page_title: Estetrol (medication)
section_title: Pharmacokinetics
hierarchical_section_title: Estetrol (medication) / Pharmacology / Pharmacokinetics
caption_attribution_description: English: "Mean estetrol plasma levels (+standard deviation) after a single oral dose of 1, 10 and 100 mg estetrol in postmenopausal women." Source of the values: &#32;(2008).&#32;"Estetrol review: profile and potential clinical applications". Climacteric&#32;11 Suppl 1: 47–58. DOI:10.1080/13697130802073425. PMID 18464023.
context_page_description: Estetrol, tentative brand names Donesta and Estelle/PeriNesta, is an estrogen medication and naturally occurring steroid hormone which is under development for use as a birth control pill in combination with a progestin, in menopausal hormone therapy to treat symptoms such as vaginal atrophy, hot flashes, and bone loss, and for the treatment of breast cancer, prostate cancer, osteoarthritis, and migraine. It is taken by mouth.
  Estetrol is a naturally occurring and bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol. Due to its estrogenic activity, estetrol has antigonadotropic effects and can inhibit fertility and suppress sex hormone production and levels in both women and men. Estetrol differs in various ways both from other natural estrogens like estradiol and from synthetic estrogens like ethinylestradiol, with implications for tolerability and safety. For instance, it appears to have minimal estrogenic effects in the breasts and liver. Due to its unique tissue-selective effects, estetrol has been described as a natural selective estrogen receptor modulator.
context_section_description: Estetrol shows high oral bioavailability. Its oral bioavailability in rats was 70% relative to subcutaneous injection. The high oral bioavailability of estetrol is in contrast to estradiol, estrone, and estriol (all very low, in the range of 5% and below), but is more similar to ethinylestradiol (38–48%). Estetrol shows a high and linear dose–response relationship across oral doses of 0.1 to 100 mg in humans, and shows low interindividual variability. Upon oral administration, estetrol is very rapidly absorbed, with maximal levels occurring within 15 to 80 minutes. At a dosage of 20 mg/day estetrol, peak levels of estetrol of 3,490 pg/mL and trough levels of 2,005 pg/mL have been reported. The high water solubility of estetrol makes it optimal for passage of the blood–brain barrier, and the drug may be expected to have effects in the central nervous system. In accordance, estetrol shows clear central effects such as alleviation of hot flashes and antigonadotropic effects in humans. In terms of plasma protein binding, estetrol is bound moderately to albumin, and is not bound to SHBG. This is in contrast to estradiol, which binds to SHBG with high affinity, but is similar to estriol and ethinylestradiol, which have only very low affinity for SHBG. Due to its lack of affinity for SHBG, the plasma distribution or availability for target tissues of estetrol is not limited or otherwise influenced by SHBG.
  Estetrol is metabolized slowly and minimally, and is not transformed into other estrogens such as estradiol, estrone, or estriol. This is related to the fact that estetrol is already an end-stage product of phase I estrogen metabolism in humans. The medication is conjugated via glucuronidation and to a lesser extent via sulfation. The biological half-life of estetrol is about 28 hours, with a range of 18 to 60 hours. The blood half-lives of estradiol and estriol, at about 1 to 2 hours and 20 minutes, respectively, are far shorter than that of estetrol, whereas the biological half-life of ethinylestradiol, at approximately 20 hours, is more similar to that of estetrol. Enterohepatic recirculation may occur with estetrol, similarly to other steroidal estrogens, although it has also been reported that estetrol does not seem to enter the enterohepatic circulation. Estetrol is excreted mostly or completely in urine, virtually entirely in the form of conjugates (unconjugated accounting for 0.2–0.7%). In one study, a median of 79.7% (range 61.1–99.0%) was recovered from urine; this was primarily as estetrol glucuronide (median 60.7%, range 47.6–77.2%), and, to a lesser extent, as estetrol sulfate (median 17.6%, range 13.2–22.1%).
caption: Estetrol levels following a single dose of different doses of oral estetrol (E4) in postmenopausal women.[1]
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