For definition of Groups, see Preamble Evaluation.
Supplement 7: (1987) (p. 308)
A. Evidence for carcinogenicity to humans (inadequate)
Progestins, when administered for at least ten days per 28-day oestrogen replacement therapy cycle, prevent adenomatous hyperplasia, a precursor of endometrial carcinoma, and cause regression of pre-existing adenomatous hyperplasia in some patients [ref: 1]. When administered alone, progestins are effective in the treatment of carcinoma in situ of the endometrium [ref: 2] and of more advanced disease [ref: 3,4].
Progestins increase the conversion of oestradiol-17b to oestrone, a biologically less active oestrogen [ref: 5], and they reduce the concentration of oestrogen receptors [ref: 6]. Maximal mitotic activity in the endometrium occurs during the follicular phase of the cycle; luteal-phase progesterone effectively stops mitotic activity and causes differentiation of endometrial cells to a secretory state [ref: 7].
Support for a protective effect of progestins against endometrial cancer risk is obtained from the results of studies of the effects of oral contraceptives on endometrial cancer risk. Case-control studies have consistently shown that, whereas ingestion of sequential oral contraceptives containing an oestrogen alone throughout most of the menstrual cycle increases risk, ingestion of combined oral contraceptives, in which each pill contains an oestrogen and a progestin, substantially decreases risk.
The effect of progestins on the breast is markedly different from that on the endometrium. Endometrial cancer risk is considerably reduced with combined oral contraceptives, but there is no evidence of a reduced risk of breast cancer, even after long periods of combined oral contraceptive use [ref: 8]. Maximal mitotic activity in breast tissue occurs during the luteal phase of the normal menstrual cycle in the face of maximal progesterone levels [ref: 9]. These results concerning the effects of combined oral contraceptives suggest strongly that progestins do not have an antioestrogen, anticancer effect on the breast. A number of studies [ref: 10-12] have addressed the relationship between oestrogen-progestin replacement therapy and cancer, but in each instance either the small size of the study or apparently inadequate study design or data analysis prevent conclusions from being drawn.
B. Other relevant data
No data were available to the Working Group.
Overall evaluation
Oestrogen-progestin replacement therapy is not classifiable as to its carcinogenicity to humans (Group 3).
For definition of the italicized terms, see Preamble Evaluation.
Also see previous evaluations: Vol. 6 (1974); Vol. 21 (1979)
Subsequent evaluation: Vol. 72 (1999)
References
1. Gambrell, R.D., Jr (1982) Clinical use of progestins in the menopausal patient. Dosage and duration. J. reprod. Med., 27, 531-538
2. Kohorn, E.I. (1976) Gestagens and endometrial carcinoma. Gynecol. Oncol., 4, 398-411
3. Thornton, J.G., Brown, L.A., Wells, M. & Scott, J.S. (1985) Primary treatment of endometrial cancer with progestogen alone. Lancet, ii, 207-208
4. Mackillop, W.J. & Pringle, J.F. (1985) Stage III endometrial carcinoma: a review of 90 cases. Cancer, 56, 2519-2523
5. Tseng, L. & Gurpide, E. (1975) Induction of human endometrial estradiol dehydrogenase by progestins. Endocrinology, 97, 825-833
6. Hsueh, A.J.W., Peck, E.J., Jr & Clark, J.H. (1975) Progesterone antagonism of the oestrogen receptor and oestrogen-induced uterine growth. Nature, 254, 337-339
7. Novak, E.R. & Woodruff, J.D. (1979) Novak's Gynaecologic and Obstetric Pathology with Clinical and Endocrine Relations, Philadelphia, PA, W.B. Saunders, pp. 171-184
8. Kelsey, J.L. (1979) A review of the epidemiology of human breast cancer. Epidemiol. Rev., 1, 74-109
9. Anderson, T.J., Ferguson, D.J.P. & Raab, G.M. (1982) Cell turnover in the 'resting' human breast: influence of parity, contraceptive pill, age and laterality. Br. J. Cancer, 46, 376-382
10. Gambrell, R.D., Jr, Massey, F.M., Castaneda, T.A., Ugenas, A.J. & Ricci, C.A. (1979) Reduced incidence of endometrial cancer among postmenopausal women treated with progestogens. J. Am. Geriatr. Soc., 27, 389-394
11. Nachtigall, L.E., Nachtigall, R.H., Nachtigall, R.B. & Beckman, E.M. (1979) Estrogen replacement therapy. II. A prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet. Gynecol., 54, 74-79
12. Gambrell, R.D., Jr, Maier, R.C. & Sanders, B.I. (1983) Decreased incidence of breast cancer in postmenopausal estrogen-progestogen users. Obstet. Gynecol., 62, 435-443
See Also:
Toxicological Abbreviations