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| Clinical data | |
|---|---|
| Trade names | Depofollan |
| Other names | E2-17-St; Estradiol octadecanoate; Estradiol 17β-stearate; Estradiol 17β-octadecanoate |
| Routes of administration | Intramuscular injection |
| Drug class | Estrogen;Estrogen ester |
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| Chemical and physical data | |
| Formula | C36H58O3 |
| Molar mass | 538.857 g·mol−1 |
| 3D model (JSmol) | |
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Estradiol stearate (E2-17-St), also known asestradiol octadecanoate and sold under the brand nameDepofollan, is anaturally occurringestrogen and anestrogen ester – specifically, the C17βstearateester ofestradiol.[1][2][3][4][5] It occurs in the body as a very long-lastingmetabolite andprohormone of estradiol.[5] The compound is one of the components that collectively constitutelipoidal estradiol, another of which isestradiol palmitate.[6][5] It is extremelylipophilic andhydrophobic.[5] Estradiol stearate has noaffinity for theestrogen receptor, requiringtransformation into estradiol viaesterases for its estrogenic activity.[7][8][9][5] The compound does not bind tosex hormone-binding globulin orα-fetoprotein, instead being transported bylipoproteins such ashigh-density lipoprotein andlow-density lipoprotein.[5]
Estradiol stearate has a prolonged duration of action relative to estradiol regardless of whether it is given byintravenous injection orsubcutaneous injection.[7] This is in contrast to short-chain fatty acid esters of estradiol, such asestradiol benzoate, which do not show a prolonged duration with intravenous injection.[10] When administered by intravenous injection in rodents, estradiol stearate has a greatly increasedterminal half-life relative to estradiol (6 hours vs. 2 minutes).[7] Estradiol stearate also had a half-life that was 60% longer than that of estradiol arachidonate, despite similar ester chain lengths.[7] In contrast to the long-chain esters, the half-lives of short-chain estradiol esters such asestradiol acetate and estradiol hexanoate were the same as that of estradiol.[7] As such, whereas short-chain estradiol esters are rapidlyhydrolyzed, long-chain estradiol esters like estradiol stearate are resistant tometabolism.[7] Thus, the prolongation of effect of short-chain estradiol esters is purely due to their increasedlipophilicity and slow release from the injected depot, whereas the prolonged duration of long-chain estradiol esters is due both to this property and to their resistance to metabolism.[7] Estradiol stearate is susceptible tofirst-pass metabolism in theliver, and hence has much greater potency by subcutaneous injection than byoral administration.[7]
In addition to itsendogenous role, estradiol stearate was previously available as apharmaceutical drug for use viadepotintramuscular injection.[1][2] The medication was introduced between 1938 and 1941 under the brand name Depofollan.[11][12] It has been used to treatprostate cancer.[13][14] Estradiol stearate is a long-acting estrogen[15][12] and is said to have been the first long-acting estrogen used in medicine, although it was never widely employed.[12] It was reported to have aduration of more than one month.[12] The medication was provided as anoil solution inampoules containing 15 mg estradiol stearate.[15][14] It was manufactured by Chinoin, aHungarianpharmaceutical company.[15][14][11][16] The compound was studied by Karl Miescher in 1938[17] and waspatented by Miescher and Chinoin in 1939 and 1941, respectively.[18][19] A similar clinically used long-acting estradiol ester isestradiol undecylate, which has 11carbonatoms instead of the 18 carbon atoms in estradiol stearate.[1][2]
| Estrogen | Other names | RBATooltip Relative binding affinity (%)a | REP (%)b | |||
|---|---|---|---|---|---|---|
| ER | ERα | ERβ | ||||
| Estradiol | E2 | 100 | 100 | 100 | ||
| Estradiol 3-sulfate | E2S; E2-3S | ? | 0.02 | 0.04 | ||
| Estradiol 3-glucuronide | E2-3G | ? | 0.02 | 0.09 | ||
| Estradiol 17β-glucuronide | E2-17G | ? | 0.002 | 0.0002 | ||
| Estradiol benzoate | EB; Estradiol 3-benzoate | 10 | 1.1 | 0.52 | ||
| Estradiol 17β-acetate | E2-17A | 31–45 | 24 | ? | ||
| Estradiol diacetate | EDA; Estradiol 3,17β-diacetate | ? | 0.79 | ? | ||
| Estradiol propionate | EP; Estradiol 17β-propionate | 19–26 | 2.6 | ? | ||
| Estradiol valerate | EV; Estradiol 17β-valerate | 2–11 | 0.04–21 | ? | ||
| Estradiol cypionate | EC; Estradiol 17β-cypionate | ?c | 4.0 | ? | ||
| Estradiol palmitate | Estradiol 17β-palmitate | 0 | ? | ? | ||
| Estradiol stearate | Estradiol 17β-stearate | 0 | ? | ? | ||
| Estrone | E1; 17-Ketoestradiol | 11 | 5.3–38 | 14 | ||
| Estrone sulfate | E1S; Estrone 3-sulfate | 2 | 0.004 | 0.002 | ||
| Estrone glucuronide | E1G; Estrone 3-glucuronide | ? | <0.001 | 0.0006 | ||
| Ethinylestradiol | EE; 17α-Ethynylestradiol | 100 | 17–150 | 129 | ||
| Mestranol | EE 3-methyl ether | 1 | 1.3–8.2 | 0.16 | ||
| Quinestrol | EE 3-cyclopentyl ether | ? | 0.37 | ? | ||
| Footnotes:a =Relative binding affinities (RBAs) were determined viain-vitro displacement oflabeledestradiol fromestrogen receptors (ERs) generally ofrodentuterinecytosol.Estrogen esters are variablyhydrolyzed into estrogens in these systems (shorter ester chain length -> greater rate of hydrolysis) and the ER RBAs of the esters decrease strongly when hydrolysis is prevented.b = Relative estrogenic potencies (REPs) were calculated fromhalf-maximal effective concentrations (EC50) that were determined viain-vitroβ‐galactosidase (β-gal) andgreen fluorescent protein (GFP)productionassays inyeast expressing humanERα and humanERβ. Bothmammaliancells and yeast have the capacity to hydrolyze estrogen esters.c = The affinities ofestradiol cypionate for the ERs are similar to those ofestradiol valerate andestradiol benzoate (figure).Sources: See template page. | ||||||
| Estrogen | Structure | Ester(s) | Relative mol. weight | Relative E2 contentb | log Pc | ||||
|---|---|---|---|---|---|---|---|---|---|
| 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 | 4.2 | |
| Estradiol benzoate |  | C3 | Benzoic 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 | Cyclic 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 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 ofester incarbonatoms forstraight-chain fatty acids or approximate length of ester in carbon atoms foraromatic orcyclic fatty acids.b = Relative estradiol content by weight (i.e., relativeestrogenic exposure).c = Experimental or predictedoctanol/water partition coefficient (i.e.,lipophilicity/hydrophobicity). Retrieved fromPubChem,ChemSpider, andDrugBank.d = Also known asestradiol normustine phosphate.e =Polymer ofestradiol phosphate (~13repeat 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. | |||||||||
Estra-1,3,5(10)-triene-3,173-diol 17-octadecanoate = 3,173-Estradiol 17-stearate = (173)-Estra-1,3,5- (10)-triene-3,17-diol 17-octadecanoate (e) S Depofollan, Estradiol stearate, Ostradiolstearat U Depot-estrogen 8103
From the middle of the vitamin D and hannincas years, the research and production of steroid sex hormones was directed by Rezső Weisz. (n) In the latter, the collection of animal raw materials, in addition to chemical operations, required considerable organizational work similar to that of insulin. The intensification of attempts to produce steroid hormones and synthetic steroids, estrogens, over four years may have surpassed even 36 studies of sulfone JDid. Weisz et al., Primarily Kálmán Lányi, developed the most important estrone derivatives of industrial and therapeutic interest, Hogival (estrone acetate), Acrafalin (estradiol propionate) and Depofollan (estradiol stearate), which were marketed in 1938-1940.
Chinoin has achieved good results in the steroid hormones, synthetic steroids, and estrogens since the twenties, protected by 36 patents. The company was one of the first in the world to produce vitamin D, but was also a successful product for Hogival (estrone acetate), Acrofollin (estradiol propionate), Depofollan (estradiol stearate), Acrolutin (progesterone).
