Estradiol dipropionate
Estradiol dipropionate (EDP), sold under the brand names Agofollin, Di-Ovocyclin, and Progynon DP among others, is an estrogen medication which has been used in hormone therapy for menopausal symptoms and low estrogen levels in women and in the treatment of gynecological disorders.[8][9][10][11][12][13] It has also been used in feminizing hormone therapy for transgender women and in the treatment of prostate cancer in men.[14][8] Although widely used in the past, estradiol dipropionate has largely been discontinued and is mostly no longer available today.[15][13][11] It appears to remain in use only in Japan, Macedonia, and Australia.[13] Estradiol dipropionate is given by injection into muscle at intervals ranging from once or twice a week to once every week and a half to two weeks.[8][16][14]
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| Clinical data | |
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| Trade names | Agofollin, Di-Ovocyclin, Progynon DP, others |
| Other names | EDP; Estradiol dipropionate; Estradiol 3,17β-dipropionate; Estra-1,3,5(10)-triene-3,17β-diol 3,17β-dipropanoate |
| Routes of administration | Intramuscular injection |
| Drug class | Estrogen; Estrogen ester |
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| Pharmacokinetic data | |
| Bioavailability | IM: High[1] |
| Protein binding | Estradiol: ~98% (to albumin and SHBG)[2][3] |
| Metabolism | Cleavage via esterases in the liver, blood, and tissues[4][5] |
| Metabolites | Estradiol, benzoic acid, and metabolites of estradiol[4][5] |
| Elimination half-life | Unknown |
| Duration of action | IM (5 mg): 5–8 days[6][7] |
| Excretion | Urine |
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| ECHA InfoCard | 100.003.660  |
| Chemical and physical data | |
| Formula | C24H32O4 |
| Molar mass | 384.509 g/mol g·mol−1 |
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Side effects of estradiol dipropionate include breast tenderness, breast enlargement, nausea, headache, and fluid retention.[17] Estradiol dipropionate is a synthetic estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol.[5][4] It is an estrogen ester and a prodrug of estradiol in the body.[4][5] Because of this, it is considered to be a natural and bioidentical form of estrogen.[4]
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 with estradiol benzoate, estradiol dipropionate was among the most widely used esters of estradiol for many years following its introduction.[15]
Medical uses
The medical uses of estradiol dipropionate are the same as those of estradiol and other estrogens.[8][9] Estradiol dipropionate is used in hormone therapy for the treatment of menopausal symptoms such as hot flashes and vaginal atrophy and in the treatment of hypoestrogenism and delayed puberty due to hypogonadism or other causes in women.[8][9] It is also used in feminizing hormone therapy for transgender women.[14] Aside from hormone therapy, estradiol dipropionate is used in the treatment of gynecological disorders such as menstrual disorders, dysfunctional uterine bleeding, and breast engorgement.[8][9] In addition, it is used as a form of high-dose estrogen therapy in the palliative treatment of prostate cancer in men.[8]
Estradiol dipropionate has typically been used at a dosage of 1 to 5 mg once or twice per week by intramuscular 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 of feminizing hormone therapy for transgender 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]
| Route/form | Estrogen | Dosage | |
|---|---|---|---|
| Oral | Estradiol | 10 mg 3x/day AI-resistant: 2 mg 1–3x/day | |
| Estradiol valerate | AI-resistant: 2 mg 1–3x/day | ||
| Conjugated estrogens | 10 mg 3x/day | ||
| Ethinylestradiol | 0.5–1 mg 3x/day | ||
| Diethylstilbestrol | 5 mg 3x/day | ||
| Dienestrol | 5 mg 3x/day | ||
| IM or SC injection | Estradiol benzoate | 5 mg 2–3x/week | |
| Estradiol dipropionate | 5 mg 2–3x/week | ||
| Estradiol valerate | 30 mg 1x/2 weeks | ||
| Polyestradiol phosphate | 40–80 mg 1x/4 weeks | ||
| Estrone | 5 mg ≥3x/week | ||
| Notes: (1) Only in women who are at least 5 years postmenopausal. (2) Dosages are not necessarily equivalent. Sources: See template. | |||
| Route/form | Estrogen | Dosage | |
|---|---|---|---|
| Oral | Estradiol | 1–2 mg 3x/day | |
| Conjugated estrogens | 1.25–2.5 mg 3x/day | ||
| Ethinylestradiol | 0.15–3 mg/day | ||
| Ethinylestradiol sulfonate | 1–2 mg 1x/week | ||
| Diethylstilbestrol | 1–3 mg/day | ||
| Dienestrol | 5 mg/day | ||
| Hexestrol | 5 mg/day | ||
| Fosfestrol | 100–480 mg 1–3x/day | ||
| Chlorotrianisene | 12–48 mg/day | ||
| Quadrosilan | 900 mg/day | ||
| Estramustine phosphate | 140–1400 mg/day | ||
| Transdermal patch | Estradiol | 2–6x 100 μg/day Scrotal: 1x 100 μg/day | |
| IM or SC injection | Estradiol benzoate | 1.66 mg 3x/week | |
| Estradiol dipropionate | 5 mg 1x/week | ||
| Estradiol valerate | 10–40 mg 1x/1–2 weeks | ||
| Estradiol undecylate | 100 mg 1x/4 weeks | ||
| Polyestradiol phosphate | Alone: 160–320 mg 1x/4 weeks With oral EE: 40–80 mg 1x/4 weeks | ||
| Estrone | 2–4 mg 2–3x/week | ||
| IV injection | Fosfestrol | 300–1200 mg 1–7x/week | |
| Estramustine phosphate | 240–450 mg/day | ||
| Note: Dosages are not necessarily equivalent. Sources: See template. | |||
Available forms
Estradiol dipropionate was previously available by itself as an oil solution for intramuscular injection provided as vials and ampoules at concentrations of 0.1, 0.2, 0.5, 1, 2.5, and 5 mg/mL.[8][22][23][24] 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/mL hydroxyprogesterone caproate under the brand name EP Hormone Depot (Teikoku Zoki Pharmaceutical Company) in Japan.[25][26][27][28][29][30][31]
| Route | Ingredient | Form | Dose | Major brand names |
|---|---|---|---|---|
| Oral | Estradiol | Tablet | 0.1, 0.2, 0.5, 1, 2, or 4 mg per tablet | Estrace, Ovocyclin |
| Estradiol acetatea | Tablet | 0.45, 0.9, or 1.8 mg per tablet | Femtrace | |
| Estradiol valerate | Tablet | 0.5, 1, 2, or 4 mg per tablet | Progynova | |
| Sublingual | Estradiola | Tablet | 0.125, 0.25, or 1 mg per tablet | Diogynets, Estradiol Membrettes |
| Intranasal | Estradiola | Nasal spray | 150 µg per spray (60 sprays per bottle) | Aerodiol |
| Transdermal | Estradiol | Patch | 14, 25, 37.5, 50, 60, 75, or 100 µg E2 per day for 3–4 or 7 days | Climara, Estraderm, Vivelle |
| Gel dispenser | 0.06% (0.87 or 1.25 g gel or 0.52 or 0.75 mg E2 per activation) | Elestrin, EstroGel | ||
| Gel packet | 0.1% (0.25, 0.5, or 1 g gel or 2.5, 5, or 10 mg E2 per packet) | DiviGel, Sandrena | ||
| Emulsion | 0.14% (1.74 g emulsion or 4.35 mg E2 per pouch; 50 µg/day E2) | Estrasorb | ||
| Spray | 1.53 mg per spray | Evamist | ||
| Vaginal | Estradiol | Tablet | 10 or 25 µg per tablet | Vagifem |
| Cream | 0.01% (0.1 mg E2 per 1 g cream) | Estrace | ||
| Suppositorya | 4 or 40 μg per suppository | Ovocyclin | ||
| Insert | 4 or 10 µg per insert (daily for 2 weeks then twice weekly) | Imvexxy | ||
| Ring | 2 mg per ring (7.5 µg/day E2 for 3 months) | Estring | ||
| Estradiol acetate | Ring | 12.4 or 24.8 mg per ring (50 or 100 µg/day E2 for 3 months) | Femring | |
| Injection (IM or SC) | Estradiol | Microspheres | 1 mg/mL | Juvenum E |
| Estradiol benzoate | Oil solution | 0.167, 0.2, 0.333, 1, 1.67, 2, 5, 10, 20, or 25 mg/mL | Progynon-B | |
| Aqueous suspensiona | 5 mg/mL | Agofollin Depot | ||
| Estradiol cypionate | Oil solution | 1, 3, or 5 mg/mL | Depo-Estradiol | |
| Aqueous suspension | 5 mg/0.5 mL (available only with a progestin) | Cyclofem, Lunelle | ||
| Estradiol dipropionatea | Oil solution | 0.1, 0.2, 0.5, 1, 2.5, or 5 mg/mL | Di-Ovocylin, Progynon-DP | |
| Estradiol enantate | Oil solution | 5 or 10 mg/mL (available only with a progestin) | Perlutal, Topasel | |
| Estradiol undecylatea | Oil solution | 100 mg/mL | Delestrec, Progynon Depot 100 | |
| Estradiol valerate | Oil solution | 5, 10, 20, or 40 mg/mL | Delestrogen, Progynon Depot | |
| Polyestradiol phosphatea | Aqueous solution | 40 or 80 mg per vial/ampoule | Estradurin | |
| Implant | Estradiola | Pellet | 20, 25, 50, or 100 mg per pellet (usually every 6 months) | Estradiol Implants, Meno-Implant |
| Abbreviations: E2 = Estradiol. Footnotes: a = Discontinued or mostly discontinued. Notes: (1): This table mostly 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 and doses have been marketed previously but may no longer be available. Sources: See template. | ||||
Contraindications
Contraindications of estrogens include coagulation problems, cardiovascular diseases, liver disease, and certain hormone-sensitive cancers such as breast cancer and endometrial cancer, among others.[32][33][34][35]
Side effects
The side effects of estradiol dipropionate are the same as those of estradiol. Examples of such side effects include breast tenderness and enlargement, nausea, bloating, edema, headache, and melasma.[17]
Overdose
Symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, heavy legs, and leg cramps.[32] These side effects can be diminished by reducing the estrogen dosage.[32]
Interactions
Inhibitors and inducers of cytochrome P450 may influence the metabolism of estradiol and by extension circulating estradiol levels.[36]
Pharmacology
Pharmacodynamics
Estradiol dipropionate is an estradiol ester, or a prodrug of estradiol.[4][5] As such, it is an estrogen, or an agonist of the estrogen receptors.[4][5] Estradiol dipropionate is of about 41% higher molecular weight than estradiol due to the presence of its C3 and C17β propionate esters.[10][11] Because estradiol dipropionate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.[4]
| Estrogen | Form | Major brand name(s) | EPD (14 days) | CIC-D (month) | Duration |
|---|---|---|---|---|---|
| Estradiol | Oil solution | – | 40–60 mg | – | 1–10 mg ≈ 1–2 days |
| Aqueous suspensiona | Mego-E | ? | 3.5 mg | 3.5 mg ≈ >5 days | |
| Microspheres | Juvenum-E, Juvenum | ? | – | 1 mg ≈ 30 days | |
| Estradiol benzoate | Oil solution | Progynon-B | 25–35 mg | – | 5 mg ≈ 3–6 days |
| Aqueous suspension | Agofollin-Depot | 20 mg | – | 10 mg ≈ 16–21 days | |
| Estradiol dipropionate | Oil solution | Agofollin, Di-Ovocyclin, Progynon DP | 25–30 mg | – | 5 mg ≈ 5–8 days |
| Estradiol valerate | Oil solution | Delestrogen, Progynon Depot, Mesigyna | 20–30 mg | 5 mg | 5 mg ≈ 7–8 days; 10 mg ≈ 10–14 days; 40 mg ≈ 14–21 days; 100 mg ≈ 21–28 days |
| Estradiol cypionate | Oil solution | Depo-Estradiol, Depofemin | 20–30 mg | – | 5 mg ≈ 11–14 days |
| Aqueous suspensiona | Cyclofem, Lunelle | ? | 5 mg | 5 mg ≈ 14–24 days | |
| Estradiol benzoate butyratea | Oil solution | Redimen, Soluna, Unijab | ? | 10 mg | 10 mg ≈ 21 days |
| Estradiol enanthatea | Oil solution | Perlutal, Topasel, Yectames | ? | 5–10 mg | 10 mg ≈ 20–30 days |
| Estradiol undecylate | Oil solution | Delestrec, Progynon Depot 100 | ? | – | 10–20 mg ≈ 40–60 days; 25–50 mg ≈ 60–120 days |
| Polyestradiol phosphate | Aqueous solution | Estradurin | 40–60 mg | – | 40 mg ≈ 30 days; 80 mg ≈ 60 days; 160 mg ≈ 120 days |
| Estrone | Oil solution | Kestrin, Theelin | ? | – | 1–2 mg ≈ 2–3 days |
| Aqueous suspension | Estrone Aqueous Suspension | ? | – | ? | |
| Estriol | Oil solution | – | ? | – | 1–2 mg ≈ 1–4 days |
| Polyestriol phosphate | Aqueous solution | Gynäsan, Klimadurin, Triodurin | ? | – | 50 mg ≈ 30 days; 80 mg ≈ 60 days |
| Notes: All by intramuscular injection. All aqueous suspensions are of microcrystalline particle size. Estradiol production during the menstrual cycle is 30–640 µg/day (6.4–8.6 mg total per month or cycle). The vaginal epithelium maturation dosage of estradiol benzoate or estradiol valerate is 5 to 7 mg/week. An effective ovulation-inhibiting dose of estradiol undecylate is 20–30 mg/month. Footnotes: a = Available only in combined injectable contraceptives (i.e., not available alone). Sources: See template. | |||||
Pharmacokinetics
Compared to estradiol benzoate, a related estradiol ester, estradiol dipropionate has enhanced and prolonged effects.[37][16] Whereas the duration 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.[38] However, newer estradiol esters have longer durations than either estradiol benzoate or estradiol dipropionate; the duration of estradiol valerate has been said to be 1 to 3 weeks, and the duration of estradiol cypionate has been said to be 3 to 4 weeks.[38][16] A single intramuscular 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.[39] Estradiol levels declined to about 90 pg/mL after 4 days.[39]
Chemistry
Estradiol dipropionate, also known as estradiol 3,17β-dipropionate, is a synthetic estrane steroid and a derivative of estradiol.[10][11] It is an estrogen ester; specifically, it is the C3,17β dipropionate ester of estradiol.[10][11]
| Estrogen | Structure | Ester(s) | Relative mol. weight | Relative E2 contentb | logPc | ||||
|---|---|---|---|---|---|---|---|---|---|
| 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 | 2.8–3.9 | |
| Estradiol benzoate |  | C3 | Benzenecarboxylic acid | Aromatic fatty acid | – (~4–5) | 1.38 | 0.72 | 4.5–5.7 | |
| Estradiol dipropionate | | C3, C17β | Propanoic acid (×2) | Straight-chain fatty acid | 3 (×2) | 1.41 | 0.71 | 4.3 | |
| Estradiol valerate |  | C17β | Pentanoic acid | Straight-chain fatty acid | 5 | 1.31 | 0.76 | 5.8–6.0 | |
| Estradiol cypionate |  | C17β | Cyclopentylpropanoic acid | Aromatic fatty acid | – (~6) | 1.46 | 0.69 | 6.5–7.1 | |
| Estradiol benzoate butyrate |  | C3, C17β | Benzoic acid, butyric acid | Mixed fatty acid | – (~6, 2) | 1.64 | 0.61 | 5.9 | |
| Estradiol enantate |  | C17β | Heptanoic acid | Straight-chain fatty acid | 7 | 1.41 | 0.71 | 7.0 | |
| Estradiol dienantate |  | C3, C17β | Heptanoic acid (×2) | Straight-chain fatty acid | 7 (×2) | 1.82 | 0.55 | 8.1–9.1 | |
| Estradiol undecylate |  | C17β | Undecanoic acid | Straight-chain fatty acid | 11 | 1.62 | 0.62 | 9.2 | |
| Estradiol stearate |  | C17β | Octadecanoic acid | Straight-chain fatty acid | 18 | 1.98 | 0.51 | 12.2 | |
| 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 of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic fatty acids. b = Relative estradiol content by weight (i.e., relative estrogenic potency). c = Experimental or predicted octanol/water partition coefficient (i.e., lipophilicity/hydrophobicity). Retrieved from PubChem and DrugBank. d = Also known as estradiol normustine phosphate. e = Polymer of estradiol phosphate (~13 repeat units). f = Relative molecular weight or estradiol content per repeat unit. g = logP of repeat unit (i.e., estradiol phosphate). Sources: See individual articles. | |||||||||
History
Along with estradiol benzoate, estradiol dipropionate was one of the first estradiol esters to be developed, having been patented in 1937,[18] assessed in clinical studies by 1939,[37] and marketed by Schering as Progynon DP and Ciba as Di-Ovocylin by 1940.[19][20] Prior to the development and introduction in the 1950s of estradiol valerate and estradiol cypionate, which are longer-acting in comparison (1–4 weeks),[38] estradiol dipropionate and estradiol benzoate were the most widely used estradiol esters.[15] However, estradiol valerate and estradiol cypionate, which are longer-acting esters that require less frequent administration, were developed and introduced in the 1950s, and have since largely superseded estradiol dipropionate and estradiol benzoate.[41]
Society and culture
Generic names
Estradiol dipropionate is the generic name of the drug and its INNM, BANM, and JAN.[10][11][12][13]
Brand names
Estradiol dipropionate has been marketed under a variety of brand names, including Agofollin, Akrofolline, Dihidrofolina "Kével", Dimenformon, Dimenformon Dipropionate, Diovocyclin, Di-Ovocyclin, Diprostron, Diprovex, Endofollicolina D.P., EP Hormone Depot (in combination with hydroxyprogesterone caproate), Estroici, Estronex, Follicyclin, Follicyclin P, Follikelmon Depot, Horiken-Depot, Nacyclyl, Oestradiol Galenika, Oestradiol Streuli, Orofollina, Ovacrin, Ovahormon Depot, Ovocyclin, Ovocyclin Dipropionate, Ovocyclin P, and Progynon DP, among others.[42][10][11][12][43][44][13] Agofollin was an oil solution of estradiol dipropionate that was previously marketed in the Czech Republic and Slovakia.[45]
Availability
Estradiol dipropionate has been discontinued in most countries, but remains available in Japan and Macedonia alone under the brand names Ovahormon and Oestradiol Galenika and/or in combination with hydroxyprogesterone caproate under the brand name EP Hormone Depot.[11][13] It is also marketed for use in veterinary medicine in combination with hydroxyprogesterone caproate and nandrolone decanoate under the brand name Reepair in Australia.[13]
References
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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.
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The estradiol dipropionate used in this case was furnished by the Ciba Co. Their trade name for this product is Di-Ovocylin.
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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;
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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.
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