Clinical Information

Estrogens are involved in development and maintenance of the female phenotype, germ cell maturation, and pregnancy. They also are important in many other nongender-specific functions in men and women. These include growth, nervous system maturation, bone metabolism, and endothelial responsiveness.

There are 3 major biologically active estrogens in humans: estrone (E1), estradiol (E2), and estriol (E3). Like all members of the steroid hormone family, they diffuse into cells and bind to specific nuclear receptors, which in turn alter gene transcription in a tissue specific manner. E2 is the most potent natural human estrogen, closely followed by E1, while E3 possess only 20% of E2's affinity for the estrogen receptor. In men and nonpregnant women, E1 and E2 are formed from the androgenic steroids androstenedione and testosterone, respectively. E3 is derived largely through conversion of E2, and to a lesser degree from 16a-metabolites of E1. E2 and E1 can also be converted into each other, and both can be inactivated via hydroxylation and conjugation.

During pregnancy E3 becomes the dominant estrogen. The fetal adrenal gland secretes dehydroepiandrosterone-sulfate (DHEAS), which is converted to E3 in the placenta and diffuses into the maternal circulation. The half-life of unconjugated E3 (uE3) in the maternal blood system is 20 to 30 minutes, since the maternal liver quickly conjugates E3 to make it more water soluble for urinary excretion. E3 levels increase throughout the course of pregnancy, peaking at term.

Measurement of serum E2 and E1 levels is an integral part of assessment of reproductive function in females, and also has applications in both men and women in osteoporosis risk assessment and monitoring of female hormone replacement therapy. By contrast, with the exception of epidemiological studies assessing breast cancer risk and other scientific studies, the main value of E3 measurements is in the diagnosis of maternal-fetal diseases. In those settings, measurement of serum uE3 levels plays a major role.

Decreased 2nd trimester uE3 has been shown to be a marker for Down and trisomy-18 syndromes. It also is low in cases of gross neural tube defects such as anencephaly. Based on these observations, uE3 has become a part of multiple marker prenatal biochemical screening, together with alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), and inhibin-A measurements (QUAD / Quad Screen (Second Trimester) Maternal, Serum). Low levels of uE3 also have been associated with pregnancy loss, Smith-Lemli-Opitz syndrome (defect in cholesterol biosynthesis), X-linked ichthyosis and contiguous gene syndrome (placental sulfatase deficiency disorders), aromatase deficiency, and primary or secondary fetal adrenal insufficiency.

High levels of uE3, or sudden increases in maternal uE3 levels, are a marker of pending labor. The rise occurs approximately 4 weeks before onset of labor. Since uE3 has been shown to be more accurate than clinical assessment in predicting labor onset, there is increasing interest in its use in assessment of pre-term labor risk.

High maternal serum uE3 levels may also be occasionally observed in various forms of congenital adrenal hyperplasia.