasma cortisol concentration increases with a nearly comparable increase in transcortin. It is extremely important, therefore, that these pregnancy-like effects be considered when evaluating laboratory tests. Lipids and Lipoproteins In general, COCs increase serum triglyceride and total cholesterol levels. Estrogen decreases concentration of lowdensity lipoprotein (LDL) cholesterol and increases highdensity lipoprotein (HDL) cholesterol. Some progestins cause the reverse (Stadel, 1981). The clinical consequences of these perturbations have almost certainly been overstated, and their impact on lipids is inconsequential for the vast majority of women (Wallach, 2000). Carbohydrate Metabolism Concern over deterioration in glucose tolerance, mediated principally by the progestin, is no longer warranted with current formulations (Speroff, 2001). In healthy women, large prospective studies with long-term surveillance 10
demonstrate that COCs do not increase the risk of diabetes (Rimm, 1992). In fact, they do not increase the risk that women with a history of gestational diabetes will progress to overt diabetes (Kjos, 1998). Combination oral contraceptives may be used in women who have diabetes not complicated by associated vascular disease. Protein Metabolism Estrogens increase hepatic production of a variety of globulins. Increased angiotensinogen production appears to be dose related, and its conversion by renin to angiotensin I has been suspected to be associated with so-called pillinduced hypertension (Hypertension). Fibrinogen, and likely factors II, VII, IX, X, XII, and XIII, are increased in direct proportion to estrogen dose (Comp, 1996; Kaunitz, 1999). The relationship of these increased clotting factors to venous and arterial thrombosis is discussed in Hypertension, but the incidences of both forms of thrombosis appear to be estrogen-dose related (Mann, 1982). Liver Disease Cholestasis and cholestatic jaundice are uncommon complications of oral contraceptives. If they develop, signs and symptoms clear when the COCs are stopped. It appears that oral contraceptives may accelerate the development of gallbladder disease in women who are susceptible, but there is no overall increased long-term risk (Royal College of General Practitioners, 1982; Strom, 1986). There is no reason to withhold oral contraceptives from women who have recovered from viral hepatitis. Neoplasia A stimulatory effect on some cancers is always a 11
concern with female sex steroids. Despite this, a number of studies indicate that it is unlikely that hormonal contraception causes cancer (Cancer and Steroid Hormone Study, 1986, 1987a, 1987b; Prentice, 1987; Schlesselman, 1988). In fact, a protective effect against ovarian and endometrial cancer was shown. There are, however, conflicting reports concerning the risks of premalignant and malignant changes of the liver, cervix, and breast. women heterozygous for BRCA1 and BRCA2 genes. The risks of unplanned pregnancy need to be considered along with those of any method of contraception (Grenader, 2005; McGuire, 2004; Milne, 2005). As a corollary, COC use for ovarian cancer prevention in these women is not currently advised (Modan, 2001).