Ovarian Hyperstimulation Syndrome: Symptoms, Types, Causes and Treatment

Ovarian Hyperstimulation Syndrome (OHSS) is a potentially serious complication that can arise during fertility treatments, particularly those involving ovarian stimulation. As the use of assisted reproductive technologies (ART) grows worldwide, understanding OHSS has become essential for both clinicians and patients. This article delves into the symptoms, types, causes, and treatment of OHSS, offering practical insights supported by the latest research.

Symptoms of Ovarian Hyperstimulation Syndrome

OHSS can present with a broad range of symptoms, varying from mild discomfort to life-threatening complications. Awareness of these symptoms is crucial for early identification and prompt management.

Symptom	Description	Severity Range	Source
Abdominal Pain	Discomfort or pain in abdomen	Mild to Severe	1 3 5 8
Nausea/Vomiting	Feeling sick or actual vomiting	Mild to Severe	1 2 5
Abdominal Distension	Swelling or bloating	Mild to Severe	2 3 5 8
Ascites	Fluid accumulation in abdomen	Moderate to Critical	1 3 8 12
Ovarian Enlargement	Swollen, cystic ovaries	Mild to Critical	1 2 5 8
Dyspnea	Difficulty breathing (from effusions)	Severe to Critical	3 8 12
Oliguria	Reduced urine output	Severe to Critical	12 15
Thromboembolism	Blood clots	Severe to Critical	3 12 15
Ovarian Torsion	Twisting of the ovary	Severe	5

Table 1: Key Symptoms of OHSS

Recognizing the Range of Symptoms

OHSS typically unfolds in a spectrum, from mild to critical. Early symptoms like abdominal discomfort and bloating may appear soon after ovulation induction. As severity increases, dangerous complications such as fluid accumulation (ascites), shortness of breath (from fluid in the chest), and reduced urine output can develop 1 3 8 12. In rare but severe cases, life-threatening events like thromboembolism (blood clots), kidney dysfunction, and even death are possible 12 15.

Mild to Moderate Symptoms

• Abdominal pain, distension, and nausea often occur first, sometimes accompanied by vomiting. Many women experience a sense of fullness or bloating 1 2 3 5.
• Ovarian enlargement is usually detectable on ultrasound, with ovaries appearing cystic and swollen 1 2 8.
• Mild ascites (fluid in the abdomen) may be present 3 8.

Severe and Critical Symptoms

• Severe forms are marked by dramatic fluid shifts, resulting in massive ascites, pleural effusions (fluid around the lungs), and sometimes pericardial effusions (fluid around the heart) 1 3 8 12.
• Oliguria (very reduced urine output) signals compromised kidney function 12 15.
• Thromboembolic events such as deep vein thrombosis or pulmonary embolism are rare but serious risks due to hemoconcentration 3 12 15.
• Ovarian torsion is a surgical emergency, arising when the ovary twists on itself due to its increased size and weight 5.

When to Seek Urgent Care

Any rapid worsening of symptoms—such as severe abdominal pain, sudden breathlessness, chest pain, or leg swelling—should prompt immediate medical attention. Early recognition and intervention are key to preventing major complications.

Types of Ovarian Hyperstimulation Syndrome

OHSS is not a one-size-fits-all condition. It varies in onset, severity, and clinical features, which helps guide management decisions.

Type	Onset/Timing	Main Features	Source
Mild	Early (post-trigger)	Abdominal discomfort, mild distension, ovarian enlargement	1 3 4 8
Moderate	Early	Symptoms above plus ascites, nausea/vomiting	1 3 8 10
Severe	Early or Late	Large ascites, pleural effusion, oliguria, hemoconcentration	1 8 10 12
Critical	Early or Late	Renal failure, thromboembolism, ARDS, shock	8 12 15
Early-onset	<9 days post-hCG	Triggered by exogenous hCG	1 4 8
Late-onset	>10 days post-hCG	Related to pregnancy (endogenous hCG)	8 10 18
Spontaneous	Variable	Not related to fertility meds, rare	2 14

Table 2: Types of OHSS

Classification by Severity

OHSS is classically divided into mild, moderate, severe, and critical forms:

• Mild OHSS: Symptoms are limited to discomfort, mild swelling, and ovarian enlargement 1 3 4 8.
• Moderate OHSS: Increased abdominal swelling, nausea, vomiting, and the presence of ascites 1 3 8 10.
• Severe OHSS: Significant fluid shifts manifest as large-volume ascites, pleural effusions, hemoconcentration (increased blood concentration), and reduced urine output 1 8 10 12.
• Critical OHSS: Life-threatening complications—renal failure, thromboembolism, acute respiratory distress syndrome (ARDS), and circulatory collapse 8 12 15.

Timing-Based Classification

• Early-onset OHSS: Develops within 9 days after administration of human chorionic gonadotropin (hCG), usually as part of fertility treatment 1 4 8.
• Late-onset OHSS: Occurs after 10 days, often triggered by rising endogenous hCG from an early pregnancy 8 10 18. If conception occurs, OHSS can be more severe and prolonged 3 8.

Rare Types

• Spontaneous OHSS: Exceptionally rare, can occur without fertility medications and is linked to underlying hormonal or genetic factors, such as pituitary adenomas or FSH receptor mutations 2 14.

Why Classification Matters

Understanding the type and severity of OHSS helps healthcare providers determine the best management strategy—ranging from outpatient monitoring to intensive hospital care.

Causes of Ovarian Hyperstimulation Syndrome

OHSS is primarily an iatrogenic condition—meaning it’s caused by medical treatment, particularly fertility drugs. However, several underlying mechanisms and risk factors are at play.

Cause	Mechanism/Trigger	Risk Factors or Populations	Source
Exogenous hCG	Stimulates ovarian VEGF, increases permeability	High-dose or sensitive response	1 3 8 12
Gonadotropins	Overstimulate ovaries, ↑ follicle/estradiol	PCOS, high ovarian reserve	1 3 6 8
Clomiphene Citrate	Rarely, excessive ovarian stimulation	High/overdose, sensitive patients	5
GnRH Agonist/Antagonist	Varies, but antagonist protocols ↓ risk	Protocol-dependent	1 3 4 17
Endogenous hCG	Early pregnancy triggers late OHSS	Pregnancy after ART	8 10 18
Spontaneous	Pituitary adenomas, FSH receptor mutations	Rare genetic/hormonal cases	2 14

Table 3: Causes and Risk Factors for OHSS

Hormonal Triggers and Pathophysiology

• Human Chorionic Gonadotropin (hCG) is central to OHSS development. hCG—whether administered during ART or produced naturally in early pregnancy—stimulates the ovaries to release vascular endothelial growth factor (VEGF) and other substances that make blood vessels leaky, leading to fluid shifts 1 3 8 12.
• Other contributors include interleukins, tumor necrosis factor-α, and substances from the renin-angiotensin system, all increasing capillary permeability 1 12.

Medication-Induced (Iatrogenic) Causes

• Gonadotropins (FSH, LH) used in ovulation induction and ovarian stimulation are the most common triggers, especially at higher doses or in women who are particularly sensitive (e.g., those with polycystic ovary syndrome [PCOS]) 1 3 6 8.
• Clomiphene citrate is generally safer, but can cause OHSS in rare cases, especially with high doses or in susceptible women. Severe cases can even lead to ovarian torsion 5.
• GnRH agonists/antagonists: Protocols using GnRH antagonists and/or agonists to trigger ovulation can reduce the risk of OHSS, though not eliminate it 1 3 4 17.

Patient-Related Risk Factors

• High ovarian reserve (young age, high antral follicle count, high anti-Müllerian hormone)
• Polycystic ovary syndrome (PCOS)
• Previous episodes of OHSS
• High number of follicles or rapidly rising estradiol levels during stimulation 3 6 16

Rare Spontaneous Causes

• Gonadotroph pituitary adenomas can cause excess FSH production, leading to spontaneous OHSS 2.
• FSH receptor mutations may allow hCG to stimulate the ovary abnormally, causing familial or gestational spontaneous OHSS 14.

Treatment of Ovarian Hyperstimulation Syndrome

Managing OHSS requires a tailored approach based on severity. Most cases resolve with conservative care, but severe or critical OHSS demands intensive intervention.

Treatment	Indications/Use	Approach Level	Source
Outpatient Support	Mild/Moderate cases	Oral fluids, monitor, analgesia	3 8 13
Hospitalization	Severe/critical cases	IV fluids, monitoring, thromboprophylaxis	1 3 8 13
Paracentesis	Symptomatic ascites	Fluid drainage	8 13 15 16
Heparin	Thrombosis prevention	Hospitalized severe cases	1 3 8 12
Albumin	Severe OHSS, hypovolemia	IV administration	1 12 16
Cabergoline	Prevention/early OHSS	Reduces VEGF effect	1 4 17
Dopamine	Renal support (rare)	Severe/critical	16
Surgery	Ovarian torsion, rupture	Emergency/rare	5 13 15
Cycle Cancellation	Prevention for high-risk	Withhold hCG, delay trigger	11 16 18
Embryo Cryopreservation	Prevention	Avoids endogenous hCG	3 11 17

Table 4: Treatment and Prevention Strategies for OHSS

Supportive and Symptomatic Management

Outpatient Care

• Mild to moderate OHSS can often be managed at home:
  • Encourage oral fluid intake, guided by thirst
  • Monitor for worsening symptoms
  • Provide pain relief and anti-nausea medication as needed 3 8 13

Hospitalization

• Severe or critical OHSS requires hospital admission:
  • IV fluid resuscitation to correct hypovolemia and electrolyte imbalances
  • Close monitoring of urine output, weight, and vital signs
  • Prevention of thromboembolism with heparin or similar agents
  • Paracentesis (drainage) for tense ascites or respiratory compromise 1 3 8 13 15 16
  • Albumin infusions to restore plasma volume and oncotic pressure 1 12 16

Management of Complications

• Ovarian torsion or rupture may require surgical intervention to preserve ovarian function 5 13 15.
• Renal support (e.g., dopamine drips) and intensive care for critical cases 16.
• Therapeutic termination of pregnancy may be considered in life-threatening, refractory OHSS 16.

Prevention Strategies

• Individualized stimulation protocols: Use the lowest effective dose of gonadotropins, especially in high-risk women 3 6 16.
• Monitoring: Regular ultrasound and estradiol measurements during ovarian stimulation 3 6 18.
• Cycle cancellation or coasting: Withhold hCG if there are too many follicles or estradiol is very high 11 16 18.
• GnRH antagonist protocols and agonist triggers: Shown to significantly reduce OHSS risk 1 3 4 17.
• Embryo cryopreservation: Freezing all embryos and postponing transfer avoids the surge in endogenous hCG from pregnancy 3 11 17.
• Dopaminergic agents (e.g., cabergoline): Reduce the effect of VEGF and capillary leak 1 4 17.

Follow-up and Patient Education

• All women at risk should receive clear information about OHSS, including symptoms to watch for and access to 24-hour care 3.
• Close follow-up during ART cycles and after embryo transfer is essential.

Conclusion

Ovarian Hyperstimulation Syndrome represents a unique and serious challenge in reproductive medicine. Its prevention, recognition, and treatment require coordinated effort and up-to-date knowledge.

Key Takeaways:

• OHSS is most commonly an iatrogenic complication of fertility treatments, with a broad spectrum of symptoms from mild discomfort to life-threatening emergencies 1 3 8 12.
• Severity and timing (early vs. late onset) help guide management and predict risks 1 3 4 8 10.
• Causes include medication-induced ovarian stimulation, endogenous hCG from early pregnancy, and rare spontaneous or genetic mechanisms 1 3 5 8 12 14.
• Management ranges from outpatient monitoring to intensive hospital care, with a strong emphasis on prevention in high-risk patients 3 8 13 17.
• Preventive strategies—such as protocol adjustment, careful monitoring, and embryo cryopreservation—can greatly reduce the incidence and severity of OHSS 1 3 4 11 17.

By recognizing the risk factors and implementing evidence-based prevention and treatment strategies, clinicians can help minimize the burden of OHSS and ensure safer fertility journeys for patients.