VOL.: 6 (1974) (p. 235)
Steroid hormones have an essential role in the growth, differentiation and function of many tissues in both animals and man. It is established by animal experimentation that modification of the hormonal environment by gonadectomy, by pregnancy or by exogenous administration of steroids can greatly increase or decrease the spontaneous occurrence of tumours or the induction of tumours by applied carcinogenic agents. In man also, there is evidence that differences in endogenous hormone levels may be associated with differences in tumour incidence. It is possible, therefore, that the incidence of human tumours could be increased or decreased by a specific mode of exogenous hormone administration, but this cannot be predicted.
For an administered oestrogen seriously to perturb the hormonal environment of man, the intake must be of the same order as, or greater than, the amounts of oestrogens produced endogenously. The intake of steroids for effective contraceptive medication has to be sufficient to disturb the hormonal environment, and in fact such a disturbance is a requisite of fertility inhibition. The possibility that a carcinogenic risk may be involved in such medication must therefore be considered. For example, the minimum effective dose of diethylstilboestrol of 6 mg/kg bw/day for mammary carcinogenesis in mice is of the same order as the doses used for therapy in women (0.5-5 mg/day). At the same time, it should be remembered in regard to both oestrogens and progestins in contraceptive medication that the steroid hormones of pregnancy have actions similar to those of the contraceptive agents.
Administration of the natural oestrogens, oestradiol-17b and oestrone, increases the incidence of tumours in a number of organs in a variety of animal species. Data on the synthetic oestrogen diethylstilboestrol indicate that this compound has a carcinogenic potential comparable with those of oestradiol-17b and of oestrone, and there is no evidence to suggest that its carcinogenic properties are due to some special biological function other than its oestrogenic activity, which is of the same order as that of oestradiol-17b. The other synthetic oestrogens, ethinyloestradiol and mestranol, have been shown to be carcinogenic in a limited number of animal studies, but there is no reason to suppose that they are more or less carcinogenic than are other oestrogens at comparable levels of oestrogenic activity. Because of lack of experimental data no attempt has been made to show a relationship between carcinogenic potential and oestrogenic activity for any of the compounds considered.
The majority of experimental animal treatments with oestrogens, which have resulted in carcinogenesis, have been at very high dose levels. There is inadequate information at present, however, to indicate the minimum dose requirements, and these could be much lower than those commonly employed in animal studies.
In the case of the natural progestin, progesterone, there is not much evidence that it has a carcinogenic potential per se. There is, however, evidence that low doses of progesterone administered over long periods act in combination with carcinogenic agents such as some viruses or chemicals. In part, therefore, the hazard of long-term administration of synthetic progestins is comparable with that associated with progesterone in increasing the incidence of tumours due to other agents. This is dependent on the degree of progestational activity possessed by the compound in question relative to its other hormonal characteristics.
The synthetic progestins, such as norethynodrel and norethisterone, have some carcinogenic potential in animal systems even when administered alone. This is increased by combination with oestrogens. The progesterone analogue, chlormadinone acetate, has not demonstrated carcinogenic properties when given alone to rodents. When combined with oestrogens, its carcinogenic potential appears to parallel that of the oestrogenic component. Evidence for its tumour-inducing capacity in the canine breast does not seem to be sufficient evidence, alone, for the prohibition of its use in women.
There is no evidence at present to suggest that steroid hormones are ultimate carcinogens; on the contrary, all the evidence suggests that they act, in part at least, by modification of pituitary hormone secretion in which prolactin is a factor. In general, it appears that steroids increase the probability of tumour occurrence in those tissues normally responsive to stimulation by such steroids.
Steroid hormones, such as those considered in this monograph, have been and are used extensively in human therapy. When they are used for the treatment of disseminated cancer such as that of the breast, prostate and endometrium, their effect on tumour growth and the severity of side-effects are the major considerations. In the use of steroid therapy for less vital reasons (for example, menstrual disorders, menopausal syndrome, pregnancy maintenance, osteoporosis, protein anabolism, gonadal deficiency), however, the question of carcinogenic hazard becomes more pertinent. With the continuing development of steroid use for the control of conception, the question of possible carcinogenic hazards has become of major importance.
As stated in the general introduction, "at the present time no attempt can be made to interpret the animal data directly in terms of human risk since no objective criteria are available to do so". There is, therefore, no substitute for direct observation in the human being, although the animal experimentation provides important clues as to where one should look for human risks. Epidemiological studies to explore the possibility of a carcinogenic effect of administered oestrogens and progestins in man, however, suffer from two major difficulties. Firstly, the interval between the commencement of administration and the possible appearance of cancer is likely to be long. Secondly, to detect a small or moderate change in risk, observations on very large numbers of subjects are required.
With these reservations in mind the following can be said:
(a) The administration of this drug to women during pregnancy is associated with an increased risk of vaginal or cervical adenocarcinoma in their exposed female offspring.
(b) There may also be an increased risk of endometrial carcinoma in women with gonadal dysgenesis treated with this drug.
(c) It is possible that the administration of the drug therapeutically to men with carcinoma of the prostate increases the risk of cancer of the breast.
2. Other oestrogens
The administration of oestrogens for treatment of the menopausal syndrome and related conditions has not been shown to be associated with a risk of cancer.
3. Oral contraceptives
The administration of these preparations has not as yet been shown to alter the risk of cancer of the breast. The evidence with respect to cancer of the cervix is somewhat less consistent.
See Also: Toxicological Abbreviations TESTOSTERONE (JECFA Evaluation) Testosterone (PIM 519) Testosterone (IARC Summary & Evaluation, Volume 6, 1974)