Pathophysiologic considerations in the treatment of menopausal patients with oestrogens; the role of oestriol in the prevention of mammary carcinoma.

At menopause, several abnormalities in oestrogen metabolism have been reported, which may increase the likelihood of cancer development in the breast or uterus following oestrone or oestradiol-17 beta supplementation. Occult hypothyroidism reduces the rate of oestrogen inactivation by C2 hydroxylation, and 15-20% of women have low rates of C16 hydroxylation to oestriol. Reduced sex hormone binding globulin concentration occurs in association with obesity, thereby increasing the biologically active unbound fraction of oestradiol in plasma. Since oestriol undergoes minimal metabolism after absorption, does not bind to sex hormone binding globulin, and has an anti-oestradiol action by decreasing the duration of nuclear binding of oestradiol-receptor proteins, it is less likely to induce proliferative changes in target organs of cancer-prone women than oestrone or oestradiol. Intermittent non-conjugated oestriol treatment has demonstrated the most significant anti-mammary carcinogenic activity of 22 tested compounds as well as anti-uterotropic activity in intact female Sprague Dawley rats fed either of two dissimilar carcinogens (7, 12 dimethylbenz(a) anthracene, procarbazine) and followed for their natural life span. The protective effect was specific for mammary carcinomas only and has been decreased in rats with a 20% increase in growth curves. Clinical experience thus far with oral oestriol therapy of post-menopausal women has indicated little hazard of cancer development.