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Commentary

^a Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan

Ichiro Sakuma, Department of Cardiovascular Medicine, Hokkaido University School of Medicine, N-15, W-7, kita-ku, Sapporo 060-8638, Japan.

Decision Editor: Jay Roberts, PhD

Estriol is a relatively weak estrogen receptor agonist being used in Japan and in some European countries. Estriol has been reported to exert desirable effects on bone mass, climacteric symptoms. In Japan, estriol has been approved as a drug to treat osteoporosis for more than 20 years.

In the present issue of the Journal (pp. B183–B190), Hayashi and colleagues reported that estriol with a concomitant CaCl₂ administration is effective in very elderly patients (mean age is 80 years) for treatment of osteoporosis. They also demonstrated that estriol can restore endothelium-dependent flow-mediated relaxation of the brachial artery, which is presumably impaired by aging. They observed a considerably elevated serum level of estradiol, which was associated with a rise in serum estriol. Thus, some of the effects elicited by estriol should have come from actions of estradiol.

When very elderly patients are to be treated by female hormones, adverse reactions encountered by estrogen use become problematic. Uterine bleeding, breast tenderness, venous thrombosis and, most importantly, the increased risk of breast cancer not only force doctors to discontinue the estrogen use, but also make them hesitate to even start hormone replacement therapy for such elderly patients. Because, compared with conjugated equine estrogen and estradiol, estriol does not often elicit uterine bleeding, does not activate coagulation, and has not been shown to induce breast cancer, estriol should be safer for elderly patients. The results in Hayashi and colleagues' article—that estriol increased bone mass in the elderly patients with osteoporosis—would promise the clinical advantages of estriol prescribed to them.

Estriol has been reported to ameliorate lipoprotein profile; however, this effect, if any, is weak. Nevertheless, because Hayashi and colleagues reported the improvement of vascular function mediated by endothelium-derived oxide, it is tempting to speculate that estriol is effective to prevent progress of atherosclerosis as expected for estradiol.

According to Hayashi and colleagues, plasma concentrations of nitrite and nitrate elevated significantly after the estriol treatment. It should be noted that blood level of nitrite and nitrate can be easily changed by their contents in food. I am concerned whether the patients' diet was controlled in the present study. Moreover, usually serum concentration of cGMP does not correlate with endothelium-derived nitric oxide. cGMP is more likely to correlate with the serum natriuretic peptide level. It is believed to be due to the location of guanylate cyclases stimulated by nitric oxide and natriuretic peptide. The membrane-bound particulate guanylate cyclase stimulated by natriuretic peptide would easily release lipid-insoluble cGMP out of the cell compared with soluble guanylate cyclase located in the cytosol that is activated by nitric oxide. If estriol treatment really caused the increase in serum cGMP, it might have been induced by the volume overload leading to natriuretic peptide release from the heart.

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