For definition of Groups, see Preamble Evaluation.
Supplement 7: (1987) (p. 296)
A. Evidence for carcinogenicity to humans (sufficient)
There is sufficient evidence that combined oral contraceptives cause benign and malignant liver tumours. There is also conclusive evidence that these agents protect against cancers of the ovary and endometrium.
Liver cancer
Numerous case reports and series of hepatic-cell adenomas occurring almost exclusively in women who had used combined oral contraceptives strongly suggest that such benign tumours may result from exposure to these products [ref: 1]. Two case-control studies [ref: 1] have shown that risk of hepatic-cell adenomas increases strongly with duration of use and have provided estimates of the relative risk in users for more than seven and nine years duration of 500 [ref: 2] and 25 [ref:3], respectively. The many reports of focal nodular hyperplasia occurring in users of oral contraceptives could also represent a causal relationship, but these lesions also occur in men and older women, and no case-control study on these populations has been conducted.
Reports of hepatocellular carcinomas occurring in conjunction with liver-cell adenomas in users of oral contraceptives have been published [ref: 1]. In addition, three case-control studies of hepatocellular carcinomas, one in the USA [ref: 4] and two in the UK [ref: 5,6], have shown strong trends of increasing risk with duration of use. Relative risks (95% confidence limits) in the three studies in users of more than five, eight and eight years' duration, respectively, were estimated to be [13.5 (1.2-152.2)] [ref: 4], 7.2 (2.0-25.7) [ref: 5] and 20.1 (2.3-175.7) [ref: 4], respectively. When data for all three studies are combined, relative risks of 2.5 (1.1-5.5) and 10.0 (3.7-27.2) in 'ever' users and users for more than five to eight years (depending on the study) were derived by the Working Group. Although all three case-control studies of liver cancers and oral contraceptives are small and have methodological deficiencies that could have resulted in biased results, the magnitude of the relative risks and the consistency of the results provide strong evidence that the results are not spurious. Case reports of cholangiocarcinoma in users of oral contraceptives have also been published, but one case-control study of 11 cases [ref: 6] showed no association with use of oral contraceptives [(relative risk, 0.3 in women who ever used oral contraceptives; 0.9 in users of four or more years)].
Ovarian cancer
Ten case-control studies have provided the following estimates of the relative risk (95% confidence limits) for ovarian cancer in women who had ever used combined oral contraceptives: 0.6 [0.3-1.1] [ref: 7], [0.7 (0.4-1.1)] [ref: 8], 0.8 (0.4-1.5) [ref: 9], 0.5 (0.2-1.5) [ref: 10], 0.6 [0.4-1.0] [ref: 11], 0.7 (0.4-1.1) [ref: 12], 0.4 (0.2-1.0) [ref: 13], 0.6 (0.4-0.9) [ref: 14], 0.6 (0.4-0.9) [ref: 15] and 0.6 (0.4-1.0) [ref: 16]. Six of these studies assessed risk in relation to duration of use and five provide at least some evidence that the risk declines with years of exposure, although this trend is less striking than that for endometrial cancer (see below). Relative risks in women who had used combined oral contraceptives for up to or more than five, five, seven and nine years were found in four different studies to be 0.3 (0.1-0.8) [ref: 14], 0.4 (0.2-0.6) [ref: 15], 0.6 [0.3-1.4] [ref: 8] and 0.4 (0.2-1.3) [ref: 11].
Endometrial cancer
Five case-control studies have provided the following estimates of the relative risk (95% confidence limits) for endometrial cancer in women who had ever used combined oral contraceptives: 0.5 (0.1-1.0) [ref: 17], 0.4 (0.2-0.8) [ref: 18], 0.4 [0.2-1.2] [ref: 19], 0.5 (0.3-0.8) [ref: 20] and 0.6 (0.2-1.3) [ref: 16]. Three of these [ref: 18-20], and two others [ref: 21,22], assessed risk in relation to duration of use, and all showed a decline in risk with duration of exposure. Relative risks in users of five or more years' duration were estimated in two studies to be 0.3 (0.1-1.3) [ref: 19] and 0.6 (0.4-0.9) [ref: 20], and one study showed a relative risk of 0.1 [ref: 22] in women with six or more years of use.
Cervical cancer
Four case-control studies [ref: 23-26] of cervical squamous dysplasia provide estimates of relative risk in women who had ever used combined oral contraceptives ranging from 1.2 to 3, and the lower limit of the 95% confidence limits of two of the estimates was greater than one. Relative risks (95% confidence limits) from two cohort studies were [5.0 (1.2-20.8)] [ref: 1], 1.5 [(0.8-2.6)] [ref: 27] and 1.1 [(0.8-1.7)] [ref: 28]. Relative risks for squamous dysplasia were found to increase with duration of use in two [ref: 24,26] of three case-control studies in which risk in relation to length of exposure was considered, and those for women who had used oral contraceptives for more than four years were found in two cohort studies to be [4.9 (1.1-21.8) [ref: 1]] and 2.0 [(1.1-3.6)] [ref: 27].
Four case-control studies of cervical carcinoma in situ [ref: 1,23-25] provide estimates of relative risks in women who had ever used combined oral contraceptives ranging from 0.6 to 1.1 [ref: 25], with 95% confidence limits that include 1.0; but one additional such study yielded an estimated relative risk of [1.6 (1.2-2.0)] [ref: 1], and estimates from three cohort studies were [3.7 (1.5-9.0)] [ref: 1], 1.6 [(0.8-3.0)] [ref: 27] and 1.2 (0.8-1.7) [ref: 28]. One case-control study showed a strong increase in risk for carcinoma in situ with duration of use [ref: 24], but two others did not [ref: 1,25]. Relative risks in users of more than four years' duration were estimated in two cohort studies to be [5.4 (2.1-13.7)] [ref: 1] and 1.7 [(0.9-3.2)] [ref: 27]. Another cohort study [ref: 1] showed the risk of progression from dysplasia to carcinoma in situ to be six times greater in users than in nonusers of oral contraceptives.
Three case-control studies of invasive cervical cancer yielded relative risks in women who had ever used combined oral contraceptives of 1.2 (1.0-1.4) [ref: 29], 1.5 (1.1-2.1) [ref: 30] and 1.7 (0.8-3.6) [ref: 16]; and three cohort studies gave incidence rates of invasive cervical cancer per 1000 women years in users and nonusers of oral contraceptives of 0.20 and 0 [ref: 27], 0.15 and 0.07 [ref: 31] and 0.12 and 0 [ref: 28]. All three case-control studies also showed that risk increased with duration of use; and the two in which relative risks were assessed in women who had used oral contraceptives for more than five years gave values of 1.5 (1.1-2.1) [ref: 29] and [1.9 (1.3-2.7)] [ref: 30].
There is evidence that one or more sexually transmitted, infective agents play an important role in the development of cervical cancer. Since this agent(s) has not been unequivocally identified, and, in particular, was not considered in the studies under review, surrogate measures were used to reflect degree of sexual activity and to adjust for this. Any observed effect of oral contraceptives on risk of cervical cancer may therefore be confounded by an association of oral contraceptive use with exposure to the putative infective agent. Since the specific factor by which the analysis should be adjusted is not known, the Working Group considered that adjusting for age at first intercourse and number of sexual partners may not be sufficient to remove the confounding and, therefore, that they could not regard a causal association of oral contraceptives and cervical cancer as proven.
Breast cancer
Relative risks for breast cancer in women who had ever used combined oral contraceptives have been assessed in 18 case-control studies [ref: 1,16,32-43] and in seven cohort studies [ref: 1,44-47]. All provide point estimates of relative risk close to unity, with 95% confidence intervals that include 1.0. Six case-control studies have provided estimates of the relative risk in women who had used combined oral contraceptives for more than a decade: four [ref: 36,39,40,43] yield relative risks between 0.7 and 1.1 with 95% confidence limits that included 1.0 in users of ten or more years' duration; another [ref: 48] provides a relative risk estimate of 2.2 (1.2-4.0) in users of 12 or more years' duration; and one [ref: 42] gives a relative risk of 0.6 (0.4-0.9) in women who had used oral contraceptives for 15 or more years. Eight case-control studies [ref: 16,36-38,40,42,43,48] and two cohort studies [ref: 44,45] give estimated relative risks for breast cancer ten or more to 20 or more years after initial exposure to combined oral contraceptives, and all are close to 1.0, with 95% confidence intervals that include unity. Eleven case-control studies have assessed risk for breast cancer among women who had used combined oral contraceptives before their first full-term pregnancy. The results are inconsistent, six studies [ref: 39,40,43,47,49,50] showing no significant elevation in risk, three [ref: 34,37,51] showing a significant trend of increasing risk with duration of use, and two [ref: 48,52] showing an increased risk without a significant trend. The reasons for these discrepant findings have not been identified. Five case-control studies have assessed risk in women who had used combined oral contraceptives before 25 years of age. The initial study of this issue showed a strong trend of increasing risk with years of use before age 25 [ref: 53]. A subsequent study from Sweden [ref: 54] showed a relative risk of 3.3 in women who had ever used oral contraceptives at age 20-24, but ascertainment of prior use was not comparable for cases and controls, rendering this finding suspect. Another study from Norway and Sweden [ref: 48] gave a relative risk of 2.7 in women who had used oral contraceptives for eight or more years before the age of 25, but the confidence limits for this included 1.0 (0.7-11.0), and no consistent trend of increasing risk with duration of use was observed. The fourth study, from New Zealand [ref: 43], showed a nonsignificant (p = 0.4) trend of declining risk with duration of use before age 25 and estimated the relative risk in users of six or more years to be 0.6. The fifth study [ref: 50] gave relative risks of 1.0 to 1.3 in six categories of duration of use (<12, 13-48 and > 48 months in women less than 20 and in women 20-24 years of age) but no trend of increasing risk with duration of use. Risk was also initially reported to be particularly enhanced by use before age 25 [ref: 53] of oral contraceptives with a high progestogen potency, but the authors' classification has been disputed; and results from a large collaborative study in the USA do not confirm their findings [ref: 50].
Other tumours
The relative risk for malignant melanoma in women who had ever taken oral contraceptives has been estimated in eight case-control [ref: 1,55-61] and in three cohort [ref: 55,62,63] studies. Values from all the case-control studies were close to unity, with 95% confidence limits that included 1.0. Values from the three cohort studies were 0.3 [0.1-0.8] [ref: 55], 1.5 (0.7-2.9) [ref: 62] and 3.5 (1.4-9.0) [ref: 63]. The reasons for these widely discrepant results are unknown. Trends of increasing risk with duration of use have been observed in some investigations but not in others. The two case-control studies in which analyses were performed to estimate the relative risk in users of more than two [ref: 56] and five [ref: 59] years' duration, ten or more years after initial exposure, showed elevated risks of 2.3 (0.8-6.9) and 1.5 (1.0-2.1), respectively. Two case-control studies showed trends of increasing risk specifically for superficial spreading melanoma with increasing duration of use [ref: 57,60], although a third did not [ref: 63]. Also, two studies have shown relative risks for superficial spreading-type melanoma to be increased in users of five or more years' duration after latent periods of over ten [ref: 59] and 12 [ref: 57] years: [1.6 (1.0-2.6)] and 4.4 (2.0-9.7), respectively.
Two case-control studies and two prospective studies have shown no increase in risk for pituitary adenomas [ref: 1,64,65].
Women who took oral contraceptives after evacuation of a hydatidiform mole were reported in one study [ref: 1] subsequently to have developed trophoblastic tumours more frequently than women who had used other methods of contraception after a molar evacuation, but this was not confirmed in another investigation [ref: 66].
A single case-control study showed a reduction in risk for carcinomas of the colon and rectum with duration of use of combined oral contraceptives [ref: 67], but two cohort studies showed no alteration in risk for these neoplasms in users [ref: 63,68].
A protective effect of combined oral contraceptives against both fibroadenoma and fibrocystic disease of the breast has been found in many investigations [ref: 1,63,69-72], although a single recent study found an increase in risk for the latter condition in postmenopausal women [ref: 73]. One study showed no protective effect of oral contraceptives against fibrocystic disease with atypical histological features [ref: 1], but one subsequent investigation did [ref: 70].
A reduction in risk for retention cysts of the ovary has been documented in two cohort studies and in one case-control study [ref: 1]. A reduction in risk for uterine leiomyoma has been documented in one case-control study [ref: 74].
B. Evidence for carcinogenicity to animals (sufficient for norethynodrel in combination with mestranol; limited for chlormadinone acetate in combination with mestranol or ethinyloestradiol, for ethynodiol acetate in combination with mestranol or ethinyloestradiol, for megestrol acetate in combination with ethinyloestradiol, for norethisterone in combination with mestranol or ethinyloestradiol, for progesterone in combination with oestradiol-17b, and for investigational contraceptives; inadequate for lynoestrenol in combination with mestranol and for norgestrel in combination with ethinyloestradiol)
Chlormadinone acetate and oestrogens
Chlormadinone acetate, in combination with mestranol, was tested for carcinogenicity by oral administration to mice; an increased incidence of pituitary tumours was observed in animals of each sex. Oral administration of chlormadinone acetate in combination with ethinyloestradiol to mice resulted in an increased incidence of mammary tumours in intact and castrated males [ref: 75].
Ethynodiol diacetate and oestrogens
Following oral administration of ethynodiol diacetate plus mestranol to mice, increased incidences of pituitary tumours were observed in animals of each sex. Ethynodiol diacetate plus ethinyloestradiol was tested for carcinogenicity by oral administration to mice and rats. In mice, it induced increased incidences of pituitary tumours in animals of each sex and of malignant tumours of connective tissues of the uterus. In rats, malignant mammary tumours were produced in animals of each sex [ref: 76].
Lynoestrenol and oestrogens
Lynoestrenol, in combination with mestranol, was tested in mice and female rats by oral administration. A slight, nonsignificant increase in the incidence of malignant mammary tumours was observed in female mice [ref: 77].
Megestrol acetate and oestrogens
Megestrol acetate plus ethinyloestradiol was tested for carcinogenicity by oral administration to mice and rats. In mice, increased incidences of malignant mammary tumours were observed in animals of each sex. No increase in tumour incidence was observed in rats [ref: 78].
Norethisterone and oestrogens
Norethisterone acetate plus ethinyloestradiol was tested for carcinogenicity by oral administration to mice, rats and monkeys. In mice, pituitary tumours were observed in animals of each sex. In rats, increased incidences of benign mammary tumours were found in males in one study and of benign liver-cell and mammary tumours in animals of each sex in the other [ref: 79]. Norethisterone acetate plus ethinyloestradiol administered orally to rats induced endometrial carcinomas [ref: 80]. Oral administration of norethisterone acetate plus ethinyloestradiol to female rats for 12 months resulted in hyperplastic nodules of the liver in all animals and a hepatocellular carcinoma in one (preliminary results) [ref: 81]. Norethisterone acetate and ethinyloestradiol given orally to monkeys for ten years did not produce malignant tumours [ref: 82].
Norethisterone plus mestranol was tested for carcinogenicity in mice and rats by oral administration. In mice, pituitaty tumours developed in animals of each sex. In rats, an increased incidence of malignant mammary tumours was found in females. Norethisterone plus ethinyloestradiol, tested in mice by oral administration, induced an increased incidence of pituitary tumours in females [ref: 79].
Norethynodrel and oestrogens
Norethynodrel in combination with mestranol was tested for carcinogenicity in mice, rats, hamsters and monkeys orally and by subcutaneous implantation. Increased incidences of pituitary, mammary, vaginal and cervical tumours were found in female mice and of pituitary tumours in male mice. In castrated male mice, the combined treatment resulted in an increase in the incidence of mammary tumours. In rats, benign liver-cell tumours were observed in males and pituitary tumours and malignant mammary tumours in animals of each sex. A study of hamsters was of too short a duration to be considered for evaluation. The combined treatment given to Macaca mulatta monkeys for five years did not increase the incidence of mammary tumours [ref: 83].
Norgestrel and oestrogens
Norgestrel plus ethinyloestradiol was tested for carcinogenicity in mice and rats by oral administration. No increase in the incidence of tumours was observed in either species [ref: 84].
Progesterone and oestrogen
Neonatal exposure of mice to progesterone plus oestradiol-17b resulted in an increased incidence of mammary tumours [ref: 85].
Investigational oral contraceptives
Three investigational oral contraceptives (ethynerone, chloroethynyl norgestrel or anagestone acetate plus mestranol) were tested for carcinogenicity by oral administration to dogs. An increased incidence of malignant mammary tumours was observed after treatment with chloroethynyl norgestrel plus mestranol or with anagestone acetate plus mestranol; no difference in the total number of mammary-gland nodules was observed with these two contraceptives. One dog given ethynerone plus mestranol had 14 malignant mammary fibrosarcomas [ref: 86].
C. Other relevant data
The results reported in the available studies related to a variety of different oral contraceptives.
Several studies showed no increase in the incidence of structural chromosomal changes in lymphocytes taken from women after oral contraceptive use (norethisterone with mestranol or ethynodiol diacetate with mestranol). In contrast to an earlier report, no increase in the incidence of sister chromatid exchanges was observed in 52 women taking oral contraceptives as compared with 63 controls when results were adjusted for smoking [ref: 87].
No significant difference in the frequency of abnormal karyotypes or in sex ratio was seen in a study of spontaneous abortuses of women who had taken oral contraceptives; the contraceptives used were norgestrel, norethisterone acetate or medroxyprogesterone acetate in combination with ethinyloestradiol; or ethynodiol acetate, megestrol acetate or lynoestrenol in combination with mestranol. Similarly, a large cohort study showed no increase in risk for chromosomal anomalies in live births and abortuses of oral contraceptive users [ref: 87].
High doses of one oral contraceptive (lynoestrenol and mestranol) administered to two strains of female mice induced dominant lethal mutations, whereas high doses of another (norethisterone and ethinyl oestradiol) did not. In a later report using even higher doses of the oral contraceptive that induced dominant lethal mutations and of another (norethisterone acetate and ethinyloestradiol), the same authors reported no increase in the incidence of dominant lethal, recessive lethal or visible mutations in mice. Combinations of progestins (norethynodrel and ethynodiol diacetate) and oestrogens (mestranol and ethinyloestradiol) did not induce sex-linked recessive lethal mutations in Drosophila [ref: 87].
Overall evaluation
Combined oral contraceptives are carcinogenic to humans (Group 1).
N.B. - There is also conclusive evidence that these agents have a protective effect against cancers of the ovary and endometrium.
For definition of the italicized terms, see Preamble Evaluation.
Also previous evaluations: Vol. 6 (1974); Vol. 21 (1979)
Subsequent evaluation: Vol. 72 (1999)
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See Also:
Toxicological Abbreviations
Oral Contraceptives, Combined (IARC Summary & Evaluation, Volume 72, 1999)