Pituitary (2008) 11:391401
DOI 10.1007/s11102-008-0086-6
Postoperative assessment of the patient after transsphenoidal
pituitary surgery
John C. Ausiello Jeffrey N. Bruce
Pamela U. Freda
Published online: 5 March 2008
Springer Science+Business Media, LLC 2008
Abstract While most transsphenoidal pituitary surgery is
accomplished without complication, monitoring is required
postoperatively for a set of disorders that are specific to this
surgery. Postoperative assessments are tailored to the early
and later postoperative periods. In the early period, which
spans the first few weeks after surgery, both monitoring of
anterior and posterior pituitary function and managing
neurosurgical issues are the focus of care. Potential dis-
ruption of pituitary-adrenal function is covered with
perioperative glucocorticoids. Various strategies exist for
ensuring the integrity of this axis, but typically this is done
by measuring a morning cortisol on the 2nd or 3rd
postoperative days. Patients with levels \10 lg/l should
continue therapy with reassessment in the later postopera-
tive period. Monitoring for water imbalances, which are
due to deficiency or excess of ADH (DI or SIADH,
respectively), is accomplished by continuous accounting of
fluid intake, urine output and specific gravities coupled
with daily serum electrolyte measurements. DI is charac-
terized by excess volumes of inappropriately dilute urine,
which can lead to hypernatremia. Most patients maintain
adequate fluid intake and euvolemia, but desmopressin
therapy is required for some. SIADH, which peaks in
incidence on 7th postoperative day, presents with hypo-
natremia that can be severe and symptomatic. Management
consists of fluid restriction. Neurosurgical monitoring is
J. C. Ausiello
P. U. Freda (&)
Department of Medicine, Columbia University,
College of Physicians & Surgeons, 650 West 168th Street,
9-905, New York, NY 10032, USA
e-mail: puf1@columbia.edu
J. N. Bruce
Department of Neurosurgery, Columbia University, College
of Physicians & Surgeons, New York, New York 10032, USA
primarily for disturbances in vision or neurological func-
tion, and although uncommon, for CSF leak and infections
such as meningitis. In the later postoperative period, the
adrenal, thyroid and gonadal axes are assessed. New
persistent hypopituitarism is rare when transsphenoidal
surgery is performed by an experienced surgeon. Various
strategies are available for assessing each axis and for
providing replacement therapy in patients with deficien-
cies. Long term monitoring with assessments of visual,
neurological and pituitary function coupled with pituitary
imaging is necessary for all patients who have undergone
surgery, irrespective of the hormone status of their tumors.
Keywords Pituitary surgery
Hypopituitarism

Diabetes insipidus
SIADH
Introduction
The care of patients who have undergone transsphenoidal
pituitary surgery involves the management of neurosurgi-
cal, endocrinological and nursing issues by a coordinated
multi-disciplinary team comprised of members of each of
these specialties [1]. Although the majority of patients who
undergo transsphenoidal surgery (TS) do not experience
complications, a main focus of postoperative assessment is
monitoring for anterior or posterior pituitary dysfunction,
which are the most common of the potential adverse out-
comes of this surgery. Phases of the post-surgical period
include an early postoperative period (immediately after
surgery through the following few weeks) and subse-
quently a later postoperative period. The focus of care is
specific to each of these phases. This review describes
the assessment and monitoring of the patient who has
undergone transsphenoidal pituitary surgery and general
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392 Pituitary (2008) 11:391401

guidelines for the treatment of the most commonly
encountered complications of this surgery.
Early postoperative period
General principles of pituitary function assessment
Monitoring of anterior pituitary function is crucial to the
peri-operative care of patients who undergo surgery for
pituitary tumors (Table 1). Although the development of
new pituitary hormone deficiencies after TS is uncommon
when performed by an experienced pituitary surgeon, all
patients require monitoring for these possible complica-
tions in the first few days after surgery. Uniform
procedures for this monitoring can be adopted and then
modified as indicated by each individual patients history
and clinical picture. For example, knowledge of the
patients preoperative endocrinologic function can help
predict the need for postoperative hormone replacement
therapy. Preoperative hypopituitarism should always be
treated in the early postoperative period as this rarely
resolves immediately. In addition, the suspicion for new
hypopituitarism should be heightened in patients with
partial hypopituitarism preoperatively.
The course of surgery and the operative findings provide
useful information for planning postoperative monitoring.
When the surgical procedure is more extensive,
hemorrhage or necrosis within the tumor are seen or other
complications occur at the time of surgery, concern for new
hypopituitarism should be heightened. In particular, the
likelihood of postoperative AI was found to be increased
four-fold in patients who had post-operative DI which may
be a consequence of more extensive surgery [2]. The type
of pituitary lesion is also relevant to the likelihood of
postoperative pituitary dysfunction as non-pituitary lesions
such as craniopharyngiomas are more likely to be accom-
panied by hypopituitarism or diabetes insipidus.
Pituitaryadrenal axis assessment
Disruption of the anterior pituitary, the stalk or the hypo-
thalamus due to manipulation or damage at the time of
surgery may impair ACTH secretion. As a result, the
pituitary adrenal axis must be assessed postoperatively.
Most centers employ a protocol for routine peri- and early
postoperative glucocorticoid coverage and early postoper-
ative monitoring of cortisol levels in order to assess the
need to continue replacement therapy on hospital dis-
charge. The protocols for and type of steroid coverage
vary, however, from one institution to another. At most
centers, all patients who undergo TS are given stress doses
of hydrocortisone (100 mg IV) or other glucocorticoid at
the time of surgery and this dose is tapered quickly over
two to three days for a total of about five doses [35].
While some favor short-acting steroids such as

Table 1 Assessments in the Early Postoperative Period after Pituitary Surgery

Pituitary Adrenal Stress glucocorticoid coverage peri-operatively and taper over 2-3 days
Axis: Morning cortisol level postoperative day 2 (see text)
Continue replacement dose of glucocorticoid on discharge if early serum cortisol \ 10 lg/L (see text) and if cortisol
10 17 lg/dl only in selected patients (see text)
Measure morning cortisol level 1 week postoperatively

Water Balance
Diabetes Insipidus Continuous strict monitoring of urine output and fluid intake
Urine specific gravity measurements
Electrolyte monitoring daily (twice daily if DI develops)
Monitoring of thirst, volume status
Diagnostic criteria: Urine specific gravity \ 1.005 and urine volume [ 250 cc/hr for 2-3 hours
Indications for desmopressin therapy: Patient unable to maintain adequate oral fluid intake, urine output [[ fluid intake,
hypernatremia

SIADH Home monitoring of fluid intake and urine output after discharge in patients with DI postoperatively
Measurement of serum sodium one week after surgery in all patients
Measure serum sodium emergently if symptoms of hyponatremia (headache, nausea and vomiting, mental status changes
or seizure)
Fluid restriction for hyponatremia

Neurosurgical Early postoperative assessment of general neurological function, visual acuity and cranial nerves
Monitoring for signs and symptoms of CSF leak
Monitoring for signs and symptoms of meningitis

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Pituitary (2008) 11:391401
hydrocortisone, which would give minimal HPA axis
suppression, our practice is to cover patients with dexa-
methasone at doses of 2 mg at the time of surgery and
1 mg bid on postoperative day 1. We prefer dexamethasone
as it will not interfere with serum determinations of cortisol
levels despite that fact that some pituitary suppression will
occur. Patients with documented preoperative secondary
adrenal insufficiency (AI) are treated peri-operatively with
stress doses of glucocorticoids that are tapered to the
patients prior replacement dose which is continued on
discharge. Pituitary function is reassessed at a later post-
operative visit [5, 6].
Treatment of all patients undergoing transsphenoidal
pituitary surgery with peri-operative glucocorticoids is not
universally undertaken. Some recommend administering
these to patients with preoperative hypopituitarism [7] but
withholding them in those with normal preoperative
pituitaryadrenal function [peak cortisol [496.8 nmol/l
(18 lg/dl) post 250 lg cosyntropin stimulation] in whom
only selective adenomectomy is planned [7]. In one study
of 83 patients without preoperative AI [ITT cortisol peak
[ 510.6 nmol/L (18.5 lg/dl) and rise [270.6 nmol/l
(10 lg/dl)] who did not receive peri-operative glucocorti-
coids, only one developed transient AI post-operatively [8].
However, this studys population was atypical for a TS
cohort (i.e. predominantly females with prolactinomas and
relatively fewer macroadenomas) which may account for
the lower incidence of AI [8].
Prior to hospital discharge after TS each patient needs
an assessment of pituitaryadrenal axis integrity. The
preferred method for this assessment is debated. The
250 lg cosyntropin stimulation test is not the test of choice
for early post-operative assessment of pituitary-adrenal
function because of its inability to detect recent onset
secondary AI. For example, in one study, 23 of 62 patients
(44%) with normal preoperative pituitaryadrenal function
and a normal cosyntropin stimulation test 1 week postop-
eratively [peak cortisol [500 nmol/l (18.1 lg/dl)]
developed an abnormal test between 1 and 3 months later
[2]. Testing with an ITT would also not be clinically
appropriate within the first few days after surgery.
As an alternative test, the accuracy of morning postop-
erative cortisol levels for the prediction of secondary AI has
been investigated. In one study, 28 patients were adminis-
tered a rapid intravenous hydrocortisone taper over
23 days postoperatively and following completion of the
taper, 24 h after the last dose, a morning cortisol was mea-
sured [9]. A cortisol level greater than 340 nmol/l (12.3 lg/
dl) predicted a normal peak cortisol during an ITT on the 8th
postoperative day and thus sufficient pituitary-adrenal
function [9]. A morning cortisol level on the 8th postoper-
ative day greater than 350 nmol/l (12.7 lg/dl) also predicted
a normal ITT [9]. In patients with normal preoperative
393
cosyntropin stimulation tests [peak cortisol greater than
530 nmol/l (19.2 lg/dl)], a serum cortisol greater than
270 nmol/l (9.8 lg/dl) on postoperative day three was 100%
specific and 94% sensitive for preserved pituitaryadrenal
function [9]. In another study of 71 patients with normal
preoperative adrenal function, a morning cortisol one week
postoperatively greater than 400 nmol/l (14.5 lg/dl) had a
93% sensitivity, 9% specificity and 77% positive predictive
value for excluding secondary AI whereas a level less than
100 nmol/l (3.6 lg/dl) had 100% specificity, 14% sensitiv-
ity and 100% predictive value for a later diagnosis of
secondary AI [2]. In a retrospective study of ITT results in
193 patients with a variety of organic hypothalamic or
pituitary diseases (many patients underwent radiotherapy
and had variable pituitary function) a baseline cortisol level
greater than 469.2 nmol/l (17 lg/dl) was predictive of a
normal ITT [10] and less than 110.4 nmol/l (4 lg/dl) was
predictive of an abnormal test [10]. In a review on this topic,
morning cortisol levels greater than 450 nmol/l (16 lg/dl)
were considered sufficient whereas those less than
100 nmol/l (3.6 lg/dl) were indicative of deficiency [7].
The authors concluded that patients with morning cortisol
levels 100250 nmol/l (3.69.1 lg/dl) should receive
replacement doses of glucocorticoids on discharge whereas
those with levels 250450 nmol/l (9.116 lg/dl) need ste-
roids only in periods of stress [7]. Definitive provocative
tests of pituitaryadrenal function were recommended
for patients with am cortisol levels 100350 nmol/l
(3.612.7 lg/dl) [7]. Using this approach fewer than 4% of
patients were misclassified [i.e. with a baseline greater than
350 nmol/l (12.7 lg/dl) but an ITT less than 550 nmol/l
(19.9 lg/dl)] [7].
In most centers, therefore, cortisol levels are measured
the morning of the 2nd or 3rd postoperative day, 24 h after
the last dose of peri-operative hydrocortisone coverage [4
6]. Patients with low cortisol levels, at one center consid-
ered two consecutive levels \220.8 nmol/L (8 lg/dl) [5]
and at our center \270 nmol/L (10 lg/dl) on post-opera-
tive day 2, are discharged on low-dose replacement
therapy. While it is clear that morning cortisol levels
[17 lg/dl do not require replacement on discharge, some
argue that patients with cortisol levels between 10 and 17
should receive further therapy. At one center, a stable
patient with a morning cortisol level [270 nmol/L (10 lg/
dl) is discharged without glucocorticoid therapy but with a
prescription for hydrocortisone to fill if signs and symp-
toms of AI arise [6]. At our center, we discharge clinically
stable patients without prior or current other hypopituita-
rism and a cortisol level greater than 270.6 nmol/l (10 lg/
dl) on postoperative day 2 without replacement glucocor-
ticoids. Our threshold cortisol level for continuation of
postoperative coverage, however, may be raised in the
patient who has postoperative DI, other hypopituitarism or
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other complications. At our center and others, morning
cortisol levels are reassessed 1 week postoperatively, 24 h
after the most recent dose of hydrocortisone [5] (Table 1).
Despite the many studies on this question, there is still
disagreement regarding the morning cortisol level that
best predicts normal HPA axis function in stressed and
unstressed situations so some centers treat all postoperative
patients with oral glucocorticoid therapy on discharge and
continue this until at least the first postoperative visit. All
patients who have undergone pituitary surgery regardless
of the aforementioned cortisol level need stress dose ste-
roids if they are clinically indicated.
Other anterior pituitary hormone assessments
Although the pituitarythyroid axis may be disrupted at the
time of TS its assessment in the first 3 days postoperatively
is unlikely to accurately predict new impairment. We
typically measure free T4 levels one week postoperatively
in patients with other abnormalities of pituitary function
or unknown preoperative thyroid function. Patients with
pituitary apoplexy may rapidly become hypopituitary and
need early assessment of their thyroid function. Those with
known preoperative hypothyroidism should be continued
on replacement therapy.
In patients with prolactinomas, who may undergo TS
because they are resistant to or intolerant of dopamine
agonists, early measurement of prolactin levels can be
undertaken as low levels may portend a better surgical
outcome. In one study of 241 patients with prolactinomas,
prolactin levels less than 10 ng/ml after TS predicted
remission in 100% of microadenomas and 93% of mac-
roadenomas [11]. With regard to gonadal function, early
postoperative assessment is rarely undertaken as the stress
of surgery and steroid administration can suppress gonadal
function. Assessment of growth hormone is also reserved
for a later postoperative visit as discussed below.
Assessments in patients with hormone secreting
pituitary tumors
Specific attention is required to assess immediate postop-
erative status in patients who have undergone TS for
ACTH secreting tumors. Many centers, including ours,
administer stress glucocorticoids and taper to about twice
replacement doses postoperatively. Other centers withhold
peri-operative and early postoperative glucocorticoids until
remission or persistent disease is documented [5]. At one
center, serum cortisol levels are measured every 6 h and
clinical signs and symptoms of AI are monitored closely
while glucocorticoids are held. If cortisol levels are less
than 55.2 nmol/l (2 lg/dl) and patients have symptoms,
remission is achieved and replacement glucocorticoids are
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Pituitary (2008) 11:391401
begun [5]. This type of protocol requires a specialized unit
and close monitoring that are not universally available.
Some prefer hydrocortisone as the initial replacement
therapy as it is short acting with less pituitary suppression
[12]. Others prefer dexamethasone as this does not interfere
with serum cortisol measurements despite greater sup-
pressive effects. In general, we begin dexamethasone
coverage postoperatively and continue this or switch to
hydrocortisone on discharge depending on need to re-
assess cortisol levels. Further monitoring of patients with
Cushings disease is discussed in other comprehensive
reviews [12, 13].
A preliminary assessment of disease status in patients
with GH secreting tumors can be undertaken by measuring
a GH level on the 3rd postoperative day. The lower the GH
level, the better the evidence for remission, but since GH
levels vary among assays, a particular cut off that predicts
long term cure based on an early postoperative level is
not universally possible. At our center, GH levels less than
1 lg/l are suggestive of remission, but higher GH levels do
not necessarily predict persistent disease especially in
patients with very high levels preoperatively.
Disorders of water balance
Disturbances in water balance, typically due to those of
ADH secretion, are among the most common disorders
encountered in the early period after TS. ADH is synthe-
sized in neurons of the supraoptic and paraventricular
nuclei of the hypothalamus that terminate in the posterior
pituitary, which stores ADH and serves as the site of ADH
release into the circulation. ADH acts on V2 receptors in
the renal collecting ducts leading to insertion of aquaporin
channels in the duct cell membrane facilitating reabsorp-
tion of water [14]. After pituitary surgery either deficiency
of ADH, diabetes insipidus, or excess of ADH (SIADH)
can develop [14].
Of the two disorders of ADH, diabetes insipidus (DI) is
more commonly encountered in the early postoperative
period. Although its incidence overall is low when TS
surgery is performed by an experienced Neurosurgeon, DI
can be challenging to treat, it can lengthen the hospital stay
and if not well managed it can be life-threatening [6]. DI
may occur due to disruption of the hypothalamic-pituitary
stalk or trauma to the posterior pituitary gland, temporarily
disrupting vasopressin secretion. Typically, unless the stalk
is transected distal to the pituitary, vasopressin secretion
recovers and DI is only transient, lasting for just the first
few days postoperatively. DI can begin any time, but most
commonly it does within the first 48 h following surgery.
DI may remit and then recur (a tri-phasic pattern) and this
may be a sign of permanent damage to the neurons. Some
patients may develop a phase of SIADH due to release of
Pituitary (2008) 11:391401
stored hormone followed later by the return of DI as
vasopressin stores are depleted [14].
A number of studies have examined the incidence of DI
after TS for pituitary adenomas. After TS dilute polyuria
and polydypsia on the first postoperative day was reported
in 34% of 1,571 patients with pituitary adenomas [4) and in
18.3% of 881 patients with a variety of sellar lesions [15].
In these studies, 24% [4] and 12.4% [15] of patients
required transient therapy with desmopressin. Persistent DI
after TS is rare and much less common than transient DI. In
one study, persistent DI was reported at 3 months in 0.9%
and at 1 year 0.25% of patients [4] and in other studies, 2%
[15] had persistent DI and 1.4% [16] had persistent DI
requiring desmopressin therapy. Predictors of increased
risk of DI include surgery for microadenomas (possibly
secondary to stalk manipulation and exploration) [4, 15],
intraoperative CSF leak [15], non pituitary sellar lesions
such as craniopharyngiomas and rathkes cleft cysts [15],
younger age, male sex and intrasellar expansion of the
tumor [4]. Transient DI is also more likely in patients with
Cushings disease [15].
DI presents clinically with large volumes of dilute urine
due to inability to concentrate the urine. As a result, plasma
osmolality rises and patients experience marked increases
in thirst, particularly craving cold liquids. If fluid intake is
not increased, serum osmolality and sodium will rise. All
patients who have undergone transsphenoidal pituitary
surgery require continuous 24 h monitoring of fluid intake
and urine output, assessment of urinary specific gravity and
daily or twice daily (if DI develops) serum electrolyte
monitoring (Table 1). A low urine specific gravity (\1.005)
combined with a high urine volume of greater than 250 cc/
h for two or three consecutive hours is consistent with DI.
We monitor serum osmolality if DI has developed or serum
sodium levels become abnormal. Urine output alone cannot
be used to diagnose DI because of other situations in the
postoperative period that can increase urine output. The
most common is the excretion of fluids administered during
the surgical procedure, but this should not be accompanied
by hypernatremia or excess thirst [5]. Patients with cured
acromegaly often have early postoperative fluid loss, which
is not necessarily dilute and distinct from DI. Lastly, DI
must be distinguished from polyuria due to diuretic use or
diabetes mellitus. The latter is more typically accompanied
by a low-normal sodium level [5].
If the patient is awake and alert most cases of postop-
erative DI can be managed with ad lib oral intake of fluids
and close monitoring only [17]. Treatment with DDAVP is
required if urine output is excessive (especially at night
preventing sleep), if urine output significantly exceeds fluid
intake or if hypernatremia develops [15] (Table 1). Patients
with impaired thirst or altered mental status clearly present
special situations after transsphenoidal surgery and in these
395
patients DI needs to be recognized quickly and treated
promptly to prevent hypernatremia. When medical therapy
is necessary the treatment of choice for acute and chronic
diabetes insipidus is DDAVP (desmopressin), a synthetic
analog of ADH that acts only at V2 receptors. DDAVP can
be administered as needed subcutaneously 12 lg [5, 14]
or intra-nasally 10 lg once the nasal packs are removed. In
the early postoperative setting DDAVP should be admin-
istered only as needed (when polyuria and increased thirst
return) as DI is likely to be transient and excess DDAVP
can lead to hyponatremia [15]. For the later assessment of
DI, patients can be instructed to hold the DDAVP for a few
hours periodically or once per week to see if polyuria and
polydipsia are still present [6].
SIADH occurs due to uncontrolled release of AVP from
either degenerating posterior pituitary tissue or from AVP-
containing neurons that have been severed [14]. In SIADH,
urine becomes very concentrated, urine output falls and in
patients who continue to drink or are administered IV
fluids, hyponatremia and hypo-osmolality ensues. In the
differential of hyponatremia are AI and secondary hypo-
thyroidism. The duration of the SIADH phase varies, but is
typically 214 days [14].
Isolated hyponatremia at some point after TS, presum-
ably SIADH without an earlier phase of polyuria, has been
reported in 25% [18] to 23% [19] of patients. A number of
studies have demonstrated that the peak time for hypona-
tremia is postoperative day 7 [4, 20]. In a series of 1,571
patients who underwent TS, 2.7% developed hyponatremia
on postoperative day one, 1.7% on day three and the
highest percentage occurred at day seven when 5% had
hyponatremia [4]. This series reported a biphasic pattern
(DI followed by SIADH) in 3.4% and triphasic (DI,
SIADH then DI again] in 1.1% of the cohort [4]. Hypo-
natremia was symptomatic in 2.1% [4]. The rate of
hyponatremia was increased among patients who had
received DDAVP transiently for polyuria (40%) above the
overall rate of hyponatremia in the cohort of 24% [4]. In
another cohort of 241 patients, 23% developed sodium
levels less than 135 nmol/l [19] and the incidence of
symptomatic hyponatremia was 5% [19]. Groups found to
be at greater risk of developing hyponatremia after TS
include females or older patients and patients with transient
DI (2-fold higher) [19], larger tumor size, nonfunctioning
tumors [20] or Cushings disease (2.8-fold higher) [4].
We routinely have all patients obtain an electrolyte
panel to check a sodium level 1 week postoperatively
(Table 1). All patients are instructed on discharge about the
potential for water balance disorders. Patients with tran-
sient DI, who are at increased risk for SIADH, are
instructed to monitor their fluid intake and output and alert
us if urine output falls markedly or increases significantly.
Symptoms of hyponatremia include headache, dizziness,
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nausea, vomiting and if severe altered mental status and
seizures. There is clear overlap with these symptoms and
those of AI and the latter should be assessed in patients
with these symptoms. If patients have signs or symptoms of
SAIDH their sodium level should be emergently measured
and if significant hyponatremia is present, patients should
be hospitalized and fluid restricted (*800 cc/24 h
depending on the severity of hyponatremia).
Monitoring for neurosurgical complications
Immediately after surgery, in addition to routine care,
patients neurological status and visual function are asses-
sed. Vision assessments include tests for acuity, extraocular
movements and visual fields. Laboratory studies include
electrolytes and a complete blood count. We continue daily
electrolyte evaluations and if necessary a CBC is repeated.
Nasal packs are removed 1224 h after surgery. Patients are
also instructed to avoid incentive spirometry, use of a straw
for drinking and other maneuvers that may increase pres-
sure at the transsphenoidal surgical site.
Routine prophylactic peri-operative antibiotic coverage
from induction of anesthesia through postoperative day 1 is
undertaken by most centers. We administer cefuroxime
every 8 h for the first 24 h after surgery. Although there are
little data on this topic, meningitis rates postoperatively
have declined and the majority of studies do suggest benefit
from prophylactic antibiotics [5, 21].
CSF leak is an uncommon, but important potential com-
plication of TS, occurring in 4% in one review [22]. It can
develop immediately after TS or weeks later [17]. Symptoms
include drainage of clear fluid from the nose, especially on
bending over and can be accompanied by headache or fever,
occurring most often in patients with large tumors who
develop intraoperative CSF leaks requiring a fat graft. The
diagnosis is made by clinical history and exam and if nec-
essary the patient can be examined for the presence of a
leak while sitting in a chair and bending forward for up to
12 min. Treatment consists of hospitalization, bed rest,
placement of a lumbar spinal drain, antibiotics and if nec-
essary in rare cases repeat TS and repacking of the site.
Late postoperative phase
Incidence of persistent anterior pituitary dysfunction
after TS
A number of studies have examined the incidence of new
persistent hypopituitarism after transsphenoidal surgery
for pituitary adenomas. In one study, 30.6% (30 of 98) of
patients with normal preoperative pituitary function and
27.8% (22 of 79) of patients with at least one hormonal
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Pituitary (2008) 11:391401
abnormality developed new hormone deficiencies [23].
Another study reported that 45% (32 of 71 patients) of
patients with normal pituitary-adrenal function preopera-
tively developed postoperative secondary AI [2]. In another
study, 16 of 22 subjects with normal preoperative values
maintained these postoperatively [24]. Contrary to these
reports one large series found that only 1.4% of patients
developed a deterioration of pituitary function with TS [25]
and similarly we have found in our experience that new
hypopituitarism is very rare after TS in patients with intact
pituitary function preoperatively. In general, most cases of
new hypopituitarism are detected very early post-opera-
tively and almost always within the first 3 months [2]. An
assessment of pituitary function between 3 and 6 months
postoperatively is predictive of long term outcome [22]
suggesting that serial stimulation testing beyond this time
is not necessary in clinically stable patients with docu-
mented normal pituitary function and no history of
radiotherapy or tumor progression.
The rate of recovery of preoperative hypopituitarism
within the first year after surgery has also been investi-
gated. In one study, 48% of 93 patients with at least one
pituitary hormone deficiency preoperatively regained some
pituitary function [23]. In another study, pituitary function
improved in 13% and worsened in 40.4% of patients [24].
Only 3.6% of patients with GHD (the most common
deficiency) recovered this axis postoperatively [24]. In a
study of 26 patients with large non-functioning pituitary
adenomas, recovery occurred in 38% with AI, 32% with
hypogonadism, 57% with hypothyroidism and 15% with
growth hormone deficiency [26]. Pituitary function has
also been reported to recover in up to two-thirds of patients
who underwent surgical decompression for apoplexy [23].
However, in our experience, patients presenting with apo-
plexy and hypopituitarism are unlikely to recover pituitary
function. Mild or recent onset or clinically silent secondary
AI [27] as well as lack of visible residual tumor portend a
greater likelihood of improvement with surgery [23].
Assessment of the pituitaryadrenal axis
Patients continued on glucocorticoids on discharge after TS
because of a low morning cortisol level are re-assessed at
follow up visit by holding hydrocortisone therapy for 24 h
and re-measuring a morning cortisol level [6] (Table 2). If
this is greater than 270.6 nmol/l (10 lg/dl) and patients are
well and have no other hypopituitarism, the replacement is
usually withdrawn [6]. Others recommend further stimu-
lation testing to exclude AI in all patients whose morning
cortisol level is \500550 nmol/l (1819 lg/dl) [28, 29].
In patients in whom morning cortisol levels are very low
further testing can be excluded. Some centers perform an
ITT to assess the need for longer-term glucocorticoid
Pituitary (2008) 11:391401 397

Table 2 Assessments in the Late Postoperative Period after Pituitary Surgery

Pituitary Insufficiency
Adrenal Axis: Measure morning cortisol at first postoperative visit (24-hrs after glucocorticoid dose if on therapy)
Assess cortisol level and clinical status - consider withdrawing glucocorticoid therapy (see text)
Consider further testing of pituitary-adrenal function: ITT, cosyntropin stimulation test (250 lg)

Thyroid Axis: Measure free thyroxine levels at first postoperative visit and over the 1st postoperative year
Assess need for continued replacement by tapering dose and monitoring free thyroxine levels (see text)

Gonadal Axes
Females Assess return of menses and if necessary status of gonadal hormones (gonadotropin and estradiol levels ) in
premenopausal women
Males Assess for symptoms of hypogonadism
Measure morning total testosterone levels (X2) and gonadotropins
Growth Hormone Axis Perform arginine/GHRH stimulation testing adjusting cut-off for GH peak for BMI (see text)
Stimulation testing may not be needed in patients with three or more additional pituitary hormone deficiencies
and low serum IGF-I levels (see text)

Disease Status in Hormone Secreting Tumors

Cushings Disease Measure 24-hr urine free cortisol
Dexamethasone suppression test and ACTH levels

Prolactinomas Assess prolactin levels and gonadal function

Acromegaly Measure serum IGF-1 level and glucose suppressed GH levels 3-months after surgery
Yearly assessments for patients in remission

Radiographic Studies
Non-secreting tumors MRI 3-months , 1 year and yearly thereafter if tumor is stable
Additional MRI in cases of residual or recurrence
Hormonally-active MRI at 3-months postoperatively
tumors Follow-up imaging will vary depending on type of tumor and extent of disease activity

replacement [6]. The ITT is contraindicated in debilitated
patients or in patients with coronary artery disease or
seizures. A 250 lg cosyntropin stimulation test can be used
as this is felt to reliably predict secondary AI when ACTH
deficiency is of at least 4 weeks duration [28]. Various
criteria have been proposed for interpretation of this test
[30, 31]. Peak cortisol levels [500550 nmol/l (18 or
20 lg/dl) are usually considered sufficient and we also
require normal baseline cortisol levels in patients with
hypopituitarism. More stringent criteria may be considered
in patients with clinical signs or symptoms that could be
consistent with mild AI such as poor appetite, weight loss
or postural dizziness. Recommended doses of glucocorti-
coid replacement have become lower with time [29, 32].
Patients with persistent secondary AI may be begun on a
total daily dose of 25 mg of hydrocortisone per day, but
typically we lower this dose to a total daily dose of
1520 mg/day divided bid. We aim for the lowest dose that
maintains patient weight, appetite and well-being while
minimizing the risks of higher doses of glucocorticoid
replacement such as weight gain, bone loss, hypertension
and glucose intolerance. In periods of illness and stress the
glucocorticoid dose is transiently increased from a range of
double the maintenance to stress dose depending on the
clinical situation.
Pituitarygonadal axes
The need for gonadal steroid replacement in women
should be decided in the months following surgery as it
may take time for menses to return [6]. In one study,
55.6% of women with adenomas other than prolactinomas
and preoperative gonadal dysfunction had return of
menses after TS [33]. In premenopausal women gonadal
function can be assessed based on menstrual history and
gonadotropin and estradiol levels if necessary (Table 2).
Gonadal steroid replacement can be begun at any time
postoperatively in premenopausal women with docu-
mented secondary hypogonadism. A variety of options for
gonadal steroid replacement in women are available and
the choice depends on the patient, their age and medical
history [29].

123
398
In men, secondary hypogonadism is diagnosed by
measuring gonadotropin levels, which should be normal
or low, and a morning total testosterone with a reliable
assay, documenting two low values [34] (Table 2). A free
testosterone may be necessary in patients at risk for
abnormal SHBG levels (most common in patients who are
elderly, obese, have thyroid illness or other significant
comorbidities) [34]. PSA is typically measured before
testosterone therapy and recent guidelines suggest defer-
ring therapy for a PSA [3 [34]. Men with hypogonadism
may have symptoms such as erectile dysfunction or
reduced libido and if prolonged and severe they are at risk
for bone loss, reduced muscle tone, anemia and loss of
body hair. The decision of when and if to treat needs to be
individualized based on the patient and the severity of
hypogonadism and its sequelae. Testosterone replacement
can be administered transdermally by patch or gel or by
intramuscular injections, all of which are efficacious [34].
As an alternative to testosterone therapy, some men with
secondary hypogonadism can be treated in the short term
with thrice weekly human chorionic gonadotropin (HCG)
injections in order to maintain normal testicular function
and fertility. Some with more profound longstanding
deficiencies will require gonadotropin therapy to restore
fertility [35]. Since the time frame for recovery of gonadal
function postoperatively varies, the optimal time for ini-
tiating therapy is uncertain, but symptomatic patients can
be treated soon after surgery with reassessment under-
taken at a later date after holding androgen replacement
therapy.
Thyroid axis
Thyroid function can be assessed by measuring free thy-
roxine levels at the first postoperative visit, again some
time within the first few months after surgery and on a
yearly basis thereafter (Table 2). Measurement of TSH is
not generally useful in patients with hypopituitarism as it
can be low due to loss of TSH secreting cells, but may be
normal despite a low T4 in some of these patients who a patients BMI can effect the GH response to provocative
secrete a form of TSH that is biologically inactive but
detectable on immunoassay [36].
If free thyroxine levels are documented to be low,
replacement therapy with thyroxine is recommended [28,
37]. A recent study suggests dosing of thyroxine should
be weight-based (1.6 lg/kg) with a target FT4 level
towards the upper end of normal [38]. Assessment of
recovery is difficult while on therapy due to the long half-
life of T4, but to do this the doses of thyroid replacement
can be gradually reduced and if serum levels of free
thyroxine remain normal, a trial off therapy can be ini-
tiated with assessment of free thyroxine levels 46 weeks
later [6].
123
Pituitary (2008) 11:391401
Growth hormone axis
A number of studies have found persistent GHD to be
common after pituitary surgery. In one study of 817 adults
at risk for pituitary dysfunction, 41% were GHD despite
preservation of all other pituitary function [39]. The like-
lihood of GHD increased as the number of other pituitary
hormone deficiencies increased (67%, 83%, 96% and 99%
with one, two, three and four additional pituitary hormone
deficiencies respectively) [39]. In another study, the overall
incidence of GHD was 80.2% on testing as early as
3 months following surgery [40]. Despite the high preva-
lence of GHD, the long term safety of GH therapy in
patients with residual tumor even after documented radio-
graphic stability is still unknown. Some recent data do
suggest that GH therapy administered for as long as 5 years
does not effect tumor growth but longer term data are still
lacking [41, 42]. The optimal time postoperatively to assess
for and begin GHD therapy is not yet established.
When testing is pursued, the method may depend on the
status of the remaining pituitary hormones. One study
calculated that the PPV of having GHD is 95% in a patient
with hypothalamic-pituitary disease and three or more
pituitary hormone deficiencies, leading the authors to
conclude that testing for GHD in such cases is not required
[39]. In this same study an IGF-1 level of 84 lg/l or less
had a PPV for GHD of 95% [39]. Yet, many patients with
GHD have normal serum IGF-1 levels [43]. Therefore, in
the majority of cases, the most definitive way to assess for
growth hormone deficiency involves provocative testing.
The insulin tolerance test (ITT) has been considered the
gold standard for testing of GH secretion but this test is not
suitable for many elderly patients or those with CV disease
or seizure disorders [43]. A recent study assessed six pro-
vocative tests of GH secretion and found the arginine/
GHRH test to be an excellent alternative to the ITT [44]. In
this study, a peak serum GH of 4.1 lg/l provided the best
combination of sensitivity and specificity for this test (95%
and 91% respectively) in diagnosing GHD. However, since
stimuli, a recent review has proposed using different cut-
offs based on weight for peak GH response to arginine/
GHRH [45]. For obese subjects a level less than 4.2 lg/l
remains appropriate but for overweight and lean subjects,
the cutoff for peak GH levels should be increased to 8 lg/l
and 11.5 lg/l respectively [45]. Furthermore, in patients
who have received radiation therapy, the arginine/GHRH
test may be falsely positive for the first five years following
XRT [46]. Nevertheless, in most centers, including ours,
the arginine/GHRH test is used as the primary test for
diagnosis of GHD [45]. Regarding therapy for GHD, a
starting dose of 300 lg/day in younger (age 3060] and
100200 lg/day in older patients is recommended [32].
Pituitary (2008) 11:391401
Higher doses may be needed in women, particularly those
on oral estrogen [47].
Postoperative radiological assessment
We perform a MRI 3 months postoperatively in all
patients. In patients with clinically non-functioning tumors
without evidence of residual, a 1 year film is obtained
followed by yearly surveillance for approximately 5 years
with eventual lengthening of the interval if no tumor
growth is detected (Table 2). Tumor recurrence many years
later, however, is possible. If significant residual tumor is
present on the initial postoperative study, earlier repeat
imaging may be considered. In patients with hormone
secreting tumors, yearly scans are typically undertaken, but
this protocol is varied depending on the type of tumor and
status of disease activity.
Evaluation of disease status of hormone secreting
tumors
Monitoring of disease status of hormone secreting tumors
is also a major focus of assessment in the late postoperative
period. A full discussion of this topic is beyond the scope
of this review, but a brief overview of our general approach
is as follows. In patients who have undergone TS for
Cushings disease we generally assess the presence or
absence of persistent disease based on the 24-h urine free
cortisol level although there are other potential strategies
for postoperative surveillance including monitoring of
dexamethasone suppression and plasma ACTH levels [12].
For patients with prolactinomas, we monitor serum pro-
lactin levels and gonadal function within 3 months of
surgery and periodically thereafter depending on the clin-
ical picture and levels. Recurrence after apparent surgical
remission in prolactinomas is not infrequent [48].
Assessment of disease status postoperatively in patients
with GH secreting pituitary tumors is determined by
measurement of serum IGF-I and glucose-suppressed GH
levels. Patients who have clear persistent acromegaly
postoperatively will have persistent and frankly elevated
IGF-I and GH levels in the first few weeks after surgery
and further therapy can be initiated. In most patients we
determine disease status based on testing done 3 months
postoperatively (Table 2). Our primary criterion for
remission is a normal age-adjusted serum IGF-I level.
Glucose suppressed GH levels \0.5 lg/l as measured
with a commercially available immunofluorometric assay
(Immulite, DPC) or \0.3 lg/l with a highly sensitive and
specific immunoradiometric assay in our laboratory [49]
are most consistent with long term remission at our center.
If testing is normal at 1 year, we will repeat testing on a
yearly basis. The recurrence rate is low when patients
399
biochemical data postoperatively meet these rigorous
criteria.
Conclusion
The assessment of patients following transsphenoidal
pituitary surgery entails monitoring for and responding to
Endocrinological and Neurosurgical issues specific to this
type of surgery. When surgery is performed by an experi-
enced Neurosurgeon, the complication rate is low, but the
multi-disciplinary team caring for these patients needs to
be aware of its possible adverse outcomes. Protocols for
monitoring hormonal axes and cuts-offs for various tests of
pituitary function (such as postoperative cortisol levels)
vary and need to be individualized to the center and its
laboratory. Endocrinologists assume a primary role for the
assessment of these patients, especially as the late post-
operative period progresses, which focuses on the
assessment for and treatment of AI, hypothyroidism,
hypogonadism and disease activity in hormone secreting
tumors. With rigorous clinical and laboratory assessments,
issues encountered after pituitary surgery can be success-
fully managed.
Acknowledgements Funded in part by NIH grants R01 DK 064720
and K24 DK 073040 to P.U.F and a Genentech Center for Clinical
Research Center Fellowship Grant to J.C.A.
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