What is the difference between estrogen and estrone for hormone replacement therapy?

Understanding Estrogen vs. Estrone in Hormone Replacement Therapy

Critical Terminology Clarification

The question conflates "estrogen" with "estrone," but these are not interchangeable terms—estrogen is a class of hormones, while estrone is one specific type of estrogen molecule. Understanding this distinction is essential for prescribing appropriate HRT.

Estrogen Types Used in HRT

The Three Main Estrogens

• Estradiol (E2) is the most potent and predominant estrogen during reproductive years, and is the preferred form for HRT in most clinical scenarios 1
• Estrone (E1) is a weaker estrogen that becomes the predominant form after menopause, produced primarily through peripheral conversion of androgens 1
• Estriol (E3) is the weakest estrogen, primarily produced during pregnancy 1

HRT Formulations

• Natural estrogens used in HRT include 17β-estradiol or its valerate ester, which have a more physiological and safer pharmacological profile compared to synthetic estrogens 1
• Conjugated equine estrogen (CEE) contains multiple estrogen compounds including estrone sulfate and is the formulation most studied in major trials like the Women's Health Initiative 2
• Synthetic ethinyl estradiol is used primarily in birth control pills and is approximately 10 times more potent than natural estradiol—20 micrograms of ethinyl estradiol equals roughly 2 mg of 17β-estradiol valerate 1

Potency and Clinical Implications

Relative Potency Hierarchy

• Estradiol is the most biologically active estrogen at tissue receptors, making it the gold standard for symptom relief and tissue effects 1
• Estrone has approximately 10-20% of estradiol's potency at estrogen receptors, which is why it provides less robust symptom control 1
• The body can interconvert estrone and estradiol through enzymatic processes, though this conversion is less efficient in postmenopausal women 1

Route of Administration Matters

• Transdermal 17β-estradiol has a neutral effect on Sex Hormone Binding Protein and carries lower thrombotic risk (odds ratio 0.9 for venous thromboembolism) compared to oral preparations 1
• Oral estradiol 2 mg increases Sex Hormone Binding Protein levels and has higher thrombotic risk (odds ratio 4.2 for venous thromboembolism) due to first-pass hepatic metabolism 1
• Transdermal administration bypasses first-pass hepatic metabolism, reducing cardiovascular and thromboembolic risks while maintaining physiological estradiol levels 3

Evidence-Based Prescribing Recommendations

For Surgical Menopause or Premature Ovarian Insufficiency

Start transdermal estradiol 0.05 mg (50 μg) patches applied twice weekly immediately after surgery or diagnosis, continuing until at least age 51. 3

• This regimen provides critical protection against cardiovascular disease, stroke, and accelerated bone loss 3
• Add micronized progesterone 200 mg daily if the uterus is intact to prevent endometrial cancer 3
• Transdermal delivery is preferred because it reduces cardiovascular and thromboembolic risks by 78% compared to oral routes 1, 3

For Natural Menopause Symptom Management

Use transdermal 17β-estradiol as first-line therapy at the lowest effective dose for the shortest duration needed for symptom control. 2, 1

• The European Society for Human Reproduction and Embryology recommends transdermal 17β-estradiol as the preferred route because it mimics physiological serum estradiol concentrations 1
• Women should be informed that risks such as venous thromboembolism, CHD, and stroke occur within the first 1-2 years of therapy, while breast cancer risk increases with longer-term use 2
• Combined estrogen-progestin therapy increases breast cancer risk (HR 1.25) after 11 years of follow-up 2

Formulations to Avoid

• Do not use birth control pills for HRT unless contraception is specifically needed, as they contain synthetic ethinyl estradiol at doses far exceeding physiological replacement needs 1
• Avoid oral estrogen preparations in women with stroke risk factors, thrombophilic disorders, or cardiovascular disease—use transdermal routes instead 1, 3

Risk-Benefit Profile by Formulation

Combined Estrogen-Progestin (for women with intact uterus)

• Benefits: Reduces hip fractures by 33% (HR 0.67), vertebral fractures by 32% (HR 0.68), and colorectal cancer by 37% (RH 0.63) 2
• Harms: Increases breast cancer by 25% (HR 1.25), stroke by 41% (RH 1.41), venous thromboembolism by 111% (RH 2.11), and CHD events by 29% 2
• Absolute risk: Per 10,000 women taking estrogen-progestin for 1 year: 7 additional CHD events, 8 more strokes, 8 more pulmonary emboli, 8 more invasive breast cancers, but 6 fewer colorectal cancers and 5 fewer hip fractures 2

Unopposed Estrogen (for women post-hysterectomy)

• Benefits: Reduces invasive breast cancer by 23% (HR 0.77) and breast cancer mortality by 63% (HR 0.37) after 11 years, plus similar fracture and colorectal cancer benefits as combined therapy 2
• Harms: Increases stroke by 36% (HR 1.36) and venous thromboembolism, but does NOT increase breast cancer risk 2
• Critical warning: Unopposed estrogen increases endometrial cancer risk 2.3-fold (RR 2.3), reaching 9.5-fold with 10 years of use—never use in women with intact uterus 2

Absolute Contraindications

Do not prescribe any form of estrogen therapy if the patient has: 3

• History of breast cancer or hormone-sensitive malignancies
• Active or history of venous thromboembolism or stroke
• Coronary heart disease or history of myocardial infarction
• Active liver disease
• Antiphospholipid syndrome or positive antiphospholipid antibodies
• Thrombophilic disorders

Common Prescribing Pitfalls

• Mistake: Prescribing oral estrogen when transdermal would be safer—oral routes increase thrombotic risk 4.7-fold compared to transdermal 1
• Mistake: Using estrogen alone in women with intact uterus—this increases endometrial cancer risk up to 9.5-fold with prolonged use 2
• Mistake: Prescribing birth control pills for HRT when contraception isn't needed—these contain synthetic estrogens at supraphysiologic doses 1
• Mistake: Continuing HRT indefinitely without reassessing risk-benefit—breast cancer risk increases with duration, particularly beyond 5 years 2