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OPTIMIZATION OF STIMULATION PROTOCOLS IN PCOS PATIENTS

OPTIMIZATION OF STIMULATION PROTOCOLS IN PCOS PATIENTS. Dr Hakan ÖZÖRNEK. OHSS. OHSS is a serious, potentially life-threatening, iatrogenic complication of “ controlled ” ovarian stimulation.

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OPTIMIZATION OF STIMULATION PROTOCOLS IN PCOS PATIENTS

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  1. OPTIMIZATION OF STIMULATION PROTOCOLS IN PCOS PATIENTS Dr Hakan ÖZÖRNEK

  2. OHSS • OHSS is a serious, potentially life-threatening, iatrogenic complication of “controlled”ovarian stimulation. • To optimize the ovarian response without provoking OHSS is the best compromise that should be reached by an ideal regimen of stimulation, which is unfortunately still not consistently achievable.

  3. PCO - OHSS • PCO-like ovarian ultrasound features (more than 10 follicles) are a predictive factor for OHSS in IVF. • Increased risk for OHSS in patients with a LH/FSH ratio of more than 2. • The incidence of OHSS in PCOS patients is 6% Tibi, 1989 Delvigne, Human Reprod 1993 Brinsden, Br J Obstet Gynecol 1995

  4. Clomiphen citrate • Nonstimulated – natural cycle • Low dose gonadotropin protocols • Agonist • Antagonist • Trigger the ovulation • Luteal phase support • Metformin • IVM • Coasting

  5. Naturel cycle • Patients with PCOS are unlikely to benefit from this procedure since their success in development of a single follicle leading to the retrieval of a single, good quality oocyte during a spontaneous cycle remains uncertain.

  6. CC • Ovulation is restored in 80%, but pregnancy is achieved in 35% of patients • 75% of the pregnancies occur within the first three cycles of CC treatment • 20-25% of PCOS patients remain resistant to CC • CC is rarely associated with severe OHSS Imani, Fertil Steril 2002 Gysler, Fertil Steril 1982 Kistner, Obstet Gynecol Surv 1965

  7. Which gonadotropin? • Two reviews from The Cochrane Library on clinical trials investigating gonadotropin therapy for ovulation induction in women with clomipheneresistant PCOS, concluded that no significant benefit could be demonstrated from urinary FSH versus hMG in terms of pregnancy rate, but a significant reduction in OHSS associated with FSH was observed. Hughes 1997, Nugent 2002

  8. Which gonadotropin? • Early reports suggested a relationship between the type of gonadotropin preparation utilized and the risk of OHSS. More recent comparisons between recombinant follicle-stimulating hormone (rFSH) and human menopausal gonadotropins (hMG) did not show significant differences among variable drug regimens.

  9. Which gonadotropin? • The clinical pregnancy rates per cycle started were higher with rFSH than uFSH, although the magnitude of the observed difference was small, 3.7%. No significant differences were detected in the rates of miscarriage, multiple pregnancy and OHSS. European and Middle East Orgalutran Study Group, Human Reprod 2001

  10. Which protocol? • During cycles without GnRH-a suppression, either a significant LH surge or at least marked luteinization will limit continued gonadotropin stimulation and thus lead to a concomitantly lower risk of OHSS.

  11. Which protocol? • FIVNAT results showed that the use of GnRH-a led to significantly higher preovulatoryestradiol concentrations, and to more frequent severe hyperstimulation (4.6% vs. 0.6% for nonGnRH-a/hMGcycles). FIVNAT, Contracept Fertil Sex 1989

  12. How to use agonist? • The type of GnRH agonist to be used in patients at risk of OHSS has not been extensively studied. It is obvious that the short protocol should not be proposed, as the initial flare-up effect could lead to an excessive ovarian response. • In the long protocol, depot formulation versus daily injection and follicular versus luteal start have not been compared prospectively in patients at risk of OHSS.

  13. Which protocol? • It has been proposed that a longer period of desensitization (30 instead of 15 days) is of benefit by reducing androgen levels. • The longer duration of treatment did not improve pregnancy rates but did apparently decrease the incidence of hyperstimulation. Salat-Baroux, Human Reprod 1988

  14. Why antagonist? • Patients receiving antagonist treatment have lower estradiol serum levels at the time of hCG administration, mostly because of a lower number of follicles, which could explain the lower incidence of OHSS. Ludwig M, Arch Gynecol Obstet 2000

  15. Which protocol? • There was a statistically significant reduction in incidence of severe OHSS with antagonist protocol. The relative risk ratio was 0.61 (P=0.01; 95% CI 0.42 -0.89). • In addition, interventions to prevent OHSS (e.g. coasting, cycle cancellation) were administered more frequently in the agonist group (P=0.03; OR 0.44, 95% CI 0.21 -0.93). Al-Inany, Cochrane Database 2006

  16. Which protocol? • The GnRH-antagonist protocol involved starting gonadotropins on day 3 of the menstrual cycle. Transvaginal ultrasound monitoring was commenced on day 5 of ovarian stimulation and repeated every 2-3 days.

  17. Antagonist protocol USG HCG USG 300 IU 225 IU 150 IU Antagonist (start at 6th day) 3th day 12th day 7th day

  18. Which dose? • The starting dose for gonadotropin is based on • age, • body mass index (BMI) • existence of PCOS, • previous history of OHSS or high response.

  19. Which protocol? • Two comparative prospective studies of the conventional regimen, with the chronic low-dose step-up protocol using urinary FSH or rhFSH for ovulation induction in PCOS patients, showed that the low-dose approach eliminated complications of OHSS and multiple pregnancies without jeopardizing the incidence of pregnancy. Homburg, Fertil Steril 1995 Hedon, Human Reprod 1998

  20. Classic step up protocol USG HCG USG 300 IU 225 IU Mid luteal 150 IU Agonist 3th day 12th day 7th day

  21. Low dose step up protocol HCG USG 150 IU 75 IU Agonist Mid luteal 3th day 7th day

  22. Chronic low dose step up protocol USG USG 150 IU 112.5 IU 75 IU 3th day 14th day 21st day

  23. Which protocol? • The step-down protocol applies decremental doses of gonadotropins once ovarian response is established, but the starting dose is higher than in the step-up approach. • Monitoring of follicular growth is, however, more stringent than with the step-up approach. In addition, the long half-life of currently available FSH preparations makes it difficult to judge the correct reduction of dose. • Clinical results are similar to those obtained with the step-up approach. van Santbrink, Human Reprod 1995

  24. Step down protocol USG 300 IU HCG 150 IU Agonist 6th day Mid luteal 3th day

  25. Which protocol? • Unlike a step-up protocol, which continuously rescues follicles from atresia, a step-down protocol will allow more follicles to undergo atresia, thus reducing the overall number of follicles capable of secretory activity by the time hCG is administered.

  26. Which protocol? • An alternative method for ovulation induction with FSH in PCOS patients is the so-called sequential protocol, which combines an initial step-up gonadotropin administration followed by a step-down regimen after follicular selection (leading follicle > 14 mm). In a comparative study with the standard low-dose step-up regimen, both approaches were shown to be safe and effective. Hugues, Human Reprod 1996

  27. Low dose HCG • More recently, Filicori et al. proposed conducting the end of stimulation using a treatment composed of low-dose hCG. Low-dose hCG as a source of LH activity was associated with FSH or was used alone in the second part of the follicular phase. Filicori, Human Reprod Update 2002

  28. Low dose HCG Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in vitro fertilization: a prospective, randomised trial Serafini, et al, Fertil Steril 2006

  29. Low dose HCG Ovarian stimulation with daily late follicular phase administration of low-dose human chorionic gonadotropin for in vitro fertilization: a prospective, randomised trial Serafini, et al, Fertil Steril 2006

  30. Monitoring • Use a combination of frequent serum estradiol measurements and ultrasonographic assessments of follicular growth.

  31. How to trigger the ovulation? • Decrease in hCGdose • 10.000 IU vs. 5.000 IU or 3.000 IU no difference • The use of GnRH antagonists could further decrease the incidence of OHSS in high-risk patients when replacing hCG by a GnRH agonist to trigger ovulation. • A recent prospective study found a lower pregnancy rate in patients in whom GnRH agonists were used to trigger ovulation.

  32. How to trigger the ovulation? • There was no statistically significant difference between rhCGvsuhCG regarding the incidence of OHSS. • A multicenter double-blind study revealed that new recombinant human LH can be as effective as hCG in inducing the final follicular maturation in IVF treatment with a lower incidence of OHSS. Al-Inany, Cochrane Database 2005 European Recombinant LH Study Group 2001

  33. Luteal phase support • The odds of OHSS were more than 2-fold higher with treatments involving hCG than with progesterone alone (OR 3.06, 95% CI 1.59 to 5.86). • Comparing routes of progesterone administration, reductions in clinical pregnancy rate with the oral route, compared to the intramuscular or vaginal routes, did not reach statistical significance, but there was evidence of benefit of the intramuscular over the vaginal route for the outcomes of ongoing pregnancy and live birth. Daya, Gunby, Cochrane Database 2004

  34. IVM • Due to the abundance of follicles in the ovary, PCOS patients present an excellent clinical opportunity for the retrieval of unstimulated immature eggs and do In Vitro Maturation.

  35. IVM • The immature oocytes are retrieved from antral follicles of unstimulated (or minimally stimulated) ovaries via the transvaginal approach. • The oocytes are subsequently matured in vitro in a special formulated culture medium for 24-48 h. The mature oocytes are fertilized, usually by intracytoplasmic sperm injection (ICSI), and the selected embryos are transferred to the uterus 2-3 days later.

  36. IVM • Because no expensive gonadotropin stimulation and no extensive monitoring scans are required, the cost of IVM treatment is lower than that of IVF. • The IVM treatment schedule is shorter, causing less stress, and it is not necessary to wait for 2 to 3 months between treatment cycles because no stimulation is involved. The risk of OHSS can be avoided by IVM treatment, especially in women with PCO/PCOS. Child, Obstet Gynecol 2002

  37. IVM Tan SL, et al. In vitro Maturation of Human Oocytes, 2007

  38. IVM • Clinical pregnancy rate 35% per cycle • Implantation rate 15% per embryo Al-Sunaidi, Fertil Steril 2007

  39. Metformin • Metformin has been studied and mostly shown to restore menstrual cycles and confirm ovulation in anywhere between 25 - 90% of cases. • A recent analysis of 13 randomized controlled trials showed that metformin increased the ovulation rate almost four times compared to placebo when it was administered in combination with clomiphene citrate.

  40. Metformin Khattab, ReprodBiomed Online, 2006

  41. Metformin * p< 0.05 Tang, Human Reprod, 2006

  42. Coasting • FirstdescribedandappliedbySher et al in 1993 • hCGadministrationpostponeduntilthepatients serum E2 leveldecreasesto a safer zone. • E2 levels usually rise rapidly in the 48 h following initiation of the coasting period, then plateaued and began to fall 96-168 h after the gonadotropins were stopped.

  43. Coasting • Cochranereviewidentified 13 studies of whichonlyonetrial met theinclusioncriteria. • Therewas no difference in theincidence of moderateand severe OHSS and in theclinicalpregnancy rate betweenthegroups. D’Angelo et al., CochraneLibrary, 2002

  44. Coasting • A recent review of ten studies showed that < 2% of women developed OHSS while maintaining acceptable pregnancyrates (36.5-63%) when coasting was continued until serum estradiol levels fell below 3000 pg/ml. Levinson-Tavor, Human Reprod 2003

  45. Coasting studies (Garcia-Velasco, et al,Fertil Steril, 2006) 34/1624 0.02%

  46. Coastingduration Mansour, et al., Fertil Steril, 2005

  47. Coasting • Coasting is a goodalternativethat can avoidcyclecancellation in highresponders, whohavehigh risk of developing severe OHSS • Evenif OHSS developsaftercoastingbothitsincidenceandseveritywill be diminished

  48. Conclusion • No one gonadotropin is superior to others for reducing the incidence of OHSS • Antagonist-low dose step up is the best protocol available • Monitoring of the E2 and USG of follicles is crucial • Luteal phase support with hCG increases the incidence of OHSS. • Progesterone intravaginally or i.m. should be used for the patients at risk of OHSS

  49. Conclusion • IVM is a novel method and must be developed for better results • Coasting is an effective method for preventing severe OHSS • No method has been developed that will completely prevent severe OHSS after ovarian stimulation.

  50. OHSS rate???

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