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

1. Progesterone rise on the day of
hcg administration (ppremature
luteinization) in ivf
Aboubakr Elnashar
Benha university Hospital

2. Outline
 INTRODUCTION
 DEFINITION
 INCIDENCE
 PATHOGENESIS
 IMPACT ON PREGNANCY OUTCOME
 PREVENTION
 SUMMARY
 RECOMMENDATION
Aboubakr Elnashar

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).
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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).
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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}.
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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. •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. 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)
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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. 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%
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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. 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.
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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. 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. 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. •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
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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).
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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. 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. 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.
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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. 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. 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. 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).
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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. 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. 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. 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. •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. •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. 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. Thanks
Aboubakr Elnashar