{"paper_id":"3a5467c3-3f17-4c30-94c9-e5c863b39e99","body_text":"Empty follicle syndrome (EFS) was first described by  Coulam  et al . (1986)  when they failed to aspirate any\noocytes from the ovaries of four patients prepared for IVF, and one of them was\nrecurrent in two cycles. It is divided into false EFS, when the level of human\nchorionic gonadotropins (HCG) on the day of ovum pick up is low and genuine EFS when\nits level is optimal ( Beck-Fruchter  et\nal ., 2012 ). In turn, this raises another question about the\noptimal level of HCG on the day of ovum pick up, which varies in different studies\nand according to different types of HCG used. A systematic review of empty follicle\nsyndrome has suggested a cutoff level of 40 mIU/mL to differentiate between the two\ntypes ( Stevenson & Lashen, 2008 ). Although\nthe estimated prevalence of empty follicle syndrome is up to 7% in the literature,\nthe prevalence of genuine cases was as low as 0.016% in a large cohort including\nmore than 12 thousand IVF patients ( Mesen  et\nal ., 2011 ). Its exact etiology is unknown and difficult to\npredict. Different treatment modalities to prevent recurrent EFS were suggested\nincluding triggering with GnRH agonists ( Lok\n et al ., 2003 ) and a second HCG dose followed by\nanother pick up ( Ndukwe  et al .,\n1997 ). Recurrent EFS or retrieval of poor quality immature oocyte after a\nfirst incidence of EFS is even more challenging. In this report we present a patient\nwho had EFS in her first trial, followed by repeated retrievals of immature oocytes.\nIVM was tried for those immature oocytes in her two IVF trials carried out at our\nunit.\n\nA 32 year-old woman with a ten-year history of primary infertility came to our unit\nfor IVF/ICSI with the diagnosis of bilateral tubal block and uncorrectable tubal\ndamage, without hydrosalpinges, and a normal semen profile for her husband. She had\na past history of open myomectomy and two laparoscopies for endometriosis treatment\n(one of them involved Laparoscopic ovarian drilling). She had a previous IVF attempt\nat another IVF/ICSI clinic, which ended up as an empty follicle syndrome (EFS) and\ncycle cancelation. In that trial she was submitted to a standard long agonist\nprotocol with highly purified urinary FSH and triggered with 10.000 IU of hCG. After\nfailure to retrieve any oocytes from one ovary she received an additional dose of\n10.000 hCF IU and egg collection was rescheduled 24 hours later. Unfortunately, the\nsecond trial ended with no eggs being retrieved.\nIn the second trial (first at our unit), the basal hormonal profile showed: FSH = 6.5\nmiu/ml, LH = 4.4 miu/ml and AMH = 4.05 ng/ml. We used a fixed antagonist protocol,\nusing Cetrorelix (Cetrotide, Merck Serono, London, UK) and HMG (Menogon, Ferring,\nKiel, Germany) 300 IU for 12 days. Dual trigger was done using 10000 IU HCG\n(Choriomon, IBSA, Lugano, Suisse) and 0.2 mg triptoreline (Decapetyl, Ferring, Kiel,\nGermany) and OPU was scheduled 36 days thereafter. On triggering day, her\ntransvaginal ultrasound scan showed seven follicles between 17-20 mm. HCG and\nDecapeptyl (for triggering) were given by a qualified nurse at the correct time.\nBefore OPU, a blood sample was withdrawn which showed E2 to be 3510 pg/ml and B-HCG\n= 166.3 miu/ml. It ended with the retrieval of one immature oocyte (Germinal vesicle\nGV) after thorough repeated flushing and aspiration of all follicles.  In\nvitro  maturation (IVM) was tried for this immature oocyte. However, it\ndegenerated on the following day.\nIn the third trial (second at our unit), she was thoroughly counseled before starting\ntreatment, when we explained that there was a great possibility of the same thing\nhappening again. She and her husband consented for the third trial. Again, we used a\nfixed antagonist protocol with Cetrorelix (Cetrotide, Merck Serono, London, UK) and\nanother highly purified HMG (Merional, IBSA, Lugano, Suisse) at a dose of 300 IU per\nday for 11 days. On the day of triggering, her transvaginal ultrasound scan showed\neight follicles between 17-20 mm. Her E2 level before triggering was 1594 pg/ml.\nDual trigger was used again, with recombinant hCG (Ovitrelle, Merck, London, UK ),\n0.2 mg triptoreline (Decapeptyl, Ferring, Kiel, Germany) and her OPU was carried out\n36 hours after triggering. Again, HCG and Decapeptyl (for triggering) were given by\na qualified nurse at the correct time. The ß-HCG level was 122.1miu/ml before\negg collection and her E2 was 1049 pg/ml. Her egg collection resulted in the\nretrieval of 2 poor quality immature germinal vesicles despite thorough, repeated\nflushing and aspiration ( Figure 1 ). Because of\nher past history of EFS, both her oocyte retrievals at our unit were performed by\nour most experienced physician. IVM was tried, again, for her two retrieved immature\noocytes. Unfortunately, none of them got mature until day five. The patient and her\nhusband gave their informed consent to use their information and photos of their\nimmature eggs for publication as they are quite eager to find a solution for their\nproblem\nRetrieved immature oocytes. A: Both oocytes together. B, C: Individual\noocytes under higher magnification (X 200).\n\nWe are reporting a case of repeated retrieval of immature oocytes in a patient with a\nprevious history of EFS. We have tried  in vitro  maturation for\nthese immature oocytes, which failed to mature further  in vitro .\nThis patient’s case has multiple noteworthy points of interest. Firstly, she is\nyoung and has a good ovarian reserve, as suggested by her basal hormonal profile.\nPrevious case reports suggested a relation between EFS and poor ovarian reserve, and\novarian aging ( Beck-Fruchter  et al .,\n2012 ). The exact mechanism for this poor outcome is not known. It might\nbe due to defective folliculogenesis or chromosomal abnormalities. Secondly, she has\na previous history of endometriosis that may suggest a role for endometriosis in the\npathogenesis of EFS, folliculogenesis or on the quality of eggs retrieved. The\nassociation of minimal endometriosis with EFS was reported in a previous cohort\nstudy on women undergoing natural IVF cycles ( Omland\n et al ., 2001 ). Thirdly, we adopted a combination of\ndifferent strategies reported in the literature to minimize the recurrence of EFS.\nThe use of an antagonist protocol may release the growing follicles from the strong\nsuppressive effect of a GnRH agonist. Additionally, dual triggering with HCG and\nGnRH agonist was used, as suggested in a previous case report ( Deepika  et al ., 2015 ). Furthermore, measuring\nHCG level on the day of ovum pick up confirmed our diagnosis. This rules out the\npossibility of drug errors (storage or manufacturer problems) and confirms that it\nis a true syndrome and not a fictional one. Repeated follicular flushing/aspiration\nduring oocyte retrieval was also used. Lastly, we obtained poor quality immature\noocytes in the last two trials. A previous case reported retrieval of four immature\noocytes following ovarian stimulation using an agonist protocol and an HCG trigger\n( Vutyavanich  et al .,\n2010 ). However, they did not try IVM. Another group retrieved five zona\nfree GV oocytes after using an antagonist protocol and a GNRH agonist trigger. They\ntried ICSI for these oocytes but failed ( Duru\n et al ., 2007 ). Rescue IVM was tried in this\ndesperate case. It has been suggested that the use of IVM has better results than\ninjecting immature oocytes. Previous trials were carried out on IVM following\nimmature oocyte retrieval with variable results. However, the immature oocytes\nretrieved in our case failed to mature further  in vitro .\n\nEmpty follicle syndrome seems to be a reality, even with the use of different\nstimulation protocols and triggering techniques. Recurrent EFS or recovery of\nimmature oocytes after a history of EFS is even more challenging, very stressful and\nfrustrating not only for the couple but also for the whole IVF team involved. The\nexact etiology of such a condition is still poorly understood. It is most likely\ncaused by abnormal or dysfunctional folliculogenesis. Management options in such\ndifficult cases are very limited. IVM was tried in our patient but unfortunately\nwithout success. Such women should be counselled for the very high risk of\nrecurrence in any subsequent IVF/ICSI trial.\nDr. Tarek Al-Hussaini, Dr. Omar Shabaan designed the report. They followed up the\npatient and Dr. Tarek Al-Hussaini performed the ovum pick up. Dr. Ihab EL-Nashar\nperformed IVM. Dr Ali Yosef assisted in patient follow up. The four authors\nparticipated in writing and final approval of the manuscript.","source_license":"CC-BY-4.0","license_restricted":false}