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EVALUATION AND INVESTIGATION OF PITUITARY DISEASE
urine collection is performed to conrm excessive urine volume (>50 mL/kg/day) and low
osmolality (<300 mOsmol/L). A water deprivation test, with close monitoring of plasma and
urinary sodium and osmolalities, will conrm the inability to appropriately concentrate the
urine in severe diabetes insipidus (DI).
A central cause of DI (such as the pituitary) can be dierentiated from a nephrogenic cause
by using desmopressin (DDAVP). With central causes, urine becomes concentrated 1-2 hr
aer the administration of desmopressin (DDAVP), whereas in nephrogenic DI, the patient
is resistant to treatment with DDAVP.
Imaging
e pituitary is typically visualised via magnetic resonance imaging (MRI) with gadolinium, in pre- and post-contrast 3-mm images. e normal pituitary gland and stalk enhance
intensely on post-contrast images. Macroadenomas (>1 cm) are visualised by merit of their
size and can extend beyond the sella, most oen superiorly. ey are usually isointense with
cortical tissue and may have hyperintense foci on T2-weighted images, ndings indicating
focal necrosis and oen a more readily excised tumour. Microadenomas take up contrast less
quickly than the surrounding gland and are visualised as a lling defect within the normal
gland on post-contrast images.
e posterior pituitary usually emits a hyperintense signal on T1-weighted images. is
‘bright spot’ is almost always reduced or absent in diabetes insipidus.
Small, incidentally discovered pituitary lesions are common. In the absence of evidence of
hormone hypersecretion, they can be monitored with serial MRI.
Ophthalmological Investigations
Tumours with suprasellar extension may lead to peripheral visual eld defects. e classical bitemporal hemianopia is not always seen; however, some degree of visual eld defect is
frequently observed even in patients who do not complain of visual symptoms. Perimetry is
the preferred method of visual eld testing. Testing should be conducted in all patients with
sellar lesions that are in contact with the optic chiasm.
KEY POINTS
• Pituitary adenomas can lead to hypersecretion or hyposecretion of pituitary hormones,
and/or local mass effects on surrounding structures. Many pituitary tumours present
incidentally on imaging performed for other indications.
• Tumours are classied by size (greater or less than 10 mm in diameter), and by whether
or not they are ‘functioning.’
• All patients with lesions involving the pituitary fossa should undergo an endocrinology
assessment.
• Thin section, multiplanar MRI with pre- and post-contrast sequences should be
performed, although some functioning microadenomas may not be visualised, despite
there being evidence of hormonal disturbance.
• Patients should have an assessment of their visual elds using perimetry techniques
if the tumour abuts the optic chiasm. Macroadenomas may not produce a classical
bitemporal eld defect.
Further Reading
Freda PU, Beckers AM, Katznelson L, Molitch ME, Montori VM, Post KD, Vance ML,
Endocrine Society. Pituitary incidentaloma: an endocrine society clinical practice
guideline. J Clin Endocrinol Metab 2011; 96(4): 894–904.
Schwartz TH, Anand VK. Endoscopic pituitary surgery. New York: ieme; 2012.
458 Head and Neck Endocrine Surgery
PRIMARY PITUITARY DISEASE
92. PRIMARY PITUITARY DISEASE
Introduction
Consisting of both an anterior and a posterior portion, termed the adenohypophysis and
the neurohypophysis, respectively, the pituitary lies immediately below the hypothalamus.
Anterior Pituitary (Adenohypophysis)
e anterior pituitary secretes thyroid-stimulating hormone (TSH), adrenocorticotropic
hormone (ACTH), growth hormone (GH), prolactin (PRL), and the gonadotropins folliclestimulating hormone (FSH) and luteinising hormone (LH). Pituitary hormone secretion is
subject to marked cyclical rhythms and varies widely among the dierent hormones. Loss
of a recognisable rhythm may indicate disease. Secretion of hormones is controlled by the
hypothalamus. Active hormones inuence pituitary hormone production both by direct
feedback on anterior pituitary cells and, more signicantly, by inducing the synthesis of neurohormones from hypophysiotropic neurohormones. See Table 92.1.
Table 92.1 Principal pituitary hormones and their regulators, secreting cells, and action
Pituitary hormone Secreting cells
Adrenocorticotro-
pic hormone
(ACTH)
hormone
Growth
hormone (GH)
Anterior pituitary
Luteinising
hormone (LH)
Follicle-
stimulating
hormone (FSH)
Prolactin (PRL) Lactotrophs Breast TRH Dopamine Lactation
Thyroid-
stimulating
hormone (TSH)
Oxytocin Supraoptic and
Antidiuretic
hormone (ADH)
Posterior pituitary
Note: CRH = corticotropin-releasing hormone; GHRH = growth hormone-releasing hormone; GnRH = gonadotropin-
releasing hormone; IGF-1 = insulin-like growth factor 1; T3 = triiodothyronine; T4 = thyroxine; TRH = thyrotropinreleasing hormone.
Corticotrophs Adrenal gland CRH Cortisol Corticosteroid
Somatotrophs Liver
Gonadotrophs Gonads GnRH
Thyrotrophs Thyroid TRH T4 and T
paraventricular
nuclei in
hypothalamus
Downstream
target
Adipose tissue
Myoepithelial
cells (uterine)
Prefrontal
cortex
Liver
Kidney
Brain
Vasculature
Positive
feedback
GHRH IGF-1
Oestrogen
Cervical
stretch
Suckling
Reduced
plasma
volume/
os-molality
Angioten-sin II
Cholecystokinin
Negative
feedback Effects
secretion
Somatostatin
Sex steroids
Inhibin
(FSH)
Atrial
natriuretic
peptide
Growth
Modulation of lipid/
carbohydrate
metabolism
(effects modulated
by insulin-like
growth factor 1;
IGF-1)
Reproductive
system
development
Gametogenesis
Thyroid hormone
3
(T4 and T3)
synthesis and
release
Supports lactation
Uterine contraction
Emotional bonding
Regulates water
retention
Induces
vasoconstriction
Head and Neck Endocrine Surgery 459
PRIMARY PITUITARY DISEASE
Posterior Pituitary (Neurohypophysis)
e posterior pituitary sits in continuity with the hypothalamus and secretes oxytocin and
antidiuretic hormone (vasopressin).
Congenital Primary Hypopituitarism
Mutations seen in genes encoding specic cell types or hormone subunits generally give rise
to isolated pituitary hormone deciencies, while mutations in genes responsible for early
pituitary development result in combined hypopituitarism.
Congenital Combined Pituitary Hormone Deciency
Combined hypopituitarism may occur as part of a syndrome or independently. Mutations in
PROP1 and POUIFI are responsible for most nonsyndromic cases. Syndromic causes include
septo-optic dysplasia, holoprosencephaly, and Rieger’s syndrome.
Congenital Isolated Pituitary Hormone Deciency
Isolated Gonadotropin Deciency (Hypogonadotropic Hypogonadism)
May be sporadic or X-linked, with autosomal dominant or autosomal recessive
•
It is characterised by hypogonadism, which may occur alone or in association with
•
anosmia (Kallmann’s syndrome).
Treatment is targeted towards stimulating gametogenesis with pulsatile GnRH or com-
•
bined gonadotropins and inducing secondary sexual characteristics with gonadal steroids.
Isolated GH Deciency
Congenital GH deciency occurs in 1 in 4,000–10,000 births.
•
ere are four distinct forms of GH deciency
•
Type la: Autosomal recessive, GH undetectable, anti-GH antibodies raised against
•
exogenous GH
Type lb: Autosomal recessive, GH low, but no anti-GH antibodies raised
•
Type II: Autosomal dominant, short stature (eectively managed with GH
•
replacement)
Type III: X-linked, associated with agammaglobulinaemia, causative gene not yet
•
known
Isolated TSH Deciency (Central Hypothyroidism)
Rare: occurs in 1 in 50,000 births.
•
Both sporadic and familial cases are described.
•
Routine neonatal screening with ‘blood spot’ test.
•
Infants may present with nonspecic symptoms and failure to thrive.
•
In cases of established central hypothyroidism, hormonal assays reveal low free thy-
•
roxine (FT4) with inappropriately normal or low TSH levels.
Isolated ACTH Deciency
Very r a re.
•
Symptoms may vary from failure to thrive to signs of acute adrenal insuciency.
•
Acquired Primary Hypopituitarism
e causes of acquired primary hypopituitarism are summarise in Table 92.2.
460 Head and Neck Endocrine Surgery
PRIMARY PITUITARY DISEASE
Table 92.2 Causes of acquired hypopituitarism
Category Examples
Neoplasia Nonfunctioning pituitary adenomas
Functioning pituitary adenomas
Parapituitary tumours
Craniopharyngioma
Meningioma
Metastatic deposits
Chordoma
Glioma
Iatrogenic Radiotherapy
Pituitary procedures
Cranial procedures
Nasopharyngeal
Surgery (see Trauma)
Systemic disease Sarcoidosis
Haemochromatosis
Langerhans cell histiocytosis
Granulomatosis with polyangiitis
(Wegener’s disease)
Lymphocytic hypophysitis
Infection Tuberculosis
Pituitary abscess
Vascular Subarachnoid haemorrhage
Pituitary apoplexy
Sheehan’s syndrome
Trauma Traumatic brain injury
Direct pituitary trauma (e.g. surgery)
Pituitary Apoplexy
A medical emergency in which infarction of the pituitary gland occurs.
•
It should be considered in all patients with sudden-onset headache, meningism,
•
reduced consciousness, and visual impairment.
Pituitary hormones should be assayed.
•
Urgent MRI or focused pituitary CT should be undertaken in all patients suspected
•
of pituitary apoplexy.
Use empirical steroid therapy if the patient is haemodynamically unstable.
•
Early decompressive surgery may support recovery in patients with severe or progres-
•
sive symptoms.
Pituitary infarction due to postpartum haemorrhage is termed Sheehan’s syndrome.
Lymphocytic Hypophysitis
Autoimmune disease that most commonly presents in late pregnancy or rst post-
•
partum year.
Oedema and brosis of the pituitary parenchyma result in mass eects and
•
hypopituitarism.
Corticosteroids may play a role in management.
•
Spontaneous recovery has been reported.
•
GH Deciency
Adult-onset GH deciency occurs in 1 in 10,000 people. It is associated with poor skeletal
health, impaired quality of life, and increased cardiovascular disease. In paediatric patients,
Head and Neck Endocrine Surgery 461
PRIMARY PITUITARY DISEASE
replacement therapy is initiated. In adults, there is no absolute evidence for a reduction in
mortality aer GH replacement.
Current NICE guidelines advocate treatment if quality of life is impaired.
•
Dose titration is required.
•
GH replacement may be contraindicated in certain circumstances.
•
TSH Deciency and Replacement
Once-daily thyroxine is sucient for hormone replacement in central thyroid hormone
deciency.
Gonadotropin Deciency and Replacement
Oestrogen and testosterone replacement are the usual method of sex hormone replacement
for males and females, respectively, with gonadotropin deciency. Gonadal steroid replacement will not, however, induce fertility. Patients who are seeking to conceive must therefore
receive gonadotropin therapy.
ACTH Deciency and Replacement
Glucocorticoids are generally required in ACTH deciency.
Empty Sella Syndrome (ESS)
Rare.
•
Occurs because of the herniation of the suprasellar subarachnoid space into the intra-
•
sellar space, causing compression of the pituitary gland.
Primary ESS—Weakness of the diaphragma sella or increased intracranial pressure
•
is thought to promote arachnoid membrane herniation. is most commonly occurs
in obese women, and both hypertension and headache are common concomitant features. Hypopituitarism is uncommon and management is supportive.
Secondary ESS follows pituitary radiation, surgery, infection, or infarction.
•
Pituitary Adenomas
Pituitary adenomas are classied by whether they produce hormones (functioning versus
nonfunctioning) and by size (tumours <1 cm are classied as microadenomas, and tumours
>1 cm are macroadenomas). ey are invariably benign. e majority produce a single
hormone, but 1–30% express more than one hormone (plurihormonal).
Functioning Pituitary Adenomas
Prolactinoma
Prolactin has an important role in preparing for lactation.
•
Mild hyperprolactinaemia may occur in stress, with use of antidopaminergic drugs,
•
and in pituitary stalk compression.
Prolactinomas can cause very high levels of prolactin and may result in galactarrhoea
•
or amenorrhoea.
Dopamine agonists are rst-line treatment.
•
Somatotroph Adenomas (GH)
Acromegaly results from GH excess occurring aer closure of the epiphyseal plate.
•
Profound changes in physical appearance occur in untreated GH excess.
•
Long-term consequences include the metabolic syndrome and increased risk of colonic
•
polyposis.
462 Head and Neck Endocrine Surgery
PRIMARY PITUITARY DISEASE
Corticotroph Adenomas
Cushing’s disease results from a functioning corticotroph adenoma.
•
Hypercortisolaemia results in mood disturbance, loss of libido, change in facial appear-
•
ance, proximal myopathy, weakened skin, easy bruising, and a ra of other signs.
TSH-Secreting Adenomas
TSH-secreting adenomas are rare and represent only a very small percentage of functioning
adenomas. ey will cause features of hyperthyroidism, but investigation will reveal inappropriately normal or elevated TSH levels.
Gonadotropinomas
Gonadotropinomas seldom present as functioning tumours.
FSHOMA
More common in men and premenopausal women
•
Usually asymptomatic
•
e clinical features vary according to gender:
•
Males—tumour mass eect and the development of hypogonadism.
•
Females—In a premenopausal woman, FSHoma can result in ovarian hyper-
•
stimulation syndrome (abdominal bloating secondary to increased ovarian
size or the accumulation of ascites). Postmenopausal women are invariably
asymptomatic.
Nonfunctioning Pituitary Adenomas
Of pituitary adenomas, 30% are nonfunctioning. ey may be associated with partial or
complete hypopituitarism. Classically, there is a progressive loss of pituitary hormone secretion, with gonadotropins (LH and FSH) aected rst, followed by GH, TSH, and ACTH.
Children may present with cessation of growth or delayed puberty.
Pituitary Carcinoma
Pituitary carcinoma accounts for <0.1% of all tumours, and it is most commonly ACTH- or
prolactin-secreting. Metastases are more likely to be systemic than craniospinal. Mass eects
predominate, and surgery forms the mainstay of management. ere is some evidence for the
use of chemotherapy. Palliation for malignant prolactinomas is provided through medical
management with dopamine agonists and radiotherapy. Prognosis is poor, and most patients
die within a year.
Familial Pituitary Tumour Syndromes
Familial syndromes account for less than 1 in 20 pituitary adenomas.
Multiple Endocrine Neoplasia Type 1
MEN 1 (Wermer’s syndrome) is characterised by dermal tumours in addition to tumours of
the parathyroid, pancreas, and pituitary. MEN 1 is the result of mutations in the MENI gene.
Multiple Endocrine Neoplasia Type 4
MEN 4 is due to mutations in the CDKN1B tumour susceptibility gene. It is rare, and there are
no current guidelines for treatment. Hyperparathyroidism is the most common feature, and
pituitary adenomas are the second most common tumour in this syndrome.
Carney Complex
Pituitary adenomas are seen in approximately 1 in 5 patients with Carney complex, a rare
autosomal dominant condition.
Familial Isolated Pituitary Adenomas (FIPAS)
FIPAs represent 2% of all pituitary adenomas. Gigantism is a feature of AIP mutations.
Head and Neck Endocrine Surgery 463
MANAGEMENT OF PITUITARY DISEASE
KEY POINTS
• The pituitary gland plays an important role in regulating reproduction, metabolism,
and growth.
• Production of pituitary hormones is subject to cyclical rhythms, necessitating dynamic
testing.
• Hypopituitarism may be congenital or acquired and may feature isolated or combined
hormone deciencies.
• Benign pituitary adenomas are common.
• With functioning adenomas, the clinical characteristics are determined by the effects
of the excess hormone.
• Extrinsic growth of a pituitary adenoma can result in visual eld impairment or, rarely,
CSF rhinorrhoea and meningitis.
Further Reading
Melmed S. e Pituitary. Academic Press; 2017.
93. MANAGEMENT OF PITUITARY DISEASE
Surgical Management of Pituitary Disease
One third of pituitary adenomas require surgical intervention. Pituitary adenoma is the third
most common intracranial tumour requiring surgical intervention.
First-line treatment for adenomas that hypersecrete or cause mass eect is transsphenoidal
decompression/excision, except for prolactinomas.
e current gold standard approach is fully endoscopic transnasal surgery.
Endoscopic surgery requires two surgeons, one to hold the endoscope, the second surgeon to
perform dissection bimanually. Ideally, the team is formed by a neurosurgeon and a skilled
endoscopic sinus surgeon.
For pre-operative assessment, see Chapter ##, ‘Evaluation and Investigation of Pituitary Disease.’
History and Examination
Visual acuity and visual elds examination.
•
Cranial nerves that pass through the cavernous sinus.
•
Nasal endoscopy.
•
Endocrinological status assessment is paramount.
•
Imaging
Computed tomography (CT) will give detailed sinus bony anatomy and anatomical
•
variations.
Magnetic resonance imaging (MRI) provides information about tumour morphology.
•
MRI should be used for intra-operative image-guided navigation.
•
Endoscopic Transsphenoidal Approach to Sella
Optimising the nasal cavity for an endoscopic approach is an important rst step. e patient
is catheterised to enable monitoring of uid balance, broad-spectrum antibiotics are given,
and the nose is decongested. e abdomen may be prepared for the harvest of fat and rectus
464 Head and Neck Endocrine Surgery
MANAGEMENT OF PITUITARY DISEASE
abdominis fascia; in addition, the right thigh can be prepared for fat and fascia lata harvest if
the potential defect is larger. e patient should be in reverse Trendelenburg position. Image
guidance should be set up.
Surgical Technique
If an extended pituitary approach is required, a nasoseptal ap (NSF) should be raised.
Generally, the vascular pedicle of the potential ap should be preserved on one side by placing an incision from the lower edge of the natural ostium of the sphenoid and carrying the
incision anterior and horizontal for about 3–4 cm. A suction Freer is used to mobilise the
ap to the level of the posterior bony choana, allowing the anterior face of the sphenoid to be
widely opened. A ap can then still be raised and utilised if required.
Bilateral access to the sella is required. e middle corridor is widened by lateralising the
middle turbinates, and the inferior half of the superior turbinate is resected. e sphenoid
ostium is identied, visually or with palpation. e ostium is entered with a blunt Freer
elevator or a sinus mushroom punch. e ostium is widened from the septum to the lamina
laterally and from the roof of the sphenoid to the oor. e mucosa of the sphenoid is elevated medially to laterally, leaving the lateral aspect still attached for further reconstruction
potential. A posterior septectomy is performed, and a diamond drill or rongeur is used to
take down the intersinus septum. ese septations frequently veer towards the carotid artery
or optic nerve (Figure 93.1). e medial and lateral opticocarotid recesses are identied with
the optic nerves and anterior genu of the carotid artery (image guidance is used to conrm
the structures). ese dene the limits of the bony exposure of the sella.
e bone of the sellar face, if not already thin due to tumour expansion, should be ‘eggshelled’ using a diamond burr. is bone is gently fractured and removed. A Kerrison punch
is used to remove bone o the dura, allowing exposure from one cavernous sinus to the other
and from just below the tuberculum sella to the pituitary fossa oor (Figure 93.2).
e dura is opened with a U-shaped incision placed a few millimetres medial to each cavernous sinus and meeting at the oor of the sella. Macroadenomas should be visible, and tissue
should be taken for histology. With microadenomas, image guidance and MRI help identify
the tumour.
Attempted complete extracapsular resection of the tumours improves the chances of complete resection. Tumours have varying consistency, and the best instruments for removal will
depend on the consistency.
Once the tumour has been removed, haemostasis is secured using Gelfoam® paste, made
from Gelfoam® powder (Pzer Inc., New York, NY) and saline. e pituitary fossa is gently
Figure 93.1 CT of the intersinus septum carotid artery. (Taken from Chapter 115, Figure 115.3(b),
in Surgical management of pituitary and parasellar disease. Philip G. Chen and Peter-John Wormald.)
Head and Neck Endocrine Surgery 465
MANAGEMENT OF PITUITARY DISEASE
Figure 93.2 Exposure for resection of a pituitary microadenoma. (a) The sphenoid sinus has
been entered; observe the bony landmarks and the relation between the septation and the right
ICA. (b) The face of the sella has been removed, from ICA to ICA and from superior to inferior
intercavernous sinuses. Note the proximity of the ICAs, narrowing the operative corridor. ICA =
internal carotid artery; LOCR = lateral opticocarotid recess. (Taken from Chapter 85, Figure 85.2, in
Surgical management of recurrent pituitary tumours. Mihir R. Patel, Leo F.S. Ditzel Filho, Daniel M.
Prevedello, Bradley A. Otto, and Ricardo L. Carrau.)
lled with the paste and the dura is replaced. e sphenoid mucosal aps are placed over the
dura and are secured with Surgicel® (Ethicon, Somerville, NJ), xed with a layer of brin glue.
No packing is placed in the sphenoid sinus.
Management of a cerebrospinal uid (CSF) leak depends on the leak size.
Small CSF Leak.
•
e defect is identied, and a small triangle of fat is placed, ensuring cessation of the
•
leak. Fat can be placed in the sella and a multilayer repair can be completed using the
dura and sphenoid mucosa, Surgicel®, and brin glue.
Large CSF Leak (or an extended approach with a defect in the arachnoid mater).
•
e NSF is raised. Fascia is placed as an underlay intracranial gra with the pedi-
•
cled septal ap placed over onto the bone of the defect. Flap edges are secured with
Surgicel® and brin glue, and the repair is covered with Gelfoam® and the sinus is
packed with ribbon gauze soaked in bismuth iodoform paran paste (BIPP) for 3
to 7 days depending on the defect size.
466 Head and Neck Endocrine Surgery
MANAGEMENT OF PITUITARY DISEASE
Complications
CSF leak is the most common complication. Tumour resection should not be compromised
due to fear of CSF leaks because they can be dealt with during the procedure. A post-operative
CSF leak is a complication. Post-operative CSF leaks should occur at a rate of 5% or less. If postoperative CSF leak occurs, strict bed rest and a lumbar drain are recommended. If the leak
persists, surgical closure is indicated.
Other complications include vision damage and both venous and arterial bleeding, with the
latter being potentially devastating.
Revision Surgery
Recurrence rates for pituitary adenomas vary between 7% and 21%. Surgical indications for
recurrent tumours are mass eect or persistent symptomatic hormonal hypersecretion. Sma ll
recurrences conned to the lateral cavernous sinus must be considered for radiotherapy.
Identify factors that lead to recurrence and possible problems that might arise during
•
the revision procedure.
Identify the sequelae of the previous procedure that may hinder the ecient creation
•
of a sinonasal corridor.
Reconstruction plan may need to include an alternative to nasal septal ap.
•
Identify contraindications.
•
Determine whether recurrent tumour is secreting or nonsecreting. is identies the
•
goal of surgery—total removal or debulking.
Identify sequelae of the previous procedure that may increase the risk of the subse-
•
quent procedure (e.g. pseudoaneurysm).
Meticulous radiological assessment is crucial. MRI of the sellar and parasellar regions is
required with a CT angiogram. A vascular study to evaluate the ICAs and to rule out a pseudoaneurysm due to previous cavernous sinus manipulation, should be considered.
Hypopituitarism requires hormone replacement to avoid peri-operative complications.
Diabetes insipidus must be ruled out and should be addressed properly if present.
Reconstruction options include the NSF and/or free tissue gras. Prior surgery may have used
a NSF. is can be carefully taken down and reused.
Adjuvant Treatment of Pituitary Disease
Complete excision is not commonplace.
•
30% of nonfunctioning pituitary adenomas increase in size 5–10 years aer the origi-
•
nal surgery.
20% of cases show some clinically signicant tumour aer resection.
•
60% of functioning pituitary macroadenomas remain biochemically active aer pri-
•
mary treatment.
Watchful waiting is now commonplace due to the availability of high-quality MRI.
•
If an adenoma extends laterally into a cavernous sinus, proximal to the carotid siphon
•
and cranial nerves, without any danger of impingement on the optic apparatus, other
treatments are likely to be the rst line.
Prolactinoma
90% of macroprolactinomas shrink with dopamine analog drug treatment.
•
First-line treatment for prolactinomas is dopaminergic drugs, such as cabergoline or
•
bromocriptine.
Surgery can be used for a microprolactinoma if drug side-eects or costs are an issue.
•
Watch for CSF leak if the sphenoid bone has been eroded by previous large tumour
•
that subsequently shrank.
Head and Neck Endocrine Surgery 467
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