Luteal phase support in IUI and ART | Dr. Laxmi Shrikhande | ShrikhandeIVF
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Dr. Laxmi Shrikhande, a prominent figure in reproductive health, discusses the complexities of luteal phase defects (LPD) and their management in infertility treatments. The document reviews various studies on luteal phase support (LPS) in natural and stimulated cycles, suggesting that LPS may not be beneficial in certain cases, particularly with clomiphene citrate. Conclusively, while some forms of LPS can improve outcomes in specific scenarios, the need for tailored approaches based on individual patient circumstances is emphasized.
![CC - Stimulated Cycles
Some authors reported luteal phase
inadequacy in up to 50% of clomiphene citrate
induced cycles in anovulatory women
[Cook et al.,1984,Keenan et al.,1989]](https://image.slidesharecdn.com/lutealphasesupportiniuiart-180606060655/85/Luteal-phase-support-in-IUI-and-ART-Dr-Laxmi-Shrikhande-ShrikhandeIVF-10-320.jpg)
Luteal phase support in IUI and ART | Dr. Laxmi Shrikhande | ShrikhandeIVF
- 1. Dr. Laxmi Shrikhande MD; FICOG; FICMCH;FICMU ▪ Director-Shrikhande Fertility Centre, Nagpur ▪ Senior Vice President FOGSI 2012 ▪ Associate member RCOG, London ▪ Member of European Society of Human Reproduction ▪ Received Bharat excellence Award for contribution to women’s health ▪ Chairperson HIV Committee FOGSI 2009-12 ▪ Received best FOGSI committee award ▪ National Editor-The Journal of OB / GY of India ▪ Vice Chairperson Elect Indian College of OB/GY ▪ Publications-Thirteen National & seven International ▪ Editor-FOGSI Focus on HIV in women ▪ Editor-FOGSI Focus on SUI- Myths & Facts ▪ Presented Papers at FIGO,SAFOG,AOFOG, IFFS
- 2. Luteal phase support in IUI and ART Dr Laxmi Shrikhande Director-Shrikhande Hospital & Research Centre, INDIA
- 3. “When a thing ceases to be a subject of controversy, it ceases to be a subject of interest.” William Hazlitt (1778–1830), English essayist
- 4. • Since the first formal description of LPD in 1949 as a possible cause of infertility and recurrent miscarriage by Jones, • innumerable investigations have been undertaken in an effort to verify its existence or to characterize its pathophysiology, diagnosis, and treatment. Jones GES: Some newer aspects of management of infertility. JAMA 141:1123, 1949
- 5. The consensus of the literature is that LPD does exist and that its cause is multifactorial- • abnormal folliculogenesis, • inadequate LH surge, • inadequate secretion of progesterone by the corpus luteum, • aberrant end-organ response by the endometrium
- 6. Scope • Is there any need for support in natural cycle / IUI / IVF cycles ? • What to give ? • When to give ? • What dose? • When to stop ?
- 7. Luteal phase in a natural cycle • Between ovulation and either pregnancy / menses • LH as the hormone to support corpus luteum and stimulate progesterone production • In ovulatory women, 92% of cycles show normal luteal function, and luteal support is unnecessary (Rosenberg et al., 1980).
- 8. Natural cycle IUI • Donor Inseminations • Cervical factor infertility • Mild/Moderate male factor infertility Luteal Phase support will unnecessarily increase the cost of the cycle without increasing the pregnancy rate.Thus not recommended
- 9. What happens to Luteal phase in stimulated cycles ▪ Multiple follicles of different size might ovulate at different times, expanding the fertilization window. ▪ Thus, both oestradiol and progesterone, after multiple ovulation is expected to be significantly higher (Macklon and Fauser, 2000). ▪ These high concentrations may not only influence the receptivity of the endometrium, but may also cause luteal insufficiency and early luteolysis (Erdem et al., 2008).
- 10. CC - Stimulated Cycles Some authors reported luteal phase inadequacy in up to 50% of clomiphene citrate induced cycles in anovulatory women [Cook et al.,1984,Keenan et al.,1989]
- 11. CC - Stimulated Cycles ▪ 400 women analysed ▪ No difference observed in ongoing pregnancy between patients who did, or did not, receive vaginal progesterone as luteal support [8.7% (17/196) versus 9.3% (19/204) ▪ Thus routine supplementation of the luteal phase with vaginal progesterone does not seem to improve pregnancy rates in normo-ovulatory women stimulated with clomiphene citrate for IUI Paul devroy, Human reproduction, vol 25, issue 10. pg 2501-2506
- 12. Studies favoring the luteal phase support in IUI • Montville et al -Fertil Steril. 2010 • Erdem et al – Fertil Steril. 2009 • Cohlen review - Reprod Biomed Online. 2009
- 13. Studies not favoring luteal phase support in IUI • Ebrahimy M.- 12th International Congress of Gynecology and Obstetrics 2010. • Kyrou D - Hum Reprod. 2010 • Bibi Shahnaz Aali, Iran J Reprod Med. Apr 2013 • Romero Nieto MI , Gynecol Endocrinol.2014
- 14. Luteal phase support after IUI Conclusion ➢ Progesterone luteal phase support may be of benefit to patients undergoing ovulation induction with gonadotropins in IUIcycles. ➢ Progesterone support did not benefit patients undergoing ovulation induction with CC, suggesting a potential difference in endogenous luteal phase function depending on the method of ovulation induction. Hill MJ Fertil Steril. 2013- a systematic review and meta-analysis.
- 15. LPS in IUI cycles • Shortened luteal phase in 20% of stimulated cycles for ovulation induction using FSH (Olson et al., 1983). • In a recent meta-analysis (Hill et al., FS, 2013) of 5 trials involving 1,938 cycles in 1,298 patients, LPS with P improves success. • Improvement seen in FSH cycles only but not in CC- induced cycles. OR (95% CI) Clinincal pregnancy 1.47 (1.15-1.98) Live birth 2.11 (1.21-3.67)
- 16. Luteal phase defect in IVF Reasons 1.Supra-physiological steroid concentrations secreted by multiple corpora lutea directly inhibit LH release (Fauser and Devroey, 2003) 2.HCG for the final oocyte maturation suppresses LH production (Miyake et al., 1979)
- 17. Luteal phase defect in IVF 3. GnRH agonist or antagonist for downregulation prevents LH rise in the luteal phase 4. Removal of large quantities of granulosa cells during oocyte retrieval
- 18. • hCG or progesterone improved pregnancy rates IVF cycles using GnRH agonist • OHSS in 5% of cycles with hCG • Conclusion: Routine use of luteal phase support in IVF cycles using GnRH agonist Meta-analysis of 18 trials
- 19. • 385 women were randomized into 3 groups hCG TUGOR ET (D3) No. of patients 130 128 127 Ongoing pregnancy rate 20.8% 22.7% 23.6%
- 20. IVF Period Egg retrieva l Embryo transfer Pregnancy tes Ovarian stimulation Antagonist GnRH agonist LUTEAL PHASE SUPPORT What? How long? When?
- 21. LPS in ART 1. Human chorionic gonadotrophin (hCG) 2. Progesterone: oral, intramuscular, vaginal 3. Progesterone and oestradiol 4. hCG and progesterone 5. Progesterone and GnRH agonist
- 22. hCG Vs Progesterone • No significant difference found between P and hCG or between P and P plus hCG in terms of pregnancy or miscarriage rates • Risk of OHSS significantly higher with treatments involving hCG than with P alone
- 23. Progesterone Vs HCG • Consensus opinion in favor of Progesterone ❖Once pregnancy is established – Supplemental hCG is not beneficial
- 24. Progesterone • Different routes of administration ❑Oral, intramuscular or vaginal
- 25. Oral progesterone • Reduced implantation rates when compared with hCG, IM and vaginal progesterone ▪ Poor bioavailability due to rapid hepatic metabolism (Maxson et al., 1984) ▪ Failure to induce uniform secretory changes in endometrium (Devroey et al., 1989; Critchley et al., 1990) • Metabolites induce significant sedative and hypnotic effects (Arafat et al., 1988)
- 26. Vaginal progesterone • Easy to administer • Avoids liver first-pass metabolism • No systemic side-effects • Higher endometrial tissue level despite low serum level due to ‘first uterine pass effect’ • Similar pregnancy rate as intramuscular progesterone
- 27. Vaginal progesterone • Associated with vaginal discharge and perineal irritation ▪ tablets: 6% ▪ gelatin capsules: 0-14% ▪ suppositories: 25-30% ▪ bioadhesive gel: 17% • Affect patients’ comfort and compliance during the IVF treatment
- 28. Intramuscular progesterone • Uncomfortable daily injections • Trained medical personnel • Allergic reactions to the oil vehicle and marked inflammation at the injection site, resulting in redness, pain and even sterile abscess formation
- 29. Dydrogesterone • It is structurally and pharmacologically similar to natural progesterone, has good oral bioavailability • has a good safety and tolerability profile • has no androgenic effects on the fetus,
- 30. • 1,373 infertile women undergoing IVF randomized into micronized P gel (Crinone 90mg daily), P capsule (Utrogestan 200mg tds), and oral dydrogesterone (Duphason 10mg bd) • Comparable PR and miscarriage rates Oral Vaginal gel Vaginal capsule Clinical PR at 7 weeks 121/422 (28.7%) 138/482 (28.6%) 104/459 (22.7%) Miscarriage rate 14/121 (11.6%) 18/138 (13.0%) 19/104 (18.3%)
- 31. Dydrogesterone / vaginal progesterone Comparison of oral dydrogesterone with suppository vaginal progesterone for luteal-phase support in in vitro fertilization (IVF): A randomized clinical trial. Salehpour S, Iran J Reprod Med. 2013 Conclusion - Oral dydrogesterone is as effective as vaginal progesterone for luteal-phase support in women undergoing IVF.
- 32. GnRH agonist in luteal phase -IUI ▪ GnRH agonist was recently suggested as a novel luteal- phase support that may act at different levels, including the pituitary gonadotrophs, the endometrium and the embryo itself ▪ Regimens for IUI : ▪ single dose triptorelin 0.1 mg 6 days after ovulation ▪ Three doses of lupride 1 mg sc 6 days after ovualation
- 33. GnRH agonist in luteal phase-IVF Evaluation of the impact of gonadotropin-releasing hormone agonist as an adjuvant in luteal-phase support on IVF outcome. Conclusion - Three 1 mg doses of Lupride administration 6 days after oocyte retrieval in the long protocol cycles does not result in an increase in ongoing pregnancy rates. Inamdar and A Majumdar.J Hum Reprod Sci. 2012.
- 34. GnRH agonist as luteal phase support in IVF
- 35. • GnRH-a can collaborate in the corpus luteum function, acting directly on the endometrium via local receptors, a direct effect on the embryos or combination. • GnRH-a administration can improve clinical outcomes after ICSI. • Premature to recommend the use of GnRH-a in the luteal phase because of heterogeneity among trials
- 36. Role of oestrogen in IUI for luteal support • The role of oestrogen along with progesterone in the luteal phase appears to be only in those cases where GnRH agonist was used instead of hCG to trigger ovulation
- 37. Estradiol as luteal phase support-IVF 1. The use of estradiol for luteal phase support in IVF / ICSI cycles: a systematic review and meta-analysis. Gelbaya TA, Fertil Steril. 2008 conclusion - The addition of E(2) to P4 for luteal phase support in IVF/ICSI cycles has no beneficial effect on pregnancy rates 2. Luteal phase support with estrogen in addition to progesterone increases pregnancy rates in IVF cycles with poor response to gonadotropins.Kutlusoy F , Gynecol Endocrinol. 2014
- 38. LPS in natural cycle FET • Controversial 1. Retrospective study: no effect on pregnancy rate following vaginal P in hCG-induced natural FET cycles (Kyrou et al., 2010) 2. RCT: significantly higher live birth rate when vaginal P was given in natural FET cycles (30% Vs 20%); no difference in clinical PR and miscarriage rate (Bjuresten et al., 2011)
- 39. • Before 1st July 2009, 2 doses of 1500 IU hCG given on the day of FET and 6 days after the transfer. • Such practice was stopped after 1st July 2009. With hCG Without hCG Clinical PR 53/205 (25.9%) 59/203 (21.1%) Miscarriage rate 12/66 (18.2%) 12/75 (16.0%)
- 40. When to stop ?
- 41. 600 mg of progesterone starting on the day of ET for 14 days after ET 150 women did NOT receive P for another 3 weeks (Study group) 150 women received P for another 3 weeks (Control group) Delivery rate +ve hCG
- 42. • Prolongation of P in the early pregnancy (up to 7 weeks of gestation) has no effect on the miscarriage and delivery rates. • P can be safely withdrawn after a positive hCG test Study Group Control group Ongoing preg. 133 (88.7) 139 (90.8) Delivery 118 (78.7) 126 (82.4) Biochemical 10 (6.7) 7 (4.0) Abortion 22 (14.6) 18 (11.8)
- 43. F&S, 2010 No difference in ongoing pregnancy and miscarriage rates on early P cessation F&S, 2012 F&S, 2010
- 44. Duration of LPS in IVF Authors Protocol Study Gp Control Gp Andersen 2002 Vaginal P Livebirth LPS till 7 wks 78.7% LPS till PT+ve (4 wks) 82.4% Aboulghar 2008 Vaginal or IM P Miscarriage LPS till 10 wks 4.6% LPS till USS (7 wks) 4.8% Goudge 2010 IM P Livebirth LPS till 8 wks 52.0% LPS till PT+ve (4 wks) 49.0% Kyrou 2011 Vaginal P Ongoing LPS till 7 wks 82.0% LPS till PT+ve (4 wks) 73.0% Kohls 2012 Vaginal P Ongoing LPS till 8 wks 73.0% LPS till USS (5 wks) 75.0%
- 45. Conclusion • Prevalence of a luteal phase defect in natural cycles is about 8.1% (Rosenberg et al., 1980). • In these cases LPS is controversial • CC stimulated cycles do not disturb the luteal phase, however there is an urgent need for prospective randomised trials. • HMG/rec-FSH with GnRH agonist and antagonist cycles must be supplemented.
- 46. Conclusion • IVF ✓vaginal P alone for about 2 weeks from day of hCG, TUGOR or ET • FET in natural cycles ✓Controversial • IUI ✓Vaginal progesterone for 2 weeks
- 47. Dr. Laxmi Shrikhande Shrikhande IVF & Surrogacy Center Ph-96234 59766 / [email protected]
- 48. 'Spiritual blossoming' simply means blossoming in life in all dimensions. Being happy, at ease with yourself and with everybody around you. Sri Sri Ravi Shankar The Art of Living