Changes in the subcellular and tissue location of estrogen and progesterone receptors in rat uterus after long-term treatment with analogs of gonadoliberin.
OBJECTIVE
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 hypothalamic-pituitary-gonadal axis. The resulting hormonal changes may influence the location and expression of estrogen and progesterone receptors, as well as their endogenous functions.


OBJECTIVE
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 ERalpha and ERbeta estrogen receptors and progesterone receptor (PR) in rat uterus, as well as explore the extent to which the changes were reversible.


METHODS
Analogs were administered to SPD adult females in the course of 3 months, at a dose of 6 microg/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 ERalpha in the lining and the glandular epithelial cells in dalarelin-treated rats, and lack of expression changes in cetrorelix-treated rats, were observed in the uterus. Epithelial ERalpha expressions were accompanied by diminished ERbeta and elevated PR expression, as well as diminished ERalpha and ERbeta expression, and unchanged PR expression in the stromal and muscle cells, in both dalarelin- and cetrorelix-treated rats. 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 ERalpha, ERbeta and PR expression, possibly influencing tissue sensitivity. These changes indicate that agonist and antagonist regulate ERalpha expression by means of different mechanisms. A functional interaction between the receptors, depending on ERbeta 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.
Kamil
K
Sołtysik
Piotr
P
Czekaj
Aleksandra
A
Suszka-Switek
Karolina
K
Kociszewska
Danuta
D
Plewka
D000818:Animals; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010053:Ovary / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014599:Uterus / Q000187:drug effects / Q000378:metabolism*
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C404725:dalarelin; D007987:Gonadotropin-Releasing Hormone; C062876:cetrorelix