Effects of Hormone Replacement Therapy on the Circadian Pattern of Atherothrombotic Risk Factors

Onset of acute atherothrombotic events (acute myocardial infarction, unstable angina, ischemic stroke) exhibit a circadian pattern that parallels 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-1) 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 postmenopausal women at multiple time points to assess hormone impact on the diurnal pattern of fibrinolytic potential. At baseline, both PAI-1 and tPA exhibited circadian variability. Estrogen alone selectively lowered 8 a.m. PAI-1 (35.8 ± 7.1 ng/ml at baseline, 19.8 ± 3.7 ng/ml on estrogen; p = 0.0002 vs baseline). There was no significant change in the noon or 4 p.m. values, and the diurnal 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 rhythm. Estrogen supplementation reduced tPA antigen at all time points, and the diurnal pattern, although blunted, persisted. Addition of progesterone to estrogen did not reverse effects of the estrogen-alone phase of either PAI-1 or tPA values. This hormone-associated reduction of PAI-1 was observed despite increased triglycerides, a known inducer of PAI-1 levels. These observations suggest that hormone replacement therapy may protect postmenopausal women from excess early morning acute ischemic events. Cardiol 1996;78:876–880)