Oral Contraceptives and Breast Cancer (1991) / Chapter Skim
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Appendix D: Animal Models of Sex Steroid Hormones and Mammary Cancer: Lessons for Understanding Studies in Humans
Appendix D: Animal Models of Sex Steroid Hormones and Mammary Cancer: Lessons for Understanding Studies in Humans
Pages 152-164
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From page 152... ...
Most important, animal models of cancer have provided useful insights into the mechanisms of chemical carcinogenesis that have enlarged our understanding of the biology of human cancer. The effect of various sex steroid hormones on the occurrence of mammary cancer has been studied in a variety of species, but the most extensive studies have been conducted in mice, rats, and beagle dogs.
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From page 153... ...
Later, FDA and other drug regulatory agencies began to require additional evaluation of contraceptive steroids in long-term studies in beagle dogs and rhesus monkeys. Information from the long-term tests conducted to obtain marketing approval constitutes a valuable data resource and is reviewed here in some depth.
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From page 154... ...
Beagle Dogs The FDA began to require long-term studies of contraceptive steroids in beagles as a precondition for approval for marketing following the observation that one progestogen (MK-665, or ethynerone) caused high rates of mammary tumors in beagles even at doses that were a low multiple of the human contraceptive dose.
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From page 155... ...
SOURCE: Committee on Safety of Medicines, 1972. TABLE D-2 Malignant Mammary Tumors in Rats Treated with Various Progestogens Alone Progestogen Norethynodrel Nor e thind r one Chlormadinone acetate Lynestrenol dl Norgestrel Megestrol acetate Percent Increase Males Females 15.0 4.2 0.0 N.a.
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From page 156... ...
These studies are representative of the other published studies of sex steroid hormones and mammary tumors in beagles. The experimental studies were all carried out according to a standard protocol.
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From page 157... ...
Statistical analysis of these data taking into account survival time and dose-response yields the same conclusion about the mammary tumorigenicity of estrogen alone in beagle dogs (Larsson and Machin, 1989~. The beagle dog as a model for studying the mammary carcinogenicity of contraceptive steroids came under close scrutiny because of observations of the effects of depomedroxyprogesterone acetate (DMPA)
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From page 159... ...
It is noteworthy that progesterone and medroxyprogesterone acetate are, like DMPA, potent mammary tumorigens in the beagle (Figure Dub. Overall, the data support the conclusion that there are important differences in the mammary tumorigenicity of different progestogens in the beagle at comparable multiples of the human contraceptive dose.
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From page 160... ...
Levonorgestrel, which is very poorly absorbed by the dog, showed high rates of mammary tumorigenicity but only at doses that are many hundreds of times a multiple of the human contraceptive dose. STUDIES OF MECHANISMS FOR MAMMARY CARCINOGENICITY OF SEX STEROID HORMONES IN MICE, RATS, AND DOGS The most important lessons from animal studies of sex steroids come not from what must be considered fairly crude attempts to study their intrinsic carcinogenicity, but from studies that have gone further to define the mechanisms for steroid-induced mammary car
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From page 161... ...
Later, E1 Etreby and coworkers (1989) showed that inhiTABLE D-5 Mammary Tumors in Mice After Treatment with Estrogen Alone and Estrogen Plus Prolactin Inhibitora Treatment Percentage with Tumors Control Ethinyl estradiol Ethinyl estradiol + CB-154a 11.0 27.3 9.0 aCB-154= 12-bromo-a-ergocryptine.
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From page 162... ...
3. The mammary carcinogenic effects of sex steroid hormones are mediated by an effect of the sex steroid on a pituitary hormone, which is the mammary mitogen.
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From page 163... ...
Last, if progestogens importantly modify the effect of estrogen on mammary carcinogenesis of sex steroid in mice, rats, and dogs, is it possible that the secular changes in the balance of estrogen and progestogen in commonly used oral contraceptives in different places explain differences in some of the risk estimates that have been derived from these studies? Better integration of information from animal studies of mammary cancer and steroid contraceptives with thinking about human epidemiological data would undoubtedly advance our understanding of
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From page 164... ...
1932. Apparition de cancers de la mamelle chez la souris male soumise a des injections de folliculine.
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