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The Pituitary Gland and Associated Pathologic States
The pituitary is often referred to as the “master” hormonal gland because of the innumerable influences it exerts over physiologic homeostasis. It is located in the sella turcica, a bony cavity at the base of the skull in close proximity to the undersurface of the brain. Pituita , latin for phlegm, was the source of the name of the pituitary gland, implying early perceptions of its function. Its true function became apparent when acromegaly was linked to the gland by Harvey Cushing in his 1912 treatise, “The pituitary gland and its disorders”.
The anatomy and physiology of the pituitary gland
Neurodevelopment
The pituitary gland, also known as the hypophysis, is composed of three substructures at maturity, namely, the anterior, intermediate, and posterior lobes. The intermediate lobe is morphologically distinct from the anterior and posterior lobes but its function is uncertain. The anterior and posterior lobes are derived from two distinct embryological structures, Rathke’s pouch and the infundibular process respectively. Rathke’s pouch is a cephalad evagination of the stomodeal ectoderm, which will later become the pharynx. The infundibular process is a caudad evagination of the floor of the portion of the diencephalon that will eventually form the hypothalamus. These two structures, Rathke’s pouch and the infundibular process, begin to come together in approximately the 4th week of gestation. With maturity, Rathke’s pouch follows the infundibular process into the intracranial cavity and these two structures merge to give rise to the mature pituitary gland. The mature pituitary gland is anatomically distinct from the brain and is connected to it by the infundibular process (the pituitary stalk). The histology of the two lobes of the mature pituitary gland reflects their embryological origins. The anterior pituitary (adenohypophysis) consists of glandular tissue while the posterior pituitary gland (neurohypophysis) is neural in character. The cells in the anterior pituitary are those that ultimately manufacture and secrete the critical trophic hormones responsible for growth, development and the maintenance of homeostasis. They are, therefore, active early in gestation. Biologically active follicular stimulating hormone (FSH) and luteinizing hormone (LH) has been detected in fetuses at 14 weeks, and biologically active thyroid stimulating hormone (TSH) at 17 weeks.
The Anatomy of the Adult Pituitary Gland
The pituitary gland weighs about 0.5 to 1 g and is approximately 1 cm in horizontal diameter in normal adults. The vertical dimension of the gland varies with age and physiologic status, but is normally less than 8 mm. The gland tends to be the greatest in height between the ages of 10 and 29 years in both sexes and in females there is another increase in height in the fifth decade of life. There is normal physiologic enlargement during the teenage years and pregnancy when it can exceed 10 mm in height.
The anterior pituitary gland makes up 75% of the gland and is the most common site of origin of pituitary adenomas. There is a small intermediate lobe, the function of which is not well established. However, it is often the location of Rathke’s pouch cysts and craniopharyngiomas. The posterior pituitary, which includes the pituitary stalk, is an extension of the hypothalamus. Lesions of the posterior pituitary are rare.
The pituitary gland resides in the sella turcica, a saddle-like structure in the superior aspect of the sphenoid bone. Its location in the roof of the sphenoid sinus has made it amenable to surgical approaches through that sinus. Since the sella turcica is a component of the skull, it is lined and enclosed by the dura. Superiorly, a reflection of the dura forms the diaphragma sella, effectively forming a dural sac in which the gland is encased. A small opening in the diaphragma sella accommodates the pituitary stalk, allowing communication between the hypothalamus and the posterior pituitary lobe. The sella is bordered laterally by the cavernous sinuses, which are venous sinuses entirely enclosed by dura. Within these sinuses are the carotid arteries and cranial nerves III, IV, VI, V 1 and V 2 ( Fig. 27.1 ). Communications between the cavernous sinuses are variably found in the dura lining the anterior wall and floor of the sella. Dural communications across the anterior surface of the pituitary sometimes complicate transsphenoidal access to the gland. Beyond the confines of the sella are structures that are essential to the genesis of symptoms from pituitary tumors. These structures must be taken into consideration in the surgical treatment of pituitary diseases. Superiorly, the subarachnoid space sits directly on the diaphragma sella. Within this latter space are the optic nerves and chiasm, which can be impinged upon should a pituitary tumor extend superiorly into the intracranial cavity. In the event that the opening in the diaphragma sella is larger than the diameter of the pituitary stalk, the subarachnoid space will extend to and make direct contact with the superior surface of the pituitary gland or tumors arising from it. In this circumstance, vigorous removal of a pituitary adenoma can lead to tearing of the thin arachnoid membrane and subsequent cerebrospinal fluid leak into the nasal cavity (CSF rhinorrhea). The sella is bordered posteriorly by the basilar sinus and the interpeduncular/prepontine cisterns, in which reside the basilar artery and the brainstem. The venous system of the skull base surrounds the pituitary gland and is important in the surgical approach.
The blood supply to the anterior and posterior pituitary gland is provided by the superior hypophyseal arteries, which branch off of the internal carotid arteries within the cavernous sinus. In addition, a portal circulation system allows for humoral communication between the hypothalamus and the anterior pituitary ( Fig. 27.2 ). This portal system is essential for the multiple feedback loops between the hypothalamus and the anterior pituitary. Sensors reside in the hypothalamus to detect the levels of the end organ hormones (e.g., thyroid hormone, cortisol). Depending on whether the end organ hormone is above or below physiologic levels, releasing or inhibitory factors are manufactured and released by specific cells in the hypothalamus. These factors then enter the portal circulation in the hypothalamus and are carried to the anterior pituitary. At the anterior pituitary, these releasing or inhibitory factors in turn act on the respective trophic hormone producing cells to stimulate or inhibit the release of trophic hormones (e.g., TSH, ACTH). These trophic hormones then enter the general circulation to influence the function of the end organs, for example, the thyroid and adrenal glands. The intricate portal vasculature thereby allows minute amounts of factors secreted by the hypothalamus to achieve precise control of hormone secretion by the target endocrine glands. There is a substantial reserve in the function of the pituitary gland. Ten percent of the gland is normally sufficient for the maintenance of endocrine homeostasis.
Radiologic Examination
The pituitary gland is effectively imaged with magnetic resonance imaging (MRI) with and without gadolinium. The anterior pituitary gland is isointense on T1 weighted imaging and the posterior pituitary is hyperintense. With contrast, the anterior lobe becomes brightly enhanced probably as a result of the lack of a “blood–brain barrier”. Evaluation of pituitary adenomas should entail studies with contrast enhancement. Microadenomas are small tumors residing entirely within the substance of the gland. These tumors appear as “punched out lesions” on contrast enhanced MRI scans in which normal gland is brightly enhanced while the tumor appears markedly “underenhanced”. In intermediate sized tumors, which often occupy the entire confines of the sella, enhancement of the tumor appears to increase. The normal gland is often visualized as a crescent at the periphery of the tumor ( Fig. 27.3B ). With large tumors extending into the intracranial cavity, tumor enhancement is increased but is often not homogeneous.
Diseases of the sellar and parasellar regions
Pathologic processes within the sella include various pituitary tumors, craniopharyngiomas, and Rathke’s pouch cysts.
Pituitary Tumors
Pituitary tumors are classified functionally into two categories – nonfunctional and functional tumors. The majority of tumors are nonfunctioning (nonsecretory) adenomas. Tumors that oversecrete a specific trophic hormone are considered functional tumors and they lead to distinct hormonal syndromes. Pituitary tumors are also classified according to size as macroadenomas (> 1 cm) or microadenomas (< 1 cm). The vast majority of pituitary tumors are benign. Pituitary cancers are distinctly rare.
Nonfunctional Pituitary Tumors
Nonfunctional pituitary tumors arise from the growth of transformed cells of the anterior pituitary. These tumors do not secrete any trophic hormones in excessive amounts. Hence, their manifestations are anatomic. As the tumor increases in size, surrounding structures are compressed. Within the sella, the normal gland is compressed and displaced around the tumor mass. This is generally well tolerated until more than 90% of the gland is rendered nonfunctional. In this event, a hypopituitary state ensues. In the female, this is manifested early with abnormalities of menstruation. In the male, a loss of libido occurs.
Growth generally follows the path of lowest structural resistance. Extension superiorly is common since the aperture in the diaphragma sella is frequently incompetent (i.e., it is larger than the diameter of the pituitary stalk). As the tumor extends superiorly above the diaphragma sella, it first occupies the subarachnoid space that separates the diaphragma from the optic nerves/chiasm. With continued growth, the optic structures are elevated and compressed leading to visual field defects. Bitemporal field cuts are the most common since the majority of optic chiasm resides directly above the sella. Variations of the optic structures do exist. These may lead to the observation of monocular or homonymous field defects from compression of the optic nerve and tract respectively.
Lateral extension of a pituitary tumor into the cavernous sinuses is typically well tolerated and seldom leads to clinical symptoms. Tumor may abut the carotid artery but actual invasion of that vessel is rare. This is presumed to be due to the slow growth and typically nonmalignant nature of these tumors. Inferior extension into the sphenoid sinus also occurs from erosion of the floor of the sella. These are seldom symptomatic as the tumor fills out the sphenoid sinus and is usually discovered before it erodes into the pharynx.
Hypersecretory Pituitary Adenomas
While the majority of tumors are nonfunctional, some secrete specific hormones in excessive amounts leading to specific clinical syndromes. These are classified as hypersecretory pituitary adenomas.
Cushing’s Disease
Cushing’s disease is a condition of glucocorticoid excess/hypercortisolism (Cushing’s syndrome) caused by excessive secretion of adrenocorticotropic hormone (ACTH) from a tumor in the anterior pituitary gland. This leads to diffuse hyperplasia of the adrenal glands. Because of high cortisol levels, endogenous ACTH secretion by nonadenomatous cells is suppressed. ACTH secreting adenomas comprise about 1–2% of all pituitary adenomas and are seen mostly in females (8:1 female to male ratio) with a peak incidence in the third and fourth decades of life. The clinical characteristics include central obesity with moon facies but sparing of the limbs, dorsocervical and supraclavicular fat pad engorgement, red-purple striae, thin fragile skin, hirsutism, easy bruising, acne, proximal myopathy, hypertension, impaired glucose tolerance, insulin resistance, osteopenia, amenorrhea, decreased libido, sexual dysfunction, psychiatric abnormalities ranging from depression and lethargy to paranoia and psychosis, and recurrent superficial fungal skin infections. Other findings may include hypokalemic alkalosis (in about 10–15% of patients), hyperlipidemia, and increased intraocular pressure and/or exophthalmos. The clinical diagnosis is confirmed using one or more of the following tests: late night salivary cortisol levels, low-dose and high dose dexamethasone suppression test, urinary free cortisol, serum ACTH levels and if necessary inferior petrosal sinus sampling to verify the location of ACTH secretion. As the duration of hypercortisolism increases, so does the risk of mortality for the patient; aggressive treatment is therefore indicated. Tumor resection is the first line treatment with success rates ranging from 69% to 98%. Although most adenomas that cause Cushing’s disease are noninvasive in nature, the relatively uncommon Crooke’s cell tumors are more invasive and often difficult to resect.
Acromegaly
The incidence of acromegaly is 3–4 cases per million per year. This condition results from the overproduction of growth hormone (GH) from an anterior pituitary adenoma. The GH in turn stimulates the overproduction of insulin-like growth factor 1 (ILGF-1) from the liver. This leads to enlargement of acral, that is, the hands and feet, and other parts of the body. In addition, there is enlargement of the heart and vasculature. The clinical characteristics include features such as hypertension, diabetes mellitus, obstructive sleep apnea, mandibular hypertrophy, facial hyperostosis and skin thickening. The diagnosis of acromegaly is based on clinical findings as well as laboratory tests including serum GH, glucose tolerance test, serum ILGF-1, and MRI findings. Laboratory findings indicative of active disease are: random GH ≥ 1 ng/mL; nadir GH after oral glucose tolerance test ≥ 0.4 ng/mL; and elevated ILGF-1 for age. Since acromegaly is associated with increased mortality, aggressive treatment is warranted, usually including surgical excision of the adenoma.
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