Estrogen ester

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]

Not to be confused with Esterified estrogens or Conjugated estrogens.

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 1933, which was followed by many more.[7][8] One of the most widely used estradiol esters is estradiol valerate, which was first introduced in 1954.[9] 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][10]

The most common vehicles for injections of steroids and steroid esters are oil solutions, but aqueous solutions, aqueous suspensions, and emulsions have also been used.[11] The durations of estrogen esters are not prolonged if they are given orally, vaginally, or by intravenous injection.[11]

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.[12] Likewise, the estrogen ether mestranol (ethinylestradiol 3-methyl ether) has about 1% of the affinity of estradiol for the estrogen receptor.[12] Estrone sulfate has less than 1% of the affinity of estradiol for the estrogen receptor.[13] As such, estrogen esters do not bind to the estrogen receptor except at extremely high concentrations.[14] The residual affinity of estrogen esters for the estrogen receptor in bioassays may actually be due to conversion into the parent estrogen, as attempts to prevent or limit this conversion have been found to abolish binding to the estrogen receptor and estrogenicity.[15][16][17]

Affinities of estrogen receptor ligands for the ERα and ERβ

Ligand	Other names	Relative binding affinities (RBA, %)^a		Absolute binding affinities (Ki, nM)^a		Action
		ERα	ERβ	ERα	ERβ
Estradiol	E2; 17β-Estradiol	100	100	0.115 (0.04–0.24)	0.15 (0.10–2.08)	Estrogen
Estrone	E1; 17-Ketoestradiol	16.39 (0.7–60)	6.5 (1.36–52)	0.445 (0.3–1.01)	1.75 (0.35–9.24)	Estrogen
Estriol	E3; 16α-OH-17β-E2	12.65 (4.03–56)	26 (14.0–44.6)	0.45 (0.35–1.4)	0.7 (0.63–0.7)	Estrogen
Estetrol	E4; 15α,16α-Di-OH-17β-E2	4.0	3.0	4.9	19	Estrogen
Alfatradiol	17α-Estradiol	20.5 (7–80.1)	8.195 (2–42)	0.2–0.52	0.43–1.2	Metabolite
16-Epiestriol	16β-Hydroxy-17β-estradiol	7.795 (4.94–63)	50	?	?	Metabolite
17-Epiestriol	16α-Hydroxy-17α-estradiol	55.45 (29–103)	79–80	?	?	Metabolite
16,17-Epiestriol	16β-Hydroxy-17α-estradiol	1.0	13	?	?	Metabolite
2-Hydroxyestradiol	2-OH-E2	22 (7–81)	11–35	2.5	1.3	Metabolite
2-Methoxyestradiol	2-MeO-E2	0.0027–2.0	1.0	?	?	Metabolite
4-Hydroxyestradiol	4-OH-E2	13 (8–70)	7–56	1.0	1.9	Metabolite
4-Methoxyestradiol	4-MeO-E2	2.0	1.0	?	?	Metabolite
2-Hydroxyestrone	2-OH-E1	2.0–4.0	0.2–0.4	?	?	Metabolite
2-Methoxyestrone	2-MeO-E1	<0.001–<1	<1	?	?	Metabolite
4-Hydroxyestrone	4-OH-E1	1.0–2.0	1.0	?	?	Metabolite
4-Methoxyestrone	4-MeO-E1	<1	<1	?	?	Metabolite
16α-Hydroxyestrone	16α-OH-E1; 17-Ketoestriol	2.0–6.5	35	?	?	Metabolite
2-Hydroxyestriol	2-OH-E3	2.0	1.0	?	?	Metabolite
4-Methoxyestriol	4-MeO-E3	1.0	1.0	?	?	Metabolite
Estradiol sulfate	E2S; Estradiol 3-sulfate	<1	<1	?	?	Metabolite
Estradiol disulfate	Estradiol 3,17β-disulfate	0.0004	?	?	?	Metabolite
Estradiol 3-glucuronide	E2-3G	0.0079	?	?	?	Metabolite
Estradiol 17β-glucuronide	E2-17G	0.0015	?	?	?	Metabolite
Estradiol 3-gluc. 17β-sulfate	E2-3G-17S	0.0001	?	?	?	Metabolite
Estrone sulfate	E1S; Estrone 3-sulfate	<1	<1	>10	>10	Metabolite
Estradiol benzoate	EB; Estradiol 3-benzoate	10	?	?	?	Estrogen
Estradiol 17β-benzoate	E2-17B	11.3	32.6	?	?	Estrogen
Estrone methyl ether	Estrone 3-methyl ether	0.145	?	?	?	Estrogen
ent-Estradiol	1-Estradiol	1.31–12.34	9.44–80.07	?	?	Estrogen
Equilin	7-Dehydroestrone	13 (4.0–28.9)	13.0–49	0.79	0.36	Estrogen
Equilenin	6,8-Didehydroestrone	2.0–15	7.0–20	0.64	0.62	Estrogen
17β-Dihydroequilin	7-Dehydro-17β-estradiol	7.9–113	7.9–108	0.09	0.17	Estrogen
17α-Dihydroequilin	7-Dehydro-17α-estradiol	18.6 (18–41)	14–32	0.24	0.57	Estrogen
17β-Dihydroequilenin	6,8-Didehydro-17β-estradiol	35–68	90–100	0.15	0.20	Estrogen
17α-Dihydroequilenin	6,8-Didehydro-17α-estradiol	20	49	0.50	0.37	Estrogen
Δ^8-Estradiol	8,9-Dehydro-17β-estradiol	68	72	0.15	0.25	Estrogen
Δ^8-Estrone	8,9-Dehydroestrone	19	32	0.52	0.57	Estrogen
Ethinylestradiol	EE; 17α-Ethynyl-17β-E2	120.9 (68.8–480)	44.4 (2.0–144)	0.02–0.05	0.29–0.81	Estrogen
Mestranol	EE 3-methyl ether	?	2.5	?	?	Estrogen
Moxestrol	RU-2858; 11β-Methoxy-EE	35–43	5–20	0.5	2.6	Estrogen
Methylestradiol	17α-Methyl-17β-estradiol	70	44	?	?	Estrogen
Diethylstilbestrol	DES; Stilbestrol	129.5 (89.1–468)	219.63 (61.2–295)	0.04	0.05	Estrogen
Hexestrol	Dihydrodiethylstilbestrol	153.6 (31–302)	60–234	0.06	0.06	Estrogen
Dienestrol	Dehydrostilbestrol	37 (20.4–223)	56–404	0.05	0.03	Estrogen
Benzestrol (B2)	–	114	?	?	?	Estrogen
Chlorotrianisene	TACE	1.74	?	15.30	?	Estrogen
Triphenylethylene	TPE	0.074	?	?	?	Estrogen
Triphenylbromoethylene	TPBE	2.69	?	?	?	Estrogen
Tamoxifen	ICI-46,474	3 (0.1–47)	3.33 (0.28–6)	3.4–9.69	2.5	SERM
Afimoxifene	4-Hydroxytamoxifen; 4-OHT	100.1 (1.7–257)	10 (0.98–339)	2.3 (0.1–3.61)	0.04–4.8	SERM
Toremifene	4-Chlorotamoxifen; 4-CT	?	?	7.14–20.3	15.4	SERM
Clomifene	MRL-41	25 (19.2–37.2)	12	0.9	1.2	SERM
Cyclofenil	F-6066; Sexovid	151–152	243	?	?	SERM
Nafoxidine	U-11,000A	30.9–44	16	0.3	0.8	SERM
Raloxifene	–	41.2 (7.8–69)	5.34 (0.54–16)	0.188–0.52	20.2	SERM
Arzoxifene	LY-353,381	?	?	0.179	?	SERM
Lasofoxifene	CP-336,156	10.2–166	19.0	0.229	?	SERM
Ormeloxifene	Centchroman	?	?	0.313	?	SERM
Levormeloxifene	6720-CDRI; NNC-460,020	1.55	1.88	?	?	SERM
Ospemifene	Deaminohydroxytoremifene	2.63	1.22	?	?	SERM
Bazedoxifene	–	?	?	0.053	?	SERM
Etacstil	GW-5638	4.30	11.5	?	?	SERM
ICI-164,384	–	63.5 (3.70–97.7)	166	0.2	0.08	Antiestrogen
Fulvestrant	ICI-182,780	43.5 (9.4–325)	21.65 (2.05–40.5)	0.42	1.3	Antiestrogen
Propylpyrazoletriol	PPT	49 (10.0–89.1)	0.12	0.40	92.8	ERα agonist
16α-LE2	16α-Lactone-17β-estradiol	14.6–57	0.089	0.27	131	ERα agonist
16α-Iodo-E2	16α-Iodo-17β-estradiol	30.2	2.30	?	?	ERα agonist
Methylpiperidinopyrazole	MPP	11	0.05	?	?	ERα antagonist
Diarylpropionitrile	DPN	0.12–0.25	6.6–18	32.4	1.7	ERβ agonist
8β-VE2	8β-Vinyl-17β-estradiol	0.35	22.0–83	12.9	0.50	ERβ agonist
Prinaberel	ERB-041; WAY-202,041	0.27	67–72	?	?	ERβ agonist
ERB-196	WAY-202,196	?	180	?	?	ERβ agonist
Erteberel	SERBA-1; LY-500,307	?	?	2.68	0.19	ERβ agonist
SERBA-2	–	?	?	14.5	1.54	ERβ agonist
Coumestrol	–	9.225 (0.0117–94)	64.125 (0.41–185)	0.14–80.0	0.07–27.0	Xenoestrogen
Genistein	–	0.445 (0.0012–16)	33.42 (0.86–87)	2.6–126	0.3–12.8	Xenoestrogen
Equol	–	0.2–0.287	0.85 (0.10–2.85)	?	?	Xenoestrogen
Daidzein	–	0.07 (0.0018–9.3)	0.7865 (0.04–17.1)	2.0	85.3	Xenoestrogen
Biochanin A	–	0.04 (0.022–0.15)	0.6225 (0.010–1.2)	174	8.9	Xenoestrogen
Kaempferol	–	0.07 (0.029–0.10)	2.2 (0.002–3.00)	?	?	Xenoestrogen
Naringenin	–	0.0054 (<0.001–0.01)	0.15 (0.11–0.33)	?	?	Xenoestrogen
8-Prenylnaringenin	8-PN	4.4	?	?	?	Xenoestrogen
Quercetin	–	<0.001–0.01	0.002–0.040	?	?	Xenoestrogen
Ipriflavone	–	<0.01	<0.01	?	?	Xenoestrogen
Miroestrol	–	0.39	?	?	?	Xenoestrogen
Deoxymiroestrol	–	2.0	?	?	?	Xenoestrogen
β-Sitosterol	–	<0.001–0.0875	<0.001–0.016	?	?	Xenoestrogen
Resveratrol	–	<0.001–0.0032	?	?	?	Xenoestrogen
α-Zearalenol	–	48 (13–52.5)	?	?	?	Xenoestrogen
β-Zearalenol	–	0.6 (0.032–13)	?	?	?	Xenoestrogen
Zeranol	α-Zearalanol	48–111	?	?	?	Xenoestrogen
Taleranol	β-Zearalanol	16 (13–17.8)	14	0.8	0.9	Xenoestrogen
Zearalenone	ZEN	7.68 (2.04–28)	9.45 (2.43–31.5)	?	?	Xenoestrogen
Zearalanone	ZAN	0.51	?	?	?	Xenoestrogen
Bisphenol A	BPA	0.0315 (0.008–1.0)	0.135 (0.002–4.23)	195	35	Xenoestrogen
Endosulfan	EDS	<0.001–<0.01	<0.01	?	?	Xenoestrogen
Kepone	Chlordecone	0.0069–0.2	?	?	?	Xenoestrogen
o,p'-DDT	–	0.0073–0.4	?	?	?	Xenoestrogen
p,p'-DDT	–	0.03	?	?	?	Xenoestrogen
Methoxychlor	p,p'-Dimethoxy-DDT	0.01 (<0.001–0.02)	0.01–0.13	?	?	Xenoestrogen
HPTE	Hydroxychlor; p,p'-OH-DDT	1.2–1.7	?	?	?	Xenoestrogen
Testosterone	T; 4-Androstenolone	<0.0001–<0.01	<0.002–0.040	>5000	>5000	Androgen
Dihydrotestosterone	DHT; 5α-Androstanolone	0.01 (<0.001–0.05)	0.0059–0.17	221–>5000	73–1688	Androgen
Nandrolone	19-Nortestosterone; 19-NT	0.01	0.23	765	53	Androgen
Dehydroepiandrosterone	DHEA; Prasterone	0.038 (<0.001–0.04)	0.019–0.07	245–1053	163–515	Androgen
5-Androstenediol	A5; Androstenediol	6	17	3.6	0.9	Androgen
4-Androstenediol	–	0.5	0.6	23	19	Androgen
4-Androstenedione	A4; Androstenedione	<0.01	<0.01	>10000	>10000	Androgen
3α-Androstanediol	3α-Adiol	0.07	0.3	260	48	Androgen
3β-Androstanediol	3β-Adiol	3	7	6	2	Androgen
Androstanedione	5α-Androstanedione	<0.01	<0.01	>10000	>10000	Androgen
Etiocholanedione	5β-Androstanedione	<0.01	<0.01	>10000	>10000	Androgen
Methyltestosterone	17α-Methyltestosterone	<0.0001	?	?	?	Androgen
Ethinyl-3α-androstanediol	17α-Ethynyl-3α-adiol	4.0	<0.07	?	?	Estrogen
Ethinyl-3β-androstanediol	17α-Ethynyl-3β-adiol	50	5.6	?	?	Estrogen
Progesterone	P4; 4-Pregnenedione	<0.001–0.6	<0.001–0.010	?	?	Progestogen
Norethisterone	NET; 17α-Ethynyl-19-NT	0.085 (0.0015–<0.1)	0.1 (0.01–0.3)	152	1084	Progestogen
Norethynodrel	5(10)-Norethisterone	0.5 (0.3–0.7)	<0.1–0.22	14	53	Progestogen
Tibolone	7α-Methylnorethynodrel	0.5 (0.45–2.0)	0.2–0.076	?	?	Progestogen
Δ^4-Tibolone	7α-Methylnorethisterone	0.069–<0.1	0.027–<0.1	?	?	Progestogen
3α-Hydroxytibolone	–	2.5 (1.06–5.0)	0.6–0.8	?	?	Progestogen
3β-Hydroxytibolone	–	1.6 (0.75–1.9)	0.070–0.1	?	?	Progestogen
Footnotes: ^a = (1) Binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. The full sets of values within the ranges can be found in the Wiki code. (2) Binding affinities were determined via displacement studies in a variety of in-vitro systems with labeled estradiol and human ERα and ERβ proteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ). Sources: See template page.

Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors

Estrogen	Other names	RBA (%)^a	REP (%)^b
		ER	ERα	ERβ
Estradiol	E2	100	100	100
Estradiol 3-sulfate	E2S; E2-3S	?	0.02	0.04
Estradiol 3-glucuronide	E2-3G	?	0.02	0.09
Estradiol 17β-glucuronide	E2-17G	?	0.002	0.0002
Estradiol benzoate	EB; Estradiol 3-benzoate	10	1.1	0.52
Estradiol 17β-acetate	E2-17A	31–45	24	?
Estradiol diacetate	EDA; Estradiol 3,17β-diacetate	?	0.79	?
Estradiol propionate	EP; Estradiol 17β-propionate	19–26	2.6	?
Estradiol valerate	EV; Estradiol 17β-valerate	2–11	0.04–21	?
Estradiol cypionate	EC; Estradiol 17β-cypionate	?^c	4.0	?
Estradiol palmitate	Estradiol 17β-palmitate	0	?	?
Estradiol stearate	Estradiol 17β-stearate	0	?	?
Estrone	E1; 17-Ketoestradiol	11	5.3–38	14
Estrone sulfate	E1S; Estrone 3-sulfate	2	0.004	0.002
Estrone glucuronide	E1G; Estrone 3-glucuronide	?	<0.001	0.0006
Ethinylestradiol	EE; 17α-Ethynylestradiol	100	17–150	129
Mestranol	EE 3-methyl ether	1	1.3–8.2	0.16
Quinestrol	EE 3-cyclopentyl ether	?	0.37	?
Footnotes: ^a = Relative binding affinities (RBAs) were determined via in-vitro displacement of labeled estradiol from estrogen receptors (ERs) generally of rodent uterine cytosol. Estrogen esters are variably hydrolyzed into estrogens in these systems (shorter ester chain length -> greater rate of hydrolysis) and the ER RBAs of the esters decrease strongly when hydrolysis is prevented. ^b = Relative estrogenic potencies (REPs) were calculated from half-maximal effective concentrations (EC50) that were determined via in-vitro β‐galactosidase (β-gal) and green fluorescent protein (GFP) expression assays in yeast expressing human ERα and human ERβ. Both mammalian cells and yeast have the capacity to hydrolyze estrogen esters. ^c = The affinities of estradiol cypionate for the ERs are similar to those of estradiol valerate and estradiol benzoate (figure). Sources: See template page.

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][10] 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.[18] Estradiol enantate (ester of 7 carbons) has a duration of around 20 days.[2][19][20] Likewise, estradiol undecylate (ester of 10 carbons) has a very extended duration, which is longer than that of all of the aforementioned esters.[10][21][22]

Pharmacokinetics of three estradiol esters by intramuscular injection

Estrogen	Dose	Peak levels	Time to peak	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.

Potencies and durations of natural estrogens by intramuscular injection

Estrogen	Form	Major brand names	EPD	CIC-D	Duration
Estradiol	Aqueous solution	–	?	–	<1 day
	Oil solution	Estradiol	40–60 mg	–	1–2 mg ≈ 1–2 days
	Aqueous suspension	Aquadiol, Diogyn, Progynon, Mego-E	?	3.5 mg	0.5–2 mg ≈ 2–7 days; 3.5 mg ≈ >5 days
	Microspheres	Juvenum-E, Juvenum	?	–	1 mg ≈ 30 days
Estradiol benzoate	Oil solution	Progynon-B	25–35 mg	–	1.66 mg ≈ 2–3 days; 5 mg ≈ 3–6 days
	Aqueous suspension	Agofollin-Depot, Ovocyclin M	20 mg	–	10 mg ≈ 16–21 days
	Emulsion	Menformon-Emulsion, Di-Pro-Emulsion	?	–	10 mg ≈ 14–21 days
Estradiol dipropionate	Oil solution	Agofollin, Di-Ovocylin, Progynon DP	25–30 mg	–	5 mg ≈ 5–8 days
Estradiol valerate	Oil solution	Delestrogen, Progynon Depot, Mesigyna	20–30 mg	5 mg	5 mg ≈ 7–8 days; 10 mg ≈ 10–14 days; 40 mg ≈ 14–21 days; 100 mg ≈ 21–28 days
Estradiol benzoate butyrate	Oil solution	Redimen, Soluna, Unijab	?	10 mg	10 mg ≈ 21 days
Estradiol cypionate	Oil solution	Depo-Estradiol, Depofemin	20–30 mg	–	5 mg ≈ 11–14 days
	Aqueous suspension	Cyclofem, Lunelle	?	5 mg	5 mg ≈ 14–24 days
Estradiol enanthate	Oil solution	Perlutal, Topasel, Yectames	?	5–10 mg	10 mg ≈ 20–30 days
Estradiol dienanthate	Oil solution	Climacteron, Lactimex, Lactostat	?	–	7.5 mg ≈ >40 days
Estradiol undecylate	Oil solution	Delestrec, Progynon Depot 100	?	–	10–20 mg ≈ 40–60 days; 25–50 mg ≈ 60–120 days
Polyestradiol phosphate	Aqueous solution	Estradurin	40–60 mg	–	40 mg ≈ 30 days; 80 mg ≈ 60 days; 160 mg ≈ 120 days
Estrone	Oil solution	Estrone, Kestrin, Theelin	?	–	1–2 mg ≈ 2–3 days
	Aqueous suspension	Estrone Aq. Susp., Kestrone, Theelin Aq.	?	–	0.1–2 mg ≈ 2–7 days
Estriol	Oil solution	–	?	–	1–2 mg ≈ 1–4 days
Polyestriol phosphate	Aqueous solution	Gynäsan, Klimadurin, Triodurin	?	–	50 mg ≈ 30 days; 80 mg ≈ 60 days
Notes: All aqueous suspensions are of microcrystalline particle size. Estradiol production during the menstrual cycle is 30–640 µg/day (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.[23][24] 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.[23] It is slowly cleaved into estradiol and phosphoric acid by phosphatases.[23] Compared to conventional estradiol esters, polyestradiol phosphate has an extremely long duration; its elimination half-life is approximately 70 days.[24] 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.[25] 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.[25] 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.[23]

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][26]

Time–concentration curves

Hormone levels with estradiol benzoate by intramuscular injection

• 
  Estradiol levels after single intramuscular injections of 0.5, 1.5, or 2.5 mg estradiol benzoate in oil in 5 premenopausal women each.[27] Assays were performed using radioimmunoassay.[27] Source was Shaw et al. (1975).[27]
• 
  Estradiol levels after single intramuscular injections of 5 mg of different estradiol esters in oil in about 10 premenopausal women each.[10] Assays were performed using radioimmunoassay with chromatographic separation.[10] Source was Oriowo et al. (1980).[10]
• 
  Estradiol levels after a short intravenous infusion of 20 mg estradiol in aqueous solution or an intramuscular injection of equimolar doses of estradiol esters in oil solution in postmenopausal women.[28][29] Assays were performed using RIA with CS.[28][29] Source was Geppert (1975).[28][29]
• 
  Simplified curves of estradiol levels after injection of different estradiol esters in women.[30] Source was Garza-Flores (1994).[30]
• 
  Vaginal cornification with a single intramuscular injection of different estradiol esters in oil solution in women.[31] Source was Schwartz & Soule (1955).[31]

Hormone levels with estradiol dipropionate by intramuscular injection

• 
  Estradiol levels after a single intramuscular injection of 50 μg/kg estradiol dipropionate in oil in pubertal girls.[32] This dose would be 1 mg in a 50-kg (110-lb) girl.[32] Source was Presl et al. (1976).[32]
• 
  Vaginal cornification with a single intramuscular injection of different estradiol esters in oil solution in women.[33] Source was Schwartz & Soule (1955).[33]

Hormone levels with estradiol valerate by intramuscular injection

• 
  Estrogen levels after a single intramuscular injection of 10 mg estradiol valerate in oil in 24 postmenopausal women.[34] Determinations were made for both Progynon Depot 10 and Estradiol Depot 10, for a total of 48 measurements per point.[34] Assays were performed using GC/MS-NCI/SIM.[34] Source was Schug et al. (2012).[34]
• 
  Hormone levels after a single intramuscular injection of 5 mg estradiol valerate in oil in 17 postmenopausal women.[35] Assays were performed using EIA.[35] Estrone levels were likely overestimated, possibly due to cross reactivity of the assay with estrogen conjugates.[34] Source was Göretzlehner et al. (2002).[35]
• 
  Estradiol levels after single intramuscular injections of 5 mg of different estradiol esters in oil in about 10 premenopausal women each.[10] Assays were performed using RIA with CS.[10] Source was Oriowo et al. (1980).[10]
• 
  Estradiol levels after a single intramuscular injection of 10 mg estradiol valerate or 100 mg estradiol undecylate in oil both in 4 individuals each.[36] Subject characteristics and assay method were not described.[36] Source was Vermeulen (1975).[36]
• 
  Estradiol and DHEA levels after a single intramuscular injection of Gynodian Depot (4 mg estradiol valerate, 200 mg prasterone enanthate in oil) or Primogyn Depot (10 mg estradiol valerate in oil) in women.[37][38][39] Assays were performed using RIA.[38][39] Sources were Düsterberg & Wendt (1983) and Rauramo et al. (1980).[37][38][39]
• 
  Estradiol levels after a short intravenous infusion of 20 mg estradiol in aqueous solution or an intramuscular injection of equimolar doses of estradiol esters in oil solution in postmenopausal women.[28][29] Assays were performed using RIA with CS.[28][29] Source was Geppert (1975).[28][29]
• 
  Estradiol levels after an intramuscular injection of 10 mg estradiol valerate in oil or Climacteron (1 mg estradiol benzoate, 7.5 mg estradiol dienanthate in oil) in ovariectomized women.[40] Assays were performed using RIA.[40] Source was Sherwin et al. (1987).[40]
• 
  Simplified curves of estradiol levels after injection of different estradiol esters in women.[30] Source was Garza-Flores (1994).[30]

Hormone levels with estradiol cypionate by intramuscular injection

• 
  Estradiol levels after subcutaneous (s.c.) or intramuscular (i.m.) injection of 5 mg estradiol cypionate in aqueous suspension.[41] Assays were performed using enzyme immunoassay.[41] Source was Sierra-Ramírez et al. (2011).[41]
• 
  Estradiol levels at steady state (after the 3rd injection) with intramuscular injections of aqueous suspensions of 5 mg estradiol cypionate per month in premenopausal women.[42][43] Assays were performed using enzyme immunoassay and LC-MS/MS.[42][43] Sources were Rahimy et al. (1999) and Thurman et al. (2013).[42][43]
• 
  Estradiol levels after a single intramuscular injection of 1.0 to 1.5 mg of estradiol cypionate in oil in hypogonadal girls.[44] Assays were performed using radioimmunoassay with chromatographic separation.[44] Source was Rosenfield et al. (1973).[44]
• 
  Estradiol levels after single intramuscular injections of 5 mg of different estradiol esters in oil in premenopausal women.[10] Assays were performed using radioimmunoassay with chromatographic separation.[10] Source was Oriowo et al. (1980).[10]
• 
  Simplified curves of estradiol levels after injection of different estradiol esters in oil solution in women.[30] Source was Garza-Flores (1994).[30]
• 
  Estradiol cypionate levels after a single injection of 5 mg microcrystalline estradiol cypionate in aqueous suspension in women.[45] Assays were performed using LC-MS/MS. Source was Martins et al. (2019).[45]
• 
  Vaginal cornification with a single intramuscular injection of different estradiol esters in oil solution in women.[31] Source was Schwartz & Soule (1955).[31]

Hormone levels with estradiol enanthate by intramuscular injection

• 
  Estradiol levels after the most recent intramuscular injection during once-monthly 5 or 10 mg estradiol enanthate and 75 or 150 mg dihydroxyprogesterone acetophenide contraception in one premenopausal woman each.[19] Assays were performed using radioimmunoassay.[19] Source was Recio et al. (1986).[19]
• 
  Estradiol levels after a single intramuscular injection of 10 mg estradiol enanthate in three postmenopausal women.[20] Assays were performed using radioimmunoassay.[20] Source was Wiemeyer et al. (1986).[20]
• 
  Estradiol and prolactin levels after the most recent intramuscular injection during once-monthly 10 mg estradiol enanthate and 150 mg dihydroxyprogesterone acetophenide contraception in 10 premenopausal women.[46] Only four determinations were made: days 0, 10, 20, and 30.[46] Assays were performed using radioimmunoassay.[46] Source was Garza-Flores et al. (1989).[46]
• 
  Simplified curves of estradiol levels after an intramuscular injection of 10 mg estradiol enanthate (E2-EN) and 150 mg dihydroxyprogesterone acetophenide (DHPA) in oil solution with single or continuous once-monthly use in women.[47][30] Source was Garza-Flores (1994).[30]
• 
  Simplified curves of estradiol levels after injection of different estradiol esters in women.[30] Source was Garza-Flores (1994).[30]

Hormone levels with estradiol benzoate/estradiol dienanthate/testosterone enanthate benzilic acid hydrazone by intramuscular injection

• 
  Estradiol and testosterone levels after an intramuscular injection of 1 mg estradiol benzoate, 7.5 mg estradiol dienanthate, and 150 mg testosterone enanthate benzilic acid hydrazone in oil (brand name Climacteron) in ovariectomized women.[48] Assays were performed using immunoassays.[48] Source was Sherwin (1987).[48]
• 
  Estradiol levels after an intramuscular injection of 10 mg estradiol valerate in oil or Climacteron (1 mg estradiol benzoate, 7.5 mg estradiol dienanthate in oil) in ovariectomized women.[49] Assays were performed using RIA.[49] Source was Sherwin et al. (1987).[49]

Hormone levels with estradiol undecylate by intramuscular injection

• 
  Estradiol levels after a single intramuscular injection of 10 mg estradiol valerate in oil or 100 mg estradiol undecylate in oil both in 4 individuals each.[50] Subject characteristics and assay method were not described.[50] Source was Vermeulen (1975).[50]
• 
  Estradiol levels after a short intravenous infusion of 20 mg estradiol in aqueous solution or an intramuscular injection of equimolar doses of estradiol esters in oil solution in postmenopausal women.[28][29] Assays were performed using radioimmunoassay with chromatographic separation.[28][29] Sources were Geppert (1975) and Leyendecker et al. (1975).[28][29]
• 
  Estradiol, testosterone, luteinizing hormone, and follicle-stimulating hormone levels with an intramuscular injection of 32.3 mg estradiol undecylate in oil in 3 postmenopausal women.[28][29] Assays were performed using radioimmunoassay with chromatographic separation.[29][28] Sources were Geppert (1975) and Leyendecker et al. (1975).[28][29]
• 
  Estradiol, testosterone, and prolactin levels with 100 mg/month estradiol undecylate in oil by intramuscular injection in 14 to 28 men with prostate cancer.[51] Source was Jacobi & Altwein (1979).[51]

Hormone levels with polyestradiol phosphate by intramuscular injection

• 
  Estradiol and testosterone levels with a single intramuscular injection of 320 mg polyestradiol phosphate in men with prostate cancer.[24]
• 
  Estradiol and testosterone levels with polyestradiol phosphate 160, 240, or 320 mg once every 4 weeks by intramuscular injection in men with prostate cancer.[52]

Chemistry

Estradiol plus the fatty acid valeric acid (valerate) equals estradiol valerate, a C17β ester of estradiol and one of the most widely used estrogen esters.[53]

Polyestradiol phosphate, a polymer of estradiol phosphate, the C17β phosphoric acid ester of estradiol. It has on average of 13 repeat units.

Estradiol esters have an ester moiety, usually a straight-chain fatty acid (e.g., valeric acid) or an aromatic fatty acid (e.g., benzoic acid), attached at the C3 and/or C17β positions of the steroid nucleus. These alkoxy moieties are substituted in place of the hydroxyl groups present in the unesterified estradiol molecule. Fatty acid esters serve to increase the lipophilicity of estradiol, increasing its solubility in fat. This causes them to form a depot with intramuscular or subcutaneous injection and gives them a long duration when administered by these routes.

Some estradiol esters have other moieties instead of fatty acids as the esters. Such esters include sulfuric acid (as in estradiol sulfate), sulfamic acid (as in estradiol sulfamate), phosphoric acid (as in estradiol phosphate), glucuronic acid (as in estradiol glucuronide, and others (e.g., estramustine phosphate (estradiol 3-normustine 17β-phosphate)). These esters are all hydrophilic, and have greater water solubility than estradiol or fatty acid estradiol esters. Unlike fatty acid estradiol esters, water-soluble estradiol esters can be administered by intravenous injection.

A few estrogen esters are polymers. These include polyestradiol phosphate and polyestriol phosphate, which are polymers of estradiol phosphate and estriol phosphate monomers, respectively. The monomers are connected in both cases by phosphate groups via the C3 and C17β positions. Polyestradiol phosphate has an average polymer chain length of approximately 13 repeat units of estradiol phosphate.[23] That is, each polyestradiol phosphate molecule is a polymer consisting on average of 13 estradiol phosphate molecules bonded together.[23] These polymeric estrogen esters are hydrophilic and water-soluble. Upon intramuscular injection, they do not form a depot and instead are rapidly absorbed into the circulation. However, they are only slowly cleaved into monomers, and as a result, have a very long duration in the body even outlasting that of many longer-chain fatty-acid estrogen esters.

Chemical structures of estradiol and major estradiol esters

• 
  Estradiol
• 
  Estradiol acetate
• 
  Estradiol benzoate
• 
  Estradiol dipropionate
• 
  Estradiol valerate
• 
  Estradiol cypionate
• 
  Estradiol enantate
• 
  Estradiol undecylate
• 
  Polyestradiol phosphate

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.

See also

• Pharmacokinetics of estradiol
• List of estrogen esters
• List of estrogens
• Steroid ester
• Progestogen ester
• Androgen ester

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53. Shellenberger, T. E. (1986). "Pharmacology of estrogens". The Climacteric in Perspective. pp. 393–410. doi:10.1007/978-94-009-4145-8_36. ISBN 978-94-010-8339-3.

Further reading

• Vermeulen A (1975). "Longacting steroid preparations". Acta Clin Belg. 30 (1): 48–55. doi:10.1080/17843286.1975.11716973. PMID 1231448.
• Oriowo MA, Landgren BM, Stenström B, Diczfalusy E (1980). "A comparison of the pharmacokinetic properties of three estradiol esters". Contraception. 21 (4): 415–24. doi:10.1016/s0010-7824(80)80018-7. PMID 7389356.
• Düsterberg B, Nishino Y (1982). "Pharmacokinetic and pharmacological features of oestradiol valerate". Maturitas. 4 (4): 315–24. doi:10.1016/0378-5122(82)90064-0. PMID 7169965.
• Sang GW (1994). "Pharmacodynamic effects of once-a-month combined injectable contraceptives". Contraception. 49 (4): 361–85. doi:10.1016/0010-7824(94)90033-7. PMID 8013220.