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Objective To analyze the effects of estrogen alone or in combination with progestogens and tibolone (TIB) on the expression of the extracellular matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), of perlecan, and of heparanase (HPSE) of the vascular walls of the carotid arteries. Methods A total of 30 250-day-old ovariectomized Wistar rats were orally treated for 5 weeks with: a) 1 mg/kg of estradiol benzoate (EB); b) EB + 0.2 mg/kg of medroxyprogesterone acetate (MPA); c) EB + 0.2mg/kg of norethisterone acetate (NETA); d) EB + 2 mg/kg of dydrogesterone (DI); e) 1 mg/kg of TIB; f) placebo (CTR). Following treatment, the expression of mRNA for MMP-2, MMP-9, and HPSE was analyzed by realtime polymerase chain-reaction (PCR), and the expression of MMP-2, of MMP-9, of tissue inhibitor of metalloproteinase 2 (TIMP-2), and of perlecan was quantified by immunohistochemistry in the carotid arteries. Results The groups showed significant differences on mRNA HPSE expression (p = 0.048), which was higher in the EB, EB + MPA, and TIB groups. There was no statistically significant difference in mRNA MMP-2 or MMP-9 expression. The immunohistochemical expression of MMP-2, of TIMP-2, of MMP-9, of HPSE, and of perlecan showed no differences between groups. Conclusion Estradiol alone or associated with MPA and TIB treatment can increase mRNA HSPE expression of the walls of the carotid arteries in ovariectomized rats. Resumo Objetivo Analisar os efeitos do estrogênio isolado ou em combinação com progestogênios e tibolona (TIB) na expressão das metaloproteinases 2 e 9 da matriz extracelular (MMP-2 e MMP-9), da perlecan e da heparanase (HPSE) das paredes vasculares das artérias carótidas. Métodos Trinta ratas Wistar ovariectomizadas com 250 dias de idade foram tratadas oralmente por 5 semanas com: a) 1 mg/kg de benzoato de estradiol (EB); b) EB + 0,2 mg/kg de acetato de medroxiprogesterona (MPA); c) EB + 0,2mg/kg de acetato de noretisterona (NETA); d) EB + 2 mg/kg de didrogesterona (DI); e) 1 mg/kg de TIB; f) placebo (CTR). Após o tratamento, a expressão de mRNA para MMP-2, MMP- 9, e HPSE foi analisada por reação em cadeia da polimerase (RCP) em tempo real, e a expressão de MMP-2, MMP-9, inibidor tecidual de metaloproteinase 2 (TIMP-2), e de perlecan foi quantificado por imunohistoquímica em artérias carótidas. Resultados Os grupos apresentaram diferenças significativas na expressão do mRNA HPSE (p = 0,048), sendo maiores nos grupos EB, EB + MPA e TIB. Não houve diferença estatisticamente significativa nas expressões de mRNA MMP-2 ou MMP-9. A expressão imunohistoquímica de MMP-2, TIMP-2, MMP-9, HPSE e perlecan não mostrou diferenças entre os grupos. Conclusão O estradiol isolado ou associado ao tratamento com MPA e TIB pode aumentar a expressão de mRNA HSPE nas paredes das artérias carótidas em ratas ovariectomizadas.

Dowrloaded from jfprhc,bmj.corn on November 7,2013 - Punished by grouytnni com =.::'«l SVVIU E ‘ME WT For nurnbened affiliations see end of article. Correspondence to Professor Dr Johan res Bitzer. Chief Physician and Chairman Department of Obnettics and Gynaecology. University Hospital Basel. Basel. Switzerland; JohartnesBitzer@usb.cl‘. Received IS March 2013 Accepted 18 March 2013 To cite: Bitzer J Amy J-J. Beerttmizer R. et al. Joumai of Fanfly Planning and Reproductive Health C are Published Online First lnlease include Day Month Year] doi: 10. l l36lifptl1(-20l3- 100624 Statement on combined hormonal contraceptives containing third- or fourth-generation progestogens or cyproterone acetate, and the associated risk of thromboembolism Johannes Bitzer Cosignatories Jean-Jacques Amy,‘ Rob Beerthuizen,2 Martin Birkhauser,3 Teresa Bombas,“ Mitchell Creinin,5 Philip D Darney,5 Lisa Ferreira Vicente,’ Kristina Gemzell-Danielsson,° Bruno lmthurn,9 Jeffrey T Jensen,” Andrew M Kaunitz,“ Ali Kubba,” Medlard M Lech,” Diana Mansour,” Gabriele Merki,” Thomas Rabe,‘6 Katarina Sedlecki,” David Serfaty,‘8Jact1ues Seydoux,” Lee P Shu|man,2° Regine Sitruk-Ware, ‘ Sven O Skouby,” Anne Szarewski, James Trussell,” Carolyn Westhoffzs A NEW PILL SCARE? HOW DID IT COME ABOUT AND HOW SHOULD WE TACKLE IT? The cotttroversy around the combined hormonal contraceptives ((IH(,'s) of the so-called third (containing gestodene or desogestrel) and fourth generation (cott- raining drospirenone. DRSP) lt-as reached .1 highly emotional political dimension in which all those who “are prol'essionall_v responsible for women's health are involved: the national health authorities, the pltarrnaceutical companies, the pro- fessional orgartis-ations, the prescrihers. the media and the public (i.e. the current or potential users of CH(Is). The — initially scientific — controversy has now led to a ptthlic health dispute that culminated in the decision of the Frenelt '.1tltht)ritlc's to withdraw the com hination containing etltinylestradiol (EE) and cyproterone acetate (CPA) from the market. The potential impact of this measure, namely the loss of confidence in .1/I (Ill(.'s. could be quite serious. WHAT TRIGGERED THIS CRISIS? Several re;.',is‘tr_v~hasei.l studies published in the Britr'.~‘l2 .\ledic.tl Irirrrmtl. partictilarlv 23 the one based on the Danish Registry. indicated that there is an increased risk of venous thrombiternholism (VTE) asso- ciated with the intake of third- and liounh-generation combined oral contra- ceptives ((ZO('.s) compared to prepara- tions containing the progestogen le\'onorges‘trel (I-.\l(§).q5 The relative risk (RR) was around 2. and the absolute attributable risk was estimated to be (dependent on the background preva- lence rate) between .2 to 8 per ll) llllll users per year.q A very recent systentatic review and meta-anal_vsis of the possible link between treatment with CHCs and VTF. con- cluded that. in this regard. (I) (3H(Zs cort- taining I.N(} or norgestimate were the safest. (.1) those containing desogestrel. DRSI’ or (IPA were associated with a sig- ttillC.‘tI1tl_\' ltiglter risk than (IH(Is contain- ing LNG, and (3) the aup,ntented risk of VTE found for pills containing gestodene compared to (l(.)(Ls with L\'(; appeared to be smaller than in earlier s'tttcllcs.7 These resultsq contrast with those of published prospective cohort studies. sponsored by It’-a_ver He-altlt(.are. at the request of the European Medicitte Bitzer J et J Journal offamily Planting and Reolodzcme Health (.19 20‘~3;0:'-at doizt 0.’ ’-36Ii?prh: 2073 ‘0062-1 1