Circulating Nitric Oxide (Nitrite/Nitrate) Levels in Postmenopausal Women Substituted With 17β-Estradiol and Norethisterone Acetate

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Abstract
Abstract Postmenopausal women (PMW) have an increased risk of cardiovascular disease that is attenuated by hormone replacement therapy (HRT). Inasmuch as hypertension and atherosclerosis are associated with diminished endothelium-derived nitric oxide (NO), we investigated whether HRT augments NO release in PMW. We determined serum levels of nitrite/nitrate (NO 2 +NO 3 ) at baseline and during the 6th, 12th, and 24th months of the study in two groups of PMW. One group (HRT-PMW, n=13) received continuous transdermal administration of 17β-estradiol (Estraderm-TTS-50) supplemented with oral norethisterone acetate (NETA) on days 1 through 12 of each month, and the other group (control PMW, n=13) did not receive HRT. Blood samples in the HRT-PMW group were collected without regard to whether subjects were taking NETA at the time of blood sampling. Serum NO 2 +NO 3 levels increased in HRT-PMW for the duration of the study, whereas serum NO 2 +NO 3 levels remained unchanged in control PMW. When all samples regardless of timing of collection with respect to NETA treatment were included in the statistical analysis, the change in NO 2 +NO 3 levels in HRT-PMW was significantly greater compared with the change in control PMW ( P =.037). Likewise, when only those samples collected when estradiol-treated subjects were not taking oral NETA were included in the statistical analysis, the change in NO 2 +NO 3 levels in the HRT-PMW group remained significant ( P =.047) compared with control PMW. In contrast, when only those samples collected when estradiol-treated subjects were taking NETA were included in the analysis, the change in NO 2 +NO 3 levels in the HRT-PMW group was not significant ( P =.23) compared with control PMW. These results indicate that HRT increases NO levels in PMW, an effect that may contribute to the cardiovascular protection afforded by HRT in PMW. In addition, our data suggest, but do not prove, that concomitant administration of a progestin may attenuate the beneficial effects of estrogen replacement therapy with regard to NO release.