Different cerebrovascular effects of medroxyprogesterone acetate and norethisterone acetate in the New Zealand White rabbit

Abstract

Objective The lack of a cardioprotective effect of hormone replacement therapy (HRT), as suggested by the Heart and Estrogen/progestin Replacement Study (HERS) and Women's Health Initiative (WHI) may in part be explained by the progestin used. The aim of this study was to elucidate the effect of different progestins on cerebrovascular reactivity in an animal model.Methods Fifty-six ovariectomized New Zealand White rabbits were randomized into seven groups receiving hormone treatment for 4 weeks: medroxyprogesterone acetate (MPA) (10 mg/day); norethisterone acetate (NETA) (3 mg/day); conjugated equine estrogens (CEE) (1.25 mg/day); 17β-estradiol (E2) (4 mg/day); MPA + CEE (10 mg/day + 1.25 mg/day); NETA + E2 (3 mg/day + 4 mg/day); or placebo. Segments from the basilar and posterior cerebral arteries were mounted in myographs for tension recordings. Concentration-response curves to potassium, acetylcholine, sodium nitroprusside, L-NAME (Nϖ-nitro-L-arginine methyl ester), calcium and endothelin-1 were established.Results Treatment with MPA caused a significant increase in vasoconstriction, expressed as Emax (mN/mm, mean ± SEM; p < 0.05), in response to potassium (3.18 ± 0.19 vs. 2.47 ± 0.19) and calcium (4.00 ± 0.22 vs. 3.34 ± 0.14) in the posterior cerebral artery, and to endothelin-1 (6.88 ± 0.69 vs. 5.22 ± 0.30) in the basilar artery, when compared with NETA. This difference was neutralized in the groups receiving the combined treatment of MPA + CEE and NETA + E2. No overall differences were seen between CEE and E2.Conclusions In rabbit cerebral arteries, MPA treatment causes a higher development in arterial tension compared with NETA, indicating that different progestins may display different cerebrovascular effects. However, when accompanied by estrogens, as in the case of HRT, this difference is eliminated.