For definition of Groups, see Preamble Evaluation.
Supplement 7: (1987) (p. 289)
CAS No.:
Chem. Abstr. Name: (6a)-17-(Acetyloxy)-6-methylpregn-4-ene-3,20-dione
A. Evidence for carcinogenicity to humans (inadequate)
The results of one cross-sectional study of the development of breast nodules in women given medroxyprogesterone acetate was difficult to interpret because of methodological considerations [ref: 1]. Two small cohort studies in the USA showed relative risks (and 95% confidence limits) of breast cancer in women exposed to medroxyprogesterone acetate of 0.69 (0.3-1.4) [ref: 2] and 1.1 (0.5-2.4) [ref: 3], but both included only women with short-term exposure and limited duration of follow-up. A case-control study of 30 women with breast cancer and 179 controls [ref: 4] yielded a relative risk of 1.0 (no confidence limits given) for use of medroxyprogesterone acetate at some time. Preliminary analyses of a collaborative case-control study in Thailand, Kenya and Mexico sponsored by the World Health Organization [ref: 5], based on 427 cases (39 'ever' users) and 5951 controls (557 'ever' users), provided estimates of relative risk (and 95% confidence limits) for breast cancer of 1.0 (0.7-1.5) in women who 'ever' used medroxyprogesterone acetate, 1.1 (0.7-1.9) for users for 1-12 months, 1.2 (0.7-2.2) for users for 13-36 months and 0.8 (0.4-1.7) for users for 37 months or more.
Medroxyprogesterone acetate causes reversible changes in the endometrium, from proliferative to secretory or suppressed [ref: 4]. In one small cohort study, one case of uterine leiomyosarcoma was found, with 0.83 cancers of the uterine corpus expected, giving a relative risk of 1.2 [0.03-6.7] [ref: 2]. In the collaborative study [ref: 5], the estimated relative risk for endometrial cancer in 'ever' users of medroxyprogesterone acetate was 0.3 (0.04-2.4), based on 57 cases, only one of which was exposed, and 316 matched controls (30 exposed).
In the small cohort study [ref: 2], one ovarian cancer case occurred in a medroxyprogesterone acetate user, with 1.16 expected, giving a relative risk of 0.86 [0.02-4.6]. Preliminary analysis of data from the collaborative study [ref: 5], based on 105 cases (seven exposed) and 637 matched controls (74 exposed) yielded a relative risk for ovarian cancer of 0.7 (0.3-1.7) in 'ever' users of medroxyprogesterone acetate.
The results of two cohort studies of dysplasia and of carcinoma in situ of the uterine cervix in women given medroxyprogesterone acetate were conflicting and difficult to interpret because of methodological problems [ref: 1]. Preliminary results from the collaborative study [ref: 5], based on 920 cases of invasive cervical carcinoma (126 exposed to medroxyprogesterone acetate) and 5833 controls (545 exposed) yielded estimated relative risks of 1.2 (0.9-1.5) in 'ever' users, after controlling for parity, history of vaginal discharge, age at first sexual relationship, number of sexual partners, number of prior Pap smears and use of an intrauterine device and oral contraceptives. Relative risks in users for 1-12, 13-24, 25-60 and 61 months or more were estimated to be 1.4 (1.0-2.0), 1.2 (0.7-2.0), 0.6 (0.4-1.1) and 1.4 (0.9-2.2), respectively.
Preliminary analyses of data from the collaborative study [ref: 5] showed the relative risk for primary liver cancer (all histological types combined) in women who had ever used medroxyprogesterone acetate to be 1.0 (0.4-2.8), based on 57 cases (seven exposed) and 290 controls (34 exposed).
B. Evidence for carcinogenicity to animals (sufficient)
Medroxyprogesterone acetate was tested by intramuscular injection in dogs and by subcutaneous implantation in mice. It induced adenocarcinomas of the mammary gland in one study in female mice [ref: 6], and produced malignant mammary tumours in dogs [ref: 1]. After four years of intramuscular treatment of dogs with a human contraceptive dose, a dose-related increase in the incidence of mammary nodules was seen; the incidence of mammary-gland nodules at that time was comparable with that seen in dogs given progesterone at 25 times the canine luteal level [ref: 7]. Female dogs treated with medroxyprogesterone acetate for at least one year had a significant increase in the incidence of large and small mammary nodules as compared with control animals in one study [ref: 8], and a dose-related increase in the incidence of large mammary nodules was found in another after intramuscular administration [ref: 9].
C. Other relevant data
No data were available on the genetic and related effects of medroxyprogesterone acetate alone in humans. See, however, the summary of data for combined oral contraceptives. Medroxyprogesterone acetate induced sister chromatid exchanges in mouse cells in vitro.
Overall evaluation
Medroxyprogesterone acetate is possibly carcinogenic to humans (Group 2B).
For definition of the italicized terms, see Preamble Evaluation.
Also see previous evaluations: Vol. 6 (1974) ; Vol. 21 (1979)
References
1. IARC Monographs, 21, 417-429, 1979
2. Liang, A.P., Levenson, A.G., Layde, P.M., Shelton, J.D., Hatcher, R.A., Potts, M. & Michelson, M.J. (1983) Risk of breast, uterine corpus, and ovarian cancer in women receiving medroxyprogesterone injections. J. Am. med. Assoc., 249, 2909-2912
3. Danielson, D.A., Jick, H., Hunter, J.R., Stergachis, A. & Madsen, S. (1982) Nonestrogenic drugs and breast cancer. Am. J. Epidemiol., 116, 329-332
4. Greenspan, A.R., Hatcher, R.A., Moore, A., Rosenberg, M.J. & Ory, H.W. (1980) The association of depo-medroxyprogesterone acetate and breast cancer. Contraception, 21, 563-569
5. Special Programme of Research, Development and Research Training in Human Reproduction (1986) Depot-medroxyprogesterone acetate DMPA and cancer. Memorandum from a WHO meeting. WHO Bull., 64, 375-382
6. Lanari, C., Molinolo, A.A. & Pasqualini, C.D. (1986) Induction of mammary adenocarcinomas by medroxyprogesterone acetate in BALB/c female mice. Cancer Lett., 33, 215-223
7. Frank, D.W., Kirton, K.T., Murchison, T.E., Quinlan, W.J., Coleman, M.E., Gilbertson, T.J., Feenstra, E.S. & Kimball, F.A. (1979) Mammary tumors and serum hormones in the bitch treated with medroxyprogesterone acetate or progesterone for four years. Fertil. Steril., 31, 340-346
8. van Os, J.L., van Laar, P.H., Oldenkamp, E.P. & Verschoor, J.S.C. (1981) Oestrus control and the incidence of mammary nodules in bitches, a clinical study with two progestogens. Vet. Q., 3, 46-56
9. Concannon, P.W., Spraker, T.R., Casey, H.W. & Hansel, W. (1981) Gross and histopathologic effects of medroxyprogesterone acetate and progesterone on the mammary glands of adult beagle bitches. Fertil. Steril., 36, 373-387
10. IARC Monographs, Suppl. 6, 359-360, 1987
Synonyms for Medroxyprogesterone acetate
See Also:
Toxicological Abbreviations
Medroxyprogesterone Acetate (IARC Summary & Evaluation, Volume 6, 1974)
Medroxyprogesterone Acetate (IARC Summary & Evaluation, Volume 21, 1979)