Estradiol dipropionate was patented in 1937[18] and was introduced for medical use by 1940.[19][20] It was one of the earliest estradiol esters to be used.[8] Along withestradiol benzoate, estradiol dipropionate was among the most widely used esters of estradiol for many years following its introduction.[15]
Estradiol dipropionate has typically been used at a dosage of 1 to 5 mg once or twice per week byintramuscular injection for relevant indications.[8][16] It has been used in the treatment of menopausal symptoms at a dosage of 1 to 5 mg initially for two to three injections and 1 to 2.5 mg for maintenance once every 10 to 14 days, and in the treatment of hypoestrogenism and delayed puberty at a dosage of 2.5 to 5 mg once per week.[8][21] As a component offeminizing hormone therapy fortransgender women, estradiol dipropionate has been used at dosages of 2 to 10 mg once per week or 5 to 20 mg once every 2 weeks.[14] In the treatment of prostate cancer, estradiol dipropionate has been used at a dosage of 5 mg once per week.[8]
Estradiol dipropionate was previously available by itself as anoil solution for intramuscular injection provided asvials andampoules at concentrations of 0.1, 0.2, 0.5, 1, 2.5, and 5 mg/mL.[8][22][23][24][25] The medication has largely been discontinued, with most of these formulations no longer being available.[11][13] Estradiol dipropionate remains available at a concentration of 1 mg/mL in combination with 50 mg/mLhydroxyprogesterone caproate under the brand name EP Hormone Depot (Teikoku Zoki Pharmaceutical Company) inJapan.[26][27][28][29][30][31][32]
Compared toestradiol benzoate, a related estradiol ester, estradiol dipropionate has enhanced and prolonged effects.[38][16] Whereas theduration of action of estradiol benzoate is said to be 2 to 3 days, the duration of estradiol dipropionate has been said to be 1 to 2 weeks.[39] However, newer estradiol esters have longer durations than either estradiol benzoate or estradiol dipropionate; the duration ofestradiol valerate has been said to be 1 to 3 weeks, and the duration ofestradiol cypionate has been said to be 3 to 4 weeks.[39][16] A singleintramuscular injection of 5 mg estradiol dipropionate has a duration of about 5 to 8 days.[6][7]
A single intramuscular injection of 50 μg/kg estradiol dipropionate in oil in 15 pubertal girls (about 1 mg for a 50-kg (110-lb) girl) was found to produce peak estradiol levels of about 215 pg/mL after 1.5 days.[40] Estradiol levels declined to about 90 pg/mL after 4 days.[40]
Hormone levels with estradiol dipropionate by intramuscular injection
Estradiol levels after a single intramuscular injection of 50 μg/kg estradiol dipropionate in oil in pubertal girls.[40] This dose would be 1 mg in a 50-kg (110-lb) girl.[40] Source was Presl et al. (1976).[40]
Vaginalcornification with a single intramuscular injection of different estradiol esters in oil solution in women.[41] Source was Schwartz & Soule (1955).[41]
Estradiol dipropionate was firstsynthesized andpatented in 1937.[43][18] It was assessed in clinical studies by 1939 and was introduced byCiba as anoil solution for use byintramuscular injection under the brand nameDi-Ovocylin by the same year.[43][38][19] Other formulations such asOvocyclin P by Ciba,Progynon DP bySchering andDimenformon Dipropionate byRoche-Organon were also marketed by the early 1940s.[44][45][20][46] Later in the 1940s the brand nameDi-Ovocylin was changed by Ciba toOvocylin Dipropionate.[22] Along withestradiol benzoate, which was introduced in 1933,[47] estradiol dipropionate was one of the firstestradiol esters to be introduced for medical use.[48][45] Prior to the development and introduction of longer-acting estradiol esters likeestradiol valerate andestradiol cypionate in the 1950s, estradiol dipropionate and estradiol benzoate were the most widely used estradiol esters.[15][49]
Estradiol dipropionate is thegeneric name of the drug and itsINNMTooltip International Nonproprietary Name,BANMTooltip British Approved Name, andJANTooltip Japanese Approved Name.[10][11][12][13]
Estradiol dipropionate has been marketed under a variety of brand names, including Agofollin, Akrofolline, Dihidrofolina "Kével", Dimenformon, Dimenformon Dipropionate, Diovocylin, Di-Ovocylin, Diprostron, Diprovex, Endofollicolina D.P., EP Hormone Depot (in combination withhydroxyprogesterone caproate), Estroici, Estronex, Follicyclin, Follicyclin P, Follikelmon Depot, Horiken-Depot, Nacyclyl, Oestradiol Galenika, Oestradiol Streuli, Orofollina, Ovacrin, Ovahormon Depot, Ovocylin, Ovocylin Dipropionate, Ovocylin P, and Progynon DP, among others.[50][10][11][12][51][52][13] Agofollin was anoil solution of estradiol dipropionate that was previously marketed in theCzech Republic andSlovakia.[53]
^Düsterberg B, Nishino Y (December 1982). "Pharmacokinetic and pharmacological features of oestradiol valerate".Maturitas.4 (4):315–324.doi:10.1016/0378-5122(82)90064-0.PMID7169965.
^Stanczyk FZ, Archer DF, Bhavnani BR (June 2013). "Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment".Contraception.87 (6):706–727.doi:10.1016/j.contraception.2012.12.011.PMID23375353.
^abcdefghOettel M, Schillinger E, Kuhnz W, Blode H, Zimmermann H (6 December 2012)."Pharmacokinetics of exogenous natural and synthetic estrogens and antiestrogens". In Oettel M, Schillinger E (eds.).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.
^abcdefghijkl"NNR: Products Recently Accepted by the A. M. A. Council on Pharmacy and Chemistry".Journal of the American Pharmaceutical Association (Practical Pharmacy Ed.).10 (11):692–694. 1949.doi:10.1016/S0095-9561(16)31995-8.ISSN0095-9561.
^abcSchwartz MM, Soule SD (July 1955). "Estradiol 17-beta-cyclopentylpropionate, a longacting estrogen".American Journal of Obstetrics and Gynecology.70 (1):44–50.doi:10.1016/0002-9378(55)90286-6.PMID14388061.
^abMcIver B, Tebben PJ, Shas P (23 September 2010)."Endocrinology". In Ghosh AK (ed.).Mayo Clinic Internal Medicine Board Review. OUP USA. pp. 222–.ISBN978-0-19-975569-1.
^abUS patent 2233025, Miescher K, Scholz C, "Estradiol-17-monoesters", published 1941-02-25, assigned to Ciba Pharmaceutical Products, Inc.
^abEscamilla RF, Lisserf H (1940). "Induction of menarche and development of secondary sexual characteristics in a woman aged 34 by injections of estradiol dipropionate".Endocrinology.27 (1): 153.doi:10.1210/endo-27-1-153.ISSN0013-7227.The estradiol dipropionate used in this case was furnished by the Ciba Co. Their trade name for this product is Di-Ovocylin.
^abShorr E (1940). "Effect of Concomitant Administration of Estroens and Proesterone on Vainal Smear in Man".Experimental Biology and Medicine.43 (3):501–506.doi:10.3181/00379727-43-11244.ISSN1535-3702.S2CID75787837.Grateful acknowledgment is made to Dr. Erwin Schwenk of the Schering Corporation for the estradiol benzoate (Progynon B), estradiol dipropionate (Progynon DP), progesterone (Proluton), and pregneninolone (Pranone) used in these experiments;
^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.
^Asanuma F, Yamada Y, Kawamura E, Lee K, Kobayashi H, Yamada T, et al. (1998). "Antitumor activity of paclitaxel and epirubicin in human breast carcinoma, R-27".Folia Microbiologica.43 (5):473–474.doi:10.1007/BF02820793.PMID9821299.S2CID22732235.
^Noguchi M, Tajiri K, Taniya T, Kumaki T, Ashikari A, Miyazaki I (1990). "Influence of hormones on proliferation of ER-positive cells and ER-negative cells of human breast cancer (MCF-7)".Oncology.47 (1):19–24.doi:10.1159/000226779.PMID2137212.
^Kubota T, Oka S, Utsumi T, Inoue S, Kuzuoka M, Suto A, et al. (July 1989). "Human breast carcinoma (ZR-75-1) serially transplanted into nude mice--with reference to estradiol dependency and sensitivity to tamoxifen".The Japanese Journal of Surgery.19 (4):446–451.doi:10.1007/BF02471626.PMID2810959.S2CID23267652.
^Midwinter A (1976). "Contraindications to estrogen therapy and management of the menopausal syndrome in these cases". In S (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.
^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 Pharmacologica Sinica.22 (2):148–154.PMID11741520.
^abSchwartz MM, Soule SD (July 1955). "Estradiol 17-beta-cyclopentylpropionate, a longacting estrogen".American Journal of Obstetrics and Gynecology.70 (1):44–50.doi:10.1016/0002-9378(55)90286-6.PMID14388061.
^abDorr EM, Greene RR (1939). "Treatment of the menopause with estradiol dipropionate".American Journal of Obstetrics and Gynecology.38 (3):458–464.doi:10.1016/S0002-9378(39)90763-5.ISSN0002-9378.
^Buschbeck H (1934). "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.S2CID72668930.
^Oriowo MA, Landgren BM, Stenström B, Diczfalusy E (April 1980). "A comparison of the pharmacokinetic properties of three estradiol esters".Contraception.21 (4):415–424.doi:10.1016/S0010-7824(80)80018-7.PMID7389356.
