Estradiol dipropionate

Estradiol dipropionate (EDP), sold under the brand names Agofollin, Di-Ovocylin, 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]

Estradiol dipropionate

Clinical data
Trade names	Agofollin, Di-Ovocylin, 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
ATC code	G03CA03 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
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
Identifiers
IUPAC name [(8R,9S,13S,14S,17S)-13-methyl-3-propanoyloxy-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] propanoate
CAS Number	113-38-2
PubChem CID	8225
ChemSpider	7932
UNII	NIG5418BXB
KEGG	D01617
ChEBI	CHEBI:31560
ChEMBL	ChEMBL1697791
CompTox Dashboard (EPA)	DTXSID8023000
ECHA InfoCard	100.003.660
Chemical and physical data
Formula	C24H32O4
Molar mass	384.516 g·mol^−1
3D model (JSmol)	Interactive image
SMILES O=C(Oc1cc3c(cc1)[C@H]2CC[C@@]4([C@@H](OC(=O)CC)CC[C@H]4[C@@H]2CC3)C)CC
InChI InChI=1S/C24H32O4/c1-4-22(25)27-16-7-9-17-15(14-16)6-8-19-18(17)12-13-24(3)20(19)10-11-21(24)28-23(26)5-2/h7,9,14,18-21H,4-6,8,10-13H2,1-3H3/t18-,19-,20+,21+,24+/m1/s1 Key:JQIYNMYZKRGDFK-RUFWAXPRSA-N

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]

Estrogen dosages for breast cancer

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
	Dimestrol	30 mg/day
	Chlorotrianisene	24 mg/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.

Estrogen dosages for prostate cancer

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

See also: Estradiol dipropionate/hydroxyprogesterone caproate

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][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/mL hydroxyprogesterone caproate under the brand name EP Hormone Depot (Teikoku Zoki Pharmaceutical Company) in Japan.[26][27][28][29][30][31][32]

Available forms of estradiol

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 acetate^a	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	Estradiol^a	Tablet	0.125, 0.25, or 1 mg per tablet	Diogynets, Estradiol Membrettes
Intranasal	Estradiol^a	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 0.25, 0.5, or 1.0 mg E2 per packet)	DiviGel, Sandrena
		Emulsion	0.25% (1.74 g emulsion or 4.35 mg E2 or 25 µg/day E2 per pouch)	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
		Suppository^a	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
	Estradiol benzoate^a	Tablet	0.125 mg	Malun 25
Injection (IM or SC)	Estradiol	Aqueous suspension^a	0.22, 0.25, 0.44, 0.5, 1.0, 1.1, or 2.0 mg/mL	Aquadiol, Diogyn, Progynon
		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 suspension^a	5 mg/mL	Agofollin Depot, Ovocyclin M
	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 dipropionate^a	Oil solution	0.1, 0.2, 0.5, 1, 2.5, or 5 mg/mL	Di-Ovocylin, Progynon-DP
	Estradiol enanthate	Oil solution	5 or 10 mg/mL (available only with a progestin)	Perlutal, Topasel
	Estradiol undecylate^a	Oil solution	100 mg/mL	Delestrec, Progynon Depot 100
	Estradiol valerate	Oil solution	5, 10, 20, or 40 mg/mL	Delestrogen, Progynon Depot
	Polyestradiol phosphate^a	Aqueous solution	40 or 80 mg per vial/ampoule	Estradurin
Implant	Estradiol^a	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

See also: Estradiol (medication) § 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.[33][34][35][36]

Side effects

Main article: Estradiol (medication) § 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

See also: Estradiol (medication) § Overdose

Symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, heavy legs, and leg cramps.[33] These side effects can be diminished by reducing the estrogen dosage.[33]

Interactions

See also: Estradiol (medication) § Interactions

Inhibitors and inducers of cytochrome P450 may influence the metabolism of estradiol and by extension circulating estradiol levels.[37]

Pharmacology

Estradiol, the active form of estradiol dipropionate.

Pharmacodynamics

See also: Pharmacodynamics of estradiol

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]

Potencies and durations of natural estrogens by intramuscular injection

Estrogen	Form	Major brand names	EPD	CIC-D	Duration
Estradiol	Aqueous solution	–	?	–	<1 day
	Oil solution	Estradiol	40–60 mg	–	1–2 mg ≈ 1–2 days
	Aqueous suspension	Aquadiol, Diogyn, Progynon, Mego-E	?	3.5 mg	0.5–2 mg ≈ 2–7 days; 3.5 mg ≈ >5 days
	Microspheres	Juvenum-E, Juvenum	?	–	1 mg ≈ 30 days
Estradiol benzoate	Oil solution	Progynon-B	25–35 mg	–	1.66 mg ≈ 2–3 days; 5 mg ≈ 3–6 days
	Aqueous suspension	Agofollin-Depot, Ovocyclin M	20 mg	–	10 mg ≈ 16–21 days
	Emulsion	Menformon-Emulsion, Di-Pro-Emulsion	?	–	10 mg ≈ 14–21 days
Estradiol dipropionate	Oil solution	Agofollin, Di-Ovocylin, 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 benzoate butyrate	Oil solution	Redimen, Soluna, Unijab	?	10 mg	10 mg ≈ 21 days
Estradiol cypionate	Oil solution	Depo-Estradiol, Depofemin	20–30 mg	–	5 mg ≈ 11–14 days
	Aqueous suspension	Cyclofem, Lunelle	?	5 mg	5 mg ≈ 14–24 days
Estradiol enanthate	Oil solution	Perlutal, Topasel, Yectames	?	5–10 mg	10 mg ≈ 20–30 days
Estradiol dienanthate	Oil solution	Climacteron, Lactimex, Lactostat	?	–	7.5 mg ≈ >40 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	Estrone, Kestrin, Theelin	?	–	1–2 mg ≈ 2–3 days
	Aqueous suspension	Estrone Aq. Susp., Kestrone, Theelin Aq.	?	–	0.1–2 mg ≈ 2–7 days
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 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 has been reported as 5 to 7 mg/week. An effective ovulation-inhibiting dose of estradiol undecylate is 20–30 mg/month. Sources: See template.

Pharmacokinetics

See also: Pharmacokinetics of estradiol

Compared to estradiol benzoate, a related estradiol ester, estradiol dipropionate has enhanced and prolonged effects.[38][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.[39] 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.[39][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.[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]
• 
  Vaginal cornification with a single intramuscular injection of different estradiol esters in oil solution in women.[41] Source was Schwartz & Soule (1955).[41]

Chemistry

See also: Estrogen ester and List of estrogen esters § Estradiol esters

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]

The experimental octanol/water partition coefficient (logP) of estradiol dipropionate is 4.9.[42]

Structural properties of selected estradiol esters

Estrogen	Structure	Ester(s)				Relative mol. weight	Relative E2 content^b	logP^c
		Position(s)	Moiet(ies)	Type	Length^a
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	Benzenecarboxylic 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	Aromatic 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 phosphate^d		C3, C17β	Normustine, phosphoric acid	Water-soluble conjugate	–	1.91	0.52	2.9–5.0
Polyestradiol phosphate^e		C3–C17β	Phosphoric acid	Water-soluble conjugate	–	1.23^f	0.81^f	2.9^g
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 exposure). ^c = Experimental or predicted octanol/water partition coefficient (i.e., lipophilicity/hydrophobicity). Retrieved from PubChem, ChemSpider, 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

Estradiol dipropionate was first synthesized and patented in 1937.[43][18] It was assessed in clinical studies by 1939 and was introduced by Ciba as an oil solution for use by intramuscular injection under the brand name Di-Ovocylin by the same year.[43][38][19] Other formulations such as Ovocyclin P by Ciba, Progynon DP by Schering and Dimenformon Dipropionate by Roche-Organon were also marketed by the early 1940s.[44][45][20][46] Later in the 1940s the brand name Di-Ovocylin was changed by Ciba to Ovocylin Dipropionate.[22] Along with estradiol benzoate, which was introduced in 1933,[47] estradiol dipropionate was one of the first estradiol esters to be introduced for medical use.[48][45] Prior to the development and introduction of longer-acting estradiol esters like estradiol valerate and estradiol cypionate in the 1950s, estradiol dipropionate and estradiol benzoate were the most widely used estradiol esters.[15][49]

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, Diovocylin, Di-Ovocylin, 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, Ovocylin, Ovocylin Dipropionate, Ovocylin P, and Progynon DP, among others.[50][10][11][12][51][52][13] Agofollin was an oil solution of estradiol dipropionate that was previously marketed in the Czech Republic and Slovakia.[53]

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]

See also

• Estradiol dipropionate/hydroxyprogesterone caproate

References

1. Düsterberg B, Nishino Y (December 1982). "Pharmacokinetic and pharmacological features of oestradiol valerate". Maturitas. 4 (4): 315–24. doi:10.1016/0378-5122(82)90064-0. PMID 7169965.
2. Stanczyk, Frank Z.; Archer, David F.; Bhavnani, Bhagu R. (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. ISSN 0010-7824. PMID 23375353.
3. Tommaso Falcone; William W. Hurd (2007). Clinical Reproductive Medicine and Surgery. Elsevier Health Sciences. pp. 22, 362, 388. ISBN 978-0-323-03309-1.
4. Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. p. 261. ISBN 978-3-642-60107-1. 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.
5. Kuhl H (2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
6. Karl Knörr; Henriette Knörr-Gärtner; Fritz K. Beller; Christian Lauritzen (8 March 2013). Lehrbuch der Geburtshilfe und Gynäkologie: Physiologie und Pathologie der Reproduktion. Springer-Verlag. pp. 508–. ISBN 978-3-662-00526-2.
7. Karl Knörr; Fritz K. Beller; Christian Lauritzen (17 April 2013). Lehrbuch der Gynäkologie. Springer-Verlag. pp. 212–213. ISBN 978-3-662-00942-0.
8. "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. ISSN 0095-9561.
9. Swyer GI (April 1959). "The oestrogens". Br Med J. 1 (5128): 1029–31. doi:10.1136/bmj.1.5128.1029. PMC 1993181. PMID 13638626.
10. J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 898–. ISBN 978-1-4757-2085-3.
11. Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 406–. ISBN 978-3-88763-075-1.
12. I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 206–. ISBN 978-94-011-4439-1.
13. https://www.drugs.com/international/estradiol.html
14. Nakatsuka M (May 2010). "Endocrine treatment of transsexuals: assessment of cardiovascular risk factors". Expert Rev Endocrinol Metab. 5 (3): 319–322. doi:10.1586/eem.10.18. PMID 30861686.
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