Zmiany morfologiczne i enzymatyczne wywołane długoterminowym podawaniem samicom szczura niskiej dawki agonisty i antagonisty gonadoliberyny.

Abstract

SummaryBackgroundLong-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.Material/MethodsWe 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.ResultsApplying 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.ConclusionsThe 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.

Expression of cytochrome P450 2C and 3A in female rat liver after long-term administration of gonadoliberin analogs

“…As a consequence, they might influence the mechanism of CYP450 expression, including the expression of transcriptional factors, independently of sex hormones. In order to investigate the GH-dependent expression of CYP2C and CYP3A subfamilies, we applied a new experimental model, in which changes of the 24-h GH secretion profile in rats occurred under the conditions of a long-term pituitary desensitization caused by application of GnRH agonist and antagonist [25]. We evaluated hepatic expression of CYP2C and CYP3A isoforms in connection with the changes of liver-enriched transcription factors: HNF4α, HNF6, STAT5b (signal transducer and activator of transcription 5b) and PXR receptor, and GH secretory pattern.…”