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Oral Contraceptives & Breast Cancer C The Evolving Formulations of Oral Contraceptives Over the past 25 years, populations of oral contraceptive users have progressed through a continuum of formulations ranging from doses as high as 150 micrograms (μg) of estrogen and 10 milligrams (mg) of progestin to the current formulations, which use 30 to 40 μg of estrogen and 1.5 mg or less of progestin. Following a recommendation by its Fertility and Maternal Health Drugs Advisory Committee, the Food and Drug Administration (FDA) recently ordered the removal from the market of all oral contraceptives with estrogen contents greater than 50 μg. As a result of this decision, there are currently 17 different formulations of the pill available in the United States, which are marketed under 29 brand names (see Table C-1, Table C-2, and Table C-3). Different regimens (i.e., 21- and 28-day) of the same formulation are considered to be one brand. The changing formulations also brought a change in the prescribing preferences and practices of physicians. Today, the most commonly prescribed oral contraceptive for new users in the United States is Ortho 7/7/7, which combines 35 μg of ethinyl estradiol with 0.5 to 1 mg of norethindrone (Contraceptive Technology Update, 1989). Four other triphasics are also available (Table C-3). Triphasic formulations are generally thought to be an improvement over the monophasic Appendix C is a product of the IOM Committee on the Relationship Between Oral Contraceptives and Breast Cancer.
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Oral Contraceptives & Breast Cancer TABLE C-1 Summary of Estrogen and Progestin Contents of Oral Contraceptives Available in the United States, 20- to 35-μg Formulations Brand Name a Estrogen per Tablet (μg) Total Estrogen (μg) Progestin Type Progestin per Tablet (mg) Total Progestin (mg) Approximate Equivalents b (mg) Loestrin 1/20 20 420 Norethindrone acetate 1.0 21.0 21.0 Loestrin 1.5/30 30 630 Norethindrone acetate 1.5 31.5 31.5 LoOvral c 30 630 Levonorgestrel 0.15 3.15 31.5-63.0 Levlen Nordette Ovcon 35 35 735 Norethindrone 0.4 8.4 8.4 Brevicon 35 735 Norethindrone 0.5 10.5 10.5 Genora 0.5/35 Modicon Genora 1/35 35 735 Norethindrone 1.0 21.0 21.0 Norcept-E 1/35 Norethin 1/35E Norinyl 1+35 Ortho-Novum 1/35 Demulen 1/35 32 735 Ethinodiol diacetate 1.0 21.0 21.0 a Regimens of both 21 and 28 days are listed as the same formulation. b Based on estimates of approximate progestin potencies (reviewed by Dorflinger, 1985). c Also contains the inactive enantiomer dextronorgestrel. formulations in that the total steroid dose can be reduced without compromising effectiveness in preventing pregnancy or cycle control. It should be noted, however, that the triphasic formulations containing norethindrone are actually slightly higher in total hormone dose than the two lowest-dose monophasic formulations that contain the same two hormones (Ovcon 35, and Brevicon/Modicon/ Genora 0.5/35; Table C-1 and Table C-3). Over the next five years, a number of new oral contraceptive formulations are likely to become available in the American market. Several of these (e.g., Cilest, Marvelon, and Femodene; see Table C-4) are already marketed in a number of countries worldwide, including many European countries. Cilest, which will be marketed as OrthoCyclen in the United States, was recently approved by the FDA. These products are all low-estrogen formulations—30 or 35 μg of ethinyl estradiol. They contain new 19-nortestosterone progestins, which are
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Oral Contraceptives & Breast Cancer TABLE C-2 Summary of Estrogen and Progestin Contents of Oral Contraceptives Available in the United States, 50-μg Formulations Brand Name a Estrogen per Tablet (μg) Total Estrogen (μg) Progestin Type Progestin per Tablet (mg) Total Progestin (mg) Approximate Norethindrone Equivalents b (mg) Genora 1/50 50 c 1,050 Norethindrone 1.0 21.0 21.0 Norethin 1/50M Norinyl 1+50 Ortho-Novum 1/50 Ovcon 50 50 1,050 Norethindrone 1.0 21.0 21.0 Norlestrin 1/50 50 1,050 Norethindrone acetate 1.0 21.0 21.0 Norlestrin 2.5/50 50 1,050 Norethindrone acetate 2.5 52.5 52.5 Demulen 1/50 50 1,050 Ethinodiol diacetate 1.0 21.0 21.0 Ovral d 50 1,050 Levonorgestrel 0.25 5.25 52.5-105 a Regimens of both 21 and 28 days are listed as the same formulation. b Based on estimates of approximate progestin potencies (reviewed by Dorflinger, 1985). c Contains Mestranol, which is metabolized to ethinyl estradiol. Mestranol is generally considered to be equivalent or slightly less potent than ethinyl estradiol. d The total progestin content (norgestrel) is 0.5 mg; however, 50 percent is the inactive enantiomer dextronorgestrel. TABLE C-3 Summary of Estrogen and Progestin Contents of Phasic Formulations of Oral Contraceptives Available in the United States Brand Name Estrogen per Tablet a (μg) Total Estrogen (μg) Progestin Type Progestin per Tablet a (mg) Total Progestin (mg) Approximate Norethindrone Equivalents b (mg) Ortho-Novum 7/7/7 35(21) 735 Norethindrone 0.5(7) 15.75 15.75 0.75(7) 1.0(7) Tri-Norinyl 35(21) 735 Norethindrone 0.5(7) 15.0 15.0 1.0(9) 0.5(5) Ortho-Novum 10/11 35(21) 735 Norethindrone 0.5(10) 16.0 16.0 1.0(11) Tri-Levlen 30(6) 680 Levonorgestrel 0.50(6) 1.925 19.25-38.5 Triphasil 40(5) 0.075(5) 30(10) 0.125(10) a Number of days at each dose. b Based on estimates of approximate progestin potencies (Dorflinger, 1985).
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Oral Contraceptives & Breast Cancer chemically related to levonorgestrel and norethindrone. Femodene contains gestodene, the most potent progestin used in oral contraceptives. Marvelon contains the progestin desogestrel, which is transformed into its active form, 3-keto-desogestrel, after ingestion. Cilest contains norgestimate, which is active in its parent form but which is also metabolized to a number of metabolites, including levonorgestrel, that have biological activity. In addition to the monophasic forms, the triphasic forms of each of these oral contraceptives will most likely also become available (see Table C-4). Publications and promotional materials on each of these new progestins have been extensive for the monophasic formulations (except Cilest), and discuss the similarities and putative advantages over the other currently available formulations. In reality, the clinical profiles, when compared with those of the norethindrone and levonorgestrel triphasics, are quite similar (Chez, 1989). The contraceptive effectiveness of these formulations is high—generally less than one pregnancy per 100 woman-years. Cycle control may be slightly better with the gestodene preparation, and slightly poorer with the desogestrel formulation, than is possible with the currently available triphasics TABLE C-4 Summary of Estrogen and Progestin Contents of Potential New U.S. Oral Contraceptive Formulations Brand Name a Estrogen per Tablet b (μg) Total Estrogen (μg) Progestin Type Progestin per Tablet b (mg) Total Progestin (mg) Cilest 35 735 Norgestimate 0.25 5.25 Marvelon 30 630 Desogestrel c 0.15 3.15 Femodene 30 630 Gestodene 0.075 1.575 Triphasic Cilest 35 735 Norgestimate 0.180(7) 4.515 0.215(7) 0.250(7) Triphasic Femodene 30(6) 680 Gestodene 0.05(6) 1.67 40(5) 0.07(5) 30(10) 0.10(10) Triphasic Marvelon 35(7) 665 Desogestrel 0.05(7) 2.10 30(7) 0.10(7) 30(7) 0.15(7) a Current European brand names, which will not necessarily be used in the United States once the formulations are approved for marketing. b Number of days at each dose. c Desogestrel must be metabolized to 3-keto-desogestrel to be active.
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Oral Contraceptives & Breast Cancer and low-dose monophasics (Chez, 1989). However, good comparative data on these formulations and cycle control are not available, and a definitive statement cannot be made without such comparative studies. The major metabolic feature that seems to set these formulations apart from older formulations, particularly the desogestrel formulation, appears to be a greater overall estrogenicity. That is, the ability of the progestins in the doses provided to counterbalance many estrogen-regulated actions, mediated by the inherent androgenicity and antiestrogenicity of the progestin, is less. Changes in sex hormone-binding globulin (SHBG) are one indicator of the estrogen/ androgen balance of a formulation. SHBG approximately triples with desogestrel and norgestimate formulations, doubles or triples with the gestodene formulation, and increases twofold or less with the triphasic levonorgestrel formulation (Chez, 1989). Finally, extensive research on lipid changes, which also reflect the estrogen/androgen balance, similarly suggests an estrogen-dominant effect of the new formulations. In both animal and human studies, gestodene has been shown to be the most progestogenic steroid, followed by 3-keto-desogestrel, levonorgestrel, norgestimate, and norethindrone. Many of the unwanted side effects of oral contraceptives relate to the inherent androgenic activity of their components (both through a direct effect and indirectly, by displacing endogenous androgens from SHBG). Consequently, researchers have compared the relative androgenicity of these progestins both in animal studies and receptor-binding assays. The results indicate that, overall, levonorgestrel is the most androgenic and gestodene is similar or slightly less androgenic, followed by 3-keto-desogestrel and norethindrone. Norgestimate has not been directly compared with the other progestins but is essentially devoid of androgenic activity. Kloosterboer and colleagues (1988) have calculated what they term a selectivity index, defined as the ratio of the relative binding affinity of each progestin for the progesterone receptor and the relative binding affinity for the androgen receptor. These authors reported that the selectivity index for 3-keto-desogestrel is the highest, followed by gestodene, levonorgestrel, and norethindrone; the study did not report on norgestimate. When compared with levonorgestrel, gestodene is about three times more selective for the progesterone receptor (i.e., at the same dose, given similar bioavailability, gestodene should have about one-third the relative androgenic effect). The selectivity ratio for 3-keto-desogestrel is three to five that of levonorgestrel. Thus, for example, because the dose of estrogen and progestin in Marvelon
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Oral Contraceptives & Breast Cancer and Nordette are the same, one might predict the 3-keto-desogestrel formulation (Marvelon) would be markedly less androgenic. This speculation is confirmed in the literature in studies that examine changes in lipids or SHBG. In a direct comparison of Marvelon and Femodene, there were no differences in 19 parameters of lipid metabolism, gonadotropins, prolactin, ovarian and adrenal steroids, and SHBG (Jung-Hoffmann et al., 1988). Like Femodene and Marvelon, the Cilest formulation appears to have little impact on the overall lipid profile, and any reported changes are in a positive direction (e.g., high-density lipoprotein [HDL]-cholesterol increases slightly and there is an improved HDL/ low-density lipoprotein [LDL] ratio). An oral contraceptive containing progestogen and melatonin is presently undergoing phase 1 and 2 clinical trials (with phase 3 trials scheduled to begin in early 1991) in the Netherlands. If contraceptive effectiveness can be demonstrated, large-scale use may provide appropriate observational data to test the hypothesis (Cohen et al., 1978) that melatonin protects against breast cancer in perimenopausal women. The combination of hypothalamic-releasing agents with low doses of progestogen has also been suggested as a possible contraceptive modality that would reduce the incidence not only of ovarian and uterine cancer but of breast cancer (Pike et al., 1989). There is insufficient clinical experience to confirm or refute these hypotheses. IMPLICATIONS FOR RESEARCH Most of the epidemiological studies to date have provided information exclusively on long-term use of older oral contraceptive formulations that had high total steroid doses. Limited information is available on long-term use of lower-dose formulations, particularly as related to breast cancer, and nothing is known about the triphasic formulations. The new progestin formulations will further complicate the study of the relationship of long-term use of the pill from an early age and breast cancer. Three important considerations with respect to studies of the potential link of oral contraceptives (and specific oral contraceptive formulations) and breast cancer loom large for the 1990s. First, there is wide variation among individuals in blood levels of ethinyl estradiol and the progestin component of an oral contractive following oral administration (Goebelsmann, 1986; Kuhl et al., 1988, Jung-Hoffman et al., 1988; Goldzieher, 1990). Given this individual variation in absorption and metabolism for each component, the average estrogen/ progestin ratio will vary for each individual and may be different
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Oral Contraceptives & Breast Cancer than that calculated from the oral contraceptive steroid dose. As a result, the composite effect at the level of the breast may vary among individuals, and within an individual over time. A question is whether this individual variation in estrogen-to-progestin ratio over months or years may in some way alter the predisposition of various women to develop breast cancer—if, in fact, the putative association of long-term early use and increased relative risk holds up. The answer to this question rests in a better understanding of the interaction of estrogen and progestin in normal breast tissue. In addition, although new biological indicators are being studied in an attempt to unravel the etiology of breast cancer, and the potential linkage of oral contraceptive use with breast cancer, pharmacokinetic and pharmacodynamic differences in the way individual women handle steroids should not be overlooked and merit further research. Second, one of the features suggested as a major advantage of the new progestins is that their total steroid content is generally lower than that of many currently available formulations. Pharmacologically and physiologically, however, this benefit may be a red herring because these new progestins are more potent than current formulations in eliciting their effects. Therefore, a lower dose produces the same antiovulatory effect, as well as the same effect on a number of other progestin-regulated parameters. There may be some differential effects of these progestins at the level of the uterus, however, in addition to a distinction in their inherent androgenicity or antiestrogenicity. Androgens have been found to inhibit estrogen-stimulated growth and reverse estrogen inhibition of a progesterone-binding breast cyst protein (GCDFP-24) by human breast cancer cells (Simard et al., 1990). If this effect holds for normal mammary tissue, the inherent androgenicity or antiestrogenicity of the progestin in oral contraceptive formulations might play a role in balancing estrogenstimulated growth effects. This issue merits closer scrutiny and additional research. How the progestogenic activity of each progestin enters this equation is unknown. Progestins are known to antagonize estrogen action, at least in part, through down-regulation of the estrogen receptor. A recent study using breast cancer cells in culture (Alexander et al., 1990) demonstrated that this down-regulation was linked to inhibition of estrogen action. A number of questions follow from this research. Is this effect the same in normal breast tissue as in breast cancer cells? Is the effect the same in various cell types of the breast (see Chapter 3)? Does ethinyl estradiol have the same effect as estradiol at the receptor level? How does receptor regulation differ with continuous and simultaneous administration of estrogen and proges-
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Oral Contraceptives & Breast Cancer tin, as opposed to the normal cycle? What is the effect of changing the ratio of estrogen and progestin (i.e., different pill types, different absorption and metabolism)? The interrelationship of estrogen, progestins, and androgens, particularly in normal breast tissue, is a priority area of research. Third, the currently available triphasics, as well as the new progestin formulations, have now become more estrogen dominant than many (although not all) of the low-estrogen oral contraceptives. One recent report indicates that increased estrogen content of oral contraceptive formulations is positively associated with an increased thymidine labeling index, an indicator of cell proliferation (Anderson et al., 1989). In that study, information was most complete for levonorgestrel- and norethindrone-containing formulations. A key question is whether it is the total estrogen content or the estrogen dominance of a formulation that is most important as far as this indicator is concerned. If possible, the effects of new formulations on thymidine labeling index rates should be studied carefully and compared with triphasics and other currently available low-estrogen oral contraceptives. In summary, four questions related to oral contraceptive formulation stand as top research priorities for the 1990s. Do individual variations in blood levels in ethinyl estradiol and the progestin component of oral contraceptives affect risk of breast cancer? What are the effects of the progestin component of the pill in modulating estrogen action? Do the inherent androgenic or antiestrogenic properties of different oral contraceptive formulations affect normal breast tissue response? How will the overall estrogen dominance of the new oral contraceptives affect breast tissue response? REFERENCES Alexander, I. E., J. Shine, and R. L. Sutherland. 1990. Progestin regulation of estrogen receptor messenger RNA in human breast cancer cells. Molecular Endocrinology 4: 821-828 Anderson, T. J., S. Battersby, R. J. B. King, K. McPherson, and J. J. Going. 1989. Oral contraceptive use influences resting breast proliferation. Human Pathology 20: 1139-1144 Chez, R. A. 1989. Clinical aspects of three new progestogens: Desogestrel, gestodene, and norgestimate. American Journal of Obstetrics and Gynecology 160: 1292-1300 Cohen, M., M. Lippman, and B. Chabner. 1978. Role of pineal gland in aetiology and treatment of breast cancer. Lancet 2: 814-816 Contraceptive Technology Update. 1989. Triphasics trendy—but what are actual benefits? Vol. 10, pp. 161-173 Dorflinger, L. J. 1985. Relative potency of progestins used in oral contraceptives. Contraception 31: 557-570
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Oral Contraceptives & Breast Cancer Goebelsmann, U. 1986. Pharmacokinetics of contraceptive steroids in humans. Pp. 67-111 in Contraceptive Steroids: Pharmacology and Safety, A. T. Gregoire and R. T. Blye, eds. New York: Plenum Press. Goldzieher, J. W. 1990. Selected aspects of the pharmacokinetics and metabolism of ethinyl estrogens and their clinical application. American Journal of Obstetrics and Gynecology 163: 318-322 Jung-Hoffmann, C., F. Heidt, and H. Kuhl. 1988. Effect of two oral contraceptives containing 30 μg ethinylestradiol and 75 μg gestodene or 150 μg desogestrel upon various hormonal parameters. Contraception 38: 593-603 Kloosterboer, H. J., C. A. Vonk-Noordegraaf, and E. W. Turpijn. 1988. Selectivity in progesterone and androgen receptor binding of progestagens used in oral contraceptives. Contraception 38: 325-332 Kuhl, H., C. Jung-Hoffmann, and F. Heidt. 1988a. Serum levels of 3-keto-desogestrel and SHBG during 12 cycles of treatment with 30 μg ethinylestradiol and 150 μg desogestrel. Contraception 38: 381-390 Kuhl, H., C. Jung-Hoffmann, and F. Heidt. 1988b. Alterations in the serum levels of gestodene and SHBG during 12 cycles of treatment with 30 μg ethinylestradiol and 75 μg gestodene. Contraception 38: 477-486 Pike, M. C., R. K. Ross, R. A. Lobo, T. J. A. Key, M. Potts, and B. E. Henderson. 1989. LHRH agonists and the prevention of breast and ovarian cancer. British Journal of Cancer 60: 142-148 Simard, J., S. Dauvois, D. E. Haagensen, C. Levesque, Y. Merand, and F. Labrie. 1990. Regulation of progesterone-binding breast cyst protein GCDFP-24 secretion by estrogens and androgens in human breast cancer cells: A new marker of steroid action in breast cancer. Endocrinology 126: 3223-3231
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