Estradiol stearate

Estradiol stearate (E2-17-St), also known as estradiol octadecanoate and sold under the brand name Depofollan, is a naturally occurring estrogen and an estrogen ester – specifically, the C17β stearate ester of estradiol.^{[1][2][3][4][5]} It occurs in the body as a very long-lasting metabolite and prohormone of estradiol.^[5] The compound is one of the components that collectively constitute lipoidal estradiol, another of which is estradiol palmitate.^[6][5] It is extremely lipophilic and hydrophobic.^[5] Estradiol stearate has no affinity for the estrogen receptor, requiring transformation into estradiol via esterases for its estrogenic activity.^[7][8][9][5] The compound does not bind to sex hormone-binding globulin or α-fetoprotein, instead being transported by lipoproteins such as high-density lipoprotein and low-density lipoprotein.^[5]

Estradiol stearate

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
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] octadecanoate
CAS Number	82205-00-3 Y
PubChem CID	67100
ChemSpider	60448
UNII	59G2KR8QBG
CompTox Dashboard (EPA)	DTXSID401002548
Chemical and physical data
Formula	C36H58O3
Molar mass	538.857 g·mol−1
3D model (JSmol)	Interactive image
SMILES CCCCCCCCCCCCCCCCCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
InChI InChI=1S/C36H58O3/c1-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-35(38)39-34-24-23-33-32-21-19-28-27-29(37)20-22-30(28)31(32)25-26-36(33,34)2/h20,22,27,31-34,37H,3-19,21,23-26H2,1-2H3/t31-,32-,33+,34+,36+/m1/s1 Key:KIADYVOYCQRXRE-IMTRJTTHSA-N

Estradiol stearate has a prolonged duration of action relative to estradiol regardless of whether it is given by intravenous injection or subcutaneous injection.^[7] This is in contrast to short-chain fatty acid esters of estradiol, such as estradiol benzoate, which do not show a prolonged duration with intravenous injection.^[10] When administered by intravenous injection in rodents, estradiol stearate has a greatly increased terminal 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 as estradiol acetate and estradiol hexanoate were the same as that of estradiol.^[7] As such, whereas short-chain estradiol esters are rapidly hydrolyzed, long-chain estradiol esters like estradiol stearate are resistant to metabolism.^[7] Thus, the prolongation of effect of short-chain estradiol esters is purely due to their increased lipophilicity 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 to first-pass metabolism in the liver, and hence has much greater potency by subcutaneous injection than by oral administration.^[7]

In addition to its endogenous role, estradiol stearate was previously available as a pharmaceutical drug for use via depot intramuscular injection.^[1][2] The medication was introduced between 1938 and 1941 under the brand name Depofollan.^[11][12] It has been used to treat prostate 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 a duration of more than one month.^[12] The medication was provided as an oil solution in ampoules containing 15 mg estradiol stearate.^[15][14] It was manufactured by Chinoin, a Hungarian pharmaceutical company.^{[15][14][11][16]} The compound was studied by Karl Miescher in 1938^[17] and was patented by Miescher and Chinoin in 1939 and 1941, respectively.^[18][19] A similar clinically used long-acting estradiol ester is estradiol undecylate, which has 11 carbon atoms instead of the 18 carbon atoms in estradiol stearate.^[1][2]

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Affinities and estrogenic potencies of estrogen esters and ethers at the estrogen receptors

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 via in-vitro displacement of labeled estradiol from estrogen receptors (ERs) generally of rodent uterine cytosol. Estrogen esters are variably hydrolyzed 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 from half-maximal effective concentrations (EC50) that were determined via in-vitro β‐galactosidase (β-gal) and green fluorescent protein (GFP) production assays in yeast expressing human ERα and human ERβ. Both mammalian cells and yeast have the capacity to hydrolyze estrogen esters. c = The affinities of estradiol cypionate for the ERs are similar to those of estradiol valerate and estradiol benzoate (figure). Sources: See template page.

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Structural properties of selected estradiol esters

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 of ester in carbon atoms for straight-chain fatty acids or approximate length of ester in carbon atoms for aromatic or cyclic 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.

See also

• List of estrogen esters § Estradiol esters