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.

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.

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.

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.

Empty Sella Syndrome

In this rare condition, there is downward prolapse of arachnoid into sella through the diaphragm. There does not exist any tumor, but sella is enlarged by CSF pressure and the pituitary gland gets compressed against the posterior wall of sella, thereby resulting in panhypopituitarism. This condition is more commonly seen in obese, hypertensive females and may be associated with benign intracranial hypertension. In them the pituitary gland seems to be missing or it assumes the shape of the sella. It may result from secondary to certain conditions causing gland regression like head trauma or radiation therapy. Patient may be asymptomatic or may complain of impotence and reduced libido, and in females, there may be menstrual irregularities.

Acromegaly

Excessive GH secretion also results in overgrowth of the soft tissues of the oral cavity, and laryngeal muscles and hypertrophy of the facial bones, especially the mandible. There is also hypertrophy of the soft tissues of nose, tongue, and lips. As a result, patient develops macroglossia and prognathism and malocclusion. Hypertrophy of pharyngeal and laryngeal soft tissues leads to reduction in the size of glottis opening, hypertrophy of the periepiglottic folds, calcinosis of the larynx, and recurrent laryngeal nerve injury. All these changes can contribute to airway obstruction and respiratory disease. Respiratory disease is the second commonest cause of death (after cardiovascular morbidity) in untreated acromegaly. Hoarseness is a sign of the possibility of laryngeal stenosis or recurrent laryngeal nerve damage. Approximately 25% of them have goiter enlargement, which may compress the trachea. Acromegaly is a well-known cause of difficult airway management and tracheal intubation. Careful airway assessment using conventional criteria should be performed. Indirect laryngoscopy, soft tissue X-ray of the neck, and flow volume studies may also be helpful. Obstructive sleep apnea (OSA) secondary to upper airway obstruction is present in 70% males and 25% females. However, central sleep apnea may also occur in them. The abnormal nocturnal breathing of acromegaly may persist even after adenoma excision. Vocal cords may become normal within 10 days of successful surgery. In acromegaly complicated by the OSA, there is a high risk of compromised airway. Therefore, narcotics and sedatives should be used with extreme caution in them.

Hypertension, which is seen in 30%, may be due to sodium-dependent mechanism, positive inotropic effect of IGF by sensitization of myocardium, and change in response of peripheral vasculature to angiotensin II. They may have myocardial hypertrophy and interstitial fibrosis. Left ventricular function fails to return to normal completely even after successful surgery in patients with long-standing disease and presence of interstitial fibrosis. Diabetes mellitus may be present in 25% of them.

Cushing Disease

Hypertension is a frequent occurrence in them, and 50% of untreated patients have diastolic pressure more than 100 mmHg. It is the result of enhanced rennin angiotensin activity and increased blood volume. High corticosteroids cause hypertension by increasing cardiac output as well as hepatic production of angiotensinogen. In addition, glucocorticoids increase the sodium influx into vascular smooth muscle cells and inhibit phospholipase A2, thereby reducing the synthesis of vasodilatory prostaglandins. They also increase the production of angiotensin II receptor and augment the inositol triphosphate production in vascular smooth muscle cells. This enhances sensitivity to endogenous vasoconstrictors such as angiotensin II, epinephrine, and norepinephrine. Sensitivity to exogenous catecholamine may also increase. They may also suppress nitric oxide. Various electrocardiographic (ECG) abnormalities, including high-voltage complexes, inverted T wave suggesting left ventricle hypertrophy, and strain may be seen. They revert to normal after surgery within 1 year. Very often they have asymmetrical interventricular septal hypertrophy on echocardiography with diastolic dysfunction. The echocardiographic changes too regress following successful surgery. They have high incidence of OSA, which may be severe in 18% of them. Overt diabetes mellitus or glucose intolerance due to decreased insulin secretion is seen in 60% of them.

They may have exophthalmos due to retro-orbital fat deposition. Therefore, care should be taken to prevent corneal injury. Hypercortisolism causes thinning as well as easy bruising of the skin, thereby making venous cannulation difficult. They have myopathy of leg muscles and of the shoulder girdle, but data on their susceptibility to muscle relaxants is lacking. High levels of glucocorticoids cause immune suppression and osteoporosis predisposing them to pathological fractures. Therefore, precaution should be taken during positioning. Obesity and gastroesophageal reflux is common in them, therefore they should be prescribed H2 blocker in premedication.

Nelson Syndrome

It is an iatrogenic, potentially life-threatening condition that results following treatment of Cushing disease by total bilateral adrenalectomy (TBA). The syndrome can develop up to 24 years, with mean development at 15 years after TBA The clinical features relate to the local pressure effects of tumor on surrounding structures with secondary deficiency of other pituitary hormones, and effects of the high serum concentrations of ACTH on the skin. Nearly all the cases result following bilateral adrenalectomy in patients with Cushing disease due to ACTH-secreting pituitary adenoma. The availability of sensitive ACTH assay and high-resolution MRI has allowed for detection of microadenomas at an early stage of Nelson syndrome. Most adenomatous corticotrophs still retain their responsiveness to CRH. Subsequent to bilateral adrenalectomy and normalization of cortisol levels that had suppressed hypothalamus CRH production, elevation in CRH occurs, which has a trophic effect on the tumor, stimulating its growth.