Estriol (E3) Test

Estriol is one of the three major human estrogens, alongside estradiol and estrone. Estrogens are steroid hormones derived from cholesterol that bind to estrogen receptors, which are proteins inside cells that regulate gene expression. Of the three, estradiol is the most potent, estrone has moderate activity, and estriol is the weakest in terms of receptor stimulation. Weak does not mean unimportant. It means that at the same concentration, estriol activates estrogen receptors less strongly than estradiol.

In pregnancy, estriol becomes the dominant estrogen in circulation. It is produced by the fetoplacental unit, a collaboration between the fetus and the placenta. The fetal adrenal glands produce precursor hormones from cholesterol. These precursors are modified in the fetal liver and then converted by the placenta into estriol. Because this pathway requires coordinated function of the fetus, liver, adrenal glands, and placenta, estriol levels in maternal blood and urine serve as a marker of fetoplacental health. Persistently low or declining levels during pregnancy can signal impaired placental function or fetal steroid production, while rising levels generally reflect normal development.

Outside pregnancy, estriol circulates at very low concentrations in both women and men. In nonpregnant adults, most estriol is formed through metabolism of estradiol and estrone in the liver. This process is part of estrogen metabolism, which includes chemical modifications such as hydroxylation, a reaction that adds an oxygen containing group to make hormones easier to process and eliminate. There is meaningful person to person variation in how efficiently estrone is converted to estriol. That variation tends to remain stable within an individual over time, which may partly explain differences in estrogen related risk profiles.

Although weaker than estradiol, estriol still binds to estrogen receptors and appears to favor certain signaling patterns. Estrogen receptors exist in two main forms, ER alpha and ER beta, which are distributed differently across tissues. Subtle differences in how estriol activates these receptors may help explain why it has been studied as a potentially safer estrogen option in specific settings.

In the immune system, estriol has immunomodulatory effects. Immunomodulation means adjusting the activity of immune cells rather than simply turning them on or off. During pregnancy, many autoimmune diseases such as multiple sclerosis tend to improve. Research suggests that high pregnancy level estriol shifts the immune response away from proinflammatory cytokines, which are signaling proteins that promote inflammation. In clinical trials, pharmacologic doses of estriol that mimic mid pregnancy levels have reduced markers of nerve injury in women with multiple sclerosis, supporting a possible neuroprotective effect. Neuroprotection refers to preserving the structure and function of nerve cells.

In urogenital tissues, particularly the vaginal epithelium, estriol can improve lubrication, elasticity, and tissue thickness. Vaginal atrophy, also called genitourinary syndrome of menopause, occurs when low estrogen leads to thinning and dryness of vaginal tissue, often causing pain with intercourse. Low dose vaginal estriol can improve these symptoms with minimal increases in systemic estrogen levels. Systemic means throughout the whole body. Because estriol is weaker and often used locally, it may carry less risk of stimulating endometrial proliferation, which is growth of the uterine lining that can increase the risk of endometrial cancer when excessive. That said, risk depends on dose, route, and individual factors.

High estriol is most physiologically meaningful in pregnancy, where it reflects normal fetoplacental hormone production. Outside pregnancy, elevated levels are usually due to supplementation, obesity related increases in aromatase activity, or increased peripheral conversion. Aromatase is the enzyme that converts androgens, which are male type hormones such as testosterone, into estrogens. Obesity increases aromatase activity in adipose tissue, which can raise overall estrogen production in both sexes.

Low estriol outside pregnancy is common after menopause, when ovarian hormone production declines sharply. It may also occur with reduced ovarian function or decreased substrate availability, meaning there is less estradiol or estrone available to be converted. In men, estriol levels are typically low and influenced by overall estrogen production and body composition.

For longevity focused adults, estriol is rarely interpreted in isolation. In pregnancy it is a valuable marker of placental and fetal health. Outside pregnancy, it is more often considered as part of the broader estrogen landscape, which influences bone density, cardiovascular risk, immune balance, and cancer biology. Context, including age, sex, body composition, and use of hormone therapy, determines whether a given estriol level is clinically meaningful.