DIFFERENTIAL-EFFECTS OF HORMONE-REPLACEMENT THERAPY ON ENDOGENOUS NITRIC-OXIDE (NITRITE NITRATE) LEVELS IN POSTMENOPAUSAL WOMEN SUBSTITUTEDWITH 17-BETA-ESTRADIOL VALERATE AND CYPROTERONE-ACETATE OR MEDROXYPROGESTERONE ACETATE/

Increased incidence of cardiovascular disease in postmenopausal women (PMW) is accompanied by ovarian dysfunction; hormone replacement thera py (HRT) can have cardioprotective effects. Because hypertension and a therosclerosis are associated with impaired release of endothelium-der ived nitric oxide (NO) and increased levels of low-density Lipoprotein s (LDL), we investigated whether HRT augments NO release, and whether these increases are accompanied by a decrease in LDL levels in PMW. We determined serum nitrite/nitrate (NO2-/NO3-) and LDL levels at baseli ne (before initiation of HRT) and during the 6th and 12th months of th e study. The PMW (n = 26) received continuous oral administration of e stradiol valerate (Progynova, 2 mg daily) for 21 days supplemented wit h either oral cyproterone acetate (CPA; 1 mg; n = 11) or medroxyproges terone acetate (MPA; 5 mg; n = 15) on days 12-21 of each treatment cyc le. Blood samples in the PMW receiving HRT were collected at times whi le the subjects were taking estradiol valerate alone and estradiol val erate plus CPA or MPA. Compared with the samples collected at baseline , serum NO2-/NO3- levels increased significantly from 20.1 +/- 1.58 mu mol/L at baseline to 30 +/- 3.7 mu mol/L (P < 0.01) in samples collec ted after 12 months of HRT while the PMW were not taking progestins (C PA or MPA), and to 25.4 +/- 2 mu mol/L (P < 0.05) when all the samples , regardless of the treatment with CPA or MPA, were included in the an alysis. Moreover, > 30% increase in serum NO2-/NO3-levels were observe d only in 13 (responders) out of 26 PMW substituted with estradiol val erate, suggesting that estradiol may improve endogenous NO synthesis i n a differential fashion. Compared with baseline, no significant incre ases in serum NO2-/NO3-were observed in samples collected while the es tradiol-treated responders were taking either CPA or MPA. In contrast to NO2-/NO3-, serum LDL levels were significantly reduced in samples c ollected after 12 months of HRT (P < 0.05 us. baseline). Furthermore, revels of NO2-/NO3 showed a significant negative correlation with the levels of LDL (r(2) = 0.17; P < 0.05) in the responders but not in non responders. These results indicate that oral administration of estradi ol valerate in PMW for HRT increases circulating NO levels, an effect that may contribute to the cardioprotective effects of HRT in PMW. In addition, our data suggests but does not prove that concomitant admini stration of a progestin may attenuate the beneficial effects of estrog en replacement therapy with regard to NO release. Finally, our data pr ovides evidence for the existence of responders and nonresponders to p ostmenopausal estrogen treatment with respect to improvement of endoge nous NO levels, suggesting that a significant number, but not all, of the hormonally substituted PMW profit fully from the beneficial proper ties of a HRT.