Estradiol Metabolites and Their Possible Role in Gynaecological Cancer Seeger H, Mueck AO J

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Estradiol Metabolites and their Possible Role in Gynaecological Cancer Seeger H, Mueck AO J. Reproduktionsmed. Endokrinol 2010; 7 (Sonderheft 1), 62-66

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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, however; 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) formulation 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 advanced platinum-resistant ovarian cancer was investigated [24]. The formulation was well tolerated and few of the patients showed stable disease.

Overall the clinical studies available so far hint at a rather high tolerable estrogenic 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-hydroxyestradiol is stronger than that of 4-hydroxyestrone [25]. In tumour models in hamsters, rats, and mice, the 4-hydroxyestrogens have carcinogenic effects leading to kidney tumours in hamsters, and to liver tumours in rats and mice [26]. In the same animal studies, however, tumour induction could not be induced 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. cancer tissues [30, 31] and in addition,

J Reproduktionsmed Endokrinol 2010; 7 (Special Issue 1) 63 Estradiol Metabolites and Gynaecological Cancer concentrations of quinones were signifi- increased tumour risk and leads to can- ratio are currently unknown. Perhaps cantly higher in the cancer tissue as com- cer development when other factors, further elucidation might be available if pared to control tissue [31]. Animal ex- such as the mouse mammary tumour epidemiologic studies using sophisti- periments showed a mutagenic effect of virus are involved. cated laboratory methods to measure es- 4-hydroxyestradiolquinones [32, 33]. trone, estradiol, 2-OHE, 4-OHE, 16- Studies of estradiol metabolism in both OHE, and estriol were conducted. Of further interest are the results of female and male patients with systemic Salama et al. [34], who demonstrated lupus erythematosus (SLE) showed that Endometrial Cancer that catecholestrogens induce oxidative D-ring metabolism with production of As in the case of breast cancer, an in- stress in human endometrial cells and 16α-hydroxyestrone was increased [39]. crease in estradiol metabolism via the D- trigger malignant transformation that Whether this increased production of the ring was also found in cancerous en- was inhibited by addition of catechol-O- D-ring metabolite is associated with the dometrial tissue [50]. The fact that these methyltransferase. increased risk of cervical cancer ob- results were found in postmenopausal served in patients with SLE remains un- women in whom no monthly endome- The toxic effects of 4-hydroxyestrogens known. trial shedding occurred leads to the ques- can probably be prevented under normal tion of whether these changes are due to conditions by various cellular defence Estrogen Metabolism in cancer cells, i.e. are the cause of the dis- mechanisms. The quinones themselves ease, or if an enhanced D-ring metabo- can be inactivated by sulfocompounds, Gynaecological Malig- lism has induced carcinogenesis of en- such as the ubiquitous glutathione. Intra- nancies dometrial cells. cellularly formed catechol estrogens are Changes in estradiol metabolism have rapidly methylated by the ubiquitous already been described for several neo- Cervical Cancer COMT. Patients with a COMT defect, plastic diseases, especially in gynaeco- In vitro studies showed that cells in the e. g. due to genetic polymorphisms, are logical malignancies. Some studies have transformation zone of the cervix can especially predisposed and currently it is investigated the ratio between the 2 main form C16-hydroxy metabolites, and the discussed as it is advantageous to inves- metabolic pathways of the A and D-ring. growth of HPV-transformed cervical tigate polymorphism e. g. in smokers at cells is stimulated by 16α-hydroxy- the beginning of any treatment with Breast Cancer estrone [51]. In women with cervical HRT [35, 36]. Observational trials have demonstrated intraepithelial neoplasias, urinary excre- that the ratio of 2- to 16α-hydroxyestrone tion of 2-hydroxyestrone and 16α-hy- 16-alpha-Hydroxyestrone is decreased in women with breast can- droxyestrone was examined and com- cer. However, existing studies had dif- pared with that of a group of healthy Using primary cultures of cells from the ferent designs, have been conducted in women [52]. The A-ring to D-ring quo- terminal duct lobular unit of the breast different populations, and some have ex- tient was significantly lowered with the (TDLU), measurements were carried out tremely small sample sizes. Thus their severity of disease, i. e. the histopatho- in low-risk patients, i. e. patients under- results are inconsistent, with some logical changes. Accordingly, growth of going mammary reduction and in high- showing a strong inverse association of HPV-affected cervical carcinoma is pre- risk patients, i. e. patients with mam- increasing levels of the 2-OHE1/16- sumably accompanied by a change in mary carcinomas. Comparing meta- OHE1 ratio with breast cancer [40, 41], estradiol metabolism in favour of D-ring bolite production, 16α-hydroxyestrone some showing a modest association [42– metabolism. synthesis was only slightly increased in 45], and still others showing no associa- low-risk patients, but was markedly in- tion [46, 47]. A study conducted in Factors Influencing Estra- creased in high-risk patients [37]. The China [43] found an inverse association authors concluded that there is a connec- of the 2/16 ratio with breast cancer using diol Metabolism tion between the incidence of tumours urine samples collected before surgery The assessment of estradiol metabolism and the upregulation of C16-estradiol but a positive association using post- has to consider factors which can influ- metabolism. surgery samples. In an own case/control ence this metabolism. For example en- study including 144 and 292 cases re- docrine diseases such as hypothyroidism Studies of estrogen metabolism showed spectively, we found lower excretion of or drugs like L-thyroxine and H2-an- that in mice with a high risk of mammary 2-hydroxyestrone and higher excretion tagonists can change estradiol metabo- carcinoma, 16-hydroxylation was sig- of 16α-hydroxyestrone in the cases as lism [2]. In addition, diet, physical activ- nificantly increased compared to mice compared to controls, but only in post- ity and possibly the type and stage of with a low tumour risk [38]. 2-hydroxy- menopausal women [48]. In a recent obesity may be of importance [53, 54]. lation showed no risk-dependent differ- large population-based case-control ences. Also surprising was the finding study an inverse association of breast Our own interest currently focuses on that infection with mammary tumour cancer risk with 2/16 ratio was found to estradiol metabolism in smokers, as de- virus was accompanied by an increase in be mostly consistent for premenopausal lineated elsewhere [55]. It is already 16α-hydroxyestrone production. The women with invasive breast cancer [49]. known that oral estrogen therapy in post- authors interpreted the results as mean- menopausal women leads to an increase ing that a genetically determined in- The reasons for these discrepancies in of 4-catechol estrogens and concomi- crease in 16-hydroxylation signifies an the clinical studies concerning the 2/16 tantly a decrease of 2-methoxyestrogens

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Artis pheno Siemens Healthcare Diagnostics GmbH Neues CRT-D Implantat Philips Azurion: Intica 7 HF-T QP von Biotronik Innovative Bildgebungslösung

Aspirator 3 Labotect GmbH

InControl 1050 Labotect GmbH

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