Is transdermal combined continuous hormone replacement therapy (HRT) with Evorel Conti (estradiol and norethisterone) safer and better tolerated than oral HRT with Kliofem (estradiol and norethisterone)?

Transdermal HRT (Evorel Conti) is Safer Than Oral HRT (Kliofem) Due to Lower Thromboembolism Risk

Transdermal combined continuous HRT (Evorel Conti) is safer than oral combined continuous HRT (Kliofem) primarily due to significantly lower risk of venous thromboembolism, with better metabolic and cardiovascular profiles. 1

Safety Comparison

Venous Thromboembolism Risk

• Transdermal estradiol administration has a significantly lower risk of venous thromboembolism compared to oral administration, with an odds ratio of 0.9 (95% CI, 0.4-2.1) for transdermal versus 4.2 (95% CI, 1.5-11.6) for oral estrogen preparations 1
• Transdermal estradiol (as in Evorel Conti) has a neutral effect on Sex Hormone Binding Protein (SHBP), a marker for VTE risk, while oral estradiol (as in Kliofem) increases SHBP levels 1
• The first-pass liver metabolism with oral estrogen increases production of clotting factors, which is avoided with transdermal delivery 1

Cardiovascular Effects

• Blood pressure levels are statistically lower with transdermal estradiol-based HRT compared to oral formulations, likely due to more physiological impact on the renin-angiotensin-aldosterone axis 1
• Oral HRT has been shown to offer no cardiovascular protection and may increase cardiovascular risk in some women 1
• Transdermal estradiol has less impact on lipid metabolism compared to oral formulations 1

Tolerability Comparison

Metabolic Profile

• Transdermal 17β-estradiol (as in Evorel Conti) has been shown to reduce LDL levels and increase HDL, creating a more favorable lipid profile than oral formulations 1
• Oral estradiol (as in Kliofem) has been associated with negative impacts on insulin tolerance compared to transdermal delivery 1
• Weight management may be better with transdermal formulations, as studies have shown BMI reduction with transdermal estradiol compared to oral formulations 2

Side Effect Profile

• Both formulations contain norethisterone acetate as the progestin component, but the delivery method affects side effect profiles 3, 4
• Transdermal delivery systems are generally well tolerated, with the most common adverse effect being local skin irritation at the application site 4
• Oral combined HRT may have more systemic side effects due to higher circulating hormone levels needed to overcome first-pass metabolism 1

Patient Preference and Compliance

• Transdermal systems offer more convenient and consistent method of hormone administration, which may improve patient compliance during long-term therapy 4
• However, some studies have shown high patient preference (91%) for continuous combined oral therapy (like Kliofem) over sequential regimens, though this wasn't comparing oral to transdermal 5

Clinical Considerations

Hormone Formulations

• Both products contain estradiol and norethisterone acetate in a continuous combined regimen 3, 4
• Kliofem is an oral tablet containing 2mg estradiol and 1mg norethisterone acetate 2
• Evorel Conti is a transdermal patch delivering approximately 50μg estradiol and 170μg norethisterone acetate daily 3

Special Considerations

• For women with higher risk of thromboembolism, transdermal estradiol (Evorel Conti) is clearly the safer option 1
• Women with diabetes may benefit from transdermal delivery due to more favorable effects on metabolic parameters 2
• Continuous regimens like both Kliofem and Evorel Conti prevent withdrawal bleeding, which many women prefer over sequential regimens 5

Common Pitfalls

• Assuming all HRT formulations carry the same risk profile regardless of administration route - the transdermal route significantly reduces thromboembolism risk 1
• Overlooking the importance of administration route when prescribing HRT to women with cardiovascular risk factors 1
• Failing to consider that the first-pass liver metabolism with oral estrogen increases production of clotting factors, which is avoided with transdermal delivery 1