What is the difference between estrogen estradiol and estrone?

Estradiol vs. Estrone: Key Physiological Differences

Estradiol is the most potent and biologically active human estrogen, substantially more powerful than estrone at the receptor level, while estrone serves primarily as a weaker circulating reservoir that can be converted to estradiol in peripheral tissues. 1

Potency and Biological Activity

• Estradiol (E2) is the principal intracellular human estrogen and is substantially more potent than estrone (E1) at the receptor level. 1
• The estradiol/estrone ratio is critical in estrogen-sensitive tissues—a high ratio (favoring estradiol) is associated with increased cell proliferation, particularly important in breast cancer mechanisms. 2
• In breast cancer cells with high expression of 17beta-hydroxysteroid dehydrogenase type 1, the estradiol/estrone ratio stabilizes around 9:1, demonstrating estradiol's dominance in these tissues. 2

Metabolic Interconversion

• Circulating estrogens exist in a dynamic equilibrium where estradiol is converted reversibly to estrone, and both can be converted to estriol (the major urinary metabolite). 1
• Estrone can be reduced to estradiol in peripheral tissues, making estrone sulfate serve as a circulating reservoir for formation of more active estrogens, especially in postmenopausal women. 1, 3
• The enzyme 17beta-hydroxysteroid dehydrogenase type 1 is the primary determinant of the estradiol/estrone ratio in the cellular environment, catalyzing the conversion of estrone to the more potent estradiol. 2

Source and Production

• In premenopausal women, the ovarian follicle secretes 70-500 mcg of estradiol daily depending on menstrual cycle phase, making it the primary estrogen source. 1
• After menopause, estrone and estrone sulfate become the most abundant circulating estrogens, produced primarily through peripheral conversion of adrenal androstenedione to estrone by aromatase in adipose tissue and skin. 1, 3
• Extraglandular aromatase activity in adipose tissue increases with body weight and advancing age, producing sufficient estrone that converts to estradiol to potentially cause uterine bleeding and endometrial hyperplasia in obese postmenopausal women. 3

Cardiovascular and Systemic Effects

• Estradiol has more pronounced effects on the renin-angiotensin-aldosterone system (RAAS), increasing angiotensinogen production more significantly than other estrogens. 4
• Estradiol demonstrates stronger cardiovascular effects, increasing stroke volume, heart rate, and contractility while reducing peripheral vascular resistance in postmenopausal women. 5, 4

Clinical Implications for Therapy

• For women using aromatase inhibitors after breast cancer, estriol-containing preparations (derived from estrone) may be preferable over estradiol-containing ones since estriol cannot be converted back to estradiol. 4, 6
• Vaginal estradiol may increase circulating estradiol levels in aromatase inhibitor users within 2 weeks, potentially reducing the efficacy of these cancer treatments. 6
• The route of estradiol administration significantly affects the estrone/estradiol ratio: oral routes produce the highest E1/E2 ratios (9.28), while injectable routes produce the lowest (0.84), with transdermal intermediate (2.22). 7

Pharmacokinetic Considerations

• In women with chronic kidney disease, estradiol serum concentrations may be over 20% greater than in women with normal renal function, suggesting these patients should receive 50-70% lower doses to achieve equivalent concentrations. 5
• Both estrogens undergo extensive first-pass hepatic metabolism and enterohepatic recirculation via sulfate and glucuronide conjugation. 1