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 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] The residual affinity of estrogen esters for the estrogen receptor in bioassays may simply 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]

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.[18] Estradiol enantate (ester of 7 carbons) has a duration of at least 30 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.[12][21][22]

Pharmacokinetics of three estradiol esters by intramuscular injection
EstrogenDosePeak levelsTime to peakDuration
Estradiol benzoate5 mgE2: 940 pg/mL
E1: 343 pg/mL		E2: 1.8 days
E1: 2.4 days		4–5 days
Estradiol valerate5 mgE2: 667 pg/mL
E1: 324 pg/mL		E2: 2.2 days
E1: 2.7 days		7–8 days
Estradiol cypionate5 mgE2: 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.
Parenteral potencies and durations of steroidal estrogens
EstrogenFormMajor brand name(s)EPD (14 days)CIC-D (month)Duration
EstradiolOil solution–40–60 mg–1–10 mg ≈ 1–2 days
Aqueous suspensionaMego-E?3.5 mg3.5 mg ≈ >5 days
MicrospheresJuvenum-E, Juvenum?–1 mg ≈ 30 days
Estradiol benzoateOil solutionProgynon-B25–35 mg–5 mg ≈ 3–6 days
Aqueous suspensionAgofollin-Depot20 mg–10 mg ≈ 16–21 days
Estradiol dipropionateOil solutionAgofollin, Di-Ovocyclin, Progynon DP25–30 mg–5 mg ≈ 5–8 days
Estradiol valerateOil solutionDelestrogen, Progynon Depot, Mesigyna20–30 mg5 mg5 mg ≈ 7–8 days; 10 mg ≈ 10–14 days;
40 mg ≈ 14–21 days; 100 mg ≈ 21–28 days
Estradiol cypionateOil solutionDepo-Estradiol, Depofemin20–30 mg–5 mg ≈ 11–14 days
Aqueous suspensionaCyclofem, Lunelle?5 mg5 mg ≈ 14–24 days
Estradiol benzoate butyrateaOil solutionRedimen, Soluna, Unijab?10 mg10 mg ≈ 21 days
Estradiol enanthateaOil solutionPerlutal, Topasel, Yectames?5–10 mg10 mg ≈ 20–30 days
Estradiol undecylateOil solutionDelestrec, Progynon Depot 100?–10–20 mg ≈ 40–60 days; 25–50 mg ≈ 60–120 days
Polyestradiol phosphateAqueous solutionEstradurin40–60 mg–40 mg ≈ 30 days; 80 mg ≈ 60 days;
160 mg ≈ 120 days
EstroneOil solutionKestrin, Theelin?–1–2 mg ≈ 2–3 days
Aqueous suspensionEstrone Aqueous Suspension?–?
EstriolOil solution–?–1–2 mg ≈ 1–4 days
Polyestriol phosphateAqueous solutionGynäsan, Klimadurin, Triodurin?–50 mg ≈ 30 days; 80 mg ≈ 60 days
Notes: All by intramuscular injection. 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 is 5 to 7 mg/week. An effective ovulation-inhibiting dose of estradiol undecylate is 20–30 mg/month. Footnotes: a = Available only in combined injectable contraceptives (i.e., not available alone). 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 intramuscular estradiol benzoate
  • 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.[12] Assays were performed using radioimmunoassay with chromatographic separation.[12] Source was Oriowo et al. (1980).[12]
  • Estradiol levels after an intravenous injection of 20 mg estradiol or an intramuscular injection of equimolar doses of different estradiol esters in oil in 3 postmenopausal women each.[28] Assays were performed using radioimmunoassay with chromatographic separation.[28] Source was Leyendecker et al. (1975).[28]
  • Idealized curves of estradiol levels after injection of different estradiol esters in women.[29] Source was Garza-Flores (1994).[29]
  • Vaginal cornification with a single intramuscular injection of different estradiol esters in oil solution in women.[30] Source was Schwartz & Soule (1955).[30]
Hormone levels with intramuscular estradiol dipropionate
  • Estradiol levels after a single intramuscular injection of 50 μg/kg estradiol dipropionate in oil in pubertal girls.[31] This dose would be 1 mg in a 50-kg (110-lb) girl.[31] Source was Presl et al. (1976).[31]
  • Vaginal cornification with a single intramuscular injection of different estradiol esters in oil solution in women.[30] Source was Schwartz & Soule (1955).[30]
Hormone levels with intramuscular estradiol valerate
  • Estrogen levels after a single intramuscular injection of 10 mg estradiol valerate in oil in 24 postmenopausal women.[32] Determinations were made for both Progynon Depot 10 and Estradiol Depot 10, for a total of 48 measurements per point.[32] Assays were performed using GC/MS-NCI/SIM.[32] Source was Schug et al. (2012).[32]
  • Hormone levels after a single intramuscular injection of 5 mg estradiol valerate in oil in 17 postmenopausal women.[33] Assays were performed using enzyme immunoassay.[33] Estrone levels were likely overestimated, possibly due to cross reactivity of the assay with estrogen conjugates.[32] Source was Göretzlehner et al. (2002).[33]
  • Estradiol levels after single intramuscular injections of 5 mg of different estradiol esters in oil in about 10 premenopausal women each.[12] Assays were performed using radioimmunoassay with chromatographic separation.[12] Source was Oriowo et al. (1980).[12]
  • Estradiol levels after a single intramuscular injection of 10 mg estradiol valerate or 100 mg estradiol undecylate in oil both in 4 individuals each.[21] Subject characteristics and assay method were not described.[21] Source was Vermeulen (1975).[21]
  • 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.[34][35][36] Assays were performed using radioimmunoassay.[35][36] Sources were Düsterberg & Wendt (1983) and Rauramo et al. (1980).[34][35][36]
  • Estradiol levels after an intravenous injection of 20 mg estradiol or an intramuscular injection of equimolar doses of different estradiol esters in oil in 3 postmenopausal women each.[37] Assays were performed using radioimmunoassay with chromatographic separation.[37] Source was Leyendecker et al. (1975).[37]
  • Idealized curves of estradiol levels after injection of different estradiol esters in women.[29] Source was Garza-Flores (1994).[29]
Hormone levels with intramuscular estradiol cypionate
  • Estradiol levels after subcutaneous (s.c.) or intramuscular (i.m.) injection of 5 mg estradiol cypionate in aqueous suspension.[38] Assays were performed using enzyme immunoassay.[38] Source was Sierra-Ramírez et al. (2011).[38]
  • 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.[39][40] Assays were performed using enzyme immunoassay and LC-MS/MS.[39][40] Sources were Rahimy et al. (1999) and Thurman et al. (2013).[39][40]
  • Estradiol levels after a single intramuscular injection of 1.0 to 1.5 mg of estradiol cypionate in oil in hypogonadal girls.[41] Assays were performed using radioimmunoassay with chromatographic separation.[41] Source was Rosenfield et al. (1973).[41]
  • Estradiol levels after single intramuscular injections of 5 mg of different estradiol esters in oil in premenopausal women.[12] Assays were performed using radioimmunoassay with chromatographic separation.[12] Source was Oriowo et al. (1980).[12]
  • Idealized curves of estradiol levels after injection of different estradiol esters in oil solution in women.[29] Source was Garza-Flores (1994).[29]
  • Estradiol cypionate levels after a single injection of 5 mg microcrystalline estradiol cypionate in aqueous suspension in women.[42] Assays were performed using LC-MS/MS. Source was Martins et al. (2019).[42]
  • Vaginal cornification with a single intramuscular injection of different estradiol esters in oil solution in women.[30] Source was Schwartz & Soule (1955).[30]
Hormone levels with intramuscular estradiol enantate
  • Estradiol levels after the most recent intramuscular injection during once-monthly 5 or 10 mg estradiol enantate 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 enantate in three postmenopausal women.[20] Assays were performed using radioimmunoassay.[20] No chromatographic separation was mentioned.[20] Source was Wiemeyer et al. (1986).[20]
  • Estradiol and prolactin levels after the most recent intramuscular injection during once-monthly 10 mg estradiol enantate and 150 mg dihydroxyprogesterone acetophenide contraception in 10 premenopausal women.[43] Only four determinations were made: days 0, 10, 20, and 30.[43] Assays were performed using radioimmunoassay.[43] Source was Garza-Flores et al. (1989).[43]
  • Idealized curves of estradiol levels after injection of different estradiol esters in women.[29] Source was Garza-Flores (1994).[29]
Hormone levels with intramuscular estradiol undecylate
  • Estradiol levels after a single intramuscular injection of 10 mg estradiol valerate or 100 mg estradiol undecylate in oil both in 4 individuals each.[21] Subject characteristics and assay method were not described.[21] Source was Vermeulen (1975).[21]
  • Estradiol levels after an intravenous injection of 20 mg estradiol or an intramuscular injection of equimolar doses of different estradiol esters in oil in 3 postmenopausal women each.[44][45] Assays were performed using radioimmunoassay with chromatographic separation.[44][45] Source was Leyendecker et al. (1975).[44][45]
  • Estradiol, testosterone, and prolactin levels with 100 mg/month estradiol undecylate by intramuscular injection in men with prostate cancer.[46] Source was Jacobi & Altwein (1979).[46]
Hormone levels with polyestradiol phosphate
  • Estradiol and testosterone levels over the course of 12 weeks following a single intramuscular injection of 320 mg polyestradiol phosphate in men.[24]
  • Estradiol levels with intramuscular injection of different dosages of polyestradiol phosphate once every 4 weeks for 6 months.[47]

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.[48]
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
Structural properties of selected estradiol esters
EstrogenStructureEster(s)Relative
mol. weight		Relative
E2 contentb		logPc
Position(s)Moiet(ies)TypeLengtha
Estradiol
––––1.001.004.0
Estradiol acetate
C3Ethanoic acidStraight-chain fatty acid21.150.872.8–3.9
Estradiol benzoate
C3Benzenecarboxylic acidAromatic fatty acid– (~4–5)1.380.724.5–5.7
Estradiol dipropionate
C3, C17βPropanoic acid (×2)Straight-chain fatty acid3 (×2)1.410.714.3
Estradiol valerate
C17βPentanoic acidStraight-chain fatty acid51.310.765.8–6.0
Estradiol cypionate
C17βCyclopentylpropanoic acidAromatic fatty acid– (~6)1.460.696.5–7.1
Estradiol benzoate butyrate
C3, C17βBenzoic acid, butyric acidMixed fatty acid– (~6, 2)1.640.615.9
Estradiol enantate
C17βHeptanoic acidStraight-chain fatty acid71.410.717.0
Estradiol dienantate
C3, C17βHeptanoic acid (×2)Straight-chain fatty acid7 (×2)1.820.558.1–9.1
Estradiol undecylate
C17βUndecanoic acidStraight-chain fatty acid111.620.629.2
Estradiol stearate
C17βOctadecanoic acidStraight-chain fatty acid181.980.5112.2
Estradiol distearate
C3, C17βOctadecanoic acid (×2)Straight-chain fatty acid18 (×2)2.960.3420.2
Estradiol sulfate
C3Sulfuric acidWater-soluble conjugate–1.290.770.3–3.8
Estradiol glucuronide
C17βGlucuronic acidWater-soluble conjugate–1.650.612.1–2.7
Estramustine phosphated
C3, C17βNormustine, phosphoric acidWater-soluble conjugate–1.910.522.9–5.0
Polyestradiol phosphatee
C3–C17βPhosphoric acidWater-soluble conjugate–1.23f0.81f2.9g
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 potency). c = Experimental or predicted octanol/water partition coefficient (i.e., lipophilicity/hydrophobicity). Retrieved from PubChem 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

References
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