Endometrial recptivity


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Endometrial receptivity

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Endometrial recptivity

  1. 1. Benha University Hospital, Egypt Aboubakr Elnashar
  2. 2. 1. Why? 2. What? 3. When? 4. How? 5. Effect of COH on endometrial receptivity 6. Effect of age on endometrial receptivity 7. Assessment of endometrial receptivity: Functional markers: 1. Biochemical 2. Histological Clinical assessment: 1.TVS 2. 3DUS 3.Doppler US 8. Improvement of endometrial receptivity Aboubakr Elnashar
  3. 3. The main causes of failure of IVF is failure embryo implantation. Embryo implantation depends on: 1.The quality of the embryo 2.Endometrial receptivity. 3. The embryo/endometrial interface Aboubakr Elnashar
  4. 4. The onset of implantation is a successful meeting of 2 separate processes: embryo development & endometrial differentiation. A synchrony between these functions is important. Aboubakr Elnashar
  5. 5. Aboubakr Elnashar
  6. 6. Understanding of 1.The mechanisms involved in this process 2. How to assess? & 3. How to treat its disorders represent the fundamental steps in the improvement of IVF. Aboubakr Elnashar
  7. 7. Temporally unique sequence of factors that make the endometrium receptive to embryonic implantation •The window of time when the uterine environment is conductive to blastocyst acceptance & subsequent implantation Aboubakr Elnashar
  8. 8. The endometrium is normally hostile environment for an embryo , except during implantation window. Implantation window: It is a period during which the endometrium is optimally receptive to implanting blastocyst Aboubakr Elnashar
  9. 9. Duration: 4 to 5 days D6 to D10 postovulation, or D7 to D11 post LH surge or D20 to D24 of 28 D cycle Aboubakr Elnashar
  10. 10. Benefits of determining the implantation window: It may be possible to • Widen the implanation window by manipulating the pre- & peri-implantation endocrine environment • Correlate endocrine, biochemical & morphological changes with endometrial receptivity • Recognize the time for ET that would best correspond with the implantation window Aboubakr Elnashar
  11. 11. •Initiation of ER depend on: the down regulation of endometrial PR & estrogen receptors induced by P (Lindhard et al,2003). •When the embryo has arrived in the endometrial cavity: a preprogrammed sequence of events occurs, which involves the secretion of a multitude of biochemical factors by the endometrium & the embryo, leading to to the formation of a receptive endometrium. Aboubakr Elnashar
  12. 12. •Some factors like integrins like  v 3 make the endometrium receptive & others like MUC1 make it resistant to implantation except in small areas Aboubakr Elnashar
  13. 13. Abnormalities of the luteal phase have been detected in all the stimulation protocols on both hormonal & endometrial levels. COH adversely affect endometrial receptivity(Devroey et al, 2004)Aboubakr Elnashar
  14. 14. Etiology: 1. High concentration of estrogens & progesterone, altered E2 to progesterone ratios. 2. Disturbed LH levels 3. Corpus luteum deficiency (Albano et al, 1998). 4. A direct effect of GnRh agonist or antagonist on the corpus luteum or on endometrium 5. Altered endometrial receptivity from endometrial asynchrony & earlier expression of pinopodes Aboubakr Elnashar
  15. 15. •Endometrial histology has revealed a wide range of abnormalities during the various ovarian stimulation protocols (Ubaldi et al, 1997). In GnRh-agonist cycles, mid-luteal biopsies has revealed: increased glandulo-stromal dyssynchrony delay in endometrial development, strong positivity of endometrial glands for PR, decreased cell adhesion molecule profiles and earliest appearance of surface epithelium pinopodes (Soliman et al, 1994). Aboubakr Elnashar
  16. 16. These factors suggest a shift forwards of implantation window. Progesterone supplementation improves endometrial histology, and its necessity has been established, at least in cycles, using GnRh agonists (Soliman et al, 1994). Aboubakr Elnashar
  17. 17. •There is increased peri-ovulatory P in the COH cycles. The early rise of P has a negative impact on endometrial receptivity but not on oocyte-embryo quality these cause premature endometrial lutenization & provide an explanation for the observed decrease in endometrial receptivity (De long et al, 2000). Aboubakr Elnashar
  18. 18. On the other hand (Levi et al,2001). Implantation & pregnancy rates did not differ between IVF-ET patients and recipients of donor oocytes. Exposure of the developing endometrium to COH during IVF cycles does not inhibit embryo implantation or affect pregnancy rate. Aboubakr Elnashar
  19. 19. •Embryo implantation rates declines in a linear fashion from 29% in women <34 yr to 5% at 42 yr (Rosenwaks et al,1995) Oocyte senescence is responsible but demised endometrial receptivity may play a role Aboubakr Elnashar
  20. 20. •Abnormal receptivity in aging subjects is due to decreased levels of P receptors promoted by the low levels of E2 receptors (Meldrum,1993). However when the P dosage for luteal support was increased, recipients aged over 40 yr had a marked increase in pregnancy rate Aboubakr Elnashar
  21. 21. On other hand: No conclusive evidence of age related histological changes in the endometrium (Sauer et al,1993). No difference in implantation, pregnancy, miscarriage or live-birth rates between younger & older patients (Abdalla et al,1997) A study of 3 groups of women ranging from 25 to 60 yr found no difference in histology, ultrasound, or steroid receptor content of the endometrium between the different age groups (Fitzgerald et al,1993) Aboubakr Elnashar
  22. 22. Aboubakr Elnashar
  23. 23. I. Biochemical markers II. Morphological markers Aboubakr Elnashar
  24. 24. I. Biochemical markers 1. Endometrial adhesion molecules Integrins • 3 integrins are expressed by the endometrium with a pattern that coincide well with the window of implantation: 11,  4 1 &  v 3 Aboubakr Elnashar
  25. 25. Aboubakr Elnashar
  26. 26. Aboubakr Elnashar
  27. 27. •They are the best markers of endometrial receptivity 1. They are co-expressed on glandular epithelium only during cycle D 20 to 24 2. Most interest has been focused on the  v 3 integrin since it appears in endometrial glands & luminal surface on cycle days 20 to 21, coincident with the opening of the window of implantation 3. In endometriosis,  v 3 expression is reduced Aboubakr Elnashar
  28. 28. Aboubakr Elnashar
  29. 29. 4. Integrin expression in the endometrium allows histologic dating for evaluation of endometrial receptivity •Type I defect: Failure to express  v 3 integrin & out of phase endometrium. P is effective Type II defect (Occult endometrial receptivity defect) : Failure to express  v 3 integrin & in-phase endometrium. Mild endometriosis, hydrosalpinx, unexplained infertility. Aboubakr Elnashar
  30. 30. 5. The expression of  4 &  3 on peripheral blood lymphocytes may correlate with endometrial cell integrin expression during peak endometrial receptive period. So, it may be used as clinical markers to assess endometrial receptivity (Reddy et al,2001). Aboubakr Elnashar
  31. 31. 2. Endometrial anti-adhesion molecules Mucin 1 3. Endometrial Cytokines Leukemia inhibitory factor Interleukin-1 Interleukin-11 Colony-stimulating factor Aboubakr Elnashar
  32. 32. 4. Endometrial growth factors Heparin binding-epidermal growth factor Insulin like growth factor binding protein 5. Other endometrial markers Mouse ascites Golgi (MAG) Laminin, fibronectin & collagen IV Glycodelin Cyclin E & p27 Aboubakr Elnashar
  33. 33. Aboubakr Elnashar
  34. 34. Endometrial function tests: The most efficient way to directly assess endometrial receptivity (Kliman et al,1995). 1. MAG test: Endometrial biopsy. It measures a sticky mucinous substances that is secreted by endometrial glands before implantation. 85% of normal fertile women express higher levels of MAG between D 5 & D 18 & no expression after D19. 70% with unexplained infertility showed abnormal MAG levels. Aboubakr Elnashar
  35. 35. Delayed pattern: MAG expressed after D19. Aboubakr Elnashar
  36. 36. 2. Cyclin E & p27: It allows dating of the endometrium & differentiating between normally & abnormally developing endometrium. Cyclin E: First appears in proliferative phase & not seen after D19 P27: First appears on D17 & remains for the rest of the cycle. Aboubakr Elnashar
  37. 37. Persistent expression of cyclin E Aboubakr Elnashar
  38. 38. B. Morphological markers 1. Pinopodes • Globular protrusions in the surface membrane of endometrial epithelial cells. • Accurate markers of the implantation window. • last for less than 2 days. Aboubakr Elnashar
  39. 39. • The timing of their formation depends on: 1. The hormone treatment applied 2. Patient's individual response. On average, they form on days 20-21 in natural, days 19-20 in COH, and days 21-22 in HC cycles Aboubakr Elnashar
  40. 40. • There is a wide (up to 5 days) variation between women in the cycle days on which pinopodes form. • Pinopode numbers correlate with implantation [Nikas et al, 1996] On other hand: there is evidence of implantation occurring in the absence of pinopodes(Redy et al.1997) Aboubakr Elnashar
  41. 41. In natural cycle: There is an inherent synchrony between the maturing endometrium & the developing embryo, ensuring that both will meet at the right stage. Fully developed pinopodes have been detected on days LH+6 to LH+9 (days 19 to 22) in different individuals Aboubakr Elnashar
  42. 42. SEM of endometrial epithelium on day LH+4 of a natural cycle. The secretory cells are bulging, covered with dense microvilli. Ciliated cells are also seen Aboubakr Elnashar
  43. 43. Day LH+7 of natural cycle: Most secretory cells bear fully developed pinopodes, which may protrude beyond the length of the ciliated cellsAboubakr Elnashar
  44. 44. Day 21 natural cycle: bulging decreases & small tips of microvilli reappear on the membrane, which are now wrinkled (Regressing pinopodes) Aboubakr Elnashar
  45. 45. In COH- IVF cycles: Embryonic development is probably delayed because of the in vitro conditions [Lopata,1996] while the endometrium may be advanced [Nikas et al, 1999] resulting in an early closure of the implantation window before the zygote eventually reaches a stage capable of initiating implantation. Aboubakr Elnashar
  46. 46. Accelerated pinopode formation correlated strongly with preovulatory progesterone rise (≥6 ng by day 13)[Develioglu et al, 1999] Consequently, it would be highly desirable if the window of receptivity in IVF cycles could be postponed for a couple of days. A low dose of mifepristone (antiprogestin) on days 14 and 15 caused delayed pinopode formation [Murphy et al, 1992] Aboubakr Elnashar
  47. 47. A strong correlation between pinopode number and implantation success after embryo transfer in a subsequent cycle. The surface endometrial morphology during the second cycle was found to be similar to that in the first cycle Fully developed pinopodes were detected in only one sample from each donor, indicating a short life span. Aboubakr Elnashar
  48. 48. In Hormone –Controlled cycles: The most receptive day of the cycle corresponds to fully developed pinopodes or is postulated to be 1 day before regressing or 1 day after developing pinopodes are observed. A transfer cycle follows in which synchronization with the embryo is arranged so that the predicted most receptive day coincides with embryonic age day 6. It is assumed that by that time the IVF embryo is ready to implant. The use of SEM in monitoring endometrial differentiation and timing of embryo transfer on an individual basis is recommended. Aboubakr Elnashar
  49. 49. Expression of pinopodes in Aboubakr Elnashar
  50. 50. Shift of endometrial receptivity & blastocyst in IVF cycles as opposed to natural cycles Aboubakr Elnashar
  51. 51. 2. Decrease in the epithelial tight junctions between D13 & 23 3. Apoptosis On D 19-20 apoptosis is detectable in the glands of the basal layer Aboubakr Elnashar
  52. 52. Tight junction Apoptosis Aboubakr Elnashar
  53. 53. Potential functional markers are expensive, invasive & circumstantial Aboubakr Elnashar
  54. 54. 1. TVS: Thickness & pattern Favorable receptivity: Trilaminar pattern (triple line), Thickness:7-14 mm Unfavorable receptivity: Hyperechoic or isoechogenic, Thickness<7 mm or >14 mm. >14mm is not associated with reduced receptivity (Ashkenzai et al,2002) Aboubakr Elnashar
  55. 55. Endometrial thickness: has a significant positive correlation with the duration of follicular stimulation & an inverse correlation with age. Endometrial parameters are not reliable (Mital et al,2002) Aboubakr Elnashar
  56. 56. 2. 3D US: Endometrial volume: 2 ml is the minimum for a receptive endometrium <1ml: no pregnancy (Ragaa et al,1999). > 4 ml. No increase in ER Aboubakr Elnashar
  57. 57. Aboubakr Elnashar
  58. 58. 3. Doppler US: Some authors reported significant correlation between pregnancy rates & uterine artery Doppler flow values (Carbillon et al,2001), while others failed to show such a relationship (Salle et al,1998) Aboubakr Elnashar
  59. 59. Aboubakr Elnashar
  60. 60. 4. 3D power Doppler US: Sub-endometrial perfusion can not predict ER (Kuupesic et al,2001). Use of subendometrial vascularization index was superior in predicting the pregnancy rate of IVF to using endometrial volume (Ming et al,2003). Aboubakr Elnashar
  61. 61. 5. MRI: High cost, not used in routine practice 6. laser blood-flowmetry A novel way to assess ER by measuring endometrial tissue blood flow, using hystero fiberscope laser blood-flowmetry. It is superior to conventional parameters for determining ER for implantation (Jinno et al,2001). Aboubakr Elnashar
  62. 62. Endometrial receptivity: practical dilemmas 1.There is doubt on the functional importance of the morphological markers (Rogers et al,1996) 2. Despite the physiologic importance of the events cited above, implantation can occur under a wide range of morphological & biochemical conditions. All factors should be investigated simultaneously, which is impracticalAboubakr Elnashar
  63. 63. 1.Tissue sampling, which is often required for the direct assessment of markers of endometrial receptivity, is impossible in actual ET cycles. It may cause trauma & bleeding at the implantation site with potential reduction in the chance of pregnancy. Aboubakr Elnashar
  64. 64. • On the other hand, Ubaldi et al (1999) found that endometrial aspiration biopsy at the time of egg collection did not reduce pregnancy rates in women treated in IVF-ET. Recently, Olivennes et al (2003), confirmed that uterine flushing on the day of egg retrieval during an IVF-ET cycle did not adversely affect pregnancy rates. These results should be confirmed in a larger sample of a prospective randomized study. Aboubakr Elnashar
  65. 65. I. To develop ovarian stimulation protocols that cause a minimum reduction in endometrial receptivity II. To avoid the endometrium during stimulated cycles altogether by freezing the embryos & replacing them in subsequent natural cycles. III. To improve uterine vascularization. IV. To treat the pathology: Aboubakr Elnashar
  66. 66. I. To develop ovarian stimulation protocols that cause a minimum reduction in endometrial receptivity: a. Ovarian stimulation protocols that do not use clomiphene citrate b. Correcting the endometrial alterations induced by CC by vaginal supplementation of E2 & P (Elkind et al, 2002) c. Return to natural cycle IVF: the disadvantages of working with a single developing follicle outweigh any advantages gained (Yaron et al,1997) Aboubakr Elnashar
  67. 67. d. Exogenic 17estradiol during IVF cycles significantly increases both implantation rate & pregnancy rates & no difference in the thickness of the endometrium (Kornilof et al,1999) e. Low dose of antiprogesterone may correct the precocious lutenization & restore endometrial receptivity (Paulson et al,1997) Aboubakr Elnashar
  68. 68. f. ‘Aromatse inhibitors: Improving implantation rates in ART by reducing the supraphysiologic levels of E2 associated with COH (Mitwally & Casper, 2001; Ziegler et al, 2004) Endometrial morphology during the implantation window in letrozole-stimulated cycles was characterized by in-phase histological dating and pinopode expression (Cortinez et al, 2005). {E2 levels similar to spontaneous cycles and higher midluteal P} Aboubakr Elnashar
  69. 69. g. Switching the FSH stimulus to that of LH (or mini HCG) in the last stages of COH(Ziegler et al, 2004) Aboubakr Elnashar
  70. 70. II. To avoid the endometrium during stimulated cycles altogether by freezing the embryos & replacing them in subsequent natural cycles: Not commonly used a. Freezing protocols cause a loss in embryo viability that negate any beneficial effect b. Practical & financial considerations Aboubakr Elnashar
  71. 71. III. To improve uterine vascularization: 1. Low dose aspirin: {inhibits the synthesis of thromboxane A2 without affecting the synthesis of prostacyclin: increase blood flow velocity in uterine & ovarian artery} (Rubinstein et al,1999). Aboubakr Elnashar
  72. 72. 2. L-arginine (nitric oxide donor): {NO is formed from arginine by NO synthetase (Chwalisz et al,2000). Relaxation of vascular smooth muscles of endometrial vessels is mediated by NO}. Oral L-arginine supplementation may improve uterine blood flow, endometrial receptivity & implantation rate Aboubakr Elnashar
  73. 73. 3. Sildenafil citrate (viagra): {is a phosphodiestrase inhibitor that prevents the break down of cGMP (Cher et al, 2000). NO relaxes vascular smooth muscles through cGMP} Dose: 25 mg vaginally 4 times daily with the beginning of COH until the day of HCG Larger studies remain necessary to confirm their effectiveness Aboubakr Elnashar
  74. 74. IV. To treat the pathology: 1. Luteal phase defect: Exogenous progestrone 2. Fibroids distorting the uterine cavity. 3. IU adhesions 4. Uterine septum Aboubakr Elnashar
  75. 75. 5. Hydrosalpinx: Negative effect on PR, IR, early pregnancy loss & live delivery rate per ET. {The fluid of hydrosalpinx: constitute a mechanical barrier to implantation by causing the embryo to float is deficient to support the developing embryo toxic to the developing embryo Inflammatory response Altered chemical composition of the tubal fluid: low K & carbonate, proteins }(Lessey et al,1994). Salpingectomy resulted in improvement of outcomes (NICE, 2004) Aboubakr Elnashar
  76. 76. 6. Endometriosis: Prolonged pituitary down regulation (Marcus et al,1994). 7. Autoimmune conditions: prednisolone & low dose aspirin: increase both implantation & pregnancy rate (Birkenfield et al,1994) Aboubakr Elnashar
  77. 77. Benha University Hospital, Egypt Aboubakr Elnashar