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Preoperative assessment for pituitary surgery

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Preoperative assessment for pituitary surgery

Olivia Pereira ? John S. Bevan

Abstract Evaluation of pituitary function is essential before pituitary surgery. In hyperprolactinaemic patients with a pituitary macrolesion, tumoral secretion of prolactin must be distinguished from ?disconnection? hyperprolacti­naemia; serum prolactin[200 mcg/l is virtually diagnostic of a macroprolactinoma whereas levels \80 mcg/l usually indicate ?disconnection?. The prolactin ?hook effect? should be excluded. A minimum set of pre-operative endocrine tests should include serum electrolytes, cortisol (at 08.00? 09.00 h), free-T4, TSH, prolactin, oestradiol/testosterone, LH, FSH and IGF-1. Some clinicians will choose to perform pre-operative Synacthen or insulin tolerance testing to fur­ther define ACTH reserve. If basal cortisol, Synacthen or insulin tolerance test results are abnormal, steroid supple­mentation is indicated for at least the first 48 h after surgery. If pre-operative basal cortisol is \100 nmol/l, replacement steroids should be continued until the time of post-operative pituitary function testing (6?8 weeks after surgery). In patients with pre-operative basal cortisol[450 nmol/l, peri­operative glucocorticoid replacement is unnecessary and further cortisol levels should be checked a few days after surgery. Most clinicians defer detailed evaluation of growth hormone reserve until after surgery. Diabetes insipidus is rarely a problem before surgery in patients with pituitary adenomas but may occur post-operatively. Close co-oper­ation between anesthetic, endocrine and surgical teams is strongly recommended.



Keywords Pituitary function Prolactin Synacthen


Insulin tolerance Pituitary surgery


O. Pereira J. S. Bevan (&)


Department of Endocrinology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, Scotland, UK e-mail: johnbevan@nhs.net




Secretion of the six principal anterior pituitary hormones? LH, FSH, prolactin (PRL), GH, ACTH and TSH?is under complex feedback control by target gland hormones and hypothalamic regulators. Varying degrees of hypopituita­rism may be present at diagnosis in patients with space-occupying pituitary or hypothalamic lesions, or may occur at a later stage, after surgery and/or radiotherapy. Accurate evaluation of pituitary function is essential at diagnosis and at intervals after treatments have been applied. Hyperpro­lactinaemia may be present, either by interruption of delivery of hypothalamic dopamine to the normal lacto­trophs or by direct secretion of PRL by a prolactinoma? this requires careful evaluation to determine whether pri­mary medical therapy or surgery is appropriate. This article describes the physiological basis for the standard pituitary function tests and highlights a number of pitfalls. Some pituitary hormones can be tested using single blood samples (eg. TSH, together with free-T4) whereas others with more complicated circadian or pulsatile patterns of secretion require dynamic stimulation tests (eg. ACTH). There is still debate over the best tests for diagnosing ACTH and GH deficiency. The preoperative assessment of patients with acromegaly and Cushing?s disease is beyond the scope of this article and has been reviewed recently by others [1?3]. In addition to endocrine evaluation, patients need specialist ophthalmological, radiological (mostly with gadolinium-enhanced MRI) and anaesthetic assessments before surgery.


Interpretation of serum prolactin levels


It is important to exclude pregnancy, PRL-elevating drugs, primary hypothyroidism and polycystic ovarian syndrome in all patients with hyperprolactinaemia. In hyperprolactinaemic patients with a pituitary mass lesion, the main challenge is to distinguish between tumoural secretion of PRL and ?discon­nection? hyperprolactinaemia. The basal PRL level is of considerable diagnostic value [4, 5]. A value greater than 200 mcg/l (5,000 mU/l) is virtually diagnostic of a macro­prolactinoma and above 400 mcg/l there is no other possible diagnosis. A serum PRL level lower than 80 mcg/l in a patient with a pituitary macrolesion usually indicates ?disconnection? rather than tumoural secretion [6]. An inter­mediate PRL level of 80?200 mcg/l presents some diagnostic uncertainty, although most patients will have true prolacti­nomas, particularly those with higher levels within this range ([120 mcg/l). Dynamic PRL function tests employing a dopamine antagonist (e.g. domperidone) or TRH yield little further information in patients with large pituitary lesions. These considerations are important because nearly all patients with prolactinomas can be treated medically and avoid sur­gery [7].


There are two potential pitfalls to remember; the PRL ?hook effect? and the presence of macroprolactin. If serum PRL concentrations are extremely high (as in some men with giant prolactinomas), the amount of PRL antigen may satu­rate the capture antibody in immunoradiometric assays (IRMAs), leading to artifactually low PRL results [8]. This ?hook effect? may lead to misdiagnosis and inappropriate surgery for some patients with macroprolactinomas. If an IRMA is used, serum PRL should always be assayed in dilution in any patient with a large pituitary lesion which might be a macroprolactinoma. Macroprolactin is a complex of PRL with an IgG antibody which is detected by most, but not all, PRL immunoassays and is present in approximately 1% of unselected sera. Patients with macroprolactinaemia do not exhibit typical hyperprolactinaemic symptoms and this prolactin variant is virtually never associated with macro­prolactinoma. If suspected, the presence of macroprolactin can be confirmed by a simple polyethylene glycol precipi­tation method [9]. In practice, however, macroprolactin rarely causes diagnostic confusion in a patient already known to have a pituitary mass.


Acquired prolactin deficiency (levels consistently below 2 mcg/l in a patient not taking PRL-lowering medication) is associated with severe hypopituitarism and reduced IGF­1 levels [10, 11].


Hypothalamo-pituitary-adrenal axis


General considerations


Assessment of the hypothalamo-pituitary-adrenal (HPA) axis, and thus defining a possible need for glucocorticoid replacement therapy, is a crucial aspect of anterior pituitary function testing. Under normal circumstances, ACTH secretion shows a marked circadian rhythm with highest levels in the early morning and lowest at around midnight. Measurement of the target hormone cortisol is common to all tests of the HPA axis and cortisol has the advantage of being a more stable hormone in serum/plasma than ACTH. It should be remembered that exogenously administered hydrocortisone or prednisolone interfere with the radio­immunoassay determination of endogenous cortisol secretion. Furthermore, dexamethasone?often adminis­tered in neurosurgical settings?will render cortisol measurements uninterpretable, both during treatment and for several days after steroid withdrawal depending on the dose and duration of therapy. Total cortisol levels are significantly raised in patients taking oral oestrogens due to an increased production of cortisol binding globulin (CBG)?if possible, oral oestrogens should be discontinued for at least 6 weeks before pituitary adrenal axis testing although, in practice, increments in serum cortisol during dynamic tests may still yield clinically useful information. Early studies of cortisol secretion in eu-adrenal patients following major abdominal surgery suggested a threshold stressed cortisol level of 580 nmol/l, measured using the older fluorimetric assay, which probably equates to a figure of 500 nmol/l using modern radioimmunoassays [12]. However, a 26% difference in basal cortisol concentration has been demonstrated using different cortisol immunoas­says [13], so knowledge of the local cortisol assay is important, and the clinician should not be overly dependent on absolute cut-off values taken from the literature.


HPA axis tests


Several tests are available to help predict whether the HPA axis is able to respond normally to significant stress including basal serum cortisol, the insulin tolerance test (ITT), the glucagon stimulation test (GST) and the short Synacthen test (SST, standard and low dose versions). Other tests using CRH or overnight metyrapone are unreliable and not in widespread use. There has been considerable con­troversy as to whether the more convenient SST can substitute for more complicated tests such as the ITT.


Basal cortisol


Ideally, basal cortisol should be measured between 08.00 and 09.00 h since HPA axis activity is maximal at this time. Random cortisol measurements, for example during afternoon clinics, are much less useful and often difficult to interpret. If the basal morning cortisol is less than 100 nmol/l this strongly suggests ACTH deficiency and glucocorticoid replacement should be commenced. If basal cortisol is greater than 450 nmol/l adrenal insufficiency is very unlikely. An intermediate value requires dynamic testing to assess ACTH reserve.



Insulin tolerance test


This test delivers a controlled stressful stimulus to the entire HPA axis by means of insulin-induced hypoglycaemia. It has the additional advantage of stimulating GH secretion and is still regarded by many as the ?gold standard? test for the evaluation of both ACTH and GH reserves. Whilst the safety of the ITT in children has been questioned, audits of the test performed in adults in specialist endocrine investigation units have shown an acceptably low level of morbidity. Nevertheless, the ITT is labour intensive, requires specialist supervision and is contraindicated in patients with ischaemic heart disease or epilepsy. Many endocrinologists avoid its use in patients over the age of 60 years who may have sub­clinical vascular disease. The standard dose of insulin is


0.15 units per kg body weight, given as an intravenous bolus of soluble insulin. Venous blood glucose should fall to less than 2.2 mmol/l; sometimes this target is not achieved and the insulin dose has to be repeated. It is prudent to check a morning cortisol level, serum potassium concentration and resting ECG before performing an ITT. The test should not be performed if the basal cortisol is less than 100 nmol/l. Most endocrinologists regard a cortisol increment of at least 200 nmol/l together with a peak cortisol level above 500 nmol/l to constitute a normal response. Others prefer to set a more stringent peak cortisol of 550, or even 600 nmol/l.


Glucagon stimulation test


This test is a useful method of assessing the HPA and GH axes for patients in whom the ITT is contraindicated. It is used quite widely in the UK [14], but less so in other parts of the world. The test has been studied less intensively than the ITT and SST. The GST uses the same cortisol criteria as those established for the ITT. The ACTH and GH responses to glucagon occur relatively later than during an ITT and blood sampling is carried out every half an hour between 90 and 240 min after the intramuscular injection of 1.0 mg of glucagon. Glucagon may cause nausea, abdominal cramps and occasional vomiting. Some normal individuals fail to mount an ACTH response to glucagon.


Short Synacthen test


Although initially employed in the investigation of patients with possible primary adrenal failure, Synacthen stimula­tion has been used as an ?indirect? test of ACTH reserve for the past 30 years. Its sensitivity in this setting depends on the secondary adrenal atrophy that results following ACTH deficiency but it should be recognised that this takes at least 3?4 weeks to develop after an acute pituitary insult, such as pituitary apoplexy or surgery. The standard SST involves the intravenous (more predictable than intramuscular) injection of a pharmacological dose (250 mcg) of the ACTH analogue. The SST is a simple test, does not require specialist supervision and takes only an hour to complete. Basal and 30 min samples for cortisol are collected.


There has been much debate as to whether the SST can substitute for the ITT. Hurel et al. [12] compared the stan­dard SST and ITT in 57 normals and 166 patients with hypothalamo-pituitary disease, none of whom were studied within 6 weeks of surgery. For normal subjects, the mean minus 2SD cortisol levels were 392 and 519 nmol/l for the 30-min SST value and ITT peak, respectively. Sixty patients failed the ITT but none had a basal cortisol[450 nmol/l and only 10% had a 30-min SST value[600 nmol/l. The authors suggested adopting the latter value as a clinically useful SST cut-off, thus reducing the number of ITTs needed to assess ACTH reserve.


Growth hormone?IGF-1 axis


Normal physiology


GH secretion is pulsatile and its short half-life means that serum GH is undetectable in normal subjects for approxi­mately two thirds of the day. It therefore follows that GH deficiency cannot be diagnosed by a single blood sample or even multiple sampling. Many of the actions of GH are mediated by insulin-like growth factor 1 (IGF-1), espe­cially in muscle, adipose tissue and bone. GH is the most important regulator of IGF-1 production by the liver, par­ticularly in children and young adults, but nutritional status also exerts important influences. GH and IGF-1 levels decrease with age in normal subjects [15].


Provocative tests


The biochemical diagnosis of GH deficiency depends on the use of pharmacological, provocative tests. As for ACTH, the ?gold standard? test is regarded by many to be the ITT, despite the caveats and contraindications dis­cussed above. The criterion for severe GH deficiency is a peak concentration of \3 mcg/l (9 mU/l). GH sufficient individuals achieve a peak GH above 7 mcg/l following hypoglycaemia, with many young adults attaining peak GH levels above 15 mcg/l [16]. Many other provocative tests of GH reserve have been developed [16?18].


Rahim et al. assessed the GH status of young males and found that the most profound GH release was seen during an ITT (mean peak 36 mcg/l, range 9?67) [16]. The next most effective test was the GST (mean peak GH 14 mcg/l, range 4?67), but on an individual basis, 2, 6 and 15 of 18 subjects failed to achieve a peak GH level above 7 mcg/l with glu­cagon, arginine and clonidine, respectively. Biller et al. reported on the sensitivity and specificity of six tests (ITT, Arginine-GHRH, Arginine-L-Dopa, Arginine, L-Dopa and IGF-1) in normal subjects and patients with minor and major degrees of anterior hypopituitarism [17]. They concluded that the Arginine-GHRH test, with 95% sensitivity and 91% specificity at a GH cutoff of 4.1 mcg/l, provided an excellent alternative to the ITT which had 96% sensitivity and 92% specificity at a GH cutoff of 5.1 mcg/l. In this combination test the arginine is presumed to reduce hypothalamic somatostatin secretion whilst the GHRH acts as a pituitary releasing agent. It is important to remember that obesity blunts the GH responses to a variety of stimuli, including Arginine-GHRH stimulation, whilst IGF-1 remains normal [19]. In patients with pituitary disease the likelihood and severity of GH deficiency increases according to the degree of hypopituitarism present. For example, a patient with proven gonadotrophin, ACTH and TSH deficiency is likely to have severe GH deficiency and the diagnosis can be made on the basis of a low IGF-1 level without the need for a GH stimulation test [20].


Insulin-like growth factor 1


Although there is some correlation between the magnitude of GH responses to provocative stimuli and IGF-1 con­centration, IGF-1 values become less useful in older subjects because of the age-related decline in GH secretion. Adults with GHD over the age of forty frequently have normal IGF-1 levels and this hormone cannot be used in isolation as a diagnostic test for GHD [15].


Hypothalamo-pituitary-thyroid axis


Secondary hypothyroidism is strongly suggested by low levels of free-T4 in association with low, normal or mini­mally elevated levels of TSH. However, it should be remembered that sick patients with non-endocrine disease (?sick euthyroid?) can also exhibit a similar pattern of thy­roid function tests. Although used extensively in the past, it is now recognised that dynamic testing using intravenous TRH does not provide any additional information for the diagnosis of secondary hypothyroidism. In addition, TRH has been implicated in the precipitation of pituitary apo­plexy in some patients with pituitary macroadenomas [21].


Hypothalamo-pituitary-gonadal axis


Similarly, it is rare for tests other than basal measurements of gonadotrophins (LH and FSH) and sex steroids (oestradiol or testosterone) levels to be required for assessment of the HPG axis. Oestradiol binds to sex hormone binding globulin (SHBG), levels of which will be raised in women using the oral contraceptive or oestrogen HRT. Testosterone in men shows a marked diurnal variation and should be measured at 08.00?09.00 h. Dynamic testing with intravenous LHRH is no longer used for the diagnosis of secondary hypogonadism.




Cranial diabetes insipidus is rarely a presenting feature in patients with pituitary adenomas, even if the tumour is very large. However, diabetes insipidus occurs commonly in patients with craniopharyngioma or other hypothalamic pathologies. In this context, it is seldom necessary to undertake a formal water deprivation test and the diagnosis can usually be established by measuring serum sodium ([143 mmol/l) and osmolality ([300 mOsm/kg), together with urine output (often [3 l/day) and osmolality (\300 mOsm/kg). The patient should be stabilised on oral or intranasal desmopressin before surgery. It should be remembered that diabetes insipidus may emerge for the first time after an ACTH-deficient patient commences steroid replacement?glucocorticoids being necessary for excretion of a water load.


Endocrine protocols before and during surgery


Baseline endocrine tests


It is important to assess pituitary function at first diagnosis in all patients with space-occupying pituitary or hypothalamic lesions in order to define the need for replacement therapy before tumour treatment and to audit the effects of surgery on general pituitary function. A reasonable set of tests includes serum electrolytes, cortisol (at 08.00?09.00 h), fT4, TSH, prolactin, oestradiol/testosterone, LH, FSH and IGF-1. If serum cortisol is \450 nmol/l or if GH deficiency is sus­pected, an ITT may be performed. However, if putting the patient through a pre-operative ITT is considered to be excessive, a SST can be used to define baseline HPA axis function.


Glucocorticoid replacement


The decision to use perioperative glucocorticoids in patients undergoing pituitary surgery can be based on the results of the pre-operative screening tests [22]. If the preoperative basal cortisol/SST/ITT results are subnormal, the patient should be commenced on hydrocortisone replacement (15?30 mg daily) with an increase to cover surgery and the first 48 h postoperatively. A standard perioperative regimen comprises 50 mg hydrocortisone at induction of anaesthesia, 50 mg every 8 h for the first day, 20 mg every 8 h for the second day and then a return to regular replacement, depending on clinical progress. In patients with preoperative basal cortisols below 100 nmol/l replacement steroids should be continued, at least until the time of definitive testing 4?6 weeks after surgery. In patients with preoperative basal cortisol above 450 nmol/l and/or a normal SST, no perioperative replacement is necessary, particularly if a selective adenomectomy proves to be possible, and sampling for basal cortisol should be carried out 3?5 days after surgery.


Salt and water balance


If diabetes insipidus is presently pre-operatively, vaso­pressin should be continued in the early post-operative period, usually parenterally for the first day or two. Dia­betes insipidus may result from the surgical intervention and can emerge either during or immediately after the operation. Clinical and biochemical vigilance is manda­tory, with close co-operation between the anaesthetic, endocrine and surgical teams.



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(Please do not copy this publicly because of copyright infringement. I'm posting the complete article on this private forum and will blog about it soon, but will only quote parts of it.)

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