ay-25-205 and cetrorelix

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.. 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.. 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).. 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.. 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.

Topics: Animals; Dose-Response Relationship, Drug; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Gonadotropin-Releasing Hormone; Ovary; Rats; Rats, Sprague-Dawley; Tissue Distribution; Uterus

Long-term treatment with gonadoliberin analogs is used to block the hypothalamic-pituitary-gonadal axis. The use of these agents is generally considered to be safe; however, some observations suggest the possibility of adverse effects.. We investigated whether a 3-months administration of a low dose (6 µg/kg b.w.) of dalarelin - a new agonist, and cetrorelix - a known antagonist of GnRH to female rats causes morphological changes in pituitary gland, ovaries, uterus and liver (HE and VG staining); effects on pituitary, hepatic and blood enzyme activities (histochemical and kinetic methods, respectively), and on the blood lipid profile (colorimetric methods); and to what extent these changes are reversible.. Applying analogs effectively inhibited ovulation, affected the uterine endometrium and changed histological appearance of the liver (e.g., steatosis). They altered activities of marker enzymes of cellular respiration, gluconeogenesis and intracellular digestion in the liver and, partially in the pituitary gland, caused undesirable changes in the activities of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and creatine kinase, and a concentration of cholesterol HDL fraction and triglycerides in the blood. Both morphological and enzymatic effects were more evident after antagonist administration; changes in the blood lipid profile were more evident after agonist administration. In both analogs histological and enzymatic changes persisted a relatively long time after the discontinuation of the treatment.. The low dose of dalarelin and cetrorelix is sufficient to cause limited damage of hepatic cells and may modify the function of pituitary, ovaries, uterus and liver as well as other organs, even after discontinuation of the treatment.

Topics: Animals; Body Weight; Densitometry; Dose-Response Relationship, Drug; Enzymes; Female; Gonadotropin-Releasing Hormone; Immunohistochemistry; Liver; Organ Size; Organ Specificity; Ovary; Pituitary Gland; Rats; Rats, Sprague-Dawley; Time Factors; Uterus