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Ivf in pcos



IVF in PCOS Aboubakr Elnashar Benha University Hospital, Egypt

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Ivf in pcos

  1. 1. IVF in PCOS Aboubakr Elnashar Benha University Hospital, Egypt ABOUBAKR ELNASHAR
  2. 2. CONTENTS  Introduction  Prevalence  Indications  Patient preparation  Gonadotropin and protocol choices  Monitoring and trigerring of ovulation  ET  Luteal phase support  Prevention of OHSS  Outcome  IVM  Conclusion ABOUBAKR ELNASHAR
  3. 3.  PCOS:  most common disorder in women of reproductive age  Primary cause of anovulatory infertility.  No clear consensus on its specific definition.  All of the diagnostic criteria include some combination of oligo-anovulation androgen excess and PCO. ABOUBAKR ELNASHAR
  4. 4.  NI (1990)  Chronic anovulation.  Cl and/or biochemical hyperandrogenism. Rotterdam (2003) 2 out of 3  Ch anovulation.  Cl and/or biochemical hyperandrogenism.  PCO on US AES (2006) AE-PCOS(2009)  Cl and/or biochemical hyperandrogenism.  Ovarian dysfunction (anovulation and/or PCO)  Exclusion of related ovulatory or other androgen excess disorders (e.g., thyroid dysfunction, hyperprolactinemia, androgen-secreting neoplasms, or non classic adrenal hyperplasia) 8% 18% 12% Prevalence of PCOS ABOUBAKR ELNASHAR
  5. 5.  Reinforced the use of Rotterdam Criteria to diagnose PCOS.  Recommended 4 phenotypes of PCOS. 1. Hyperandrogenism + ch anovulation (H-CA). 2. Hyperandrogenism + PCO (H-PCO). 3. Ch anovulation + PCO (PCO-CA). 4. Hyperandrogenism + ch anovulation + PCO (HCA-PCO). Evidence-Based Methodology ABOUBAKR ELNASHAR
  6. 6. Four different phenotypes of PCOS based on Rotterdam Criteria PCOS phenotypes Oligo or anovulation Biochemical or clinical manifestations of hyperandrogemia PCO in TVS 1-Severe PCOS + + + 2-Oligo- or anovulation and hyperandrogenemia + + - 3-Ovulatory PCOS - + + 4-Mild PCO + - + ABOUBAKR ELNASHAR
  7. 7. PCOS is associated with a range of reproductive, obstetric, and metabolic features.  Reproductive manifestations: hyperandrogenism, menstrual dysfunction, anovulation, and PCO on ultrasound.  Obstetric manifestations: early pregnancy loss, gestational diabetes, and pregnancy-induced hypertension.  Metabolic manifestations: obesity, insulin resistance, IGT, DM , and metabolic syndrome. ABOUBAKR ELNASHAR
  8. 8. Reproductive manifestations 1.Hyperandrogenism  Hirsutism: 60% of PCOS.  Acne: 30% of PCOS.  Androgenic alopecia.  Menstrual irregularity {anovulation}  Ovulatory dysfunction: oligoamenorrhea: 80%  Definition of ch anovulation in PCOS is based on:  Exclusion of other causes of anovulation.  Measurement of midluteal progesterone.  Absence of corpus luteum by TVS. 2. Ovulatory and menstrual dysfunction ABOUBAKR ELNASHAR
  9. 9. PCO on ultrasound Criteria of polycystic ovarian morphology 12 or more follicles, 2 - 9 mm in diameter and/or Ovarian volume >10 cm3. ABOUBAKR ELNASHAR
  11. 11. Weight reduction Oral anti-estrogens (CC) Obese &overweight Normal weight &No weight loss & No ovulation LODGnT No ovulation after 3 cycles. No pregnancy after 6 cycles. No pregnancy after 6 cycles. No pregnancy after spontaneous, CC, FSH ovulation IVF Other surgical indication Difficult follow up Less aggressive No desire for surgery Add metformin IGT &IR ABOUBAKR ELNASHAR
  12. 12. Causes of chronic anovulation in PCOS 1-Relative FSH deficiency 2-Hypersecretions of: -LH -Insulin -Estrogen -Androgen -Inhibin B 3-Attenuated apoptosis. 4-Aberrant expression of growth factors. 5-Abnormalities in ovarian steroid production. -Theca cells hyper secrete androgens -Granulosa cells have increased aromatase activity ABOUBAKR ELNASHAR
  13. 13. PREVALENCE 33% of women attending for IVF had PCO. (MacDougall et al. 1993). PCO occur in 20–30% of IVF Patients (Sherif, 2012) ABOUBAKR ELNASHAR
  14. 14. INDICATIONS IVF is not 1st line of tt in PCOS. 1-Other factors: tubal factor, male factor 50% of subjects had other factors. (Tannys, 2010) 2. Failure to conceive despite at least 6 ovulatory cycles (Adam, 2007). ABOUBAKR ELNASHAR
  15. 15.  1. Failure to conceive on Gnt therapy alone/ IUI (Araki, 2011) 2. Failure of wt reduction, antiestrogen therapy or LOD, it may be argued that induction of ovulation with Gnt should be omitted and replaced by ovarian stimulation and IVF. (Eijkemans et al., 2005) 3. High response to FSH (4 or more follicles) despite low Gnt dose. 4. To eliminate the chances of MP particularly for some older women: single ET (Papanikolaou et al., 2006;Heijnen et al., 2007)ABOUBAKR ELNASHAR
  16. 16. PATIENT PREPARATION I. Counseling & information: How pregnancy occur Indication, steps, PR, problems, Financial II. Evaluation 1. General: history, Gyn Exam, Screen for Hepatitis, DM, 2. Semen analysis 3. ORT 4. Hormonal: 5. TVS. 6. Hysteroscopy?? III. Management of associated conditions: Habits, Obesity, DM IV. Preventive treatment. ABOUBAKR ELNASHAR
  17. 17. I. Counseling and information  increased obstetric risk (gestational diabetes, PET and fetal morbidity) if overweight.  Potential problems as OHSS and multiple pregnancy. II. Evaluation: Screen for DM III. TT of associated condition: Cessation of smoking, Weight reduction IV. Preventive TT: Doxycyclin: 100mg 1x2x7d., Diflucan or Flucoral one caps. Flagentyl 4 tablet Folic acid 0.5mg. Aspirin 75mg /day are continued Prevention of OHSS in PCOS: Metformin: given in the period prior to ART LOD ABOUBAKR ELNASHAR
  18. 18. CHOICE OF GONADOTROPINS Type: No difference in outcome between ovarian stimulation with hMG preparations or urinary derived FSH, in studies using the long protocol of GnRH desensitization. (MA: Agrawal et al. 2000) No significant clinical differences between hMG and rFSH. (Nugent et al., Cochrane Data base Syst Rev 2000; van Wely et al, 2003) hMG, uFSH, and r-FSH: equally effective for achieving pregnancy in PCOS. (Al-lnany et al.,2005) ABOUBAKR ELNASHAR
  19. 19. STIMULATION PROTOCOLS GNt dose: low dose in either a long protocol, or short GnRHa protocol 50–150 IU depending on age and other factors Protocols 1-GnRHa (Griesinger et al., 2006) 2-GnRHan (Griesinger et al., 2006) ABOUBAKR ELNASHAR
  20. 20. Short protocol should not be proposed {initial flare-up effect could lead to an excessive ovarian response}. Metformin {reduce risk of OHSS} (dose 850mg twice daily from the start of down-regulation to the day of oocyte retrieval). History of severe OHSS GnRHan and use a single-shot of agonists for final oocyte maturation. ABOUBAKR ELNASHAR
  21. 21. GnRHan Vs GnRHa protocol Effective Shorter duration of Gnt stimulation. Lower total dose of Gnt. Improved patient acceptance interventions to prevent OHSS (e.g. coasting, cycle cancellation) less (European Orgalutran Study Group 2000 ; North American Ganirelix Study Group 2001; Schultzer Mosgau et al , 2005) ABOUBAKR ELNASHAR
  22. 22. MONITORING RESPONSE TO STIMULATION US and E2 1. US: Evaluate whether the dose of GnT is adequate or not. 1st US  D4 Stimulation In PCO  D 5 or 6 stimulation In normal responder Number: 6-8 each ovary  With diameter: 11- 12 mm ABOUBAKR ELNASHAR
  23. 23. US in day of HCG  High risk of OHSS  Number of follicles >20  Number of small & intermediate size (10-14 mm) >15  No risk of OHSS  immature follicles are < 15. {Number of the immature follicles is more important than the number of mature follicles in predicting OHSS. ABOUBAKR ELNASHAR
  24. 24. 2. E2: Level: <1000 pg/ml: No OHSS >3000-4000 pg/ml: HCG should be withheld <3500 pg/mL: No OHSS (Asch et al 2005) 3500-5999 pg/mL: 1.5% 6000 pg/mL: 38% Slope: Cases with severe OHSS are seen with E2 <1500 pg/ml. slope of rise of E2 is more accurate (considered if the value is doubled). ABOUBAKR ELNASHAR
  25. 25. Do not trigger ovulation with the intention of fresh ET in women who have: E2>3500 pg/ml or >20 follicles on US (NICE, 2013) ABOUBAKR ELNASHAR
  26. 26. HOW TO TRİGGER THE OVULATİON 1.Decrease HCG dose: As low as 3300 IU as low as 2500 IU is effective in PCOS. (Kashyap et al.,2010) 2000 IU: ineffective, lower successful oocyte recovery (Kashyab et al, 2010). does not prevent OHSS (Kol, Dor, 2009) There is no clear published evidence that lowering HCG dose will result in a decrease in the rate of OHSS. (III) 2-GnRHa trigger -0% incidence of OHSS (Humaidan et al.,2011) ABOUBAKR ELNASHAR
  27. 27. EMBRYO TRANSFER Maximum of 2 embryos: reduces MPR Single ET Young women significantly reducing MPR ABOUBAKR ELNASHAR
  28. 28. LUTEAL PHASE SUPPORT  HCG 2-fold increase in OHSS than tt with progesterone alone (Daya, Gunby, Cochrane Database 2004) Progesterone -No superiority of IM progesterone over vaginal (Zarutskie and Phillips, 2009; Fatemi,2009; Mitwally et al., 2010) ABOUBAKR ELNASHAR
  29. 29. Triggered by agonist a. Intensive progesterone and estradiol b. Single bolus of hCG (1500 IU) on the day of OPU in addition to a standard LPS with vaginal progesterone and oral E2. (Humaidan et al., 2006, 2009; 2010) c. Repeated boluses of hCG (500 IU) 3 doses started on the day after OPU with every 3rd day (OR + 1, OR + 4 and OR + 7). d. Repeated doses of Rec LH -6 alternate doses of 300 IU rLH were administered starting on the day of OR and repeated on days OR + 2, OR + 4, OR+6, OR + 8 and OR + 10.ABOUBAKR ELNASHAR
  30. 30. PREVENTION OF OHSS The incidence of severe OHSS: significantly higher in PCOS (15%) compared with normal ovaries (3%). (Swanton et al., 2010) ABOUBAKR ELNASHAR
  31. 31. Primary prevention 1. Prediction of OHSS from history, exam, and US 2. LOD in PCOS 3. Metformin in PCOS 5. Low-dose Gnt in PCOS 6. GnRHan protocol 7. Rec LH to trigger ovulation 8. GnRHa to trigger ovulation 9. IVM of oocytes 10. Replacement of only one embryo (Rizk B., 2006) ABOUBAKR ELNASHAR
  32. 32. 2ndry prevention 1. Withholding hCG ± continuation of GnRHa/GnRHan 2. Coasting or delaying hCG: currently most popular method 3. Use of GnRHa to trigger ovulation 4. Follicular aspiration 5. Cryopreservation and replacement of frozen– thawed embryos at a subsequent cycle 6. Progesterone for luteal phase 7. Dopamine agonist 8. Albumin: administration at time of retrieval 9. Glucocorticoid administration 10. Aromatase inhibitors Rizk (2006) ABOUBAKR ELNASHAR
  33. 33. Cancelling hCG -It is usually reserved for patients at high risk cases -Presence of several risk factors -Patients with total loss of cycle control (Delvigne and Rozenberg; 2002) Cryopreservation of oocytes and embryos : higher cumulative PR than coasting to avoid OHSS. (Sills et al., 2008; Fitzmaurice et al., 2008.; Gera et al., 2010). Can be applied when GnRHa triggering rec hCG instead of urinary hCG No statistically significant difference (Al-Inany, Cochrane Database 2005; Kashyap S et al., Semin Reprod Med 2010) ABOUBAKR ELNASHAR
  34. 34. Coasting -no evidence to suggest a benefit of coasting to prevent OHSS compared with no coasting or other interventions. (D'AngeloA et al., Cochrane Database Syst Rev 2011) Use of dopamine agonist from the day of hCG trigger -Women with PCOS are less responsive to cabergoline compared with those without PCOS. (Gomez R et al., 2011; Manzanares et al., 2010) ABOUBAKR ELNASHAR
  35. 35. Hydroxyethyl starch (HES) a significant reduction in the incidence of OHSS without affecting PR. (Jee BC et al., 2010) In vitro maturation of oocytes (IVM) -It avoids exogenous Gnt (avoiding the risk of OHSS) -IVM may be a promising alternative to conventional IVF. (Child et al., 2002) ABOUBAKR ELNASHAR
  36. 36. OUTCOME OF IVF IN PCOS PCOS or isolated PCO-only morphology Behave exactly in the same manner during all stages of ART Response to ovarian stimulation: better than that for women with normal ovaries Cycle cancellation rate: significantly increased in PCOS (12.8 Vs 4.1%). Duration of stimulation: significantly longer in PCOS (1.2 days), even when the daily dose of FSH is similar to that of women without PCOS. ABOUBAKR ELNASHAR
  37. 37. Retrieval Cumulus–oocyte complexes: Significantly more in women with PCOS Fertilization rates similar as compared with women without PCOS. (MA: Heijnen et al., 2006) CPR/ET: Higher compared with isolated male factor infertility. (Esinler et al.,2005) Outcome of pregnancy: similar. (Esmailzadeh et al., 2005) ABOUBAKR ELNASHAR
  39. 39. IVF vs IVM in PCOS  No RCT:  The number of mature oocytes No significant difference (Shavit et al, 2014)  The average dose of gonadotropin, fertilization rate and high-quality embryo rate: significantly higher in the GnRHan group compared with the IVM group.  PR, LBR/pregnancy and abortion rates: comparable. ABOUBAKR ELNASHAR
  40. 40. CONCLUSIONS  PCOS patient is the most difficult to treat with IVF  Cycle cancellation rates and risk of OHSS are higher  PR in women with and without PCOS are similar, this suggests that implantation is not compromised in PCOS.  Fine tailoring of ovarian stimulation is necessary to avoid complications  hMG, uFSH, and r-FSH are equally effective for achieving pregnancy in PCOS.  Antagonist protocol with GnRHa triggering is associated with a very low risk of OHSS. ABOUBAKR ELNASHAR
  41. 41. Thanks ABOUBAKR ELNASHAR