Overview
The pituitary gland is a pea-sized endocrine gland that sits at the base of the brain. Often referred to as the “master gland”, the pituitary gland synthesizes and releases various hormones that affect several organs throughout the body (see the images below).
Embryologic development
The pituitary gland is entirely ectodermal in origin but is composed of 2 functionally distinct structures that differ in embryologic development and anatomy: the adenohypophysis (anterior pituitary) and the neurohypophysis (posterior pituitary).
The adenohypophysis develops from Rathke’s pouch, which is an upward invagination of oral ectoderm from the roof of the stomodeum; in contrast, the neurohypophysis develops from the infundibulum, which is a downward extension of neural ectoderm from the floor of the diencephalon (see the image below). The oral ectoderm and neural ectoderm that form the pituitary anlagen are in close contact during early embryogenesis, and this connection is critical for pituitary development. [2, 3]
Development of pituitary gland. A: Infundibulum and Rathke's pouch develop from neural ectoderm and oral ectoderm, respectively. B: Rathke's pouch constricts at base. C: Rathke's pouch completely separates from oral epithelium. D: Adenohypophysis is formed by development of pars distalis, pars tuberalis, and pars intermedia; neurohypophysis is formed by development of pars nervosa, infundibular stem, and median eminence.
Over several weeks, Rathke’s pouch undergoes constriction at its base until it completely separates from the oral epithelium and nears its final position as the adenohypophysis. [4]
The transition from Rathke’s pouch to the adenohypophysis involves the formation of the pars distalis from the rapidly proliferating anterior wall, the pars intermedia from the less active posterior wall, and the pars tuberalis from an upward outgrowth of the anterior wall. The incomplete obliteration of Rathke’s pouch can lead to remnants that form Rathke’s cleft cysts.
The neurohypophysis develops from the differentiation of neural ectoderm into the pars nervosa, the infundibular stem, and the median eminence. The infundibular stem is surrounded by the pars tuberalis.
Gross Anatomy
The fully developed pituitary gland (see the image below) is pea-sized and weighs approximately 0.5 g. The adenohypophysis constitutes roughly 80% of the pituitary and manufactures an array of peptide hormones. The release of these pituitary hormones is mediated by hypothalamic neurohormones that are secreted from the median eminence (a site where axon terminals emanate from the hypothalamus) and that reach the adenohypophysis via a portal venous system.
Unlike the adenohypophysis, the neurohypophysis is not glandular and does not synthesize hormones. Instead, it is a site where axons project from neuronal cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus. These hypothalamic cell bodies produce hormones that undergo axonal transport through the pituitary stalk and into terminal axons within the neurohypophysis. The hormones are then stored and released directly into the systemic vasculature.
The pituitary gland is enveloped by dura and sits within the sella turcica of the sphenoid bone. The sella turcica is a saddle-shaped depression that surrounds the inferior, anterior, and posterior aspects of the pituitary. The superior aspect of the pituitary is covered by the diaphragma sellae, which is a fold of dura mater that separates the cerebrospinal fluid–filled subarachnoid space from the pituitary. The infundibulum pierces the diaphragma sellae in order to connect the pituitary to the hypothalamus.
The lateral aspects of the pituitary are adjacent to the cavernous sinuses (see the image below). From superior to inferior, the cavernous sinus contains cranial nerves III (oculomotor), IV (trochlear), VI (abducens), V1 (ophthalmic branch of trigeminal nerve), and V2 (maxillary branch of trigeminal nerve). The internal carotid artery also courses through the cavernous sinus, medial to these nerves.
Coronal depiction of pituitary gland and surrounding structures. Lateral aspects of pituitary gland are in close proximity to internal carotid artery and several cranial nerves.
Different pneumatization patterns of the sphenoid sinus (conchal, presellar, sellar, and postsellar) describe the location of the sphenoid sinus relative to the sella turcica and thus dictate the extent of exposure of the sellar floor. In the conchal type, pneumatization is absent, and thus the sphenoid sinus does not contain an air cavity. In the presellar type, there is minimal posterior extension of an air cavity, whereas in the postsellar type, there is posterior extension of an air cavity past the level of the sella turcica.
Vasculature
The adenohypophysis receives the majority of its blood supply from the paired superior hypophyseal arteries, which arise from the medial aspect of the internal carotid artery, within the ophthalmic segment. The superior hypophyseal artery commonly emerges within 5 mm distal to the origin of the ophthalmic artery [5] and eventually forms the primary capillary network found in the median eminence.
The neurohypophysis is supplied by the inferior hypophyseal arteries (see the image below). These vessels are terminal branches of the meningohypophyseal trunk, which arises from the cavernous portion of the internal carotid artery. [6]
Vasculature of pituitary gland. Adenohypophysis and neurohypophysis receive majority of their blood supply from superior hypophyseal arteries and inferior hypophyseal arteries, respectively.
The hypophyseal portal veins drain the primary capillary plexus formed by the superior hypophyseal arteries, which deliver blood to the pars distalis. The pars distalis in turn houses the secondary capillary plexus. Thus, a portal venous system allows delivery of hypothalamic prohormones to the adenohypophysis, and the neurohypophysis secretes hormones directly into the venous draining system of the pituitary.
Microscopic Anatomy
The pars distalis forms the majority of the adenohypophysis and resembles a typical endocrine gland. Cords and clusters of cuboidal secretory cells within the pars distalis contain hormones stored in cytoplasmic granules that are released via exocytosis and taken up by nearby sinusoidal capillaries. Histochemical staining of these granules with pH-dependent dyes allows categorization of the cells into acidophils, basophils, or chromophobes.
In general, acidophilic cells contain polypeptide hormones, basophilic cells contain glycoprotein hormones, and chromophobes have minimal to no hormone content. The most common cell type is the acidophilic somatotrope, which is concentrated in the lateral regions of the adenohypophysis and secretes growth hormone (GH). Lactotropes are also acidophilic but are more scattered throughout the adenohypophysis and secrete prolactin (PRL).
The basophilic cells include corticotropes, thyrotropes, and gonadotropes. Although corticotropes secrete nonglycosylated polypeptides such as adrenocorticotropic hormone (ACTH), these cells are basophilic as a result of the glycoprotein composition of the precursor hormone pro-opiomelanocortin (POMC). Thyrotropes are among the least prevalent secretory cells of the pars distalis; they release thyroid-stimulating hormone (TSH), whereas gonadotropes secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
There is growing evidence that the various hormones released by the pars distalis are not restricted to synthesis by a single secretory cell type, as classically described. [7, 8] In particular, thyrotropes have been shown to have a significantly mixed phenotype that contains several hormones, including a high percentage of LH and PRL. [9] In addition, pituitary secretory cells have been shown to be multiresponsive and thus capable of releasing hormones in response to a noncorresponding hypothalamic releasing hormone. [10]
The pars intermedia of the adenohypophysis lies between the pars distalis and the pars nervosa of the neurohypophysis. In humans, this region is not well developed and has poor vascularization. Although secretory cells within the pars intermedia, like the corticotropes of the pars distalis, produce POMC, the principal hormones synthesized by the pars intermedia include melanocyte-stimulating hormone (MSH) and ß-endorphin. [11, 12]
The pars tuberalis is a thin, highly vascularized component of the adenohypophysis that surrounds the infundibular stem. The principal secretory cell type within this tissue is the gonadotrope, which contains FSH and LH. [13, 14, 15] In addition, melatonin receptors exist within the pars tuberalis that may play a role in rhythmic gene expression. [16, 17, 18, 19]
The pars nervosa of the neurohypophysis contains unmyelinated axons that project from neuronal cell bodies in the hypothalamus. Oxytocin and antidiuretic hormone (ADH) synthesized in the cell bodies are transported via the axons and accumulate at the terminal ends within swellings called Herring bodies. A network of capillaries surrounds the axon terminals and facilitates the uptake of released hormones into the vasculature.
Specialized glial cells known as pituicytes are also interspersed within the pars nervosa and have been hypothesized to actively participate in the modulation of hormone release. [20]
Pathophysiologic Variants
Pituitary tumors are relatively common, accounting for about 15% of all primary brain tumors. [21] The vast majority originate in the adenohypophysis and are typically nonsecretory benign adenomas. These adenomas frequently go undiagnosed, and meta-analyses of postmortem studies have demonstrated an 11-14% overall prevalence of silent pituitary adenomas in the general population. [22, 23] Tumors of the neurohypophysis are rare and include metastasis, granular cell tumors, and potentially any primary tumor of the neuraxis.
Pituitary adenomas are arbitrarily classified as microadenomas (< 1 cm) or macroadenomas (> 1 cm). Macroadenomas, when large, have a mass effect on adjacent structures, with clinical consequences. Compression of the pituitary gland itself may cause hypopituitarism, and compression of the optic chiasm results in bitemporal hemianopsia. Headache is also a common symptom of pituitary tumors.
Secretory adenomas are typically monoclonal--that is, they secrete a single hormone. Approximately 1 to 2% of adenomas secrete 2 or more hormones, with growth hormone (GH) and prolactin (PRL) being the hormones most commonly elevated concomitantly. [28, 29]
Prolactinomas are the most common secretory adenomas. [24] Even small microadenomas can involve secretion sufficient to produce symptoms, but there is also a direct correlation between the tumor mass of prolactinomas and hormone production. [25] Although prolactinomas classically present with galactorrhea, this symptom is not always present.
GH-secreting adenomas are next most common adenomas, followed by adrenocorticotropic hormone (ACTH)-secreting tumors and gonadotroph adenomas (tumors that secrete luteinizing hormone [LH] and follicle-stimulating hormone [FSH]); thyrotroph tumors account for fewer than 1% of pituitary adenomas. Pituitary carcinomas are quite rare, requiring the demonstration of metastasis for diagnosis. [26, 27]
Macroadenomas, particularly those with suprasellar extension, and head trauma may cause hyperprolactinemia unrelated to prolactinoma. Normally, dopamine is secreted by the hypothalamus and is transported via the pituitary stalk to the adenohypophysis, where it inhibits the high basal secretory rate of the pituitary lactotrophs. When tumors grow large enough, a “stalk effect” occurs, and this transport is disrupted. As a result, prolactin secretion is no longer inhibited appropriately, and pituitary lactotroph hyperplasia develops.
Remnants of Rathke’s pouch have the potential to produce signs and symptoms associated with mass effect. Although commonly asymptomatic, Rathke’s cleft cysts can accumulate proteinaceous fluid and subsequently expand, compressing nearby structures. Vestigial remnants of Rathke’s pouch can also form craniopharyngiomas, slow-growing benign tumors that most often present in either the very young or the very old.
Although craniopharyngiomas can be encapsulated and solid, they are often cystic and multiloculated. The adamantinomatous form frequently contains calcifications and projects into adjacent brain tissue, eliciting an intense inflammatory reaction. It is often filled with a rich, cholesterol-containing cystic fluid. The papillary form lacks calcification, keratin, and cysts and therefore is much more amenable to surgical resection.
Inflammatory conditions can affect the pituitary but are rare. Lymphocytic hypophysitis is a primary inflammatory disorder that typically presents during or shortly after pregnancy. [30] Although of unknown etiology, lymphocytic hypophysitis is believed to be caused by an autoimmune process.
Sarcoidosis, a systemic inflammatory disease, is characterized by noncaseating granulomas that can affect any organ system. Sarcoidosis can be differentiated from infectious processes such as tuberculosis and syphilis by means of hypersensitivity skin testing, serology, and stains and cultures. In addition, granulomas formed as a result of infectious disease are more commonly associated with necrosis.
Empty sella syndrome describes a sella turcica that appears to be empty on radiologic imaging as a consequence of a shrunken or flattened pituitary gland. Primary empty sella syndrome is thought to result from chronic intracranial hypertension with a defect in the diaphragma sella that allows intradural contents to herniate into the sella, compressing the pituitary and resulting in endocrine abnormalities and even visual symptoms from mass effect. This condition is most commonly seen in obese women with a history of multiple pregnancies.
Secondary empty sella syndrome results from either iatrogenic treatment of a sellar mass or spontaneous (typically ischemic) necrosis of such a mass. Hypopituitarism can be seen in both primary and secondary empty sella syndrome.
The most common genetic disorder to affect the pituitary is multiple endocrine neoplasia-1 (MEN-1), characterized by neoplasms of the pituitary, parathyroid, and pancreas. Additional genetic causes of disease include mutations in pit-1, a pituitary transcription factor whose loss results in concomitant deficiencies of GH, PRL, and thyroid-stimulating hormone (TSH).
Sheehan syndrome, also referred to as postpartum hypopituitarism, is attributed to infarction of the pituitary gland caused by hypovolemia from obstetric hemorrhage. The first clinical manifestation of the syndrome is typically the absence of milk production during the postpartum period. Multiple hormone deficiencies are common, and pituitary function can decline further over time. [31]
Pituitary apoplexy is a potentially life-threatening syndrome that occurs as a result of hemorrhage, infarction, or hemorrhagic infarction within a pituitary tumor. [32] The pressure resulting from edema and the accumulation of blood compresses adjacent structures and leads to symptoms that include sudden onset of visual dysfunction, severe headache, and pituitary insufficiency. This syndrome is a neurosurgical emergency that calls for immediate treatment.
Other Considerations
Diagnostic imaging
Magnetic resonance imaging (MRI) is the study of choice for evaluating the pituitary gland. [33, 34] This multiplanar imaging modality has the advantages of providing superior contrast differentiation of soft tissues and not exposing the subject to potentially harmful ionizing radiation. Coronal and sagittal T1-weighted sequences with 3 mm thick sections are typically recommended for detecting pituitary lesions. [35, 36] As a supplement, T2-weighted images are often useful.
Hyperintense signals on T1-weighted images can be due to numerous disease processes, such as hemorrhage, Rathke’s cleft cyst, and craniopharyngioma. However, several normal conditions, such as vasopressin storage in the posterior lobe, can also present as hyperintensities. [37] Microadenomas commonly appear hypointense on noncontrast T1-weighted images but can occasionally appear isointense.
The sensitivity of lesion detection with MRI can be improved by repeating T1-weighted sequences after administration of a gadolinium-containing contrast agent. [38] Although a single dose (0.1 mmol/kg) of gadolinium (Magnevist, Berlex, Wayne, NJ) is effective, a half dose and a double dose have also been demonstrated to be advantageous. [39, 40, 41]
In the setting of an intact blood-brain barrier, the normal pituitary gland and infundibulum present with homogeneous contrast enhancement, whereas the hypothalamus and optic chiasm remain unaffected. Because of temporal variations in the enhancement patterns of lesions, dynamic MRI after intravenous (IV) gadolinium bolus injection can potentially provide additional valuable information. [42]
Computed tomography (CT) is useful as an adjunct to MRI when increased detail of bone structure is required. CT is superior in demonstrating erosions of bone and calcifications and can also be used in evaluating bone anatomy before transsphenoidal surgery. [43, 44] Furthermore, CT can detect many pituitary lesions and provides a reasonable screening method when MRI is not available.
Surgical approaches
Transsphenoidal surgery is currently the principal technique employed for resecting pituitary lesions within the sellar and parasellar region. This operative procedure commonly involves using an endonasal incision to create a route to the anterior wall of the sphenoid sinus. If greater exposure is required, a sublabial incision can be employed instead. Once the sphenoid bone is reached, it is fractured to provide entry into the sphenoid sinus. The sellar floor is then penetrated, and a durotomy is performed to provide an unobstructed view into the sellar region.
For more than half a century, the transsphenoidal approach has been coupled with the operative microscope to enhance visualization of the surgical field. However, the relatively recent development of endoscopic transnasal transsphenoidal techniques offers a significant advance from microscopic methods.
Since the initial reports of endoscopic pituitary surgery by Jho and Carrau (1996) [45] and Cappabianca et al (1998) [46] , this technique has been disseminated worldwide, it now represents the most frequently utilized surgical approach to the sella. The advantages of the endoscopic technique include increased patient comfort, decreased use of nasal packing, and decreased hospital stay. [47, 48] In addition, with the use of angled endoscopes, this technique permits a wider panoramic view of the surgical field. [49]
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Pituitary gland, sagittal section.
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Hormones secreted by adenohypophysis (anterior pituitary).
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Hormones secreted by neurohypophysis (posterior pituitary).
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Development of pituitary gland. A: Infundibulum and Rathke's pouch develop from neural ectoderm and oral ectoderm, respectively. B: Rathke's pouch constricts at base. C: Rathke's pouch completely separates from oral epithelium. D: Adenohypophysis is formed by development of pars distalis, pars tuberalis, and pars intermedia; neurohypophysis is formed by development of pars nervosa, infundibular stem, and median eminence.
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Coronal depiction of pituitary gland and surrounding structures. Lateral aspects of pituitary gland are in close proximity to internal carotid artery and several cranial nerves.
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Vasculature of pituitary gland. Adenohypophysis and neurohypophysis receive majority of their blood supply from superior hypophyseal arteries and inferior hypophyseal arteries, respectively.
