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COMMENTARY |
a Department of Geriatrics, Nagoya University School of Medicine, Nagoya, Japan
Decision Editor: Jay Roberts, PhD
In response to the commentary of Kwang Kon Koh and Seong Hee Yang, the Heart Estrogen/progestin Replacement Study (HERS) trial in our study did report that the risk of venous thromboemboli was higher in postmenopausal women. We believe, however, that this was due to their having a higher incidence of coronary heart disease, such as a past myocardial infarction or recent angina pectoris (1). It is well known that for individuals in their sixties the incidence of coronary heart disease is rarer among women than men; furthermore, the Framingham Study in the United States reported fewer than 25 cases per 1,000 per year for women 60–69 years old (2). In addition, the effectiveness of hormone replacement therapy (HRT) for primary prevention should be distinguished from that for secondary prevention. Nevertheless, coagulant and fibrinolytic factors, such as Factor VIIIc or fibrinogen, may affect the incidence of thromboembolic side effects, especially in women receiving HRT. We agree with the commentators' suggestion that there should be further investigation of the effect of estriol (E3) on coagulation and fibrinolysis in octogenarian women.
Second, the commentators suggest that an increase of nitric oxide (NO) levels might be affected by the nitrate contents in food intake. As our Methods section noted, our study was conducted in a Japanese geriatric home where the food supplied is basically the same, including drinks, for all residents, and the amount of food taken is monitored by a nurse at each meal. Therefore, there was no chance for a significant diet effect on plasma nitric oxide metabolites level in this study.
Regarding the correlation between the degree of change in flow-mediated dilatation (FMD) and the degree of change in plasma nitric oxide metabolites, we agree this is important. Our preliminary calculation showed a weak correlation in this study; it would be helpful to replicate the finding in a larger-scale and long-term study using E3.
It is possible that E3 improved FMD via NO or an estrogen-like action or both. We are currently investigating the dose effect of E3 and the long-term effect of E3 in elderly women. Our prelimary findings show that E3 increased HDL levels when used for more than one year in octogenarian women. Estrogen was reported to inhibit oxidation of LDL, and E3 was speculated to bind E2 receptors, as mentioned in the Discussion section of our article. We speculate that E3 may have the same effect as E2 in vitro, further study is necessary to establish this point. E3 was reported to have no significant side effects in breast cancer or endometrial cancer over a year's trial; however, the long-term risk cannot be ruled out. (3)
Finally, we would like to emphasize the need to measure plasma estrogen levels, which are variable, especially in elderly women receiving HRT. Our ongoing study suggests that higher plasma estrogen levels (more than about 80 pg/ml) may become harmful for elderly patients' health. The usual dose of conjugated equine estrogen (CEE) as HRT (0.625 mg/day) easily increases plasma estrogen concentration up to these levels, especially in elderly patients. E3 treatment increases E2 concentration. E2 is a well-known antiatherosclerotic agent. We hypothesized, therefore, that E3 may have an antiatherosclerotic effect via E2 or other mechanisms. Further study is needed for the clarification of the effect of E3 on atherosclerosis.
Let us respond now to Ichiro Sakuma's commentary. As our preliminary study showed, plasma cGMP concentration is regulated by BNP and ANP, not by NO in individuals who are not yet 70 years old. In very elderly people, however, the situation may be more complex. In some cases, cGMP did not increase despite very high concentrations of BNP and, in some cases, of E3-treated women in this study. The increased cGMP appears to correlate with NOx, in spite of a low concentration of BNP. We are measuring BNP and ANP levels in our ongoing study to determine the increased cGMP in elderly people after HRT.
References
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