Empty Sella Syndrome

Key Points at a Glance

Key Points of This Disease

• Empty sella syndrome (ESS) is a condition in which cerebrospinal fluid herniates into the sella turcica, compressing the pituitary gland.
• It is classified into primary (PESS) and secondary (SESS) types.
• It is found in 5.5–12% of autopsy cases and approximately 12% of neuroimaging studies.
• About half of cases are asymptomatic and discovered incidentally on imaging.
• The complication rate of hypopituitarism is approximately 52%, with the growth hormone axis and gonadal axis being most susceptible to impairment.
• Ophthalmologically, visual field defects such as bitemporal hemianopsia and binasal hemianopsia may occur.
• Symptoms can be improved by hormone replacement therapy, making appropriate diagnosis and treatment important.

1. What is Empty Sella Syndrome?

Empty Sella Syndrome (ESS) is an anatomical condition in which the pituitary tissue within the sella turcica appears clearly absent. It occurs when cerebrospinal fluid (CSF) herniates from the subarachnoid space into the sella turcica, compressing and displacing the pituitary gland against the sellar floor.

History

In 1951, Busch first reported this condition after identifying a flattened pituitary gland during an autopsy of a patient with no history of pituitary disease.

Classification

ESS is classified into primary empty sella syndrome (Primary ESS: PESS) and secondary empty sella syndrome (Secondary ESS: SESS). PESS is idiopathic and often discovered incidentally on imaging. SESS results from underlying conditions such as treatment of pituitary tumors or increased intracranial pressure.

It is also subclassified based on the degree of CSF filling within the sella turcica as follows:

• Partial empty sella: CSF occupies less than 50% of the sella, and pituitary tissue is 3 mm or more in thickness.
• Complete empty sella: CSF occupies 50% or more of the sella, and pituitary tissue is <2 mm in thickness.

Epidemiology

ESS is found in 5.5–12% of autopsy cases and up to 12% on neuroimaging ¹⁾. It is more common in women, with a female-to-male ratio of 4–5:1 ¹⁾. The prevalence of primary ESS is reported to be 2–20% ¹⁾. The peak age of onset is around 30–40 years, and empty sella is observed in approximately 70% of patients with idiopathic intracranial hypertension (IIH) ¹⁾. About 50% of cases are asymptomatic and discovered incidentally on imaging ²⁾.

Q Is empty sella syndrome a rare disease?

A

Since it is found in up to 12% of imaging studies, it is not rare at all. Most cases are asymptomatic and discovered incidentally. However, the frequency of symptomatic presentation with endocrine or visual field disturbances is lower.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

The most common symptom of ESS is nonspecific headache. However, a direct causal relationship between ESS and headache has not been proven, and it may be an incidental finding.

• Visual abnormalities: decreased visual acuity, blurred vision, diplopia, tunnel vision. Common in SESS, but visual field defects have been reported in up to 16% of PESS cases.
• General fatigue: due to adrenal insufficiency or hypothyroidism associated with hypopituitarism. May be accompanied by a history of repeated hospitalizations¹⁾.
• Menstrual abnormalities: observed in approximately 40% of female patients¹⁾.
• Hyponatremia: develops due to a SIADH-like condition caused by adrenal insufficiency. Severe cases with sodium levels dropping to 102–111 mmol/L have been reported⁴⁾⁶⁾.
• Rhinorrhea: may be recognized as cerebrospinal fluid rhinorrhea.

Clinical Findings (Findings Confirmed by Physician Examination)

Ophthalmologic Findings

Compression or traction of the optic chiasm causes various visual field defects.

• Bitemporal hemianopia: The most typical visual field defect due to chiasmal herniation.
• Binasal hemianopia: Occurs when the optic chiasm is pulled downward by negative pressure from the sella turcica.
• Other visual field defects: Arcuate scotoma, visual field constriction, central scotoma, junctional visual field defect (Traquair’s junctional scotoma), and enlargement of the blind spot.
• Optic atrophy: In the chronic phase, band-shaped optic atrophy is observed.
• Papilledema: Seen in SESS with increased intracranial pressure.
• Oculomotor nerve palsy: Rarely associated.

Ophthalmologic Findings

Bitemporal hemianopsia: The most typical finding due to chiasmal herniation.

Binasal hemianopsia: Caused by downward traction of the optic chiasm.

Optic atrophy: Sectoral atrophy in the chronic phase.

Papilledema: In cases with increased intracranial pressure.

Endocrine findings

Growth hormone deficiency: Most frequent endocrine disorder.

Hypogonadism: Amenorrhea, decreased libido.

Adrenal insufficiency: Cause of hypotension and fatigue.

Central hypothyroidism: Low FT4.

Endocrine findings

Hypopituitarism occurs in approximately 52% of ESS cases ¹⁾. The following are listed in order of decreasing frequency.

• Growth hormone deficiency: Most frequent. Observed in both children and adults ¹⁾.
• Hypogonadism: In women, menstrual abnormalities (40%), galactorrhea (26%), and hirsutism (18%) are observed. In men, gynecomastia (12%) and sexual dysfunction (53%) are present ¹⁾.
• Adrenal insufficiency: Central hypocortisolemia occurs, which may lead to severe hyponatremia ³⁾⁴⁾.
• Central hypothyroidism: FT4 is low, but TSH can be low, normal, or mildly elevated¹⁾.
• Hyperprolactinemia: Caused by compression of the pituitary stalk.

Q What visual field defects occur in empty sella syndrome?

A

Bitemporal hemianopsia due to herniation of the optic chiasm is most typical. Binasal hemianopsia due to downward traction of the optic chiasm has also been reported. Other patterns such as arcuate scotoma, central scotoma, junctional scotoma, and enlargement of the blind spot may occur. For details, see the “Clinical Findings” section.

3. Causes and Risk Factors

Primary (PESS)

Diaphragma sellae defect: Congenitally large opening, allowing CSF to herniate into the sella turcica. Found in up to 20% of the normal population.

Idiopathic: No clear underlying disease.

Genetic factors: Associations with CHD7 gene mutations and PROP1 gene deletions have been reported⁵⁾.

Secondary (SESS)

Post-transsphenoidal surgery: The most common cause.

Increased intracranial pressure: Including idiopathic intracranial hypertension (IIH).

Pituitary apoplexy: Sheehan syndrome, etc.

Others: Radiation therapy, infections, autoimmune diseases, immune checkpoint inhibitors⁷⁾.

Primary risk factors

• Obesity: Approximately 73% of PES patients are overweight, 14% are obese⁸⁾.
• Female: About 5 times higher risk than males.
• Hypertension: Stress on bone structure is involved.
• Multiparous women: Pregnancy-related changes in pituitary volume are involved.
• Age: Peak onset is around 30–40 years of age.

Hypertensive, multiparous, middle-aged obese women have the highest risk profile.

Secondary Causes

• Transsphenoidal surgery: Most common after pituitary adenoma resection.
• Idiopathic intracranial hypertension: Sustained elevation of intracranial pressure is the cause.
• Pituitary apoplexy (Sheehan syndrome): Pituitary ischemia and necrosis due to massive hemorrhage during childbirth.
• Radiation therapy: After irradiation of the sellar region.
• Pituitary infections and lymphocytic hypophysitis: Pituitary destruction due to autoimmune mechanisms.
• Immune checkpoint inhibitors: ESS has been reported after administration of PD-1 inhibitors such as pembrolizumab⁷⁾.

Prevention and Daily Care

There is no established method to prevent empty sella syndrome itself. Since obesity is an important risk factor, try to maintain a healthy weight. Even if discovered incidentally, regular endocrine function tests are recommended. If symptoms such as fatigue, menstrual abnormalities, or vision changes appear, seek medical attention promptly.

Q Who is likely to develop empty sella syndrome?

A

Primary empty sella syndrome is more common in middle-aged (30–40 years) obese women. Hypertension and multiple pregnancies are also risk factors. Secondary empty sella syndrome is more common in patients with a history of pituitary tumor surgery or increased intracranial pressure.

4. Diagnosis and Testing Methods

Imaging Tests

The diagnosis of ESS is primarily made by MRI. Brain and orbital MRI with and without contrast is recommended.

• MRI findings: Depression of the sella turcica and downward displacement of the pituitary gland are observed. The pituitary gland is flattened along the sellar floor, often appearing crescent-shaped. Sagittal and coronal views are more useful than axial views.
• Pituitary stalk: Located in the midline and elongated. A normal midline pituitary stalk helps differentiate from an arachnoid cyst.
• Optic chiasm: Deformation of the optic chiasm due to extension of the arachnoid into the sella turcica is rare, and in most cases, morphological changes of the optic chiasm do not occur.
• CT scan: Used adjunctively when MRI is contraindicated.

Endocrine Testing

Consider hormone testing even in asymptomatic patients.

• Cortisol: Assessed by morning levels. ACTH stimulation test is useful for differentiation⁴⁾.
• Free thyroxine (FT4): In central hypothyroidism, FT4 may be low even if TSH is normal, so FT4 measurement is essential¹⁾.
• Estradiol or testosterone: Assessment of gonadal function.
• Insulin-like growth factor 1 (IGF-1): Assessment of the growth hormone axis.
• Prolactin: Confirmation of hyperprolactinemia.
• FSH and LH: Differential diagnosis of hypogonadism. If FSH is below the normal menopausal range after menopause, it suggests central hypogonadism¹⁾.

Differential diagnosis

The following diseases need to be differentiated.

Disease name	Key points for differentiation
Arachnoid cyst	Associated with deviation of the pituitary stalk
Rathke’s cleft cyst	Intrasellar cystic lesion
Cystic pituitary adenoma	Wall enhancement on contrast imaging
Craniopharyngioma	Associated with calcification
Idiopathic intracranial hypertension	Associated with papilledema

5. Standard Treatment

Asymptomatic Cases

If PESS is discovered incidentally and endocrine function is normal, regular follow-up is the basic approach. However, secondary causes must be ruled out.

Hormone Replacement Therapy

If hypopituitarism is confirmed, replacement of deficient hormones is performed. The order of replacement is important¹⁾.

1. Hydrocortisone: Initiated as a priority for adrenal insufficiency. Usually 15–20 mg/day³⁾⁴⁾. Dose increase to stress doses is necessary during stress.
2. Levothyroxine: Start after adrenal function is stable. Starting without adrenal replacement carries a risk of inducing adrenal crisis¹⁾.
3. Sex hormones: After the condition is stable, administer testosterone or estrogen/progesterone replacement¹⁾.

Hormone replacement can dramatically improve symptoms. Hyponatremia quickly normalizes with glucocorticoid replacement⁴⁾.

Surgical Treatment

Surgery is indicated in some cases where visual function deterioration progresses.

• Chiasmopexy: A surgery to elevate and fix the descended optic chiasm. It is performed via a transsphenoidal or transcranial approach.
• Intrasellar fat packing: A method of filling the sella with autologous fat to prevent ESS after pituitary adenoma resection. It is expected to prevent rapid postoperative descent of the pituitary gland and pituitary stalk rupture ⁸⁾.

Precautions and side effects in treatment

Incorrect order of hormone replacement can lead to serious complications. Thyroid hormone replacement should be started after cortisol replacement. Administering levothyroxine in the presence of untreated adrenal insufficiency can accelerate cortisol metabolism and trigger an adrenal crisis. In patients receiving immune checkpoint inhibitors, steroid therapy may mask symptoms of adrenal insufficiency, which may become apparent after steroid discontinuation ⁷⁾.

Q In what order should hormone replacement be started?

A

First, start hydrocortisone (adrenal replacement). Once adrenal function is stable, add levothyroxine (thyroid replacement). Then, if necessary, initiate sex hormone replacement. Following this order can avoid the risk of adrenal crisis. For details, see the section on “Hormone Replacement Therapy”.

6. Pathophysiology and detailed pathogenesis

Pathophysiology of Primary ESS

Two factors define the pathophysiology of primary ESS.

1. Elevated intracranial CSF pressure: Persistent or intermittent intracranial hypertension forces CSF into the sella turcica.
2. Diaphragma sellae defect: The diaphragma sellae is normally an extension of the dura covering the sella turcica, but if its opening is congenitally large, CSF herniation occurs. This diaphragmatic insufficiency is found in up to 20% of the normal population.

Continuous CSF pressure flattens the pituitary gland against the sellar floor, leading to compression and atrophy of the pituitary parenchyma. This reduces hormone secretion capacity ¹⁾.

Mechanism of Endocrine Dysfunction

Hyponatremia associated with adrenal insufficiency occurs through the following mechanism⁴⁾⁶⁾.

• Cortisol deficiency leads to increased CRH production in the paraventricular nucleus of the hypothalamus.
• Since CRH also stimulates antidiuretic hormone (ADH) secretion, ADH secretion increases.
• Furthermore, cortisol directly suppresses ADH synthesis.
• Under cortisol deficiency, this suppression is removed, further enhancing ADH secretion.
• As a result, renal water reabsorption increases, leading to dilutional hyponatremia (SIADH-like condition).

Genetic Background

Candidate gene groups involved in the onset of ESS have been identified⁵⁾.

• Group 1 (ESS onset-related): PRL, GH1, POMC, TRH, IGF1
• Group 2 (ESS pathway-related): TRH, PRL, POMC, NPY, GNRH1, GH1
• Group 3 (Cell component-related): PRL, POMC, NPY, IGFBP3, IGF1

Familial ESS is rare, but there have been reports of empty sella in familial combined pituitary hormone deficiency due to PROP1 gene mutations⁵⁾.

Pathogenesis of Secondary ESS

In ESS after transsphenoidal surgery, the residual pituitary gland rapidly descends into the sella turcica after tumor removal, causing excessive traction on the pituitary stalk. This results in rupture of the pituitary stalk, leading to panhypopituitarism and diabetes insipidus ⁸⁾.

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7. Latest Research and Future Perspectives (Research Stage Reports)

For Patients: Please Read Carefully

The following content is currently in the research or clinical trial stage and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

CHD7 gene and familial ESS

Petrov et al. (2023) reported a 35-year-old monozygotic twin male with partial empty sella, hypogonadotropic hypogonadism, and growth hormone deficiency. Genetic testing identified a c.2615T>C (p.Ile872Thr) mutation in the CHD7 gene. CHD7 is essential for the development of GnRH neurons and olfactory neurons and is also a major causative gene for CHARGE syndrome. The authors suggested that CHD7 gene mutations may be an unproven genetic cause of ESS⁵⁾.

Immune checkpoint inhibitor-induced ESS

Iwamoto et al. (2024) reported a 63-year-old man with non-small cell lung cancer who developed adrenal insufficiency as an immune-related adverse event during pembrolizumab treatment, which was masked by prednisolone. After prednisolone discontinuation, ACTH deficiency became apparent, and pituitary MRI revealed ESS findings. ICI-induced ESS cases have been reported only with PD-1 inhibitors, and the incidence and mechanism remain unknown⁷⁾.

Turner syndrome complicated cases

Lin and Zeng (2025) reported a 29-year-old woman with Turner syndrome (45,X/46,XX mosaic) who developed partial empty sella and combined pituitary hormone deficiency after puberty. A literature review identified 10 cases of ESS complicated with Turner syndrome, and familial cases suggested a genetic basis⁹⁾.

Postoperative ESS Prevention Techniques

Winograd et al. (2021) reported rapid endocrine deterioration with pituitary stalk transection in 2 of 2000 cases (0.1%) after transsphenoidal surgery. As a preventive measure, they introduced intraoperative sellar autologous fat packing in high-risk patients and reported that no similar complications occurred thereafter⁸⁾.

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8. References

1. Ahamed MA, Shetty S, Hegde S, et al. The Emptiness Within: A Case of Empty Sella Syndrome. Cureus. 2022;14(9):e28941.
2. Khanna K, Khanna R, Kumar S. Retrospection of Seldom-Known Causes and Presentations of Partial Empty Sella Syndrome. Cureus. 2023;15(8):e44494.
3. Rajesh M, Omer T, Chinniah S. Anterior hypopituitarism due to primary empty sella syndrome in a critically unwell patient. BMJ Case Rep. 2023;16:e255879.
4. Takkavatakarn K, Wipattanakitcharoen A, Katavetin P, et al. Severe hyponatremia as the presenting manifestation of primary empty sella syndrome. Clin Case Rep. 2022;10:e05369.
5. Petrov S, Babadzhanova E, Orbetzova M, et al. A clinical case of identical twins with hypogonadotropic hypogonadism, primary empty sella syndrome and identified rare CHD7 gene variant. Clin Case Rep. 2023;11:e7492.
6. Alkhyeli F, Boharoon H, Almarzouqi A. Severe Hyponatremia in a 46-Year-Old Female With Pituitary Stalk Duplication and Primary Empty Sella Syndrome. Cureus. 2023;15(8):e43851.
7. Iwamoto Y, Tatsumi F, Ohnishi M, et al. A case of Empty Sella syndrome with adrenal insufficiency masked by prednisolone after administration of immune checkpoint inhibitors. Medicine. 2024;103(10):e37204.
8. Winograd E, Kortz MW, Lillehei KO. Radiographic pituitary stalk disruption: A rare sequela of secondary empty sella syndrome. Surg Neurol Int. 2021;12:385.
9. Lin F, Zeng J. Turner syndrome and postpubertal Empty sella syndrome: a case report and literature review. Front Endocrinol. 2025;16:1552724.