Presentation on theme: "Luteal Phase Support in ART Cycles"— Presentation transcript:
1 Luteal Phase Support in ART Cycles Hsin-Yang LiOB/GYN Dept.,Taipei Veterans General Hospital
2 Luteal Phase Support in ART Cycles Why is luteal phase support needed in ART cycles?What are the important elements of luteal phase support? An evidence-based approach.Promising methods to improve embryo implantation rates of ART that await more evidence.
3 Ovarian Stimulation in Assisted Reproductive Technology (ART) to Obtain Multiple OocytesMulti-follicular Ovarian StimulationOocyte Recovery(Textbook of ART, 2nd Ed., 2004)
7 Ovarian hyperstimulation is associated with endometrial advancement in early luteal phase andendometrial delay in mid-luteal phase(Hum. Reprod., 2001; Trends Endocrinol. Metabol., 2004)
8 Pregnancy rates are significantly reduced in GnRHa ovarian stimulation without luteal phase support
9 Abnormal Luteal Function After Ovarian Stimulation for IVF: Mechanisms Continued down-regulation by GnRHa LH Induction of multiple follicles per seRemoval of large quantities of granulosa cells at oocyte retrievalSupraphysiological E2/P4 in early luteal phase negative feedback LH
10 The luteal phase is also defective in GnRHant cotreated ovarian stimulation for IVF. Luteolysis started prematurely due tonegative feedback. Luteal phase support remains mandatoryfor ovarian stimulation with GnRHant cotreatment in ART cycles.(J. Clin. Endocrinol. Metab., 2003)
11 Timing of Luteal Support Starting P4 at d3 after OR: better pregnancy rate than startingat d6 after ORdays of P4 therapy before ET is best for pregnancy3. Suggestion: P4 supplement beginning on the day of OR andcontinuing till 7-10 wks GA(Textbook of ART, 2nd Ed., 2004)
12 Elements of Luteal Phase Support HCG: IU i.m. q3d for 4 doses from oocyte retrievalP4: from oocyte retrieval to 7-10 weeks ) progesterone in oil mg i.m. qd ) utrogestan 200 mg p.o. or vag. tid-qid ) Crinone gel 90 mg vag. qdE2: from oocyte retrieval to 7-10 weeks E2 valerate 2 mg p.o. bid
13 Routes of P4 SupportOral route: Only 10% of the oral dose of P4 circulates as active P4because of the first pass effect; dizzinessVaginal Route: “Targeted drug delivery” from vagina to uterus, betterendometrial histology; vaginal dischargeIntramuscular route: Serum P4 levels well above the physiological range;painful, sterile abscess and allergic response(Textbook of ART, 2nd Ed., 2004)
16 (a bioadhesive vaginal gel containing 90 mg micronized P4) Crinone 8%: the first and only FDA-approved system for pregnancy support(a bioadhesive vaginal gel containing 90 mg micronized P4)Longer half lifeLower pt. to pt. variability(Textbook of ART, 2nd Ed., 2004; Cocrane Rev., 2004)
17 The addition of E2 to progesterone in the luteal phase does not enhance the probability of pregnancy.
19 Possible Roles of NSAID in ART Low dose aspirin TXA2/PGI2 vasodilatation and decreased platelet aggregation increased ovarian and endometrial blood flow ovarian responsiveness, endometrial thickness, implantation rateNSAID may decrease uterine contraction at the time of ETThe results of randomized controlled trials are controversial.
20 Low-dose aspirin (100 mg/d from GnRHa D1) significantly improves ovarian responsiveness, blood flow, and pregnancy rates in IVF patients.Low-dose aspirin (100 mg/d from stimulation D1) does not improve ovarian responsiveness and pregnancy rates in IVF/ICSI patients.(Hum. Reprod., 2005)
21 An oral dose 10 mg piroxicam 1-2 h before ET significantly improves pregnancy ratesIndomethacin 100 mg q12h rectally for 3 doses from the night before ETdid not improve pregnancy rates in pregnancy rates in oocyte recipients
22 Heparin 5000 IU bid and aspirin 100 mg/day from the day of ET did not improve pregnancy or implantation rates inAPA- or ANA-positive patients with IVF implantation failure.Prednisolone 10 mg/d and aspirin 81 mg/d from stimulation D1may increase pregnancy rates in patients with ANA and/or APA
23 Possible Roles of Viagra (sildenafil) in ART: Improve uterine artery blood flowImprove endometrial thicknessIncrease embryo implantation rates
24 105 infertile women aged < 40 years, with normal ovarian reserve and at least two consecutive prior IVF failures attributed to inadequate endometrial development (< 9 mm), were given viagra 25 mg qid vaginally from stimulation D1 to hCG day. Of 105 patients, 73 (70%; Group A) attained an endometrial thickness of 9 mm, whereas 32 (30%; Group B) did not.(G. Sher,Fertil. Steril.,2002)
25 10 patients with 1-7 failed cycles of ART and thin endometrium (< 8 mm) at previous ET were given viagra 25 mg qid vaginally from stimulation D3to the evening before oocyte retrieval. Endometrial thickness increasedsignificantly after viagra treatment. 3 of the 10 patients conceived.
26 Possible Roles of GnRHa in Enhancing Embryo Implantation Inadvertent GnRHa administration in the luteal phase does not compromise pregnancy but rather seems to improve implantationGnRH receptor is expressed in the human preimplantation embryos, endometrium, and corpus luteum, implicating a direct effect of GnRHa on the these targetsGnRHa has been shown to stimulate trophoblast production of hCG.
27 Oocytes from each donor were shared by two recipients, one of whom received a single dose of GnRHa (0.1 mg triptorelin) 6 days after ICSI,and the other received placebo at the same time.Recipient: pituitary down-regulation by GnRHa oral E2 valerate oral E2 valerate + vaginal utrogestan ( GnRHa 6 days after ICSI)GnRH agonist administration at the time of implantation enhances embryo developmental potential, probably by a direct effect on the embryo.(Hum. Reprod., 2004)
28 Beneficial Effect of Luteal-phase GnRHa on Embryo Implantation in GnRHa-treated Ovarian Stimulation CyclesHCGETPlacebo orGnRHaGnRHaICSIFSH + HMGMCHCGICSI+3 dICSI+6 d1212E2 4 mg po + Utrogestan400 mg Vag. qdLuteal-phase GnRHa(Triptorelin 0.1 mg 6 d after ICSI)enhances embryo implantationand live birth rates(Hum. Reprod., 2006)
29 Beneficial Effect of Luteal-phase GnRHa on Embryo Implantation in GnRHant-treated Ovarian Stimulation CyclesHCGETPlacebo orGnRHaGnRHantOral pillICSIFSH + HMG121MC26HCGICSI+3 dICSI+6 dE2 4 mg po + Utrogestan400 mg Vag. qdLuteal-phase GnRHa(Triptorelin 0.1 mg 6 d after ICSI)enhances embryo implantationand live birth rates(Hum. Reprod., 2006)
30 ConclusionAbnormal luteal function after ovarian stimulation in ART is probably due to LH suppression by supraphysiologic ovarian steroidsPatients not at risk of OHSS: hCG + vaginal or i.m. P4Patients at risk of OHSS (E2>3000 pg/ml or follicles > 15): vaginal or i.m. P4Thin endometrium and adequate E2 on stimulation D7-8: consider use of aspirin or viagra till hCG dayPatients with multiple failures of ART despite adequate follicular development and embryo quality: consider aspirin and viagra from stimulation D1 and GnRHa in the mid-luteal phase