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

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VOL.: 72 (1999) (p. 399)

5. Summary of Data Reported and Evaluation

5.1 Exposure

The numbers of women who have used post-menopausal oestrogen therapy vary between countries and within regions of individual countries. The prevalence of use has been greater in the United States than in most other countries; use of oestrogen therapy after the menopause is rare in developing countries but is increasing. Conjugated equine oestrogens are the most widely prescribed preparation for oestrogen therapy for women in the United States, but oestradiol and its esters have greater use in most of Europe. Oral administration is the most popular route, but percutaneous methods are becoming commoner; use of injections, the first form of post-menopausal oestrogen therapy, has been declining.

Information on the relationship between post-menopausal oestrogen therapy and risk for breast cancer is available from many epidemiological studies. A pooled analysis of the original data from 51 of those studies and a review of data from 15 cohort and 23 case–control studies showed that in the majority of the studies there is a small increase in risk with longer duration of use (five years or more) in current and recent users. Although there is far less information about women who used post-menopausal oestrogen therapy and then ceased use, the increase in risk appears to cease several years after use has stopped. The increase in risk is predominantly for small localized carcinomas of the breast. There are insufficient data to determine whether the risk varies with type of compound or dose.

Three cohort and more than 30 case–control studies consistently showed an association between use of post-menopausal oestrogen therapy and an increased risk for endometrial cancer. The risk increases with increasing duration of use. It decreases with time since last use but remains higher than that of untreated women for at least 10 years.

Only one cohort and two case–control studies were available on the relationship between use of post-menopausal oestrogen therapy and the risk for invasive cervical cancer; in none of them were the possible confounding effects of oncogenic human papillomaviruses considered. On balance, the limited evidence available suggests that post-menopausal oestrogen therapy is not associated with an increased risk for invasive cervical carcinoma. The results provide some suggestion that post-menopausal oestrogen therapy is associated with a reduced risk for cervical cancer, but the finding could be due to more active screening for pre-invasive disease among women who have received post-menopausal oestrogen therapy.

The four cohort and 12 case–control studies that addressed the risk for ovarian cancer (largely epithelial) among women undergoing post-menopausal oestrogen therapy gave mixed results. One cohort study and one large case–control study showed a significant excess risk for ovarian cancer in women who used this therapy, but a pooled analysis of the individual data from case–control studies showed no excess risk. There is therefore no clear association between post-menopausal oestrogen therapy and the risk for ovarian cancer.

The two cohort and two case–control studies that addressed the association between use of post-menopausal oestrogen therapy and the risk for cancers of the liver or biliary tract showed no alteration in risk.

Seven cohort and 12 case–control studies have provided information on use of post-menopausal oestrogen therapy and the risk for colorectal cancer. The risk was not increased and appeared to be reduced in one-half of the studies. The reduced risk tended to be observed among recent users and did not appear to be related to duration of use.

One cohort and nine case–control studies addressed the risk for cutaneous malignant melanoma in relation to use of post-menopausal oestrogen therapy. Most suggested no alteration in risk.

Seven case–control studies that provided information on thyroid cancer and use of post-menopausal oestrogen therapy suggested no effect on risk.

Hydrolysed conjugated equine oestrogens, equilin and d-equilenin were tested in male hamsters by subcutaneous implantation. The hydrolysed oestrogens and equilin induced microscopic renal carcinomas, whereas d-equilenin was inactive.

Oestradiol and its esters were tested in mice by oral administration, in mice, rats, hamsters, guinea-pigs and monkeys by subcutaneous injection or implantation and in mice by neonatal exposure.

Oral administration of oestradiol to mice bearing murine mammary tumour virus increased the incidences of uterine (endometrial and cervical) adenocarcinomas and mammary tumours. Its subcutaneous administration to mice resulted in increased incidences of mammary, pituitary, uterine, cervical, vaginal and lymphoid tumours and interstitial-cell tumours of the testis.

Invasive pituitary tumours were induced in rats treated with oestradiol dipropionate. In hamsters, a high incidence of malignant kidney tumours occurred in intact and castrated males and in ovariectomized females treated with oestradiol, but not in intact females. In guinea-pigs, diffuse fibromyomatous uterine and abdominal lesions were observed. Subcutaneous injections to neonatal mice resulted in precancerous and cancerous cervical and vaginal lesions in later life and an increased incidence of mammary tumours. The 4-hydroxy metabolite of oestradiol induced renal-cell carcinomas in castrated male hamsters.

Oestradiol was tested in two-stage carcinogenesis models in mice with the known carcinogens N-methyl-N-nitrosourea, N-ethyl-N-nitrosourea or 3-methylcholanthrene and in two-stage carcinogenesis models in rats with N-methyl-N-nitrosourea, 2-acetylaminofluorene, N-nitrosodiethylamine, 7,12-dimethylbenz[a]anthracene or N-butyl-N-nitrosourea. In mice, oestradiol enhanced the incidences of endometrial adenomatous hyperplasia, atypical hyperplasia and adenocarcinomas induced by N-methyl-N-nitrosourea and N-ethyl-N-nitrosourea. A continuously high serum concentration of oestradiol and a low concentration of progesterone appeared to be important for the development of endometrial adenocarcinomas in mice. Oestradiol suppressed the development of uterine cervical carcinomas induced by 3-methylcholanthrene. In rats, large doses of oestradiol alone or oestradiol with progesterone suppressed the development of mammary carcinomas induced by N-methyl-N-nitrosourea. Combined treatment of ovariectomized rats with oestradiol and N-methyl-N-nitrosourea-induced vaginal polyps. In a two-stage model of liver carcinogenesis in rats, oestradiol showed no initiating activity. It did not show promoting effects in the livers of rats initiated with N-nitrosodiethylamine. In one study pretreatment with oestradiol increased the number of liver foci positive for

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