Anterior Pituitary

The Pituitary Axis

The pituitary gland secretes adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and growth hormone, largely regulated by signals from the hypothalamus ( Chapter 204 ), and it also secretes prolactin, largely regulated by dopamine as well as by thyrotropin-releasing hormone (see Fig. 205-1 ). The multitude of effects that the hormones of the pituitary have on the physiology and metabolism of the entire body provides exquisite control of hormone secretion regulated via multiple feedback loops and stimuli, not only from the hypothalamus, but also from higher in the brain and in the environment. All pituitary hormones are regulated and secreted with a highly reproducible diurnal variation and with superimposed episodic secretion throughout the day and night and influenced by sleep and wakefulness ( Chapter 204 ). Therefore, measurement of hormone levels must account for the episodic secretion of the hormones, and a single point in time may not reflect the overall activity of the axis. For example, the stress and pain (although minimal) of phlebotomy itself can be sufficient to cause an increase in prolactin and cortisol.

One example of axis regulation is the release of thyroid hormone from the thyroid under the control of thyroid-stimulating hormone from the pituitary thyrotrophs. The more TSH stimulates the TSH receptors on the thyroid cells (thyrocytes), the more thyroid hormone is released. The thyroid hormone then feeds back to the pituitary to downregulate further secretion of TSH, which then turns off thyroid hormone release from the thyrocytes. Superimposed on this process is the hypothalamus, which secretes TRH (thyrotropin-releasing hormone) and stimulates the release of TSH. However, thyroid hormone also provides feedback to the hypothalamus and, independent of TSH, turns off TRH secretion. Therefore the pituitary’s thyrotrophs need to integrate the positive stimulation of TRH and at the same time the inhibition by the thyroid hormone levels in order to modulate the level of TSH release. The story is still not complete, because dopamine and other neurotransmitters from centers in the brain above the hypothalamus can stimulate and inhibit TRH, thereby providing an additional level of control over thyroid hormone secretion. Similar multilevel feedback control mechanisms can be described for cortisol from the adrenal gland as well as other pituitary hormones such as the gonadotropins, prolactin, and growth hormone. Understanding the basis for hypothalamic-pituitary-target endocrine gland axis regulation is essential for the diagnosis of abnormalities at specific levels of the axis as interpreted from provocative and suppressive tests used clinically to assess the pituitary axes.

Epidemiology and Pathobiology

Hypopituitarism is a deficiency of one or more pituitary hormones. The prevalence is between 290 and 455 cases per million, with an incidence of 42 cases per million per year. Hypopituitarism can be congenital (with known and unknown genetic causes) and acquired ( Table 205-1 ). Panhypopituitarism refers to a defect in all pituitary hormone lines.

The most common cause of hypopituitarism is a tumor, specifically a macroadenoma in the sella. Tumor enlargement within the confines of the bony sella turcica can compress the normal pituitary cells, thereby resulting in their failure to function. Irradiation of the pituitary, pituitary infarction (such as Sheehan syndrome, which is caused by severe postpartum bleeding ), surgical intrusion, and infiltrative disease also can compromise normal pituitary functioning.

Genetic defects have been reported at every level of the hypothalamic pituitary axis, including defects in the hypothalamic factors, receptors for the hypothalamic factors, and the genes for the pituitary hormones. Defects in the genes coding for the specific hormone almost always result in a low serum concentration of the hormone.

Although congenital hypopituitarism may involve deficiency of a single or multiple pituitary hormones, acquired types of hypopituitarism usually simultaneously involve more than one of the pituitary hormones. Defects in genes encoding for factors such as the PIT1 and PROP1 genes may impair pituitary cell differentiation. Furthermore, the pituitary hormone receptor in the respective glands may be defective, thereby resulting in resistance to the action of the pituitary hormones. Finally, genetic defects in the gene coding for the hormone or the hormone’s receptor can result in profound hormone deficiency.

Functional causes of defective pituitary function can be seen in severe malnutrition ( Chapter 197 ), in anorexia nervosa ( Chapter 200 ), or in critically ill patients who are in a state of severe calorie deprivation. In these situations, central (hypothalamic and higher) mechanisms and molecular mediators (e.g., cachexins and tumor necrosis factor) inhibit the release of pituitary hormone. This form of hypopituitarism is generally reversible when the caloric situation improves.

Traumatic brain injury ( Chapter 368 ) is an increasingly recognized cause of hypopituitarianism. Deposition and infiltration of amyloid protein in amyloidosis ( Chapter 174 ), iron in hemochromatosis ( Chapter 196 ) or granulomas (in sarcoidosis [ Chapter 83 ], tuberculosis [ Chapter 299 ], or granulomatosis with polyangiitis [ Chapter 249 ]) also can cause hypopituitarism. Invasion of the hypothalamus and pituitary by histiocytosis ( Chapter 155 ) or metasteses from breast cancer, lung cancer, melanoma, and rarely, colon cancer can impair pituitary function. Hypopituitarism is also a rare complication of infection with human immunodeficiency virus (HIV) or severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).

In addition to congenital and acquired pituitary defects, hypopituitarism may result from a hypothalamic disorder ( Chapter 204 ). Concurrent diabetes insipidus, which is indicative of dysfunction of the posterior pituitary ( Chapter 206 ), usually suggests combined hypothalamic and pituitary defects. Hyperprolactinemia, which suggests interruption of the hypothalamic dopaminergic inhibition of prolactin, also can be a result of hypothalamic defects.

Clinical Manifestations

Congenital defects are usually noted soon after birth when an absent pituitary hormone results in growth retardation or failure to develop. Patients may also present with congenital failure of a specific pituitary function and manifest with early-onset growth defects, delayed puberty, or hypothyroidism.

Acquired hypopituitarism presents earlier in its course in women of reproductive age because any perturbation in the hypothalamic pituitary milieu will likely result in an abnormality of the menstrual cycle ( Chapter 218 ), which requires orchestration of multiple hormones that are exquisitely sensitive to changes in the pituitary hormones. By comparison, males of all ages and women of postreproductive age usually have hypopituitarism for several years before the diagnosis is made. In such patients, the symptoms can be nondescript (e.g., fatigue, decreased muscle strength and muscle mass, and increased body fat) and not appreciated for many years after the onset of hypopituitarism.

Although growth hormone deficiency can exist in up to 60% of patients with hypopituitarism, such deficiency in an adult is not likely to cause the same remarkable symptoms as the short stature that is seen in children. When multiple hormones are deficient, the manifestations in adulthood may be as subtle as skin changes, decreased sexual functioning, decreased muscle mass, and increased fat mass.

Diagnosis

Diagnosis of hypopituitarism in patients with secreting or nonsecreting pituitary masses usually involves a combination of static and stimulatory blood tests ( Table 205-2 ) beginning with morning fasting level of ACTH, TSH, FSH, LH, growth hormone, and prolactin. If multiple deficiencies are found, panhypopituitarism is likely. Isolated deficiencies in only one pituitary hormone can occur, but if two or more are deficient, it is likely that all are deficient. Testing ( Table 205-2 ) often depends on the age of the patient and the clinical setting. Oftentimes, no single gold-standard test is available for each hormone, so equivocal results on one test may require another test. For example, growth hormone reserve in children is usually best documented with an arginine stimulation test, whereas an insulin tolerance test would be more appropriate in an adult in whom the ACTH axis should be evaluated at the same time. Sometimes multiple tests may be performed if results of one test are equivocal.

The next diagnostic imperative is to image the pituitary to determine the cause. Magnetic resonance imaging (MRI) is the preferred radiologic method for anatomic definition of the pituitary and its surrounding structures. The normal pituitary is less than 1 cm in height, and a small tumor (microadenoma) can be as small as 1 mm, so high-quality imaging is necessary. Sagittal and coronal images are the most useful to obtain ( Fig. 205-2 ). Intravenous contrast can enhance MRI images because normal pituitary generally enhances more than tumors. When the use of a contrast agent is not contraindicated, T2 images may be helpful to distinguish normal pituitary from a tumor ( Fig. 205-3 ). In such cases, helical computed tomography (CT) also can be useful with noncontrast and immediate postcontrast imaging.

Treatment

Hypophysitis

Epidemiology and Pathobiology

Inflammation of the pituitary is known as hypophysitis and can be classified clinically as primary hypophysitis when isolated inflammation of the pituitary is not associated with other inflammatory conditions, infections, or medications, including checkpoint inhibitors. Lymphocytic hypophysitis, which is the most common form of this rare condition, occurs three times more frequently in women, typically in the fourth decade and often related to the end of pregnancy or the first few months after delivery. Lymphocytic hypophysitis is also seen in about 3 to 8% of patients treated with immune checkpoint inhibitors, specifically with the anti–CTLA-4 class of inhibitors, with peak onset at a median of 2.3 months after starting therapy. The other histologic types, granulomatous and xanthomatous hypophysitis, are not associated with pregnancy although they are more common in females. The least common form, plasmacytic or IgG4-related hypophysitis, occurs in males in a 2:1 ratio, usually presents in the seventh decade, and may include orbital inflammation, hypertrophic pachymeningitis, and central nervous system parenchymal disease.

Clinical Manifestations and Diagnosis

Patients with hypophysitis usually present with headaches and multiple deficiencies of anterior pituitary hormones. Diabetes insipidus ( Chapter 206 ) is reported in about 50% of patients, and most have associated mild hyperprolactinemia.

On MRI, hypophysitis usually causes diffuse pituitary enlargement and thickening of the midline stalk, with a normal sellar size, but MRI cannot reliably differentiate hypophysitis from a pituitary adenoma.

Definitive diagnosis is usually made by biopsy. A clinical diagnosis can, however, be inferred based on radiologic and clinical characteristics during or just after pregnancy or if there is a proximal history of use of anti–CTLA-4 agents several months prior to the onset of symptoms (headaches and weakness).

Treatment and Prognosis

Pituitary Apoplexy

The pituitary can be involved with hemorrhage, infarction, or both. When abrupt, and sometimes catastrophic, hemorrhagic infarction occurs in the pituitary, it is defined as apoplexy.

Epidemiology and Pathobiology

Certain conditions predispose a patient to pituitary apoplexy ( Table 205-4 ). Although all large pituitary tumors are at risk for hemorrhagic infarction, certain functional pituitary tumors, such as those in Cushing disease or acromegaly, may be particularly prone. In women who have microprolatinomas treated with dopamine agonists, stopping the agonist while pregnant can precipitate pituitary apoplexy. Nearly 25% of all patients with apoplexy have inadequately treated hypertension. The main symptoms and consequences of apoplexy are due to the increased pressure present within the bony walls of the sella turcica in which the pituitary resides. A sudden increase in the sellar contents, due to blood and edema, results in increased pressure. This increased pressure and meningeal irritation are responsible for the neurologic symptoms, including the increased pressure in the cavernous sinus and the cranial nerve palsies, as well as bitemporal hemianopsia. Extravasation of blood into the subarachnoid space causes meningeal irritation. Asymptomatic hemorrhage and infarction into a pituitary tumor can occur in 10 to 25% of patients, but true apoplexy occurs in only 2 to 10% of pituitary tumor patients.

Clinical Manifestations

The most common presenting complaint, headache, can present variably from retro-orbital to unilateral to bilateral temporal headaches during the acute phase of apoplexy. The constellation of headache, vomiting, visual impairment, and altered consciousness with hemodynamic instability is not specific for pituitary apoplexy but raises suspicion for the diagnosis ( Table 205-5 ). Often, this dramatic presentation is the first time the patient is aware of a potential pituitary tumor. As the hemorrhagic infarction resolves, the patient often is left with hypopituitarism.

Diagnosis

Prompt recognition of patients presenting with the triad of headache, vomiting, and visual disturbances is required to prevent death or irreversible neurologic impairment. Clinical evaluation of the patient should begin with a thorough history from the patient, if sufficiently conscious to give one, or from family members. A history of a pituitary tumor should raise the suspicion of apoplexy. More subtle abnormalities associated with pituitary dysfunction (hypofunctioning of thyroid, adrenal, or gonadal systems) may be helpful.

The cornerstone for diagnosis is urgent MRI T2-weighted images. A CT scan can be useful when an MRI is not available or possible.

Urgent measurement of blood chemistries, including electrolytes, kidney function, liver function, complete blood count with platelets, and prothrombin time, can be useful. Because more than 80% of patients will have endocrine dysfunction, urgent measurement of free T ₄ , TSH, prolactin, and random cortisol can be helpful. Less rapidly available and helpful (and less important in the initial diagnosis and management) are other pituitary hormones such as LH, FSH, estradiol or testosterone, growth hormone, and IGF-I.

Examination of cerebrospinal fluid (CSF) is usually not diagnostic and is unnecessary if the diagnosis of apoplexy is certain. However, if there is bleeding into the CSF as a result of the apoplexy, red blood cells as well as an elevated protein level and xanthochromia can be seen.

The differential diagnosis of pituitary apoplexy should include other conditions that result in the symptoms of headache, vomiting, visual disturbances, and hemodynamic instability such as infection (meningitis [ Chapter 381 ]), cavernous sinus thrombosis ( Chapter 376 ), migraine ( Chapter 367 ), Rathke cyst hemorrhage ( Chapter 377 ), and hyperemesis gravidarum ( Chapter 221 ). Each of these conditions is itself a medical emergency that requires specific treatment.

Treatment and Prognosis

Empty Sella

Empty sella is a radiologic diagnosis that refers to the observation on imaging of the presence of CSF in the sella turcica accompanied by a flattened pituitary gland ( Fig. 205-4 ). An empty sella is usually noted as an incidental finding when an MRI or CT scan of the skull is performed because of problems unrelated to the pituitary. It can be primary or acquired when a defect in the diaphragma sella allows the arachnoid membrane to herniate into the sella. Patients with acquired empty sella may have a prior history of an infarcted pituitary, surgery, or radiation. If the herniation has been present for years, the sella enlarges, probably owing to persistent exposure to intracranial pressure. Primary empty sella is more frequent in women and may be accompanied by benign intracranial hypertension ( Chapters 175 and 367 ).

In asymptomatic patients, there is no need to measure hormone levels unless there is suspicion of a clinical abnormality related to the pituitary. Pituitary function is usually normal, but about 10% of patients also have mild hyperprolactinemia, probably owing to stretching of the pituitary stalk. Because pituitary function is usually normal, no specific treatment is required. However, if there is concern about possible hypopituitarism, investigation as outlined earlier for hypopituitarism (see Table 205-2 ) should be undertaken.

Epidemiology and Pathobiology

Pituitary adenomas have an incidence of about 4 to 7 cases per 100,000 and a prevalence of about 1/1000 population. Clonal proliferation of any of the different cell types in the pituitary result in the formation of tumors. Pituitary tumors are classified clinically as functioning if they produce one or more hormones in excess or nonfunctioning if they do not produce excess hormone in blood. Because most functional tumors do not have appropriate physiologic feedback owing to their oncologic nature, they usually cause the clinical syndrome of the excess hormone. However, some functional tumors do not result in excess blood levels of the hormone, owing to a defect in intracellular processing or release.

Prolactinomas, which may account for up to 50% of pituitary tumors, are likely caused when proliferation of the lactotroph results in excess prolactin, with subsequent galactorrhea and hypogonadism. Somatotrophs producing growth hormone, corticotrophs making ACTH, and gonadotrophs making LH and FSH together account for 10 to 20% of adenomas. Nonfunctioning tumors, which mainly cause a mass effect or hypopituitarism, account for 10 to 25%. In addition to functioning and nonfunctioning, tumors are classified by their anatomy based on imaging studies. Microadenomas are less than 10 mm in diameter, whereas macroadenomas are greater than 10 mm in diameter (and typically with extrasellar extension).

Pituitary adenomas are monoclonal and can be locally invasive, but they are rarely malignant. The somatic mutations causing most pituitary tumors remain unknown, but at least six types of inherited predispositions to pituitary tumors are recognized ( Table 205-6 ). When macroadenomas are found in children or when there is a family history of pituitary adenomas, genetic testing is warranted so that appropriate monitoring can occur before the patient is symptomatic. Local expansion of the tumor can cause headaches. The mass effect of the tumor is also responsible for the temporal visual field defects associated with macroadenomas that expand into the suprasellar region and abut against the optic chiasm.

Clinical Manifestations

The clinical manifestations of pituitary tumors depend in large part on whether they are functional and whether their size compromises the normal function of the pituitary gland and thereby results in clinical symptoms of hypopituitarism. In general, the diagnosis of a tumor due to excess or diminishing hormone secretion presents the greater clinical challenge.

The size of the tumor usually is proportional to the amount of hormone it produces when functioning. Certain tumors are usually diagnosed sooner and therefore are usually smaller on diagnosis than others. For example, gonadotropinomas are usually diagnosed as macroadenomas because their symptoms are usually more subtle than TSH-secreting tumors, in which the symptoms present early so the tumors are usually smaller at the time of diagnosis.

As is true for hypopituitarism of all causes, pituitary tumors have historically been diagnosed more frequently in women of reproductive age because even a slight perturbation in hormonal milieu will disrupt the multiple hormone interactions necessary for a normal menstrual period ( Chapter 219 ). In men or postmenopausal women, slight perturbations in hormone levels (either excess or deficiency) are usually not noticed for several years. More recently, the diagnosis of pituitary adenomas is often an incidental finding on an imaging study obtained for unrelated reasons (e.g., a motor vehicle accident, headaches, or a nonpituitary intracerebral mass effect), and a pituitary microadenoma is an incidental finding. These findings are referred to as “incidentalomas” that otherwise would have avoided clinical detection because they are either silent or subclinical. Incidentalomas can be found in up to 10% of some autopsy series, so they are more common than pituitary tumors found during life. Even after careful endocrine evaluation of patients with incidental tumors, hyper- or hyposecretion of pituitary hormones is found in only a small percentage, and such incidental tumors usually do not increase in size over time.

Other than hormonal effects, reasons for suspicion of a pituitary mass are headaches and visual field abnormalities. A reported 33 to 72% of patients with a pituitary lesion have headaches, a percentage that is greater than the 22% of women and 11% of men in the general population who complain of headaches ( Chapter 367 ), but discerning which patients have a headache from the pituitary lesion and which ones have an unrelated cause for the headache is challenging. Headaches due to pituitary lesions are more common in females and in patients with Rathke cleft cysts and apoplexy.

Severely impaired visual fields can be revealed on examination by confrontation testing. The superior and temporal visual fields are most affected.

MRI is the cornerstone of diagnosis for nonfunctioning tumors and key for the evaluation of functioning tumors. If there is any evidence on MRI that the tumor is close to or abuts the chiasm, formal visual field testing should be performed. Specific diagnosis of pituitary adenomas that are actively secreting a hormone is based on basal hormone levels followed by provocative testing ( Table 205-7 ).

Treatment

Prognosis

About two-thirds of incidental, asymptomatic pituitary microadenomas remain unchanged in size or even become smaller For other adenomas, however, the sooner treatment is initiated to decompress the chiasm (with surgery, or in the case of a medically responsive prolactinoma, with appropriate medication), the more likely vision will be restored. Nevertheless, visual improvement has been noted even after months of visual field impairment. Even after apparent surgical cure, about 10 to 20% of tumors recur within several years, as manifested by oversecretion of their hormones, and recurrence is more likely if the tumor extended into the suprasellar space or fragmented upon removal.

Pathobiology

Growth hormone is the main regulator of the growth of bone and other tissues. The human growth hormone gene, along with four other related genes, is located at the growth hormone locus on chromosome 17 where, by gene duplication, these genes are interspersed in the same transcriptional orientation. The five genes not only have a high degree of sequence identity but also exist as multiple isoforms based on variable splicing. The variant expressed in the somatotrophs of the pituitary gives rise to two isoforms. Growth can occur in the fetus and early postnatal state independent of growth hormone; but soon after birth, growth hormone controls growth, and its deficiency results in dwarfism.

Growth hormone is a peptide hormone whose receptor is located on the cell surface. Growth hormone promotes the dimerization of two growth hormone receptors and activates JAK2 by phosphorylation of tyrosine residues. The activated JAK2 in turn activates STAT and an entire cascade of signal factors, thereby resulting in nuclear activation.

The metabolic effects of growth hormone are both direct, by interaction with its tissue receptors, as well as mediated by a serum factor secreted by the liver (somatomedin or insulin-like growth factor-I [IGF-I]). IGF-I in turn acts on a variety of tissues to stimulate body growth. IGF-I is also produced in a variety of tissues including smooth muscle, skin, lung, bone, and cartilage. However, in addition to IGF-I production in the various tissues, growth hormone causes hydrolysis of triglycerides in adipose tissue. In skeletal muscle, growth hormone enhances uptake of amino acids and retention of nitrogen, similar to what would be expected in exercising muscle. Growth hormone also stimulates glycogenolysis and gluconeogenesis.