Progesterone elevation on the day of HCG administration in ivf

1. Progesterone elevation on the day of
HCG administration in ivf
Aboubakr Elnashar
Benha university Hospital
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2. Outline
 INTRODUCTION
 DEFINITION
 INCIDENCE
 PATHOGENESIS
 IMPACT ON PREGNANCY OUTCOME
 PREVENTION
 SUMMARY
 RECOMMENDATION
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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 PE
(Hofmann et al., 1993; Legro et al., 1993; Ubaldi et al., 1996a; Bosch et al., 2003).
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4. PE:.
aroused interest {some authors reported decreased
IR& PR}
(Silverberg et al, 1991; Fanchin et al, 1993; Harada et al., 1995)
:Cryopreservation and ET 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 PE
(Harada et al., 1996).
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5. DEFINITION
•Terminology:
PL: Many authors in the past have adopted this
term for PE 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)
PE in the late follicular phase may be unrelated to
any luteinizing process attributable to effects of
follicular cells to LH
(Adonakis et al, 1998)
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7. P level
(Most studies)
cutoff level 0.8 to 2 ng/mL.
Up to 3 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.
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8. AboubakrElnashar
 P of the day of HCG and the day after HCG
(Liu et al, 2014).
P on both days were normal: IR: 36%
PE on both days: IR: 22%: embryos should be
frozen and transfer deferred to a subsequent cycle.

9. INCIDENCE
Marked variation: discrepancies in:
Definition
Population characteristics
Treatment protocols.
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10. AboubakrElnashar
PE in fresh IVF cycles
The pooled rates varied
according to
Thresholds
0.4–0.6 ng/ml: 46.7%
1.9–3.0 ng/ml: 12.3%
(Venetis et al, 2013)
Protocol
>1.5 ng/ml
Agonist: 24.1%
Antagonist: 23.0%
(Papanikolaou et al, 2012)

11. AboubakrElnashar
Threshold
(ng/ml)
%PE
Overall Agonist Antagonist
0.4-0.6 46.7 46.7 n.a
0.8-1.1 33.5 31.5 56.0
1.2-1.4 29.0 31.6 29.8
1.5-1.75 17.2 20.3 11.1
1.9-3.0 12.3 13.0 n.a
(Venetis et al, 2013)

12. 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
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13. 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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14. 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).
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15. 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)
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16. AboubakrElnashar
The origin of production of P in the early follicular
phase is adrenal which shifts toward the ovaries
prior to the ovulation.
Several factors contribute to the etiology of PE:
1. Number of multiple follicles
2. Overdose of gonadotropins
3. Poor ovarian response.

17. 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)
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18. 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; )
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19. 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, 1997).
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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20. 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:
narrows the time-frame for implantation
(Forman et al. 1989, Sharma et al. 1990; Silverberg et al. 1991)
P supplementation for LPS 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).
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21. AboubakrElnashar
Direct evidence for an effect of PE on the
endometrium has been provided by endometrial
gene expression analysis
(Labarta et al., 2011; Li et al., 2011; Van Vaerenbergh et al., 2011).
It has been suggested that ovarian response might
be a moderating factor on the association of PE
with the probability of pregnancy
(Fanchin et al., 1997b; Xu et al., 2012),
although others have challenged this idea
(Bosch et al., 2010).

22. PE: lower insignificant difference in PR
(SR, Venetis et al., 2007).
PE GnRHan cycles: significantly lower PR
(SR, Kolibianakis et al.,2012).
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23. SR and MA of more than 60 000 cycles
(Venetis et al, 2013)
PE on the day of hCG: significant decreased PR
after fresh ET in ovarian stimulation using GnT and
GnRH analogues for IVF.
This finding was present in all PE threshold
groups evaluated, with the exception of the lowest
PE threshold group (0.4–0.6 ng/ml).
No adverse effect of PE on PR in the frozen–
thawed and the donor/recipient cycles.
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24. PE is associated with
1. Retrieval of more oocytes
2. Increased E2 levels on the day of hCG. This
was significant in all PE threshold groups with
the exception of the 1.2–1.4 ng/ml group.
3. Increase in the total amount of FSH used for
ovarian stimulation, noted in 3 out of PE
threshold groups.
No evidence that the duration of ovarian
simulation is different between women with and
those without PE
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25. AboubakrElnashar
A detrimental effect of PE
0.8 to 1.1 ng/ml in the general IVF population and
in the poor responders.
1.9–3.0 ng/ml. in high responders
{increased oocyte yield might compensate for the
detrimental effect of PE on the endometrium}

26. 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 PE
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27. II. Flexible antagonist protocol
(Lainas et al, 2005)
GnRHan 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 PE (normal P levels on HCG day).
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28. 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 PE
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29. 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
IR was significantly higher
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30. 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.
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31. AboubakrElnashar
VI. use milder stimulation protocols
(Kasum et al, 2013)

32. AboubakrElnashar
CONCLUSION
Marked variation: discrepancies in:
Definition
Population characteristics
Treatment protocols.
A detrimental effect of PE on PR
General IVF population and poor responders:
0.8-1.1 ng/ml
High responders:
1.9–3.0 ng/ml.

33. 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
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34. 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
use milder stimulation protocols
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35. Thanks
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