 | |
 Skeletal structure of polyestradiol phosphate (top) andball-and-stick model ofestradiol phosphate (onemonomer of polyestradiol phosphate) (bottom) | |
| Clinical data | |
|---|---|
| Trade names | Estradurin, Estradurine |
| Other names | PEP; Polymeric estradiol phosphate; Polymeric estradiol 17β-phosphate; Estradiol phosphate polymer; Estradiol 17β-phosphate polymer; Estradiol polymer with phosphoric acid; Leo-114 |
| AHFS/Drugs.com | International Drug Names |
| Pregnancy category |
|
| Routes of administration | Intramuscular injection[1][2] |
| Drug class | Estrogen;Estrogen ester |
| ATC code | |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Bioavailability | IM: High |
| Protein binding | Estradiol: ~98% (toalbumin andSHBGTooltip sex hormone-binding globulin)[3][4][1] |
| Metabolism | Mainly in theliver, to a lesser extent in thekidneys,gonads, andmuscle (byphosphatases)[1] |
| Metabolites | Estradiol,phosphoric acid, andmetabolites of estradiol[5][6] |
| Eliminationhalf-life | PEP: 70 days (10 weeks)[7] Estradiol: 1–2 hours[8] |
| Excretion | Urine (asconjugates)[1] |
| Identifiers | |
| |
| CAS Number | |
| PubChem SID | |
| DrugBank |
|
| ChemSpider |
|
| UNII | |
| KEGG |
|
| ChEMBL | |
| Chemical and physical data | |
| Formula | (C18H23O4P)n (n = variable;n = 13) |
| Molar mass | Polymer: Variable Repeat unit: 334.347 g/mol |
| Melting point | 195 to 202 °C (383 to 396 °F) |
| (verify) | |
Polyestradiol phosphate (PEP), sold under the brand nameEstradurin, is anestrogen medication which is used primarily in the treatment ofprostate cancer in men.[1][9][2][10] It is also used in women to treatbreast cancer, as a component ofhormone therapy to treatlow estrogen levels andmenopausalsymptoms, and as a component offeminizing hormone therapy fortransgender women.[1][11] It is given byinjection into muscle once every four weeks.[1][2][12]
Commonside effects of PEP includeheadache,breast tenderness,breast development,feminization,sexual dysfunction,infertility, andvaginal bleeding.[1][2] PEP is anestrogen and hence is anagonist of theestrogen receptor, thebiological target ofestrogens likeestradiol.[2][6][5] It is anestrogen ester in the form of apolymer and is an extremely long-lastingprodrug ofestradiol in the body.[2][12][5][6] Thebiological half-life of PEP is more than two months.[7] Because PEP works by being converted into estradiol, it is considered to be anatural andbioidentical form of estrogen.[5][2] Thesafety profile ofparenteral estradiol esters like PEP is greatly improved relative tosyntheticoral estrogens likeethinylestradiol anddiethylstilbestrol.[2]
PEP was discovered around 1953 and was introduced for medical use in theUnited States in 1957.[12][13][14] Along withestradiol undecylate andestradiol valerate, it has been frequently used in the United States andEurope as a parenteral form of estrogen to treat men with prostate cancer.[15] However, it is no longer available in the United States.[13][16]
PEP is used as anintramuscular injection forestrogen therapy of prostate cancer in men.[1][2] It is also used to treatbreast cancer in women who are at least 5 yearspostmenopausal.[1][17][18] In addition, PEP is used inhormone replacement therapy forlow estrogen levels due tohypogonadism ormenopause in women.[1] It is also used infeminizing hormone therapy fortransgender women.[11][19] PEP is a form ofhigh-dose estrogen therapy.[2] After an injection, it very slowly releases the active agentestradiol over at least several months.[20][7]
PEP has been compared tocombined androgen blockade (CAB;castration plusflutamide) for the treatment of prostate cancer in a large randomizedclinical trial of 915 patients.[21][22] At 18.5 months, there was no difference insurvival orcardiovascular toxicity between the two treatment modalities.[21][22] These findings suggest thatparenteral forms of estradiol may have similareffectiveness andsafety relative toandrogen deprivation therapy (ADT) in the treatment of prostate cancer.[21][22] In addition, estrogens may have significant advantages relative to ADT in terms ofbone loss andfractures,hot flashes,sexual function, andquality of life, as well as considerable cost savings with parenteral forms of estradiol compared toGnRH analogue therapy.[21][22] On the other hand,breast tenderness andgynecomastia occur at very high rates with estrogens, whereas incidences are low with castration and CAB.[23] However, gynecomastia with estrogens is generally only mild-to-moderate in severity and is usually only modestly discomforting.[2] In addition, gynecomastia caused by estrogens can be prevented withprophylacticirradiation of the breasts or can be remediated withmastectomy.[2]
PEP has been studied for the treatment of prostate cancer at dosages of 160 mg/month (three studies) and 240 mg/month (four studies).[24] At a dosage of 160 mg/month, PEP incompletely suppressestestosterone levels, failing to reach the castrate range, and is significantly inferior toorchiectomy in slowing disease progression.[24][2] Conversely, PEP at a dosage of 240 mg/month results in greater testosterone suppression, into the castrate range similarly to orchiectomy, and is equivalent to orchiectomy in effectiveness.[24][2]
For prostate cancer in men, PEP is usually given at a dosage of 80 to 320 mg every 4 weeks for the first 2 to 3 months to rapidly build up estradiol levels.[1] Thereafter, to maintain estradiol levels, the dosage is adjusted down usually to 40 to 160 mg every 4 weeks based on clinical findings and laboratory parameters.[1] For breast cancer and low estrogen levels in women, the dosage is 40 to 80 mg every 4 weeks.[1] For transgender women, the dosage is 80 to 160 mg every 4 weeks.[11][19][25][5]
PEP is provided in the form of powder or anaqueous solution invials andampoules alone or in combination withmepivacaine and/ornicotinamide (vitamin B3) for administration viaintramuscular injection.[1][26][27] Mepivacaine is alocal anaesthetic and is used to avoid aburning sensation during injection of PEP.[1] Each vial/ampoule of Estradurin contains 80 mg PEP, 5 mg mepivacaine hydrochloride, 40 mg nicotinamide, and 2 mL water.[27]
Thecontraindications of PEP are largely the same as those of estradiol and include:[1][28][29][30][31]
Systematic studies of theside effects of PEP are lacking.[1] However, its side effects are assumed to be identical to those ofestradiol and otherestradiol esters.[1] The side effects of PEP are partially dependent on sex.[1] Common or frequent (>10%) side effects are considered to includeheadache,abdominal pain,nausea,rash,pruritus,loss of libido,erectile dysfunction,breast tenderness,gynecomastia,feminization,demasculinization,infertility, andvaginal bleeding or spotting.[1][32] Side effects that occur occasionally or uncommonly (0.1–1%) includesodium andwater retention,edema,hypersensitivity,breast tension,depression,dizziness,visual disturbances,palpitations,dyspepsia,erythema nodosum,urticaria, andchest pain.[1] All other side effects of PEP are considered to be rare.[1]
The rare (<0.1%) side effects of PEP are considered to includeweight gain,impaired glucose tolerance,mood changes (elation ordepression),nervousness,tiredness,headache,migraine, intolerance ofcontact lenses,hypertension,thrombosis,thrombophlebitis,thromboembolism,heart failure,myocardial infarction,vomiting,bloating,cholestatic jaundice,cholelithiasis, transient increases intransaminases andbilirubin,erythema multiforme,hyperpigmentation,muscle cramps,dysmenorrhea,vaginal discharge,premenstrual-like symptoms,breast enlargement,testicular atrophy,allergic reactions (e.g.,urticaria,bronchial asthma,anaphylactic shock) due tomepivacaine, andinjection site reactions (e.g.,pain,sterile abscesses,inflammatory infiltrates).[1]
Asthromboembolic and othercardiovascular complications are associated mainly withsyntheticoral estrogens likeethinylestradiol anddiethylstilbestrol, they occur much less often withparenteral bioidentical forms of estrogen like PEP.[1][2]
PEP produces minimal undesirable effects oncoagulation factors and is thought to increase the risk ofblood clots little or not at all.[33][34] This is in spite of the fact that estradiol levels can reach high concentrations of as much as 700 pg/mL with high-dose (320 mg/month) PEP therapy.[35] It is also in contrast to oral synthetic estrogens such asdiethylstilbestrol andethinylestradiol, which produce marked increases in coagulation factors and high rates of blood clots at the high doses used to achieve castrate levels of testosterone in prostate cancer.[33][34][6] The difference between the two types of therapies is due to thebioidentical andparenteral nature of PEP and its minimal influence onliver protein synthesis.[33][34][6] PEP might actually reduce the risk of blood clots, due to decreases in levels of certain procoagulatory proteins.[33][34] Although PEP does not increase the hepatic production or levels of procoagulatory factors, it has been found to significantly decrease levels of the anticoagulatoryantithrombin III, which may indicate a potential risk ofthromboembolic and cardiovascular complications.[2] On the other hand, PEP significantly increases levels ofHDL cholesterol and significantly decreases levels ofLDL cholesterol, changes which are thought to protect againstcoronary artery disease.[2] It appears that PEP may have beneficial effects on cardiovascular health at lower dosages (e.g., 160 mg/day) due to its beneficial effects on HDL and LDL cholesterol levels, but these are overshadowed at higher dosages (e.g., 240 mg/day) due to unfavorable dose-dependent effects onhemostasis, namely antithrombin III levels.[2]
Small early pilot studies of PEP for prostate cancer in men found no cardiovascular toxicity with the therapy.[33] A dosage of PEP of 160 mg/month specifically does not appear to increase the risk of cardiovascular complications.[2] In fact, potential beneficial effects on cardiovascular mortality have been observed at this dosage.[2] However, PEP at a higher dosage of 240 mg/month has subsequently been found in large studies to significantly increase cardiovascularmorbidity relative toGnRH modulators andorchiectomy in men treated with it for prostate cancer.[33][34][2] The increase in cardiovascular morbidity with PEP therapy is due to an increase in non-fatal cardiovascular events, includingischemic heart disease andheart decompensation, specificallyheart failure.[34][36][37] Conversely, PEP has not been found to significantly increase cardiovascularmortality relative to GnRH modulators and orchiectomy.[33][34] Moreover, numerically more patients with preexisting cardiovascular disease were randomized to the PEP group in one large study (17.1% vs. 14.5%; significance not reported), and this may have contributed to the increased incidence of cardiovascular morbidity observed with PEP.[34] In any case, some studies have found that the increased cardiovascular morbidity with PEP is confined mainly to the first one or two years of therapy, whereas one study found consistently increased cardiovascular morbidity across three years of therapy.[33] A longitudinal risk analysis that projected over 10 years suggested that the cardiovascular risks of PEP may be reversed with long-term treatment and that the therapy may eventually result in significantly decreased cardiovascular risk relative to GnRH modulators and orchiectomy, although this has not been confirmed.[33]
The cardiovascular toxicity of PEP is far less than that of oral synthetic estrogens like diethylstilbestrol and ethinylestradiol, which increase the risk ofvenous andarterial thromboembolism, consequently increase the risk oftransient ischemic attack,cerebrovascular accident (stroke), andmyocardial infarction (heart attack), and result in substantial increases in cardiovascular mortality.[33][34] It is thought that the relatively minimal cardiovascular toxicity of parenteral forms of estradiol, like PEP and high-dose transdermal estradiol patches,[38] is due to their absence of effect on hepatic coagulation factors.[33][34]
Acute toxicity studies have not indicated a risk of acute side effects withoverdose of PEP.[1] Themedian lethal dose (LD50) of PEP in mice is approximately 700 mg/kg.[39] PEP has been administered in total amounts of 2,000 to 3,000 mg over several months in patients with cancer withouttoxicity observed.[39] The most likely sign of overdose is reversiblefeminization, namelygynecomastia.[1] Othersymptoms of estrogenoverdosage may includenausea,vomiting,bloating,increased weight,water retention,breast tenderness,vaginal discharge,heavy legs, andleg cramps.[28] These side effects can be diminished by reducing the estrogen dosage.[28] There is no specificantidote for overdose of PEP.[1] Treatment of PEP overdose should be based onsymptoms.[1]
Known potentialinteractions of PEP are mostly the same as those of estradiol and include:[1]
Interactions with PEP may be less than with oral estrogens due to the lack of thefirst-pass through theliver.[1]
PEP is anestradiol ester in the form of apolymer and is an extremely long-lastingprodrug ofestradiol.[2][7][5][6] As such, it is anestrogen, or anagonist of theestrogen receptors.[2][6][5] PEP hasantigonadotropic and functionalantiandrogenic effects due to its estrogenic activity.[35] A singlerepeat unit of PEP, corresponding toestradiol phosphate (minus OH2), is of about 23% highermolecular weight than estradiol due to the presence of its C17βphosphate ester.[42][15] Because PEP is a prodrug of estradiol, it is considered to be anatural andbioidentical form of estrogen.[5]
PEP is a stronginhibitor of severalenzymes, includingacid phosphatase,alkaline phosphatase, andhyaluronidase,in vitro.[43][44][45] In light of the fact thatphosphatases, which cleave PEP into estradiol and phosphoric acid, are present in most tissues in the body, it has been said that the longelimination half-life and slow release of PEP are somewhat surprising.[46] It is thought that PEP may inhibit its ownmetabolism.[46]
| Estrogen | Form | Dose (mg) | Duration by dose (mg) | ||
|---|---|---|---|---|---|
| EPD | CICD | ||||
| Estradiol | Aq. soln. | ? | – | <1 d | |
| Oil soln. | 40–60 | – | 1–2 ≈ 1–2 d | ||
| Aq. susp. | ? | 3.5 | 0.5–2 ≈ 2–7 d; 3.5 ≈ >5 d | ||
| Microsph. | ? | – | 1 ≈ 30 d | ||
| Estradiol benzoate | Oil 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 dipropionate | Oil soln. | 25–30 | – | 5 ≈ 5–8 d | |
| Estradiol valerate | Oil soln. | 20–30 | 5 | 5 ≈ 7–8 d; 10 ≈ 10–14 d; 40 ≈ 14–21 d; 100 ≈ 21–28 d | |
| Estradiol benz. butyrate | Oil soln. | ? | 10 | 10 ≈ 21 d | |
| Estradiol cypionate | Oil soln. | 20–30 | – | 5 ≈ 11–14 d | |
| Aq. susp. | ? | 5 | 5 ≈ 14–24 d | ||
| Estradiol enanthate | Oil soln. | ? | 5–10 | 10 ≈ 20–30 d | |
| Estradiol dienanthate | Oil soln. | ? | – | 7.5 ≈ >40 d | |
| Estradiol undecylate | Oil soln. | ? | – | 10–20 ≈ 40–60 d; 25–50 ≈ 60–120 d | |
| Polyestradiol phosphate | Aq. soln. | 40–60 | – | 40 ≈ 30 d; 80 ≈ 60 d; 160 ≈ 120 d | |
| Estrone | Oil soln. | ? | – | 1–2 ≈ 2–3 d | |
| Aq. susp. | ? | – | 0.1–2 ≈ 2–7 d | ||
| Estriol | Oil soln. | ? | – | 1–2 ≈ 1–4 d | |
| Polyestriol phosphate | Aq. soln. | ? | – | 50 ≈ 30 d; 80 ≈ 60 d | |
Notes and sources Notes: Allaqueous suspensions are ofmicrocrystallineparticle size.Estradiol production during themenstrual cycle is 30–640 µg/d (6.4–8.6 mg total per month or cycle). Thevaginalepithelium maturation dosage ofestradiol benzoate orestradiol valerate has been reported as 5 to 7 mg/week. An effectiveovulation-inhibiting dose ofestradiol undecylate is 20–30 mg/month.Sources: See template. | |||||
PEP hasantigonadotropic effects due to its estrogenic activity.[36] It has been found to suppress testosterone levels in men by 55%, 75%, and 85% at intramuscular dosages of 80, 160, and 240 mg every 4 weeks, respectively.[46] A single intramuscular injection of 320 mg PEP in men has been found to suppress testosterone levels to within the castrate range (< 50 ng/dL) within 3 weeks.[7] This was associated with circulating estradiol levels of just over 200 pg/mL.[35] The suppression of testosterone levels that can be achieved with PEP is equal to that withorchiectomy.[47] However, to achieve such concentrations of testosterone, which are about 15 ng/dL on average, higher concentrations of estradiol of around 500 pg/mL were necessary.[35][47][48] This was associated with a dosage of intramuscular 320 mg PEP every four weeks and occurred by 90 days of treatment.[35] However, 240 mg PEP every four weeks has also been reported to eventually suppress testosterone levels in the castrate range.[49][50]
The growth of prostate cancer is generally stimulated bydihydrotestosterone (DHT), and unless the cancer iscastration-resistant, it can be treated bydepriving it of androgens. Estradiol produces its therapeutic benefits mainly via exertion ofnegative feedback on thehypothalamic–pituitary–gonadal axis.[36][46][7] This blocks thesecretion ofluteinizing hormone, which in turn reducestestosteroneproduction in theLeydig cells of thetestes.[36][46][7] Estradiol also decreases the free percentage of testosterone by increasingsex hormone-binding globulin (SHBG) levels.[7] In addition, it exhibits directcytotoxicity on prostate cancer cells.[51][20]
| Factors | Oral estrogensa | Parenteral estrogensb |
|---|---|---|
| Factor VII | Increases | No change |
| Factor VIII activity | Increases | No change |
| Antithrombin III activity | Decreases | Decreases |
| Prothrombin fragment 1+2 | Increases | No change |
| Activated protein C resistance | Increases | No change |
| Fibrinogen | Decreases | No change |
| Footnotes:a = E.g.,DESTooltip diethylstilbestrol,EETooltip ethinylestradiol.b = PEP.Sources:[34] | ||
Estrogens have effects onliver protein synthesis, including on thesynthesis ofplasma proteins,coagulation factors,lipoproteins, andtriglycerides.[47] These effects can result in an increased risk ofthromboembolic andcardiovascular complications, which in turn can result in increasedmortality.[47] Studies have found a markedly increased 5-year risk of cardiovascular mortality of 14 to 26% in men treated with oral synthetic estrogens likeethinylestradiol anddiethylstilbestrol for prostate cancer.[47] However, whereas oral synthetic estrogens have a strong influence on liver protein synthesis, the effects of parenteral bioidentical estrogens like PEP on liver protein synthesis are comparatively very weak or even completely abolished.[47] This is because thefirst-pass through theliver with oral administration is avoided and because bioidentical estrogens are efficiently inactivated in the liver.[47] In accordance, PEP has minimal effect on theliver at a dosage of up to at least 240 mg/month.[52]
A study found that whereas 320 mg/month intramuscular PEP increased SHBG levels to 166% in men with prostate cancer, the combination of 80 mg/month intramuscular polyestradiol phosphate and 150 μg/day oral ethinylestradiol increased levels of SHBG to 617%, an almost 8-fold difference in increase and almost 4-fold difference in absolute levels between the two treatment regimens.[35][7][53] In addition, whereas there were no cardiovascular complications in the PEP-only group, there was a 25% incidence of cardiovascular complications over the course of a year in the group that was also treated with ethinylestradiol.[7] Another study found no change in levels ofcoagulation factor VII, a protein of particular importance in the cardiovascular side effects of estrogens, with 240 mg/month intramuscular PEP.[52] These findings demonstrate the enormous impact of synthetic oral estrogens like ethinylestradiol on liver protein production relative to parenteral bioidentical forms of estrogen like PEP.[7]
Originally, PEP was typically used at a dosage of 80 mg per month in combination with 150 μg per day oral ethinylestradiol in the treatment of prostate cancer.[46][54] This combination was found to produce a considerable incidence of cardiovascular toxicity,[47] and this toxicity was inappropriately attributed to PEP in some publications.[55] Subsequent research has shown that the toxicity is not due to PEP but rather to the ethinylestradiol component.[56][46][47]
A study found that therapy with intramuscular PEP resulting in estradiol levels of around 400 pg/mL in men with prostate cancer did not affectgrowth hormone orinsulin-like growth factor 1 levels, whereas the addition of oralethinylestradiol significantly increased growth hormone levels and decreased insulin-like growth factor 1 levels.[57][58]
PEP has a very long duration and is given by intramuscular injection once every 4 weeks.[35] In men, an initial intramuscular injection of PEP results in a rapid rise in estradiol levels measured at 24 hours followed by a slow and gradual further increase in levels up until at least day 28 (the time of the next injection).[35] Subsequent injections result in a progressive and considerable accumulation in estradiol levels up to at least 6 months.[35] The meanelimination half-life of PEP has been found to be 70 days (10 weeks) with a single 320 mg intramuscular dose of the medication.[7] Thetmax (time to maximal concentrations) for estradiol was about 16 days.[7] PEP has aduration of approximately 1 month with a single dose of 40 mg, 2 months with 80 mg, and 4 months with 160 mg.[59][60][61][62][39]
PEP reaches thebloodstream within hours after an injection (90% after 24 hours), where it circulates, and is accumulated in thereticuloendothelial system.[51] Estradiol is thencleaved from the polymer byphosphatases, although very slowly.[63] Levels of estradiol in men with intramuscular injections of PEP once every 4 weeks were about 350 pg/mL with 160 mg, 450 pg/mL with 240 mg, and almost 700 pg/mL with 320 mg, all measured after 6 months of treatment.[35] With monthly injections,steady-state estradiol concentrations are reached after 6 to 12 months.[51] Estradiol is metabolized primarily in theliver byCYP3A4 and othercytochrome P450enzymes, and is metabolized to a lesser extent in extrahepatic tissues.[20][1] Themetabolites are mainlyexcreted inurine via thekidneys.[1]
Early studies found that a dosage of 80 mg PEP every 4 weeks rapidly produced relatively high mean estradiol levels of about 400 to 800 pg/mL.[64] These levels are similar to those of 100 mg estradiol undecylate every month, which has been found to produce estradiol levels of around 500 to 600 pg/mL.[65][66] As a result, it has previously been said that 80 mg PEP per month and 100 mg estradiol undecylate per month are roughly equivalent.[67][68][7] However, subsequent studies showed that this dosage of PEP actually achieves much lower estradiol levels than originally demonstrated.[35]
PEP is asyntheticestranesteroid and the C17βphosphoric acid (phosphate)ester ofestradiol (estradiol 17β-phosphate) in the form of apolymer.[69][15][46][70] It is also known as estradiol polymer with phosphoric acid or as estradiol 17β-phosphate polymer, as well as estra-1,3,5(10)-triene-3,17β-diol 17β-phosphate polymer.[15][69][46][70] It has been determined viaultracentrifugation that the meanmolecular weight of PEP corresponds to a chain length of approximately 13 repeat units of estradiol 17β-phosphate.[46] PEP is closely related topolyestriol phosphate (Gynäsan, Klimadurin, Triodurin) andpolytestosterone phloretin phosphate (never commercialized), which areestriol andtestosterone esters in the forms ofpolymers, respectively.[59][71] It is also related topolydiethylstilbestrol phosphate (never commercialized), adiethylstilbestrol ester in the form of apolymer.[72]
| 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. | |||||||||
PEP is of very lowsolubility inwater,acetone,chloroform,dioxane, andethanol, but dissolves readily inbases, especially inaqueouspyridine.[51]
Like polyphosphates ofpolyphenols, PEP can be prepared from themonomer (in this case estradiol) andphosphoryl chloride. The latter reacts with both the phenolichydroxyl group in position 3 and thealiphatic one in position 17β. Themolecular mass of the resulting polymer can be controlled by interrupting the reaction after a given time: the longer the reaction is allowed to continue, the higher the mass.[63][73]
Pharmacological experiments onestradiol phosphates conducted around 1950 gave rise to the hypothesis that estradiol 3,17β-diphosphate acted as an inhibitor of kidneyalkaline phosphatase.[63] When the same scientists wanted to synthesize simple phosphates ofphloretin, a compound found in apple tree leaves,[74] they accidentally created a polymer instead.[73] This was later shown to exhibit the same anti-phosphatase properties as estradiol diphosphate, and so it was hypothesized that the original finding was due to contamination with estradiol phosphate polymers.[63] Consequently, these polymers were studied in more detail, which resulted in the development of PEP as early as 1953[12] and its subsequent introduction for medical use in 1957 in theUnited States.[13][14][75] PEP remained on the market in the United States until at least 2000 but was eventually discontinued both in this country and in most or all other countries.[15][13][42][76][77]
Polyestradiol phosphate is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name andBANTooltip British Approved Name.[15][69][42] It is also known by its developmental code nameLeo-114.[15][42]
PEP is marketed exclusively under the brand name Estradurin or Estradurine.[15][42]
PEP has been marketed in theUnited States and widely throughoutEurope, including inAustria,Belgium, theCzech Republic,Denmark,Finland,Germany,Italy, theNetherlands,Norway,Russia,Spain,Sweden,Switzerland,Ukraine, and theUnited Kingdom.[15][26][1][76][77][14] It is no longer available in the United States, Switzerland, and certain other countries however,[13][16] but is still known to be marketed in Austria, Belgium, Denmark, Finland, the Netherlands, Norway, and Sweden.[42][76][77][1]
PEP has been studied as a means of hormonal breast enhancement in women.[78]
A combination of PEP andmedroxyprogesterone acetate was studied in women as a long-lastingcombined injectable contraceptive for use byintramuscular injection once every three months.[79][80][81]
Orchiectomy and estrogens have been used for over 50 years in the treatment of advanced prostatic cancer. Although orchiectomy is a simple procedure, it may cause psychological stress. Oral estrogen therapy is as effective as orchiectomy in terms of cancer inhibitory effect, but its acceptance as primary hormonal treatment is overshadowed by an increased risk of cardiovascular complications. Parenteral estrogen, polyestradiol phosphate (PEP), is effective, but also associated with cardiovascular complications, although to a lesser extent. During the last 20 years, well tolerated luteinizing hormone releasing hormone (LHRH) analogues have been replacing orchiectomy and estrogens. Efforts have been made to increase the efficacy of the treatment by adding antiandrogens to LHRH analogues and also to orchiectomy (combined androgen blockade, CAB). However, the efficacy of LHRH analogues and CAB has not proved to be superior to that of simple orchiectomy and, moreover, they are expensive treatment modalities. Orchiectomy and LHRH analogues are associated with negative effects on bone mass and may cause osteoporosis, whereas PEP treatment has an opposite effect. Parenteral polyestradiol phosphate is still a cheap potential treatment for advanced prostatic cancer, but further studies should be conducted to establish its future role, e.g. combining acetylsalicylic acid to prevent cardiovascular complications.
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.
More than 50 years ago, orally given estrogen was already used in the treatment of prostate cancer. Due to cardiovascular side-effects with a high morbidity of 25%, this treatment has not become standard. Recent investigations show that parenteral application reduces the risk of cardiovascular side-effects, because it avoids the first passage through the liver with high concentrations of estrogen which normally occur after oral application. Therefore, an increased synthesis of so-called "steroid-sensitive" liver proteins, such as coagulation factors (especially factor VII) can be avoided. This newer parenteral estrogen application shows encouraging results of a cheap and effective hormonal therapy with a low rate of side-effects in patients with prostate cancer.
[...] In a study with parenteral estrogen therapy of patients with metastatic breast cancer, 14/24 patients obtained an objective response (including patients with stable disease >6 months) [13]. The only side effect reported was bleeding from a hyperplastic endometrium.
Treatment with estrogen has the highest incidence of gynecomastia, at 40 – 80%, anti-androgens, including flutamide, bicalutamide and nilutamide, are next, with a 40 – 70% incidence, followed by GnRH analogs (goserelin, leuprorelin) and combined androgen deprivation, both with incidences of 13% each.
Polyestradiol phosphate is a polymeric ester of estradiol -17 beta and phosphoric acid. The large molecule has very weak estrogenic properties but is a strong inhibitor of several enzymes, e.g. acid and alkaline phosphatases and hyaluronidase.
Polyestradiol phosphate (PEP) has been demonstrated to have inhibitory activity against hyaluronidase, acid phosphatase and alkaline phosphatase (Fernö et al., 1958).
The castrate level was defined as testosterone being less than 50 ng/dL (1.7 nmol/L), many years ago. However contemporary laboratory testing methods showed that the mean value after surgical castration is 15 ng/dL [1]. Thus, recently the level is defined as being less than 20 ng/dL (1 nmol/L).
The polymer of estradiol or estriol and phosphoric acid has an excellent depot action when given intramuscularly (polyestriol phosphate or polyestradiol phosphate) (Table 16). Phosphoric acid combines with the estrogen molecule at C3 and C17 to form a macromolecule. The compound is stored in the liver and spleen where the estrogen is steadily released by splitting off of the phosphate portion due to the action of alkaline phosphatase. [...] Conjugated estrogens and polyestriol and estradiol phosphate can also be given intravenously in an aqueous solution. Intravenous administration of ovarian hormones offers no advantages, however, and therefore has no practical significance. [...] The following duarations of action have been obtained with a single administration (WlED, 1954; LAURITZEN, 1968): [...] 50 mg polyestradiol phosphate ~ 1 month; 50 mg polyestriol phosphate ~ 1 month; 80 mg polyestriol phosphate ~ 2 months.
