01 August 2012
Morphological and enzymatic changes caused by a long-term treatment of female rats with a low dose of gonadoliberin agonist and antagonistAleksandra Suszka-ŚwitekABCDEFG, Piotr CzekajABCDEFG, Jacek PająkCD, Rafał SkowronekB, Katarzyna Wrona-BogusB, Danuta PlewkaB, Danuta Kozłowska-RupB, Ryszard WiaderkiewiczEG, Andrzej JankowskiEG
Med Sci Monit 2012; 18(8): BR315-330
Background: 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.
Material/Methods: 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.
Results: 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.
Conclusions: 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.
Keywords: Ovary - enzymology, Pituitary Gland - enzymology, Organ Specificity - drug effects, Organ Size - drug effects, Liver - enzymology, Gonadotropin-Releasing Hormone - pharmacology, Enzymes - metabolism, Dose-Response Relationship, Drug, Densitometry, Body Weight - drug effects, Time Factors, Uterus - enzymology
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