What is Endogenous Estrogen
Endogenous estrogen refers to the naturally occurring estrogen hormones produced within the body, primarily by the ovarian follicles in premenopausal women, with estradiol (E2) being the most potent form at the cellular receptor level. 1, 2
Primary Endogenous Estrogens
There are four principal endogenous estrogens produced in the human body 3:
- Estrone (E1): The predominant circulating estrogen in postmenopausal women, primarily produced through peripheral conversion of androstenedione secreted by the adrenal cortex 2
- Estradiol (E2): The most potent intracellular human estrogen, substantially more active than its metabolites at the receptor level; secreted at 70-500 mcg daily by the ovarian follicle depending on menstrual cycle phase in premenopausal women 2
- Estriol (E3): A weaker metabolite that serves as the major urinary excretion product 2, 3
- Estetrol (E4): Produced exclusively during pregnancy and has emerged as having therapeutic potential 3
Mechanism of Action
Endogenous estrogens exert their effects through binding to nuclear estrogen receptors present in target tissues 1:
- Two receptor subtypes exist: Estrogen receptor-alpha (ER-α) and estrogen receptor-beta (ER-β), which vary in proportion across different tissues 1, 2
- Transcription factor function: Estrogen-receptor complexes serve as transcription factors that promote gene expression, resulting in wide-ranging vascular effects including regulation of vasomotor tone and response to injury 1
- Tissue distribution: Receptors are expressed in cardiovascular cells, reproductive tissues, bone, liver, brain, and vascular endothelial cells 1, 4
Physiological Effects
Cardiovascular System
Endogenous estrogen provides vasoprotective effects in premenopausal women 5:
- Rapid vasodilation: Occurs within minutes through ER-α-mediated activation of endothelial nitric oxide synthase enzyme 1
- Long-term vascular protection: Effects over hours to days involve alterations in vascular gene expression that may protect against atherosclerosis development 1
- Lipid metabolism: Favorable reductions in LDL cholesterol and lipoprotein(a), with increases in HDL cholesterol 1
Reproductive System
Endogenous estrogens are largely responsible for development and maintenance of the female reproductive system and secondary sexual characteristics 2
Bone Health
Estrogen increases calcium uptake into blood and deposition into bone, with peak bone mass occurring around age 19 in women 1
Metabolic Effects
During exercise at approximately 65% VO2max, endogenous estrogen causes a protein-sparing effect with higher rates of lipid oxidation and lower rates of carbohydrate and protein metabolism 1
Metabolism and Circulation
Endogenous estrogens undergo extensive metabolic processing 2, 3:
- Dynamic equilibrium: Circulating estrogens exist in constant metabolic interconversion, with estradiol converting reversibly to estrone, and both converting to estriol 2, 3
- Protein binding: Estrogens circulate largely bound to sex hormone-binding globulin (SHBG) and albumin 2
- Hepatic metabolism: Primary site of transformation through phase I (hydroxylation, oxidation, reduction) and phase II (conjugation) reactions 3
- Enterohepatic recirculation: Involves sulfate and glucuronide conjugation in the liver, biliary secretion, intestinal hydrolysis, and reabsorption 2
Postmenopausal Changes
After menopause, endogenous estrogen production shifts dramatically 2:
- Primary source: Most endogenous estrogen comes from peripheral tissue conversion of adrenal androstenedione to estrone 2
- Circulating forms: Estrone and estrone sulfate become the most abundant circulating estrogens, with estrone sulfate serving as a reservoir for more active estrogen formation 2
- Reduced levels: The decline in endogenous estrogen removes the vasoprotective effects present in premenopausal women 5
Clinical Significance
Disease Risk Associations
Higher levels of endogenous estrogens in postmenopausal women correlate with increased breast cancer risk 6:
- Women who subsequently developed breast cancer showed higher levels of estrone, total estradiol, and free estradiol compared to those who remained cancer-free 6
- Lower percentage of estradiol bound to SHBG (meaning more free, bioavailable estradiol) was associated with increased breast cancer risk 6
Athletic Performance
Low endogenous estrogen from functional hypothalamic amenorrhea in female athletes leads to multiple adverse effects 1: