Două declanșări, niciun ovocit: un caz rar de sindrom autentic al foliculilor goi rezolvat cu protocolul de declanșare duală

Introduction

Empty follicle syndrome (EFS) is an infrequent yet distressing phenomenon encountered during in vitro fertilization (IVF) cycles, defined by the inability to retrieve oocytes from seemingly mature follicles despite adequate ovarian response and properly timed administration of a trigger for final oocyte maturation. First described in the early 1980s, EFS has since posed significant challenges in both diagnosis and management. The condition is broadly classified into two types: genuine EFS, where serum human chorionic gonadotropin (hCG) levels are within the expected therapeutic range at the time of oocyte retrieval, and false EFS, which occurs due to suboptimal hCG administration, errors in drug delivery, or rapid drug degradation⁽¹⁾. The reported incidence of EFS varies between 0.045% and 7% across different IVF populations⁽²⁾. Although considered rare, the emotional and financial burden on patients is considerable, particularly when cycles are unexpectedly canceled. While various hypotheses have been proposed – ranging from genetic mutations affecting folliculogenesis to dysfunctional LH/hCG receptor signaling –, the precise pathophysiology of genuine EFS remains elusive. Polycystic ovary syndrome (PCOS) patients, owing to their elevated antral follicle count and altered hormonal milieu, are often hyper-responders to gonadotropins and may paradoxically be at increased risk for EFS⁽³⁾. One emerging strategy to overcome this issue involves the use of a dual trigger – a combination of gonadotropin-releasing hormone (GnRH) agonist and low-dose hCG – which has been shown to enhance both oocyte maturation and retrieval rates by leveraging two physiological pathways for final follicular maturation. In this report, we describe a unique case of genuine EFS in a young woman with PCOS undergoing IVF, which was successfully managed in a subsequent cycle using a dual trigger protocol. This case contributes to the growing evidence supporting individualized trigger strategies to improve ART outcomes in select populations.

Case report

A 28-year-old woman, with a Body Mass Index (BMI) of 24 kg/m², diagnosed with PCOS based on the Rotterdam criteria, presented for her first IVF cycle due to anovulatory infertility of three years duration. She had no prior history of assisted reproductive technology. A GnRH antagonist protocol was planned. Controlled ovarian stimulation was initiated using 225 IU of recombinant FSH (rFSH) subcutaneously from the second day of the cycle. A GnRH antagonist (cetrorelix 0.25 mg/day) was introduced on the sixth day to prevent premature luteinizing hormone (LH) surge. By day 12, transvaginal ultrasound revealed 18 follicles ≥14 mm in diameter across both ovaries. Serum estradiol was 2850 pg/ml. Final oocyte maturation was triggered using 250 mcg of recombinant hCG. Oocyte retrieval was performed 36 hours later. Ten follicles from the right ovary were aspirated, but no oocytes were retrieved. The aspiration fluid was examined carefully, and follicular flushing was also performed, with no success. Given the suspicion of EFS, serum b-hCG was measured, revealing a level of 120 mIU/mL on the day of pick-up, confirming genuine EFS⁽⁴⁾. A second dose of hCG was administered that night, and oocyte retrieval from the left ovary was scheduled 36 hours later. However, no oocytes were retrieved again, and serum b-hCG before the second retrieval was 96 mIU/mL. In the subsequent cycle, a modified approach using a dual trigger was planned. Final oocyte maturation was induced with a combination of 0.2 mg GnRH agonist and 250 mcg of recombinant hCG when at least three follicles reached 18 mm. Oocyte retrieval after 36 hours resulted in the successful collection of 14 mature oocytes. Fertilization was achieved in 11 of them, and a single top-grade blastocyst was transferred on the fifth day. A clinical pregnancy was confirmed by the presence of a gestational sac and fetal heartbeat at six weeks of gestation.

Discussion

Empty follicle syndrome represents a rare but distressing complication in assisted reproductive technology (ART), especially when encountered unexpectedly in well-responding cycles. It is defined by the failure to retrieve oocytes despite adequate follicular development and appropriate timing of ovum pick-up (OPU), leading to significant psychological and clinical dilemmas. The estimated incidence ranges from 0.045% to 7%, and it is broadly categorized as false or genuine, depending on serum b-hCG levels at retrieval^(4,5). False EFS, commonly attributed to improper hCG administration or drug errors, is potentially salvageable with timely intervention. In contrast, genuine EFS – characterized by serum b-hCG levels higher than 40 mIU/mL – occurs despite correct pharmacologic triggering, suggesting a deeper pathophysiological dysfunction. The proposed mechanisms include impaired LH/hCG receptor function, aberrant folliculogenesis, premature luteinization, or disrupted cumulus-oocyte complex detachment⁽⁶⁾. The management pivots on prompt b-hCG assessment to differentiate genuine from false EFS. In genuine cases, “rescue” triggers are rarely successful, and subsequent cycles warrant strategic modification. The dual trigger protocol, which combines a GnRH agonist with low-dose hCG, has shown promise. It capitalizes on a physiological FSH and LH surge to enhance final oocyte maturation and cumulus expansion⁽⁷⁾. Our case underscores the potential of the dual trigger to overcome genuine EFS, particularly in polycystic ovary syndrome (PCOS) patients, who may be predisposed to follicular dysmaturity. Following failed oocyte retrieval with r-hCG alone, the patient achieved successful oocyte recovery, fertilization and blastocyst formation with the dual trigger. This experience reinforces the clinical utility of dual triggering in selected patients – especially high responders and those with previous failed retrievals. It highlights the importance of early recognition, appropriate categorization and personalized protocol refinement in overcoming this elusive ART challenge⁽⁸⁾.

Conclusions

Genuine empty follicle syndrome is a rare but distressing complication of in vitro fertilization. The dual trigger approach may be an effective solution in overcoming this challenge, particularly in patients with polycystic ovary syndrome and previous failed retrievals. This case adds to the growing body of evidence supporting the role of dual trigger in improving oocyte retrieval outcomes.   

Corresponding author: Smit Bharat Solanki E-mail: drsmitbharat@gmail.com

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.