Effects of chronic hormone replacement on the renin–angiotensin system in cynomolgus monkeys

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Abstract
To characterize the effects of estrogen, estrogen combined with progestin, and no treatment in ovariectomized cynomolgus monkeys during long-term reproductive hormone replacement. Forty-five surgically postmenopausal cynomolgus monkeys fed a lipid-lowering diet were administered a conjugated equine estrogen (Premarin, 7.2 μg/day for the first 8 months, then 166 μg/day for the remaining 22 months), alone or in combination with 650 μg/day medroxyprogesterone acetate (Cycrin) for 30 months, or left with no hormone replacement therapy. Animals were anesthetized with ketamine–pentobarbital, and samples were taken for measurements of plasma renin activity, angiotensin converting enzyme activity, and angiotensin peptides, angiotensin I (Ang I), angiotensin II (Ang II), and angiotensin-(1-7) [Ang-(l-7)]. Chronic replacement therapy with estrogen resulted in a significant elevation of the plasma renin activity [11.7 ± 2.0 ng/ml per h control versus 22.8 ± 4.6 ng/ml per h with estrogen (P < 0.05) versus 32.8 ± 4.9 ng/ml per h with combination therapy (P < 0.01)], whereas estrogen or combination therapy caused a significant reduction in angiotensin converting enzyme activity [229 ± 8 nmol/ml per min control versus 189 ± 10 nmol/ml per min with estrogen (P < 0.05) versus 196 ± 11 nmol/ml per min with combination therapy (P < 0.05)]. Both of these changes in angiotensin processing enzymes observed during replacement therapy resulted in significant increases in plasma Ang I levels [46.7 ± 12.5 pg/ml control versus 175.5 ± 65.9 pg/ml with estrogen (P < 0.05) and 561.7 ± 373.6 pg/ml with combination therapy (P < 0.05)]. Plasma Ang II and Ang-(1–7) levels were not significantly changed. The mean blood pressure did not change with either treatment. These studies reveal that, although chronic estrogen replacement activates renin activity and Ang I, it causes a shift in the processing of angiotensin peptides such that the concurrent reduction in angiotensin converting enzyme activity leads to unchanged plasma Ang II levels. Thus, the potentially harmful effects of estrogen-induced hyperreninemia are balanced by its actions interfering with the formation of the vasoactive product Ang II.