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EMPTY FOLLICLE SYNDROME
1. EMPTY FOLLICLE SYNDROME
- Dr. Meenakshi Vempalli
MS OG, DNB OG ,
Dept of Reproductive Medicine, CIMAR
2. EMPTY FOLLICLE SYNDROME (EFS)
First described by Coulam et al (1986).
EFS - a condition where no oocytes can be retrieved despite
repeated aspiration & flushing ;
after adequate ovarian response to stimulation
( serial ultrasound & adequate steroidogenesis).
3. Impact
• Cycle cancellation
• Stress & anxiety for both patients & clinicians
Incidence – Sporadic event rather than a syndrome.
0.045 – 7% (Ben – Shlomo et al)
Wide range :
• Lack of hCG threshold to differentiate between GEFS & FEFS
• Choice of patient population ( Ovarian stimulation cycles with good
ovarian response underestimates the incidence
– 30% of IVF population are poor or suboptimal responders )
4. • Exclusion criteria – poor responders
• In GnRH agonist & GnRH antagonist protocols , prevalence is
2.4%(comparable)
Kim & Jee (2012) in
705 IVF cycles
• Prevalence is 1.7%, miniflare GnRH protocol( for low ovarian
reserve in older women, Franco et al 2006)- EFS is associated
with ovarian aging
Madani & Jahangiri
(2015)in 3356 IVF
cycles
• 2034 egg donor cycles with GnRH trigger Vs 1433 IVF cycles with
self eggs ( inc. poor responders of any age with hCG trigger )
• Similar prevalence.
Castillo et al (2012)
6. GEFS
Rare.
Failure to retrieve oocytes from
mature follicles with optimal hCG
levels on the day of oocyte
retrieval or optimal LH levels 12
hours post agonist trigger.
Cycle cannot be
rescued with
repeat trigger
FEFS
Most common.
Failure to retrieve oocytes with
low hCG levels due to error in
administration or decreased
bioavailability of hCG or
inappropriately administered
agonist trigger .
Cycle can be
rescued with
repeat trigger
7. 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)
• May be explained by a defect in process that results in
oocyte maturation and cumulus cell expansion.
8. • Stevenson et al (2008), incidence of GEFS was 33% & FEFS was 67%.
• CUT OFFs to differentiate GEFS & FEFS:
hCG trigger:5-160 hCG IU/L after 36 hrs from exogenous
trigger(Stevenson et al,2008)
• Ndukwe et al (1996)- 10mIU/L – 100% specificity & sensitivity for predicting EFS.
Post agonist trigger Sr.LH of 15IU/L (Blazquez et al,2014)
9. Recurrence
• Very high
• Counselling is of profound importance especially in advanced
age group
• Velasco et al : One EFS cycle , 20% risk of recurrence in later
IVF cycles.
10. RISK FACTORS
• Previous h/o EFS
• Advanced age
• Diminished ovarian reserve
• Longer duration of infertility
• Ovarian resistance to various stimulations
• Obesity
• Higher baseline FSH levels
• Lower estradiol levels on the day of trigger
Consistent with risk factors of poor ovarian response.
Recurrent EFS – variant phenotype of poor response.
11. ETIOPATHOPHYSIOLOGY
False Empty Follicle Syndrome
• Following hCG trigger:
Inadequate or Absent LH Surge
• Growing oocyte surrounded by cumulus cells, linked to mural
granulosa cells by cell to cell junctions. The junctions tightly bind
the egg to the follicle wall.
• LH peak ( hCG or GnRHa )- rupture of intercellular junctions &
releases COC to freely float in follicular fluid , thereby available
for aspiration.
12. Oocyte – Follicle cross talk
Cooperation between oocyte and follicular cells in growing
follicle is extremely important.
OOCYTE CUMULUS CELLS
Regulates cumulus cell
functions
By agents such as
GDF9, BMP15 etc
Coordinate oocyte development
and maturation, provide energy
substrate for oocyte meiosis
resumption, regulate oocyte
transcription, promote nuclear and
cytoplasmic maturation of oocyte.
13. The final triggering simulating endogenous LH peak –
FUNDAMENTAL STEP OF OVULATION & absence or
any inadequacy of LH/LH like activity in IVF cycles-
FEFS.
1)Errors in administration of the trigger
2)Error in timing of the injection
3)Improper timing of oocyte retrieval
4)Manufacturing defects & potency defects
5)Low bioavailability due to variation in absorption or clearance
6)Ovarian low bioavailability of hCG
The pharmaceutical industry syndrome!
14. • Following GnRH trigger :
Wrong trigger
Inadequate response to agonist trigger
15. Genuine Empty Follicle Syndrome
Dysfunctional folliculogenesis
Granulosa cells have increased proapoptotic genes &
decreased transcripts (PAPP-A & MAPK 3 ) ---oocytes lost in
late folliculogenesis due to apoptosis.
Ovarian aging
Poor ovarian response & failure to retrieve oocytes,EFS
represents advanced stage of ovarian aging ( residual
responsiveness of granulosa cells & oocytes fail to develop
adequately)
16. • Faulty oocyte development and maturation
• Strong attachment of cumulus cell complexes to follicular
wall,dysfunctional signaling between cumulus cells & oocyte.
• Receptor polymorphism- LH/hCG receptor (LHCGR) mutation
– recessive trait. Causes irreversible block in transmission
pathway of LH signal.
• Pericentric inversion in fragile site of Chromosome 2(gene
coding for inhibin βb -POI).
• Hence, EFS linked with ovarian aging , POI or both.
17. Triggers
hCG trigger
• Acts directly on the ovary.
• Abnormal folliculogenesis / response of ovary to triggering
stimulus/errors in administration of trigger.
18. GnRH agonist trigger
Inability of pituitary to release adequate LH
Failure of the receptors on the ovary to mediate action of LH
Polymorphism of LH β gene.
• Hypogonadotropic hypogonadism (WHO type 1) : Endogenous
FSH & LH <1.2 IU/L.
• Borderline hypothalamic pituitary dysfunction
• Temporary hyposensitivity of pituitary to agonist trigger
• GnRH receptor polymorphism
• Variant LH β gene polymorphism – homozygous form – less
bioactive LH
19. Diagnosis
1) hCG in urine or follicular fluid (home
pregnancy kit ) or blood (>40mIU/L)
2) 12 hour Post Trigger LH of 15mIU/L
3)12 hour post trigger progesterone >
3.5 ng/mL
20. • Post trigger progesterone concentration with borderline or
LH – Successful OPU.
• Post trigger progesterone concentration with LH > 15
IU/mL – Inadequate response.
• Peak LH levels post agonist trigger occurs after 4 hours
followed by rapid decline,
• Shorter intervals , higher LH & lower P levels & vice versa.
22. Management of EFS in the current cycle
• Readminstering hCG & reaspiration in case of FEFS
A repeat, rescue dose of hCG first proposed by Ndukwe et al in
1997.
• Kummer et al in 2013, 42.8% of cycles ( 6 out of 14) rescued with
repeat hCG resulted in healthy live borns.
• Reichman et al. in his large study- 72 hour unintended ‘coasting’
results in post maturity of some oocytes.
• Delayed retrieval if there was en error in timing
23. Management of subsequent cycles after EFS
• Check for risk factors before stimulation
• Trigger next cycle with r-hCG or r-LH
• GnRH agonist trigger to induce more physiological LH surge
in antagonist cycle
27. Endometriosis & EFS
A case of EFS who conceived in the 5th IVF cycle after
aspiration of an endometrial cyst. So, endometriosis might
have been involved in the dysfunction of folliculogenesis and
EFS.
29. Conclusion
• Though affects minor proportion of IVF cycles, has a large
impact.
• Patients who experience this face psychological
consequences, doubts arise about possibility of finally
achieving a pregnancy. Hence, counselling is of prime
importance.
• Treatment of GEFS is largely empirical with very little case
studies that do not help to reach conclusion about optimal
treatment.
• Wider knowledge is needed & large multicentric studies
need to be done.
