Progesterone

Carcinogenicity

Description of key information

Since progesterone is a naturally occurring hormone in humans, no relevant tumorigenic potential has to be assumed for this compound. However, also during the handling of progesterone it has to be kept in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.

Justification for classification or non-classification

It has to be taken into account that gestagens in general can promote the growth of specific hormone dependent tissues and tumours.

Classified according to German legislation (TRGS-905) for gestagenic steroids as Carc. Cat. 3 (EEC criteria).

Classified as Category 3, R40 according to Directive 67/548/EEC.

Classified as Category 2 according to Regulation (EC) 1272/2008/EC (CLP).

Additional information

Carcinogenicity Animal Data

Test system	Substance	Application	Test concentration	End point/Effect	Literature
16 ovariectomized C3H mice with mouse tumor virus [MTV+]	Progesterone	Intramuscular weekly intravaginal applications of 1% solution of DMBA	0.2 mg twice weekly	Incidence of squamous- cell carcinomas increased from 5/15 to 9/16; no change in the incidence of mixed carcinomas (3/8 to 4/16)	Glucksmann, A & Cherry, C.P. (1962) The effect of castration and of additional hormonal treatments on the induction of cervical and vulval tumours in mice. Br. J. Cancer 16, 634-652.
C3H female mouse [MTV+]	Progesterole in peanut oil	Subcutaneous 5 times/week/19 weeks	2.5 mg	Incidence of breast tumors induced by 3- methyl-cholanthrene to 23/23, compared with 5/24 for 3- methylcholanthrene alone & 2/25 for progesterole alone.	IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V6 139 (1974)
BALB/C mouse	Progesterone	Subcutaneous implantation, 18 months treatment	59-900 µg/day	Ovarian granulosa cell tumors were found in 27/83 balb/c mice; most of them measuring less than 0.5 mm in diameter. One microscopic tumor occurred among 33 control mice killed after 18 months.	IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V6 141 (1974)
BALB/C mouse	Progesterone	Subcutaneous Implantation, 18 months treatment	18-900 µg/day	Sarcomas of the endometrial stroma in 15/142 mice after 18 months. No tumors in the 33 control animals	Lipschütz, A., Iglesias, R, Panasevich, V.I. & Salinas, S. (1967). Granulosa-cell tumors induced in mice by progesterone. Br. J. Cancer 21, 144-152; Lipschütz, A., Iglesias, R, Panasevich, V.I. & Salinas, S. (1967). Pathological changes induced in the uterus of mice withnthe prolonged administration of progesterone and 19-nor- contraceptives. Br. J. Cancer 21, 160-165.
Neonatal female Balb/cfC3H mouse [MTV+]	Progesterone	Subcutaneous	100 µg/day, alone or in combination with 5 or 20 µg/day Oestradiol 17β	Persistent vaginal cornification in all 32 mice treated with progesterone alone; simultaneous administration reduced occurrence of vaginal cornification significantly. Mammary tumor incidence was enhanced by progesterone alone (23/32) or in combination with oestradiol (5 µg, 20/32; 20 µg, 33/44), when compared to control animals /5/17). Age of onset was significantly lower in mice given progesterone.	Jones, L.A. & Bern, H.A. (1977) Long-term effects of neonatal treatment with progesterone, alone or in combination with estrogen, on the mammary gland and reproductive tract of female BALB/cfC3H mice. Cancer Res. 37, 67-75.
Female C3HXA hybrid mouse [MTV+]		Implantation (subcutaneous) every 28 days during 104 weeks)	14 mg pellets	Breast carcinomas significantly earlier age higher incidence (88% at 70 week) than among 58 untreated control mice (62% at 93 week). No mammary tumors in 27 progestrone- treated, intact males.	IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Geneva: World Health Organization, International Agency for Research on Cancer, 1972-present. (Multivolume work)., p. V6 141(1974)
27 C3H mice [MTV-]	Progesterone	42 weeks		No induction of tumors	IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V6 139 (1974)
Mouse		Subcutaneous		Tumors : mammary gland; ovaries; uterus	IARC Monographs on the Evaluation of the carcinogenic Risk of Chemicals to Humans, International Agency for Research on Cancer,,, P. V6 135 Y74]/[IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, International Agency for Research on Cancer, Lyon, France, P. V21 491 Y79
BALB/cCrgl female mouse	Progesterone	Subcutaneous, 5 days after birth	100 µg/ 0.02 ml sesame oil	Induction of genital tract lesions in 15/24 mice [MTV-] at about 1.5-2 years of age. No lesions in control animals.	Jones, H.A. & Wong, L.M. (1977) Cervicovaginal and mammary gland abnormalities in old BALB/cCrgl mice treated neonatally with progesterone. J.Toxicol. Environ. Health´3, 360 -361.
13 CBA mouse with mouse tumor virus	Progesterone	Subcutaneous, weekly until death	10 mg	Mice were given an intrauterine implantation of 0.1 mg 3-methylcholanthrene, mice were ovariectomized. At week 20-29, 2 sarcomas of the uterine horn in 4 mice, 2 sarcomas in 4 other mice that died at 40- 49 weeks. In control mice only receiving MCA, 5 adenocarcinomas, 2 squamos carcinomas and 1 sarcoma were observed.	Kaslaris, E. & Jull, J.W. (1962) The induction of tumours following the direct implantation of four chemical carcinogens into the uterus of mice and the effect of strain and hormones thereon. B. J. Cancer 16, 479-483.
C57BL6 mouse	Progesterone	Every 3 weeks for 9 weeks	15 mg after local application of MCA	Increased incidence of vaginal-cervical invasive squamous- cell carcinomas, from 6/50 with MCA alone to 45/50.	Muñoz, N. (1973) Effect of herpesvirus type 2 and hormonal imbalance on the uterine cervix of the mouse. Cancer Res. 33, 1504 -1508.
AXC rat	Progesterone	Implantation (subcutaneous) 40 weeks	20 mg /100 g body wt	An INCR incidence of liver cell carcinomas induced by N-2 - fluorenyldiacetamide observed in intact male rats (11/11 VS 7/12), in castrated males (5/13 VS 1/9) & in ovariectomized females (4/12 vs 0/14)	IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-present. (Multivolume work). p. V6 142 (1974)
Female AXC rat	Progesterone /and/or diethylstilbestrol (DES) plus irradiation	Intramuscular implantation	20 mg / plus irradiation	Development of mammary tumors inhibited by progesterone. Incidence reduced from 12/21 with DES & irradiation to 1/21 with DES & progesterone + irradiation; incidence 0/11 with progesterone & irradiation.	IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-present. (Multivolume work)., p. V6 142 (1974)
AXC rat, hysterectomized and ovariectomized	Progesteron	Subcutaneous injection or implantation	2 mg (injection) 20 mg (implantation)	No affection of incidence of mammary tumors induced by simultaneous administration of DES by 82 weeks of age (18/39 or 17/33 vs. 21/38).	Segaloff, A. (974) The role of the ovary in estrogen production of mammary cancer in the rat. Cancer Res 34, 2708-2710.
Female SD rat	Progesterone	Subcutaneous, i.g. installation of 20 mg DMBA at 55 days	1.25 mg in 0.05 mL sesame oil, 5 days of age	Tumor development in 23/30 animals by 190 days of age. Incidence was similar to that in controls given DMBA only. (20/33). Local number of adeno- carcinomas was higher in progesterone- treated rats (44 vs 27).	Shellabarger, C.J & Soo, V.A. (1973) Effects of neonatally administered sex steroids on DMBA-induced mammary neoplasia in rats. Cancer Res 33, 1567-1569.
Female rat	Progesterone	Subcutaneous	0.3 mg, three times weekly for 21 weeks	Increase of latent period of induction of mammary tumors from 37 to 50 weeks. No change in tumor incidence.	Cutts, J.H. (1964) Estrone- induced mammary tumors in the rat. II. Effect of alterations in the hormonal environment on tumor induction, behaviour and growth. Cancer Res., 24, 1124-1130.
Rat	Progesterone	Intramuscular	1 mg twice weekly	Retardation of app. 4 times the induction of sarcomas of the cervix and vagina produced by local administration of DMBA weekly for life; induction of papillomas was promoted by 19 weeks; progesterone alone did not increase the effects of the carcinogen in ovariectomized animals; when given with oestrogen, the incidence but not the latent period of tumor induction was restored to that of intact females.	Glucksmann, A & Cherry, C.P. (1968) The effect of oestrogens, testosterone and progesterone on the induction of cervico-vaginal tumours in intact and castrate rats. Br. J. Cancer, 22, 545-562.
SD Rat	Progesterone	Subcutaneous	3 mg twice weekly for 28 weeks	Reduction of age at onset of mammary tumors induced by 30 mg DMBA given intragastrically at 50 days of age (52 vs. 115 days) and increased the number of tumors per rat when compared to controls. Mammary tumor incidence not affected (19/20 vs. 16/20).	Jabara, A.G. & Maritz, J.S. (1973) Effetcts of hypothyroidism and progesterone on mammary tumours induced by DMBA in Sparague-Dawley rats. Br. J. Cancer, 28, 161-172.
SD Rat	Progesterone	Subcutaneous	4 mg daily for 20 days	Injection before and after a single iv injection of 5 mg DMBA resulted in a lowered incidence (from 100 to 20) and almost complete inhibition of the tumors for 4 months after the DMBA injection. No mammary tumors appeared in rats treated with progesterone in combination with oestradiol benzoate (5 µg/day) during the same period	Kledzik, G.S., Bradley, C.J. & Meites, J. (1974) Reduction of carcinogen-induced mammary cancer incidence in rats by early treatment with hormones or drugs. Cancer Res. 34, 2953- 2956.
Female Beagle dog	Progesterone	Subcutaneous,   74 weeks	0.08-22.5 mg daily	Endometrial hyperplasia; no tumors in animals killed 24 hr after last dose, but fibro-adenomatous nodules occurred in 2/5 dogs given highest doses	IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V6 141 (1974)