EFFECTS OF CHRONIC HORMONE REPLACEMENT ON THE RENIN-ANGIOTENSIN SYSTEM IN CYNOMOLGUS MONKEYS

Objective To characterize the effects of estrogen, estrogen combined w ith progestin, and no treatment in ovariectomized cynomolgus monkeys d uring long-term reproductive hormone replacement. Methods Forty-five s urgically postmenopausal cynomolgus monkeys fed a lipid-lowering diet were administered a conjugated equine estrogen (Premarin, 7.2 mu g/day for the first 8 months, then 166 mu g/day for the remaining 22 months ), alone or in combination with 650 mu g/day medroxyprogesterone aceta te (Cycrin) for 30 months, or left with no hormone replacement therapy . Animals were anesthetized with ketamine-pentobarbital, and samples w ere taken for measurements of plasma renin activity, angiotensin conve rting enzyme activity, and angiotensin peptides, angiotensin I (Ang I) , angiotensin II (Ang II), and angiotensin-(1-7) [Ang-(1-7)]. Results Chronic replacement therapy with estrogen resulted in a significant el evation 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 estr ogen or combination therapy caused a significant reduction in angioten sin converting enzyme activity [229 +/- 8 nmol/ml per min control vers us 189 +/- 10 nmol/ml per min with estrogen (P < 0.05) versus 196 +/- nmol/ml per min with combination therapy (P < 0.05)]. Both of these ch anges in angiotensin processing enzymes observed during replacement th erapy 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)]. P lasma Ang II and Ang-(1-7) levels were not significantly changed. The mean blood pressure 0did not change with either treatment. Conclusion These studies reveal that, although chronic estrogen replacement activ ates 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. T hus, the potentially harmful effects of estrogen-induced hyperreninemi a are balanced by its actions interfering with the formation of the va soactive product Ang II.