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Once upon a time…

Once upon a time…. Birth after reimplantation of a human embryo Steptoe P.C. / Edwards R.G. Lancet 2 (1978): 366. 07/78 Louise Brown was born. The hypothalamic-pituitary endocrine system. Oestrogen. 15. brain. follicle-stimulating hormone (FSH). pituitary gland. ovary. oestrogen.

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Once upon a time…

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  1. Once upon a time… Birth after reimplantation of a human embryo Steptoe P.C. / Edwards R.G. Lancet 2 (1978): 366 07/78 Louise Brown was born

  2. The hypothalamic-pituitaryendocrine system

  3. Oestrogen 15 brain follicle-stimulating hormone (FSH) pituitary gland ovary oestrogen oestrogen uterus

  4. Primordial follicles • Primordial follicle is the earliest stage of follicular development • Appears in the prenatal • Consists of oocyte surrounded by single layer of squamous follicle cells PRIMARY FOLLICLE • Appears in baby after he was born • Consists of oocyte surrounded by single layer of squamous follicle cells • Histological appearance is like primordial follicle

  5. OVARY CORTEX MEDULA

  6. Evaluation of Ovulatory Function(Continued) • Enlarged ovarian follicle filled with fluid and a mature ooctye Image provided by author. Reprinted with permission. (Figure 4)

  7. Evaluation of Ovulatory Function (Continued) • Mature oocyte Image provided by author. Reprinted with permission. (Figure 5)

  8. Endometrial changes in luteal phase • Glandular secretions – nutrients, enzymes, etc • Lumina epithelial surface – mucins etc • Within luminal epithelial cells – changes in functional complexes, growth factors etc

  9. History of ovarian stimulation • 1970 Clomifen hMG • 1980 GnRH-agonist / hMG • 1990 recFSH GnRH-antagonist / hMG or recFSH • 2000 long acting FSH

  10. Rationale of ov.induction G

  11. How do we optimise??

  12. Ovulation Induction:ClomipheneCitrate • The “first line” of fertility therapy • Used to treat mildly disordered ovulation and luteal-phase insufficiency • Establish tubal patency and sperm adequacy before use. • Letrozole….XXXXXXXXXXXXXXXXX • 17 10 2011 from ministry of health.

  13. Normogonadotropic, Normoprolactinemic, Euthyroid women (WHO class 2) • The primary indication • secondary to oligo ovulation or • Anovulation • polycystic ovary syndrome.

  14. Hypergonadotropic women (WHO class 3) • In contrast, • with FSH concentrations at or above 40 mIU/Ml , have diminished follicular reserve, • have little or • no response • to clomiphene.

  15. Ovulation Induction: Clomiphene Citrate(Continued) In appropriately selected patients, • 80 percent ovulate and • 40 percent conceive with clomiphene • (Imani, Eijkemans, te Velde, Habbema & Fauser, 1999). • Cumulative conception rate is 60to 70% • (Dickey & Holtkamp, 1996).

  16. Monitering • Size of the follicles • Estradiol levels • LH • P4 surge

  17. Ovulation Induction: Clomiphene Citrate(Continued) • Multiples rate is about 10 percent • (Imani, Eijkemans, te Velde, Habbema & Fauser, 2002). • After 6 months, • women should move on to • more aggressive therapy.

  18. What next • Gonadotropin injection • Pregnancy rate in one large NIH study • in control group 2% /cycle • In FSH plus IUI 9%, • with timed sex 4% • Another study pushed up the FSH+IUI to 26%

  19. InjectableGonadotropins • Mature ovarian follicles from gonadotropin stimulation

  20. Ovulation rate/ CycleAlt. dose vs Daily dose 40 38 29 25 19 19 15 13 50 35 24 17 50 33 21 14

  21. Cumulative pregnancy rateAlt. dose vs Daily dose

  22. Fixed or flexible protocol • There was no statistically significant difference in pregnancy rate between flexible and fixed protocols. • There was a statistically significant reduction in the amount of recombinant FSH with the flexible protocol.

  23. CONCLUSION of this study • Study strongly suggests that a alternate Day rec.FSH therapy is equally effective as daily dose therapy. • Risk of multiple pregnancies and OHSS is less then daily dose therapy and is cost effective.

  24. How many FSH+IUI • 3 cycles • 6 cycles • Till patient withdraws?

  25. 1 Homeostasis www.ecosystema.ru/eng/

  26. GnRH Antagonist //Long GnRH Agonist Cycles FSH Long AgonistProtocol GnRH agonist FSH AntagonistProtocol GnRH antagonist Flare-up Pituitary downregulation Directgonadotropin suppression LH Time Reproduced with permission from Borm and Mannaerts. Hum Reprod. 2000;15:1490.Adapted from Hodgen. Contemp Rev Obstet Gynaecol. 1990;35:10.

  27. GnRH-agonist and antagonist protocol G LHRH-agonist: daily injection/ depot/ nasal spray OPU 8 d -14 HCG 6 4 Ampoules HMG ET 2 Menses 0 17 16 -16 -14 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 day of cycle antagonist 8 d 6 HCG 6 OPU ET 4 Ampoules Gonadotropins 2 Menses 0 17 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 day of cycle „long protocol“ „Lübeck protocol“

  28. Complications of FSH use • Multiples • in follicles • in fetuses.

  29. Prison sentence up to three years or financial penalty for § 1, Abs. 1, Nr. 3 „a person transfering more than 3 embryos to the womb in the course of one treatment cycle“ § 1, Abs. 1, Nr. 5 „a person fertilizing more oocytes than he or she intends to tranfer in the course of one treatment cycle“

  30. Trigerring • 3 or more follicles 17 mm • Expect cohort to be more heterogenous

  31. Poor responders • Are always poor responders • No difference between flexible and fixed protocol

  32. Cycle programming • Delay of trigger can be deleterious No difference in CPR in a day of delay 25% vs 35%, on going pregnancy rate when trigerring 2 days vs 3 days after follicles are 17 mm respectively

  33. Orgalutran Phase 3 Trials:Duration of FSH Stimulation Orgalutran Buserelin Leuprolide Triptorelin Days of FSH stimulation EU/MEtrial EUtrial NAtrial Out and Mannaerts. Hum Fertil. 2002;5:G5.

  34. Orgalutran Phase 3 Trials:Amount of recFSH Required Orgalutran Buserelin Leuprolide Triptorelin IU of FSH required EU/MEtrial EUtrial NAtrial Out and Mannaerts. Hum Fertil. 2002;5:G5.

  35. Orgalutran Phase 3 Trials: Number of Oocytes and Good Quality Embryos Oocytes Good Quality Embyros Orgalutran Buserelin Leuprolide Triptorelin Number Number EUtrial NAtrial EU/MEtrial EUtrial NAtrial EU/MEtrial EU = European; NA = North American; ME = Middle East. Out and Mannaerts. Hum Fertil. 2002;5:G5.

  36. Orgalutran Phase 3 Trials: Ongoing Pregnancy Rate per Started Cycle Orgalutran Buserelin Leuprolide Triptorelin Ongoing pregnancy rate (%) EU/MEtrial EUtrial NAtrial Out and Mannaerts. Hum Fertil. 2002;5:G5.

  37. If results from the 2 sites with outlier results are excluded, pregnancy rate is similar for antagonist and agonist cycles Orgalutran vs GnRH Agonist:Success Rates Vary Between Centers 45 38.8 Orgalutran 38 40 36.4 Leuprolide 35 31.3 30.8 30 Ongoing pregnancy rate per attempt (%) 25 20 14.6 15 10 5 0 9 USA sites Overall 2 Canadian sites (n=93) (n=204) (n=297) Values represent unadjusted means Data on file, North American Ganirelix Study Group.

  38. Orgalutran vs GnRH Agonist: Success Rates Better in Centers With Experience 40 27.6 25.7 24.2 23.6 30 20.3 16.5 Orgalutran Ongoing pregnancy rate per attempt (%) 20 Buserelin 10 0 10 sites with 10 sites without Overall experience experience (n=337) (n=363) (n=700) Values represent unadjusted means and SE. Borm and Mannaerts. Hum Reprod. 2000;15:1490.

  39. GnRH Antagonists Are Associated With More Favorable Outcomes vs GnRH Agonists Among Women at High Risk for OHSS Investigator-driven, prospective observational study of women (N=87) at high risk for OHSS, who were treated with a GnRH antagonist protocol following a previous cycle with a GnRH agonist protocol P=0.003 P<0.001 P<0.001 Percent P=0.006 Ragni et al. Hum Reprod. 2005;20:2421.

  40. Endometrial abnormalities in stimulated cycles • Advanced endometrial maturation by 2-4 days • This effect not seen if frozen embryos transferred in natural cycle.

  41. Antagonist vsLong GnRH Agonist: Effects on the Endometrium • No relevant alteration in endometrial thickness • Endometrial dating, estrogen and progesterone receptor expression, and endometrial surface structure were unaffected • Agonist was associated with indications of an arrest in endometrial development • Expression of “window of implantation” genes with antagonist treatment more closely paralleled the pattern observed during a natural cycle compared with agonist Simon et al. Hum Reprod. 2005;20:3318.

  42. Best Practices for GnRH Antagonist Protocols: Evidence Does Not Support Supplementation of LH Activity Bosch et al1 Meta-analysis2 P=0.61 P=NS Ongoing pregnancy rate (%) Ongoing pregnancy rate (%) hMG recFSH recFSH + rLH recFSH 1. Bosch et al. Hum Reprod. 2008;23:2346.2. Baruffi et al. Reprod Biomed Online. 2007;14:14.

  43. GnRH Antagonist Strategy Is Associated With a Lower Dropout Rate vs Long GnRH Agonist Strategy Continuation of therapy following each cycle GnRH antagonist plus SET GnRH agonist plus DET 95.9% 88.3% 93.7% Likelihood of continuing therapy (%) 78.6% 75.9% P=0.034 Cycle number SET = single embryo transfer; DET = double embryo transfer. Adapted from Verberg et al. Hum Reprod. 2008;23:2050.

  44. GnRH Antagonist and Long GnRH AgonistStrategies Result in ComparableCumulative Pregnancy Rates Proportion of pregnancies leading to cumulativeterm live birth within 12 months after starting IVF GnRH agonist with DET GnRH antagonist with SET % of pregnancies leading to term live birth Singleton term live birth Months since randomization Adapted from Heijnen et al. Lancet. 2007;369:743.

  45. GnRH Antagonist and GnRH Agonist Strategies Result in Shorter Treatment, Better Safety, and Lower Cost Heijnen et al. Lancet. 2007;369:743.

  46. The low dose protocol • Indication - PCOS patients • Start with 37.5u rFSH • Scan after a week • If no improvement increase by 37.5 • Maintain dose if dominant follicle grows • Trigger with agonist

  47. Low dose FSH protocol • Weekly increment if no increase in size 107 75 37.5 u

  48. CC- D2- D5 days • D6 HMG/FSH 50-150 u /day • Lead follicle 13mm, or 6 follicles of 1.2,E2 400ng • Add antagonist 0.25mgm/day • Follicle – 17mm • Trigger -1mgm of agonist/HCG 5000iu • IUI or ART 36 hrs later Cardone FS2003

  49. Newer forms of isomers. • it is unlikely that isoforms of FSH with half-lives longer than present preparations would have much clinical application except for stimulation of spermatogenesis. For induction of ovulation, a range of products with relatively short half-lives would permit more sensitive manipulation of the therapeutic dose and facilitate achieving mono-ovulation. The current preparations of FSH are likely to continue to dominate clinical use for ovarian stimulation prior to IVF.

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