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Empty follicle syndrome 

Genuine empty follicle syndrome (GEFS)

GEFS is presumably related to intrinsic ovarian dysfunction and various hypotheses have been suggested which include:


  1. Dysfunctional folliculogenesis or premature apoptosis of the oocytes that still continued follicular growth.

  2. Defective granulosa cell function.

  3. Faulty oocyte development and maturation. Abnormal oocytes like immature oocytes that were zona-free or that had zona which was lacking in oocytes could be the cause in some cases.

  4. Strong attachment of cumulus cell complexes to the follicular wall.

  5. Dysfunctional ovulation induction.

  6. Rare cases,follicles may need longer exposure to hCG to undergo cumulus expansion and separate from the follicular wall.

  7. Biological abnormality in the supply of mature oocytes.

  8. Genetic factors a) LH/hCG receptor mutations. (b) altered expression of genes regulating cumulus expansion. (c) Altered expression of genes involved in cellular processes and apoptosis resulting in increased apoptotic gene expression and reduction in transcripts with lose of oocytes during late folliculogenesis due to apoptosis. (d) Pericentric inversion of chromosome . (e) Advanced ovarian ageing through altered folliculogenesis which is considered as a risk factor for EFS recurrence.


False empty follicle syndrome (FEFS)

The various reasons for FEFS include:  

  1. Drug-related causes due to an abnormality in the in-vivobiological activity of some batches of commercially available urinary hCG preparations  

  2. Human errors-inappropriate timing, administration, and dosage of hCG.  

  3. Low bioavailability resulting from variation in the absorption or clearance of hCG with some batches of urinary hCG.  

  4. Pharmacological problems.  

  5. Variation in the threshold for follicular response to hCG.  

  6. Variation in the time needed from hCG exposure to the maturation of oocyte–cumulus complexes.  

  7. Rapid breakdown of products that contained desialylated hCG by the liver, resulting in a lack of exposure to biologically active hCG.  

  8. As with any other metabolic process, individuals vary in their rate of clearance of hCG and some may metabolize hCG quite rapidly.


The various strategies suggested to prevent the occurrence of EFS in a subsequent ART cycle are:

  1. Changing the batch of hCG

  2. Using R-hCG to trigger an endogenous LH surge. R-hCG with its high purity (≥99%) and consistency between batches, may be a better choice than urinary hCG, which contains miscellaneous urinary proteins and the biological activity of which may be affected by missing peptide bonds and alterations of the glycosylation profile.

  3. Shifting from an agonist to antagonist protocol

  4. Use of recombinant LH as trigger 

  5. Using GnRHa as trigger in an antagonist cycle 

  6. Prolonging the interval between ovulation trigger and OPU 

  7. Dual trigger agonist + 6 hrs later hcg egg collection 36 hrs after last dose


In patients who experience an empty cycle, EFS should be considered as a borderline form of poor response to ovarian stimulation and could be a recurrent event. If EFS has occurred once, the risk of recurrence is 20%. As age advances, the risk of recurrence increases and is about 24% in patients between 35 and 39 years of age whereas it is about 57% for those >40 years of age. In this subset of population, empty cycle could be a good predictor that a subsequent stimulated cycle may be an unfavourable one and such patients need to be counseled regarding the risk of recurrence and might benefit with oocyte donation. 

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