Estetrol (E4), or oestetrol, is one of the four natural estrogenic

steroid hormone A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). Withi ...

s found in humans, along with

estrone Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized ...

(E1),

estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...

(E2), and

estriol Estriol (E3), also spelled oestriol, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estrone. Levels of estriol in women who are not pregnant are almost ...

(E3), estetrol is a major estrogen in the body. In contrast to estrone and estradiol, estetrol is a native estrogen of

fetal A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal develo ...

life. Estetrol is produced exclusively by the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

and is found in detectable levels only during pregnancy, with relatively high levels in the fetus and lower levels in the maternal circulation. In addition to its physiological role as a native hormone, estetrol can be used as a

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...

, see estetrol (medication). Estetrol, in combination with

drospirenone Drospirenone is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy and in menopausal hormone therapy, among other uses. It is available both alone under the brand name Slynd and in combination wi ...

, has recently been approved as a new estrogenic component of a combined oral contraceptive (COC) and estetrol alone is in clinical development for the treatment of menopausal symptoms as well as breast and prostate cancer.

Biological function

So far, the physiological function of estetrol remains unknown. The potential role of estetrol as a marker for fetal well-being has been studied quite extensively, but no correlation was found due to the large intra- and inter-individual variation in maternal estetrol plasma levels during pregnancy.

Biological activity

Estetrol has a moderate affinity for estrogen receptors alpha (

ERα Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein) that is activated by the sex h ...

) and beta (

ERβ Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by ...

), with K_i values of 4.9 nM and 19 nM, respectively. As such, estetrol has 4- to 5-fold preference for ERα over ERβ. In different animal models, the potency of estetrol regarding its estrogenic effect observed ''in vivo'' is generally 10 to 20 times lower than the potency of ethinyl estradiol (EE) and is also lower than the potency of estradiol. Estetrol displays a highly selective binding to its primary targets

and

, which ensures that estetrol has a low risk of non-specific side effects.

Mode of action

Tissue-selective effect

Estetrol shows selective estrogenic, neutral or anti-estrogenic activities in certain cell types and tissues. In rodent models, estetrol has shown to elicit potent estrogenic activity on ovulation, brain, bone tissue, cardiovascular system, and uterus, associated with ovulation inhibition, prevention of bone demineralization, cardioprotective effects and maintenance of uterovaginal tissues, respectively. Data from preclinical studies also suggest that estetrol has ''anti-estrogenic like effects'' on the breast and a limited impact on normal or malignant breast tissue when used at therapeutic concentration. This property of estetrol is associated with antagonistic effects on breast cell proliferation, migration and invasion in the presence of estradiol. The molecular mechanisms of action driving its tissue-selective actions rely on a specific profile of ERα activation, uncoupling nuclear and membrane activation. In the liver, Estetrol has a neutral activity, which is reflected by a minimal impact on synthesis of hepatic coagulation factors, minimal impact on

sex hormone-binding globulin Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it has also been called androgen ...

(SHBG) synthesis and limited impact on lipid parameters, including triglycerides. Estetrol can therefore be described as the first Native Estrogen with Selective Tissue activity (NEST).

Differences vs SERMs

The selective tissue activity of estetrol is different from the effects of selective estrogen receptor modulators (SERMs), like tamoxifen and raloxifene. Estetrol, like SERMs, has selective tissue activity. However, SERMs interact with the ligand binding domain of ERα in a manner that is distinct from that of estrogens, including estetrol. Estetrol recruits the same co-regulators as other estrogens, while SERMs recruit other co-regulators.

ERα activation

Estrogens can elicit their effects via nuclear ERα and/or membrane ERα signaling pathways. Estetrol presents a distinctive mode of action in terms of ERα activation. Like other estrogens, estetrol binds to, and activates the nuclear ERα to induce gene transcription. However, estetrol induces very limited activity via membrane ERα in several tissues (e.g. in the breast) and antagonizes this pathway in the presence of estradiol, thereby uniquely uncoupling nuclear and membrane activation.

Biochemistry

Biosynthesis

In the

, estetrol is synthesized from

(E2) and

(E3) by two fetal liver

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

s, 15α- and 16α-hydroxylase, through hydroxylation. Estetrol can be detected in maternal urine from the 9th week of gestation. After birth, the neonatal liver rapidly loses its capacity to synthesize estetrol. During the second trimester of pregnancy, high levels of estetrol can be found in maternal plasma, with steadily rising concentrations of unconjugated estetrol to about 1 ng/mL (>3 nM) towards the end of pregnancy. Fetal plasma levels have been reported to be over 10 times higher than maternal plasma levels at parturition.

Distribution

In terms of

plasma protein binding Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse t ...

, estetrol displays moderate binding to

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...

, and shows no binding to SHBG. The overall low plasma protein binding results in a ~50% free active fraction. This compares to a 1% active form for EE and ~2% for estradiol. Estetrol is equally distributed between red blood cells and plasma.

Metabolism

Cytochrome P450 (CYP) enzymes do not play a major role in the metabolism of estetrol. Instead, estetrol undergoes extensive phase 2 metabolism in the liver to form glucuronide and sulphate conjugates. The two main metabolites, estetrol-3-glucuronide and estetrol-16-glucuronide, have negligible estrogenic activity. ''(see

Drospirenone/estetrol Drospirenone/estetrol, sold under the brand name Nextstellis among others, is a fixed-dose combination medication containing drospirenone, a progestin, and estetrol, an estrogen, which is used as a combined birth control pill for the prevention o ...

)''

Excretion

Estetrol is mainly excreted in

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellular ...

. Estetrol is an end-stage product of metabolism, which is not converted back into active metabolites like estriol, estradiol or estrone.

Chemistry

Estetrol, also known as 15α-hydroxyestriol or as estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol, is an estrane steroid and

derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...

of estrin (estratriene). It is structurally different from the other estrogens because of the presence of four hydroxyl groups, which explains the abbreviation E4.

Synthesis

Estetrol itself is a naturally-produced estrogen by the human fetal liver. However, for human use, estetrol is synthesized from estrone, which is obtained from phytosterols extracted from soybeans. The synthesis of estetrol results in very pure estetrol (>99.9%) without contaminants.

History

Estetrol was first described in 1965 by Egon Diczfalusy and coworkers at the Karolinska Institute in Stockholm, Sweden, who identified and isolated this novel, native estrogen from late pregnancy urine and from the urine of newborn infants.

References

{{Estrogen receptor modulators Animal reproductive system Estranes Estrogens Hormones of the hypothalamus-pituitary-gonad axis Hormones of the pregnant female Human female endocrine system Phenols Polyols Sex hormones Orphan drugs