Luteal Phase Support Luteal Phase Support in ART Cyclesin ART Cycles

Hsin-Yang LiHsin-Yang LiOB/GYN Dept.,OB/GYN Dept.,

Taipei Veterans General HospitalTaipei Veterans General Hospital

Luteal Phase Support Luteal Phase Support in ART Cyclesin ART Cycles

Why is luteal phase support needed in ARWhy is luteal phase support needed in ART cycles?T cycles?

What are the important elements of luteal What are the important elements of luteal phase support? An evidence-based approphase support? An evidence-based approach.ach.

Promising methods to improve embryo imPromising methods to improve embryo implantation rates of ART that await more eviplantation rates of ART that await more evidence.dence.

Multi-follicular Ovarian Stimulation Oocyte Recovery

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

Ovarian Stimulation in Assisted Reproductive Technology (ART) to Obtain Multiple Oocytes

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

(Textbook of ART, 2nd Ed., 2004; Semin. Reprod. Med., 2002 )

Two Commonly Used Ovarian Stimulation Protocols

(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

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

Abnormal Luteal Function After Abnormal Luteal Function After Ovarian Stimulation for IVF: MechanismsOvarian Stimulation for IVF: Mechanisms

Continued down-regulation by GnRHaContinued down-regulation by GnRHa LH LH

Induction of multiple follicles Induction of multiple follicles per seper seRemoval of large quantities of granulosa cRemoval of large quantities of granulosa c

ells at oocyte retrievalells at oocyte retrievalSupraphysiological E2/P4Supraphysiological E2/P4 in early luteal in early luteal

phase phase negative feedback negative feedback LH LH

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

The luteal phase is also defective in GnRHant cotreated ovarianstimulation for IVF. Luteolysis started prematurely due to negative feedback. Luteal phase support remains mandatory for ovarian stimulation with GnRHant cotreatment in ART cycles.

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

Timing of Luteal Support1. Starting P4 at d3 after OR: better pregnancy rate than starting at d6 after OR2. 4-5 days of P4 therapy before ET is best for pregnancy3. Suggestion: P4 supplement beginning on the day of OR and continuing till 7-10 wks GA

Elements of Luteal Phase SupportElements of Luteal Phase Support

HCG: 1500-2000 IU i.m. q3d for 4 doses froHCG: 1500-2000 IU i.m. q3d for 4 doses from oocyte retrievalm oocyte retrieval

P4: from oocyte retrieval to 7-10 weeks P4: from oocyte retrieval to 7-10 weeks 1) progesterone i 1) progesterone in oil 25-100 mg i.m. qd 2) utrogestan oil 25-100 mg i.m. qd 2) utrogestan 200 mg p.o. or vag. tid-qid 3) Crinon 200 mg p.o. or vag. tid-qid 3) Crinone gel 90 mg vag. qdne gel 90 mg vag. qd

E2: from oocyte retrieval to 7-10 weeks E2: from oocyte retrieval to 7-10 weeks E2 valerate 2 mg p.o. bid E2 valerate 2 mg p.o. bid

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; Serum P4 levels well above the physiological range; painful, sterile abscess and allergic responsepainful, sterile abscess and allergic response

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

Routes of P4 Support

(Cocrane Rev., 2004)

Pregnancy rate: I.M. P4 > Vag. P4 > Oral P4

(Cocrane Rev., 2004)

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.

(CocraneRev., 2004)

Possible Roles of NSAID in ARTPossible Roles of NSAID in ART

Low dose aspirin Low dose aspirin TXA TXA22/PGI/PGI22 vasodilatation and decreased platelet vasodilatation and decreased platelet aggregationaggregation increased ovarian and increased ovarian and endometrial endometrial blood flowblood flow ovarian ovarian responsiveness, responsiveness, endometrial thickness, endometrial thickness, implantation rateimplantation rate

NSAID may NSAID may decrease uterine contractiondecrease uterine contraction at at the time of ETthe time of ET

The results of randomized controlled trials are The results of randomized controlled trials are controversial. controversial.

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.

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 ETdid not improve pregnancy rates in pregnancy rates in oocyte recipients

Prednisolone 10 mg/d and aspirin 81 mg/d from stimulation D1may 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 inAPA- or ANA-positive patients with IVF implantation failure.

Possible Roles of Viagra (sildenafil) in ART:1. Improve uterine artery blood flow2. Improve endometrial thickness3. Increase embryo implantation rates

(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.

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.

Possible Roles of GnRHa in EnhanPossible Roles of GnRHa in Enhancing Embryo Implantationcing Embryo Implantation

Inadvertent GnRHa administration in the luteal pInadvertent GnRHa administration in the luteal phase does not compromise pregnancy but rather hase does not compromise pregnancy but rather seems to seems to improve implantationimprove implantation

GnRH receptorGnRH receptor is expressed in the human is expressed in the human preipreimplantation embryos, endometrium, and cormplantation embryos, endometrium, and corpus luteumpus luteum, implicating a , implicating a directdirect effect of GnRH effect of GnRHa on the these targetsa on the these targets

GnRHa has been shown to stimulate GnRHa has been shown to stimulate trophoblatrophoblast production of hCGst 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)

1 21 MC

2

FSH + HMG

HCG

GnRHa ICSIPlacebo or

GnRHa

ICSI + 6 d

HCGET

ICSI + 3 d

E2 4 mg po + Utrogestan 400 mg Vag. qd

Beneficial Effect of Luteal-phase GnRHa on Embryo Implantationin 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

Beneficial Effect of Luteal-phase GnRHa on Embryo Implantationin GnRHant-treated Ovarian Stimulation Cycles

1 21 MC

2

FSH + HMG

HCG

GnRHant ICSI

Placebo orGnRHa

ICSI + 6 d

HCGET

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)

ConclusionConclusion Abnormal luteal function after ovarian stimulation in Abnormal luteal function after ovarian stimulation in

ART is probably due to ART is probably due to LH suppression by suprapLH suppression by supraphysiologic ovarian steroidshysiologic ovarian steroids

Patients not at risk of OHSS: hCG + Patients not at risk of OHSS: hCG + vaginalvaginal or i.m. or i.m. P4P4

Patients at risk of OHSS (E2>3000 pg/ml or follicles Patients at risk of OHSS (E2>3000 pg/ml or follicles > 15): vaginal or > 15): vaginal or i.m.i.m. P4 P4

Thin endometrium and adequate E2 on stimulation Thin endometrium and adequate E2 on stimulation D7-8: consider use of aspirin or viagra till hCG dayD7-8: consider use of aspirin or viagra till hCG day

Patients with multiple failures of ART despite adequPatients with multiple failures of ART despite adequate follicular development and embryo quality: consiate follicular development and embryo quality: consider aspirin and viagra from stimulation D1 and GnRder aspirin and viagra from stimulation D1 and GnRHa in the mid-luteal phase Ha in the mid-luteal phase