The dose-effect relationship between 'unopposed' oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk

Br J Cancer. 1988 Feb;57(2):205-12. doi: 10.1038/bjc.1988.44.


The 'unopposed oestrogen hypothesis' for endometrial cancer maintains that risk is increased by exposure to endogenous or exogenous oestrogen that is not opposed simultaneously by a progestagen, and that this increased risk is due to the induced mitotic activity of the endometrial cells. Investigation of the mitotic rate during the menstrual cycle shows that increases in plasma oestrogen concentration above the relatively low levels of the early follicular phase do not produce any further increase in the mitotic rate of endometrial cells. A modification of the unopposed oestrogen hypothesis which includes this upper limit in the response of endometrial cells to oestrogen is consistent with the known dose-effect relationships between endometrial cancer risk and both oestrogen replacement therapy and postmenopausal obesity; it also suggests that the mechanism by which obesity increases risk in premenopausal women involves progesterone deficiency rather than oestrogen excess, and that the protective effect of cigarette smoking may be greater in postmenopausal than in premenopausal women. Detailed analysis of the age-incidence curve for endometrial cancer in the light of this hypothesis suggests that there will be lifelong effects of even short duration use of exogenous hormones. In particular, 5 years of combination-type oral contraceptive use is likely to reduce a woman's lifetime risk of endometrial cancer by some 60%; whereas 5 years of unopposed oestrogen replacement therapy is likely to increase her subsequent lifetime risk by at least 90%; and even 5 years of 'adequately' opposed therapy is likely to increase subsequent lifetime risk by at least 50%.

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Contraceptives, Oral
  • Dose-Response Relationship, Drug
  • Endometrium / cytology
  • Estradiol / blood
  • Estrogens / administration & dosage
  • Estrogens / adverse effects*
  • Female
  • Humans
  • Menopause
  • Menstrual Cycle
  • Middle Aged
  • Mitosis / drug effects
  • Obesity / complications
  • Progesterone / blood
  • Risk Factors
  • Smoking / adverse effects
  • Uterine Neoplasms / chemically induced*


  • Contraceptives, Oral
  • Estrogens
  • Progesterone
  • Estradiol