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. In the past, it was used at even higher doses of 10 to 40 every 1 to 4 weeks for estrogen replacement. 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. 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.
Footnotes:a = No longer used or recommended, due to health concerns. b = As a single patch applied once or twice per week (worn for 3–4 days or 7 days), depending on the formulation. Note: Dosages are not necessarily equivalent. Sources: See template.
Estradiol valerate is and has been available in the form of vials and ampoules of oil solution for intramuscular injection in concentrations of 4, 5, 10, 20, and 40 mg/mL and in the form of oral tablets at doses of 0.5, 1, 2, and 4 mg per tablet. In the United States, it is specifically available in formulations of 10, 20, and 40 mg/mL in oil solution (as Delestrogen, as well as generics). Aside from estradiol valerate, the only other injectable estrogen formulations that remain available in the United States are estradiol cypionate (5 mg/mL in oil solution) and conjugated estrogens (25 mg/vial in solution). Some or all oral estradiol valerate tablets are micronized, similarly to oral estradiol tablets.
20, 25, 50, or 100 mg per implant (usually replaced every 6 months)
Estradiol Implants, Meno-Implant
Abbreviations: E2 = Estradiol. Footnotes:a = Encapsulated in microspheres. b = Discontinued. c = Mostly discontinued. Notes: (1): This table does not include combination products, for instance estradiol formulated in combination with a progestogen or androgen. (2): This table does not include compounded estradiol products; only approved pharmaceutical preparations are included. (3): The availability of pharmaceutical estradiol products differs by country (see Estradiol (medication) § Availability). (4): Some of these formulations have been marketed previously but may no longer be available. Sources: See template.
Estradiol valerate is an estradiol ester, or a prodrug of estradiol. As such, it is an estrogen, or an agonist of the estrogen receptors. The affinity of estradiol valerate for the estrogen receptor is approximately 50 times lower than that of estradiol. In addition, estradiol valerate is rapidly cleaved into estradiol and is unable to reach target tissues in concentrations of significance, if at all. As such, estradiol valerate is essentially inactive in terms of estrogenic effect itself, acting solely as a prodrug to estradiol. The molecular weight of estradiol valerate is about 131% of that of estradiol due to the presence of its C17β valerate ester, and hence estradiol valerate contains about 76% of the amount of estradiol of an equal dose of estradiol. Aside from dose adjustment to account for the difference in molecular weight, oral estradiol valerate is considered to be equivalent to oral estradiol. Because estradiol valerate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.
Note: All are via i.m. injection of oil solution, unless noted otherwise (except for PEP and PE3P, which are used as aqueous solutions). Footnotes:a = Studied but never marketed. b = An effective OID of EU is 20–30 mg/month. c = The t1/2 of PEP after a 320-mg dose is 70 days. Sources: See template.
Estradiol levels after a single dose of 2 mg oral estradiol or 2 mg oral estradiol valerate and with continuous administration of 2 mg/day oral estradiol or 2 mg/day oral estradiol valerate (at steady state) in postmenopausal women.
Esterification of the C17β position of estradiol as in estradiol valerate reduces the metabolism of estradiol valerate by 17β-hydroxysteroid dehydrogenase (17β-HSD). As approximately 80% of estradiol is metabolized into estrone (and estrone sulfate) by 17β-HSD during first-pass metabolism, this improves the metabolic stability and hence bioavailability of estradiol valerate. However, estradiol valerate is hydrolyzed into estradiol and valeric acid in the intestines, and hence, is still subject to extensive first-pass metabolism. As such, the oral bioavailability of estradiol valerate is only around 3 to 5%, and is similar to that of oral estradiol. All oral tablets in the cases of both estradiol and estradiol valerate seem to be micronized. Due to its nature as a rapidly converted prodrug of estradiol, the pharmacokinetics of oral estradiol valerate are similar to those of oral estradiol. Moreover, the pharmacodynamics and potency (after differences in molecular weight are taken into account) of oral estradiol valerate are considered to be equivalent to those of oral estradiol. This is also notably true for effects on hepatic protein synthesis (e.g., of SHBG), again after differences in molecular weight between the two compounds are considered.
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. These concentrations of estradiol and estrone are comparable to those observed with 1 and 2 mg/day oral estradiol. 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. A study found that, in accordance with their differences in molecular weights, oral estradiol produced higher levels of estradiol than oral estradiol valerate. Likewise, another study found that levels of estradiol and estrone were very similar after oral administration of roughly equimolar doses of estradiol (1.5 mg) and estradiol valerate (2 mg). 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.
Hormone levels with 2-mg oral micronized estradiol valerate tablets (Progynova, Schering) taken continuously 3 or 4 times per day by the sublingual route in premenopausal women.
Estradiol valerate has been studied by sublingual administration in premenopausal women for the purpose of cycle control and ovulation suppression in egg donation and surrogacy. It has been investigated for this indication, along with vaginal and transdermal estradiol, because oral estradiol valerate is sometimes unable to achieve adequate estradiol levels and hence proper cycle control in this situation. Sublingual administration of estradiol valerate bypasses the first pass that occurs with the oral route and results in higher levels of estradiol and improved cycle control. Sublingual estradiol valerate is also used in hormone therapy for transgender women.
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).Steady-state levels of estradiol were achieved within about 2 or 3 days. Levels of progesterone, luteinizing hormone, and follicle-stimulating hormone were all considerably suppressed, and ovulation, as well as the associated mid-cycle hormonal surges, were prevented. 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.
In contrast to oral administration, the bioavailability of estradiol valerate is complete (i.e., 100%) via intramuscular injection. 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. 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. Estradiol valerate, when given intramuscularly in oil, has a relatively long duration due to the formation of an intramuscular depot from which the medication is slowly released and absorbed. Upon intramuscular injection of estradiol valerate in an oil solution, the solvent (i.e., oil) is absorbed, and a primary microcrystalline depot is formed within the muscle at the site of injection. In addition, a secondary depot may also be formed in adipose tissue. The slow release of estradiol valerate is caused by the increased lipophilicity of the medication, which in turn is due to its long fatty acid valeric acid ester moiety. The elimination half-life of intramuscularly administered estradiol valerate in oil is reported to be 4 to 5 days.
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. 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. 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. The duration of estradiol valerate at this dose and in this study was considered to be 7 to 8 days. Other studies have found that larger doses of intramuscular estradiol valerate exceeding 20 mg have a duration of more than 15 days. 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.
A study of high-dose combined intramuscular administration of 40 mg estradiol valerate and 250 mg hydroxyprogesterone caproate per week for 6 months (described as a "pseudopregnancy" regimen) in hypogonadal women found that circulating levels of estradiol increased from 27.8–34.8 pg/mL to 3028–3226 pg/mL after three months and to 2491–2552 pg/mL after 6 months of treatment.
Pharmacokinetics of three estradiol esters by intramuscular injection
Hormone levels with intramuscular estradiol valerate
Estrogen levels after a single intramuscular injection of 10 mg estradiol valerate in oil in 24 postmenopausal women. Determinations were made for both Progynon Depot 10 and Estradiol Depot 10, for a total of 48 measurements per point. Assays were performed using GC/MS-NCI/SIM. Source was Schug et al. (2012).
Hormone levels after a single intramuscular injection of 5 mg estradiol valerate in oil in 17 postmenopausal women. Assays were performed using enzyme immunoassay. Estrone levels were likely overestimated, possibly due to cross reactivity of the assay with estrogen conjugates. Source was Göretzlehner et al. (2002).
Estradiol levels after single intramuscular injections of 5 mg of different estradiol esters in oil in about 10 premenopausal women each. Assays were performed using radioimmunoassay with chromatographic separation. Source was Oriowo et al. (1980).
Estradiol levels after a single intramuscular injection of 10 mg estradiol valerate or 100 mg estradiol undecylate in oil both in 4 individuals each. Subject characteristics and assay method were not described. Source was Vermeulen (1975).
Estradiol levels after an intravenous injection of 20 mg estradiol or an intramuscular injection of equimolar doses of different estradiol esters in oil in 3 postmenopausal women each. Assays were performed using radioimmunoassay with chromatographic separation. Source was Leyendecker et al. (1975).
Idealized curves of estradiol levels after injections of different estradiol esters in oil in women. Curves were generated from 4 data points (day 0, peak day, a 3rd day, day 30). Measurements from which points were drawn were taken at 24-hour intervals. Additional information was not given. Source was Garza-Flores (1994).
The administration of estradiol valerate by intravenous injection has been studied. It has been found to be very rapidly cleaved into estradiol. The bioavailability and metabolism of estradiol valerate does not differ with intravenous versus intramuscular injection. Conversely, intravenous injection of estradiol valerate has a very short duration, whereas intramuscular injection has a long duration and elimination half-life.
Oral estradiol valerate is used primarily in Europe, under the brand name Progynova. Although oral estradiol valerate was previously available in the United States, it is no longer available in this country except in combination with dienogest as a combined oral contraceptive (under the brand name Natazia). Estradiol valerate by intramuscular injection is available under the brand name Delestrogen in the United States and Canada and under the brand name Progynon Depot in Europe and elsewhere in the world.
SH-834 was a combination of 90 mg estradiol valerate and 300 mg gestonorone caproate for weekly intramuscular injection that was developed by Schering in the 1970s. It was investigated clinically as a treatment for breast cancer and was found to be effective, but does not seem to have been marketed.
^ abcdefghMichael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. p. 261. ISBN978-3-642-60107-1. Natural estrogens considered here include: [...] Esters of 17β-estradiol, such as estradiol valerate, estradiol benzoate and estradiol cypionate. Esterification aims at either better absorption after oral administration or a sustained release from the depot after intramuscular administration. During absorption, the esters are cleaved by endogenous esterases and the pharmacologically active 17β-estradiol is released; therefore, the esters are considered as natural estrogens.
^ abWesp LM, Deutsch MB (March 2017). "Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons". Psychiatr. Clin. North Am. 40 (1): 99–111. doi:10.1016/j.psc.2016.10.006. PMID28159148.
^ abSmith KP, Madison CM, Milne NM (December 2014). "Gonadal suppressive and cross-sex hormone therapy for gender dysphoria in adolescents and adults". Pharmacotherapy. 34 (12): 1282–97. doi:10.1002/phar.1487. PMID25220381.
^Palmieri C, Patten DK, Januszewski A, Zucchini G, Howell SJ (January 2014). "Breast cancer: current and future endocrine therapies". Mol. Cell. Endocrinol. 382 (1): 695–723. doi:10.1016/j.mce.2013.08.001. PMID23933149.
^American Medical Association. Dept. of Drugs; Council on Drugs (American Medical Association); American Society for Clinical Pharmacology and Therapeutics (1 February 1977). "Estrogens, Progestagens, Oral Contraceptives, and Ovulatory Agents". AMA drug evaluations. Publishing Sciences Group. pp. 540–572. ISBN978-0-88416-175-2. Intramuscular: For replacement therapy, (Estradiol, Estradiol Benzoate) 0.5 to 1.5 mg two or three times weekly; (Estradiol Cypionate) 1 to 5 mg weekly for two or three weeks; (Estradiol Dipropionate) 1 to 5 mg every one to two weeks; (Estradiol Valerate) 10 to 40 mg every one to four weeks.
^ abDevroey P, Pados G (1998). "Preparation of endometrium for egg donation". Hum. Reprod. Update. 4 (6): 856–61. doi:10.1093/humupd/4.6.856. PMID10098476. Oestradiol valerate and oestradiol in a micronized form are the most widely used oestrogen per os for steroid substitution therapy. Our regimen, as of most other groups [...] is oestradiol valerate (Progynova; Schering, Berlin, Germany) given in various concentrations throughout the cycle [...]. According to Norfolk's protocol, 2 mg of micronized oestradiol valerate are given on cycle days 1–5. [...] In tablet form, micronized oestradiol valerate is also efficiently absorbed [...]
^Midwinter, Audrey (1976). "Contraindications to estrogen therapy and management of the menopausal syndrome in these cases". In Campbell, Stuart (ed.). 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. MTP Press Limited. pp. 377–382. doi:10.1007/978-94-011-6165-7_33. ISBN978-94-011-6167-1.
^ abBishop BM (December 2015). "Pharmacotherapy Considerations in the Management of Transgender Patients: A Brief Review". Pharmacotherapy. 35 (12): 1130–9. doi:10.1002/phar.1668. PMID26684553.
^Gunther Göretzlehner; Christian Lauritzen; Ulf Göretzlehner (10 December 2008). "Hormontherapie bei gynäkologischen Erkrankungen". Praktische Hormontherapie in der Gynäkologie. Walter de Gruyter. pp. 245–314. ISBN978-3-11-020864-1. Dosierungsbeispiele bei Mammahypoplasie und Infantilismus [...] Parenteral 1. 40 mg Estradiolvalerat (Estradiol-Depot 10 mg JENAPHARM) und 250 mg Hydroxyprogesteroncaproat (Progesteron-Depot JENAPHARM, Proluton Depot) i. m. einmal wöchentlich über 15–20 Wochen lang. 2. 20–40 mg Estradiolvalerat (Estradiol-Depot 10 mg JENAPHARM) i. m. in der ersten und zweiten Woche. 40 mg Estradiolvalerat (Estradiol-Depot 10 mg JENAPHARM) und 250 mg Hydroxyprogesteroncaproat (Progesteron-Depot JENAPHARM, Proluton Depot) i. m. in der dritten und vierten Woche. Therapiedauer 4–5 Monate. Evtl. Abstand zwischen 2 Injektionen auf 2 Wochen erweitern (Abb. 6.2).
^ abUlrich U, Pfeifer T, Lauritzen C (1994). "Rapid increase in lumbar spine bone density in osteopenic women by high-dose intramuscular estrogen-progestogen injections. A preliminary report". Horm. Metab. Res. 26 (9): 428–31. doi:10.1055/s-2007-1001723. PMID7835827.
^Notter G, Kaigas M (September 1966). "Behandlung des inoperablen und metastasierenden Mammakarzinoms mit gestagenen und östrogenen Hormonen" [The treatment of inoperable and metastasizing breast carcinoma with gestational and estrogenic hormones]. Munchener medizinische Wochenschrift (1950) (in German). 108 (39): 1920–1923. ISSN0027-2973. PMID6014870.
^Berndt G, Stender HS (November 1970). "Die Östrogen-Gestagen-Kombinationsbehandlung des metastasierenden Mammakarzinoms mit SH 834" [The combined estrogen-gestagen treatment of metastasizing mammary carcinoma using with SH 834]. Dtsch. Med. Wochenschr. (in German). 95 (48): 2399–2404. doi:10.1055/s-0028-1108843. ISSN0012-0472. PMID5529652.
^Firusian N, Schietzel M (September 1976). "Zur additiven Therapie des metastasierenden Mamma-Karzinoms unter Berücksichtigung des Postmenopausalaltes (Ergebnisse einer randomisierten Studie)" [Additive treatment of metastasizing breast cancer with special reference to postmenopausal age (results of a randomized study)]. Strahlentherapie (in German). 152 (3): 235–47. ISSN0039-2073. PMID968923.
^Ziegler, H.; Völter, D.; Schubert, G. E. (1974). "Morphological criteria for the control of carcinoma of the prostate with estrogen therapy". International Urology and Nephrology. 6 (3–4): 195–200. doi:10.1007/BF02089265. ISSN0301-1623. PMID4142482.
^Harry Benjamin; Gobind Behari Lal; Richard Green; Robert E. L. Masters (1966). The Transsexual Phenomenon. Ace Publishing Company. p. 107. In my own practice, Squibb's Delestrogen for intramuscular injections was employed with much satisfaction and positive results. This is a slowly absorbing, well-tolerated, potent preparation (chemically, Estradiol Valerate), and was applied in doses of 20 to 60 mg. (½ to 1 ½ cc.). Usually 30 to 60 mg. of Delalutin (Squibb) was added, an equally potent progesterone. This combination was given once a week or once in two to three weeks, according to the response as measured by the patient's emotional balance and physical feminization symptoms. Generally I found that dosage seems less important than length and regularity of administration.
^Benjamin, Harry (1967). "Transvestism and Transsexualism in the male and female1". Journal of Sex Research. 3 (2): 107–127. doi:10.1080/00224496709550519. ISSN0022-4499. Estrogen treatment—as already indicated—helps greatly but does not cure. I have employed either Squibb's Delestrogen, a slowly absorbing, highly potent preparation which is, chemically, estradiol valerate (40 mg. to 1 cc); or the still more potent Delestrec, which is estradiol undecylate (100 mg. to 1 cc). This preparation, however, is not yet on the market in this country, though it is widely used in Europe. In the majority of cases, I used from 30 to 100 mg. weekly, or every two to three weeks, by intramuscular injection.
^Cheng ZN, Shu Y, Liu ZQ, Wang LS, Ou-Yang DS, Zhou HH (February 2001). "Role of cytochrome P450 in estradiol metabolism in vitro". Acta Pharmacol. Sin. 22 (2): 148–54. PMID11741520.
^ abWiegratz I, Fink T, Rohr UD, Lang E, Leukel P, Kuhl H (September 2001). "Überkreuz-Vergleich der Pharmakokinetik von Estradiol unter der Hormonsubstitution mit Estradiolvalerat oder mikronisiertem Estradiol" [Cross-over comparison of the pharmacokinetics of estradiol during hormone replacement therapy with estradiol valerate or micronized estradiol]. Zentralbl Gynakol (in German). 123 (9): 505–12. doi:10.1055/s-2001-18223. PMID11709743.
^ abcdeDüsterberg B, Schmidt-Gollwitzer M, Hümpel M (1985). "Pharmacokinetics and biotransformation of estradiol valerate in ovariectomized women". Horm. Res. 21 (3): 145–54. doi:10.1159/000180039. PMID2987096.
^ abcDüsterberg B, Wendt H (1983). "Plasma levels of dehydroepiandrosterone and 17 beta-estradiol after intramuscular administration of Gynodian-Depot in 3 women". Horm. Res. 17 (2): 84–9. doi:10.1159/000179680. PMID6220949.
^ abcRauramo L, Punnonen R, Kaihola LH, Grönroos M (January 1980). "Serum oestrone, oestradiol and oestriol concentrations in castrated women during intramuscular oestradiol valerate and oestradiolbenzoate-oestradiolphenylpropionate therapy". Maturitas. 2 (1): 53–8. doi:10.1016/0378-5122(80)90060-2. PMID7402086.
^Sierra-Ramírez JA, Lara-Ricalde R, Lujan M, Velázquez-Ramírez N, Godínez-Victoria M, Hernádez-Munguía IA, Padilla A, Garza-Flores J (2011). "Comparative pharmacokinetics and pharmacodynamics after subcutaneous and intramuscular administration of medroxyprogesterone acetate (25 mg) and estradiol cypionate (5 mg)". Contraception. 84 (6): 565–70. doi:10.1016/j.contraception.2011.03.014. PMID22078184.
^Junkmann, Karl (1953). "Über protrahiert wirksame Östrogene" [Over protracted effective estrogens]. Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie. 220 (5). doi:10.1007/BF00246561. ISSN0028-1298.
^Ehrengut, Wolfgang (1954). "Über ovarielle Agenesie". Zeitschrift für Kinderheilkunde. 75 (3): 224–234. doi:10.1007/BF00439822. ISSN0340-6199. Um die "Menarche" sollte eine verstärkte Substitutionstherapie (20 Tage lang tgl. 0,1 mg Follikelhormon per os oder einmalig Progynon-Depot (10 mg i.m.), [...]
^Dapunt O (September 1967). "Behandlung klimakterischer Beschwerden mit Östradiolvalerianat (Progynova)" [The management of climacteric disorders using estradiol valerate (Progynova)]. Med Klin (in German). 62 (35): 1356–61 passim. ISSN0025-8458. PMID5593020.
^Velikay L (March 1968). "Die perorale Behandlung des klimakterischen Syndroms mit Ostradiolvalerianat" [The peroral treatment of the climacteric syndrome with estradiol valerate]. Wien. Klin. Wochenschr. (in German). 80 (12): 229–33. ISSN0043-5325. PMID5728263.
^Koed J (May 1972). "Zur Behandlung klimakterischer Ausfallserscheinungen mit Progynova" [Therapy of climacteric deficiency symptoms using Progynova]. Med Welt (in German). 23 (22): 834–6. ISSN0025-8512. PMID5045321.
^Buschbeck, Herbert (2009). "Neue Wege der Hormontherapie in der Gynäkologie" [New ways of hormonal therapy in gynecology]. Deutsche Medizinische Wochenschrift. 60 (11): 389–393. doi:10.1055/s-0028-1129842. ISSN0012-0472.
^Biskind, Morton S. (1935). "Commercial Glandular Products". Journal of the American Medical Association. 105 (9): 667. doi:10.1001/jama.1935.92760350007009a. ISSN0002-9955. Progynon-B, Schering Corporation: This is crystalline hydroxyestrin benzoate obtained by hydrogenation of theelin and subsequent conversion to the benzoate. [...] Progynon-B is marketed in ampules containing 1 cc. of a sesame oil solution of hydroxyestrin benzoate of either 2,500, 5,000, 10,000 or 50,000 international units.