Progesterone rise on the day of hcg administration (ppremature luteinization) in ivf

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Progesterone rise on the day of hcg administration (ppremature luteinization) in ivf

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Progesterone rise on the day of hcg administration (ppremature luteinization) in ivf

  1. 1. Progesterone rise on the day of hcg administration (ppremature luteinization) in ivf Aboubakr Elnashar Benha university Hospital
  2. 2. Outline  INTRODUCTION  DEFINITION  INCIDENCE  PATHOGENESIS  IMPACT ON PREGNANCY OUTCOME  PREVENTION  SUMMARY  RECOMMENDATION Aboubakr Elnashar
  3. 3. INTRODUCTION •The introduction of GnRH analogues for pituitary suppression in ivf significantly decreased the incidence of premature LH surge (Smitz et al., 1992). •However, several researchers have described a phenomenon reported as PL (Hofmann et al., 1993; Legro et al., 1993; Ubaldi et al., 1996a; Bosch et al., 2003). Aboubakr Elnashar
  4. 4. PL: Rise in serum P on the day of hCG administration. has aroused interest {some authors reported decreased implantation& PR} (Silverberg et al, 1991; Fanchin et al, 1993; Harada et al., 1995) :Cryopreservation of the embryos& their transfer in a subsequent cycle (Silverberg et al., 1991; Legro et al., 1993; Silverberg et al., 1994) or HCG administration at an earlier time, prior to P elevation (Harada et al., 1996). Aboubakr Elnashar
  5. 5. DEFINITION •Terminology: PL: Many authors in the past have adopted this term for P elevation on the day of hCG administration (Hofmann et al., 1996; Legro et al., 1993;Ubaldi et al., 1996; Bosch et al., 2003). {Excessive amount of P is produced by granulosa cells that have started the process of luteinization}. Aboubakr Elnashar
  6. 6. Use of the term ‘PL’ in the presence of normal LH levels is not appropriate, at least when GnRHa is used to inhibit LH surge (Venetis et al,2007) Increase in P in the late follicular phase may be unrelated to any luteinizing process attributable to effects of follicular cells to LH (Adonakis et al, 1998) Aboubakr Elnashar
  7. 7. •P level (Most studies) cutoff level 0.8 to 2 ng/mL. •P/E2 ratio of > 1 (Younis et al, 2001, Ou et al, 2007)  Ovarian response, rather than the serum P only DD between the P secretion from dysmature follicles & physiologic secretion from multiple healthy mature follicles. Aboubakr Elnashar
  8. 8. INCIDENCE •Marked variation: discrepancies in: Definition Population characteristics Treatment protocols. •Even among studies in which the same definition (P>0.9 ng/mL) & same protocol (GnRH a): 12.4%; 52.3% (Silverberg et al., 1991; Martinez et al., 2004) Using P only to define: 13% to 71% Using the definition of P/E2 ratio > 1: 41% (Younis et al 2001, Ou et al, 2007) Aboubakr Elnashar
  9. 9. •GnRHa, combined with Gnt: 5-35% (Edelstein et al, 1990; Silverberg et al, 1991, Fanchin et al, 1993;Givens et al, 1994; Harada et al, 1995;Ubaldi et al, 1995, 1996). •Flare-up protocol: 85% (P>1.0 ng/ml) (Sims et al, 1994) •GnRH antagonist: (P >1.2 ng/mL): 38.3% (Bosch et al, 2003) (P >1.1 ng/mL): 20% (Ubaldi et al, 1996) Aboubakr Elnashar
  10. 10. Study Protocol Definition Incidence Silverberg et al., 1991 GnRHa P >0.9 ng/mL 12.4% Martinez et al., 2004 GnRHa P >0.9 ng/mL 52.3% Edelstein et al, 1990; Silverberg et al, 1991, Fanchin et al, 1993; Givens et al, 1994; Harada et al, 1995; Ubaldi et al, 1995, 1996 GnRHa P>.8-2 ng/mL. 5-35% Younis et al 2001; Ou et al, 2007 GnRHa P/E2>1 41% Ubaldi et al, 1996 GnRH antagonist P >1.1 ng/mL 20% Bosch et al, 2003 GnRH antagonist P >1.2 ng/mL 38.3% Sims et al, 1994 Flare up P>1.0 ng/ml 85% Aboubakr Elnashar
  11. 11. PATHOGENESIS Poorly understood (Melo et al, 2006) Several hypotheses I. Elevation of follicular LH levels  Pituitary desensitization induced by GnRHa is incomplete:The rising E2: induce increased LH sufficient to stimulate granulose cells to produce P but inadequate to trigger ovulation (Peluso, 1990; Hofmann et al, 1993,Ubaldi et al., 1995)  long GnRHa protocol can prevent premature LH elevation in 95–98% (Ron , 1990; Penzias et al, 1992)  Increased LH is not the only pathogenic factor in PL Aboubakr Elnashar
  12. 12. II. Serum accumulation of HCG from HMG (Copperman et al, 1995) hCG is higher in women who experienced a serum P rise, during GnRHa HMG protocol, despite pituitary suppression with GnRHa Use of rFSH (with negligible intrinsic LH bioactivity) should not provoke PL (Peluso, 1990). Serum P rise was similar (13.4%) with the use of HMG or rFSH (Ubaldi et al, 1996). HCG content of HMG is not the only cause of serum P rise. Aboubakr Elnashar
  13. 13. III. Increased LH receptor sensitivity of the granulosa cells to FSH. { higher cumulative exposure to E2, in conjunction with FSH} (Peluso, 1990; Ubaldi et al, 1996; Filicori et al., 2002; Bosch et al., 2003; Glamoclija et al., 2005). Aboubakr Elnashar
  14. 14. IV. Poor ovarian response with increased LH sensitivity PL (defined by the P/E2) was more prevalent in poor ovarian responders in long GnRHa cycles with rFSH stimulation. (Younis et al 2001; Ou et al, 2007) PL is not necessarily an LH dependent event PL is related to an adversely affected cumulus–oocyte complex. Increase in P in the late follicular phase is unrelated to any luteinizing process attributable to effects of follicular cells to LH (Adonakis et al, 1998) Aboubakr Elnashar
  15. 15. IMPACT ON IVF OUTCOME •Controversial •No effect on PR (Howles et al., 1988; Mahadevan et al., 1988; Ben-Nun et al., 1990; Hassiakos et al., 1990; Antoine et al., 1992; Hoffman et al. 1993, 1996; Check et al., 1994; Givens et al., 1994; Bustillo et al., 1995; Levy et al., 1995; Ubaldi et al., 1995; Abuzeid and Sasy, 1996; Huang et al., 1996; Miller et al., 1996; Moffit et al., 1997; Doldi et al., 1999; Lindheim et al., 1999; Urman et al., 1999; Martinez et al., 2004) 20 studies Aboubakr Elnashar
  16. 16. •Deleterious effect PR has been inversely related to serum P levels on the day of HCG administration (Hamori et al., 1987; Edelstein et al., 1990; Schoolcraft et al., 1991; Silverberg et al., 1991; Kagawa et al., 1992; Mio et al., 1992; Fanchin et al., 1993; Check et al., 1994; Givens et al., 1994; Mio and Terakawa, 1995; Harada et al., 1995; Shulman et al., 1996; Fanchin et al.,1997; Bosch et al., 2003; Ozcakir et al., 2004 Ou et al, 2007; ) 16 studies Aboubakr Elnashar
  17. 17. •Ovarian: Adverse effects on oocyte maturation, fertilization or early cleavage (Fanchimont et al., 1989; Schoolcraft et al., 1991; Silverberg et al., 1991; Fanchin et al., 1993, 1997a). On the other hand, poorer embryo quality was not found (Legro et al., 1993; Hofmann et al., 1993, 1996; Check et al., 1994; Silverberg et al., 1994;Bustillo et al., 1995; Yovel et al., 1995; Fanchin et al., 1996). Aboubakr Elnashar
  18. 18. •Endometrium: Adverse effects on implantation& subsequent embryo development (Garcia et al., 1984; Forman et al., 1989; Sharma et al., 1990; Silverberg et al., 1991; Mio et al., 1992; Burns et al., 1994; Borman et al., 2004). Abnormally accelerated endometrial maturation: impaired endometrial receptivity (Forman et al. 1989, Sharma et al. 1990; Silverberg et al. 1991) P supplementation for luteal phase support started on the day of HCG: No negative impact on PR (Howles et al., 1988; Mahadevan et al., 1988; Ben-Nun et al., 1990; Hassiakos et al., 1990). Aboubakr Elnashar
  19. 19. Is P elevation on the day of HCG administration associated with the probability of pregnancy in IVF? A systematic review and meta-analysis C.A.Venetis, E.M.Kolibianakis, E.Papanikolaou, J.Bontis, P.Devroey and B.C.Tarlatzis1, Hum Rep, 2007 Aim: To evaluate whether P elevation on the day of hCG administration is associated with the probability of pregnancy. Aboubakr Elnashar
  20. 20. Material & Methods: Eligible studies were considered those in which patients did not participate more than once. A literature search in MEDLINE, EMBASE& CENTRAL identified 12 eligible studies, 10 of which were retrospective. Aboubakr Elnashar
  21. 21. Results The majority (n=10) of these studies did not detect a statistically significant association between P elevation& the probability of pregnancy. Metaanalysis was performed only for the studies (n=5) that provided data on clinical pregnancy per patient reaching hCG administration for final oocyte maturation. No statistically significant association between P elevation& the probability of clinical pregnancy. Aboubakr Elnashar
  22. 22. Conclusion: Best available evidence does not support an association between P elevation on the day of hCG administration& the probability of clinical pregnancy in women undergoing ovarian stimulation with GnRH analogues& Gnt for IVF. Aboubakr Elnashar
  23. 23. PREVENTION I. Low-dose hCG alone in the late COH stages: (Filicori et al, 2005) rFSH/hMG followed by low-dose hCG (200 IU/d) alone : Reduced rFSH/hMG consumption ICSI outcome was comparable to traditional COH regimens Stimulated follicle growth and maturation independent of FSH administration Reduced number of small preovulatory follicles More estrogenic intrafollicular environment. No PL Aboubakr Elnashar
  24. 24. II. Flexible antagonist protocol (Lainas et al, 2005) GnRH antagonist was initiated according to at least one of the following (i) at least one follicle >14 mm (ii)E2 >600 pg/ml (iii)LH levels >10 IU/l.  Antagonist initiation earlier than on stimulation D6  Higher PR  Prevention of premature LH surges  Absence of PL (normal P levels on HCG day). Aboubakr Elnashar
  25. 25. III. Mifepristone (Escudero et al, 2005) :long protocol with GnRHa Mifepristone: 40 mg daily, 50 mg progesterone were administered IM at the time of hCG administration {counteract residual antiprogestogenic activity of mifepristone}. Mifepristone is effective for the prevention of premature LH surges and/or PL Aboubakr Elnashar
  26. 26. VI. hCG injection when serum P >1.0 ng/mL ("rescued" subtle P rise). (Harada et al, 1996) •Serum P was determined daily or/ 12 h from D7 until the administration of hCG. improves embryo quality implantation rate was significantly higher Aboubakr Elnashar
  27. 27. V. Aspiration of a single leading follicle (Barash et al, 1990) •Single leading follicle developed, whereas the other follicles were 6 mm smaller Efficient method to avoid premature LH surge enabling other follicles to develop up to the preovulatory stage. Aboubakr Elnashar
  28. 28. SUMMARY PL •Subtle rise of P on the day of hCG administration (0.8 to 2 ng/Ml) •There is a marked variation in the incidence (13% to 71%), due to discrepancies in Definition Population characteristics Treatment protocols. Aboubakr Elnashar
  29. 29. •Several hypotheses: Elevation of follicular LH levels Serum accumulation of HCG from HMG Increased LH receptor sensitivity of the granulosa cells to FSH Poor ovarian response with increased LH sensitivity Aboubakr Elnashar
  30. 30. •Impact on IVF outcome is controversial. A recent systematic review& meta-analysis affirmed that no effect •For prevention: Use of Low-dose hCG alone in the late COH stages Flexible antagonist protocol Use of mifepristone hCG administration when the levels of P>1.0 ng/mL. Aspiration of a single leading follicle Aboubakr Elnashar
  31. 31. RECOMMENDATION A well-designed prospective studies are required to answer the question: What is the role of P elevation on IVF outcome? Aboubakr Elnashar
  32. 32. Thanks Aboubakr Elnashar

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