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Dr. Moşe Benhabib Acıbadem İnternational Hospital.

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... konulu sunumlar: "Dr. Moşe Benhabib Acıbadem İnternational Hospital."— Sunum transkripti:

1 Dr. Moşe Benhabib Acıbadem İnternational Hospital

2 Definitions ‘The presence of endometrial-like tissue outside the uterus… induces a chronic, inflammatory reaction’ 1 ‘…found predominantly in women of reproductive age, from all ethnic and social groups’ 1 ‘…associated symptoms can impact on general physical, mental and social well-being’ 1 1.Kennedy S, Berggvist A, Chapron C et al. Hum Reprod 2005.

3 Critical Aspects of Pathogenesis Endometrial-like cells attach to peritoneal tissue/other sites Cellular infiltration/invasion, involving angiogenesis Cellular proliferation Inflammation which can cause Nerve irritation Adhesions Individual variation Mahutte NG, Kayisli U, Arici A. Endometriosis in Clinical Practice. 2005; Fraser IS. J Hum Reprod Sci 2008.

4 Sites Commonly Affected ‘Extent of disease varies from a few, small lesions on otherwise normal pelvic organs to large, ovarian endometriotic cysts (endometriomas), and/or extensive fibrosis and adhesion formation causing marked distortion of pelvic anatomy’ 1 Pelvic cavity: Peritoneum, ovaries, pouch of Douglas, uterosacral ligaments Other sites: Vagina, bowel, bladder, ureters Rare sites: Lungs, brain 1.Kennedy S, Berggvist A, Chapron C et al. Hum Reprod 2005.

5 Risk Factors Pathophysiology unclear Certain characteristics lead to increased/decreased risk 1.Mounsey AL et al. Am Fam Phys 2006; 2.Missmer SAet al. Obstet Gynecol 2004; 3.Bischoff F et al. Ann N Y Acad Sci 2004; 4.Eskenazi B et al. Obstet Gynecol Clin North Am 1997; 5.Cramer DW et al. Ann N Y Acad Sci 2002; 6.Hediger ML et al. Fertil Steril Increased RiskDecreased Risk Increased exposure to endometrial material – short menstrual cycles, heavy/longer bleeding, early menarche, late menopause 1,2 Increased number of live births 1 Family history 3 Longer duration of lactation 1 Low exercise 4-6

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9 Diagnosis 1.Kennedy S, Bergqvist A, Chapron C, et al. Hum Reprod 2005; 2.Mounsey AL, Wilgus A, Slawson DC. Am Fam Phys 2006; 3.Matorras R, Rodríguez F, Pijoan JI, et al. Am J Obstet Gynecol 1996; 4.Bazot et al. J Minim Invasive Gynecol 2005; 5.Bedawy et al. Clin Chem Acta 2004; 6.Matalliotakis et al. Arch Gynecol Obstet 2005; 7.Fraser et al. J Hum Reprod Sci Diagnosis often delayed (average 8.3 years 1 ) Typical clinical symptoms and signs (e.g. uterosacral nodularity) 2,3 Magnetic resonance imaging and ultrasound 4 Laboratory tests currently fail to show predictive value 5,6 New semi-quantitative procedures being assessed 7 Laparoscopic visualisation – ideally with confirmatory histology 1 New techniques Suggestive Definitive

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11 Surgical Therapy Aimed at removing endometrial implants and restoring fertility Efficacy reflects the skill of the surgeon Recurrence is common: 40–50% at 5 years 1,2 1.Mounsey AL, Wilgus A, Slawson DC. Am Fam Phys 2006; 2.Guo SW. Hum Reprod Update 2009.

12 Cerrahi Her 4 kadından yaklaşık 1’inde ilk ameliyattan sonra 4 yıl içinde ek cerrahi tedavi gerekir 1 İlk ameliyatını genç yaşta olan kadınlarda yeniden operasyon riski artar 2,3 Kadınların % 20-40’ı konservatif cerrahi sonrasi iyilesme belirtileri göstermez 1 Lezyonlar tamamıyla eksize edilmeyebilir Endometrioma cerrahisinden dolayı over rezervinin zarar görmesi olasıdır 2 1.Weir E et al. J Minim Invasive Gynecol 2005; 12: 486−93 2.Cheong Y et al. J Obstet Gynaecol 2008; 28: 82−85 3.Shakiba K et al. Obstet Gynecol 2008; 111: 1285– Leyland N, et al. J Obstet Gynaecol Can 2010;32(7 Suppl 2):S1–S32. 2.Guo S-W. Hum. Reprod Update 2009;15(4):441–461..

13 Tedaviye yaklaşım Endometriozis hayat boyu tedavi planı gerektiren kronik bir hastalık olup; hedef, mümkün olduğunca tekrarlanan cerrahi müdahalelerden kaçınıp, medikal tedaviyi maksimum düzeyde kullanmaktır. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 2008.

14 WES international consensus on endometriosis Pelvik ağrıya erken ve etkin bir şekilde müdahale etmeyi önerir. “Pelvik ağrıya müdahale, endometriosisin cerrahi olarak kanıtı beklenmeksizin yapılmalı ve gecikmeye neden olunmamalıdır.” 14 Johnson NP and Hummelsoj L. Hum Reprod 2013; 28(6): 1552–1568.

15 Growing support for empirical treatment Two key publications in 2013 advocate the use of initiating empirical medical treatment in the absence of laparoscopically confirmed diagnosis 15 ESHRE Clinical guidelines ESHRE=European Society of Human Reproduction and Embryology; WES=World Endometriosis Society. WES International consensus statement

16 Medikal Tedavi Progestinler Danazol Kombine oral kontraseptifler GnRH agonistleri Levonorgestrel-IUD NSAI Aromatase inhibitörler Progesteron reseptör modülatörleri

17 Endometriozis odakları baskılanmalı - engellenmeli Semptomlar ortadan kalkmalı Yaşam kalitesini yükseltmeli Tedavi kesildikten sonrada etkisi devam etmeli (rekürensini engellemeli) Menstrüel siklus etkilenmemeli Yan etki profili kabul edilebilir olmalı, uzun süreli kullanıma uygun olmalı Gebe kalmak isteyen kadınlar için güvenli olmalı Ucuz olmalı İdeal endometriozis ilacı

18 Non-specific Therapies

19 Medical therapy – NSAIDs In primary dysmenorrhea: NSAIDs have been shown to be effective compared to placebo 1 But in endometriosis: NSAIDs show no clear benefit; limited data – only 1 RCT in 24 women 2 1.Marjoribanks J et al. Cochrane Database Syst Rev Allen C et al. Cochrane Database Syst Rev 2009 Non-specific therapies – not approved in endometriosis Including non-steroidal anti-inflammatory drugs and combined oral contraceptives

20 NSAIDs General, non-specific pain relief Controlled trial data lacking 1,2 No single NSAID shows superior efficacy 1 Potential adverse effects in gastrointestinal tract 1,2 NSAID, non-steroidal anti-inflammatory drug. 1.Allen C, Hopewell S, Prentice A. Cochrane Database Syst Rev 2005; 2.Kennedy S et al. Hum Reprod 2005.

21 Kombine Oral Kontraseptifler Kombine oral kontraseptifler, endometriozisin tedavisindeki yerleri kanıtlanmamasına rağmen yaygın olarak kullanılmaktadır. RCT eksikliği Endometrioziste oral kontraseptiflerin östrojen komponentinin varlığı tedaviye tezat teşkil etmektedir. Estrogenik yan etkiler(bulantı, kilo alınımı, su retansiyonu, artmış tromboemboli riski) 1 1.Davis LJ, Kennedy SS, Moore J et al. Cochrane Database Syst Rev 2007; 2.Crosignani P, Olive D, Bergqvist A et al. Hum Reprod Update 2006.

22 Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: a placebo-controlled, double-blind, randomized trial N: 100 Tasuku Harada, 2008

23 Randomized trial of leuprolide versus continuous oral contraceptives in the treatment of endometriosis-associated pelvic pain (n: 47, 48 w) David S. Guzick, 2011

24 Specific Therapies

25 GnRH agonists (suppression of FSH/LH via desensitisation and down-regulation of pituitary GnRH receptors) Leuprolin Goserelin Buserelin Triptorelin Nafarelin Avorelin * Not all products available in all countries. FSH, follicle stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; MPA, medroxyprogesterone acetate Vercellini et al. Best Pract Res Clin Obstet Gynaecol 2008; Mihalyi et al. Expert Opin Emerg Drugs Hormonal Therapy * Progestins (suppression of FSH/LH, some have additional properties, e.g. anti- inflammatoric) MPA (oral/im/sc) Dydrogesterone Norethisterone Dienogest Gestrinone Androgens (suppression of FSH/LH, anti-estrogenic and hyperandrogenism) Danazol

26 GnRH Agonists

27 . Effect of Gonadotropin-Releasing Hormone (GnRH) Agonists on Endometriosis

28 GnRH Agonists Considered ‘gold-standard’ treatment for endometriosis due to high efficacy in pain relief GnRH agonists promote atrophy of endometriotic lesions and induce amenorrhea Hypoestrogenic side-effects (e.g. hot flushes, vaginal dryness, loss of libido), including BMD decrease Limited to short-term use (6 months) in absence of ‘add-back’ therapy Caution in younger women not reached maximum BMD GnRH, gonadotropin-releasing hormone; BMD, bone mineral density. 1.Winkel CA et al. J Women’s Health Gender-Based Med 2001; 2.Sinaii N et al. Fertil Steril 2007; 3.Crosignani P et al. Hum Reprod Update 2006; 4.Mounsey AL et al. Am Fam Phys 2006.

29 Estradiol Concentration (pg/mL) Percent of Maximal Response Bone Loss Substantial Bone Turnover Therapeutic Window Bone Loss Minimal Stimulation of Endometriosis Lesions Atrophy of Endometriosis Lesions Endometriosis Growth Endometriosis Overview The Estrogen Threshold Hypothesis Barbieri (1992)

30 Add-Back Therapy Estrogens ± Progestins (Do not use OCP) Progestins Progestins ± Bisphosphonate Tibolone GnRHa  3 mo No need for Add-back GnRHa  6 mo Add-back (Optional), Ca GnRHa > 6 mo or retreatment Mandatory Add-back, Ca, BMD, Lipids ?

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32 Treatment with leuprolide acetate and hormonal add-back for up to 10 years in stage IV endometriosis patients with chronic pelvic pain (n: 5) Mohamed A. Bedaiwy, 2006

33 Gonadotropin-releasing hormone agonist and add-back therapy: what do the data show? Eric S. Surrey, 2010 Effective add-back therapy should be initiated concomitantly with the GnRHa to minimize side effects. For the woman who requires retreatment with a GnRHa or whose therapy is anticipated to extend beyond 6 months, add-back should be considered mandatory

34 Progestins

35 Endometriozis tedavisinde sentetik progesteron kullanımının temeli Lazzeri L, et al. J Endometriosis 2010;2:169–181; Kappou D, et al. Minerva Ginecol 2010;62:415–432; CrosignanI P, et al. Hum Reprod Update 2006;12:179–189 Reduction of serum estrogen levels Immunomodulatory effect Anti-inflammatory effect Decidualisation + atrophy of endometrial tissue Inhibition of matrix metalloproteinases Anti-angiogenic effect Progestins

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37 Endometriozisin medikal tedavisinde kullanılan progestinler Oral yol Noretisteron asetat Didrogesteron MPA Dienogest İntramusküler yol Medroksiprogesteron asetat İntrauterin yol Levonorgestrel salgılayan RIA Implant Etonogestrel

38 Endometrioziste sentetik progesteron tedavisi

39 Dienogest:Farmakolojik Özellikler 19-nortestosteron türevlerinin özellikleri Endometriyum üzerinde güçlü progestasyonel etki Yaklaşık 9-10 saatlik görece kısa plazma yarı ömrü >% 90 yüksek oral biyoyararlanım Progesteron türevlerinin özellikleri İyi tolere edilebilirlik Anti-androjenik etkiler Anti-proliferatif etkiler Görece düşük gonadotropin sekresyonu inhibisyonu CV ve metabolik sistem üzerine nötr etki Dienogest, 19-nortestosteron türevleri ile progesteron türevlerinin özelliklerini birleştiren bir progestindir Oettel M et al. Drugs Today 1995; Sasagawa S et al. Steroids Additional double bond (Strong affinity to progesterone receptors) Cyanomethyl instead of an ethinyl group in the 17α position (Low interaction with hepatic proteins e.g Cytochrome P450)

40 15 haftaya kadar uzayan dienogest tedavisi sırasında bildirilen istenmeyen ilaç reaksiyonları (İAR) Düşük sıklıkta ve Genellikle hafif-orta şiddettedirler, Genellikle ilk 3 ay içinde ortadan kalkarlar. Dienogest tedavisi sırasında istenmeyen ilaç reaksiyonlarının sıklığı (Toplu Analiz) En sık bildirilen İAR’lerHastaların oranı Baş ağrısı%9.0 Memelerde hassasiyet%5.4 Depresif duygudurum%5.1 Akne%5.1 Köhler G, et al. Int J Gynaecol Obstet 2010; 108: 21–25 Strowitzki T, et al. Eur J Obstet Gynecol Reprod Biol 2010 ;151: 193–198 Strowitzki T, et al. Hum Reprod 2010; 25: 633–641 Petraglia F, et al. Arch Gynecol Obstet 2012; 285(1): 167 ‒ 173

41 Uzun süreli endometriozis tedavisinde dienogest deneyimleri Tedaviden önce: hastaları kanamanın ilaç etkisinin yetersizliğine ait bir belirti olmadığı konusunda bilgilendirin Hastaların ~ %20’sinde ilk 3 ayda düzensiz kanama görülmektedir Siklusun ilk gününde başlanır Yüksek risk gruplarında, ilk 6 ya da 8 hafta 4 mg (off-label) dienogest ile iyi sonuç alınmaktadır (başlangıçtaki düzensiz kanama oranları daha düşük olmaktadır) Halen dienogest kullanmakta olan hastalar Atrofik (ince) endometriumdan kanama Kanamanın sorun yaratması halinde  tedaviyi kesin ve 5 gün sonra yeniden başlatın Hastalar tek başına kanamadan çok, kanamaya ağrının eşlik etmesi durumunda endişe duymaktadır Hastaların, kanama paternindeki değişiklikler konusunda uyarılması önemlidir

42 MPA, medroxyprogesterone acetate. 1.Crosignani PG et al. Hum Reprod 2006; 2.Physician information. 2009; 3.Vercellini P et al. Hum Reprod Update Depot MPA in Endometriosis Depot MPA 150 mg intramuscularly investigated Lower dose formulation (104 mg, subcutaneously) approved in USA 1 Effect on bone mineral density 2 Black box warning: ‘Women who use depo-subQ provera 104 may lose significant bone mineral density’ ‘Bone loss is greater with increasing duration of use and may not be completely reversible’ Delay in resumption of ovulation at discontinuation 2,3

43 Label includes black box warning regarding bone mineral density BMD, bone mineral density. Modelled means and standard errors. Adapted from Clark MK, Sowers M, Levy B et al. Fertil Steril Depot MPA 150 mg: BMD Decline Percentage change, spine BMD Months from baseline Controls Depot MPA

44 Sadece progesteron içeren hormonal kontraseptif kullanımının endometriozisin primer önlenmesinde yeri var mıdır? Progestin kullanımı ile sağlanan terapötik amenore endometriozis yönetiminde faydalı bir yöntemdir. Endometriozis kronik ve rekürren bir hastalık olduğundan uzun süreli hormonal tedavinin uygulanması endometriozis olgularında tavsiye edilmektedir. Uzun süreli progestojen tedavisinin bir formu olan LNG-IUS, endometrial atrofiyi sağlayarak, apoptotik aktiviteyi arttırarak, antienflamatuar ve immunomodulator etkileri ile endometriozise bağlı şikayetlerin tedavisinde kesin etkilidir.

45 Revised guidelines, 2007 A The levonorgestrel intra- uterine system (LNG IUS) reduces endometriosis associated pain. Evidence Level 1a A systematic review identified two RCTs and three prospective observational studies, all involving small numbers and a heterogeneous group of patients (Varma et al., 2005). Nevertheless, the evidence suggests that the LNG IUS reduces endometriosis associated pain (Petta et al., 2005; Vercellini et al., 1999a) with symptom control maintained over 3 years (Lockhat et al., 2004; Lockhat et al., 2005).Varma et al., 2005Petta et al., 2005Vercellini et al., 1999aLockhat et al., 2004Lockhat et al., 2005

46 Progestinler Destek Dokümentasyonu, 2007 ESHRE AFS skorları ve ağrıyı danazol ve GnRH analogları kadar azaltabildiği, daha düşük maliyetli olduğu ve yan etki insidansı danazol ve GnRH analoglarından daha düşük bulunduğu için endometriozis tedavisinde ilk seçenek olarak kabul edilebilirler. Vercellini. 1997

47 Danazol

48 Oral androgenic steroid Derived from 17α-ethinyl testosterone Mechanism of action – induces amenorrhea via suppression of estrogen and progesterone Androgens (testosterone) first used to treat endometriosis in 1943 First use of danazol described in 1971 Use is limited by anabolic and androgenic side-effects 1.Olive DL et al. N Engl J Med 2001; 2.Crosignani P et al. Hum Reprod Update 2006; 3.Hirst JC. Am J Obst Gynecol 1943; 4.Greenblatt RB et al. Fertil Steril 1971; 5.Winkel CA et al. J Women’s Health Gender-Based Med 2001; 6.Sinaii N et al. Fertil Steril 2007.

49 Danazol – side effects Due to hyperandrogenism and hypo- oestrogenemia Weight gain Fluid retention Fatigue Nausea Acne Hirsutism Oily skin Muscle cramps Reduced libido Reduced breast size Emotional disturbances Atrophic vaginitis Hot flushes Hepatocellular damage Irreversible deepening of voice

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51 Vaginal danazol for the treatment of endometriosis-related pelvic pain (n: 21) Sudhindra M. Bhattacharya, 2011 Vaginal danazol (200 mg) daily for 6 months.

52 Gestrinone Gestrinone is a 19-nortestosterone derivative with androgenic, antiprogestagenic, antiestrogenic, and antigonadotropic properties. Gestrinone causes cellular inactivation and degeneration of endometriotic implants but not their disappearance. Amenorrhea occurs in 50% to 100% of women and is dose dependent. The standard dose is 2,5mg twice a week.

53 Gestrinone The clinical side effects include nause, muscle cramps, and androgenic effects such as weight gain, acne, sebborrhea, and oily hair and skin. In a multicenter, randomized, double-blind study, gestrinone was as effective as GnRH for the treatment of pelvic pain associated with endometriosis, with fewer side effects and the added advantage of twice- weekly administration.

54 Endometriosis :alternative methods of medical treatment GnRH antagonists Aromatase inhibitors Selective progesterone receptor modulators Anti-tumor necrosis factor-alfa Antiangiogenic factors

55 Oral GnRH Antagonists Elagolix a new GnRH Antagonist Drug

56 Nándor Ács, Chris O’Brien, Ping Jiang, Joshua Burke, Roland Jimenez, Elizabeth Garner, Kristof Chwalisz

57 Treatment- related adverse events were generally mild to moderate in severity: headache, nausea, anxiety, hot flashes, BMD changes

58 Bruce Carr, Linda Giudice, W.Paul Dmowski, Chris O’Brien, Ping Jiang, Joshua Burke, Roland Jimenez,Steven Hass, Ma hesh Fuldeore, Kristof Chwalisz These studies demonstrated that elagolix 150 mg reduces endometriosis- associated pain, partially suppresses estradiol and results in minimal changes in BMD. Elagolix is in clinical development as a potential treatment option for women with endometriosis.

59 Investigational agents for the treatment of endometriosis-associated pain

60 Aromatase inhibitors No clear evidence of their effectiveness for the treatment of pain related to endometriosis. Severe side effects (headaches, hot flashes, mood changes, muscle aches, breakthrough bleeding, change in BMD)and cost. ESHRE recommends the use of aromatase inhibitors associated to another hormonal treatment ( O.C., progestogens, or GnRHa) only in women in whom all surgical and medical treatments have failed.

61 Selective progesterone receptor modulators SPRMs exhibit both progesterone agonistic and antagonistic activities. İn the absence of progesterone, the SPRMs act like weak progestins. İn the presence of progesterone, they may also show weak antiprogestagenic properties in some tissues, particularly in the endometrium. This property justifies their use in the treatment of myomas and endometriosis. Mifepristone Ulipristal acetate

62 Anti-tumor necrosis factor-alfa A feature of endometriotic tissue is inflammation. A nonhormanal alternative in endometriosis treatment could be modulating inflammation by means of TNF-alfa blocckers as currently used in other inflammatory diseases such as Crohn’s disease os rheumatoid arthritis. There is not enough evidence to recommend the use of anti-TNF-alfa drugs for the treatment of pain associated to endometriosis.

63 Antiangiogenic factors Endometriosis is classified as an angiogenic disease. Several studies concentrate on antiangiogenic compounds as a promising therapy for endometriosis. The future in antiangiogenic therapy for endometriosis seems to be factors which blockade different pathways in the angiogenic cascade.

64 Conclusion There is a need to find effective treatments that do not block ovarian function. Upcoming researches and controlled clinical trials should focus on these drugs, in order to establish if they are really effective in relieving pain without affecting fertility.


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