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

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.

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

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

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

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

Pregnancy rates are significantly reduced in GnRHa ovarian stimulation without luteal phase support

Abnormal Luteal Function After Ovarian Stimulation for IVF: Mechanisms Continued down-regulation by GnRHa  LH  Induction of multiple follicles per se Removal of large quantities of granulosa cells at oocyte retrieval Supraphysiological E2/P4 in early luteal phase  negative feedback  LH 

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. (J. Clin. Endocrinol. Metab., 2003)

Timing of Luteal Support Starting P4 at d3 after OR: better pregnancy rate than starting at d6 after OR 2. 4-5 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 (Textbook of ART, 2nd Ed., 2004)

Elements of Luteal Phase Support HCG: 1500-2000 IU i.m. q3d for 4 doses from oocyte retrieval P4: from oocyte retrieval to 7-10 weeks 1) progesterone in oil 25-100 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

Routes of P4 Support 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 Intramuscular route: Serum P4 levels well above the physiological range; painful, sterile abscess and allergic response (Textbook of ART, 2nd Ed., 2004)

(Cocrane Rev., 2004)

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

(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 life Lower pt. to pt. variability (Textbook of ART, 2nd Ed., 2004; Cocrane Rev., 2004)

The addition of E2 to progesterone in the luteal phase does not enhance the probability of pregnancy.

(Cocrane Rev., 2004)

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 rate NSAID may decrease uterine contraction at the time of ET The results of randomized controlled trials are controversial.

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)

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

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. Prednisolone 10 mg/d and aspirin 81 mg/d from stimulation D1 may increase pregnancy rates in patients with ANA and/or APA

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

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)

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.

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 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.

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)

Beneficial Effect of Luteal-phase GnRHa on Embryo Implantation in GnRHa-treated Ovarian Stimulation Cycles HCG ET Placebo or GnRHa GnRHa ICSI FSH + HMG M C H C G ICSI + 3 d ICSI + 6 d 1 21 2 E2 4 mg po + Utrogestan 400 mg Vag. qd Luteal-phase GnRHa (Triptorelin 0.1 mg 6 d after ICSI) enhances embryo implantation and live birth rates (Hum. Reprod., 2006)

Beneficial Effect of Luteal-phase GnRHa on Embryo Implantation in GnRHant-treated Ovarian Stimulation Cycles HCG ET Placebo or GnRHa GnRH ant Oral pill ICSI FSH + HMG 1 21 M C 2 6 H C G ICSI + 3 d ICSI + 6 d E2 4 mg po + Utrogestan 400 mg Vag. qd Luteal-phase GnRHa (Triptorelin 0.1 mg 6 d after ICSI) enhances embryo implantation and live birth rates (Hum. Reprod., 2006)

Conclusion 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 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 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