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Differential Effects of Hormone-Replacement Therapy on Endogenous Nitric Oxide (Nitrite/Nitrate) Levels in Postmenopausal Women Substituted with 17ß-Estradiol Valerate and Cyproterone Acetate or Medroxyprogesterone Acetate¹

Clinic of Endocrinology (B.I., M.R., P.J.K.), Department of Gynecology and Obstetrics, University Hospital Zurich; and Schering (Schweiz) AG (A.E.J.), Zurich, Switzerland; and Department of Medicine, Center for Clinical Pharmacology (R.K.D.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213

Address all correspondence and requests for reprints to: Raghvendra K. Dubey, Center for Clinical Pharmacology, Department of Medicine, 200 Lothrop Street, 623 Scaife Hall, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213-2582.

Increased incidence of cardiovascular disease in postmenopausal women (PMW) is accompanied by ovarian dysfunction; hormone replacement therapy (HRT) can have cardioprotective effects. Because hypertension and atherosclerosis are associated with impaired release of endothelium-derived nitric oxide (NO) and increased levels of low-density lipoproteins (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 baseline (before initiation of HRT) and during the 6th and 12th months of the study. The PMW (n = 26) received continuous oral administration of estradiol valerate (Progynova, 2 mg daily) for 21 days supplemented with either oral cyproterone acetate (CPA; 1 mg; n = 11) or medroxyprogesterone acetate (MPA; 5 mg; n = 15) on days 12–21 of each treatment cycle. Blood samples in the PMW receiving HRT were collected at times while the subjects were taking estradiol valerate alone and estradiol valerate plus CPA or MPA. Compared with the samples collected at baseline, serum NO₂-/NO₃- levels increased significantly from 20.1 ± 1.58 µmol/L at baseline to 30 ± 3.7 µmol/L (P < 0.01) in samples collected after 12 months of HRT while the PMW were not taking progestins (CPA or MPA), and to 25.4 ± 2 µmol/L (P < 0.05) when all the samples, regardless of the treatment with CPA or MPA, were included in the analysis. Moreover, >30% increase in serum NO₂-/NO₃- levels were observed only in 13 (responders) out of 26 PMW substituted with estradiol valerate, suggesting that estradiol may improve endogenous NO synthesis in a differential fashion. Compared with baseline, no significant increases in serum NO₂-/NO₃- were observed in samples collected while the estradiol-treated responders were taking either CPA or MPA. In contrast to NO₂-/NO₃-, serum LDL levels were significantly reduced in samples collected after 12 months of HRT (P < 0.05 vs. baseline). Furthermore, levels of NO₂-/NO₃ showed a significant negative correlation with the levels of LDL (r² = 0.17; P < 0.05) in the responders but not in nonresponders. These results indicate that oral administration of estradiol 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 administration of a progestin may attenuate the beneficial effects of estrogen replacement therapy with regard to NO release. Finally, our data provides evidence for the existence of responders and nonresponders to postmenopausal estrogen treatment with respect to improvement of endogenous NO levels, suggesting that a significant number, but not all, of the hormonally substituted PMW profit fully from the beneficial properties of a HRT. (J. Clin Endocrinol Metab 82: 388–394, 1997)

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