PEP was discovered around 1953 and was introduced for medical use in the United States in 1957.[12][13][14] 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.[15] However, it is no longer available in the United States.[13][16]
PEP has been studied for the treatment of prostate cancer at dosages of 160 mg/month (three studies) and 240 mg/month (four studies).[24] At a dosage of 160 mg/month, PEP incompletely suppresses testosterone levels, failing to reach the castrate range, and is significantly inferior to orchiectomy in slowing disease progression.[24][2] Conversely, PEP at a dosage of 240 mg/month results in greater testosterone suppression, into the castrate range similarly to orchiectomy, and is equivalent to orchiectomy in effectiveness.[24][2]
For prostate cancer in men, PEP is usually given at a dosage of 80 to 320 mg every 4 weeks for the first 2 to 3 months to rapidly build up estradiol levels.[1] Thereafter, to maintain estradiol levels, the dosage is adjusted down usually to 40 to 160 mg every 4 weeks based on clinical findings and laboratory parameters.[1] For breast cancer and low estrogen levels in women, the dosage is 40 to 80 mg every 4 weeks.[1] For transgender women, the dosage is 80 to 160 mg every 4 weeks.[11][19][25][5]
PEP produces minimal undesirable effects on coagulation factors and is thought to increase the risk of blood clots little or not at all.[33][34] This is in spite of the fact that estradiol levels can reach high concentrations of as much as 700 pg/mL with high-dose (320 mg/month) PEP therapy.[35] It is also in contrast to oral synthetic estrogens such 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.[33][34][6] 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.[33][34][6] PEP might actually reduce the risk of blood clots, due to decreases in levels of certain procoagulatory proteins.[33][34] Although PEP does not increase the hepatic production or levels of procoagulatory factors, it has been found to significantly decrease levels of the anticoagulatory antithrombin III, which may indicate a potential risk of thromboembolic and cardiovascular complications.[2] 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.[2] It appears that PEP may have beneficial effects on cardiovascular health at lower dosages (e.g., 160 mg/day) due to its beneficial effects on HDL and LDL cholesterol levels, but these are overshadowed at higher dosages (e.g., 240 mg/day) due to unfavorable dose-dependent effects on hemostasis, namely antithrombin III levels.[2]
Small early pilot studies of PEP for prostate cancer in men found no cardiovascular toxicity with the therapy.[33] A dosage of PEP of 160 mg/month specifically does not appear to increase the risk of cardiovascular complications.[2] In fact, potential beneficial effects on cardiovascular mortality have been observed at this dosage.[2] However, PEP at a higher dosage of 240 mg/month has subsequently been found in large studies to significantly increase cardiovascular morbidity relative to GnRH modulators and orchiectomy in men treated with it for prostate cancer.[33][34][2] The increase in cardiovascular morbidity with PEP therapy is due to an increase in non-fatal cardiovascular events, including ischemic heart disease and heart decompensation, specifically heart failure.[34][36][37] Conversely, PEP has not been found to significantly increase cardiovascular mortality relative to GnRH modulators and orchiectomy.[33][34] Moreover, numerically more patients with preexisting cardiovascular disease were randomized to the PEP group in one large study (17.1% vs. 14.5%; significance not reported), and this may have contributed to the increased incidence of cardiovascular morbidity observed with PEP.[34] In any case, some studies have found that the increased cardiovascular morbidity with PEP is confined mainly to the first one or two years of therapy, whereas one study found consistently increased cardiovascular morbidity across three years of therapy.[33] A longitudinal risk analysis that projected over 10 years suggested that the cardiovascular risks of PEP may be reversed with long-term treatment and that the therapy may eventually result in significantly decreased cardiovascular risk relative to GnRH modulators and orchiectomy, although this has not been confirmed.[33]
The cardiovascular toxicity of PEP is far less than that of oral synthetic estrogens like diethylstilbestrol and ethinylestradiol, which increase the risk 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.[33][34] It is thought that the relatively minimal cardiovascular toxicity of parenteral forms of estradiol, like PEP and high-dose transdermal estradiol patches,[38] is due to their absence of effect on hepatic coagulation factors.[33][34]
Hormone levels with polyestradiol phosphate by intramuscular injection
Estradiol and testosterone levels with a single intramuscular injection of 320 mg polyestradiol phosphate in men with prostate cancer.[7]
Estradiol and testosterone levels with polyestradiol phosphate 160, 240, or 320 mg once every 4 weeks by intramuscular injection in men with prostate cancer.[35]
Antigonadotropic effects
PEP has antigonadotropic effects due to its estrogenic activity.[36] It has been found to suppress testosterone levels in men by 55%, 75%, and 85% at intramuscular dosages of 80, 160, and 240 mg every 4 weeks, respectively.[46] A single intramuscular injection of 320 mg PEP in men has been found to suppress testosterone levels to within the castrate range (< 50 ng/dL) within 3 weeks.[7] This was associated with circulating estradiol levels of just over 200 pg/mL.[35] The suppression of testosterone levels that can be achieved with PEP is equal to that with orchiectomy.[47] However, to achieve such concentrations of testosterone, which are about 15 ng/dL on average, higher concentrations of estradiol of around 500 pg/mL were necessary.[35][47][48] This was associated with a dosage of intramuscular 320 mg PEP every four weeks and occurred by 90 days of treatment.[35] However, 240 mg PEP every four weeks has also been reported to eventually suppress testosterone levels in the castrate range.[49][50]
SHBG levels with 1) i.m. injection of 320 mg PEP every 4 weeks; 2) i.m. injection of 320 mg PEP every 4 weeks plus 150 μg/day oral ethinylestradiol; 3) orchiectomy.[35]
Estrogens have effects on liver protein synthesis, including on the synthesis of plasma proteins, coagulation factors, lipoproteins, and triglycerides.[47] These effects can result in an increased risk of thromboembolic and cardiovascular complications, which in turn can result in increased mortality.[47] 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.[47] However, whereas oral synthetic estrogens have a strong influence on liver protein synthesis, the effects of parenteral bioidentical estrogens like PEP on liver protein synthesis are comparatively very weak or even completely abolished.[47] This is because the first-pass through the liver with oral administration is avoided and because bioidentical estrogens are efficiently inactivated in the liver.[47] In accordance, PEP has minimal effect on the liver at a dosage of up to at least 240 mg/month.[52]
A study found that whereas 320 mg/month intramuscular PEP increased SHBG levels to 166% in men with prostate cancer, the combination of 80 mg/month intramuscular polyestradiol phosphate and 150 μg/day oral ethinylestradiol increased levels of SHBG to 617%, an almost 8-fold difference in increase and almost 4-fold difference in absolute levels between the two treatment regimens.[35][7][53] In addition, whereas there were no cardiovascular complications in the PEP-only group, there was a 25% incidence of cardiovascular complications over the course of a year in the group that was also treated with ethinylestradiol.[7] Another study found no change in levels of coagulation factor VII, a protein of particular importance in the cardiovascular side effects of estrogens, with 240 mg/month intramuscular PEP.[52] These findings demonstrate the enormous impact of synthetic oral estrogens like ethinylestradiol on liver protein production relative to parenteral bioidentical forms of estrogen like PEP.[7]
Originally, PEP was typically used at a dosage of 80 mg per month in combination with 150 μg per day oral ethinylestradiol in the treatment of prostate cancer.[46][54] This combination was found to produce a considerable incidence of cardiovascular toxicity,[47] and this toxicity was inappropriately attributed to PEP in some publications.[55] Subsequent research has shown that the toxicity is not due to PEP but rather to the ethinylestradiol component.[56][46][47]
A study found that therapy with intramuscular PEP resulting in estradiol levels of around 400 pg/mL in men with prostate cancer did not 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.[57][58]
PEP has a very long duration and is given by intramuscular injection once every 4 weeks.[35] In men, an initial intramuscular injection of PEP results in a rapid rise in estradiol levels measured at 24 hours followed by a slow and gradual further increase in levels up until at least day 28 (the time of the next injection).[35] Subsequent injections result in a progressive and considerable accumulation in estradiol levels up to at least 6 months.[35] The mean elimination half-life of PEP has been found to be 70 days (10 weeks) with a single 320 mg intramuscular dose of the medication.[7] The tmax (time to maximal concentrations) for estradiol was about 16 days.[7] PEP has a duration of approximately 1 month with a single dose of 40 mg, 2 months with 80 mg, and 4 months with 160 mg.[59][60][61][62][39]
PEP reaches the bloodstream within hours after an injection (90% after 24 hours), where it circulates, and is accumulated in the reticuloendothelial system.[51] Estradiol is then cleaved from the polymer by phosphatases, although very slowly.[63] Levels of estradiol in men with intramuscular injections of PEP once every 4 weeks were about 350 pg/mL with 160 mg, 450 pg/mL with 240 mg, and almost 700 pg/mL with 320 mg, all measured after 6 months of treatment.[35] With monthly injections, steady-state estradiol concentrations are reached after 6 to 12 months.[51] Estradiol is metabolized primarily in the liver by CYP3A4 and other cytochrome P450enzymes, and is metabolized to a lesser extent in extrahepatic tissues.[20][1] The metabolites are mainly excreted in urine via the kidneys.[1]
Early studies found that a dosage of 80 mg PEP every 4 weeks rapidly produced relatively high mean estradiol levels of about 400 to 800 pg/mL.[64] These levels are similar to those of 100 mg estradiol undecylate every month, which has been found to produce estradiol levels of around 500 to 600 pg/mL.[65][66] As a result, it has previously been said that 80 mg PEP per month and 100 mg estradiol undecylate per month are roughly equivalent.[67][68][7] However, subsequent studies showed that this dosage of PEP actually achieves much lower estradiol levels than originally demonstrated.[35]
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.[63][73]
History
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.[63] When the same scientists wanted to synthesize simple phosphates of phloretin, a compound found in apple tree leaves,[74] they accidentally created a polymer instead.[73] This was later shown to exhibit the same anti-phosphatase properties as estradiol diphosphate, and so it was hypothesized that the original finding was due to contamination with estradiol phosphate polymers.[63] Consequently, these polymers were studied in more detail, which resulted in the development of PEP as early as 1953[12] and its subsequent introduction for medical use in 1957 in the United States.[13][14][75] PEP remained on the market in the United States until at least 2000 but was eventually discontinued both in this country and in most or all other countries.[15][13][42][76][77]
Society and culture
Generic names
Polyestradiol phosphate is the generic name of the drug and its INNTooltip International Nonproprietary Name and BANTooltip British Approved Name.[15][69][42] It is also known by its developmental code name Leo-114.[15][42]
Brand names
PEP is marketed exclusively under the brand name Estradurin or Estradurine.[15][42]
^ abcdefghijklmnopqrstuvwMikkola 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". Annales Chirurgiae et Gynaecologiae. 88 (1): 18–21. PMID10230677. 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.
^Stanczyk FZ, Archer DF, Bhavnani BR (June 2013). "Ethinyl estradiol and 17β-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment". Contraception. 87 (6): 706–727. doi:10.1016/j.contraception.2012.12.011. PMID23375353.
^ abcdefghKuhnz W, Blode H, Zimmermann H (6 December 2012). "Pharmacokinetics of Exogenous Natural and Synthetic Estrogens". In Oettel M, Schillinger E (eds.). Estrogens and Antiestrogens II: Pharmacology and Clinical Application of Estrogens and Antiestrogen. Springer Science & Business Media. p. 261,544. ISBN978-3-642-60107-1. 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.
^Düsterberg B, Nishino Y (December 1982). "Pharmacokinetic and pharmacological features of oestradiol valerate". Maturitas. 4 (4): 315–324. doi:10.1016/0378-5122(82)90064-0. PMID7169965.
^Stege R, Carlström K, Hedlund PO, Pousette A, von Schoultz B, Henriksson P (September 1995). "[Intramuscular depot estrogens (Estradurin) in treatment of patients with prostate carcinoma. Historical aspects, mechanism of action, results and current clinical status]" [Intramuscular depot estrogens (Estradurin) in treatment of patients with prostate carcinoma. Historical aspects, mechanism of action, results and current clinical status]. Der Urologe. Ausg. A (in German). 34 (5): 398–403. PMID7483157. 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.
^Mikkola A, Aro J, Rannikko S, Ruutu M (March 2007). "Ten-year survival and cardiovascular mortality in patients with advanced prostate cancer primarily treated by intramuscular polyestradiol phosphate or orchiectomy". The Prostate. 67 (4): 447–455. doi:10.1002/pros.20547. PMID17219379. S2CID20549248.
^ abcUrdl W (2009). "Behandlungsgrundsätze bei Transsexualität" [Therapeutic principles in transsexualism]. Gynäkologische Endokrinologie (in German). 7 (3): 153–160. doi:10.1007/s10304-009-0314-9. ISSN1610-2894. S2CID8001811.
^ abcdSteinbach T, Wurm FR (May 2015). "Poly(phosphoester)s: A New Platform for Degradable Polymers". Angewandte Chemie. 54 (21): 6098–6108. doi:10.1002/anie.201500147. PMID25951459.
^Ostrowski MJ, Jackson AW (1979). "Polyestradiol phosphate: a preliminary evaluation of its effect on breast carcinoma". Cancer Treatment Reports. 63 (11–12): 1803–1807. PMID393380.
^Brunner N, Spang-Thomsen M, Cullen K (1996). "The T61 human breast cancer xenograft: an experimental model of estrogen therapy of breast cancer". Breast Cancer Research and Treatment. 39 (1): 87–92. doi:10.1007/bf01806080. PMID8738608. S2CID27430232. [...] 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.
^ abcdHedlund PO, Henriksson P (March 2000). "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". Urology. 55 (3): 328–333. doi:10.1016/s0090-4295(99)00580-4. PMID10699602.
^Deepinder F, Braunstein GD (September 2012). "Drug-induced gynecomastia: an evidence-based review". Expert Opinion on Drug Safety. 11 (5): 779–795. doi:10.1517/14740338.2012.712109. PMID22862307. S2CID22938364. 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.
^Midwinter A (1976). "Contraindications to estrogen therapy and management of the menopausal syndrome in these cases". In Campbell S (ed.). 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. MTP Press Limited. pp. 377–382. doi:10.1007/978-94-011-6165-7_33. ISBN978-94-011-6167-1.
^ abcdefghijkOckrim J, Lalani EN, Abel P (October 2006). "Therapy Insight: parenteral estrogen treatment for prostate cancer--a new dawn for an old therapy". Nature Clinical Practice. Oncology. 3 (10): 552–563. doi:10.1038/ncponc0602. PMID17019433. S2CID6847203.
^ abcdefghijkLycette JL, Bland LB, Garzotto M, Beer TM (December 2006). "Parenteral estrogens for prostate cancer: can a new route of administration overcome old toxicities?". Clinical Genitourinary Cancer. 5 (3): 198–205. doi:10.3816/CGC.2006.n.037. PMID17239273.
^ abcdefghijklmStege R, Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A (1988). "Single drug polyestradiol phosphate therapy in prostatic cancer". American Journal of Clinical Oncology. 11 (Suppl 2): S101–S103. doi:10.1097/00000421-198801102-00024. PMID3242384. S2CID32650111.
^ abcDiczfalusy E, Westman A (April 1956). "Urinary excretion of natural oestrogens in oophorectomized women treated with polyoestradiol phosphate (PEP)". Acta Endocrinologica. 21 (4): 321–336. doi:10.1530/acta.0.0210321. PMID13312990.
^Cheng ZN, Shu Y, Liu ZQ, Wang LS, Ou-Yang DS, Zhou HH (February 2001). "Role of cytochrome P450 in estradiol metabolism in vitro". Acta Pharmacologica Sinica. 22 (2): 148–154. PMID11741520.
^Mazer NA (2004). "Interaction of estrogen therapy and thyroid hormone replacement in postmenopausal women". Thyroid. 14 (Suppl 1): S27–S34. doi:10.1089/105072504323024561. PMID15142374.
^Lindstedt E (1980). "Polyestradiol phosphate and ethinyl estradiol in treatment of prostatic carcinoma". Scandinavian Journal of Urology and Nephrology. Supplementum. 55: 95–97. PMID6938044. 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.
^Steven FS, Griffin MM (1982). "Inhibition of thrombin cleavage of fibrinogen by polyestradiol phosphate; interaction with the crucial arginine residues in fibrinogen required for enzymic cleavage". The International Journal of Biochemistry. 14 (8): 699–700. doi:10.1016/0020-711X(82)90004-0. PMID7117668. Polyestradiol phosphate (PEP) has been demonstrated to have inhibitory activity against hyaluronidase, acid phosphatase and alkaline phosphatase (Fernö et al., 1958).
^ abcdefghivon Schoultz B, Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A, Stege R (1989). "Estrogen therapy and liver function--metabolic effects of oral and parenteral administration". The Prostate. 14 (4): 389–395. doi:10.1002/pros.2990140410. PMID2664738. S2CID21510744.
^Hurmuz P, Akyol F, Gultekin M, Yazici G, Sari SY, Ozyigit G (1 August 2017). "The Role of Hormonal Treatment in Prostate Cancer". In Ozyigit G, Selek U (eds.). Principles and Practice of Urooncology: Radiotherapy, Surgery and Systemic Therapy. Springer. pp. 334–. ISBN978-3-319-56114-1. 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).
^Mikkola AK, Ruutu ML, Aro JL, Rannikko SA, Salo JO (July 1998). "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". British Journal of Urology. 82 (1): 63–68. doi:10.1046/j.1464-410x.1998.00688.x. PMID9698663.
^Stege R, Carlström K, Collste L, Eriksson A, Henriksson P (1987). "Single drug polyestradiol phosphate (PEP) therapy in prostatic cancer (CAP)". European Journal of Cancer and Clinical Oncology. 23 (8): 1249. doi:10.1016/0277-5379(87)90236-7. ISSN0277-5379.
^ abcdDinnendahl V, Fricke U, eds. (2010). Arzneistoff-Profile (in German). Vol. 4 (23 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN978-3-7741-98-46-3.
^ abHenriksson P, Carlström K, Pousette A, Gunnarsson PO, Johansson CJ, Eriksson B, et al. (July 1999). "Time for revival of estrogens in the treatment of advanced prostatic carcinoma? Pharmacokinetics, and endocrine and clinical effects, of a parenteral estrogen regimen". The Prostate. 40 (2): 76–82. doi:10.1002/(sici)1097-0045(19990701)40:2<76::aid-pros2>3.0.co;2-q. PMID10386467. S2CID12240276.
^Carlström K, Collste L, Eriksson A, Henriksson P, Pousette A, Stege R, von Schoultz B (1989). "A comparison of androgen status in patients with prostatic cancer treated with oral and/or parenteral estrogens or by orchidectomy". The Prostate. 14 (2): 177–182. doi:10.1002/pros.2990140210. PMID2523531. S2CID25516937.
^Cox RL, Crawford ED (December 1995). "Estrogens in the treatment of prostate cancer". The Journal of Urology. 154 (6): 1991–1998. doi:10.1016/S0022-5347(01)66670-9. PMID7500443.
^Wenderoth UK, Jacobi GH (1983). "Gonadotropin-releasing hormone analogues for palliation of carcinoma of the prostate". World Journal of Urology. 1 (1): 40–48. doi:10.1007/BF00326861. ISSN0724-4983. S2CID23447326.
^Oh WK (September 2002). "The evolving role of estrogen therapy in prostate cancer". Clinical Prostate Cancer. 1 (2): 81–89. doi:10.3816/CGC.2002.n.009. PMID15046698.
^Stege R, Fröhlander N, Carlström K, Pousette A, von Schoultz B (1987). "Steroid-sensitive proteins, growth hormone and somatomedin C in prostatic cancer: effects of parenteral and oral estrogen therapy". The Prostate. 10 (4): 333–338. doi:10.1002/pros.2990100407. PMID2440014. S2CID36814574.
^von Schoultz B, Carlström K (February 1989). "On the regulation of sex-hormone-binding globulin--a challenge of an old dogma and outlines of an alternative mechanism". Journal of Steroid Biochemistry. 32 (2): 327–334. doi:10.1016/0022-4731(89)90272-0. PMID2646476.
^ abSchreiner WE (6 December 2012). "The Ovary". In Labhart A (ed.). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 551–. ISBN978-3-642-96158-8. 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.
^Knörr K, Knörr-Gärtner H, Beller FK, Lauritzen C (8 March 2013). "Prinzipien der Hormonbehandlung". Lehrbuch der Geburtshilfe und Gynäkologie: Physiologie und Pathologie der Reproduktion. Springer-Verlag. pp. 508–. ISBN978-3-662-00526-2.
^ abcdDiczfalusy E (April 1954). "Poly-estradiol phosphate (PEP); a long-acting water soluble. estrogen". Endocrinology. 54 (4): 471–477. doi:10.1210/endo-54-4-471. PMID13151143.
^Jacobi GR (1 December 1982). "Experimental Rationale for the Investigation of Antiprolactins as Palliative Treatment for Prostate Cancer". In Jacobi G, Hohenfellner R (eds.). Prostate Cancer. Williams & Wilkins. p. 426. ISBN978-0-683-04354-9.
^Jacobi GH, Altwein JE (1979). "[Bromocriptine for palliation of advanced prostatic carcinoma. Experimental and clinical profile of a drug (author's' transl)]" [Bromocriptine as Palliative Therapy in Advanced Prostate Cancer: Experimental and Clinical Profile of a Drugjournal=Urologia Internationalis]. Urologia Internationalis. 34 (4): 266–290. doi:10.1159/000280272. PMID89747.
^Jacobi GH, Altwein JE, Kurth KH, Basting R, Hohenfellner R (June 1980). "Treatment of advanced prostatic cancer with parenteral cyproterone acetate: a phase III randomised trial". British Journal of Urology. 52 (3): 208–215. doi:10.1111/j.1464-410x.1980.tb02961.x. PMID7000222.
^US patent 2928849, Bertil HK, Birger FO, Enok LT, Jakob FH, Rihardt DE, "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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![Estradiol and testosterone levels with a single intramuscular injection of 320 mg polyestradiol phosphate in men with prostate cancer.[7]](File:Estradiol_and_testosterone_levels_with_a_single_intramuscular_injection_of_320_mg_polyestradiol_phosphate_in_men.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.[35]](File:Estradiol_and_testosterone_levels_with_polyestradiol_phosphate_in_men_with_prostate_cancer.png)
