Estriol (medication)

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This article is about estriol as a medication. For its role as a hormone, see Estriol.
Estriol (medication)
ファイル:Estriol.svg
ファイル:Estriol molecule ball.png
Systematic (IUPAC) name
(8R,9S,13S,14S,16R,17R)-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,16,17-triol
Clinical data
Trade names Ovestin, others[1][2]
Pregnancy cat. ?
Legal status ℞ Prescription only
Routes By mouth, vaginal, intramuscular injection[3][4][5]
Pharmacokinetic data
Bioavailability Oral: ~1–2%[3][5]
Vaginal: ~10–20%[4][3][5]
Protein binding 92%:[3]
• Albumin: 91%[3]
• SHBGTooltip Sex hormone-binding globulin: 1%[3]
• Free: 8%[3]
Metabolism Liver, intestines (conjugation (glucuronidation, sulfation), oxidation, hydroxylation)[3]
Half-life Oral: 5–10 hours[6][7]
IMTooltip Intramuscular injection: 1.5–5.3 hours (as E3)[4]
IVTooltip Intravenous injection: 20 minutes (as E3)[8][9]
Excretion Urine: >95% (as conjugates)[3][4]
Identifiers
CAS number 50-27-1 YesY
1306-04-3
514-68-1 (succinate)
ATC code G03CA04
G03CC06 (WHO)
PubChem CID 5756
IUPHAR ligand 2821
DrugBank DB04573
ChemSpider 5553 YesY
UNII FB33469R8E YesY
KEGG C05141 YesY
ChEBI CHEBI:27974 YesY
ChEMBL CHEMBL193482 YesY
Synonyms Oestriol; E3; 16α-Hydroxyestradiol; Estra-1,3,5(10)-triene-3,16α,17β-triol
Chemical data
Formula C18H24O3 
Physical data
Melt. point 82–86 °C (180–187 °F) (experimental)
Solubility in water 0.119 mg/mL (20 °C)
 YesY (what is this?)  (verify)

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.[10][3][5][11] It is also used in veterinary medicine as Incurin to treat urinary incontinence due to estrogen deficiency in dogs.[12][13][14][15] 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.[3][4][5]

Estriol is well-tolerated and produces relatively few adverse effects.[10][16] Side effects may include breast tenderness, vaginal discomfort and discharge, and endometrial hyperplasia.[10][16] Estriol is a naturally occurring and bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol.[3] It is an atypical and relatively weak estrogen, with much lower potency than estradiol.[3][5][17] When present continuously at adequate concentrations however, estriol produces full estrogenic effects similarly to estradiol.[18][19]

Estriol was first discovered in 1930,[20][21] and was introduced for medical use shortly thereafter.[22][23] Estriol esters such as estriol succinate are also used.[3][16][2] Although it is less commonly employed than other estrogens like estradiol and conjugated estrogens, estriol is widely available for medical use in Europe and elsewhere throughout the world.[3][1][2][5]

Medical uses

Estriol is used in menopausal hormone therapy to treat menopausal symptoms, such as hot flashes, vulvovaginal atrophy, and dyspareunia (difficult or painful sexual intercourse).[10][3][11][24][16] The benefits of estriol on bone mineral density and osteoporosis prevention have been inconsistent and are less clear.[16][10] Estriol has been found to reduce the risk of urinary tract infections and other urogenital symptoms.[3][10] A combination of estriol and lactobacilli as a dual estrogen and probiotic has been marketed for the treatment of vaginal atrophy and urinary tract infections.[25]

テンプレート:Estrogen dosages for menopausal hormone therapy

Available forms (except USA)

Estriol is available in oral tablet, vaginal cream, and vaginal suppository forms.[11] It is also available over-the-counter or from compounding pharmacies in the form of topical creams.[26] The medication is available both as estriol and in the form of estriol ester prodrugs such as estriol succinate, estriol acetate benzoate, and estriol tripropionate, as well as the polymeric ester prodrug polyestriol phosphate.[3][16][27][1][2]

Estriol was originally marketed in the 1930s in the form of oral capsules containing 0.06, 0.12, or 0.24 mg estriol under the brand names Theelol (Parke-Davis) and Estriol (Lilly, Abbott).[28][29][30][31][32] Subsequently, many decades later, oral tablets containing 0.35, 1, or 2 mg estriol were introduced under brand names such as Gynäsan, Hormomed, Ovestin, and Ovo-Vinces.[33]

Contraindications

See also: Estrogen (medication) § Contraindications, and Estradiol (medication) § Contraindications

General contraindications of estrogens include breast cancer, endometrial cancer, and others.[17] In animals, estriol is contraindicated during pregnancy and in ferrets.[15]

Side effects

Estriol is well-tolerated and produces relatively few adverse effects.[10][16] Breast tenderness may sometimes occur as a side effect of estriol.[10] Local reactions with vaginal estriol such as discomfort (irritation, burning, itching) and discharge may occur.[10] Estriol may produce endometrial hyperplasia similarly to estradiol and other estrogens, and hence should be combined with a progestogen in women with intact uteruses to prevent this risk.[34][3] However, it appears that typical clinical dosages of vaginal estriol are not associated with an important risk of endometrial proliferation or hyperplasia.[10][24] As such, combination with a progestogen may not be needed in the case of vaginal estriol.[10][24] Some studies suggest that this may also be true for oral estriol.[16] However, dosage and frequency of administration, as well as meal consumption, may be determining factors as to whether or not estriol produces endometrial proliferation.[3]

Overdose

See also: Estrogen (medication) § Overdose, and Estradiol (medication) § Overdose

Estrogens and other steroids are relatively safe in acute overdose.[citation needed] Estriol has been assessed in single oral doses of up to 75 mg.[35][36] General symptoms of estrogen overdose in humans may include nausea, vomiting, vaginal bleeding, and reversible feminization.[37][14] While there are no known studies describing the acute toxicity of estrogen overdose in dogs, this species is known to be more sensitive to the toxic effects of estrogens than humans and other animals.[14] The most serious short-term adverse effect of estrogens in dogs is bone marrow suppression and consequent pancytopenia, which can be life-threatening.[14]

Interactions

See also: Estrogen (medication) § Interactions, and Estradiol (medication) § Interactions

Interactions with estriol might be expected to be similar to those of estradiol.[38] No interactions with estriol have been reported in animals.[15] However, it should not be used in combination with other drugs that suppress bone marrow production in dogs.[15]

Pharmacology

Pharmacodynamics

Estriol is an estrogen, or an agonist of the estrogen receptors (ERs), ERα and ERβ.[3][39][40] In terms of relative binding affinities (RBA) for the ERs compared to estradiol, it was found in one study to possess 11 to 14% of the RBA for the human ERα and 18 to 21% of the RBA for the human ERβ.[40] Its relative transactivational capacities at the ERs compared to estradiol were 11% at ERα and 17% at ERβ.[40] In addition to being a ligand of the classical nuclear ERs, estriol is an antagonist of the G protein-coupled estrogen receptor (GPER), a membrane estrogen receptor (mER), at high concentrations (~1,000–10,000 μM).[41][42][39][43] This is in contrast to estradiol, which is an agonist of this receptor.[42][39][43] Like other estrogens, estriol does not importantly interact with other steroid hormone receptors.[44][45][46][47][48]

Estriol is a much less potent estrogen than is estradiol, and is somewhat weak and atypical in its properties.[3][40][42][17] Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.[49] With clinical use, estriol is said to be weakly estrogenic in certain tissues, such as the liver and endometrium, but produces pronounced and full estrogenic responses in the vaginal epithelium.[3] The medication has been found to reduce hot flashes, improve vaginal atrophy, reverse the postmenopausal decline in skin thickness and collagen content, suppress gonadotropin secretion, and produce proliferation of breast epithelium.[3] Conversely, estriol does not consistently affect bone resorption or fracture risk, does not seem to increase breast density, and, at oral doses of 2 to 4 mg/day, does not affect liver proteins, lipid metabolism, or hemostatic parameters.[3][16] Additionally, vaginal estriol does not appear to produce endometrial proliferation or increase the risk of endometrial hyperplasia, and some studies have found this to be the case for oral estriol as well.[3][16][50] On the other hand, it appears that estriol may be able to stimulate the growth of active breast cancer.[16][10] In rodents, estriol induces mammary gland development similar to that with estrone.[51] By the oral route in women, estriol has approximately 30% of the potency of estradiol in terms of hot flashes relief and suppression of follicle-stimulating hormone secretion, and about 20% of the potency of estradiol on stimulation of liver production of high-density lipoprotein (HDL) cholesterol.[3] A study of ovulation inhibition by estrogens in women found that prevention of ovulation occurred with 5 mg/day oral estriol in only 1 of 7 cycles.[52][53] Due to its differing effects from those of estradiol, estriol may be considered a safer estrogen in certain regards.[10]

ファイル:Nuclear retention of the uterine receptor estrogen complex with an injection of estradiol, estriol, or a combination of estradiol and estriol in rats.png
Nuclear retention of the receptor estrogen complex in the uterus with a single short-acting subcutaneous injection of 0.1 μg estradiol (E2), 1.0 μg estriol (E3), or a combination of 0.1 μg estradiol and 1.0 μg estriol in aqueous solution in rats.[54][55] Estriol displaces estradiol from the estrogen receptors and, due to the shorter nuclear retention of estriol, it thereby antagonizes overall nuclear retention.[54][55] No antagonism occurs when long-acting subcutaneous pellets of estriol are used instead.[54][55]

The weak and atypical estrogenicity of estriol is thought to be related to its short duration in the body and hence the fact that it stays bound to the ER for a relatively short amount of time.[3][19] Whereas estradiol remains bound to the ER for 6 to 24 hours with a single short-acting injection, estriol dissociates from the receptor much more rapidly and stays bound for only 1 to 6 hours.[3][19][56][57] As a result, estriol can only induce estrogenic effects which require short-term interaction with the ERs.[3][19] Induction of endometrial mitoses requires the ligand to remain bound for at least 9 to 12 hours, and this is thought to be responsible for the lack of endometrial proliferation with estriol in many studies.[3][19] If estriol is delivered more continuously than a single administration per day however, for instance if it is given as a subcutaneous pellet, as a depot injection, or in multiple doses two or three times per day, this results in more sustained exposure to estriol and full estrogenic responses equivalent to those of estradiol occur.[3][19][10] For these reasons, estriol has been described as a "short-acting" estrogen and it has been said that descriptors like "weak" and "impeded" are inaccurate.[19] Consumption of food after oral administration of estriol also results in more prolonged exposure to estriol, due to enterohepatic recycling and resurgences in estriol levels.[3] As such, if avoidance of endometrial hyperplasia or other full estrogenic effects is intended, it may be preferable to take estriol in a single dose, as low as possible, once per day at night before bedtime.[3][50]

Although estriol is an estrogen, it has also been reported to have mixed agonist–antagonist or partial agonist activity at the ERs.[3][19][17] On its own, it is said to be weakly estrogenic, but in the presence of estradiol, it has been found to be antiestrogenic.[3][42] However, this is again due to the fact that estriol is a "short-acting" estrogen.[19] If estriol is present continuously with estradiol, it shows no antagonism of estradiol.[19] The co-administration of estriol with estradiol has been found not to influence the effects of the latter in women, including neither enhancing nor antagonizing the effects of estradiol.[50][58]

Affinities of estrogen receptor ligands for the ERα and ERβ
Ligand Other names Relative binding affinities (RBA, %)a Absolute binding affinities (Ki, nM)a Action
ERα ERβ ERα ERβ
Estradiol E2; 17β-Estradiol 100 100 0.115 (0.04–0.24) 0.15 (0.10–2.08) Estrogen
Estrone E1; 17-Ketoestradiol 16.39 (0.7–60) 6.5 (1.36–52) 0.445 (0.3–1.01) 1.75 (0.35–9.24) Estrogen
Estriol E3; 16α-OH-17β-E2 12.65 (4.03–56) 26 (14.0–44.6) 0.45 (0.35–1.4) 0.7 (0.63–0.7) Estrogen
Estetrol E4; 15α,16α-Di-OH-17β-E2 4.0 3.0 4.9 19 Estrogen
Alfatradiol 17α-Estradiol 20.5 (7–80.1) 8.195 (2–42) 0.2–0.52 0.43–1.2 Metabolite
16-Epiestriol 16β-Hydroxy-17β-estradiol 7.795 (4.94–63) 50 ? ? Metabolite
17-Epiestriol 16α-Hydroxy-17α-estradiol 55.45 (29–103) 79–80 ? ? Metabolite
16,17-Epiestriol 16β-Hydroxy-17α-estradiol 1.0 13 ? ? Metabolite
2-Hydroxyestradiol 2-OH-E2 22 (7–81) 11–35 2.5 1.3 Metabolite
2-Methoxyestradiol 2-MeO-E2 0.0027–2.0 1.0 ? ? Metabolite
4-Hydroxyestradiol 4-OH-E2 13 (8–70) 7–56 1.0 1.9 Metabolite
4-Methoxyestradiol 4-MeO-E2 2.0 1.0 ? ? Metabolite
2-Hydroxyestrone 2-OH-E1 2.0–4.0 0.2–0.4 ? ? Metabolite
2-Methoxyestrone 2-MeO-E1 <0.001–<1 <1 ? ? Metabolite
4-Hydroxyestrone 4-OH-E1 1.0–2.0 1.0 ? ? Metabolite
4-Methoxyestrone 4-MeO-E1 <1 <1 ? ? Metabolite
16α-Hydroxyestrone 16α-OH-E1; 17-Ketoestriol 2.0–6.5 35 ? ? Metabolite
2-Hydroxyestriol 2-OH-E3 2.0 1.0 ? ? Metabolite
4-Methoxyestriol 4-MeO-E3 1.0 1.0 ? ? Metabolite
Estradiol sulfate E2S; Estradiol 3-sulfate <1 <1 ? ? Metabolite
Estradiol disulfate Estradiol 3,17β-disulfate 0.0004 ? ? ? Metabolite
Estradiol 3-glucuronide E2-3G 0.0079 ? ? ? Metabolite
Estradiol 17β-glucuronide E2-17G 0.0015 ? ? ? Metabolite
Estradiol 3-gluc. 17β-sulfate E2-3G-17S 0.0001 ? ? ? Metabolite
Estrone sulfate E1S; Estrone 3-sulfate <1 <1 >10 >10 Metabolite
Estradiol benzoate EB; Estradiol 3-benzoate 10 ? ? ? Estrogen
Estradiol 17β-benzoate E2-17B 11.3 32.6 ? ? Estrogen
Estrone methyl ether Estrone 3-methyl ether 0.145 ? ? ? Estrogen
ent-Estradiol 1-Estradiol 1.31–12.34 9.44–80.07 ? ? Estrogen
Equilin 7-Dehydroestrone 13 (4.0–28.9) 13.0–49 0.79 0.36 Estrogen
Equilenin 6,8-Didehydroestrone 2.0–15 7.0–20 0.64 0.62 Estrogen
17β-Dihydroequilin 7-Dehydro-17β-estradiol 7.9–113 7.9–108 0.09 0.17 Estrogen
17α-Dihydroequilin 7-Dehydro-17α-estradiol 18.6 (18–41) 14–32 0.24 0.57 Estrogen
17β-Dihydroequilenin 6,8-Didehydro-17β-estradiol 35–68 90–100 0.15 0.20 Estrogen
17α-Dihydroequilenin 6,8-Didehydro-17α-estradiol 20 49 0.50 0.37 Estrogen
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
Relative affinities of estrogens for steroid hormone receptors and blood proteins
Estrogen Relative binding affinities (%)
ERTooltip Estrogen receptor ARTooltip Androgen receptor PRTooltip Progesterone receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor SHBGTooltip Sex hormone-binding globulin CBGTooltip Corticosteroid binding globulin
Estradiol 100 7.9 2.6 0.6 0.13 8.7–12 <0.1
Estradiol benzoate ? ? ? ? ? <0.1–0.16 <0.1
Estradiol valerate 2 ? ? ? ? ? ?
Estrone 11–35 <1 <1 <1 <1 2.7 <0.1
Estrone sulfate 2 2 ? ? ? ? ?
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 100–112 1–3 15–25 1–3 <1 0.18 <0.1
Mestranol 1 ? ? ? ? <0.1 <0.1
Methylestradiol 67 1–3 3–25 1–3 <1 ? ?
Moxestrol 12 <0.1 0.8 3.2 <0.1 <0.2 <0.1
Diethylstilbestrol ? ? ? ? ? <0.1 <0.1
Selected biological properties of endogenous estrogens in rats 折り畳む
Estrogen ERTooltip Estrogen receptor RBATooltip relative binding affinity (%) Uterine weight (%) Uterotrophy LHTooltip Luteinizing hormone levels (%) SHBGTooltip Sex hormone-binding globulin RBATooltip relative binding affinity (%)
Control – 100 – 100 –
Estradiol (E2) 100 506 ± 20 +++ 12–19 100
Estrone (E1) 11 ± 8 490 ± 22 +++ ? 20
Estriol (E3) 10 ± 4 468 ± 30 +++ 8–18 3
Estetrol (E4) 0.5 ± 0.2 ? Inactive ? 1
17α-Estradiol 4.2 ± 0.8 ? ? ? ?
2-Hydroxyestradiol 24 ± 7 285 ± 8 +b 31–61 28
2-Methoxyestradiol 0.05 ± 0.04 101 Inactive ? 130
4-Hydroxyestradiol 45 ± 12 ? ? ? ?
4-Methoxyestradiol 1.3 ± 0.2 260 ++ ? 9
4-Fluoroestradiola 180 ± 43 ? +++ ? ?
2-Hydroxyestrone 1.9 ± 0.8 130 ± 9 Inactive 110–142 8
2-Methoxyestrone 0.01 ± 0.00 103 ± 7 Inactive 95–100 120
4-Hydroxyestrone 11 ± 4 351 ++ 21–50 35
4-Methoxyestrone 0.13 ± 0.04 338 ++ 65–92 12
16α-Hydroxyestrone 2.8 ± 1.0 552 ± 42 +++ 7–24 <0.5
2-Hydroxyestriol 0.9 ± 0.3 302 +b ? ?
2-Methoxyestriol 0.01 ± 0.00 ? Inactive ? 4
Notes: Values are mean ± SD or range. ER RBA = 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.

テンプレート:Relative oral potencies of estrogens

テンプレート:Oral potencies of estrogens

テンプレート:Parenteral potencies and durations of steroidal estrogens

テンプレート:Classification of estrogens and antiestrogens after a single injection

Pharmacokinetics

ファイル:Levels of estriol with administration of 8 mg oral estriol or 0.5 mg vaginal estriol in women.png
Estriol (E3) levels after a single dose during continuous daily administration of 8 mg oral estriol (with or without a meal at 4 hours) or 0.5 mg vaginal estriol.[3] Note the second peak with oral estriol caused by consumption of a meal at 4 hours, which is due to enterohepatic recycling of the compound and a consequent resurgence in levels.[3]

Absorption

Estriol has significant bioavailability, but its potency is limited by rapid metabolism and excretion and its relatively weak estrogenic activity.[5][16] With oral administration, during first-pass metabolism, a considerable portion of estriol is conjugated via sulfation into estriol sulfate and rapidly excreted.[5][3][50] Only about 10 to 20% of a dose of estriol remains in the circulation, and of this, only about 1 to 2% is present in its active, unconjugated form.[3][5][50] Peak levels of estriol occur about 1 to 3 hours after an oral dose.[3][4] Similarly to the case of progesterone, taking oral estriol with food greatly enhances its absorption.[5] In addition, due to enterohepatic recycling, consuming a meal 4 hours after taking oral estriol can produce a second peak in estriol levels.[3][4] Dosages of oral estriol of 4 to 10 mg have been found to result in a fairly large range of maximal estriol levels of 80 to 340 pg/mL.[4] After a single oral dose of 8 mg estriol in postmenopausal women, maximal levels of 65 pg/mL estriol and 60 ng/mL estriol conjugates were produced within an hour.[3] With continued daily administration, this increased to peak levels of 130 pg/mL estriol, whereas maximal levels of estriol conjugates remained at 60 ng/mL.[3] Levels of estriol rapidly decreased to low levels following occurrence of peak levels.[3] Consumption of a meal 4 hours after taking an oral dose of 8 mg estriol during continuous daily administration resulted in a second estriol peak 2 hours later of 120 pg/mL, with estriol levels declining slowly thereafter to about 25 pg/mL after 24 hours.[3]

The bioavailability of estriol is markedly increased with vaginal administration compared to oral administration.[5] The relative bioavailability of oral estriol was found to be about 10% of that of vaginal estriol.[4] In accordance, a single dose of 8 mg oral estriol and of 0.5 mg vaginal estriol have been found to produce similar circulating concentrations of estriol.[3] It has been said that 0.5 to 1 mg vaginal estriol may be equivalent in clinical effect to 8 to 12 mg oral estriol.[16] The high bioavailability of vaginal estriol is due to rapid absorption and low metabolism in atrophic vaginal mucosa.[3] Vaginal estriol at typical clinical dosages results both in high local concentrations of estriol in the vagina and in systemic action.[3] Vaginal administration of low doses of 30 μg estriol and of higher doses of 0.5 and 1 mg estriol have been found to produce equivalent local effects in the vagina and improvement of vaginal symptoms, suggesting that a saturation of estrogenic effect of vaginal estriol has been reached in the vagina by a dose of only 30 μg estriol.[3] In contrast to higher doses of vaginal estriol however, 30 μg/day estriol is not associated with systemic effects.[3] Similarly, the use of 0.5 mg vaginal estriol twice a week instead of daily has been said to largely attenuate the systemic effects of estriol.[3] Whereas oral estriol results in high levels of estriol conjugates which greatly exceed those of unconjugated estriol, vaginal estriol has been found to produce levels of unconjugated estriol and estriol conjugates that are similar.[3]

The absorption of estrogens by the skin is described as low for estriol, moderate for estradiol, and high for estrone.[3] This is related to the number of hydroxyl groups in the molecules; the more hydroxyl groups, the lower the skin permeability.[3] This may account for the relative lack of use of transdermal or topical estriol.[5]

Rectal administration of estriol has been assessed in one study.[59] Administration of a rectal suppository containing 100 mg estriol resulted in estriol levels in pregnant women at term increasing by about 53%.[59] Estriol levels at term are normally between 5,000 and 20,000 pg/mL, which suggests that estriol levels may have increased following the suppository by about 5,000 to 10,000 pg/mL (precise levels were not provided).[60][61][62]

Estriol succinate is an ester prodrug of estriol which is used medically via oral and vaginal routes similarly.[3] In estriol succinate, two of the hydroxyl groups of estriol, those at the C16α and C17β positions, are esterified with succinic acid.[3] As such, when adjusted for differences in molecular weight, a dose of 2 mg estriol succinate is equivalent to 1.18 mg unconjugated estriol.[3] Unlike other estrogen esters, such as estradiol valerate, estriol succinate is hydrolyzed almost not at all in the intestinal mucosa when taken orally, and in relation to this, is absorbed more slowly than is estriol.[3] Consequently, oral estriol succinate is a longer-acting form of estriol than oral estriol.[18] Instead of in the gastrointestinal tract, oral estriol succinate is cleaved into estriol mainly in the liver.[3] After a single 8 mg oral dose of estriol succinate, maximum levels of circulating estriol of 40 pg/mL are attained within 12 hours, and this increases up to 80 pg/mL with continued daily administration.[3]

Distribution

Similarly to estradiol, but unlike estrone, estriol is accumulated in target tissues.[3][63] The plasma protein binding of estriol is approximately 92%, with about 91% bound to albumin, 1% bound to sex hormone-binding globulin (SHBG), and 8% free or unbound.[3] Estriol has very low affinity for SHBG, with only about 0.3% of the affinity of testosterone for this protein (or about 0.6% of that of estradiol).[3][64][65] Relative to estradiol, which is about 98% plasma protein-bound, a significantly greater fraction of estriol is unbound in the circulation and hence available for biological activity (2% relative to 8%, respectively).[65][3][16] This appears to account for the greater than expected biological activity of estriol relative to estradiol when considering its affinities for the estrogen receptors.[66]

Metabolism

Estriol is metabolized extensively via conjugation, including glucuronidation and sulfation.[3][5][4][67] Glucuronidation of estriol takes place mainly in the intestinal mucosa, while sulfation occurs in the liver.[3] More minor amounts of estriol can be oxidized and hydroxylated at various positions.[3] One such reaction is transformation into 16α-hydroxyestrone.[3] Estriol is an end-product of phase I estrogen metabolism and cannot be converted into estradiol or estrone.[3][50] The main metabolites of estriol are estrogen conjugates, including estriol sulfates, estriol glucuronides, and mixed estriol sulfate/glucuronide conjugates.[3] 16α-Hydroxyestrone is known to occur as a metabolite of estriol as well.[68][69][63]

The biological half-life of oral estriol has been reported to be in the range of 5 to 10 hours.[6][7][50] The elimination half-life of estriol following an intramuscular injection of 1 mg estriol has been found to be 1.5 to 5.3 hours.[4] The blood half-life of unconjugated estriol has been reported to be 20 minutes.[8][9] The metabolic clearance rate of estriol is approximately 1,110 L/day/m2, which is about twice that of estradiol.[3] Hence, estriol is eliminated from the body more rapidly than is estradiol.[3] Enterohepatic recycling may extend the duration of oral estriol.[16]

A single 1 to 2 mg dose of estriol in oil solution by intramuscular injection has a duration of about 3 or 4 days.[70] Estriol esters such as estriol dipropionate and estriol dihexanoate, when administered via intramuscular injection in an oil solution, have been found to maintain elevated levels of estriol for much longer amounts of time than oral or vaginal estriol, in the range of days to months.[4] These two estriol esters have not been marketed, but estriol acetate benzoate and estriol tripropionate are medically used estriol esters which are given via depot intramuscular injection and are long-acting similarly.[27] Polyestriol phosphate is an ester of estriol in the form of a polymer, and has a very long duration of action.[71][49]

Excretion

Estriol is excreted more than 95% in urine.[3] This is due to the fact that estriol conjugates in the colon are completely hydrolyzed via bacterial enzymes and in turn estriol in this part of the body is reabsorbed into the body.[3] The main urinary metabolites of exogenous estriol administered via intravenous injection in baboons have been found to be estriol 16α-glucuronide (65.8%), estriol 3-glucuronide (14.2%), estriol 3-sulfate (13.4%), and estriol 3-sulfate 16α-glucuronide (5.1%).[4][67] The metabolism and excretion of estriol in these animals closely resembled that which has been observed in humans.[67]

Chemistry

テンプレート:Chemical structures of major endogenous estrogens medication version

Estriol, also known as 16α-hydroxyestradiol or as estra-1,3,5(10)-triene-3,16α,17β-triol, is a naturally occurring estrane steroid with double bonds between the C1 and C2, C3 and C4, and C5 and C10 positions and hydroxyl groups at the C3, C16α, and C17β positions.[27][1] The name estriol and the abbreviation E3 were derived from the chemical terms estrin (estra-1,3,5(10)-triene) and triol (three hydroxyl groups).[72]

Analogues

A variety of analogues of estriol are known, including both naturally occurring isomers and synthetic substituted derivatives and esters.[27][1] 16β-Epiestriol (epiestriol), 17α-epiestriol, and 16β,17α-epiestriol are isomers of estriol that are endogenous weak estrogens.[27] Mytatrienediol (16α-methyl-16β-epiestriol 3-methyl ether) is a synthetic derivative of 16β-epiestriol that was never marketed.[27] Estriol acetate benzoate, estriol succinate, and estriol tripropionate are synthetic estriol esters that have been marketed for medical use, whereas estriol dihexanoate, estriol dipropionate, and estriol triacetate have not been introduced.[27][1] Quinestradol is the 3-cyclopentyl ether of estriol and has also been marketed.[27][1] Polyestriol phosphate, an ester of estriol in the form of a polymer, has been marketed previously as well.[71][73][49][74] These esters, ethers, and polymers are prodrugs of estriol.[3] Ethinylestriol and nilestriol are synthetic C17α ethynylated derivatives of estriol.[27][1] Ethinylestriol has not been marketed, but nilestriol, which is the 3-cyclopentyl ether of ethinylestriol and a prodrug of it, has been.[27][1]

Estetrol (E4), also known as 15α-hydroxyestriol, is a naturally occurring analogue of estriol with an additional hydroxyl group, at the C15α position.[75][76] It is closely related to estriol and has similar but non-identical pharmacological properties.[75][76] Like estriol, estetrol is a relatively weak and atypical estrogen.[75][76] Estetrol is under development for potential clinical use for a variety of indications, such as menopausal hormone therapy and hormonal birth control.[77][78]

History

See also: Estriol § History

Estriol was discovered in 1930.[20][21] Subsequently, it was introduced for medical use in oral and transdermal formulations under brand names such as Estriol, Oestrosalve, Theelol, and Tridestrin.[79][80][81][23][82][83][22] In addition, conjugated estriol, containing mainly estriol glucuronide, was marketed in the 1930s, under the brand names Emmenin and Progynon.[79][81][23][82][84][85] They were the first orally active estrogen preparations to be introduced in medicine.[84][85] In contrast to estrone, free estriol was never introduced for use by intramuscular injection.[86] Estriol continues to be used medically today, widely throughout the world and in a variety of different formulations and brand names.[1][2][5]

Society and culture

Generic names

Estriol is the generic name of estriol in American English and its INNTooltip International Nonproprietary Name, USPTooltip United States Pharmacopeia, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, and JANTooltip Japanese Accepted Name.[27][1][87][2] It is pronounced /ˌɛstraɪoʊl/ ess-TREE-ohl.[88] Estriolo is the name of estriol in Italian[2] and estriolum is its name in Latin, whereas its name remains unchanged as estriol in Spanish, Portuguese, French, and German.[2][1] Oestriol, in which the "O" is silent, was the former BANTooltip British Approved Name of estriol and its name in British English,[27][87][1] but the spelling was eventually changed to estriol.[2]

Brand names

Estriol is or has been marketed under a variety of brand names throughout the world, including Aacifemine, Colpogyn, Elinol, Estriel, Estriol, Estriosalbe, Estrokad, Evalon, Gydrelle, Gynäsan, Gynest, Gynoflor (in combination with lactobacilli), Incurin (veterinary), Klimax-E, OeKolp, Oestro-Gynaedron, Orgestriol, Ortho-Gynest, Ovesterin, Ovestin, Ovestinon, Ovestrion, Ovo-Vinces, Pausanol, Physiogine, Sinapause, Synapause, Synapause-E, Trophicrème, Vago-Med, Vacidox, and Xapro.[1][2]

Estriol succinate has been marketed under the brand names Blissel, Evalon, Gelistrol, Hemostyptanon, Orgastyptin, Ovestin, Pausan, Sinapause, Styptanon, Synapsa, Synapasa, Synapausa, and Synapause.[27][1][2] Estriol diacetate benzoate has been marketed under the brand name Holin-Depot and estriol tripropionate has been marketed under the brand name Estriel.[27] Polyestriol phosphate has been marketed under the brand names Gynäsan, Klimadurin, and Triodurin.[73][89][90] Emmenin and Progynon were estriol products marketed in the 1930s which were manufactured from the urine of pregnant women and contained estriol conjugates, primarily estriol glucuronide.[84][85]

Estriol for multiple sclerosis had the tentative brand name Trimesta but did not complete development and was never marketed.[91]

Availability

Estriol is marketed widely throughout the world, including in Europe, South Africa, Australia, New Zealand, Asia, Latin America, and elsewhere.[1][2] The medication is also available in some countries in the form of estriol succinate, an ester prodrug of estriol.[1][27][92] Estriol and its esters are not approved for use in the United States or Canada, although estriol has been produced and sold by compounding pharmacies in North America for use as a component of bioidentical hormone therapy.[34][93] In addition, topical creams containing estriol are not regulated in the United States and are available over-the-counter in this country.[26]

Research

Estriol may have immunomodulatory effects and has been of investigational interest in the treatment of multiple sclerosis and a number of other conditions.[16] Estriol succinate was under development for the treatment of multiple sclerosis in the United States and worldwide, and reached phase II clinical trials for this indication, but development was discontinued due to insufficient effectiveness.[91] It had the tentative brand name Trimesta.[91]

Veterinary use

Estriol is used in veterinary medicine, under the brand name Incurin, in the treatment of urinary incontinence due to estrogen deficiency in dogs.[12][13][14][15] Certain estrogens, like estradiol, can cause bone marrow suppression in dogs, which can be fatal, but estriol appears to pose less or possibly no risk.[15][94]

References

  1. ↑ 以下の位置に戻る: 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 407–. ISBN 978-3-88763-075-1.
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  4. ↑ 以下の位置に戻る: 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 Oettel M, Schillinger E (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. pp. 265, 273. ISBN 978-3-642-60107-1.
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  28. ↑ Mazer C, Israel SL, Charny CW (1946). Diagnosis and treatment of menstrual disorders and sterility. Hoeber. p. 525. 8. PREPARATIONS OF ESTRIOL. Estriol is the least active of all commercially available natural estrogenic substances. A milligram of estriol yields approximately 350 Allen-Doisy rat units. Estriol (Abbott). Capsules containing 0.06, 0.12, and 0.24 mg. Estriol (Lilly). Puvules containing 0.06, 0.12, and 0.24 mg. Theelol (Parke-Davis). Capsules containing 0.06, 0.12, and 0.24 mg.
  29. ↑ Barr DP (1940). Modern Medical Therapy in General Practice. William & Wilkins Company. p. 194. ISBN 978-0-598-66833-2. Estriol. Estriol (theelol) is trihydroxyestrin. It is a crystalline estrogenic steroid obtained from the urine of pregnant women. It is less actively estrogenic than estrone. Several pharmaceutical houses supply capsules containing 0.06 or 0.12 mg. These may be obtained as Theelol (Parke-Davis), Estriol (Abbott), and Estriol (Lilly).
  30. ↑ Sollmann TH (1948). A manual of pharmacology and its applications to therapeutics and toxicology. W. B. Saunders. Estriol (Theelol), N.N.R.; characters and solubility as for estrone; considerably less potent. Marketed as capsules of 0.06, 0.12 and 0.24 mg. Dose, 0.06 to 0.12 mg. once to four times daily.
  31. ↑ Council on Drugs (American Medical Association) (1950). New and Nonofficial Drugs. Lippincott. p. 322. Abbott Laboratories Capsules Estriol: 0.12 mg. and 0.24 mg. Eli Lilly and Company Pulvules Estriol: 0.06 mg., 0.12 mg. and 0.24 mg. Parke, Davis & Company Kapseals Theelol: 0.24 mg.
  32. ↑ New York State Journal of Medicine. Medical Society of the State of New York. 1939. p. 1760.
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  49. ↑ 以下の位置に戻る: 49.0 49.1 49.2 Labhart A (6 December 2012). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 548, 551. ISBN 978-3-642-96158-8. The polymer of estradiol or estriol and phosphoric acid has an excellent depot action when given intramuscularly (polyestriol phosphate or polyestradiol phosphate) (Table 16). Phosphoric acid combines with the estrogen molecule at C3 and C17 to form a macromolecule. The compound is stored in the liver and spleen where the estrogen is steadily released by splitting off of the phosphate portion due to the action of alkaline phosphatase. [...] Conjugated estrogens and polyestriol and estradiol phosphate can also be given intravenously in an aqueous solution. Intravenous administration of ovarian hormones offers no advantages, however, and therefore has no practical significance. [...] The following duarations of action have been obtained with a single administration (WlED, 1954; LAURITZEN, 1968): [...] 50 mg polyestradiol phosphate ~ 1 month; 50 mg polyestriol phosphate ~ 1 month; 80 mg polyestriol phosphate ~ 2 months.
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  56. ↑ Rabe T, Runnebaum B, Kellermeier-Wittlinger S (17 April 2013). "Hormontherapie". In Runnebaum B, Rabe T (eds.). Gynäkologische Endokrinologie und Fortpflanzungsmedizin: Band 1: Gynäkologische Endokrinologie. Springer-Verlag. pp. 88–. ISBN 978-3-662-07635-4.
  57. ↑ Kopera H (1991). "Hormone der Gonaden". Hormonelle Therapie für die Frau. Kliniktaschenbücher. Springer. pp. 59–124. doi:10.1007/978-3-642-95670-6_6. ISBN 978-3-540-54554-5. ISSN 0172-777X.
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  72. ↑ Cole LA, Kramer PR (13 October 2015). Human Physiology, Biochemistry and Basic Medicine. Elsevier Science. pp. 122–. ISBN 978-0-12-803717-1.
  73. ↑ 以下の位置に戻る: 73.0 73.1 Bachmann FF (January 1971). "[Treatment of menopausal complants with polyoestriol-phosphate. Experiences with Gynäsan injections]" [Treatment of menopausal complants with polyoestriol-phosphate. Experiences with Gynäsan injections]. Munchener Medizinische Wochenschrift (in Deutsch). 113 (5): 166–169. PMID 5107471.
  74. ↑ Campbell S (6 December 2012). The Management of the Menopause & Post-Menopausal Years: The Proceedings of the International Symposium held in London 24–26 November 1975 Arranged by the Institute of Obstetrics and Gynaecology, The University of London. Springer Science & Business Media. pp. 395–. ISBN 978-94-011-6165-7. In the Federal Republic of Germany between 10 and 20% of all climacteric women are on estrogen treatment. We have the following oral estrogens for a treatment. (t) Conjugated estrogens, (2) estradiol valerate, (3) ethinyl-estradiol and its cyclopentyl-enol ether, (4) stilbestrol, (5) ethinyl-estradiol-methyltestosterone, (6) estriol and estriol succinate, most of them as coated tablets. Several long acting injectable preparations are available: several esters of combined estradiol-testosterone, one of estradiol-dehydroepiandrosterone enanthate and a prolonged polyestriol phosphate are also available. Lastly, depot injections of estradiol- and stilbestrol-esters are on the market.
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  78. ↑ "Drospirenone/Estetrol - Mithra Pharmaceuticals". AdisInsight. Springer Nature Switzerland AG.
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  83. ↑ Macpherson AI (June 1940). "The Use of Œstrogens in Obstetrics and Gynæcology". Edinburgh Medical Journal. 47 (6): 406–424. PMC 5306594. PMID 29646930.
  84. ↑ 以下の位置に戻る: 84.0 84.1 84.2 Rooke T (1 January 2012). The Quest for Cortisone. MSU Press. pp. 54–. ISBN 978-1-60917-326-5.
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  86. ↑ Cantor EB (September 1956). "A survey of estrogens". Postgraduate Medicine. 20 (3): 224–231. doi:10.1080/00325481.1956.11691266. PMID 13359169.
  87. ↑ 以下の位置に戻る: 87.0 87.1 Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 206, 905. ISBN 978-94-011-4439-1.
  88. ↑ 引用エラー: 無効な <ref> タグです。「Dictionary.com」という名前の注釈に対するテキストが指定されていません
  89. ↑ Negwer M, Scharnow HG (4 October 2001). Organic-chemical drugs and their synonyms: (an international survey). Wiley-VCH. ISBN 978-3-527-30247-5. 8075-01 (6628-01) 37452-43-0 R Polymeric ester with phosphoric acid S Klimadurin, Polyestriol phosphate, Polyostriolphosphat, Triodurin U Depot-estrogen
  90. ↑ Martindale W, et al. (Royal Pharmaceutical Society of Great Britain. Dept. of Pharmaceutical Sciences) (1993). The Extra Pharmacopoeia. Pharmaceutical Press. p. 2258. ISBN 978-0-85369-300-0. Polyoestriol Phosphate. [...] ingredient of Klimadurin. [...] Triodurin [...].
  91. ↑ 以下の位置に戻る: 91.0 91.1 91.2 "Estriol succinate - Synthetic Biologics". AdisInsight. Springer Nature Switzerland AG.
  92. ↑ Platt D (6 December 2012). Geriatrics 3: Gynecology · Orthopaedics · Anesthesiology · Surgery · Otorhinolaryngology · Ophthalmology · Dermatology. Springer Science & Business Media. pp. 6–. ISBN 978-3-642-68976-5.
  93. ↑ Files JA, Ko MG, Pruthi S (July 2011). "Bioidentical hormone therapy". Mayo Clinic Proceedings. 86 (7): 673–80, quiz 680. doi:10.4065/mcp.2010.0714. PMC 3127562. PMID 21531972.
  94. ↑ Feldman EC, Nelson RW (1 January 2004). Canine and Feline Endocrinology and Reproduction. Elsevier Health Sciences. pp. 839–. ISBN 0-7216-9315-6.

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