Polyestradiol phosphate explained

Polyestradiol phosphate (PEP), sold under the brand name Estradurin, is an estrogen medication which is used primarily in the treatment of prostate cancer in men.[1] [2] [3] [4] 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.[5]

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.[6] 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.[7] 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.[8] [9] 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.[10]

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.[11] [12] 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.[13] [14] 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.[15]

PEP has been compared to combined androgen blockade (CAB; castration plus flutamide) for the treatment of prostate cancer in a large randomized clinical trial of 915 patients.[16] [17] 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 (ADT) 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.[18] 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 (three studies) and 240 mg/month (four studies).[19] 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.[20]

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 (vitamin B3) for administration via intramuscular injection.[21] [22] 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:[23] [24] [25]

Side effects

Systematic studies 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 (>10%) 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.[26] Side effects that occur occasionally or uncommonly (0.1–1%) 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 (<0.1%) side effects of PEP are considered to include weight gain, impaired glucose tolerance, mood changes (elation or depression), 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 (e.g., urticaria, bronchial asthma, anaphylactic shock) due to mepivacaine, and injection site reactions (e.g., pain, sterile abscesses, inflammatory infiltrates).

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.[27] [28] 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. 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 (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.

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.[29] 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 (17.1% vs. 14.5%; significance not reported), 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 (stroke), and myocardial infarction (heart attack), 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,[30] is due to their absence of effect on hepatic coagulation factors.

Overdose

Acute toxicity studies have not indicated a risk of acute side effects with overdose of PEP. The median lethal dose (LD50) of PEP in mice is approximately 700 mg/kg.[31] PEP has been administered in total amounts of 2,000 to 3,000 mg over several months in patients with cancer without toxicity observed. The most likely sign of overdose is reversible feminization, namely gynecomastia. Other symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, heavy legs, and leg cramps.[32] These side effects can be diminished by reducing the estrogen dosage. There is no specific antidote for overdose of PEP. Treatment of PEP overdose should be based on symptoms.

Interactions

Known potential interactions of PEP are mostly the same as those of estradiol and include:

Interactions with PEP may be less than with oral estrogens due to the lack of the first-pass through the liver.

Pharmacology

Pharmacodynamics

See also: Pharmacodynamics of estradiol.

PEP is an estradiol ester in the form of a polymer and is an extremely long-lasting prodrug of estradiol. As such, it is an estrogen, or an agonist of the estrogen receptors. PEP has antigonadotropic and functional antiandrogenic effects due to its estrogenic activity. A single repeat unit of PEP, corresponding to estradiol phosphate (minus OH2), is of about 23% higher molecular weight than estradiol due to the presence of its C17β phosphate ester. Because PEP is a prodrug of estradiol, it is considered to be a natural and bioidentical form of estrogen.

PEP is a strong inhibitor of several enzymes, including acid phosphatase, alkaline phosphatase, and hyaluronidase, in vitro.[35] [36] [37] In light of the fact that phosphatases, which cleave PEP into estradiol and phosphoric acid, are present in most tissues in the body, it has been said that the long elimination half-life and slow release of PEP are somewhat surprising. It is thought that PEP may inhibit its own metabolism.

Antigonadotropic effects

PEP has antigonadotropic effects due to its estrogenic activity.[38] 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.[39] 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. This was associated with circulating estradiol levels of just over 200 pg/mL. The suppression of testosterone levels that can be achieved with PEP is equal to that with orchiectomy.[40] 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.[41] [42] This was associated with a dosage of intramuscular 320 mg PEP every four weeks and occurred by 90 days of treatment. However, 240 mg PEP every four weeks has also been reported to eventually suppress testosterone levels in the castrate range.[43] [44]

Mechanism of action in prostate cancer

The growth of prostate cancer is generally stimulated by dihydrotestosterone (DHT), and unless the cancer is castration-resistant, it can be treated by depriving it of androgens. Estradiol produces its therapeutic benefits mainly via exertion of negative feedback on the hypothalamic–pituitary–gonadal axis. This blocks the secretion of luteinizing hormone, which in turn reduces testosterone production in the Leydig cells of the testes. Estradiol also decreases the free percentage of testosterone by increasing sex hormone-binding globulin (SHBG) levels. In addition, it exhibits direct cytotoxicity on prostate cancer cells.[45]

Differences from other estrogens

Effects of estrogens on coagulation factors
Factors Oral estrogensa Parenteral estrogensb
Increases No change
Factor VIII activity Increases No change
Antithrombin III activity Decreases Decreases
Increases No change
Increases No change
Decreases No change
Footnotes: a = E.g.,, . b = PEP. Sources:

Estrogens have effects on liver protein synthesis, including on the synthesis of plasma proteins, coagulation factors, lipoproteins, and triglycerides. These effects can result in an increased risk of thromboembolic and cardiovascular complications, which in turn can result in increased mortality. 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. 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. This is because the first-pass through the liver with oral administration is avoided and because bioidentical estrogens are efficiently inactivated in the liver. In accordance, PEP has minimal effect on the liver at a dosage of up to at least 240 mg/month.

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.[46] 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. 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.[47] 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.

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.[48] This combination was found to produce a considerable incidence of cardiovascular toxicity, and this toxicity was inappropriately attributed to PEP in some publications.[49] Subsequent research has shown that the toxicity is not due to PEP but rather to the ethinylestradiol component.[50]

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.[51] [52]

Pharmacokinetics

See also: Pharmacokinetics of estradiol.

PEP has a very long duration and is given by intramuscular injection once every 4 weeks. 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). Subsequent injections result in a progressive and considerable accumulation in estradiol levels up to at least 6 months. 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.[53] The tmax (time to maximal concentrations) for estradiol was about 16 days. 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.[54] [55] [56]

PEP reaches the bloodstream within hours after an injection (90% after 24 hours), where it circulates, and is accumulated in the reticuloendothelial system. Estradiol is then cleaved from the polymer by phosphatases, although very slowly.[57] 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. With monthly injections, steady-state estradiol concentrations are reached after 6 to 12 months. Estradiol is metabolized primarily in the liver by CYP3A4 and other cytochrome P450 enzymes, and is metabolized to a lesser extent in extrahepatic tissues. The metabolites are mainly excreted in urine via the kidneys.

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.[58] 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.[59] [60] As a result, it has previously been said that 80 mg PEP per month and 100 mg estradiol undecylate per month are roughly equivalent.[61] [62] However, subsequent studies showed that this dosage of PEP actually achieves much lower estradiol levels than originally demonstrated.

Chemistry

See also: Estrogen ester.

PEP is a synthetic estrane steroid and the C17β phosphoric acid (phosphate) ester of estradiol (estradiol 17β-phosphate) in the form of a polymer.[63] [64] [65] It is also known as estradiol polymer with phosphoric acid or as estradiol 17β-phosphate polymer, as well as estra-1,3,5(10)-triene-3,17β-diol 17β-phosphate polymer. It has been determined via ultracentrifugation that the mean molecular weight of PEP corresponds to a chain length of approximately 13 repeat units of estradiol 17β-phosphate. PEP is closely related to polyestriol phosphate (Gynäsan, Klimadurin, Triodurin) and polytestosterone phloretin phosphate (never commercialized), which are estriol and testosterone esters in the forms of polymers, respectively.[66] [67] It is also related to polydiethylstilbestrol phosphate (never commercialized), a diethylstilbestrol ester in the form of a polymer.[68]

Solubility

PEP is of very low solubility in water, acetone, chloroform, dioxane, and ethanol, but dissolves readily in bases, especially in aqueous pyridine.

Synthesis

Like polyphosphates of polyphenols, PEP can be prepared from the monomer (in this case estradiol) and phosphoryl chloride. The latter reacts with both the phenolic hydroxyl group in position 3 and the aliphatic one in position 17β. The molecular mass of the resulting polymer can be controlled by interrupting the reaction after a given time: the longer the reaction is allowed to continue, the higher the mass.[69]

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. When the same scientists wanted to synthesize simple phosphates of phloretin, a compound found in apple tree leaves,[70] they accidentally created a polymer instead. 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. Consequently, these polymers were studied in more detail, which resulted in the development of PEP as early as 1953 and its subsequent introduction for medical use in 1957 in the United States.[71] 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.

Society and culture

Generic names

Polyestradiol phosphate is the generic name of the drug and its and .[72] It is also known by its developmental code name Leo-114.

Brand names

PEP is marketed exclusively under the brand name Estradurin or Estradurine.

Availability

See also: List of estrogens available in the United States.

PEP has been marketed in the United States and widely throughout Europe, including in Austria, Belgium, the Czech Republic, Denmark, Finland, Germany, Italy, the Netherlands, Norway, Russia, Spain, Sweden, Switzerland, Ukraine, and the United Kingdom.[73] [74] It is no longer available in the United States, Switzerland, and certain other countries however, but is still known to be marketed in Austria, Belgium, Denmark, Finland, the Netherlands, Norway, and Sweden.

Research

PEP has been studied as a means of hormonal breast enhancement in women.[75]

A combination of PEP and medroxyprogesterone acetate was studied in women as a long-lasting combined injectable contraceptive for use by intramuscular injection once every three months.[76] [77] [78]

See also

Further reading

Notes and References

  1. Web site: Estradurin® – Pharmanovia . 1 January 2018 . https://web.archive.org/web/20180102072958/http://pharmanovia.com/product/estradurin/ . 2 January 2018 . dead .
  2. Stege R, Carlström K, Hedlund PO, Pousette A, von Schoultz B, Henriksson P . [Intramuscular depot estrogens (Estradurin) in treatment of patients with prostate carcinoma. Historical aspects, mechanism of action, results and current clinical status] . de . Der Urologe. Ausg. A . 34 . 5 . 398–403 . September 1995 . 7483157 . Intramuscular depot estrogens (Estradurin) in treatment of patients with prostate carcinoma. Historical aspects, mechanism of action, results and current clinical status . 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. .
  3. Mikkola A, Ruutu M, Aro J, Rannikko S, Salo J . 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 . 1999 . 10230677 . 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. .
  4. Mikkola A, Aro J, Rannikko S, Ruutu M . 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 . March 2007 . 17219379 . 10.1002/pros.20547 . 20549248 .
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  8. Web site: Drugs@FDA: FDA Approved Drug Products: Estradurin . United States Food and Drug Administration . 24 June 2018 .
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  13. Urdl W . Behandlungsgrundsätze bei Transsexualität . Therapeutic principles in transsexualism . de . Gynäkologische Endokrinologie . 7 . 3 . 2009 . 153–160 . 1610-2894 . 10.1007/s10304-009-0314-9. 8001811 .
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  17. Hedlund PO, Henriksson P . 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 . March 2000 . 10699602 . 10.1016/s0090-4295(99)00580-4 .
  18. Deepinder F, Braunstein GD . Drug-induced gynecomastia: an evidence-based review . Expert Opinion on Drug Safety . 11 . 5 . 779–795 . September 2012 . 22862307 . 10.1517/14740338.2012.712109 . 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. . 22938364 .
  19. Norman G, Dean ME, Langley RE, Hodges ZC, Ritchie G, Parmar MK, Sydes MR, Abel P, Eastwood AJ . 6 . Parenteral oestrogen in the treatment of prostate cancer: a systematic review . British Journal of Cancer . 98 . 4 . 697–707 . February 2008 . 18268497 . 2259178 . 10.1038/sj.bjc.6604230 .
  20. Schlatterer K, von Werder K, Stalla GK . Multistep treatment concept of transsexual patients . Experimental and Clinical Endocrinology & Diabetes . 104 . 6 . 413–419 . 1996 . 9021341 . 10.1055/s-0029-1211479 . 25099676 .
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