Estradiol valerate (β-estradiol 17-valerate) 979-32-8_Estrogenprogestogen Receptor_Endocrinology & Hormones_Signaling Pathways_Products

Estradiol valerate (β-estradiol 17-valerate; Estraval; Progynova; Valergen; Altadiol; Deladiol; Delestrogen), the 17β-valerate ester of estradiol, is a synthetic, steroidal estrogen and an estrogen ester commonly used in combination with other steroid hormones in hormone replacement therapies. It acts as a prodrug of estradiol, and hence, is considered to be a natural, bioidentical form of estrogen. Along with estradiol cypionate, estradiol valerate is one of the most widely used esters of estradiol. Estradiol, or more precisely, the 17-beta-isomer of estradiol, is a human sex hormone and steroid, and the primary female sex hormone.

Physicochemical Properties

Molecular Formula

C23H32O3

Molecular Weight

356.5

Exact Mass

356.235

Elemental Analysis

C, 77.49; H, 9.05; O, 13.46

CAS #

979-32-8

Related CAS #

Estradiol valerate;979-32-8; Alpha-Estradiol;57-91-0;Estradiol (Standard);50-28-2;Estradiol-d3;79037-37-9;Estradiol-d4;66789-03-5;Estradiol-d5;221093-45-4;Estradiol-13C2;82938-05-4;Estradiol (cypionate);313-06-4;Estradiol benzoate;50-50-0;Estradiol enanthate;4956-37-0;Estradiol hemihydrate;35380-71-3;Estradiol-d2;53866-33-4;Estradiol-13C6;Estradiol-d2-1;3188-46-3;rel-Estradiol-13C6; 979-32-8 (valerate); 113-38-2 (dipropionate); 57-63-6 (ethinyl); 172377-52-5 (sulfamate); 3571-53-7 (undecylate)

PubChem CID

13791

Appearance

White to off-white solid powder

Density

1.1±0.1 g/cm3

Boiling Point

486.2±45.0 °C at 760 mmHg

Melting Point

144°C

Flash Point

191.1±21.5 °C

Vapour Pressure

0.0±1.3 mmHg at 25°C

Index of Refraction

1.568

LogP

6.62

Hydrogen Bond Donor Count

Hydrogen Bond Acceptor Count

Rotatable Bond Count

Heavy Atom Count

Complexity

518

Defined Atom Stereocenter Count

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 Key

RSEPBGGWRJCQGY-RBRWEJTLSA-N

InChi Code

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

Chemical Name

(17β)-3-hydroxyestra-1,3,5(10)-trien-17-yl valerate

Synonyms

Estraval; Progynova; Valergen;Altadiol; Deladiol; Delestrogen; oestradiol valerate; Estradiol 17-valerate; Estradiol valerianate; Delestrogen; Oestradiol valerate; Estraval; Neofollin;

HS Tariff Code

2934.99.9001

Storage

Powder-20°C 3 years

4°C 2 years

In solvent -80°C 6 months

-20°C 1 month

Shipping Condition

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets

Metabolite; ER; steroid hormone

ln Vitro

In vitro activity: Estradiol (10 nM) rapidly activates sphingosine kinase isoenzyme SphK1 as determined by enhanced phosphorylation on Ser225 in MCF-7 cells. Estradiol (20 nM) stimulates rapid release of sphingosine 1-phosphate (S1P) and dihydro-S1P from MCF-7 cells. SphK1 and estrogen receptor α are mainly responsible for formation of S1P and dihydro-S1P. Down-regulation of ABCC1 or ABCG2 with siRNAs or pharmacological inhibitors decreases Estradiol (10 nM)-mediated release of S1P or dihydro-S1P from MCF-7 cells. Estradiol (10 nM) inhibits miR-21 expression in MCF-7 human breast cancer cells mediated by estrogen receptor α. Estradiol (10 nM) activates several miR-21 target gene reporters activity in MCF-7 cells through inhibiting miR-21 expression. Estradiol (10 nM) increases endogenous miR-21 target genes expression in protein but not RNA levels in MCF-7 cells.

ln Vivo

β-estradiol 17-valerate (EV) is a synthetic estrogen widely used in combination with other steroid hormones in hormone replacement therapy drugs and is detected in natural waters. Although EV is known as an estrogenic chemical, there is still a lack of data on its developmental and reproductive toxicities in fish following exposure to EV during embryo-larval-, juvenile- and adult-life stages in Japanese medaka (Oryzias latipes). At the early life stage, the fertilized eggs of medaka were exposed to 1, 10, 100 and 1000 ng/L EV for 15 days, and hatched larval fish were continually exposed to the same concentration range for an additional 15 days. The results showed that exposure to 10 ng/L or above resulted in adverse effects on hatchability and time to hatching, and the number of hatched females was twice that of males at 10 ng/L or above. When the hatched fish were continually exposed to 1, 10 and 100 ng/L of EV for another 40 days, the hepatosomatic index (HSI) was increased in both males and females, and the gonadosomatic index (GSI) was decreased in females, and increased in males. Sex reversal was found in fish exposed to 1 ng/L and above. Quantitative real-time RT-PCR showed that mRNA levels of estrogen receptor α (ER-α) and vitellogenin-I (VTG-I) in the liver of females were significantly down-regulated, while those of vitellogenin-I (VTG-I) in the liver of males were significantly up-regulated at all concentrations. These findings suggest that EV is a reproductive toxicant and estrogenic chemical in both male and female fish.[3]

Estradiol (80 μg/kg/day, s.c.) significantly decreases the absolute numbers of total peritoneal cell and macrophages, characterized by a double F4/80- and CD11b-positive staining, in ovariectomized C57BL/6J mice. Estradiol (80 μg/kg/day, s.c.) enhances the LPS-induced expression of proinflammatory cytokines by TGC-elicited macrophages through inhibition of PI3K activity in ovariectomized C57BL/6J mice. Proinflammatory effect of Estradiol is abolished by downregulate estrogen receptor α activity in thioglycolate-elicited macrophages.

Cell Assay

Previous studies have shown that estradiol induces new dendritic spines and synapses on hippocampal CA1 pyramidal cells. We have assessed the consequences of estradiol-induced dendritic spines on CA1 pyramidal cell intrinsic and synaptic electrophysiological properties. Hippocampal slices were prepared from ovariectomized rats treated with either estradiol or oil vehicle. CA1 pyramidal cells were recorded and injected with biocytin to visualize spines. The association of dendritic spine density and electrophysiological parameters for each cell was then tested using linear regression analysis. We found a negative relationship between spine density and input resistance; however, no other intrinsic property measured was significantly associated with dendritic spine density. Glutamate receptor autoradiography demonstrated an estradiol-induced increase in binding to NMDA, but not AMPA, receptors. We then used input/output (I/O) curves (EPSP slope vs stimulus intensity) to determine whether the sensitivity of CA1 pyramidal cells to synaptic input is correlated with dendritic spine density. Consistent with the lack of an estradiol effect on AMPA receptor binding, we observed no relationship between the slope of an I/O curve generated under standard recording conditions, in which the AMPA receptor dominates the EPSP, and spine density. However, recording the pharmacologically isolated NMDA receptor-mediated component of the EPSP revealed a significant correlation between I/O slope and spine density. These results indicate that, in parallel with estradiol-induced increases in spine/synapse density and NMDA receptor binding, estradiol treatment increases sensitivity of CA1 pyramidal cells to NMDA receptor-mediated synaptic input; further, sensitivity to NMDA receptor-mediated synaptic input is well correlated with dendritic spine density[1].

Animal Protocol

We have found that the density of synapses in the stratum radiatum of the hippocampal CA1 region in the adult female rat is sensitive to estradiol manipulation and fluctuates naturally as the levels of ovarian steroids vary during the 5 d estrous cycle. In both cases, low levels of estradiol are correlated with lower synapse density, while high estradiol levels are correlated with a higher density of synapses. These synaptic changes occur very rapidly in that within approximately 24 hr between the proestrus and estrus stages of the estrous cycle, we observe a 32% decrease in the density of hippocampal synapses. Synapse density then appears to cycle back to proestrus values over a period of several days. To our knowledge, this is the first demonstration of such short-term steroid-mediated synaptic plasticity occurring naturally in the adult mammalian brain.[1]

Paired stock fish are maintained in the laboratory. Spontaneously spawned eggs were carefully collected from the ventral side of stock females (about 40 females) within a few hours of natural fertilization. Eggs were obtained from clutches by gently rolling them with a finger. Eggs were disinfected by placing them in a 0.9% solution of hydrogen peroxide for 10 min (Marking et al., 1994, Sun et al., 2007), and then checked for fertilization using a dissecting microscope. Based on the results of an initial range-finding study (data not shown), embryos were exposed to nominal β-estradiol-17-valerate (EV) concentrations of 1, 10, 100 and 1000 ng/L in dilution water (charcoal-dechlorinated tap water) for 15 days. In addition, dilution water controls (DWC) and solvent controls (SC) were included in the experimental design. The SC and all EV exposure groups contained 0.1 ml/L DMSO and 1% methylene blue whereas the DWC groups contained 1% methylene blue only. Treated and control embryos were randomly assigned to different treatments in glass dishes containing 100 mL each test solution (30 embryos/dish). Three replicates were used for each concentration and control. Embryos were incubated in a 16:8 h light:dark photoperiod cycle at 25 ± 1 °C. Eighty percent of each test solution was renewed every 24 h. Embryos were observed twice daily at which time dead embryos (identified by the incorporation of methylene blue) were removed. Hatchability, time to hatching and gross abnormalities were recorded.[3]

80 μg/kg/day, s.c.

Mice

ADME/Pharmacokinetics

Absorption, Distribution and Excretion
IM Injection: When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks. Natazia: After oral administration of estradiol valerate, cleavage to 17β-estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage. This gives rise to estradiol and its metabolites, estrone and other metabolites. Maximum serum estradiol concentrations of 73.3 pg/mL are reached at a median of approximately 6 hours (range: 1.5–12 hours) and the area under the estradiol concentration curve [AUC(0–24h)] was 1301 pg·h/mL after single ingestion of a tablet containing 3 mg estradiol valerate under fasted condition on Day 1 of the 28-day sequential regimen.
Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Metabolism / Metabolites
Exogenous estrogens are metabolized using the same mechanism as endogenous estrogens. Estrogens are partially metabolized by cytochrome P450.

Toxicity/Toxicokinetics

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Estradiol valerate has not been studied during breastfeeding. Injectable estradiol valerate has been used to suppress lactation, usually in combination with testosterone. Generally, it should be avoided in mothers wishing to breastfeed, especially if started before the milk supply is well established at about 6 weeks postpartum. The decrease in milk supply can happen over the first few days of estrogen exposure.
Oral estradiol valerate is only available in the United States in a combination oral contraceptive product that also contains dienogest. Based on the available evidence, expert opinion holds that nonhormonal methods are preferred during breastfeeding and progestin-only contraceptives are preferred over combined oral contraceptives in breastfeeding women, especially during the first 4 weeks postpartum. For further information, consult the record entitled, Contraceptives, Oral, Combined.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Estradiol valerate injection was previously used therapeutically to suppress lactation, usually in combination with testosterone.
A retrospective cohort study compared 371 women who received high-dose estrogen (either 3 mg of diethylstilbestrol or 150 mcg of ethinyl estradiol daily) during adolescence for adult height reduction to 409 women who did not receive estrogen. No difference in breastfeeding duration was found between the two groups, indicating that high-dose estrogen during adolescence has no effect on later breastfeeding.

References

[1]. J Neurosci.1997 Mar 1;17(5):1848-59.
[2]. J Neurosci.1992 Jul;12(7):2549-54.
[3]. Aquat Toxicol. 2013 Jun 15:134-135:128-34.

Additional Infomation

Pharmacodynamics
Estrogen mediates its effects across the body through potent agonism of the Estrogen Receptor (ER), which is located in various tissues including in the breasts, uterus, ovaries, skin, prostate, bone, fat, and brain. Estradiol binds to both subtypes of the Estrogen Receptor: Estrogen Receptor Alpha (ERα) and Estrogen Receptor Beta (ERβ). Estradiol also acts as a potent agonist of G Protein-coupled Estrogen Receptor (GPER), which has recently been recognized as a major mediator of estradiol's rapid cellular effects.

Solubility Data

Solubility (In Vitro)

DMSO:71 mg/mL (199.1 mM)

Water:<1 mg/mL

Ethanol:<1 mg/mL

Solubility (In Vivo)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

Injection Formulations
(e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).
Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.8050 mL	14.0252 mL	28.0505 mL
	5 mM	0.5610 mL	2.8050 mL	5.6101 mL
	10 mM	0.2805 mL	1.4025 mL	2.8050 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

PeptideDB

Estradiol valerate (β-estradiol 17-valerate) 979-32-8

CAS No.: 979-32-8

Physicochemical Properties

Biological Activity

Solubility Data