E3 Estrogen (Estriol)

Estriol is one of the three main estrogens produced by the human body, the others being estradiol and estrone. It is primarily produced during pregnancy by the placenta and is considered a weak estrogen compared to the other two forms. Estriol plays a significant role in various physiological processes, particularly during the menstrual cycle and pregnancy.

Biological activity

Estriol is an estrogen and acts as an agonist at the estrogen receptors ERα and ERβ. It is significantly less potent than estradiol, making it a relatively weak estrogen.

One in vitro study found that the relative binding affinity (RBA) of estriol for human ERα and ERβ was 11.3% and 17.6% of that of estradiol, respectively, and its relative transactivational capacity at ERα and ERβ was 10.6% and 16.6% of that of estradiol, respectively. Another in vitro study, however, reported the RBA of estriol for ERα and ERβ as 14% and 21% of those of estradiol, respectively, suggesting that unlike estradiol and estrone, estriol might have a preferential affinity for ERβ.

While estriol is an effective agonist of the ERs, it is noted to have mixed agonist–antagonist (partial agonist) activity at the ER. Alone, it exhibits weak estrogenic effects, but in the presence of estradiol, it acts as an antiestrogen. In mice, when administered via subcutaneous injection, estradiol is approximately 10 times more potent than estrone and about 100 times more potent than estriol. Unlike estriol, estrone can be converted into estradiol, and its potency in vivo is largely due to this conversion.

Besides being an agonist of the nuclear ERs, at high concentrations (around 1,000–10,000 nM), estriol also acts as an antagonist of the GPER, a membrane estrogen receptor, where estradiol acts as an agonist. Estradiol promotes breast cancer cell growth via GPER (in addition to the ER), while estriol has been shown to inhibit estradiol-induced proliferation of triple-negative breast cancer cells by blocking the GPER. Estriol plays a significant role in both the menstrual cycle and pregnancy, supporting reproductive health and fetal development, making it an essential hormone in women's health.

Biosynthesis

In non-pregnant women, estriol is produced in minimal amounts, making circulating levels almost undetectable. Unlike estradiol and estrone, estriol is not synthesized or secreted by the ovaries but is primarily derived from the 16α-hydroxylation of estradiol and estrone by cytochrome P450 enzymes (e.g., CYP3A4), mainly in the liver. In non-pregnant women, estriol is rapidly cleared from the circulation, resulting in very low circulating levels, although its concentration in urine is relatively high.

Even though estriol levels in the bloodstream are very low outside of pregnancy, parous women have been found to have somewhat higher levels of estriol compared to nulliparous women.

In pregnant women, Estriol is produced in quantities that are notable only during pregnancy. Levels of estriol increase 1,000-fold during pregnancy, whereas levels of estradiol and estrone increase 100-fold, and estriol accounts for 90% of the estrogens in the urine of pregnant women. At term, the daily production of estriol by the placenta is 35 to 45 mg, and levels in the maternal circulation are 8 to 13 ng/dL.

The placenta produces pregnenolone and progesterone from circulating cholesterol. Pregnenolone is taken up by the fetal adrenal glands and converted into dehydroepiandrosterone (DHEA), which is then sulfated by steroid sulfotransferase into dehydroepiandrosterone sulfate (DHEA-S). DHEA-S is hydroxylated by high CYP3A7 expression and activity into 16α-hydroxy-DHEA-S (16α-OH-DHEA-S) in the fetal liver and to a limited extent in the fetal adrenal glands. 16α-OH-DHEA-S is then taken up by the placenta.

Due to high expression of steroid sulfatase in the placenta, 16α-OH-DHEA-S is rapidly cleaved into 16α-OH-DHEA. Then, 16α-OH-DHEA is converted by 3β-hydroxysteroid dehydrogenase type I (3β-HSD1) into 16α-hydroxyandrostenedione (16α-OH-A4) and 16α-OH-A4 is converted by aromatase into 16α-hydroxyestrone (16α-OH-E1), which is subsequently converted into estriol by 17β-hydroxysteroid dehydrogenase and then secreted predominantly into the maternal circulation. Approximately 90% of precursors in estriol formation originate from the fetus.

During pregnancy, 90 to 95% of estriol in the maternal circulation is conjugated in the form of estriol glucuronide and estriol sulfate, and levels of unconjugated estriol are slightly less than those of unconjugated estradiol and similar to those of unconjugated estrone. As such, target tissues are likely to be exposed to similar amounts of free estriol, estradiol, and estrone during pregnancy.

Estrone and estradiol are also produced in the placenta during pregnancy. However, in the case of estrone and estradiol, DHEA-S is taken up by the placenta and cleaved by steroid sulfatase into dehydroepiandrosterone (DHEA), DHEA is converted by 3β-hydroxysteroid dehydrogenase type I into androstenedione, and androstenedione is aromatized into estrone. Then, placental 17β-hydroxysteroid dehydrogenase interconverts estrone and estradiol and the two hormones are secreted into the maternal circulation. DHEA-S that is taken up by the placenta is mainly produced by the fetal adrenal glands.

Distribution

Estriol has a low binding affinity to sex hormone-binding globulin (SHBG) compared to estradiol, resulting in a larger portion being available for biological activity.

Metabolism

Estriol undergoes metabolism through glucuronidation and sulfation.

Excretion

The primary urinary metabolites of exogenous estriol administered through intravenous injection in baboons have been identified as estriol 16α-glucuronide (65.8%), estriol 3-glucuronide (14.2%), estriol 3-sulfate (13.4%), and estriol 3-sulfate 16α-glucuronide (5.1%). The metabolism and excretion of estriol in these animals closely resemble what is observed in humans. In non-pregnant women, urinary excretion of estriol ranges from 0.02–0.1 mg every 24 hours. In contrast, in near-term pregnant women, urinary excretion of estriol ranges from 50–150 mg every 24 hours.

Chemistry

Estriol, also referred to as 16α-hydroxyestradiol or estra-1,3,5(10)-triene-3,16α,17β-triol, is a naturally occurring estrane steroid characterized by double bonds between the C1 and C2, C3 and C4, and C5 and C10 positions, along with hydroxyl groups at the C3, C16α, and C17β positions. The term estriol and its abbreviation E3 originate from the chemical terms estrin (estra-1,3,5(10)-triene) and triol (indicating three hydroxyl groups).

Availability of Estriol Medication

Estriol medication can be found in various forms and formulations. Here are some common options:

• Oral Tablets: Estriol is available in tablet form for oral administration.

• Topical Creams: Estriol is often formulated as a cream for topical application.

• Vaginal Suppositories: Estriol can be found in suppository form for vaginal use.

• Injectable Forms: In some cases, estriol may be available as an injectable medication.

Considerations

• Consult with a healthcare professional before starting estriol.

• Discuss potential side effects and contraindications.

• Regular monitoring may be necessary during treatment.