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International Agency for Research on Cancer (IARC) - Summaries & Evaluations

PROGESTINS
(Group 2B)

For definition of Groups, see Preamble Evaluation.

Supplement 7: (1987) (p. 289)

Medroxyprogesterone acetate

CAS No.: 71-58-9
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 a 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.

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

Chlormadinone acetate

CAS No.: 302-22-7
Chem. Abstr. Name: 17-(Acetyloxy)-6-chloropregna-4,6-diene-3,20-dione

A. Evidence for carcinogenicity to animals (limited)

Chlormadinone acetate was tested in mice, rats and dogs by oral administration. In dogs, it produced mammary tumours in one study [ref: 1] and increased the incidence of mammary-gland hyperplasia and mammary nodules in another [ref: 2].

B. Other relevant data

No data were available on the genetic and related effects of chlormadinone acetate alone in humans. See, however, the summary of data for combined oral contraceptives. Chlormadinone acetate did not induce chromosomal aberrations in cultured human lymphocytes and was not mutagenic to bacteria [ref: 3].

References

1. IARC Monographs, 21, 365-375, 1979

2. El Etreby, M.F. & Gräf, K.-J. (1979) Effect of contraceptive steroids on mammary gland of beagle dog and its relevance to human carcinogenicity. Pharmacol. Ther., 5, 369-402

3. IARC Monographs, Suppl. 6, 148-149, 1987

Synonyms for Chlormadinone acetate

Dimethisterone

CAS No.: 79-64-1
Chem. Abstr. Name: (6a,17b)-17-Hydroxy-6-methyl-17-(1-propynyl)-androst-4-en-3-one

A. Evidence for carcinogenicity to animals (inadequate)

Dimethisterone was reported to have been tested in monkeys in one study. No increase in tumour incidence was found [ref: 1].

B. Other relevant data

No data were available on the genetic and related effects of dimethisterone in humans. It did not induce chromosomal aberrations in cultured human lymphocytes [ref: 2].

References

1. Weikel, J.H., Jr & Nelson, L.W. (1977) Problems in evaluating chronic toxicity of contraceptive steroids in dogs. J. Toxicol. environ. Health, 3, 167-177

2. IARC Monographs, Suppl. 6, 260-261, 1987

Synonyms for Dimethisterone

Ethynodiol diacetate

CAS No.: 297-76-7
Chem. Abstr. Name: (3b,17a)-19-Norpregn-4-en-20-yne-3,17-diol diacetate

A. Evidence for carcinogenicity to animals (limited)

Ethynodiol diacetate was tested in mice and rats by oral administration. It increased the incidence of benign liver tumours in male mice and of mammary tumours in castrated male mice, and produced benign mammary tumours in male rats [ref: 1].

B. Other relevant data

No data were available on the genetic and related effects of ethynodiol diacetate alone in humans. See, however, the summary of data for combined oral contraceptives. Ethynodiol diacetate did not induce sex-linked recessive lethal mutations in Drosophila [ref: 2].

References

1. IARC Monographs, 21, 387-398, 1979

2. IARC Monographs, Suppl. 6, 308-309, 1987

Synonyms for Ethynodiol diacetate

17a-Hydroxyprogesterone caproate

CAS No.: 630-56-8
Chem. Abstr. Name: 17-[(1-Oxohexyl)oxy]pregn-4-ene-3,20-dione

A. Evidence for carcinogenicity to animals (inadequate)

17a-Hydroxyprogesterone caproate was tested in rabbits by repeated intramuscular injection, giving inconclusive results [ref: 1]. It was reported to have accelerated the growth of a transplantable cervical tumour line in mice [ref: 2].

B. Other relevant data

No data were available to the Working Group.

References

1. IARC Monographs, 21, 399-406, 1979

2. Umancheeva, A.F., Novikova, A.I. & Anisomov, V.N. (1981) Stimulating effect of pregnancy on the growth of cervical cancer (Russ.). Akush. Ginekol., 1, 53-55

Synonyms for 17a-Hydroxyprogesterone caproate

Lynoestrenol

CAS No.: 52-76-6
Chem. Abstr. Name: (17a)-19-Norpregn-4-en-20-yn-17-ol

A. Evidence for carcinogenicity to animals (inadequate)

Lynoestrenol was tested by oral administration in mice and rats. It induced a slight increase in the incidence of benign liver-cell tumours in male mice and of malignant mammary tumours in female mice. In female rats, a slight but nonsignificant increase in the incidence of malignant mammary tumours was observed after administration of lynoestrenol [ref: 1].

B. Other relevant data

No data were available to the Working Group.

Reference

1. IARC Monographs, 21, 407-415, 1979

Synonyms for Lynoestrenol

Megestrol acetate

CAS No.: 595-33-5
Chem. Abstr. Name: 17a-(Acetyloxy)-6-methylpregna-4,6-diene-3,20-dione

A. Evidence for carcinogenicity to animals (limited)

Megestrol acetate was tested by oral administration in mice, rats, dogs and monkeys. It produced nodular hyperplasia, and benign and malignant mammary tumours in dogs [ref: 1]. No tumour was reported in monkeys [ref: 2].

B. Other relevant data

No data were available on the genetic and related effects of megestrol acetate alone in humans. See, however, the summary of data for combined oral contraceptives (p. 297). Megestrol acetate did not induce chromosomal aberrations in cultured human lymphocytes [ref: 3].

References

1. IARC Monographs, 21, 431-439, 1979

2. Weikel, J.H., Jr & Nelson, L.W. (1977) Problems in evaluating chronic toxicity of contraceptive steroids in dogs. J. Toxicol. environ. Health, 3, 167-177

3. IARC Monographs, Suppl. 6, 361-362, 1987

Synonyms for Megestrol acetate

Norethisterone

CAS No.: 68-22-4
Chem. Abstr. Name: (17a)-17-Hydroxy-19-norpregn-4-en-20-yn-3-one

Norethisterone acetate

CAS No.: 51-98-9
Chem. Abstr. Name: (17a)-17-(Acetyloxy)-19-norpregn-4-en-20-yn-3-one

A. Evidence for carcinogenicity to animals (sufficient)

Norethisterone and its acetate were tested by oral administration in mice and rats, and by subcutaneous implantation in mice. In mice, norethisterone and its acetate increased the incidence of benign liver-cell tumours in males; norethisterone increased the incidence of pituitary tumours in females and produced granulosa-cell tumours in the ovaries of females. Norethisterone increased the incidence of benign liver-cell tumours and benign and malignant mammary tumours in male rats [ref: 1]. Rats fed 3-4 mg/kg bw per day norethisterone acetate (about 100 times the daily human dose) for two years had an increased incidence of neoplastic nodules of the liver; an increase in the incidence of uterine polyps was seen in females [ref: 2]. In rats given weekly intramuscular injections for 104 weeks of norethisterone enanthate at doses of 10, 30 and 100 mg/kg bw (20, 60 and 200 times the daily human contraceptive dose), there was a dose-related increase in pituitary-gland tumours in males, whereas in females no effect on pituitary glands was observed with the lowest dose and a reduction in pituitary tumours was observed with the highest dose. Benign mammary tumours were observed in males at all doses, but there was little effect in females; the incidence of malignant mammary tumours was greatly increased in both males and females given the two higher dose levels and was dose-related. A dose-related increase in the incidence of liver tumours was also seen in animals of each sex [ref: 3].

B. Other relevant data

No data were available on the genetic and related effects of norethisterone alone in humans. See, however, the summary of data for combined oral contraceptives.

Aneuploidy was observed in oocytes of mice treated with high doses of norethisterone acetate. In a test for dominant lethal mutations in which female mice were exposed orally to norethisterone acetate, no increase was seen in one strain of mice, and a second strain showed an increase only when females were mated within two weeks after treatment. The compound did not induce aneuploidy or chromosomal aberrations in cultured human lymphocytes. Neither norethisterone nor its acetate was mutagenic to bacteria [ref: 4].

References

1. IARC Monographs, 21, 441-460, 1979

2. Schardein, J.L. (1980) Studies on the components of an oral contraceptive agent in albino rats. II. Progestogenic component and comparison of effects of the components and the combined agent. J. Toxicol. environ. Health, 6, 895-906

3. El Etreby, M.F. & Neumann, F. (1980) Influence of sex steroids and steroid antagonists on hormone-dependent tumors in experimental animals. In: Iacobelli, S., King, R.J.B., Lindner, H.R. & Lippman, M.E., eds, Hormones and Cancer, New York, Raven Press, pp. 321-336

4. IARC Monographs, Suppl. 6, 427-429, 1987

Synonyms for Norethisterone

Synonyms for Norethisterone acetate

Norethynodrel

CAS No.: 68-23-5
Chem. Abstr. Name: (17a)-17-Hydroxy-19-norpregn-5(10)-en-20-yn-3-one

A. Evidence for carcinogenicity to animals (limited)

Norethynodrel was tested by oral administration in mice and rats and by subcutaneous implantation in mice. It increased the incidence of pituitary tumours in mice of each sex and that of mammary tumours in castrated males of one strain. It also increased the incidence of benign and malignant liver-cell, pituitary and mammary (benign and malignant) tumours in male rats [ref: 1]. Feeding of norethynodrel to rats following partial hepatectomy and treatment with N-nitrosodiethylamine increased the number of g-glutamyl transpeptidase-positive hepatic foci at four months, but there was no significant difference by nine months [ref: 2].

B. Other relevant data

No data were available on the genetic and related effects of norethynodrel alone in humans. See, however, the summary of data for combined oral contraceptives. Norethynodrel did not induce aneuploidy in human cells in culture or unscheduled DNA synthesis in rat hepatocytes in vitro. It inhibited intercellular communication in Chinese hamster V79 cells. The compound was not mutagenic to bacteria [ref: 3].

References

1. IARC Monographs, 21, 461-477, 1979

2. Yager, J.D. & Yager, R. (1980) Oral contraceptive steroids as promoters of hepatocarcinogenesis in female Sprague-Dawley rats. Cancer Res., 40, 3680-3685

3. IARC Monographs, Suppl. 6, 430-431, 1987

Synonyms for Norethynodrel

Norgestrel

CAS No.: 797-63-7
Chem. Abstr. Name: (17a)(+)-13-Ethyl-17-hydroxy-18,19-dinorpregn-4-en-20-yn-3-one

A. Evidence for carcinogenicity to animals (inadequate)

Norgestrel was tested by oral administration in mice and rats. No increase in the incidence of tumours was observed in either species [ref: 1].

B. Other relevant data

No data were available of the genetic and related effects of norgestrel alone in humans. See, however, the summary of data for combined oral contraceptives. Norgestrel gave inconclusive results in tests for sex-linked recessive lethal mutations in Drosophila. It was not mutagenic to bacteria [ref: 2].

References

1. IARC Monographs, 21, 479-490, 1979

2. IARC Monographs, Suppl. 6, 432-433, 1987

Synonyms for Norgestrel

Progesterone

CAS No.: 57-83-0
Chem. Abstr. Name: Pregn-4-ene-3,20-dione

A. Evidence for carcinogenicity to animals (sufficient)

Progesterone was tested by subcutaneous and by intramuscular injection in mice, rabbits and dogs, and by subcutaneous implantation in mice. It increased the incidences of ovarian, uterine and mammary tumours in mice. Neonatal treatment with progesterone enhanced the occurrence of precancerous and cancerous lesions of the genital tract and increased mammary tumorigenesis in female mice [ref: 1]. Dogs treated with progesterone for four years at one to 25 times the luteal-phase levels for that species developed a dose-related incidence of mammary-gland nodules [ref: 2].

B. Other relevant data

No data were available on the genetic and related effects of progesterone in humans.

Progesterone did not induce dominant lethal mutations in mice or chromosomal aberrations in rats treated in vivo. It did not induce chromosomal aberrations or sister chromatid exchanges in cultured human cells, nor chromosomal aberrations or DNA strand breaks in rodent cells. Studies on transformation of rodent cells in vitro were inconclusive: a clearly positive result was obtained for rat embryo cells, a weakly positive result for mouse cells and a negative result for Syrian hamster embryo cells. Progesterone was not mutagenic to bacteria [ref: 3].

References

1. IARC Monographs, 21, 491-515, 1979

2. 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

3. IARC Monographs, Suppl. 6, 479-481, 1987

Synonyms for Progesterone

Overall evaluation

Progestins are 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)

Subsequent evaluation: Vol. 72 (1999)


Last updated: 3 March 1998




















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