EMPTY FOLLICLE SYNDROME Aboubakr Elnashar

Benha University, Egypt

ABOUBAKR ELNASHAR

1. INTRODUCTION

First described: Coulam et al. [1986].

Define:

Failure to aspirate or retrieve mature oocytes

from mature ovarian follicles following ovulation

induction for in vitro fertilization (IVF) treatment in

spite of meticulous aspiration and repeated

flushing

No oocytes retrieved in good responder patients

undergoing ovarian stimulation with at least 5

mature follicles (≥15 mm) on the day of hCG (Coskun et al. 2010)

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Borderline form of EFS

Very few mature or immature oocytes are recovered

from several mature follicles (Isik and Vicdan, 2000; Nikolettos et al., 2004; Duru et al.,2007; Desai et al., 2009; Vutyavanich et al., 2010).

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Types:

1. Genuine: 33%

Failure to retrieve oocytes despite optimal hCG levels on the day of OR. it does not respond to the rescue protocol.

2. False: 67%

Failure to retrieve oocytes in the presence of low

hCG (<40 IU/L) due to an error in the

administration or

bioavailability of hCG (Stevenson and Lashen, 2008)

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Impact

frustrating complication of IVF:

cycle cancellation

stress and anxiety for both patients and

physicians

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Incidence

uncommon event

0.05% to 7% of patients undergoing OR.

{different inclusion criteria}.

In some studies, patients with a poor ovarian

response or premature ovulation were included

while in others they were not.

No specific stimulation or triggering protocol is

related to the occurrence of EFS. (Castillo et al., 2012)

GEFS:

0–1.1%. (Beck-Fruchter et al, 2012)

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2. MECHANISM

I. FALSE EFS 1. hCG-related faults: main mechanism.

•hCG injection later than scheduled (11 h before

retrieval)

•Failure of the hCG injection, confirmed by the

undetectable hCG serum concentrations. .

1. Forgott to dissolve the powder in the solvent ,

and taken only the inert solvent

2. Taken an HMG injection instead of the hCG

3. Mis-timed it

4. Spilled the drug

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2. Rapid metabolic clearance

3. Manufacturer defects in hCG production: Reduced in vivo biological activity of some batches: EFS is

pharmaceutical industry syndrome (Zegers-Hochschild et al.1995).

4. Low bioavailability of hCG

after bariatric surgery. {Hirshfeld-Cytron and Kim, 2008]

Abdominal skin redundancy alter absorption of SC hCG: IM

is recommended.

5. individual variation in the threshold for the

follicular response to urinary hCG, [Abdalla et al, 1987]

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II. GENUINE EFS Early oocyte atresia (Awonuga et al.2003)

Absence of oocytes might be due to increased

apoptotic gene expression and reduction of

transcripts whose products are responsible for

healthy follicular growth. (Inan et al. 2006)

Associated with ovarian ageing (Lorusso et al, 2005)

manifestation of low ovarian reserve [Baum et al, 2001].

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Does genuine EFS really exist?

Some suggest that genuine EFS does exist and

that it might be a real cause of infertility.

1. Microscopic evidence of genuine EFS with a

case of borderline EFS. (Desai et al.2009)

2. Borderline form of EFS:

very few mature or immature oocytes are

recovered from several mature follicles [Duru et al, 2007 Desai et al, 2009 Vutyavanich et al, 2010 ].

3. The genetic basis for EFS provides strong

evidence for the existence of genuine EFS [Yariz et al,2011].

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Genetic causes

1. Presence of a pericentric inversion of

chromosome 2:46, XX,inv(2)(p11q21) in a patient

who had multiple failed OR. (Vujisic et al. 2005)

2. An inherited condition of EFS with moderate

sensorineural deafness affecting two sisters. (Onalan et al. 2003)

3. An inherited mutation of LH/hCG receptor was

identified in two sisters with EFS (Vujisic et al, 2005).

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Risk factors

1) Advanced age (37.7±6.0 y vs. 34.2±6.0 y, p<

0.001),

2) longer infertility duration (8.8±10.6 y vs. 6.3±8.4

y, p<0.05),

3) higher baseline FSH levels (8.7±4.7 IU/L vs.

6.7±2.9 IU/L, p<0.001),

4) lower E2 levels before the hCG injection (499.9±

480.9 pg/mL vs. 1,516.3±887.5 pg/mL, p<0.001)

EFS may be a gradual biological occurrence

related to ovarian ageing.

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Prognosis after EFS

Sporadic event with good clinical outcomes in

most of the cases except the 15% that are

recurrent cases. (Aktas et al., 2005; Baum et al. 2012)

Poor outcome in subsequent cycles. (Lorusso et al., 2005; Coskun et al., 2010)

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Risk of recurrence.

20% (Zreik et al., 2000)

had a poor success rate.

2 consecutive cases of EFS: no further

pregnancies or successful OR

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Risk factors of recurrence

1. Advanced age:

35 to 39y: 24% recurrence rate

>40: 57%

2. Prolonged infertility

3. Lower E2 levels:

consistent with the risk factors of poor ovarian

response.

Recurrent EFS may be a variant phenotype of

poor response.

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3. THERAPEUTIC APPROACH

False EFS:

Readministering hCG and reaspiration

-24-36 h after this second hCG shot.

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PREVENTATION

1. Assessment of serum hCG the day after the

trigger if the βhCG concentration is

<100 mIU/ml [Zreik et al, 2000] or <40 mIU/ml [Stevenson,

Lashen,2008] second bolus of hCG: OR 24–36 h later

2. Prolonging the interval between ovulation

triggering and OPU.

the strategy little evidence to be generally

recommended.

3. Increase the dose of hCG to 20000 IU (instead

of the standard 10000 IU we use routinely)

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4. Prolonging the interval between ovulation

triggering and OPU and inducing ovulation using

GnRHa. in a GnRH antagonist cycle

ovulation was triggered using GnRHa 40 h prior

to OPU and hCG was added 6 hours after the first

trigger. (Beck-Fruchter et al, 2012)

5. Use recombinant hCG (Ovitrelle) or LH

(Luveris) to trigger ovulation

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GEFS can be managed in subsequent cycles by

using recombinant hCG, recombinant LH, or

triggering oocyte maturation with the GnRH agonist

in an antagonist cycle

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MANAGEMENT if the embryologist does not get any eggs after

flushing 3 mature follicles:

1. stop the procedure

2. ensure patient has taken the trigger injection at the

right time

3. rapid home urine pregnancy test (obtained by

catherisation) for the presence of hCG

(Instead of urine, it’s also possible to do the test on the

aspirated follicular fluid)

4. If the patient has taken her hCG properly: positive

pregnancy test is expected.

This rules out the diagnosis of EFS, and we can then

continue with the egg collection. ABOUBAKR ELNASHAR

5. if the pregnancy test is negative: diagnosis of

EFS is confirmed: stop the procedure, leaving

the rest of the follicles intact, and wheel the

patient out of the OR .

a. Give the patient an additional HMG injection

to support follicular growth ; and do a blood test

to measure estrogen and Hcg

levels. (Remember that we will get the results of

the blood tests only after a few hours. )

b. Give the patient another hCG injection , and

reschedule the egg collection 36h after this

second hCG shot.

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c. If we are worried about the quality of the hCG

injection, we may use recombinant hCG ( such

as Ovitrelle) to trigger ovulation ; and we may

also increase the dose of hCG to 20000 IU

(instead of the standard 10000 IU we use

routinely) .

d. The next day, we review the blood test results.

We would expect the estradiol levels to be high;

and the hCG level to be less than 100 mIU/ml,

thus confirming the diagnosis of EFS. An

ultrasound scan at this time confirms that the

follicles are still intact.

e. At the time of the second egg retrieval , which is

planned 36 hours after the second hCG shot ,

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we expect to see intact follicles ; and expect to

retrieve eggs from each of these follicles. In

order to document the diagnosis , we repeat the

blood hCG level again , and expect this to be

more than 100 mIU/ml.

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INVITATION