Effects of prenatal exposure of mice to “low-dose” diethylstilbestrol and the development of adenomyosis associated with evidence of hyperprolactinemia

Abstract

The developing genital tract of the fetal mouse was exposed to diethylstillbestrol (DES) and the induction of noncyclic ovarian function in adult life was circumvented. Female mice of two inbred strains, BALB/c and C3H, were mated with BALB/c male mice and on the seventh day of pregnancy were fed a diet containing 0.2 μg of DES/gm continuously until the morning after delivery of the young. This regimen did not interfere appreciably with continuance of pregnancy, and offspring of normal body weight were delivered. When the mice reached maturity, the fertility and fecundity of the cycling exposed female mice were, however, reduced significantly. Virgin exposed BALB/c female mice, observed until 18 months of age, developed neoplasms with the same low frequency normally encountered in this strain, while the exposed hybrids developed mammary carcinomas almost twice as often as did an unexposed population. In addition, two benign lesions of the genital tract occurred frequently in the exposed hybrid female mice. The most extensive of these resembled adenomyosis as seen in the female human in that foci of nonneoplastic endometrium penetrated the muscular layers of the uterus, often forming small, fluid-filled blebs evaginating the serosal surface. This lesion was reproduced by grafting day-old female mice with a single ectopic hypophysis, indicating that chronic hyperprolactinemia was a major endocrine factor in its genesis. The second was an enlargement of the cervix with extensive mucoid alterations within the muscularis, a lesion that could be produced by the continuous estrogenization of adult animals. Both lesions occurred to a much lesser extent in BALB/c female mice, and neither was felt to contribute to the reduced fecundity noted in DES-exposed female mice.