Journal für Reproduktionsmedizin und Endokrinologie – Journal of Reproductive Medicine and Endocrinology – Andrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik Gynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie Estradiol Metabolites and their Possible Role in Gynaecological Cancer Seeger H, Mueck AO J. Reproduktionsmed. Endokrinol 2010; 7 (Sonderheft 1), 62-66 www.kup.at/repromedizin Online-Datenbank mit Autoren- und Stichwortsuche Offizielles Organ: AGRBM, BRZ, DVR, DGA, DGGEF, DGRM, D·I·R, EFA, OEGRM, SRBM/DGE Indexed in EMBASE/Excerpta Medica/Scopus Krause & Pachernegg GmbH, Verlag für Medizin und Wirtschaft, A-3003 Gablitz FERRING-Symposium digitaler DVR 2021 Mission possible – personalisierte Medizin in der Reproduktionsmedizin Was kann die personalisierte Kinderwunschbehandlung in der Praxis leisten? Freuen Sie sich auf eine spannende Diskussion auf Basis aktueller Studiendaten. SAVE THE DATE 02.10.2021 Programm 12.30 – 13.20Uhr Chair: Prof. Dr. med. univ. Georg Griesinger, M.Sc. 12:30 Begrüßung Prof. Dr. med. univ. Georg Griesinger, M.Sc. & Dr. Thomas Leiers 12:35 Sind Sie bereit für die nächste Generation rFSH? Im Gespräch Prof. Dr. med. univ. Georg Griesinger, Dr. med. David S. Sauer, Dr. med. Annette Bachmann 13:05 Die smarte Erfolgsformel: Value Based Healthcare Bianca Koens 13:15 Verleihung Frederik Paulsen Preis 2021 Wir freuen uns auf Sie! Estradiol Metabolites and Gynaecological Cancer Estradiol Metabolites and their Possible Role in Gynaecological Cancer H. Seeger, A. O. Mueck Evidence is growing that certain estradiol metabolites are biologically active, especially in the field of cancer. Currently research focuses on the anticancerogenic effects of 2-hydroxyestrone and particularly 2-methoxyestradiol, as well as the possible carcinogenic properties of 4-hydroxyestrogens and 16α-hydroxyestrone. The clinical relevance of these activities, demonstrated in in vitro and animal experiments, remains unclear – it is proven, however, that the metabolite production can be altered in certain malignancies such as endometrial-, breast- and cervical carcinoma. Clinical studies, including own investigations, demonstrated a negative correlation between the ratio of 2-hydroxyestrone to 16α-hydroxyestrone and breast cancer risk. However, the design and interpretation of such studies should consider factors influencing metabolic pattern such as diet, physical activity, smoking as well as internal diseases and certain drugs. J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1): 62–6. Key words: estradiol metabolites, gynaecological malignancies Introduction the near future, due to the new possibil- found in the plasma in pg quantities and ity of measuring even small concentra- in bile, urine and faeces in µg quantities Estradiol metabolites appear to have im- tion changes in the systemic circulation. [11, 12]. 16α-hydroxyestrone has an es- portant physiological functions, such as trogenic effect, which, when measured maintenance of homeostasis in the car- Kinetic studies have shown that 2- by the increase in uterine weight of ova- diovascular system, demonstrated in hydroxyestrone is metabolized very rap- riectomized rats, is equal to or even several studies and also in own research idly in the blood; more rapidly than other stronger than that of estradiol [10]. work [1]. In addition it is becoming more known natural steroids [4]. The conver- and more evident that estradiol metabo- sion takes place in the blood by the en- The metabolites which are currently the lites also can influence carcinogenesis. zyme catechol orthomethyltransferase subject of intensive research are 2-me- (COMT) which is found in erythrocytes thoxyestradiol (2-ME), 4-hydroxyestro- The main metabolites formed by A-ring [4]. Evidence that there are differences gens and 16α-hydroxyestrone. metabolism are 2-hydroxyestrone and 4- in the biological behaviour of the methy- hydroxyestrone, and by D-ring metabo- lated and non-methylated forms has 2-Methoxyestradiol lism 16α-hydroxyestrone and estriol. been obtained in studies which revealed These metabolites are the ones most the antiestrogenic actions of 2-hydroxy- The growth of cells of different tumours highly involved in the metabolic process estrone after preventing methylation [5]; such as lung cancer [13], colon cancer in the human body. Most estrogen meta- it suppressed the growth of the breast [13], tumours of the nervous system [13, bolites undergo an additional degrada- cancer cell line MCF-7 [6, 7]. 14], melanoma [13], ovarian cancer [13], tion step by conjugation, either by glu- renal cancer [13], prostate cancer [13], curonidation, sulfation, or methylation 2-Methoxyestradiol (2-ME) has no es- muscle tumours [14], tumours of the eye [2]. trogenic activity and has only a low rela- [14], cervical cancer [13] and breast can- tive binding affinity to the rat uterine cy- cer [13, 15] has been inhibited by 2-ME. Most Important Estradiol tosol receptor [8]. Different levels of sensitivity exist, how- ever; breast cancer cells showed the Metabolites Both the catechol estrogen metabolites most sensitive response to 2-ME. A find- Recent investigations indicate that local of oxidative C4 metabolism, 4-hydroxy- ing of major significance for tumour re- estradiol metabolism particularly may estrone and 4-hydroxyestradiol are de- search was the detection of an antiangio- have a high biological significance [3]. tected in only very small amounts in hu- genic action of 2-ME [6, 13, 15]. Measurements in tissues, blood or urine man blood [9]. They still possess estro- may reflect such local changes, and are genic properties, as murine studies on In our own studies we demonstrated that subject to intensive, and also our own the uterus have shown, and exert a the combination of 2-ME with tamoxi- research which can only be conducted in stimulatory effect on the growth of fen elicits additive antiproliferative ac- a few specialised groups due to the MCF-7 cells [10]. tions in human breast cancer cells [16]. highly sophisticated laboratory methods In addition, 2-ME was able to increase needed. The measurement of metabo- 16α-hydroxyestrone, the main primary the effect of certain cytostatics in breast lites may achieve more significance in metabolite of D-ring metabolism, is cancer cells as well as in ovarian cancer Received: July 26, 2010, accepted: July 27, 2010. From the University Women’s Hospital of Tuebingen, Germany Correspondence: A.O. Mueck, MD, PharmD, PhD. Head of Dept. Endocrinology and Menopause. University Women’s Hospital, Calwerstraße 7, D-72076 Tübingen, Germany; e-mail: [email protected] 62 J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. Estradiol Metabolites and Gynaecological Cancer To overcome the problems with the lim- ited bioavailability of 2-ME capsules a NanoCrystal Dispersion (NCD) formu- lation of 2-ME was tested in a recent study in patients with refractory solid tumours [23]. The treatment was gener- ally well tolerated, results on the effi- cacy are still awaited. In a very recent study the activity and safety of NCD in 18 patients with ad- vanced platinum-resistant ovarian can- cer was investigated [24]. The formula- tion was well tolerated and few of the patients showed stable disease. Overall the clinical studies available so far hint at a rather high tolerable estro- genic compound up to very high concen- Figure 1: Estradiol metabolism – primary metabolites. trations. However, no data are known as yet in as far 2-ME at high concentrations may have negative effects in the fibrino- lytic/coagulation system and in terms of thrombogenesis, side effects that are fa- miliar for endogenous estrogens. 4-Hydroxyestrogens The 4-catechol estrogens can stimulate growth of the human breast cancer cell line MCF-7; the effect of 4-hydroxy- estradiol is stronger than that of 4-hy- droxyestrone [25]. In tumour models in hamsters, rats, and mice, the 4-hydroxy- estrogens have carcinogenic effects leading to kidney tumours in hamsters, and to liver tumours in rats and mice [26]. In the same animal studies, how- ever, tumour induction could not be in- duced with 2-hydroxyestrogens. Figure 2: Estradiol metabolism – secondary metabolites. They are relatively unstable, i.e. they can be transformed into highly reactive cells [17, 18]. Own investigations sug- ited oral bioavailability with the avail- quinones, with the formation of semi- gest a similar inhibition of the aromatase able capsule formulation, still showed quinones as an intermediate stage [27] enzyme by 2-ME as compared to letro- some anticancer activity at 1,200 mg/d. (Fig. 2). zole [17]. NMU-induced mammary tumours of the rat were stimulated by In a phase I trial in men and women with Adducts of DNA with 4-hydroxy- 2-ME at a dosage of 1 mg/kg and inhib- solid tumours, the toxicity profile of an estrogen quinones, as recent studies have ited at a dosage of 5 mg/kg [19]. oral formulation of 2-ME was deter- demonstrated, are unstable DNA com- mined [21]. pounds, which lead via depurination to Some clinical studies have already been destruction of the DNA. The DNA ad- conducted investigating the possible First results of a phase I study of the ducts with 2-hydroxyestrogen quinones, anti-tumour potency of 2-ME in prostate combination of 2-ME with docetaxel re- in contrast, are believed to be more cancer, recurrent and metastatic breast vealed a good tolerability [22]. 2-ME did stable, and are reversible without DNA cancer and solid malignancies [20–23]. not significantly alter the pharmaco- destruction [27, 28]. Elevated 4-hy- kinetics of docetaxel and vice versa. Se- droxylase enzyme activity has also been In a phase II trial, 31 men with hormone- rum levels of 2-ME achieved after treat- found in human breast cancer specimens refractory prostate cancer were enrolled ment with a dosage of 1 mg were in the [29]. 4-hydroxyestradiol was found in [20]. 2-ME was well tolerated and, de- range of 100 to 600 nM, but remained high concentrations in human breast spite suboptimal plasma levels and lim- below the expected therapeutic range.