Neuroendocrine Lesions - Clinical Tree

The neuroendocrine system is responsible for the maintenance of milieu interior and facilitation of reproduction through secretion of various hormones. These hormones are regulated by interactions and feedback loops between the central nervous system, the endocrine glands, and the target organs. The hypothalamus is the chief signaling station, producing neurohormones, which are then transported to the pituitary gland. The latter in turn, produces hormones that regulate the fluid and electrolytes as well as the metabolic and reproductive functions.

The close association between the nervous and endocrine systems is not given due importance. Most discussions of neuroanesthesia traditionally center around the intracranial hemodynamics and effects of anesthetics on it. Lack of recognition of neuroendocrine relationship may be because the adrenal insufficiency is the only endocrine disturbance that presents as serious hemodynamic instability in the perioperative period. Even this life-threatening condition is rarely encountered by neuroanesthesiologist because, almost all patients who undergo neurosurgery receive glucocorticoids in the preoperative period. Nonetheless, neuroendocrine disorders play a significant role in the management of these patients.

This chapter will highlight the anatomy and physiology of the pituitary gland, hypothalamic-pituitary-adrenal (HPA) axis, pathophysiology of various disorders associated with hypo- or hypersecretion of various pituitary hormones, anesthetic management, and complications following pituitary adenoma removal.

Hypothalamic-Pituitary–Adrenal Axis Evaluation

The HPA axis is an example of the close interactions of the nervous and endocrine systems in the maintenance of milieu interior.

The metyrapone test is highly sensitive to determine the integrity of the HPA axis. It is based on the premise that lowering the serum cortisol concentration will increase the adrenocorticotropic hormone (ACTH) secretion. However, utility of this test has decreased these days following the introduction of plasma ACTH assay. Metyrapone blocks 11-β-hydroxylase and thereby, inhibits conversion of 11-deoxycortisol to cortisol. This results in decreased serum levels of cortisol and increased level of 11-deoxycortisol. However, the latter does not downregulate ACTH. Therefore, in a normally functioning HPA axis, there is an increase in 11-deoxycortisol, which can be can be measured in the serum. It can also be measured in the urine as 17-hydrocorticoid. It can be performed as an overnight test. Metyrapone is administered orally (30 mg/kg, or 2 g for <70 kg, 2.5 g for 70–90 kg, and 3 g for >90 kg body weight) at midnight. Serum 11-deoxycortisol and cortisol are measured at 8 a.m. the next morning; plasma ACTH can also be measured.

Interpretation of results : The 8 a.m. serum 11-deoxycortisol concentrations should be 7–22 μg/dL (200–660 nmol/L) with serum cortisol less than 5 μg/dL (138 nmol/L) to confirm adequate metyrapone blockade. The plasma ACTH concentration at 8 a.m. should exceed 75 pg/mL (17 pmol/L), confirming that increases in serum 11-deosycortisol concentrations are ACTH dependent, thereby, distinguishing primary from secondary adrenal insufficiency. The test can also be conducted by measuring urinary 17-hydrocorticoids following oral administration of 750 mg of metyrapone every 4 h, for six doses. Serum 11-deoxycortisol concentration less than 7 μg/dL (210 nmol/L) with concomitant suppressed cortisol values indicate adrenal insufficiency. Metyrapone test cannot be done if the patient is taking any glucocorticoids.

Another method to test ACTH as well as growth hormone (GH) reserves is to induce hypoglycemia by intravenous (IV) administration of insulin. This is the gold standard to evaluate the integrity of HPA axis.

Measures should be at hand to treat symptomatic hypoglycemia before starting the test. This test is not recommended in patients with uncontrolled seizures and significant coronary artery disease. This test is usually done in the morning in under fasting condition. If the patient is on hydrocortisone, it is stopped for at least 12 h. This test gives false results if the patient is taking dexamethasone, due to suppression of hypothalamic pathways necessary to respond to hypoglycemia.

In the presence of normal pituitary function, hypoglycemia (blood glucose less than 40 mg/dL) should result in significant increase in plasma cortisol as well as GH. Failure of the plasma cortisol level to increase is an indication of low ACTH reserve.

If a patient is taking insulin for diabetes mellitus, it must be kept in mind that patient may be resistant to insulin. In such situation, the patient will require a higher dose of insulin. The test is started with 0.1 unit/kg of insulin, and then the bolus is repeated depending on the response to the first dose (repeat the same dose if the patient showed insufficient response, double the dose if the patient’s response was only minimal, or administer half the dose if the hypoglycemic response was close to the desired level).

Interpretation of results : Serum cortisol should increase within 30 min of hypoglycemic response to greater than 20 μg/dL (550 nmol/L). If cortisol level at baseline is 18 μg/dL the test may not be diagnostic. If the baseline serum cortisol is higher than 19 μg/dL, adrenal insufficiency is unlikely. Although the response of cortisol is more reproducible than that of GH in insulin test, intrasubject differences do exist.

It should be noted that the use of a cutoff level of 550 nmol/L is somewhat arbitrary and method dependent. Due to methodological differences between various laboratories, it is advisable that each laboratory establishes its own reference value for cortisol.

Neuroendocrine Response Related to Anesthesia and Surgery

Pain, anxiety, acidosis, local tissue factors, hypoxia, etc., are various neural and humoral factors that activate the stress response. Surgical trauma alters the neuroendocrine system, leading to changes in the secretion of pituitary, adrenal, thyroid, and pancreatic hormones along with profound changes in the autonomous nervous system activity. The stress response to surgery and anesthesia is therefore, a result of the release of a combination of neuroendocrine hormones and of local release of cytokines.

Neuroendocrine changes alter the physiology of various body systems. Heightened activity of sympathetic system may be potentially harmful in a patient with coronary artery disease. Increased production of GH, glucagon, cortisol, and adrenaline result in hyperglycemia, commonly noted in the intraoperative and postoperative period. Therefore, various physiological changes arising from surgical stress (blood pressure and heart rate changes) may cause complications, especially in the presence of comorbid conditions like cardiovascular and cerebrovascular diseases. Therefore, techniques and pain management strategies should be directed to minimize the neurohormonal response for the benefit of patient.

Many studies have demonstrated that the neuroendocrine response can be modified in the perioperative period by anesthetic techniques like parenteral administration of high dose of opioids, neural blockade of local anesthetics, and extradural or subarachnoid deposition of narcotics.

Pituitary Gland Adenomas

Pituitary adenomas are the most frequent cause of pituitary hormone hyper/hyposecretion. Adenomas are usually benign pituitary tumors. They occur in adults, with a peak incidence during the fourth to sixth decade of life. They are classified as micoradenoma (tumor less than 10 mm in diameter) and macroadenomas (tumor more than 10 mm diameter). They are also grouped as functioning and nonfunctioning, depending on the amount of hormone secreted from the pituitary gland.

The usual opinion is that pituitary tumors account for only 10% of all intracranial tumors; actually however, an autopsy study has found an incidence of 26.7%. High-resolution neuroimaging methods, especially magnetic resonance imaging (MRI), has led to the discovery of incidental pituitary tumors of 3 mm diameter and bigger in about 20% of normal pituitary glands. Based on their analysis of patients with brain tumors presenting to their hospital, (Tata Cancer Hospital, Mumbai), Jalali and Datta reported pituitary adenomas in 8.38%. However, this figure may not be representative of incidence in the Indian population. Most pituitary tumors arise from the anterior part of the gland. Proposed etiologic mechanisms include malfunction of normal growth-regulating genes, abnormal tumor suppression genes, and changes in genes that control programmed cell death ( Figs. 22.1 and 22.2 ).

Figure 22.1, Coronal, T1-weighted, enhanced magnetic resonance image (MRI) showing pituitary gland and its anatomical relations.

Figure 22.2, Sagittal MRI showing large pituitary macroadenom ( arrow ) with suprasellar extension.

The transsphenoidal procedure that allows neurosurgeon to approach the lesion located in the middle of the skull base was described almost a century ago by Cushing and Hirsch. This approach is now considered the procedure of choice for most patients with pituitary tumors with sellar extension. Many subsequent technical refinements have been described.

Knowledge of tumor anatomy and pathophysiology is required, because pituitary hormonal hyper- or hyposecretion and its consequences, and tumor mass effect, cause problems relevant to anesthesia. In addition, specific issues arise according to the surgical approach, either transsphenoidal or, less commonly, transcranial.

Anatomy of the Pituitary Region

The pituitary gland sits in a saddle-shaped bone called the sella turcica. The dimensions of the gland are 6 × 13 × 9 cm. Its weight ranges from 0.50 to 0.90 g. Sella turcica lies directly above the sphenoid sinus, a relationship that provides direct access to the pituitary gland via the nasal cavity. Directly above the gland is the optic chiasm and immediately above the chiasm is the hypothalamus. The diaphragm sella is a roof formed by duramater. It is pierced by pituitary stalk with its arachnoid membrane, which extends to the hypothalamus. The pituitary stalk is anterior to the chiasm. The floor and anterior wall of sella are formed by the roof of the sphenoid air sinus, the posterior wall by the clivus, and the lateral walls by the cavernous sinuses. Within the cavernous sinus are the internal carotid arteries (ICAs) and the third, fourth, sixth, and first, and second divisions of fifth cranial nerve. The distance between the tubeculum sella and the chiasm ranges from 2 to 9 mm (average 4 mm).

The distance between the ICA and gland ranges from 2 to 7 mm. The arterial supply to the gland comes from inferior and superior hypophyseal arteries, which are branches of the ICA. The venous drainage is to cavernous sinus and internal jugular vein. Thus, arterial bleeding during the transsphenoidal tumor removal may be from the ICA or its branches, and the venous bleeding results from the cavernous sinus. To control arterial bleeding, measures adopted intraoperatively (packing and coagulation) may produce contralateral hemiparesis or deficit of ipsilateral nerves present in the cavernous sinus. ICA handling itself may result in vasospasm, thrombosis, or distal embolism. The hypothalamus and third ventricle may be compressed by large pituitary adenoma leading to hypothalamic abnormalities and hydrocephalus, respectively. Pituitary adenoma may outgrow the sellar boundaries and spread superiorly into the suprasellar region and the medial temporal lobes or invade inferiorly into the sphenoid sinus or laterally into the cavernous sinuses.

Physiology of Pituitary Gland

The pituitary gland is made of two lobes. The smaller posterior pituitary (neurohypophysis) is derived as an outpouching of floor of the third ventricle and is an extension of the central nervous system. It receives terminal axons from magnocellular neurons of the hypothalamus; primarily in supraoptic or paraventricular nuclei. The posterior pituitary is devoid of the blood–brain barrier. The larger anterior pituitary (adenohypophsis) is derived from Rathke pouch. The anterior lobe forms two-third of the gland. It is made of distinct cell types that produce many hormones. Various immunocytochemical techniques have identified at least five different kinds of cell within the anterior lobe. Somatotrophs account for about 50% of the cells and produce GH. Prolactin-producing lactotrophs account for 10–25% and ACTH-producing corticotrophs for another 15%. Melanocyte stimulating hormone (MSH) is an analog of ACTH. There are 5–10% thyrotrophs that produce thyrotropin (TSH), and gonadotrophs (10%), which produce follicle-stimulating hormone (FSH) and luteinizing hormones (LH). The gland also has functionally inert cells (null cells) from which may arise nonfunctional pituitary adenomas.

Hypothalamus regulates the anterior pituitary hormones. Axons from hypothalamic neurons terminate on the median eminence where capillaries carry arterial blood down to anterior pituitary through the hypophyseal portal system. Peptide hormones stimulate or inhibit the release of the corresponding pituitary hormones. Prolactin release is stimulated by prolactin-releasing hormone (PRH) and inhibited by prolactin-inhibiting hormone, that is, dopamine. GH release is stimulated by growth hormone–releasing hormone (GRH) and inhibited by somatostatin. Thyroid-releasing hormone (TRH) stimulates the production and release of thyroid-stimulating hormone. Similarly, corticotropin-releasing hormone (CRH) stimulates ACTH release.

Anterior pituitary hormones influence the specific target organs and tissues. In females, prolactin promotes milk secretion from the breasts. In men, its role is unclear. GH acts on a variety of tissues, both directly and through release of insulinlike growth factor 1 (IGF-1). IGF-1 is released from the liver in response to GH. Beside stimulation of bone and cartilage growth, GH and IGF-1 promote protein synthesis and lipolysis but decreasing insulin sensitivity and causing sodium retention. TSH stimulates iodine binding by the thyroid gland and increases synthesis and release of triiodothyronine and thyroxin. ACTH acts on high-affinity membrane receptors of adrenocortical cells resulting in increased concentrations of intracellular cholesterol, which is then converted into cortisol within the mitochondria. Role of FSH is to cause maturation of ovarian follicles, while LH is responsible for ovulation. In males, FSH stimulates spermatogenesis and LH causes testosterone secretion.

Anterior pituitary hormones are under feedback control. GH increases circulation of IGF-1, which in turn inhibits GH secretion from the anterior pituitary. It also stimulates somatostatin secretion. Thyroid hormones provide feedback to inhibit TRH and TSH, and cortisol inhibits CRH and ACTH. Secretion of FSH and LH is controlled by a single releasing factor, LH-releasing factor. The feedback from gonadal hormones from the pituitary and hypothalamus may be inhibitory or stimulatory. The function of MSH in humans is unclear, but it is controlled by the hypothalamus through stimulatory and inhibitory factors.

The posterior pituitary is responsible for the storage and release of two hormones, oxytocin and vasopressin [also known as antidiuretic hormone (ADH)]. These octapeptide hormones synthesized in the paraventricular and supraoptic nuclei of the hypothalamus are then attached to specific carrier proteins, neurophysin, for transport along the pituitary stalk in secretory granules. The secretory granules travel along the axons of the supraoptic and paraventricular cells through the median eminence and pituitary stalk into the posterior pituitary gland. Axonal transport time of these hormones varies from 30 to 60 min.

Presentation of Pituitary Lesions

Pituitary lesions may have varied presentation.

1.
Hormonal hypersecretion syndrome, such as prolactinoma, Cushing disease, and acromegaly
2.
Mass effect, for example, visual symptoms or raised intracranial pressure (ICP)
3.
Nonspecific effects, such as infertility, headache, or pituitary hypofunction
4.
Rarely, a patient may present with pituitary apoplexy following hemorrhage into the adenoma.

Besides, pituitary tumors may be found during investigation for unrelated conditions (incidentaloma).

Hormonal hypersecretion : This usually occurs secondary to overproduction of hormones by a discrete adenoma. Prolactinomas are the most common hormonal hypersecreting adenomas. Adenomas causing Cushing disease and acromegaly are uncommon.

Mass effect : Mass effect is more likely to occur with nonfunctioning macroadenomas because patient develops symptoms quite late resulting in increased size of the adenoma. The structures most commonly affected include optic nerves and chiasm, causing characteristically bitemporal hemianopia. Large tumors (macroadenoma) may obstruct CSF flow, resulting in hydrocephalus and raised ICP. A pituitary tumor may increase ICP from the tumor itself also. Occasionally, third nerve palsy may be the presenting symptom especially, following pituitary apoplexy.

Nonspecific symptoms : Patient may present with infertility or pituitary hypofunction or seizures. Pituitary hypofunction results commonly from compression of normal pituitary tissues by a nonfunctioning adenoma, rarely by pituitary apoplexy, and extremely rarely by postpartum pituitary infarction (Sheehan syndrome).

Incidentalomas : Pituitary adenoma has been detected incidentally in patients undergoing cranial imaging for some unrelated conditions in more than 10% of patients. Autopsy studies have revealed that the incidence of asymptomatic pituitary adenomas in general population is between 2% and 27%. The term incidentaloma was coined by Reinecke et al. to describe small pituitary tumors diagnosed incidentally on MRI or computed tomographic scanning.

Endocrine Diseases

Preoperative assessment is incomplete without considering the clinical disease associated with each tumor. Available medical therapy may suppress some of the systemic effects of functional adenomas. Unique features of acromegaly and Cushing disease challenge the anesthesiologist’s skill.

Hypothyroidism

Intrinsic pituitary disease can lead to secondary hypothyroidism. Hypothyroidism result in slow mentation, slow movements, dry skin, cold intolerance, depression of ventilator responses to hypoxia and hypercarbia, impaired gastric emptying, and bradycardia. In extreme cases, patient may develop cardiomegaly, heart failure, and pericardial and pleural effusions manifested as fatigue, dyspnea, and orthopnonea. Tongue may be enlarged, which may hamper intubation. In the presence of full-blown myxedema, the patient shows cold intolerance, apathy, hoarseness, constipation, anemia, hearing loss, and bradycardia.

Preparation of Patient With Hypothyroidism for Surgery

Hypothyroidism decreases the anesthetic requirement. Thyroid function should be restored to normal. Continue morning dose of T3 or T4, even though these drugs have long half-lives from 1.4 to 10 days. Both T4 and TSH serum levels return to normal range in satisfactorily treated patients.

Perioperatively, in these patients maintenance of cardiovascular function and temperature is the main concern.

Prolactinoma

Nearly 50% of the functional pituitary tumors are prolactinomas. Majority are microadenomas and occur mainly in females (90%). In them, hyperprolacteneima results in secondary amenorrhea and galactorrhea. Males with prolactinomas usually present with secondary hypogonadism, decreased libido, premature ejaculation, impotence, and erectile dysfunction. Prolactinoma may be a part of multiple endocrine neoplasia syndrome (adenoma of parathyroid gland and islet of pancreas with Zollinger–Ellison syndrome). Isolated prolactinoma has no anesthetic implications.

Diagnosis : Elevated plasma prolactin levels in the presence of pituitary tumor confirms the diagnosis. Levels more than 400 mU/L or 20 ng/mL are generally taken to be elevated. Levels of 1000–4000 mU/L are found in microadenoma, while more than 6000 mU/L are indicative of macroadenoma.

Treatment : Since prolactin is under the dominant inhibitory control of dopamine, therefore, the first line of treatment is dopamine agonists, such as bromocriptine, which reduces prolactin levels to near normal in 60–90% of patients. First, 1 mg oral is given and then and increased to 5–15 mg daily. Cabergoline is a longer acting alternative to bromocriptine. Treatment may be needed lifelong. Surgery is performed when patients do not tolerate medical treatment (nausea, lethargy, nasal stuffiness) or for failure of medical treatment. In patients with macroadenoma, morning cortisol should be checked if symptoms suggest hypopituitarism, although it is rare. Although there is no evidence of teratogenicity, dopamine agonists are usually stopped during pregnancy. If the tumor enlarges during this period, its administration may be restarted as this does not affect the outcome of pregnancy.

Growth Hormone–Secreting Tumor

Excess of GH produces acromegaly in adults and gigantism in children before epiphyseal closure. Patient develops enlargement of jaw, hands, and feet and increased soft tissue growth. Patient with acromegaly may present to the hospital to seek treatment for diabetes mellitus and hypertension, rather than for acral enlargement.

Diagnosis : Random serum GH levels in healthy male is less than 5 ng/mL, in healthy females it is less than 10 ng/mL, and in children its range is 0–20 ng/mL. The diagnosis is based on an increased GH concentration, which remains unsuppressed following an oral glucose tolerance test (OGTT) with 75 g glucose and, increased IGF-1. Isolated measurement of GH may be misleading because it is released in three or four bursts per day and has a short half-life. GH results in secretion from liver a family of peptides called somatomedins. Unlike GH, somatomedin C (IGF-1) is the most popular somatomedin measured in practice because of its longer half-life and the absence of diurnal variation. Serum levels of IGF-1 are age dependent, and the levels tend to decrease with advancing age (182–780 ng/mL for 16–24 years, 114–492 ng/mL for 25–39 years, 90–360 ng/mL for 40–54 years, and 71–290 ng/mL for 55–70 years). According to a consensus statement of American Association of Clinical Endocrinologists, a GH value less than 1 ng/mL after an OGTT (75 g glucose followed by GH measurement every 30 min for 120 min) is considered normal. The panel also suggests that serum GH nadir after glucose administration be lowered to 0.4 ng/mL to increase the sensitivity of testing. L-Dopa administration in a normal person increases the GH; however, in acromegalic patients it remains unchanged and even decreases.

Treatment : The primary treatment of acromegaly is surgery, with or without subsequent radiotherapy Some patients may be on medical therapy such as dopamine agonists, analogs of somatostatin (octreotide), or the GH receptor antagonist pegvisomant. Another slow -release preparation of somatostatin, somatotuline, given parenterally every 1–2 weeks has been investigated. Medical pretreatment improves more florid acromegaly.

ACTH-Secreting Tumor

Approximately 4% of functioning pituitary adenomas are ACTH secreting, and the majority are microadenomas. It is mostly seen in females. It results in adrenal hyperplasia, clinically leading to Cushing disease. High concentration of cortisol results in Cushing syndrome, which may result from extracranial tumors (primarily oat cell carcinoma of lungs). Cushing syndrome may also result from adrenal tumor or prolonged use of glucocorticoids.

Diagnosis : To begin with, exclude exogenous administration of glucocorticoids. In a suspected case of Cushing syndrome, urinary cortisol, late night salivary cortisol, 1 mg overnight, or 2 mg 48-h dexamethasone suppression test should be conducted. Patients with abnormal test results undergo one of the above tests a second time or in some cases, a midnight serum cortisol or dexamethasone–CRH test. Patients with concordant abnormal results should undergo testing for the cause of Cushing syndrome. Patients with normal concordant test should not undergo further evaluation. There is loss of diurnal variation of cortisol. High concentrations of circulating ACTH are indicated by urinary cortisol more than 275 nmol/L per 24 h and failure to suppress to less than 138 nmol/L following an oral dexamethasone 1 mg the night before sampling. Plasma ACTH concentrations should be measured in such situations. An undetectable ACTH is suggestive of adrenal mass; concentrations between 10 and 100 ng/L suggest pituitary-dependent disease, while concentration greater than 200 ng/L indicates ectopic ACTH-secreting tumor. An exaggerated secretary response to CRH administration suggests pituitary tumor, whereas a low or absent response suggests adrenal or ectopic ACTH disease. The high-dose dexamethasone suppression test involves giving dexamethasone 2 mg every 6 h for 48 h. Pituitary-dependent Cushing syndrome usually responds with decrease in both early morning plasma cortisol and urinary free cortisol concentrations on the second day. Inferior petrosal sinus (IPS) sampling to measure ACTH concentrations following CRH stimulation is the final confirmatory test for pituitary Cushing disease. A raised ACTH level in a sample from this sinus (compared to periphery) is suggestive of Cushing disease. Bilateral IPS sampling in the diagnosis of Cushing disease is increasingly becoming the gold standard method. To interpret the results, the ratio of IPS/peripheral ACTH level is calculated. Baseline IPS/peripheral ACTH level more than 2 or CRH (1 μg/kg) stimulated ratio more than 3 confirms pituitary Cushing syndrome.

Treatment : Surgery is the cornerstone of treatment and is curative in 80%. Pretreatment with metyrapone or betakenazole reverses the side effects of increased levels of plasma cortisol, thereby decreasing the perioperative complications. In children, pituitary radiotherapy and adrenalectomy are very effective.

Nonfunctioning Tumors

Nonfunctional (null cell) adenomas are the second most common type of pituitary tumors, accounting for 20–25% of them. They compress the gland tissue and cause hypopituitarism. These patients present with either visual disturbances caused by optic chiasm compression or headache from raised ICP. In the absence of any signs or symptoms of pressure effects, patients are reviewed at regular intervals. Whenever the tumor grows in size and causes vision deterioration or other symptoms, surgical decompression is indicated. They must be screened for hypopituitarism with associated hypothyroidism and adrenal insufficiency. Gonadotropin function is lost first, followed by loss of GH function, then loss of thyroid function, and finally loss of ACTH function. Loss of ADH function almost never occurs.

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