Luteal phase support in art - revisited
- 1. LUTEAL PHASE SUPPORT IN ART -- REVISITED Dr. Jyoti Bhaskar MD MRCOG Director - LIFECARE IVF Consultant – Pushpanjali Crosslay Hospital Lifecare Centre
- 2. ∗ LPD - 5 - 10 % ∗ Unexplained infertility - 15- 20 % ∗ A large fraction of unexplained infertility may be because of LPD which is difficult to diagnose ∗ Recurrent pregnancy loss – 8 -12 % ∗ 40% of women with recurrent pregnancy loss may be having LPD HARD FACTS
- 3. ∗ What is LPD? ∗ Why is luteal support required ? ∗ Who requires the support ? ∗ What are the options? ∗ Which route ? ∗ How much & how long ? OVERVIEW
- 4. Inadequate Endometrial Maturation due to Qualitative or Quantitative disorder in Corpus Luteum Function. LPD ------DEFINITION Decreased progesterone receptors in endometrium Inadequate Secretion of progesterone by Corpus luteum
- 5. Inadequate Luteal Phase Follicular Phase Secretory Phase Inadequate FSH secretion Abnormal Gonadotrophin pulses Defective Folliculogenesis Inadequate Estrogen Insufficient endometrial priming by estrogen Poor mid cycle LH surge Hyperprolactinemia Inadequate LH secretion Inadequate Progesterone receptors Defects in CL Decreased Progesterone synthesis Poor Secretory response
- 6. Lpd --- diagnosis PROBLEMATIC AND CONTROVERSIAL as No practical diagnostic method has been validated
- 7. LPD -- Diagnosis When the luteal phase is shorter than 12 days, it is usually treated BBT is a poor indicator of the quality of luteal phase and is therefore not an adequate diagnostic tool. Midluteal progesterone level of less than 10 ng/mL was considered to be abnormal, the probability of falsely diagnosing LPD was as low as 4%
- 8. SONOGRAPHIC CRITERIA ∗Rupture of follicle < 17 mm ∗Poorly formed or ill defined dominant follicle ∗Luteinised unruptured follicle ∗Lutein cyst formation ∗Absence of corpus luteum ∗Lack of endometrial echogenicity on 7th postovulatory day LPD -- Diagnosis
- 9. Endometrial biopsy ---- was GOLD STANDARD It is imprecise, invasive, not reproducible LPD -- Diagnosis Currently there is no reproducible, physiologically relevant and practically clinical standard test to diagnose LPD
- 10. Treatment ∗ Correction of underlying causes ∗ Emperical – supplemental progesterone, HCG or ovulation Induction with CC or gonadotrophins Ovulation induction strategies improve fertility by inducing multiple ovulation and not correcting LPD
- 11. ∗ Confirmed cases of luteal phase defect ∗ Unexplained infertility ∗ Advanced reproductive age ∗ ART techniques – IUI / IVF / ICSI ∗ Hyper- prolactinaemia ∗ All down regulated cycles ∗ Recurrent pregnancy loss ∗ PCOS ∗ Women with strenous exercises and underweight Who require luteal support ?
- 12. ∗ Supraphysiological estrogen levels may induce premature luteolysis ∗ Follicular phase downregulation may impair luteal phase LH release ∗ Pure FSH protocols lead to low LH values ∗ OPU causes granulosa cell disruption ∗ COH accelerates endometrial maturation ∗ To overcome any LPD if present Why in ART Cycles
- 13. Luteal Support : Drug ? ∗ PROGESTERONE ∗ Human Chorionic Gonadotropins ∗ Estrogen ∗ GnRH agonist
- 14. It should be luteomimatic and not luteolytic Micronized progesterone is the drug of choiceMicronized progesterone is the drug of choice Ideal Drug
- 17. Various routes Oral Intramuscular Vaginal Easy route Micronized form Only 10 % absorbs Not very effective. First hepatic pass Side effects like sedation & hypnosis P4 in oil base, Reliable & consistent n plasma level of P4 Rapidly absorb in 2-8 hrs. P4 level maintain for > 72 hrs. Difficult & very painful inj Local reaction & abscess. Non compliance by pt. Targeted organ delivery High conc. In ut & endometrium First uterine pass effect Mini systemic side effect Good Pt. compliance Self administration, no prick of needle
- 19. ∗ Immunomodulator ∗ High affinity for progesterone receptors ∗ Safe, well tolerated, non androgenic, less side effects ∗ Orally active at lower doses Oral Dydrogesterone Dose : 20 – 30 mg orally per day
- 20. When to start ? ∗ Not too early / not too late – both are detrimental ∗ Acceptable window 0f 24 – 48 hrs after oocyte retrieval / release ∗ From the same day of IUI dal preto et al , 2008 , fertil steril 2010 , fertil steril 2009
- 21. How much? ∗ 300-600 mg / day seen to provide same effect as with 90 mg of vaginal gel ∗ Vaginal Progesterone yields lower serum concentration but endometrial concentration is 30 fold greater than intramuscular. (Fert. Steril 1994) Most studies demonstrated equal efficacy involving 600 mg micronized vaginal progesterone
- 22. How long ? - Not established firmly - Often continued unnecessarily till 12 week - Most evidence based studies suggest to continue till 9 weeks gestation
- 23. Outcome of different studies remains controversial - Optimal route of administration has not been established - Equal number of studies support both vaginal & intramuscular route - Recent Cochrane review concluded that no significant difference between different routes.
- 24. ∗ Exact mechanism not known ∗ Single dose of 0.5 mg S/C on 6 th day after ICSI ∗ Increases implantation rate, CPR per transfer, increases live birth rate Single dose GnRH agonist Addition of GnRH agonist to progesterone improved outcome of live birth, clinical pregnancy and ongoing pregnancy -- Cochrane 2011
- 25. ∗ Most of the time, luteal cells are incompetent – HCG is not effective ∗ HCG supplementation is effective when specific defect of post ovulatory secretion of LH exists Why HCG is not an ideal choice? 10,000 iu for ovulation and then 2500 u every 3-4 days HCG associated with higher risk of OHSS – Avoid it ( Cochrane 2011)
- 26. Luteal phase support for assisted reproduction cycles COCHRANE 2011 ∗ Significant effect in favor of Progesterone ∗ (Dydrogeston) fares better than micronized progesterone ∗ No evidence favouring a specific route or duration of administration of progesterone. ∗ HCG, or hCG plus progesterone, was associated with a higher risk of OHSS. The use of hCG should therefore be avoided.
- 27. ∗ Benefit from addition of GnRH agonist to progesterone ∗ Overall, the addition of other substances such as estrogen or hCG did not seem to improve outcomes Progesterone seems to be the best option as luteal phase support,
- 28. Take Home Message ∗ Abnormal Luteal Phase may occur due to medical conditions – Thyroid and prolactin disorders . Infertile women should be investigated and treated appropriately. ∗ No diagnostic test for luteal Phase insufficiency has been proven to be reliable
- 29. Take home message ∗ No treatment for LPD has shown to improve pregnancy rates in unstimulated, natural cycles ∗ Identify patients who require luteal phase support. ∗ ALL PATIENTS OF ART NEED LUTEAL SUPPORT
- 30. Take Home Message ∗ VAGINAL progesterone is equally efficacious and better tolerated than I.M. preparations ∗ Adequate dosage must be prescribed to achieve better outcome
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