Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

Pituitary incidentaloma
Israel B. Orija, Attending Physician and Director of Endocrine Section a,
Robert J. Weil, Director of the Neurological Institute Surgical Operation and
Director of Laboratory Research in Rose Ella Burkhardt Brain Tumor and
Neuro-Oncology Center b, Amir H. Hamrahian, Director, Clinical Research
Endocrinology and Metabolism Institute c, *
a
Department of Medicine, Endocrine section, Atlanta Medical Center, Atlanta GA, USA
b
Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Department of Neurosurgery, The Neurological Institute,
Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
c
Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk F20,
Cleveland, OH 44195, USA

Keywords: Pituitary incidentalomas (PIs) are commonly encountered in clinical

pituitary practice. While most are microincidentalomas (<1 cm) and not
incidentaloma functional, in some cases their identification may lead to discovery of
headache unrecognized abnormalities such as pituitary hormonal deficiencies,
apoplexy excess hormone secretion or visual field defects. Although the
hormonal evaluation
majority are pituitary adenomas, the potential list of differential
transsphenoidal surgery
diagnosis is extensive. A limited biochemical work up for asymp-
tomatic patients with microincidentalomas, to include measurement
of prolactin and IGF-1, is reasonable, with further studies to be
tailored based on the clinical picture. All patients with macro-
incidentalomas (
1 cm) should be evaluated for hypopituitarism and
undergo visual field testing if the sellar mass abuts or compresses the
optic chiasm. Most PIs can be followed, closely without surgery over
time, but some may require surgical removal, especially if they are
found to be macroincidentalomas at presentation, encroaching on or
abutting the optic chiasm, or are found to be functional, excluding
prolactinomas. Recovery of pituitary function may be seen in some
patients with mass effect following resection of a sellar mass. The
association of headache and pituitary incidentalomas remains
a diagnostic challenge. There are no randomized controlled studies to
guide the follow up approach when surgery is not indicated; most of
the follow up algorithms in the literature are based on personal
experience. Most retrospective series on natural history indicate that
microincidentalomas tend not to grow; without a need for long-term

* Corresponding author. Tel.: þ1 216 445 8538; Fax: þ1 216 445 1565.
E-mail address: hamraha@ccf.org (A.H. Hamrahian).

1521-690X/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.beem.2011.07.003
48 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68

follow up unless the patient becomes symptomatic. Macro-

incidentalomas, on the other hand, have a propensity to grow and
need a more aggressive follow up approach to minimize morbidity.
Ó 2011 Elsevier Ltd. All rights reserved.

Introduction

The use of sensitive diagnostic imaging modalities to evaluate the brain continues to increase. It is
estimated that about 3 million computed tomography (CT) scans were done in the US in 1980,
compared to 62 million in 2006, an annual increase of about 11.5%.1,2 It is also estimated that the rate
of magnetic resonance (MR) imaging usage in 1983 was about 1 per 1000 population per year,
compared to about 100 per 1000 population in 2005 with an average annual rate increase of 16–22%
between 1998 and 2002.3 These numbers are expected to increase. With the surge in diagnostic
imaging, as well as improved imaging techniques, a new diagnostic entity has arisen, the so called
“incidentaloma”.4
The pituitary incidentaloma (PI) is a lesion in the pituitary gland found by either CT or MRI eval-
uation of the brain for an unrelated indication, in a patient without overt signs or symptoms of pituitary
disease. While this definition may include imaging studies done for nonspecific symptoms such as
headache or other head or neck neurological symptoms or head trauma; it should exclude those
patients who had inadequate medical history or physical exam that otherwise would have led to
a suspicion of an underlying pituitary disorder. The first report describing 2 pituitary adenomas among
patients not suspected to have pituitary dysfunction was described by Erdheim in 1903.5 Although
pituitary incidentalomas are not functional by definition, this term should not be used interchangeably
with clinically non-functional pituitary adenomas (CNFPAs), since the latter usually present with mass
effect.6 Pituitary incidentalomas are common and their appropriate and cost effective evaluation and
management pose a dilemma for endocrinologists. There are no randomized controlled studies to
guide their evaluation and therapy. Current data on the natural history of PIs are from prospective and
retrospective cohort studies with relatively small sample sizes. Recently, a clinical practice guideline by
the Endocrine Society on this topic has been published, which will be reviewed, particularly in the
areas that our approach is different.7 This article will review the epidemiology, evaluation, manage-
ment and long-term follow up of patients with pituitary incidentalomas based on an extensive review
of the literature and the authors’ personal experience.

Prevalence of pituitary incidentalomas

The prevalence of pituitary incidentalomas (PIs) has been estimated from data derived from autopsy
as well as imaging studies in patients who underwent CT or MRI of the head for reasons unrelated to
pituitary disease. Incidentally discovered pituitary adenomas represented 12% of the pituitary tumours
in a series of 353 consecutive patients in one institution over a 14 year period with a presumptive
diagnosis of pituitary tumour.8
Several autopsy series reveal a prevalence of incidental pituitary adenomas of 9.3% with a range of
1.5–26.7%5,9–26 (Table 1). The tumours are typically identified in adults and are equally distributed
between men and women. The vast majority are microadenomas, with only a few isolated reports of
truly asymptomatic pituitary macroadenomas at autopsy.27,28 While the natural history of incidentally
discovered pituitary adenomas is not well characterized, the lack of a significant number of macro-
adenomas in these autopsy series suggest that the growth from micro- to macroadenomas is
uncommon, and almost all macroadenomas come to clinical attention during a patient’s lifetime.29
In a study by Hall et al, 10% of apparently healthy individuals harboured focal areas of decreased
signal densities on contrast enhanced MRI, which was mostly compatible with a diagnosis of an
asymptomatic pituitary adenoma; all were <10 mm.30 Among healthy volunteers, 4–20% of brain CT
scans done for unrelated problems harbour discrete areas of low density > 3 mm in the sella, which
may be due to a pituitary adenoma.31,32 Pituitary macroadenomas have been found in 0.11–0.3% of MRI
scans in healthy population33–35 and 0.2% of CT scans in an observational study at a VA hospital in
Cleveland, Ohio.36
 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68 49

Table 1
Summary of Autopsy data on Pituitary incidentalomas.

Year Author(s) Number of pituitary Number of pituitaries Prevalence

glands studied with adenomas (%)
1933 Susman 260 22 8.5
1934 Close 130 39 22.3
1936 Costello 1000 225 22.5
1969 Hardy 1000 27 2.7
1971 McCormick & Halmi 1600 140 8.8
1980 Kovacs et al. 150 20 13
1981 Burrow et al. 120 32 26.7
1981 Muhr et al. 205 3 1.5
1981 Parent et al. 500 42 8.5
1984 De Stephano et al. 100 14 14
1984 Sequeira et al. 450 36 8
1986 Char et al. 350 35 10
1991 Kontogeorgos et al. 470 49 10.4
1994 Uei et al. 1117 36 3.2
1994 Teramoto et al. 1000 31 3.1
1995 Camaris et al. 434 14 3.2
1999 Tomita & Gates 100 24 24
2001 Kurosaki et al. 692 79 11.4
2006 Buurman & Saeger 3038 306 10.4
2007 Kim et al. 120 8 6.7

A meta-analysis involving 3577 patients from 10 studies revealed an overall pituitary adenoma
prevalence of 16.7%; 22.5% at autopsy; and 14.4% at imaging studies (CT and MRI). Imaging studies
yielded a pituitary macroadenoma prevalence of 0.16–0.2%.37

Differential diagnosis of sellar masses

Pituitary adenomas are the most common pathology in patients with pituitary incidentalomas (PIs);
however, the potential list of the differential diagnosis is extensive (Table 2). Most of the lesions are

Table 2
Differential diagnosis of sellar lesions.

Pituitary adenoma
Pituitary hyperplasia
Germ cell tumors
Germinoma
Teratoma
Dysgerminoma
Benign neoplasia
Meningioma
Enchondroma
Cell rest tumors
Craniopharyngioma
Rathke’s cleft cyst
Chordoma
Colloid cyst
Inflammatory & granulomatous
Pituitary abscess
Sarcoidosis
Lymphocytic hypophysitis
Histiocytosis X
Tuberculosis
Gliomas (astracytoma, oligodendoglioma, optic nerve glioma)
Pituitary metastases (breast, lung, renal, melanoma, colon)
Vascular
Aneurysms
Cavernous angiomas
50 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68

<1 cm (microincidentalomas) and their proportion varies among series, depending on the population
studied. Based on four large surgical series most pituitary masses (85–95%) were pituitary adenomas:
prolactinomas 9–40%; GH adenomas 11–16%; ACTH adenomas 6–15% and TSH adenomas 0.7–1.5%.8,38–40
In a review article by Freda et al., among 1120 patients with sellar masses that underwent trans-
sphenoidal surgery over a 17 year period, 91% were pituitary adenomas. Craniopharyngiomas and
Rathke’s cleft cysts were the most common non-adenoma pathologies.41 Most incidentally found non-
functional pituitary adenomas are of gonadotrope origin based on immunocytochemical studies.42,43
MR imaging is the modality of choice to evaluate a pituitary mass, since it provides multiplanar
high-contrast images of the pituitary and its adjacent structures. In contrast, computed tomography
(CT) is better at evaluating bony changes and calcifications.44 Pituitary adenomas generally are not well
visualized on CT scans and may appear as hypoattenuated lesions on both unenhanced and enhanced
images compared to the normal pituitary gland.45 Larger tumours can usually be picked up on CT scan
due to the remodelling of sella (Fig. 1). Pituitary adenomas may appear hypointense or isointense to the
normal pituitary gland on noncontrast T1-weighted MR images; however, since they are less vascular
than the normal pituitary gland they usually appear hypodense following gadolinium administration
(Fig. 2).45 MR imaging is a useful adjunct to evaluate patients in whom the sellar mass is initially seen
on CT. All patients should undergo a complete history and physical examination.
In some cases, it may be difficult to distinguish a non-adenomatous lesion from a non-functional
pituitary adenoma. However, there are several endocrine, radiographic and neurological features
that may help to differentiate pituitary tumours from other less common sellar disorders.41 For
instance, diabetes insipidus is extremely rare in patients with pituitary adenomas at presentation
without significant suprasellar extension of the tumour. Therefore its presence is highly suggestive of
a non-pituitary etiology such as hypophysitis, sarcoidosis, or metastatic lesions.46
Some radiological features that may suggest sellar lesions other than pituitary tumours include:
calcifications on CT scan, which are frequently seen in patients with craniopharyngiomas and
meningiomas; or a rapidly enlarging mass with lack of sellar enlargement (sellar remodelling), which is
suggestive of a metastatic lesion. Cranial neuropathy is much less common in patients with pituitary
adenomas compared to non-adenomatous lesions (for example a metastasis or a meningioma),
although the acute onset of cranial neuropathy may accompany a hemorrhagic infarction of a pre-
existing pituitary adenoma (pituitary apoplexy).41 Meningiomas typically have a broad dural base;
are typically isointense to grey matter on unenhanced MRI, and typically show intense, homogeneous
enhancement with contrast and may be associated with dural tail sign; hyperostosis, best appreciated
on CT scan or plain films, may be present (Fig. 3).47 An intrasellar meningioma may be difficult to
distinguish from a pituitary adenoma.44 Both CT and MRI can usually demonstrate the cystic and solid
heterogeneous patterns seen in a Rathke’s cleft cyst or a craniopharyngioma. The cystic part of a sellar
mass or a cystic lesion such as Rathke’s cleft cyst appears hyperintense on T2 weighted MR images
(Fig. 4). CT scan most delineates calcifications in patients with craniopharyngiomas.44

Fig. 1. Large incidental sellar mass diagnosed during a CT scan study in a patient with a history of worsening of migraine headache.
The sellar mass has caused remodelling of the sellar contour (A). CT of a normal sella is shown for comparison (B).
 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68 51

Fig. 2. Pre- (A, C) and post-contrast (B, D) coronal and sagittal MR images of a patient with a small pituitary mass suggestive of
a pituitary adenoma. The pituitary lesion enhances less than the normal pituitary gland following gadolinium and appears hypo-
dense compared to the normal pituitary gland (B, D). The normal posterior lobe can be seen on precontrast sagittal view (C, long
arrow).

Fig. 3. Sellar meningioma appearing isointense on precontrast T1-weighted image (A) and hyperintense post gadolinium (B). The
Rat tail sign is seen on the post-contrast study (B, arrow).
52 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68

Fig. 4. Coronal MR images of a patient with an incidental sellar mass diagnosed during the work up for an episode of near syncope.
The MRI shows a sellar mass with mild pressure on optic chiasm. The mass is isointense with normal pituitary gland on precontrast
T1-weighted image (A), hypointense following gadolinium administration (B) and hyperintense on T2 weighted image suggestive of
a Rathke’s cleft cyst. The patient was found to have bilateral partial temporal visual field defect which resolved after surgery. The
final pathology was consistent with a Rathke’s cleft cyst.

Physiologic enlargement of the pituitary gland is not an uncommon reason for referring a young
woman or adolescent girl for the evaluation of a sellar mass and its proper identification is important to
prevent unnecessary surgery. Chanson et al. reported pituitary incidentalomas secondary to “normal
pituitary hypertrophy” among 7 young women, age 15–27 years. They were asymptomatic and had
brain imaging done for reasons unrelated to the pituitary gland. Detailed imaging of the pituitary
shows diffuse pituitary enlargement, with the maximum height between 9 and 12 mm. Pre and post-
contrast MRI changes were consistent with a normal pituitary gland (a homogenous, isointense gland
that enhanced homogenously post-contrast). Extensive pituitary hormonal evaluation was normal. The
patients were followed over 2–8 years and there was no change in clinical, laboratory and imaging
characteristics. Two patients had a pituitary biopsy done showing normal pituitary histology. The
authors concluded that such patients do not need surgery or extensive evaluation at follow up.48
Similarly, we receive a few referrals every year to evaluate women with an incidentally discovered
sellar lesion. The patients have a symmetric enlargement of the pituitary gland, which enhances
 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68 53

uniformly, with some extension towards optic chiasm but without clinically significant chiasmal
syndrome (Fig. 5). The clinical picture in such patients is mostly consistent with pituitary hypertrophy
and may be seen in postmenopausal patients with FSH levels usually exceeding 100 mU/mL, preg-
nancy, untreated primary hypogonadism and primary hypothyroidism. The pituitary enlargement
typically resolves following completion of pregnancy or with adequate thyroid hormone replacement
in a patient with primary hypothyroidism.
Intrasellar aneurysms should be considered among the differential diagnosis of sellar masses
(Fig. 6). Precise preoperative diagnostic evaluation including carotid angiography or MR angiogram is
very important, since if diagnosed as a pituitary tumour, surgery may have serious consequences.49 In
our institution, we use MR angiogram as part of imaging protocol for intrasellar masses that are
suspicious for an aneurysm prior to surgical intervention, although CT angiography may also be used.
Cerebral angiography is rarely indicated if either CT or MR angiography cannot be done.

Fig. 5. Pre (A) and post (B) gadolinium coronal MR images of a 53 year-old woman that was referred for an incidental sellar mass
found during a work up for tinnitus. The patient had menopause at age 45 with onset of hot flashes. She had normal pituitary
function including appropriate high levels of FSH 106 mU/mL and LH 75.7 mU/mL consistent with menopause. A normal pituitary
gland is shown for comparison (C).
54 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68

Fig. 6. An incidental sellar mass during MR image for headache. The mass is slightly hypodense on precontrast coronal T1-weighted
image (A) and enhances after gadolinium administration on coronal and axial views (B, C). The lesion is round with a flow void
around the periphery, with thrombus inside (A, C). The MR angiogram can confirm the diagnosis of an aneurysm arising from the
anterior communicating artery (D).

Clinical features

Pituitary incidentalomas are mostly asymptomatic. The vast majority are microincidentalomas but
endocrinologists may see a larger portion of patients with macroincidentalomas referred to them for
further evaluation. The initial approach to a patient with pituitary incidentaloma should be guided by
two questions: is there a mass effect; and, is the tumour hormonally active?

Evaluation for mass effect

Large tumours may present with signs of compression of neighbouring structures (mass effect)
including headaches, visual field deficits, decreased visual acuity and features of hypopituitarism,
which may have been unrecognized by the patient or the physician.

Visual field deficit

The optic chiasm lies about 1 cm above the pituitary fossa and can be affected by the superior
extension of a pituitary macroadenoma. Some patients with pituitary tumours may be unaware of the
visual field (VF) deficit, which typically progresses gradually, since most sellar masses grow slowly
(Fig. 7). Patients may complain of progressive loss of central visual acuity and a decrease of visual fields
in the bilateral temporal fields. Bitemporal hemianopsia is the typical manifestation of chiasmal
compression, however variable degrees of visual field defects may be seen depending on which part of
the optic apparatus is affected. Visual field loss usually begins in the superior temporal fields due to
pressure on optic chiasm from beneath by a sellar mass, which may be the reason why patients may not
notice it initially; then, with continued growth and compression, vision loss extends into the inferior
 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68 55

Fig. 7. Mild early left partial superior temporal visual field defect in a patient with an incidentally discovered pituitary incidenta-
loma. The patient did not complain of any visual problem at the time of referral. The sharp border of the visual field defect at midline
(arrow) is consistent with a chiasmal compression and not suggestive of an artifact or droopy eye lid.

temporal fields with further progression as the tumour enlarges. Formal visual field testing is needed if
the tumour compresses or abuts the optic chiasm.

Headache

Headaches are common (19–75%) and may be associated with pituitary tumours regardless of size,
but the underlying pathophysiology remains uncertain. Possible mechanisms include structural
causes such as dural stretching or cavernous sinus invasion.50 It has also been suggested that an
increase in the intrasellar pressure or tumour activity may play a role in the headache associated with
pituitary tumours.51,52 The link between headache and tumour activity is also supported by the
resolution of headache in some of patients with acromegaly shortly after initiation of somatostatin
analogues.53
Migraine may be the most common type of headache reported in patients with pituitary adenomas;
however, short lasting unilateral neuralgiform headache with conjunctival injection and tearing
(SUNCT) has been associated with pituitary tumours.53 It is also interesting to note that there seems to
be a strong association between pituitary associated headache and a family history of headache.53 At
the same time headache is a common symptom in the general population and establishing a cause and
effect relationship prior to surgical removal of a pituitary tumour can be challenging. Approximately
50% of patients with headache who undergo an operation for a pituitary tumour will have relief or
improvement after surgery; 35% report no change and up to 15% will have a worsening of their
headaches.53

Hypopituitarism

Hypopituitarism may range from deficiency of one pituitary hormone to the loss of all anterior
pituitary hormones (panhypopituitarism) and is typically associated with pituitary macroadenomas.54
One or more anterior pituitary hormone deficiencies have been reported in more than 30% of patients
with a pituitary macroadenoma.36,37,55 With some exceptions, including pituitary apoplexy, the loss of
pituitary hormone secretion is slowly progressive; symptoms tend to be nonspecific and may be
missed initially. The important role of increased intrasellar pressure in the pathogenesis of hypopi-
tuitarism in patients with pituitary tumours has been suggested by some studies.52 The decreased
blood flow through the portal vessels may result in diminished delivery of hypothalamic hormones to
pituitary cells and/or lead to variable ischemia/necrosis of the normal gland along with direct mass
effect on the normal pituitary gland by the sellar mass.
56 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68

Hormonal evaluation

A careful history and physical examination may reveal symptoms and/or signs of hypopituitarism or
hypersecretion of a specific hormone, which can be evaluated in detail to establish the diagnosis. In
patients in whom a family or personal history suggests a possible underlying multiple endocrine
neoplasia, additional hormonal evaluation would be indicated.

Hormonal evaluation for hypopituitarism

A recent paper described variable degrees of hypopituitarism in patients with non-functional

pituitary microadenomas.56 In the study by Yuen et al, about 50% of patients with a pituitary micro-
adenoma had partial hypopituitarism involving at least one pituitary axis.56 Such observation is not in
line with the authors’ experience in more than 100 patients with non-functional pituitary micro-
adenomas (unpublished data). The underlying reason for such discrepancy is not known. A recent
Endocrine Society Task Force on Pituitary incidentalomas recommends routine screening laboratory
testing for hypopituitarism in patients with large microincidentalomas, for example 6–9 mm in size.7
Further studies are needed to clarify the prevalence of hypopituitarism in patients with pituitary
microadenomas.
All patients with pituitary macroadenoma should undergo hormonal evaluation to assess pituitary
hormone deficiency. In general, pituitary hormone deficiencies from an expanding pituitary tumour
tend to begin with growth hormone and/or the gonadotropins (LH and FSH).57 Deficiencies of TSH and
ACTH secretion may follow as the tumour expands. In the authors’ experience, the thyrotropin axis is
usually affected prior to corticotropin axis.
Serum TSH along with free T4 or the free thyroxine index (FTI) should be measured to evaluate
the thyrotropin axis. The presence of a low free T4 with a low or normal TSH is consistent with
secondary hypothyroidism. A single measurement of TSH in a patient with pituitary disorder is
inappropriate and cannot be relied upon, since a normal level in a patient with hypopituitarism is
not uncommon.
The ACTH Stimulation Test or an early morning (8am) serum cortisol are both reasonable initial tests
to evaluate the hypothalamic-pituitary-adrenal (HPA) axis. The authors prefer the ACTH Stimulation
Test since it may be performed anytime during the day. An early morning cortisol level <3 mg/dL
confirms adrenal insufficiency, while a value >15 mg/dL makes the diagnosis highly unlikely. Cortisol
levels in the range of 3–15 mg/dL are indeterminate and should be further evaluated by ACTH Stimu-
lation Test. The standard dose (SD) ACTH Stimulation Test utilizes an intravenous or intramuscular
injection of 250 mg cosyntropin. A normal response is a plasma cortisol concentration >18 mg/dL at
30 min. The sensitivity of the ACTH Stimulation Test to identify mild, partial adrenal insufficiency
improves with the use of low dose (LD) cosyntropin (1 mg ACTH1–24 given intravenously). However, this
may result in a higher false positive rate.58 In most clinical situations, the 30 min cortisol value during
SD ACTH Stimulation Test has a diagnostic accuracy close to the LD ACTH Stimulation Test.59 Patients
with recent onset ACTH deficiency (e.g. in pituitary apoplexy or within 2–4 weeks following pituitary
surgery) may have a normal response to cosyntropin since the adrenal glands have not undergone
sufficient atrophy and may still respond to ACTH stimulation. The insulin tolerance test (ITT) is
considered the gold standard method to evaluate the hypothalamic-pituitary-adrenal (HPA) axis, but it
needs to be performed by an experienced clinician and is usually not needed for everyday clinical
practice.
Low serum testosterone in men (estradiol in women) along with normal/low FSH and LH levels
(premenopausal levels in women) are consistent with gonadotropin deficiency in males and amen-
orrheic premenopausal women. Failure to elevate FSH and LH in postmenopausal women is also
consistent with gonadotropin deficiency. The presence of regular menses almost always indicates
a normal gonadotropin axis. In women with irregular menstruation, the interpretation of hormonal
evaluation for gonadotropin axis can be challenging and is usually not indicated.
Patients with three or more pituitary axes deficiency, with a low IGF-1 level, may be presumed to
have GH deficiency and usually do not need dynamic testing. When indicated, the GH axis is best
evaluated by dynamic testing, using either a Glucagon Stimulation Test or ITT.
 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68 57

Hormonal evaluation for pituitary hyperfunction

The majority of incidentally discovered pituitary adenomas are clinically non-functional pituitary
adenomas, but up to 18% of incidentalomas may be clinically functional; most functional PIs are pro-
lactinomas or GH-secreting adenomas.34,55,60–62
The prevalence of prolactinoma is expected to be higher in postmenopausal women and men with
pituitary incidentalomas compared to women in reproductive age, since the latter group usually seek
medical attention when menstruation is absent or irregular.61 The elevated prolactin level in patients
with pituitary incidentalomas needs to be interpreted with caution since a number of medications and
disorders may result in mild to moderate elevations of prolactin (Table 3). A prolactin level
250 mg/L
(>100 mg/L in the authors’ experience) is almost always consistent with a diagnosis of prolactinoma
except during pregnancy and in some patients being treated with metoclopramide or antipsychotic
medications.63 In patients on drugs that may be associated with hyperprolactinemia re-testing after
a drug holiday would be informative, if it is clinically safe to hold or switch such a medication. Prolactin
levels 100 mg/L may be related to a microprolactinoma or be due to stalk effect secondary to
disruption of the dopamine inhibitory pathways from the hypothalamus to the pituitary.63 Rarely, the
“hook effect” may result in mild to moderate elevation of prolactin level in the setting of a true giant

Table 3
Differential diagnosis of hyperprolactinemia.

Pituitary/hypothalamic disease
Pituitary adenoma
Lymphocytic hypophysitis
Pituitary stalk section
Empty sella syndrome
Craniopharyngiomas
Meningiomas
Dysgerminomas
Sarcoidosis
Histiocytosis X
Cranial irradiation
Neurogenic
Chest wall lesions (Herpes zoster)
Nipple piercing
Spinal cord lesions
Breast stimulation
Drugs
Antipsychotics (neuroleptics, phenothiazines, butyrophenones)
Monoamine oxidase inhibitors
Tricyclic antidepressants
Reserpine
Methyldopa
Metoclopramide
Verapamil
Cocaine
Protease inhibitors
Opiates
Cimetidine (?)
Serotonin reuptake inhibitors (?)
Miscellaneous
Macroprolactinemia
Primary hypothyroidism
Cirrhosis
Renal failure
Idiopathic
Physiologic
Pregnancy
Early postpartum in lactating women
Stress (physical and psychological)
58 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68

macroprolactinoma which are almost always >3 cm in size. This artefact is readily corrected by a 1:100
dilution of the serum sample or using a two step assay for prolactin measurement.63,64 Macro-
prolactinemia is another consideration in hyperprolactinemia, where the prolactin level is elevated due
to the presence of prolactin polymers, typically without symptoms or signs of hyperprolactinemia.63
The true prevalence of patients with silent somatotroph adenomas is unknown. Growth hormone
(GH) hypersecretion has been reported in patients with pituitary tumours without clinical stigmata of
acromegaly.34,55,65–68 Moreover, acral changes may not correlate with the metabolic consequences of
GH excess.69 Most of the cases reported in the literature involve young women, age 19–49 years,
presenting with mass effect from a macroadenoma and may be associated with hyperprolactinemia. In
a study by Reincke et al, one of eighteen patients with pituitary incidentaloma and no apparent
acromegalic features, harboured a GH-secreting pituitary adenoma.55 For this reason, looking for the so
called “silent “ GH hypersecretion may be warranted in patients with incidental pituitary tumours,
especially in those with macroadenomas.65 They typically have biochemical evidence of GH hyper-
secretion with elevated IGF-1 and failure of adequate GH suppression after an oral glucose tolerance
test. A normal age and sex adjusted IGF-1 almost always rules out acromegaly. A few conditions such as
poorly controlled type 1 diabetes, malnutrition, estrogen therapy, liver disease, renal failure, and
critical illness may be associated with falsely low IGF-1 level.70
Silent corticotroph adenomas are typically macroadenomas and not associated with typical clinical
features of Cushing’s syndrome. They account for 1.1–6% of all surgically resected adenomas.71 Patients
present with mass effect and these tumours may be associated with a higher risk of recurrence after
surgery; in fact, some patients may develop features of clinical Cushing’s syndrome during follow up.71
A close follow up of such patients is indicated.
TSH secreting adenomas are rare72; they typically present as macroadenomas with mass effect and
features of thyrotoxicosis.72 They account for 0.9–1.5% of all pituitary tumours in surgical series.38,40
There are a few cases of TSH micro- and macroincidentalomas described in the literature.73,74 Yama-
kita et al reported a 46-year-old woman who had presented with vertigo and nystagmus. Her symp-
toms resolved spontaneously, but she was found to have a large pituitary tumour with suprasellar and
left cavernous sinus invasion. The only hyperthyroid signs noted were moist skin and exaggerated
ankle jerks. She had surgical debulking and the tumour stained strongly for TSH, prolactin and GH
being consistent with a plurihormonal TSH producing pituitary adenoma. Her thyroid function tests
normalized after surgery.74

Other incidental sellar findings

In addition to pituitary incidentalomas, endocrinologists may be consulted about other incidental

sellar findings such as empty sella syndrome (ESS), anatomical variations, or a prominent posterior
pituitary that is mistaken for a sellar mass.
An empty sella is partially or completely filled with cerebrospinal fluid (CSF) due to an extension
of the suprasellar subarachnoid space into the sella turcica through a defect in the diaphragma sellae,
associated with some degree of flattening of the pituitary gland (Fig. 8). It may be associated with
enlargement of the sella turcica. Primary ESS occurs when this defect is idiopathic. Secondary ESS
occurs in the setting of a known pituitary event, such as previous pituitary adenoma resection,
radiation, trauma or a pituitary tumour infarction. The pathogenesis of primary ESS is unclear but has
been associated with congenital defects in the diaphragma sellae, raised intracranial pressure, CSF
pulsations or spontaneous necrosis of a pre-existing pituitary adenoma.75,76 Some degree of ESS has
been reported in 5.5–23% of autopsies and 8–35% of the general population.76 It is mostly asymp-
tomatic, but it may be associated with headaches and other features of raised intracranial pressure
such as papilloedema and visual disturbances. Endocrine dysfunction may be associated with ESS,
and may even be a presenting feature.75 ESS may be associated with hyperprolactinemia up to
100 mg/L and up to 25% of patients may have some degree of hypopituitarism. Forty two percent of an
Italian cohort had endocrine dysfunction, mainly menstrual irregularities in women and erectile
dysfunction in men.76
Sellar anatomical variations may be another reason for referral of patients to endocrinologists.
Rarely, patients may have medial deviation of carotid arteries into the sella which may appear as
 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68 59

Fig. 8. Postcontrast coronal (A, C) and sagittal views (B, D) of a patient with empty sella. A small rim of pituitary tissue is seen at the
floor of the sella. The patient was found to have partial hypopituitarism during biochemical evaluation.

a pituitary cyst on coronal view (Fig. 9). We have not identified any hormonal deficiency in the few
cases that have been evaluated in our centre; most patients require assurance.

Natural history of pituitary incidentalomas

The ideal study of the natural history of pituitary incidentalomas should report on the surgical
pathology of all the patients that have been initially followed conservatively, but such data is not
available. The evidence on the natural history of pituitary incidentalomas is scarce and overall of low
quality.77 Eleven studies have reported the natural history of pituitary incidentalomas34,55,60–62,78–83
(Table 4a & b). In some of these studies (3/11) less than 40% of patients had pituitary incidentalo-
mas. Among 166 patients with microadenomas, 17 (10.2%) showed a 10% increase in tumour size (3–
40%) over a mean follow up of 4.3 years. The majority (80%) remained unchanged while 10%
demonstrated a reduction in tumour size (Table 4a). In the same studies, there were 356 macro-
adenomas; 87 (24%) increased in size, 45 (13%) decreased and 224 (63%) remained unchanged over the

Fig. 9. Patient with incidental finding of medial deviation of carotid arteries on pre- (A) and post-contrast (B) coronal T1-weighted
MR images was referred for further evaluation. Patient had normal pituitary function studies.
60 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68

Table 4a
Summary of studies in the literature on tumour size change in patients with pituitary incidentalomas (microadenomas).
Some studies did not exclusively report on patients with incidentalomas.

Authors/year Microadenomas
of publication
Incidental Total, Increased, Decreased, No change, Duration of
findings, n n n n n follow up years
(months)
Reincke et al., 1990 18 (100%) 7 1 (14.3%) 1 (14.3%) 5 (71.4%) 1.8 y (22 m)
Donovan & Corenblum 31 (100%) 15 0 4 (27%) 11 (73%) 6.4 y (76.8 m)
1995
Nishizawa et al., 1998 28 (100%) 0 0 0 0 5.6 y (67.2 m)
Feldkamp et al., 1999 67 (100%) 31 1 (3.2%) 1 (3.2%) 29 (93.6%) 2.7 y (32.4 m)
Igarashi et al., 1999 4/23 (17.4%) 1 0 0 1 (100%) 5.1 y (61.2 m)
Sanno et al., 2003 248 (100%) 74 10 (13.5%) 7 (9.5%) 57 (77%) 2.3 y (27 m)
Fainstein Day et al., 46 (100%) 11 1 (9%) 0 10 (91%) 3.2 y (38.4 m)
2004
Arita et al., 2006 42 (100%) 5 2 (40%) 0 3 (60%) 5.2y (61.9m)
Karavitaki et al., 2007 15/40 (37.5%) 16 2 (12.5%) 1 (6.3%) 13 (81.2%) 3.5 y (42 m)
Dekkers et al., 2007 6/28 (21%) 0 0 0 0 7.1 y (85 m)
Anagnostis et al., 2011 61 (100%) 6 0 1 (17%) 5 (83%) 4y (48 m)

same mean follow up of 4.3 years (Table 4b). Karavitaki et al reported an increase in tumour size in 12/
24 (50%) of patients with non-functional macroadenomas during a mean follow up of 43 months
(range 9–98). Among these patients, 8/12 (66%) showed a new or worsening visual field deficit.82
Similarly, Arita and colleagues found that 21/42 (50%) of patients with non-functional adenomas
(mean size 18 mm) increased by at least 10% over an average of 5 years follow up, among whom 10
patients became symptomatic with visual field defects, double vision, and panhypopituitarism.34
Dekkers et al reported on 28 patients with non-functional pituitary macroadenomas, followed over
a mean duration of 85 months. Tumour growth occurred in 50% of the patients including six patients
who required surgery because of visual field deficits. All experienced improvement in vision after
surgery.81 It appears that the longer the duration of follow up the higher the chance of tumour
growth.81 In a recent meta-analysis, which included patients with PIs and non-functional pituitary
adenomas, the incidence of growth was higher for macroadenomas at 12.5 per 100 person years (PYs)
compared to 3.3 and 0.05 per 100 PYs in those with microadenomas and cystic lesions, respectively.77
In general, the studies on natural history of PIs suffer from a variety of problems including low quality,

Table 4b
Summary of studies in the literature on tumour size change in patients with pituitary incidentalomas (macroadenomas).
Some studies did not exclusively report on patients with incidentalomas.

Authors/year Macroadenomas
of publication
Incidental Total Increased Decreased No change Duration of
findings n n n n n follow up years
(months)
Reincke et al., 1990 18 (100%) 7 2 (28.6%) 0 5 (71.4%) 1.8 y (22 m)
Donovan & Corenblum 31 (100%) 16 5 (31.3%) 0 11 (68.7%) 6.4 y (76.8 m)
1995
Nishizawa et al., 1998 28 (100%) 28 2 (7%) 0 26 (93%) 5.6 y (67.2 m)
Feldkamp et al., 1999 67 (100%) 19 5 (26.3%) 1 (5.3%) 13 (68.4%) 2.7 y (32.4 m)
Igarashi et al., 1999 4/23 (17.4%) 22 6 (27%) 10 (46%) 6 (27%) 5.1 y (61.2 m)
Sanno et al., 2003 248 (100%) 165 20 (12%) 22 (13%) 123 (75%) 2.3 y (27 m)
Fainstein Day et al., 46 (100%) 7 1 (14%) 0 6 (86%) 3.2 y (38.4 m)
2004
Arita et al., 2006 42 (100%) 37 19 (51%) 0 18 (49%) 5.2 y (61.9 m)
Karavitaki et al., 2007 15/40 (37.5%) 24 12 (50%) 4 (17%) 8 (33%) 3.5 y (42 m)
Dekkers et al., 2007 6/28 (21%) 28 14 (50%) 8 (29%) 6 (21%) 7.1 y (85 m)
Anagnostis et al., 2011 61 (100%) 3 1 (33%) 0 2 (67%) 4 y (48 m)
 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68 61

significant heterogeneity, methodological limitations, lack of distinction between PIs and non-
functional adenomas, small numbers of subjects and small number of adverse events.77
Most of the series reporting the natural history of pituitary adenomas have not found any reliable
predictors for tumour growth, being unrelated to gender, age and the presence of visual field deficits or
cavernous sinus invasion.34,81,82 However, a few studies have found longer tumour doubling time in
patients older than 60 years old.34,84 Tanaka et al looked at growth patterns in 40 patients with residual
non-functioning pituitary adenoma following initial surgical resection.84 Thirty eight adenomas (95%)
increased and two adenomas (5%) decreased over a mean follow up of 52.5 months. The growth pattern
was exponential in the 38 patients with tumour growth. The tumour volume doubling time (TVDT) was
506–5378 days (mean 1836 days). There was a positive correlation between log TVDT and the age of the
patient, with a significant difference between the TVDT for patients <61 years of age (1106 days)
compared to 2566 days in those that were older.84 More frequent follow up in patients less than 60
years old may be warranted.
Eight of 11 studies of the natural history of pituitary incidentalomas reported the pathology of
patients referred for surgery (Table 5). While the numbers are small, the majority of PIs turned out to be
pituitary adenomas (Table 5). Most incidental, non-functional pituitary adenomas are of gonadotrope
origin based on immunocytochemical studies.42,43 In about 73% of patients with pituitary micro-
incidentalomas, TRH elicited an increase in gonadotropin beta subunits raising the possibility that most
non-functioning pituitary adenomas originate in a common ancestor cell type, probably a pituitary
gonadotrope.85 It has been hypothesized that the increase in the prevalence of incidental pituitary
adenomas with age may result from an age related decrease in the activity of sex hormones, which
reduces feedback inhibition on the hypothalamic trophic factors, with subsequent gonadotroph
stimulation of pituitary tumours.86
The follow up of PIs by MRI may be best characterized by volume changes rather than by changes in
linear measurements. More accurate and reproducible data may be utilized in the follow up of patients
with residual or recurrent tumour following initial surgical resection using tumour volume
changes.84,87,88 However, tumour volume calculations are more complex and may not be readily
applicable for everyday clinical practice. Regardless of the method of measurement, the growth
changes should be interpreted in concert with the clinical picture, especially development of visual
field deficits, cranial neuropathies and/or new or worsening pituitary function. Dekkers et al estimated
that non-functional pituitary macroadenomas grow at a rate of about 0.6 mm per year,81 but other
studies have shown that the growth kinetics of non-functional pituitary adenomas follow either an
exponential84,88 or a logistic and non-linear model,88 which makes it difficult to predict the growth
pattern for a particular incidentaloma.

Table 5
Summary of pathologic diagnosis at surgery in patients with pituitary incidentalomas.

Authors/year publication Number of cases, n Surgical pathology

Reincke et al., 1990
Donovan & Corenblum 1995
Nishizawa et al., 1998
Igarashi et al., 1999
Sanno et al., 2003
Fainstein Day et al., 2004
Karavitaki et al., 2007
Anagnostis et al., 2011
n, 4 Pituitary adenomas, n 3 (75%)
Chondroid chordoma, n 1 (25%)
n, 1 Cystic craniopharyngioma, n 1 (100%)
n, 2 Pituitary adenomas, n 2 (100%)
n, 8 Pituitary adenomas, n 4 (50%)
Rathke’s cyst, n 3 (38%)
Meningioma, n 1 (12%)
n, 258 Non-functioning pituitary adenoma, n 209 (81%)
Rathke’s cyst, n 41 (16%)
Arachnoid cyst, n 5 (2%)
Craniopharyngioma, n 3 (1%)
n, 17 Pituitary adenomas, n 16 (94%)
Craniopharyngioma, n 1 (6%)
n, 8 Pituitary adenomas, n 7 (88%)
Normal pituitary, n 1 (12%)
n, 8 Null cell pituitary adenomas, n 7 (87.5%)
Hypophysiocytoma, n 1 (12.5%)
62 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68

Risk of pituitary apoplexy

It is important to educate patients and family members about symptoms associated with pituitary
apoplexy especially in patients with pituitary macroadenomas (Fig. 10). Apoplexy is a hemorrhagic
infarction of the tumour that manifests clinically as sudden onset of severe headache, nausea/vomiting,
vision loss and cranial nerve palsies. If unrecognized and untreated, these patients may suffer from
hypotension and shock secondary to adrenal insufficiency as well as irreversible vision loss or diplopia.
Surgical intervention is generally recommended in cases with progressive vision loss or cranial
neuropathy, preferably within 24–48 h of onset if feasible, to minimize the risk of permanent neuro-
logical deficit. While most cases of pituitary apoplexy are spontaneous, precipitating factors may
include head injury, anticoagulant therapy, dopamine agonists, radiation therapy, or dynamic endo-
crine tests.89 It occurs in 1.6–12.8% of all pituitary adenomas, but clinically significant pituitary
apoplexy is a rare event in patients with pituitary microadenomas.90 In the study by Arita et al, the risk
of pituitary apoplexy during 5 years follow up was 9.5% and all such tumours were macroadenoma in
size.34 The patients presented with severe headache, visual symptoms, and/or acute onset of hypo-
pituitarism. Three out of four patients underwent transsphenoidal surgery. The rate of pituitary
apoplexy reported by this study is higher than some other studies, where the risk of apoplexy ranged
from 0.4% to 7% during a mean follow up of 2–6 years.78–80 In a recently published meta-analysis of 11
studies with a median follow up of 3.9 years looking at the natural history of pituitary incidentalomas
and non-functional pituitary macroadenomas, the authors found a trend for greater incidence of
pituitary apoplexy in macroadenomas (1.1 per 100 PYs) compared to microadenomas (0.4 per 100 PYs)
that did not reach statistical significance.77

Management and follow up of pituitary incidentalomas

There are no randomized studies on the management and follow up of patients with pituitary
incidentalomas. Most published data represents personal or institutional approaches.29,91–93 Despite
the high prevalence of PIs, the literature remains uncertain about a standard or optimal approach to
such patients.77 A clinical practice guideline by Endocrine Society on pituitary incidentalomas has been
published recently.7 Here we summarize our approach to patients with pituitary incidentalomas
(Fig. 11).
In the presence of hormonal hypersecretion, transsphenoidal surgery by an experienced surgeon for
maximal cure rates and reduced post operative complications is usually the treatment of choice, except
in prolactinomas where dopamine agonists can resolve symptoms and shrink the tumour in the
majority of cases. Even in patients with a visual field defect associated with macroprolactinoma, the
initiation of dopamine agonist therapy is usually associated with a rapid improvement in vision even

Fig. 10. Patient with a history of pituitary adenoma experienced sudden onset severe headache. Noncontrast coronal (A) and sagittal
(B) T1-weighted MR images show a sellar mass with signal hyperintensity being consistent with a subacute haemorrhage in the
pituitary adenoma. The pituitary stalk is pushed towards the right.
 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68 63

Fig. 11. Approach to patients with a pituitary incidentaloma.

before a significant change in tumour size is observed with neuroimaging. However, close follow up
(2–4 weeks after initiation of therapy) to establish response to dopamine agonist therapy, with formal
improvement in vision, is necessary; non-responders would require surgical intervention.
If the tumour is hormonally inactive, further evaluation depends on the size of the tumour and the
presence of mass effect. In the authors’ experience a complete hormonal evaluation for hypopituita-
rism in asymptomatic patients with microincidentalomas has a low yield and is likely not warranted.
However, biochemical evaluation in patients with clinical features suggestive of hypopituitarism would
be indicated. A recent consensus guideline by the Endocrine Society on this topic recommends
biochemical evaluation in patients with larger microincidentalomas (6–9 mm) with a need for further
studies in this area.7 In an analysis by King et al, serum prolactin was the single most cost effective
screening test in patients with incidentally discovered pituitary microadenomas.94 We recommend
measurement of a single serum prolactin and an IGF-1 level in patients with microincidentalomas,
with any further work up tailored to the clinical picture. The majority of microincidentalomas that are
non-functional can be followed conservatively. In some selected cases, headache may be an indication
for surgery especially when there is evidence of haemorrhage in the tumour. However, the patient
needs to be informed that headache may not improve after surgery or may worsen.53 The majority of
microincidentalomas do not grow and there is no good evidence that a non-functional tumour
transforms to a functional one with time. For most patients MRI should be repeated in 12 months after
the initial imaging study; if the lesion is stable, there is no need for further routine imaging, unless the
patient develops new symptoms suggestive of mass effect, about which the patient should be coun-
selled. The authors do not endorse the recent Endocrine Society Practice Guideline recommending
follow up imaging yearly for 3 years and then less frequently thereafter for microincidentalomas
without any stopping date for follow up imaging.7 Even in the presence of tumour enlargement in
64 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68

a small fraction of patients with microincidentalomas, such tumour growth is usually not associated
with new visual field abnormalities that necessitate surgery.34,55,61,78,80–83
In patients with a non-functional pituitary macroadenoma, a comprehensive hormonal evaluation
for hypopituitarism should be done. Biochemical evaluation should also include measurement of
prolactin and IGF-1 levels to assess potential, subclinical hormone hypersecretion. We have found very
little yield from routine evaluation for hypercortisolism in patients with pituitary incidentalomas in the
absence of any clinical features suggesting Cushing syndrome. However, an elevated random plasma
ACTH level may suggest an underlying silent corticotroph adenoma in the absence of clinical manifes-
tations of cortisol excess.71 Screening for a gonadotroph-secreting pituitary adenoma through
measurement of FSH, LH and gonadotropin alpha subunit is not routinely indicated, since almost all such
tumours are clinically silent and generally come to clinical attention secondary to mass effect. We do not
repeat hormonal evaluation in patients with PIs unless there is a change in tumour size or clinical status
of the patient, since we have found very little meaningful information from such routine hormonal
evaluation in our practice.55,81 Patients with a visual field defect or cranial neuropathy should undergo
tumour resection. The approach to patients with macroincidentalomas with normal visual field testing is
less straight forward and may depend on a number of factors such as age, proximity of the tumour to
optic chiasm and patient preference. We recommend surgery for most patients with pituitary macro-
adenomas abutting the optic chiasm, which has also been recommended by others.7,78,80 Similarly, one
may argue for surgical resection in young patients with a pituitary macroadenoma even in the absence of
mass effect. Worsening headaches and the presence of macroadenoma in a young woman contem-
plating pregnancy may also be potential indicators for surgery. Our approach in patients with macro-
incidentalomas is to obtain a follow up MRI at 6 months, then yearly for 5 years followed by every 2–3
years imaging study if pituitary tumour is stable. A similar approach has been recommended in the
Endocrine Society Clinical Practice Guidelines.7 Surgical intervention would be indicated if there is
evidence of tumour growth or mass effect. Pituitary function testing should be repeated if the tumour
grows or there is clinical evidence suggestive of hypopituitarism. Patients with macroadenomas need
follow up for life, even after surgical resection because of the potential risk for tumour regrowth.
Surgical removal of the tumour has been shown to improve pituitary function in some but not all
studies.6,95–98 Predictors of recovery included a normal or slightly elevated prolactin, a rise in TSH and
LH after TRH and GnRH stimulation and, likely, surgical expertise.95,96 In a comprehensive review,
Dekkers et al, reported that, in contrast to the beneficial effects of surgery on compromised visual
function, pituitary function is often not restored after transsphenoidal surgery, although data from
studies concerning post operative pituitary function are conflicting: 5/8 studies (62%) showed an
improvement while 3/8 (38%) showed no significant improvement or some deterioration in pituitary
function after surgery.6 We agree with the authors in their discussion that the aim of transsphenoidal
surgery should be to protect and, if possible, improve visual function, rather than improvement of
pituitary function. At best, hypopituitarism should be considered a relatively weak indication for
pituitary surgery. The likelihood of recovery may be less common in non-functioning pituitary mac-
roadenomas compared to functional macroadenomas.99

Summary

Pituitary incidentalomas are common in clinical practice and are encountered by most endocri-
nologists. Most incidentalomas are pituitary adenomas, but the differential diagnosis is extensive. The
majority are microincidentaloma (<1 cm) and clinically non-functional, but they may lead to discovery
of unrecognized abnormalities such as pituitary hormonal deficiencies or visual field defects. All
patients with pituitary macroadenoma should undergo hormonal evaluation to assess for hypopitu-
itarism. A single measurement of prolactin and IGF-1 may be a reasonable approach to evaluate
subclinical hormone hypersecretion, with additional studies to be guided by the clinical picture.
Patients with visual field deficits and cranial neuropathy and most patients with tumours abutting the
optic chiasm should be referred for transsphenoidal surgery. Most microincidentalomas can be fol-
lowed conservatively with a single follow up imaging in one year, unless there is evidence for mass
effect. Macroincidentalomas should be followed for life, gradually increasing the interval between
imaging studies if the tumour is stable.
 I.B. Orija et al. / Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 47–68 65

Practice points

 Most PIs are pituitary adenomas and microincidentalomas (<1 cm) in size.
 A limited biochemical work up for asymptomatic patients with microincidentalomas is
reasonable, with further studies to be tailored based on the clinical picture.
 All patients with macroincidentalomas (
1 cm) should be evaluated for hypopituitarism and
undergo visual field testing if the sellar mass abuts or compresses the optic chiasm.
 Functional PIs, excluding prolactinomas, and those encroaching on or abutting the optic
chiasm should be surgically removed.
 Most PIs <1 cm should be followed with a onetime repeat MRI at 12 months without a need
for long-term follow up unless the patient becomes symptomatic.
 Macroincidentalomas have a propensity to grow and need a more aggressive follow up
approach to minimize morbidity.
 Patients and their family members should be educated about symptoms associated with
pituitary apoplexy especially in those with pituitary macroadenomas

Research agenda

 The association of pituitary microincidentalomas and hypopituitarism needs further

investigation.
 The natural history of PIs is not well characterised; current studies of natural history have
major methodological limitations including but not limited to small sample sizes.
 The association of headache and pituitary incidentalomas remains a diagnostic challenge and
require further investigation.

Acknowledgements

We wish to thank the Melvin Burkhardt chair in neurosurgical oncology and the Karen Colina
Wilson research endowment within the Rose Ella Burkhardt Brain Tumor and Neuro-oncology Center
at the Cleveland Clinic Foundation for additional support and funding.

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