Does transdermal estrogen (oestrogen) have a positive effect on cholesterol levels in a postmenopausal woman with a history of hypercholesterolemia (high cholesterol)?

Does Transdermal Oestrogen Have a Positive Effect on Cholesterol?

Transdermal oestrogen has a modest positive effect on cholesterol by lowering LDL and total cholesterol levels, though it is less effective than oral oestrogen at raising HDL cholesterol. However, transdermal oestrogen offers the important advantage of lowering triglycerides rather than raising them, making it the preferred route for women with elevated triglycerides 1, 2.

Lipid Effects of Transdermal Oestrogen

LDL and Total Cholesterol Reduction

• Transdermal oestradiol significantly reduces total cholesterol and LDL cholesterol levels in postmenopausal women, with reductions comparable to oral formulations 1, 3.
• After 6 months of transdermal oestradiol (50 μg/day), significant declines in total and LDL cholesterol are observed 1.
• Long-term studies demonstrate that transdermal oestradiol produces mean reductions of 6.5-18% in total and LDL cholesterol over one year 3.

HDL Cholesterol Effects

• Transdermal oestrogen has a less favorable effect on HDL cholesterol compared to oral formulations 1, 2.
• After 6 months of transdermal therapy, 60% of women achieved HDL cholesterol levels above 40 mg/dL, compared to 87% with oral oestrogen 1.
• Some studies show transdermal oestradiol actually decreases HDL cholesterol levels, whereas oral oestrogen increases HDL by 15-18% 2, 3.
• The HDL/LDL cholesterol ratio does not significantly change with transdermal therapy, unlike oral oestrogen which improves this ratio 3.

Triglyceride Effects: A Key Advantage

• Transdermal oestrogen significantly lowers triglyceride levels, which is a critical advantage over oral formulations 1, 2, 3.
• Transdermal oestradiol reduces triglycerides by approximately 11% after one year 3.
• In contrast, oral oestrogen increases triglycerides by 24-42% depending on dose 2.
• For postmenopausal women with elevated triglycerides, transdermal oestrogen should be the preferred route 1.

Mechanism of Differential Effects

• Transdermal oestrogen avoids first-pass hepatic metabolism, which explains its different metabolic profile compared to oral formulations 4.
• Because transdermal oestrogen does not reach the liver in high concentrations, it likely has minimal effect on hepatic PPAR activity and PUFA metabolism 4.
• Oral oestrogen increases production of large, triglyceride-rich VLDL by 82%, whereas transdermal oestrogen does not have this effect 2.

Clinical Context: Cardiovascular Risk Considerations

When Lipid Effects Matter Most

• During the menopausal transition, LDL levels generally rise and HDL levels decline, making lipid management particularly important 4.
• In the general population, hormone replacement therapy lowers LDL cholesterol and lipoprotein(a), and increases HDL and triglycerides 4.
• The ACC/AHA 2018 guideline on cholesterol management includes premature menopause as a risk-enhancing factor in cholesterol management decisions 4.

Important Safety Considerations

• Despite favorable lipid effects, hormone therapy should not be used solely for cardiovascular disease prevention 4, 5.
• Transdermal oestrogen formulations (especially low dose) are not associated with increased stroke risk, unlike oral formulations 4, 6.
• Transdermal oestrogen does not increase venous thromboembolism risk (OR 0.9), whereas oral oestrogen significantly increases VTE risk (OR 4.2) 5.
• The Menopause Society recommends using the lowest effective dose of oestrogen in women <60 years of age with low cardiovascular, thromboembolic, and breast cancer risk profiles 4, 5.

Practical Algorithm for Route Selection Based on Lipid Profile

For Women with Elevated Triglycerides (>150 mg/dL)

• Choose transdermal oestrogen as first-line therapy to avoid worsening triglycerides 1, 3.
• Transdermal oestradiol 50 μg/day is an appropriate starting dose 1.
• Monitor triglyceride levels at 3 and 6 months to confirm improvement 1.

For Women with Low HDL (<50 mg/dL) and Normal Triglycerides

• Oral oestrogen may provide greater HDL benefit (16-18% increase) compared to transdermal formulations 1, 2.
• However, cardiovascular risk factors (age >60, history of VTE, stroke risk factors) should take precedence over lipid optimization when choosing route 6, 5.

For Women with Hypercholesterolemia (LDL ≥140 mg/dL)

• Both oral and transdermal oestrogen effectively reduce LDL cholesterol by 15-19% 1, 2, 7.
• The beneficial effect on LDL is maintained over 3 years with either route 7.
• Route selection should be based primarily on safety profile (stroke risk, VTE risk) rather than lipid efficacy alone 6, 5.

Important Clinical Caveats

• Lipid benefits alone do not justify initiating hormone therapy—the primary indication remains treatment of menopausal symptoms 4, 5.
• Women with intact uterus require progestin addition to any oestrogen formulation to prevent endometrial hyperplasia 4, 5.
• Progestogens can partially oppose oestrogen's favorable lipid effects, with the magnitude depending on progestogen type 8.
• In women with chronic kidney disease, oestrogen dosing may need to be reduced by 50-70% to achieve equivalent blood concentrations 4.