Estetrol
Encyclopedia
Estetrol is an estrogen
steroid
hormone, found in detectable levels in maternal serum
at around week 20.
Estetrol (E4) is a human steroid, produced by the fetal liver during pregnancy only. This natural hormone was discovered in urine of pregnant women by Diczfalusy and coworkers in 1965. Estetrol has the structure of an estrogenic steroid with four hydroxyl groups which explains the acronym E4. Estetrol is synthesized in the fetal liver from estradiol
(E2) and estriol
(E3) by the two enzymes 15α- and 16α-hydroxylase. After birth the neonatal liver rapidly looses its capacity to synthesize E4 because these two enzymes are no longer expressed.
Estetrol reaches the maternal circulation through the placenta and was already detected at nine weeks of pregnancy in maternal urine. During the second trimester of pregnancy high levels were found in maternal plasma, with steadily rising concentrations of unconjugated E4 to about 1 ng/mL (> 3 nmol/L) towards the end of pregnancy. So far the physiological function of E4 is unknown. The possible use of E4 as a marker for fetal well-being has been studied quite extensively. However, due to the large intra- and inter-individual variation of maternal E4 plasma levels during pregnancy this appeared not to be feasible.
Since 2001 E4 has been studied extensively. High oral absorption and bioavailability
with a 2-3 hours elimination half-life in the rat has been established. In the human E4 showed a high and dose-proportional oral bioavailability and a long terminal elimination half-life of about 28 hours.
Results from in vitro studies showed that E4 binds highly selective to the estrogen receptor
s with preference for the ERα form of the receptor unlike ethinyl estradiol (EE) and 17β-estradiol (E2). Also in contrast with EE and especially with E2, E4 does not bind to sex hormone binding globulin (SHBG) and does not stimulate the production of SHBG in vitro.
The properties of E4 have also been investigated in a series of highly predictive, well validated pharmacological in vivo rat models. In these models, E4 exhibited estrogenic effects on the vagina, the uterus (both myometrium and endometrium), body weight, bone mass, bone strength, hot flushes and on ovulation (inhibition). All these effects of E4 were dose-dependent with maximal effects at comparable dose levels. Surprisingly, E4 prevented tumour development in a DMBA mammary tumour model to an extent and at a dose level similar to the anti-estrogen tamoxifen and to ovariectomy. This anti-estrogenic effect of E4 in the presence of E2 has also been observed in in vitro studies using human breast cancer cells [in-house data Pantarhei Bioscience B.V., The Netherlands].
The data indicate that E4 may be suitable for use in several indications e.g. contraception
, hormone replacement therapy
(both vasomotor symptoms and vulvar vaginal atrophy), breast cancer
and osteoporosis
. Estetrol is being developed as estrogenic component in the oral contraceptive pill by Estetra (Belgium). Pantarhei Bioscience B.V. (The Netherlands) is developing estetrol for hormone replacement therapy, breast cancer and osteoporosis.
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
hormone, found in detectable levels in maternal serum
Serum
Serum may refer to:*Blood serum, a component of blood which is collected after coagulation.**Antiserum, blood serum with specific antibodies for passive immunity*Serous fluid, any clear bodily fluid*any drug derived from an animal's blood or serous fluid...
at around week 20.
Estetrol (E4) is a human steroid, produced by the fetal liver during pregnancy only. This natural hormone was discovered in urine of pregnant women by Diczfalusy and coworkers in 1965. Estetrol has the structure of an estrogenic steroid with four hydroxyl groups which explains the acronym E4. Estetrol is synthesized in the fetal liver from estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
(E2) and estriol
Estriol
Estriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human...
(E3) by the two enzymes 15α- and 16α-hydroxylase. After birth the neonatal liver rapidly looses its capacity to synthesize E4 because these two enzymes are no longer expressed.
Estetrol reaches the maternal circulation through the placenta and was already detected at nine weeks of pregnancy in maternal urine. During the second trimester of pregnancy high levels were found in maternal plasma, with steadily rising concentrations of unconjugated E4 to about 1 ng/mL (> 3 nmol/L) towards the end of pregnancy. So far the physiological function of E4 is unknown. The possible use of E4 as a marker for fetal well-being has been studied quite extensively. However, due to the large intra- and inter-individual variation of maternal E4 plasma levels during pregnancy this appeared not to be feasible.
Since 2001 E4 has been studied extensively. High oral absorption and bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
with a 2-3 hours elimination half-life in the rat has been established. In the human E4 showed a high and dose-proportional oral bioavailability and a long terminal elimination half-life of about 28 hours.
Results from in vitro studies showed that E4 binds highly selective to the estrogen receptor
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
s with preference for the ERα form of the receptor unlike ethinyl estradiol (EE) and 17β-estradiol (E2). Also in contrast with EE and especially with E2, E4 does not bind to sex hormone binding globulin (SHBG) and does not stimulate the production of SHBG in vitro.
The properties of E4 have also been investigated in a series of highly predictive, well validated pharmacological in vivo rat models. In these models, E4 exhibited estrogenic effects on the vagina, the uterus (both myometrium and endometrium), body weight, bone mass, bone strength, hot flushes and on ovulation (inhibition). All these effects of E4 were dose-dependent with maximal effects at comparable dose levels. Surprisingly, E4 prevented tumour development in a DMBA mammary tumour model to an extent and at a dose level similar to the anti-estrogen tamoxifen and to ovariectomy. This anti-estrogenic effect of E4 in the presence of E2 has also been observed in in vitro studies using human breast cancer cells [in-house data Pantarhei Bioscience B.V., The Netherlands].
The data indicate that E4 may be suitable for use in several indications e.g. contraception
Contraception
Contraception is the prevention of the fusion of gametes during or after sexual activity. The term contraception is a contraction of contra, which means against, and the word conception, meaning fertilization...
, hormone replacement therapy
Hormone replacement therapy
Hormone replacement therapy may refer to:*Hormone replacement therapy *Hormone replacement therapy *Hormone replacement therapy *Androgen replacement therapy -See also:...
(both vasomotor symptoms and vulvar vaginal atrophy), breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
and osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
. Estetrol is being developed as estrogenic component in the oral contraceptive pill by Estetra (Belgium). Pantarhei Bioscience B.V. (The Netherlands) is developing estetrol for hormone replacement therapy, breast cancer and osteoporosis.