What is the difference between estrone and estradiol (estrogen)?

Estrone, Estradiol, and Estrogen: Key Differences

Estradiol is the most potent and biologically active form of estrogen in the human body, while estrone is a weaker estrogen that serves primarily as a reservoir form, and both exist in dynamic metabolic equilibrium with continuous interconversion. 1

Potency and Biological Activity

• Estradiol (E2) is substantially more potent than estrone (E1) at the receptor level, making it the principal intracellular human estrogen responsible for most estrogenic effects 1
• The estradiol-to-estrone ratio is critical for understanding estrogen-sensitive conditions: a high estradiol/estrone ratio (approximately 9:1) promotes greater estrogenic activity and cell proliferation, while a lower ratio (1:5) indicates reduced estrogenic stimulation 2
• Estradiol demonstrates the highest binding affinity to estrogen receptors, followed by estriol, then estrone, with estrone showing the weakest receptor binding 3

Sources and Production

Premenopausal Women

• The ovarian follicle is the primary source, secreting 70-500 mcg of estradiol daily depending on menstrual cycle phase 1
• Estradiol is continuously converted to estrone through reversible metabolic pathways 1, 4

Postmenopausal Women

• Estrone becomes the predominant circulating estrogen after menopause, produced through peripheral conversion of adrenal androstenedione in liver, adipose tissue, skeletal muscle, kidney, brain, and hair follicles 1, 4
• Estrone sulfate serves as a circulating reservoir that can be converted back to more active estrogens as needed 1
• Extraglandular aromatase activity in adipose tissue increases with body weight and advancing age, contributing significantly to postmenopausal estrogen levels 5

Metabolic Interconversion

• Estradiol and estrone exist in dynamic equilibrium with continuous reversible conversion between the two forms, primarily occurring in the liver 1, 4
• The enzyme 17beta-hydroxysteroid dehydrogenase type 1 is the primary determinant of the estradiol/estrone ratio, converting estrone to the more potent estradiol 2
• Type 2 of this enzyme catalyzes the reverse reaction, converting estradiol back to estrone, though it plays a secondary role compared to type 1 2
• Both estradiol and estrone can be further metabolized to estriol (E3), which is the major urinary metabolite and represents a terminal pathway since estriol cannot be converted back to estradiol 6

Cardiovascular and Systemic Effects

• Estradiol exerts more pronounced cardiovascular effects than estrone, including stronger impacts on the renin-angiotensin-aldosterone system with greater increases in angiotensinogen production 7, 6
• Estradiol increases stroke volume, heart rate, and contractility while reducing peripheral vascular resistance in postmenopausal women 7, 6
• Estradiol provides neuroprotective effects through antioxidant mechanisms, reduction of reactive oxygen species, stimulation of dendritic spine production, and enhancement of brain-derived neurotrophic factor (BDNF) 8

Clinical Implications

Breast Cancer Considerations

• For women using aromatase inhibitors after breast cancer, estriol-containing preparations (derived from estrone) are preferable over estradiol-containing preparations since estriol cannot be converted back to estradiol, avoiding interference with cancer treatment 7, 6
• Vaginal estradiol may increase circulating estradiol levels within 2 weeks in aromatase inhibitor users, potentially reducing treatment efficacy 7
• Excessive estradiol/estrone ratios (9:1) in breast tissue promote proliferation of estrogen-sensitive cancer cells 2

Dosing Considerations

• In women with chronic kidney disease, estradiol serum concentrations may exceed normal levels by over 20%, requiring 50-70% dose reduction to achieve equivalent concentrations 7

Distribution and Metabolism

• Both estrogens circulate bound to sex hormone-binding globulin (SHBG) and albumin, with higher concentrations in sex hormone target organs 1
• Estrone sulfate is the most abundant circulating estrogen in postmenopausal women, serving as a storage form that is freely converted back to active estrone and estradiol 1, 4
• Both undergo enterohepatic recirculation through hepatic conjugation to sulfate and glucuronide forms, biliary secretion, intestinal hydrolysis, and reabsorption 1