Estrone (medication)

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Estrone (medication)
Estron.svg
Estrone molecule ball.png
Clinical data
Trade names Estragyn, Kestrin, Theelin, many others
Other namesOestrone; E1; Follicular hormone; Folliculin; Folliculine; Follikulin; Theelin; Ketohydroxyestrin; Oxohydroxyestrin; 3-Hydroxyestra-1,3,5(10)-trien-17-one
Routes of
administration 		Intramuscular injection, vaginal, by mouth (as E2/E1/E3 Tooltip estradiol/estrone/estriol or as estrone sulfate) [1] [2] [3] [4] [5]
Drug class Estrogen
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Oral: very low [6]
Protein binding 96.0–98.0%: [5] [7]
• Albumin: ~80%
• SHBG: ~16%
• Free: 2.0–4.0%
Metabolism Liver (via hydroxylation, sulfation, glucuronidation) [5]
Metabolites • Estradiol [5]
• Estrone sulfate [5]
• Estrone glucuronide [5]
• Others [5]
Elimination half-life IV Tooltip Intravenous injection: 20–30 minutes [5]
Excretion Urine [5]
Identifiers
  • (8R,9S,13S,14S)-3-hydroxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-17-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C18H22O2
Molar mass 270.372 g·mol−1
3D model (JSmol)
Melting point 254.5 °C (490.1 °F)
  • O=C4[C@]3(CC[C@@H]2c1ccc(O)cc1CC[C@H]2[C@@H]3CC4)C
  • InChI=1S/C18H22O2/c1-18-9-8-14-13-5-3-12(19)10-11(13)2-4-15(14)16(18)6-7-17(18)20/h3,5,10,14-16,19H,2,4,6-9H2,1H3/t14-,15-,16+,18+/m1/s1 X mark.svgN
  • Key:DNXHEGUUPJUMQT-CBZIJGRNSA-N X mark.svgN
   (verify)

Estrone (E1), sold under the brand names Estragyn, Kestrin, and Theelin among many others, is an estrogen medication and naturally occurring steroid hormone which has been used in menopausal hormone therapy and for other indications. [5] [8] [9] [10] [1] [2] It has been provided as an aqueous suspension or oil solution given by injection into muscle and as a vaginal cream applied inside of the vagina. [1] [2] [3] [4] It can also be taken by mouth as estradiol/estrone/estriol (brand name Hormonin) and in the form of prodrugs like estropipate (estrone sulfate; brand name Ogen) and conjugated estrogens (mostly estrone sulfate; brand name Premarin). [11] [2] [5]

Contents

Side effects of estrogens like estrone include breast tenderness, breast enlargement, headache, nausea, fluid retention, and edema, among others. [5] Estrone is a naturally occurring and bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol. [5] It is a relatively weak estrogen, with much lower activity than estradiol. [5] However, estrone is converted in the body into estradiol, which provides most or all of its estrogenic potency. [5] [12] As such, estrone is a prodrug of estradiol. [5]

Estrone was first discovered in 1929, and was introduced for medical use shortly thereafter. [13] [14] [15] Although it has been used clinically in the past, estrone has largely been discontinued and is mostly no longer marketed. [9] [16]

Medical uses

Estrone has been marketed in intramuscular and vaginal formulations and was used as an estrogen in the treatment of symptoms of low estrogen levels such as hot flashes and vaginal atrophy in postmenopausal or ovariectomized women. [14] Estrone has also been used as an antigonadotropin and form of high-dose estrogen to treat prostate cancer in men as well as a form of high-dose estrogen to treat breast cancer in women. [17] [18] It has since largely been discontinued and is mostly no longer available, having been superseded by other estrogens with better potency and pharmacokinetics (namely oral bioavailability and duration). [19] [16]

Regardless of route of administration, if estrone is taken by a woman with an intact uterus, it should be combined with a progestogen such as progesterone to offset the risk of endometrial hyperplasia and cancer. [1] [5]

Estrone has been used by intramuscular injection at a dosage of 0.1 to 2 mg per week, or 0.1 to 0.5 mg given 2 or 3 times per week, for the treatment of menopausal symptoms such as hot flashes and vaginal atrophy, [20] [21] and at a dosage of 0.1 to 1.0 mg weekly in single or divided doses for the treatment of female hypogonadism, surgical castration, and primary ovarian failure. [22] The range of single doses of estrone by intramuscular injection that are typically used clinically in women is 0.1 to 5 mg. [23] High doses of intramuscular estrone have been used for prostate cancer in men and for breast cancer in women. [17] [18]

Available forms

Estrone for intramuscular injection was provided as 1, 2, 2.5, 3, 4, and 5 mg/mL aqueous suspensions and/or oil solutions. [24] [17] [25] [26] [27] [28] It has also been available in the form of vaginal creams (1 mg/g (0.1%)) and suppositories (0.2 mg, 0.25 mg) as well as subcutaneous pellet implants and oral tablets (1.25 mg). [23] [3] [1] [25] [26] [27] A combined oral tablet formulation containing estradiol (0.3 mg, 0.6 mg), estrone (0.7 mg, 1.4 mg), and estriol (0.135 mg, 0.27 mg) has been marketed under the brand name Hormonin as well. [25] [29] [11] [30] [31] In addition, a combined injectable preparation containing estrone (1 mg) and progesterone (10 mg) is available in the form of ampoules under the brand name Synergon. [32] [33] [34] [35]

Although estrone by intramuscular injection was originally formulated as an oil solution, it was soon replaced by formulations of estrone as an aqueous suspension due to a longer duration of action of these formulations. [36] [37] [27] [18] [38] [39] [40]

Side effects

Side effects of estrogens like estrone include breast tenderness, breast enlargement, headache, nausea, fluid retention, and edema, among others. [5] It can also cause endometrial hyperplasia. [41] [42] [43]

Pharmacology

Pharmacodynamics

Mechanism of action

Estrone is an estrogen, specifically an agonist of the estrogen receptors (ERs) ERα and ERβ. [5] [44] It is a far less potent estrogen than is estradiol, and as such is a relatively weak estrogen. [5] [44] Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol. [45] According to one study, the relative binding affinities of estrone for the human ERα and ERβ were 4.0% and 3.5% of those estradiol, respectively, and the relative transactivational capacities of estrone at the ERα and ERβ were 2.6% and 4.3% of those of estradiol, respectively. [44] In accordance, the estrogenic activity of estrone has been reported to be approximately 4% of that of estradiol. [5] Other studies have reported that estrone has about one-tenth of the potency of estradiol in activating the ERs in vitro. [46] [47] [48] Because estrone can be transformed into estradiol, which is far more potent as an estrogen in comparison, most or all of the estrogenic potency of estrone in vivo is actually due to conversion into estradiol. [5] [12] As such, similarly to the case of estrone sulfate, estrone is considered to be a prodrug of estradiol. [5] [49] Some in vitro research has suggested that estrone might be able to partially antagonize the actions of estradiol, [50] [51] [52] but this does not appear to be of clinical significance. [5] [53] [54] [55] In contrast to estradiol and estriol, estrone is not a ligand of the G protein-coupled estrogen receptor (affinity >10,000 nM). [56]

Affinities of estrogen receptor ligands for the ERα and ERβ
Ligand Other names Relative binding affinities (RBA, %)a Absolute binding affinities (Ki, nM)aAction
ERα ERβ ERα ERβ
Estradiol E2; 17β-Estradiol1001000.115 (0.04–0.24)0.15 (0.10–2.08)Estrogen
EstroneE1; 17-Ketoestradiol16.39 (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-E212.65 (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-E24.03.04.919Estrogen
Alfatradiol 17α-Estradiol20.5 (7–80.1)8.195 (2–42)0.2–0.520.43–1.2Metabolite
16-Epiestriol 16β-Hydroxy-17β-estradiol7.795 (4.94–63)50 ? ?Metabolite
17-Epiestriol 16α-Hydroxy-17α-estradiol55.45 (29–103)79–80 ? ?Metabolite
16,17-Epiestriol 16β-Hydroxy-17α-estradiol1.013 ? ?Metabolite
2-Hydroxyestradiol 2-OH-E222 (7–81)11–352.51.3Metabolite
2-Methoxyestradiol 2-MeO-E20.0027–2.01.0 ? ?Metabolite
4-Hydroxyestradiol 4-OH-E213 (8–70)7–561.01.9Metabolite
4-Methoxyestradiol 4-MeO-E22.01.0 ? ?Metabolite
2-Hydroxyestrone 2-OH-E12.0–4.00.2–0.4 ? ?Metabolite
2-Methoxyestrone 2-MeO-E1<0.001–<1<1 ? ?Metabolite
4-Hydroxyestrone 4-OH-E11.0–2.01.0 ? ?Metabolite
4-Methoxyestrone 4-MeO-E1<1<1 ? ?Metabolite
16α-Hydroxyestrone 16α-OH-E1; 17-Ketoestriol2.0–6.535 ? ?Metabolite
2-Hydroxyestriol 2-OH-E32.01.0 ? ?Metabolite
4-Methoxyestriol 4-MeO-E31.01.0 ? ?Metabolite
Estradiol sulfate E2S; Estradiol 3-sulfate<1<1 ? ?Metabolite
Estradiol disulfate Estradiol 3,17β-disulfate0.0004 ? ? ?Metabolite
Estradiol 3-glucuronide E2-3G0.0079 ? ? ?Metabolite
Estradiol 17β-glucuronide E2-17G0.0015 ? ? ?Metabolite
Estradiol 3-gluc. 17β-sulfate E2-3G-17S0.0001 ? ? ?Metabolite
Estrone sulfate E1S; Estrone 3-sulfate<1<1>10>10Metabolite
Estradiol benzoate EB; Estradiol 3-benzoate10 ? ? ?Estrogen
Estradiol 17β-benzoate E2-17B11.332.6 ? ?Estrogen
Estrone methyl ether Estrone 3-methyl ether0.145 ? ? ?Estrogen
ent-Estradiol 1-Estradiol1.31–12.349.44–80.07 ? ?Estrogen
Equilin 7-Dehydroestrone13 (4.0–28.9)13.0–490.790.36Estrogen
Equilenin 6,8-Didehydroestrone2.0–157.0–200.640.62Estrogen
17β-Dihydroequilin 7-Dehydro-17β-estradiol7.9–1137.9–1080.090.17Estrogen
17α-Dihydroequilin 7-Dehydro-17α-estradiol18.6 (18–41)14–320.240.57Estrogen
17β-Dihydroequilenin 6,8-Didehydro-17β-estradiol35–6890–1000.150.20Estrogen
17α-Dihydroequilenin 6,8-Didehydro-17α-estradiol20490.500.37Estrogen
Δ8-Estradiol 8,9-Dehydro-17β-estradiol68720.150.25Estrogen
Δ8-Estrone 8,9-Dehydroestrone19320.520.57Estrogen
Ethinylestradiol EE; 17α-Ethynyl-17β-E2120.9 (68.8–480)44.4 (2.0–144)0.02–0.050.29–0.81Estrogen
Mestranol EE 3-methyl ether ?2.5 ? ?Estrogen
Moxestrol RU-2858; 11β-Methoxy-EE35–435–200.52.6Estrogen
Methylestradiol 17α-Methyl-17β-estradiol7044 ? ?Estrogen
Diethylstilbestrol DES; Stilbestrol129.5 (89.1–468)219.63 (61.2–295)0.040.05Estrogen
Hexestrol Dihydrodiethylstilbestrol153.6 (31–302)60–2340.060.06Estrogen
Dienestrol Dehydrostilbestrol37 (20.4–223)56–4040.050.03Estrogen
Benzestrol (B2) –114 ? ? ?Estrogen
Chlorotrianisene TACE1.74 ?15.30 ?Estrogen
Triphenylethylene TPE0.074 ? ? ?Estrogen
Triphenylbromoethylene TPBE2.69 ? ? ?Estrogen
Tamoxifen ICI-46,4743 (0.1–47)3.33 (0.28–6)3.4–9.692.5SERM
Afimoxifene 4-Hydroxytamoxifen; 4-OHT100.1 (1.7–257)10 (0.98–339)2.3 (0.1–3.61)0.04–4.8SERM
Toremifene 4-Chlorotamoxifen; 4-CT ? ?7.14–20.315.4SERM
Clomifene MRL-4125 (19.2–37.2)120.91.2SERM
Cyclofenil F-6066; Sexovid151–152243 ? ?SERM
Nafoxidine U-11,000A30.9–44160.30.8SERM
Raloxifene –41.2 (7.8–69)5.34 (0.54–16)0.188–0.5220.2SERM
Arzoxifene LY-353,381 ? ?0.179 ?SERM
Lasofoxifene CP-336,15610.2–16619.00.229 ?SERM
Ormeloxifene Centchroman ? ?0.313 ?SERM
Levormeloxifene 6720-CDRI; NNC-460,0201.551.88 ? ?SERM
Ospemifene Deaminohydroxytoremifene0.82–2.630.59–1.22 ? ?SERM
Bazedoxifene – ? ?0.053 ?SERM
Etacstil GW-56384.3011.5 ? ?SERM
ICI-164,384 –63.5 (3.70–97.7)1660.20.08Antiestrogen
Fulvestrant ICI-182,78043.5 (9.4–325)21.65 (2.05–40.5)0.421.3Antiestrogen
Propylpyrazoletriol PPT49 (10.0–89.1)0.120.4092.8ERα agonist
16α-LE2 16α-Lactone-17β-estradiol14.6–570.0890.27131ERα agonist
16α-Iodo-E2 16α-Iodo-17β-estradiol30.22.30 ? ?ERα agonist
Methylpiperidinopyrazole MPP110.05 ? ?ERα antagonist
Diarylpropionitrile DPN0.12–0.256.6–1832.41.7ERβ agonist
8β-VE2 8β-Vinyl-17β-estradiol0.3522.0–8312.90.50ERβ agonist
Prinaberel ERB-041; WAY-202,0410.2767–72 ? ?ERβ agonist
ERB-196 WAY-202,196 ?180 ? ?ERβ agonist
Erteberel SERBA-1; LY-500,307 ? ?2.680.19ERβ agonist
SERBA-2 – ? ?14.51.54ERβ agonist
Coumestrol –9.225 (0.0117–94)64.125 (0.41–185)0.14–80.00.07–27.0Xenoestrogen
Genistein –0.445 (0.0012–16)33.42 (0.86–87)2.6–1260.3–12.8Xenoestrogen
Equol –0.2–0.2870.85 (0.10–2.85) ? ?Xenoestrogen
Daidzein –0.07 (0.0018–9.3)0.7865 (0.04–17.1)2.085.3Xenoestrogen
Biochanin A –0.04 (0.022–0.15)0.6225 (0.010–1.2)1748.9Xenoestrogen
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-PN4.4 ? ? ?Xenoestrogen
Quercetin –<0.001–0.010.002–0.040 ? ?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-Zearalanol48–111 ? ? ?Xenoestrogen
Taleranol β-Zearalanol16 (13–17.8)140.80.9Xenoestrogen
Zearalenone ZEN7.68 (2.04–28)9.45 (2.43–31.5) ? ?Xenoestrogen
Zearalanone ZAN0.51 ? ? ?Xenoestrogen
Bisphenol A BPA0.0315 (0.008–1.0)0.135 (0.002–4.23)19535Xenoestrogen
Endosulfan EDS<0.001–<0.01<0.01 ? ?Xenoestrogen
Kepone Chlordecone0.0069–0.2 ? ? ?Xenoestrogen
o,p'-DDT –0.0073–0.4 ? ? ?Xenoestrogen
p,p'-DDT –0.03 ? ? ?Xenoestrogen
Methoxychlor p,p'-Dimethoxy-DDT0.01 (<0.001–0.02)0.01–0.13 ? ?Xenoestrogen
HPTE Hydroxychlor; p,p'-OH-DDT1.2–1.7 ? ? ?Xenoestrogen
Testosterone T; 4-Androstenolone<0.0001–<0.01<0.002–0.040>5000>5000Androgen
Dihydrotestosterone DHT; 5α-Androstanolone0.01 (<0.001–0.05)0.0059–0.17221–>500073–1688Androgen
Nandrolone 19-Nortestosterone; 19-NT0.010.2376553Androgen
Dehydroepiandrosterone DHEA; Prasterone0.038 (<0.001–0.04)0.019–0.07245–1053163–515Androgen
5-Androstenediol A5; Androstenediol6173.60.9Androgen
4-Androstenediol –0.50.62319Androgen
4-Androstenedione A4; Androstenedione<0.01<0.01>10000>10000Androgen
3α-Androstanediol 3α-Adiol0.070.326048Androgen
3β-Androstanediol 3β-Adiol3762Androgen
Androstanedione 5α-Androstanedione<0.01<0.01>10000>10000Androgen
Etiocholanedione 5β-Androstanedione<0.01<0.01>10000>10000Androgen
Methyltestosterone 17α-Methyltestosterone<0.0001 ? ? ?Androgen
Ethinyl-3α-androstanediol 17α-Ethynyl-3α-adiol4.0<0.07 ? ?Estrogen
Ethinyl-3β-androstanediol 17α-Ethynyl-3β-adiol505.6 ? ?Estrogen
Progesterone P4; 4-Pregnenedione<0.001–0.6<0.001–0.010 ? ?Progestogen
Norethisterone NET; 17α-Ethynyl-19-NT0.085 (0.0015–<0.1)0.1 (0.01–0.3)1521084Progestogen
Norethynodrel 5(10)-Norethisterone0.5 (0.3–0.7)<0.1–0.221453Progestogen
Tibolone 7α-Methylnorethynodrel0.5 (0.45–2.0)0.2–0.076 ? ?Progestogen
Δ4-Tibolone 7α-Methylnorethisterone0.069–<0.10.027–<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.
Relative affinities of estrogens for steroid hormone receptors and blood proteins
Estrogen Relative binding affinities (%)
ER Tooltip Estrogen receptor AR Tooltip Androgen receptor PR Tooltip Progesterone receptor GR Tooltip Glucocorticoid receptor MR Tooltip Mineralocorticoid receptor SHBG Tooltip Sex hormone-binding globulin CBG Tooltip Corticosteroid binding globulin
Estradiol 1007.92.60.60.138.7–12<0.1
Estradiol benzoate  ? ? ? ? ?<0.1–0.16<0.1
Estradiol valerate 2 ? ? ? ? ? ?
Estrone11–35<1<1<1<12.7<0.1
Estrone sulfate 22 ? ? ? ? ?
Estriol 10–15<1<1<1<1<0.1<0.1
Equilin 40 ? ? ? ? ?0
Alfatradiol 15<1<1<1<1 ? ?
Epiestriol 20<1<1<1<1 ? ?
Ethinylestradiol 100–1121–315–251–3<10.18<0.1
Mestranol 1 ? ? ? ?<0.1<0.1
Methylestradiol 671–33–251–3<1 ? ?
Moxestrol 12<0.10.83.2<0.1<0.2<0.1
Diethylstilbestrol  ? ? ? ? ?<0.1<0.1
Notes: Reference ligands (100%) were progesterone for the PR Tooltip progesterone receptor, testosterone for the AR Tooltip androgen receptor, estradiol for the ER Tooltip estrogen receptor, dexamethasone for the GR Tooltip glucocorticoid receptor, aldosterone for the MR Tooltip mineralocorticoid receptor, dihydrotestosterone for SHBG Tooltip sex hormone-binding globulin, and cortisol for CBG Tooltip Corticosteroid-binding globulin. Sources: See template.
Selected biological properties of endogenous estrogens in rats
Estrogen ER Tooltip Estrogen receptor RBA Tooltip relative binding affinity (%) Uterine weight (%) Uterotrophy LH Tooltip Luteinizing hormone levels (%) SHBG Tooltip Sex hormone-binding globulin RBA Tooltip relative binding affinity (%)
Control–100–100–
Estradiol (E2) 100506 ± 20+++12–19100
Estrone (E1)11 ± 8490 ± 22+++ ?20
Estriol (E3) 10 ± 4468 ± 30+++8–183
Estetrol (E4) 0.5 ± 0.2 ?Inactive ?1
17α-Estradiol 4.2 ± 0.8 ? ? ? ?
2-Hydroxyestradiol 24 ± 7285 ± 8+b31–6128
2-Methoxyestradiol 0.05 ± 0.04101Inactive ?130
4-Hydroxyestradiol 45 ± 12 ? ? ? ?
4-Methoxyestradiol 1.3 ± 0.2260++ ?9
4-Fluoroestradiol a180 ± 43 ?+++ ? ?
2-Hydroxyestrone 1.9 ± 0.8130 ± 9Inactive110–1428
2-Methoxyestrone 0.01 ± 0.00103 ± 7Inactive95–100120
4-Hydroxyestrone 11 ± 4351++21–5035
4-Methoxyestrone 0.13 ± 0.04338++65–9212
16α-Hydroxyestrone 2.8 ± 1.0552 ± 42+++7–24<0.5
2-Hydroxyestriol 0.9 ± 0.3302+b ? ?
2-Methoxyestriol 0.01 ± 0.00 ?Inactive ?4
Notes: Values are mean ± SD or range. ERRBA = Relative binding affinity to estrogen receptors of rat uterine cytosol. Uterine weight = Percentage change in uterine wet weight of ovariectomized rats after 72 hours with continuous administration of 1 μg/hour via subcutaneously implanted osmotic pumps. LH levels = Luteinizing hormone levels relative to baseline of ovariectomized rats after 24 to 72 hours of continuous administration via subcutaneous implant. Footnotes:a = Synthetic (i.e., not endogenous). b = Atypical uterotrophic effect which plateaus within 48 hours (estradiol's uterotrophy continues linearly up to 72 hours). Sources: See template.

Effects in the body and brain

In clinical research in the 1930s, estrone was given via intramuscular injection to ovariectomized women in order to study its effects and to elucidate the biological properties of estrogens in humans. [41] [42] [43] In these studies, prior to administration of estrone, amenorrhea, atrophy of the breasts (as well as flaccidity and small and non-erectile nipples), vagina, and endometrium, vaginal dryness, and subjective symptoms of ovariectomy (e.g., hot flashes, mood changes) were all present in the women. [41] [42] [43] Treatment with estrone was found to dose- and time-dependently produce a variety of effects, including breast changes, reproductive tract changes of the vagina, cervix, and endometrium/uterus, and relief from the subjective symptoms of ovariectomy, as well as increased libido. [41] [42] [43] Breast changes specifically included enlargement and a sense of fullness, increased sensitivity and pigmentation of the nipples as well as nipple erection, tingling within the breast mammary glandular tissue, and aching and soreness of the breasts. [41] [42] [43] Reproductive tract changes included increased growth, thickness, and differentiation of the endometrium, and reversal of vaginal and cervical atrophy, which were accompanied by increased congestion of the cervix and mucous discharge from the cervix, uterine cramps and needle-like pains, pelvic fullness, a "bearing-down" sensation, and increased vaginal lubrication, as well as uterine bleeding both during treatment and in the days following cessation of injections. [41] [42] [43] Endometrial hyperplasia also occurred with sufficiently high doses of estrone. [41] [42] [43]

Clinical research has confirmed the nature of estrone as an inactive prodrug of estradiol. [5] [53] [54] [55] With oral administration of estradiol, the ratio of estradiol levels to estrone levels is about 5 times higher on average than under normal physiological circumstances in premenopausal women and with parenteral (non-oral) routes of estradiol. [5] Oral administration of menopausal replacement dosages of estradiol results in low, follicular phase levels of estradiol, whereas estrone levels resemble the high levels seen during the first trimester of pregnancy. [5] [57] [58] In spite of markedly elevated levels of estrone with oral estradiol but not with transdermal estradiol, clinical studies have shown that doses of oral and transdermal estradiol achieving similar levels of estradiol possess equivalent and non-significantly different potency in terms of measures including suppression of luteinizing hormone and follicle-stimulating hormone levels, inhibition of bone resorption, and relief of menopausal symptoms such as hot flashes. [5] [53] [54] [55] [59] In addition, estradiol levels were found to correlate with these effects, while estrone levels did not. [53] [54] These findings confirm that estrone has very low estrogenic activity, and also indicate that estrone does not diminish the estrogenic activity of estradiol. [5] [53] [54] [55] This contradicts some cell-free in-vitro research suggesting that high concentrations of estrone might be able to partially antagonize the actions of estradiol. [50] [51] [52]

Relative oral potencies of estrogens
Estrogen HF Tooltip Hot flashes VE Tooltip Vaginal epithelium UCa Tooltip Urinary calcium FSH Tooltip Follicle-stimulating hormone LH Tooltip Luteinizing hormone HDL Tooltip High-density lipoprotein-C Tooltip Cholesterol SHBG Tooltip Sex hormone-binding globulin CBG Tooltip Corticosteroid-binding globulin AGT Tooltip AngiotensinogenLiver
Estradiol 1.01.01.01.01.01.01.01.01.01.0
Estrone ? ? ?0.30.3 ? ? ? ? ?
Estriol 0.30.30.10.30.30.2 ? ? ?0.67
Estrone sulfate  ?0.90.90.8–0.90.90.50.90.5–0.71.4–1.50.56–1.7
Conjugated estrogens 1.21.52.01.1–1.31.01.53.0–3.21.3–1.55.01.3–4.5
Equilin sulfate  ? ?1.0 ? ?6.07.56.07.5 ?
Ethinylestradiol 12015040060–150100400500–600500–6003502.9–5.0
Diethylstilbestrol  ? ? ?2.9–3.4 ? ?26–2825–37205.7–7.5
Sources and footnotes
Notes: Values are ratios, with estradiol as standard (i.e., 1.0). Abbreviations:HF = Clinical relief of hot flashes. VE = Increased proliferation of vaginal epithelium. UCa = Decrease in UCa Tooltip urinary calcium. FSH = Suppression of FSH Tooltip follicle-stimulating hormone levels. LH = Suppression of LH Tooltip luteinizing hormone levels. HDL-C, SHBG, CBG, and AGT = Increase in the serum levels of these liver proteins. Liver = Ratio of liver estrogenic effects to general/systemic estrogenic effects (hot flashes/gonadotropins). Sources: See template.
Potencies and durations of natural estrogens by intramuscular injection
EstrogenFormDose (mg)Duration by dose (mg)
EPDCICD
Estradiol Aq. soln. ?–<1 d
Oil soln.40–60–1–2 ≈ 1–2 d
Aq. susp. ?3.50.5–2 ≈ 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.20–3055 ≈ 7–8 d; 10 ≈ 10–14 d;
40 ≈ 14–21 d; 100 ≈ 21–28 d
Estradiol benz. butyrate Oil soln. ?1010 ≈ 21 d
Estradiol cypionate Oil soln.20–30–5 ≈ 11–14 d
Aq. susp. ?55 ≈ 14–24 d
Estradiol enanthate Oil soln. ?5–1010 ≈ 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
EstroneOil 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.
Pharmacology of estrone
Sources: See template page.

Pharmacokinetics

Absorption

Like estradiol, estrone has poor oral bioavailability. [11] [6] It has been said that, taken by mouth in non-micronized form, a dose of 25 mg estrone is approximately equivalent to 2.5 mg conjugated estrogens, 50 μg ethinylestradiol, or 1 mg diethylstilbestrol in terms of estrogenic potency. [60] Due to its weak oral activity, estrone has been used parenterally instead, for instance by intramuscular injection or vaginal administration. [2] [3] [4] The pharmacokinetics of vaginal estrone have been studied. [61]

Estrone in oil solution by intramuscular injection has a shorter duration than estrone in aqueous suspension by intramuscular injection. [36] Estrone in oil solution by intramuscular injection is rapidly absorbed, while estrone in aqueous suspension has a prolonged period of absorption. [62] Upon intramuscular injection of estrone in aqueous solution, the water from the preparation is absorbed and a microcrystalline depot of estrone that is slowly absorbed by the body is formed. [37] This is responsible for the prolonged duration of estrone in aqueous suspension compared to oil solution. [36] [37]

Distribution

Unlike estradiol and estriol, estrone is not accumulated in target tissues. [5] [63] In terms of plasma protein binding, estrone is bound approximately 16% to sex hormone-binding globulin (SHBG) and 80% to albumin, [5] with the remainder (2.0 to 4.0%) circulating free or unbound. [7] Estrone has about 24% of the relative binding affinity of estradiol for SHBG, and hence is relatively poorly bound to SHBG. [5] [11]

Metabolism

Interactive icon.svg
Description: The metabolic pathways involved in the metabolism of estradiol and other natural estrogens (e.g., estrone, estriol) in humans. In addition to the metabolic transformations shown in the diagram, conjugation (e.g., sulfation and glucuronidation) occurs in the case of estradiol and metabolites of estradiol that have one or more available hydroxyl (–OH) groups. Sources: See template page.

Estrone is conjugated into estrogen conjugates such as estrone sulfate and estrone glucuronide by sulfotransferases and glucuronidases, and can also be hydroxylated by cytochrome P450 enzymes into catechol estrogens such as 2-hydroxyestrone and 4-hydroxyestrone or into estriol. [5] Both of these transformations take place predominantly in the liver. [5] Estrone can also be reversibly converted into estradiol by 17β-hydroxysteroid dehydrogenases (17β-HSDs), and this accounts for most or all of its estrogenic activity. [5] [12] 17β-HSD isoforms that are involved in the conversion of estrone into estradiol include 17β-HSD1, 17β-HSD3, 17β-HSD4, 17β-HSD7, 17β-HSD8, and 17β-HSD12, although the relative contributions of the different isoforms is unknown. [64] [ additional citation(s) needed ]

The biological half-lives of estrone and estradiol in the circulation are both about 10 to 70 minutes, whereas the biological half-life of estrone sulfate in the circulation is about 10 to 12 hours. [5] [65] [66] The metabolic clearance rate of estrone is 1,050 L/day/m2 and of estradiol is 580 L/day/m2, while that of estrone sulfate is 80 L/day/m2. [5] For comparison, the metabolic clearance rate of estriol is 1,110 L/day/m2. [5] A single 1 to 2 mg dose of estrone in oil solution by intramuscular injection has a duration of about 2 or 3 days. [45] [67] [68] As an aqueous suspension by intramuscular injection, estrone was used at a dose of 0.1 to 0.5 mg 2 to 3 times per week, or at a dose of 0.1 to 2 mg once a week or in divided doses. [69] In one rodent study, exogenous estrone was administered and increased circulating estradiol levels by about 10-fold; co-administration of a selective 17β-HSD1 inhibitor decreased estradiol levels by about 50%. [70]

The ratio of circulating estrone to circulating estradiol is the same at about 5:1 with both oral estradiol and oral estrone sulfate. [5] An investigational estrone vaginal ring was found to result in a ratio of estrone to estradiol of 4:1 or 5:1 initially, but this decreased to about 1:1 with continuous therapy. [71]

Excretion

Estrone is excreted in urine in the form of estrogen conjugates such as estrone sulfate and estrone glucuronide. [5] Following an intravenous injection of labeled estrone in women, almost 90% is excreted in urine and feces within 4 to 5 days. [65] Enterohepatic recirculation causes a delay in excretion of estrone. [65]

Chemistry

Estrone, also known as estra-1,3,5(10)-trien-3-ol-17-one, is a naturally occurring estrane steroid with double bonds at the C1, C3, and C5 positions, a hydroxyl group at the C3 position, and a ketone group at the C17 position. [8] [9] The name estrone was derived from the chemical terms estrin (estra-1,3,5(10)-triene) and ketone. [8] [9]

A variety of estrone esters have been synthesized and described. [8] [9] These include the marketed esters estrone acetate, estrone sulfate, estrone tetraacetylglucoside, and estropipate (piperazine estrone sulfate), and the never-marketed esters estrone benzoate, estrone cyanate, estrone glucuronide, and estrone sulfamate. [8] [9]

History

In 1927, Bernhard Zondek and Selmar Aschheim discovered that large amounts of estrogens were excreted in the urine of pregnant women. [72] [73] This rich source of estrogens allowed the development of potent estrogenic formulations for scientific and clinical use. [73] [13] In 1929, pure crystalline estrone was isolated from the urine of pregnant women by various researchers. [13] [74] By 1929, pharmaceutical preparations including Amniotin (Squibb), Progynon (Schering), and Theelin (Parke-Davis), purified from pregnancy urine, placentas, and/or amniotic fluid and containing purified estrone or mixtures of estrogens that included estrone, were being sold commercially for use by intramuscular injection. [75] [13] [14] [76] [15] [77] Other products and brand names of estrone marketed in the 1930s included Estrone (Abbott, Lilly), Oestroform (British Drug Houses), Folliculin (Organon), Menformon (Organon), and Ketodestrin (Paines & Byrne), among others. [14] [76] [77] [78] These formulations included ampoules of oil or aqueous solution for intramuscular injection, oral tablets, and vaginal suppositories. [77] [14] [23] [79] Estrone in aqueous suspension for use by intramuscular injection was first described in 1941 and was introduced for medical use under the brand name Theelin Aqueous Suspension by 1944. [36] [23] [80]

Society and culture

Generic names

Estrone is the generic name of estrone in American English and its INN Tooltip International Nonproprietary Name, USP Tooltip United States Pharmacopeia, BAN Tooltip British Approved Name, DCF Tooltip Dénomination Commune Française, DCIT Tooltip Denominazione Comune Italiana, and JAN Tooltip Japanese Accepted Name. [8] [9] [10] [16] Oestrone, in which the "O" is silent, was the former BAN Tooltip British Approved Name of estrone and its name in British English, [8] [10] [9] but the spelling was eventually changed to estrone. [16]

Brand names

Estrone has been marketed under a variety of brand names, including Andrestraq, Aquacrine, A.T.V., Bestrone, Centrogen, Cicatral, Cormone, Crinovaryl, Cristallovar, Crystogen, Destrone, Disynformon, Endofolliculina, Estragyn, Estroject, Estrol, Estrone, Estrone Aqueous Suspension, Estrone-A, Estrugenone, Estrusol, Femestrone, Femidyn, Folikrin, Folipex, Folisan, Folliculin, Follicunodis, Follidrin, Gineburno, Glandubolin, Grietalgen, Grietalgen Hidrocort, Gynogen, Hiestrone, Hormofollin, Hormonin, Hormovarine, Kestrin, Kestrone, Ketodestrin, Kolpon, Ladies Pearl, Livifolin, Menagen, Metharmon-F, Neo-Estrone, Oestrilin, Oestrin, Oestroform, Oestroperos, Ovex, Ovifollin, Perlatan, Progynon, Senikolp, Solliculin, Solutio Folliculinum, Synergon (in combination with progesterone), Theelin, Thynestron, Tokokin, Unden, Unigen, Wehgen, and Wynestron. [8] [10] [9] [1] [16] [81] [82]

Brand names of estrone in aqueous suspension specifically include Bestrone, Estaqua, Estrofol, Estroject, Estrone-A, Estronol, Femogen, Foygen Aqueous, Gravigen Aqueous, Gynogen, Hormogen-A, Kestrin Aqueous, Kestrone, Theelin Aqueous, Theogen, Unigen, and Wehgen. [83]

Availability

Although estrone has been widely marketed in the past, it has mostly been discontinued and remains available in only a few countries. [9] [16] These countries reportedly include Canada, Georgia, Monaco, and Taiwan. [16] However, estrone remains widely available throughout the world in the form of estrone sulfate, which can be found in estropipate (piperazine estrone sulfate), conjugated estrogens (Premarin), and esterified estrogens (Estratab, Menest). [9] [84]

Research

An estrone vaginal ring was developed and studied for use in menopausal hormone therapy. [71] It increased estrogen levels, suppressed gonadotropin levels, and relieved menopausal symptoms. [71] Subcutaneous pellet implantation of estrone has also been studied. [85] [86]

See also

Related Research Articles

<span class="mw-page-title-main">Estrone</span> Chemical compound

Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized from cholesterol and secreted mainly from the gonads, though they can also be formed from adrenal androgens in adipose tissue. Relative to estradiol, both estrone and estriol have far weaker activity as estrogens. Estrone can be converted into estradiol, and serves mainly as a precursor or metabolic intermediate of estradiol. It is both a precursor and metabolite of estradiol.

<span class="mw-page-title-main">Estriol</span> Chemical compound

Estriol (E3), also spelled oestriol, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estrone. Levels of estriol in women who are not pregnant are almost undetectable. However, during pregnancy, estriol is synthesized in very high quantities by the placenta and is the most produced estrogen in the body by far, although circulating levels of estriol are similar to those of other estrogens due to a relatively high rate of metabolism and excretion. Relative to estradiol, both estriol and estrone have far weaker activity as estrogens.

<span class="mw-page-title-main">Estradiol valerate</span> Chemical compound

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.

<span class="mw-page-title-main">Estradiol benzoate</span> Chemical compound

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.

<span class="mw-page-title-main">Estradiol cypionate</span> Chemical compound

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.

<span class="mw-page-title-main">Estriol succinate</span> Chemical compound

Estriol succinate, sold under the brand name Synapause among others, is an estrogen medication which is used in the treatment of menopausal symptoms. It is taken by mouth, in through the vagina, and by injection.

<span class="mw-page-title-main">Estradiol undecylate</span> Chemical compound

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. The medication has been given by injection into muscle usually once a month.

<span class="mw-page-title-main">Estradiol dipropionate</span> Chemical compound

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.

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. Esterification renders estradiol into a prodrug of estradiol with increased resistance to first-pass metabolism, slightly improving its oral bioavailability. 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. Conversely, this is not the case with intravenous injection or oral administration. Estrogen esters are rapidly hydrolyzed into their parent estrogen by esterases once they have been released from the depot. Because estradiol esters are prodrugs of estradiol, they are considered to be natural and bioidentical forms of estrogen.

<span class="mw-page-title-main">Conjugated estrogens</span> Estrogen medication

Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin among others, is an estrogen medication which is used in menopausal hormone therapy and for various other indications. It is a mixture of the sodium salts of estrogen conjugates found in horses, such as estrone sulfate and equilin sulfate. CEEs are available in the form of both natural preparations manufactured from the urine of pregnant mares and fully synthetic replications of the natural preparations. They are formulated both alone and in combination with progestins such as medroxyprogesterone acetate. CEEs are usually taken by mouth, but can also be given by application to the skin or vagina as a cream or by injection into a blood vessel or muscle.

<span class="mw-page-title-main">Estradiol pivalate</span> Chemical compound

Estradiol pivalate, also known as estradiol trimethyl acetate (E2-TMA) and sold under the brand name Estrotate, is an estrogen medication and an estrogen ester; specifically, a pivalic acid ester of estradiol. Literature sources are conflicting as to whether the ester is located at the C3 position or at the C17β position. It was marketed as an oil solution for intramuscular injection in the 1940s and 1950s. A combination of estradiol pivalate (1 mg/mL) and progesterone (10 mg/mL) in oil solution for intramuscular injection was available in 1949. An aqueous suspension of estradiol pivalate was also developed by 1950 although whether it was ever marketed is unclear.

<span class="mw-page-title-main">Estradiol sulfate</span> Chemical compound

Estradiol sulfate (E2S), or 17β-estradiol 3-sulfate, is a natural, endogenous steroid and an estrogen ester. E2S itself is biologically inactive, but it can be converted by steroid sulfatase into estradiol, which is a potent estrogen. Simultaneously, estrogen sulfotransferases convert estradiol to E2S, resulting in an equilibrium between the two steroids in various tissues. Estrone and E2S are the two immediate metabolic sources of estradiol. E2S can also be metabolized into estrone sulfate (E1S), which in turn can be converted into estrone and estradiol. Circulating concentrations of E2S are much lower than those of E1S. High concentrations of E2S are present in breast tissue, and E2S has been implicated in the biology of breast cancer via serving as an active reservoir of estradiol.

<span class="mw-page-title-main">Estradiol (medication)</span> Steroidal hormone medication

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.

<span class="mw-page-title-main">Estradiol glucuronide</span> Chemical compound

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.

<span class="mw-page-title-main">Estrone glucuronide</span> Chemical compound

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.

<span class="mw-page-title-main">Estriol (medication)</span> Chemical compound

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.

<span class="mw-page-title-main">Estrone sulfate (medication)</span> Chemical compound

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.

<span class="mw-page-title-main">Pharmacokinetics of estradiol</span>

The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

<span class="mw-page-title-main">Polyestriol phosphate</span> Chemical compound

Polyestriol phosphate, sold under the brand names Gynäsan, Klimadurin, and Triodurin, is an estrogen medication which was previously used in menopausal hormone therapy and is no longer available.

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  21. ↑ Thomas JA, Keenan EJ (6 December 2012). "Estrogen and Antiestrogenic Drugs". Principles of Endocrine Pharmacology. Springer Science & Business Media. pp. 153–. ISBN   978-1-4684-5036-1.
  22. ↑ Rivlin ME (1990). Handbook of drug therapy in reproductive endocrinology and infertility. Little, Brown. p. 23. ISBN   978-0-316-74772-1. The following are dosages for parenteral [estrogens]: [...] Estrone. For vasomotor symptoms or atrophic vaginitis, 0.1 to 0.5 mg is given 2 or 3 times weekly. For female hypogonadism, castration, or primary ovarian failure, 0.1 to 1.0 mg is given weekly in single or divided doses. Further dosage adjusted according to response.
  23. 1 2 3 4 Fluhmann CF (1944). "Clinical use of extracts from the ovaries". Journal of the American Medical Association. 125 (1): 1. doi:10.1001/jama.1944.02850190003001. ISSN   0002-9955.
  24. ↑ Misra D, Magee MF, Nylén ES (2001). "Compendium of Endocrine-Related Drugs". In Becker KL (ed.). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 2153–. ISBN   978-0-7817-1750-2.
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  27. 1 2 3 Deghenghi R (6 December 2012). "Chemistry and biochemistry of natural estrogens". In Paoletti R, Pasetto N, Ambrus JL (eds.). The Menopause and Postmenopause: The Proceedings of an International Symposium held in Rome, June 1979. Springer Science & Business Media. pp. 3–. ISBN   978-94-011-7230-1.
  28. ↑ University of California (1868-1952) (1952). Hospital Formulary and Compendium of Useful Information. University of California Press. pp. 49–. GGKEY:2UAAZRZ5LN0.{{cite book}}: CS1 maint: numeric names: authors list (link)
  29. ↑ Krishna UR, Sheriar NK, Mandlekar A (1996). "Hormone Replacement Therapy". In Krishna UR, Sheriar NK (eds.). Menopause. Orient Blackswan. pp. 70–. ISBN   978-81-250-0910-8.
  30. ↑ Campbell G, Compston J, Crisp A (25 November 1993). "Osteoporosis". The Management of Common Metabolic Bone Disorders. Cambridge University Press. pp. 48–. ISBN   978-0-521-43623-6.
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  32. ↑ Sweetman SC, ed. (2009). "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. pp. 2101, 2127. ISBN   978-0-85369-840-1. Estrone [...] Progesterone [...] Multi-ingredient: [...] Fr.: Synergon [...] Turk.: Synergon
  33. ↑ Addo VN, Tagoe-Darko ED (June 2009). "Knowledge, practices, and attitudes regarding emergency contraception among students at a university in Ghana". Int J Gynaecol Obstet. 105 (3): 206–9. doi:10.1016/j.ijgo.2009.01.008. PMID   19232600. S2CID   22216977. Synergon, a combination of progesterone and oestrone in an injectable form, is marketed to induce withdrawal bleeding in women with nongravid amenorrhea; however, it can be used as an arbortifacient [11].
  34. ↑ Kongnyuy EJ, Ngassa P, Fomulu N, Wiysonge CS, Kouam L, Doh AS (July 2007). "A survey of knowledge, attitudes and practice of emergency contraception among university students in Cameroon". BMC Emerg Med. 7: 7. doi: 10.1186/1471-227X-7-7 . PMC   1933435 . PMID   17634106.
  35. ↑ McDonnell K (1986). Adverse Effects: Women and the Pharmaceutical Industry. International Organization of Consumers Unions, Regional Office for Asia and the Pacific. p. 15. ISBN   978-967-9973-17-4. Synergon. 10 mg progesterone. 1 mg folliculine [estrone].
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  61. ↑ Schiff I, Tulchinsky D, Ryan KJ (October 1977). "Vaginal absorption of estrone and 17beta-estradiol". Fertil. Steril. 28 (10): 1063–6. doi: 10.1016/S0015-0282(16)42855-4 . PMID   908445.
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  69. ↑ Micromedex (1 January 2003). USP DI 2003: Drug Information for Healthcare Professionals. Thomson Micromedex. p. 1246. ISBN   978-1-56363-429-1. ESTRONE Parenteral Dosage Forms ESTRONE INJECTABLE SUSPENSION USP Usual adult dose Atrophic vaginitis or Menopausal (vasomotor) symptoms or Vulvar atrophy—Intramuscular, 100 to 500 mcg (0.1 to 0.5 mg) two or three times a week, cyclically or continuously as appropriate. Estrogen deficiency, due to ovariectomy or Female hypogonadism or Primary ovarian failure—Intramuscular, 100 mcg (0.1 mg) to 1 mg a week, administered as a single dose or in divided doses, cyclically or continuously. A few patients may need doses of up to 2 mg a week.
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