Polyestradiol phosphate: Difference between revisions

{{Short description|Chemical compound}}{{Use dmy dates|date=December 2023}}{{cs1 config|name-list-style=vanc}}{{Use PMID reference names|date=December 2023}}{{Distinguish|Polyestriol phosphate|Estradiol phosphate}}

| Verifiedfields = verified

| Watchedfields = verified

| verifiedrevid = 488624854

| IUPAC_name = Estra-1,3,5(10)-triene-3,17β-diol, polymer with phosphoric acid

| image = Polyestradiol phosphate.svg

| width = 250px

| image2 = Estradiol phosphate molecule ball.png

| width2 = 225px

| caption2 = [[Skeletal formula|Skeletal structure]] of polyestradiol phosphate (top) and [[ball-and-stick model]] of [[estradiol phosphate]] (one [[monomer]] of polyestradiol phosphate) (bottom)

<!-- Clinical data -->

| tradename = Estradurin, Estradurine

| pregnancy_category = Contraindicated<ref name="Pharmanovia-Estradurin" />

| routes_of_administration = [[Intramuscular injection]]<ref name="Pharmanovia-Estradurin" /><ref name="pmid10230677" />

| class = [[Estrogen (medication)|Estrogen]]; [[Estrogen ester]]

<!-- Pharmacokinetic data -->

| bioavailability = {{abbr|IM|Intramuscular injection}}: High

| protein_bound = Estradiol: ~98% (to [[human serum albumin|albumin]] and {{abbrlink|SHBG|sex hormone-binding globulin}})<ref name="pmid23375353">{{cite journal | vauthors = Stanczyk FZ, Archer DF, Bhavnani BR | title = Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment | journal = Contraception | volume = 87 | issue = 6 | pages = 706–727 | date = June 2013 | pmid = 23375353 | doi = 10.1016/j.contraception.2012.12.011 }}</ref><ref name="FalconeHurd2007">{{cite book| vauthors = Gupta MK, Chia SY | chapter = Ovarian Hormones: Structure, Biosynthesis, function, Mechanism of Action, and Laboratory Diagnosis| veditors = Falcone T, Hurd WW |title=Clinical Reproductive Medicine and Surgery| chapter-url = https://books.google.com/books?id=fOPtaEIKvcIC&pg=PA22 |year=2007|publisher=Elsevier Health Sciences|isbn=978-0-323-03309-1|pages=22,362,388}}</ref><ref name="Pharmanovia-Estradurin" />

| metabolism = Mainly in the [[liver]], to a lesser extent in the [[kidney]]s, [[gonad]]s, and [[muscle]] (by [[phosphatase]]s)<ref name="Pharmanovia-Estradurin" />

| metabolites = [[Estradiol (medication)|Estradiol]], [[phosphoric acid]], and [[metabolite]]s of estradiol<ref name="Kuhnz-2012" /><ref name="pmid16112947" />

| elimination_half-life = PEP: 70 days (10 weeks)<ref name="pmid8610057" /><br />Estradiol: 1–2 hours<ref name="pmid7169965">{{cite journal | vauthors = Düsterberg B, Nishino Y | title = Pharmacokinetic and pharmacological features of oestradiol valerate | journal = Maturitas | volume = 4 | issue = 4 | pages = 315–324 | date = December 1982 | pmid = 7169965 | doi = 10.1016/0378-5122(82)90064-0 }}</ref>

| excretion = [[Urine]] (as [[conjugate (biochemistry)|conjugate]]s)<ref name="Pharmanovia-Estradurin" />

<!-- Identifiers -->

| CAS_number_Ref = {{cascite|correct|CAS}}

| DrugBank = DB09369

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = None

| UNII_Ref = {{fdacite|correct|FDA}}

| KEGG_Ref = {{keggcite|correct|kegg}}

| PubChemSubstance = 51091766

| synonyms = PEP; Polymeric estradiol phosphate; Polymeric estradiol 17β-phosphate; Estradiol phosphate polymer; Estradiol 17β-phosphate polymer; Estradiol polymer with phosphoric acid; Leo-114

<!-- Chemical data -->

| chemical_formula = (C₁₈H₂₃O₄P)_n<br />(n = variable; {{Overline|n}} = 13)

| molecular_weight = [[Polymer]]: Variable<br />[[Repeat unit]]: 334.347&nbsp;g/mol

<!--Physical data-->

| melting_point = 195

| melting_high = 202

<!-- Definition and medical uses -->

'''Polyestradiol phosphate''' ('''PEP'''), sold under the brand name '''Estradurin''', is an [[estrogen (medication)|estrogen]] medication which is used primarily in the treatment of [[prostate cancer]] in men.<ref name="Pharmanovia-Estradurin">{{Cite web |url=http://pharmanovia.com/product/estradurin/ |title=Estradurin® – Pharmanovia |access-date=1 January 2018 |archive-url=https://web.archive.org/web/20180102072958/http://pharmanovia.com/product/estradurin/ |archive-date=2 January 2018 |url-status=dead }}</ref><ref name="pmid7483157">{{cite journal | vauthors = Stege R, Carlström K, Hedlund PO, Pousette A, von Schoultz B, Henriksson P | title = [Intramuscular depot estrogens (Estradurin) in treatment of patients with prostate carcinoma. Historical aspects, mechanism of action, results and current clinical status] | language = de | journal = Der Urologe. Ausg. A | volume = 34 | issue = 5 | pages = 398–403 | date = September 1995 | pmid = 7483157 | trans-title = Intramuscular depot estrogens (Estradurin) in treatment of patients with prostate carcinoma. Historical aspects, mechanism of action, results and current clinical status | quote = 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. }}</ref><ref name="pmid10230677">{{cite journal | vauthors = Mikkola A, Ruutu M, Aro J, Rannikko S, Salo J | title = The role of parenteral polyestradiol phosphate in the treatment of advanced prostatic cancer on the threshold of the new millennium | journal = Annales Chirurgiae et Gynaecologiae | volume = 88 | issue = 1 | pages = 18–21 | year = 1999 | pmid = 10230677 | quote = 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. }}</ref><ref name="pmid17219379">{{cite journal | vauthors = Mikkola A, Aro J, Rannikko S, Ruutu M | title = Ten-year survival and cardiovascular mortality in patients with advanced prostate cancer primarily treated by intramuscular polyestradiol phosphate or orchiectomy | journal = The Prostate | volume = 67 | issue = 4 | pages = 447–455 | date = March 2007 | pmid = 17219379 | doi = 10.1002/pros.20547 | s2cid = 20549248 }}</ref> It is also used in women to treat [[breast cancer]], as a component of [[menopausal hormone therapy|hormone therapy]] to treat [[hypoestrogenism|low estrogen level]]s and [[menopause|menopausal]] [[symptom]]s, and as a component of [[feminizing hormone therapy]] for [[transgender women]].<ref name="Pharmanovia-Estradurin" /><ref name="Urdl-2009" /> It is given by [[intramuscular injection|injection into muscle]] once every four weeks.<ref name="Pharmanovia-Estradurin" /><ref name="pmid10230677" /><ref name="pmid25951459">{{cite journal | vauthors = Steinbach T, Wurm FR | title = Poly(phosphoester)s: A New Platform for Degradable Polymers | journal = Angewandte Chemie | volume = 54 | issue = 21 | pages = 6098–6108 | date = May 2015 | pmid = 25951459 | doi = 10.1002/anie.201500147 }}</ref>

<!-- Side effects and mechanism -->

Common [[side effect]]s of PEP include [[headache]], [[breast tenderness]], [[gynecomastia|breast development]], [[feminization (biology)|feminization]], [[sexual dysfunction]], [[infertility]], and [[vaginal bleeding]].<ref name="Pharmanovia-Estradurin" /><ref name="pmid10230677" /> PEP is an [[estrogen (medication)|estrogen]] and hence is an [[agonist]] of the [[estrogen receptor]], the [[biological target]] of [[estrogen]]s like [[estradiol]].<ref name="pmid10230677" /><ref name="pmid16112947">{{cite journal | vauthors = Kuhl H | title = Pharmacology of estrogens and progestogens: influence of different routes of administration | journal = Climacteric | volume = 8 | issue = Suppl 1 | pages = 3–63 | date = August 2005 | pmid = 16112947 | doi = 10.1080/13697130500148875 | s2cid = 24616324 }}</ref><ref name="Kuhnz-2012" /> It is an [[estrogen ester]] in the form of a [[polymer]] and is an extremely long-lasting [[prodrug]] of [[estradiol (medication)|estradiol]] in the body.<ref name="pmid10230677" /><ref name="pmid25951459" /><ref name="Kuhnz-2012" /><ref name="pmid16112947" /> The [[biological half-life]] of PEP is more than two months.<ref name="pmid8610057" /> Because PEP works by being converted into estradiol, it is considered to be a [[natural product|natural]] and [[bioidentical hormone replacement therapy|bioidentical]] form of estrogen.<ref name="Kuhnz-2012">{{cite book| vauthors = Kuhnz W, Blode H, Zimmermann H | chapter = Pharmacokinetics of Exogenous Natural and Synthetic Estrogens | veditors = Oettel M, Schillinger E |title=Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen|chapter-url=https://books.google.com/books?id=wBvyCAAAQBAJ&pg=PA261|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-60107-1|page=261,544|quote=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.}}</ref><ref name="pmid10230677" /> The [[drug safety|safety]] profile of [[parenteral]] estradiol esters like PEP is greatly improved relative to [[synthetic compound|synthetic]] [[oral administration|oral]] estrogens like [[ethinylestradiol]] and [[diethylstilbestrol]].<ref name="pmid10230677" />

<!-- History, society, and culture -->

PEP was discovered around 1953 and was introduced for medical use in the [[United States]] in 1957.<ref name="pmid25951459" /><ref name="Drugs@FDA2">{{cite web | title = Drugs@FDA: FDA Approved Drug Products: Estradurin | publisher = United States Food and Drug Administration | access-date = 24 June 2018 | url = https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=010753}}</ref><ref name="Publishing2013">{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA2935-IA381|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=2934–2935}}</ref> 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.<ref name="IndexNominum2000" /> However, it is no longer available in the United States.<ref name="Drugs@FDA2" /><ref name="Mosby2009">{{cite book|author=Mosby|title=Mosby's Pocket Dictionary of Medicine, Nursing & Health Professions|url=https://books.google.com/books?id=_QGaoiFCIDMC&pg=PT3672|date=11 February 2009|publisher=Elsevier Health Sciences|isbn=978-0-323-06604-4|pages=3672–}}</ref>

{{TOC limit|3}}

==Medical uses==

{{See also|Estradiol (medication)#Medical uses}}

PEP is used as an [[intramuscular injection]] for [[estrogen therapy (oncology)|estrogen therapy]] of prostate cancer in men.<ref name="Pharmanovia-Estradurin" /><ref name="pmid10230677" /> It is also used to treat [[breast cancer]] in women who are at least 5&nbsp;years [[menopause|postmenopausal]].<ref name="Pharmanovia-Estradurin" /><ref name="pmid393380">{{cite journal | vauthors = Ostrowski MJ, Jackson AW | title = Polyestradiol phosphate: a preliminary evaluation of its effect on breast carcinoma | journal = Cancer Treatment Reports | volume = 63 | issue = 11–12 | pages = 1803–1807 | date = 1979 | pmid = 393380 }}</ref><ref name="pmid8738608">{{cite journal | vauthors = Brunner N, Spang-Thomsen M, Cullen K | title = The T61 human breast cancer xenograft: an experimental model of estrogen therapy of breast cancer | journal = Breast Cancer Research and Treatment | volume = 39 | issue = 1 | pages = 87–92 | date = 1996 | pmid = 8738608 | doi = 10.1007/bf01806080 | quote = [...] 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. | s2cid = 27430232 }}</ref> In addition, PEP is used in [[hormone replacement therapy]] for [[hypoestrogenism|low estrogen level]]s due to [[hypogonadism]] or [[menopause]] in women.<ref name="Pharmanovia-Estradurin" /> It is also used in [[feminizing hormone therapy]] for [[transgender women]].<ref name="Urdl-2009">{{cite journal | vauthors = Urdl W | title = Behandlungsgrundsätze bei Transsexualität | trans-title = Therapeutic principles in transsexualism | language = de | journal = Gynäkologische Endokrinologie | volume = 7 | issue = 3 | year = 2009 | pages = 153–160 | issn = 1610-2894 | doi = 10.1007/s10304-009-0314-9| s2cid = 8001811 }}</ref><ref name="Arver-2015">{{cite web | vauthors = Arver DS | title = Transsexualism, könsdysfori | trans-title = Transsexualism, gender dysphoria | date = 2015 | access-date = 12 November 2018 | url = https://www.internetmedicin.se/page.aspx?id=3422}}</ref> PEP is a form of [[high-dose estrogen]] therapy.<ref name="pmid10230677" /> After an injection, it very slowly releases the active agent [[estradiol (medication)|estradiol]] over at least several months.<ref name="Austria-Codex">{{cite book|title=Austria-Codex|veditors = Jasek W |publisher=Österreichischer Apothekerverlag|location=Vienna|year=2007|edition=62nd|isbn=978-3-85200-181-4|pages=2992–4|language=de}}</ref><ref name="pmid8610057" />

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.<ref name="pmid14644018">{{cite journal | vauthors = Sayed Y, Taxel P | title = The use of estrogen therapy in men | journal = Current Opinion in Pharmacology | volume = 3 | issue = 6 | pages = 650–654 | date = December 2003 | pmid = 14644018 | doi = 10.1016/j.coph.2003.07.004 }}</ref><ref name="pmid10699602">{{cite journal | vauthors = Hedlund PO, Henriksson P | title = Parenteral estrogen versus total androgen ablation in the treatment of advanced prostate carcinoma: effects on overall survival and cardiovascular mortality. The Scandinavian Prostatic Cancer Group (SPCG)-5 Trial Study | journal = Urology | volume = 55 | issue = 3 | pages = 328–333 | date = March 2000 | pmid = 10699602 | doi = 10.1016/s0090-4295(99)00580-4 }}</ref> At 18.5 months, there was no difference in [[survival rate|survival]] or [[cardiovascular toxicity]] between the two treatment modalities.<ref name="pmid14644018" /><ref name="pmid10699602" /> These findings suggest that [[parenteral]] forms of estradiol may have similar [[efficacy|effectiveness]] and [[drug safety|safety]] relative to [[androgen deprivation therapy]] (ADT) in the treatment of prostate cancer.<ref name="pmid14644018" /><ref name="pmid10699602" /> In addition, estrogens may have significant advantages relative to ADT in terms of [[osteoporosis|bone loss]] and [[bone fracture|fracture]]s, [[hot flash]]es, [[sexual function]], and [[quality of life]], as well as considerable cost savings with parenteral forms of estradiol compared to [[GnRH analogue|{{abbr|GnRH|gonadotropin-releasing hormone}} analogue]] therapy.<ref name="pmid14644018" /><ref name="pmid10699602" /> On the other hand, [[breast tenderness]] and [[gynecomastia]] occur at very high rates with estrogens, whereas incidences are low with castration and CAB.<ref name="pmid22862307">{{cite journal | vauthors = Deepinder F, Braunstein GD | title = Drug-induced gynecomastia: an evidence-based review | journal = Expert Opinion on Drug Safety | volume = 11 | issue = 5 | pages = 779–795 | date = September 2012 | pmid = 22862307 | doi = 10.1517/14740338.2012.712109 | quote = 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. | s2cid = 22938364 }}</ref> However, gynecomastia with estrogens is generally only mild-to-moderate in severity and is usually only modestly discomforting.<ref name="pmid10230677" /> In addition, gynecomastia caused by estrogens can be prevented with [[prophylaxis|prophylactic]] [[radiotherapy|irradiation]] of the breasts or can be remediated with [[mastectomy]].<ref name="pmid10230677" />

PEP has been studied for the treatment of prostate cancer at dosages of 160&nbsp;mg/month (three studies) and 240&nbsp;mg/month (four studies).<ref name="pmid18268497">{{cite journal | vauthors = Norman G, Dean ME, Langley RE, Hodges ZC, Ritchie G, Parmar MK, Sydes MR, Abel P, Eastwood AJ | display-authors = 6 | title = Parenteral oestrogen in the treatment of prostate cancer: a systematic review | journal = British Journal of Cancer | volume = 98 | issue = 4 | pages = 697–707 | date = February 2008 | pmid = 18268497 | pmc = 2259178 | doi = 10.1038/sj.bjc.6604230 }}</ref> At a dosage of 160&nbsp;mg/month, PEP incompletely suppresses [[testosterone]] levels, failing to reach the castrate range, and is significantly inferior to [[orchiectomy]] in slowing disease progression.<ref name="pmid18268497" /><ref name="pmid10230677" /> Conversely, PEP at a dosage of 240&nbsp;mg/month results in greater testosterone suppression, into the castrate range similarly to orchiectomy, and is equivalent to orchiectomy in effectiveness.<ref name="pmid18268497" /><ref name="pmid10230677" />

For prostate cancer in men, PEP is usually given at a dosage of 80 to 320&nbsp;mg every 4&nbsp;weeks for the first 2 to 3&nbsp;months to rapidly build up estradiol levels.<ref name="Pharmanovia-Estradurin" /> Thereafter, to maintain estradiol levels, the dosage is adjusted down usually to 40 to 160&nbsp;mg every 4&nbsp;weeks based on clinical findings and laboratory parameters.<ref name="Pharmanovia-Estradurin" /> For breast cancer and low estrogen levels in women, the dosage is 40 to 80&nbsp;mg every 4&nbsp;weeks.<ref name="Pharmanovia-Estradurin" /> For transgender women, the dosage is 80 to 160&nbsp;mg every 4&nbsp;weeks.<ref name="Urdl-2009" /><ref name="Arver-2015" /><ref name="pmid9021341">{{cite journal | vauthors = Schlatterer K, von Werder K, Stalla GK | title = Multistep treatment concept of transsexual patients | journal = Experimental and Clinical Endocrinology & Diabetes | volume = 104 | issue = 6 | pages = 413–419 | date = 1996 | pmid = 9021341 | doi = 10.1055/s-0029-1211479 | s2cid = 25099676 }}</ref><ref name="Kuhnz-2012" />

===Available forms===

PEP is provided in the form of powder or an [[aqueous solution]] in [[vial]]s and [[ampoule]]s alone or in combination with [[mepivacaine]] and/or [[nicotinamide]] ([[vitamin B3|vitamin B₃]]) for administration via [[intramuscular injection]].<ref name="Pharmanovia-Estradurin" /><ref name="Muller1998B">{{cite book| vauthors = Muller NF, Dessing RP |title=European Drug Index: European Drug Registrations | edition = Fourth |url=https://books.google.com/books?id=2HBPHmclMWIC&pg=PA455|date=19 June 1998|publisher=CRC Press|isbn=978-3-7692-2114-5|pages=455–}}</ref><ref name="Pfizer-Estradurin">{{cite web | title = Estradurine | work = Material Safety Data Sheet | publisher = Pfizer | date = 2 January 2007 | url = https://www.pfizer.com/sites/default/files/products/material_safety_data/ESTRADURINE.pdf | archive-url = https://web.archive.org/web/20130820062917/https://www.pfizer.com/sites/default/files/products/material_safety_data/ESTRADURINE.pdf | archive-date = 20 August 2013 }}</ref> Mepivacaine is a [[local anaesthetic]] and is used to avoid a [[burning sensation]] during injection of PEP.<ref name="Pharmanovia-Estradurin" /> Each vial/ampoule of Estradurin contains 80&nbsp;mg PEP, 5&nbsp;mg mepivacaine hydrochloride, 40&nbsp;mg nicotinamide, and 2&nbsp;mL water.<ref name="Pfizer-Estradurin" />

{{See also|Estradiol (medication)#Contraindications}}

The [[contraindication]]s of PEP are largely the same as those of estradiol and include:<ref name="Pharmanovia-Estradurin" /><ref name="pmid2215269" /><ref name="Lauritzen-2005">{{cite book| vauthors = Lauritzen C | chapter = Practice of hormone substitution | veditors = Lauritzen C, Studd JW |title=Current Management of the Menopause|chapter-url=https://books.google.com/books?id=WD7S7677xUUC&pg=PA95|date=22 June 2005|publisher=CRC Press|isbn=978-0-203-48612-2|pages=95–98,488}}</ref><ref name="Laurtizen-2001">{{cite book | vauthors = Laurtizen C | chapter = Hormone Substitution Before, During and After Menopause | pages = 67–88 | chapter-url = https://www.kup.at/kup/pdf/4978.pdf | veditors = Fisch FH | title = Menopause – Andropause: Hormone Replacement Therapy Through the Ages | year = 2001 | publisher = Krause & Pachernegg: Gablitz | isbn = 978-3-901299-34-6}}</ref><ref name="Midwinter-1976">{{cite book| vauthors = Midwinter A |chapter=Contraindications to estrogen therapy and management of the menopausal syndrome in these cases|pages=377–382|doi=10.1007/978-94-011-6165-7_33| veditors = Campbell S |title=The Management of the Menopause & Post-Menopausal Years: The Proceedings of the International Symposium held in London 24–26 November 1975 Arranged by the Institute of Obstetrics and Gynaecology, The University of London|year=1976|isbn=978-94-011-6167-1|publisher=MTP Press Limited}}</ref>

* [[Hypersensitivity]] to PEP, [[mepivacaine]], or other ingredients

* Known, previous, or suspected [[breast cancer]] or other [[estrogen-dependent condition|estrogen-dependent]] [[hormone-sensitive cancer|malignant tumor]]s (e.g., [[endometrial cancer]])

* [[Vaginal bleeding]] of unknown cause or untreated [[endometrial hyperplasia]]

* [[Thrombosis]] and related, including active [[thrombophlebitis]], former or current [[venous thromboembolism]] ([[deep vein thrombosis]], [[pulmonary embolism]]), active or recent [[arterial thrombosis|arterial thromboembolism]] (e.g., [[angina]], [[myocardial infarction]]), or known [[thrombophilia]] (e.g., [[protein C deficiency]], [[protein S deficiency]], [[antithrombin deficiency]])

* Severe [[Heart arrhythmia|arrhythmia]], [[hypotension]], [[hypertension]], or [[lipid metabolism disorder]]s

* [[Cerebrovascular event]]s (i.e., [[stroke]])

* [[Acute liver disease]] or previously confirmed [[liver disease]], with abnormal [[liver function tests]] or [[jaundice]] (e.g., [[Dubin–Johnson syndrome]], [[Rotor syndrome]])

* Severe [[hepatic dysfunction]]

* Others including [[porphyria]], [[sickle cell anemia]], [[otosclerosis]], or [[myasthenia gravis]]

* [[Pregnancy]], [[lactation]], and [[breastfeeding]]

==Side effects==

{{See also|Estradiol (medication)#Side effects}}

[[Clinical study|Systematic studies]] of the [[side effect]]s of PEP are lacking.<ref name="Pharmanovia-Estradurin" /> However, its side effects are assumed to be identical to those of [[estradiol (medication)|estradiol]] and other [[estradiol ester]]s.<ref name="Pharmanovia-Estradurin" /> The side effects of PEP are partially dependent on sex.<ref name="Pharmanovia-Estradurin" /> 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 (biology)|feminization]], [[demasculinization]], [[infertility]], and [[vaginal bleeding|vaginal bleeding or spotting]].<ref name="Pharmanovia-Estradurin" /><ref name="Altwein-2013">{{cite book| vauthors = Altwein JE | chapter = Therapie des virginellen metastasierten Prostatakarzinoms | veditors = Helpap B, Rübben H |title=Prostatakarzinom — Pathologie, Praxis und Klinik: Pathologie, Praxis und Klinik| chapter-url=https://books.google.com/books?id=5yCWBwAAQBAJ&pg=PA126|date=12 March 2013|publisher=Springer-Verlag|isbn=978-3-642-72110-6|pages=126–}}</ref> Side effects that occur occasionally or uncommonly (0.1–1%) include [[sodium retention|sodium]] and [[water retention (medicine)|water retention]], [[edema]], [[hypersensitivity]], [[breast tension]], [[depression (mood)|depression]], [[dizziness]], [[visual disturbance]]s, [[palpitation]]s, [[dyspepsia]], [[erythema nodosum]], [[urticaria]], and [[chest pain]].<ref name="Pharmanovia-Estradurin" /> All other side effects of PEP are considered to be rare.<ref name="Pharmanovia-Estradurin" />

The rare (<0.1%) side effects of PEP are considered to include [[weight gain]], [[impaired glucose tolerance]], [[mood (psychology)|mood]] changes ([[mood elation|elation]] or [[depression (mood)|depression]]), [[anxiety|nervousness]], [[tiredness]], [[headache]], [[migraine]], intolerance of [[contact lens]]es, [[hypertension]], [[thrombosis]], [[thrombophlebitis]], [[thromboembolism]], [[heart failure]], [[myocardial infarction]], [[vomiting]], [[bloating]], [[cholestatic jaundice]], [[cholelithiasis]], transient increases in [[transaminase]]s and [[bilirubin]], [[erythema multiforme]], [[hyperpigmentation]], [[muscle cramp]]s, [[dysmenorrhea]], [[vaginal discharge]], [[premenstrual syndrome|premenstrual-like symptoms]], [[breast enlargement]], [[testicular atrophy]], [[allergic reaction]]s (e.g., [[urticaria]], [[bronchial asthma]], [[anaphylactic shock]]) due to [[mepivacaine]], and [[injection site reaction]]s (e.g., [[pain]], [[sterile abscess]]es, [[inflammatory infiltrate]]s).<ref name="Pharmanovia-Estradurin" />

As [[thromboembolism|thromboembolic]] and other [[cardiovascular]] complications are associated mainly with [[synthetic compound|synthetic]] [[oral administration|oral]] estrogens like [[ethinylestradiol]] and [[diethylstilbestrol]], they occur much less often with [[parenteral]] bioidentical forms of estrogen like PEP.<ref name="Pharmanovia-Estradurin" /><ref name="pmid10230677" />

===Cardiovascular effects===

PEP produces minimal undesirable effects on [[coagulation factor]]s and is thought to increase the risk of [[blood clot]]s little or not at all.<ref name="pmid17019433">{{cite journal | vauthors = Ockrim J, Lalani EN, Abel P | title = Therapy Insight: parenteral estrogen treatment for prostate cancer--a new dawn for an old therapy | journal = Nature Clinical Practice. Oncology | volume = 3 | issue = 10 | pages = 552–563 | date = October 2006 | pmid = 17019433 | doi = 10.1038/ncponc0602 | s2cid = 6847203 }}</ref><ref name="pmid17239273">{{cite journal | vauthors = Lycette JL, Bland LB, Garzotto M, Beer TM | title = Parenteral estrogens for prostate cancer: can a new route of administration overcome old toxicities? | journal = Clinical Genitourinary Cancer | volume = 5 | issue = 3 | pages = 198–205 | date = December 2006 | pmid = 17239273 | doi = 10.3816/CGC.2006.n.037 }}</ref> This is in spite of the fact that estradiol levels can reach high concentrations of as much as 700&nbsp;pg/mL with high-dose (320&nbsp;mg/month) PEP therapy.<ref name="pmid3242384" /> 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.<ref name="pmid17019433" /><ref name="pmid17239273" /><ref name="pmid16112947" /> The difference between the two types of therapies is due to the [[bioidentical hormone therapy|bioidentical]] and [[parenteral]] nature of PEP and its minimal influence on [[liver protein synthesis]].<ref name="pmid17019433" /><ref name="pmid17239273" /><ref name="pmid16112947" /> PEP might actually reduce the risk of blood clots, due to decreases in levels of certain procoagulatory proteins.<ref name="pmid17019433" /><ref name="pmid17239273" /> Although PEP does not increase the hepatic production or levels of procoagulatory factors, it has been found to significantly decrease levels of the anticoagulatory [[antithrombin III]], which may indicate a potential risk of [[thromboembolism|thromboembolic]] and cardiovascular complications.<ref name="pmid10230677" /> On the other hand, PEP significantly increases levels of [[HDL cholesterol]] and significantly decreases levels of [[LDL cholesterol]], changes which are thought to protect against [[coronary artery disease]].<ref name="pmid10230677" /> It appears that PEP may have beneficial effects on cardiovascular health at lower dosages (e.g., 160&nbsp;mg/day) due to its beneficial effects on HDL and LDL cholesterol levels, but these are overshadowed at higher dosages (e.g., 240&nbsp;mg/day) due to unfavorable dose-dependent effects on [[hemostasis]], namely antithrombin III levels.<ref name="pmid10230677" />

Small early pilot studies of PEP for prostate cancer in men found no cardiovascular toxicity with the therapy.<ref name="pmid17019433" /> A dosage of PEP of 160&nbsp;mg/month specifically does not appear to increase the risk of cardiovascular complications.<ref name="pmid10230677" /> In fact, potential beneficial effects on cardiovascular mortality have been observed at this dosage.<ref name="pmid10230677" /> However, PEP at a higher dosage of 240&nbsp;mg/month has subsequently been found in large studies to significantly increase cardiovascular [[morbidity]] relative to [[GnRH modulator]]s and [[orchiectomy]] in men treated with it for prostate cancer.<ref name="pmid17019433" /><ref name="pmid17239273" /><ref name="pmid10230677" /> The increase in cardiovascular morbidity with PEP therapy is due to an increase in non-fatal cardiovascular events, including [[ischemic heart disease]] and [[heart decompensation]], specifically [[heart failure]].<ref name="pmid17239273" /><ref name="Denmeade-2010" /><ref name="pmid28667081">{{cite journal | vauthors = Russell N, Cheung A, Grossmann M | title = Estradiol for the mitigation of adverse effects of androgen deprivation therapy | journal = Endocrine-Related Cancer | volume = 24 | issue = 8 | pages = R297–R313 | date = August 2017 | pmid = 28667081 | doi = 10.1530/ERC-17-0153 | doi-access = free }}</ref> Conversely, PEP has not been found to significantly increase cardiovascular [[mortality rate|mortality]] relative to GnRH modulators and orchiectomy.<ref name="pmid17019433" /><ref name="pmid17239273" /> 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.<ref name="pmid17239273" /> 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.<ref name="pmid17019433" /> A longitudinal risk analysis that projected over 10&nbsp;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.<ref name="pmid17019433" />

The cardiovascular toxicity of PEP is far less than that of oral synthetic estrogens like diethylstilbestrol and ethinylestradiol, which increase the risk of [[venous thromboembolism|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.<ref name="pmid17019433" /><ref name="pmid17239273" /> It is thought that the relatively minimal cardiovascular toxicity of parenteral forms of estradiol, like PEP and high-dose transdermal estradiol patches,<ref name="pmid23465742">{{cite journal | vauthors = Langley RE, Cafferty FH, Alhasso AA, Rosen SD, Sundaram SK, Freeman SC, Pollock P, Jinks RC, Godsland IF, Kockelbergh R, Clarke NW, Kynaston HG, Parmar MK, Abel PD | display-authors = 6 | title = Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09) | journal = The Lancet. Oncology | volume = 14 | issue = 4 | pages = 306–316 | date = April 2013 | pmid = 23465742 | pmc = 3620898 | doi = 10.1016/S1470-2045(13)70025-1 }}</ref> is due to their absence of effect on hepatic coagulation factors.<ref name="pmid17019433" /><ref name="pmid17239273" />

==Overdose==

{{See also|Estradiol (medication)#Overdose}}

[[Acute toxicity]] studies have not indicated a risk of acute side effects with [[overdose]] of PEP.<ref name="Pharmanovia-Estradurin" /> The [[median lethal dose]] (LD₅₀) of PEP in mice is approximately 700&nbsp;mg/kg.<ref name="pmid13312990">{{cite journal | vauthors = Diczfalusy E, Westman A | title = Urinary excretion of natural oestrogens in oophorectomized women treated with polyoestradiol phosphate (PEP) | journal = Acta Endocrinologica | volume = 21 | issue = 4 | pages = 321–336 | date = April 1956 | pmid = 13312990 | doi = 10.1530/acta.0.0210321 }}</ref> PEP has been administered in total amounts of 2,000 to 3,000&nbsp;mg over several months in patients with cancer without [[toxicity]] observed.<ref name="pmid13312990" /> The most likely sign of overdose is reversible [[feminization (biology)|feminization]], namely [[gynecomastia]].<ref name="Pharmanovia-Estradurin" /> Other [[symptom]]s of estrogen [[overdose|overdosage]] may include [[nausea]], [[vomiting]], [[bloating]], [[weight gain|increased weight]], [[water retention (medicine)|water retention]], [[breast tenderness]], [[vaginal discharge]], [[heavy legs]], and [[leg cramps]].<ref name="pmid2215269">{{cite journal | vauthors = Lauritzen C | title = Clinical use of oestrogens and progestogens | journal = Maturitas | volume = 12 | issue = 3 | pages = 199–214 | date = September 1990 | pmid = 2215269 | doi = 10.1016/0378-5122(90)90004-P }}</ref> These side effects can be diminished by reducing the estrogen dosage.<ref name="pmid2215269" /> There is no specific [[antidote]] for overdose of PEP.<ref name="Pharmanovia-Estradurin" /> Treatment of PEP overdose should be based on [[symptom]]s.<ref name="Pharmanovia-Estradurin" />

== Interactions ==

{{See also|Estradiol (medication)#Interactions}}

Known potential [[drug interaction|interaction]]s of PEP are mostly the same as those of estradiol and include:<ref name="Pharmanovia-Estradurin" />

* [[Cytochrome P450]] [[enzyme inhibitor|inhibitor]]s, especially of [[CYP3A4]], can reduce the [[metabolism]] of estradiol and thereby increase estradiol levels; examples include [[anti-infective]]s (e.g., [[erythromycin]], [[clarithromycin]], [[ketoconazole]], [[itraconazole]]), [[cimetidine]], and [[grapefruit juice]]<ref name="Pharmanovia-Estradurin" /><ref name="pmid11741520">{{cite journal | vauthors = Cheng ZN, Shu Y, Liu ZQ, Wang LS, Ou-Yang DS, Zhou HH | title = Role of cytochrome P450 in estradiol metabolism in vitro | journal = Acta Pharmacologica Sinica | volume = 22 | issue = 2 | pages = 148–154 | date = February 2001 | pmid = 11741520 }}</ref>

* Cytochrome P450 [[enzyme inducer|inducer]]s, especially of CYP3A4, can induce the metabolism of estradiol and thereby decrease estradiol levels; examples include [[anticonvulsant]]s (e.g., [[phenobarbital]], [[carbamazepine]], [[phenytoin]]), [[anti-infective]]s ([[rifampicin]], [[rifabutin]], [[nevirapine]], and [[efavirenz]]), and [[St. John's wort]]; in addition, while [[ritonavir]] and [[nelfinavir]] are known as strong inhibitors, they have an inducing effect in combination with [[steroid hormone]]s<ref name="Pharmanovia-Estradurin" />

* Certain [[antibiotic]]s (e.g., [[ampicillin]], [[tetracycline]]s) may decrease estradiol levels by limiting [[enterohepatic recirculation]] of estradiol<ref name="Pharmanovia-Estradurin" />

* [[Paracetamol]] (acetaminophen), certain [[beta blocker]]s (e.g., [[metoprolol]]), and some [[benzodiazepine]]s may increase the effects of PEP<ref name="Pharmanovia-Estradurin" />

* The [[coagulation]]-promoting effects of PEP may enhance those of [[aminocaproic acid]]<ref name="Pharmanovia-Estradurin" />

* [[Polystyrene phosphate]] can reduce the effects of [[anticoagulant]]s<ref name="Pharmanovia-Estradurin" />

* Estrogens increase [[thyroxine-binding globulin]] levels and may result in increased total [[thyroid hormone]] levels (but not free thyroid hormone levels in [[euthyroid]] individuals);<ref name="pmid15142374">{{cite journal | vauthors = Mazer NA | title = Interaction of estrogen therapy and thyroid hormone replacement in postmenopausal women | journal = Thyroid | volume = 14 | issue = Suppl 1 | pages = S27–S34 | date = 2004 | pmid = 15142374 | doi = 10.1089/105072504323024561 }}</ref> interpretation of [[thyroid function tests]] should consider this<ref name="Pharmanovia-Estradurin" />

* Due to [[reduced glucose tolerance]], there may be an influence on need for [[insulin (medication)|insulin]] or oral [[antidiabetic medication]]s<ref name="Pharmanovia-Estradurin" />

* PEP may impair the effects of [[fibrate]]s (e.g., [[bezafibrate]]) and certain [[nonsteroidal anti-inflammatory drug]]s (e.g., [[phenazone]])<ref name="Pharmanovia-Estradurin" />

* Concurrent use of [[hepatotoxic]] medications, especially [[dantrolene]], may increase the risk of hepatotoxicity<ref name="Pharmanovia-Estradurin" />

* [[Alkaline phosphatase#Inhibitors|Phosphatase inhibitor]]s like [[levamisole]] may inhibit the cleavage of PEP into estradiol

Interactions with PEP may be less than with oral estrogens due to the lack of the [[first-pass metabolism|first-pass]] through the [[liver]].<ref name="Pharmanovia-Estradurin" />

==Pharmacology==

===Pharmacodynamics===

{{See also|Pharmacodynamics of estradiol}}

[[File:Estradiol.svg|thumb|right|225px|[[Estradiol (medication)|Estradiol]], the [[active metabolite|active form]] of PEP.]]

PEP is an [[estradiol ester]] in the form of a [[polymer]] and is an extremely long-lasting [[prodrug]] of [[estradiol (medication)|estradiol]].<ref name="pmid10230677" /><ref name="pmid8610057" /><ref name="Kuhnz-2012" /><ref name="pmid16112947" /> As such, it is an [[estrogen (medication)|estrogen]], or an [[agonist]] of the [[estrogen receptor]]s.<ref name="pmid10230677" /><ref name="pmid16112947" /><ref name="Kuhnz-2012" /> PEP has [[antigonadotropic]] and functional [[antiandrogen]]ic effects due to its estrogenic activity.<ref name="pmid3242384" /> 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 [[phosphoric acid|phosphate]] ester.<ref name="Drugs.com2" /><ref name="IndexNominum2000" /> Because PEP is a prodrug of estradiol, it is considered to be a [[natural product|natural]] and [[bioidentical hormone replacement therapy|bioidentical]] form of estrogen.<ref name="Kuhnz-2012" />

PEP is a strong [[enzyme inhibitor|inhibitor]] of several [[enzyme]]s, including [[acid phosphatase]], [[alkaline phosphatase]], and [[hyaluronidase]], ''[[in vitro]]''.<ref name="pmid6938044">{{cite journal | vauthors = Lindstedt E | title = Polyestradiol phosphate and ethinyl estradiol in treatment of prostatic carcinoma | journal = Scandinavian Journal of Urology and Nephrology. Supplementum | volume = 55 | pages = 95–97 | date = 1980 | pmid = 6938044 | quote = 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. }}</ref><ref name="pmid7117668">{{cite journal | vauthors = Steven FS, Griffin MM | title = Inhibition of thrombin cleavage of fibrinogen by polyestradiol phosphate; interaction with the crucial arginine residues in fibrinogen required for enzymic cleavage | journal = The International Journal of Biochemistry | volume = 14 | issue = 8 | pages = 699–700 | date = 1982 | pmid = 7117668 | doi = 10.1016/0020-711X(82)90004-0 | quote = Polyestradiol phosphate (PEP) has been demonstrated to have inhibitory activity against hyaluronidase, acid phosphatase and alkaline phosphatase (Fernö et al., 1958). }}</ref><ref name="Fernö-1958">{{cite journal | vauthors = Fernö O, Fex H, Högberg B, Linderot T, Veige S | title = High Molecular Weight Enzyme Inhibitors. 3. Polyestradiol Phosphate (PEP), a Long-acting Estrogen | journal = Acta Chemica Scandinavica | volume = 12 | issue = 8 | year = 1958 | pages = 1675–1689 | doi = 10.3891/acta.chem.scand.12-1675| doi-access = free }}</ref> In light of the fact that [[phosphatase]]s, which cleave PEP into estradiol and phosphoric acid, are present in most tissues in the body, it has been said that the long [[elimination half-life]] and slow release of PEP are somewhat surprising.<ref name="pmid3217277" /> It is thought that PEP may inhibit its own [[metabolism]].<ref name="pmid3217277" />

{{Parenteral potencies and durations of steroidal estrogens}}

{{Gallery

| title=Hormone levels with polyestradiol phosphate by intramuscular injection

| width=450 | height=325

| align=center

| style="font-size:small;"

| File:Estradiol and testosterone levels with a single intramuscular injection of 320 mg polyestradiol phosphate in men.png | Estradiol and testosterone levels with a single intramuscular injection of 320&nbsp;mg polyestradiol phosphate in men with prostate cancer.<ref name="pmid8610057" />

| File:Estradiol and testosterone levels with polyestradiol phosphate in men with prostate cancer.png | Estradiol and testosterone levels with polyestradiol phosphate 160, 240, or 320 mg once every 4 weeks by intramuscular injection in men with prostate cancer.<ref name="pmid3242384" />

====Antigonadotropic effects====

PEP has [[antigonadotropic]] effects due to its estrogenic activity.<ref name="Denmeade-2010">{{cite book| vauthors = Denmeade SR | chapter = Androgen Deprivation Strategies in the Treatment of Advanced Prostate Cancer | veditors = Hong WK, Holland JF |title=Holland-Frei Cancer Medicine 8|chapter-url=https://books.google.com/books?id=R0FbhLsWHBEC&pg=PA753|year=2010|publisher=PMPH-USA|isbn=978-1-60795-014-1|pages=753–}}</ref> It has been found to suppress testosterone levels in men by 55%, 75%, and 85% at intramuscular dosages of 80, 160, and 240&nbsp;mg every 4&nbsp;weeks, respectively.<ref name="pmid3217277">{{cite journal | vauthors = Gunnarsson PO, Norlén BJ | title = Clinical pharmacology of polyestradiol phosphate | journal = The Prostate | volume = 13 | issue = 4 | pages = 299–304 | year = 1988 | pmid = 3217277 | doi = 10.1002/pros.2990130405 | s2cid = 33063805 }}</ref> A single intramuscular injection of 320&nbsp;mg PEP in men has been found to suppress testosterone levels to within the castrate range (< 50&nbsp;ng/dL) within 3&nbsp;weeks.<ref name="pmid8610057" /> This was associated with circulating estradiol levels of just over 200&nbsp;pg/mL.<ref name="pmid3242384" /> The suppression of testosterone levels that can be achieved with PEP is equal to that with [[orchiectomy]].<ref name="pmid2664738">{{cite journal | vauthors = von Schoultz B, Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A, Stege R | title = Estrogen therapy and liver function--metabolic effects of oral and parenteral administration | journal = The Prostate | volume = 14 | issue = 4 | pages = 389–395 | year = 1989 | pmid = 2664738 | doi = 10.1002/pros.2990140410 | s2cid = 21510744 }}</ref> However, to achieve such concentrations of testosterone, which are about 15&nbsp;ng/dL on average, higher concentrations of estradiol of around 500&nbsp;pg/mL were necessary.<ref name="pmid3242384">{{cite journal | vauthors = Stege R, Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A | title = Single drug polyestradiol phosphate therapy in prostatic cancer | journal = American Journal of Clinical Oncology | volume = 11 | issue = Suppl 2 | pages = S101–S103 | date = 1988 | pmid = 3242384 | doi = 10.1097/00000421-198801102-00024 | s2cid = 32650111 }}</ref><ref name="pmid2664738" /><ref name="Hurmuz-2017">{{cite book| vauthors = Hurmuz P, Akyol F, Gultekin M, Yazici G, Sari SY, Ozyigit G | chapter = The Role of Hormonal Treatment in Prostate Cancer | veditors = Ozyigit G, Selek U |title=Principles and Practice of Urooncology: Radiotherapy, Surgery and Systemic Therapy| chapter-url=https://books.google.com/books?id=Rx8vDwAAQBAJ&pg=PA334|date=1 August 2017|publisher=Springer|isbn=978-3-319-56114-1|pages=334–|quote=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).}}</ref> This was associated with a dosage of intramuscular 320&nbsp;mg PEP every four weeks and occurred by 90&nbsp;days of treatment.<ref name="pmid3242384" /> However, 240&nbsp;mg PEP every four weeks has also been reported to eventually suppress testosterone levels in the castrate range.<ref name="pmid9698663">{{cite journal | vauthors = Mikkola AK, Ruutu ML, Aro JL, Rannikko SA, Salo JO | title = Parenteral polyoestradiol phosphate vs orchidectomy in the treatment of advanced prostatic cancer. Efficacy and cardiovascular complications: a 2-year follow-up report of a national, prospective prostatic cancer study. Finnprostate Group | journal = British Journal of Urology | volume = 82 | issue = 1 | pages = 63–68 | date = July 1998 | pmid = 9698663 | doi = 10.1046/j.1464-410x.1998.00688.x }}</ref><ref name="Stege-1987">{{cite journal| vauthors = Stege R, Carlström K, Collste L, Eriksson A, Henriksson P |title=Single drug polyestradiol phosphate (PEP) therapy in prostatic cancer (CAP)|journal=European Journal of Cancer and Clinical Oncology|volume=23|issue=8|year=1987|pages=1249|issn=0277-5379|doi=10.1016/0277-5379(87)90236-7}}</ref>

====Mechanism of action in prostate cancer====

The growth of prostate cancer is generally stimulated by [[dihydrotestosterone]] (DHT), and unless the cancer is [[castration-resistant prostate cancer|castration-resistant]], it can be treated by [[androgen deprivation therapy|depriving it of androgens]]. Estradiol produces its therapeutic benefits mainly via exertion of [[negative feedback]] on the [[hypothalamic–pituitary–gonadal axis]].<ref name="Denmeade-2010" /><ref name="pmid3217277" /><ref name="pmid8610057" /> This blocks the [[secretion]] of [[luteinizing hormone]], which in turn reduces [[testosterone]] [[biosynthesis|production]] in the [[Leydig cell]]s of the [[testicle|testes]].<ref name="Denmeade-2010" /><ref name="pmid3217277" /><ref name="pmid8610057" /> Estradiol also decreases the free percentage of testosterone by increasing [[sex hormone-binding globulin]] (SHBG) levels.<ref name="pmid8610057" /> In addition, it exhibits direct [[cytotoxicity]] on prostate cancer cells.<ref name="Arzneistoff-Profile">{{cite book|title=Arzneistoff-Profile| veditors = Dinnendahl V, Fricke U |publisher=Govi Pharmazeutischer Verlag|location=Eschborn, Germany|year=2010|edition=23|volume=4|isbn=978-3-7741-98-46-3|language=de}}</ref><ref name="Austria-Codex" />

====Differences from other estrogens====

[[File:SHBG levels with polyestradiol phosphate, ethinylestradiol, and orchiectomy.png|thumb|right|400px|SHBG levels with 1) {{abbr|i.m.|intramuscular}} injection of 320&nbsp;mg PEP every 4&nbsp;weeks; 2) {{abbr|i.m.|intramuscular}} injection of 320&nbsp;mg PEP every 4&nbsp;weeks plus 150 μg/day oral [[ethinylestradiol]]; 3) [[orchiectomy]].<ref name="pmid3242384" />]]

{| class="wikitable floatright"

|+ Effects of estrogens on coagulation factors

|-

! Factors !! Oral estrogens^a !! Parenteral estrogens^b

|-

| [[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

|- class="sortbottom"

| colspan="3" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Footnotes:''' ^a = E.g., {{abbrlink|DES|diethylstilbestrol}}, {{abbrlink|EE|ethinylestradiol}}. ^b = PEP. '''Sources:'''<ref name="pmid17239273" />

|}

Estrogens have effects on [[liver protein synthesis]], including on the [[biosynthesis|synthesis]] of [[plasma protein]]s, [[coagulation factor]]s, [[lipoprotein]]s, and [[triglyceride]]s.<ref name="pmid2664738" /> These effects can result in an increased risk of [[thromboembolism|thromboembolic]] and [[cardiovascular]] complications, which in turn can result in increased [[mortality rate|mortality]].<ref name="pmid2664738" /> 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.<ref name="pmid2664738" /> 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.<ref name="pmid2664738" /> This is because the [[first-pass metabolism|first-pass]] through the [[liver]] with oral administration is avoided and because bioidentical estrogens are efficiently inactivated in the liver.<ref name="pmid2664738" /> In accordance, PEP has minimal effect on the [[liver]] at a dosage of up to at least 240&nbsp;mg/month.<ref name="pmid10386467" />

A study found that whereas 320&nbsp;mg/month intramuscular PEP increased SHBG levels to 166% in men with prostate cancer, the combination of 80&nbsp;mg/month intramuscular polyestradiol phosphate and 150&nbsp;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.<ref name="pmid3242384" /><ref name="pmid8610057" /><ref name="pmid2523531">{{cite journal | vauthors = Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A, Stege R, von Schoultz B | title = A comparison of androgen status in patients with prostatic cancer treated with oral and/or parenteral estrogens or by orchidectomy | journal = The Prostate | volume = 14 | issue = 2 | pages = 177–182 | date = 1989 | pmid = 2523531 | doi = 10.1002/pros.2990140210 | s2cid = 25516937 }}</ref> 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.<ref name="pmid8610057" /> 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&nbsp;mg/month intramuscular PEP.<ref name="pmid10386467">{{cite journal | vauthors = Henriksson P, Carlström K, Pousette A, Gunnarsson PO, Johansson CJ, Eriksson B, Altersgård-Brorsson AK, Nordle O, Stege R | display-authors = 6 | title = Time for revival of estrogens in the treatment of advanced prostatic carcinoma? Pharmacokinetics, and endocrine and clinical effects, of a parenteral estrogen regimen | journal = The Prostate | volume = 40 | issue = 2 | pages = 76–82 | date = July 1999 | pmid = 10386467 | doi = 10.1002/(sici)1097-0045(19990701)40:2<76::aid-pros2>3.0.co;2-q | s2cid = 12240276 }}</ref> 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.<ref name="pmid8610057" />

Originally, PEP was typically used at a dosage of 80&nbsp;mg per month in combination with 150&nbsp;μg per day oral ethinylestradiol in the treatment of prostate cancer.<ref name="pmid3217277" /><ref name="pmid7500443">{{cite journal | vauthors = Cox RL, Crawford ED | title = Estrogens in the treatment of prostate cancer | journal = The Journal of Urology | volume = 154 | issue = 6 | pages = 1991–1998 | date = December 1995 | pmid = 7500443 | doi = 10.1016/S0022-5347(01)66670-9 }}</ref> This combination was found to produce a considerable incidence of cardiovascular toxicity,<ref name="pmid2664738" /> and this toxicity was inappropriately attributed to PEP in some publications.<ref name="Wenderoth-1983">{{cite journal| vauthors = Wenderoth UK, Jacobi GH |title=Gonadotropin-releasing hormone analogues for palliation of carcinoma of the prostate|journal=World Journal of Urology|volume=1|issue=1|year=1983|pages=40–48|issn=0724-4983|doi=10.1007/BF00326861|s2cid=23447326}}</ref> Subsequent research has shown that the toxicity is not due to PEP but rather to the ethinylestradiol component.<ref name="pmid15046698">{{cite journal | vauthors = Oh WK | title = The evolving role of estrogen therapy in prostate cancer | journal = Clinical Prostate Cancer | volume = 1 | issue = 2 | pages = 81–89 | date = September 2002 | pmid = 15046698 | doi = 10.3816/CGC.2002.n.009 }}</ref><ref name="pmid3217277" /><ref name="pmid2664738" />

A study found that therapy with intramuscular PEP resulting in estradiol levels of around 400&nbsp;pg/mL in men with prostate cancer did not affect [[growth hormone]] or [[insulin-like growth factor 1]] levels, whereas the addition of oral [[ethinylestradiol]] significantly increased growth hormone levels and decreased insulin-like growth factor 1 levels.<ref name="pmid2440014">{{cite journal | vauthors = Stege R, Fröhlander N, Carlström K, Pousette A, von Schoultz B | title = Steroid-sensitive proteins, growth hormone and somatomedin C in prostatic cancer: effects of parenteral and oral estrogen therapy | journal = The Prostate | volume = 10 | issue = 4 | pages = 333–338 | date = 1987 | pmid = 2440014 | doi = 10.1002/pros.2990100407 | s2cid = 36814574 }}</ref><ref name="pmid2646476">{{cite journal | vauthors = von Schoultz B, Carlström K | title = On the regulation of sex-hormone-binding globulin--a challenge of an old dogma and outlines of an alternative mechanism | journal = Journal of Steroid Biochemistry | volume = 32 | issue = 2 | pages = 327–334 | date = February 1989 | pmid = 2646476 | doi = 10.1016/0022-4731(89)90272-0 }}</ref>

===Pharmacokinetics===

{{See also|Pharmacokinetics of estradiol}}

PEP has a very long duration and is given by intramuscular injection once every 4&nbsp;weeks.<ref name="pmid3242384" /> In men, an initial intramuscular injection of PEP results in a rapid rise in estradiol levels measured at&nbsp;24 hours followed by a slow and gradual further increase in levels up until at least day&nbsp;28 (the time of the next injection).<ref name="pmid3242384" /> Subsequent injections result in a progressive and considerable accumulation in estradiol levels up to at least 6&nbsp;months.<ref name="pmid3242384" /> The mean [[elimination half-life]] of PEP has been found to be 70&nbsp;days (10&nbsp;weeks) with a single 320&nbsp;mg intramuscular dose of the medication.<ref name="pmid8610057">{{cite journal | vauthors = Stege R, Gunnarsson PO, Johansson CJ, Olsson P, Pousette A, Carlström K | title = Pharmacokinetics and testosterone suppression of a single dose of polyestradiol phosphate (Estradurin) in prostatic cancer patients | journal = The Prostate | volume = 28 | issue = 5 | pages = 307–310 | date = May 1996 | pmid = 8610057 | doi = 10.1002/(SICI)1097-0045(199605)28:5<307::AID-PROS6>3.0.CO;2-8 | s2cid = 33548251 }}</ref> The [[tmax (pharmacology)|t_max]] (time to maximal concentrations) for estradiol was about 16&nbsp;days.<ref name="pmid8610057" /> PEP has a [[duration of action|duration]] of approximately 1&nbsp;month with a single dose of 40&nbsp;mg, 2&nbsp;months with 80&nbsp;mg, and 4&nbsp;months with 160&nbsp;mg.<ref name="Schreiner-2012" /><ref name="KnörrKnörr-Gärtner2013">{{cite book| vauthors = Knörr K, Knörr-Gärtner H, Beller FK, Lauritzen C | chapter = Prinzipien der Hormonbehandlung |title=Lehrbuch der Geburtshilfe und Gynäkologie: Physiologie und Pathologie der Reproduktion|chapter-url=https://books.google.com/books?id=OjvMBgAAQBAJ&pg=PA508|date=8 March 2013|publisher=Springer-Verlag|isbn=978-3-662-00526-2|pages=508–}}</ref><ref name="KnörrBeller2013">{{cite book| vauthors = Knörr K, Beller FK, Lauritzen C | chapter = Prinzipien der Hormonbehandlung |title=Lehrbuch der Gynäkologie| chapter-url = https://books.google.com/books?id=ACybBwAAQBAJ&pg=PA213|date=17 April 2013|publisher=Springer-Verlag|isbn=978-3-662-00942-0|pages=213}}</ref><ref name="Brambilla-1961">{{cite journal | vauthors = Brambilla F, Berczeller PH, Epstein JA, Blatt MH, Kupperman HS | title = Experiences with the Use of Polyestradiol Phosphate, a Long-acting Estrogen | journal = Obstetrics & Gynecology | year = 1961 | volume = 17 | issue = 1 | pages = 115–118 | url = https://journals.lww.com/greenjournal/Citation/1961/01000/Experiences_with_the_Use_of_Polyestradiol.24.aspx}}</ref><ref name="pmid13312990" />

PEP reaches the [[bloodstream]] within hours after an injection (90% after 24&nbsp;hours), where it circulates, and is accumulated in the [[reticuloendothelial system]].<ref name="Arzneistoff-Profile" /> Estradiol is then [[bond cleavage|cleaved]] from the polymer by [[phosphatase]]s, although very slowly.<ref name="pmid13151143">{{cite journal | vauthors = Diczfalusy E | title = Poly-estradiol phosphate (PEP); a long-acting water soluble. estrogen | journal = Endocrinology | volume = 54 | issue = 4 | pages = 471–477 | date = April 1954 | pmid = 13151143 | doi = 10.1210/endo-54-4-471 }}</ref> Levels of estradiol in men with intramuscular injections of PEP once every 4&nbsp;weeks were about 350&nbsp;pg/mL with 160&nbsp;mg, 450&nbsp;pg/mL with 240&nbsp;mg, and almost 700&nbsp;pg/mL with 320&nbsp;mg, all measured after 6&nbsp;months of treatment.<ref name="pmid3242384" /> With monthly injections, [[steady state (pharmacokinetics)|steady-state]] estradiol concentrations are reached after 6 to 12&nbsp;months.<ref name="Arzneistoff-Profile" /> Estradiol is metabolized primarily in the [[liver]] by [[CYP3A4]] and other [[cytochrome P450]] [[enzyme]]s, and is metabolized to a lesser extent in extrahepatic tissues.<ref name="Austria-Codex" /><ref name="Pharmanovia-Estradurin" /> The [[metabolite]]s are mainly [[excretion|excreted]] in [[urine]] via the [[kidney]]s.<ref name="Pharmanovia-Estradurin" />

Early studies found that a dosage of 80&nbsp;mg PEP every 4&nbsp;weeks rapidly produced relatively high mean estradiol levels of about 400 to 800&nbsp;pg/mL.<ref name="Jacobi-1982">{{cite book| vauthors = Jacobi GR |chapter=Experimental Rationale for the Investigation of Antiprolactins as Palliative Treatment for Prostate Cancer| veditors = Jacobi G, Hohenfellner R |title=Prostate Cancer|url=https://books.google.com/books?id=4HNrAAAAMAAJ|date=1 December 1982|publisher=Williams & Wilkins|isbn=978-0-683-04354-9<!--|pages=419–431-->|page=426}}</ref> These levels are similar to those of 100&nbsp;mg estradiol undecylate every month, which has been found to produce estradiol levels of around 500 to 600&nbsp;pg/mL.<ref name="pmid1231448">{{cite journal | vauthors = Vermeulen A | title = Longacting steroid preparations | journal = Acta Clinica Belgica | volume = 30 | issue = 1 | pages = 48–55 | year = 1975 | pmid = 1231448 | doi = 10.1080/17843286.1975.11716973 }}</ref><ref name="pmid89747">{{cite journal | vauthors = Jacobi GH, Altwein JE | title = [Bromocriptine for palliation of advanced prostatic carcinoma. Experimental and clinical profile of a drug (author's' transl)] | journal = Urologia Internationalis | volume = 34 | issue = 4 | pages = 266–290 | year = 1979 | pmid = 89747 | doi = 10.1159/000280272 | trans-title = Bromocriptine as Palliative Therapy in Advanced Prostate Cancer: Experimental and Clinical Profile of a Drugjournal=Urologia Internationalis }}</ref> As a result, it has previously been said that 80&nbsp;mg PEP per month and 100&nbsp;mg estradiol undecylate per month are roughly equivalent.<ref name="pmid7000222">{{cite journal | vauthors = Jacobi GH, Altwein JE, Kurth KH, Basting R, Hohenfellner R | title = Treatment of advanced prostatic cancer with parenteral cyproterone acetate: a phase III randomised trial | journal = British Journal of Urology | volume = 52 | issue = 3 | pages = 208–215 | date = June 1980 | pmid = 7000222 | doi = 10.1111/j.1464-410x.1980.tb02961.x }}</ref><ref name="Altwein-2013-2">{{cite book|vauthors= Altwein J | chapter = Controversial Aspects of Hormone Manipulation in Prostatic Cancer | veditors = Smith PH |title=Cancer of the Prostate and Kidney| chapter-url = https://books.google.com/books?id=gtAFCAAAQBAJ&pg=PA307|date=29 June 2013|publisher=Springer Science & Business Media|isbn=978-1-4684-4349-3|pages=307–}}</ref><ref name="pmid8610057" /> However, subsequent studies showed that this dosage of PEP actually achieves much lower estradiol levels than originally demonstrated.<ref name="pmid3242384" />

==Chemistry==

{{See also|Estrogen ester|List of estrogen esters#Estradiol esters}}

PEP is a [[synthetic compound|synthetic]] [[estrane]] [[steroid]] and the C17β [[phosphoric acid]] (phosphate) [[ester]] of [[estradiol (medication)|estradiol]] ([[estradiol 17β-phosphate]]) in the form of a [[polymer]].<ref name="Gangolli-1999">{{cite book| vauthors = Gangolli S |title=The Dictionary of Substances and Their Effects: O-S|url=https://books.google.com/books?id=CXinC8gW6BEC&pg=PA425|year=1999|publisher=Royal Society of Chemistry|isbn=978-0-85404-833-5|pages=425–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA856|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=856–}}</ref><ref name="pmid3217277" /><ref name="pmid10861754">{{cite journal | vauthors = Johansson CJ, Gunnarsson PO | title = Pharmacodynamic model of testosterone suppression after intramuscular depot estrogen therapy in prostate cancer | journal = The Prostate | volume = 44 | issue = 1 | pages = 26–30 | date = June 2000 | pmid = 10861754 | doi = 10.1002/1097-0045(20000615)44:1<26::AID-PROS4>3.0.CO;2-P | s2cid = 30678644 }}</ref> 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.<ref name="IndexNominum2000" /><ref name="Gangolli-1999" /><ref name="pmid3217277" /><ref name="pmid10861754" /> It has been determined via [[ultracentrifugation]] that the mean [[molecular weight]] of PEP corresponds to a chain length of approximately 13&nbsp;[[repeat unit]]s of estradiol 17β-phosphate.<ref name="pmid3217277" /> PEP is closely related to [[polyestriol phosphate]] (Gynäsan, Klimadurin, Triodurin) and [[polytestosterone phloretin phosphate]] (never commercialized), which are [[estriol ester|estriol]] and [[testosterone ester]]s in the forms of [[polymer]]s, respectively.<ref name="Schreiner-2012">{{cite book| vauthors = Schreiner WE | chapter = The Ovary | veditors = Labhart A |title=Clinical Endocrinology: Theory and Practice| chapter-url = https://books.google.com/books?id=DAgJCAAAQBAJ&pg=PA551|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-96158-8|pages=551–|quote=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.}}</ref><ref name="US2928849">{{cite patent |country = US | number = 2928849 | status = patent | title = High-molecular weight derivatives of steroids containing hydroxyl groups and method of producing the same | pubdate = 15 March 1960 | fdate = 8 November 1954 | pridate = 20 November 1953 | inventor = Bertil HK, Birger FO, Enok LT, Jakob FH, Rihardt DE | assign1 = Leo AB | url = https://www.google.com/patents/US2928849}}</ref> It is also related to [[polydiethylstilbestrol phosphate]] (never commercialized), a [[diethylstilbestrol ester]] in the form of a [[polymer]].<ref name="Diczfalusy-1959">{{cite journal | vauthors = Diczfalusy E, Fernö H, Fex B, Högberg B, Kneip P | title = High Molecular Weight Enzyme Inhibitors. IV. Polymeric Phosphates of Synthetic Estrogens. | journal = Acta Chem. Scand. | volume = 13 | issue = 5 | pages = 1011–1018 | date = 1959 | doi = 10.3891/acta.chem.scand.13-1011| url = http://actachemscand.org/pdf/acta_vol_13_p1011-1018.pdf}}</ref>

{{Structural properties of major estradiol esters}}

===Solubility===

PEP is of very low [[solubility]] in [[water]], [[acetone]], [[chloroform]], [[dioxane]], and [[ethanol]], but dissolves readily in [[base (chemistry)|base]]s, especially in [[aqueous]] [[pyridine]].<ref name="Arzneistoff-Profile" />

===Synthesis===

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.<ref name="pmid13151143" /><ref name="Diczfalusy-1953">{{cite journal| vauthors = Diczfalusy E, Ferno O, Fex H, Hogberg B, Linderot T, Rosenberg T |title=Synthetic high molecular weight enzyme inhibitors. I. Polymeric phosphates of phloretin and related compounds|url=http://actachemscand.org/pdf/acta_vol_07_p0913-0920.pdf|journal=Acta Chem Scand|volume=7|issue=6|year=1953|pages=921–7|doi=10.3891/acta.chem.scand.07-0913}}</ref>

==History==

Pharmacological experiments on [[estradiol phosphate]]s conducted around 1950 gave rise to the hypothesis that estradiol 3,17β-diphosphate acted as an inhibitor of kidney [[alkaline phosphatase]].<ref name="pmid13151143" /> When the same scientists wanted to synthesize simple phosphates of [[phloretin]], a compound found in apple tree leaves,<ref name="Picinelli-1995">{{cite journal | doi = 10.1021/jf00056a057 | url = http://ria.asturias.es/RIA/bitstream/123456789/1685/1/Archivo.pdf | title = Polyphenolic pattern in apple tree leaves in relation to scab resistance. A preliminary study | vauthors = Picinelli A, Dapena E, Mangas JJ | year = 1995 | journal = Journal of Agricultural and Food Chemistry | volume = 43 | issue = 8 | pages = 2273–78 | access-date = 23 April 2012 | archive-date = | archive-url = | url-status = }}</ref> they accidentally created a polymer instead.<ref name="Diczfalusy-1953" /> 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.<ref name="pmid13151143" /> Consequently, these polymers were studied in more detail, which resulted in the development of PEP as early as 1953<ref name="pmid25951459" /> and its subsequent introduction for medical use in 1957 in the [[United States]].<ref name="Drugs@FDA2" /><ref name="Publishing2013" /><ref name="Sveriges Apotekareförbunds-1973">{{cite book|title=Svensk Farmaceutisk Tidskrift|url=https://books.google.com/books?id=ffEtAAAAIAAJ|year=1973|publisher=Sveriges Apotekareförbunds|pages=728}}</ref> 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.<ref name="IndexNominum2000" /><ref name="Drugs@FDA2" /><ref name="Drugs.com2" /><ref name="Micromedex" /><ref name="Martindale" />

==Society and culture==

===Generic names===

''Polyestradiol phosphate'' is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}} and {{abbrlink|BAN|British Approved Name}}.<ref name="IndexNominum2000" /><ref name="Gangolli-1999" /><ref name="Drugs.com2">{{Cite web|url=https://www.drugs.com/international/polyestradiol-phosphate.html|title = Polyestradiol Phosphate - Drugs.com International|archive-url = https://web.archive.org/web/20180629131523/https://www.drugs.com/international/polyestradiol-phosphate.html|archive-date = 29 June 2018}}</ref> It is also known by its developmental code name ''Leo-114''.<ref name="IndexNominum2000" /><ref name="Drugs.com2" />

===Brand names===

PEP is marketed exclusively under the brand name Estradurin or Estradurine.<ref name="IndexNominum2000" /><ref name="Drugs.com2" />

===Availability===

{{See also|List of estrogens available in the United States}}

[[File:Polyestradiol phosphate availability.png|thumb|right|300px|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]].<ref name="IndexNominum2000" /><ref name="Muller1998B" /><ref name="Pharmanovia-Estradurin" /><ref name="Micromedex">{{cite web |url=http://www.micromedexsolutions.com |title = IBM Watson Health Products}}</ref><ref name="Martindale">{{cite book | veditors = Sweetman SC |chapter=Sex hormones and their modulators |title=Martindale: The Complete Drug Reference |edition=36th |year=2009 |page=2082 |publisher=Pharmaceutical Press |location=London|isbn=978-0-85369-840-1|chapter-url=https://www.medicinescomplete.com/mc/martindale/2009/mg-9020-r.htm}}</ref><ref name="Publishing2013" /> It is no longer available in the United States, Switzerland, and certain other countries however,<ref name="Drugs@FDA2" /><ref name="Mosby2009" /> but is still known to be marketed in Austria, Belgium, Denmark, Finland, the Netherlands, Norway, and Sweden.<ref name="Drugs.com2" /><ref name="Micromedex" /><ref name="Martindale" /><ref name="Pharmanovia-Estradurin" />

==Research==

PEP has been studied as a means of hormonal breast enhancement in women.<ref name="pmid9610425">{{cite journal | vauthors = Hartmann BW, Laml T, Kirchengast S, Albrecht AE, Huber JC | title = Hormonal breast augmentation: prognostic relevance of insulin-like growth factor-I | journal = Gynecological Endocrinology | volume = 12 | issue = 2 | pages = 123–127 | date = April 1998 | pmid = 9610425 | doi = 10.3109/09513599809024960 }}</ref>

A combination of PEP and [[medroxyprogesterone acetate]] was studied in women as a long-lasting [[combined injectable contraceptive]] for use by [[intramuscular injection]] once every three months.<ref name="Goldzieher-1994">{{cite book| vauthors = Goldzieher JW, Fotherby K |title=Pharmacology of the contraceptive steroids|url=https://books.google.com/books?id=bJRsAAAAMAAJ|year=1994|publisher=Raven Press|isbn=978-0-7817-0097-9|page=154}}</ref><ref name="pmid5925038">{{cite journal | vauthors = Zañartu J, Rice-Wray E, Goldzieher JW | title = Fertility control with long-acting injectable steroids. A preliminary report | journal = Obstetrics and Gynecology | volume = 28 | issue = 4 | pages = 513–515 | date = October 1966 | pmid = 5925038 | url = https://journals.lww.com/greenjournal/citation/1966/10000/fertility_control_with_long_acting_injectable.11.aspx }}</ref><ref name="Beckman-1967">{{cite book| vauthors = Beckman H |title=The Year Book of Drug Therapy|url=https://books.google.com/books?id=sRc-AQAAIAAJ|year=1967|publisher=Year Book Publishers}}</ref>

{{Clear}}

== See also ==

* [[Polyestradiol phosphate/medroxyprogesterone acetate]]

== References ==

{{Reflist}}

== Further reading ==

{{refbegin|30em}}

* {{cite journal | vauthors = Henriksson P | title = Estrogen in patients with prostatic cancer. An assessment of the risks and benefits | journal = Drug Safety | volume = 6 | issue = 1 | pages = 47–53 | date = 1991 | pmid = 2029353 | doi = 10.2165/00002018-199106010-00005 | s2cid = 39861824 }}

* {{cite journal | vauthors = Stege R, Sander S | title = [Endocrine treatment of prostatic cancer. A renaissance for parenteral estrogen] | language = no | journal = Tidsskrift for den Norske Laegeforening | volume = 113 | issue = 7 | pages = 833–835 | date = March 1993 | pmid = 8480286 | trans-title = Endocrine treatment of prostatic cancer. A renaissance for parenteral estrogen }}

* {{cite journal | vauthors = Stege R, Carlström K, Hedlund PO, Pousette A, von Schoultz B, Henriksson P | title = [Intramuscular depot estrogens (Estradurin) in treatment of patients with prostate carcinoma. Historical aspects, mechanism of action, results and current clinical status] | language = de | journal = Der Urologe. Ausg. A | volume = 34 | issue = 5 | pages = 398–403 | date = September 1995 | pmid = 7483157 | trans-title = Intramuscular depot estrogens (Estradurin) in treatment of patients with prostate carcinoma. Historical aspects, mechanism of action, results and current clinical status }}

* {{cite journal | vauthors = Smith PH, Robinson MR | title = [Renaissance of estrogen therapy in advanced prostate carcinoma?] | language = de | journal = Der Urologe. Ausg. A | volume = 34 | issue = 5 | pages = 393–397 | date = September 1995 | pmid = 7483156 | trans-title = Renaissance of estrogen therapy in advanced prostate carcinoma? }}

* {{cite journal | vauthors = Ockrim J, Abel PD | title = Androgen deprivation therapy for prostate cancer – the potential of parenteral estrogen | journal = Central European Journal of Urology | volume = 62 | issue = 3 | pages = 132–140 | year = 2009 | doi = 10.5173/ceju.2009.03.art1 }}

* {{cite journal | vauthors = Wibowo E, Schellhammer P, Wassersug RJ | title = Role of estrogen in normal male function: clinical implications for patients with prostate cancer on androgen deprivation therapy | journal = The Journal of Urology | volume = 185 | issue = 1 | pages = 17–23 | date = January 2011 | pmid = 21074215 | doi = 10.1016/j.juro.2010.08.094 }}

* {{cite journal | vauthors = Wibowo E, Wassersug RJ | title = The effect of estrogen on the sexual interest of castrated males: Implications to prostate cancer patients on androgen-deprivation therapy | journal = Critical Reviews in Oncology/Hematology | volume = 87 | issue = 3 | pages = 224–238 | date = September 2013 | pmid = 23484454 | doi = 10.1016/j.critrevonc.2013.01.006 }}

* {{cite journal | vauthors = Phillips I, Shah SI, Duong T, Abel P, Langley RE | title = Androgen Deprivation Therapy and the Re-emergence of Parenteral Estrogen in Prostate Cancer | journal = Oncology & Hematology Review | volume = 10 | issue = 1 | pages = 42–47 | date = 2014 | pmid = 24932461 | pmc = 4052190 | doi = 10.17925/OHR.2014.10.1.42 }}

* {{cite journal | vauthors = Ali Shah SI | title = Emerging potential of parenteral estrogen as androgen deprivation therapy for prostate cancer | journal = South Asian Journal of Cancer | volume = 4 | issue = 2 | pages = 95–97 | date = 2015 | pmid = 25992351 | pmc = 4418092 | doi = 10.4103/2278-330X.155699 | doi-access = free }}

{{refend}}

{{Estradiol}}

{{Estrogens and antiestrogens}}

{{Estrogen receptor modulators}}

[[Category:Antigonadotropins]]

[[Category:Estradiol esters]]

[[Category:Estranes]]

[[Category:Hormonal antineoplastic drugs]]

[[Category:Phosphatase inhibitors]]

[[Category:Phosphate esters]]

[[Category:Prodrugs]]

[[Category:Prostate cancer]]

[[Category:Synthetic estrogens]]