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Ovulation Induction - Simplified - Dr Dhorepatil Bharati
The document discusses ovulation stimulation and factors that influence ovarian response, including hormonal profiles, ovarian reserve, and age-related fertility decline. It explores strategies for improving IVF procedures in developing countries, focusing on cost-effectiveness and optimizing ovarian stimulation protocols. Additionally, it emphasizes the importance of monitoring hormonal surges and follicular quality for successful ovulation induction and embryo viability.
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Ovulation Induction - Simplified - Dr Dhorepatil Bharati
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- 3. What are factorsto be considered • Ovarian reserve • Previous ovarian response • Basic hormone profile • Role of FSH & LH • Trigger • Luteal phase support • Pregnancy rate/cycle Dr.Bharati Dhorepatil 3
- 4. After effects ofthe stimulation • Oocyte quality • Endo quality • Embryo quality comparision between conventional Vs minimal stimulation • Difficulties with this approach • Can we make it truly costeffective …to make low cost IVF procedure in our developing country..INDIA Dr.Bharati Dhorepatil 4
- 5. Decision making investigations •AMH • USG..Blood flow indices in folliculometry • PCOS..Hormonal parameters & interpretaion • Statistical evaluation of success of treatment • Sperm function tests Dr.Bharati Dhorepatil 5
- 6. Age and Fertility Optimal Fertility Declining Fertility Menopause Endof Fertility Irregular Cycles Dr.Bharati Dhorepatil 6
- 7. Ovarian reserve testsprovide an indirect measure of the cohort of recruitable antral follicles present in the FSH window at the beginning of each menstrual cycle..Functional Ovarian Reserve Fauser and Van Heusden, 1997; McGee and Hsueh, 2000. Dr.Bharati Dhorepatil 7
- 8. Concept to remember •Up to 30 years of age, the loss of follicles (and oocytes) in the human ovary is mainly due to atresia of resting follicles. • After reaching a critical threshold in the number of follicles (estimated at 25,000), the recruitment of growing follicles is increased twofold and thereafter the loss of follicles is mainly due to atresia of growing follicles Gougeon 1996, Erickson 2000. Dr.Bharati Dhorepatil 8
- 9. On the basisof a fixed interval of 13 years between onset of accelerated decline of fertility (25,000 remaining follicles) and the menopause, it can be speculated that women who become menopausal by the age of 45 years, have experienced an accelerated decline of fertility around the age of 32. These women can be classified under a separate clinical entity, “early ovarian ageing” Dr.Bharati Dhorepatil 9
- 10. Asymptomatic group… Epidemiological studieshave shown that • 10% of women in the general population become menopausal by the age of 45 (Treloar, 1981; van Noord et al., 1997), Dr.Bharati Dhorepatil 10
- 11. Clinical suspects….. • Age30-35yrs • Women with a family history of an early menopause • Unexplained Infertility • Poor stimulation • Recurrent cyst formation • A short follicular phase, • Early LH surge, • Premature elevation of progesterone (P4) • Requiring very high gonadotrophin doses • Idiopathic Recurrent abortions with anupleidies (Farhi et al., 1997; Crosignani et al., 2000; De Boer et al., 2002; Nikolaou et al., 2002;Lawson et al., 2003) Dr.Bharati Dhorepatil 11
- 12. • Chemotherapy • Radiotherapy •Pelvic surgery (Lass et al., 1998;Tulandi et al., 2002), • Pelvic infections or tubal disease (Keayet al., 1998; Sharara1998), • Severe endometriosis (Barnhart et al., 2002), • Heavy smoking (Augood et al., 1998). • Single ovary • Long Standing Hypothyriod status Dr.Bharati Dhorepatil 12
- 13. Antral follicle count(AFC) • Number of antral follicles (early follicular phase) • Low numbers of antral follicles - sign of DOR and observable earlier than a rise in FSH serum level • But - cycle–cycle variation • Intra-observer variation • AFC ~ AMH • Scheffer et al Fertil Steril 1999 • Broekmans et al Fertil Steril March 2008 Epub Dr.Bharati Dhorepatil 13
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- 15. • Prospective evaluationof automated follicle monitoring in 58 in vitro fertilization cycles: follicular volume as a new indicator of oocyte maturity • Conclusion(s) • SonoAVC allows reliable evaluation of stimulated ovaries, and may help us establish new criteria for timing hCG administration based on follicular volume estimation rather than follicular size. Software improvements are needed to improve universal patient use. • Fertility and Sterility Volume 93, Issue 2 , Pages 616-620, 15 January 2010 Dr.Bharati Dhorepatil 15
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- 17. • Folliculogenesis • Co-relationwith endocrinology • Ways of monitoring • Tips to improve ovulation induction.. Dr.Bharati Dhorepatil 17
- 18. Aim • Monofollicular development •Multifollicular..2 to 3 • Controlled Ovarian Hyperstimulatio Dr.Bharati Dhorepatil 18
- 19. Dr.Bharati Dhorepatil 19 Monofollicular Response… Early follicular Mid Late Surge
- 20. Dr.Bharati Dhorepatil 20 2to 3 follicle Early follicular Mid Late Surge
- 21. COH Dr.Bharati Dhorepatil 21 Earlyfollicular Mid Late Surge
- 22. Basic facts.. • Folliclesare present in the ovary at different stages of development, at any given point of the menstrual cycle • It is unknown as yet which factors regulate initiation of growth of primordial follicle • An increase in the number of granulosa cells is critically important for the advancement in developmental stages of the follicle. Dr.Bharati Dhorepatil 22
- 23. • Stimulation byFSH is an absolute requirement for development of large antral preovulatory follicles. Duration and magnitude of FSH stimulation will determine the number of follicles with augmented aromatase enzyme activity and subsequent E2 biosynthesis. • High FSH levels usually occurring during the luteo- follicular transition give rise to continued growth of a limited number (cohort) of follicles. • Subsequent development of this cohort during the follicular phase becomes dependent on continued stimulation by gonadotropins. Dr.Bharati Dhorepatil 23
- 24. • The entryof FSH into follicular fluid at cavitation is believed to provide the induction stimulus that initiates the process of graafian follicle growth and development. • At the cellular level, it is the FSH receptor on the granulosa cell that is the fundamental player in this process. Dr.Bharati Dhorepatil 24
- 25. FSH Threshold &Window FSH Threshold and Recruitment Window Threshold Window Rekruitment Selection Dominance The longer and higher FSH is above threshold the more follicles are recruitet Atresia The longer and higher FSH is above threshold the more follicles are recruitet. Fauser and Heusden, Endocrine Rev. 1997; 18; 71-106 Dr.Bharati Dhorepatil 25
- 26. Protocols…. 1. CC. 2. Enclomiphene..stepup,extended 3. CC ± FSH or ± HMG. 4. Gn. Standard step-up protocol. 5. Gn. Low dose step-up protocol. 6. Gn. Low dose step-up, step-down protocol. 7. Adjuvants Dr.Bharati Dhorepatil 26
- 27. Gonadotrophins.. • Conventional • Lowdose protocol • Chronic Low dose Protocol • Chronic step up AND step down protocol Dr.Bharati Dhorepatil 27
- 28. • The goalof folliculogenesis is to produce a single or multiple dominant follicles from a pool of growing follicles… Four major regulatory events : • Recruitment • Follicle development • Selection, • Surge (maturity) Dr.Bharati Dhorepatil 28
- 29. Role of FSHand LH • Both FSH and LH are required for promoting follicular growth and differentiation… • FSH..principal stimulator and regulator of antral follicular growth… • Some LH ..preantral stage..to stimulate secretion of androgens by thecal cells…then mid follicular phase to nourish.. then late follicular phase for surge Dr.Bharati Dhorepatil 29
- 30. Follicular monitoring..Basic CycleProfile Pivotal Scan…D2 or D3 • Both Ovaries…AFC, residual cyst • Endometrium…Complete Shedding D10 to D14..Pre ovulatory Scan D20-21…Luteal Scan Dr.Bharati Dhorepatil 30
- 31. What to achievebefore ovulation? Dr.Bharati Dhorepatil 31
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- 33. Monitoring starts.. • D7,D8,D9…anyday could be a start • Growth pattern to be followed..Day X 2mm appro. • Alternate day monitoring is advisable if required changed according to the need • Sustained growth…is must In healthy follicles, genes direct cytodifferentiation, proliferation, and follicular fluid formation. Dr.Bharati Dhorepatil 33
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- 35. • The moststriking change in LH secretion occurs at the end of the follicular phase, when there is an abrupt rise in its concentration. • This is the preovulatory gonadotropin surge that initiates the ovulatory process. Dr.Bharati Dhorepatil 35
- 36. Timing of events.. LHsurge: • 0hr…….GV with nucleolus • +15 hours………… GVBD • +20 hours………… first meiotic metaphase • +35 hours………… second meiotic metaphase • +38 hours………… ovulation Dr.Bharati Dhorepatil 36
- 37. • The largeincrease in LH inhibits androgen production, and as a result estradiol concentrations decrease drastically from the preovulatory peak. • Granulosa cells become 'luteinized', and consequently a small preovulatory rise in progesterone occurs within one hour of the LH surge completion Dr.Bharati Dhorepatil 37
- 38. Recent advances.. • Assessmentof the ovarian volume, number and volume of follicles and ovarian/perifollicular vascularity by three- dimensional ultrasonography and power Doppler angiography on the HCG day • Computarised automated assesment of follicular size Dr.Bharati Dhorepatil 38
- 39. Dr.Bharati Dhorepatil 39 •Assesmentof the follicular maturity and endo receptivity and the time of HCG Is one of the Key factors for the success of all ART procedures •Vascular changes are the reflection of the biochemical changes. •3D power doppler gives not only qualitative but also quantitaive idea of the global vasularity •Thus it is reflection of Functional/physiological maturity
- 40. Dr.Bharati Dhorepatil 40 •Follicularvasularity distribution and flow indices.. Better parameters of follicular quality and can be guideline for the time of HCG and IUI
- 41. Dr.Bharati Dhorepatil 41 Vasularitygrades… 1.<25%, 2.25to 50%, 3.50to75%, 4.>75% of follicular circumference Conception rates are higher with Gr.III & IV vasularity…. Chug et al
- 42. When to giveHCG.. • Perifollicular and subendometrial Hallo…oedema • Cumulus presence..30-40% • Follicular volume..3-7ml • Flow Indices…PSV>10,RI<0.5 • Perifollicular Vasularity..3/4th • Sub Endo vasularity..minimum 5 spiral vessels reaching to zone 4,ant &post,RI<0.6 • Endo peristalsis 3to5/ min • Uterine A..on dominent sidePI<3.2 Dr.Bharati Dhorepatil 42
- 43. Subendometrial Blood flow Dr.BharatiDhorepatil 43
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- 45. Timeline of ovulation •Case A..Day 11…DF..18mm,..endo..8mm,triple line • but RI<0.48,PSV 6-7,poor flow Timeline…Wait…HCG next Day or when parameters improves as PSV low Dr.Bharati Dhorepatil 45
- 46. • Case B…Day10…DF 18-19mm, Endo..7mm,triple line • RI..<0.5,PSV >15, 85 % good flow • Timeline…Give HCG right away as it is a sign of impending LH surge ( LH surge starts UA PI is v.high) Dr.Bharati Dhorepatil 46
- 47. • Case C.. •Day 11…DF..19.9mm,Endo 6.5mm • PSV 7,RI>0.45,v.poor perifollicular flow • Timeline…LUF.. Dr.Bharati Dhorepatil 47
- 48. When one ortwo IUI • Depends on PSV>25…just one IUI,no trigger..with in 12 to 14hrs • PSV<15…RI<0.5…Trigger comfortably..34 hrs and 48hrs IUI Dr.Bharati Dhorepatil 48
- 49. Test.. • 29yr old,BMI 28,AFC 6,AMH 3ng/ml pt comes with three cycles of CC 100mg taken with TIC..with tubal patency,no male factor..D2 of the menses.. • What Is your choice of gonadotropins • What dose to start and maintenance • When will be your first scan,what will you expect? Dr.Bharati Dhorepatil 49
- 50. • 29yr old,BMI 34,AFC 20,AMH 10ng/ml pt comes with three cycles of CC 100mg taken with TIC..with tubal patency,no male factor..D2 of the menses.. • What Is your choice of gonadotropins • What dose to start and maintenance • When will be your first scan,what will you expect? Dr.Bharati Dhorepatil 50
- 51. Tips… successful ovulationInduction • You are not doing Ovarian stimulation, but • You are preparing egg from given ovary to get pregnancy out of it.. Dr.Bharati Dhorepatil 51
- 52. • Synchronus Folliculargrowth..small dose to start,early follicular phase recruitment, small incremental dose • Critical time of trigger for adequate LH surge • Appropriate Choice of Injection for stimulation & trigger • Right amount of doses • Avoid Premature LH surge & leutinization • Constant look for endometrial quality development to have good functioning endo for implantaion • Appropriate and right amount of luteal support Dr.Bharati Dhorepatil 52
- 53. • The productionof a viable embryo requires ovulation of a competent oocyte, adequate progesterone production by the CL, and an adequate uterine environment. Dr.Bharati Dhorepatil 53
- 54. • Evidence maychange with more trials: concepts to be kept in mind. Dr.Bharati Dhorepatil 54
- 55. Learn from yesterday, livefor today, hope for tomorrow The important thing is…not to stop questioning Albert Einstein Dr.Bharati Dhorepatil 55
- 56. • Three theoriesof follicle recruitment have been postulated to date: • (i) the ‘continuous recruitment’ theory, • (ii) the ‘single recruitment episode’ theory and • (iii) the ‘wave’ theory.
- 57. • to treatpoor prognosis or oncological patients through • Duostim, • LPS-only or • random-start ovarian stimulation approaches.
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