Polyestradiol phosphate


Polyestradiol phosphate, sold under the brand name Estradurin, is an estrogen medication which is used primarily in the treatment of prostate cancer in men. It is also used in women to treat breast cancer, as a component of hormone therapy to treat low estrogen levels and menopausal symptoms, and as a component of feminizing hormone therapy for transgender women. It is given by injection into muscle once every four weeks.
Common side effects of PEP include headache, breast tenderness, breast development, feminization, sexual dysfunction, infertility, and vaginal bleeding. PEP is an estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol. It is an estrogen ester in the form of a polymer and is an extremely long-lasting prodrug of estradiol in the body. The biological half-life of PEP is more than two months. Because PEP works by being converted into estradiol, it is considered to be a natural and bioidentical form of estrogen. The safety profile of parenteral estradiol esters like PEP is greatly improved relative to synthetic oral estrogens like ethinylestradiol and diethylstilbestrol.
PEP was discovered around 1953 and was introduced for medical use in the United States in 1957. 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. However, it is no longer available in the United States.

Medical uses

PEP is used as an intramuscular injection for estrogen therapy of prostate cancer in men. It is also used to treat breast cancer in women who are at least 5 years postmenopausal. In addition, PEP is used in hormone replacement therapy for low estrogen levels due to hypogonadism or menopause in women. It is also used in feminizing hormone therapy for transgender women. PEP is a form of high-dose estrogen therapy. After an injection, it very slowly releases the active agent estradiol over at least several months.
PEP has been compared to combined androgen blockade for the treatment of prostate cancer in a large randomized clinical trial of 915 patients. At 18.5 months, there was no difference in survival or cardiovascular toxicity between the two treatment modalities. These findings suggest that parenteral forms of estradiol may have similar effectiveness and safety relative to androgen deprivation therapy in the treatment of prostate cancer. In addition, estrogens may have significant advantages relative to ADT in terms of bone loss and fractures, hot flashes, sexual function, and quality of life, as well as considerable cost savings with parenteral forms of estradiol compared to analogue therapy. On the other hand, breast tenderness and gynecomastia occur at very high rates with estrogens, whereas incidences are low with castration and CAB. However, gynecomastia with estrogens is generally only mild-to-moderate in severity and is usually only modestly discomforting. In addition, gynecomastia caused by estrogens can be prevented with prophylactic irradiation of the breasts or can be remediated with mastectomy.
PEP has been studied for the treatment of prostate cancer at dosages of 160 mg/month and 240 mg/month. 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. 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.
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. 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. For breast cancer and low estrogen levels in women, the dosage is 40 to 80 mg every 4 weeks. For transgender women, the dosage is 80 to 160 mg every 4 weeks.

Available forms

PEP is provided in the form of powder or an aqueous solution in vials and ampoules alone or in combination with mepivacaine and/or nicotinamide for administration via intramuscular injection. Mepivacaine is a local anaesthetic and is used to avoid a burning sensation during injection of PEP. Each vial/ampoule of Estradurin contains 80 mg PEP, 5 mg mepivacaine hydrochloride, 40 mg nicotinamide, and 2 mL water.

Contraindications

The contraindications of PEP are largely the same as those of estradiol and include:
of the side effects of PEP are lacking. However, its side effects are assumed to be identical to those of estradiol and other estradiol esters. The side effects of PEP are partially dependent on sex. Common or frequent side effects are considered to include headache, abdominal pain, nausea, rash, pruritus, loss of libido, erectile dysfunction, breast tenderness, gynecomastia, feminization, demasculinization, infertility, and vaginal bleeding or spotting. Side effects that occur occasionally or uncommonly include sodium and water retention, edema, hypersensitivity, breast tension, depression, dizziness, visual disturbances, palpitations, dyspepsia, erythema nodosum, urticaria, and chest pain. All other side effects of PEP are considered to be rare.
The rare side effects of PEP are considered to include weight gain, impaired glucose tolerance, mood changes, nervousness, tiredness, headache, migraine, intolerance of contact lenses, hypertension, thrombosis, thrombophlebitis, thromboembolism, heart failure, myocardial infarction, vomiting, bloating, cholestatic jaundice, cholelithiasis, transient increases in transaminases and bilirubin, erythema multiforme, hyperpigmentation, muscle cramps, dysmenorrhea, vaginal discharge, premenstrual-like symptoms, breast enlargement, testicular atrophy, allergic reactions due to mepivacaine, and injection site reactions.
As thromboembolic and other cardiovascular complications are associated mainly with synthetic oral estrogens like ethinylestradiol and diethylstilbestrol, they occur much less often with parenteral bioidentical forms of estrogen like PEP.

Cardiovascular effects

PEP produces minimal undesirable effects on coagulation factors and is thought to increase the risk of blood clots little or not at all. This is in spite of the fact that estradiol levels can reach high concentrations of as much as 700 pg/mL with high-dose PEP therapy. 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. 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. PEP might actually reduce the risk of blood clots, due to decreases in levels of certain procoagulatory proteins. 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. 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. It appears that PEP may have beneficial effects on cardiovascular health at lower dosages due to its beneficial effects on HDL and LDL cholesterol levels, but these are overshadowed at higher dosages due to unfavorable dose-dependent effects on hemostasis, namely antithrombin III levels.
Small early pilot studies of PEP for prostate cancer in men found no cardiovascular toxicity with the therapy. A dosage of PEP of 160 mg/month specifically does not appear to increase the risk of cardiovascular complications. In fact, potential beneficial effects on cardiovascular mortality have been observed at this dosage. 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. 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. Conversely, PEP has not been found to significantly increase cardiovascular mortality relative to GnRH modulators and orchiectomy. Moreover, numerically more patients with preexisting cardiovascular disease were randomized to the PEP group in one large study, and this may have contributed to the increased incidence of cardiovascular morbidity observed with PEP. 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. 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.
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, and myocardial infarction, and result in substantial increases in cardiovascular mortality. It is thought that the relatively minimal cardiovascular toxicity of parenteral forms of estradiol, like PEP and high-dose transdermal estradiol patches, is due to their absence of effect on hepatic coagulation factors.