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Ovarian Stimulation in IUI- Overview. Dr. jyoti Bhaskar, Dr. Sharda Jain, Dr. Jyoti Agarwal & Team
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Ovarian Stimulation in IUI- Overview. Dr. jyoti Bhaskar, Dr. Sharda Jain, Dr. Jyoti Agarwal & Team

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    • 1. Ovarian Stimulation in IUI- Overview Dr. Jyoti Bhaskar Dr. Sharda Jain Dr. Jyoti Agarwal
    • 2. At Certificate Course IUI & Ovarian Stimulation
    • 3. # Faculty • Dr. Sharda Jain Prog. Director , Course Chairperson • Dr Jyoti Agarwal Director /Course Co- Chair person • Dr. Aruna saxena Director Course Co- Chairperson • Dr. Jyoti Bhaskar Director • Dr. Abhishek Singh Parihar Director • Dr. Sushma Ved Director
    • 4. # Rationale for COH in IUI • Increasing the number of eggs available for fertilisation • Overcoming subtle defects in ovulatory function and luteal phase.
    • 5. # Aim of COH 1. Recruiting multiple follicles 2. Control timing of ovulation 3. Prevention of premature LH surge 4. To time the insemination 5. Increase the pregnancy rate
    • 6. # Optimum Ovarian Stimulation for IUI  2 – 3 follicles with Ø 18 – 20 mm.  Endometrium ≥ 8 mm thick & trilaminar.  IUI between Cycle D13 and D16, 36-40 hrs. from HCG inj.
    • 7. # Classification WHO • I - Hypothalamic pituitary failure (Hypogonadotrophic hypogonadism) Kallman’s, Sheehan’s, anorexia • II - Hypothalamic pituitary dysfunction (PCOS) • III – Ovulatory Failure – Hypergonadotrophic hypogonadism, Turner’s, autoimmune, mumps, RT, CT
    • 8. # Drugs for Ovarian Stimulation • Clomiphene Citrate, Tamoxifen • Gonadotrophins: • HMG • Highly purified urinary FSH • Recombinant. FSH • GnRH Agonist/ AntagonistGnRH Agonist/ Antagonist
    • 9. # CLOMIPHENE CITRATE • Most widely • Simple to use,  Minimal side effects,  Cost effective
    • 10. # CLOMIPHENE CITRATE ( SERM)CLOMIPHENE CITRATE ( SERM) HYPOTHALAMUS ERHYPOTHALAMUS ER Binds GnRH PituitaryPituitary FSH OVARYOVARY Folliculogenesis Blocks ER Cervix Endometrium Vagina
    • 11. # DOSAGE • Single dose -- together • Monitor Cycle with USG • If ovulation confirmed – maintain same dose • Max to 150 mg Starting Dose 100mg day 2 onwards for 5 daysStarting Dose 100mg day 2 onwards for 5 days
    • 12. # CC CHECK Evaluation of the patient on Day 2 • Previous cycles • TVS – ET , AFC and cysts • Review reports of FSH, LH if available
    • 13. # CC FAILURE ( 40%) No Pregnancy 3 CYCLES OF CC WITH OVULATION AND TIMED INTERCOURSE CC FAILURE ( 40%) No Pregnancy 3 CYCLES OF CC WITH OVULATION AND TIMED INTERCOURSE 2 CYCLES OF CC WITH IUI2 CYCLES OF CC WITH IUI
    • 14. # CC RESISTANCE (20%) 3 CYCLES OF CC NO OVULATION CC RESISTANCE (20%) 3 CYCLES OF CC NO OVULATION CC + GONADOTROPHINS LOD CC + GONADOTROPHINS LOD GONADOTROPHINSGONADOTROPHINS COST , PT’S CHOICE COUNSELLING Wt loss, extended CC, adjuvants – metformin, dexamethasone
    • 15. # Antioestrogenic Effect • Thin Endometrium • Poor cervical Mucus Start early in cycle – Day 2 or Day 1 Add oestradiol valearate from day 8/9 Use all gonadotrophin cycle Start early in cycle – Day 2 or Day 1 Add oestradiol valearate from day 8/9 Use all gonadotrophin cycle
    • 16. # TAMOXIFEN • 20-40 mg/day D2- D7,max 60 mg/day • Off label use for OI • Ovulation rates- 65 to 75% • Pregnancy rates- 30 to 35%. • Advantage- – No anti-estrogenic effect on endometrium. – Improve bone density & lipid profile • 2-3 times increased risk of endometrial Ca & DVT • No evidence of a difference in effect between CC and tamoxifen (Cochrane library, 2009)
    • 17. # Gonadotrophins - Indications CC Resistance CC Failure WHO 1
    • 18. # • HMG • Highly purified Urinary HMG/FSH • Recombinant. FSH Choice of Gonadotrophins Day 2 LH/FSHDay 2 LH/FSH FSHFSH LH PCOS FSH WHO group1 HMGHMG
    • 19. # DOSE • BMI • Ovarian reserve • Age • Cause of Infertility • Dose needed in previous cycle
    • 20. # Complications Multifetal pregnancy • OHSS - Life threatening Monitoring Experience Strict protocols Monitoring Experience Strict protocols
    • 21. # 1. CC only with TI or IUI 2. CC ± FSH or ± HMG with IUI 3. Gonadotrophin only n Conventional regime n Gn. Low dose step-up protocol n Gn. step-down protocol 4. Gonadotrophin with GnRH antag Protocols
    • 22. # 2 3 4 5 6 7 8 9 10 11 12 13 14 15 21 DAYS OF CYCLE TVS – ET AND AFC CC 100 MG DAILY Day 2-6 TVS – FOLLICLE SIZE, ET IF ET< 5MM OV 2MG BD DAILY TVS – FOLLICLE , ET , CERVICAL MUCUS STUDY, POST COITAL TEST FOLLICLE >20MM -- LH SURGE + VE -VE Inj HCG 5000 U i/m Timed Intercourse 8pmstat IUI 36 hrs later at 8am at Lifecare24hrs later at 8am Sexual relation at same night and for 2 days Luteal support – ETV ES/ Susten vaginally at night Serum Progesterone 7 days after IUI/Ovulation CC ONLY PROTOCOL -- +/- IUI B LONG F ONCE DAILY ALL THROUGH OUT THE CYCLE UPT 18 days after IUI/Ovulation
    • 23. # Unripe follicle Ripening follicle Ovulation Corpus luteum Regression of Corpus luteum Clomiphene 100 mg day2 for 5 days Gonadotrophin stimulation HCG Leading follicle > 18mm Oocyte mature 38 hrs
    • 24. # CC - GONADOTROPINS SEQUENCE oCC in ovulatory disorders decreases the total dose of gonadotropins used . oConcurrent use of Gn allows follicular development to desired extent. oEndometrium is not adversely affected. oOHSS is less common. oCost is less.
    • 25. # Days 7 14 21 28 hCG 150IU 112.5IU 75IU hCG Foll. ≥ 10 mm 75-150 U daily 12 hCG Foll. ≥ 16mm Gonadotrophin Regimens 37.5 IU 75 IU 112.5 IU 150 IU Chronic Low dose Step up regimen Step down Conventional Regime 2 6
    • 26. # EFFICACY OF GONADOTROPINS Low dose regimens result in: • Monofollicular ovulation rate of- 70%. • Pregnancy rate of -20% • Multiple live birth rate of -5.7% • Severe OHSS <1% (all comparable with that of CC) The duration of Gn therapy should not exceed 6 ovulatory cycles.
    • 27. # Gonadotrophins with Antagonists 15-20% cycles with Gonadotrophins have premature LH surge 15-20% cycles with Gonadotrophins have premature LH surge
    • 28. # Advantages of Antagonist Protocol • Helps avoid IUI at weekends • Prevents premature surge • Compared to agonist – simple and inexpensive • Lower rates of OHSS
    • 29. # Laparoscopic Ovarian Drilling • Main Indications 1. CC Resistance 2. Pts. who persistently hypersecrete LH • Methods – Monopolar cautery or Laser • Efficacy 50% of LOS treated Pts. adjuvant therapy will be reqd. Addition of CC after 12 weeks if no ovulation detected Addition of FSH should be considered after 6 months. • Complications Haemorrhage, bowel injury, adhesions, premature menopause
    • 30. # MECHANISM OF ACTION A.) Drilling of follicles releases androgen rich follicular fluid and decreases androgen producing stroma. B.) There is transient reduction in inhibin and precipitous fall in LH, which increases secretion and expression of FSH. C.) Crowding of cortex decreases which allows progress of normal follicles to the surface resulting in resumption of normal ovulation. LOD appears to be as effective as routine gonadotropin therapy in the treatment of clomiphene-insensitive PCOS.
    • 31. # LAPAROSCOPIC OVARIAN DRILLING (LOD) Advantages • High success rate • Prolonged response • ↓Multiple births • ↓ OHSS Disadvantages • Adhesion formation • Requires surgery • 1/3 require ovulation medications • POF risk • Less successful in smokers 25% vs 95% Technique: 4 puncture/ovary,4-5 mm depth,40 watt coagulation for 4 sec
    • 32. # PATIENTS RESISTANT FOR LOS • Increased duration of infertility (>3yr) • Women with marked obesity, BMI>35kg/m2 • Increased free testosterone and free androgen index
    • 33. # Anti-oestrogens Cost effective but less effective when compared to gonadotrophins. Do not prevent multiple pregnancies Have anti-oestrogenic effect on the endometrium Gonadotrophins Most effective drugs for IUI Low dose protocols (50 to 75 IU per day) are advised Pregnancy rates do not seem to differ significantly from pregnancy rates with high dose regimens (> 75 IU per day) whereas the changes to encounter negative effects from ovarian stimulation, such as the risk of multiples and the risk of OHSS might be higher with high dose protocols. 34 The Cochrane Library 2011, Issue 6 Cantineau AEP, Cohlen BJThe Cochrane Library 2011, Issue 6 Cantineau AEP, Cohlen BJ
    • 34. # GnRH-agonists There seems to be no role in IUI programs Increase costs Increase multiples without increasing the probability of conception Urinary gonadotrophins versus Recombinant products There is no significant difference GnRH-antagonists Whether or not are going to play a role in mild ovarian hyperstimulation/IUI programs needs to be determined in future trials. Letrozole There is no convincing evidence that Letrozole is superior to clomiphene citrate and therefore the cost should be taken into account when using anti-oestrogens. The Cochrane Library 2011, Issue 6 Cantineau AEP, Cohlen BJThe Cochrane Library 2011, Issue 6 Cantineau AEP, Cohlen BJ
    • 35. # Ovarian stimulation protocols (anti-oestrogens, gonadotrophins with and without GnRH agonists/antagonists) for intrauterine insemination (IUI) in women with subfertility (Review) The Cochrane Library 2011, Issue 6 Cantineau AEP, Cohlen BJ 36 Gonadotrophins might be the most effective drugs with IUI Low dose protocols are advised No studies using CC + gonadotrophins Gonadotrophins might be the most effective drugs with IUI Low dose protocols are advised No studies using CC + gonadotrophins
    • 36. # • There is evidence that IUI with OH increases the live birth rate compared to IUI alone. • The likelihood of pregnancy was also increased for treatment with IUI compared to TI both in stimulated cycles. • There is insufficient data on multiple pregnancies and other adverse events for treatment with OH. • Therefore, couples should be fully informed about the risks of IUI and OH as well as alternative treatment options. 37
    • 37. # Conclusion Ovarian Stimulation protocol • Simple • Cost Effective • Minimal side effects • Best success rates
    • 38. # Conclusion • Choice depends on doctors expertise and patient selection and choice • Gonadotrophin only protocol offers the best success rate TIME TO MOVE ON TO TOTAL GONADOTROPHIN CYCLE
    • 39. # Thank you
    • 40. # Failed ovulation induction in PCOS Obesity Hyper-insulinemia Androgen excess LH over-activity Hyper-prolactinemia Late onset CAH