EFFECTS OF HORMONE REPLACEMENT THERAPY ON THE CIRCADIAN PATTERN OF ATHEROTHROMBOTIC RISK-FACTORS

Onset of acute atherothrombotic events (acute myocardial infarction, u nstable angina, Ischemic stroke) exhibit a circadian pattern that para llels the diurnal pattern of endogenous fibrinolytic activity. Hormone replacement therapy in postmenopausal women has been shown to enhance fibrinolytic capacity by lowering plasminogen activator inhibitor-1 ( PAI-I) and tissue plasminogen activator inhibitor (tPA) antigen values . We evaluated the impact of 4 weeks of estrogen alone (Premarin 0.625 mg/day) and 2 weeks of estrogen plus progesterone (Provera 2.5 mg/day ) on PAI-1 and tPA in 17 post; menopausal women at multiple time point s to assess hormone impact on the diurnal pattern of fibrinolytic pote ntial, At baseline, both PAI-1 and tPA exhibited circadian variability , Estrogen alone selectively towered 8 A.M. PAI-I (35.8 +/- 7.1 ng/ml at baseline, 19.8 +/- ng/ml on estrogen; p = 0.0002 vs baseline). Ther e was no significant change in the noon or 4 P.M. values, and the diur nal pattern was attenuated. The 8 A.M. PAI-1 remained low at 17.1 +/- 3.6 ng/ml (p = 0.0001 vs baseline) with total loss of the circadian rh ythm. Estrogen supplementation reduced tPA antigen at all time points, and the diurnal pattern, although blunted, persisted, Addition of pro gesterone to estrogen did not reverse effects of the estrogen-alone ph ase of either PAI-1 or tPA values, This hormone-associated reduction o f PAI-1 was observed despite increased triglycerides, a known inducer of PAI-1 levels. These observations suggest that hormone replacement t herapy may protect postmenopausal women from excess early morning acut e ischemic events.