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OVULATION INDUCTION FOR IUI BY DR SHASHWAT JANI

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OVULATION INDUCTION FOR IUI BY DR SHASHWAT JANI

  1. 1. Dr. Shashwat Jani. M. S. ( Obs – Gyn ) Diploma in Advance Laparoscopy. Consultant Assistant Professor, Smt. N.H.L. Municipal Medical College. Sheth V. S. General Hospital , Ahmedabad. Mobile : +91 99099 44160. E-mail : drshashwatjani@gmail.com
  2. 2. 1.Improvement of Follicular Growth 2.Increasing the Number of Follicles 3.Treatment of Anovulation (PCOS) 4.Better Timing 5.Improvement of Luteal Phase 24-Apr-17 Dr Shashwat Jani. 9909944160 2
  3. 3. Optimum Ovarian Stimulation for IUI  2 – 3 follicles with 18 – 19 mm size.  Endometrium  9 mm thick & trilaminar.  IUI between Cycle D13 and D16, 36-40 hrs. from HCG inj. 24-Apr-17 Dr Shashwat Jani. 9909944160 3
  4. 4.  Provides more number of follicles with good quality.  Timing of HCG injection predicts ovulation better, so as to schedule IUI near ovulation time.  C.O.H. offers more over for fertilization & implantation, hence increases success.  C.O.H. corrects subtle endocrinopathies which block ovulation, implantation 24-Apr-17 Dr Shashwat Jani. 9909944160 4
  5. 5.  Retrograde Ejaculation  Impotence or Ejaculatory Dysfunction  Hypospadias  Hypospermia (Low Volume)  Non Liquefying / highly viscous semen  ‘Subnormal’ semen parameters  Seminal Antisperm Antibody  Unexplained Infertility. Dr Shashwat Jani. 9909944160 524-Apr-17
  6. 6.  Vaginismus  Cervical Hostility  Ovulatory Dysfunction  Mild Endometriosis  Allergy to seminal plasma  Unexplained infertility Dr Shashwat Jani. 9909944160 624-Apr-17
  7. 7.  Azoospermia with testicular failure  Severely abnormal semen parameters Use Discretion)  Hereditary disease in man  Severe untreatable Rh isoimmunisation in wife  Repeated failures with IVF/ICSI  Single women, lesbian couples Dr Shashwat Jani. 9909944160 724-Apr-17
  8. 8. Simple Cost Effective Minimal side effects Best success rates Patients requiring ovarian stimulation or induction can be categorized in two groups : 24-Apr-17 Dr Shashwat Jani. 9909944160 8
  9. 9.  In these patients there is an established ovulatory pattern.  Multiple studies have shown improved pregnancy rates with ovarian stimulation in these patients as compared to nonstimulated natural cycles.  Aim : Multiple follicle development Dr Shashwat Jani. 9909944160 924-Apr-17
  10. 10.  20 – 30 % cases of female infertility  Anovulatory patients are further divided by WHO into 3 categories: Group I: Hypogonadotrophic hypogonadism Group II: PCOS Group III: Ovarian failure  Aim : Monofollicular development Dr Shashwat Jani. 9909944160 1024-Apr-17
  11. 11. Natural cycle + IUI 3.3% CC + IUI 9.5% CC + hmG + IUI 13.3% hmG + IUI 17.26% Stimulation Protocol 24-Apr-17 Dr Shashwat Jani. 9909944160 11
  12. 12. Number of follicles Pregnancies per cycle (%) ONE 5.7% TWO 13.6% THREE 16.3% FOUR OR MORE 13.9% Number Of Follicles Higher pregnancy rate with three preovulatory follicles (Huttenen et al 1999) 24-Apr-17 Dr Shashwat Jani. 9909944160 12
  13. 13. D 2 FSH ( >10 mlU/ml is s/o low ovarian reserve ) AFC Ovarian Volume AMH HSG / Lap Dr Shashwat Jani. 9909944160 1324-Apr-17
  14. 14. 1. Clomiphene citrate (CC) 2. Letrozole 3. Gonadotropins 4. Clomiphene with Gonadotrophins 5. Letrozole with gonadotrophins 6. Gonadotrophins with GnRH analogues 7. Gonadotrophins with GnRH antagonists Dr Shashwat Jani. 9909944160 1424-Apr-17
  15. 15.  The cumulative pregnancy rate per couple was 33% for IUI & COH, & 18% for IUI alone.  COH has independent positive effect on pregnancy rate when combined with IUI.  In young patients without a prior pelvic surgery & with good-post-wash semen quality COH doubles IUI pregnancy rate. Hendin B, Falcone T, Hallak J, Nelson D, Vemullapalli S, Goldberg J, et al. Effect of clinical & semen charachteristics on efficacy of ovulatory stimulation in patients undergoing IUI. J Assist Reprod Genet 200;17:189-93.24-Apr-17 15 Dr Shashwat Jani. 9909944160
  16. 16.  Most widely used  Simple to use,  Minimal side effects,  Cost effective 24-Apr-17 Dr Shashwat Jani. 9909944160 16
  17. 17. Depletion of ER in pituitary & hypothalamus due to prolonged stimulation Estrogen feedback loop gets interrupted FSH secretion increased leading to multiple follicle growth Hypothalamus Pituitary CC binds to ER & depletes receptor concentrations More smaller follicles are rescued Multiple follicles develop estrogen –ve feedback interrupted FSH stimulation continues 1 2 3 4 5 17 Clomiphene citrate: Mechanism of action Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.
  18. 18.  50-100mg per day for five days . (up to 200mg per day)  There is no difference in pregnancy rate whether clomiphene is commenced on day 2, 3, 4 or 5 of the cycle, although there is perhaps a tendency to multiple follicular development the closer the agent is commenced to menses. 24-Apr-17 Dr Shashwat Jani. 9909944160 18
  19. 19. Pregnancy: 30% Failure (no pregnancy despite ovulation): 40% Resistance: no ovulation: 25% Antiestrogenic effect: 5% Dr Shashwat Jani. 9909944160 1924-Apr-17
  20. 20.  Shows excellent result in ….  CC Resistant  CC Failure .  Associated with thicker endometrium and increased stromal blood flow, thereby providing a better uterine environment more favorable for implantation.  Compared to CC, letrozole has been shown to have higher pregnancy rates. Dr Shashwat Jani. 9909944160 2024-Apr-17
  21. 21. • Inhibits aromatase in ovaries & peripheral tissues reducing estrogen levels • Negative feed back being active stimulates hypothalamus-pituitary axis • GnRH release produces FSH • FSH-mediated stimulation of follicle • Rising estrogen level from follicle • suppresses FSH leaving a single dominant-follicle Hypothalamus Pituitary -ve feedback stimulation Smaller follicles undergo atresia Single follicle develop estrogen –ve feedback FSH stimulation 1 2 3 4 6 androstenedione  estrogen aromatase inhibition GnRH released Falling FSH 5 21 Letrozole: Mechanism of action Casper RF, et al. J Clin Endocrinol Metab. 2006; 91: 760-771.
  22. 22.  Dose  2.5 mg/day start cycle day 3-7, max 7.5 mg/day (AL-Fadhli et al., 2006; Legro et al., 2014 N Engl J Med)  Comparison with CC (Casper et al., 2006)  High rate of monofolliculer  No direct antiestrogenic adverse effect on endometrium  Shorter half-life (48hr and 2 wks)  Lower serum E2 24-Apr-17 Dr Shashwat Jani. 9909944160 22
  23. 23.  In a recent study conducted by Badawy et al, extended letrozole therapy (2.5mg daily from day-1 of menses for 10 days) was used for CC resistant PCOS women…  Higher number of patients ovulated  No of dominant follicles were more  Pregnancy rates were significantly greater  No extra cost Dr Shashwat Jani. 9909944160 2324-Apr-17
  24. 24.  Reported by Mitwally et al.  In this protocol letrozole was administered in the step up doses consisting of one, two, three, and four tablets of letrozole (2.5mg) daily on menstrual cycle days 2, 3, 4 and 5 respectively.  Multifollicular development  Higher pregnancy rate Dr Shashwat Jani. 9909944160 2424-Apr-17
  25. 25.  Indicated in : - CC Failure - Letrozole failure - WHO Group 1 (Hypogonadotrophic hypogonadism )  Cochrane ( 2007 ) … “ Gonadotropins might be the most effective drugs when IUI is combined with ovarian hyperstimulation .” Dr Shashwat Jani. 9909944160 2524-Apr-17
  26. 26.  FSH or hMG administered daily from early in the Menstrual Cycle.  Monitoring with USG ( and Hormonal assays ) is mandatory  Trigger ovulation with hCG when follicular maturity attained  Significantly improve pregnancy rates from IUI, in contrast to natural cycle IUI.  Risk of multiple pregnancy Dr Shashwat Jani. 9909944160 2624-Apr-17
  27. 27. Advantages:  high efficacy: ovulation rate : >95 % per cycle conception rate: 20 - 30 % per ovulatory cycle Limitations:  Serious complications can occur: multiple pregnancies ▪ Twins 25% ▪ Higher order 5 % ovarian hyperstimulation syndrome long term complication ? ovarian cancer  require intensive monitoring in specialist centre  expensive 24-Apr-17 Dr Shashwat Jani. 9909944160 27
  28. 28.  Depends on the D2 LH / FSH /E2 levels.  If LH FSH containing gonadotrophins are indicated,  Whereas if serum FSH (>10 mIU/ml), LH + FSH is used for ovarian stimulation.  For ovarian stimulation in patients with hypogonadotrophic hypogonadism, a combination of LH and FSH is used. Dr Shashwat Jani. 9909944160 2824-Apr-17
  29. 29. A. Conventional regimen B. Low dose step up regime C. Step down regime Dr Shashwat Jani. 9909944160 2924-Apr-17
  30. 30. Days 7 14 21 28 hCG 150 IU 112.5 IU 75 IU hCG Foll.  10 mm 75-150 U daily 6 12 hCG Foll.  16mm 37.5 IU 75 IU 112.5 IU 150 IU Chronic Low dose Step up regimen Step down Conventional Regime 24-Apr-17 Dr Shashwat Jani. 9909944160 30
  31. 31. CC resistant OR CC Failure Cases Started from D2 / D3 75 - 150 IU /day Serial USG for monitoring D 8 S. estradiol Widely accepted protocol . PR up to 30 % Dr Shashwat Jani. 9909944160 3124-Apr-17
  32. 32.  Useful in PCOS  AIM : To find the “threshold“ level of FSH which will lead to the development of a single preovulatory follicle.  Less complication  But , unphysiological as FSH is very high in late follicular phase compared to natural cycle. Dr Shashwat Jani. 9909944160 3224-Apr-17
  33. 33.  Low starting dose (37.5- 75 units/day )  Stepwise increase in subsequent doses  E2 & USG on D7  D8 E2 > 200 pg/ml OR follicle > 10mm Ct. Same dose.  If E2 or Follicle size not achieved on D8 increase dose by 37.5 IU /day . Dr Shashwat Jani. 9909944160 3324-Apr-17
  34. 34.  HMG / FSH 150 IU/day from D2  Continued till Dominant follicle become 10mm on USG  Decrease the dose .  112.5 IU/day for next 3 days  75 IU day till time of HCG. Dr Shashwat Jani. 9909944160 3424-Apr-17
  35. 35.  Sequential use of CC f / b FSH or HMG.  CC ( 100 mg ) 1 daily from D2 to D6.  FSH or HMG ( 75 / 150 IU ) on D6 & D8.  TVS on D8 onwards  Additional FSH / HMG given. Dr Shashwat Jani. 9909944160 3524-Apr-17
  36. 36.  Higher pregnancy rate than with CC alone .  More cost effective, as the dosage of gonadotrophins is reduced .  Lesser multiple pregnancy rate than with gonadotrophins alone .  Lower incidence of OHSS, as compared to the conventional regime.  Kemmann E, Jones J R. Sequential clomiphene Citrate menotrophin therapy for induction or enhancement of ovulation.Fertil Steril 1983;39:772-9  Dickey R P, Olar T T, Taylor S N, Curole D N, Rye P H . Sequential clomiphene citrate and Human menopausal Gonadotrophin for ovulation induction: comparison to clomiphene citrate alone and human menopausal gonadotrophin alone.. Human Reprod 1993; 8:56- 59Dr Shashwat Jani. 9909944160 3624-Apr-17
  37. 37.  Good alternative to CC in patients with unexplained infertility undergoing gonadotrophin stimulated COH cycles combined with IUI therapy.  In a prospective nonrandomized study by Mitwally and Casper it was shown that aromatase inhibition with letrozole reduced the dosage of FSH required for COH without any undesirable antiestrogenic effects, Dr Shashwat Jani. 9909944160 3724-Apr-17
  38. 38.  The pregnancy rate achieved was also significantly lower in the CC + FSH group (10.5%) compared with the letrozole + FSH group (19.1%) and FSH only group (18.7%). Dr Shashwat Jani. 9909944160 3824-Apr-17
  39. 39.  In almost 15-20 % of cycles of CC or HMG  Due to multi follicular development, Estradiol Increases Premature LH surge Cycle Cancellation. Dr Shashwat Jani. 9909944160 3924-Apr-17
  40. 40.  To avoid this endogenous LH interference, Exogenous Gonadotrophins & GnRH analogues are used for OI.  Mainly useful in IVF.  Recent Cochrane review has concluded that GnRH analogues do not significantly improve pregnancy rates in IUI. Dr Shashwat Jani. 9909944160 4024-Apr-17
  41. 41.  Act by competitive inhibition of GnRH receptors, which results in rapid decline in FSH /LH levels, thus preventing premature LH surge.  Can be given in a single dose or daily dose regimen. Dr Shashwat Jani. 9909944160 4124-Apr-17
  42. 42. 1. Lubeck Protocol: Gonadotrophins are started as usual and antagonist is started when the follicle reaches a size of 14 mm, or from 6 day of stimulation onwards in a dose of 0.25mg / day till the day of HCG injection. Dr Shashwat Jani. 9909944160 42 Diedrich K , Diedrich C , Santos E , Zoll C , Al-Hasani S , Reissmann T , et al. Suppression of the endogenous luteinizing hormone surge by the gonadotrophin-releasing hormone antagonist Cetrorelix during ovarian stimulation . Hum Reprod. 1994; 9:788-791. 24-Apr-17
  43. 43. 2. French Protocol : Gonadotrophins are started as usual and a single dose (3 mg) of antagonist is given when serum E2 level is about 150-200 pg/ml and follicular size is 14 mm . Dr Shashwat Jani. 9909944160 43 Olivennes F , Fanchin R , Bouchard P , de Ziegler D , Taieb J , Selva J , et al. . The single or dual administration of the gonadotropin-releasing hormone antagonist Cetrorelix in an in vitro fertilizationembryo transfer program. Fertil Steril. 1994;62:468 24-Apr-17
  44. 44. 1. Allows the manipulation of follicular development so that IUI can be avoided at weekends without any detrimental effect on PR. 2. Compared to agonist , it is relatively simple and inexpensive. There is no suppression of oestrogen and the effects are easily reversible. 3. Antagonists are associated with lower rates of OHSS. Dr Shashwat Jani. 9909944160 4424-Apr-17
  45. 45. Dr Shashwat Jani. 9909944160 4524-Apr-17
  46. 46.  D2 TVS  Serial TVS from D8  to look for follicular development ( Number & Size ).  Normally follicle grow 2 – 3 mm/day  helps in determining exact time to trigger ovulation  Prevent OHSS  Endometrium: look for thickness & appearance.  Triple line ET of > 9 – 10 mm is ideal . Dr Shashwat Jani. 9909944160 4624-Apr-17
  47. 47.  In Natural Cycle : Serum E2 level correlates with development of dominant follicle.  In Stimulated cycle: it reflects the total output of all developing follicle irrespective of size.  Problem : Inconvenience , Cost , daily Prick  Mainly used in Gonadotrophin cycle on D8 , Value > 200 pg/ml  Good response. Dr Shashwat Jani. 9909944160 4724-Apr-17
  48. 48.  > 4 follicles of > 16 mm OR > 8 follicles of > 12 mm  Serum Estradiol  > 1500 – 2000 pg / ml Cancel the cycle  If < 1500 pg/ ml  use GnRH analogue to trigger ovulation Dr Shashwat Jani. 9909944160 4824-Apr-17
  49. 49.  Premature LH surge is known to occur in 20 to 24% of patients undergoing ovarian stimulation after the leading follicle reaches 16 mm.  The LH surge can be detected either by doing a daily blood or urinary LH assay, once the leading follicle exceeds 16 mm.  When LH surge detected  Inj. HCG given & IUI planned. Dr Shashwat Jani. 9909944160 4924-Apr-17
  50. 50.  Ideally 36 -38 after HCG administration OR After Confirmation of Ovulation. 50 Dr Shashwat Jani. 990994416024-Apr-17
  51. 51.  The HCG injection is necessary as the LH secreted by the body may not be adequate enough, to induce the necessary maturational changes in all oocytes, if there are many follicles in the ovary.  Numerous urinary LH kits are available to detect LH surge. They are easy to use and are cost effective. Dr Shashwat Jani. 9909944160 5124-Apr-17
  52. 52. 24-Apr-17 52 Dr Shashwat Jani. +91 9909944160

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