Chemistry:Estradiol cypionate

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Short description: Chemical compound
Estradiol cypionate
Estradiol 17 beta-cypionate.svg
Estradiol cypionate molecule ball.png
Clinical data
Pronunciation/ˌɛstrəˈdaɪoʊl sɪˈpaɪoʊneɪt/
ES-trə-DY-ohl sih-PY-oh-nate[1]
Trade namesDepo-Estradiol, Depofemin, Estradep, many others
Other namesEC; E2C; Estradiol cipionate; Estradiol cyclopentylpropionate; ECP; Estradiol 17β-cyclopentylpropionate; Estradiol 17β-cyclopentanepropionate
Routes of
administration		Intramuscular injection, subcutaneous injection[2]
Drug classEstrogen; Estrogen ester
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityIM: High[3]
MetabolismCleavage via esterases in the liver, blood, and tissues[4][5]
MetabolitesEstradiol, cypionic acid, and metabolites of estradiol[4][5]
Elimination half-lifeIM (aqueous suspension): 8–10 days[6][7]
Duration of actionIM (oil): 5 mg ≈ 11–14 days[8]
IM (aqueous suspension): 5 mg ≈ 14–24 days[6][9][10]
ExcretionUrine
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC26H36O3
Molar mass396.571 g·mol−1
3D model (JSmol)
Melting point151 to 152 °C (304 to 306 °F)

Estradiol cypionate (EC), sold under the brand name Depo-Estradiol among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for trans women, and in hormonal birth control for women.[11][5][12][13] It is given by injection into muscle once every 1 to 4 weeks.[11][14]

Side effects of estradiol cypionate include breast tenderness, breast enlargement, nausea, headache, and fluid retention.[11][5] Estradiol cypionate is an estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol.[5][4] Estradiol cypionate is an estrogen ester and a long-lasting prodrug of estradiol in the body.[11][5][4] Because of this, it is considered to be a natural and bioidentical form of estrogen.[4][15][9]

Estradiol cypionate was first described as well as introduced for medical use in 1952.[16][17] Along with estradiol valerate, it is one of the most commonly used esters of estradiol.[18] Estradiol cypionate has mostly been used in the United States , but is also marketed in a few other countries.[19][20][21] The medication is not available in Europe.[22] It is not currently available as a generic medication in the United States.[23]


Medical uses

The medical uses of estradiol cypionate are the same as those of estradiol and other estrogens. Examples of indications for the drug include hormone therapy and hormonal contraception. In regard to the latter, estradiol cypionate has been used in combination with medroxyprogesterone acetate as a combined injectable contraceptive.[12][13][24] Along with estradiol valerate, estradiol undecylate, and estradiol benzoate, estradiol cypionate is used as a form of high-dose estrogen therapy in feminizing hormone therapy for transgender women.[25][14][26][27] The medication has been used to induce puberty in girls with delayed puberty due to hypogonadism.[28][22]

Estradiol cypionate is usually used at a dosage of 1 to 5 mg by intramuscular injection every 3 to 4 weeks in the treatment of menopausal symptoms such as hot flashes and vaginal atrophy, at a dosage of 1.5 to 2 mg by intramuscular injection once a month in the treatment of female hypoestrogenism due to hypogonadism, and at a dosage of 2 to 10 mg by intramuscular injection once every 1 or 2 weeks for hormone therapy in transgender women.[11][14][26][25][29] The doses used to induce puberty in girls are 0.2 to 2.5 mg per month, gradually increased over a period of 4 years.[28][22]


Available forms

Estradiol cypionate is and has been available as an oil solution for intramuscular injection provided in vials and ampoules at concentrations of 1, 3, and 5 mg/mL (and containing 5, 10, 15, 25, or 50 mg estradiol cypionate total).[23][30][31] The 1 and 3 mg/mL concentrations (containing 5 and 15 mg estradiol cypionate total) have been discontinued in the United States , but the 5 mg/mL concentration (containing 25 mg estradiol cypionate total) remains available.[23][32] Aside from estradiol cypionate, the only other injectable estrogen formulations that remain available in the United States are estradiol valerate (10 mg/mL, 20 mg/mL, and 40 mg/mL in oil) and conjugated estrogens (25 mg/vial in solution).[23]

In addition to single-drug formulations, estradiol cypionate has been marketed in combination with medroxyprogesterone acetate as a microcrystalline aqueous suspension (brand name Lunelle) and in combination with testosterone cypionate as an oil solution (brand name Depo-Testadiol).[23]


5-mL vials of Depo-Estradiol (5 mg/mL estradiol cypionate in cottonseed oil solution for use by intramuscular injection) in the United States .[11]

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

The side effects of estradiol cypionate are the same as those of estradiol. Examples of such side effects include breast tenderness and enlargement, nausea, vomiting, bloating, edema, headache, migraine, and melasma.[37][38] High-dose estrogen therapy with estradiol cypionate injections may also cause an increased risk of thromboembolism, changes in blood lipid profile, increased insulin resistance, and increased levels of prolactin.[38]

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

Inhibitors and inducers of cytochrome P450 may influence the metabolism of estradiol and by extension circulating estradiol levels.[39]

Pharmacology

Estradiol, the active form of estradiol cypionate.

Pharmacodynamics

Estradiol cypionate is an estradiol ester, or a prodrug of estradiol.[5][4] As such, it is an estrogen, or an agonist of the estrogen receptors.[5][4] The affinity of estradiol valerate for the estrogen receptor has been reported to be 50 times less than that of estradiol,[3] and estradiol valerate and estradiol cypionate have been found to possess similar affinity for the estrogen receptor.[40] Both estradiol cypionate and estradiol valerate are rapidly cleaved into estradiol in the body,[5][41] and estradiol valerate has been found to be unable to reach target tissues in any concentration of significance.[3] As such, estradiol valerate is regarded as essentially inactive in terms of estrogenic effect itself, acting solely as a prodrug to estradiol,[3] and estradiol cypionate is described as a prodrug of estradiol similarly.[4] Estradiol cypionate is of about 46% higher molecular weight than estradiol due to the presence of its C17β cypionate ester, and contains about 69% of the amount of estradiol by weight.[42][19][22] Because estradiol cypionate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.[4][15][9]


v · d · e Potencies and durations of natural estrogens by intramuscular injection
Estrogen Form Major brand names EPD CIC-D Duration
Estradiol Oil solution – 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.

Effects on liver protein synthesis

A study compared the combination of 5 mg estradiol cypionate and 25 mg medroxyprogesterone acetate as a combined injectable contraceptive (which has been associated with peak estradiol levels of around 300 pg/mL) with an ethinylestradiol-containing combined birth control pill and found that whereas the birth control pill produced significant changes in coagulation parameters, there were no significant prothrombotic effects of the combined injectable contraceptive on levels of fibrinogen, factors VII and X, plasminogen, or the activated prothrombin time.[43] As such, it appears that similarly to depot medroxyprogesterone acetate, combined injectable contraceptives with 5 mg estradiol cypionate and 25 mg medroxyprogesterone acetate have less or no procoagulant effect relative to combined birth control pills.[43]

Pharmacokinetics

Intramuscular injection

In contrast to oral administration, which is associated with very low bioavailability (<10%), the bioavailability of both estradiol and estradiol esters like estradiol valerate is complete (i.e., 100%) via intramuscular injection.[3][5] In addition, estradiol esters like estradiol cypionate and estradiol valerate when given as an injection of oil solution or microcrystalline aqueous suspension have a relatively long duration due to the formation of an intramuscular depot from which they are slowly released and absorbed.[3][44][45] Upon intramuscular injection of estradiol cypionate 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.[5] In addition, a secondary depot may be formed in adipose tissue.[5] The slow release of estradiol cypionate from the tissue depot is caused by the high lipophilicity of the estradiol ester, which in turn is due to its long fatty acid cypionic acid ester moiety.[3] Estradiol cypionate is formulated for use alone and in combination with testosterone cypionate as an oil solution, and for use in combination with medroxyprogesterone acetate as a microcrystalline aqueous suspension.[23][30][31][32] Aqueous suspensions of steroid esters generally have longer durations by intramuscular injection than oil solutions.[45]

A single intramuscular injection of 5 mg estradiol cypionate has been found to result in peak circulating concentrations of 338 pg/mL estradiol and 145 pg/mL estrone, which occurred at about 4 and 5 days post-injection, respectively (see right table).[8] Compared to two other commonly used estradiol esters (which were also assessed in the study), estradiol cypionate had the longest duration, at approximately 11 days, whereas estradiol benzoate and estradiol valerate were found to last for 4 to 5 days and 7 to 8 days, respectively.[8] This is because estradiol cypionate has a more extensive fatty acid chain and in relation to this is comparatively more lipophilic.[5] For a given estradiol ester, the longer or more extensive the fatty acid chain is, the more lipophilic, longer-lasting, and more uniform/plateau-like the resultant levels of estradiol are as well as the lower the peak/maximal levels are (and hence less spike-like).[5]

Estradiol cypionate/medroxyprogesterone acetate (brand names Lunelle, Cyclofem) is a combined injectable contraceptive containing 5 mg estradiol cypionate and 25 mg medroxyprogesterone acetate in microcrystalline aqueous suspension for once-monthly intramuscular administration.[9][10] With this formulations, estradiol levels peak 2 to 3 days post-injection with average maximal circulating levels of about 250 pg/mL.[6][9][10] The elimination half-life of estradiol with these formulations is 8.4 to 10.1 days, and circulating estradiol levels return to a baseline of about 50 pg/mL approximately 14 to 24 days post-injection.[6][9][10][7]

Hormone levels with estradiol cypionate by intramuscular injection

  • Estradiol levels after subcutaneous (s.c.) or intramuscular (i.m.) injection of 5 mg estradiol cypionate in aqueous suspension.[2] Assays were performed using enzyme immunoassay.[2] Source was Sierra-Ramírez et al. (2011).[2]

  • Estradiol levels after a single intramuscular injection of 1.0 to 2.0 mg (average 1.67 mg) of estradiol cypionate in oil (Depo-Estradiol) in hypogonadal girls.[46][47] Assays were performed using radioimmunoassay with chromatographic separation.[46][47] Sources were Rosenfield et al. (1973, 1974).[46][47]

  • Estradiol levels after single intramuscular injections of 5 mg of different estradiol esters in oil in premenopausal women.[8] Assays were performed using radioimmunoassay with chromatographic separation.[8] Source was Oriowo et al. (1980).[8]

  • Simplified curves of estradiol levels after injection of different estradiol esters in oil solution in women.[48] Source was Garza-Flores (1994).[48]

  • Vaginal cornification with a single intramuscular injection of different estradiol esters in oil solution in women.[49] Source was Schwartz & Soule (1955).[49]

Subcutaneous injection

Estradiol cypionate in a microcrystalline aqueous suspension has been found to have equivalent effectiveness and virtually identical pharmacokinetics when administered by subcutaneous injection versus intramuscular injection.[2] However, subcutaneous injection is considered to be easier and less painful relative to intramuscular injection, and for these reasons, may result in comparatively greater satisfaction and compliance.[2]

Chemistry

Estradiol cypionate is a synthetic estrane steroid and the C17β cyclopentylpropionate (cypionate) fatty acid ester of estradiol.[42][19] It is also known as estra-1,3,5(10)-triene-3,17β-diol 17β-cyclopentylpropionate.[42][19] Other common esters of estradiol in use include estradiol valerate, estradiol enantate, and estradiol acetate, the former two of which are C17β esters of estradiol similarly to estradiol cypionate and the latter of which is the C3 acetate ester of estradiol.

The experimental octanol/water partition coefficient (logP) of estradiol cypionate is 6.9.[50]


History

Estradiol cypionate was patented by Upjohn in 1952, with a priority date of 1951.[30] It was first introduced for medical use by Upjohn in 1952 under the brand name Depo-Estradiol in the United States .[16][17][51] Subsequently, it was also marketed in other countries such as European countries and Japan .[30][17][19] The first clinical reports of estradiol cypionate were published in 1952 and thereafter.[52][53][54][55][49] It was initially known as estradiol cyclopentylpropionate (ECP), and did not become known as estradiol cypionate until over a decade later in the mid-to-late 1960s.[53][54][56] Along with estradiol valerate (1954)[17][57] and estradiol benzoate (1933),[58][59][60] estradiol cypionate has become one of the most commonly used esters of estradiol.[18]

When estradiol cypionate was to be combined with medroxyprogesterone acetate as a once-a-month injectable contraceptive, there was a problem in that estradiol cypionate was prepared as an oil solution while medroxyprogesterone acetate was used as a microcrystalline aqueous suspension.[61] This issue was resolved by switching to a microcrystalline aqueous suspension in the case of estradiol cypionate, allowing it to be combined with medroxyprogesterone acetate in a single suspension.[61] As a result, single-drug preparations of estradiol cypionate are oil solutions, while the combination of estradiol cypionate and medroxyprogesterone acetate are microcrystalline aqueous suspensions.[61]

Society and culture

Generic names

Estradiol cypionate is the generic name of the drug and its INN and USAN.[42][19][20] It is also known as estradiol cyclopentylpropionate (ECP).[53][54]

Brand names

Estradiol cypionate has been marketed under the brand names Cicloestradiolo, D-Est, depGynogen, Depo-Estradiol, Depoestra, Depofemin, Depogen, Dura-Estrin, E-Cypionate, E-Ionate, Estradep, Estro-Cyp, Estrofem, Estroject, Estromed-PA, Estronol, Femovirin, Neoginon Depositum, Oestradiol-Retard, Pertradiol, Spendepiol, and T-E Cypionate, among others.[42][19][17][20]

Availability

Estradiol cypionate is available in the United States .[23][20][22] It was previously marketed in Spain and Italy, but was discontinued in these countries and is no longer available in Europe.[19][22] Estradiol cypionate has mostly been used in the United States, similarly to testosterone cypionate, with both of these medications having been developed by Upjohn, an American pharmaceutical company.[19][21] Besides the United States, estradiol cypionate has been marketed in France , Germany , Italy, Spain, and Japan , among other countries.[30][17][19] Estradiol cypionate is not available in Canada , although it is marketed in several veterinary formulations in this country.[62]

Estradiol cypionate is available in Taiwan in combination with testosterone cypionate.[20] It is also available as a combined injectable contraceptive in combination with medroxyprogesterone acetate in at least 18 countries, mostly in Latin America and Southeast Asia.[63][64][65][13][66][67][68] Estradiol cypionate/testosterone cypionate and estradiol cypionate/medroxyprogesterone acetate were both formerly marketed in the United States, but have been discontinued in this country.[23]

See also

  • Estradiol cypionate/medroxyprogesterone acetate
  • Estradiol cypionate/testosterone cypionate

References

  1. ↑ "Estradiol: Uses, Dosage & Side Effects". https://www.drugs.com/estradiol.html. Retrieved 21 April 2023. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "Comparative pharmacokinetics and pharmacodynamics after subcutaneous and intramuscular administration of medroxyprogesterone acetate (25 mg) and estradiol cypionate (5 mg)". Contraception 84 (6): 565–70. 2011. doi:10.1016/j.contraception.2011.03.014. PMID 22078184. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "Pharmacokinetic and pharmacological features of oestradiol valerate". Maturitas 4 (4): 315–24. December 1982. doi:10.1016/0378-5122(82)90064-0. PMID 7169965. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. 6 December 2012. p. 261. ISBN 978-3-642-60107-1. https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA261. "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. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric 8 (Suppl 1): 3–63. 2005. doi:10.1080/13697130500148875. PMID 16112947. http://hormonebalance.org/images/documents/Kuhl%2005%20%20Pharm%20Estro%20Progest%20Climacteric_1313155660.pdf. 
  6. ↑ 6.0 6.1 6.2 6.3 "Medroxyprogesterone acetate and estradiol cypionate injectable suspension (Cyclofem) monthly contraceptive injection: steady-state pharmacokinetics". Contraception 87 (6): 738–43. June 2013. doi:10.1016/j.contraception.2012.11.010. PMID 23265980. 
  7. ↑ 7.0 7.1 "LUNELLE' Monthly Contraceptive Injection". 2000. https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20874lbl.pdf. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 "A comparison of the pharmacokinetic properties of three estradiol esters". Contraception 21 (4): 415–24. April 1980. doi:10.1016/S0010-7824(80)80018-7. PMID 7389356. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 "Injectable Contraceptives till Date". Progress in Obstetrics and Gynecology--3. Jaypee Brothers Medical Publishers Pvt. Ltd.. 15 December 2012. pp. 416–419. ISBN 978-93-5090-575-3. https://books.google.com/books?id=AS3UBAAAQBAJ&pg=PA416. 
  10. ↑ 10.0 10.1 10.2 10.3 "Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): steady-state pharmacokinetics of MPA and E2 in surgically sterile women". Contraception 60 (4): 209–214. October 1999. doi:10.1016/S0010-7824(99)00086-4. PMID 10640167. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 "Estradiol cypionate injection, USP". 2005. https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/085470s015lbl.pdf. 
  12. ↑ 12.0 12.1 "A review of "once-a-month" combined injectable contraceptives". J Obstet Gynaecol (Lahore) 4 (Suppl 1): S1–34. 1994. doi:10.3109/01443619409027641. PMID 12290848. 
  13. ↑ 13.0 13.1 13.2 "Increasing use of long-acting reversible contraception: safe, reliable, and cost-effective birth control". World J Pharm Pharm Sci 3 (10): 364–392. 2014. ISSN 2278-4357. http://www.wjpps.com/download/article/1412071798.pdf. 
  14. ↑ 14.0 14.1 14.2 "Gonadal suppressive and cross-sex hormone therapy for gender dysphoria in adolescents and adults". Pharmacotherapy 34 (12): 1282–1297. December 2014. doi:10.1002/phar.1487. PMID 25220381. 
  15. ↑ 15.0 15.1 "Bioidentical hormone therapy: a review of the evidence". J Womens Health (Larchmt) 16 (5): 600–31. June 2007. doi:10.1089/jwh.2006.0311. PMID 17627398. 
  16. ↑ 16.0 16.1 Pharmaceutical Manufacturing Encyclopedia. William Andrew. 1 January 1988. pp. 575–576. ISBN 978-0-8155-1144-1. https://books.google.com/books?id=X2EyLsG4bcUC&pg=PA576. Retrieved 20 May 2012. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia (3rd ed.). Elsevier. pp. 1476–1477. ISBN 978-0-8155-1856-3. https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1476. 
  18. ↑ 18.0 18.1 Reproductive endocrinology: physiology, pathophysiology, and clinical management. Saunders. 1991. ISBN 978-0-7216-3206-3. https://books.google.com/books?id=RN1qAAAAMAAJ. Retrieved 20 May 2012. 
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 19.6 19.7 19.8 19.9 Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 405. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA405. Retrieved 20 May 2012. 
  20. ↑ 20.0 20.1 20.2 20.3 20.4 "Estradiol". https://www.drugs.com/international/estradiol.html. 
  21. ↑ 21.0 21.1 Anabolics. Molecular Nutrition Llc. 2011. pp. 426–. ISBN 978-0-9828280-1-4. https://books.google.com/books?id=afKLA-6wW0oC&pg=PT426. 
  22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 "From Primary Hypergonadotropic Amenorrhea to "POI": Aetiology and Therapy". Frontiers in Gynecological Endocrinology: Pediatric and Adolescent Gynecological Endocrinology. ISGE Series. 4. Springer. 2017. pp. 67–109. doi:10.1007/978-3-319-41433-1_7. ISBN 978-3-319-41431-7. 
  23. ↑ 23.0 23.1 23.2 23.3 23.4 23.5 23.6 23.7 "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. http://www.accessdata.fda.gov/scripts/cder/daf/. 
  24. ↑ "New technologies in contraception". BJOG 116 (2): 230–239. January 2009. doi:10.1111/j.1471-0528.2008.01985.x. PMID 19076955. http://wrap.warwick.ac.uk/28852/1/WRAP_Rowlands_NewtechnologiesincontraceptionBJOG2008_Uni_repos_version.pdf. 
  25. ↑ 25.0 25.1 "Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons". The Psychiatric Clinics of North America 40 (1): 99–111. March 2017. doi:10.1016/j.psc.2016.10.006. PMID 28159148. 
  26. ↑ 26.0 26.1 "Transgender Youth: Endocrine Management". Principles of Transgender Medicine and Surgery. Routledge. 20 May 2016. pp. 216–. ISBN 978-1-317-51460-2. https://books.google.com/books?id=LwszDAAAQBAJ&pg=PA216. 
  27. ↑ "Transgender Hormone Adiministration". Transgender Care: Recommended Guidelines, Practical Information, and Personal Accounts. Temple University Press. 1 March 2001. pp. 64–. ISBN 978-1-56639-852-7. https://books.google.com/books?id=IlPX6E5glDEC&pg=PA64. 
  28. ↑ 28.0 28.1 "Physiologic induction of puberty in Turner syndrome with very low-dose estradiol". International Congress Series 1298: 71–79. 2006. doi:10.1016/j.ics.2006.07.003. ISSN 0531-5131. 
  29. ↑ 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. ISBN 978-0-88416-175-2. https://books.google.com/books?id=0h7s_rfEZgkC. "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." 
  30. ↑ 30.0 30.1 30.2 30.3 30.4 Pharmaceutical Substances: Syntheses, Patents and Applications of the most relevant APIs (5th ed.). Thieme. 2014. pp. 1167–1174. ISBN 978-3-13-179525-0. https://books.google.com/books?id=fO2IAwAAQBAJ&pg=PA1167. 
  31. ↑ 31.0 31.1 "Endocrine Drugs and Values". Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. 2001. pp. 2153–. ISBN 978-0-7817-1750-2. https://books.google.com/books?id=FVfzRvaucq8C&pg=PA2153. 
  32. ↑ 32.0 32.1 Food and Drug Administration (2011). Approved Drug Products with Therapeutic Equivalence Evaluations - FDA Orange Book (31st ed.). DrugPatentWatch.com. pp. 586–. ISBN 978-1-934899-81-6. https://books.google.com/books?id=JDZ4DAAAQBAJ&pg=PR586. 
  33. ↑ 33.0 33.1 33.2 "Clinical use of oestrogens and progestogens". Maturitas 12 (3): 199–214. September 1990. doi:10.1016/0378-5122(90)90004-P. PMID 2215269. 
  34. ↑ "Practice of Hormone Substitution". Current Management of the Menopause. CRC Press. 22 June 2005. pp. 95–98,488. ISBN 978-0-203-48612-2. https://books.google.com/books?id=WD7S7677xUUC&pg=PA95. 
  35. ↑ "Hormone Substitution Before, During and After Menopause". Menopause – Andropause: Hormone Replacement Therapy Through the Ages. Krause & Pachernegg: Gablitz. 2001. pp. 67–88. ISBN 978-3-901299-34-6. https://www.kup.at/kup/pdf/4978.pdf. 
  36. ↑ "Contraindications to estrogen therapy and management of the menopausal syndrome in these cases". 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. 1976. pp. 377–382. doi:10.1007/978-94-011-6165-7_33. ISBN 978-94-011-6167-1. 
  37. ↑ "Endocrinology". Mayo Clinic Internal Medicine Board Review. OUP USA. 23 September 2010. pp. 222–. ISBN 978-0-19-975569-1. https://books.google.com/books?id=LS65jBzoD40C&pg=PA222. 
  38. ↑ 38.0 38.1 "Pharmacotherapy Considerations in the Management of Transgender Patients: A Brief Review". Pharmacotherapy 35 (12): 1130–9. December 2015. doi:10.1002/phar.1668. PMID 26684553. 
  39. ↑ "Role of cytochrome P450 in estradiol metabolism in vitro". Acta Pharmacol. Sin. 22 (2): 148–54. February 2001. PMID 11741520. 
  40. ↑ "Clinically used estrogens differentially inhibit human aortic smooth muscle cell growth and mitogen-activated protein kinase activity". Arterioscler. Thromb. Vasc. Biol. 20 (4): 964–72. 2000. doi:10.1161/01.atv.20.4.964. PMID 10764660. 
  41. ↑ "Actions of an estradiol-17-fatty acid ester in estrogen target tissues of the rat: comparison with other C-17 metabolites and a pharmacological C-17 ester". Endocrinology 124 (1): 318–24. January 1989. doi:10.1210/endo-124-1-318. PMID 2909371. 
  42. ↑ 42.0 42.1 42.2 42.3 42.4 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 898–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA898. 
  43. ↑ 43.0 43.1 "Injectable contraception. New and existing options". Obstet. Gynecol. Clin. North Am. 27 (4): 741–80. December 2000. doi:10.1016/S0889-8545(05)70171-6. PMID 11091987. 
  44. ↑ "Steroids". Medicinal Chemistry. Pearson Education India. 2007. p. 427. ISBN 978-81-317-0031-0. https://books.google.com/books?id=9HSoZrcBRl0C&pg=PA427. Retrieved 20 May 2012. 
  45. ↑ 45.0 45.1 "Long-acting contraceptive agents: design of the WHO Chemical Synthesis Programme". Steroids 41 (3): 243–253. March 1983. doi:10.1016/0039-128X(83)90095-8. PMID 6658872. 
  46. ↑ 46.0 46.1 46.2 "The effects of low doses of depot estradiol and testosterone in teenagers with ovarian failure and Turner's syndrome". J. Clin. Endocrinol. Metab. 37 (4): 574–80. October 1973. doi:10.1210/jcem-37-4-574. PMID 4742538. 
  47. ↑ 47.0 47.1 47.2 "The effects of prolonged physiologic estradiol therapy on the maturation of hypogonadal teen-agers". J Pediatr 85 (6): 830–7. December 1974. doi:10.1016/s0022-3476(74)80355-0. PMID 4370903. 
  48. ↑ 48.0 48.1 "Pharmacokinetics of once-a-month injectable contraceptives". Contraception 49 (4): 347–59. April 1994. doi:10.1016/0010-7824(94)90032-9. PMID 8013219. 
  49. ↑ 49.0 49.1 49.2 "Estradiol 17-beta-cyclopentylpropionate, a long-acting estrogen". Am. J. Obstet. Gynecol. 70 (1): 44–50. July 1955. doi:10.1016/0002-9378(55)90286-6. PMID 14388061. 
  50. ↑ "Estradiol cypionate | C26H36O3 | ChemSpider". http://www.chemspider.com/Chemical-Structure.9033.html. 
  51. ↑ Ott, A. C. (1952). U.S. Patent No. 2,611,773. Washington, DC: U.S. Patent and Trademark Office. https://patents.google.com/patent/US2611773A/en
  52. ↑ "Responses of the vaginal epithelium of postmenopausal women to single doses of estrogens". Journal of Gerontology 7 (4): 549–554. October 1952. doi:10.1093/geronj/7.4.549. PMID 13000121. 
  53. ↑ 53.0 53.1 53.2 "A comparison of the influence of alpha-estradiol dipropionate and of estradiol cyclopentylpropionate on the vaginal mucosa of nonmenstruating and irregularly menstruating women". American Journal of Obstetrics and Gynecology 66 (1): 178–181. July 1953. doi:10.1016/0002-9378(53)90300-7. PMID 13057994. 
  54. ↑ 54.0 54.1 54.2 "Estradiol cyclopentylpropionate: a new, long-acting, injectable estrogen". The Journal of Clinical Endocrinology and Metabolism 13 (10): 1279–1280. October 1953. doi:10.1210/jcem-13-10-1279. PMID 13096552. 
  55. ↑ "Estradiol 17-cyclopentyl-propionate". Missouri Medicine 50 (5): 345–346. May 1953. PMID 13072193. 
  56. ↑ "Conception control by monthly injections of medroxyprogesterone suspension and long-acting oestrogen". Journal of Reproduction and Fertility 15 (2): 209–214. March 1968. doi:10.1530/jrf.0.0150209. PMID 5643482. 
  57. ↑ Research and development, market power, and patent policy in ethical drugs. University of Wisconsin--Madison. 1969. p. 95. https://books.google.com/books?id=4vdsAAAAMAAJ. 
  58. ↑ "Die Behandlung der Amenorrhöe mit Hohen Dosen der Ovarialhormone". Klinische Wochenschrift 12 (40): 1557–1562. 1933. doi:10.1007/BF01765673. ISSN 0023-2173. 
  59. ↑ "Neue Wege der Hormontherapie in der Gynäkologie". Deutsche Medizinische Wochenschrift 60 (11): 389–393. 2009. doi:10.1055/s-0028-1129842. ISSN 0012-0472. 
  60. ↑ "Commercial Glandular Products". Journal of the American Medical Association 105 (9): 667. 1935. doi:10.1001/jama.1935.92760350007009a. ISSN 0002-9955. "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.". 
  61. ↑ 61.0 61.1 61.2 Pharmacology of the contraceptive steroids. Raven Press. 1994. p. 164. ISBN 978-0-7817-0097-9. https://books.google.com/books?id=bJRsAAAAMAAJ. 
  62. ↑ "Drug Product Database online query". 25 April 2012. https://health-products.canada.ca/dpd-bdpp/. 
  63. ↑ "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. 2009. p. 2082. ISBN 978-0-85369-840-1. 
  64. ↑ "Micromedex Products: Please Login". https://www.micromedexsolutions.com/micromedex2/librarian. Retrieved 21 April 2023. 
  65. ↑ IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; International Agency for Research on Cancer (1 January 1999). Hormonal Contraception and Post-menopausal Hormonal Therapy. IARC. p. 65. ISBN 978-92-832-1272-0. https://monographs.iarc.fr/wp-content/uploads/2018/06/mono72.pdf. 
  66. ↑ "Hormonal Contraception" (in en). Atlas of Contraception (Second ed.). CRC Press. 2008. p. 51. ISBN 9780203347324. https://books.google.com/books?id=7dDKBQAAQBAJ&pg=PA51. 
  67. ↑ IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. pp. 431–. ISBN 978-92-832-1291-1. https://books.google.com/books?id=aGDU5xibtNgC&pg=PA431. 
  68. ↑ "Still waiting for the contraceptive revolution". Fam Plann Perspect 27 (6): 246–53. 1995. doi:10.2307/2136177. PMID 8666089. 



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