Endometriosis adversely affects oocyte quality.

Posted By Braverman IVF & Reproductive Immunology || 18-April-2018


Learn how our mitochondrial restoration program will help improve your fertility!



Endometriosis is a condition where ectopic endometrial tissue implants throughout the pelvis and was shown to negatively impacts fertility (1-2) in approximately 30% to 50% of women diagnosed with the disease (3). There are several mechanisms that may be involved in endometriosis-associated infertility including:

  • decreased oocyte quality:

    In a mice model for endometriosis, a decrease in oocyte quality and embryo number has been reported in addition to cell divisions and spindle abnormalities (4). Endometriosis is associated with chronic inflammation, an increase in ROS generation and a decrease in anti-oxidant levels, all leading to significant increase in oxidative stress shown to disrupt egg quality in women affected by endometriosis (5).

  • decreased endometrial receptivity:

    Many genes related to implantation failure as well as inflammation were found to be increased in endometriosis patients when compared to endo-free patients thus disrupting the embryo implantation process (6-10)

  • altered sperm-oocyte interaction mostly due to inflammation:

    Very high levels of prostaglandin E2, RANTES (known inflammatory molecules) and vascular endothelial growth factor, associated with the severity of endometriosis, were found to inhibit sperm motility, acrosome reaction, and sperm-oocyte interaction in endometriosis women (11-12).

    In a recent study published in the journal Gynecological Endocrinology, the authors focused on oocyte quality being a key factor in endometriosis-related infertility.

    The retrospective cohort study included:

  • N=72 women affected by endometriosis (diagnosed by laparoscopy) undergoing ICSI (intra cytoplasmic sperm injection)
  • N=60 endo-free women undergoing ICSI cycles strictly due to male infertility After oocyte retrieval, the oocytes’ evaluation showed that:
  • a lower number of oocytes were retrieved in endometriosis patients (10.5) when compared to controls (12.5)
  • a lower number of oocytes in metaphase II (mature oocyte) were retrieved in endometriosis patients (6) when compared to controls (10)
  • Out of the abnormal oocytes, 60% were coming from endometriosis-affected women versus 40% coming from endo-free patients
  • Microscopic observations revealed common abnormalities of oocytes from women with endometriosis including brownish oocytes, dark and granular cytoplasm, disrupted zona pellucida (dark, thin or large) and fragmented and/or flat polar body

    In addition, gonadotropin doses administered to endometriosis patients were higher as compared to the controls and AMH levels were significantly lower in endometriosis women as compared to controls (2.1 ng/mL versus 3.09 ng/mL). Many studies reported similar findings in patients with endometriosis including lower oocyte quality (13) that is worsened with the severity of the disease (14). Further, recent studies have shown the central role of oxidative stress in altering women fertility with:

  • Higher levels of lipid peroxidation
  • Higher levels of protein oxidation
  • Higher levels of oxidative DNA damage as seen by higher 8OHdG levels
    in the serum and follicular fluid of women with endometriosis as compared to control endo-free women, undergoing IVF cycles (15) Indeed, a negative correlation has been shown between 8OHdG concentrations in granulosa cells of infertile women and fertilization rate and embryo quality (16), and higher 8OHdG levels in the follicular fluid have been found in women with higher rates of oocytes degeneration (17). Other marker of oxidative stress in the follicular environment such as advanced oxidation protein products (AOPPs) have also been shown to be predictive marker of poor oocyte and embryo quality (18).

    In addition, when bovine oocytes are incubated with follicular fluid (19) or peritoneal fluid (20) from infertile women with endometriosis, the meiosis process is disrupted, with spindle and chromosome abnormalities being reported (21-23). This could be due to an impaired oocyte mitochondrial function (structure providing energy for cellular division). Indeed, women with minimal or mild endometriosis exhibit abnormal mitochondrial structure and decreased mitochondria mass. (24).

    Altogether, these studies highlight the damaging and even toxic impact of oxidative stress and inflammation on oocyte development and maturation.

    So, what can we do at Braverman Reproductive Immunology to help improve your egg quality?

    OUR OOCYTE MITOCHONDRIAL RESTORATION PROGRAM

    At Braverman IVF & Reproductive Immunology we have initiated a COMPLETE program to minimize damage to oocyte (egg) mitochondria and to maximize oocyte mitochondrial function and overall egg quality:

    1. Surgery: laparoscopic excision of endometriotic lesions  Endometriosis is an inflammatory disease that create a noxious environment in the whole peritoneal cavity. As mentioned above, several studies have shown that oocyte quality is severely altered by endometriomas (lesions localized on the ovary) or more generally by endometriotic lesions regardless of their localization (25). The benefits of laparoscopy in endometriosis-related infertility cases have been shown in moderate (26) and stage 3 endometriosis subjects (27) where higher pregnancy rate have been reported post-surgery. In our practice, laparoscopy surgery with endometrial lesions excision and peritoneal destruction (ELE+PD) has shown dramatic benefit in our patients, many of them conceiving spontaneously post surgery. For more information, read our blog on the topic.

    2. Dietary Supplements

    a- Endo-Optimize supplement: the best solution to counteract oxidative stress induced-DNA damage, inflammation and optimize your egg quality:

    We have created a line of supplements that may help improve mitochondrial function by lowering levels of inflammatory cytokines that have been associated with mitochondrial damage in patients with endometriosis. Our "all in one" dietary supplement, the Endo-Optimize, has beneficial effects on egg quality, endometriosis and PCOS-associated symptoms by reducing ROS and free-radicals’ production.

    The many ingredients in our Endo-Optimize supplement (myo-inositol, melatonin, resveratrol, curcumin, CoQ10, pycnogenol) have beneficial effects on fertility with:

  • Anti-oxidative properties (reducing ROS levels): enhancing the number and quality of mature oocytes leading to increased rate of high quality embryos.
  • Enhancer of the mitochondrial function: increasing oocyte and embryo quality with significant lower rate of aneuploid embryos
  • Anti-inflammatory effects: supporting the development and maturation of follicles.
  • Improvement of the ovarian function: through the promotion of sex steroid hormones synthesis (involved in oocyte development and maturation).

    To learn more about the benefits of every ingredient on egg quality, read our blog.

    a- Omega 3-Optimize supplement: a natural Approach to restore optimal fatty acid profile, reduce your inflammation and improve your egg quality

    A healthy pregnancy switches the maternal immune system toward a more tolerant, low inflammatory state. 

    Many autoimmune diseases or other conditions such as endometriosis or PCOS may lead to systemic inflammation and oxidative stress negatively impacting oocyte/embryo quality and may be involved in infertility and recurrent pregnancy loss (RPL). Similarly, leptin (a marker of follicle hypoxia leading to oxidative stress in the oocyte) whose serum concentration is related to the amount of adipose tissue (28) can severely impact the quality of your oocyte (gamete) by disrupting:

  • Follicle growth with reduced number of mature oocytes (29)
  • Leading to poor embryo development (30)
  • Leading to reduced rate of embryo implantation (31)

    An increased ω3 intake prior to conception was shown to positively impact embryo morphology in a study on women undergoing IVF cycle (32). ω3 appear to promote vascular development in the endometrium as seen by in vitro study (33). In addition, many other studies showed that a higher ω3 intake:

  • can reduce leptin levels (34) thus improving your oocyte/embryo quality
  • can reduce the risk of miscarriage (35).
  • Increase uterine blood flow (36).
  • Increase the length of pregnancy and reduce preterm birth (37).
  • Reduce placental inflammation when taking during the first trimester and through the pregnancy (38). For more information, read our blog

    We have a thorough, research-based understanding of parameters affecting your egg quality including mitochondrial dysfunction, as well as the various ways to treat this condition.

    We would be happy to help you take control of your fertility journey and answer any questions you may have. Questions? Call 516.584.8710

    Our diet supplements are available for purchase. For more information about our supplements range, please consult our website.  

    References

    1. de Ziegler D, Borghese B, Chapron C. Endometriosis and infertility: pathophysiology and management. Lancet. 2010 Aug 28;376(9742):730-8.

    2. Kohl Schwartz AS, Wölfler MM, Mitter V, Rauchfuss M, Haeberlin F, Eberhard M, von Orelli S, Imthurn B, Imesch P, Fink D, Leeners B. Endometriosis, especially mild disease: a risk factor for miscarriages. Fertil Steril. 2017 Nov;108(5):806-814.e2.

    3. Evans MB, Decherney AH. Fertility and Endometriosis. Clin Obstet Gynecol. 2017 Sep;60(3):497-502.

    4. Cohen J, Ziyyat A, Naoura I, et al. Effect of induced peritoneal endometriosis on oocyte and embryo quality in a mouse model. J Assist Reprod Genet 2015; 32:263–70.

    5. Da Broi MG, Navarro PA. Oxidative stress and oocyte quality: ethiopathogenic mechanisms of minimal/mild endometriosis-related infertility. Cell Tissue Res 2016; 364:1–7.

    6. Velarde MC, Aghajanova L, Nezhat CR, Giudice LC. Increased mitogen-activated protein kinase kinase/extracellularly regulated kinase activity in human endometrial stromal fibroblasts of women with endometriosis reduces 3’,5’-cyclic adenosine 5’-monophosphate inhibition of cyclin D1. Endocrinology. 2009;150: 4701–4712.

    7. Santulli P, Borghese B, Noël J-C, Fayt I, Anaf V, de Ziegler D, et al. Hormonal therapy deregulates prostaglandin-endoperoxidase synthase 2 (PTGS2) expression in endometriotic tissues. J Clin Endocrinol Metab. 2014;99: 881–890.

    8. Houshdaran S, Nezhat CR, Vo KC, Zelenko Z, Irwin JC, Giudice LC. Aberrant Endometrial DNA Methylome and Associated Gene Expression in Women with Endometriosis. Biol Reprod. 2016;95: 93.

    9. Kao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor RN, et al. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology. 2003;144: 2870–2881. pmid:12810542

    10. Ahn SH, Khalaj K, Young SL, Lessey BA, Koti M, Tayade C. Immune-inflammation gene signatures in endometriosis patients. Fertil Steril. 2016;106: 1420–1431.e7. 

    11. Lee TC, Ho HC. Effects of prostaglandin E2 and vascular endothelial growth factor on sperm might lead to endometriosis-associated infertility. Fertil Steril. 2011 Jan;95(1):360-2.

    12. Barbonetti A, Vassallo MR, Antonangelo C, Nuccetelli V, D'Angeli A, Pelliccione F, Giorgi M, Francavilla F, Francavilla S. RANTES and human sperm fertilizing ability: effect on acrosome reaction and sperm/oocyte fusion. Mol Hum Reprod. 2008 Jul;14(7):387-91.

    13. Ceviren AK, Ozcelik NT, Urfan A, et al. Characteristic cytoplasmic morphology of oocytes in endometriosis patients and its effect on the outcome of assisted reproduction treatments cycles. IVF Lite 2014; 1:88–93.

    14. Shebl O, Sifferlinger I, Habelsberger A, et al. Oocyte competence in in vitro fertilization and intracytoplasmic sperm injection patients suffering from endometriosis and its possible association with subsequent treatment outcome: a matched case-control study. Acta Obstet Gynecol Scand 2017; 96:736–44.

    15. Da Broi MG, Jordão AA Jr, Ferriani RA, Navarro PA. Oocyte oxidative DNA damage may be involved in minimal/mild endometriosis-related infertility. Mol Reprod Dev. 2018 Feb;85(2):128-136.

    16. Seino, T., Saito, H., Kaneko, T., Takahashi, T., Kawachiya, S., & Kurachi, H. (2002). Eight-hydroxy-2'-deoxyguanosine in granulosa cells is correlated with the quality of oocytes and embryos in an in vitro fertilization-embryo transfer program. Fertility and Sterility, 77(6),1184–1190.

    17. Tamura, H., Takasaki, A., Miwa, I., Taniguchi, K., Maekawa, R., Asada, H, Sugino, N. (2008). Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. Journal of Pineal Research, 44(3), 280–287.

    18. Song Y, Liu J, Qiu Z, Chen D, Luo C, Liu X, Hua R, Zhu X, Lin Y, Li L, Liu W, Quan S. Advanced oxidation protein products from the follicular microenvironment and their role in infertile women with endometriosis. Exp Ther Med. 2018 an;15(1):479-486.

    19. Giorgi VS, Da Broi MG, Paz CC, Ferriani RA, Navarro PA. N-Acetyl-Cysteine and l-Carnitine Prevent Meiotic Oocyte Damage Induced by Follicular Fluid From Infertile Women With Mild Endometriosis. Reprod Sci. 2016 Mar;23(3):342-51.

    20. Jianini BTGM, Giorgi VSI, Da Broi MG, de Paz CCP, Rosa E Silva JC, Ferriani RA, Navarro PA. Peritoneal Fluid from Infertile Women with Minimal/Mild Endometriosis Compromises the Meiotic Spindle of Metaphase II Bovine Oocytes: A Pilot Study. Reprod Sci. 2017 Sep;24(9):1304-1311.

    21. Sharma RK, Azeem A, Agarwal A. Spindle and chromosomal alterations in metaphase II oocytes. Reprod Sci 2013;20: 1293–301.

    22. Dib LA, Ara_ujo MCPM, Giorgenon RC, et al. Noninvasive imaging of the meiotic spindle of in vivo matured oocytes from infertile women with endometriosis. Reprod Sci 2013; 20:456–62.

    23. Liu L, Trimarchi JR, Navarro P, et al. Oxidative stress contributes to arsenic-induced telomere attrition, chromosome instability, and apoptosis. J Biol Chem 2003; 278:31998–2004.

    24. Xu B, Guo N, Zhang XM, Shi W, Tong XH, Iqbal F, Liu YS. Oocyte quality is decreased in women with minimal or mild endometriosis. Sci Rep. 2015 May 29; 5:10779.

    25. Lessey BA, Lebovic DI, Taylor RN. Eutopic endometrium in women with endometriosis: ground zero for the study of implantation defects. Semin Reprod Med. 2013 Mar; 31(2):109-24.

    26. Słabuszewska-Jóźwiak A, Ciebiera M, Baran A, Jakiel G. Effectiveness of laparoscopic surgeries in treating infertility related to endometriosis. Ann Agric Environ Med. 2015; 22(2):329-31.

    27. Jin X, Ruiz Beguerie J. Laparoscopic surgery for subfertility related to endometriosis: a metaanalysis. Taiwan J Obstet Gynecol. 2014 Sep; 53(3):303-8. Review.

    28. Budak E, Fernández Sánchez M, Bellver J, Cerveró A, Simón C, Pellicer A. Interactions of the hormones leptin, ghrelin, adiponectin, resistin, and PYY3-36 with the reproductive system. Fertil Steril. 2006 Jun;85(6):1563-81. Review.

    29. Anifandis G, Koutselini E, Stefanidis I, Liakopoulos V, Leivaditis C, Mantzavinos T, Vamvakopoulos N. Serum and follicular fluid leptin levels are correlated with human embryo quality. Reproduction. 2005 Dec;130(6):917-21.

    30. Kawamura K, Sato N, Fukuda J, Kodama H, Kumagai J, Tanikawa H, Nakamura A, Tanaka T. Leptin promotes the development of mouse preimplantation embryos in vitro. Endocrinology. 2002 May;143(5):1922-31.

    31. Castellucci M, De Matteis R, Meisser A, Cancello R, Monsurrò V, Islami D, Sarzani R, Marzioni D, Cinti S, Bischof P. Leptin modulates extracellular matrix molecules and metalloproteinases: possible implications for trophoblast invasion. Mol Hum Reprod. 2000 Oct;6(10):951-8.

    32. Hammiche F, Vujkovic M, Wijburg W, de Vries JH, Macklon NS, Laven JS, Steegers-Theunissen RP. Increased preconception omega-3 polyunsaturated fatty acid intake improves embryo morphology

    33. Johnsen GM, Basak S, Weedon-Fekjær MS, Staff AC, Duttaroy AK. Docosahexaenoic acid stimulates tube formation in first trimester trophoblast cells, HTR8/SVneo. Placenta. 2011 Sep;32(9):626-32.

    34. Hariri M, Ghiasvand R, Shiranian A, Askari G, Iraj B, Salehi-Abargouei A. 
Does omega-3 fatty acids supplementation affect circulating leptin levels? Asystematic review and meta-analysis on randomized controlled clinical trials. Clin Endocrinol (Oxf). 2015 Feb;82(2):221-8.

    35. Di Cintio E, Parazzini F, Chatenoud L, Surace M, Benzi G, Zanconato G, La Vecchia C. Dietary factors and risk of spontaneous abortion. Eur J Obstet Gynecol Reprod Biol. 2001 Mar;95(1):132-6.

    36. Lazzarin N, Vaquero E, Exacoustos C, Bertonotti E, Romanini ME, Arduini D. Low-dose aspirin and omega-3 fatty acids improve uterine artery blood flow velocity in women with recurrent miscarriage due to impaired uterine perfusion. Fertil Steril. 2009 Jul;92(1):296-300.

    37. Olsen SF, Sørensen JD, Secher NJ, Hedegaard M, Henriksen TB, Hansen HS, Grant A. Randomised controlled trial of effect of fish-oil supplementation on pregnancy duration. Lancet. 1992 Apr 25;339(8800):1003-7.

    38. Haghiac M, Yang XH, Presley L, Smith S, Dettelback S, Minium J, Belury MA, Catalano PM, Hauguel-de Mouzon S. Dietary Omega-3 Fatty Acid Supplementation Reduces Inflammation in Obese Pregnant Women: A Randomized Double-Blind Controlled Clinical Trial. PLoS One. 2015 Sep 4;10(9): e0137309.


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