Estriol (medication)

applied in the vagina, and by injection into muscle.^[4][5][6]

endogenous estradiol.^[4] It is an atypical and relatively weak estrogen, with much lower potency than estradiol.^[4][6][19] When present continuously at adequate concentrations however, estriol produces full estrogenic effects similarly to estradiol.^[20][21]

Estriol esters such as estriol succinate are also used.^[4][18][3] 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.^[4][2][3][6]

lactobacilli as a dual estrogen and probiotic has been marketed for the treatment of vaginal atrophy and urinary tract infections.^[27]

estriol ester prodrugs such as estriol succinate, estriol acetate benzoate, and estriol tripropionate, as well as the polymeric ester prodrug polyestriol phosphate.^{[4][18][29][2][3]}

itching) and discharge may occur.^[12] 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.^[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]

overdose.^{[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 include nausea, vomiting, vaginal bleeding, and reversible feminization.^[39][16] 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.^[16] The most serious short-term adverse effect of estrogens in dogs is bone marrow suppression and consequent pancytopenia, which can be life-threatening.^[16]

G protein-coupled estrogen receptor (GPER), a membrane 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 other steroid hormone receptors.^{[46][47][48][49][50]}

endometrial proliferation or increase the risk of endometrial 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 active breast 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 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.^[4] 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.^[54][55] Due to its differing effects from those of estradiol, estriol may be considered a safer estrogen in certain regards.^[12]

enterohepatic 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]

agonist–antagonist or partial 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 be antiestrogenic.^[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]

postmenopausal 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]

vaginal 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 the vagina 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]

topical estriol.^[6]

mucosa 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 the gastrointestinal tract, oral estriol succinate is cleaved into estriol mainly in the liver.^[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]

affinity for SHBG, with only about 0.3% of the affinity of testosterone for this protein (or about 0.6% of that of estradiol).^[4][92][93] 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).^[93][4][18] This appears to account for the greater than expected biological activity of estriol relative to estradiol when considering its affinities for the estrogen receptors.^[94]

16α-hydroxyestrone.^[4] Estriol is an end-product of phase I estrogen metabolism and cannot be converted into estradiol or estrone.^[4][52] The main metabolites of estriol are estrogen conjugates, including estriol sulfates, estriol glucuronides, and mixed estriol sulfate/glucuronide conjugates.^[4] 16α-Hydroxyestrone is known to occur as a metabolite of estriol as well.^[95][96][91]

Enterohepatic recycling may extend the duration of oral estriol.^[18]

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.^[5] 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.^[29] Polyestriol phosphate is an ester of estriol in the form of a polymer, and has a very long duration of action.^[98][51]

estriol 3-sulfate 16α-glucuronide (5.1%).^[5][7] The metabolism and excretion of estriol in these animals closely resembled that which has been observed in humans.^[7]

estrin (estra-1,3,5(10)-triene) and triol (three hydroxyl groups).^[99]

estriol esters that have been marketed for medical use, whereas estriol dihexanoate, estriol dipropionate, and estriol triacetate have not been introduced.^[29][2] Quinestradol is the 3-cyclopentyl ether of estriol and has also been marketed.^[29][2] Polyestriol phosphate, an ester of estriol in the form of a polymer, has been marketed previously as well.^{[98][100][51][101]} These esters, ethers, and polymers are prodrugs of estriol.^[4] Ethinylestriol and nilestriol are synthetic C17α ethynylated 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]

hormonal birth control.^[104][105]

transdermal formulations under brand names such as Estriol, Oestrosalve, Theelol, and Tridestrin.^{[106][107][108][25][109][110][24]} In addition, conjugated estriol, containing mainly estriol glucuronide, was marketed in the 1930s, under the brand names Emmenin and Progynon.^{[106][108][25][109][111][112]} They were the first orally active estrogen preparations to be introduced in medicine.^[111][112] In contrast to estrone, free estriol was never introduced for use by intramuscular injection.^[113] Estriol continues to be used medically today, widely throughout the world and in a variety of different formulations and brand names.^[2][3][6]

INNTooltip International Nonproprietary Name, USPTooltip United States Pharmacopeia, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, and JANTooltip Japanese Accepted Name.^{[29][2][114][3]} It is pronounced /ˌɛstraɪoʊl/ ESS-TREE-ohl.^[1] Estriolo is the name of estriol in Italian^[3] and estriolum is its name in Latin, whereas its name remains unchanged as estriol in Spanish, Portuguese, French, and German.^[3][2] Oestriol, in which the "O" is silent, was the former BANTooltip British Approved Name of estriol and its name in British English,^[29][114][2] but the spelling was eventually changed to estriol.^[3]

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.^[2][3]

estriol conjugates, primarily estriol glucuronide.^[111][112]

over-the-counter in this country.^[28]

immunomodulatory effects and has been of investigational interest in the treatment of multiple sclerosis and a number of other conditions.^[18] 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.^[117] It had the tentative brand name Trimesta.^[117]

estrogen deficiency in dogs.^{[14][15][16][17]} 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.^[17][120]