Estriol (medication)

Clinical data
Pronunciation	/ˈɛstriɒl,-traɪɒl/[1] ESS-TREE-ohl[1]
Trade names	Ovestin, others[2][3]
Other names	Oestriol; E3; 16α-Hydroxyestradiol; Estra-1,3,5(10)-triene-3,16α,17β-triol
Routes of administration	By mouth,vaginal,intramuscular injection[4][5][6]
Drug class	Estrogen
ATC code	G03CA04 (WHO) G03CC06 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	Oral: ~1–2%[4][6] Vaginal: ~10–20%[5][4][6]
Protein binding	92%:[4] •Albumin: 91%[4] •SHBGTooltip Sex hormone-binding globulin: 1%[4] • Free: 8%[4]
Metabolism	Liver,intestines (conjugation (glucuronidation,sulfation),oxidation,hydroxylation)[4]
Metabolites	•Estriol 16α-glucuronide[7][5] •Estriol 3-glucuronide[7][5] •Estriol 3-sulfate[7][5] •Estriol 3-sulfate 16α-gluc.[7][5] •16α-Hydroxyestrone[4][8] • Others (minor)[4]
Eliminationhalf-life	Oral: 5–10 hours[9][8] IMTooltip Intramuscular injection: 1.5–5.3 hours (asE3)[5] IVTooltip Intravenous injection: 20 minutes (asE3)[10][11]
Excretion	Urine: >95% (asconjugates)[4][5]
Identifiers
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
CAS Number	50-27-1 Y 1306-04-3 514-68-1 (succinate)
PubChemCID	5756
IUPHAR/BPS	2821
DrugBank	DB04573 Y
ChemSpider	5553 Y
UNII	FB33469R8E
KEGG	C05141 Y
ChEBI	CHEBI:27974 Y
ChEMBL	ChEMBL193482 Y
Chemical and physical data
Formula	C18H24O3
Molar mass	288.387 g·mol−1
3D model (JSmol)	Interactive image
Melting point	82 to 86 °C (180 to 187 °F) (experimental)
Solubility in water	0.119 mg/mL (20 °C)
SMILES Oc1cc3c(cc1)[C@H]2CC[C@@]4([C@@H](O)[C@H](O)C[C@H]4[C@@H]2CC3)C
InChI InChI=1S/C18H24O3/c1-18-7-6-13-12-5-3-11(19)8-10(12)2-4-14(13)15(18)9-16(20)17(18)21/h3,5,8,13-17,19-21H,2,4,6-7,9H2,1H3/t13-,14-,15+,16-,17+,18+/m1/s1 Y Key:PROQIPRRNZUXQM-ZXXIGWHRSA-N Y
(verify)

Estriol (E3), sold under the brand nameOvestin among others, is anestrogen medication andnaturally occurringsteroid hormone which is used inmenopausal hormone therapy.^{[12][4][6][13]} It is also used inveterinary medicine asIncurin to treaturinary incontinence due toestrogen deficiency in dogs.^{[14][15][16][17]} The medication is takenby mouth in the form oftablets, as acream that isapplied to the skin, as a cream orpessary that isapplied in the vagina, and byinjection into muscle.^[4][5][6]

Estriol is well-tolerated and produces relatively fewadverse effects.^[12][18] Side effects may includebreast tenderness,vaginal discomfort anddischarge, andendometrial hyperplasia.^[12][18] Estriol is anaturally occurring andbioidentical estrogen, or anagonist of theestrogen receptor, thebiological target ofestrogens likeendogenousestradiol.^[4] It is an atypical and relatively weak estrogen, with much lowerpotency thanestradiol.^[4][6][19] When present continuously at adequate concentrations however, estriol produces fullestrogenic effects similarly to estradiol.^[20][21]

Estriol was first discovered in 1930,^[22][23] and was introduced for medical use shortly thereafter.^[24][25]Estriol esters such asestriol succinate are also used.^[4][18][3] Although it is less commonly employed than other estrogens like estradiol andconjugated estrogens, estriol is widely available for medical use inEurope and elsewhere throughout the world.^[4][2][3][6]

Estriol is used inmenopausal hormone therapy to treatmenopausal symptoms, such ashot flashes,vulvovaginal atrophy, anddyspareunia (difficult or painfulsexual intercourse).^{[12][4][13][26][18]} The benefits of estriol onbone mineral density andosteoporosis prevention have been inconsistent and are less clear.^[18][12] Estriol has been found to reduce the risk ofurinary tract infections and otherurogenital symptoms.^[4][12] A combination of estriol andlactobacilli as a dual estrogen andprobiotic has been marketed for the treatment of vaginal atrophy and urinary tract infections.^[27]

Estriol is available inoraltablet,vaginalcream, and vaginalsuppository forms.^[13] It is also availableover-the-counter or fromcompounding pharmacies in the form oftopicalcreams.^[28] The medication is available both as estriol and in the form ofestriol esterprodrugs such asestriol succinate,estriol acetate benzoate, andestriol tripropionate, as well as thepolymeric ester prodrugpolyestriol phosphate.^{[4][18][29][2][3]}

Estriol was originally marketed in the 1930s in the form of oralcapsules containing 0.06, 0.12, or 0.24 mg estriol under the brand names Theelol (Parke-Davis) and Estriol (Lilly,Abbott).^{[30][31][32][33][34]} 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.^[35]

Generalcontraindications of estrogens includebreast cancer,endometrial cancer, and others.^[19] In animals, estriol is contraindicated duringpregnancy and inferrets.^[17]

Estriol is well-tolerated and produces relatively fewadverse effects.^[12][18]Breast tenderness may sometimes occur as a side effect of estriol.^[12] Local reactions with vaginal estriol such asdiscomfort (irritation,burning,itching) anddischarge may occur.^[12] Estriol may produceendometrial hyperplasia similarly to estradiol and other estrogens, and hence should be combined with aprogestogen in women with intactuteruses to prevent this risk.^[36][4] However, it appears that typical clinical dosages of vaginal estriol are not associated with an important risk of endometrial proliferation or hyperplasia.^[12][26] As such, combination with a progestogen may not be needed in the case of vaginal estriol.^[12][26] Some studies suggest that this may also be true for oral estriol.^[18] However, dosage and frequency of administration, as well as meal consumption, may be determining factors as to whether or not estriol produces endometrial proliferation.^[4]

Estrogens and othersteroids are relatively safe in acuteoverdose.^{[citation needed]} Estriol has been assessed in single oral doses of up to 75 mg.^[37][38] General symptoms of estrogen overdose in humans may includenausea,vomiting,vaginal bleeding, and reversiblefeminization.^[39][16] While there are no known studies describing the acutetoxicity of estrogen overdose in dogs, this species is known to be more sensitive to the toxic effects of estrogens than humans and other animals.^[16] The most serious short-term adverse effect of estrogens in dogs isbone marrow suppression and consequentpancytopenia, which can be life-threatening.^[16]

Interactions with estriol might be expected to be similar to those ofestradiol.^[40] No interactions with estriol have been reported in animals.^[17] However, it should not be used in combination with other drugs thatsuppress bone marrow production in dogs.^[17]

Estriol is an estrogen, or anagonist of theestrogen receptors (ERs),ERα andERβ.^[4][41][42] In terms ofrelative binding affinities (RBA) for the ERs compared toestradiol, 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.^[42] Itsrelative transactivational capacities at the ERs compared to estradiol were 11% at ERα and 17% at ERβ.^[42] In addition to being aligand of the classicalnuclear ERs, estriol is anantagonist of theG protein-coupled estrogen receptor (GPER), amembrane estrogen receptor (mER), at high concentrations (~1,000–10,000 μM).^{[43][44][41][45]} This is in contrast to estradiol, which is an agonist of this receptor.^[44][41][45] Like other estrogens, estriol does not importantly interact with othersteroid hormone receptors.^{[46][47][48][49][50]}

Estriol is a much lesspotent estrogen than is estradiol, and is somewhat weak and atypical in its properties.^{[4][42][44][19]} Given bysubcutaneous injection in mice, estradiol is about 10-fold more potent thanestrone and about 100-fold more potent than estriol.^[51] With clinical use, estriol is said to be weakly estrogenic in certaintissues, such as theliver andendometrium, but produces pronounced and full estrogenic responses in thevaginalepithelium.^[4] The medication has been found to reducehot flashes, improvevaginal atrophy, reverse thepostmenopausal decline inskin thickness andcollagen content, suppressgonadotropin secretion, and produceproliferation ofbreast epithelium.^[4] Conversely, estriol does not consistently affectbone resorption orfracture risk, does not seem to increasebreast density, and, at oral doses of 2 to 4 mg/day, does not affectliver proteins,lipid metabolism, orhemostatic parameters.^[4][18] Additionally, vaginal estriol does not appear to produceendometrial proliferation or increase the risk ofendometrial hyperplasia, and some studies have found this to be the case for oral estriol as well.^[4][18][52] On the other hand, it appears that estriol may be able to stimulate the growth of activebreast cancer.^[18][12] In rodents, estriol induces mammary gland development similar to that with estrone.^[53] By the oral route in women, estriol has approximately 30% of the potency of estradiol in terms ofhot flashes relief and suppression offollicle-stimulating hormonesecretion, and about 20% of the potency of estradiol on stimulation ofliverproduction ofhigh-density lipoprotein (HDL)cholesterol.^[4] A study ofovulation inhibition by estrogens in women found that prevention of ovulation occurred with 5 mg/day oral estriol in only 1 of 7 cycles.^[54][55] Due to its differing effects from those of estradiol, estriol may be considered a safer estrogen in certain regards.^[12]

The weak and atypical estrogenicity of estriol is thought to be related to its shortduration in the body and hence the fact that it stays bound to the ER for a relatively short amount of time.^[4][21] Whereas estradiol remains bound to the ER for 6 to 24 hours with a single short-actinginjection, estriol dissociates from the receptor much more rapidly and stays bound for only 1 to 6 hours.^{[4][21][58][59]} As a result, estriol can only induce estrogenic effects which require short-term interaction with the ERs.^[4][21] Induction ofendometrialmitoses 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.^[4][21] If estriol is delivered more continuously than a single administration per day however, for instance if it is given as asubcutaneous pellet, as adepot 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.^[4][21][12] 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.^[21] Consumption of food after oral administration of estriol also results in more prolonged exposure to estriol, due toenterohepatic recycling and resurgences in estriol levels.^[4] 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.^[4][52]

Although estriol is an estrogen, it has also been reported to have mixedagonist–antagonist orpartial agonist activity at the ERs.^[4][21][19] On its own, it is said to be weakly estrogenic, but in the presence of estradiol, it has been found to beantiestrogenic.^[4][44] However, this is again due to the fact that estriol is a "short-acting" estrogen.^[21] If estriol is present continuously with estradiol, it shows no antagonism of estradiol.^[21] 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.^[52][60]

Estriol has significantbioavailability, but itspotency is limited by rapidmetabolism andexcretion and its relatively weak estrogenic activity.^[6][18] Withoral administration, duringfirst-pass metabolism, a considerable portion of estriol isconjugated viasulfation intoestriol sulfate and rapidly excreted.^[6][4][52] 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.^[4][6][52]Peak levels of estriol occur about 1 to 3 hours after an oral dose.^[4][5] Similarly to the case ofprogesterone, taking oral estriol with food greatly enhances itsabsorption.^[6] In addition, due toenterohepatic recycling, consuming a meal 4 hours after taking oral estriol can produce a second peak in estriol levels.^[4][5] 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.^[5] After a single oral dose of 8 mg estriol inpostmenopausal women, maximal levels of 65 pg/mL estriol and 60 ng/mL estriol conjugates were produced within an hour.^[4] 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.^[4] Levels of estriol rapidly decreased to low levels following occurrence of peak levels.^[4] 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.^[4]

The bioavailability of estriol is markedly increased withvaginal administration compared to oral administration.^[6] The relative bioavailability of oral estriol was found to be about 10% of that of vaginal estriol.^[5] 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.^[4] 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.^[18] The high bioavailability of vaginal estriol is due to rapid absorption and low metabolism in atrophic vaginal mucosa.^[4] Vaginal estriol at typical clinical dosages results both in high local concentrations of estriol in thevagina and in systemic action.^[4] 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.^[4] In contrast to higher doses of vaginal estriol however, 30 μg/day estriol is not associated with systemic effects.^[4] 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.^[4] 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.^[4]

The absorption of estrogens by the skin is described as low for estriol, moderate for estradiol, and high for estrone.^[4] This is related to the number ofhydroxyl groups in the molecules; the more hydroxyl groups, the lower the skin permeability.^[4] This may account for the relative lack of use oftransdermal ortopical estriol.^[6]

Rectal administration of estriol has been assessed in one study.^[96] Administration of a rectalsuppository containing 100 mg estriol resulted in estriol levels inpregnant womenat term increasing by about 53%.^[96] 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).^[97][98][99]

Estriol succinate is anesterprodrug of estriol which is used medically via oral and vaginal routes similarly.^[4] In estriol succinate, two of thehydroxyl groups of estriol, those at the C16α and C17β positions, are esterified withsuccinic acid.^[4] As such, when adjusted for differences inmolecular weight, a dose of 2 mg estriol succinate is equivalent to 1.18 mg unconjugated estriol.^[4] Unlike other estrogen esters, such asestradiol valerate, estriol succinate ishydrolyzed almost not at all in theintestinalmucosa when taken orally, and in relation to this, is absorbed more slowly than is estriol.^[4] Consequently, oral estriol succinate is a longer-acting form of estriol than oral estriol.^[20] Instead of in thegastrointestinal tract, oral estriol succinate iscleaved into estriol mainly in theliver.^[4] 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.^[4]

Similarly to estradiol, but unlikeestrone, estriol is accumulated in target tissues.^[4][100] Theplasma protein binding of estriol is approximately 92%, with about 91% bound toalbumin, 1% bound tosex hormone-binding globulin (SHBG), and 8% free or unbound.^[4] Estriol has very lowaffinity for SHBG, with only about 0.3% of the affinity oftestosterone for this protein (or about 0.6% of that of estradiol).^{[4][101][102]} 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).^[102][4][18] This appears to account for the greater than expected biological activity of estriol relative to estradiol when considering its affinities for theestrogen receptors.^[103]

Estriol ismetabolized extensively viaconjugation, includingglucuronidation andsulfation.^[4][6][5][7] Glucuronidation of estriol takes place mainly in theintestinalmucosa, while sulfation occurs in theliver.^[4] More minor amounts of estriol can beoxidized andhydroxylated at various positions.^[4] One such reaction is transformation into16α-hydroxyestrone.^[4] Estriol is an end-product ofphase I estrogen metabolism and cannot be converted into estradiol or estrone.^[4][52] The mainmetabolites of estriol areestrogen conjugates, includingestriol sulfates,estriol glucuronides, and mixedestriol sulfate/glucuronide conjugates.^[4]16α-Hydroxyestrone is known to occur as a metabolite of estriol as well.^{[104][105][100]}

Thebiological half-life of oral estriol has been reported to be in the range of 5 to 10 hours.^[9][8][52] Theelimination half-life of estriol following anintramuscular injection of 1 mg estriol has been found to be 1.5 to 5.3 hours.^[5] Theblood half-life of unconjugated estriol has been reported to be 20 minutes.^[10][11] Themetabolic clearance rate of estriol is approximately 1,110 L/day/m², which is about twice that of estradiol.^[4] Hence, estriol iseliminated from the body more rapidly than is estradiol.^[4]Enterohepatic recycling may extend the duration of oral estriol.^[18]

A single 1 to 2 mg dose of estriol in oil solution by intramuscular injection has a duration of about 3 or 4 days.^[106]Estriol esters such asestriol dipropionate andestriol dihexanoate, when administered via intramuscular injection in anoil 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.^[5] These two estriol esters have not been marketed, butestriol acetate benzoate andestriol tripropionate are medically used estriol esters which are given viadepot intramuscular injection and are long-acting similarly.^[29]Polyestriol phosphate is an ester of estriol in the form of apolymer, and has a very long duration of action.^[107][51]

Estriol isexcreted more than 95% inurine.^[4] This is due to the fact that estriol conjugates in thecolon are completelyhydrolyzed viabacterialenzymes and in turn estriol in this part of the body is reabsorbed into the body.^[4] The main urinarymetabolites ofexogenous estriol administered viaintravenous injection inbaboons have been found to beestriol 16α-glucuronide (65.8%),estriol 3-glucuronide (14.2%),estriol 3-sulfate (13.4%), andestriol 3-sulfate 16α-glucuronide (5.1%).^[5][7] Themetabolism andexcretion of estriol in these animals closely resembled that which has been observed in humans.^[7]

v t e Structures of major endogenous estrogens Estrone (E1) Estradiol (E2) Estriol (E3) Estetrol (E4) Note thehydroxyl (–OH)groups: estrone (E1) has one, estradiol (E2) has two, estriol (E3) has three, and estetrol (E4) has four.

Estriol, also known as 16α-hydroxyestradiol or as estra-1,3,5(10)-triene-3,16α,17β-triol, is anaturally occurringestranesteroid withdouble bonds between the C1 and C2, C3 and C4, and C5 and C10 positions andhydroxyl groups at the C3, C16α, and C17β positions.^[29][2] The nameestriol and the abbreviationE3 were derived from the chemical termsestrin (estra-1,3,5(10)-triene) andtriol (three hydroxyl groups).^[108]

A variety ofanalogues of estriol are known, including both naturally occurringisomers andsyntheticsubstitutedderivatives andesters.^[29][2]16β-Epiestriol (epiestriol),17α-epiestriol, and16β,17α-epiestriol are isomers of estriol that are endogenous weak estrogens.^[29]Mytatrienediol (16α-methyl-16β-epiestriol 3-methyl ether) is a synthetic derivative of 16β-epiestriol that was never marketed.^[29]Estriol acetate benzoate,estriol succinate, andestriol tripropionate are syntheticestriol esters that have been marketed for medical use, whereasestriol dihexanoate,estriol dipropionate, andestriol triacetate have not been introduced.^[29][2]Quinestradol is the 3-cyclopentylether of estriol and has also been marketed.^[29][2]Polyestriol phosphate, an ester of estriol in the form of apolymer, has been marketed previously as well.^{[107][109][51][110]} These esters, ethers, and polymers areprodrugs of estriol.^[4]Ethinylestriol andnilestriol are synthetic C17αethynylated derivatives of estriol.^[29][2] Ethinylestriol has not been marketed, but nilestriol, which is the 3-cyclopentyl ether of ethinylestriol and a prodrug of it, has been.^[29][2]

Estetrol (E4), also known as 15α-hydroxyestriol, is anaturally occurring analogue of estriol with an additionalhydroxyl group, at the C15α position.^[111][112] It is closely related to estriol and has similar but non-identicalpharmacological properties.^[111][112] Like estriol, estetrol is a relatively weak and atypical estrogen.^[111][112] Estetrol is under development for potential clinical use for a variety of indications, such as menopausal hormone therapy andhormonal birth control.^[113][114]

Estriol was discovered in 1930.^[22][23] Subsequently, it was introduced for medical use inoral andtransdermal formulations under brand names such asEstriol,Oestrosalve,Theelol, andTridestrin.^{[115][116][117][25][118][119][24]} In addition,conjugated estriol, containing mainlyestriol glucuronide, was marketed in the 1930s, under the brand namesEmmenin andProgynon.^{[115][117][25][118][120][121]} They were the first orally active estrogen preparations to be introduced in medicine.^[120][121] In contrast to estrone, free estriol was never introduced for use byintramuscular injection.^[122] Estriol continues to be used medically today, widely throughout the world and in a variety of different formulations and brand names.^[2][3][6]

Estriol is thegeneric name of estriol inAmerican English and itsINNTooltip International Nonproprietary Name,USPTooltip United States Pharmacopeia,BANTooltip British Approved Name,DCFTooltip Dénomination Commune Française, andJANTooltip Japanese Accepted Name.^{[29][2][123][3]} It is pronounced/ˌɛstraɪoʊl/ESS-TREE-ohl.^[1]Estriolo is the name of estriol inItalian^[3] andestriolum is its name inLatin, whereas its name remains unchanged asestriol inSpanish,Portuguese,French, andGerman.^[3][2]Oestriol, in which the "O" is silent, was the formerBANTooltip British Approved Name of estriol and its name inBritish English,^[29][123][2] but the spelling was eventually changed toestriol.^[3]

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 withlactobacilli), 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.^[2][3]

Estriol succinate has been marketed under the brand names Blissel, Evalon, Gelistrol, Hemostyptanon, Orgastyptin, Ovestin, Pausan, Sinapause, Styptanon, Synapsa, Synapasa, Synapausa, and Synapause.^[29][2][3]Estriol diacetate benzoate has been marketed under the brand name Holin-Depot andestriol tripropionate has been marketed under the brand name Estriel.^[29]Polyestriol phosphate has been marketed under the brand names Gynäsan, Klimadurin, and Triodurin.^{[109][124][125]}Emmenin andProgynon were estriol products marketed in the 1930s which were manufactured from theurine ofpregnant women and containedestriol conjugates, primarilyestriol glucuronide.^[120][121]

Estriol formultiple sclerosis had the tentative brand name Trimesta but did not complete development and was never marketed.^[126]

Estriol is marketed widely throughout the world, including inEurope,South Africa,Australia,New Zealand,Asia,Latin America, and elsewhere.^[2][3] The medication is also available in some countries in the form ofestriol succinate, anesterprodrug of estriol.^[2][29][127] Estriol and its esters are not approved for use in theUnited States orCanada, although estriol has been produced and sold bycompounding pharmacies inNorth America for use as a component ofbioidentical hormone therapy.^[36][128] In addition, topical creams containing estriol are not regulated in the United States and are availableover-the-counter in this country.^[28]

Estriol may haveimmunomodulatory effects and has been of investigational interest in the treatment ofmultiple sclerosis and a number of other conditions.^[18]Estriol succinate was under development for the treatment of multiple sclerosis in theUnited States and worldwide, and reachedphase IIclinical trials for this indication, but development was discontinued due to insufficient effectiveness.^[126] It had the tentative brand name Trimesta.^[126]

Estriol is used inveterinary medicine, under the brand name Incurin, in the treatment ofurinary incontinence due toestrogen deficiency in dogs.^{[14][15][16][17]} Certain estrogens, likeestradiol, can causebone marrow suppression in dogs, which can be fatal, but estriol appears to pose less or possibly no risk.^[17][129]