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Luteal Phase Support in ART Cycles Hsin-Yang Li OB/GYN Dept., Taipei Veterans General Hospital.

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Presentation on theme: "Luteal Phase Support in ART Cycles Hsin-Yang Li OB/GYN Dept., Taipei Veterans General Hospital."— Presentation transcript:

1 Luteal Phase Support in ART Cycles Hsin-Yang Li OB/GYN Dept., Taipei Veterans General Hospital

2 Luteal Phase Support in ART Cycles Why is luteal phase support needed 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. 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. Promising methods to improve embryo implantation rates of ART that await more evidence.

3 Multi-follicular Ovarian Stimulation Oocyte Recovery (Textbook of ART, 2nd Ed., 2004) Ovarian Stimulation in Assisted Reproductive Technology (ART) to Obtain Multiple Oocytes

4 (Textbook of ART, 2nd Ed., 2004)

5 (Textbook of ART, 2nd Ed., 2004; Semin. Reprod. Med., 2002 ) Two Commonly Used Ovarian Stimulation Protocols

6

7 (Hum. Reprod., 2001; Trends Endocrinol. Metabol., 2004) Ovarian hyperstimulation is associated with endometrial advancement in early luteal phase and endometrial delay in mid-luteal phase

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  Continued down-regulation by GnRHa  LH  Induction of multiple follicles per se Induction of multiple follicles per se Removal of large quantities of granulosa cells at oocyte retrieval Removal of large quantities of granulosa cells at oocyte retrieval Supraphysiological E2/P4 in early luteal phase  negative feedback  LH  Supraphysiological E2/P4 in early luteal phase  negative feedback  LH 

10 (J. Clin. Endocrinol. Metab., 2003) The luteal phase is also defective in GnRHant cotreated ovarian stimulation for IVF. Luteolysis started prematurely due to negative feedback. Luteal phase support remains mandatory for ovarian stimulation with GnRHant cotreatment in ART cycles.

11 (Textbook of ART, 2nd Ed., 2004) Timing of Luteal Support 1.Starting P4 at d3 after OR: better pregnancy rate than starting at d6 after OR days of P4 therapy before ET is best for pregnancy 3. Suggestion: P4 supplement beginning on the day of OR and continuing till 7-10 wks GA

12 Elements of Luteal Phase Support HCG: IU i.m. q3d for 4 doses from oocyte retrieval HCG: IU i.m. q3d for 4 doses from oocyte retrieval P4: from oocyte retrieval to 7-10 weeks 1) progesterone in oil mg i.m. qd 2) utrogestan 200 mg p.o. or vag. tid-qid 3) Crinone gel 90 mg vag. qd P4: from oocyte retrieval to 7-10 weeks 1) progesterone in oil mg i.m. qd 2) utrogestan 200 mg p.o. or vag. tid-qid 3) Crinone gel 90 mg vag. qd E2: from oocyte retrieval to 7-10 weeks E2 valerate 2 mg p.o. bid E2: from oocyte retrieval to 7-10 weeks E2 valerate 2 mg p.o. bid

13 Oral route: Only 10% of the oral dose of P4 circulates as active P4 because of the first pass effect; dizziness Vaginal Route: “Targeted drug delivery” from vagina to uterus, better endometrial histology; vaginal discharge Serum P4 levels well above the physiological range; Intramuscular route: Serum P4 levels well above the physiological range; painful, sterile abscess and allergic response painful, sterile abscess and allergic response (Textbook of ART, 2nd Ed., 2004) Routes of P4 Support

14 (Cocrane Rev., 2004)

15 Pregnancy rate: I.M. P4 > Vag. P4 > Oral P4 (Cocrane Rev., 2004)

16 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.

18 (Cocrane Rev., 2004)

19 Possible Roles of NSAID in ART Low dose aspirin   TXA 2 /PGI 2  vasodilatation and decreased platelet aggregation  increased ovarian and endometrial blood flow   ovarian responsiveness,  endometrial thickness,  implantation rate Low dose aspirin   TXA 2 /PGI 2  vasodilatation and decreased platelet aggregation  increased ovarian and endometrial blood flow   ovarian responsiveness,  endometrial thickness,  implantation rate NSAID may decrease uterine contraction at the time of ET NSAID may decrease uterine contraction at the time of ET The results of randomized controlled trials are controversial. The results of randomized controlled trials are controversial.

20 Low-dose aspirin (100 mg/d from stimulation D1) does not improve ovarian responsiveness and pregnancy rates in IVF/ICSI patients. (Hum. Reprod., 2005) Low-dose aspirin (100 mg/d from GnRHa D1) significantly improves ovarian responsiveness, blood flow, and pregnancy rates in IVF patients.

21 An oral dose 10 mg piroxicam 1-2 h before ET significantly improves pregnancy rates Indomethacin 100 mg q12h rectally for 3 doses from the night before ET did not improve pregnancy rates in pregnancy rates in oocyte recipients

22 Prednisolone 10 mg/d and aspirin 81 mg/d from stimulation D1 may increase pregnancy rates in patients with ANA and/or APA Heparin 5000 IU bid and aspirin 100 mg/day from the day of ET did not improve pregnancy or implantation rates in APA- or ANA-positive patients with IVF implantation failure.

23 Possible Roles of Viagra (sildenafil) in ART: 1.Improve uterine artery blood flow 2.Improve endometrial thickness 3.Increase embryo implantation rates

24 (G. Sher, Fertil. Steril., 2002) 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.

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 D3 to the evening before oocyte retrieval. Endometrial thickness increased significantly 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 implantation Inadvertent GnRHa administration in the luteal phase does not compromise pregnancy but rather seems to improve implantation GnRH receptor is expressed in the human preimplantation embryos, endometrium, and corpus luteum, implicating a direct effect of GnRHa on the these targets GnRH receptor is expressed in the human preimplantation embryos, endometrium, and corpus luteum, implicating a direct effect of GnRHa on the these targets GnRHa has been shown to stimulate trophoblast production of hCG. GnRHa 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)

28 121 MCMC 2 FSH + HMG HCGHCG GnRHaICSI Placebo or GnRHa ICSI + 6 d HCG ET ICSI + 3 d E2 4 mg po + Utrogestan 400 mg Vag. qd Beneficial Effect of Luteal-phase GnRHa on Embryo Implantation in GnRHa-treated Ovarian Stimulation Cycles (Hum. Reprod., 2006) Luteal-phase GnRHa (Triptorelin 0.1 mg 6 d after ICSI) enhances embryo implantation and live birth rates

29 Beneficial Effect of Luteal-phase GnRHa on Embryo Implantation in GnRHant-treated Ovarian Stimulation Cycles 121 MCMC 2 FSH + HMG HCGHCG GnRH ant ICSI Placebo or GnRHa ICSI + 6 d HCG ET ICSI + 3 d E2 4 mg po + Utrogestan 400 mg Vag. qd 6 Oral pill Luteal-phase GnRHa (Triptorelin 0.1 mg 6 d after ICSI) enhances embryo implantation and live birth rates (Hum. Reprod., 2006)

30 Conclusion Abnormal luteal function after ovarian stimulation in ART is probably due to LH suppression by supraphysiologic ovarian steroids Abnormal luteal function after ovarian stimulation in ART is probably due to LH suppression by supraphysiologic ovarian steroids Patients not at risk of OHSS: hCG + vaginal or i.m. P4 Patients not at risk of OHSS: hCG + vaginal or i.m. P4 Patients at risk of OHSS (E2>3000 pg/ml or follicles > 15): vaginal or i.m. P4 Patients at risk of OHSS (E2>3000 pg/ml or follicles > 15): vaginal or i.m. P4 Thin endometrium and adequate E2 on stimulation D7-8: consider use of aspirin or viagra till hCG day Thin endometrium and adequate E2 on stimulation D7-8: consider use of aspirin or viagra till hCG day Patients 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 Patients 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


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