Estetrol (medication)

This article is about estetrol as a medication. For its role as a hormone, see Estetrol.
Estetrol
Skeletal formula of estetrol
Ball-and-stick model of the estetrol molecule
Clinical data
Trade namesWith drospirenone: Estelle, Nextstellis
Other namesOestetrol; E4; 15α-Hydroxyestriol; Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol
Pregnancy
category
Routes of
administration		By mouth[2][3]
Drug classEstrogen
ATC code
  • None
Pharmacokinetic data
BioavailabilityHigh[4]
Protein bindingModerately to albumin, not to SHBGTooltip sex hormone-binding globulin[4][5]
MetabolismMinimal, conjugation (glucuronidation, sulfation)[2][6]
MetabolitesEstetrol glucuronide[6][2]
Estetrol sulfate[6]
Elimination half-lifeMean: 28 hours[4][6]
Range: 18–60 hours[4]
ExcretionUrine: 79.7% (as conjugates)[2][6]
Identifiers
  • (8R,9S,13S,14S,15R,16R,17R)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,15,16,17-tetrol
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
Chemical and physical data
FormulaC18H24O4
Molar mass304.386 g·mol−1
3D model (JSmol)
Solubility in water1.38
  • C[C@]12CC[C@H]3[C@H]([C@@H]1[C@H]([C@H]([C@@H]2O)O)O)CCC4=C3C=CC(=C4)O
  • InChI=1S/C18H24O4/c1-18-7-6-12-11-5-3-10(19)8-9(11)2-4-13(12)14(18)15(20)16(21)17(18)22/h3,5,8,12-17,19-22H,2,4,6-7H2,1H3/t12-,13-,14-,15-,16-,17+,18+/m1/s1 checkY
  • Key:AJIPIJNNOJSSQC-NYLIRDPKSA-N checkY
  (verify)

Estetrol (E4) is an estrogen medication and naturally occurring steroid hormone which is used in combination with a progestin in combined birth control pills and is under development for various other indications. These investigational uses include menopausal hormone therapy to treat symptoms such as vaginal atrophy, hot flashes, and bone loss and the treatment of breast cancer and prostate cancer.[2][3][7][8] It is taken by mouth.[2][3]

Estetrol is a naturally occurring and bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol.[2][3] 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.[2][4][9] Estetrol differs in various ways both from other natural estrogens like estradiol and synthetic estrogens like ethinylestradiol, with implications for tolerability and safety.[2][4] For instance, it appears to have minimal estrogenic effects in the breasts and liver.[2][4][10][6] Estetrol interacts with nuclear ERα in a manner identical to that of the other estrogens [11] and distinct from that observed with Selective Estrogen Receptor Modulators (SERMs).[12]

Estetrol was first discovered in 1965, and basic research continued up until 1984.[2][13] It started to be studied again as well as investigated for potential medical use in 2001, and by 2008, was of major interest for possible medical use.[2][3] As of 2021, estetrol is in mid- to late-stage clinical development for a variety of indications.[7][8]

Estrogen dosages for menopausal hormone therapy
Route/form Estrogen Low Standard High
Oral Estradiol 0.5–1 mg/day 1–2 mg/day 2–4 mg/day
Estradiol valerate 0.5–1 mg/day 1–2 mg/day 2–4 mg/day
Estradiol acetate 0.45–0.9 mg/day 0.9–1.8 mg/day 1.8–3.6 mg/day
Conjugated estrogens 0.3–0.45 mg/day 0.625 mg/day 0.9–1.25 mg/day
Esterified estrogens 0.3–0.45 mg/day 0.625 mg/day 0.9–1.25 mg/day
Estropipate 0.75 mg/day 1.5 mg/day 3 mg/day
Estriol 1–2 mg/day 2–4 mg/day 4–8 mg/day
Ethinylestradiola 2.5–10 μg/day 5–20 μg/day –
Nasal spray Estradiol 150 μg/day 300 μg/day 600 μg/day
Transdermal patch Estradiol 25 μg/dayb 50 μg/dayb 100 μg/dayb
Transdermal gel Estradiol 0.5 mg/day 1–1.5 mg/day 2–3 mg/day
Vaginal Estradiol 25 μg/day – –
Estriol 30 μg/day 0.5 mg 2x/week 0.5 mg/day
IMTooltip Intramuscular or SC injection Estradiol valerate – – 4 mg 1x/4 weeks
Estradiol cypionate 1 mg 1x/3–4 weeks 3 mg 1x/3–4 weeks 5 mg 1x/3–4 weeks
Estradiol benzoate 0.5 mg 1x/week 1 mg 1x/week 1.5 mg 1x/week
SC implant Estradiol 25 mg 1x/6 months 50 mg 1x/6 months 100 mg 1x/6 months
Footnotes: a = No longer used or recommended, due to health concerns. b = As a single patch applied once or twice per week (worn for 3–4 days or 7 days), depending on the formulation. Note: Dosages are not necessarily equivalent. Sources: See template.
  1. ^ "Updates to the Prescribing Medicines in Pregnancy database". Therapeutic Goods Administration (TGA). 21 December 2022. Retrieved 2 January 2023.
  2. ^ a b c d e f g h i j k l Coelingh Bennink HJ, Holinka CF, Diczfalusy E (2008). "Estetrol review: profile and potential clinical applications". Climacteric. 11 (Suppl 1): 47–58. doi:10.1080/13697130802073425. PMID 18464023. S2CID 24003341.
  3. ^ a b c d e Visser M, Coelingh Bennink HJ (March 2009). "Clinical applications for estetrol" (PDF). J. Steroid Biochem. Mol. Biol. 114 (1–2): 85–9. doi:10.1016/j.jsbmb.2008.12.013. PMID 19167495. S2CID 32081001.
  4. ^ a b c d e f g Visser M, Holinka CF, Coelingh Bennink HJ (2008). "First human exposure to exogenous single-dose oral estetrol in early postmenopausal women". Climacteric. 11 (Suppl 1): 31–40. doi:10.1080/13697130802056511. PMID 18464021. S2CID 23568599.
  5. ^ Hammond GL, Hogeveen KN, Visser M, Coelingh Bennink HJ (2008). "Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells". Climacteric. 11 (Suppl 1): 41–6. doi:10.1080/13697130701851814. PMID 18464022. S2CID 22715507.
  6. ^ a b c d e f Mawet M, Maillard C, Klipping C, Zimmerman Y, Foidart JM, Coelingh Bennink HJ (2015). "Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives". Eur J Contracept Reprod Health Care. 20 (6): 463–75. doi:10.3109/13625187.2015.1068934 (inactive 2024-09-19). PMC 4699469. PMID 26212489.{{cite journal}}: CS1 maint: DOI inactive as of September 2024 (link)
  7. ^ a b "Estetrol - Mithra Pharmaceuticals - AdisInsight".
  8. ^ a b "Drospirenone/estetrol - Mithra Pharmaceuticals". AdisInsight. Springer Nature Switzerland AG.
  9. ^ Cite error: The named reference DutmanZimmerman2017 was invoked but never defined (see the help page).
  10. ^ Cite error: The named reference pmid25359896 was invoked but never defined (see the help page).
  11. ^ Abot A, Fontaine C, Buscato M, Solinhac R, Flouriot G, Fabre A, et al. (October 2014). "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. doi:10.15252/emmm.201404112. PMC 4287935. PMID 25214462.
  12. ^ Foidart, JM; et al. (2019). "30th Annual Meeting of The North America Menopause Society September 25 – 28, 2019, Chicago, IL". Menopause. 26 (12): 1445–1481. doi:10.1097/GME.0000000000001456. ISSN 1530-0374
  13. ^ Cite error: The named reference pmid14303250 was invoked but never defined (see the help page).