Chemistry:Estetrol

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Estetrol
Skeletal formula of estetrol
Ball-and-stick model of the estetrol molecule
Names
IUPAC name
Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol
Systematic IUPAC name
(1R,2R,3R,3aS,3bR,9bS,11aS)-11a-Methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[a]phenanthrene-1,2,3,7-tetrol
Other names
Oestetrol; E4; 15α-Hydroxyestriol
Identifiers
3D model (JSmol)
ChEBI
KEGG
UNII
Properties
C18H24O4
Molar mass 304.386 g/mol
1.38 mg/mL
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references
Tracking categories (test):

Estetrol (E4), or oestetrol, is one of the four natural estrogenic steroid hormones found in humans, along with estrone (E1), estradiol (E2), and estriol (E3). Estetrol is a major estrogen in the body.[1][2] In contrast to estrone and estradiol, estetrol is a native estrogen of fetal life. Estetrol is produced exclusively by the fetal liver[1] and is found in detectable levels only during pregnancy, with relatively high levels in the fetus and lower levels in the maternal circulation.[1][2]

In addition to its physiological role as a native hormone, estetrol can be used as a medication, see estetrol (medication). Estetrol, in combination with drospirenone, 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[3] due to the large intra- and inter-individual variation in maternal estetrol plasma levels during pregnancy.[4][5][6][7]

Biological activity

Estetrol has a moderate affinity for estrogen receptors alpha (ERα) and beta (ERβ), with Ki values of 4.9 nM and 19 nM, respectively.[8][9] As such, estetrol has 4- to 5-fold preference for ERα over ERβ.[8][9] 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.[1][8] Estetrol displays a highly selective binding to its primary targets ERα and ERβ,[8][9] 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.[9][10][11] In rodent models, estetrol has shown to elicit potent estrogenic activity on ovulation,[12] brain,[13] bone tissue,[14] cardiovascular system,[15] and uterus, associated with ovulation inhibition, prevention of bone demineralization, cardioprotective effects and maintenance of uterovaginal tissues, respectively.[15][16]

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.[11][17] This property of estetrol is associated with antagonistic effects on breast cell proliferation, migration and invasion in the presence of estradiol.[11][18]

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.[19]

Estetrol can therefore be described as the first Native Estrogen with Selective Tissue activity (NEST).[20][21]

Differences vs SERMs

The selective tissue activity of estetrol is different from the effects of selective estrogen receptor modulators (SERMs), like tamoxifen and raloxifene.[22] 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.[22] Estetrol recruits the same co-regulators as other estrogens, while SERMs recruit other co-regulators.[21]

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.[15]

Biochemistry

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.[23][24][25][26] Estetrol can be detected in maternal urine from the 9th week of gestation.[2][27][28] 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.[1]

Distribution

In terms of plasma protein binding, estetrol displays moderate binding to albumin, and shows no binding to SHBG.[29][30] The overall low plasma protein binding results in a ~50% free active fraction.[29] This compares to a 1% active form for EE and ~2% for estradiol.[31] Estetrol is equally distributed between red blood cells and plasma.[3]

Metabolism

Cytochrome P450 (CYP) enzymes do not play a major role in the metabolism of estetrol.[8] Instead, estetrol undergoes extensive phase 2 metabolism in the liver to form glucuronide and sulphate conjugates.[8][10][32][33] The two main metabolites, estetrol-3-glucuronide and estetrol-16-glucuronide, have negligible estrogenic activity.[32][33] (see Drospirenone/estetrol)

Excretion

Estetrol is mainly excreted in urine.[8][10] Estetrol is an end-stage product of metabolism, which is not converted back into active metabolites like estriol, estradiol or estrone.[9][29]

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 of estrin (estratriene).[8][34] It is structurally different from the other estrogens because of the presence of four hydroxyl groups, which explains the abbreviation E4.[8][34]

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%)[35] without contaminants.

History

Estetrol was first described in 1965 by Egon Diczfalusy and coworkers at the Karolinska Institute in Stockholm, Sweden,[36][23][24][37] who identified and isolated this novel, native estrogen from late pregnancy urine and from the urine of newborn infants. Basic research on estetrol was conducted from 1965 to 1984.[1][2] It was established that estetrol is exclusively synthesized in the human fetal liver. Since 1984, further research was virtually abandoned because estetrol was regarded as a weak and unimportant pregnancy estrogen.[1][2] In 2001 Herjan Coelingh Bennink at Pantarhei Bioscience in the Netherlands re-started the investigation of estetrol as a potentially useful natural estrogen for human use,[1] resulting in the introduction of E4 as the estrogenic component of a combined oral contraceptive in 2021.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 "Estetrol: a unique steroid in human pregnancy". The Journal of Steroid Biochemistry and Molecular Biology 110 (1–2): 138–143. May 2008. doi:10.1016/j.jsbmb.2008.03.027. PMID 18462934. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management (3rd ed.). Copyright Elsevier/Saunders. 1991. pp. 936–981. 
  3. ↑ 3.0 3.1 "Estetrol: A New Choice for Contraception". Journal of Clinical Medicine 10 (23): 5625. November 2021. doi:10.3390/jcm10235625. PMID 34884326. 
  4. ↑ "Urinary excretion of estriol and 15 alpha-hydroxyestriol in complicated pregnancies". American Journal of Obstetrics and Gynecology 110 (4): 509–21. June 1971. doi:10.1016/0002-9378(71)90692-2. PMID 5582006. 
  5. ↑ "Plasma estetrol as an index of fetal well-being". The Journal of Clinical Endocrinology and Metabolism 40 (4): 560–7. April 1975. doi:10.1210/jcem-40-4-560. PMID 805156. 
  6. ↑ "Radioimmunoassay of 15alpha-hydroxyestriol (estetrol) in pregnancy serum". Steroids 27 (6): 785–96. June 1976. doi:10.1016/0039-128x(76)90138-0. PMID 941193. 
  7. ↑ "Comparison of serum unconjugated estriol and estetrol in normal and complicated pregnancies". Obstetrics and Gynecology 58 (3): 276–81. September 1981. PMID 7266946. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 "Estetrol review: profile and potential clinical applications". Climacteric 11 (Suppl 1): 47–58. 2008. doi:10.1080/13697130802073425. PMID 18464023. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 "In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism". Climacteric 11 (Suppl 1): 64–68. 2008. doi:10.1080/13697130802050340. PMID 18464025. 
  10. ↑ 10.0 10.1 10.2 "Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives". The European Journal of Contraception & Reproductive Health Care 20 (6): 463–475. 2015. doi:10.3109/13625187.2015.1068934. PMID 26212489. 
  11. ↑ 11.0 11.1 11.2 "Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation". The Journal of Endocrinology 224 (1): 85–95. January 2015. doi:10.1530/JOE-14-0549. PMID 25359896. 
  12. ↑ "Ovulation inhibition by estetrol in an in vivo model" (in English). Contraception 77 (3): 186–190. March 2008. doi:10.1016/j.contraception.2007.11.014. PMID 18279689. 
  13. ↑ "Effect of estetrol administration on brain and serum allopregnanolone in intact and ovariectomized rats". The Journal of Steroid Biochemistry and Molecular Biology 143: 285–290. September 2014. doi:10.1016/j.jsbmb.2014.04.011. PMID 24787659. 
  14. ↑ "Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model". Climacteric 11 (sup1): 2–14. 2008-01-01. doi:10.1080/13697130701798692. PMID 18464016. 
  15. ↑ 15.0 15.1 15.2 "The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation". EMBO Molecular Medicine 6 (10): 1328–1346. October 2014. doi:10.15252/emmm.201404112. PMID 25214462. 
  16. ↑ "Estetrol, a Fetal Selective Estrogen Receptor Modulator, Acts on the Vagina of Mice through Nuclear Estrogen Receptor α Activation" (in English). The American Journal of Pathology 187 (11): 2499–2507. November 2017. doi:10.1016/j.ajpath.2017.07.013. PMID 28827141. 
  17. ↑ "Estetrol Combined to Progestogen for Menopause or Contraception Indication Is Neutral on Breast Cancer". Cancers 13 (10): 2486. May 2021. doi:10.3390/cancers13102486. PMID 34065180. 
  18. ↑ "Effects of Estetrol on Migration and Invasion in T47-D Breast Cancer Cells through the Actin Cytoskeleton". Frontiers in Endocrinology 5: 80. 2014-05-26. doi:10.3389/fendo.2014.00080. PMID 24904530. 
  19. ↑ "Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone". Contraception 103 (4): 213–221. April 2021. doi:10.1016/j.contraception.2021.01.001. PMID 33428907. 
  20. ↑ "Estetrol, a natural estrogen with selective tissue activity (NEST). Poster Abstract". International Journal of Gynecology & Obstetrics 155: 127–532. 2021. 
  21. ↑ 21.0 21.1 "Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause". Expert Review of Clinical Pharmacology 15 (2): 121–137. February 2022. doi:10.1080/17512433.2022.2054413. PMID 35306927. 
  22. ↑ 22.0 22.1 "Role of androgens, progestins and tibolone in the treatment of menopausal symptoms: a review of the clinical evidence" (in English). Clinical Interventions in Aging 3 (1): 1–8. 2008-03-07. doi:10.2147/CIA.S1043. PMID 18488873. 
  23. ↑ 23.0 23.1 "15a-hydroxylation: A new pathway of estrogen metabolism in the human fetus and newborn". Biochimica et Biophysica Acta 100: 313–6. April 1965. doi:10.1016/0304-4165(65)90464-2. PMID 14323645. 
  24. ↑ 24.0 24.1 "Metabolism of oestrone sulphate by the previable human foetus". Acta Endocrinologica 50 (4): 597–610. December 1965. doi:10.1530/acta.0.0500597. PMID 5897909. 
  25. ↑ "Studies on the metabolism of C-19 steroids in the human foeto-placental unit. 4. Aromatisation and hydroxylation products formed by previable foetuses perfused withandrostenedione and testosterone". Acta Endocrinologica 57 (2): 208–27. February 1968. doi:10.1530/acta.0.0570208. PMID 4229819. 
  26. ↑ Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management. Elsevier Health Sciences. 2009. pp. 262. ISBN 978-1-4160-4907-4. https://books.google.com/books?id=NudwnhxY8kYC&pg=PA262. 
  27. ↑ "A method for the determination of urinary 15α-hydroxyestriol and estriol: Preliminary results of 15α-hydroxyestriol determinations in pregnancy urine.". Journal of Steroid Biochemistry 1 (3): 243–253. September 1970. doi:10.1016/0022-4731(70)90020-8. 
  28. ↑ "Excretion of 15α-hydroxyestriol and estriol in maternal urine during normal pregnancy.". Journal of Steroid Biochemistry 2 (83–93): 83–93. February 1971. doi:10.1016/0022-4731(71)90012-4. 
  29. ↑ 29.0 29.1 29.2 "First human exposure to exogenous single-dose oral estetrol in early postmenopausal women". Climacteric 11 (Suppl 1): 31–40. 2008. doi:10.1080/13697130802056511. PMID 18464021. 
  30. ↑ "Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells". Climacteric 11 (Suppl 1): 41–46. 2008. doi:10.1080/13697130701851814. PMID 18464022. 
  31. ↑ "Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment" (in English). Contraception 87 (6): 706–727. June 2013. doi:10.1016/j.contraception.2012.12.011. PMID 23375353. 
  32. ↑ 32.0 32.1 "Nexstellis Label". https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214154s000lbl.pdf. 
  33. ↑ 33.0 33.1 "Drovelis Label". https://www.ema.europa.eu/en/documents/product-information/drovelis-epar-product-information_en.pdf. 
  34. ↑ 34.0 34.1 "Clinical applications for estetrol". The Journal of Steroid Biochemistry and Molecular Biology 114 (1–2): 85–89. March 2009. doi:10.1016/j.jsbmb.2008.12.013. PMID 19167495. http://www.kup.at/kup/pdf/9090.pdf. 
  35. ↑ "A new route of synthesis of estetrol". Climacteric 11 (Suppl 1): 59–63. 2008. doi:10.1080/13697130802054078. PMID 18464024. 
  36. ↑ "METABOLISM OF 17β-OESTRADIOL-4-14C IN EARLY INFANCY". Acta Endocrinologica 49 (2): 207–220. June 1965. doi:10.1530/acta.0.0490207. PMID 14303250. 
  37. ↑ "Isolation of 15-alpha-hydroxy-oestriol from pregnancy urine and from the urine of newborn infants". Acta Endocrinologica 56 (3): 413–423. November 1967. doi:10.1530/acta.0.0560413. PMID 6072461. 



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