Index

A

Abortion , 131

Activation, of oncogenes , 45–46

Age

and breast cancer rate, 10–11, 12, 20, 21, 29, 57–58

at diagnosis, 128–129

and duration of exposure, 97

and effect of hormones, 2

and epithelial proliferation, 32

at first live birth, 112, 114

less than 25, 87–88, 94–98, 118–124, 137, 169, 170–172

and oral contraceptive use, 9, 10, 13, 14

Alleles, 31

Amplification, of int-2 and myc , 47

Animal studies

direct tests of carcinogenicity, 153–159

of mechanisms of mammary

carcinogenicity of sex steroid

hormones, 160–162

of pharmacokinetics of various steroids , 160

potential contributions of, 19, 48

questions raised by, 163–164

Athymic mice, 53

B

Barrier methods, recommendations on research with , 5

bcl-1 gene, 47

Beagle dogs

direct tests of carcinogenicity in, 154–159

mechanisms of carcinogenicity in, 161–162

pharmacokinetics in, 160

risk factors in, 163

Benefits, of oral contraceptive use, 55–57, 165–172

Benign breast disease, 42–43, 89, 114–118, 136–137

Biological knowledge, recommendations on research for, 7, 65–66

Biological markers, recommendations on, 4, 7, 66

Birth cohort, oral contraceptive use by, 10, 13, 14

Blood levels, of ethinyl estradiol and progestin , 148–149



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Oral Contraceptives & Breast Cancer Index A Abortion , 131 Activation, of oncogenes , 45–46 Age and breast cancer rate, 10–11, 12, 20, 21, 29, 57–58 at diagnosis, 128–129 and duration of exposure, 97 and effect of hormones, 2 and epithelial proliferation, 32 at first live birth, 112, 114 less than 25, 87–88, 94–98, 118–124, 137, 169, 170–172 and oral contraceptive use, 9, 10, 13, 14 Alleles, 31 Amplification, of int-2 and myc , 47 Animal studies direct tests of carcinogenicity, 153–159 of mechanisms of mammary carcinogenicity of sex steroid hormones, 160–162 of pharmacokinetics of various steroids , 160 potential contributions of, 19, 48 questions raised by, 163–164 Athymic mice, 53 B Barrier methods, recommendations on research with , 5 bcl-1 gene, 47 Beagle dogs direct tests of carcinogenicity in, 154–159 mechanisms of carcinogenicity in, 161–162 pharmacokinetics in, 160 risk factors in, 163 Benefits, of oral contraceptive use, 55–57, 165–172 Benign breast disease, 42–43, 89, 114–118, 136–137 Biological knowledge, recommendations on research for, 7, 65–66 Biological markers, recommendations on, 4, 7, 66 Birth cohort, oral contraceptive use by, 10, 13, 14 Blood levels, of ethinyl estradiol and progestin , 148–149

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Oral Contraceptives & Breast Cancer Body mass index, 114, 116 Breast(s), development of, 18, 35, 36–37 Breast cancer age and, 10–11, 12, 20, 21, 29, 57–58 age at diagnosis of, 128–129 breastfeeding and, 23 carcinogenesis potential for, 13 cell lines, 49–50 in developed countries, 104–109 in developing countries, 16, 109–111, 136 endogenous hormones and, 12, 102 etiology of, 12–13, 78 genetic susceptibility to, 29–31, 43, 112, 115 histological typing of, 43–44, 111, 129 incidence of, 1, 9–10, 11, 75 molecular changes associated with , 45–48 mortality rate for, 1, 10 ovariectomy and, 38 postmenopausal, 2–3, 7, 12 premenopausal, 15 risk factors for, 57–58, 78, 102, 111–116, 136 survival rates for, 137 in women vs. men, 38 Breastfeeding and breast cancer, 23 breast tissue during, 35 protective effect of, 41–42 Breast self-examination, 129–131 Breast tissue during breastfeeding, 35, 41–42 calcium in, 44 critical time periods for, 41 estrogen effect on, 78 during menstrual cycle, 35 pathological, 42–44 during pregnancy, 35, 41–42 progestin effect on, 78 receptors in, 40–41 relationships among cell types in, 40 signal complexity in development and differentiation of , 36–37 time domain and, 35, 40 2-Bromo-α-ergocryptine, and mammary tumors , 161, 162 C Calcium deposits, in breast, 44 Cancer and steroid hormones (CASH) Study , 62, 76, 81, 87 Carcinogenesis potential, 13 Carcinogenicity in beagle dogs, 154–159, 161–162 direct tests of, 153–159 in mice and rats, 153–154, 155, 161, 162 studies of mechanisms for, 160–162 Cardiovascular disease, oral contraceptives and , 20, 22, 57, 58, 166–167 Case-control studies, 26–27 of benign breast disease, 114–116, 117 design of, 92–93, 97 of developing countries, 109–111 disadvantages of, 26 of early use, 120–124 of ever use of oral contraceptives, 104–105, 124–125 of latency, 107, 108 of long-term use, 106, 125–126 recommendations on, 7, 26–27 and relative risk, 26 size of, 26 of use before first full-term pregnancy , 116–120 Catechol estrogens, 39 Cell lines, 49–50 Cell types, relationships among, 40 Cervical cancer, oral contraceptives and , 23, 167, 168 Children, number of, 112, 114 Chlamydial infection, 56 Chlorethinyl-norgestrel, carcinogenicity of , 158, 159 Chlormadinone, 138

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Oral Contraceptives & Breast Cancer Cigarette smoking, oral contraceptives and , 22 Cilest, 144–146, 148 Clinical practice, recommendations on assessing knowledge for use in, 4, 6, 64–65 c-myc gene, 47 Cohort effect, of oral contraceptives, 16 Cohort studies, 27–28 cost of, 34 of ever use of oral contraceptives, 105, 126, 127 of latency, 108–109 of long-term use, 106–108 vs. postmarketing studies, 18–19 recommendations on, 7 of use before first full-term pregnancy , 117, 121 Combination pills, 76 Committee on Safety of Medicines (CSM) , 153–154, 155 Comparison groups, 28 Confounding variables, 170 Consensus conferences, recommendations on , 6, 65 Contraceptives, developing broader array of , 64 Controls, selection of, 92, 170 Cost, of long-term prospective studies , 34, 67 Critical time periods, 41 Cultures organ, 52–53 short-term mammary epithelial cell , 50–52 Cysts, 42–43 Cytokeratin, 14, 52 D Deletion, of genes, 48 Depomedroxyprogesterone acetate (DMPA) , 138, 157–159 DES, 29 Desogestrel, 146–147 Detection bias, 94 Developed countries, risk in, 104–109 Developing countries benefits in, 166, 167 risk in, 16, 109–111, 136 Diethylstilbestrol (DES), 29 DMPA, 138, 157–159 DNA repair deficiency, 30 Dogs direct tests of carcinogenicity in, 154–159 mechanisms of carcinogenicity in, 161–162 pharmacokinetics in, 160 risk factors in, 163 Dose-response relationship, 79–84 Duration of oral contraceptive use, 13–15, 79–84, 106–108, 125–128 since first oral contraceptive use, 88–89, 96, 107, 108–109, 118, 122 E Early diagnostic bias, with casecontrol studies , 27 ECM (extracellular matrix) proteins, 37, 40 Ecological studies, 19, 28–29 Ectopic pregnancy, 56–57 EGF (epidermal growth factor), 36, 37 receptor for, 46 Endogenous hormones and breast cancer, 12, 102 synthetic vs., 39 Endometrial carcinoma, 56, 166 Epidemiological studies case-control method, 26–27 cohort studies, 27–28 comparison groups in, 28 cost of, 34 defined, 25 design and conduct of, 90–93 discussion of, 94–96 on duration of use, 79–84 on duration since first use, 88–89, 96 early, 78–79

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Oral Contraceptives & Breast Cancer ecological studies, 28–29 on estrogen metabolism, 31–32 on “ever” use of oral contraceptives 79, 80 on genetic susceptibility, 29–31 on high-risk subgroups, 89 on hormones other than oral contraceptives 29 issues to consider with, 90–93 on oral contraceptive formulations 33, 89–90 on progestins, 32 recommendations on, 7, 33–34, 66, 96–97 response rates for, 90–91 results of, 2–3 sample size of, 92 special studies, 29–32 on use before first full-term pregnancy or before age 25, 84–88, 94–96 Epidermal growth factor (EGF), 36, 37 receptor for, 46 Epithelial cell cultures, 50–52 Epithelial proliferation, and menstrual cycle 32 erbB-2 gene, 46–47 erbB-3 gene, 47 Estriol, 39 Estrogen(s) and breast cancer, 12 and breast tissue, 78 catechol, 39 content in oral contraceptives, 143–145, 150 and growth factors, 36–37 in hormone replacement therapy, 16–17 during menstrual cycle, 38–39 metabolism of, 31–32, 39 with ovariectomy, 39 during pregnancy, 39 qualitative effect of, 39 quantitative effect of, 38–39 synthetic vs. endogenous, 39 temporal effect of, 39 Estrogenicity, 147 Estrogen receptors, down-regulation by progestins of 149–150 Estrone, 39 Ethinyl estradiol blood levels of, 148–149 direct tests of carcinogenicity of, 154, 155, 157 epidemiological studies on, 133, 134, 138 metabolism of, 39 in oral contraceptive formulations 17 Ethynerone, carcinogenicity of, 154 Ethynodiol diacetate, carcinogenicity of 158, 159 “Ever” use, of oral contraceptives, 79, 80, 104–105, 124–127 Exposure opportunity, 93 Extracellular matrix (ECM) proteins, 37, 40 F Family history, 29–31, 43, 112, 115 Femodene, 146, 148 Fibroadenomas, 42–43, 115 Fibroblast growth factor, 36, 37 Fibrocystic disease, 116 First full-term pregnancy (FFTP), 13, 14, 58–59, 84–88, 116–122, 169 Food and Drug Administration (FDA) recommendations on premarketing and postmarketing requirements by, 5, 63, 64 surveillance requirements of, 63–64 Funding, recommendations on, 4, 8 G Genetic susceptibility, 29–31, 43, 112, 115 Gestodene, 146–147 G-proteins, 45 Growth factors in breast cancer, 40, 161–162, 163

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Oral Contraceptives & Breast Cancer in breast development and differentiation, 36–37 Growth stimulation, 128–129, 137 H Ha-ras oncogenes, 31, 45 Hepatocellular adenoma, oral contraceptives and, 57, 58, 167 Hepatocellular carcinoma, oral contraceptives and, 57, 58, 167 her-2 gene, 46–47 High-risk groups, oral contraceptive use in, 89 Histological typing, of breast cancer, 43–44, 111, 129 Hormone replacement therapy (HRT), 11, 16–17 hst gene, 47 Human immunodeficiency virus (HIV) infection, 167 Human tissue models, see In vitro human tissue models Human trials, of drugs, 18 16α-Hydroxyestrone, 32, 39 17α-Hydroxyprogesterone derivatives, 133, 138 Hysterectomy, 11 I Incidence of breast cancer, 1, 9–10, 11, 75 of oral contraceptive use, 1, 9 Information, recommendations on dissemination of, 4, 6, 65 Insulin-like growth factors, 36, 37 int-1 gene, 47 int-2 gene, 47 In vitro human tissue models athymic mice, 53 organ cultures, 52–53 potential contributions of, 19 recommendations for, 7 short-term mammary epithelial cell cultures, 50–52 tumor cell lines, 49–50 Iron-deficiency anemia, 55–56 K 3-Keto-desogestrel, 146, 147–148 Kl-ras oncogenes, 45 L Lactation, see Breastfeeding Latency effects, 88–89, 96, 107, 108–109, 118, 122 Levonogestrel androgenicity of, 147 carcinogenicity of, 157–159, 160 Longitudinal studies, see Cohort studies M Mammary epithelial cell cultures, 50–52 Mammary tissue, see Breast tissue Mammographic screening, 75–76, 129–131, 137 Mammoplasties, reduction, epithelial cell cultures from, 51 Manufacturers, premarketing and postmarketing testing by, 5, 18–19 Marital status, oral contraceptive use by, 10 Marvelon, 146, 147–148 Medicare data bases, 62 Medroxyprogesterone acetate (MPA), carcinogenicity of, 159 Megestrol acetate, carcinogenicity of, 158, 159 Melatonin, 148 Menopause, oral contraceptive use near, 131–132, 137–138 Menorrhagia, 55–56 Menstrual cycle breast tissue during, 35 epithelial proliferation and, 32 estrogen levels during, 38–39 oral contraceptives and, 55–56 Mestranol direct tests of carcinogenicity of, 154, 155, 157 epidemiological studies on, 133, 134, 138

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Oral Contraceptives & Breast Cancer metabolism of, 39 in oral contraceptive formulations , 17 Mice athymic, 53 direct tests of carcinogenicity in, 153–154, 155 mechanisms of carcinogenicity in, 161, 162 risk factors in, 163 Milk, cell cultures derived from, 51 Minipills, 77 MK-665, carcinogenicity of, 154 Molecular changes, associated with breast cancer , 45–48 Mortality rate, for breast cancer, 1, 10 MPA (medroxyprogesterone acetate), carcinogenicity of , 159 Myocardial infarction, with oral contraceptives , 57, 58, 167 N National Institute of Health (NIH) consensus conferences, recommendations on, 6, 65 neu gene, 46–47 Nonresponse bias, 170 Nonsteroidal methods, recommendations on research with , 5 Norethindrone acetate carcinogenicity of, 158, 159 progestogenicity of, 147 Norethynodrel, carcinogenicity of, 154, 155 Norgestimate, 146, 147 19-Nortestosterone, in oral contraceptive formulations , 17, 144–146 N-ras oncogenes, 45 Nude mouse model, 53 Nulliparous women, 111–112, 113 Nurses' health study, 84, 170 O Obesity, 112–114, 116 2-OH metabolite, 32 Oncogenes, 44–45 Oophorectomy, 11 Oral contraceptive formulations blood levels of, 148–149 developing alternatives to, 4, 5–6, 64 direct tests of carcinogenicity of, 153–159 epidemiological studies on, 17, 33, 95–96, 132–135, 138 estrogen and progestin content of , 143–145, 150 implications for research on, 148–150 list of current, 144, 145 mechanisms of carcinogenicity of, 160–162 most commonly prescribed, 143 number of, 1, 143 phasic, 77, 143–144, 145, 146 potential new, 144–148 quantitative effect of, 38–39 steroid level vs. potency of, 149–150 steroidal potency of, 89–90 trends in, 1, 77 types of, 76–77 Oral contraceptive use before age 25, 87–88, 94–98, 118–124, 137, 169, 170–172 before first full-term pregnancy, 13, 14, 58–59, 84–88, 116–122, 169 benefits of, 55–57, 165–172 by birth cohort, 10, 13, 14 and cardiovascular disease, 20, 22 and cervical cancer, 23 changing profile of, 76–78 contraindications to, 59 current controversy over, 57–59 duration of, 13–15, 79–84, 106–108, 125–128 duration since first, 88–89, 96, 107, 108–109, 118, 122 “ever” use, 79, 80, 104–105, 124–127 in high-risk subgroups, 89

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Oral Contraceptives & Breast Cancer and hormone replacement therapy, 16–17 incidence of, 1, 9 information needed on, 15–16 latency of, 88–89, 96, 107, 108–109, 118, 122 by marital status, 10 misconceptions over, 55 near menopause, 131–132, 137–138 and premenopausal breast cancer, 15 prescribing problems for, 59–60 promotional vs. cohort effect of, 16 protective effect of, 20–21, 22, 55–57 recent, 171 and reproductive cancers, 20, 21, 22 risk factors for, 59, 89 risks of, 57, 58, 165–172 side effects of, 21–22, 57, 58 and unplanned pregnancies, 21 Organ culture, 52–53 Ortho-Cyclen, 144–146 Ovarian cancer, oral contraceptives and, 20, 21, 22, 56, 166, 168 Ovariectomy and breast cancer, 38 and estrogen level, 39 Overexpression, of tyrosine kinases, 46–47 P Parity, and epithelial proliferation, 32 Patient information, recommendations on, 4, 6 PCR (polymerase chain reaction), 31, 45 Pedigrees, 29–31 Pelvic inflammatory disease, 56 Phase III clinical trials, 63 Phasic oral contraceptives, 77, 143–144, 145, 146 Pituitary mammary mitogen, 162–163 Platelet-derived growth factor, 36, 37 Polycystic ovaries, 29 Polymerase chain reaction (PCR), 31, 45 Postmarketing surveillance, 27–28, 63–64 Postmenopausal breast cancer increased incidence of, 12 oral contraceptive use and, 2–3 recommendations for research on, 7 Pregnancy and breast cancer, 41–42 breast tissue during, 35 ectopic, 56–57 estrogen level during, 39 first full-term, 13, 14, 58–59, 84–88, 116–122, 169 protective effect of, 41–42 unplanned, 21, 166, 167–168 Premarketing testing, 5, 18, 63–64 Premenopausal breast cancer, oral contraceptive use and, 15 Progesterone, carcinogenicity of, 159 Progestin(s) blood levels of, 148–149 and breast cancer, 12 and breast tissue, 78 content in oral contraceptives of, 144, 145 down-regulation of estrogen receptor by, 149–150 epidemiological studies on, 32, 132–133, 134, 138 in hormone replacement therapy, 16–17 level vs. potency of, 149–150 19-nortestosterone, 144–146 progestogenic activity of, 149–150 Progestin-only pills, 77 Progestogen direct tests of carcinogenicity of, 154, 155 and melatonin in formulation, 148 pharmacokinetics of, 160

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Oral Contraceptives & Breast Cancer Progestogenic activity, 149–150 Prolactin, and mammary tumors, 161, 162, 163 Promotional effect, of oral contraceptives, 16 Prospective studies, see Cohort studies Protective effects, of oral contraceptives, 20–21, 22, 55–57 Puerto Rico contraceptive study, 165 Pulmonary embolism, with oral contraceptives, 57, 58 R ras oncogenes, 31, 45–46 Rats direct tests of carcinogenicity in, 153–154, 155 mechanisms of carcinogenicity in, 161, 162 risk factors in, 163 Recall bias, 92, 95, 97 Receptors, in breast tissue, 40–41 Recommendations, 3, 4 on assessing knowledge for use in clinical practice, 4, 6, 64–65 on developing broader array of contraceptives, 4, 5–6, 64 on filling gaps in biological and epidemiological knowledge, 4, 7–8, 65–67 on maintaining surveillance, 4, 5, 61–64 Reduction mammoplasties, epithelial cell cultures from, 51 Relative risks, in case-control studies, 26 Research costs of, 34, 67 international, cooperative, 5, 63 multidisciplinary, 7 recommendations on, 4, 5–7 Response rates, 90–91 Restriction fragment length polymorphisms (RFLPs), 31, 45 Retrospective studies, see Case-control studies Risk assessment methodology, 3, 19–20 Risk factors for breast cancer, 57–58, 78, 102, 111–116, 136 in epidemiological study design, 93 in mice, rats, dogs, and humans, 163 for oral contraceptive use, 59, 89, 165–172 S Sample size, 92 Screening bias, 75–76, 129–131, 137 sea gene, 47 SEER Program, 34, 62, 75 Selection bias, 92, 170 Selectivity index, 147–148 Sequential pills, 76–77 Sex hormone-binding globulin (SHBG), 147 Short-term mammary epithelial cell cultures, 50–52 Side effects, of oral contraceptives, 21–22, 57, 58 Socioeconomic status, 111, 112 Special studies, 29–32 Stem cells, 40 Stillbirth, 131 Stroke, with oral contraceptives, 57, 58 Surveillance postmarketing, 27–28, 63–64 recommendations on maintaining, 4, 5, 61–64 Surveillance, Epidemiology, and End Results (SEER) Program, 34, 62, 75 Survival rates, 137 T Thymidine labeling index (TLI), 32, 150 Time domain, and breast physiology, 35, 40

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Oral Contraceptives & Breast Cancer Transforming growth factors (TGFs), 36, 37, 46 Triphasic oral contraceptives, 77, 143–144, 145, 146 Tumor cell lines, 49–50 Turner's syndrome, 29 Tyrosine kinases, overexpression of, 46–47 V Venous thrombosis, with oral contraceptives, 57, 58 W Weaning, cell cultures derived during, 51 World Health Organization (WHO) study, 81, 109, 111, 131

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