Estetrol Explained

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 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, 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. 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 ERα and ERβ, 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.[10] In rodent models, estetrol has shown to elicit potent estrogenic activity on ovulation,[11] brain,[12] bone tissue,[13] cardiovascular system,[14] and uterus, associated with ovulation inhibition, prevention of bone demineralization, cardioprotective effects and maintenance of uterovaginal tissues, respectively.[15]

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

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.[18]

Estetrol can therefore be described as the first Native Estrogen with Selective Tissue activity (NEST).[19] [20]

Differences vs SERMs

The selective tissue activity of estetrol is different from the effects of selective estrogen receptor modulators (SERMs), like tamoxifen and raloxifene.[21] 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 fetal liver, estetrol is synthesized from estradiol (E2) and estriol (E3) by two fetal liver enzymes, 15α- and 16α-hydroxylase, through hydroxylation.[22] [23] [24] [25] Estetrol can be detected in maternal urine from the 9th week of gestation.[26] [27] 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.[28] [29] 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.[30] 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.[31] [32] [33] The two main metabolites, estetrol-3-glucuronide and estetrol-16-glucuronide, have negligible estrogenic activity. (see Drospirenone/estetrol)

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.

Chemistry

See also: List of estrogens.

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).[34] 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%)[35] without contaminants.

History

Estetrol was first described in 1965 by Egon Diczfalusy and coworkers at the Karolinska Institute in Stockholm, Sweden,[36] [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.

Notes and References

  1. Holinka CF, Diczfalusy E, Coelingh Bennink HJ . Estetrol: a unique steroid in human pregnancy . The Journal of Steroid Biochemistry and Molecular Biology . 110 . 1–2 . 138–143 . May 2008 . 18462934 . 10.1016/j.jsbmb.2008.03.027 . 28007341 .
  2. Book: Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management . 3rd . Yen SS, Jaffe RB . 936–981 . Copyright Elsevier/Saunders . 1991 .
  3. Fruzzetti F, Fidecicchi T, Montt Guevara MM, Simoncini T . Estetrol: A New Choice for Contraception . Journal of Clinical Medicine . 10 . 23 . 5625 . November 2021 . 34884326 . 8658652 . 10.3390/jcm10235625 . free .
  4. Heikkilä J, Luukkainen T . Urinary excretion of estriol and 15 alpha-hydroxyestriol in complicated pregnancies . American Journal of Obstetrics and Gynecology . 110 . 4 . 509–21 . June 1971 . 5582006 . 10.1016/0002-9378(71)90692-2 .
  5. Tulchinsky D, Frigoletto FD, Ryan KJ, Fishman J . Plasma estetrol as an index of fetal well-being . The Journal of Clinical Endocrinology and Metabolism . 40 . 4 . 560–7 . April 1975 . 805156 . 10.1210/jcem-40-4-560 .
  6. Kundu N, Grant M . Radioimmunoassay of 15alpha-hydroxyestriol (estetrol) in pregnancy serum . Steroids . 27 . 6 . 785–96 . June 1976 . 941193 . 10.1016/0039-128x(76)90138-0 . 54373667 .
  7. Kundu N, Wachs M, Iverson GB, Petersen LP . Comparison of serum unconjugated estriol and estetrol in normal and complicated pregnancies . Obstetrics and Gynecology . 58 . 3 . 276–81 . September 1981 . 7266946 .
  8. Coelingh Bennink HJ, Holinka CF, Diczfalusy E . 2008 . Estetrol review: profile and potential clinical applications . Climacteric . 11 . Suppl 1 . 47–58 . 10.1080/13697130802073425 . 18464023 . 24003341.
  9. Visser M, Foidart JM, Coelingh Bennink HJ . In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism . Climacteric . 11 . Suppl 1 . 64–68 . 2008 . 18464025 . 10.1080/13697130802050340 . 11027782 .
  10. Gérard C, Blacher S, Communal L, Courtin A, Tskitishvili E, Mestdagt M, Munaut C, Noel A, Gompel A, Péqueux C, Foidart JM . 6 . Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation . The Journal of Endocrinology . 224 . 1 . 85–95 . January 2015 . 25359896 . 10.1530/JOE-14-0549 . free .
  11. Coelingh Bennink HJ, Skouby S, Bouchard P, Holinka CF . Ovulation inhibition by estetrol in an in vivo model . English . Contraception . 77 . 3 . 186–190 . March 2008 . 18279689 . 10.1016/j.contraception.2007.11.014 .
  12. Pluchino N, Santoro AN, Casarosa E, Giannini A, Genazzani A, Russo M, Russo N, Petignat P, Genazzani AR . 6 . 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 . 24787659 . 10.1016/j.jsbmb.2014.04.011 . 21359519 .
  13. Coelingh Bennink HJ, Heegaard AM, Visser M, Holinka CF, Christiansen C . Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model . Climacteric . 11 . sup1 . 2–14 . 2008-01-01 . 18464016 . 10.1080/13697130701798692 . 42275885 .
  14. Abot A, Fontaine C, Buscato M, Solinhac R, Flouriot G, Fabre A, Drougard A, Rajan S, Laine M, Milon A, Muller I, Henrion D, Adlanmerini M, Valéra MC, Gompel A, Gerard C, Péqueux C, Mestdagt M, Raymond-Letron I, Knauf C, Ferriere F, Valet P, Gourdy P, Katzenellenbogen BS, Katzenellenbogen JA, Lenfant F, Greene GL, Foidart JM, Arnal JF . 6 . 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 . 25214462 . 4287935 . 10.15252/emmm.201404112 .
  15. Benoit T, Valera MC, Fontaine C, Buscato M, Lenfant F, Raymond-Letron I, Tremollieres F, Soulie M, Foidart JM, Game X, Arnal JF . 6 . Estetrol, a Fetal Selective Estrogen Receptor Modulator, Acts on the Vagina of Mice through Nuclear Estrogen Receptor α Activation . English . The American Journal of Pathology . 187 . 11 . 2499–2507 . November 2017 . 28827141 . 10.1016/j.ajpath.2017.07.013 . free .
  16. Gallez A, Blacher S, Maquoi E, Konradowski E, Joiret M, Primac I, Gérard C, Taziaux M, Houtman R, Geris L, Lenfant F, Marangoni E, Sounni NE, Foidart JM, Noël A, Péqueux C . 6 . Estetrol Combined to Progestogen for Menopause or Contraception Indication Is Neutral on Breast Cancer . Cancers . 13 . 10 . 2486 . May 2021 . 34065180 . 8160902 . 10.3390/cancers13102486 . free .
  17. Giretti MS, Montt Guevara MM, Cecchi E, Mannella P, Palla G, Spina S, Bernacchi G, Di Bello S, Genazzani AR, Genazzani AD, Simoncini T . 6 . 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 . 24904530 . 4033260 . 10.3389/fendo.2014.00080 . free .
  18. Klipping C, Duijkers I, Mawet M, Maillard C, Bastidas A, Jost M, Foidart JM . Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone . Contraception . 103 . 4 . 213–221 . April 2021 . 33428907 . 10.1016/j.contraception.2021.01.001 . 231585130 . free .
  19. Gérard C, Jost M, Oligschläger Y, Foidart JM . 2021 . Estetrol, a natural estrogen with selective tissue activity (NEST). Poster Abstract . International Journal of Gynecology & Obstetrics . 155 . 127–532.
  20. Gérard C, Arnal JF, Jost M, Douxfils J, Lenfant F, Fontaine C, Houtman R, Archer DF, Reid RL, Lobo RA, Gaspard U, Coelingh Bennink HJ, Creinin MD, Foidart JM . 6 . 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 . 35306927 . 10.1080/17512433.2022.2054413 . 247583084 . free .
  21. Garefalakis M, Hickey M . Role of androgens, progestins and tibolone in the treatment of menopausal symptoms: a review of the clinical evidence . English . Clinical Interventions in Aging . 3 . 1 . 1–8 . 2008-03-07 . 18488873 . 2544356 . 10.2147/CIA.S1043 . free .
  22. Schwers J, Eriksson G, Diczfalusy E . 15a-hydroxylation: A new pathway of estrogen metabolism in the human fetus and newborn . Biochimica et Biophysica Acta . 100 . 313–6 . April 1965 . 14323645 . 10.1016/0304-4165(65)90464-2 .
  23. Schwers J, Govaerts-Videtsky M, Wiqvist N, Diczfalusy E . Metabolism of oestrone sulphate by the previable human foetus . Acta Endocrinologica . 50 . 4 . 597–610 . December 1965 . 5897909 . 10.1530/acta.0.0500597 .
  24. Mancuso S, Benagiano G, Dell'Acqua S, Shapiro M, Wiqvist N, Diczfalusy E . 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 . 4229819 . 10.1530/acta.0.0570208 .
  25. Book: Strauss JF, Barbieri RL . Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management . 2009. Elsevier Health Sciences. 978-1-4160-4907-4. 262.
  26. Heikkilä J, Adlercreutz H . A method for the determination of urinary 15α-hydroxyestriol and estriol: Preliminary results of 15α-hydroxyestriol determinations in pregnancy urine. . Journal of Steroid Biochemistry . September 1970 . 1 . 3 . 243–253 . 10.1016/0022-4731(70)90020-8 .
  27. Heikkilä J . Excretion of 15α-hydroxyestriol and estriol in maternal urine during normal pregnancy. . Journal of Steroid Biochemistry . February 1971 . 2 . 83–93 . 83–93 . 10.1016/0022-4731(71)90012-4 .
  28. Visser M, Holinka CF, Coelingh Bennink HJ . First human exposure to exogenous single-dose oral estetrol in early postmenopausal women . Climacteric . 11 . 31–40 . 2008 . Suppl 1 . 18464021 . 10.1080/13697130802056511 . 23568599 .
  29. Hammond GL, Hogeveen KN, Visser M, Coelingh Bennink HJ . Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells . Climacteric . 11 . 41–46 . 2008 . Suppl 1 . 18464022 . 10.1080/13697130701851814 . 22715507 .
  30. Stanczyk FZ, Archer DF, Bhavnani BR . Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment . English . Contraception . 87 . 6 . 706–727 . June 2013 . 23375353 . 10.1016/j.contraception.2012.12.011 .
  31. Mawet M, Maillard C, Klipping C, Zimmerman Y, Foidart JM, Coelingh Bennink HJ . 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 . 26212489 . 4699469 . 10.3109/13625187.2015.1068934 . 31 January 2024 .
  32. Web site: Nexstellis Label . 2022-04-12 . FDA.
  33. Web site: Drovelis Label . 2022-04-12 . EMA.
  34. Visser M, Coelingh Bennink HJ . Clinical applications for estetrol . The Journal of Steroid Biochemistry and Molecular Biology . 114 . 1–2 . 85–89 . March 2009 . 19167495 . 10.1016/j.jsbmb.2008.12.013 . 32081001 .
  35. Warmerdam EG, Visser M, Coelingh Bennink HJ, Groen M . A new route of synthesis of estetrol . Climacteric . 11 . 59–63 . 2008 . Suppl 1 . 18464024 . 10.1080/13697130802054078 . 42017011 .
  36. Hagen AA, Barr M, Diczfalusy E . METABOLISM OF 17β-OESTRADIOL-4-14C IN EARLY INFANCY . Acta Endocrinologica . 49 . 2 . 207–220 . June 1965 . 14303250 . 10.1530/acta.0.0490207 .
  37. Zucconi G, Lisboa BP, Simonitsch E, Roth L, Hagen AA, Diczfalusy E . Isolation of 15-alpha-hydroxy-oestriol from pregnancy urine and from the urine of newborn infants . Acta Endocrinologica . 56 . 3 . 413–423 . November 1967 . 6072461 . 10.1530/acta.0.0560413 .

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