Estrogen exposure during female reproductive system development

Abstract

From the 1940's to 1971 treatment of pregnant women with the synthetic estrogen diethylstilbestrol (DES) was a popular treatment for women with pregnancy complications and high risk pregnancies. DES was thought to stimulate placental progesterone synthesis and was widely used as it was cheap and did not have any obvious side effects. More than two million women in the USA were treated with DES during pregnancy. This treatment was less popular in Europe and DES was never used in Sweden.In 1971 an association between clear cell adenocarcinoma of the vagina in teenage girls and exposure to DES during fetal life was reported from Boston. The risk of vaginal cancer after DES exposure fortunately turned out to be low (1 : 1000). Reproductive disorders, such as infertility, spontaneous abortion and ectopic pregnancy have since been shown to be a much more common disorder in DES exposed women. Most of these problems have been thought to be due to structural malformation of the uterus and oviduct, which has been reported in up to 50% of DES exposed women.The main aim of the present thesis was to identify mechanisms whereby infertility occurs in adult female mice after estrogen exposure during reproductive system development. The female pups were given DES during the first five days after birth. This week corresponds with respect to reproductive system development to a period before the 20th pregnancy week in women.Estrogen treatment of perinatal rodents has been shown to interfere with the development of the ventral hypothalamus which causes masculinization and results in an acyclic secretion of gonado-Abbreviation: DES: synthetic estrogen diethylstilbestrol. 0 Acta Obstet Gynecol Scand 72 (1993) tropins which in turn leads to anovulation. The pituitary content and tonic levels of serum luteinizing hormone and follicle stimulating hormone were markedly reduced before puberty in DES exposed mice. In parallel, a reduced in vitro synthesis of ovarian steroids when using pregnenolone as a precursor was seen before day 28. Before puberty the only morphological disturbance in DES exposed ovaries was the occurrence of polyoocyte follicles. No differences were found in tonic gonadotropin levels after day 28. Adult females exposed neonatally to DES had an abnormal ovarian morphology with no corpora lutea, hypertrophic interstitial cell tissue, follicles at various stages of development and an aberrant pattern of in vitro steroid synthesis.After superovulation and artificial insemination, DES females were able to ovulate. In spite of this these females never became pregnant, whereas approximately 30% of the similarly treated unexposed females had litters. The oocytes of ovaries exposed neonatally to DES were not permanently disturbed and when such ovaries were transplanted to unexposed females they were able to give rise to offspring in the same incidence as unexposed females transplanted with unexposed ovaries.To investigate preimplantation embryo development in DES females, such females were superovulated, inseminated and the ...