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Thin Endometrium & Infertility (Part – II) , Dr. Sharda Jain, Life Care Centre

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Thin Endometrium & Infertility (Part – II) , Dr. Sharda Jain, Life Care Centre

  1. 1. Thin Endometrium & Infertility (Part – II) Dr. Sharda Jain Dr. Jyoti Agarwal Dr. Jyoti Bhaskar
  2. 2. OUR TEAM
  3. 3. Healthy seed in not enough to get a healthy sapling unless it grown on fertile soil. Similarly healthy embryo needs receptive endometrium for successful implantation. Hard Facts
  4. 4. Optimum endometrium i.e. 7 mm preovulatory is must for achieving pregnancy – Management of This endometrium is challenging problem for infertility experts There is no consensus regarding management of thin endometrium found at the time of ovulation induction in IUI & IVF. Treatment of Thin endometrium in infertility
  5. 5. Important causes of poor endometrium growth during ovulation induction are: Endometrial resistance to oestrogen.  Reduced blood flow.  Over -exposure to testosterone. Permanent damage to the basal endometrium Causes of Thin Endometrium
  6. 6. Based on aetiology, number of drugs/methods has been used with aims of improvement oestrogen level in endometrium and increase blood supply to basal endometrium. Principle of Treatment of thin Endometrium in infertility
  7. 7. Treatment strategy For Anti oestrogens effect of clomiphene
  8. 8. In the group of patients where clomiphene induction is associated with thin Endometrium, LETROZOLE TAMOXIFEN Can be alternative drugs Use Alternative drugs to clomiphene induction Letrozole / Tamoxiten
  9. 9. However, these drugs remain off – label for ovulation induction and hence cannot be recommended at present. Use for ovulation induction with LETROZOLE / TAMOXITEN have the advantage of avoiding peripheral anti estrogenic effects.
  10. 10. OESTROGEN – is second alternative In this group of patients, addition of oestrogen is seen as the logical step in combating antiestrogenic effect on endometrium. However, the dose, the regimen and type of oestrogen used vary widely with little consensus to the treatment approach.
  11. 11. In a meta-analysis done by Torres RF et al examined the use of pure ethinyl estradiol (EE) for treatment of thin endometrium, observed that use of Ethinyl estradiol 0.02- 0.05mg/day given from 7th day of cycle for 5 days, does improve the endometrial thickness in comparison to patients where only placebo was used. Torres R.F, A Meta-Analysis. Fertil steril 2005; 84:S162-S163 The Famous Meta analysis On oestrogen use
  12. 12. Other oestrogen preparation and dose schedule reported in literature are : Conjugated equine Oestrogen : 0.625 mg from day 7TH FOR 5 DAYS. Transdermal ethinyl Oestradiol : 4 mg / day from day 8th till the day of ovulation Vaginally administered Local estrogen : To avoid the first pass of systemic oestrogen
  13. 13. OESTROGEN USED VAGINALLY  Kadir Cetinkaya et al used vaginally administered local oestrogen 25mcgms from 4th day for 15 days in CC induced cycle. They reported significant increase in ET on the day of ovulation (7.6 +/-1.4 mm vs 8.3+/-2.1 mm) than the group where only CC was used, but there was no change in pregnancy rate. Cetin kaya k e al Ja. Tuk . Ger. Gynaecol. Assoc 2012 , 13CB), 157-61
  14. 14. ORAL OESTROGENS Oral oestrogens are now routinely used for preparation of endometrium for frozen embryo transfer, where previous IVF failure was thought to be due to thin endometrium. Dose schedule is different from fresh cycle. Most use oral estradiol 2mg thrice daily from day one for 12 days. The appropriate development of endometrium in seen in good 70 – 80 % cases
  15. 15. Few IVF experts use step wise increased dose of oestradiol, 2mg/day from Ist to 4th day , 4 mg from 5th to 8th day and 6 mg from 9th to 12th day of cycle and reported better ET development. Oestrogen is also found to improve blood circulation to radial artery which is evident by improved flow in radial artery. ORAL OESTROGENS
  16. 16. Vitamin EVitamin E the dose of 600 mg / day (200 mg three times daily ) orally given throughout the menstrual cycle to improve ET. Akihisa Takasaki et al observed adequate ET in 52% patients following treatment. 72% showed improved RA – RI and 20 % conceived. Each of these parameters registered statically significant improvement when compared to previous untreated cycle. Vitamin E improves growth of the glandular epithelium and number of blood vessels VEGE protein expression. Takasaki A et al ferpil . Stoni 2010, 93 (6) 1851 -8
  17. 17. L arginine treatment : Akihisa Takasaki et al tried L arginine in patient with thin endometrium at the dose 1.5gms four times (6gms) from ist day till the day of hCG injection. It improved RA-RI in 89% of patients and 67% patients developed endometrium more than 8 mm this difference was statistically significant when compared to previous cycle in these patients. Takasaki A et al ferpil . Stoni 2010, 93 (6) 1851 -8
  18. 18. SILDENAFIL CITRATE Sildenafil citrate, a type 5 – specific phosphodiesterase inhibitor, augments the action of Nitric Oxide on vascular smooth muscle. It is thought to improve uterine blood flow and along with oestrogen -- leads to oestrogen induced proliferation of endometrial lining.
  19. 19. Tumor suppressor factor (p53), Plasminogen activator inhibitor 1 (PAI – 1), and Vascular endothelial growth factor (VEGF) need to produced necessary to digest the endometrial cellular matrix to regulate cell growth and angiogenesis to facilitate implantation. Sildenafil citrate markedly enhanced p53 ,PAI – 1 with increased VEGF. Sildenafil Citrate
  20. 20. Many studies have been conducted to evaluate the role of sildenafil to improve THIN ENDOMETRIUM in patients of infertility
  21. 21. Study Dose of Silden afil Duration of therapy Mode of administ ration Results Takasaki et al 2 100 mg Ist day till day of ovulation Intravaginal 92% patients showed improvement in endometrial thickness andd RA – RI Intravaginal route reduces side effects llike headache and hypotension. Firouzabadi et al 6 50 mg Ist day till 45-72 hours prior to embryo transfer Oral Endometrial thickness and triple line pattern significantly higher with sildenafil and estadiol valerate as compared to estradiol alone clinical pregnancy rate was higher but not significant Malgorzata Jerzak et al7 2.5 mg X four Times a day 3-6 days Intravaginal Suppostory Endometrial thickness was significantly increased Dose independent reduction in NK cell activity Successful use of sildenafil in two infertility patients with Asherman
  22. 22. Pentoxifyline• Pentoxifyline, a xanthine derivative, which is primarily used in medicine for treatment of Intermittent Claudication resulting from peripheral arterial disease has also been tried to increase endometrial circulation--- with no conclusive result
  23. 23. Micronized low dose ASPIRIN Micronized low dose aspirin has been tried left and right But no randomised trial is available literature to show whatever it is worth white !!
  24. 24. GRANULOCYTE COLONY STIMULATING FACTOR (GCSF )-- A new promise G-CSF has shown potential of improving ET in patients with poor endometrial growth especially when it is due to destruction of subendothelial layer where other common treatment for vasodilatation have failed. Gleicher in et all Fertil . Senl 2011, 95(6)2123
  25. 25. Norbert Gleicher et al 2011 was the first to use it in four patients with dramatic improvement in ET. Various reported studies are shown in next slide but this is still in experimental stage and it needs more well planned research with large sample size to be able to recommend it as a standard treatment. Granulocyte colony stimulating factor (GCSF ) new promise Gleicher in et all Fertil . Senl 2011, 95(6)2123
  26. 26. Evaluation of the role G-CSF in thin endometrium Study Dose of GCSF Duration of therapy Results Nobert Gleicher et al 2011 8 1 ml 30 MU (300mcg) 2-7 days before embryo transfer (ET)by ET catheter Dramatic improvement in endometrial thickness all four patients conceived with one intramural ectopic pregnancy. Y Kim et al 2012 1 ml 30MU (300mcg) On the day of hCG injection Significantly higher endometrial thickness (85% showed improvement), implantation and ongoing pregnancy rate Maryam Eftekhar 2014 1 ml 30 MU (300mcg) 12th – 13th day of cycle but repeated once more if endometrial thickness below 7 mm within 48 – 72 hours. No difference in endometrial thickness Chemical pregnancy rate and clinical pregnancy rate were found to be better (39.30%vs, 14.30% & 32.10%vs. 12.00% respectively ) Not statistically significant
  27. 27. NEUROMUSCULAR ELECTRICAL STIMULATION and biofeedback therapy is another very recent experiment on improvement of poor endometrial growth. However , more work need to be due.
  28. 28. Endometrial scratch Few randomized controlled trial has shown that endometrial scratching in the luteal phase of one cycle prior to IVF CYCLE  INCREASES PREGNANCY RATE
  29. 29. RATIONALE of endometrial scratch Tissue injury procedures like endometrial biopsy or hysteroscopy in the cycle prior to IVF treatment induces stem cell differentiation and increases the endometrial receptively during the IVF treatment cycle. Most expert doing IVF & IUI have started doing it.
  30. 30. Endometrial Reconstruction with Stem cell therapy  Ideal candidates The patients with persistent thin endometrium with repeated implantation failure. Treated cases of tuberclosis with thin endometrium Asherman syndrome grade III are the patient who need it most
  31. 31. Recent case report of endometrial reconstruction using autologous bone Marrow stem cells followed by conception by IVF in two patients has gained considerable attention and seems to provide ‘break through’ for conception in IVF cycle. Stem cell and thin endometrium
  32. 32. Life care IVF  We have used autogous stem cells therpy along with use of stem cells in locally in the endometrium in 2 cases.  In both cases endometrial growth was 8 mm plus & pregnancy occurred in one
  33. 33. Dr. Manjula Agnani (Padamshree) from Hyderabad Personal communication to Dr. sharda jain Autologous stem cells therapy from bone marrow was used in 4 cases of refractory thin endometrium All four responded with endometrial growth 8 mm plus.
  34. 34. ConclusionEvaluation and detection of any endometrial abnormality is one the cornerstone in the management of infertility Optimum endometrium thickness i.e. 7 mm preovulatory is must for achieving pregnancy Various modalities have been studied for improving the endometrium (thickness and vascularity)
  35. 35. -- But treatment modalities for achieving adequate endometrium this are still evolving G-CSF, endometrium scratch & stem cells therapy are new entry Conclusion
  36. 36. ADDRESS 11 Gagan Vihar, Near Karkari Morh Flyover, Delhi - 51 CONTACT US 9650588339 011-22414049 WEBSITE : ISO 14001:2004 (EMS) …..Caring hearts, healing hands ISO 9001:2008 Helpline : 9599044257 Helpline : 9910081484