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
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
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
genetic susceptibility to, 29–31, 43, 112, 115
histological typing of, 43–44, 111, 129
molecular changes associated with , 45–48
ovariectomy and, 38
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
progestin effect on, 78
receptors in, 40–41
relationships among cell types in, 40
signal complexity in development and differentiation of , 36–37
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
of developing countries, 109–111
disadvantages of, 26
of early use, 120–124
of ever use of oral contraceptives, 104–105, 124–125
of long-term use, 106, 125–126
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
Chlamydial infection, 56
Chlorethinyl-norgestrel, carcinogenicity of , 158, 159
Chlormadinone, 138
Cigarette smoking, oral contraceptives and , 22
Clinical practice, recommendations
on assessing knowledge for
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
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
Diethylstilbestrol (DES), 29
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
Ectopic pregnancy, 56–57
EGF (epidermal growth factor), 36, 37
receptor for, 46
Endogenous hormones
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
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
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
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
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 development and
differentiation, 36–37
Growth stimulation, 128–129, 137
H
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
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
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
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
progestogenicity of, 147
Norethynodrel, carcinogenicity of, 154, 155
19-Nortestosterone, in oral contraceptive formulations , 17, 144–146
N-ras oncogenes, 45
Nude mouse model, 53
Nulliparous women, 111–112, 113
O
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
mechanisms of carcinogenicity of, 160–162
most commonly prescribed, 143
potential new, 144–148
quantitative effect of, 38–39
steroid level vs. potency of, 149–150
steroidal potency of, 89–90
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
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
and hormone replacement therapy, 16–17
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
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
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
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
Rats
direct tests of carcinogenicity in, 153–154, 155
mechanisms of carcinogenicity in, 161, 162
risk factors in, 163
Receptors, in breast tissue, 40–41
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
international, cooperative, 5, 63
multidisciplinary, 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
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
recommendations on maintaining, 4, 5, 61–64
Surveillance, Epidemiology, and
End Results (SEER) Program, 34, 62, 75
Survival rates, 137