This article includes discussion of ulnar neuropathies, Guyon canal neuropathy, ulnar neuropathy at the wrist, and flexor carpi ulnaris exit compression.
Jun. 07, 2021
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The pituitary gland sits in the sella and is divided into 2 parts, the anterior and posterior. Hypopituitarism results from the partial or complete loss of 1 or more of 6 hormones made and released by the anterior pituitary gland. Non-tumoral causes constitute a major group of childhood hypopituitarism. Traumatic brain injury has emerged as an important cause of hypopituitarism. Once fully established and prolonged (greater than 6 months), it is generally permanent, although spontaneous recovery can rarely occur. There are many causes of hypopituitarism, including tumors in or around the pituitary gland, whole brain radiation therapy or focused radiation therapy that includes the sella in the treatment field, chemotherapy, damage intraoperatively, major head trauma, subarachnoid hemorrhage, infections, and peri and prenatal causes, which will all be discussed in this update.
• Hypopituitarism results from the partial or complete loss of 1 or more of 6 hormones made and released by the anterior pituitary gland.
• Non-tumoral causes constitute a major group of childhood hypopituitarism.
• Once fully established and prolonged (greater than 6 months), it is generally permanent, although spontaneous recovery can rarely occur.
• Not all sellar enhancing lesions causing hypopituitarism are pituitary adenomas.
• A pituitary abscess is an intrasellar infection; it responds to antibiotic therapy and surgery, and although the abscess resolves eventually, hypopituitarism often remains protracted, requiring prolonged hormone replacement therapy.
• It is imperative that anterior pituitary hormonal function be assessed to attain maximal improvement in cognitive and physical function as well as quality of life for victims of traumatic brain injury.
Hypopituitarism results from the partial or complete loss of 1 or more of the 6 hormones made and released by the anterior pituitary gland: growth hormone, adrenocorticotropic hormone, prolactin, thyroid stimulating hormone, luteinizing hormone, and follicle-stimulating hormone. The posterior pituitary is the storage gland for the hypothalamic hormones, antidiuretic hormone, and oxytocin. Although complete deficiency of anterior pituitary hormones is often called "panhypopituitarism," this term should be reserved to describe the clinical effects of complete loss of anterior and posterior pituitary hormones, including the neuropeptides vasopressin and oxytocin.
The crucial physiologic roles of the pituitary gland were not suspected until the late 19th century and were not clearly defined until the first third of the 20th century. Galen (second century AD) believed that the hypophysis acted as a funnel for secreted mucus (pituita) made by the brain to pass into the nasopharynx. This concept was generally accepted with minor modifications, such as Vesalius's hypothesis that phlegm from the cerebral ventricles passed down the infundibulum into the gland and finally out the nose. The first evidence suggesting a more important role for the pituitary gland was published in 1886. Marie described the disease of acromegaly, which was associated with the replacement of the pituitary body by tumor (38). Cushing suspected that a clinical disorder was associated with pituitary destruction (14), but Simmonds provided the first clear description of pituitary insufficiency, which he termed "pituitary cachexia" (61). Simmonds detailed the necroscopic findings of a 46-year-old woman whose illness began after childbirth complicated by severe puerperal fever. The clinical findings were a marked weight loss, premature aging, marked muscular weakness, and anemia. Subsequent reports stressed a common relationship between childbirth and the clinical syndrome, which led Reye to speculate in 1926 that pituitary destruction was caused by thrombosis in the setting of pituitary hyperplasia during pregnancy (52). This view was fully confirmed by the 1937 report of Sheehan in his classic article on postpartum necrosis of the pituitary (59).
The initial clinical presentation of hypopituitarism can span a spectrum from the rare life-threatening episode of acute adrenal insufficiency to a slow, insidious development of nonspecific symptoms such as lassitude and fatigue, which are often ignored by patients, their families, and physicians. Hypopituitarism tends to have a slow and gradual presentation over a time period of weeks to months. This is largely due to the slow depletion of pituitary hormones. It can remain clinically silent until a stressful event catalyzes the presentation of marked symptoms (72). Detection of hypopituitarism is especially difficult in elderly patients who frequently present with nonspecific symptoms. Specific signs and symptoms depend on the organ system(s) affected, the degree and rapidity with which hormonal deficiencies develop, and whether the patient is a child or adult. When hypopituitarism arises from pituitary destruction by masses, mechanical symptoms such as headache and visual loss often predominate. Frequently, hormonal deficiencies are not complete and are clinically silent unless a patient is under a physiological stress.
The signs and symptoms of hypopituitarism depend on the particular hormone that has been diminished. For instance, low cortisol can present as hypotension, hypoglycemia, hyponatremia, or hyperkalemia. Low thyroid hormones can lead to altered mental status, hypothermia, lethargy, or edema. If the sex hormones, testosterone or estrogen, are affected there may be decreased libido, hair loss, or amenorrhea. Growth hormone deficiency can present as decreased muscle mass or lethargy (72).
Although the majority of the symptoms of hypopituitarism are similar to those that occur with failure of the target gland, there are some important differences. Hypocortisolism from hypopituitarism lacks the hyperpigmentation that occurs in primary adrenal failure (Addison disease). Symptoms of hypothyroidism from this disease do not include myxedema coma because the thyroid gland continues to make and release small amounts of thyroid hormone even without activation by thyroid stimulating hormone. Hypoprolactinemia is unusual and is detected only as the inability to lactate appropriately in the puerperium.
More commonly, mild elevations in serum prolactin occur (less than 150 ng/mL), frequently producing galactorrhea in women, although rarely in men. Growth hormone deficiency has traditionally been thought to be asymptomatic in adults. However, study has demonstrated a clustering of characteristics that comprise the adult growth hormone deficiency syndrome. These include increased body fat, decreased lean body mass, decreased oxygen consumption, abnormal lipid profiles, osteopenia, fatigue, and decreased sense of well-being. Many of these features improve with replacement therapy (Inzucchi 1997).
Diabetes insipidus is characterized by polyuria and polydipsia. In the frequent setting of partial deficiencies, thirst and urination are not abnormal until the individual is osmotically stressed and subsequently utilizes a diminished reserve of vasopressin. Oxytocin deficiency is generally coincident with diabetes insipidus and is infrequently observed independently. Deficiency is only recognizable in women who are unable to lactate because of the absence of milk ejection (“let-down”).
Finally, loss of more than one hormone can lead to "masking" of symptoms. For example, ACTH deficiency (hypocortisolism) will mask diabetes insipidus because cortisol is required for the distal tubule of the kidney to maintain water impermeability. The presentation of hypopituitarism can be different in children than in adults. For example, in children, GH deficiency causes growth delay and hypoglycemia, and gonadotropin deficiency prevents pubertal development.
Regarding prognosis, hypopituitarism may progressively increase in severity, particularly when the etiology is neoplastic, infiltrative, or radiation-induced. Once fully established and prolonged (greater than 6 months), it is generally permanent, although spontaneous recovery can rarely occur.
Quality of life may not return to normal. Some patients treated for hypopituitarism have associated depression, anxiety, memory loss, and emotional distress that were not present prior to presentation (12). Several studies have documented a reduced quality of life in patients treated for hypopituitarism due to persisting psychological and physical impairments. It is likely that these complaints are partly caused by intrinsic imperfections of hormone replacement strategies in mimicking normal hormone secretion. Also, even with long-term growth hormone therapy, residual impairments are present. Hypopituitarism has also important socioeconomic effects, with increased annual health costs compared to the normal population (70).
Patients with hypopituitarism have increased mortality (66). Women have even higher mortality. It is unknown if the increased mortality is attributable to the treatments such as sex hormone supplementation. The disease has also been associated with increased mortality from other disorders. For instance, deaths from vascular disorders are more common in the hypopituitarism population compared to the general population. Age at presentation of hypogonadism has been found to be a predictive factor for survival (49).
The following are fictitious vignettes demonstrating examples of patients with hypopituitarism.
Case 1. A 24-year-old gravida 1 para 1 (G1P1) female with no significant past medical history presents to her primary care physician on postpartum day 4 with a chief complaint of inability to breastfeed her child. She was never able to lactate. She states that she had a vaginal delivery and that her doctors were concerned because “I had a lot of bleeding.” Physical exam was unremarkable.
Blood tests revealed low free thyroxine, low cortisol, low TSH, and low ACTH levels. All other hormones were within normal limits. MRI brain did not show any mass lesions, but the sella appeared empty, only containing cerebrospinal fluid.
A diagnosis of Sheehan syndrome was made. The patient was started on hormone replacement therapy and scheduled a follow-up appointment in 2 weeks.
Case 2. A 60-year-old right-handed female with a past medical history of smoking (1 pack per day for 40 years), hypertension, and poorly-controlled diabetes presents to the emergency department with the worst headache of her life. She becomes lethargic in the waiting room, requiring intubation. A CT of the head demonstrates diffuse subarachnoid hemorrhage with intraventricular extension and hydrocephalus. A ventriculostomy catheter is inserted, and she is taken for a cerebral angiogram, where an 8 mm anterior communicating artery aneurysm is identified and primarily coiled by the interventional neuroradiologist. She is extubated after the procedure. On postoperative day 1, her urine output is noted to be greater than 500 ml per hour for 3 hours, and her sodium jumped from 134 to 156. She was assessed by the endocrinology team who recommended as needed the use of 2 micrograms of intravenous DDAVP with strict q6 hour basic metabolic panel, urinalysis, urine and serum osmolarities, and recording of strict ins and outs. The patient was discharged on oral dosing of desmopressin and was weaned off the desmopressin by 3 months.
The causes of hypopituitarism are many. The anterior pituitary and hypothalamus form a functional unit with each anterior pituitary hormone under direct control by hypothalamic centers. This regulation occurs by the release of specific hypothalamic hormones into the portal capillary plexus of the infundibulum that targets the anterior pituitary. Disturbances at any level of this anatomical unit—at hypothalamic, stalk, or pituitary level—can potentially lead to hypopituitarism (67).
For lesions that directly affect the pituitary gland, the observed probability of hormone loss has been roughly GH > LH/FSH >> ACTH > TSH >> PRL. The most common lesions are masses within the pituitary gland. The most prevalent of these are large pituitary adenomas (macroadenomas) that may secrete hormones or may be nonfunctional. A macroadenoma is defined by a size greater than 10 mm. The potential for hypopituitarism increases as macroadenomas invade the suprasellar space, compressing the optic chiasm, and ultimately the hypothalamus. Virtually all of these individuals will have growth hormone deficiency, and approximately 30% will also lose other hormones, although the loss may not be permanent if the tumor is removed (02) or reduced by medical therapy (43). In a study of 269 patients with nonfunctioning pituitary adenomas, 49% of patients were asymptomatic, whereas 51% showed some symptomatology. The rate of hypopituitarism was 59% in symptomatic patients and 27% in the asymptomatic group (19). The rate of macroadenomas in the study was 87% (19).
Secretory tumors generally produce clinical syndromes such as acromegaly that may conceal or draw attention away from hypopituitarism arising from destruction of the pituitary or interference with the hypothalamic-pituitary unit. Diabetes insipidus (DI) with anterior hypopituitarism that arises from intrasellar macroadenomas is unusual. However, lesions that arise from the suprasellar region (such as craniopharyngiomas, meningiomas, lymphomas, and germ cell tumors) or that are immediately adjacent to the posterior lobe (such as Rathke cleft cysts), typically affect the neurohypophysis. This is typically associated with clinical diabetes insipidus. Occasionally, acute infarction and bleeding within a pituitary macroadenoma occur, producing the dramatic syndrome of apoplexy. This state is characterized by headache, visual disturbances including field defects and ocular cranial nerve abnormalities (arising from compression of III, IV, and VI within the cavernous sinus), and if the hypothalamus is appreciably compressed, vegetative symptoms and signs including vascular instability. Pituitary apoplexy virtually always produces acute hypocortisolism due to ACTH deficiency.
A normal pituitary gland can also be acutely destroyed in other ways to produce hypopituitarism. The most common and classic case is that of postpartum pituitary necrosis, Sheehan syndrome (59). This clinical entity occurs in the setting of difficult parturition associated with hypotension and blood loss, which produces a generally painless destruction of the pituitary gland. Rarely, diabetes insipidus ensues (less than 1% to 2% of the time), but it is often masked by coincident hypocortisolism. Therefore, the diagnosis of ischemic necrosis is often missed. Rarely, diabetes insipidus can be the only damage observed (60). Subsequent to pituitary destruction, there is no lactation (due to loss of PRL), and secondary amenorrhea prevails. Hypothyroidism and hypocortisolism may be missed due to their insidious onset, and the condition may go undetected for many years. A similar syndrome can develop, often spontaneously, in other conditions in which portal blood supply is limited due to vascular disease or obstruction, particularly in diabetes mellitus. Multiple risk factors (eg, pregnancy and sickle cell disease) raise the possibility of necrosis (65). Rarely, hemorrhage and necrosis can occur in normal pituitaries, due to hantaviral disease. A study of 27 patients with Sheehan syndrome and 14 controls has demonstrated that patients with Sheehan syndrome have an impairment of neurohypophyseal function. The thirst center may be affected by ischemic damage, and the osmotic threshold for the onset of thirst in patients with Sheehan syndrome is increased (04).
Pituitary apoplexy, a potentially lethal event, results from hemorrhage into or impaired blood supply to the pituitary gland, and it may result in headaches, visual field deficits (bitemporal hemianopsia) via optic chiasm compression or double vision from cranial neuropathy via expansion into the cavernous sinuses, nausea, vomiting, neck rigidity, and altered or depressed mental status. Often times, apoplexy becomes symptomatic via neurologic deficits or through severe adrenal crisis as a result of the acute lack of adrenocorticotropic hormone.
Pituitary injury may also be caused by medical treatment. Direct destruction of the pituitary frequently occurs as a complication of surgical treatment of pituitary lesions and often produces hormonal deficiencies of growth hormone and the gonadotropins. Anterior hypopituitarism is a common result of radiation therapy, especially when delivered for treatment of pituitary tumors. However, pituitary injury also commonly occurs after whole brain radiation, and occasionally as a consequence of radiation delivered to treat head and neck tumors, which includes the pituitary-hypothalamic unit within the treatment field. Radiation-induced damage typically has a prolonged time of onset. The pattern of pituitary hormone deficiency is extremely variable and may occur many years after radiation. In 1 study of 66 patients who received standard pituitary radiation at 5 years after the treatment, 100% had growth hormone deficiency, 91% had gonadotropin deficiency, 77% had ACTH deficiency, and 42% had TSH deficiency (34). Because of the prolonged time of onset of insufficiency, patients receiving radiotherapy must be followed throughout life for the development of hypopituitarism.
There are many less common causes of hypopituitarism. These include congenital causes, eg, septo-optic dysplasia, empty sella syndrome, direct trauma, and infiltrative or autoimmune diseases.
Neonatal hypopituitarism may be due to aberrations in embryological development, de novo and inherited genetic mutations, and perinatal and neonatal events. They are usually detected in childhood due to growth arrest, but they are occasionally detected during adult years. The anterior pituitary gland is derived from ectoderm, whereas the posterior pituitary is derived from neural ectoderm. Neonatal hypopituitarism can be further broken down into congenital and perinatal/neonatal causes. The congenital causes include maternal hyperglycemia, congenital infections (such as syphilis and toxoplasmosis), hypothalamic-pituitary developmental defects, severe midline defects (such as cleft lip/palate), and genetic mutations. There are over 19 genetic mutations identified to date, and they can result in anterior pituitary hypoplasia, an ectopic posterior pituitary gland, as well as isolated loss of hormone producing cells (Kurtoglu et al 2018).
Perinatal causes of hypopituitarism include birth trauma/asphyxiation, which can result in damage to the pituitary stalk, neonatal sepsis, and hemochromatosis, which often leads to a transient hypopituitarism (31).
Empty sella syndrome (ie, little or no pituitary tissue visible within the sella on imaging) can be primary or secondary to other causes such as the infarction of an adenoma. Primary empty sella, especially if accompanied by a ballooned sella, can be associated with hypopituitarism. Commonly, hyperprolactinemia causes hypogonadism, which may be confused with true hypopituitarism.
Traumatic brain injury has emerged as an important cause of hypopituitarism (29). Direct trauma, such that may occur from accidents (17), projectiles such as bullets (36), and carotid aneurysms (48), can also cause hypopituitarism either immediately after the injury or a delay of several years. Although pituitary dysfunction, present months or years after traumatic brain injury, it is now well recognized in adults. A review of pediatric data has also confirmed that hypopituitarism may occur after both mild and severe traumatic brain injury, with growth hormone and gonadotrophin deficiencies appearing to be most common abnormalities (01). Frequently, basilar skull fractures accompanying these lesions transect the infundibulum and cause diabetes insipidus as well. Recovery of function with these lesions are rare, but some have been reported.
Based on data in the current literature, approximately 15% to 20% of traumatic brain injury patients develop chronic hypopituitarism, which clearly suggests that traumatic brain injury-induced hypopituitarism is frequent in contrast with previous assumptions. It is now thought to be a major cause of treatable morbidity among traumatic brain injury survivors (28). The pathophysiology of hypopituitarism after traumatic brain injury is not fully understood, and most theories revolve around transection of the pituitary stock, venous infarction of the venous system surrounding the pituitary, sequela of the injury including hypotension, elevated intracranial pressure, hypoxic brain injury, and more. Salehi and colleagues demonstrated that approximately 27.5% of patients who were in the chronic phase after traumatic brain injury and 47% of those who had aneurysmal subarachnoid hemorrhage develop hypopituitarism (55). Cuesta and colleagues confirm that symptoms of gonadal dysfunction are more predictive of hypopituitarism than nonspecific symptoms for pituitary dysfunction following moderate or severe traumatic brain injury (13). Tanriverdi and Kelestimur further confirm that symptoms of hypogonadism are sufficiently predictive of hypopituitarism to justify screening for hypopituitarism after moderate/severe traumatic brain injury (64). Nonspecific symptoms of hypopituitarism are no more predictive than unselected screening.
Many systemic diseases can infiltrate the pituitary and produce hypopituitarism. All granulomatous diseases, including tuberculosis, Wegener granulomatosis, and fungal diseases, but especially sarcoidosis, can infiltrate the hypothalamus and the pituitary. This usually produces a basilar meningitis and panhypopituitarism (both anterior and posterior hormone deficiencies). Rarely, an intrasellar mass lesion such as a tuberculoma or syphilitic gumma will directly destroy only pituitary tissue. Langerhans cell histiocytosis ("histiocytosis X") has a predilection for the basal hypothalamus as well. Lymphocytic infiltration can occur, producing a pituitary mass and hypopituitarism, and has been termed lymphocytic hypophysitis (03). This generally occurs in young women in the postpartum period but has been reported in a postmenopausal woman (42), as well as in men (50). Pituitary destruction is also part of the spectrum of the autoimmune polyglandular failure syndrome, which can produce simultaneous central and end-organ dysfunction. The iron overload that results from hemochromatosis targets the anterior pituitary gland (as well as other endocrine glands), especially the gonadotrophs. Finally, many tumors metastasize to the pituitary, including breast, lung, prostate, and renal cell cancers. The initial lesion generally occurs within the posterior pituitary due to its excellent blood supply, so the clinical presentation is often with partial or, more rarely, complete diabetes insipidus. A rare case of metastatic involvement of the pituitary gland from a peripherally located pulmonary atypical carcinoid tumor manifesting with evidence of functional hypopituitarism has been reported (27). Although hypopituitarism is common and often transient following traumatic brain injury, 1 study found that 78% of patients developed inappropriately low plasma cortisol following traumatic brain injury (24). In addition, low plasma cortisol and cranial diabetes insipidus were predictive of mortality and long-term pituitary deficits in traumatic brain injury patients. Long-lasting traumatic brain injury patients who develop hypopituitarism frequently present metabolic alterations, in particular altered glucose levels, insulin resistance, and hypertriglyceridemia (51). Because of these alterations, in addition to the risk of premature cardiovascular death in hypopituitaric patients, greater caution is emphasized in dealing with patients with hypopituitarism and traumatic brain injury.
Hannon and colleagues studied 100 patients with acute subarachnoid hemorrhage from the time of presentation, and 41 of those patients attended follow-up for 7 to 30 months, with a median of 15 months (23). Only 2 of 41 had chronic adrenocorticotrophic hormone deficiency, and 4 of 41 had growth hormone deficiency. None of the patients had chronic cranial diabetes insipidus, hyponatremia, thyrotrophic stimulation hormone, or gonadotrophin deficiency. Hypopituitarism was not predictable by acute clinical, hemodynamic, or endocrinological parameters. Based on their findings, the authors concluded that both anterior and posterior hypopituitarism are very uncommon following subarachnoid hemorrhage.
Posttraumatic hypopituitarism is a frequent complication in patients after traumatic brain injury. In a study of posttraumatic hypopituitarism, Nourollahi and colleagues found that the condition further impairs quality of life, without affecting earning capacity (47). It is hypothesized that hormone substitution might improve quality of life in posttraumatic hypopituitarism patients.
The clinical result of hypopituitarism depends on the hormones affected and the magnitude of deficiency. Macroadenomas potentially cause hypopituitarism by a variety of mechanisms, including compression of the normal pituitary gland, occlusion of the portal capillary flow of hypothalamic hormones, and compression of the hypothalamus. In ischemic necrosis, the anterior pituitary is at high risk for vascular compromise because the nurturing blood flow arises mainly from the portal capillary plexus. In conditions in which the vascular supply is compromised, eg, microvascular disease of diabetes mellitus or reduced blood flow to the hyperplastic gland during pregnancy, necrosis ensues. The pituitary gland is also a target for autoimmune destruction in the polyglandular failure syndrome and lymphocytic hypophysitis. The pituitary gland secretes 6 hormones from 5 different cell types (39). In the murine models, transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, PITX1, PITX2, SOX2, and SOX3 are involved in the etiology of congenital hypopituitarism. The highly variable phenotypes consist of isolated hypopituitarism to more complex disorders such as septo-optic dysplasia and holoprosencephaly, and many genes remain to be identified.
The following epidemiological data are derived from a study performed by Schneider and colleagues (57). Hypopituitarism in an adult Caucasian population in northwestern Spain showed a prevalence of 45.5 cases per 100,000. This prevalence was age-dependent. The most common cause in children are congenital disorders and sequelae from whole brain irradiations. In young adults, non-adenomatous tumors, particularly craniopharyngiomas and dysgerminomas, are the most common causes. For adults, the predominant causes of hypopituitarism are large pituitary adenomas or damage from medical treatment such as surgery, radiation, and chemotherapy.
The literature shows that one fourth to one half of patients experiencing traumatic brain injury or aneurysmal subarachnoid hemorrhage develop hypopituitarism. Pituitary irradiation is another well-known cause of hypopituitarism.
When using the most conservative data, application of frequencies of hypopituitarism to these incidences would result in an estimated incidence of 31 cases of hypopituitarism attributable to traumatic brain injury and subarachnoid hemorrhage per 100 000 per year (58).
Some studies have shown the association between the severity of traumatic brain injury with hypopituitarism, but others have found hypopituitarism to be more frequent in patients with severe traumatic brain injury. Diffuse axonal injury and basal skull fracture have been shown to be risk factors for posttraumatic hypopituitarism. Patients with hypopituitarism and traumatic brain injury usually have abnormalities in pituitary MRIs or CT scans.
Traumatic causes of hypopituitarism can be prevented by wearing a seatbelt while driving or being in a motor vehicle, wearing a properly fitted helmet while cycling, skating, skateboarding, using a scooter etc., ensuring proper gun safety while operating a firearm, and taking general precautions for safety from slips, falls, etc. The risk of developing Sheehan syndrome can be mitigated with proper anesthesia and fluid resuscitation in patients who are delivering. Subarachnoid hemorrhage has known risk factors including smoking and hypertension, or it can result from genetic/familial aneurysms. Special attention should be paid for severe traumatic brain injury, basal skull fractures, diffuse axonal injuries, increased intracranial pressure, and prolonged stays in intensive care units.
Surgeons may take extra precautions while operating on the pituitary gland on pituitary-hypothalamic masses or recommending interventional therapy, including both surgery and radiation; however, judiciously following labs postoperatively and preventing severe hypo or hypernatremia, and early identification of pituitary dysfunction, may serve more important. There have been many breakthroughs in imaging technology and surgical guidance as well as visualization of the sella intraoperatively with angled endoscopes, which may lead to decreased postoperative complications.
The differential diagnosis always includes primary endocrine gland failure, which usually involves only 1 hormone class but is multiple in the polyendocrine failure syndrome. Measurement of pituitary hormones as well as end hormones will usually distinguish these cases. Occasionally, polyendocrine failure syndrome will also involve the pituitary, and as such, is a cause of hypopituitarism. This distinction is of practical importance only in order to recognize the presence of concomitant adrenal failure that will require the addition of mineralocorticoids to glucocorticoids as maintenance therapy.
Anorexia nervosa, a psychiatric illness most common among young women, will produce some of the endocrine findings of hypopituitarism (secondary amenorrhea and borderline biochemical central hypothyroidism) as a consequence of severe starvation. The marked weight loss that is present in this condition is unlike hypopituitarism and, therefore, is a critical diagnostic feature. Interestingly, the original descriptions of pituitary cachexia by Simmonds stressed marked weight loss, so patients with anorexia nervosa were inappropriately categorized as having this disease until Sheehan's work clarified this issue (61; 59). In addition, patients with anorexia usually have activation of the hypothalamic-pituitary-adrenal axis, as opposed to the central hypoadrenalism encountered in those with true hypopituitarism. Features of Oliver-McFarlane syndrome include chorioretinopathy, pituitary dysfunction with hypopituitarism, and trichomegaly-chorioretinopathy (56; 22). This condition may mimic choroideremia-hypopituitarism association (41). However, the latter is associated with family history of progressive blindness and similar maternal fundoscopic appearances. In addition, mutations occur in the choroideremia gene. (The choroideremia gene encodes for a protein, the Rab escort protein-1, or REP1, which is involved in membrane trafficking.)
Liu and colleagues report their experience with 33 cases of pituitary abscess, along with their recommendations for management of this rare disorder (35). Symptoms often included that of a sellar mass, generally without any symptomatic evidence for infection. Diabetes insipidus, hypopituitarism, and headaches were the most salient features. MR imaging with and without gadolinium characteristically revealed a sellar mass with an enhancing rim. Thirty cases were treated with antibiotics and surgery (a transsphenoidal evacuation), whereas 3 patients were treated with antibiotics only. In spite of recurrences, abscesses resolved in nearly all cases, though hypopituitarism remained protracted, necessitating hormone replacement therapy. In congenital hypopituitarism, pituitary stalk interruption is a well-known entity, but rarely a known genetic cause has been assigned to these cases. Reynaud and colleagues report PROKR2 variants in the above clinical set up, suggesting a potential role of the prokineticin pathway in pituitary development (53).
Mitochondrial inherited disorders can occur in syndromic forms (MELAS, MERRF, NARP, LHON, etc.). When they occur in a nonsyndromic form, hypopituitarism is a well-known manifestation among the multitude of neurologic abnormalities that occur with this condition. A high index of suspicion often promotes the correct diagnosis. Upreti and colleagues report the occurrence of Gitelman syndrome with hypopituitarism, a first such case report (68). Gitelman syndrome is an inherited tubulopathy affecting thiazide-sensitive sodium chloride cotransporter, which manifests with hypokalemic alkalosis, hypomagnesemia, and hypocalciuria. In addition to the features of Gitelman syndrome, their patient also had features of hypothyroidism, hypocortisolism, and hypogonadism. Replacement therapy with electrolytes and hormones resulted in excellent recovery. It is unclear at this stage whether multiple pituitary hormone deficiencies are a chance finding or if they share a common genetic link with Gitelman syndrome.
Diagnosis of hypopituitarism depends largely on certain laboratory values. Measurement of basal anterior pituitary and target organ hormone levels are useful in diagnostic pituitary disorders. Usual tests include TSH, thyroxine, FSH, LH, estradiol in women or testosterone in men, prolactin, insulin-like growth factor 1, and 9 AM cortisol (49).
If growth hormone deficiency is suspected, at least 1 growth hormone provocative test should be done. An insulin tolerance test is the gold standard. Following administration of insulin, growth hormone deficiency is defined as a peak growth hormone response of less than 3 ug/L. After an overnight fast, intravenous insulin 0.05 to 0.15 units/kg is injected, and blood glucose and growth hormone levels are measured at 0, 30, 60, 90, and 120 minutes. A normal growth hormone response is a peak of at least 5 mg/l.
Thyroid stimulating hormone deficiency is exemplified by low basal serum free/total thyroxine with a normal to low TSH level. Routine use of a thyrotrophin releasing hormone (TRH) stimulation test is not indicated in adults. Gonadotrophin deficiency is associated with low serum testosterone in the presence of normal or low gonadotrophin levels in men and low serum estradiol concentrations in premenopausal women. The use of a gonadotrophin releasing hormone (GnRH) provocation test has not been found to provide any additional information in adults (10).
Normally, antidiuretic hormone (ADH) release from the posterior pituitary is influenced by changes in plasma osmolality. However, in cranial diabetes insipidus, the lack of this response results in large urine output classically with low osmolality. The standard 8 hour water deprivation test is used diagnostically in these cases. It entails closely supervised dehydration of a previously well-hydrated patient. Basal and hourly plasma and urine osmolalities, and urine volumes are measured. After 8 hours, intramuscular desmopressin 2 mg is injected followed by remeasuring blood and urine osmolalities. Initially dilute urine (less than 300 mOsmol/kg) at the end of fluid deprivation becomes concentrated after desmopressin in patients with cranial diabetes insipidus but remains dilute in nephrogenic diabetes insipidus. Screening for hypocortisolism is more problematic. An excellent assessment can be made based on a morning serum cortisol level. If this level is above 10 µgm/dL, the hypothalamic-pituitary-adrenal axis is likely normal. Stimulation by synthetic ACTH (cosyntropin test) is also useful, but it may be misleading in states of acute ACTH deficiency in which the adrenal cortex has not yet atrophied (49).
Biochemical assessment of hormone deficiencies requires the simultaneous determination of both pituitary and end organ hormones, which will allow the determination of whether the lesion is central (hypopituitarism) or at the end organ level (primary deficiency syndrome).
Multiple hormone deficiencies strongly suggest a cranial/pituitary etiology. Occasionally, mechanical factors predominate, such as bitemporal hemianopsia, resulting from upward mass effect on the optic chiasm. Because the macula and, therefore, central vision, is usually spared, profound losses in peripheral vision often occur without the patient's knowledge.
Complete hormonal deficiency syndromes are usually easy to diagnose after the initial suspicion is raised by determining that the end organ hormone level is low, with correspondingly low or inappropriately normal central hormone levels. Partial hormonal deficiencies, however, are often characterized by hormone levels that are within the normal range, and they must be assessed by dynamic testing.
Once hypopituitarism has been biochemically defined or in patients with symptoms or signs of central lesions, imaging studies of the hypothalamic and pituitary region should be obtained. Pituitary microadenomas measure less than 10 mm in diameter and are usually intrasellar, whereas macroadenomas are greater than 10 mm and reside within an enlarged sella turcica. There may be extension into the suprasellar cistern, sphenoid sinus, or cavernous sinus (46).
A simple noncontrast CT scan may demonstrate most lesions, but follow-up imaging with thin slice MRI imaging of the brain with and without contrast is the gold standard. On T1-weighted imaging, adenomas are hypo to isointense. They also have poor uptake of gadolinium. On T2-weighted imaging, the adenomas are isointense to white matter (46). Currently, MR imaging provides the most complete anatomical information and should be employed whenever possible. Although hypopituitarism is not excluded by normal MRI of the sellar and parasellar region, traumatic damage can present with pituitary-stalk deviation, with signal inhomogeneity attributable to hemorrhage or infarction, or as empty sella (08).
Lee and colleagues report a case of a giant aneurysm of internal carotid artery causing hypopituitarism, highlighting the fact that not all sellar enhancing lesions causing hypopituitarism are pituitary adenomas (33). Although symptoms are similar to pituitary adenomas, the presence of rim-like calcification around the sellar mass on CT and flow-related effects on T2-weighted MRI support the diagnosis of an aneurysm, and a cerebral angiogram confirms it (32). It is good practice to pursue vessel imaging via CTA or MRA to assess the cranial vasculature, which is a key factor in determining the surgical plan for macroadenomas. The prevalence of intrasellar giant aneurysms is estimated at 0.2% (25).
Nakata and colleagues, in their comparative study between patients with lymphocytic hypophysitis and those with pituitary adenomas, report that although MR imaging findings of these conditions are similar, the presence of the parasellar T2 dark sign in lymphocytic hypophysitis can be a specific finding and distinguishes it from the pituitary adenoma (44).
The Congress of Neurological Surgeons recommends ophthalmologic evaluation including both functional and anatomic assessment. The evaluation may provide prognostic factors for recovery and can help monitor postoperative changes (46). Danesh-Meyer and colleagues demonstrated that a normal retinal nerve fiber layer thickness demonstrated on optical coherence tomography shows an increased propensity for visual recovery, whereas those with a thin retinal nerve fiber layer show limited improvement over a longer time frame (months) (15).
Mehta and colleagues suggest that individuals presenting with optic nerve hypoplasia are at high risk for neuroradiologic and endocrine abnormalities (40). The neuroradiologic features are predictive of the presence and the type of hypopituitarism, though the etiology remains unidentified in the majority of cases.
The treatment of hypopituitarism may require a multidisciplinary team of endocrinologists, neurosurgeons, ophthalmologists, and otorhinolaryngologists. It must include therapies directed at the underlying disease process and endocrine replacement therapy. Tumors may be treated with medical therapy, surgery, radiotherapy, or a combination. A macroprolactinoma, for instance, is amenable to treatment with dopamine agonists, but a recurrent ACTH producing pituitary neoplasm is likely to require a combination of surgical and nonsurgical treatments. The goals of hormone replacement therapy in hypopituitarism are to achieve normal levels of the circulating hormones with minimal side effects (49).
For isolated hormone deficiencies, treatment consists of replacing individual hormones and periodically checking for the effectiveness of treatment as well as development of additional hormone deficiencies. For panhypopituitarism, full hormonal replacement therapy must be undertaken, generally for life. For the initiation of chronic maintenance therapy, it is imperative that coexistent thyroid and glucocorticoid deficiency be identified; an increase in metabolic rate associated with thyroid replacement therapy without appropriate glucocorticoid replacement can precipitate an adrenal crisis, which can be fatal. Prolactin and oxytocin deficiencies are typically not replaced. Growth hormone replacement therapy should also be considered for symptomatic adult patients.
Adrenocorticotrophic hormone deficiency is best treated with glucocorticoid replacement therapy using steroids with moderate biological half-lives such as prednisone. To mimic the diurnal variation, these steroids are given twice a day, with two thirds of the dose after rising and one third of the dose in the late afternoon. For prednisone, this is 5 and 2.5 mg, respectively. Use of short-acting glucocorticoids such as cortisone acetate (25 mg/12.5 mg) or hydrocortisone (20 mg/10 mg) works in many individuals, but the rapid peaks and troughs produce severe cyclical symptoms of fatigue, weakness, and mild nausea in some patients. These symptoms can sometimes be minimized by changing the dosage to 3 times daily. Occasionally, individuals will require even longer-acting steroids such as dexamethasone to feel well. Mineralocorticoid treatment is not required in hypopituitarism because aldosterone biosynthesis by the adrenal cortex remains functional via the renin-angiotensin system.
Thyroid hormone is administered daily as levothyroxine (generally in the 0.075 to 0.2 mg range). In many instances, hypopituitarism arises from macroadenomas in the older patient population, and thyroid hormone replacement therapy should be undertaken conservatively because occult cardiovascular disease may be coincidentally present. Initial therapy using 0.0125 to 0.025 mg per day will generally be sufficient to prevent myxedematous symptoms and avoid hyperkinetic cardiovascular status, which can result in dysrhythmias (atrial fibrillation, tachycardia, etc.), which in the long term result in cardiac remodeling and systolic heart failure (09). The thyroid replacement dosage can then be gradually increased over months to a full replacement level while following serum thyroxine levels. (Thyroid stimulating hormone levels, in contrast to the more common primary hypothyroidism, should not be followed.)
Thyroxine is the treatment of choice taken once a day, starting with 100 mg in young patients and in the absence of cardiac disease, and 25 mg in elderly patients and those with coronary artery disease. ACTH deficiency should be identified and treated if present before starting thyroxine replacement. In patients with pituitary disease, TSH monitoring is unhelpful and, therefore, its measurement is pointless; the goals of thyroxine replacement should be clinical improvement along with the placing of the serum free thyroxine level within the normal range (49).
Sex steroid replacement therapy should be considered to preserve remaining bone mass, possibly restore libido, and provide a feeling of well-being. In men, testosterone therapy also helps preserve muscle mass. However, this should not be undertaken in individuals with macroadenomas until it is clear that they do not harbor macroprolactinomas, which may become enlarged when stimulated by sex steroids (50; 21). Estrogen is given as for postmenopausal women and is administered with progesterone for women with intact uteri to avoid endometrial hyperplasia. Young women often will not cycle well on the low postmenopausal estrogen dosages (eg, 0.625 mg of conjugated estrogens daily) and may require 2 to 3 times higher dosages of estrogen to experience withdrawal bleeding. Oral contraceptive therapy is another reasonable alternative. Prevalence of hypopituitarism has increased as a result of increases in causes such as traumatic brain injury and cranial irradiation. Although treatment with estrogen with or without progestogen is accepted as conventional therapy in women with hypopituitarism, testosterone supplementation in physiological doses for androgen-deficient women with hypopituitarism may improve psychological well-being and sexual function and increase bone mineral density and lean body mass (73). Population-based studies reveal that low testosterone levels predict development of type 2 diabetes mellitus, metabolic syndrome, and survival. Also, testosterone replacement therapy has been shown to have positive effects on sexual function, mood, body composition, muscle mass, and bone density in men with hypogonadism as well (07). Testosterone is currently available as depot injection (200 to 300 mg every 2 to 3 weeks) and by scrotal or dermal patches.
Diabetes insipidus is not life-threatening unless thirst is also deficient or the patient cannot access fluids. The polyuria and polydipsia are treated only to relieve symptoms. Therapy consists of the use of desmopressin, a long-acting analog of vasopressin. Both a nasal solution and oral tablets are currently available. Patients should be instructed to use the minimum amount to provide symptomatic relief (typically 0.05 to 0.2 mL [5 to 20 mcg] intranasally once or twice a day).
Patients and their families need to be made aware of the potential seriousness of stressful situations that increase the requirements for glucocorticoids. Patients should carry identification at all times in case of traumatic injury or sudden illness, requiring assistance from emergency medical personnel. Glucocorticoids should be doubled or tripled in mild to moderate organic illnesses, especially those associated with fever. No increases are required for mental stressors or mild upper respiratory syndromes not accompanied by fever. For vomiting, the patient should assume medication taken within the past hour is not absorbed and repeat the dose. If vomiting or diarrhea preclude adequate administration, parenteral glucocorticoids are necessary. Reliable patients should be given a syringe prefilled with dexamethasone (4 mg) for intramuscular self-injection to use in emergencies prior to presentation to a medical facility. This would be especially important for those who reside in remote areas or who travel to underdeveloped countries.
Both fractionated radiotherapy and stereotactic radiosurgery are efficient treatment modalities for the control of tumor growth in patients with pituitary adenomas. One study indicated that single-dose radiosurgery more promptly produces an effect on the hypersecretion of pituitary hormones and may be recommended over fractionated radiotherapy for suitable patients (30). Szerlip and colleagues report the use of iMRI for pituitary adenoma resection (63). They find its use helpful in clinical decision making, guiding safe resection, identification and preservation of pituitary stalk and normal pituitary gland and potential avoidance of hypopituitarism. iMRI also helps to detect postoperative complications sooner helping with improved outcomes. Hypopituitarism in patients presenting with a pituitary adenoma is generally considered to be permanent. However, it has been suggested that in a significant number of patients, pituitary function recovers after transsphenoidal adenomectomy. This may be due to normalization of intrasellar pressure and blood flow (70).
Because of the proven association between traumatic brain injury and hypopituitarism, it is imperative that anterior pituitary hormonal function be assessed to attain maximal improvement in mental and physical functioning as well as in quality of life for victims of traumatic brain injury. It is proposed that appropriate hormone replacement therapy for those patients with both traumatic brain injury and traumatic brain injury-induced pituitary function impairment could lead to correction of underlying causes of traumatic brain injury sequelae (69).
With appropriate hormonal replacement therapy, patients with hypopituitarism can expect to lead reasonably normal lives. Some (54), but not all (06) studies have demonstrated increased mortality compared to age-matched control groups, however, with most of the increased risk attributable to death from cardiovascular diseases. The principal complications are those of inappropriately replaced hormonal milieu. In compliant patients, acute adrenal insufficiency often develops in the setting of severe stressors such as major surgery, illness, or accidents, if glucocorticoid administration is not appropriately increased. Central hypogonadism produces infertility, which can be overcome only by intensive hormonal therapy. Adequate replacement of pituitary hormones can greatly enhance quality of life, morbidity, and mortality associated with hypopituitarism (57). Srimanee and colleagues describe osmotic demyelination syndrome in 2 cases of preoperative sellar region tumor associated with hypopituitarism and secondary adrenal insufficiency (62). Both patients had hyponatremia, and the neurologic manifestations were generalized dystonia and osmotic demyelination syndrome followed by rapid correction of hyponatremia. Persistent hyponatremia has been reported with Sheehan syndrome (05).
The pituitary gland can become damaged during surgery either via direct trauma or ischemia from blood loss or vessel manipulation. Hypopituitarism can even occur in transsphenoidal pituitary surgeries. Some patients experience gradual loss in pituitary function after sphenoid surgeries. One case report included a patient who sequentially lost the ability to produce sufficient amounts of various hormones, in order, growth hormone, luteinizing hormone, thyroid stimulating hormone, and then adrenocorticotropic hormone. It is important to monitor these hormone levels in the postoperative period (18).
The first documentation of enlargement of the pituitary gland during pregnancy was recorded in a doctoral dissertation by the French physician Comte in 1898 (11). Uterine atony results in significant bleeding immediately after delivery, or the puerperium period, and is usually accompanied by significant hypotension or severe anemia, leading to hypoperfusion of the enlarged gland. Essential criteria for the diagnosis of Sheehan syndrome include severe postpartum uterine bleeding, at least 1 pituitary hormone deficiency, and/or a partial or complete empty sella on MRI or CT imaging. Severe hypotension during delivery, postpartum amenorrhea, or postpartum agalactia are strongly suggestive of Sheehan syndrome as well (16).
The principal problem concerning hypopituitarism and pregnancy is that the hypogonadal state makes it unlikely that future spontaneous pregnancy can occur. Once pregnancy occurs, however, only thyroid hormone needs to be adjusted (increased by about 50% on average) (37). At the onset of labor, "stress doses" of glucocorticoids (eg, 100 mg of hydrocortisone every 8 hours) should be given until the first day postpartum and then quickly tapered back to maintenance dosages. Patients with diabetes insipidus often require exogenous infusion of oxytocin to initiate and maintain labor. Both oxytocin- and prolactin-deficient women cannot effectively breastfeed.
Vila and colleagues studied pregnancies associated with growth hormone deficiency and hypopituitarism (71). A large group from 85 outpatient clinics at medical centers in 15 countries participated in the trial. The authors investigated potential factors determining pregnancy outcomes and pregnancy complications. They found that pregnancy outcomes and pregnancy complications were not related to growth hormone replacement therapy treatment patterns, method of conception, or number of additional pituitary deficiencies.
The physiological stress response to surgery includes an increase in circulating cortisol. This response to stress was a primitive way of aiding survival. In a patient with hypopituitarism, this cortisol response must be artificially created; however, using the minimal amount of steroid replacement will optimize postoperative recovery and avoid deleterious side-effects.
The necessary amount of perioperative hydrocortisone varies depending on the length and type of surgery. For those taking high-dose steroids as home medications, it is imperative to closely manage the dose of steroids during the perioperative period (Nicholson and Hall 1998).
Generally, 150 to 300 mg of hydrocortisone is given on the day of surgery with around 60 to 200 mg given on postoperative day 1 with a following taper over several days (20).
Mousa K Hamad MD
Dr. Hamad of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
Ryan M Holland MD
Dr. Holland of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
Aisha S Obeidallah BA
Ms. Obeidallah of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
Reza Yassari MD MS
Dr. Yassari of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
Douglas J Lanska MD FAAN MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health, the Medical College of Wisconsin, and IM Sechenov First Moscow State Medical University has no relevant financial relationships to disclose.See Profile
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