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E NDOMETRIYOZIS - OOSIT KALITESI Pınar ÖZCAN, MD, PhD Bezmialem Universitesi Tıp Fakültesi Kadın Hastalıkları ve Doğum ABD.

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... konulu sunumlar: "E NDOMETRIYOZIS - OOSIT KALITESI Pınar ÖZCAN, MD, PhD Bezmialem Universitesi Tıp Fakültesi Kadın Hastalıkları ve Doğum ABD."— Sunum transkripti:

1 E NDOMETRIYOZIS - OOSIT KALITESI Pınar ÖZCAN, MD, PhD Bezmialem Universitesi Tıp Fakültesi Kadın Hastalıkları ve Doğum ABD

2 Endometriyoma cerrahisi over rezervini azaltabilir Cerrahi öncesi endometriyomanın varlığının fertilite üzerindeki olumsuz etkisi ENDOMETRİYOZİS İLİŞKİLİ İNFERTİLİTENİN PATOJENİK MEKANİZMASI Neden ve etki ilişkisi

3 MİLD MODERATE SEVERE Olive, Fertil Steril 1985 Dmowski, Fertil Steril 2002 E NDOMETRIYOZIS FEKUNDITEYI AZALTıR

4 ENDOMETRİYOZİS İLİŞKİLİ İNFERTİLİTENİN PATOJENİK MEKANİZMASI Follikülogeneziste değişiklikler Ovulatuar disfonksiyon Kötü oosit kalitesi Luteal faz defekti Azalmış fertilizasyon Anormal embriyogenezis

5 Folliküler mikroçevre kalitesi Kumulus hücreleri-oosit arasındaki çift yönlü iletişimin yeterli olması Oosit kalitesi Granuloza hücre fonksiyonu, hormon reseptivitesi, hormon biosentezi

6 Uzamış foliküler faz Azalmış foliküler büyüme hızı Azalmış dominant folikül büyüklüğü Azalmış foliküler östradiol konsantrasyonu Bozulmuş LH surge Folliküler LH reseptörlerinde yetersizlik Mural ve oositi çevreleyen kumulus granuloza hücrelerinde apopitozis ENDOMETRİYOZİS İLİŞKİLİ İNFERTİLİTENİN PATOJENİK MEKANİZMASI

7 I NFLAMATUAR RESPONSE - OXIDATIVE STRESS

8 Theca externa cells Theca interna cells Capillary network Basement membrane Cumulus Oophorus cells Oocyte Zona pellucida Granulosa cells Follicular antrum LH receptors on theca cells FSH receptors on granulosa cells E2E2E2E2 FSH LH A

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10 Gupta S, Fertil Steril 2008

11 Barcelos, RBM online 2015

12 Ono YJ, PLOS one, 2014 The mechanism underlying the anti-apoptotic effects of testosterone on granulosa cells, and found that a low-testosterone status is a potentially important step in the development of premature ovarian insufficiency in patients with endometriosis.

13 Saito H, Gynecol Obstet Invest 2002

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15 Changes reflected ovarian interstitial microvascular injury of OEC, pathologically supported the findings of blood flow changes within ovarian interstitial arteries, and prospectively predicted OEC-induced ovarian interstitial vessel injury. Qui JJ, Arch Gynecol Obstet 2012

16 Opeion H, Hum Repr 2013

17 Kitajima M, Fertil Steril 2014 The‘‘burnout’’ hypothesis may explain the mechanism partly responsible for the reduced ovarian reserve in women with endometriomas. Formation of endometriomas may cause focal inflammation in ovarian cortex. This inflammation could result in structural alteration to the ovarian cortex, which manifest as massive fibrosis and loss of cortex-specific stroma that maintains follicular nests. Focal loss of follicular density may be associated with a vicious circle of dysregulated folliculogenesis that eventually results in burnout of the stockpile of dormant follicles Reduced vascularizationIncreased oxidative stress Dysregulated folliculogenesis Oocyte apoptosis Follicular atresia

18 Kitajima M, Fertil Steril 2014 Ovaries with endometriomas, which may be more prone to local pelvic inflammation, showed activated follicular recruitment and atresia of early follicles. The potential contribution of inflammation to follicle ‘‘burnout’’ in case of endometriomas is discussed

19 Eritrositler Apopitotik endometrioma hücreleri aktive olmuş makrofajlar Granuloza hücre disfonksiyonu, mitokondrial defektler ve oosit telomer kısalması O XıDATIVE STRESS

20 Jomova K, Current Pharmaceutical Design, 2011

21 Iron and its major storage proteins represent molecular signs of the gonadotoxic insult to individual follicles developing adjacent to the cyst during IVF cycles. This is reflected by the low rate of oocyte retrieval from endometrioma-proximal follicles Sanchez AM Hum Rep 2014

22 Fertilization rate and percentage of Grades I and II embryo formation were observed to be significantly lower and DNA fragmented embryo significantly higher in women with endometriosis Janaa SK, Reproductive Toxicology 2010

23 Singh A, Reproductive Toxicology 2013 Increased ROS and NO in endometriosis and infertility associated with poor oocytes and embryo quality

24 The normal ovarian cortex surrounding endometriotic tissues was affected more severely by oxidative stress, granulosa cells from patients with infertility and endometriosis exhibit more signs of severe oxidative DNA damage Matsuzaki S, Fertil Steril 2010

25 Goud PT, Fertil Steril 2014 Altered follicular microenvironment with increased oxidative stress and NO insufficiency, and their secondary impact on GCs and oocytes, is the likely mechanism to explain poor oocyte quality in women with endometriosis that fail to conceive after ART.

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27 T ELOMERAZ - DNA HASARı

28 Alteration of oocyte cytoskeleton might be one of the causes of poor oocyte quality in patients with endometriosis. Mansour G, Fertil Steril 2009

29 Da Broi MG, Hum Reprod 2014 FF of infertile women with mild endometriosis can impair nuclear maturation and promote meiotic anomalies in bovine oocytes matured in vitro. These findings provide evidence about the mechanisms associated with infertility in women with early stage endometriosis

30 Cohen J, J Assist Reprod Genet 2015 Induced peritoneal endometriosis in a mouse model is associated with a decrease in oocyte quality and embryo number

31 E VE GÖTÜRÜLECEK MESAJ Endometriyozis oosit kalitesi üzerinde detrimental etkiye sahip Kortex-spesifik stroma kaybı Ovarian angiogenezisin inhibisyonu Artmış granuloza hücre apoptozisi Ovarian steroid enzime pathwaylerinde değişiklikler Hücre siklusu kinetiklerinde değişimler DNA hasarı, kromozomal instabilite Gene ekspresyonlarında değişiklikler

32 T EŞEKKÜRLER

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35 Filippi F, Fertil Steril 2014

36 Benaglia L, Fertil Steril 2013

37 Wallach EE, Fertil Steril 2008

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39 Somigliana E, Fertil Steril 2006 The presence of ovarian endometriomas is associated with a reduced responsiveness to gonadotropins

40 Barcelos IDES, RBM online 2015 A lower expression of the CYP19A1 in cumulus cells of infertile patients with endometriosis undergoing ovarian stimulation for ICSI compared with infertile women without endometriosis. A lower number of fertilized oocytes in these women. On the basis of these results, the reduced expression of the CYP19A1 gene in cumulus cells might be involved in the impairment of oocyte quality associated with endometriosis, indicating a new perspective for understanding the pathogenesis of endometriosisrelated infertility.


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