Estradiol acetate

Estradiol acetate (EA), sold under the brand names Femtrace, Femring, and Menoring, is an estrogen medication which is used in hormone therapy for the treatment of menopausal symptoms in women.[3][4][5][6] It is taken by mouth once daily or given as a vaginal ring once every three months.[2]

Estradiol acetate

Clinical data
Pronunciation	/ˌɛstrəˈdaɪoʊl ˈæsəteɪt/ ES-trə-DY-ohl ASS-ə-tayt[1]
Trade names	Femtrace, Femring, Menoring
Other names	EA; E2A; E3A; Estradiol 3-acetate
Routes of administration	By mouth, vaginal (ring)[2]
Drug class	Estrogen; Estrogen ester
ATC code	G03CA03 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Identifiers
IUPAC name [(8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] acetate
CAS Number	4245-41-4
PubChem CID	9818306
DrugBank	DB13952
ChemSpider	7994056
UNII	5R97F5H93P
KEGG	D04061
ChEMBL	ChEMBL1200430
CompTox Dashboard (EPA)	DTXSID20938492
ECHA InfoCard	100.110.039
Chemical and physical data
Formula	C20H26O3
Molar mass	314.425 g·mol^−1
3D model (JSmol)	Interactive image
SMILES CC(=O)OC1=CC2=C(C=C1)[C@H]3CC[C@]4([C@H]([C@@H]3CC2)CC[C@@H]4O)C
InChI InChI=1S/C20H26O3/c1-12(21)23-14-4-6-15-13(11-14)3-5-17-16(15)9-10-20(2)18(17)7-8-19(20)22/h4,6,11,16-19,22H,3,5,7-10H2,1-2H3/t16-,17-,18+,19+,20+/m1/s1 Key:FHXBMXJMKMWVRG-SLHNCBLASA-N

Side effects of estradiol acetate include breast tenderness, breast enlargement, nausea, headache, and fluid retention.[7][5][6] Estradiol acetate is a synthetic estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol.[8][9] It is an estrogen ester and a prodrug of estradiol in the body.[9][8] Because of this, it is considered to be a natural and bioidentical form of estrogen.[9][10]

Estradiol acetate was introduced for medical use in 2001.[11] It is available in the United States and the United Kingdom.[11][3] The formulation for use by mouth has been discontinued in the United States.[12]

Medical uses

See also: Estradiol (medication) § Medical uses

Estradiol acetate is used as a component of menopausal hormone therapy to treat and prevent menopausal symptoms such as hot flashes and osteoporosis in women.[13][14][15][16]

The Women's Health Initiative studies report increased health risks for menopausal women when using unopposed estrogens.[6] Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.[6]

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
	Ethinylestradiol^a	2.5 μg/day	5–15 μg/day	–
Nasal spray	Estradiol	150 μg/day	300 μg/day	600 μg/day
Transdermal patch	Estradiol	25 μg/day^b	50 μg/day^b	100 μg/day^b
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
IM 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.

Available forms

Estradiol acetate comes in the form of 0.45, 0.9, and 1.8 mg oral tablets (Femtrace) and in the form of 12.4 or 24.8 mg vaginal rings that release 50 or 100 μg/day estradiol for 3 months (Femring, Menoring).[5][6][17] However, the Femtrace product was discontinued in the United States.[12]

Available forms of estradiol

Route	Ingredient	Form	Dose	Major brand names
Oral	Estradiol	Tablet	0.1, 0.2, 0.5, 1, 2, or 4 mg per tablet	Estrace, Ovocyclin
	Estradiol acetate^a	Tablet	0.45, 0.9, or 1.8 mg per tablet	Femtrace
	Estradiol valerate	Tablet	0.5, 1, 2, or 4 mg per tablet	Progynova
Sublingual	Estradiol^a	Tablet	0.125, 0.25, or 1 mg per tablet	Diogynets, Estradiol Membrettes
Intranasal	Estradiol^a	Nasal spray	150 µg per spray (60 sprays per bottle)	Aerodiol
Transdermal	Estradiol	Patch	14, 25, 37.5, 50, 60, 75, or 100 µg E2 per day for 3–4 or 7 days	Climara, Estraderm, Vivelle
		Gel dispenser	0.06% (0.87 or 1.25 g gel or 0.52 or 0.75 mg E2 per activation)	Elestrin, EstroGel
		Gel packet	0.1% (0.25, 0.5, or 1 g gel or 0.25, 0.5, or 1.0 mg E2 per packet)	DiviGel, Sandrena
		Emulsion	0.25% (1.74 g emulsion or 4.35 mg E2 or 25 µg/day E2 per pouch)	Estrasorb
		Spray	1.53 mg per spray	Evamist
Vaginal	Estradiol	Tablet	10 or 25 µg per tablet	Vagifem
		Cream	0.01% (0.1 mg E2 per 1 g cream)	Estrace
		Suppository^a	4 or 40 μg per suppository	Ovocyclin
		Insert	4 or 10 µg per insert (daily for 2 weeks then twice weekly)	Imvexxy
		Ring	2 mg per ring (7.5 µg/day E2 for 3 months)	Estring
	Estradiol acetate	Ring	12.4 or 24.8 mg per ring (50 or 100 µg/day E2 for 3 months)	Femring
	Estradiol benzoate^a	Tablet	0.125 mg	Malun 25
Injection (IM or SC)	Estradiol	Aqueous suspension^a	0.22, 0.25, 0.44, 0.5, 1.0, 1.1, or 2.0 mg/mL	Aquadiol, Diogyn, Progynon
		Microspheres	1 mg/mL	Juvenum E
	Estradiol benzoate	Oil solution	0.167, 0.2, 0.333, 1, 1.67, 2, 5, 10, 20, or 25 mg/mL	Progynon-B
		Aqueous suspension^a	5 mg/mL	Agofollin Depot, Ovocyclin M
	Estradiol cypionate	Oil solution	1, 3, or 5 mg/mL	Depo-Estradiol
		Aqueous suspension	5 mg/0.5 mL (available only with a progestin)	Cyclofem, Lunelle
	Estradiol dipropionate^a	Oil solution	0.1, 0.2, 0.5, 1, 2.5, or 5 mg/mL	Di-Ovocylin, Progynon-DP
	Estradiol enanthate	Oil solution	5 or 10 mg/mL (available only with a progestin)	Perlutal, Topasel
	Estradiol undecylate^a	Oil solution	100 mg/mL	Delestrec, Progynon Depot 100
	Estradiol valerate	Oil solution	5, 10, 20, or 40 mg/mL	Delestrogen, Progynon Depot
	Polyestradiol phosphate^a	Aqueous solution	40 or 80 mg per vial/ampoule	Estradurin
Implant	Estradiol^a	Pellet	20, 25, 50, or 100 mg per pellet (usually every 6 months)	Estradiol Implants, Meno-Implant
Abbreviations: E2 = Estradiol. Footnotes: ^a = Discontinued or mostly discontinued. Notes: (1): This table mostly does not include combination products, for instance estradiol formulated in combination with a progestogen or androgen. (2): This table does not include compounded estradiol products; only approved pharmaceutical preparations are included. (3): The availability of pharmaceutical estradiol products differs by country (see Estradiol (medication) § Availability). (4): Some of these formulations and doses have been marketed previously but may no longer be available. Sources: See template.

Contraindications

See also: Estradiol (medication) § Contraindications

Contraindications of estrogens include coagulation problems, cardiovascular diseases, liver disease, and certain hormone-sensitive cancers such as breast cancer and endometrial cancer, among others.[18][19][20][21]

Side effects

See also: Estradiol (medication) § Side effects

The side effects of estradiol acetate are the same as those of estradiol. Examples of such side effects include breast tenderness and enlargement, nausea, bloating, edema, headache, and melasma.[7]

Overdose

See also: Estradiol (medication) § Overdose

Symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, heavy legs, and leg cramps.[18] These side effects can be diminished by reducing the estrogen dosage.[18]

Interactions

See also: Estradiol (medication) § Interactions

Inhibitors and inducers of cytochrome P450 may influence the metabolism of estradiol and by extension circulating estradiol levels.[22]

Pharmacology

Estradiol, the active form of estradiol acetate.

Pharmacodynamics

See also: Pharmacodynamics of estradiol

Estradiol acetate is an estradiol ester, or a prodrug of estradiol.[9][8] As such, it is an estrogen, or an agonist of the estrogen receptors.[8][9] Estradiol acetate is of about 15% higher molecular weight than estradiol due to the presence of its C3 acetate ester.[3] Because estradiol acetate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.[9][10]

Pharmacokinetics

See also: Pharmacokinetics of estradiol

Estradiol acetate is converted into estradiol in the body.[9][8]

Chemistry

See also: Estrogen ester and List of estrogen esters § Estradiol esters

Estradiol acetate is a synthetic estrane steroid and the C3 acetate ester of estradiol.[3] It is also known as estradiol 3-acetate or as estra-1,3,5(10)-triene-3,17β-diol 3-acetate.[3] Another common ester of estradiol in use for oral administration is estradiol valerate, which is a C17β ester of estradiol.[8][23]

The experimental octanol/water partition coefficient (logP) of estradiol acetate is 4.2.[24]

Structural properties of selected estradiol esters

Estrogen	Structure	Ester(s)				Relative mol. weight	Relative E2 content^b	logP^c
		Position(s)	Moiet(ies)	Type	Length^a
Estradiol		–	–	–	–	1.00	1.00	4.0
Estradiol acetate		C3	Ethanoic acid	Straight-chain fatty acid	2	1.15	0.87	4.2
Estradiol benzoate		C3	Benzenecarboxylic acid	Aromatic fatty acid	– (~4–5)	1.38	0.72	4.7
Estradiol dipropionate		C3, C17β	Propanoic acid (×2)	Straight-chain fatty acid	3 (×2)	1.41	0.71	4.9
Estradiol valerate		C17β	Pentanoic acid	Straight-chain fatty acid	5	1.31	0.76	5.6–6.3
Estradiol benzoate butyrate		C3, C17β	Benzoic acid, butyric acid	Mixed fatty acid	– (~6, 2)	1.64	0.61	6.3
Estradiol cypionate		C17β	Cyclopentylpropanoic acid	Aromatic fatty acid	– (~6)	1.46	0.69	6.9
Estradiol enanthate		C17β	Heptanoic acid	Straight-chain fatty acid	7	1.41	0.71	6.7–7.3
Estradiol dienanthate		C3, C17β	Heptanoic acid (×2)	Straight-chain fatty acid	7 (×2)	1.82	0.55	8.1–10.4
Estradiol undecylate		C17β	Undecanoic acid	Straight-chain fatty acid	11	1.62	0.62	9.2–9.8
Estradiol stearate		C17β	Octadecanoic acid	Straight-chain fatty acid	18	1.98	0.51	12.2–12.4
Estradiol distearate		C3, C17β	Octadecanoic acid (×2)	Straight-chain fatty acid	18 (×2)	2.96	0.34	20.2
Estradiol sulfate		C3	Sulfuric acid	Water-soluble conjugate	–	1.29	0.77	0.3–3.8
Estradiol glucuronide		C17β	Glucuronic acid	Water-soluble conjugate	–	1.65	0.61	2.1–2.7
Estramustine phosphate^d		C3, C17β	Normustine, phosphoric acid	Water-soluble conjugate	–	1.91	0.52	2.9–5.0
Polyestradiol phosphate^e		C3–C17β	Phosphoric acid	Water-soluble conjugate	–	1.23^f	0.81^f	2.9^g
Footnotes: ^a = Length of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic fatty acids. ^b = Relative estradiol content by weight (i.e., relative estrogenic exposure). ^c = Experimental or predicted octanol/water partition coefficient (i.e., lipophilicity/hydrophobicity). Retrieved from PubChem, ChemSpider, and DrugBank. ^d = Also known as estradiol normustine phosphate. ^e = Polymer of estradiol phosphate (~13 repeat units). ^f = Relative molecular weight or estradiol content per repeat unit. ^g = logP of repeat unit (i.e., estradiol phosphate). Sources: See individual articles.

History

Estradiol acetate is relatively recent to the market, having been first approved in a vaginal ring formulation as Menoring in the United Kingdom in 2001,[13] followed by a vaginal ring formulation as Femring in the United States in 2002,[2] and finally as an oral preparation as Femtrace in the United States in 2004.[2][11]

Society and culture

Generic names

Estradiol acetate is the generic name of the drug and its USAN.[3]

Brand names

Estradiol acetate is marketed under the brand names Femtrace, Femring, and Menoring.[3][25][26]

Availability

Estradiol acetate is available in the United States and the United Kingdom.[11][3]

References

1. https://www.drugs.com/cdi/estradiol-acetate.html
2. Sivanandy MS, Masimasi N, Thacker HL (May 2007). "Newer hormonal therapies: lower doses; oral, transdermal, and vaginal formulations". Cleveland Clinic Journal of Medicine. 74 (5): 369–75. doi:10.3949/ccjm.74.5.369. PMID 17506242.
3. https://www.drugs.com/international/estradiol-acetate.html
4. Buckler H, Al-Azzawi F (2003). "The effect of a novel vaginal ring delivering oestradiol acetate on climacteric symptoms in postmenopausal women". BJOG. 110 (8): 753–9. doi:10.1016/s1470-0328(03)02908-2. PMID 12892687.
5. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021633s005lbl.pdf
6. "FEMRING". DailyMed. U.S. National Library of Medicine.
7. Amit K. Ghosh (23 September 2010). Mayo Clinic Internal Medicine Board Review. OUP USA. pp. 222–. ISBN 978-0-19-975569-1.
8. Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
9. Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. p. 261. ISBN 978-3-642-60107-1. Natural estrogens considered here include: [...] Esters of 17β-estradiol, such as estradiol valerate, estradiol benzoate and estradiol cypionate. Esterification aims at either better absorption after oral administration or a sustained release from the depot after intramuscular administration. During absorption, the esters are cleaved by endogenous esterases and the pharmacologically active 17β-estradiol is released; therefore, the esters are considered as natural estrogens.
10. Cirigliano M (June 2007). "Bioidentical hormone therapy: a review of the evidence". J Womens Health (Larchmt). 16 (5): 600–31. doi:10.1089/jwh.2006.0311. PMID 17627398.
11. Ballagh SA (2004). "Vaginal rings for menopausal symptom relief". Drugs Aging. 21 (12): 757–66. doi:10.2165/00002512-200421120-00001. PMID 15382956.
12. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=021633
13. Speroff L (October 2003). "Efficacy and tolerability of a novel estradiol vaginal ring for relief of menopausal symptoms". Obstetrics and Gynecology. 102 (4): 823–34. doi:10.1016/s0029-7844(03)00764-6. PMID 14551014.
14. Al-Azzawi F, Lees B, Thompson J, Stevenson JC (2005). "Bone mineral density in postmenopausal women treated with a vaginal ring delivering systemic doses of estradiol acetate". Menopause. 12 (3): 331–9. doi:10.1097/01.gme.0000163870.03388.4d. PMID 15879923.
15. Utian WH, Speroff L, Ellman H, Dart C (2005). "Comparative controlled trial of a novel oral estrogen therapy, estradiol acetate, for relief of menopause symptoms". Menopause. 12 (6): 708–15. doi:10.1097/01.gme.0000184220.63459.a8. PMID 16278614.
16. Speroff L, Haney AF, Gilbert RD, Ellman H (2006). "Efficacy of a new, oral estradiol acetate formulation for relief of menopause symptoms". Menopause. 13 (3): 442–50. doi:10.1097/01.gme.0000182802.06762.b2. PMID 16735941.
17. Deitra Leonard Lowdermilk; Shannon E. Perry; Mary Catherine Cashion; Kathryn Rhodes Alden (18 December 2014). Maternity and Women's Health Care - E-Book. Elsevier Health Sciences. pp. 137–. ISBN 978-0-323-39019-4.
18. Lauritzen C (September 1990). "Clinical use of oestrogens and progestogens". Maturitas. 12 (3): 199–214. doi:10.1016/0378-5122(90)90004-P. PMID 2215269.
19. Christian Lauritzen; John W. W. Studd (22 June 2005). Current Management of the Menopause. CRC Press. pp. 95–98, 488. ISBN 978-0-203-48612-2.
20. Laurtizen, Christian (2001). "Hormone Substitution Before, During and After Menopause" (PDF). In Fisch, Franz H. (ed.). Menopause – Andropause: Hormone Replacement Therapy Through the Ages. Krause & Pachernegg: Gablitz. pp. 67–88. ISBN 978-3-901299-34-6.
21. Midwinter, Audrey (1976). "Contraindications to estrogen therapy and management of the menopausal syndrome in these cases". In Campbell, Stuart (ed.). The Management of the Menopause & Post-Menopausal Years: The Proceedings of the International Symposium held in London 24–26 November 1975 Arranged by the Institute of Obstetrics and Gynaecology, The University of London. MTP Press Limited. pp. 377–382. doi:10.1007/978-94-011-6165-7_33. ISBN 978-94-011-6167-1.
22. Cheng ZN, Shu Y, Liu ZQ, Wang LS, Ou-Yang DS, Zhou HH (February 2001). "Role of cytochrome P450 in estradiol metabolism in vitro". Acta Pharmacol. Sin. 22 (2): 148–54. PMID 11741520.
23. Düsterberg B, Nishino Y (December 1982). "Pharmacokinetic and pharmacological features of oestradiol valerate". Maturitas. 4 (4): 315–24. doi:10.1016/0378-5122(82)90064-0. PMID 7169965.
24. http://www.chemspider.com/Chemical-Structure.5254726.html
25. U.S. Food and Drug Administration (2009). Menopause - Medicines to Help You. GPO FCIC. pp. 3–. ISBN 978-1-61221-026-1.
26. Marc A. Fritz; Leon Speroff (28 March 2012). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. pp. 757–. ISBN 978-1-4511-4847-3.