Background-Synthetic, not natural, progestagen may negate the favorable effects of estrogen. Nonetheless, observational studies report no differences in risk for clinical cardiovascular events between users of unopposed estrogen and users of estrogen combined with synthetic progestin. Methods and Results-In a double-blind study, we randomly assigned 20 healthy postmenopausal women to micronized progesterone (MP) 200 mg or medroxyprogesterone acetate (MPA) 10 mg for 10 days with conjugated equine estrogen (CEE) 0.625 mg for 25 days and the remaining 5 days off cyclically during 2 months, followed by crossover to the alternate therapy. CEEϩMP and CEEϩMPA significantly improved the percent flow-mediated dilator response to hyperemia relative to baseline measurements (Pϭ0.004 by ANOVA) by a similar degree (Pϭ0.863).

The effects of estrogen on endothelial, vascular dilatory and other homeostatic functions were less apparent in type II diabetic postmenopausal women, despite the beneficial effects of estrogen on lipoprotein levels.

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 CaCl 2 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 (4-6) 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 ϩ 2 (F 1 ϩ 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 Ϯ 46.1 to 46.4 Ϯ 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...