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Effects of hormone replacement therapy on the circadian pattern of atherothrombotic risk factors
1Department of Medicine, George Washington University School of Medicine, Washington, D.C., USA.
Insights
Hormone replacement therapy, particularly estrogen, reduces early morning levels of plasminogen activator inhibitor-1 (PAI-1), potentially protecting postmenopausal women from acute ischemic events.
Area of Science:
- Cardiovascular Medicine
- Endocrinology
- Thrombosis Research
Background:
- Acute atherothrombotic events show a circadian pattern linked to diurnal fibrinolytic activity.
- Hormone replacement therapy (HRT) may improve fibrinolysis by reducing PAI-1 and tPA.
- Postmenopausal women are at increased risk for atherothrombotic events.
Purpose of the Study:
- To evaluate the impact of estrogen alone and estrogen plus progesterone on PAI-1 and tPA levels.
- To assess how HRT affects the diurnal pattern of fibrinolytic potential in postmenopausal women.
Main Methods:
- 17 postmenopausal women received 4 weeks of estrogen alone, followed by 2 weeks of estrogen plus progesterone.
- PAI-1 and tPA antigen levels were measured at multiple time points to assess diurnal variability.
- Baseline measurements established the circadian pattern of fibrinolytic markers.
Main Results:
- Estrogen alone significantly reduced morning PAI-1 levels, attenuating the diurnal rhythm.
- Estrogen supplementation reduced tPA antigen at all time points, though the diurnal pattern persisted.
- Progesterone addition did not alter the effects of estrogen on PAI-1 or tPA.
Conclusions:
- HRT, specifically estrogen, reduces morning PAI-1 levels, suggesting a protective effect against early morning ischemic events.
- The reduction in PAI-1 occurred despite increased triglycerides, indicating a direct hormonal influence.
- HRT may mitigate the risk of acute atherothrombotic events in postmenopausal women.
Abstract:
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.