Etablierte und Alternative Universitätsklinik für Frauenheilkunde Wien Endometriose Etablierte und Alternative Therapien C Tempfer Universitätsklinik für Frauenheilkunde Wien

Jede 10. Frau im reproduktiven Lebensalter hat Endometriose. Endometriose Epidemiologie Jede 10. Frau im reproduktiven Lebensalter hat Endometriose. Ann NY Acad Sci 2002

Endometriose Epidemiologie 30% aller Frauen mit primärer Infertilität haben Endometriose. Ann NY Acad Sci 2002

Endometriose Epidemiologie 50-75% aller jungen Frauen mit sekundär aufgetretenen, schmerzhaften Regelblutungen haben Endometriose. Ann NY Acad Sci 2002

Endometriose Entstehung /Pathogenese Risikofaktoren Lokalisation Symptomatik Therapie

Retrograde Menstruation Metaplasie des Coelomepithels Endometriose Ätiologie I Retrograde Menstruation Ektope Transplantation von Endometrium Metaplasie des Coelomepithels Spontanmutation von Peritonealzellen zu Endometrium Genetische Faktoren 7x häufiger bei Verwandten 1.Grades

Immunologie & Stress Umwelt Endometriose Ätiologie II Reduzierte zelluläre Abwehr am Peritoneum Umwelt Gehäuft in Ballungs- & Industriegebieten, Dioxin

Endometriose Endometriose Pathogenese Exzessive retrograde Menstruation (mit Abflußbehinderung) Normale retrogr. Menstruation plus Immunschwäche, daher keine „Reinigung“ des Zell-Abfalls Endometriose Andere Entstehung Coelom-Metaplasie „Normale“ retrograde Menstruation mit hormoneller Stimulation Modell für die Entstehung der Endometriose auf Basis der retrograden Menstruation (nach Cramer & Missmer, Ann NY Acad Sci 2002)

Endometriose Entstehung /Pathogenese Risikofaktoren Lokalisation Symptomatik Therapie

Endometriose Risikofaktoren Frühe erste Menstruation Kurze Zyklen Schmerzhafte Regelblutung Körpergröße Alkohol Koffein Positive Familienanamnese Umwelt (Dioxin, PCB) Ann NY Acad Sci 2002

Endometriose Risikofaktoren Zahl der Schwangerschaften Körpergewicht ? Bewegung Ann NY Acad Sci 2002

Endometriose Entstehung /Pathogenese Risikofaktoren Lokalisation Symptomatik Therapie

Endometriose Entstehung /Pathogenese Risikofaktoren Lokalisation Symptomatik Therapie

Endometriose Kardinalsymptom Schmerzen während der Regelblutung beim Geschlechtsverkehr beim Stuhlgang beim Urinieren chronisch im Unterbauch

Endometriose Chronische Unterbauchschmerzen (CPP) Dauer > 6 Monate Insuffiziente vorangegangene Schmerztherapie 0-Relation Schmerzintensität : Organpathologie Beeinträchtigung von Körperfunktionen Zeichen von Depression Psychosoziale Belastung

Endometriose Entstehung /Pathogenese Risikofaktoren Lokalisation Symptomatik Therapie

Endometriose Chirurgie Schmerztherapie Hormonelle Therapie Neue Therapieansätze Alternative Therapieformen Ernährung

Endometriose Operation Bauchspiegelung oder Bauchschnitt ? Keine wissenschaftlichen Daten für die Überlegenheit der einen oder anderen Methode Nicht der Zugang, sondern das chirurgische Ergebnis ist relevant

Endometriose Rezidivraten Eierstock (Endo-Zysten) 12% Bauchfell (peritoneal) 20% rectovaginal 35% (ohne Darmresektion)

Endometriosis: absence of recurrence after endometrial ablation Bulletti et al., Hum Reprod 2001 Patients Treatment Dysmenorrhoea 2nd-look LSK before 3mo 24mo recurrences 14 LSK+EA 4 1 3 0 (0%) 14 LSK 4 3 4 9 (64%)

Endometriose & Schmerz OP Diag.LSK vs. OP-LSK (rAFS I, II,III)* OP + Med GnRH-Analoga, Danazol, MPA, Ar. *Sutton et al., Fertil Steril 1994, n=74 nach Olive & Pritts, NEJM 2001

Endometriose & Infertilität OP rAFS I & II1, III + IV Med GnRH-Analoga, Danazol, OCP OP + Med nein, ausser IVF 1 Marcaux et al., NEJM 1997, n=341 (7.7 OP´s/Grav!) nach Olive & Pritts, NEJM 2001

Drug therapy for infertility assoc. with endometriosis Cochrane review 2000

Endometriose Chirurgie Schmerztherapie Hormonelle Therapie Neue Therapieansätze Alternative Therapieformen Ernährung

NSAIDs - Stromazelle Steroidogener Faktor (SF) - 1 Aromatase C19 COUP-TF = Aromatase-Promotor Aromatase PGE2 COX2 Transkription / Aromatase-Gens C19 Östrogene

Endometriose Chirurgie Schmerztherapie Hormonelle Therapie Neue Therapieansätze Alternative Therapieformen Ernährung

Endometriose Med.Therapie „Pille“ keine eindeutigen Daten aber first line – Therapie gutes Nebenwirkungsprofil Dysmenorrhoe, Dyspareunie long cycle Moore J. et al: Cochrane 2001

Cochrane Database Syst Rev 2001 Danazol is effective in treating the symptoms and signs of endometriosis. However, its use is limited by the occurrence of androgenic side effects. Cochrane Database Syst Rev 2001

Topische Danazol Therapie Novel vaginal danazol ring therapy for pelvic endometriosis, in particular deeply infiltrating endometriosis.1 Direct effect of danazol on endometrial hyperplasia in adenomyotic women: treatment with danazol containing IUD.2 Novel conservative medical therapy for uterine adenomyosis with a danazol-loaded IUD.3 1Igarashi et al., Hum Reprod 1998 2Tamaoka et al., Hum Cell 2000 3Igarashi et al., Fertil Steril 2000

Endometriose Nebenwirkungsprofil Danazol Danokrin 200mg Kps, Scheidenzäpfchen Gewichtszunahme Blutungstörungen Haarwuchs, Stimmungsschwankungen Vertiefung der Stimme Libidoveränderungen Leberschäden

Effects of vaginal danazol ring on endometriotic mass Disapp. Reduced Unchanged Total Deeply infiltrating 36 6 0 42 (86%) endometriosis Ovarian endo-cyst 0 3 11 14 (21%) Novel vaginal danazol ring therapy for pelvic endometriosis, in particular deeply infiltrating endometriosis. Igarashi et al., Hum Reprod 1998

Effects of vaginal danazol ring on dysmenorrhoea Disapp. Reduced Unchanged Total Deeply infiltrating 32 9 1 42 (98%) endometriosis Ovarian endo-cyst 5 3 2 10 (80%) Novel vaginal danazol ring therapy for pelvic endometriosis, in particular deeply infiltrating endometriosis. Igarashi et al., Hum Reprod 1998

Rp. Danazoli 0.2 g Adipis neutralis q.s. Misce f. supp. d.t.dos.Nr.XXX

Endometriose Nebenwirkungsprofil Gestagene-MPA Tabletten, Scheidenzäpfchen, Spritze Blutungsstörungen Übelkeit, Brustspannen Depression Wasserstau, Gewichtszunahme NWs reversibel !

Endometriose Nebenwirkungsprofil GnRH-Analoga i.m.-Injektion alle 4 Wo, Nasenpsray Künstlicher Wechsel ! Keine Monatsblutung Hitzewallungen Trockene Scheide Libidoverlust Brustspannen Müdigkeit Osteoporose

Adjuvante Studien Hum Reprod 1999;14(5):1335-7 Ergebnis no adjuvant therapy vs. danazol 600mg/d for 3 mos n=77; AFS III/IV; 12 mos follow-up Ergebnis Rezidive (Schmerz) gleich 7/31 (23%) vs. 9/29 (31%); p=n.s. objektivierbare Rezidive (Sono, Tastbef.) gleich 8% vs. 15% SS-Raten gleich 6/11 vs. 8/16 The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about 120-200 cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

Adjuvante Studien Hum Reprod 2002;17(4):1128-9 Ergebnis no adjuvant therapy vs. GnRH-Analogon (Leuprolidazetat 3.75mg) q28x3 n=89; AFS III/IV; 6 mos follow-up Ergebnis Rezidive (Schmerz) gleich 23% vs. 24% objektivierbare Rezidive (Sono, Tastbef.) gleich 9% vs. 9% The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about 120-200 cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

Low-Dose Danazol Hum Reprod 1999;14(9):2371-4 Ergebnis alle: surgery + GnRH-Analogon (triptorelin 3.75mg) q28x6 rand.: danazol 100mg/d f. 6 mos vs. no further therapy n=28; AFS III/IV; 24 mos follow-up Ergebnis Schmerzscore besser p<0.01 Rezidive 44 vs. 67% p<0.05 side effects gleich The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about 120-200 cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

Goserelin Br J Obstet Gynaecol 1999;106(7):672-7 Ergebnis no therapy vs. goserelin (Zoladex®) s.c. q28x6 n=269; AFS II/IV; 24 mos Ergebnis weniger Rezidive n. 1a: 13% vs. 21% weniger Rezidive n. 2a: 23% vs. 36% rezidivfreies Intervall sign. länger The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about 120-200 cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

GnRH + Anastrozol Hum Reprod 2004;19(1):160-7 Ergebnis OP + Goserelin 3.6mg q28x6 +/- Anastrozol 1mg/d 6 mos n=97; severe endometriosis (rASRM score >40); 24 mos follow-up Ergebnis länger rez.-frei 2.4 vs. 1.7 mos (p=0.009) weniger Schmerzrezidive 35% vs. 8% BMD-Verlust höher; QOL gleich The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about 120-200 cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

Mirena® Hum Reprod; E-publ. March 24, 2005 n= 82; Endometriose + CPP/Dysmenorrhoe LNG-IUD vs. GnRH-Analogon (Lupron dep. 3.75mg q28 x 6) Ergebnis gleich effektiv CPP kein Unterschied (p=0.9) 1. Monat blutungsfrei 34% vs. 71% 6. Monat blutungsfrei 70% vs. 98% A range of systemic drugs can be delivered intranasaly, which is more comfortable and convenient than the parenteral route. Some drugs such as demopressin are delivered sucessfully via the intranasal route, whereas others such as insulin are not. Pharmacologically active polypeptides such as hormones and vaccines avoid both the hepatic first pass effect and metabolism by enzymes in the gut lumen or wall. The nasal route is potentially important for the long term administration of proteins or peptides. The long term compliance of patients taking systemeic drugs delivered intranasally is good. At present several systemic drugs are licensed for transnasal delivery : Desmopressin : Diabetes insipidus LHRH : contraceptive agents assessing the reserve of luteinising hormones and follicle-stimulating hormones from the pituitary gland may have a role in the differential diagnosis of hypogonadism and delayed puberty. Synthetic salmon calcitonin : osteoporosis (Hong Kong) COMPLIANCE: Hirvonene Br J Obstet Gynaecol

Mirena® post OP? Schmerzrezidive seltener Fertil Steril 2003;80(2):305-9 n= 40; randomisiert; surgery +/- IUD alle Stadien; 12 mos follow-up Ergebnis Schmerzrezidive seltener 2/20 (10%) vs. 9/20 (45%) höhere Zufriedenheit 15/20 (75%) vs. 10/20 (50%) A range of systemic drugs can be delivered intranasaly, which is more comfortable and convenient than the parenteral route. Some drugs such as demopressin are delivered sucessfully via the intranasal route, whereas others such as insulin are not. Pharmacologically active polypeptides such as hormones and vaccines avoid both the hepatic first pass effect and metabolism by enzymes in the gut lumen or wall. The nasal route is potentially important for the long term administration of proteins or peptides. The long term compliance of patients taking systemeic drugs delivered intranasally is good. At present several systemic drugs are licensed for transnasal delivery : Desmopressin : Diabetes insipidus LHRH : contraceptive agents assessing the reserve of luteinising hormones and follicle-stimulating hormones from the pituitary gland may have a role in the differential diagnosis of hypogonadism and delayed puberty. Synthetic salmon calcitonin : osteoporosis (Hong Kong) COMPLIANCE: Hirvonene Br J Obstet Gynaecol

Endometriose add-back Enantone-Gyn R (s.c., i.m.) Zoladex R (i.m.) Decapeptyl-Depot R (i.m.) immer zusätzlich „add back“ Therapie! lindert klimakterische Beschwerden keine Reduktion der Effektivität ab 1. Monat der Therapie

Add-back Therapie Alternativen der Begleittherapie zu LHRHa: Gestagen (z.B. Norethisteronazetat 5mg) Kombination eines Östrogens und Gestagens (z.B. NETA 5mg + konj. equine Östrogene 0,625 mg) Synthetisches Steroid (Tibolon)

12-Monatstherapie mit Enantone-Gyn Therapie: Enantone-Gyn mit und ohne Gestagene/ Östrogene Add-Back Therapie Patientinnen: 201 Studiendauer: 1 Jahr Endpunkte: Schmerzevaluierung, Knochendichtemessung Hornstein et al Obstet Gynecol. 1998 Jan; 91(1):16-24

Knochendichte unter L+Add-Back Knochendichte (g/cm2) Ena®-Gyn Ena®-Gyn + NETA 5 mg Ena®-Gyn + NETA 5 mg + CCE 0,625 mg Ena®-Gyn + NETA 5 mg + CCE 1,25 mg Hornstein et al Obstet Gynecol. 1998 Jan; 91(1):16-24

Langzeit Follow-Up: 24 Monate Enantone®-Gyn Enantone®-Gyn + NETA 5 mg Enantone®-Gyn + NETA 5 mg + CCE 0,625 mg Enantone®-Gyn + NETA 5 mg + CCE 1,25 mg Knochendichte im Vergleich zum Ausgangswert vor LHRHa (%) Surrey et al. Obstet Gynecol. 2002 May;99(5 Pt 1):709-19

Endometriose Med.Therapie GnRH-Analoga (Zoladex, Decapeptyl, Enantone-Gyn) Danazol (Danazol 200mg Tbl) MPA (3-Monatsspritze = Depot-Provera = Depocon) Ähnliche Effektivität Nebenwirkungsprofil Merke: Alle Präparate sind besser als Placebo, aber keines ist besser als die anderen. Prentice A. et al: Cochrane 2001

Drug therapy for infertility assoc. with endometriosis Cochrane review 2000

Schwangerschaftsraten bei Endometriose nach Vortherapie mit Leuprorelin Gruppe 1: Leuprorelin Depot 3,75mg f. 3 Monate, anschließend COH Gruppe 2: Leuprorelin 0,5-1mg/d s.c. für 7-10d, anschließend COH 51 Pat. mit laparoskopisch ges. Endometriose Stadium I- IV Behandlungsdauer: 6 Monate postoperativ Endpunkte: Implantationsraten, Schwangerschaftsraten Surrey et al. Fertil Steril. 2002 Oct;78(4):699-704

Schwangerschaftsraten/Zyklus *p<0,05 ® * Kontrollierte ovarielle Hyperstimulation Surrey et al. Fertil Steril. 2002 Oct;78(4):699-704

Implantationsraten bei Endometriose nach Vortherapie mit Leuprorelin ® * Kontrollierte ovarielle Hyperstimulation Surrey et al. Fertil Steril. 2002 Oct;78(4):699-704

Endometriose Med.Therapie Wann Hormontherapie? Vorbehandlung vor geplanter OP Kausale Schmerztherapie Vor COS/IVF Nachbehandlung nach OP Verzögerung eines Rezidivs Verlängerung der Schmerzfreiheit

Endometriose Chirurgie Schmerztherapie Hormonelle Therapie Neue Therapieansätze Alternative Therapieformen Ernährung

Neue Therapiekonzepte Endometriose Perspektiven Neue Therapiekonzepte Aromatasehemmer - systemisch, lokal COXII – Hemmer Antigestagene – RU486 SERMs – Selektive Östrogenrezeptormodulatoren - Raloxifen SPRMs - Selektive Progesteronezeptormodulatoren hCG Blockade der Neoangiogenese VEGF-Blockade – Levonorgestrel-IUD Angiostatin TNF-Antagonisten – Infliximab (M.Crohn) Hemmung der MMP – Progesteron

Neue Therapiekonzepte Endometriose Perspektiven Neue Therapiekonzepte Aromatasehemmer - systemisch, lokal COXII – Hemmer Antigestagene – RU486 SERMs – Selektive Östrogenrezeptormodulatoren - Raloxifen SPRMs - Selektive Progesteronezeptormodulatoren hCG Blockade der Neoangiogenese VEGF-Blockade – Levonorgestrel-IUD Angiostatin TNF alpha-Antagonisten – Infliximab (M.Crohn) Hemmung der MMP – Progesteron

E2 Stromazelle NN AROMATASE Fett / Haut Ovar Östrogensynthese IL-1ß, TNF- Androstendion AROMATASE PGE2 PGH2 E1 Fett / Haut E2 PG-Synthase (COX) 2 Ovar Östrogensynthese

Endometriose Nebenwirkungsprofil Aromatase-Hemmer zB ArimidexR, FemaraR Reduktion E2 – 95% Blutungsstörungen Hitzewallungen Übelkeit, Erbrechen, Obstipation Kopfschmerz, Schwindel Gliederschmerzen Osteopenie/-porose

Treatment of severe postmenopausal endometriosis with an aromatase inhibitor Takayama et al., Fertil Steril 1998 35a St.p.TAH+BSO St.p.ERT 53a 2xLSK - bilateral ureteral obstruction (53a) 56a 30x20mm endometriotic nodule - vag.apex (aromatase mRNA+++) 9 mos Anastrozole 1mg/d + 10mg alendronate+Ca/VitD Pain disappeared completely after 2nd month of treatment 3mm gray tissue at vag. apex (aromatase mRNA neg.)

Rp. Anastrozoli 0.25 mg Adipis neutralis q.s. Misce f. supp. d.t.dos.Nr.CXII

Vaginally administered anastrozole in women with rectovaginal endometriosis Treatment: 0.25mg anastrozole vag.suppositories plus 5mg risedronate+Ca+VitD3 Endpoints - decrease of pain during treatment (I) - decrease in size of endometriotic lesion (II) - decrease of pain after end of treatment (II) - not be associated with significant side-effects (II) Assessments: n=10; Dysmenorrhoe besser, nicht Dyspareunie, CPP Hefler & Nagele

hCG ektopes Endometrium exprimiert hCG/LH-R (Lincoln et al. 1992) hcG/LH-R in 12/23 Proben ektopes EM (Hudelist et al. 2008)

hCG Fibroblasten aus Endometriose (Huber et al. 1992) hCG-Expression Gene: Apoptose, ECM remodelling, Zytokine-Inflammation

Fallserie (Huber et al. 2004) vorbehandeltes Kollektiv, n=31 hCG Fallserie (Huber et al. 2004) vorbehandeltes Kollektiv, n=31 offenes Studiendesign subjektive Verbesserung pain (p<0.001), sleeplessness (p<0.001), irritability (p<0.001), overall discomfort (p<0.001), depressive moods (p<0.001), painful defecation (p=0.01), dyspareunia and dysmenorrhea (both p<0.001), dysuria (p=0.6)

TNF-alpha TNF-alpha: Mediator der lokalen Inflammation Pavianmodell (D‘Hooge 2006) Klinische Daten Anti-TNF-alpha (Infliximab®) RCT; n=21 vs. Plazebo kein Unterschied Schmerzreduktion nach OP gleich

Endometriose Chirurgie Schmerztherapie Hormonelle Therapie Neue Therapieansätze Alternative Therapieformen, Ernährung

Endometriose Therapie Medizinische Behandlungsstrategien Alternatives Schmerzmanagement Einstellung/coping Lebensstil Ernährung

ENDO-GIFTE Nahrung Kaffee Schokolade Raffinierter Zucker, Limonade Haltbar-, Konservenprodukte Tierische Produkte Genußmittel Alkohol Nikotin Umwelt Blei, Dioxin, Kadmium, Quecksilber, Pestizide, Fungizide

Endometriose Gesättigte Fettsäuren Fleisch, Milchprodukte Arachidonsäure proinflammatorische PG2 Thromboxan A2 Cyclooxygenase Leukotriene Entzündung Abwehrschwäche Zellschaden Muskelkrämpfe

Endometriose Ungesättigte Fettsäuren Omega-6-Fettsäuren mehrfach ungesättigt, essentiell Linolsäure Gamma-Linolensäure PGE1 entzündungshemmend krampflösend Vorkommen: Pflanzliche Öle Sonnenblumen- Soja-, Distel-, Olivenöl Borretsch-, Nachtkerzenöl Borretsch Distel Nachtkerze

Endometriose Ungesättigte Fettsäuren Omega-3-Fettsäuren mehrfach ungesättigt, essentiell, lebenswichtig Alpha-Linolensäure & Metabolite PG&Thromboxane Cholesterin&Triglyceride HDL-Cholesterin Schutz vor Arteriosklerose und Gerinnselbildung entzündungshemmend, krampflösend Vorkommen: Pflanzliche Öle & Fische Lein-, Soja-, Weizenkeim,-Walnussnöl Kaltwasserfische (Lachs!!!)

Endometriose Freie Radikale Quellen Körperliche Belastung Psychischer Stress O2-Mangel UV-Strahlen Zigarettenrauch Luftschadstoffe (Ozon, Industrie) Organische Lösungsmittel Hohe Eisenzufuhr (Fleisch) Gebratene, Gebackene, Gegrillte Nahrung Stärkste Antioxidantien Vitamin C, A, E und Selen

Endometriose Vitamin C Tgl. Bedarf 75mg-10g Wirkung Antioxidans – Radikalfänger Kollagensynthese Bindegwebe, Knochen, Zähne Immunsystem – Cortisonynthese Schmerzbekämpfung Vorkommen Zitrusfrüchte, Beeren, Kiwi Brokkoli, Paprika, Kartoffel Petersilie

Endometriose Vitamin E Tgl. Bedarf 6-9 mg Wirkung - Antioxidans – Radikalfänger - entzündungshemmend - PG-Synthese-Hemmer - analgetisch - hemmt Gerinnselbildung - stimuliert Antikörperbildung Vorkommen Weizenkeim-, Sonnenblumenöl Nüsse, Fenchel, Paprika, Soja

Endometriose Magnesium Wirkung entspannt Muskulatur - krampflösend Zellenergie (ATP) Synthese der Myelinscheiden um Nerven beruhigend, ausgleichend steigert körperliche Leistungsfähigkeit „Schlankmacher“-Mineralstoff Vorkommen Grünes Gemüse, Vollkornprodukte Sojabohnen, Nüsse, Min.wasser

Endometriose SELEN Wirkung antioxidativ Radikalfänger Schutz vor Arteriosklerose Schwermetallentgiftung Vorkommen Vollkorngetreide, Sojabohnen Meerestiere, Knoblauch

Supplemente Studien/Endom./CPP Vitex agnus castus - RCT (Schellenberg 2001) Krill-Öl – RCT (Sampalis 2003) Cochrane: Magnesium (n=3), Vitamin B1 (n=1), Vitamin B6 (n=1), Vitamin E (n=1) wirksamer als Plazebo

Ernährung Studien Experimentelle Daten (Netsu 2008) 3+3 Ratten; EPA (Omega-3) vs. LA (Omega-6) EPA: Dicke Endometrioseläsion reduziert; Zystengrösse reduziert Reduktion Interleukine

Ernährung Studien n=222; rAFS III-IV ; OP +: Vit., Min., Fischöl, Fermente vs. Plaz. vs. GnRH

Ernährung Ergebnis: Schmerzen: alle Gruppen effektiv; Diät besser nicht menstruationsabhängig QoL: Diät besser

Ernährung Studien n=222; rAFS III-IV ; OP +: Vit., Min., Fischöl, Fermente vs. Plaz. vs. GnRH vs. long cycle Dysmenorrhoe GnRH, OC besser non-menstrual pain GnRH, OC, Diät gleich; besser als Plazebo (p<0.001)

Ernährung Studien Lebensqualität Diät besser Plazebo Diät besser Hormontherapie

Experimentelle Therapien Ernährung/Supplemente Zusammenfassung Chirurgie Schmerztherapie Hormontherapie add back-Therapie Experimentelle Therapien Ernährung/Supplemente

Endometriose ist eine chronische Erkrankung. und ermöglicht deshalb kaum verlässliche prognostische Perspektiven. Endometriose ist oft nicht vollständig und dauerhaft heilbar. Daher ist die Einbeziehung aller medizinischen und paramedizinischen Strategien der erfolgreichste Weg zur bestmöglichen Behandlung.