What are the differences in cardiovascular outcomes between oral and transdermal estrogen (estrogen administered through the skin) therapy in women?

Cardiovascular Outcomes in Women on Oral vs Transdermal Estrogen

Transdermal estrogen therapy is significantly safer than oral estrogen for cardiovascular outcomes in women, with substantially lower risk of venous thromboembolism and no increased risk of stroke compared to oral formulations. 1, 2

Venous Thromboembolism (VTE) Risk

• Transdermal estrogen does not increase the risk of venous thromboembolism, with odds ratio of 0.9 (95% CI, 0.4-2.1) compared to 4.2 (95% CI, 1.5-11.6) for oral estrogen preparations in postmenopausal women 1
• Meta-analysis data confirms this difference with pooled risk ratios for VTE of 1.9 (95% CI 1.3-2.3) for oral estrogen versus 1.0 (95% CI 0.9-1.1) for transdermal estrogen 2
• Transdermal estrogen appears safe even in women with pre-existing risk factors for VTE, while oral estrogen (especially with synthetic progestogens) significantly increases risk 3

Mechanism of Differential VTE Risk

• Oral estrogen undergoes first-pass hepatic metabolism, leading to increased levels of estrone, which correlates with increased thrombin generation (R=0.451, P<0.001) 4
• Transdermal estrogen bypasses hepatic metabolism, resulting in:
  • Neutral effect on Sex Hormone Binding Protein (SHBP) levels, while oral 17β-estradiol 2 mg and oral ethinyl estradiol 20 μg increase SHBP levels 1
  • Minimal effects on hemostatic variables compared to oral estrogen, which increases thrombin generation and induces resistance to activated protein C 2

Stroke and Cardiovascular Disease Risk

• FDA labeling warns that estrogen therapy increases risk of stroke and myocardial infarction, particularly with oral formulations 5
• Transdermal estrogen formulations have a superior safety profile for cardiovascular outcomes due to avoidance of liver metabolism 6
• While oral estrogen increases stroke risk, transdermal formulations (especially low dose) were not associated with a clear risk of stroke 1

Blood Pressure and Metabolic Effects

• Blood pressure levels in women with premature ovarian insufficiency treated with transdermal 17β-estradiol were statistically lower than after combined oral contraceptives, likely due to more physiological impact on the renin-angiotensin-aldosterone axis 1
• 17β-estradiol reduces LDL levels and increases HDL, while ethinyl estradiol has a negative impact on insulin tolerance 1

Bone Mineral Density Effects

• Transdermal estradiol and vaginal progesterone had more beneficial effects on lumbar spine bone mineral density than standard hormone replacement therapy using oral ethinyl estradiol and oral norethisterone 1
• In a randomized study of 30 women, 17β-estradiol 2 mg daily with levonorgestrel 75 μg showed more favorable effects on lumbar spine bone mineral density compared to ethinyl estradiol 30 μg with levonorgestrel 150 μg 1

Special Populations

• For women with prothrombotic mutations (Factor V Leiden or prothrombin G20210A):
  • Oral estrogen combined with these mutations increases VTE risk 25-fold compared to non-users without mutations 7
  • Transdermal estrogen does not confer additional risk beyond the baseline risk of the mutation itself 7

Clinical Recommendations

• Transdermal estrogen should be preferred over oral estrogen for most women requiring hormone therapy, particularly those with:
  • History of or risk factors for venous thromboembolism 3
  • Cardiovascular risk factors including hypertension 1
  • Need for bone mineral density preservation 1
• According to the Menopause Society, estrogen-based hormone therapy may be most appropriate using the lowest effective dose of estrogen in women <60 years of age with low cardiovascular, thromboembolic, and breast cancer risk profiles 1
• Hormone therapy is not recommended for primary prevention of cardiovascular disease in women 1

Important Caveats

• All hormone therapy carries risks, including increased risk of endometrial cancer in women with intact uterus if estrogen is used without progestin 5
• Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals 5
• Women with history of hormone-dependent cancers should generally avoid hormone therapy 1
• For women with intact uterus requiring hormone therapy, progestin must be added to prevent endometrial hyperplasia and cancer 1