What is the difference between estrone and estrogen in hormone replacement therapy (HRT)?

Estrone vs. Estrogen in Hormone Replacement Therapy

Key Distinction

Estrogen is a class of hormones that includes estradiol (E2), estrone (E1), and estriol (E3), while estrone is one specific type of estrogen—estradiol is the most potent form at the receptor level, and the route of administration dramatically affects the estrone-to-estradiol ratio, which has significant clinical implications. 1

Understanding the Terminology

• "Estrogen" is an umbrella term encompassing multiple hormone molecules, with estradiol being the principal intracellular human estrogen and substantially more potent than estrone or estriol at the receptor level 1
• Circulating estrogens exist in dynamic equilibrium through metabolic interconversions, meaning they continuously convert between forms 1, 2
• In postmenopausal women, estrone and its sulfate conjugate (estrone sulfate) become the most abundant circulating estrogens, as the primary source shifts from ovarian production to peripheral conversion of adrenal androgens 1, 2

Potency and Receptor Activity

• Estradiol (E2) is the most biologically active estrogen, with estrone being significantly weaker in estrogenic effects 1, 3
• All estrogen agonists (E2, E1, E3, conjugated equine estrogens) work through the same estrogen receptors (ER-α and ER-β) without convincing evidence of qualitative differences—only quantitative differences exist due to receptor affinity, metabolism, and route of administration 3, 4
• Estrone may actually function as a partial estradiol antagonist at high concentrations, potentially interfering with estradiol's biological effects in tissues like breast tissue 5

Route of Administration Matters Critically

Oral estradiol produces dramatically different estrone/estradiol ratios compared to other routes, which fundamentally changes the hormonal profile:

• Oral estradiol: Highest E1/E2 ratio (9.28), meaning predominantly estrone exposure due to first-pass hepatic metabolism 6
• Sublingual estradiol: High E1/E2 ratio (6.88), still favoring estrone 6
• Transdermal estradiol: Low E1/E2 ratio (2.22), more balanced profile 6
• Injectable estradiol: Lowest E1/E2 ratio (0.84), predominantly estradiol exposure with highest mean estradiol levels (1557 pmol/L) 6

Clinical Implications for HRT Selection

The route of administration should be chosen based on desired estrone/estradiol balance, with non-oral routes avoiding excessive estrone production:

• Oral preparations undergo substantial first-pass hepatic metabolism, converting estradiol to estrone, estriol, and conjugated forms, resulting in disproportionately high estrone levels 2, 6
• Transdermal and injectable routes bypass first-pass metabolism, providing more physiologic estradiol-predominant profiles without excessive estrone conversion 2, 6
• The clinical significance of high estrone exposure remains debated, but estrone's potential role as a partial estradiol antagonist suggests that excessive E1/E2 ratios may reduce therapeutic efficacy 5

Practical Prescribing Algorithm

For postmenopausal HRT, prioritize route selection based on metabolic profile:

1. First-line consideration: Transdermal estradiol (patch or gel) provides E1/E2 ratio of ~2.22 with consistent serum levels and avoids hepatic first-pass effects 6, 2
2. Alternative: Injectable estradiol for lowest E1/E2 ratio (0.84) but requires monitoring for supraphysiologic estradiol levels 6
3. Avoid as first-line: Oral estradiol produces 9-fold higher estrone than estradiol, creating non-physiologic hormone ratios 6

Important Caveats

• Women's Health Initiative data primarily used oral conjugated equine estrogen (0.625 mg/d), so risk/benefit profiles may differ with other formulations and routes 4
• All systemic HRT carries risks: increased stroke (HR 1.36 for estrogen alone), thromboembolic events (HR 1.47-1.88 for DVT), and gallbladder disease (HR 1.61-1.79) regardless of estrogen type 4
• Combined estrogen-progestin increases breast cancer risk (HR 1.25), while estrogen-alone unexpectedly reduced it (HR 0.77)—this discrepancy remains unexplained 4
• HRT should not be used for cardiovascular disease prevention at any age, despite favorable lipid effects, due to increased stroke and CHD risk 4