Conversion of tibolone to 7α-methyl-ethinyl estradiol using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry: Interpretation and clinical implications

Menopause

Volumn 13, Issue 6, 2006, Pages 926-934

  Zacharia, Lefteris C ^a   Jackson, Edwin K ^a   Kloosterboer, Helenius J ^b   Imthurn, Bruno ^c   Dubey, Raghvendra K ^a,c,d  

^a UNIVERSITY OF PITTSBURGH MEDICAL CENTER   (United States)

^b NV Organon   (Netherlands)

^c UNIVERSITY OF ZURICH   (Switzerland)

^d UNIVERSITY HOSPITAL ZURICH   (Switzerland)

Author keywords

Cancer; Climacteric; Hormone therapy; Menopause; Selective tissue estrogen activity regulator; Steroid metabolism; Tibolone

Indexed keywords

7ALPHA METHYLETHINYL ESTRADIOL; ESTRADIOL DERIVATIVE; TIBOLONE; UNCLASSIFIED DRUG; 7ALPHA METHYL ETHINYLESTRADIOL; 7ALPHA-METHYL ETHINYLESTRADIOL; DRUG DERIVATIVE; ESTRADIOL; PREGNANE DERIVATIVE; SELECTIVE ESTROGEN RECEPTOR MODULATOR;

ARTICLE; ARTIFACT; DERIVATIZATION; DRUG DETERMINATION; DRUG METABOLISM; GAS CHROMATOGRAPHY; HORMONE METABOLISM; LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; CHEMISTRY; MASS FRAGMENTOGRAPHY; METABOLISM;

CHROMATOGRAPHY, LIQUID; ESTRADIOL; ESTROGEN RECEPTOR MODULATORS; GAS CHROMATOGRAPHY-MASS SPECTROMETRY; NORPREGNENES;

EID: 33751051583     PISSN: 10723714     EISSN: None     Source Type: Journal    
DOI: 10.1097/01.gme.0000227331.49081.d7     Document Type: Article

References (40)

1. Modelska K, Cummings S. Tibolone for postmenopausal women: systematic review of randomized clinical trials. J Clin Endocrinol Metab 2002;87:16-23.
2. Kloosterboer HJ. Tissue-selectivity: the mechanism of action of tibolone. Maturitas 2004;48(Suppl 3):S30-S40.
3. Kloosterboer HJ. Tibolone: a steroid with a tissue-specific mode of action. J Steroid Biochem Mol Biol 2001;76:231-238.
4. Wiegratz I, Sänger N, Kuhl H. Formation of 7α-methyl-ethinyl estradiol during treatment with tibolone. Menopause 2002;9:293-295.
5. De Gooyer ME, Oppers-Tiemissen HM, Leysen D, Verheul HAM, Kloosterboer HJ. Tibolone is not converted by human aromatase to 7α-methyl-17α- ethynylestradiol (7α-MEE): analyses with sensitive bioassays for estrogens and androgens and with LC-MSMS. Steroids 2003;68:235-243.
6. Bodine PVN, Harris HA, Lyttle CR, Komm BS. Estrogenic effects of 7α-methyl-17α-ethynylestradiol: a newly discovered tibolone metabolite. Steroids 2002;67:681-686.
7. Tang B, Markiewicz L, Kloosterboer HJ, Gurpide E. Human endometrial 3β-hydroxysteroid dehydrogenase/isomerase can locally reduce intrinsic estrogenic/progestagenic activity ratios of a steroidal drug (Org OD 14). J Steroid Biochem Mol Biol 1993;45:345-351.
8. Tan L, Muto N. Purification and reconstitution properties of human placental aromatase. A cytochrome P-450-type monooxygenase. Eur J Biochem 1986;156:243-250.
9. Silberzahn P, Gaillard JL, Quincey D, Dintinger T, Al-Timini I. Aromatization of testosterone and 19-nortestosterone by a single enzyme from equine testicular microsomes: differences from human placental microsomes. J Steroid Biochem 1988;29:119-125.
10. Dintinger T, Gaillard JL, Moslemi S, Zwain I, Silberzahn P. Androgen and 19-norandrogen aromatization by equine and human placental microsomes. J Steroid Biochem 1989;33:949-954.
11. Amri H, Gaillard JL, Al-Timimi I, Zilberzahn P. Equine ovarian aromatase: evidence for a species specificity. Biochem Cell Biol 1993;71:296-302.
12. Khalil MW, Chung N, Morley P, Glasier MA, Armstrong DT. Formation and metabolism of 5(10)-estrene-3 β, 17 β-diol, a novel 19-norandrogen produced by porcine granulosa cells from C19 aromatizable androgens. Biochem Biophys Res Commun 1988;155:144-150.
13. Raeside JI, Renaud RL, Friendship RM. Aromatization of 19-norandrogens by porcine Leydig cells. J Steroid Biochem 1989;32:729-735.
14. Sundaram K, Kumar N, Bardin CW. 7-α-Methyl-19-nortestosterone: an ideal androgen for replacement therapy. Recent Prog Horm Res 1994;49:373-376.
15. LaMorte A, Kumar N, Bardin CW, Sundaram K. Aromatization of 7 α-methyl-19-nortestosterone by human placental microsomes. J Steroid Biochem Mol Biol 1994;48:297-304.
16. Kuhnz W, Heuner A, Humpel M, Seifert W, Michaelis K. In vivo conversion of norethisterone and norethisterone acetate to ethinyl estradiol in postmenopausal women. Contraception 1997;56:379-385.
17. Reed MJ, Ross MS, Lai LC, Ghilchik MW, James VH. In vivo conversion of norethisterone to ethynylestradiol in perimenopausal women. J Steroid Biochem Mol Biol 1990;37:301-303.
18. Klehr-Bathmann I, Kuhl H. Formation of ethinylestradiol in postmenopausal women during continuous treatment with a combination of estradiol, estriol and norethisterone acetate. Maturitas 1995;21:245-250.
19. Osawa Y, Yarborough C, Osawa Y. Norethisterone, a major ingredient of contraceptive pills, is a suicide inhibitor of estrogen synthesis. Science 1982;215:1249-1251.
20. Covey DF, Hood WF, McMullan PC. Studies of the inactivation of human placental aromatase by 17 α-ethynyl-substituted 10-β-hydroperoxy and related 19-nor steroids. Biochem Pharmacol 1986;35:1671-1674.
21. Johnston JO, Wright CL, Leeson GA. Regioselectivity of metabolic activation of acetylynic steroids by hepatic cytochrome P450 isozymes. Steroids 1991;56:180-184.
22. Yamamoto Y, Taumura T, Kitawaki J, Osawa Y, Okada H. Suicide inactivation of aromatase in human placenta and uterine leiomyoma by 5 α- dihydronorethindrone, a metabolite of norethindrone, and its effect on steroid-producing enzymes. Eur J Endocrinol 1991;130:634-640.
23. Barbieri PL, Petro Z, Canick JA, Ryan KJ. Aromatization of norethindrone to ethinyl estradiol by human placental microsomes. J Clin Endocrinol Metab 1983;57:299-303.
24. Yamamoto Y, Yoshiji S, Yasuda J, et al. Aromatization of norethindrone to ethynylestradiol in human adult liver. Endocrinol Jpn 1986;33:527-531.
25. Yamamoto T, Kitawaki J, Shiroshita K, Urabe M, Sasaki J, Fukuoka M. The conformation of norethindrone aromatization in primary human hepatocytes by the Vitafiber-II cell culture system. Acta Obstet Gynecol Jpn 1988;40:87-89.
26. Thompson RM, Horning EC. Aromatization of the A-ring of norethynodrel, a steroidal oral contraceptive, during trimethylsilylation. Steroids Lipid Res 1973;4:135-142.
27. Marshall DE, Mortishire-Smith RJ, Houghton E, Gower DB. Isolation and characterisation of a C18 neutral steroid, oestra-5(10),7-diene-3,17-diol, from pregnant mare urine and allantoic fluid. Facile oxidation to yield oestra-5(10),6,8-triene-3,17diol (diol of Heard's ketone). J Steroid Biochem Mol Biol 2000;74:33-43.
28. Sandker GW, Vos RM, Delbressine LP, Sloof MJ, Meijer DK, Groothuis GM. Metabolism of three pharmacologically active drugs in isolated human and rat hepatocytes: analysis of interspecies variability and comparison with metabolism in vivo. Xenobiotica 1994;24:143-155.
29. Vos RME, Krebbers SFM, Verhoeven CHJ, Delbressine LPC. The in vivo metabolism of titolone. Drug Metab Dispos 2002;30:106-112.
30. Jones MEE, Reuters AT, Boon WC, Erderveen AG, Kloosterboer HJ, Simpson ER. The aromatase knockout (Arko) mouse as a model to study the oestrogenic action of tibolone. In: Proceedings of the 46th Annual Scientific Meeting of the Endocrine Society of Australia; Melbourne, Australia; 2003 Abstract 157.
31. Townsley JD, Brodie HJ. A new placental metabolite of oestr-4-ene-3,17-dione: a possible source of error in oestrogen estimation. Biochem J 1966;101:25c-27c.
32. Simpson E, Clijne C, Rubin G, et al. Aromatase: a brief overview. Annu Rev Physiol 2002;64:93-127.
33. Sasano H, Harada N. Intratumoral aromatase in human breast endometrial and ovarian malignancies. Endocr Rev 1998;19:593-607.
34. Voelker W, Coelingh Bennink HJT, Helmond FA. Effects of tibolone on the endometrium. Climacteric 2001;4:203-208.
35. Connor P, Register TC, Skoog L, Tani E, Von Schoultz B, Cline JM. Expression of p53 and markers for apoptosis in breast tissue during long-term hormone therapy in cynomolgus monkeys. Am J Obstet Gynecol 2005;193:58-63.
36. Heger-Mahn D, Entezami M, Schutt B, Kuhnz W, Richert K, Lubbert H. Ostrogene effecte nach 14tägiger Gabe von 006 mg Ethinylestradiol bei postmenopausalen Frauen. Geburtsh Frauenheilk 1996;6:221-225.
37. Dören M, Rubig A, Coelingh Bennink HJ, Holzgreve W. Differential effects on the androgen status of postmenopausal women treated with tibolone and continuous combined estradiol and norethindrone acetate replacement therapy. Fertil Steril 2001;5:554-559.
38. Carr BR, Parker CR Jr, Madden JD, MacDonald PC, Porter JC. Plasma levels of adrenocorticotropin and cortisol in women receiving oral contraceptive steroid treatment. J Clin Endocrinol Metab 1979;49:346-349.
39. Kicovic PM, Cortes-Prieto J, Luisi M, Milojevic S, Franci F. Placebo-controlled cross over study of effects of Org OD14 in menopausal women. Reproduction 1982;6:81-91.
40. Helgason S. Estrogen replacement therapy after the menopause. Estrogenicity and metabolic effects. Acta Obstet Gynecol Scand 1982;107:1-29.