Recurrent Genuine Empty Follicle Syndrome: Diagnostic Dilemma and Management Challenges – A Case Report

INTRODUCTION

Empty follicle syndrome (EFS), first described by Coulam et al. in 1986, is a rare and perplexing phenomenon in assisted reproductive technology (ART) characterised by the failure to retrieve any oocytes despite apparently normal follicular development and appropriate hormonal responses after standard ovarian stimulation and retrieval protocols.^[1] The incidence of EFS varies between 0.2% and 7%, depending on patient populations and stimulation protocols employed.^[2,3]

EFS is categorised into two types: genuine and false. Genuine EFS occurs despite adequate serum β-human chorionic gonadotropin (β-hCG) concentrations, optimal follicular development, correct timing, and appropriate retrieval technique. False EFS typically results from errors such as improper drug administration, incorrect timing of oocyte retrieval, or reduced bioavailability and absorption of medications.^[4,5]

The exact pathophysiology underlying genuine EFS remains elusive. Potential mechanisms suggested include intrinsic ovarian dysfunction, anomalies of granulosa cell function, impaired detachment of the oocyte-cumulus complex, genetic mutations, and receptor abnormalities, particularly involving luteinising hormone/human chorionic gonadotropin (LH/hCG) receptors.^[6–8] Several studies have identified mutations in genes associated with follicular development and ovulation, such as LH receptor gene mutations, potentially contributing to the syndrome.^[9,10]

Despite advancements in ART techniques, recurrent genuine EFS poses significant diagnostic and therapeutic challenges, often leading to emotional distress and frustration for affected patients. Accurate diagnosis requires meticulous attention to technical details, hormonal assays, and exclusion of potential pharmacological or procedural errors.^[4]

We present a case of recurrent genuine EFS, highlighting diagnostic difficulties, underlying potential genetic implications, and current management dilemmas.

CASE REPORT

A 22-year-old female with primary infertility presented to us after 4 years of marriage. She was diagnosed with bilateral tubal blockage and low ovarian reserve (serum AMH 0.68 ng/ml). Her husband’s semen analysis revealed severe oligoasthenoteratozoospermia. Given their medical history, intracytoplasmic sperm injection was recommended.

The patient underwent controlled ovarian stimulation with a gonadotropin releasing hormone (GnRH) antagonist protocol, initiating stimulation with 300 IU human menopausal gonadotropin (hMG). On stimulation day 6, ultrasound monitoring showed five follicles measuring 11–12 mm, prompting the addition of a GnRH antagonist (0.25 mg) to prevent premature ovulation. On day 9, five follicles measuring 17–18 mm and two follicles of 13–14 mm were observed. Hormonal assays were not performed, as we routinely monitor ovarian response solely via ultrasound. Ovulation was triggered with 250 μg recombinant hCG, and oocyte retrieval was performed 35 hours later under ultrasound guidance using a 16G aspiration needle. All follicles were meticulously aspirated, and the follicular fluid was carefully examined by two experienced embryologists; no oocyte was retrieved despite visible follicles. Her β-hCG level was checked; the card test was positive, and the serum β-hCG was 86 mIU/ml, thereby confirming genuine EFS.

DISCUSSION

Genuine EFS is a rare and perplexing clinical condition defined by the failure to retrieve oocytes despite adequate follicular growth and optimal ovarian stimulation. As per current consensus, it remains a diagnosis of exclusion after ruling out pharmacological, technical, or timing-related errors in ovum pickup.^[11,12] In the present case, all known confounding factors, such as inadequate β-hCG exposure, premature ovulation, or procedural flaws, were meticulously excluded. Serial monitoring showed an adequate ovarian response to gonadotropins, a timely hCG trigger with appropriate serum levels, and standardised aspiration techniques with follicular flushing.

Ben-Shlomo et al.^[13] proposed that EFS may occur sporadically, especially in patients with prior successful retrievals. However, our patient experienced EFS in both IVF cycles, supporting the possibility of a recurrent and potentially intrinsic cause. Dysfunctional folliculogenesis has been hypothesised as a mechanism in some patients, yet our patient had normal follicular morphology and hormonal parameters throughout stimulation, arguing against this theory.^[2,14]

Another theory involves delayed oocyte-cumulus detachment due to inadequate hCG exposure. Studies have shown that extending the oocyte retrieval window may allow more time for detachment from the follicular wall.^[15,16] Nevertheless, in our case, even after optimising the retrieval timing during the second cycle (by extending the interval to 40 hours), no oocytes were retrieved, further reinforcing the diagnosis of genuine rather than false EFS.

Genetic aetiologies are emerging as potential contributors to recurrent EFS. Matzuk and Lamb ^[17] through gene knockout models in mice, identified several candidate genes essential for folliculogenesis and oocyte maturation. They highlighted that LH-mediated cumulus expansion depends on the interaction between mural granulosa cells and epidermal growth factor-like peptides (amphiregulin, epiregulin, and betacellulin), which in turn upregulate Ptgs2, TNFAIP6, and HAS2—all crucial for cumulus-oocyte complex maturation and detachment.^[18] Any mutations in this pathway may interfere with oocyte release despite morphologically normal follicles.

Further, Onalan et al.^[8] described EFS in two sisters with congenital sensorineural hearing loss, suggesting an autosomal recessive inheritance. Although no common syndromic association has been conclusively linked to EFS, candidate gene sequencing for FSH receptor (FSHR), luteinising hormone/choriogonadotropin receptor, and zona pellucida genes (ZP1–ZP4) has been proposed in such recurrent cases.^[19,20] Unfortunately, our patient did not consent to genetic testing, and there was no history of congenital anomalies or familial infertility.

The management of EFS remains largely empirical. Strategies such as dual triggering (GnRH agonist + hCG), delayed retrieval, and altered gonadotropin protocols have shown mixed results.^[21,22] Despite these adjustments, persistent failure often necessitates transition to donor oocyte programmes, as in our case.

Although EFS appears to be sporadic in most cases, recurrent forms likely reflect deeper pathophysiological abnormalities, potentially of genetic origin. However, the low recurrence rate reported in large IVF cohorts (0.5%–7%) supports the notion of a stochastic or multifactorial aetiology in most cases.^[23] There remains a pressing need for multicentric registries and molecular studies to better understand the biological underpinnings and standardise the management approach for EFS.

CONCLUSION

Recurrent genuine EFS remains one of the most challenging and least understood complications in ART. Despite optimal stimulation, appropriate trigger protocols, and rigorous procedural accuracy, the absence of oocyte retrieval—as seen in this case—underscores the diagnostic complexity and therapeutic limitations of genuine EFS. While sporadic cases may be attributed to random or technical factors, repeated occurrences, especially in young patients with otherwise normal ovarian morphology, raise the possibility of an underlying genetic or molecular aetiology. The lack of definitive diagnostic biomarkers and the limited availability of genetic testing further compound clinical decision-making. This case highlights the importance of a thorough and systematic approach to exclude false EFS, the utility of individualised modifications such as dual triggers and extended retrieval windows, and the eventual need to consider third-party reproduction in refractory cases. Future multicentric research and molecular studies are essential to unravel the pathogenesis, develop predictive markers, and refine management protocols for this elusive syndrome.