Morphological Changes Induced in the Human Uterus and Fallopian Tube by Exogenous Estrogens

Abstract

Although the estrogens do show fine distinctions in their effects that are of clinical importance, most of these hormones are extremely potent, even in tiny doses, since the target cells they stimulate are exquisitely responsive to low concentrations and promptly react by characteristic changes. On the other hand, prolonged high doses seem to overwhelm the receptors of the target cells and apparently exhaust the cytoplasmic structures that produce them so that specific enzyme systems become blocked, and the cells become unable to respond to further estrogen. Atrophy ensues.

The administration of estrogen alone from the first day of a menstrual cycle prolongs the proliferative phase and suppresses the secretion of gonadotropins by the pituitary, especially FSH. Development of a corpus luteum is inhibited until the estrogen is discontinued. Menstruation consequently is delayed. Treatment with estrogen during the secretory phase results in severe stromal edema, delay in secretory transformation of glands and stroma and a disruption of the nucleolar channel-system. If the estrogen is discontinued after prolonged therapy, an estrogen “withdrawal bleeding” ensues; if the estrogen is given over a long period in consistently small doses, a spontaneous “breakthrough bleeding” occurs. With prolonged administration of small doses of estrogen (20–100 μg daily) the endometrium responds with glandular-cystic hyperplasia. Only estriol is less harmful to the endometrium. From time to time portions of these hyperplastic endometria may undergo hemorrhagic necrosis and be discharged, but when the estrogen stimulus continues, unopposed by progesterone, they may progress to precancerous adenomatous hyperplasias. Droplets of fat appear in stromal cells of the upper layers of the endometrium and foam cells eventually develop. In contrast to the hyperplasias arising in the pre- and postclimacteric periods because of endogenous causes, those developing after many years of estrogen therapy are characterized by special morphological features: they develop multicentrically and even in the adenomatous stage may be circumscribed or polypoid. In the adenomatous regions the appearance of the nuclei and cytoplasm of the epithelial cells varies from gland to gland. Both flattened and nodular formations of metaplastic squamous epithelium are especially common.

Whereas the endocervix shows no effect, the ectocervical epithelium reacts with hyperproliferation and keratinization. When estrogen is given to neonatal mice, these changes as well as squamous metaplasia and dysplasia may persist throughout life.

The epithelium of the fallopian tube is also induced to proliferate atypically.