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COMMENTARY |
a Division of Cardiology, Gachon Medical School, Inchon, Korea
b Menopause Clinic, Gachon Medical School, Inchon, Korea
Kwang Kon Koh, Associate Professor, Division of Cardiology, Heart Center, Gachon Medical School, 1198 Kuwol-Dong, Namdong-Gu, Inchon, Korea 405-760 E-mail: kwangk{at}ghil.com.
Decision Editor: Jay Roberts, PhD
POSTMENOPAUSAL women who take estrogen therapy have fewer cardiovascular events over time compared with untreated women. However, this finding has been observed mostly in healthy, postmenopausal women in their mid-50s. Hayashi and his coworkers (1) reported a very interesting observation in this issue of the journal. They used estriol (E3), a weak estrogen, in very elderly women. Each of 12 very elderly women took CaCl2 with or without E3 2 mg daily for 30 weeks. The endothelium-dependent flow-mediated dilatation (FMD) was improved following hormone replacement therapy (HRT), as were the plasma nitrite/nitrate values. E3 significantly improved bone mineral density (BMD) by inhibiting bone resorption. Overall, E3 was well tolerated.
Despite a small number of participants and short period of treatment, this well-designed study provides the scientific background of E3 as the possible important HRT in octogenarian women. However, it is too early to recommend E3 to very elderly women now, because in the Heart Estrogen/progestin Replacement Study (HERS), the risk of venous thromboemboli in postmenopausal women with coronary artery disease randomized to placebo was over 10-fold higher (22 events per 10,000 women-years) than previously reported (2). The recent report from Postmenopausal Estrogen/Progestin Interventions (PEPI) trial may in part account for the higher risk of thromboemboli in placebo from HERS. Factor VIIIc, von Willebrand factor antigen concentration, and fibrinogen increased over time (3). We should keep in mind the participants' characteristics in HERS, including pretty old age (mean 66.7 years). Recently, Koh and colleagues (4)(5)(6) studied the effects of HRT on plasminogen activator inhibitor (PAI-1) levels. Conjugated equine estrogen (CEE) reduced PAI-1 levels by 50%. The degree of reduction in PAI-1 levels was significantly associated with the degree of increase in the levels of D-dimer, thus providing evidence of enhanced fibrinolysis (4). To determine whether estrogen-enhanced fibrinolytic potential is a primary or secondary effect of HRT, Koh and colleagues (7) measured indicators of coagulation system activation and fibrinolysis. The increases in fibrinolytic potential (the t-PA activity:PAI-1 activity ratio) did not correlate with the minimal changes observed in prothrombin fragment 1+2 (F1+2) or thrombin-antithrombin (TAT) levels after CEE 0.625 mg daily. The effects of E3 on coagulation and fibrinolysis should be more investigated in octogenarian women.
HRT increased nitric oxide levels (8). However, this observation had not been done under a strict nitrate-restricted diet. Koh and colleagues (5)(6) found that a nitrate-restricted diet reduced serum nitrogen oxide levels from 66.2 ± 46.1 to 46.4 ± 26.1 mol/L in 30 healthy subjects. Although CEE therapy significantly improved FMD, serum nitrate/nitrite levels did not change with CEE. This observation may reflect competing stimuli to reduce and increase nitric oxide synthesis required for endothelial homeostasis. Hayashi's observation was in contrast to Koh's observation. Dietary effect should be discussed. Further, Hayashi did not mention the correlation between the degree of change in FMD and the degree of change in plasma nitrogen oxides. That would be intriguing.
E3 improved FMD despite no changes in plasma lipids and apolipoproteins. May this effect be mediated by other mechanisms? Oxidized LDL and its membrane components have been shown to induce the gene transcription and expression of adhesion molecules on the endothelial cell surface that tether circulating inflammatory cells to the endothelium and facilitate their entry into the vessel wall (9). Koh and colleagues (5)(6) reported that CEE reduced levels of the cell adhesion molecules relative to respective pretreatment values. What is the plausible mechanism of E3 regarding prevention of coronary heart disease?
Clinically, hip fracture is more important than lumbar or wrist fracture in the elderly population. Measurement at the hip is superior to those at other sites in predicting hip fracture. Thus, the hip is the site of choice to assess BMD in elderly individuals (10). Finally, does E3 alone not result in breast cancer or endometrial cancer over long-term years? Hayashi's study deserves to be appraised in driving further intriguing studies in the future.
References
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