EMPTY FOLLICLE SYNDROME

1. EMPTY FOLLICLE SYNDROME
Aboubakr Elnashar
Benha University, Egypt
ABOUBAKR ELNASHAR

2. 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)
ABOUBAKR ELNASHAR

3. 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).
ABOUBAKR ELNASHAR

4. 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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5. Impact
frustrating complication of IVF:
cycle cancellation
stress and anxiety for both patients and
physicians
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6. 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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7. 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
ABOUBAKR ELNASHAR

8. 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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9. 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].
ABOUBAKR ELNASHAR

10. 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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11. 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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12. 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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13. 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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14. 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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15. 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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16. 3. THERAPEUTIC APPROACH
False EFS:
Readministering hCG and reaspiration
-24-36 h after this second hCG shot.
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17. 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)
ABOUBAKR ELNASHAR

18. 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
ABOUBAKR ELNASHAR

19. 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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20. 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.
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21. 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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22. 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 ,
ABOUBAKR ELNASHAR

23. 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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24. ABOUBAKR ELNASHAR
INVITATION