Chemical compound
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Estradiol undecylate (EU, EUn, E2U), also known as estradiol undecanoate and formerly sold under the brand names Delestrec and Progynon Depot 100 among others, is an estrogen medication which has been used in the treatment of prostate cancer in men. It has also been used as a part of hormone therapy for transgender women. Although estradiol undecylate has been used in the past, it was discontinued. The medication has been given by injection into muscle usually once a month.
Side effects of estradiol undecylate in men may include breast tenderness, breast development, feminization, sexual dysfunction, infertility, fluid retention, and cardiovascular issues. Estradiol undecylate is an estrogen and hence is an agonist of the estrogen receptor, the biological target of estrogens like estradiol. It is an estrogen ester and a very long-lasting prodrug of estradiol in the body. Because of this, it is considered to be a natural and bioidentical form of estrogen. An injection of estradiol undecylate has a duration of about 1 to 4 months.
Estradiol undecylate was first described in 1953 and was introduced for medical use by 1956. It remained in use as late as the 2000s before being discontinued. Estradiol undecylate was marketed in Europe, but does not seem to have ever been available in the United States. It was used for many years as a parenteral estrogen to treat prostate cancer in men, although it was not employed as often as polyestradiol phosphate.
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Medical uses.
Estradiol undecylate has been used as a form of high-dose estrogen therapy to treat prostate cancer, but has since largely been superseded for this indication by newer agents with fewer adverse effects (e.g., gynecomastia and cardiovascular complications) like GnRH analogues and nonsteroidal antiandrogens. It has been assessed for this purpose in a number of clinical studies. It has been used at a dosage of 100 mg every 3 to 4 weeks (or once a month) by intramuscular injection for this indication.
Estradiol undecylate has been used to suppress sex drive in sex offenders. It has been used for this indication at a dosage of 50 to 100 mg by intramuscular injection once every 3 to 4 weeks.
Estradiol undecylate has also been used to treat breast cancer in women. It has been used in menopausal hormone therapy as well, for instance in the treatment of hot flashes and other menopausal symptoms. Along with estradiol valerate, estradiol cypionate, and estradiol benzoate, estradiol undecylate has been used as an intramuscular estrogen in feminizing hormone therapy for transgender women. It has been used at doses of 100 to as much as 800 mg per month by intramuscular injection for this purpose.
Available forms.
Estradiol undecylate was available as an oil solution for intramuscular injection provided in ampoules at a concentration of 100 mg/mL.
Contraindications.
Contraindications of estrogens include coagulation problems, cardiovascular diseases, liver disease, and certain hormone-sensitive cancers such as breast cancer and endometrial cancer, among others.
Side effects.
Estradiol undecylate and its side effects have been evaluated for the treatment of advanced prostate cancer in a phase III international multicenter randomized controlled trial headed by Jacobi and colleagues of the Department of Urology, University of Mainz. The study consisted of 191 patients from 12 treatment centers, who were treated for 6 months with intramuscular injections of either 100 mg/month estradiol undecylate (96 men) or 300 mg/week cyproterone acetate (95 men). Findings for a subgroup of 42 men at the University of Mainz center were initially reported in 1978 and 1980. These men were age 51 to 84 years (mean 68 years), and men with pre-existing cardiovascular disease were excluded. A considerable incidence of cardiovascular complications was reported for the estradiol undecylate group (76%; 16/21 incidence total); there was a 67% (14/21) incidence of cardiovascular morbidity and a 9.5% (2/21) incidence of cardiovascular mortality. The cardiovascular morbidity in this group included peripheral edema and superficial thrombophlebitis (38%; 8/21), coronary heart disease (24%; 5/21), and a deep vein thrombosis (4.8%; 1/21), while the cardiovascular mortality included a myocardial infarction (4.8%; 1/21) and a pulmonary embolism (4.8%; 1/21). Eight of the cases of cardiovascular complications in the estradiol undecylate group, including the two deaths, were regarded as "severe". Conversely, no incidence of cardiovascular toxicity occurred in the cyproterone acetate comparison group (0%; 0/21). Other side effects of estradiol undecylate included gynecomastia (100%; 21/21) and erectile dysfunction (90%; 19/21). The cardiovascular complications with estradiol undecylate in this relatively small study are in contrast to large and high-quality clinical studies of high-dose polyestradiol phosphate and transdermal estradiol for prostate cancer, in which minimal to no cardiovascular toxicity has been observed.
An expanded report of 191 patients, which included the 42 patients from the University of Mainz center plus an additional 149 patients from 11 other centers, was published in 1982. The antitumor effectiveness of estradiol undecylate and cyproterone acetate in this study was equivalent. The rates of improvement, no response, and deterioration were 52%, 41%, and 7% in the estradiol undecylate group and 48%, 44%, and 8% in the cyproterone acetate group, respectively. However, the incidence of a selection of specific side effects, including gynecomastia, breast tenderness, and edema, was significantly lower in the cyproterone acetate group than in the estradiol undecylate group (37% vs. 94%, respectively). Gynecomastia specifically occurred in 13% (12/96) of the patients in the cyproterone acetate group and 77% (73/95) of the patients in the estradiol undecylate group. Erectile dysfunction occurred in "essentially all" patients in both groups. Leg edema occurred in 18% (17/95) of the estradiol undecylate group and 4.2% (4/96) of the cyproterone acetate group, while the incidences of superficial thrombophlebitis and coronary heart disease both were not described. The incidence of thrombosis was 4.2% (4/95) in the estradiol undecylate group and 5.3% (5/96) in the cyproterone acetate group. There were five deaths in total, three in the estradiol undecylate group and two in the cyproterone acetate group. Two of the deaths in each of the treatment groups were due to cardiovascular events, while the remaining death in the estradiol undecylate group was due to unknown causes. The similar rate of cardiovascular complications besides edema between estradiol undecylate and cyproterone acetate that was observed is in contrast to the initial 42-patient report and to findings with other estrogens, such as diethylstilbestrol and estramustine phosphate, which have been shown to possess significantly higher cardiovascular toxicity than cyproterone acetate. On the basis of the expanded study, the researchers concluded that cyproterone acetate was an "acceptable alternative" to estrogen therapy with estradiol undecylate, but with a "considerably more favorable" side-effect profile.
After the completion of the initial expanded study, a 5-year extension trial primarily of the Ruhr University Bochum center subgroup, led by Tunn and colleagues, was conducted. In this study, the cyproterone acetate group was changed from intramuscular injections to 100 mg/day oral cyproterone acetate. Of the 39 patients in the study, the global 5-year survival rate was not significantly different between the estradiol undecylate and cyproterone acetate groups (24% and 26%, respectively). In patients without metastases, the 5-year survival rate was 51% in the cyproterone acetate group relative to 43% in the estradiol undecylate group, although the difference was not statistically significant. In terms of non-prostate cancer deaths, there were 5 in the CPA group and 6 in the EU group. The incidence of cardiovascular-related mortality was 3 deaths in the CPA group and 3 deaths in the EU group.
The side effects of estradiol undecylate have also been studied and reported beyond the preceding clinical trial programme and for other patient populations, for instance women. Side effects during therapy with massive doses of estradiol undecylate (200mg three times per week, or 600mg per week and around 2,400mg per month total) in postmenopausal women with advanced breast cancer have included appetite loss, nausea, vomiting, vaginal bleeding, vaginal discharge, nipple pigmentation, breast pain, rash, urinary incontinence, edema, drowsiness, hypercalcemia, and local injection-site reactions. Like with other estrogens, treatment with estradiol undecylate has been found to produce testicular abnormalities and disturbances of spermatogenesis in men. In transgender women, estradiol undecylate by intramuscular injection at extremely high doses (200–800mg/month) was associated with greater incidence of hyperprolactinemia (high prolactin levels) than ethinylestradiol orally at a dose of 100μg/day (or about 3mg/month total) (rates of 40% and 16% for prolactin levels greater than 1,000mU/L, respectively). Switching from estradiol undecylate to ethinylestradiol resulted in a decrease in prolactin levels in many individuals. The preceding dosage of estradiol undecylate corresponds to much greater estrogenic exposure than the dosage of ethinylestradiol. Cyproterone acetate was also used in combination with estrogen in the study.
Overdose.
Estradiol undecylate has been used clinically at massive doses of as much as 800 to 2,400 mg per month by intramuscular injection, given in divided doses of 100 to 200 mg per injection two to three times per week. For purposes of comparison, a single 100 mg intramuscular injection of estradiol undecylate has been reported to produce estradiol levels of about 500 pg/mL. Symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, heavy legs, and leg cramps. These side effects can be diminished by reducing the estrogen dosage.
Interactions.
Inhibitors and inducers of cytochrome P450 may influence the metabolism of estradiol and by extension circulating estradiol levels.
Pharmacology.
Pharmacodynamics.
Esters of estradiol like estradiol undecylate are readily hydrolyzed prodrugs of estradiol, but have an extended duration when administered in oil via intramuscular injection due to a depot effect afforded by their fatty acid ester moiety. As prodrugs of estradiol, estradiol undecylate and other estradiol esters are estrogens. Estradiol undecylate is of about 62% higher molecular weight than estradiol due to the presence of its C17β undecylate ester. Because estradiol undecylate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.
The effects of estradiol undecylate on cortisol, dehydroepiandrosterone sulfate, testosterone, prolactin, and sex hormone-binding globulin levels as well as on the hypothalamic–pituitary–adrenal axis have been studied in men with prostate cancer and compared with those of high-dose cyproterone acetate therapy. The effects of estradiol undecylate on serum lipids and ceruloplasmin levels have been studied as well. Additionally, the influence of estradiol undecylate on SHBG levels and free testosterone fraction in women has been described.
Antigonadotropic activity.
A phase III clinical trial comparing high-dose intramuscular cyproterone acetate (300 mg/week) and high-dose intramuscular estradiol undecylate (100 mg/month) in the treatment of prostate cancer found that estradiol undecylate suppressed testosterone levels into the castrate range ( ; 50 ng/dL) within at least 3 months whereas testosterone levels with cyproterone acetate were significantly higher and above the castrate range even after 6 months of treatment. With estradiol undecylate, testosterone levels fell from 416 ng/dL to 38 ng/mL (–91%) after 3 months and to 29.6 ng/dL (–93%) after 6 months, whereas with cyproterone acetate, testosterone levels fell from 434 ng/dL to 107 ng/mL (–75%) at 3 months and to 102 ng/mL (–76%) at 6 months. In another study using the same dosages, estradiol undecylate suppressed testosterone levels by 97% while CPA suppressed them by 70%. In accordance, whereas estrogens are well-established as able to suppress testosterone levels into the castrate range at sufficiently high dosages, progestogens like cyproterone acetate on their own are able to decrease testosterone levels only up to an apparent maximum of around 70 to 80%. Besides effects on testosterone levels, the long-term effects of estradiol undecylate on testicular morphology in transgender women have been studied.
Pharmacokinetics.
The pharmacokinetics of estradiol undecylate have been assessed limitedly in a few studies. Following a single intramuscular injection of 100 mg estradiol undecylate in oil, mean levels of estradiol were about 500 pg/mL a day after injection and about 340 pg/mL 14 days after injection in 4people. Levels of estradiol with intramuscular estradiol undecylate were reported to be very irregular and to vary by as much as 10-fold between individuals. In another study, following a single intramuscular injection of 32.2 mg estradiol undecylate, levels of estradiol peaked at around 400 pg/mL after 3 days and decreased from this peak to around 200 pg/mL after 6 days in 3postmenopausal women. In a repeated administration study of 100 mg per month estradiol undecylate in 14men with prostate cancer, estradiol levels at trough were about 560 pg/mL at 3 months and about 540 pg/mL at 6 months following initiation of therapy. In a larger follow-up of the study with 21men, estradiol levels at trough were about 36pg/mL at baseline, 486pg/mL at 3months, and 598pg/mL at 6months of therapy. In one further study, levels of estradiol in an unspecified number of postmenopausal women following a single injection of 100mg estradiol undecylate were said to be between 300pg/mL and 600pg/mL six days post-injection.
Due to its more protracted duration, doses of