What are the cardiovascular risks associated with progesterone therapy in women with pre-existing heart disease or risk factors for cardiovascular disease?

Progesterone and Heart Disease

Progesterone therapy should not be initiated or continued for cardiovascular disease prevention in women with pre-existing heart disease or cardiovascular risk factors, as it increases the risk of coronary events, stroke, and venous thromboembolism, particularly in the first year of use. 1

Cardiovascular Risks in Women with Pre-existing Heart Disease

Coronary Heart Disease Events

• In women with established coronary disease, combined estrogen plus progestin therapy (conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg) does not reduce cardiovascular events and shows a 52% increased risk of CHD events in the first year of treatment (42.5 vs 28.0 per 1000 person-years). 2
• The Heart and Estrogen/Progestin Replacement Study (HERS) demonstrated no cardiovascular benefit after 4.1 years of follow-up in 2,763 postmenopausal women with documented heart disease, with early harm followed by a non-significant trend toward benefit in years 4-5. 3, 2
• The FDA label explicitly warns that an increased risk of myocardial infarction has been reported with estrogen plus progestin therapy, and treatment should be discontinued immediately if MI occurs or is suspected. 1

Stroke Risk

• Progesterone combined with estrogen increases stroke risk by approximately 41% (RH 1.41,95% CI 0.86-2.31), with the highest risk in women with pre-existing cardiovascular risk factors such as hypertension, smoking, or age over 35. 4
• The Women's Health Initiative found a statistically significant increased risk of stroke in women receiving combined hormone therapy (33 vs 25 per 10,000 women-years), with the increase demonstrated after the first year and persisting throughout follow-up. 1
• Current use of combined oral contraceptives containing progesterone is associated with a 1.5-1.9-fold increased risk of stroke. 3

Venous Thromboembolism

• Venous thromboembolism risk is doubled (RR 2.14,95% CI 1.64-2.81) with hormone therapy containing progesterone, with the highest risk occurring in the first year of use. 4
• The WHI demonstrated a statistically significant 2-fold greater rate of VTE (deep vein thrombosis and pulmonary embolism) in women receiving combined therapy (35 vs 17 per 10,000 women-years). 1
• The HERS trial showed significantly more venous thromboembolic events in the hormone group compared to placebo (34 vs 12; RH 2.89,95% CI 1.50-5.58). 2

Mechanism of Cardiovascular Harm

Endothelial Dysfunction

• Progesterone promotes leptin-mediated endothelial dysfunction in obese premenopausal women through aldosterone and endothelial mineralocorticoid receptors, which may further enhance sodium sensitivity. 3
• This mechanism is particularly relevant in women with obesity, a common cardiovascular risk factor. 3

Prothrombotic Effects

• Combined hormone therapy increases C-reactive protein levels, suggesting a proinflammatory effect that may contribute to cardiovascular risk. 3
• Increases in factor VII, prothrombin fragments 1 and 2, and activated protein C resistance occur with hormone therapy, along with decreased antithrombin III. 3

Clinical Contraindications

Absolute Contraindications

• Women with documented coronary heart disease should not receive progesterone-containing hormone therapy for cardiovascular protection. 3
• Risk factors requiring extreme caution include: active or history of venous thromboembolism, stroke, myocardial infarction, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, obesity, and systemic lupus erythematosus. 1

High-Risk Populations Requiring Special Consideration

• Women with uterine fibroids have independent associations with hypertension and cardiovascular disease, making progesterone therapy particularly concerning in this population. 3
• Women with polycystic ovary syndrome already have elevated cardiovascular risk (obesity, insulin resistance, hypertension) and should avoid additional progesterone-related cardiovascular burden. 3
• Women over age 65 face increased risk, as demonstrated in the WHIMS study showing increased dementia risk (RR 2.05) in this age group. 1

Important Clinical Caveats

Timing and Duration Effects

• The pattern of cardiovascular risk is time-dependent: highest risk occurs in year 1 (hazard ratio 1.81 for CHD), with a trend toward decreasing relative risk in years 2-5. 5
• This early hazard period is critical for women with pre-existing cardiovascular disease or risk factors. 1, 5

Progesterone Type Matters

• The cardiovascular data primarily reflect medroxyprogesterone acetate combined with conjugated equine estrogen; micronized progesterone may have different vascular effects, though large outcome trials are lacking. 6, 7
• The PEPI trial suggested that micronized progesterone (200 mg/day for 12 days/month) had more favorable effects on HDL-C compared to medroxyprogesterone acetate, but cardiovascular event data were not reported. 6

Route of Administration

• Transdermal routes show lower thrombotic risk (odds ratio 0.9 vs 4.2 for oral) compared to oral administration, though this applies primarily to estrogen formulations. 4

Definitive Guideline Recommendations

The 2004 American Heart Association guidelines explicitly state that combined estrogen plus progestin hormone therapy should not be initiated to prevent cardiovascular disease in postmenopausal women (Class III, Level A) and should not be continued for cardiovascular disease prevention (Class III, Level C). 3

The 2006 European Society of Cardiology guidelines recommend against routine use of hormone replacement therapy for chronic conditions, advising current users to taper doses downward toward discontinuation. 3