Estradiol valerate

Clinical data
Pronunciation	/ˌɛstrəˈdaɪoʊlˈvæləreɪt/ ⓘ ES-trə-DY-ohlVAL-ə-rayt[1]
Trade names	Delestrogen, Progynon Depot, Progynova, many others
Other names	EV; E2V; Oestradiol valerate; Estradiol pentanoate; Estradiol valerianate
Routes of administration	By mouth,sublingual,intramuscular injection,[2]subcutaneous injection
Drug class	Estrogen;Estrogen ester
ATC code	G03CA03 (WHO)
Legal status
Legal status	US: ℞-only In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	Oral: 3–5%[3][4] IM injection: 100%[5][3]
Protein binding	Estradiol: ~98% (toalbumin andSHBGTooltip sex hormone-binding globulin)[6][7]
Metabolism	Cleavage viaesterases in theliver,blood, andtissues[3]
Metabolites	Estradiol,valeric acid, andmetabolites of estradiol[3]
Eliminationhalf-life	Oral: 12–20 hours (asE2)[3][6] IM injection: 3.5 (1.2–7.2) days[8]
Duration of action	IM injection: • 5 mg: 7–8 days[9] • 10 mg: 10–14 days[10][11] • 40 mg: 2–3 weeks[10] • 100 mg: 3–4 weeks[10]
Excretion	Urine (80%)[3]
Identifiers
IUPAC name [(8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] pentanoate
CAS Number	979-32-8
PubChemCID	13791
DrugBank	DB13956
ChemSpider	13194
UNII	OKG364O896
KEGG	D01413
ChEBI	CHEBI:31561
ChEMBL	ChEMBL1511
CompTox Dashboard(EPA)	DTXSID8023004
ECHA InfoCard	100.012.327
Chemical and physical data
Formula	C23H32O3
Molar mass	356.506 g·mol−1
3D model (JSmol)	Interactive image
Melting point	144 to 145 °C (291 to 293 °F)
SMILES CCCCC(=O)O[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CCC4=C3C=CC(=C4)O)C
InChI InChI=1S/C23H32O3/c1-3-4-5-22(25)26-21-11-10-20-19-8-6-15-14-16(24)7-9-17(15)18(19)12-13-23(20,21)2/h7,9,14,18-21,24H,3-6,8,10-13H2,1-2H3/t18-,19-,20+,21+,23+/m1/s1 Key:RSEPBGGWRJCQGY-RBRWEJTLSA-N

Estradiol valerate (EV), sold for useby mouth under the brand nameProgynova and for use byinjection under the brand namesDelestrogen andProgynon Depot among others, is anestrogen medication. It is used inhormone therapy formenopausal symptoms andlow estrogen levels,hormone therapy fortransgender people, and inhormonal birth control.^{[4][3][12][13]} It is also used in the treatment ofprostate cancer.^[12] The medication is takenby mouth or byinjection into muscle orfat once every 1 to 4 weeks.^[12][13]

Side effects of estradiol valerate includebreast tenderness,breast enlargement,nausea,headache, andfluid retention.^[14][12][13] Estradiol valerate is anestrogen and hence is anagonist of theestrogen receptor, thebiological target ofestrogens likeestradiol.^[4][3][15] It is anestrogen ester and aprodrug ofestradiol in the body.^[15][4][3] Because of this, it is considered to be anatural andbioidentical form of estrogen.^{[15][16][3][17]}

Estradiol valerate was first described in 1940 and was introduced for medical use in 1954.^[18][19][20] Along withestradiol cypionate, it is one of the most widely used esters of estradiol.^[21] Estradiol valerate is used in theUnited States,Canada,Europe, and throughout much of the rest of the world.^[22][23] It is available as ageneric medication.^[24]

Themedical uses of estradiol valerate are the same as those of estradiol and other estrogens. Examples of indications for the medication includehormone therapy andhormonal contraception. In regard to the latter, estradiol valerate is available in combination with aprogestin as acombinedestradiol-containing oral contraceptive (withdienogest)^[25] and as acombined injectable contraceptive.^[26][27] Along withestradiol cypionate,estradiol undecylate, andestradiol benzoate, estradiol valerate is used as a form ofhigh-dose estrogen therapy infeminizing hormone therapy fortransgender women.^{[28][29][30][31]} It is also used as a form of high-dose estrogen therapy in the treatment of prostate cancer in men.^[12] Low-dose oral estradiol valerate (2–6 mg/day) has been used in the treatment ofbreast cancer in women who were previously treated with and benefited from but acquired resistance toaromatase inhibitors as well.^[32][33] Injectable estradiol valerate has been used to suppresssex drive insex offenders.^[34]

In theUnited States, the approved indications of estradiol valerate injections include the treatment of moderate to severehot flashes andvaginal atrophy associated withmenopause in women, the treatment ofhypoestrogenism due tohypogonadism,castration, orprimary ovarian failure in women, and thepalliative treatment ofadvanced prostate cancer in men.^[12] Elsewhere in the world, oral estradiol valerate is similarly approved for the treatment of symptoms associated with menopause or hypoestrogenism due to castration in women.^[13] Such symptoms may include hot flashes,outbreaks of sweat,sleep disturbances,depressive moods,irritability,headaches, anddizziness.^[13]

Estradiol valerate by intramuscular injection is usually used at a dosage of 10 to 20 mg every 4 weeks in the treatment of menopausal symptoms and hypoestrogenism due to hypogonadism, castration, or primary ovarian failure in women.^[12] In the past, it was used at even higher doses of 10 to 40 every 1 to 4 weeks for estrogen replacement.^[35] Estradiol valerate is usually used in the treatment of advanced prostate cancer in men at a dosage of 30 mg or more every 1 to 2 weeks by intramuscular injection.^[12] In transgender women, estradiol valerate given by intramuscular injection is usually used at a dosage of 5 to 20 mg, but up to 30 to 40 mg, once every 2 weeks.^[29][30][28] Estradiol valerate has also been used at a dose of 10 to 40 mg by intramuscular injection tolimit bleeding in women withhemorrhage due todysfunctional uterine bleeding.^{[36]: 318 [37]: 60}

Estradiol valerate is and has been available in the form ofvials andampoules ofoil solution for intramuscular injection in concentrations of 4, 5, 10, 20, and 40 mg/mL and in the form of oraltablets at doses of 0.5, 1, 2, and 4 mg per tablet.^{[38][18][39][40]} In theUnited States, it is specifically available in formulations of 10, 20, and 40 mg/mL in oil solution (as Delestrogen, as well asgenerics).^[38] Aside from estradiol valerate, the only other injectable estrogen formulations that remain available in the United States areestradiol cypionate (5 mg/mL in oil solution) andconjugated estrogens (25 mg/vial in solution).^[38] Some or all oral estradiol valerate tablets aremicronized, similarly to oral estradiol tablets.^[41]

In addition to single-drug formulations, oral estradiol valerate is available in combination with theprogestindienogest as acombined oral contraceptive and intramuscular estradiol valerate is marketed at a concentration of 5 mg/mL in combination with the progestinhydroxyprogesterone caproate and with the progestinnorethisterone enantate ascombined injectable contraceptives.^{[38][25][26][27][1]} Intramuscular estradiol valerate is also marketed at a concentration of 4 mg/mL in combination with the weakandrogen andneurosteroidprasterone enanthate (DHEA enanthate) and with the androgentestosterone enantate for use in menopausal hormone therapy, but the latter formulation has been discontinued.^[42][38] The availability of estradiol valerate-containing products varies throughout the world.^[1]

Contraindications of estrogens includecoagulation problems,cardiovascular diseases,liver disease, and certainhormone-sensitive cancers such asbreast cancer andendometrial cancer, among others.^{[57][58][59][60]}

Theside effects of estradiol valerate are the same as those of estradiol. Examples of such side effects includebreast tenderness andenlargement,nausea,bloating,edema,headache, andmelasma.^[14][61]High-dose estrogen therapy with estradiol valerate injections may also cause an increased risk ofthromboembolism, changes inblood lipidprofile, increasedinsulin resistance, and increased levels ofprolactin.^[61]

Estradiol valerate has been used at very high doses of 40 to 100 mg once per week in women and men, without overt signs of acutetoxicity observed.^{[62][63][64][65][66][67][68][69][70][71][72]}Symptoms of estrogenoverdosage may includenausea,vomiting,bloating,increased weight,water retention,breast tenderness,vaginal discharge,heavy legs, andleg cramps.^[57] These side effects can be diminished by reducing the estrogen dosage.^[57]

Inhibitors andinducers ofcytochrome P450 may influence themetabolism of estradiol and by extension circulating estradiol levels.^[73]

Estradiol valerate is anestradiol ester, or aprodrug ofestradiol.^[15][4] As such, it is anestrogen, or anagonist of theestrogen receptors.^[4][15] Theaffinity of estradiol valerate for theestrogen receptor is approximately 50 times lower than that of estradiol.^[3] In addition, estradiol valerate is rapidly cleaved into estradiol and is unable to reach target tissues in concentrations of significance, if at all.^[3] As such, estradiol valerate is essentially inactive in terms of estrogenic effect itself, acting solely as aprodrug to estradiol.^[3] Themolecular weight of estradiol valerate is about 131% of that of estradiol due to the presence of its C17βvalerate ester, and hence estradiol valerate contains about 76% of the amount of estradiol of an equal dose of estradiol.^[22][23] Aside from dose adjustment to account for the difference in molecular weight, oral estradiol valerate is considered to be equivalent to oral estradiol.^[3] Because estradiol valerate is a prodrug of estradiol, it is considered to be anatural andbioidentical form of estrogen.^[15][16][17]

The influence of 2 mg/day oral estradiol valerate oncoagulation factors is less than that of 10 μg/day oralethinylestradiol.^{[92][25][93][94][95]} Oral ethinylestradiol at 10 μg/day has been found to have about 1.5- to 2.5-fold the impact of 2 mg/day oral estradiol valerate onHDL cholesterol andtriglycerides.^[96][97][98] The influence of 20 or 50 μg/day oral ethinylestradiol on coagulation factors and HDL cholesterol is markedly greater than that of 2 mg/day oral estradiol valerate.^[96][99]

Estradiol-containing birth control pills, which contain 1 to 3 mg/day estradiol or estradiol valerate, have been found to increasesex hormone-binding globulin (SHBG) levels by 1.5-fold.^[100][101] Oral estradiol valerate at 6 mg/day has been found to increase SHBG levels by 2.5- to 3-fold intransgender women.^[102][103] For comparison,combined birth control pills containing ethinylestradiol and a progestin with minimal androgenic or antiandrogenic activity have been found to increase SHBG levels by about 3- to 4-fold.^[104]

Regardless of theroute of administration, estradiol valerate behaves as aprodrug of estradiol viacleavage byesterases into estradiol and the naturalfatty acidvaleric acid.^{[4][15][3][105]} This cleavage occurs not only in theliver, but also in theblood and intissues, and thehydrolysis of estradiol valerate into estradiol and valeric acid is complete regardless of whether the medication is administeredorally orparenterally.^[3] High levels of circulating estradiol are found after anintravenous injection of estradiol valerate, and this indicates very rapid cleavage of the medication upon entering circulation.^[3]

Esterification of the C17β position of estradiol as in estradiol valerate reduces themetabolism of estradiol valerate by17β-hydroxysteroid dehydrogenase (17β-HSD).^[4] As approximately 80% of estradiol is metabolized into estrone (and estrone sulfate) by 17β-HSD duringfirst-pass metabolism, this improves themetabolic stability and hencebioavailability of estradiol valerate.^[15] However, estradiol valerate is hydrolyzed into estradiol and valeric acid in theintestines, and hence, is still subject to extensive first-pass metabolism.^[4] As such, the oral bioavailability of estradiol valerate is only around 3 to 5%, and is similar to that of oral estradiol.^[3][4][106] All oral tablets in the cases of both estradiol and estradiol valerate seem to be micronized.^[41] Due to its nature as a rapidly converted prodrug of estradiol, thepharmacokinetics of oral estradiol valerate are similar to those of oral estradiol.^[3][4] Moreover, thepharmacodynamics andpotency (after differences inmolecular weight are taken into account) of oral estradiol valerate are considered to be equivalent to those of oral estradiol.^[3] This is also notably true for effects onhepatic protein synthesis (e.g., ofSHBGTooltip sex hormone-binding globulin), again after differences in molecular weight between the two compounds are considered.^[3]

A dosage of 1 mg/day oral estradiol valerate has been found to produce approximate circulating concentrations of 50 pg/mL estradiol and 160 pg/mL estrone, while a dosage of 2 mg/day results in circulating levels of 60 pg/mL estradiol and 300 pg/mL estrone.^[107] These concentrations of estradiol and estrone are comparable to those observed with 1 and 2 mg/day oral estradiol.^[107] A review of selected studies reported a range of mean peak estradiol levels of 24 to 140 pg/mL occurring 1 to 12 hours after administration of 2 mg oral estradiol valerate.^[3] A study found that, in accordance with their differences in molecular weights, oral estradiol produced higher levels of estradiol than oral estradiol valerate.^[108] Likewise, other studies found that levels of estradiol and estrone are very similar after oral administration of roughly equimolar doses of estradiol (1.5 mg) and estradiol valerate (2 mg).^{[109][110][111]} A study of high-dose oral estradiol valerate found levels of estradiol of about 250 pg/mL after a single 10-mg dose in three women.^[106]

Estradiol valerate has been studied bysublingual administration in premenopausal women for the purpose ofcycle control andovulation suppression inegg donation andsurrogacy.^[113][114] It has been investigated for this indication, along withvaginal andtransdermal estradiol, because oral estradiol valerate is sometimes unable to achieve adequate estradiol levels and hence proper cycle control in this situation.^[113][114] Sublingual administration of estradiol valerate bypasses thefirst pass that occurs with the oral route and results in higher levels of estradiol and improved cycle control.^[113][114] Sublingual estradiol valerate is also used in hormone therapy for transgender women.^[115]

The administration of 2 mg oral micronized estradiol valerate tablets (Progynova, Schering) sublingually 3 or 4 times per day has been found to result in circulating estradiol levels of about 290 pg/mL to 460 pg/mL in premenopausal women (time of measurements not given).^[113][114]Steady-state levels of estradiol were achieved within about 2 or 3 days.^[113][114] Levels ofprogesterone,luteinizing hormone, andfollicle-stimulating hormone were all considerably suppressed, and ovulation, as well as the associated mid-cycle hormonal surges, were prevented.^[113][114] Similarly to oral administration of estradiol, but in contrast to the vaginal and transdermal routes, the ratio of estradiol to estrone is decreased with sublingual administration of either estradiol valerate or estradiol.^{[113][114][116]}

In contrast to oral administration, the bioavailability of estradiol valerate is complete (i.e., 100%) via intramuscular injection.^[5][3][4] Due to the far greater bioavailability of intramuscular estradiol valerate relative to oral, the former is substantially stronger (in terms of potency) than the latter.^[3] As an example, a single 4 mg intramuscular injection is said to be approximately equivalent to 2 mg/day of the medication administered orally over the course of 3 weeks.^[3] Estradiol valerate, when given intramuscularly inoil, has a relatively long duration due to the formation of an intramusculardepot from which the medication is slowly released and absorbed.^[3][117] Upon intramuscular injection of estradiol valerate in an oil solution, the solvent (i.e., oil) is absorbed, and a primarymicrocrystalline depot is formed within themuscle at the site of injection.^[4] In addition, a secondary depot may also be formed inadipose tissue.^[4] The slow release of estradiol valerate is caused by the increasedlipophilicity of the medication, which in turn is due to its long fatty acid valeric acid estermoiety.^[3] Theelimination half-life of estradiol valerate in oil by intramuscular injection (brand names Estradiol-Depot 10 mg, Progynon Depot-10) is about 3.5 days, with a range of 1.2 days to 7.2 days in different individuals.^[8] Α couple of older studies from the 1980s withsample sizes of only 2 or 3 individuals reported an elimination half-life of 4 to 5 days.^{[3][118][119]}

A single intramuscular injection of 4 mg estradiol valerate has been found to result in maximal circulating levels of estradiol of about 390 pg/mL within 3 days of administration, with levels declining to 100 pg/mL (baseline, in the study) by 12 to 13 days.^[42] Studies in general have found that a single intramuscular injection of 4 mg estradiol valerate results in peak levels of estradiol of 240 to 540 pg/mL after 1 to 5 days following administration.^[119] A study found that a single intramuscular injection of 5 mg estradiol valerate resulted in peak circulating levels of 667 pg/mL estradiol and 324 pg/mL estrone within approximately 2 and 3 days, respectively.^[9] The duration of estradiol valerate at this dose and in this study was considered to be 7 to 8 days.^[9] Other studies have found that larger doses of intramuscular estradiol valerate exceeding 20 mg have a duration of more than 15 days.^[9] A third study, in contrast to the preceding study, found that a single 10 mg intramuscular injection of estradiol valerate resulted in maximal estradiol levels of 506 to 544 pg/mL and maximal estrone levels of 205 to 219 pg/mL in postmenopausal women.^[8]

With intramuscular injections of estradiol valerate, it has been reported that a dose of 5 mg has a duration of 7 to 8 days, 10 mg a duration of 10 to 14 days, 40 mg a duration of 2 to 3 weeks (14 to 21 days), and 100 mg a duration of 3 to 4 weeks (21 to 28 days).^[10][11][9]

A study ofpseudopregnancy withintramuscular injections of 40 mg/week estradiol valerate and 250 mg/weekhydroxyprogesterone caproate in women withestrogen deficiency observed estradiol levels of about 3,100 pg/mL at 3 months of therapy and 2,500 pg/mL at 6 months of therapy.^[63]

Estradiol esters like estradiol valerate andestradiol cypionate can be given bysubcutaneous injection instead of intramuscular injection.^[129][130]

The administration of estradiol valerate by intravenous injection has been studied.^[3][119] It has been found to be very rapidly cleaved into estradiol.^[3][119] The bioavailability and metabolism of estradiol valerate does not differ with intravenous versus intramuscular injection.^[119] Conversely, intravenous injection of estradiol valerate has a very short duration, whereas intramuscular injection has a long duration andelimination half-life.^[119]

Estradiol valerate is asyntheticestranesteroid and the C17βvalerate (pentanoate)fatty acidester ofestradiol.^[22][23] It is also known as estradiol 17β-valerate or as estra-1,3,5(10)-triene-3,17β-diol 17β-pentanoate.^[22][23] Other common esters of estradiol in use includeestradiol cypionate,estradiol enantate, andestradiol acetate, the former two of which are C17β esters of estradiol similarly to estradiol valerate and the latter of which is the C3acetate ester of estradiol.^[22][23]

The experimental logoctanol/water partition coefficient (log P) of estradiol valerate is 5.6.^[131]

• v
• t
• e

Structural properties of selected estradiol esters

Estrogen	Structure	Ester(s)				Relative mol. weight	Relative E2 contentb	log Pc
		Position(s)	Moiet(ies)	Type	Lengtha
Estradiol		–	–	–	–	1.00	1.00	4.0
Estradiol acetate		C3	Ethanoic acid	Straight-chain fatty acid	2	1.15	0.87	4.2
Estradiol benzoate		C3	Benzoic acid	Aromatic fatty acid	– (~4–5)	1.38	0.72	4.7
Estradiol dipropionate		C3, C17β	Propanoic acid (×2)	Straight-chain fatty acid	3 (×2)	1.41	0.71	4.9
Estradiol valerate		C17β	Pentanoic acid	Straight-chain fatty acid	5	1.31	0.76	5.6–6.3
Estradiol benzoate butyrate		C3, C17β	Benzoic acid,butyric acid	Mixed fatty acid	– (~6, 2)	1.64	0.61	6.3
Estradiol cypionate		C17β	Cyclopentylpropanoic acid	Cyclic fatty acid	– (~6)	1.46	0.69	6.9
Estradiol enanthate		C17β	Heptanoic acid	Straight-chain fatty acid	7	1.41	0.71	6.7–7.3
Estradiol dienanthate		C3, C17β	Heptanoic acid (×2)	Straight-chain fatty acid	7 (×2)	1.82	0.55	8.1–10.4
Estradiol undecylate		C17β	Undecanoic acid	Straight-chain fatty acid	11	1.62	0.62	9.2–9.8
Estradiol stearate		C17β	Octadecanoic acid	Straight-chain fatty acid	18	1.98	0.51	12.2–12.4
Estradiol distearate		C3, C17β	Octadecanoic acid (×2)	Straight-chain fatty acid	18 (×2)	2.96	0.34	20.2
Estradiol sulfate		C3	Sulfuric acid	Water-soluble conjugate	–	1.29	0.77	0.3–3.8
Estradiol glucuronide		C17β	Glucuronic acid	Water-soluble conjugate	–	1.65	0.61	2.1–2.7
Estramustine phosphated		C3, C17β	Normustine,phosphoric acid	Water-soluble conjugate	–	1.91	0.52	2.9–5.0
Polyestradiol phosphatee		C3–C17β	Phosphoric acid	Water-soluble conjugate	–	1.23f	0.81f	2.9g
Footnotes:a = Length ofester incarbonatoms forstraight-chain fatty acids or approximate length of ester in carbon atoms foraromatic orcyclic fatty acids.b = Relative estradiol content by weight (i.e., relativeestrogenic exposure).c = Experimental or predictedoctanol/water partition coefficient (i.e.,lipophilicity/hydrophobicity). Retrieved fromPubChem,ChemSpider, andDrugBank.d = Also known asestradiol normustine phosphate.e =Polymer ofestradiol phosphate (~13repeat units).f = Relative molecular weight or estradiol content per repeat unit.g = log P of repeat unit (i.e., estradiol phosphate).Sources: See individual articles.

Estradiol valerate waspatented byCiba in 1940 and 1941, with apriority date of 1936.^[18][132] It wassynthesized and studied, along with a variety of otherestradiol esters, by Karl Junkmann ofSchering AG in 1953.^[133][134] The medication was first introduced for medical use viaintramuscular injection in 1954 by Schering inEurope under the brand name Progynon Depot and bySquibb in theUnited States under the brand name Delestrogen.^{[19][20][135]} In 1966, oral estradiol valerate was introduced by Schering for medical use in Europe under the brand name Progynova.^{[136][137][138][139][140]} A report of its metabolism was published in 1967.^[141]Esterification of estradiol, as in estradiol valerate, has been claimed to improve itsmetabolic stability with oral administration.^[4][3][142] In 1968,micronized preparations of oral estradiol valerate were first introduced under the brand names Progynova 21 and Progynova 21 mite.^[136] Along withestradiol benzoate (1933)^{[143][144][145]} andestradiol cypionate (1952),^[146] estradiol valerate is one of the most widely used esters of estradiol.^[21]

Estradiol valerate is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANMTooltip British Approved Name, andJANTooltip Japanese Accepted Name, whileoestradiol valerate was formerly itsBANMTooltip British Approved Name.^{[22][23][147]}

Estradiol valerate has been marketed under the brand names Altadiol, Androtardyl-Oestradiol, Ardefem, Climaval, Cyclabil, Cyclocur, Deladiol, Delahormone Unimatic, Delestrogen, Delestrogen 4X, Depogen, Diol-20, Dioval, Ditate, Dura-Estate, Dura-Estradiol, Duratrad, Duragen, Estate, Estra-L, Estradiol Depot, Estraval, Estraval Depot, Estraval PA, Estravel, Femogen, Femogex, Gynogen L.A., Gynokadin, Lastrogen, Menaval, Merimono, Neofollin, Nuvelle, Oestrogynal, Ostrin Depo, Pelanin, Pharlon, Postoval, Primogyna, Primogyn, Primogyn Depot, Progynon, Progynon Depot, Progynova, Repestrogen, Repo-Estra, Reposo-E, Retestrin, Ronfase, Span-Est, Testaval, and Valergen, among others.^{[22][23][19][148][147]} Neofollin is anoil solution of estradiol valerate.^[149][150]

Oral estradiol valerate is used primarily inEurope, under the brand name Progynova.^[151] Although oral estradiol valerate was previously available in theUnited States,^[23] it is no longer available in the country except in combination withdienogest as acombined oral contraceptive (under the brand name Natazia).^[38] Estradiol valerate by intramuscular injection is available under the brand name Delestrogen in the United States andCanada and under the brand name Progynon Depot in Europe and elsewhere in the world.^[38][23]

SH-834 was a combination of 90 mg estradiol valerate and 300 mggestonorone caproate for weekly intramuscular injection that was developed by Schering in the 1970s.^{[67][152][153]} It was investigated clinically as a treatment forbreast cancer and was found to be effective, but was never marketed.^[67][65]

• Estradiol valerate/hydroxyprogesterone caproate
• Estradiol valerate/norethisterone enantate
• Estradiol valerate/prasterone enanthate
• Estradiol valerate/testosterone enanthate

• Antigonadotropins
• Estradiol esters
• Hormonal antineoplastic drugs
• Hormonal contraception
• Hydroxyarenes
• Synthetic estrogens
• Valerate esters

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