Estradiol enantate

Estradiol enantate
Clinical data
Trade namesPerlutal, Topasel, Unalmes, Yectames, others
Other namesEE; E2E; E2-EN; EEn; Estradiol enanthate; Estradiol heptanoate; SQ-16150
Routes of
administration		Intramuscular injection[1][2]
Drug classEstrogen; Estrogen ester
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityIM: High
Protein bindingEstradiol: ~98% (to albumin and SHBG)[3][4]
MetabolismCleavage via esterases in the liver, blood, and tissues[5][6]
MetabolitesEstradiol, heptanoic acid, and metabolites of estradiol[5][6]
Elimination half-lifeIM: 5.6–7.5 days[7][1][8][9]
Duration of actionIM (10 mg): ~20–30 days[10][5]
ExcretionUrine[1]
Identifiers
IUPAC name
  • [(8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] heptanoate
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.023.272
Edit this at Wikidata
Chemical and physical data
FormulaC25H36O3
Molar mass384.560 g·mol−1
3D model (JSmol)
SMILES
  • CCCCCCC(=O)O[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CCC4=C3C=CC(=C4)O)C
InChI
  • InChI=1S/C25H36O3/c1-3-4-5-6-7-24(27)28-23-13-12-22-21-10-8-17-16-18(26)9-11-19(17)20(21)14-15-25(22,23)2/h9,11,16,20-23,26H,3-8,10,12-15H2,1-2H3/t20-,21-,22+,23+,25+/m1/s1
  • Key:RFWTZQAOOLFXAY-BZDYCCQFSA-N

Estradiol enantate (E2-EN or EEn), also spelled estradiol enanthate and sold under the brand names Perlutal and Topasel among others, is an estrogen medication which is used in hormonal birth control for women.[1][2][11] It is formulated in combination with dihydroxyprogesterone acetophenide (DHPA; algestone acetophenide), a progestin, and is used specifically as a combined injectable contraceptive.[1][2] Estradiol enantate is not available for medical use alone.[12][13][14][15] The medication, in combination with DHPA, is given by injection into muscle once a month.[1][2]

Side effects of estradiol enantate include breast tenderness, breast enlargement, nausea, headache, and fluid retention.[16] Estradiol enantate is a synthetic estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol.[6][5] It is an estrogen ester and a long-lasting prodrug of estradiol in the body.[5][6] Because of this, it is considered to be a natural and bioidentical form of estrogen.[5][17]

Estradiol enantate was first described by 1954,[18] and was first studied in combination with DHPA as a combined injectable contraceptive in 1964.[19][20] The combination was introduced for clinical use by the mid-1970s.[21][22][23] Estradiol enantate is not available as a standalone medication (i.e., by itself without DHPA).[15] The combination is available in Latin America and Hong Kong, and was also previously marketed in Spain and Portugal.[15][2][13]

Medical uses

Estradiol enantate is used in combination with the progestin DHPA as a once-monthly combined injectable contraceptive for women in Latin America and Hong Kong.[1][2][24][15] Estradiol enantate has been studied in feminizing hormone therapy for transgender women as well.[25] The combination of estradiol enantate and DHPA has likewise been used by transgender women for such purposes.[26]

Available forms

The following forms of estradiol enantate are or have been available for use:[11][27][28][23][2]

  • Estradiol enantate 10 mg and DHPA 150 mg (brand names Perlutal, Topasel, many others)
  • Estradiol enantate 5 mg and DHPA 75 mg (brand names Anafertin, Patector NF, Yectames)
  • Estradiol enantate 10 mg and DHPA 120 mg (brand names Unalmes, Yectuna)
  • Estradiol enantate 10 mg and DHPA 75 mg (brand name Ova Repos; discontinued)

A 6 mg estradiol enantate and 90 mg DHPA formulation was also studied, but was never marketed.[29][30][31] The combination of estradiol enantate and DHPA has also been studied at other doses ranging from 5 to 50 mg estradiol enantate and 75 to 200 mg DHPA.[32]

The combination of estradiol enantate and DHPA is provided in ampoules at estradiol enantate concentrations of 5 mg/mL and 10 mg/mL.

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 enantate are the same as those of estradiol. Examples of such side effects include breast tenderness and enlargement, nausea, bloating, edema, headache, and melasma.[16] The combination of estradiol enantate and DHPA as a combined injectable contraceptive has shown no adverse effects on liver function, lipid metabolism, or coagulation.[37][2]

A Brazilian case report of a prolactinoma in a transgender woman treated with 10 mg estradiol enantate every 2 weeks exists.[38][39] While DHPA was not mentioned in this instance,[38][39] estradiol enantate is normally formulated in combination with DHPA including in Brazil.[12][14]

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.[40]

Pharmacology

Estradiol, the active form of estradiol enantate.

Pharmacodynamics

Estradiol enantate is an estradiol ester, or a prodrug of estradiol.[5][6] As such, it is an estrogen, or an agonist of the estrogen receptors.[5][6] Estradiol enantate is of about 41% higher molecular weight than estradiol due to the presence of its C17β enantate ester.[41][15] Because estradiol enantate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.[5][17]

The combination of 10 mg estradiol enantate and 150 mg DHPA as a once-monthly combined injectable contraceptive (which achieves levels of estradiol of around 350 pg/mL)[10][42][43] has been found to have little to no effect on many markers of estrogen-modulated liver protein synthesis, including circulating levels of HDL and LDL cholesterol, copper, ceruloplasmin, total and free cortisol, corticosteroid-binding globulin, and sex hormone-binding globulin.[44][45] However, it was found to significantly increase levels of triglycerides and to significantly decrease levels of total and free testosterone.[45] In contrast to the estradiol enantate-containing combined injectable contraceptive, low-dose ethinylestradiol-containing birth control pills produce highly significant changes in all of the preceding parameters.[44][45]

Studies in women and female capuchin monkeys have found that injections of estradiol enantate and DHPA significantly alter levels of coagulation factors.[46][47]

The clinical estrogenic effects of estradiol enantate and ethinylestradiol have been compared in other studies as well.[48]

Potencies and durations of natural estrogens by intramuscular injection
EstrogenFormDose (mg)Duration by dose (mg)
EPDCICD
EstradiolAq. soln. ?–<1 d
Oil soln.40–60–1–2 ≈ 1–2 d
Aq. susp. ?3.50.5–2 ≈ 2–7 d; 3.5 ≈ >5 d
Microsph. ?–1 ≈ 30 d
Estradiol benzoateOil soln.25–35–1.66 ≈ 2–3 d; 5 ≈ 3–6 d
Aq. susp.20–10 ≈ 16–21 d
Emulsion ?–10 ≈ 14–21 d
Estradiol dipropionateOil soln.25–30–5 ≈ 5–8 d
Estradiol valerateOil soln.20–3055 ≈ 7–8 d; 10 ≈ 10–14 d;
40 ≈ 14–21 d; 100 ≈ 21–28 d
Estradiol benz. butyrateOil soln. ?1010 ≈ 21 d
Estradiol cypionateOil soln.20–30–5 ≈ 11–14 d
Aq. susp. ?55 ≈ 14–24 d
Estradiol enanthateOil soln. ?5–1010 ≈ 20–30 d
Estradiol dienanthateOil soln. ?–7.5 ≈ >40 d
Estradiol undecylateOil soln. ?–10–20 ≈ 40–60 d;
25–50 ≈ 60–120 d
Polyestradiol phosphateAq. soln.40–60–40 ≈ 30 d; 80 ≈ 60 d;
160 ≈ 120 d
EstroneOil soln. ?–1–2 ≈ 2–3 d
Aq. susp. ?–0.1–2 ≈ 2–7 d
EstriolOil soln. ?–1–2 ≈ 1–4 d
Polyestriol phosphateAq. soln. ?–50 ≈ 30 d; 80 ≈ 60 d
Notes and sources
Notes: All aqueous suspensions are of microcrystalline particle size. Estradiol production during the menstrual cycle is 30–640 µg/d (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

When estradiol enantate is administered in an oil solution by intramuscular injection, a depot effect occurs, and this results in it having a long duration of action.[10][6][49] The duration of action of estradiol enantate is considerably longer than that of various other estradiol esters, such as estradiol benzoate, estradiol valerate, and estradiol cypionate, whereas its duration is shorter than that of estradiol undecylate.[10][50][51] In general, the longer the fatty acid ester chain, the more lipophilic the estradiol ester, the more slowly it is released from the depot and absorbed into the circulation, and the longer its duration of action.[6][49]

The pharmacokinetics of estradiol enantate have been assessed in a number of studies.[10][52][42][7][43][53] It has usually been studied in combination with DHPA.[10][52][42][43] Following an intramuscular injection of estradiol enantate, levels of estradiol have been found to peak after 3 to 8 days.[10][43][7] Maximal levels of estradiol after a 5 mg injection of estradiol enantate have been found to be about 163 to 209 pg/mL and after a 10 mg injection of estradiol enantate have been found to be about 283 to 445 pg/mL.[10][42][43] However, one outlying study reported peak estradiol levels of 850 pg/mL after an intramuscular injection of 10 mg estradiol enantate in three postmenopausal women.[7] It used radioimmunoassay for the determinations, with no mention of chromatographic separation.[7] Estradiol levels following an intramuscular injection of 10 mg estradiol enantate have been found to return to baseline levels of around 50 pg/mL after about 20 to 30 days.[42][7][5][53][10] However, a metabolic study found that traces of radiolabeled estradiol enantate remained detectable in blood for at least 30 to 40 days and for as long as 60 days.[52] Studies have reported that the elimination half-life of estradiol enantate after a single 10 mg intramuscular injection was 5.6 to 7.5 days.[7][1][8] The volume of distribution of estradiol enantate has been reported to be 5.087 L.[9] Estradiol enantate is excreted preferentially in urine.[22]

There were concerns about possible accumulation of estradiol enantate and consequent estrogenic overexposure with once-monthly combined injectable contraceptives containing the medication due its long duration, and this may have limited the use of such combined injectable contraceptives.[8][10] Subsequent clinical studies have found that there is very limited or no accumulation of estradiol enantate when it is used in once-a-month injectable contraceptives.[8][37][2]

Chemistry

Estradiol enantate, also known as estradiol 17β-enantate or estra-1,3,5(10)-triene-3,17β-diol 17β-heptanoate, is a synthetic estrane steroid and the C17β enantate (heptanoate) fatty acid ester of estradiol.[41][15] Other common esters of estradiol used clinically include estradiol benzoate, estradiol cypionate, estradiol undecylate, and estradiol valerate.[15] Estradiol dienantate (component of Climacteron), or estradiol 3,17β-dienantate, has also been used.[41][54][55][56]

The experimental octanol/water partition coefficient (logP) of estradiol enanthate is 6.7.[57]

Structural properties of selected estradiol esters
EstrogenStructureEster(s)Relative
mol. weight		Relative
E2 contentb		log Pc
Position(s)Moiet(ies)TypeLengtha
Estradiol
––––1.001.004.0
Estradiol acetate
C3Ethanoic acidStraight-chain fatty acid21.150.874.2
Estradiol benzoate
C3Benzenecarboxylic acidAromatic fatty acid– (~4–5)1.380.724.7
Estradiol dipropionate
C3, C17βPropanoic acid (×2)Straight-chain fatty acid3 (×2)1.410.714.9
Estradiol valerate
C17βPentanoic acidStraight-chain fatty acid51.310.765.6–6.3
Estradiol benzoate butyrate
C3, C17βBenzoic acid, butyric acidMixed fatty acid– (~6, 2)1.640.616.3
Estradiol cypionate
C17βCyclopentylpropanoic acidAromatic fatty acid– (~6)1.460.696.9
Estradiol enanthate
C17βHeptanoic acidStraight-chain fatty acid71.410.716.7–7.3
Estradiol dienanthate
C3, C17βHeptanoic acid (×2)Straight-chain fatty acid7 (×2)1.820.558.1–10.4
Estradiol undecylate
C17βUndecanoic acidStraight-chain fatty acid111.620.629.2–9.8
Estradiol stearate
C17βOctadecanoic acidStraight-chain fatty acid181.980.5112.2–12.4
Estradiol distearate
C3, C17βOctadecanoic acid (×2)Straight-chain fatty acid18 (×2)2.960.3420.2
Estradiol sulfate
C3Sulfuric acidWater-soluble conjugate–1.290.770.3–3.8
Estradiol glucuronide
C17βGlucuronic acidWater-soluble conjugate–1.650.612.1–2.7
Estramustine phosphated
C3, C17βNormustine, phosphoric acidWater-soluble conjugate–1.910.522.9–5.0
Polyestradiol phosphatee
C3–C17βPhosphoric acidWater-soluble conjugate–1.23f0.81f2.9g
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 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 = log P of repeat unit (i.e., estradiol phosphate). Sources: See individual articles.

History

Estradiol enantate was first described, along with a variety of other estradiol esters, by Karl Junkmann of Schering AG in 1953.[58][18][59][60][51][61][62] The first clinical study of estradiol enantate and DHPA as a combined injectable contraceptive was conducted in 1964.[19][20] The combination was marketed by the mid-1970s.[21][22][23]

Society and culture

Generic names

Estradiol enantate is the British English generic name of the medication and its INNM and BANM, while estradiol enanthate is its USAN and American English generic name.[41][15][12][63] Its generic names in other languages are as follows:[13][12]

  • French: enantate d'estradiol and estradiol enantate
  • German: estradiol enantat
  • Italian: estradiolo enantato
  • Portuguese and Spanish: enantato de estradiol and estradiol enantato

Estradiol enantate is also known by its former developmental code name SQ-16150.[64] It has been referred to as estradiol heptanoate.[15][41][14][12][13]

Brand names

Estradiol enantate has been marketed under a wide variety of brand names.[13][12][65][66][11][67][28][68][23][2][10] It has been marketed in a few different preparations, with varying doses of estradiol enantate and DHPA.[28][11][67][27][23][2][10] These formulations all have different brand names, which include the following († = discontinued):[13][12][65][66][27][28][11][67][2][69]

  • E2-EN 10 mg / DHPA 150 mg: Acefil, Agurin†, Atrimon†, Ciclomes, Ciclovar, Ciclovular, Cicnor†, Clinomin, Cycloven, Daiva, Damix, Deprans, Deproxone, Exuna, Ginestest, Ginoplan†, Gynomes, Horprotal, Listen, Luvonal, Neogestar, Neolutin, Nomagest, Nonestrol, Normagest, Normensil, Novular, Oterol, Ovoginal, Patector, Patectro, Perludil, Perlumes, Perlutal, Perlutale, Perlutan, Perlutin, Perlutin-Unifarma, Permisil, Preg-Less, Pregnolan, Progestrol†, Protegin, Proter, Seguralmes, Synovular, Topasel, Unigalen, Uno-Ciclo, and Vagital.
  • E2-EN 10 mg / DHPA 120 mg: Anafertin†, Patector NF, and Yectames.
  • E2-EN 5 mg / DHPA 75 mg: Unalmes and Yectuna.
  • E2-EN 10 mg / DHPA 75 mg: Ova Repos†.
  • Unsorted: Evitas†, Femineo†, and Primyfar†.

The combination of E2-EN 10 mg and DHPA 150 mg was developed under the developmental brand name Deladroxate, but this brand name was never used commercially.[23][2]

Availability

Known availability of estradiol enantate in countries throughout the world (as of September 2018).

Estradiol enantate (E2-EN) has been marketed in combination with DHPA as a combined injectable contraceptive in at least 19 countries, mostly in Latin America.[11][67][28][68][13][12][65][66] A few different preparations, with varying doses of E2-EN and DHPA and varying availability, have been introduced.[28][11][67][27][23][2][10] These formulations have the following approval and availability († = discontinued in this country):[13][12][65][66][27][28][11][67][2]

  • E2-EN 10 mg / DHPA 150 mg: at least 19 countries, including Argentina, Belize, Brazil, Chile, Colombia, Costa Rica, the Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Hong Kong, Mexico, Nicaragua, Panama, Paraguay, Peru, Portugal†, and Spain†.
  • E2-EN 10 mg / DHPA 120 mg: at least 3 countries, including Brazil†, Chile, and Paraguay.
  • E2-EN 5 mg / DHPA 75 mg: at least 9 countries, including Costa Rica, the Dominican Republic, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, and Spain†.

E2-EN is also available in Canada in combination with estradiol benzoate and testosterone enantate for veterinary use as Uni-Bol.[70]

Usage

E2-EN/DHPA is the most widely used combined injectable contraceptive in Latin America.[71] It was estimated in 1995 that E2-EN/DHPA was used as a combined injectable contraceptive in Latin America by at least 1 million women.[28] However, combined injectable contraceptives like E2-EN/DHPA are unlikely to constitute a large proportion of total contraceptive use in the countries in which they are available.[28]

See also

References

  1. 1 2 3 4 5 6 7 8 Jarquín González JD, Elda de Aguirre L, Rodríguez C, Abrego de Aguilar M, Carrillo F, León DA, Lima M, Trigueros S, Acosta R (September 1996). "Dihydroxyprogesterone acetophenide 150 mg + estradiol enantate 10 mg as monthly injectable contraceptives". Adv Contracept. 12 (3): 213–25. doi:10.1007/BF01849664. PMID 8910663. S2CID 2522426.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Newton JR, D'arcangues C, Hall PE (1994). "A review of "once-a-month" combined injectable contraceptives". J Obstet Gynaecol (Lahore). 4 Suppl 1: S1–34. doi:10.3109/01443619409027641. PMID 12290848.
  3. ↑ 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.
  4. ↑ Tommaso Falcone; William W. Hurd (2007). Clinical Reproductive Medicine and Surgery. Elsevier Health Sciences. pp. 22, 362, 388. ISBN 978-0-323-03309-1.
  5. 1 2 3 4 5 6 7 8 9 10 Michael Oettel; Ekkehard Schillinger (6 December 2012). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. pp. 261, 271. 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. [...] Wiemeyer et al. (1986) measured elevated estradiol levels up to 31 days after an intramuscular dose of 10mg estradiol enanthate.
  6. 1 2 3 4 5 6 7 8 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. S2CID 24616324.
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  9. 1 2 "Bula do Algestona Acetofenida + Enantato de Estradiol". Consulta Remédios. Archived from the original on 2018-09-18. Retrieved 2018-09-18.
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  20. 1 2 Taymor ML, Planck S, Yahia C (1964). "Ovulation Inhibition with a Long-acting Parenteral Progestogen-Estrogen Combination". Fertil. Steril. 15 (6): 653–60. doi:10.1016/s0015-0282(16)35411-5. PMID 14236842.
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  26. ↑ Don Kulick (12 January 2009). Travesti: Sex, Gender, and Culture among Brazilian Transgendered Prostitutes. University of Chicago Press. pp. 64–66. ISBN 978-0-226-46101-4.
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  29. ↑ d’Arcangues, Catherine; Snow, Rachel C. (1999). Injectable Contraceptives. In: Fertility Control — Update and Trends. pp. 121–149. doi:10.1007/978-3-642-86696-8_6.
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  51. 1 2 Percy Roberts Wilde; Carey Franklin Coombs; Arthur J. Rendle Short (1959). The Medical Annual: A Year Book of Treatment and Practitioner's Index ... Publishing Science Group. As in the case of progestogens the esters of oestradiol vary in the duration of their effect. Oestradiol benzoate is short-acting (three days to a week). Oestradiol valerianate is somewhat longer-acting, and oestradiol enanthate and undecylate have considerably more prolonged duration of effectiveness. The undecylate may remain effective for some months, and should not be employed, [...]
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  58. ↑ 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. ISSN 0028-1298. S2CID 20753905.
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  60. ↑ Acta Cytologica. International Academy of Cytology. 1958. p. 378.
  61. ↑ Gauthier, B; Le Dreff, L; Aubry, R (1958). "Hormone derivatives of long-lasting action. I. Esters of estradiol". Annales Pharmaceutiques Françaises. 16: 757–66. ISSN 0003-4509. Treating 10 g. estradiol benzoate in 30 cc.dry C5H5N dropwise with 4.3 g. n-C6H13COCl (b20 71-2°), heating 1 hr. at 50-60°, pouring into 100 cc. 10% H2SO4, sepg. the oil after its solidification, washing with petr. ether, heating with 50 cc. MeOH, and cooling gave 10 g. 17-heptoyl-3β-benzoylestradiol, m. 95-8°. Dissolving 10 g. of this in 210 cc. 0.1N NaOH in MeOH and 40 cc. Me2CO with stirring, adding HCl to pH 7, filtering, evapg. in vacuo, and stirring the residue with petr. ether gave 7.9 g. 17-heptoyl-β-estradiol, m. 94-6° (iso-Pr2O). Adding to 5 g. estradiol stirred in 10 cc. anhyd. pyridine 8 g. n-C10H21COCl (b20 135-6°), keeping 1 hr. at 100°, cooling, adding 50 cc. 10% H2SO4, dissolving the sepd. ester in 50 cc. iso-Pr2O, washing with satd. NaHCO3 soln. and H2O, drying, and evapg. at room temp. gave 10.7 g. 3,17-diundecanoylestradiol, m. 48-9° (MeOH-Me2CO, then Me2O-Et2O), λmax. (0.005% in MeOH contg. 4% iso-Pr2O) 268 mμ, λmin. 282 and 250 mμ, inflexion 215 mμ. Stirring 8.8 g. estradiol divalerate in 90 cc. MeOH and 0.4 g. NaOH under N 210 min. to soln., adding 20% HCl to pH 7, evapg. in vacuo to 10 cc., keeping overnight at a low temp., and washing with H2O, MeOH, and petr. ether gave 4.4 g. 17-valeryl-β-estradiol, m. 145-6°, λmax. (0.005% in EtOH) 282 mμ, λmin. 248 mμ, inflexion 215 mμ. A single dose of 25 mg. of the diundecanate gave a therapeutic effect lasting 3 weeks.
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  66. 1 2 3 4 "Progestin Oral, Parenteral, Vaginal Advanced Patient Information".
  67. 1 2 3 4 5 6 Pramilla Senanayake; Malcolm Potts (14 April 2008). Atlas of Contraception, Second Edition. CRC Press. pp. 50–. ISBN 978-0-203-34732-4.
  68. 1 2 Thomas Rabe; Benno Runnebaum (6 December 2012). Fertility Control — Update and Trends: Update and Trends. Springer Science & Business Media. pp. 183–. ISBN 978-3-642-86696-8. Two additional monthly, combined injectable methods warrant mention. Deladroxate (commercially labelled as Perlutan, Topasel, Agurin, Horprotal and Uno-Ciclo in various countries), is a combination of 150 mg dihydroxyprogesterone acetophenide and 10 mg estradiol enanthate, and is available in many Latin American countries and Spain. The method is highly effective, without a single pregnancy reported in large clinical trials (Koetsawang 1994). Although available since the 1960s, the method has not been studied as extensively as Cyclofem or Mesigyna. The original manufacturer withdrew support due to toxicological concerns with dihydroxyprogesterone acetophenide, and clinical evaluations continue to be published. A recent dose-finding trial compared the standard available dose of 150/10 with a lower dose of 90/6, and concluded the lower dose was equally effective (Coutinho et al., 1997).
  69. ↑ Gallo MF, Grimes DA, Lopez LM, Schulz KF, d'Arcangues C (2013). "Combination injectable contraceptives for contraception". Cochrane Database Syst Rev. 3: CD004568. doi:10.1002/14651858.CD004568.pub3. PMC 6513542. PMID 23641480.
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  71. ↑ Leon Speroff; Marc A. Fritz (2005). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. pp. 969–. ISBN 978-0-7817-4795-0.
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