Spontaneous ovarian hyperstimulation syndrome mimicking ovarian cancer in a nonpregnant woman: A case report and literature review

Abstract

Spontaneous ovarian hyperstimulation syndrome is an extremely rare condition, especially in nonpregnant women who do not exhibit exogenous ovarian stimulation. Herein, we present a case of spontaneous ovarian hyperstimulation syndrome in a 28-year-old nonpregnant woman who presented with life-threatening multiorgan dysfunction. Initial imaging studies and tumor marker assessment suggested the presence of a malignant ovarian tumor, posing substantial diagnostic challenges. The patient underwent emergency surgery due to severe hemorrhagic shock. Intraoperative findings revealed irregular and deformed ovaries; however, histologic examination showed luteinizing hemorrhagic cysts, leading to a diagnosis of spontaneous ovarian hyperstimulation syndrome. This case highlights the importance of considering spontaneous ovarian hyperstimulation syndrome in the differential diagnosis of ovarian enlargement with ascites, even in the absence of pregnancy or ovarian stimulation. It also underscores the critical role of expert radiological interpretation in such complex cases.

Introduction

Ovarian hyperstimulation syndrome (OHSS) is typically an iatrogenic condition associated with assisted reproductive technologies, occurring in 1%–14% of cases of in vitro fertilization or intracytoplasmic sperm injection. ¹ OHSS is characterized by enlarged multicystic ovaries and third-space fluid accumulation due to increased vascular permeability. Young women with polycystic ovary syndrome or a history of OHSS are more susceptible to spontaneous OHSS (sOHSS); however, it can occur without exogenous ovarian stimulation.

sOHSS is an extremely rare condition, constituting <1% of all OHSS cases. It is frequently reported as a consequence of pregnancy, typically in the context of multiple gestations or molar pregnancies.^2,3 Furthermore, cases of sOHSS induced by follicle-stimulating hormone (FSH)–producing pituitary adenomas, neuroendocrine tumors, or severe hypothyroidism are even rarer. ⁴

The pathophysiology of sOHSS is linked to excessive stimulation of FSH receptors (FSHRs), which can occur due to pregnancy-related human chorionic gonadotropin (hCG), mutant FSHRs, or cross-stimulation with elevated thyroid-stimulating hormone (TSH) in hypothyroidism. This excessive stimulation leads to the overproduction of vasoactive substances, particularly vascular endothelial growth factor (VEGF), by the corpora lutea, resulting in the characteristic features of this syndrome.^5,6

Herein, we present an exceptionally rare case of sOHSS in an euthyroid, nonpregnant young woman who presented with life-threatening multiorgan dysfunction. This case was initially misdiagnosed as ovarian cancer, highlighting the diagnostic challenges associated with this rare condition. Through this case report, we aim to increase the awareness of sOHSS as a potential differential diagnosis in cases of ovarian enlargement with ascites, even in the absence of pregnancy or ovarian stimulation.

Case presentation

In April 2022, a 28-year-old woman (G1P1A0) presented to the Imam Khomeini Hospital Complex, Tehran, Iran, a tertiary hospital, with progressive abdominal pain, ascites, bilateral pleural effusion, and oliguria. She reported regular menstrual cycles and no history of abnormal uterine bleeding. Her medical history included hyperprolactinemia, which had resolved after cabergoline therapy, with prolactin levels returning to normal in recent years. She had a healthy 7-year-old son and a family history of cancer among multiple second-degree relatives. She reported infrequent alcohol use and consumption of an emergency contraceptive pill (levonorgestrel) a few weeks before presentation.

Abdominopelvic and transvaginal ultrasonography revealed bilateral ovarian enlargement with mixed solid and hemorrhagic cystic components, thick septations, and increased vascularity, consistent with the features of the Ovarian-Adnexal Reporting Data System (ORADS) 5 classification. Additional findings of moderate-to-severe ascites and omental nodularity further raised suspicion for malignancy. However, given the acute clinical presentation, the application of ORADS 5 classification in this setting should be interpreted with caution.

Initial laboratory examination showed abnormal coagulation along with disseminated intravascular coagulation (DIC), mild thrombocytopenia, elevated lactate dehydrogenase level, aminotransferase level exceeding 1000 U/L, and severe renal failure. The beta-hCG test was negative, with normal TSH level. The prolactin level was 29.4 ng/mL, human epididymis protein-4 level was 773 (normal range: <70) pmol/L, cancer antigen 125 level was 150 U/mL, and the Risk of Ovarian Malignancy Algorithm index was 98, with other ovarian tumor markers being normal.

Paracentesis of ascitic fluid revealed a pink-colored fluid with a high serum–ascites albumin gradient, high protein levels, polymorphonuclear cell-dominant leukocytes (240/µL), and a substantial number of red cells. Cytology analysis showed no malignant cells.

Supportive care was initiated. Owing to acute anuric renal failure, two sessions of hemodialysis were conducted. To assess the possibility of a Krukenberg tumor, upper endoscopy was performed, which yielded nonspecific findings without any evidence of a mass. Positron emission tomography–computed tomography (PET–CT) revealed an extensive, mild metabolically active mass in the pelvis and lower abdomen, along with retroperitoneal metastatic lymphadenopathies.

A few days after admission, the patient’s condition deteriorated. Her abdominal girth increased, leading to abdominal pain and dyspnea. Ascitic fluid was drained; however, this time, bloody fluid was extracted. As the progressive accumulation of ascitic fluid caused respiratory compromise and renal dysfunction, multiple paracentesis procedures were performed. However, the patient subsequently developed hemorrhagic shock, with a hematocrit drop from 34% to 16% and hemoglobin levels falling to 2.5 g/dL. Contrast-enhanced CT revealed clot density in the ascitic fluid and a massive retro-uterine hematoma adjacent to the ovary, with active bleeding from the left adnexa (Figure 1), necessitating emergency surgical intervention. At the time of surgical decision-making, the primary differential diagnoses included ovarian malignancy with peritoneal spread and hemorrhagic ovarian cyst rupture.

Figure 1.

(a) Coronal contrast-enhanced abdominopelvic computed tomography (CT) showing bilateral enlarged ovaries (red arrow) and severe ascites. (b) Axial contrast-enhanced pelvic CT revealing bilateral enlarged multicystic ovaries in the anterior pelvis (red arrow) and a large hematoma containing several fluid–fluid levels in the posterior pelvis (red star) and (c) Axial contrast-enhanced CT of the upper abdomen indicating severe ascites and a soft tissue nodule in the left subphrenic space, which was initially interpreted as a tumoral implant but was later identified as a clot.

Prophylactic anticoagulation was discontinued, and the patient underwent massive transfusion therapy, including packed red blood cells, fresh frozen plasma, and platelets, to stabilize hemodynamics and correct DIC. Given the risk of respiratory compromise due to tense ascites and pleural effusion, rapid sequence induction with endotracheal intubation was performed to secure the airway. Diagnostic laparoscopic surgery was then conducted, revealing a large retroperitoneal hematoma with active bleeding from the left adnexa. Intraoperative hemodynamic management focused on goal-directed fluid therapy with balanced crystalloids and colloids, while central venous pressure monitoring was utilized to guide fluid resuscitation and prevent volume overload. During surgery, approximately 2 L of hematoma was suctioned from the abdominal cavity. The right ovary appeared completely deformed and irregular, leading to the decision to perform right oophorectomy, while the left ovary with cystic changes was biopsied.

After 2 weeks of hospitalization, the patient’s condition stabilized, and she recovered well, with urinary output returning to normal levels. She was subsequently discharged home. During a follow-up visit 3 weeks later, the patient’s health remained stable, and the histology report revealed a multiloculated luteal hemorrhagic cyst without any other specific changes. Abdominopelvic ultrasonography showed no signs of ascites, and the spleen size appeared normal. The previously hyperstimulated left ovary also appeared completely normal. The patient’s menstrual cycle resumed normally, and all laboratory tests, including liver and renal function tests and complete blood counts, returned to normal levels. This case report was prepared following the Case Report (CARE) guidelines. ⁷ All patient details have been de-identified to ensure anonymity.

Discussion

Spontaneous and iatrogenic OHSS share a similar presentation; excessive stimulation and luteinization of ovarian follicles lead to the overproduction of vasoactive substances, particularly VEGF, by the corpora lutea. This excessive production induces an extravascular fluid shift to the peritoneal, pleural, or pericardial spaces. The ensuing hypovolemic shock may cause life-threatening complications, such as organ dysfunction, especially renal failure, hemoconcentration, thromboembolic events, or death in severe cases.^2,4,8

Chorionic gonadotropin is considered one of the major causative factors in the pathophysiology of OHSS. The prescription of exogenous hCG for ovarian stimulation, intrinsic hCG from pregnancy products, or hypersensitivity of mutant FSHRs to hCG confirm the importance of hCG in OHSS development. Additionally, OHSS appears to be more prevalent in hydatidiform moles with higher hCG levels.^2–4,8 Genetic research on recurrent and familial cases of OHSS has identified certain individuals with mutations in the FSHR gene. These findings shed light on the underlying molecular mechanisms that enable FSHRs to interact with various hormones. Patients with OHSS have been found to possess mutant FSHRs that exhibit heightened responsiveness to glycoprotein hormones and increased intrinsic activity.^1,9 The mutations are located in the transmembrane helices, extracellular domain, and receptor’s cytoplasmic tail, affecting FSHR density on the cell surface and influencing the activation of signaling pathways within the cells.^10–12 A pituitary adenoma secreting FSH may also lead to continuous hyperstimulation of the ovaries. ¹³ This condition is characterized by an increase in the ovarian size due to multiple cysts and high levels of estradiol, consistent with the clinical features of OHSS. However, unlike OHSS, ovarian hyperstimulation caused by a pituitary adenoma does not result in pleural effusion or accumulation of ascites. ¹⁴ Therefore, the accumulation of fluid in the extracellular space serves as an effective method to distinguish OHSS from ovarian hyperstimulation caused by a pituitary adenoma.

The present case involves a nonpregnant woman with normal hCG levels and normal thyroid function who exhibited multicystic ovaries, multiorgan failure including ischemic hepatitis, dialysis-dependent renal failure, DIC, extravascular third spacing, and no history of ovulatory stimulation drug use. The retroperitoneal hemorrhage was most likely caused by spontaneous ovarian rupture secondary to sOHSS. The hyperstimulated ovaries, influenced by excessive VEGF production, became highly vascular and prone to spontaneous bleeding. Additionally, prophylactic anticoagulation therapy, given to mitigate the thromboembolic risks associated with sOHSS, may have contributed to uncontrolled hemorrhage. Although repeated paracentesis was performed to relieve respiratory distress and renal dysfunction, it may have exacerbated intravascular volume depletion and coagulation abnormalities, indirectly worsening the bleeding. However, the hemorrhage itself was not directly attributable to the paracentesis procedures.

Although genetic testing for FSHR mutations was not conducted, the patient’s clinical course strongly suggests FSHR hypersensitivity as a potential mechanism underlying OHSS development. The absence of exogenous gonadotropin stimulation, coupled with severe ovarian enlargement and third-space fluid shifts, aligns with the reported cases of sOHSS due to altered FSHR activity. ¹⁵ Studies have shown that certain FSHR mutations result in heightened receptor sensitivity to endogenous gonadotropins, leading to excessive follicular stimulation and increased VEGF-mediated vascular permeability. ¹¹ Additionally, the patient’s history of hyperprolactinemia, although resolved, indicates an underlying neuroendocrine predisposition that contributed to the dysregulated ovarian response. Given the absence of pregnancy and controlled ovarian stimulation, spontaneous FSHR hyperresponsiveness remains the most plausible etiology in this case. The patient’s imaging studies and family history of cancer initially led to a misdiagnosis. Although the ORADS 5 classification system is typically used for risk stratification in ovarian masses, its application in acute cases remains controversial. This classification system is designed for nonacute adnexal lesions and does not account for emergency conditions such as ovarian torsion, hemorrhagic cysts, or sOHSS. In this case, the high ORADS score contributed to an initial misdiagnosis of malignancy, highlighting the need for integrating clinical presentation with imaging findings rather than relying solely on structured scoring systems in emergency settings. Due to the patient’s unstable clinical condition and hemoperitoneum, surgery was performed. However, upon review of CT images by an experienced radiology professor, a diagnosis of OHSS was made. This indicates that in the context of this particular case, the expertise of a skilled radiologist interpreting CT images holds greater diagnostic value than other advanced imaging techniques such as PET–CT. This underscores the importance of strategically utilizing imaging methods based on clinical settings. Furthermore, in this case, the normal hCG levels highlight the potential role of other factors in the pathophysiology of sOHSS.

The management of OHSS is primarily conservative and focuses on supportive care, including hydration, correction of electrolyte and acid–base imbalances, symptomatic paracentesis as needed, and thrombosis prophylaxis. Surgery is indicated only in critical situations, such as ovarian rupture, torsion, or intraperitoneal hemorrhage. Fortunately, most OHSS cases are mild and self-limiting but require careful long-term follow-up, particularly in patients with severe presentations.^3,4,16 In this case, the patient was advised to undergo regular gynecologic follow-ups with serial ultrasound assessments to monitor ovarian morphology and detect any abnormal follicular activity. Given the potential risk of recurrent OHSS, especially in future pregnancies, she was counseled on the importance of preconception consultation and hormonal evaluations before attempting conception. If recurrent follicular overstimulation is observed, hormonal regulation, including combined oral contraceptive therapy, may be considered to prevent complications. Additionally, further endocrinologic assessment may be warranted if symptoms suggest FSHR hyperresponsiveness. To the best of our knowledge, sOHSS in a nonpregnant woman with normal hCG levels and normal thyroid function is an extremely rare condition, with only a few cases reported in the literature. ¹⁶ Although previous reports have described sOHSS in the context of pregnancy or hormonal disorders, this case is unique as the condition occurs in a nonpregnant, euthyroid woman with no exogenous stimulation, thereby expanding the differential diagnosis for ovarian enlargement with ascites.

Conclusion

This case highlights the importance of considering sOHSS as a differential diagnosis in nonpregnant women presenting with ovarian enlargement, ascites, and multiorgan dysfunction. Although sOHSS frequently occurs in the context of assisted reproductive techniques, it has also been reported in women with natural ovulatory cycles. However, cases occurring in nonpregnant euthyroid women without exogenous ovarian stimulation are extremely rare. Given the potential risk of recurrence, careful gynecologic and endocrinologic follow-up is recommended. In cases of recurrent ovarian hyperstimulation, hormonal therapy may be an option to prevent complications; however, further research is needed to better understand the mechanisms of sOHSS.