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 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] [ additional citation(s) needed ] The durations of estrogen esters are not prolonged if they are given orally, vaginally, or by intravenous injection. [11]
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]
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 |
Δ8-Estradiol | 8,9-Dehydro-17β-estradiol | 68 | 72 | 0.15 | 0.25 | Estrogen |
Δ8-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 | 0.82–2.63 | 0.59–1.22 | ? | ? | 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 |
Δ4-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. |
Estrogen | Other names | RBA Tooltip Relative binding affinity (%)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) production 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]
Estrogen | Dose | Cmax | Tmax | 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. |
Estrogen | Form | Dose (mg) | Duration by dose (mg) | ||
---|---|---|---|---|---|
EPD | CICD | ||||
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 | |
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 | |
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. [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]
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.
Estrogen | Structure | Ester(s) | Relative mol. weight | Relative E2 contentb | log Pc | ||||
---|---|---|---|---|---|---|---|---|---|
Position(s) | Moiet(ies) | Type | Lengtha | ||||||
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 | – | 1.23f | 0.81f | 2.9g | ||
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. |
Estradiol valerate (EV), sold for use by mouth under the brand name Progynova and for use by injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen medication. It is used in hormone therapy for menopausal symptoms and low estrogen levels, hormone therapy for transgender people, and in hormonal birth control. It is also used in the treatment of prostate cancer. The medication is taken by mouth or by injection into muscle or fat once every 1 to 4 weeks.
Polyestradiol phosphate (PEP), sold under the brand name Estradurin, is an estrogen medication which is used primarily in the treatment of prostate cancer in men. It is also used in women to treat breast cancer, as a component of hormone therapy to treat low estrogen levels and menopausal symptoms, and as a component of feminizing hormone therapy for transgender women. It is given by injection into muscle once every four weeks.
Combined injectable contraceptives (CICs) are a form of hormonal birth control for women. They consist of monthly injections of combined formulations containing an estrogen and a progestin to prevent pregnancy.
Estradiol benzoate (EB), sold under the brand name Progynon-B among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for transgender women, and in the treatment of gynecological disorders. It is also used in the treatment of prostate cancer in men. Estradiol benzoate is used in veterinary medicine as well. When used clinically, the medication is given by injection into muscle usually two to three times per week.
Estradiol cypionate (EC), sold under the brand name Depo-Estradiol among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for trans women, and in hormonal birth control for women. It is given by injection into muscle once every 1 to 4 weeks.
Estradiol enantate, also spelled estradiol enanthate and sold under the brand names Perlutal and Topasel among others, is an estrogen medication which is used in hormonal birth control for women. It is formulated in combination with dihydroxyprogesterone acetophenide, a progestin, and is used specifically as a combined injectable contraceptive. Estradiol enantate is not available for medical use alone. The medication, in combination with DHPA, is given by injection into muscle once a month.
Estradiol undecylate, also known as estradiol undecanoate and formerly sold under the brand names Delestrec and Progynon Depot 100 among others, is an estrogen medication which has been used in the treatment of prostate cancer in men. It has also been used as a part of hormone therapy for transgender women. Although estradiol undecylate has been used in the past, it was discontinued and hence is no longer available. The medication has been given by injection into muscle usually once a month.
Estradiol dipropionate (EDP), sold under the brand names Agofollin, Di-Ovocylin, and Progynon DP among others, is an estrogen medication which has been used in hormone therapy for menopausal symptoms and low estrogen levels in women and in the treatment of gynecological disorders. It has also been used in feminizing hormone therapy for transgender women and in the treatment of prostate cancer in men. Although widely used in the past, estradiol dipropionate has largely been discontinued and is mostly no longer available today. It appears to remain in use only in Japan, Macedonia, and Australia. Estradiol dipropionate is given by injection into muscle at intervals ranging from once or twice a week to once every week and a half to two weeks.
Estradiol stearate (E2-17-St), also known as estradiol octadecanoate and sold under the brand name Depofollan, is a naturally occurring estrogen and an estrogen ester – specifically, the C17β stearate ester of estradiol. It occurs in the body as a very long-lasting metabolite and prohormone of estradiol. The compound is one of the components that collectively constitute lipoidal estradiol, another of which is estradiol palmitate. It is extremely lipophilic and hydrophobic. Estradiol stearate has no affinity for the estrogen receptor, requiring transformation into estradiol via esterases for its estrogenic activity. The compound does not bind to sex hormone-binding globulin or α-fetoprotein, instead being transported by lipoproteins such as high-density lipoprotein and low-density lipoprotein.
A steroid ester is an ester of a steroid. They include androgen esters, estrogen esters, progestogen esters, and corticosteroid esters. Steroid esters may be naturally occurring/endogenous like DHEA sulfate or synthetic like estradiol valerate. Esterification is useful because it is often able to render the parent steroid into a prodrug of itself with altered chemical properties such as improved metabolic stability, water solubility, and/or lipophilicity. This, in turn, can enhance pharmacokinetics, for instance by improving the steroid's bioavailability and/or conferring depot activity and hence an extended duration with intramuscular or subcutaneous injection.
Estradiol benzoate butyrate (EBB), sold under the brand names Neolutin N, Redimen, Soluna, and Unijab and formerly known under the developmental code name Unimens, is an estrogen medication which is used in hormonal birth control for women. It is formulated in combination with dihydroxyprogesterone acetophenide, a progestin, and is used specifically as a combined injectable contraceptive. EBB is not available for medical use alone. The medication, in combination with DHPA, is given by injection into muscle once a month.
Lipoidal estradiol (LE2) is the variety of endogenous C17β long-chain fatty acid esters of estradiol which are formed as metabolites of estradiol. Important examples of these esters include estradiol arachidonate, estradiol lineolate, estradiol oleate, estradiol palmitate, and estradiol stearate. LE2 are estrogens but do not bind to the estrogen receptor, instead acting as prohormones of estradiol. Relative to estradiol, they have far longer-lasting durations of effect due to their much slower rates of metabolism and clearance. It has been hypothesized that LE2 may serve as a store of estrogen for when estradiol levels become low. LE2 are highly lipophilic and hydrophobic and are found in highest concentrations in adipose tissue and other estrogen-sensitive tissues and in low but detectable concentrations in circulation, with none excreted in urine. They have been referred to as the "endogenous counterparts of the synthetic esters of estrogens" like estradiol valerate and estradiol cypionate.
Estradiol (E2) is a medication and naturally occurring steroid hormone. It is an estrogen and is used mainly in menopausal hormone therapy and to treat low sex hormone levels in women. It is also used in hormonal birth control for women, in feminizing hormone therapy for transgender women, and in the treatment of hormone-sensitive cancers like prostate cancer in men and breast cancer in women, among other uses. Estradiol can be taken by mouth, held and dissolved under the tongue, as a gel or patch that is applied to the skin, in through the vagina, by injection into muscle or fat, or through the use of an implant that is placed into fat, among other routes.
Estradiol glucuronide, or estradiol 17β-D-glucuronide, is a conjugated metabolite of estradiol. It is formed from estradiol in the liver by UDP-glucuronyltransferase via attachment of glucuronic acid and is eventually excreted in the urine by the kidneys. It has much higher water solubility than does estradiol. Glucuronides are the most abundant estrogen conjugates.
Estrone glucuronide, or estrone-3-D-glucuronide, is a conjugated metabolite of estrone. It is formed from estrone in the liver by UDP-glucuronyltransferase via attachment of glucuronic acid and is eventually excreted in the urine by the kidneys. It has much higher water solubility than does estrone. Glucuronides are the most abundant estrogen conjugates and estrone glucuronide is the dominant metabolite of estradiol.
Estriol (E3), sold under the brand name Ovestin among others, is an estrogen medication and naturally occurring steroid hormone which is used in menopausal hormone therapy. It is also used in veterinary medicine as Incurin to treat urinary incontinence due to estrogen deficiency in dogs. The medication is taken by mouth in the form of tablets, as a cream that is applied to the skin, as a cream or pessary that is applied in the vagina, and by injection into muscle.
Estrone sulfate (E1S) is an estrogen medication and naturally occurring steroid hormone. It is used in menopausal hormone therapy among other indications. As the sodium salt, it is the major estrogen component of conjugated estrogens (Premarin) and esterified estrogens. In addition, E1S is used on its own as the piperazine salt estropipate. The compound also occurs as a major and important metabolite of estradiol and estrone. E1S is most commonly taken by mouth, but in the form of Premarin can also be taken by parenteral routes such as transdermal, vaginal, and injection.
The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.
The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.
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.