Progesterone elevation on the day of

HCG administration in ivf

Aboubakr Elnashar Benha university Hospital

Aboubakr Elnashar

Outline

INTRODUCTION

DEFINITION

INCIDENCE

PATHOGENESIS

IMPACT ON PREGNANCY OUTCOME

PREVENTION

SUMMARY

RECOMMENDATION

Aboubakr Elnashar

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).

Aboubakr Elnashar

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).

Aboubakr Elnashar

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}.

Aboubakr Elnashar

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)

Aboubakr Elnashar

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.

Aboubakr Elnashar

Aboubakr Elnashar

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.

INCIDENCE

Marked variation: discrepancies in:

Definition

Population characteristics

Treatment protocols.

Aboubakr Elnashar

Aboubakr Elnashar

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)

Aboubakr Elnashar

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)

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

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

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

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

Aboubakr Elnashar

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.

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)

Aboubakr Elnashar

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; )

Aboubakr Elnashar

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).

Aboubakr Elnashar

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).

Aboubakr Elnashar

Aboubakr Elnashar

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).

PE: lower insignificant difference in PR (SR, Venetis et al., 2007).

PE GnRHan cycles: significantly lower PR (SR, Kolibianakis et al.,2012).

Aboubakr Elnashar

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.

Aboubakr Elnashar

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

Aboubakr Elnashar

Aboubakr Elnashar

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}

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

Aboubakr Elnashar

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).

Aboubakr Elnashar

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

Aboubakr Elnashar

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

Aboubakr Elnashar

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

Aboubakr Elnashar

VI. use milder stimulation protocols (Kasum et al, 2013)

Aboubakr Elnashar

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.

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

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

Aboubakr Elnashar

Thanks

Aboubakr Elnashar