Pharmacodynamics Of Nomegestrol Acetate On Rats Model Of Endometriosis And Mechanism Of Action

ObjectivesTo investigate the pharmacodynamics effects of Nomegestrol acetate (NOMAc)on endometriosis (EMs) in rat model and study the mechanism involved in it.Materials and Methods1. Animals and groupingThe model of EMs in adult female SD rats was established by surgicallyautotransplanting endometrium to peritoneum. After success of establishing the model,60model rats were selected and randomly divided into5groups (n=12), including acontrol group, a positive control group and3experimental groups. Rats inexperimental groups were orally administered with NOMAc (0.5,1.5,15mg kg-1)for21days.2. MethodsRats were sacrificed within24h after the last treatment. Immediately afteranatomizing, size of ectopic endometrium was evaluated in terms of its length, widthand height. Histopathological changes of eutopic and ectopic endometria were testedby haematoxylin-eosin staining.Body weights of rats were recorded after administration and sera were collected.Indexes of liver (AST, ALP, ALT) and thyroid function (T3, T4) were determined.ELISA was used to detect the sera levels of E2, P, CA125and EMAb. Apoptotic cells were labeled by TUNEL, while the levels of Bax, Bcl-2,Caspase-9and Caspase-3were determined by Western blotting.All data were expressed as mean±SD (x±s). Data were analyzed by SPSS11.0.The criterion for statistical significance was P value less than0.05.Results1. Effects of NOMAc on the volume of ectopic endometriumOut of these140rats, EMs was successfully surgically induced in115rats (82%).Before administration, the volumes of ectopic endometria did not differ amongcontrol group and experimental groups (P＞0.05). However, after administration, thevolumes of ectopic endometria in all experimental groups were reduced. Furthermore,statistical significances were noticed in NOMAc-1, NOMAc-2and NOMAc-3groupscompared with control group (P＜0.05).2. Effects of NOMAc on the morphology of the eutopic and ectopicendometriumNo obvious anomalies were noticed in the morphology of eutopic endometriaamong all groups. After administration, NOMAc could cause regression of ectopicendometria in rats, and atrophy became severe with increase of dosage. The volumesof ectopic endometria and the quantity of endometrial glands decreased. The activityof glandular secretion was significantly reduced after NOMAc treatment comparedwith control group (P＜0.05).3. Effects of NOMAc on body weight of ratThere was no difference in rat body weight between experimental groups andmodel group before administration(P＞0.05).While body weights significantlyincrease in NOMAc-2and NOMAc-3groups after administration(P＜0.05). 4. Effects of NOMAc on liver and thyroid functionBefore administration, similar levels of the biochemical parameters indicatingliver (AST, ALT, ALP) and thyroid (T3,T4) functions were noted among experimentalgroups and model group (P＞0.05). After administration, AST in NOMAc-3groupwas significantly decreased compared with control group (P＜0.05), while otherindicators did not change.5. Effects of NOMAc on the levels of E2, P, CA125and EMAbAll experimental groups could significantly decrease the levels of E2, Pcompared with control group (P＜0.05), NOMAc-3could significantly decrease theEMAb level (P＜0.05). Nevertheless, NOMAc treatment had no significant impact onthe CA125expression (P＞0.05).6. Effects of NOMAc on the expression of apoptosis factorsNOMAc could increase the apoptosis of ectopic endometrial cells(P＜0.05), asindicated by an increased level of Bcl-2accompanied with the decreased levels ofBax, Caspase-9, Caspase-3and cleaved Caspase-3. Bcl-2, Caspase-9, Caspase-3andcleaved Caspase-3in NOMAc-3group were increased significantly compared withthat of control group (P＜0.05); Bax in NOMAc-2and NOMAc-3groups weresignificantly decreased (P＜0.05).Conclusions1. NOMAc can cause the regression and atrophy of ectopic endometrium in rat, asindicated by the reduced volume of ectopic endometrium and the decreased number ofendometrial gland, in that the activity of glandular secretion in ectopic endometriumwill be suppressed. Furthermore, it has no negative impact on eutopic endometrium.2. NOMAc-3can significantly increase rat body weight without having anyinfluence on the levels of ALT, ALP, T3and T4. Although NOMAc can slightlyreduce AST level, such decrease seems to have little effects on the liver function. 3. NOMAc can cause the apoptosis of eutopic endometrium in terms of reducing thelevels of E2, P and EMAb. An increased level of Bax with a reduced Bcl-2can resultin the activations of Caspase-9and Caspase-3, recognized as two essential factorsinvolved in endogenous apoptosis, and such Bax-related caspase activation may beimplicated in the mechanism by which NOMAc induces apoptosis of the ectopicendometrial cells.