Changes in the subcellular and tissue location of estrogen and progesterone receptors in rat uterus after long-term treatment with analogs of gonadoliberin

Abstract

Objectives: Certain therapies with the use of analogs of gonadotropin-releasing hormone (GnRH, gonadoliberin) aim at achieving the effect of desensitization of the pituitary gland that causes inhibition of the hypothalamicpituitary-gonadal axis. The resulting hormonal changes may influence the location and expression of estrogen and progesterone receptors, as well as their endogenous functions. The aim: The aim of the study was to investigate whether long-term administration of low doses of dalarelin (GnRH agonist) and cetrorelix (GnRH antagonist) affected subcellular and tissue-specific location of ERα and ERβ estrogen receptors and progesterone receptor (PR) in rat uterus, as well as explore the extent to which the changes were reversible. Material and methods: Analogs were administered to SPD adult females in the course of 3 months, at a dose of 6 μg/kg b.w. Afterwards, the ovaries and the uterus were resected – in the course of 4 weeks after treatment completion. Tissue paraffin-embedded samples were stained with hematoxyline-eosin for morphological studies or incubated with specific antibodies for the immunohistochemical studies (ABC method). Results: GnRH analogs induced desensitization, resulting in specific and relatively persistent histological changes in the ovaries and the uterus. Strong nuclear reaction for ERα in the lining and the glandular epithelial cells in dalarelintreated rats, and lack of expression changes in cetrorelix-treated rats, were observed in the uterus. Epithelial ERα expressions were accompanied by diminished ERβ and elevated PR expression, as well as diminished ERα andERβ expression, and unchanged PR expression in the stromal and muscle cells, in both dalarelin- and cetrorelixtreatedrats. The majority of the changes were reversible after treatment discontinuation. Conclusions: Long-term exposure to low doses of GnRH analogs causes morphological changes in the uterine tissues, accompanied by reversible changes of the ERα, ERβ and PR expression, possibly influencing tissue sensitivity. These changes indicate that agonist and antagonist regulate ERα expression by means of different mechanisms. A functional interaction between the receptors, depending on ERβ expression, direct influence of analogs on the local hormonal axes, and dose-dependent effects, cannot be excluded. After discontinuation of the analog treatment, the time needed for stabilization of ER and PR expression is shorter than the period of time required to restore histological structure of the uterus.