Polyestradiol phosphate

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Polyestradiol phosphate
Polyestradiol phosphate.svg
Polyestradiol phosphate structure
Estradiol phosphate molecule ball.png
Structure of estradiol phosphate, similar to one repeat unit of polyestradiol phosphate
Clinical data
Trade namesEstradurin, Estradurine
SynonymsPEP; Estradiol phosphate polymer; Estradiol 17β-phosphate polymer; Estradiol polymer with phosphoric acid; Leo-114
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
  • Contraindicated[1]
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 binding>95% (estradiol)[1]
MetabolismMainly in the liver, to a lesser extent in the kidneys, gonads, and muscle (by phosphatases)[1]
MetabolitesEstradiol, phosphoric acid, and metabolites of estradiol[3][4]
Elimination half-lifePEP: 70 days (10 weeks)[5]
Estradiol: 1–2 hours[6]
ExcretionUrine (as conjugates)[1]
Identifiers
CAS Number
PubChem SID
DrugBank
ChemSpider
  • None
UNII
KEGG
ChEMBL
Chemical and physical data
Formula(C18H23O4P)n
(n = variable; n = 13)
Molar massPolymer: Variable
Repeat unit: 334.347 g/mol
Melting point195 to 202 °C (383 to 396 °F)
  (verify)

Polyestradiol phosphate (PEP), sold under the brand name Estradurin, is an estrogen medication which is used primarily in the treatment of prostate cancer in men.[1][2][7][8][9] It is also used in women to treat breast cancer and as a component of hormone therapy to treat low estrogen levels and menopausal symptoms.[1] It is given by injection into muscle once every four weeks.[1][2][10]

Common side effects of PEP include headache, breast tenderness, breast development, feminization, sexual dysfunction, infertility, and vaginal bleeding.[1][2] PEP is a synthetic estrogen and hence is an agonist of the estrogen receptor (ER), the biological target of estrogens like estradiol.[2][4][3] It is an estrogen ester in the form of a polymer and is an extremely long-lasting prodrug of estradiol in the body.[2][10][3][4] Because it works by being converted into estradiol, PEP is considered to be a natural and bioidentical form of estrogen.[3][2] The safety profile of parenteral estradiol esters like PEP is greatly improved relative to synthetic oral estrogens like ethinylestradiol and diethylstilbestrol.[2]

PEP was discovered around 1953 and was introduced for medical use in the United States in 1957.[10][11][12] Along with estradiol undecylate and estradiol valerate, it has been frequently used in the United States and Europe as a parenteral form of estrogen to treat men with prostate cancer.[8] However, it is no longer available in the United States.[11][13]

Medical uses[edit]

PEP is used as an intramuscular injection for estrogen therapy of prostate cancer in men.[1][2] It is also used to treat breast cancer in women who are at least 5 years postmenopausal.[1] In addition, PEP is used in hormone replacement therapy for low estrogen levels due to hypogonadism or menopause in women.[1] PEP is a form of high-dose estrogen therapy.[2] After an injection, it very slowly releases the active agent estradiol over at least several months.[14][5]

PEP has been compared to combined androgen blockade (CAB; castration plus flutamide) for the treatment of prostate cancer in a large randomized clinical trial of 915 patients.[15][16] At 18.5 months, there was no difference in survival or cardiovascular toxicity between the two treatment modalities.[15][16] These findings suggest that parenteral forms of estradiol may have similar effectiveness and safety relative to androgen deprivation therapy (ADT) in the treatment of prostate cancer.[15][16] In addition, estrogens may have significant advantages relative to ADT in terms of bone loss and fractures, hot flashes, sexual function, and quality of life, as well as considerable cost savings with parenteral forms of estradiol compared to GnRH analogue therapy.[15][16] On the other hand, breast tenderness and gynecomastia occur at very high rates with estrogens, whereas incidences are low with castration and CAB.[17] 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 with prophylactic irradiation of the breasts or can be remediated with mastectomy.[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]

Available forms[edit]

PEP is available in the form of vials and ampoules alone or in combination with mepivacaine and/or nicotinamide (vitamin B3) for administration via intramuscular injection.[1][18] Mepivacaine is a local anaesthetic and is used to avoid a burning sensation during injection of PEP.[1]

Contraindications[edit]

The contraindications of PEP are mostly the same as those of estradiol and include:[1]

Side effects[edit]

Systematic studies of the side effects of PEP are lacking.[1] However, its side effects are assumed to be identical to those of estradiol and other estradiol esters.[1] The side effects of PEP are partially dependent on sex.[1] Common or frequent (>10%) side effects are considered to include headache, abdominal pain, nausea, rash, pruritus, loss of libido, erectile dysfunction, breast tenderness, gynecomastia, feminization, demasculinization, infertility, and vaginal bleeding or spotting.[1][19] Side effects that occur occasionally or uncommonly (0.1–1%) include sodium and water retention, edema, hypersensitivity, breast tension, depression, dizziness, visual disturbances, palpitations, dyspepsia, erythema nodosum, urticaria, and chest 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 include weight gain, impaired glucose tolerance, mood changes (elation or depression), nervousness, tiredness, headache, migraine, intolerance of contact lenses, hypertension, thrombosis, thrombophlebitis, thromboembolism, heart failure, myocardial infarction, vomiting, bloating, cholestatic jaundice, cholelithiasis, transient increases in transaminases and bilirubin, 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 to mepivacaine, and injection site reactions (e.g., pain, sterile abscesses, inflammatory infiltrates).[1]

As thromboembolic and other cardiovascular complications are associated mainly with synthetic oral estrogens like ethinylestradiol and diethylstilbestrol, they occur much less often with parenteral bioidentical forms of estrogen like PEP.[1][2]

Cardiovascular effects[edit]

PEP does not produce undesirable effects on coagulation factors and is not believed to increase the risk of blood clots.[20][21] This is in spite of the fact that estradiol levels can reach high concentrations of as much as 700 pg/mL with high-dose PEP therapy.[22] It is also in contrast to oral synthetic estrogens such as diethylstilbestrol and ethinylestradiol, 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.[20][21][4] The difference between the two types of therapies is due to the bioidentical and parenteral nature of PEP and its minimal influence on liver protein synthesis.[20][21][4] PEP might actually reduce the risk of blood clots, due to decreases in levels of certain procoagulatory proteins.[20][21]

Small early pilot studies of PEP for prostate cancer in men found no cardiovascular toxicity with the therapy.[20] However, PEP has subsequently been found in large studies to significantly increase cardiovascular morbidity relative to GnRH modulators and orchiectomy in men treated with it for prostate cancer.[20][21] The increase in cardiovascular morbidity with PEP therapy is due to an increase in non-fatal ischemic heart events and heart decompensation.[23][24] Conversely, PEP has not been found to significantly increase cardiovascular mortality relative to GnRH modulators and orchiectomy.[20][21] 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.[20] 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.[20]

The cardiovascular toxicity of PEP is far less than that of oral synthetic estrogens like diethylstilbestrol and ethinylestradiol, which increase the risk of venous and arterial thromboembolism, consequently increase the risk of transient ischemic attack, cerebrovascular accident (stroke), and myocardial infarction (heart attack), and result in substantial increases in cardiovascular mortality.[20][21] It is thought that the relatively minimal cardiovascular toxicity of parenteral forms of estradiol, like PEP and high-dose transdermal estradiol patches,[25] is due to their absence of effect on hepatic coagulation factors.[20][21]

Overdose[edit]

Acute toxicity studies have not indicated a risk of acute side effects with overdose of PEP.[1] The most likely sign of overdose is reversible feminization, namely gynecomastia.[1] There is no specific antidote for overdose of PEP, and treatment should be symptomatic.[1]

Interactions[edit]

Known potential interactions 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 the first-pass through the liver.[1]

Pharmacology[edit]

Pharmacodynamics[edit]

Estradiol, the active form of PEP.

PEP is an estradiol ester in the form of a polymer and is an extremely long-lasting prodrug of estradiol.[2][5][3][4] As such, it is an estrogen, or an agonist of the estrogen receptors.[2][4][3] PEP has antigonadotropic and functional antiandrogenic effects due to its estrogenic activity.[22] A single repeat unit of PEP, corresponding to estradiol phosphate (minus OH2), is of about 23% higher molecular weight than estradiol due to the presence of its C17β phosphate ester.[27][8] Because PEP is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.[3]

Parenteral potencies of estrogens

Estrogen Type EPD (14 days) Duration
Estradiol Bioidentical ND 10 mg ≈ 2 days
Estradiol benzoate Bioidentical 25–30 mg 5 mg ≈ 5–6 days
Estradiol dipropionate Bioidentical 25–30 mg 5 mg ≈ 5–8 days
Estradiol valerate Bioidentical 20 mg 10 mg ≈ 10–14 days
Estradiol cypionate Bioidentical 25–30 mg 5 mg ≈ 14 days
Estradiol enanthate Bioidentical ND 10 mg ≈ 30 days
Estradiol undecylate Bioidentical ND 10 mg ≈ 40–60 days
25 mg ≈ 60–120 days
Polyestradiol phosphate Bioidentical 40–60 mg 40 mg ≈ 28 days
320 mg ≈ >84 days
Polyestriol phosphate Bioidentical ND 50 mg ≈ 30 days
80 mg ≈ 60 days
Diethylstilbestrol Synthetic 20 mg 3 mg ≈ 3 days
Diethylstilbestrol dipropionate Synthetic 15 mg 2.5 mg ≈ 5 days
Addendum: An effective ovulation-inhibiting dose of estradiol undecylate is 20–30 mg/month.[28] Notes: All of the estrogens are by intramuscular injection. Abbreviations: EPD = Endometrial proliferation dose. Sources: [29][30][31][32][33][5]

Antigonadotropic effects[edit]

Estradiol and testosterone levels over the course of 12 weeks following a single intramuscular injection of 320 mg polyestradiol phosphate in men.[5]
Testosterone levels with intramuscular injection of different dosages of polyestradiol phosphate once every 4 weeks for 6 months in men.[22] Less than 50 ng/dL is considered to be the castrate range.[22]

PEP has powerful antigonadotropic effects due to its estrogenic activity.[23] 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.[34] 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.[5] This was associated with circulating estradiol levels of just over 200 pg/mL.[22] The suppression of testosterone levels that can be achieved with PEP is equal to that with orchiectomy.[35] 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.[22][35][36] This was associated with a dosage of intramuscular 320 mg PEP every four weeks and occurred by 90 days of treatment.[22]

Mechanism of action in prostate cancer[edit]

The growth of prostate cancer is generally stimulated by dihydrotestosterone (DHT), and unless the cancer is castration-resistant, it can be treated by depriving it of androgens. Estradiol produces its therapeutic benefits mainly via exertion of negative feedback on the hypothalamic–pituitary–gonadal axis.[23][34][5] This blocks the secretion of luteinizing hormone, which in turn reduces testosterone production in the Leydig cells of the testes.[23][34][5] Estradiol also decreases the free percentage of testosterone by increasing sex hormone-binding globulin (SHBG) levels.[5] In addition, it exhibits direct cytotoxicity on prostate cancer cells.[37][14]

Differences from other estrogens[edit]

SHBG levels with 1) intramuscular injection of 320 mg polyestradiol phosphate once every 4 weeks alone; 2) the combination of intra- muscular injection of 320 mg polyestradiol phosphate once every 4 weeks plus 150 µg/day oral ethinylestradiol; 3) orchiectomy alone.[22]

Estrogens have effects on liver protein synthesis, including on the synthesis of plasma proteins, coagulation factors, lipoproteins, and triglycerides.[35] These effects can result in an increased risk of thromboembolic and cardiovascular complications, which in turn can result in increased mortality.[35] Studies have found a markedly increased 5-year risk of cardiovascular mortality of 14 to 26% in men treated with oral synthetic estrogens like ethinylestradiol and diethylstilbestrol for prostate cancer.[35] 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.[35] This is because the first-pass through the liver with oral administration is avoided and because bioidentical estrogens are efficiently inactivated in the liver.[35]

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.[22][5][38] 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.[5] Another study found no change in levels of coagulation factor VII, a protein of particular importance in the cardiovascular side effects of estrogens, with 240 mg/month intramuscular PEP.[39] 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.[5]

Pharmacokinetics[edit]

Estradiol levels with intramuscular injection of different dosages of polyestradiol phosphate once every 4 weeks for 6 months.[22]

PEP reaches the bloodstream within hours after an injection (90% after 24 hours), where it circulates, and is accumulated in the reticuloendothelial system.[37] Estradiol is then cleaved from the polymer by phosphatases, although very slowly.[40] 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.[22] With monthly injections, steady-state estradiol concentrations are reached after 6 to 12 months.[37] Estradiol is metabolized primarily in the liver by CYP3A4 and other cytochrome P450 enzymes, and is metabolized to a lesser extent in extrahepatic tissues.[14][1] The metabolites are mainly excreted in urine via the kidneys.[1]

PEP has a very long duration and is given by intramuscular injection once every 4 weeks.[22] 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).[22] Subsequent injections result in a progressive and considerable accumulation in estradiol levels up to at least 6 months.[22] The mean terminal half-life of PEP has been found to be 70 days (10 weeks) with a single 320 mg intramuscular dose of the medication.[5] The tmax (time to maximal concentrations) for estradiol was about 16 days.[5]

In light of the fact that phosphatases, which cleave PEP into estradiol and phosphoric acid, are present in most tissues in the body, it has been said that the long terminal half-life and slow release of PEP are somewhat surprising.[34] Research has found that PEP acts as an inhibitor of alkaline phosphatase in vitro, and it is thought that PEP may inhibit its own metabolism.[34]

Chemistry[edit]

PEP is a synthetic estrane steroid and the C17β phosphoric acid (phosphate) ester of estradiol (estradiol 17β-phosphate) in the form of a polymer.[8][9][34][41] 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.[8][9][34][41] It has been determined via ultracentrifugation that the mean molecular weight of PEP corresponds to a chain length of approximately 13 repeat units of estradiol 17β-phosphate.[34] PEP is closely related to polyestriol phosphate (Gynäsan, Klimadurin, Triodurin) and polytestosterone phloretin phosphate (never commercialized), which are estriol and testosterone esters in the forms of polymers, respectively.[42][43]

Solubility[edit]

PEP is of very low solubility in water, acetone, chloroform, dioxane, and ethanol, but dissolves readily in bases, especially in aqueous pyridine.[37]

Synthesis[edit]

Estradiol
Phosphoryl chloride

Like polyphosphates of polyphenols, PEP can be prepared from the monomer (in this case estradiol) and phosphoryl chloride. The latter reacts with both the phenolic hydroxyl group in position 3 and the aliphatic one in position 17β. The molecular 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.[40][44]

History[edit]

Pharmacological experiments on estradiol phosphates conducted around 1950 gave rise to the hypothesis that estradiol 3,17β-diphosphate acted as an inhibitor of kidney alkaline phosphatase.[40] When the same scientists wanted to synthesize simple phosphates of phloretin, a compound found in apple tree leaves,[45] they accidentally created a polymer instead.[44] 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.[40] Consequently, these polymers were studied in more detail, which resulted in the development of PEP as early as 1953[10] and its subsequent introduction for medical use in 1957 in the United States.[11][12]

Society and culture[edit]

Generic names[edit]

Polyestradiol phosphate is the generic name of the drug and its INN and BAN.[8][9][27] It is also known by its developmental code name Leo-114.[8][27]

Brand names[edit]

PEP is marketed exclusively under the brand name Estradurin or Estradurine.[8][27]

Availability[edit]

Availability of polyestradiol phosphate in countries throughout the world as of March 2018. Blue is currently marketed, green is formerly marketed.

PEP has been marketed in the United States and widely throughout Europe, including in Austria, Belgium, the Czech Republic, Denmark, Finland, Germany, Italy, the Netherlands, Norway, Russia, Spain, Sweden, Switzerland, Ukraine, and the United Kingdom.[8][18][1][46][47][18][12] It is no longer available in the United States and possibly certain other countries however,[11][13] but is still known to be marketed in Austria, Belgium, Denmark, Finland, the Netherlands, Norway, Sweden, and Switzerland.[27][46][47][1]

Research[edit]

PEP has been studied as a means of hormonal breast enhancement in women.[48]

References[edit]

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  36. ^ Gokhan Ozyigit; Ugur Selek (1 August 2017). Principles and Practice of Urooncology: Radiotherapy, Surgery and Systemic Therapy. Springer. pp. 334–. ISBN 978-3-319-56114-1. 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).
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  39. ^ Henriksson P, Carlström K, Pousette A, Gunnarsson PO, Johansson CJ, Eriksson B, Altersgård-Brorsson AK, Nordle O, Stege R (1999). "Time for revival of estrogens in the treatment of advanced prostatic carcinoma? Pharmacokinetics, and endocrine and clinical effects, of a parenteral estrogen regimen". Prostate. 40 (2): 76–82. doi:10.1002/(sici)1097-0045(19990701)40:2<76::aid-pros2>3.0.co;2-q. PMID 10386467.
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  42. ^ A. Labhart (6 December 2012). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 551–. ISBN 978-3-642-96158-8. 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.
  43. ^ US patent 2928849, Hogberg Knut Bertil; Ferno Ove Birger & Linderot Torsten Ove Enok et al., "High-molecular weight derivatives of steroids containing hydroxyl groups and method of producing the same", published 15 March 1960, assigned to Leo Ab 
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  45. ^ Picinelli, A; Dapena, E; Mangas, JJ (1995). "Polyphenolic pattern in apple tree leaves in relation to scab resistance. A preliminary study". Journal of Agricultural and Food Chemistry. 43 (8): 2273–78. doi:10.1021/jf00056a057.
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  48. ^ Hartmann BW, Laml T, Kirchengast S, Albrecht AE, Huber JC (1998). "Hormonal breast augmentation: prognostic relevance of insulin-like growth factor-I". Gynecol. Endocrinol. 12 (2): 123–7. doi:10.3109/09513599809024960. PMID 9610425.

Further reading[edit]

  • Gunnarsson PO, Norlén BJ (1988). "Clinical pharmacology of polyestradiol phosphate". Prostate. 13 (4): 299–304. doi:10.1002/pros.2990130405. PMID 3217277.
  • Mikkola A, Ruutu M, Aro J, Rannikko S, Salo J (1999). "The role of parenteral polyestradiol phosphate in the treatment of advanced prostatic cancer on the threshold of the new millennium". Ann Chir Gynaecol. 88 (1): 18–21. PMID 10230677.