Hormonmangel und Alterungsprozesse- Was ist Ursache, was Wirkung Hormonmangel und Alterungsprozesse- Was ist Ursache, was Wirkung? Hormonsubstitution- Was macht Sinn, was ist riskant? Prof. Dr. Markus Metka

History of HRT Use ? HRT RCT’s Feminine Forever,’65 Estrogens lower CHD risk Estrogens prevent bone loss Progestins protect endometrium “Feminine Forever” Estrogens cause breast cancer Estrogens Cause endometrial cancer “In the entire realm of medicine, there are few forms of therapy with a more consistent record of beneficence.” Robert Wilson, MD Feminine Forever,’65 HRT RCT’s ? Observational Epidemiology Animal Models Vascular Biology Clinical Intermediate Endpoints Lipids/Lp(a) Endothelial Function Antioxidant Homocysteine Carbohydrate Metabolism Vascular stiffness …. 10 20 30 40 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 Prescriptions/yr (millions) Progestin Estrogen

WHI HRT Study Patient Characteristics Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333. 1/3 2/3 3/4 n=5522 n=7510 n=3576 n=3262 n=1035 n=12 304 % of Enrolled Population % of Enrolled Population Roter Kasten li, dann rechter Age (yrs) Hormone Use Prior to Study Entry Patientinnen der WHI Studie waren symptomlos Östrogenmangelsymptome waren Ausschlusskriterien

Early Initiation: the replacement concept Overhead 74 Early Initiation: the replacement concept Late therapy (HT) HRT Administration of hormones to symptomatic, estrogen-deficient women such as those in the observational studies is hormone replacement therapy Administration of hormones to asymptomatic women such as those in the RCT´s is hormone therapy Late perimenopausal YSM 1-3 years YSM > 3-5 years The Importance of EICON Overall, EICON presents the possibility to distinguish Activelle® from direct competition while expanding the potential business opportunity. For women, Activelle® will make it possible for more of them to receive the benefits of period-free HRT, because of its rapid symptom relief and excellent bleeding profile, as early as one year after the menopause. For physicians, Activelle® enables them to provide more of their postmenopausal patients the benefits of period-free HRT, while minimising some of the risks associated with HRT (through meeting the expected trends towards use of HRT for 5 years). For Novo Nordisk, adopting EICON will help seize an untapped opportunity within the period-free HRT market with Activelle®, while avoiding the increasing non-HRT competition (bisphosphonates, estrogen analogues) for older women. LM 1 2 3 4 Years since menopause LM = Last Menstruation YSM = Years Since Menopause

Risk of Incident AD: The Effect of HT Mean Age, 74 Years Men Women: No HT Use Past HT Use <3 Years Past HT Use 3-10 Years Past HT Use >10 Years Current HT Use <3 years Current HT Use 3-10 Years Current HT Use >10 Years Among Cache County participants, AD was less common among women with a history of HT use compared with nonusers. The figure above illustrates that longer duration of use was associated with additional reductions in AD risk. Women who used HT at any time had a 41% reduced risk of developing AD (RH, 0.59;95% CI, 0.36–0.96), and women who used HT for 10 years or longer had a 59% reduced risk of AD (RH, 0.41; 95% CI, 0.17–0.86). Healthy user bias and level of education were controlled for both of these assessments.1 Use of calcium or multivitamins was not associated with reductions in AD risk. Current HT use was associated with decreased risk only if HT use exceeded 10 years (RH, 0.55; 95% CI, 0.21–1.23), although statistical significance was not reached. The seeming null effect of current use may not merely be a factor of duration of use. There may be a limited window of time, possibly early in the postmenopause, during which HT is most protective. The end of this period may coincide with onset of the preclinical stage of AD (which may begin 10 or more years before AD can be diagnosed) after which HT is less likely to reduce AD risk.1,2 It has also been suggested that estrogen-responsive neurons may be less responsive after a prolonged period of estrogen depletion,3-5 such that intervention early in the postmenopause may offer more protection. Additional study of these mechanisms is warranted. Relative Hazard (95% CI) Zandi PP, et al. JAMA. 2002;288:2123-9. 1Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA. 2002;288:2123-2129. 2Resnick SM, Henderson VW. Hormone therapy and risk of Alzheimer disease: a critical time. JAMA. 2002;288:2170-2172. 3Toran-Allerand CD. Estrogen as a treatment for Alzheimer disease. JAMA. 2000;284:307-308. 4Crespo D, Cos S, Fernandez-Viadero C, Gonzalez C. Ultrastructural changes in hypothalamic supraoptic nucleus neurons of ovariectomized estrogen-deprived young rats. Neurosci Lett. 1991;133:253-256. 5Simpkins JW, Green PS, Gridley KE, Singh M, de Fiebre NC, Rajakumar G. Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer's disease. Am J Med. 1997;103:19S-25S.

HRT HRT (adapted from Mikkola et al.)

NEOVASKULARISIERUNG DER INTIMA ÜBER VASA VASORUM DER ADVENTITIA VERSTÄRKT VERKALKUNG UND INFLAMMATION Am Pathol 1993; 143:164-72.

Baseline Characteristics: NHS Versus WHI age (years)* Smokers (past and current) BMI (mean) HRT regimen Menopausal symptoms (flushing) 30-55 6.9% 25.1 kg/m2 unopposed sequential predominant 63 49.9% 28.5 kg/m2 continuous combined excluded Although both NHS1,2 and WHI3 were designed to examine primary prevention of CVD, the populations they investigated were markedly different. Patients in the WHI were generally older at study onset than those in the NHS. Thus, while patients in the NHS generally began HRT use around the time of the menopause (personal communication, M. Stampfer, August 2002), WHI participants began the trial (and therefore HRT) at an average age of 63 years—more than 10 years past the average age of natural menopause. Participants in WHI were 7-times more likely to smoke, were more overweight (34% of the participants in the WHI had an average BMI of 30 kg/m²), and were less frequent aspirin users than patients examined in NHS. The rates of hypertension and diabetes were similar between the two study groups. Although both NHS and WHI were designed as primary prevention studies, the two study populations were markedly different. In summary, the NHS enrolled younger women with a more favorable health status than did the WHI. *Mean age or age range at enrollment (years) *34.1% had BMI 30 kg/m2. 1Grodstein F et al. Ann Intern Med. 2000;133:933-41. 2Grodstein F et al. N Engl J Med. 1996;335:453-61. 3Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-33. 1Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000;133:933-941. 2Grodstein F, Stampfer MJ, Manson J, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med. 1996;335:453-461. 3Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.

Kumulatives Brustkrebsrisiko 70 Übergewicht JAMA, Nov. 5. 1997 Vol 278, No. 17 Alkohol JAMA, Feb. 18, 1998 Vol 279, No. 7 10 Jahre HRT keine HRT 5 Jahre HRT 60 50 Kumulatives Brustkrebsrisiko /1000 Frauen 40 Sport N. Engl. J.o. Med. 1997 Vol 336, No. 18 30 20 10 45 50 55 60 65 70 Alter (Jahre) (Lancet, 350, 1997)

Östradiol

Aromatasehemmer Aromatase OESTRADIOL

HRT: Indikationen morgen: vorzeitige/frühe Menopause: absolute Indikation (unverändert) zeitgerechte Menopause: klimakterisches Syndrom schlechte Lebensqualität wegen Oestrogenmangel Osteoporose-Prävention Antwort offen: Primärprävention kardio- vaskulär / M. Alzheimer MB 2005

Die Säulen des Anti-Aging Ernährung Hormone Bewegung Umwelt Spiritualität

Risikofaktoren Risiko: Oxidativer Stress Risiko: Entzündung

Risikofaktoren Risiko: Oxidativer Stress Risiko: Entzündung

Osteoporosis Depression Dementia Arteriosklerosis Interleukin 6 „Two Sides of one Medal“ Münch. Med. Wo. 2003 Arteriosklerosis Dementia Nathalie Dijsselbloem, et al Soy isoflavone phyto-pharmaceuticals in interleukin-6 affections Multi-purpose nutraceuticals at the crossroad of hormone replacement, anti-cancer and anti-inflammatory therapy Biochemical Pharmacology 68 (2004) 1171–1185

Phytoestrogen: Genistein ? Osteoporosis Major Depression Interleukin 6 Phytoestrogen: Genistein Arteriosklerosis Dementia ? Nathalie Dijsselbloem, Wim Vanden Berghe, An De Naeyer, Guy Haegeman* Soy isoflavone phyto-pharmaceuticals in interleukin-6 affections Multi-purpose nutraceuticals at the crossroad of hormone replacement, anti-cancer and anti-inflammatory therapy Biochemical Pharmacology 68 (2004) 1171–1185

Keywords for succesful aging Antiphlogistisch Antiviral Antimikrobiell Antioxidativ Canceroprotektiv Hypoglykämisch Hypotensiv

Wo finden wir die wichtigsten Isoflavone? Sie kommen vor z. B.: in Soja, in Rotklee etc. Formononetin Daidzein Genistein Biochanin A

Was sind Phytoöstrogene? M. Kurzer, X. Xu, Annu. Rev. Nurt, 1997. 17:353 - 381 Broadly defined, phytoestrogens include isoflavones, coumestanes and lignans. A number of these compounds have been identified in fruits, vegetables and whole grains commonly consumed by humans. Soybeans, clover and alfalfa sprouts and oilseeds are the most significant dietary sources of isoflavones, coumestanes and lignans.

Wo kommen Phytohormone in der Natur vor? Flavonoide z.B.: Resveratrol Quercetin Tangeretin Myricetin Was sind Flavonoide und Isoflavone? Polyphenole Isoflavone, Lignane z.B.: Genistein Biochanin A Daidzein Formononetin Soja: Granatapfel: Glycine max Granatus imperialis Rotklee: Hopfen Trifolium pratense Humulus lupulus

Isoflavone – potentielle Anwendungen und Wirkungsweise Prävention Prostata,- Mamma- und Kolonkarzinom Wirkungsweise Bei Blutungsanomalien prämenopausaler Frauen Linderung peri- und postmenopausaler Beschwerden

Isoflavone – potentielle Anwendungen und Wirkungsweise Prävention Prostata,- Mamma- und Kolonkarzinom Wirkungsweise Bei Blutungsanomalien prämenopausaler Frauen Linderung peri- und postmenopausaler Beschwerden

Korrelation Vitamin D Versorgung, Phytoöstrogenkonsumation und Krebsinzidenz Epidemiologische Daten: höhere Inzidenz von Mamma-, Prostata und Kolonkarzinom in Länder mit weniger Sonneneinstrahlung weniger Fischkonsum (beides Vitamin D-Quellen) geringer Phytoöstrogenkonsumation

Krebsvorbeugung/-behandlung mit Isoflavonen und VitaminD? Hypothese: Verteidigungsmechanismus gegen Tumorprogression durch gewebelokalisierte Akkumulation des aktiven Hormonmetaboliten 1,25-Dihydroxyvitamin D3 Isoflavone, wie z. B. Genistein unterstützen diesen Akkumulationsmechanismus

Vitamin D Metabolismus Vitamin D3 bei UV-Einstrahlung in der Haut produziert Umwandlung in Leber/Niere durch Cytochrom P450 Enzyme (CYP27A1 bzw. CYP27B1) in aktiven Hormonmetaboliten 1,25-Dihydroxyvitamin D3 Zu starke Akkumulation wird durch Abbau bzw. präferentielle 24-Hydroxylierung durch CYP24 vermieden Limitierung essentiell für Kalziumhomöostase – aber Nichterreichung nanomolarer Spiegel für antimitotische prodifferenzierende Wirkung von 1,25-D3 Leber Niere Inhibierung durch Isoflavone Induktion durch Isoflavone Isoflavone bewirken Akkumulation von 1,25-D3 Aus Hesso Farhan et al. 2002 : Isoflavonoids inhibit catabolism of vitamin D in prostate cancer cells Journal of Chromatography B 777 (2002) 261-268

Isoflavone bewirken Akkumulation von 1,25-D3 In höheren Konzentrationen hat 1,25-D3 antikanzerogenes Potential Nachweis vermehrter Vitamin D Metabolismus und Katabolismus in Mamma-, Prostata- und Kolonkarzinomzellen – in dedifferenzierten Zellen hingegen nicht Gewebelokalisierte Akkumulation von 1,25-D3 potentieller autokriner/parakriner Verteitigungsmechanismus gegen weitere Tumorprogression

Isoflavone -vielfältige Funktionen Strukturähnlichkeit mit 17 ß-Estradiol Interaktion mit Steroidrezeptoren (Östrogen-, Androgen- and Progesteronrezeptoren) - selective estrogen rezeptor modulator - SERMs Inhibierung von Enzymen – selective enzym modulator – SEMs Antioxidative Wirkung - Radikalfängerkapazität

Strukturähnlichkeit von Östrogen und Isoflavonen

Isoflavone: vielfältige Funktionen Strukturähnlichkeit mit 17 ß-Estradiol Interaktion mit Steroidrezeptoren (Östrogen-, Androgen- and Progesteronrezeptoren) - selective estrogen rezeptor modulator - SERMs Inhibierung von Enzymen – selective enzym modulator – SEMs Antioxidative Wirkung - Radikalfängerkapazität Rezeptor - Induktion SERM‘s Selektive Östrogen Rezeptor Modulatoren

Selective Bindung am -ER Knochen Blutgefäße ZNS Uterus Brust  a

Enzym - Induktion SEM‘s Selektive Enzym Isoflavone: vielfältige Funktionen Strukturähnlichkeit mit 17 ß-Estradiol Interaktion mit Steroidrezeptoren (Östrogen-, Androgen- and Progesteronrezeptoren) - selective estrogen rezeptor modulator - SERMs Inhibierung von Enzymen – selective enzym modulator – SEMs Antioxidative Wirkung - Radikalfängerkapazität Enzym - Induktion SEM‘s Selektive Enzym Modulatoren

Dehydroepiandrostendion (DHEA) – (-S) Ubiquitäre Wirkung: 3 b-Hydroxy-Steroid-Dehydrogenase-Isomerase Sulfatase Androstendion 17 b-Hydroxy-Steroid-Dehydrogenase Testosteron 5 a-Reduktase Aromatase Dihydrotestosteron Östradiol

Summary – Isoflavonoid phytoestrogens and lignans in plants are known to be consistuents of animal and human food .........................are moderate or weak inhibitors of human estrogen synthase (aromatase) and.......The inhibition is competitive with respect to testosterone and androstenedione,...... HERMANN ADLERCREUTZ ET AL. J. Steroid Biochem. Molec. Biol. Vol. 44, No. 2, pp. 147-153, 1993

5-Reductase

B A J EVANS ET AL.,. Journal of Endocrinology (1995) 147, 295 - 302 ....This report describes the inhibition of 5-reductase and 17ß-hydroxysteroid dehydrogenase by six isoflavonoids and....... In genital skin fibroplasts, genistein, biochanin A and equol were the most potent inhibitors of 5-reductase activity........ It is possible that a life-long dietary exposure to these lignans and isoflavones may have a significant influence on the development of hormone-dependent tumors. B A J EVANS ET AL.,. Journal of Endocrinology (1995) 147, 295 - 302

Isoflavone: vielfältige Funktionen Strukturähnlichkeit mit 17 ß-Estradiol Interaktion mit Steroidrezeptoren (Östrogen-, Androgen- and Progesteronrezeptoren) - selective estrogen rezeptor modulator - SERMs Inhibierung von Enzymen – selective enzym modulator – SEMs Antioxidative Wirkung - Radikalfängerkapazität

Isoflavonoid compounds from red clover (Trifolium pratense) Photochem Photobiol 2001 Sept; 74(3):465 - 70 Isoflavonoid compounds from red clover (Trifolium pratense) protect from inflammation and immune suppression induced By UV radiation Widyarini S, Spinks N, Husband AJ, Reeve VE. Faculty of Veterinary Science, University of Sydney, NSW 2006, Australia. Isoflavones derived from many edible plants have been reported to possess significant antioxidant, estrogenic and tyrosine kinase inhibitory activity. Genistein has been found previously to provode protection from oxidative damage induced by UV radiation both in vitro and following dietary administration.

Pharmakologische Wirkungen von Resveratrol: Direkte und indirekte gefäßerweiternde Wirkung HDL↑, LDL↓ Hemmung der Thrombozytenaggregation Hemmt die Entstehung von Krebszellen und auch deren Entwicklung (Brust, Darm, Prostata, Haut, Lunge) Antitumorwirkung Entzündungshemmend (COX1 und COX2 1:1) Starkes Antioxidans (sowohl fett als auch wasserlöslich) Dosisabhängige östrogene Effekte Lebensverlängerung von Zellen (Anti Aging)