Luteal phase support in art cycles
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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.

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Luteal Phase Support in ART Cycles

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Luteal phase support in art cycles

Luteal Phase Support in ART Cycles

Hsin-Yang Li

OB/GYN Dept.,

Taipei Veterans General Hospital


Luteal phase support in art cycles1

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.


Luteal phase support in art cycles

Ovarian Stimulation in Assisted Reproductive Technology (ART)

to Obtain Multiple Oocytes

Multi-follicular Ovarian Stimulation

Oocyte Recovery

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


Luteal phase support in art cycles

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


Luteal phase support in art cycles

Two Commonly Used Ovarian Stimulation Protocols

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

Semin. Reprod. Med., 2002 )


Luteal phase support in art cycles

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)


Luteal phase support in art cycles

Pregnancy rates are significantly reduced in

GnRHa ovarian stimulation without luteal phase support


Abnormal luteal function after ovarian stimulation for ivf mechanisms

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 


Luteal phase support in art cycles

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)


Luteal phase support in art cycles

  • 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

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


Luteal phase support in art cycles

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)


Luteal phase support in art cycles

(Cocrane Rev., 2004)


Luteal phase support in art cycles

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

(Cocrane Rev., 2004)


Luteal phase support in art cycles

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)


Luteal phase support in art cycles

The addition of E2 to progesterone in the luteal phase

does not enhance the probability of pregnancy.


Luteal phase support in art cycles

(Cocrane

Rev., 2004)


Possible roles of nsaid in art

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.


Luteal phase support in art cycles

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)


Luteal phase support in art cycles

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


Luteal phase support in art cycles

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


Luteal phase support in art cycles

  • Possible Roles of Viagra (sildenafil) in ART:

  • Improve uterine artery blood flow

  • Improve endometrial thickness

  • Increase embryo implantation rates


Luteal phase support in art cycles

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)


Luteal phase support in art cycles

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

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.


Luteal phase support in art cycles

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)


Luteal phase support in art cycles

Beneficial Effect of Luteal-phase GnRHa on Embryo Implantation

in GnRHa-treated Ovarian Stimulation Cycles

Placebo or

GnRHa

HCG

ET

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)


Luteal phase support in art cycles

Beneficial Effect of Luteal-phase GnRHa on Embryo Implantation

in GnRHant-treated Ovarian Stimulation Cycles

Placebo or

GnRHa

HCG

ET

GnRH

ant

ICSI

Oral pill

FSH + HMG

M

C

H

C

G

ICSI

+

3 d

ICSI

+

6 d

1

21

2

6

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

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


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