Overview

Empty Sella Syndrome (ESS) is a condition that affects a small space at the base of the skull called the sella turcica. Normally, this space holds the pituitary gland, which is a tiny, but very important gland that produces hormones controlling growth, fertility, stress, metabolism and many other body functions.

There are two main types of ESS:

• Primary ESS: develops on its own, often because the thin membrane covering the sella is weak, or because of increased pressure inside the skull
• Secondary ESS: happens after something has damaged the pituitary, such as surgery, radiation, bleeding or tumour shrinkage

For many years, doctors thought ESS didn’t matter because many people had it without symptoms. But newer research shows that in some people, ESS can cause problems with hormones, vision and headaches.

One of the most striking features is that ESS is much more common in those assigned female at birth (AFAB)than those assigned male at birth (AMAB). Those who are AFAB are affected about four times more often, especially in those who are middle-aged, overweight or who have had several pregnancies.¹ Those who are AMAB, though less often affected, usually have more severe hormone problems when ESS does occur.

Epidemiology

How common is ESS?

The frequency of ESS depends on how you look for it:

• MRI scans show ESS is prevalent in up to 35% of the general population and is often an incidental finding when scanning for other conditions²
• Clinical cases (patients with symptoms) are less common, but ESS is still found in around 2% of people who undergo brain scans for headaches or vision problems³

Symptomatic vs incidental

• Many cases of ESS are discovered by accident during imaging for unrelated reasons, but in others, ESS is linked to clear symptoms like hormone imbalance and headaches

Gender differences

People who are AFAB:⁴

• Make up around 65–80% of ESS cases
• Peak diagnosis age is 30–50 years
• ESS is strongly linked with obesity, multiple pregnancies and idiopathic intracranial hypertension (IIH)

People who are AMAB:⁴

• Make up only 20–35% of ESS cases
• Often diagnosed later in life
• More likely to have secondary ESS after pituitary surgery, radiation or bleeding into a pituitary tumour

Age and global patterns

• In those AFAB, ESS is most often found during childbearing and menopausal years
• In those AMAB, ESStends to appear after 50, often related to previous pituitary disease
• Countries with high MRI availability (like the US and Europe) report more cases of ESS, but true global rates are unknown due to underdiagnosis in low-resource areas

Causes and pathophysiology

Why does ESS happen?

ESS develops for several different reasons depending on whether it is primary or secondary.

Primary ESS:⁵

• Weakness in the diaphragma sellae, the thin tissue that normally keeps fluid out of the sella
• Repeated enlargement and shrinking of the pituitary during pregnancy
• Raised pressure inside the skull 
• Hormonal influences (estrogen and progesterone make the pituitary gland change in size and blood supply)

Secondary ESS:⁶

• Pituitary surgery for adenomas (tumours)
• Radiotherapy, which shrinks the pituitary tissue
• Bleeding into the pituitary (pituitary apoplexy)
• Sheehan’s syndrome 
• Trauma or severe infection

Why are AFAB more affected

• The pituitary gland grows during pregnancy and shrinks after childbirth. Repeated cycles of stretching and shrinking may weaken the protective tissues
• More prone to raised intracranial pressure
• Hormonal changes throughout life (menstruation, pregnancy, and menopause) affect the pituitary structure

Why do those AMABend to have more severe symptoms

• ESS in those AMABis often secondary, caused by destruction of pituitary tissue
• By the time ESS is detected, hormone damage is usually advanced
• Those AMAB are less likely to be scanned for headaches or infertility, so diagnosis is often delayed

Clinical signs and symptoms

Not everyone with ESS has symptoms. In fact, up to half of all cases are found by accident during brain scans. But in others, ESS can cause significant problems.

Hormonal symptoms⁷

In those AFAB

• High prolactin levels (hyperprolactinemia):
  
  • Irregular or missed periods
  • Inability to conceive
  • Breast milk production is unrelated to pregnancy
• Subtle hormone deficiencies:
  • Low thyroid activity (weight gain, tiredness, feeling cold)
  • Low cortisol (exhaustion, low blood pressure, dizziness)
• Reproductive problems: difficulty conceiving or higher miscarriage risk

In those AMAB

• Low testosterone (hypogonadism):
  • Low sex drive
  • Erectile dysfunction
  • Infertility
  • Muscle loss and weight gain
• Other hormone problems:
  • Low cortisol (weakness, dizziness)
  • Low thyroid hormone (tiredness, cold intolerance)
  • Low growth hormone (low energy, increased body fat)
• Long-term effects: osteoporosis, metabolic syndrome, and increased heart risk

Neurological symptoms⁷

In those AFAB

• Headaches are very common, often linked to IIH
• May be accompanied by:
  • Dizziness
  • Nausea

In those AMAB

• Headaches are less common as a first symptom
• When present, they often appear after surgery or tumour-related ESS

Eye and vision symptoms⁷

In those AFAB 

• Caused mainly by raised pressure inside the skull:
  • Blurred or double vision
  • Episodes of temporary vision loss
  • Swelling at the back of the eye (papilledema)
• Severe, untreated cases may cause blindness

In those AMAB

• Caused more by direct compression of the optic nerves:
  • Visual field loss, especially bitemporal hemianopia (losing side vision)

Mental health and cognitive symptoms⁷

• In those AFAB, mood changes may relate to hormonal imbalances (like prolactin or thyroid)
• In those ABAM, low testosterone often contributes to fatigue, irritability and depression

Associated conditions

ESS is often linked to other medical problems:

• Idiopathic Intracranial Hypertension (IIH), which is very common in obese people who are AFAB
• Obesity and metabolic syndrome, such as Diabetes, high blood pressure and obesity, often coexist with ESS
• Autoimmune diseases as those who are AFAB with ESS, have been found to have higher rates of autoimmune thyroid disease
• Heart and circulation problems in people who are AMAB, such as low testosterone, which increases the risk of heart disease

Diagnosis

Imaging

• MRI scans 
• CT scans 

Hormone tests

Doctors usually test for:

• Prolactin
• Sex hormones (testosterone, estrogen, FSH, LH)
• Thyroid hormones (TSH, T4)
• Cortisol and ACTH
• Growth hormone activity (via IGF-1 levels)

Differential diagnosis

Other conditions that can look like ESS include:

• Pituitary tumours
• Pituitary inflammation (hypophysitis)
• Rathke’s cleft cysts
• Arachnoid cysts

Gender bias in diagnosis

• Those AFAB are more often diagnosed because they undergo scans for headaches, fertility problems or menstrual issues
• Those AMAB  are often missed until severe hormone deficiency or vision problems develop

Management and treatment

Those AFAB

• High prolactin: Treated with medicines such as cabergoline or bromocriptine
• IIH (raised intracranial pressure): Weight loss, acetazolamide (reduces fluid production) or surgery in severe cases⁸
• Fertility support: Ovulation-inducing drugs or assisted reproductive techniques

Those AMAB

• Testosterone replacement therapy
• Often need multiple hormones replaced (thyroid, cortisol, growth hormone)
• Monitoring and prevention of osteoporosis

Both sexes

• Surgery: Rare, used if vision is threatened by optic nerve compression
• Lifestyle management: Weight control, healthy diet, regular monitoring
• Team care: Endocrinologists, neurologists, ophthalmologists and sometimes neurosurgeons work together

Complications and prognosis

• Those AFAB: Primary ESS is often stable. Main problems are headaches, fertility issues or IIH-related vision changes
• Those AMAB: Secondary ESS more often causes severe hormone loss, requiring lifelong treatment
• Both sexes:⁵
  • Infertility
  • Osteoporosis
  • Cardiovascular disease
  • Depression and reduced quality of life

Research gaps and future directions

• Those who are AMAB are under-studied, leaving many unanswered questions
• Some experts argue that ESS is more of a radiological sign than a true disease unless symptoms are present
• The role of hormones in those AFAB in pituitary changes is still unclear
• Genetic factors may explain why some people develop ESS while others don’t
• Screening high-risk groups (obese multiparous people AFAB, people AMAB after pituitary surgery) may allow earlier diagnosis

FAQ’s

Is ESS more common in people AFAB or people AMAB?

 ESS is about three times more common in those AFAB.

Can ESS cause infertility?

Yes. Those AFAB may have irregular cycles or fail to ovulate. Those AMAB may have low sperm counts and low testosterone.

Does ESS always cause headaches?

No. Many people have no symptoms. Headaches are more frequent in those AFAB with IIH.

Does ESS always cause hormone problems?

No. Some people have normal pituitary function. Those AMAB are more likely to show clear hormone loss.

Can ESS lead to blindness?

Rarely. Those AFAB risk blindness from untreated IIH. Those AMAB risk vision loss from optic nerve compression in secondary ESS.

How is ESS treated?

Treatment depends on the symptoms:

• Hormone replacement
• Medicines for raised intracranial pressure
• Weight loss
• Surgery only if vision is threatened

Summary

Empty Sella Syndrome is a condition where brain fluid fills the sella turcica, flattening the pituitary gland. Those assigned female at birth (AFAB) are far more likely to develop primary ESS, which is often linked to obesity, multiple pregnancies and raised intracranial pressure. They usually present with headaches, high prolactin and fertility problems. Those assigned male at birth (AMAB), though less often diagnosed, usually develop secondary ESS after pituitary damage and often present with severe hormone deficiencies like low testosterone, adrenal failure and thyroid dysfunction.

While many cases are harmless, ESS can significantly affect quality of life. Recognising the differences in the condition between those AMAB  and those AFAB is crucial for proper diagnosis and tailored treatment.  Those who are AFAB often have a more stable course, while those ABAM require more intensive hormone replacement and monitoring.

Future research should explore the role of hormones, genetics and screening strategies to detect ESS.