Postmenopausal sex hormones and cancer of the endometrium and breast
Authors: Kenemans P , Van Unnik Ga 
Published: August 2004

The controversial issue of a possible relationship between hormone replacement therapy (HRT) and an increased incidence of endometrial and breast cancer will be reviewed, taking into account data from recent case control and cohort studies, as well as the results obtained in re- and meta-analyses. In modern concepts, cancer is a DNA disease and carcinogenesis is a multi-step process, requiring generally 4-6 different alterations in cell cycle regulators, such as proto-oncogenes(HER-2/neu), suppressor genes (P53 and BRCA1/2) and DNA repair genes. Classically, substances related to cancer are either cancer initiators (mutagens) or tumour growth stimulators (promoters). Oestrogens are regarded to be late-stage promoters, and not mutagens. Oestradiol can activate oestrogen target genes in endometrial or breast cells very rapidly, resulting in up-regulation of diverse substances as growth factors (TGF-α, TGF-β) and proto-oncogenes (c-fos, c-myc and HER-2/neu). The result is cellular proliferation and growth of subclinical tumours. Incessant DNA replication could lead to accumulation of DNA damage and ultimately malignant cell transformation. Thus, although oestrogens are not mutagens, there is a significant multifold increased risk of endometrial cancer in current and past long-term users with unopposed oestrogen replacement. A small increase in risk might be present with sequentially combined replacement therapy, but not with continuous combined treatment. Biological mechanisms of endometrial protection differ between the two combined regimens. The protection offered by progestogens within the sequentially combined cycle, results from conversion of proliferative endometrium at the end of the oestrogen-only phase into terminally differentiated, secretory endometrium in the combined phase, with subsequent shedding of a substantial part, but not all, of the endometrium. The biological mechanism of endometrial protection with continuous combined treatment is totally different. Here, a more or less non-proliferative stage is induced resulting in a thin inactive endometrium with bleeding not coming from the endometrium itself, but from fragile vessels underneath. Whether long-term hormone replacement therapy induces breast cancer or only accelerates already present occult tumours remains controversial. A small, but significant increase in risk with unopposed oestrogen use cannot be excluded, although there are many studies that find no increase. The addition of a progestogen, does not seem to influence breast cancer risk. It has been postulated that progestogens activate the cell cycle at the start, but that prolonged daily stimulation would turn the cell cycle off. Breast cancers that are diagnosed in HRT users are more localised and less aggressive than cancers in neverusers. Whether this results from an earlier detection among HRT treated women who have better medical surveillance or from the exogenous hormone use itself, is unclear. The lower mortality rates found in a majority of studies could also, at least in part, be explained on the grounds of selection surveillance bias.