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An estrogen ester is an ester of an estrogen, most typically of estradiol but also of other estrogens such as estrone, estriol, and even nonsteroidal estrogens like diethylstilbestrol.^[1]^[2]^[3] Esterification renders estradiol into a prodrug of estradiol with increased resistance to first-pass metabolism, slightly improving its oral bioavailability.^[1]^[2]^[4] In addition, estrogen esters have increased lipophilicity, which results in a longer duration when given by intramuscular or subcutaneous injection due to the formation of a long-lasting local depot in muscle and fat.^[1]^[2]^[3] Conversely, this is not the case with intravenous injection or oral administration.^[1]^[5] Estrogen esters are rapidly hydrolyzed into their parent estrogen by esterases once they have been released from the depot.^[1]^[2] Because estradiol esters are prodrugs of estradiol, they are considered to be natural and bioidentical forms of estrogen.^[2]^[1]^[6]

Estrogen esters are used in hormone therapy, hormonal contraception, and high-dose estrogen therapy (e.g., for prostate cancer and breast cancer), among other indications.^[1]^[2] The first estrogen ester to be marketed was estradiol benzoate in 1936,^[7]^[8] which was followed by many more.^[9]^[10] One of the most widely used estradiol esters is estradiol valerate, which was first introduced in 1954.^[11] Other major estradiol esters that are or have been used in medicine include estradiol acetate, estradiol cypionate, estradiol dipropionate, estradiol enantate, estradiol undecylate, and polyestradiol phosphate (an estrogen ester polymer), as well as the nitrogen mustard alkylating antineoplastic agent estramustine phosphate (estradiol normustine phosphate).^[2]^[12]

Pharmacology

Estrogen esters are essentially inactive themselves, with esters such as estradiol valerate and estradiol sulfate having about 2% of the affinity of estradiol for the estrogen receptor.^[13] Likewise, the estrogen ether mestranol (ethinylestradiol 3-methyl ether) has about 1% of the affinity of estradiol for the estrogen receptor.^[13] Estrone sulfate has less than 1% of the affinity of estradiol for the estrogen receptor.^[14]

In general, the longer the fatty acid ester chain of an estrogen ester, the greater its lipophilicity, and the longer the duration of the estrogen ester with intramuscular injection.^[1]^[12] It has been said that, via intramuscular injection, the duration of estradiol benzoate (with an ester of length 1 carbon plus a benzene ring) is 2 to 3 days, of estradiol dipropionate (with two esters each of length 2 carbons) is 1 to 2 weeks, of estradiol valerate (ester of 5 carbons) is 1 to 3 weeks, and of estradiol cypionate (ester of 3 carbons plus a cyclopentane ring) is 3 to 4 weeks.^[15] Estradiol enantate (ester of 7 carbons) has a duration of at least 30 days.^[2]^[16]^[17] Likewise, estradiol undecylate (ester of 10 carbons) has a very extended duration, which is longer than that of all of the aforementioned esters.^[12]^[18]^[19]

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Pharmacokinetics of three estradiol esters by intramuscular injection
Estrogen	Dose	C_max	T_max	Duration
Estradiol benzoate	5 mg	E2: 940 pg/mL E1: 343 pg/mL	E2: 1.8 days E1: 2.4 days	4–5 days
Estradiol valerate	5 mg	E2: 667 pg/mL E1: 324 pg/mL	E2: 2.2 days E1: 2.7 days	7–8 days
Estradiol cypionate	5 mg	E2: 338 pg/mL E1: 145 pg/mL	E2: 3.9 days E1: 5.1 days	11 days
Notes: All via i.m. injection of oil solution. Determinations via radioimmunoassay with chromatographic separation. Sources: See template.

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Potencies and durations of natural estrogens by intramuscular injection
Estrogen	Form	Dose (mg)		Duration by dose (mg)
Estrogen	Form	EPD	CICD	Duration by dose (mg)
Estradiol	Aq. soln.	?	–	<1 d
	Oil soln.	40–60	–	1–2 ≈ 1–2 d
	Aq. susp.	?	3.5	0.5–2 ≈ 2–7 d; 3.5 ≈ >5 d
	Microsph.	?	–	1 ≈ 30 d
Estradiol benzoate	Oil soln.	25–35	–	1.66 ≈ 2–3 d; 5 ≈ 3–6 d
	Aq. susp.	20	–	10 ≈ 16–21 d
	Emulsion	?	–	10 ≈ 14–21 d
Estradiol dipropionate	Oil soln.	25–30	–	5 ≈ 5–8 d
Estradiol valerate	Oil soln.	20–30	5	5 ≈ 7–8 d; 10 ≈ 10–14 d; 40 ≈ 14–21 d; 100 ≈ 21–28 d
Estradiol benz. butyrate	Oil soln.	?	10	10 ≈ 21 d
Estradiol cypionate	Oil soln.	20–30	–	5 ≈ 11–14 d
Estradiol cypionate	Aq. susp.	?	5	5 ≈ 14–24 d
Estradiol enanthate	Oil soln.	?	5–10	10 ≈ 20–30 d
Estradiol dienanthate	Oil soln.	?	–	7.5 ≈ >40 d
Estradiol undecylate	Oil soln.	?	–	10–20 ≈ 40–60 d; 25–50 ≈ 60–120 d
Polyestradiol phosphate	Aq. soln.	40–60	–	40 ≈ 30 d; 80 ≈ 60 d; 160 ≈ 120 d
Estrone	Oil soln.	?	–	1–2 ≈ 2–3 d
Estrone	Aq. susp.	?	–	0.1–2 ≈ 2–7 d
Estriol	Oil soln.	?	–	1–2 ≈ 1–4 d
Polyestriol phosphate	Aq. soln.	?	–	50 ≈ 30 d; 80 ≈ 60 d
Notes and sources Notes: All aqueous suspensions are of microcrystalline particle size. Estradiol production during the menstrual cycle is 30–640 µg/d (6.4–8.6 mg total per month or cycle). The vaginal epithelium maturation dosage of estradiol benzoate or estradiol valerate has been reported as 5 to 7 mg/week. An effective ovulation-inhibiting dose of estradiol undecylate is 20–30 mg/month. Sources: See template.

Polyestradiol phosphate is an atypical estradiol ester.^[20]^[21] It is a phosphoric acid ester of estradiol in the form of a polymer, with an average polymer chain length of approximately 13 repeat units of estradiol phosphate.^[20] That is, each polyestradiol phosphate molecule is a polymer consisting on average of 13 estradiol phosphate molecules bonded together.^[20] Polyestradiol phosphate is slowly cleaved into estradiol and phosphoric acid by phosphatases.^[20] Compared to conventional estradiol esters, polyestradiol phosphate has an extremely long duration; its elimination half-life is approximately 70 days.^[21] Whereas conventional estradiol esters form a long-lasting depot in muscle and fat at the site of injection,^[1] this is not the case with polyestradiol phosphate.^[22] Instead, polyestradiol phosphate is taken up rapidly into the bloodstream following injection (by 90% within 24 hours), where it circulates, and is accumulated in the reticuloendothelial system.^[22] Unlike other estradiol esters, polyestradiol phosphate is resistant to hydrolysis, which may be because it is a phosphatase inhibitor and may inhibit its own metabolism.^[20]

Estrogen esters also occur naturally in the body, for instance estrogen conjugates like estrone sulfate and estrone glucuronide and the very long-lived lipoidal estradiol, which is constituted by ultra-long-chain esters like estradiol palmitate (ester of 16 carbons) and estradiol stearate (ester of 18 carbons).^[1]^[2]^[23]

Time–concentration data

Levels of estradiol with injections of major estradiol esters

Normal menstrual cycle, estradiol benzoate, estradiol valerate, estradiol cypionate, estradiol enantate, estradiol undecylate, and polyestradiol phosphate
Estradiol benzoate, estradiol valerate, and estradiol cypionate
Estradiol benzoate, estradiol valerate, estradiol cypionate, and estradiol enanthate
Estradiol valerate and estradiol undecylate (i.m.)
Estradiol (i.v.), estradiol benzoate, estradiol valerate, and estradiol undecylate (i.m.)
Estradiol cypionate
Polyestradiol phosphate (every 4 weeks)
Polyestradiol phosphate (320 mg i.m.)

Chemistry

Chemical structures of estradiol and major estradiol esters

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Structural properties of selected estradiol esters
Estrogen	Structure	Ester(s)				Relative mol. weight	Relative E2 content^b	log P^c
Estrogen	Structure	Position(s)	Moiet(ies)	Type	Length^a	Relative mol. weight	Relative E2 content^b	log P^c
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	Benzoic 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	Cyclic 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 or cyclic 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 = log P of repeat unit (i.e., estradiol phosphate). Sources: See individual articles.

References

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j 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.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. pp. 235–237, 261, 271. 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.
^ ^a ^b R. S. Satoskar; S. D. Bhandarkar &nirmala N. Rege (1969). Pharmacology And Pharmacotherapeutics (New Revised 21 St Ed.). Popular Prakashan. p. 24. ISBN 978-81-7991-527-1. Retrieved 29 May 2012.
^ Gordon L. Amidon; Ping I. Lee; Elizabeth M. Topp (2000). Transport Processes in Pharmaceutical Systems. CRC Press. pp. 188–189. ISBN 978-0-8247-6610-8. Retrieved 29 May 2012.
^ Parkes AS (February 1938). "Effective Absorption of Hormones" (PDF). Br Med J. 1 (4024): 371–3. PMC 2085798. PMID 20781252.
^ 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.
^ Enrique Raviña; Hugo Kubinyi (16 May 2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. p. 175. ISBN 978-3-527-32669-3. Retrieved 20 May 2012.
^ Folley SJ (December 1936). "The effect of oestrogenic hormones on lactation and on the phosphatase of the blood and milk of the lactating cow" (PDF). The Biochemical Journal. 30 (12): 2262–72. PMC 1263335. PMID 16746289.
^ J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 897–. ISBN 978-1-4757-2085-3.
^ Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. pp. 404–406. ISBN 978-3-88763-075-1. Retrieved 13 September 2012.
^ William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 1477–. ISBN 978-0-8155-1856-3.
^ ^a ^b ^c Cite error: The named reference pmid7389356 was invoked but never defined (see the help page).
^ ^a ^b Gudermann, T. (2005). "Endokrinpharmakologie": 187–220. doi:10.1007/3-540-26406-X_10. {{cite journal}}: Cite journal requires |journal= (help)
^ Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA (March 1997). "Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta". Endocrinology. 138 (3): 863–70. doi:10.1210/endo.138.3.4979. PMID 9048584.
^ H.J. Buchsbaum (6 December 2012). The Menopause. Springer Science & Business Media. pp. 62–. ISBN 978-1-4612-5525-3.
^ Recio R, Garza-Flores J, Schiavon R, Reyes A, Diaz-Sanchez V, Valles V, Luz de la Cruz D, Oropeza G, Perez-Palacios G (1986). "Pharmacodynamic assessment of dihydroxyprogesterone acetophenide plus estradiol enanthate as a monthly injectable contraceptive". Contraception. 33 (6): 579–89. doi:10.1016/0010-7824(86)90046-6. PMID 3769482.
^ Wiemeyer JC, Fernandez M, Moguilevsky JA, Sagasta CL (1986). "Pharmacokinetic studies of estradiol enantate in menopausic women". Arzneimittelforschung. 36 (11): 1674–7. PMID 3814225.
^ Vermeulen A (1975). "Longacting steroid preparations". Acta Clin Belg. 30 (1): 48–55. doi:10.1080/17843286.1975.11716973. PMID 1231448.
^ R. S. Satoskar; S. D. Bhandarkar &nirmala N. Rege (1973). Pharmacology and Pharmacotherapeutics. Popular Prakashan. pp. 934–. ISBN 978-81-7991-527-1.
^ ^a ^b ^c ^d ^e Gunnarsson PO, Norlén BJ (1988). "Clinical pharmacology of polyestradiol phosphate". Prostate. 13 (4): 299–304. doi:10.1002/pros.2990130405. PMID 3217277.
^ ^a ^b Cite error: The named reference pmid8610057 was invoked but never defined (see the help page).
^ ^a ^b Dinnendahl, V; Fricke, U, eds. (2010). Arzneistoff-Profile (in German). Vol. 4 (23 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-98-46-3.
^ Hochberg RB, Pahuja SL, Larner JM, Zielinski JE (1990). "Estradiol-fatty acid esters. Endogenous long-lived estrogens". Ann. N. Y. Acad. Sci. 595: 74–92. doi:10.1111/j.1749-6632.1990.tb34284.x. PMID 2197972.
^ Shellenberger, T. E. (1986). "Pharmacology of estrogens": 393–410. doi:10.1007/978-94-009-4145-8_36. {{cite journal}}: Cite journal requires |journal= (help)

@@ Line 14: / Line 14: @@
 {{Parenteral potencies and durations of estrogens}}
-Polyestradiol phosphate is an atypical estradiol ester.<ref name="pmid3217277">{{cite journal | vauthors = Gunnarsson PO, Norlén BJ | title = Clinical pharmacology of polyestradiol phosphate | journal = Prostate | volume = 13 | issue = 4 | pages = 299–304 | year = 1988 | pmid = 3217277 | doi = 10.1002/pros.2990130405| url = }}</ref><ref name="pmid8610057">{{cite journal | vauthors = Stege R, Gunnarsson PO, Johansson CJ, Olsson P, Pousette A, Carlström K | title = Pharmacokinetics and testosterone suppression of a single dose of polyestradiol phosphate (Estradurin) in prostatic cancer patients | journal = Prostate | volume = 28 | issue = 5 | pages = 307–10 | year = 1996 | pmid = 8610057 | doi = 10.1002/(SICI)1097-0045(199605)28:5<307::AID-PROS6>3.0.CO;2-8 | url = }}</ref> It is a [[phosphoric acid]] ester of estradiol in the form of a [[polymer]], with an average polymer chain length of approximately 13&nbsp;[[repeat unit]]s of [[estradiol phosphate]].<ref name="pmid3217277" /> That is, each polyestradiol phosphate [[molecule]] is a polymer consisting on average of 13&nbsp;estradiol phosphate molecules bonded together.<ref name="pmid3217277" /> Polyestradiol phosphate is slowly [[bond cleavage|cleaved]] into estradiol and phosphoric acid by [[phosphatase]]s.<ref name="pmid3217277" /> Compared to conventional estradiol esters, polyestradiol phosphate has an extremely long duration; its [[elimination half-life]] is approximately 70&nbsp;days.<ref name="pmid8610057" /> Whereas conventional estradiol esters form a long-lasting depot in muscle and fat at the site of injection,<ref name="pmid16112947" /> this is not the case with polyestradiol phosphate.<ref name="Arzneistoff-Profile">{{cite book|title=Arzneistoff-Profile|editor1-last=Dinnendahl|editor1-first=V|editor2-last=Fricke|editor2-first=U|publisher=Govi Pharmazeutischer Verlag|location=Eschborn, Germany|year=2010|edition=23|volume=4|isbn=978-3-7741-98-46-3|language=German}}</ref> Instead, polyestradiol phosphate is taken up rapidly into the bloodstream following injection (by 90% within 24&nbsp;hours), where it circulates, and is accumulated in the [[reticuloendothelial system]].<ref name="Arzneistoff-Profile" /> Unlike other estradiol esters, polyestradiol phosphate is resistant to hydrolysis, which may be because it is a [[phosphatase inhibitor]] and may inhibit its own [[metabolism]].<ref name="pmid3217277" />
+Polyestradiol phosphate is an atypical estradiol ester.<ref name="pmid3217277">{{cite journal | vauthors = Gunnarsson PO, Norlén BJ | title = Clinical pharmacology of polyestradiol phosphate | journal = Prostate | volume = 13 | issue = 4 | pages = 299–304 | year = 1988 | pmid = 3217277 | doi = 10.1002/pros.2990130405| url = }}</ref><ref name="pmid8610057"/> It is a [[phosphoric acid]] ester of estradiol in the form of a [[polymer]], with an average polymer chain length of approximately 13&nbsp;[[repeat unit]]s of [[estradiol phosphate]].<ref name="pmid3217277" /> That is, each polyestradiol phosphate [[molecule]] is a polymer consisting on average of 13&nbsp;estradiol phosphate molecules bonded together.<ref name="pmid3217277" /> Polyestradiol phosphate is slowly [[bond cleavage|cleaved]] into estradiol and phosphoric acid by [[phosphatase]]s.<ref name="pmid3217277" /> Compared to conventional estradiol esters, polyestradiol phosphate has an extremely long duration; its [[elimination half-life]] is approximately 70&nbsp;days.<ref name="pmid8610057" /> Whereas conventional estradiol esters form a long-lasting depot in muscle and fat at the site of injection,<ref name="pmid16112947" /> this is not the case with polyestradiol phosphate.<ref name="Arzneistoff-Profile">{{cite book|title=Arzneistoff-Profile|editor1-last=Dinnendahl|editor1-first=V|editor2-last=Fricke|editor2-first=U|publisher=Govi Pharmazeutischer Verlag|location=Eschborn, Germany|year=2010|edition=23|volume=4|isbn=978-3-7741-98-46-3|language=German}}</ref> Instead, polyestradiol phosphate is taken up rapidly into the bloodstream following injection (by 90% within 24&nbsp;hours), where it circulates, and is accumulated in the [[reticuloendothelial system]].<ref name="Arzneistoff-Profile" /> Unlike other estradiol esters, polyestradiol phosphate is resistant to hydrolysis, which may be because it is a [[phosphatase inhibitor]] and may inhibit its own [[metabolism]].<ref name="pmid3217277" />
 Estrogen esters also occur naturally in the body, for instance [[estrogen conjugate]]s like [[estrone sulfate]] and [[estrone glucuronide]] and the very long-lived [[lipoidal estradiol]], which is constituted by ultra-long-chain esters like [[estradiol palmitate]] (ester of 16&nbsp;carbons) and [[estradiol stearate]] (ester of 18&nbsp;carbons).<ref name="pmid16112947" /><ref name="OettelSchillinger2012" /><ref name="pmid2197972">{{cite journal | vauthors = Hochberg RB, Pahuja SL, Larner JM, Zielinski JE | title = Estradiol-fatty acid esters. Endogenous long-lived estrogens | journal = Ann. N. Y. Acad. Sci. | volume = 595 | issue = | pages = 74–92 | year = 1990 | pmid = 2197972 | doi = 10.1111/j.1749-6632.1990.tb34284.x| url = }}</ref>

v t e Estradiol
Topics	Estradiol (as a hormone) Estradiol (as a medication) Pharmacodynamics of estradiol Pharmacokinetics of estradiol Estrogen (as a hormone) Estrogen (as a medication) Menopausal hormone therapy Feminizing hormone therapy Estradiol-containing birth control pill Combined injectable birth control High-dose estrogen Hydroxylation of estradiol
Esters	Estradiol acetate Estradiol acetylsalicylate Estradiol anthranilate Estradiol benzoate butyrate Estradiol benzoate cyclooctenyl ether Estradiol benzoate Estradiol butyrylacetate Estradiol cyclooctyl acetate Estradiol cypionate Estradiol decanoate Estradiol diacetate Estradiol dibutyrate Estradiol dienantate Estradiol dipropionate Estradiol distearate Estradiol disulfate Estradiol diundecylate Estradiol diundecylenate Estradiol enantate Estradiol furoate Estradiol glucuronide Estradiol hemisuccinate Estradiol hexahydrobenzoate Estradiol monopropionate Estradiol mustard Estradiol palmitate Estradiol phenylpropionate Estradiol phosphate Estradiol pivalate Estradiol propoxyphenylpropionate Estradiol salicylate Estradiol stearate Estradiol sulfamate Estradiol sulfate Estradiol undecylate Estradiol undecylenate Estradiol valerate Estramustine phosphate (estradiol normustine phosphate) Estrogen ester Polyestradiol phosphate
Related	Estrone Estriol Estetrol Ethinylestradiol Conjugated estrogens Esterified estrogens Estrone sulfate Estropipate (piperazine estrone sulfate)