Rauchen, Estradiolstoffwechsel und Hormonsubstitution

Zusammenfassung

In der abgebrochenen Womens' Health Initiative waren 50 % der 8500 Frauen unter HRT vor oder während der Studie Raucherinnen - demnach ist die Frage äußerst relevant, inwieweit Rauchen den Estradiolstoffwechsel verändern kann. Durch Rauchen kann die Wirksamkeit von oral verabreichten Estrogenen reduziert bis völlig aufgehoben werden, abhängig von Art, Dauer und Intensität des Nikotinkonsums. Dies betrifft die positiven Estrogenwirkungen auf Hitzewallungen, urogenitale Beschwerden sowie den Lipidstoffwechsel, Osteoporoseprävention und möglicherweise auch günstige vaskuläre Effekte. Wichtigste Ursache ist eine dosisabhängige Erhöhung der hepatischen Clearance, häufig in Verbindung mit erniedrigten Estrogenspiegeln. Eine kompensatorische Erhöhung der Dosen für Raucherinnen sollte aber nicht in Betracht gezogen werden, da dies zu der Bildung von toxischen, sogar potenziell mutagenen Estrogenmetaboliten führen könnte - Substanzen, die kürzlich auch mit einem erhöhten Brustkrebsrisiko in Verbindung gebracht wurden. Bei einer transdermalen Applikation bleiben die günstigen Estrogenwirkungen auch bei Raucherinnen erhalten. Dieser Applikationsweg ermöglicht niedrige Dosierungen und vermeidet gleichzeitig die Bildung unphysiologischer Metaboliten, da die Leber primär umgangen wird. Wenn demnach Frauen trotz aller Warnungen weiter rauchen und eine HRT benötigen, wird die transdermale Applikation empfohlen.

Abstract

In the recent discontinued Women's Health Initiative (WHI) 50 % of the 8500 women on HRT had smoked before or continued to smoke during the study - thus the question as to whether smoking may influence estradiol metabolism is of special relevance. Smoking can reduce or completely cancel the efficacy of orally administered estrogens depending on the type, duration and intensity of nicotine consumption. Not only does smoking diminish the beneficial effects of estrogen on hot flashes, urogenital symptoms, lipid metabolism and osteoporosis prevention, but smoking also may influence positive estrogenic effects on the vasculature. Main cause seems to be a dose-dependent elevated hepatic clearance, partially in conjunction with lower estrogen levels. Compensation by increasing the estrogen dose in smokers should be avoided as this might result in the production of toxic, even potentially mutagenic estrogen metabolites - compounds recently associated with a higher risk of breast cancer. The favorable effects of estrogens are not lost in smokers when they are treated transdermally. This route enables low dosage and also avoids the formation of unphysiological metabolites by bypassing the liver. Women who continue to smoke despite all warnings should therefore be treated via the transdermal route.

Literatur

• 1 Aloia J G, Cohn S H, Vaswani A, Yeh J K, Yuen K, Ellis K. Risk factors for menopausal osteoporosis.  Am J Med. 1985;  78 95-100
• 2 American Cancer Society .Cancer, facts and figures. Atlanta, Ga; American Cancer Society 1993: 1-28
• 3 Barbieri R L, Gochberg J, Ryan K J. Nicotine, cotinine, and anabasine inhibit aromatase in human trophoblast in vitro.  J Clin Invest. 1986;  77 1727-1733
• 4 Barbieri R L, McShane J, Ryan K J. Constituents of cigarette smoking inhibit human granulosa cell aromatase.  Fertil Steril. 1984;  46 232-236
• 5 Baron J A, Farahmand B Y, Weiderpass E, Michaelsson K, Alberts A, Persson I, Ljunghall S. Cigarette smoking, alcohol consumption, and risk of hip fracture in women.  Arch Intern Med. 2001;  161 983-988
• 6 Berstein L M, Tsyrlina E V, Kolesnik O S, Gamajunova V B, Adlercreutz H. Catecholestrogens excretion in smoking and non-smoking postmenopausal women receiving estrogen replacement therapy.  J Steroid Biochem Mol Biol. 2000;  72 143-147
• 7 Bumb R G, McClish D K. Cigarette smoking and urinary incontinence in women.  Am J Obstet Gynecol. 1992;  167 1213-1218
• 8 Bolton J L, Trush M A, Penning T M, Dryhurst G, Monks T J. Role of quinones in toxicology.  Chem Res Toxicol. 2000;  13 135-160
• 9 Cassidenti D L, Vijod A G, Vijod M A, Stanczyk F Z, Lobo R A. Short-term effects of smoking on the pharmacokinetic profiles of micronized estradiol in postmenopausal women.  Am J Obstet Gynecol. 1990;  163 1953-1960
• 10 Collaborative Group on Hormonal Factors in Breast Cancer . Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiologic studies with 52 705 women with breast cancer and 108, 411 women without breast cancer.  Lancet. 1997;  350 1047-1059
• 11 Craig W Y, Palomaki G E, Haddow J E. Cigarette smoking and serum lipid and lipoprotein concentration: an analysis of published data.  Br Med J. 1989;  298 784-788
• 12 Cramer D W, Harlow B L, Huijuan X, Fraer C, Barbieri R. Cross-sectional and case-controlled analyses of the association between smoking and early menopause.  Maturitas. 1995;  22 79-87
• 13 Cramer D W, Huijuan X. Predicting age at menopause.  Maturitas. 1996;  23 319-326
• 14 Cramer D W, Wilson E, Stillman R J, Berger M J, Belisle S, Schiff I, Albrecht B, Gibson M, Stadel B V, Schoenbaum S C. The relationship of endometriosis to menstrual characteristics, smoking and exercise.  JAMA. 1986;  255 1904-1908
• 15 Cubrilo-Turek M, Stavljenic-Rukavina A, Turek S, Kusec V, Durakovic Z. The usefulness of biochemical markers in predicting the response of hormone replacement therapy in perimenopausal smoking healthy women.  Coll Antropol. 1999;  23 195-201
• 16 Felson D T, Zhang Y, Hannan M T, Kiel D P, Wilson P W, Anderson J J. The effect of postmenopausal estrogen therapy on bone density in elderly women.  N Engl J Med. 1993;  329 1141-1146
• 17 Fishman J. Role of 2-hydroxyestrone in estrogen metabolism.  J Clin Endocrinol Metab. 1963;  23 207-210
• 18 Franks A L, Kendricks J S, Tyler C W. Postmenopausal smoking, estrogen replacement therapy, and the risk of endometrial cancer.  Am J Obstet Gynecol. 1987;  156 20-23
• 19 Friedman A J, Ravnikar V A, Barbieri R I. Serum steroid hormone profiles in postmenopausal smokers and nonsmokers.  Fertil Steril. 1987;  47 398-401
• 20 Furberg C D, Vittinghoff E, Davidson M, Herrington D M, Simon J A, Wenger N K, Hulley S. Subgroup interactions in the heart and estrogen/progestin replacement study. Lessons learned.  Circulation. 2002;  105 917-922
• 21 Geisler J, Omsjo I H, Helle S I, Ekse D, Silsand T, Lonning P E. Plasma oestrogen fractions in postmenopausal women receiving hormone replacement therapy: influence of route of administration and cigarette smoking.  J Endocrinology. 1999;  162 265-270
• 22 Girdler S S, Hinderliter A L, West S G, Grewen K, Steege J, Light K C. Postmenopausal smokers show reduced hemodynamic benefit from oral hormone replacement.  Am J Cardiology. 2000;  86 590-592
• 23 Grainge M J, Coupland C A, Cliffe S J, Chilvers C E, Hosking D J. Cigarette smoking, alcohol and coffein consumption, and bone mineral density in postmenopausal women. The Nottingham EPIC Study Group.  Osteoporosis Int. 1998;  8 355-363
• 24 Greenberg G, Thompson S G, Meade T W. Relation between cigarette smoking and use of hormonal replacement therapy for menopausal symptoms.  J Epidemiol Comm Health. 1987;  41 26-29
• 25 Hammond E C. Smoking in relation to physical complaints.  Arch Environ Health. 1961;  3 28-164
• 26 Harlow B L, Signorello L B. Factors associated with early menopause.  Maturitas. 2000;  35 3-9
• 27 Henderson B E, Paganini-Hill A, Ross R K. Estrogen replacement therapy and protection from acute myocardial infarction.  Am J Obstet Gynecol. 1988;  159 312-317
• 28 Hu F B, Grodstein F, Hennekens C H, Colditz G A, Johnson M, Manson J E, Rosner B, Stampfer M J. Age at natural menopause and risk of cardiovascular disease.  Arch Intern Med. 1999;  159 1061-1066
• 29 Hu F B, Stampfer M J, Manson J E, Grodstein F, Colditz G A, Speizer F E, Willett W C. Trends in the incidence of coronary heart disease and changes in diet and lifestyle in women.  N Engl J Med. 2000;  343 530-537
• 30 Jensen G F. Osteoporosis of the slender smoker revisited by epidemiologic approach.  Eur J Clin Invest. 1986;  16 239-242
• 31 Jensen J, Christiansen C, Rodbror P. Cigarette smoking, serum estrogen, and bone loss during hormone replacement therapy early after menopause.  N Engl J Med. 1985;  313 973-975
• 32 Jensen J, Christiansen C. Effects of smoking on serum lipoproteins and bone mineral content during postmenopausal hormone replacement therapy.  Am J Obstet Gynecol. 1988;  159 820-825
• 33 Jusko W J. Role of tobacco smoking in pharmacokinetics.  J Pharmacokinet Biopharm. 1978;  6 7-39
• 34 Key T JA, Pike M C, Brown J B, Hermon C, Allen D S, Wang D Y. Cigarette smoking and urinary oestrogen excretion in premenopausal and postmenopausal women.  Br J Cancer. 1996;  74 1313-1316
• 35 Kiel D P, Baron J A, Anderson J J, Hannan M T, Felson D T. Smoking eliminates the protective effect of oral estrogen on the risk for hip fracture among women.  Ann Internal Med. 1992;  116 716-721
• 36 Komulainen M, Kroeger H, Tuppurainen M T, Heikkinen A M, Honkanen R, Saarikoski S. Oral estradiol - identification of early postmenopausal women with no bone response to HRT.  Osteoporosis Int. 2000;  11 211-218
• 37 Krauss R M, Periman J A, Ray R, Petitti D. Effects of estrogen dose and smoking on lipid and lipoprotein levels in postmenopausal women.  Am J Obstet Gynecol. 1988;  158 1606-1611
• 38 Leino A, Impivaara O, Kaitsaari M. Effects of HRT on bone in women smokers and alcohol consumers.  J Bone Miner Res. 1997;  12 (Suppl 1) S355
• 39 Lesko S M, Rosenberg L, Kaufman D W, Helmrich S P, Miller D R, Strom B, Schottenfeld D, Rosenshein N B, Knapp R C, Lewis J. Cigarette smoking and risk of endometrial cancer.  N Engl J Med. 1985;  313 593-596
• 40 Lippert C, Seeger H, Mueck A O, Lippert T H. The effect of endogenous estradiol metabolites on the proliferation of vascular endothelial cells.  Life Science. 2000;  67 1653-1658
• 41 Lippert T H, Seeger H, Mueck A O. Beurteilung des Östrogenmetabolismus bei hormonabhängigen Neoplasien unter klinisch-pharmakologischen Aspekten.  Arzneimittelforschung. 1999;  49 649-662
• 42 Lippert T H, Seeger H, Mueck A O. Endogenous estradiol metabolism. Oettel M, Schillinger E Handbook of Experimental Pharmacology. Vol. 135/I: Estrogens and Antiestrogens. Heidelberg, New York; Springer 1999: 243-271
• 43 Lippert T H, Seeger H, Mueck A O. Estrogens and the cardiovascular system: Role of estradiol metabolites in hormone replacement therapy.  Climacteric. 1999;  1 296-301
• 44 Lippert T H, Seeger H, Mueck A O. Pharmacology and toxicology of different estrogens.  Gynecol Endocrinol. 2001;  15 (Suppl 4) 26-33
• 45 Lippert T H, Seeger H, Mueck A O. The impact of estrogen metabolites on carcinogenesis.  Steroids. 2000;  65 357-369
• 46 Longcope C, Johnston C C. Androgens and estrogen dynamics in pre- and postmenopausal women: a comparison between smokers and nonsmokers.  J Clin Endocrinol Metab. 1988;  67 379-383
• 47 MacMahon B, Trichopoulos D, Cole P, Brown J. Cigarette smoking and urinary estrogens.  N Engl J Med. 1982;  307 1062-1065
• 48 Mann R D, Lis Y, Chukwujindu J, Chanter D O. A study of the association between hormone replacement therapy, smoking and the occurrence of myocardial infarction in women.  J Clin Epidemiol. 1994;  47 307-312
• 49 Mattison D R. Morphology of oocyte and follicle destruction by polycyclic aromatic hydrocarbons in mice.  Toxicol Appl Pharmacol. 1980;  53 249-259
• 50 McMurtry R J, Hagerman D D. Carbon monoxide inhibition of progesterone hydroxylation and chain cleavage catalyzed by rat testis microsomes.  Steroid Lipid Res. 1972;  3 8-13
• 51 Michnovicz J J, Hershcopf R J, Naganuma H, Bradlow H L, Fishman J. Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking.  N Engl J Med. 1986;  315 1305-1309
• 52 Michnovicz J J, Naganuma H, Hershcopf R J, Bradlow H L, Fishman J. Increased urinary catechol estrogen excretion in female smokers.  Steroids. 1988;  52 69-83
• 53 Mueck A O, Lippert T H. Hormonsubstitution in der Peri- und Postmenopause bei gleichzeitigem Vorliegen internistischer Erkrankungen.  Münch med Wochenschr. 1997;  139 495-500
• 54 Mueck A O, Seeger H, Gräser T, Lippert T H. Effect of postmenopausal HRT and of oral contraceptives on estradiol metabolism.  Hormone Metab Res. 2001;  33 744-747
• 55 Mueck A O, Seeger H, Lippert C, Wallwiener D. Angiogenetic and antiangiogenetic effects of estradiol and of its metabolites.  J Clin Basic Cardiology. 2001;  4 153-155
• 56 Mueck A O, Brucker C, Teichmann A T. für SiKuS (Arbeitsgemeinschaft „Steroide in Kontrazeption und Substitution“ des Berufsverbandes der Frauenärzte . Genetische Polymorphismen. Bedeutung für Diagnostik und individualisierte Therapie.  Frauenarzt. 2002;  43 424-429
• 57 Nisker J A, Marunlic M A. Cigarette smoking and bone loss during hormone replacement after menopause (Letter). N Engl.  J Med. 1986;  314 854
• 58 Paganini-Hill A, Ross R K, Gerkins V R, Henderson B E, Arthur M, Mack T M. Menopausal estrogen therapy and hip fractures.  Ann Intern Med. 1981;  95 28-31
• 59 Ross R K, Pike M C, Vesey M P. Risk factors for uterine fibroids.  Br Med J. 1986;  293 359-362
• 60 Seeger H, Mueck A O, Lippert T H. Effect of estradiol metabolites on prostacyclin synthesis in human endothelial cell cultures.  Life Science. 1999;  65 167-170
• 61 Seeger H, Mueck A O, Lippert T H. Estradiol metabolism during oral and transdermal estradiol replacement therapy in the postmenopause.  Hormone Metab Res. 1998;  30 598-601
• 62 Seeger H, Mueck A O, Lippert T H. The antiproliferative effect of 17β-estradiol metabolites on human coronary artery smooth muscle cells.  Med Sci Res. 1998;  26 481-482
• 63 Seeger H, Mueck A O, Lippert T H. The inhibitory effect of endogenous estrogen metabolites on copper-mediated oxidation of LDL.  Int J Clin Pharm Therap. 1998;  36 383-385
• 64 Seeger H, Mueck A O. Effect of norethisterone acetate on estrogen metabolism in postmenopausal women.  Horm Metab Res. 2000;  32 436-439
• 65 Statistisches Bundesamt Wiesbaden . Mitteilungen.  DMW. 1994;  119 324
• 66 Stockwell H G, Lyman G H. Cigarette smoking and the risk of female reproductive cancer.  Am J Obstet Gynecol. 1987;  157 35-39
• 67 Surgeon General's Report on Women and Smoking .. Miami; Roper ASW Press Release 1.Nov.2001
• 68 Teede H J, Liang Y L, Shiel L M, McNeil J J, McGrath B P. Hormone replacement therapy in postmenopausal women protects against smoking-induced changes in vascular function and function.  J Am Coll Cardiol. 1999;  34 131-137
• 69 Thompson P A, Ambrosone C. Molecular epidemiology of genetic polymorphisms in estrogen metabolizing enzymes in human breast cancer.  J Natl Cancer Inst Monogr. 2000;  27 125-134
• 70 Torgerson D J, Avenell A, Russell I T, Reid D M. Factors associated with onset of menopause in women aged 45 - 49.  Maturitas. 1994;  19 83-92
• 71 Tuppurainen M, Honkanen R, Kröger H, Saarikoski S, Alhava E. Osteoporosis risk factors, gynaecological history and fractures in perimenopausal women - results of the Kuopio Osteoporosis Risk Factor and Prevention Study.  Maturitas. 1993;  17 89-100
• 72 Valk-de Roo G W, Netelenbos J C, Peters-Muller I RA, Voetberg G A, van de Weijer P HM, Bouman A A, Popp-Snijders C P, Kenemans P. Continuously combined hormone replacement therapy and bone turnover: the influence of dydrogesterone dose, smoking and initial degree of bone turnover.  Maturitas. 1997;  28 153-162
• 73 Wack J T, Rodin J. Smoking and its effects on body weight and the systems of caloric regulation.  Am J Clin Natr. 1982;  35 366-380
• 74 Willett W, Stampfer M J, Bain C, Lipnick R, Speizer F E, Rosner B, Cramer D W, Hermekens C H. Cigarette smoking, relative weight and menopause.  Am J Epidemiol. 1983;  117 615-618
• 75 Wilson P WF, Garrison R J, Castelli W P. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50. The Framingham Study.  N Engl J Med. 1985;  313 1038-1043
• 76 Yager J D, Liehr J G. Molecular mechanisms of estrogen carcinogenesis.  Annu Rev Pharmacol Toxicol. 1996;  36 203-232
• 77 Ylikorkala O, Cacciatore B, Paakari I, Tikkanen M J, Viinikka L, Toivonen J. The long-term effects of oral and transdermal postmenopausal hormone replacement therapy on nitric oxide, endothelin-1, prostacyclin, and thromboxane.  Fertil Steril. 1998;  69 883-888