S Chiloiro and others Empty sella 177:6 R275–R285

Review

DIAGNOSIS OF ENDOCRINE DISEASE

Primary empty sella: a comprehensive review
S Chiloiro1, A Giampietro1, A Bianchi1, T Tartaglione2, A Capobianco3, C Anile4 and
L De Marinis1
Correspondence
1
Pituitary Unit, Department of Endocrinology, 2Institute of Radiology, 3Institute of Opthalmology, and 4 Institute of should be addressed
Neurosurgery, Catholic University of the Sacred Heart, Agostino Gemelli Foundation, Rome, Italy to L De Marinis
Email
laura.demarinis@rm.unicatt.itit

Abstract
Primary empty sella (PES) is characterized by the herniation of the subarachnoid space within the sella, which is often
associated with variable degrees of flattening of the pituitary gland in patients without previous pituitary pathologies.
PES pathogenetic mechanisms are not well known but seem to be due to a sellar diaphragm incompetence, associated
to the occurrence of upper sellar or pituitary factors, as intracranial hypertension and change of pituitary volume.
As PES represents in a majority of cases, a neuroradiological findings without any clinical implication, the occurrence
European Journal of Endocrinology

of endocrine, neurological and opthalmological symptoms, due to the above describes anatomical alteration, which
delineates from the so called PES syndrome. Headache, irregular menses, overweight/obesity and visual disturbances
compose the typical picture of PES syndrome and can be the manifestation of an intracranial hypertension, often
associated with PES. Although hyperprolactinemia and growth hormone deficit represent the most common endocrine
abnormalities, PES syndrome is characterized by heterogeneity both in clinical manifestation and hormonal alterations
and can sometime reach severe extremes, as occurrence of papilledema, cerebrospinal fluid rhinorrhea and worsening
of visual acuity. Consequently, a multidisciplinary approach, with the integration of endocrine, neurologic and
ophthalmologic expertise, is strongly advocated and recommended for a properly diagnosis, management,
treatment and follow-up of PES syndrome and all of the related abnormalities.

European Journal of
Endocrinology
(2017) 177, R275–R285

Introduction
Empty sella is characterized by the herniation of the
subarachnoid space within the sella, which is often
associated with variable degree of flattening of the
pituitary gland (1, 2). Empty sella is classified as primary or
secondary (3). Primary empty sella (PES) is defined in cases
with unknown etiology, after excluding history of previous
pituitary pathological condition such as previous surgical,
pharmacological or radiotherapy treatment of the sellar

Invited Author’s profile

L De Marinis is an Associate Professor and Chief of the Pituitary Unit at the Department of Endocrinology
of Agostino Gemelli Foundation, Catholic University of the Sacred Heart, Rome, Italy. Her research focuses on
neuroendocrine and pituitary physiology in relation to dependent glands and to neoplastic pathology of the
hypothalamus–pituitary region, with respect to the physiology of the pituitary hormonal secretion in normal
subjects and in patients with pathologies of this complex region, such as GH-, ACTH- and PRL-secreting
pituitary adenomas, not functioning pituitary adenomas, craniopharyngiomas, teratomas, empty sella
syndrome and primary autoimmune hypophysitis. She studied the genetic background, prognostic marker,
efficacy and safety of the different treatments both in pituitary neoplasia and in neuroendocrine tumors.

www.eje-online.org © 2017 European Society of Endocrinology Published by Bioscientifica Ltd.

DOI: 10.1530/EJE-17-0505 Printed in Great Britain
 Review S Chiloiro and others
region (3). Instead, secondary empty sella (SES) can occur
following successful trans-sphenoidal pharmacological or
radiotherapy treatment or trans-sphenoidal neurosurgery
of pituitary tumors; it can lead to spontaneous necrosis
(ischemia or hemorrhage) of chiefly adenomas; can result
from pituitary infectious processes, pituitary autoimmune
disease or brain trauma (4). Moreover, SES can develop
in patients who have undergone surgical procedures,
radiotherapy and pharmacological treatments of brain
tumors, not located in the pituitary fossa (5): particularly
in older patients affected by larger brain neoplasia and
meningiomas (5).
History
The term ‘empty sella’ was first used by Bush in 1951 (6)
to describe ‘a peculiar anatomical condition, observed in 40 of
788 human cadavers, particularly females, characterized by a
sella turcica with a diaphragma sellae incomplete or that forms
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only a small peripheral rim, with a pituitary gland not absent,
but flattened in such a manner as to form a thin layer of tissue
at the bottom of the sella turcica’. In the following years,
more details were reported. Particularly Kaufman (7), in
1968, speculated that ‘…empty sella is a distinct anatomical
and radiographic entity, function of an incompleteness of the
diaphragma sellae and of the cerebrospinal fluid (CSF) pressure,
normal or elevated … The role of the normal fluctuations
of CSF pressures and the effect of a superimposed prolonged
increase in CSF pressure were related to the anatomic changes
involving the bony wall of the <empty sella>’.
Epidemiology of PES
Epidemiology data of PES are strongly influenced by
collection methods. Particularly, at autopsy, PES is
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Empty sella 177:6 R276
described as incidentally finding in approximately 5.5%–
12% of cases (6, 7). Instead, at neuroimaging, the overall
incidence of empty sella has been estimated at 12%. In
clinical practice, according to different series, PES is
reported in around 8–35% of the general population (3,
8, 9, 10), with a female-to-male ratio of 5:1 (8). In fact,
a large prevalence of PES results among women with a
history of at least one completed pregnancy in their
physiological history (11). The peak incidence of PES
occurs between 30 and 40  years, being sometimes early
in women than that in males. PES in children occurs less
frequently than in adults and is frequently associated to
hypothalamic–pituitary dysfunction, genetic disorders or
perinatal complication, as Turner syndrome, Moyamoya
disease, Bartter’s syndrome, nevoid basal cell carcinoma
syndrome, Hunter syndrome, Prader–Labhart–Willi
syndrome, Alstrom syndrome, Meniere’s Disease and
Erdheim–Chester disease (12, 13, 14, 15, 16, 17, 18, 19).
Pathogenesis of PES
PES etiology is not clear. The possible involved
pathogenetic mechanisms are not well known. Numerous
etiopathogenetic hypotheses have been developed
and included the incomplete formation of the sellar
diaphragm and the occurrence of upper sellar factors
(as CSF’s pulsatility, stable or intermittent increase in
intracranial pressure) or the occurrence of pituitary factors
(as variation in the pituitary volume) (Fig. 1).
Sellar diaphragm deficiency
The sellar diaphragm is a deflection of the dura mater,
which separates the suprasellar cistern from the
pituitary fossa, also called sella turcica. This diaphragm
Figure 1
Schematic representation of the
pathogenic mechanism of the PES. The
incomplete formation of the sellar
diaphragm, pituitary and/or upper sellar
factors determine the genesis of PES.
 Review S Chiloiro and others
also allows the pituitary stalk to pass through a very
small opening in its center. Incompetence of the sellar
diaphragm is considered crucial in the formation of PES
and has been demonstrated in 22–77% of cases, while
a total absence of diaphragm sella has been reported
in 20.5% of normal subjects (20). Increased pressure in
the suprasellar subarachnoid space or pituitary volume
reduction predispose to the development of an intra-
sellar subarachnoid hernia. When the sellar diaphragm
is incomplete, an unobstructed pathway exists between
the chiasmatic cistern and the pituitary fossa, allowing
the unopposed brisk pulsatile movements of the CSF to
enter the sella turcica. These pulsations slowly flatten
the pituitary gland into the floor of the sella and may
occasionally erode through the bony wall of the sella
into the sphenoid sinus, producing CSF rhinorrhea (21).
However, most of these defects alone do not result in
herniation of the subarachnoid space, and this confirms
that the anomaly of the sellar diaphragm is essential for
the development of PES, although other factors seem to
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be relevant as well.
Upper sellar factors
The role of intracranial hypertension in the genesis
of PES has been proposed by many authors. Various
intracranial conditions that elevate CSF pressure have
been associated with PES, including hydrocephalus,
thrombosis, meningitis, brain tumors and Arnold–Chiari
malformations (22). Up to 94% of patients affected by
intracranial idiopathic hypertension (IIH) also had empty
sella (3). IIH, also known as pseudotumor cerebri, is a
syndrome of unknown etiology that results in elevated
intracranial pressure, in the absence of intracranial mass
lesion or hydrocephalus. IIH can be due to impaired CSF
absorption, increased CSF secretion, increased cerebral
hemodynamics and, at least, increased cerebral capillary
permeability (22). Impaired circulation and dynamics of
CSF were found up to 77% of patients affected by PES
(3): impaired CSF absorption at the arachnoid villi has
been proven in 80–84% of patients with PES (3), leading
to the elevation of CSF pressures and, subsequently, the
herniation of meninges and CSF, through an incompetent
sellar diaphragm.
In some cases, normal pulsations of CSF are sufficient
to produce the empty sella in the presence of a deficient
diaphragm sellae; in fact, in some patients increase of
intracranial pressure occurred only during sleeping (3).
The spectrum of intracranial hypertension probably
begins with silent, milder and intermittent form that
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evolves in empty sella and ends with more severe forms
of IIH, characterized by papilledema, severe headache
and visual field symptoms. This would explain why, only
in some cases (from 8 to 15%), empty sella progress to
develop IIH, but conversely up to 94% of IIH-affected
patients already carried an empty sella.
PES has been reported to be associated with obesity
and hypertension (23), particularly in females (8). In
various series of PES, the percentage of obese hypertensive
females achieved 70–80% (24). BMI values are positively
correlated to the occurrence on IIH (25). The link between
obesity, systemic hypertension and PES is not completely
understood, but alterations in the sellar diaphragm
and stable or intermittent increase of intracranial
pressure may play an etiologic role in the development
and maintenance of PES in obesity. In fact, in obese
patients with hypercapnia and obstructive sleep apnea
syndrome (OSAS), intermittent or persistent elevation
of intracranial pressure was described. Moreover, it was
postulated that central obesity raises intra-abdominal
pressure, with a consequent increase of both pleural
and cardiac filling pressures, which obstructs venous
return from the brain, leading to increased intracranial
venous pressure and intracranial pressure (26, 27, 28).
One other mechanism proposed is that obesity, directly
or through cytokines and adipokines, can induce the
activation of the 11β-HSD1 enzyme, which increases
the cortisol production. Cortisol excess increases the
intracranial pressure, through the increment of CSF
production and through the reduction of CSF drainage
(29). Moreover, obesity is associated to thrombophilic-
ipofibrinolytic coagulator disorders, which could induce
microvascular thrombosis and, consequently, reduction
of CSF resorption and increase of intracranial pressure
(30, 31, 32).
Pituitary factors
Various factors are associated with pituitary gland volume
changes, which first determines an expansion and then a
reduction of the suprasellar subarachnoid space. If there
is no corresponding reduction of both pituitary gland
and sella turcica volume, a space can be created, which
can allow suprasellar chiasmatic cistern herniation, in
cases of hypoplasic diaphragm sellae and in cases of CSF
hypertension, even if moderate and temporary.
Increase in the size of the pituitary gland is observed
during pregnancy and lactation, when pituitary gland
volume can duplicate, enlarging the sella turcica
(33). Instead, in women in the fourth decade of life,
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 Review S Chiloiro and others
pituitary involution is associated with menopause,
which explains why PES syndrome predominates in
middle-age women. On some occasions, in cases
of primary hormonal deficiency (such as primary
hypothyroidism, primary hypoadrenalism and primary
hypogonadism), a compensatory pituitary hypertrophy
occurs (20). At least, also in hypophysitis, which
represents an emerging and more frequently diagnosed
disease (34), pituitary hyperplasia could evolve in
empty sella, as last stage of disease, as suggested by the
presence of antipituitary antibodies in around 6% of PES
cases (35).
Presenting clinical manifestations
PES is often incidentally discovered and represents
a relatively common finding in autopsy (5–23%) (6,
7) and in radiological imaging (8–35% in the general
population) (36, 37, 38, 39). Empty sella is present in
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approximately 70% of patients with IIH (40), representing
the most commonly described imaging sign in the setting
of IIH. In contrast, the incidence of IIH is relatively
rare, estimated at approximately 1 case per 100,000
individuals. Therefore, most patients showing an empty
sella turcica on imaging will not have IIH. Consequently,
PES can be an incidental radiological finding and may
usually not present symptoms (41). Instead, when PES is
associated with endocrine, neurologic, ophthalmologic
and psychiatric symptoms (caused by be above
anatomic alteration), the picture of ‘primary empty sella
syndrome’ (PESS) is configured (8). Headache, menstrual
irregularities, galactorrhea, hirsutism and sterility are the
most common clinical manifestation in PES syndrome
(8). Particularly, headache and obesity are considered
the most common clinical manifestations respectively
in men and in women (3). Occurrence and frequency of
signs and symptoms are influenced according to the series
and typologies of symptoms for which patients referred to
medical attention.
Endocrinological picture
The clinical picture in patients with PES is often quite
complex and it is not always possible to differentiate
symptoms and biochemical findings that are the
consequences of the empty sella from those casually found
that are merely the reason for medical referral. Therefore,
the same symptom may likely be a direct consequence or
casually found in patients with PES.
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Empty sella 177:6 R278
Overweight and obesity involve respectively 73% and
14% of PES-affected patients and, in particular, females: in
fact, around 50% of females with PES presents obesity (3).
Irregular menses (hypo, hyper, oligo, poly, amenorrhea,
anovular cycles or short luteal phases, etc.) were reported
by 40%, galactorrhea by 26% and hypertrichosis by 18%
of female patients (3). Instead, among male patients,
sexual disturbances were reported in around 53% and
gynecomastia in around 12% of cases (3).
Endocrine abnormalities are documented in around
19% of patients (8). Insufficient glandular secretion
can be caused by the compression of the pituitary
parenchyma against the sellar cavity walls, associated to
pituitary stalk posteriorly stretched and attracted down
to the thin residual pituitary. This insufficiency can be
of varied degrees, ranging from panhypopituitarism with
a prolactin (PRL) deficit, to hypopituitarism or isolated
hormonal deficit, with hyper or normal PRL value. From
the revision of papers published in the last 20 years (3, 8,
11, 42, 43, 44, 45, 46), GHD represents the most frequent
pituitary deficit, both in the adult and pediatric population,
occurring between 4% and 57.1% of PES syndrome cases.
Instead, a similar frequency is identified for secondary
hypoadrenalism, hypothyroidism and hypogonadism,
which ranges from 2.3 to 32% of PES syndrome cases.
At least, hyperprolactinemia is documented in 7–10%
of PES syndrome affected patients. Almost half of the
patients had a PRL value between 50 and 100  µg/L
(median prolactin level: 31  µg/L) (8). Furthermore, it
must be noted that menstrual irregularities (hypo, hyper,
oligo, poly, amenorrhea, anovular cycles or short luteal
phases) may also occur while there is a normal PRL level:
this can be explained as hypersensibility to normal PRL
values or transient hyperprolactinemia, which are not
possible to observe with a single basal blood sample.
In fact, an alteration of PRL circadian rhythm has been
described in PES, associated with a chronic or intermittent
altered intracranial pressure: the nightly PRL increment is
reduced or completely lacked in patients with intracranial
hypertension, even just during the REM phase (47, 48).
Rarely, pituitary hypersecretion condition was described
in patients with PES associated to ectopic GH- and ACTH-
secreting pituitary adenomas (49, 50), located within the
midline intersphenoidal septum.
Prolactin and dopaminergic and serotonin tone
Endocrine disturbances can also arise from a
neurotransmitter derangement, partly related to CSF
 Review S Chiloiro and others
dynamics and possible immune system reactions.
These factors highlight a complex network of primary
and secondary effects resulting from the initial
anatomic alteration.
As PRL response to dynamic tests is altered in patients
with increased CSF pressure, it has been hypothesized
that this neuroanatomic finding can influence neuronal
dopamine reuptake. In fact, intracranial hypertension
interferes with dopamine reuptake, strengthening
dopamine’s action at the pituitary level and lowering
PRL’s reaction to nomifensine, an indirect dopaminergic
agonist (51).
In PES with normal PRL values, for the increased
dopaminergic tone, the average peak response to the
single TRH and MCP test is not significantly different
from that in normal subjects, although there is a trend
of higher and more prolonged PRL release and although
the PRL percent increment, with respect to basal levels,
is often inferior as compared to normal subjects.
Moreover, an inverse correlation between basal PRL
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levels and the post-MCP administration peak increment
occurred (52).
In PES with quite high PRL value, laboratory
differential diagnosis with PRL-secreting pituitary
adenoma represents a great challenge, and pituitary
neuroimaging plays a crucial and central role. In fact, an
increased central dopaminergic activity with respect to
TSH secretion is characteristic of prolactinomas and, when
a reaction to TSH and MCP is not present, it is possible
to exclude a PRL-secreting pituitary adenoma (53). At
least, in pre- and post-menopausal PES-affected patients,
PRL dynamics differ, as estrogen-mediated dopamine
activation is presumably of a lesser entity than in post-
menopausal women. Consequently, in post-menopausal
PES-affected patients, PRL response to TRH is often greater
that in normal subjects and, in premenopausal PES
patients, PRL response to TRH is similar to that in normal
women (54).
In young fertile women affected by PES with normal
PRL levels, increase of the highest nightly value and
re-establish of PRL’s circadian rhythm were observed
in patients on treatment with tryptophan, suggesting
an alteration of the serotoninergic system, which in
physiological condition stimulates PRL secretion through
central mechanisms (55).
In conclusion, multiple factors can influence PRL
dynamic tests in PES, as intracranial pressure, integrity of
pituitary stalk, basal PRL value and gonadal status.
Empty sella 177:6 R279
Neurological and opthalmological picture
Neurological and opthalmological signs in PES syndrome
are predominantly due to the presence of increased
intracranial pressure: values from 14 to 24 mm/Hg were
insufficient to provoke a clear instance of intracranial
hypertension but sufficient to maintain the neurological
symptomatology of PES syndrome, such as headache and
visual disturbances.
In fact, around 84–88% of PES syndrome cases
are affected by headache, typically described as
lateral, persistent and datable from years (3, 8). In a
lower percentage of cases (around 20%), headache is
accompanied by symptoms of intracranial hypertension
as papilledema and visual disturbances (3, 8). Neurological
disturbances such as dizziness, syncope, cranial nerve
disorders, convulsion or depression occurred in around
40% of patients (3). Rarely, CSF rhinorrhea may occur in
combination with the empty sella syndrome, increasing
the risk of retrograde meningitis.
Ophtalmological picture also includes worsening of
visual acuity (13–37%), blurred vision (29%), diplopia
(2%), defect in oculomotor nerve (1%) and optical neuritis
(1%) (3, 8).
Diagnosis
Imaging studies
ES can be confirmed through magnetic resonance (MR)
study of the sellar and suprasellar regions and with
computed tomography (CT), in selected patients with
absolute contraindication to the MR. Typical finding of
ES (56), both in CT and MR, are intra-sellar CSF filling in
continuity with overlying subarachnoid spaces, residual
pituitary gland, with a semi-lunate morphology, flattened
against the sellar floor and, often, enlarged bony sella
(Fig. 2). Pituitary stalk is usually thinned and located on
midline. In rare cases, optic chiasm, anterior 3rd ventricle
can herniate into the sella. Instead, if intra-sellar CSF
herniation is asymmetric, pituitary stalk can be tilted to
a site. Sagittal and coronal T1-weighted (T1W) contrast-
enhanced images and coronal T2-weighted (T2W) images
are strongly recommended for an accurate MR study of ES.
T1W and T2W images particularly show a fluid signal within
the sella that looks exactly like CSF. On FLAIR sequences,
intra-sellar fluid completely suppresses and it presents
without restriction in DWI sequences. After contrast,
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 Review S Chiloiro and others
T1W images evidence normal enhancement of residual
pituitary gland and stalk, without any abnormalities. In
SES, T1W images before and after contrast injection can
prove stalk and pituitary remnants scarred or distorted
and adhered to a side or to the bottom of sella turcica
(56) (Fig. 3). Asymmetry and erosion of sellar floor can be
suggestive of SES (as for previous pituitary neoplasia) (8).
MR imaging can focalize also indirect signs of intracranial
hypertension (Fig.  4), such as flattening of the posterior
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sclera, prominent subarachnoid spaces along the optic
nerves, vertical tortuosity of the optic nerve sheath
complex, protrusion or enhancement of the prelaminar
optic nerve (57) and nerve sheath volumes >201.30 mm3
with an hypophysis volume <611.21 mm3 (58).
Endocrinological assessment
As hormonal alterations caused by the empty sella
syndrome is not clear-cut, an accurate hormone diagnosis
is advocated. Therefore, in all patients having an empty
sella, basal pituitary hormonal dosage has to be prescribed
and, if indicated, dynamic tests are also suggested for
identifying hormonal deficit, particularly GHD and
secondary hypoadrenalism.
Ophtalmological assessment
In the later years, ophthalmic echography has taken
up a primary role in the diagnosis of endocranial
hypertension, as it is brief, non-invasive, extremely
specific and able to provide an indirect evaluation
through the observation of the optic nerves’ morphology
and the perioptic subarachnoid spaces. The correlation
between intracranial CSF dynamic parameters and
optic nerve diameters was well established: optic nerve
diameters are correlated by a direct, biphasic, positive
relation with diastolic intracranial pressure and by a
direct relation with the intracranial absorptive reserve
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Empty sella 177:6 R280
Figure 2
Primary empty sella MR study: (A and B)
Sagittal and coronal post-contrast T1w
images show enlarged sella with marked
thinning of the pituitary gland and of the
stalk. The latter shows normal
enhancement after contrast injection;
(C) Coronal T2w image confirms sella
partially filled with arachnoid-lined CSF
collection.
(59). Moreover, optic nerve diameters rapidly change
in response to variation of intracranial pressure (59).
Consequently, the safety, low cost and, above all, the
patient’s tranquillity, render ophthalmic echography the
chosen methodology both in the initial screening and
in the follow-up of PES syndrome. Moreover, in cases
of ophthalmic echography suggestive of intracranial
hypertension, ophthalmological evaluation has to be
Figure 3
Secondary empty sella in patient affected by primary
autoimmune hypophysitis MR study: (A and B) Sagittal and
coronal post-contrast T1w images show increased volume of
the whole pituitary gland and pituitary stalk related to
inflammatory changes. (C and D) Sagittal and coronal
post-contrast T1w images obtained two years later, show
complete response to the therapy with marked thinning of
pituitary gland and stalk; the latter is slightly located to
the left.
 Review S Chiloiro and others
completed with computerized field view and visual
evoked potential, to detect a possible neurological
damage. All these examinations should be performed
at PES diagnosis and during follow-up, according to
the clinical features, for surveillance and for evaluating
possible treatment efficacy.
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Differential diagnosis
Empty sella has to be distinguished from other pituitary
abnormalities or cystic lesions, as arachnoid and
epidermoid cysts and congenital pituitary anomalies.
Suprasellar arachnoid cyst may in fact herniate into
bony sella, which may appear enlarged or eroded. The
3rd ventricle or the optic chiasm may be displaced by
Figure 5
Flow-chart of the diagnosis and management of empty sella syndrome according to the symptoms referred by the patients.
Empty sella 177:6 R281
Figure 4
Primary empty sella associated with
intracranial hypertension MR study:
(A and B) Sagittal and coronal post-
contrast T1w images show marked and
slightly asymmetric thinning of the central
portion of the pituitary gland. The stalk is
very thin, tilted backward and shows
normal enhancement after contrast
injection. (C) Coronal fat-saturated T2w
image shows prominent subarachnoid
spaces along the optic nerves.
CSF-containing mass, whose walls can be easily
recognizable on thin-section imaging (56). Instead, intra-
sellar epidermoid cysts are very rare, as usually are localized
off midline, with an extension from cerebellopontine
angle epidermoid (56). Moreover, some congenital
pituitary abnormalities can mimic a partial empty sella, as
the persistence of the embryonal infundibular recess of the
3rd ventricle, the presence of a pituitary stalk duplication
or the presence of an ectopic posterior pituitary ‘bright
spot’, also characterized by small pituitary gland, short
infundibular stalk, often small bony sella (56).
Therefore, empty sella syndrome requires a
multidisciplinary diagnosis and management with the
integration of endocrine, neurologic and ophthalmologic
experts (Fig. 5).
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 Review S Chiloiro and others
Treatment strategies
Hypopituitarism
Replacement hormone therapy in PES syndrome must
be assessed for every single hormone and administered
according to the appropriate temporal sequence. In the
presence of multiple pituitary hormone deficiencies, it
is recommended that hormonal replacement treatment
starts with hydrocortisone, followed by levothyroxine.
Hormonal replacement treatment with sexual hormones
should be introduced when the patient’s conditions are
stabilized. The therapeutic plan should be completed
with the administration of rhGH, when indicated and
in patients not affected by intracranial hypertension.
Hyperprolactinemia should be treated with dopamine-
agonist drugs, as patients can improve biochemically and
clinically (8).
Intracranial hypertension
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Intracranial hypertension has always to be treated.
In overweight or obese patients, the first suggested
therapeutic approach is the weight loss, which
can improve neurological symptoms (60) through
personalized hypocaloric diet or bariatric surgery. In
fact, grade of papilledema and percentage of weight
loss are positively correlated (61). However, in patients
affected by hypopituitarism, an accurate evaluation
of the risk of a malabsorption syndrome has to be
performed to assure the patients an optimal management
of hormonal replacement therapies. Moreover, in PES
syndrome affected patients, with signs or symptoms of
intracranial hypertension, the best therapy is based on
the administration of osmotic diuretics per os, such as
Figure 6
Flow-chart of the multidisciplinar management and follow-up of PES syndrome.
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Empty sella 177:6 R282
acetazolamide (acetazolamide, Diamox tab 250 mg, with
a dose range of 250–500 mg/day) or escin (Reparil tab
40 mg, with a dose range of 100–250 mg/day), which can
improve neurological manifestation, as showed in other
intracranial hypertension condition (62). According to
recent evidence, in obese patients (60) with intracranial
hypertension, bariatric surgery should represent the first
surgery procedure, if not contraindicated and after the
failure of treatment with personalized hypocaloric diet or
in cases resistant to medical treatment. Lumboperitoneal
shunt is generally reserved for very selected patients
with severe visual impairment (63) or in patients with
progressive visual loss despite other medical or bariatric
surgery intervention (63). The appearance of rhinorrhea
and the worsening of the visual alterations makes
peritoneal-ventricular surgery necessary, in order to avoid
serious intracranial hypertension complications such
as progressive reduction of visual acuity, campimeter
deficits, papilledema and optical atrophy (63). However,
treatment of CSF rhinorrhea remains a challenge and
requires a safe and effective therapeutic strategy. Direct
surgical repair of the skull defect should be performed in
cases with normal CSF pressure and dynamics, instead
CSF drainage should be performed in cases with abnormal
CSF pressure and dynamics.
Therefore, empty sella syndrome requires a
multidisciplinary therapeutic approach and follow-up
with the integration of endocrine, neurologic and
ophthalmologic experts (Fig. 6).
Follow-up
Empty sella represents a very heterogeneous condition,
ranged from a merely occasional neuroradiological
 Review S Chiloiro and others
finding without any clinical involvement, to the empty
sella syndrome, characterized by the occurrence of
endocrine, ophthalmological and neurological symptoms
or a combination of these. Consequently, management
of these patients should be modulated according to the
clinical context.
Patients who had empty sella, without any clinical
manifestation or abnormalities at the time of diagnosis,
because of the theoretical risk of PES syndrome occurrence,
should be re-evaluated with a larger follow-up (after
24–36 months) to early recognize occurrence of endocrine
or ophthalmological alteration, if there are no clinical
indications before. In particular, neuroradiological study
should be able to recognize early the possible signs of
IIH (8). If progression is not observed, additional control
evaluation could be even less frequent and limited to
those patients requiring it clinically (8).
In PES syndrome cases, patients medically treated
for endocrine, opthalmological or neurological should
be re-evaluated according to appropriate well-established
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guidelines and at least twice in the year. Patients treated
surgically for IIH should also be re-evaluated for assessing
long-term results and side effects at least twice in the year
after surgery (8).
In SES cases, all patients should be evaluated
according diagnosis and management of hypopituitarism
and according to the etiology of SES (8).
Conclusion
ES, in the majority of cases, is only a neuroradiological
finding, without any clinical implication. Instead, PES
syndrome should be distinguished and properly managed,
as it represents a peculiar clinical entity, characterized
by heterogeneity both in clinical manifestations and in
hormonal alterations, sometime reaching severe extremes.
For a proper diagnosis, management and follow-up of
PES syndrome a multidisciplinary approach with the
integration of endocrine, neurologic and ophthalmologic
experts is strongly advocated.
Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in
the public, commercial or not-for-profit sector.
Empty sella 177:6 R283
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Received 25 June 2017

Revised version received 23 July 2017
Accepted 31 July 2017

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