Estradiol undecylate (EU or 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.[9][10][11][12][1] It has also been used as a part of hormone therapy for transgender women.[13][14][15] Although estradiol undecylate has been used in the past, it was discontinued [11][16].The medication has been given by injection into muscle usually once a month.[1][17][12]
Estradiol undecylate was first described in 1953 and was introduced for medical use by 1956.[7][21][8][22] It remained in use as late as the 2000s before being discontinued.[23][11][24] Estradiol undecylate was marketed in Europe, but does not seem to have ever been available in the United States.[14][25][11] 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.[12]
Estradiol undecylate has been used to suppress sex drive in sex offenders.[33] It has been used for this indication at a dosage of 50 to 100 mg by intramuscular injection once every 3 to 4 weeks.[33]
Estradiol undecylate and its side effects have been evaluated for the treatment of advanced prostate cancer in a phase III international multicenterrandomized controlled trial headed by Jacobi and colleagues of the Department of Urology, University of Mainz.[17][43][44][45][46][28][47] 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).[43][45][46][28][47][48][49] Findings for a subgroup of 42 men at the University of Mainz center were initially reported in 1978 and 1980.[50][17][28][47] These men were age 51 to 84 years (mean 68 years), and men with pre-existing cardiovascular disease were excluded.[12][17][51] 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.[12][17][51] 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).[17][51] Eight of the cases of cardiovascular complications in the estradiol undecylate group, including the two deaths, were regarded as "severe".[51][52] Conversely, no incidence of cardiovascular toxicity occurred in the cyproterone acetate comparison group (0%; 0/21).[12][17][51] Other side effects of estradiol undecylate included gynecomastia (100%; 21/21) and erectile dysfunction (90%; 19/21).[17] 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 transdermalestradiol for prostate cancer, in which minimal to no cardiovascular toxicity has been observed.[53][54][55][56][57]
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.[43][49] The antitumor effectiveness of estradiol undecylate and cyproterone acetate in this study was equivalent.[43][45][58][46][28][47] 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.[43][46] 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).[43][45][46][59] 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.[43][45]Erectile dysfunction occurred in "essentially all" patients in both groups.[49]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.[43] The incidence of thrombosis was 4.2% (4/95) in the estradiol undecylate group and 5.3% (5/96) in the cyproterone acetate group.[43][48][49] There were five deaths in total, three in the estradiol undecylate group and two in the cyproterone acetate group.[43] 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.[43][46][49] 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.[45] 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.[46]
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.[29][44][45][28][48][47] In this study, the cyproterone acetate group was changed from intramuscular injections to 100 mg/day oral cyproterone acetate.[29][45] 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).[29][45][28][48][47] 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.[29][45] In terms of non-prostate cancer deaths, there were 5 in the CPA group and 6 in the EU group.[29] The incidence of cardiovascular-related mortality was 3 deaths in the CPA group and 3 deaths in the EU group.[29]
Notes: For 6 months in 191 men age 51 to 88 years with prostate cancer. Footnotes: * = Differences in incidences between groups were statistically significant. a = Due to unknown causes. Sources: See template.
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.[34] Like with other estrogens, treatment with estradiol undecylate has been found to produce testicular abnormalities and disturbances of spermatogenesis in men.[60] 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).[35] Switching from estradiol undecylate to ethinylestradiol resulted in a decrease in prolactin levels in many individuals.[35] The preceding dosage of estradiol undecylate corresponds to much greater estrogenic exposure than the dosage of ethinylestradiol.[35]Cyproterone acetate was also used in combination with estrogen in the study.[35]
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.[34][15][35][36][37] 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.[61]Symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, heavy legs, and leg cramps.[39] These side effects can be diminished by reducing the estrogen dosage.[39]
Esters of estradiol like estradiol undecylate are readily hydrolyzedprodrugs 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.[5] As prodrugs of estradiol, estradiol undecylate and other estradiol esters are estrogens.[4][5] Estradiol undecylate is of about 62% higher molecular weight than estradiol due to the presence of its C17β undecylate ester.[9][11] Because estradiol undecylate is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.[4][18][19]
Testosterone levels with 300 mg/week cyproterone acetate or 100 mg/month estradiol undecylate both by intramuscular injection.[17] The solid lines are the average levels and the dashed lines are the highest and lowest observed levels.Estradiol, testosterone, and prolactin levels with 100 mg/month estradiol undecylate by intramuscular injection in men with prostate cancer.[65]
A phase IIIclinical 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)[76] 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.[17] 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.[17] In another study using the same dosages, estradiol undecylate suppressed testosterone levels by 97% while CPA suppressed them by 70%.[67] In accordance, whereas estrogens are well-established as able to suppress testosterone levels into the castrate range at sufficiently high dosages,[77]progestogens like cyproterone acetate on their own are able to decrease testosterone levels only up to an apparent maximum of around 70 to 80%.[78][79] Besides effects on testosterone levels, the long-term effects of estradiol undecylate on testicular morphology in transgender women have been studied.[60]
The pharmacokinetics of estradiol undecylate have been assessed limitedly in a few studies.[80][81][82][83][65][84][7][8] 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.[80] Levels of estradiol with intramuscular estradiol undecylate were reported to be very irregular and to vary by as much as 10-fold between individuals.[80] 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.[81][85] 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.[65] 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.[70] 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.[75]
Due to its more protracted duration, doses of estradiol undecylate that are typical of other estradiol esters produce only "subthreshold" estradiol levels, and for this reason, higher single doses of estradiol undecylate are necessary for similar effects.[86][80][81] However, the relatively low levels of estradiol produced by lower doses of estradiol undecylate are favorable for menopausal replacement therapy.[86]
The duration of estradiol undecylate is markedly prolonged relative to that of estradiol benzoate, estradiol valerate, and many other estradiol esters.[61][6][20][18] A single intramuscular injection of 10 to 12.5 mg estradiol undecylate has a duration of 40 to 60 days (~1–2 months) and of 25 to 50 mg estradiol undecylate has an estimated duration of effect of 2 to 4 months in postmenopausal women.[7][8][6][20] A single intramuscular injection of 20 to 30 mg estradiol undecylate has been found to inhibit ovulation when used as an estrogen-only injectable contraceptive in premenopausal women for 1 to 3 months (mean 1.7 months) as well.[87] When used at a higher dose of 100 mg per injection in men with prostate cancer, estradiol undecylate has been given usually once a month.[17][32] After a single subcutaneous injection of estradiol undecylate in rats, its duration of effect was 80 days (about 2.5 months).[88][89][90] Due to its very prolonged duration, estradiol undecylate has been described in general as a favorable alternative to estradiol implants.[8]
The excretion of estradiol undecylate has been studied as well.[83]
Estradiol undecylate has not been used via oral administration. However, a closely related estradiol ester, estradiol decanoate (estradiol decylate), has been studied via the oral route, and has been found to possess significant oral bioavailability, to produce relatively high estradiol levels of about 100 pg/mL after a single 0.5 mg oral dose and about 100 to 150 pg/mL with continuous 0.25 mg/day oral therapy, and to have a much higher estradiol-to-estrone ratio than oral estradiol of about 2:1.[91][92][93] It is thought that this is due to absorption of estradiol decanoate by the lymphatic system and a consequent partial bypass of first-pass metabolism in the liver and intestines,[91][92][93] which is similarly known to occur with oral testosterone undecanoate.[94][95]
Hormone levels with estradiol undecylate by intramuscular injection
Estradiol levels after a single intramuscular injection of 10 mg estradiol valerate in oil or 100 mg estradiol undecylate in oil both in 4 individuals each.[61] Subject characteristics and assay method were not described.[61] Source was Vermeulen (1975).[61]
Estradiol levels after a short intravenous infusion of 20 mg estradiol in aqueous solution or an intramuscular injection of equimolar doses of estradiol esters in oil solution in 3 postmenopausal women each.[82][96] Assays were performed using radioimmunoassay with chromatographic separation.[82][96] Sources were Geppert (1975) and Leyendecker et al. (1975).[82][96]
Estradiol, testosterone, and prolactin levels with 100 mg/month estradiol undecylate in oil by intramuscular injection in 14 to 28 men with prostate cancer.[65] A follow-up of the study with more men and with additional hormones was also subsequently published.[70] Sources were Jacobi & Altwein (1979) and Derra (1981).[65][70]
Estradiol undecylate is a relatively long-chain ester of estradiol.[10][11] Its undecylate ester contains 11 carbonatoms.[10][11] For comparison, the ester chains of estradiol acetate, estradiol valerate, and estradiol enantate have 2, 5, and 7 carbon atoms, respectively.[10][11] As a result of its longer ester chain, estradiol undecylate is the most lipophilic of these estradiol esters, and for this reason, has by far the longest duration when administered in oil solution by intramuscular injection.[61][98][99] An example of an estradiol ester with a longer ester chain than estradiol undecylate is estradiol stearate (Depofollan), which has 18 carbon atoms and has been used in medicine as an estrogen as well.
Estradiol undecylate is the generic name of the drug and its INNTooltip International Nonproprietary Name and USANTooltip United States Adopted Name.[9][10][11][16] It is also spelled in some publications as estradiol unducelate and is also known as estradiol undecanoate.[61][9][10][11][16] In German, it is known under a variety of spellings including as estradiolundecylat, östradiolundecylat, östradiolundezylat, oestradiolundecylat, oestradiolundezylat, and others.[104] Estradiol undecylate is known by its former developmental code names RS-1047 and SQ-9993 as well.[9][10][11][16]
Brand names
The major brand name of estradiol undecylate is Progynon Depot 100.[9][10][11] It has also been marketed under other brand names including Delestrec, Depogin, Estrolent, Oestradiol D, Oestradiol-Retard Theramex, and Primogyn Depot [0,1 mg/ml], among others.[9][10][11][23][24]
Estradiol undecylate was studied by Schering alone as an estrogen-only injectable contraceptive in premenopausal women at a dose of 20 to 30 mg once a month.[85][87][107][108] It was effective, lacked breast and thromboembolic complications, lacked other side effects besides amenorrhea, and prevented ovulation for 1 to 3 months (mean 1.7 months) following a single dose.[87] However, uterine growth of 1 to 2 cm was observed after one year, and endometrial hyperplasia was occasionally encountered.[85][87][107] The preparation was not further developed as a form of birth control due to the risks of endometrial hyperplasia and cancer associated with long-term unopposed estrogen therapy.[87]
^ abcdefgOettel M, Schillinger E (6 December 2012). 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.
^ abcdefWied GL (January 1954). "[Estradiol valerate and estradiol undecylate, two new estrogens with prolonged action; comparison with estradiol benzoate]" [Estradiol valerate and estradiol undecylate, two new estrogens with prolonged action; comparison with estradiol benzoate]. Geburtshilfe und Frauenheilkunde (in German). 14 (1): 45–52. PMID13142295.
^ abcdefghGouygou C, Gueritee N, Pye A (1956). "[A fat-soluble, delayed estrogen : the estradiol undecylate]" [A fat-soluble, delayed estrogen: the estradiol undecylate]. Therapie (in French). 11 (5): 909–917. PMID13391788.
^ abcSchlatterer K, von Werder K, Stalla GK (1996). "Multistep treatment concept of transsexual patients". Experimental and Clinical Endocrinology & Diabetes. 104 (6): 413–419. doi:10.1055/s-0029-1211479. PMID9021341. S2CID25099676.
^ abcdeBenjamin H, Lal GB, Green R, Masters RE (1966). The Transsexual Phenomenon. Ace Publishing Company. p. 107. Another preparation of even higher potency is Squibb's Delestrec, which at this writing is not yet on the market in the United States, but is well known in Germany and other European countries under the name of Progynon Depot (Schering). It is chemically Estradiol Undecylate in oil, likewise slowly absorbing, and containing 100 mg. to 1 cc. Injections of 1 cc. once or twice a month can be sufficient. Occasionally, however, larger doses are required to influence the patient's emotional distress.
^ abcdefghijklmnoJacobi 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.
^ abcInternational Society of Urology (1973). Reports of the Congress. Livingstone. p. 252. Progynon-Depot ist eine Oestrogenpräparat mit einem Depoteffekt von 4-6 Wochen. 1 ml Progynon Depot 100 mg enthält 100 mg Oestra- diolundecylat in öliger Lösung. Oestradiolundecylat ist ein Ester des natürlichen Oestrogens Oestradiol.
^ abcWilde PR, Coombs CF, Short AJ (1959). The Medical Annual: A Year Book of Treatment and Practitioner's Index ... Publishing Science Group. As in the case of progestogens the esters of oestradiol vary in the duration of their effect. Oestradiol benzoate is short-acting (three days to a week). Oestradiol valerianate is somewhat longer-acting, and oestradiol enanthate and undecylate have considerably more prolonged duration of effectiveness. The undecylate may remain effective for some months, and should not be employed, [...]
^ abHalkerston ID, Hillman J, Palmer D, Rundle A (July 1956). "Changes in the excretion pattern of neutral 17-ketosteroids during oestrogen administration to male subjects". The Journal of Endocrinology. 13 (4): 433–438. doi:10.1677/joe.0.0130433. PMID13345960.
^ abcBishop PM (1958). "Endocrine Treatment of Gynaecological Disorders". In Gardiner-Hill H (ed.). Modern Trends in Endocrinology. Vol. 1. London: Butterworth & Co. pp. 231–244.
^Enfedjieff M (March 1974). "[Experiences with hormonal treatment of prostatic carcinoma]" [Experiences with hormonal treatment of prostatic carcinoma]. Zeitschrift für Urologie und Nephrologie (in German). 67 (3): 171–173. PMID4848715. Archived from the original on 2018-11-23. Treatment of prostatic carcinoma in 256 patients using parenteral injections of Progynon Depot (a depto estradiol preparation) is reproted. 58% of patients survived 3 or more years from beginning of treatment, and in 70% therapeutic results were considered good with regression of tumor mass, reduction or disappearance of pain, normalization of miction, and improved general status. Results of estrogen treatment are evident within 3 months in most cases. Side effects include gynecomastia in 95% of cases, impotence in almost all patients, and atrophic changes in the testicles, which may actually be desirable. Prostatectomy is not recommended because of the high incidence of metastases even when prostatic disease is still small, because of the high operative mortality, and because of the undesirable after-effects. Orchidectomy was performed in patients in whom the prostatic capsule had been invaded, or who had distant metastases. Estrogen therapy for prostatic carcinoma gives excellent results, and is very easy for both patient and physician.
^ abcdefgTunn UW (1987). "Antiandrogene in der Therapie des fortgeschrittenen Prostatakarzinoms" [Antiandrogens in the Treatment of Advanced Prostate Cancer]. Konservative Therapie des Prostatakarzinoms [Conservative Therapy of Prostate Cancer] (in German). pp. 113–121. doi:10.1007/978-3-642-72613-2_12. ISBN978-3-540-17724-1.
^Mollard P (March 1963). "[Clinical action of estradiol undecylate in the treatment of prostatic cancer]" [Clinical action of estradiol undecylate in the treatment of prostatic cancer]. Lyon Medical (in French). 209: 759–765. PMID13935867.
^ abMorgan HG, Morgan MH (1984). Aids to Psychiatry. Churchill Livingstone. p. 75. ISBN978-0-443-02613-3. Treatment of sexual offenders. Hormone therapy. [...] Oestrogens may cause breast hypertrophy, testicular atrophy, osteoporosis (oral ethinyl oestradiol 0.01-0.05 mg/day causes least nausea). Depot preparation: oestradiol [undecyleate] 50-100mg once every 3–4 weeks. Benperidol or butyrophenone and the antiandrogen cyproterone acetate also used.
^ abcSweetman SC, ed. (2009). "Sex hormones and their modulators". Martindale: The Complete Drug Reference (36th ed.). London: Pharmaceutical Press. p. 2098. ISBN978-0-85369-840-1.
^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.
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^ abTunn UW, Graff J, Senge T (June 1982). "Treatment of inoperable prostatic cancer with cyproterone acetate". In Schröder FH (ed.). Proceedings Androgens and Anti-androgens, International Symposium, Utrecht, June 5th, 1982. Schering Nederland BV. pp. 149–159. ISBN978-9090004327. OCLC11786945.
^ abcdefghijTunn UW, Radlmaier A, Neumann F (1988). "Antiandrogens in Cancer Treatment". In Stoll BA (ed.). Endocrine Management of Cancer: Contemporary Therapy. pp. 43–56. doi:10.1159/000415355. ISBN978-3-8055-4686-7.
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^Jacobi GH, Wenderoth UK (1982). "Gonadotropin-releasing hormone analogues for prostate cancer: untoward side effects of high-dose regimens acquire a therapeutical dimension". European Urology. 8 (3): 129–134. doi:10.1159/000473499. PMID6281023.
^Ockrim 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.
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^Schröder FH (1996). "Cyproterone Acetate — Results of Clinical Trials and Indications for Use in Human Prostate Cancer". Antiandrogens in Prostate Cancer. ESO Monographs. pp. 45–51. doi:10.1007/978-3-642-45745-6_4. ISBN978-3-642-45747-0.
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^Schürmeyer T, Graff J, Senge T, Nieschlag E (March 1986). "Effect of oestrogen or cyproterone acetate treatment on adrenocortical function in prostate carcinoma patients". Acta Endocrinologica. 111 (3): 360–367. doi:10.1530/acta.0.1110360. PMID2421511.
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^ abcdefJacobi GH, Altwein JE (1979). "Bromocriptin als Palliativtherapie beim fortgeschrittenen Prostatakarzinom:Experimentelles und klinisches Profil eines Medikamentes" [Bromocriptine as Palliative Therapy in Advanced Prostate Cancer: Experimental and Clinical Profile of a Drug]. Urologia Internationalis. 34 (4): 266–290. doi:10.1159/000280272. PMID89747.
^Schulze H, Senge T (1987). "Klassische Methoden des Androgenentzugs in der Therapie des fortgeschrittenen Prostatakarzinoms". Konservative Therapie des Prostatakarzinoms. pp. 89–98. doi:10.1007/978-3-642-72613-2_8. ISBN978-3-540-17724-1.
^ abNeumann F, El Etreby MF, Habenicht U, Radlmaier A, Bormacher K (1987). "Möglichkeiten des Androgenentzugs und der totalen Blockade". Konservative Therapie des Prostatakarzinoms. pp. 61–86. doi:10.1007/978-3-642-72613-2_6. ISBN978-3-540-17724-1.
^Tunn UW, Senge T, Neumann F (1981). "Serumkonzentrationen von Testosteron und Prolaktin nach operativer und medikamentöser Kastration — eine Langzeitstudie bei Prostatakarzinom-Patienten". Verhandlungsbericht der Deutschen Gesellschaft für Urologie [Serum concentrations of testosterone and prolactin after surgical and medical castration-A long-term study in prostate cancer patients]. Vol. 32. pp. 419–421. doi:10.1007/978-3-642-81706-9_123. ISBN978-3-540-11017-0.
^Baba S, Janetschek G, Wenderoth U, Jacobi GH (1981). "Beeinflussung des intraprostatischen Testosteron-Stoffwechsels durch Cyproteronazetat und Östradiolundecylat bei Patienten mit Prostatakarzinom: In vivo-Untersuchungen". Verhandlungsbericht der Deutschen Gesellschaft für Urologie [Influence of intraprostatic testosterone metabolism by cyproterone acetate and estradiol undecylate in patients with prostate cancer: in vivo studies]. Vol. 32. pp. 464–466. doi:10.1007/978-3-642-81706-9_138. ISBN978-3-540-11017-0.
^Jacobi GH, Altwein JE (1980). "Testosterone plasma kinetics in patients with prostatic carcinoma treated with estradiol undecylate, cyproterone acetate and estramustine phosphate: a preliminary report". Steroid receptors, metabolism and prostatic cancer: proceedings of a workshop of the Society of Urologic Oncology and Endocrinology, Amsterdam, 27-28 April, 1979. Vol. 494. Excerpta Medica. pp. 144–151.
^Nagel R, Schillinger E, Kölln CP, Pochhammer K (1973). "Das Verhalten der Serumlipide bei Patienten mit Prostatacarcinom nach Behandlung mit Oestradiolundecylat". 24. Tagung vom 13. Bis 16. September 1972 in Hannover [The behavior of serum lipids in patients with prostate cancer after treatment with estradiol undecylate]. Verhandlungsbericht der Deutschen Gesellschaft für Urologie. Vol. 24. pp. 298–301. doi:10.1007/978-3-642-80738-1_75. ISBN978-3-540-06186-1.
^Götz H, Ehrmeier H (June 1971). "[Estrogens and ceruloplasmine level]" [Estrogens and ceruloplasmin levels]. Archiv für Gynäkologie. 211 (1): 204–206. doi:10.1007/BF00682878. PMID5108847. S2CID38378905.
^ abVermeulen A (1977). "Transport and distribution of androgens at different ages". In Martini L, Motta M (eds.). Androgens and Antiandrogens. New York: Raven Press. pp. 53–65. ISBN9780890041413. OCLC925036459. In postmenopausal women, however, estrogen administration does not change the androgen levels significantly. The increase in TeBG capacity after injection of 100 mg Progynon Depot® (estradiol undecylate), therefore, is unequivocally the result of the estrogens: 6 days after injection, when plasma estradiol levels varied between 30 ng/100 ml [300 pg/mL] and 60 ng/100 ml [600 pg/mL], TeBG levels were nearly doubled (1.4–1.6 ✕ 107 M), whereas the free testosterone fraction decreased from 1.25% to 0.70%.
^Kjeld JM, Puah CM, Kaufman B, Loizou S, Vlotides J, Gwee HM, et al. (November 1979). "Effects of norgestrel and ethinyloestradiol ingestion on serum levels of sex hormones and gonadotrophins in men". Clinical Endocrinology. 11 (5): 497–504. doi:10.1111/j.1365-2265.1979.tb03102.x. PMID519881. S2CID5836155.
^ abcLeyendecker G, Geppert G, Nocke W, Ufer J (May 1975). "[Estradiol-17beta, estrone, LH and FSH in serum after administration of estradiol-17beta, estradiolbenzoate, estradiol-valeriate and estradiol-undecylate in the female (author's transl)]" [Estradiol 17β, estrone, LH and FSH in serum after administration of estradiol 17β, estradiol benzoate, estradiol valeriate and estradiol undecylate in the female]. Geburtshilfe und Frauenheilkunde (in German). 35 (5): 370–374. PMID1150068. Estradiol 17β, estradiol benzoate, estradiol valerianate, and estradiol undecylate were injected intravenously and intramuscularly to postmenopausal woman and to female castrates. Equal doses were used corresponding to 20 mg of free estradiol 17β. Estradiol 17β, estrone, FSH and LH were measured in serum by radioimmunoassay before and after application of the hormone and the estradiol esters. Thus the depot effect of the different esters could be compared.
^ abZimmermann W, Buescher HK, Taupitz A, Thewalt K (1964). "Steroidhormonausscheidung bei Patienten mit Erkrankungen der Prostata Unter Behandlung mit Natürlichen und Synthetischen Oestrogenen" [Steroid Hormone Excretion of Patients with Diseases of the Prostate under Treatment with Natural and Synthetic Estrogens]. Acta Endocrinologica (in German). 45 (4 Suppl 90): SUPPL90:211–SUPPL90:225. doi:10.1530/acta.0.045S211. PMID14111328.
^Oriowo MA, Landgren BM, Stenström B, Diczfalusy E (April 1980). "A comparison of the pharmacokinetic properties of three estradiol esters". Contraception. 21 (4): 415–424. doi:10.1016/S0010-7824(80)80018-7. PMID7389356.
^ abcdefToppozada M (June 1977). "The clinical use of monthly injectable contraceptive preparations". Obstetrical & Gynecological Survey. 32 (6): 335–347. doi:10.1097/00006254-197706000-00001. PMID865726.
^Kuhl H, Taubert HD (July 1973). "A new class of long-acting hormonal steroid preparation: synthesis of oligomeric estradiol derivatives". Steroids. 22 (1): 73–87. doi:10.1016/0039-128X(73)90072-X. PMID4737545.
^Kuhl H, Taubert HD (September 1973). "[Proceedings: New type of long-acting steroids: Synthesis and biological effect]" [A New Type of Long-Acting Steroid Preparation: Synthesis and Biological Efficacy]. Archiv für Gynäkologie. 214 (1): 127–128. doi:10.1007/BF00671087. PMID4801412. S2CID26261148.
^Kuhl H, Auerhammer W, Taubert HD (October 1976). "Oligomeric oestradiol esters: a new class of long-acting oestrogens". Acta Endocrinologica. 83 (2): 439–448. doi:10.1530/acta.0.0830439. PMID989671.
^ abKicovic PM, Luisi M, Franchi F, Alicicco E (July 1977). "Effects of orally administered oestradiol decanoate on plasma oestradiol, oestrone and gonadotrophin levels, vaginal cytology, cervical mucus and endometrium in ovariectomized women". Clinical Endocrinology. 7 (1): 73–77. doi:10.1111/j.1365-2265.1977.tb02941.x. PMID880735. S2CID13639429.
^ abLuisi M, Kicovic PM, Alicicco E, Franchi F (April 1978). "Effects of estradiol decanoate in ovariectomized women". Journal of Endocrinological Investigation. 1 (2): 101–106. doi:10.1007/BF03350355. PMID755846. S2CID38187367.
^ abcdefLeyendecker G, Geppert G, Nocke W, Ufer J (May 1975). "[Estradiol-17beta, estrone, LH and FSH in serum after administration of estradiol-17beta, estradiolbenzoate, estradiol-valeriate and estradiol-undecylate in the female (author's transl)]" [Estradiol 17β, estrone, LH and FSH in serum after administration of estradiol 17β, estradiol benzoate, estradiol valeriate and estradiol undecylate in the female]. Geburtshilfe und Frauenheilkunde (in German). 35 (5): 370–374. PMID1150068.
^Armstrong NA, James KC (1980). "Drug release from lipid-based dosage forms. I". International Journal of Pharmaceutics. 6 (3–4): 185–193. doi:10.1016/0378-5173(80)90103-9.
^ abel-Mahgoub S, Karim M (February 1972). "Depot estrogen as a monthly contraceptive in nulliparous women with mild uterine hypoplasia". American Journal of Obstetrics and Gynecology. 112 (4): 575–576. doi:10.1016/0002-9378(72)90319-5. PMID5008627.
^Karim M, el-Mahgoub S (July 1971). "Conception control by cyclic injections of norethisterone enanthate and estradiol unducelate". American Journal of Obstetrics and Gynecology. 110 (5): 740–742. doi:10.1016/0002-9378(71)90268-7. PMID5563241.
![Estradiol levels after a single intramuscular injection of 10 mg estradiol valerate in oil or 100 mg estradiol undecylate in oil both in 4 individuals each.[61] Subject characteristics and assay method were not described.[61] Source was Vermeulen (1975).[61]](https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Estradiol_levels_after_a_single_intramuscular_injection_of_10_mg_estradiol_valerate_and_100_mg_estradiol_undecylate.png/400px-Estradiol_levels_after_a_single_intramuscular_injection_of_10_mg_estradiol_valerate_and_100_mg_estradiol_undecylate.png)
Estradiol levels after a single intramuscular injection of 10 mg estradiol valerate in oil or 100 mg estradiol undecylate in oil both in 4 individuals each.[61] Subject characteristics and assay method were not described.[61] Source was Vermeulen (1975).[61]![Estradiol levels after a short intravenous infusion of 20 mg estradiol in aqueous solution or an intramuscular injection of equimolar doses of estradiol esters in oil solution in 3 postmenopausal women each.[82][96] Assays were performed using radioimmunoassay with chromatographic separation.[82][96] Sources were Geppert (1975) and Leyendecker et al. (1975).[82][96]](https://upload.wikimedia.org/wikipedia/commons/thumb/b/b1/Estradiol_levels_after_injections_of_estradiol%2C_estradiol_benzoate%2C_estradiol_valerate%2C_and_estradiol_undecylate_in_women.png/381px-Estradiol_levels_after_injections_of_estradiol%2C_estradiol_benzoate%2C_estradiol_valerate%2C_and_estradiol_undecylate_in_women.png)
Estradiol levels after a short intravenous infusion of 20 mg estradiol in aqueous solution or an intramuscular injection of equimolar doses of estradiol esters in oil solution in 3 postmenopausal women each.[82][96] Assays were performed using radioimmunoassay with chromatographic separation.[82][96] Sources were Geppert (1975) and Leyendecker et al. (1975).[82][96]![Estradiol, testosterone, luteinizing hormone, and follicle-stimulating hormone levels with an intramuscular injection of 32.3 mg estradiol undecylate in oil in 3 postmenopausal women.[82][96] Assays were performed using radioimmunoassay with chromatographic separation.[96][82] Sources were Geppert (1975) and Leyendecker et al. (1975).[82][96]](https://upload.wikimedia.org/wikipedia/commons/thumb/0/0d/Hormone_levels_with_an_intramuscular_injection_of_estradiol_undecylate_in_postmenopausal_women.png/400px-Hormone_levels_with_an_intramuscular_injection_of_estradiol_undecylate_in_postmenopausal_women.png)
Estradiol, testosterone, luteinizing hormone, and follicle-stimulating hormone levels with an intramuscular injection of 32.3 mg estradiol undecylate in oil in 3 postmenopausal women.[82][96] Assays were performed using radioimmunoassay with chromatographic separation.[96][82] Sources were Geppert (1975) and Leyendecker et al. (1975).[82][96]![Estradiol, testosterone, and prolactin levels with 100 mg/month estradiol undecylate in oil by intramuscular injection in 14 to 28 men with prostate cancer.[65] A follow-up of the study with more men and with additional hormones was also subsequently published.[70] Sources were Jacobi & Altwein (1979) and Derra (1981).[65][70]](https://upload.wikimedia.org/wikipedia/commons/thumb/d/dd/Estradiol%2C_testosterone%2C_and_prolactin_levels_during_therapy_with_100_mg_per_month_estradiol_undecylate_in_men_with_prostate_cancer.png/363px-Estradiol%2C_testosterone%2C_and_prolactin_levels_during_therapy_with_100_mg_per_month_estradiol_undecylate_in_men_with_prostate_cancer.png)
Estradiol, testosterone, and prolactin levels with 100 mg/month estradiol undecylate in oil by intramuscular injection in 14 to 28 men with prostate cancer.[65] A follow-up of the study with more men and with additional hormones was also subsequently published.[70] Sources were Jacobi & Altwein (1979) and Derra (1981).[65][70]
![Estradiol levels after a single intramuscular injection of 10 mg estradiol valerate in oil or 100 mg estradiol undecylate in oil both in 4 individuals each.[61] Subject characteristics and assay method were not described.[61] Source was Vermeulen (1975).[61]](/en/File:Estradiol_levels_after_a_single_intramuscular_injection_of_10_mg_estradiol_valerate_and_100_mg_estradiol_undecylate.png)
![Estradiol levels after a short intravenous infusion of 20 mg estradiol in aqueous solution or an intramuscular injection of equimolar doses of estradiol esters in oil solution in 3 postmenopausal women each.[82][96] Assays were performed using radioimmunoassay with chromatographic separation.[82][96] Sources were Geppert (1975) and Leyendecker et al. (1975).[82][96]](/en/File:Estradiol_levels_after_injections_of_estradiol,_estradiol_benzoate,_estradiol_valerate,_and_estradiol_undecylate_in_women.png)
![Estradiol, testosterone, luteinizing hormone, and follicle-stimulating hormone levels with an intramuscular injection of 32.3 mg estradiol undecylate in oil in 3 postmenopausal women.[82][96] Assays were performed using radioimmunoassay with chromatographic separation.[96][82] Sources were Geppert (1975) and Leyendecker et al. (1975).[82][96]](/en/File:Hormone_levels_with_an_intramuscular_injection_of_estradiol_undecylate_in_postmenopausal_women.png)
