Biology of female sex hormone action in relation to contraceptive agents and neoplasia

Abstract

This article will present an overview of estrogen and progestin action at a cellular level, with emphasis on points that are relevant to neoplasia. In breast, endometrium and ovary, these two classes of hormone are clearly implicated in carcinogenesis, but their involvement with cancers of the liver, cervix and other tissues is more problematic. In the latter situations, I will highlight the major points to be considered if the hormones are involved without wishing to judge whether there actually is a causal involvement.

PIP: This review of the action of estrogens and progestagens, the steroids in oral contraceptives, on cells in the endometrium, breast, ovary, cervix and other tissues, regarding possible causative role in cancer development focuses on the level of steroid receptors and observed actions of these hormones on the cellular level. The steroid hormones are thought to interact with cells by binding to a specific receptor on the cell surface, especially estrogen receptors, while progestagen receptors overlap with glucocorticoids and androgens. Oral contraceptives typically have progestin dosages at the plateau of the dose-response curve, but lower estrogen doses may possible improve the cancer risk. Plasma levels are not reliable estimates of estrogen influence; moreover, estrogens are synthesized locally. Carcinogenesis is a multi-stage process requiring cell proliferation, involving an initiating event, and probably promotion agents, resulting in tumor growth. Estrogens increase cell replication in endometrium, and progestins counter it. Breast cancer evolves in several cell types in the epithelium of the terminal ductal lobular unit, with a 20-year latency. Estrogens stimulate ductal growth and progestins its development, and both are required for full stimulation, as in pregnancy. Estrogens usually stimulate cancer growth, but the precise sensitivity to steroids depends on the timing in the life cycle of the tumor. Ovarian cancer is unique in that neoplasms arise from the epithelium, not the hormone-sensitive tissue. Therefore the suppressive effect of steroids on ovarian neoplasia is thought to be via down- regulation of the gonadotropins, prevention of follicular rupture and consequent cell division of the epithelium, or some effect on growth regulating factors. The effect of steroids on the cervix is unclear, since cervical cancers are hormone-resistant, but there may be a step in transformation by human papilloma virus that involves a glucocorticoid- or progesterone receptor. Steroid receptors are also known to exist in tumors of liver, skin, colon, kidney and anterior pituitary, but their function is neoplasia is unknown.