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Effects of Long-Term Estrogen Replacement Therapy Versus Combined Hormone Replacement Therapy on Nitric Oxide-Dependent Vasomotor Function

Center for Laboratory Medicine and Laboratory of Atherosclerosis Genetics (H.J., R.R., A.S., T.L.) and Departments of Diagnostic Radiology (P.D.) and Gynecology and Obstetrics (K.T., R.P.), Tampere University Hospital; and Department of Clinical Chemistry, University of Tampere Medical School (R.R., T.L.), FIN-33521 Tampere, Finland

Address all correspondence and requests for reprints to: Hannu Jokela, Ph.D., Department of Clinical Chemistry, Tampere University Hospital, Center for Laboratory Medicine, P.O. Box 2000, FIN-33521 Tampere, Finland. E-mail: hannu.jokela{at}tays.fi.

Postmenopausal hormone replacement therapy (HRT) with estrogen may increase production of the predominant endothelium-derived vasodilator nitric oxide (NO) and consequently improve vascular reactivity. In contrast, concurrent progestin therapy may oppose this beneficial effect. We studied the effect of long-term estrogen HRT and combined HRT on vasomotor function and on plasma nitrate, which reflects the amount of NO in the circulation. As lipid peroxidation affects NO production and impairs endothelial function, we also measured the amount of the in vivo lipid peroxidation marker urinary 8-iso-prostaglandin F₂. The study group comprised 15 women receiving estradiol valerate HRT (mean age, 56 yr; treatment duration, 10.5 yr) and 15 women receiving combined HRT with estradiol valerate and levonorgestrel (mean age, 58 yr; treatment duration, 11.3 yr). The peak flow velocity (PFV) and pulsatility index of the common carotid and internal carotid artery and the abdominal aorta were measured by ultrasonography after long-term HRT (baseline), after a 4-wk pause and again 3 wk after reintroducing HRT. A statistically significant interaction between the groups and time points was observed in the PFV of the internal carotid artery (P = 0.011). In women taking estradiol valerate, the PFV values decreased significantly after withdrawal of HRT (P = 0.007) and increased again to the baseline level after reintroduction of therapy (P < 0.001). In women receiving combined HRT, the PFV remained stable over all study periods. At baseline, the PFV of women taking estradiol valerate correlated with the plasma nitrate concentration in the common carotid artery (r = 0.646; P = 0.009) and in the abdominal aorta (r = 0.579; P = 0.024). For pulsatility index and urinary 8-iso-prostaglandin F₂ excretion, there were no significant differences between the groups. Our results suggest that the favorable effects of long-term estrogen treatment on blood flow are at least partly mediated through NO. The addition of levonorgestrel to the treatment regimen appears to abolish this effect.

This work was supported by the Medical Research Fund of Tampere University Hospital.

Abbreviations: apo, Apolipoprotein; HDL, high density lipoprotein; HRT, hormone replacement therapy; iNOS, inducible nitric oxide synthase; 8-iso-PGF₂, 8-iso-prostaglandin F₂; LDL, low density lipoprotein; Lp(a), lipoprotein(a); MPA, medroxyprogesterone acetate; NO, nitric oxide; NO₃, nitrate; PFV, peak flow velocity; PI, pulsatility index; RANOVA, ANOVA for repeated measures.

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