E4 Estrogen (Estetrol)

Estetrol is a naturally occurring estrogen that is produced by the human fetal liver during pregnancy. It is a member of the estrane family of hormones and is recognized for its unique properties compared to other estrogens.

Biological Function

Estetrol plays a crucial role in maintaining pregnancy and supporting fetal development. It is involved in various physiological processes, including the regulation of uterine growth and the preparation of the maternal body for childbirth.

Biological Activity

Estetrol exhibits estrogenic activity, influencing various target tissues such as the uterus, breast, and bone. It binds to estrogen receptors, primarily ERα, to exert its effects on gene expression and cellular function.

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 (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.

Biosynthesis

In the fetal liver, estetrol is synthesized from estradiol (E2) and estriol (E3) by two fetal liver enzymes, 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, estetrol displays moderate binding to albumin, 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.

Excretion

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

Estetrol Medication is Available in

• Estetrol (as monohydrate) 15 mg and drospirenone 3 mg Nextstellis (CA, US and Australia) – combined oral contraception.

  
  

• Estetrol (as monohydrate) 15 mg and drospirenone 3 mg Drovelis (EU) – combined oral contraception.

  
  

• Estetrol (as monohydrate) 15 mg and drospirenone 3 mg Lydisilka (EU) – combined oral contraception.

Considerations

• Consult with a healthcare professional before starting estetrol.

• Discuss potential side effects and contraindications.

• Regular monitoring may be necessary during treatment.