Clinical manifestations

Presentation and course

The initial clinical presentation of hypopituitarism spans a spectrum from rare life-threatening episodes of acute adrenal insufficiency to the slow, insidious development of nonspecific symptoms such as lassitude and fatigue, which are often ignored by patients, their families, and their physicians. Hypopituitarism tends to have a slow and gradual presentation over a time period of weeks to months due to the slow depletion of pituitary hormones. Hypopituitarism can remain clinically silent until a stressful event catalyzes the presentation of marked symptoms (96). 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 hormones that have been diminished. For instance, low cortisol levels can present as hypotension, hypoglycemia, hyponatremia, or hyperkalemia. Hyponatremia with hypopituitarism-induced adrenal insufficiency may result in recurrent episodes of altered sensorium (09). Low levels of 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 (96).

Although most symptoms of hypopituitarism are similar to those that occur with failure of the target gland, there are some important differences. For example, hypocortisolism from hypopituitarism lacks the hyperpigmentation that occurs in primary adrenal failure (Addison disease). Symptoms of hypothyroidism from hypopituitarism 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 with hypopituitarism 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 (and rarely in men).

Growth hormone deficiency had traditionally been thought to be asymptomatic in adults. However, a cluster of characteristics are now recognized as features of 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. With 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, growth hormone deficiency causes growth delay and hypoglycemia, and gonadotropin deficiency prevents pubertal development.

Prognosis and complications

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 (26; 86). Several studies have documented a reduced quality of life in patients treated for hypopituitarism due to persisting psychological and physical impairments. These complaints are partly caused by intrinsic imperfections of hormone replacement strategies in mimicking normal hormone secretion.

Hypopituitarism has also important socioeconomic effects, with increased annual health costs compared to the normal population (94).

Patients with hypopituitarism have increased mortality (92). Affected women have higher mortality than affected men, but 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 is a predictive factor for survival (72).

Clinical vignette

The following are fictitious vignettes demonstrating examples of patients with hypopituitarism.

Case 1. A 24-year-old woman (gravida 1 para 1) with no significant past medical history presented 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 stated 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 levels of free thyroxine, cortisol, thyroid stimulating hormone, and ACTH. All other hormones were within normal limits. MRI of the brain did not show any mass lesions, but the sella turcica appeared empty, apparently containing only cerebrospinal fluid.

A diagnosis of Sheehan syndrome was made, and she was started on hormone replacement therapy.

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 presented to the emergency department with the worst headache of her life. She became lethargic in the waiting room, requiring intubation. A CT of the head demonstrated diffuse subarachnoid hemorrhage with intraventricular extension and hydrocephalus. A ventriculostomy catheter was inserted. A cerebral angiogram demonstrated an 8 mm anterior communicating artery aneurysm, which was coiled by the interventional neuroradiologist. She was extubated after the procedure. On postoperative day 1, her urine output was noted to be greater than 500 ml per hour for 3 hours, and her sodium jumped from 134 to 156. The endocrinology team recommended as needed the use of 2 micrograms of intravenous DDAVP with close monitoring, including 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, which was tapered and discontinued by 3 months.

Biological basis

Etiology and pathogenesis

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 (93).

For lesions that directly affect the pituitary gland, the observed probability of hormone loss is 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, whereas microadenomas are smaller than this. Macroadenomas may cause hypopituitarism by various mechanisms, including compression of the normal pituitary gland, occlusion of the portal capillary flow of hypothalamic hormones, and compression of the hypothalamus. The potential for hypopituitarism increases as macroadenomas invade the suprasellar space, compressing the optic chiasm, and ultimately the hypothalamus. Virtually all of these individuals develop growth hormone deficiency, and approximately 30% also lose other pituitary hormones, although the loss may not be permanent if the tumor is removed (03) or is reduced by medical therapy (64). In a study of 269 patients with nonfunctioning pituitary adenomas, half (49%) of the patients were asymptomatic; the prevalence of hypopituitarism was 59% in symptomatic patients and 27% in the asymptomatic group (36). Eighty-seven percent of the pituitary adenomas in this study were macroadenomas (36).

Secretory tumors generally produce clinical syndromes such as acromegaly that may conceal or draw attention away from hypopituitarism arising either from destruction of the pituitary or interference with the hypothalamic-pituitary unit. Diabetes insipidus is unusual with anterior hypopituitarism that arises from intrasellar macroadenomas. 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 and are often associated with clinical diabetes insipidus.

Pituitary apoplexy is a potentially lethal event that results from hemorrhage into the pituitary gland, typically hemorrhage into a pituitary macroadenoma. Pituitary apoplexy becomes symptomatic via neurologic deficits or through severe adrenal crisis resulting from the acute lack of adrenocorticotropic hormone. This clinical state is characterized by headache, visual disturbances including field defects (bitemporal hemianopsia) and diplopia from ocular cranial nerve abnormalities (arising from compression of cranial nerves III, IV, and VI within the cavernous sinus), nausea, vomiting, neck rigidity, altered or depressed mental status, and if the hypothalamus is appreciably compressed, vegetative symptoms and signs including vascular instability. Pituitary apoplexy almost always produces acute hypocortisolism due to ACTH deficiency.

Another cause of acute hypopituitarism is postpartum pituitary necrosis (also known as Reye-Sheehan syndrome or Sheehan syndrome) (83). This typically occurs with difficult parturition associated with hypotension and blood loss, which produces a generally painless destruction of the pituitary gland. In ischemic pituitary 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. Rarely, diabetes insipidus ensues (less than 1% to 2% of the time), but it is often masked by coincident hypocortisolism. Rarely, diabetes insipidus can be the only damage observed (84; 70). Subsequent to pituitary destruction, there is an absence of lactation (due to loss of prolactin) and amenorrhea. 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 the 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 (91). Rarely, hemorrhage and necrosis can occur in normal pituitaries, due to hantaviral disease (22; 88). 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 (06).

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 from radiation delivered to treat head and neck tumors, which also 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 a 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 thyroid stimulating hormone deficiency (54). Because of the prolonged time of onset of insufficiency, patients receiving radiotherapy must be followed throughout life for the development of hypopituitarism.

Empty sella syndrome (ie, little or no pituitary tissue visible within the sella turcica on imaging) is sometimes reported as a "cause" of hypopituitarism (eg, with increased intracranial pressure), but it may be instead a consequence of pituitary damage, or it may be incidental without disrupted pituitary function. Increased intracranial pressure can lead to herniation of the subarachnoid space, which can in turn lead to compression of the pituitary gland. The term “empty sella” was coined to refer to the neuroradiological or pathological-anatomical finding of an apparently empty sella turcica (18). This situation develops because the sella turcica is filled with cerebrospinal fluid and the hypophyseal tissue at its base is flattened. Consequently, an empty sella is often regarded as a herniation of the subarachnoid space into the sella turcica (60). A distinction is made between partial empty sella syndrome, with less than 50% of the volume of the sella turcica filled with CSF, and "complete" empty sella syndrome, with more than 50% of the volume of the sella turcica filled with CSF (07).

Traumatic brain injury is now recognized as an important cause of hypopituitarism (49; 82). Direct trauma, such that may occur from accidents (33), projectiles such as bullets (56), and carotid aneurysms (71), can also cause hypopituitarism either immediately after the injury or following a delay of several years. Pituitary dysfunction, present months or years after traumatic brain injury, 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 the most common abnormalities (01).

Chronic hypopituitarism is a major cause of treatable morbidity among survivors of traumatic brain injury (48; 23). The pathophysiology of hypopituitarism after traumatic brain injury is not fully understood, and most theories involve transection of or damage to the pituitary stock (eg, associated with basilar skull fracture), but some have suggested venous infarction of the venous system surrounding the pituitary gland, pituitary injury from trauma-associated hypotension or elevated intracranial pressure, hypoxic brain injury, and more. Symptoms of gonadal dysfunction are more predictive of hypopituitarism than nonspecific symptoms for pituitary dysfunction following moderate or severe traumatic brain injury (27). Symptoms of hypogonadism are sufficiently predictive of hypopituitarism to justify screening for hypopituitarism after moderate/severe traumatic brain injury (90; 23). Nonspecific symptoms of hypopituitarism are no more predictive than unselected screening. One study found that 78% of patients developed inappropriately low plasma cortisol following traumatic brain injury (41). In addition, low plasma cortisol and cranial diabetes insipidus were predictive of mortality and long-term pituitary deficits in traumatic brain injury patients. Patients with traumatic brain injury who develop hypopituitarism frequently present metabolic alterations, in particular altered glucose levels, insulin resistance, and hypertriglyceridemia (74).

Many systemic diseases can infiltrate the pituitary and produce hypopituitarism. 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. In addition, 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, directly destroys pituitary tissue. Langerhans cell histiocytosis ("histiocytosis X") has a predilection for the basal hypothalamus. Lymphocytic infiltration can produce a pituitary mass and hypopituitarism—a condition termed “lymphocytic hypophysitis” (05); this generally occurs in young women in the postpartum period but has been reported in a postmenopausal woman (63) as well as in men (73).

Pituitary destruction is also part of the spectrum of the autoimmune polyglandular failure syndrome, which can produce simultaneous central and end organ dysfunction. Hypophysitis is one of the immune-related adverse events associated with immunotherapy, including immune checkpoint inhibitors (eg, CTLA-4, PD-1, and PD-L1 inhibitors), which typically involve the corticotrophic, thyrotrophic, and gonadotrophic axes or produce pananterior hypopituitarism (40; 25; 45). A paraneoplastic autoimmune hypophysitis, anti-PIT-1 hypophysitis, results from ectopic expression of pituitary antigens present in tumors causing production of autoantibodies and autoreactive cytotoxic T cells that specifically harm pituitary cells (12; 13; 43; 46; 47).

The iron overload that results from hemochromatosis targets the anterior pituitary gland (as well as other endocrine glands), especially the gonadotrophs (basophilic cells of the anterior pituitary gland specialized to secrete gonadotropins in response to elevation in intracellular calcium concentration).

There are many less common causes of hypopituitarism. These include congenital causes, eg, septo-optic dysplasia, direct trauma, and infiltrative diseases.

Neonatal hypopituitarism may be due to aberrations in embryological development, de novo and inherited genetic mutations, and perinatal and neonatal events (65; 66; 15). Neonatal onset hypopituitarism is usually detected in childhood due to growth arrest, but diagnosis may occasionally be delayed until adulthood. The anterior pituitary gland is derived from ectoderm, whereas the posterior pituitary is derived from neural ectoderm. Neonatal hypopituitarism can be further divided into congenital and perinatal/neonatal causes. Congenital causes include maternal hyperglycemia, congenital infections (such as syphilis and toxoplasmosis), hypothalamic-pituitary developmental defects, severe midline defects (such as those associated with cleft lip/palate), and genetic mutations. There are over 19 genetic mutations identified that can result in anterior pituitary hypoplasia, an ectopic posterior pituitary gland, or isolated loss of hormone producing cells (51).

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) (51).

Epidemiology

The overall prevalence of hypopituitarism in an adult Caucasian population in northwestern Spain was 45.5 cases per 100,000 population (81).

In a systematic review, the pooled prevalence of hypopituitarism was 28% in the chronic phase after traumatic brain injury but 47% in the chronic phase after aneurysmal subarachnoid hemorrhage (82). Another study found an even higher prevalence of pituitary dysfunction after aneurysmal subarachnoid hemorrhage, but this does not affect 6- to 12-month clinical outcomes: pituitary dysfunction (particularly dysfunction of the pituitary-gonadal axis) was present in 92% of cases in the acute phase, in 83% in the subacute phase, and in 83% in the chronic phase (78). Some studies have shown an association between the severity of traumatic brain injury and development of post-traumatic hypopituitarism, with hypopituitarism more frequent among patients with severe traumatic brain injury. The rates of neuroendocrine dysfunction after acute aneurysmal subarachnoid hemorrhage have been extremely variable, ranging from 4% to 92% in different studies less but still considerable variability in patients with chronic aneurysmal subarachnoid hemorrhage (47% to 83%) (10).

In the 2016 systematic review and evidence-based guidelines, the Congress of Neurological surgeons found a high prevalence of hypopituitarism (37% to 85%) among patients evaluated for pretreatment endocrinological evaluation of nonfunctioning pituitary adenomas (35). The most common hormonal axis deficiency was growth hormone deficiency (61% to 100%), followed by hypogonadism (36% to 95%), adrenal insufficiency (17% to 62%), and hypothyroidism (8% to 81%) (35). No point estimates were provided (35). Hyperprolactinemia was seen in 25% to 65% of patients, with a mean level of 39 ng/mL and with a minority of patients exceeding a serum prolactin level of 200 ng/mL.

A later retrospective study from two medical centers found that hypopituitarism was present in 80% of 246 patients with nonfunctioning pituitary macroadenomas (02).

Prevention

Traumatic causes of hypopituitarism can be prevented: appropriate measures to decrease the frequency and severity of head injury (highway speed limits, seat belts, bicycle and motorcycle helmets, 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.

Differential diagnosis

Confusing conditions

The differential diagnosis always includes most importantly primary endocrine gland failure, which usually involves only one 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 to recognize the presence of concomitant adrenal failure that will require the addition of mineralocorticoids to glucocorticoids as maintenance therapy.

Associated or underlying disorders

The differential diagnosis of hypopituitarism depends on age (81). The most common causes of hypopituitarism in children were congenital disorders and sequelae from whole brain irradiation. In young adults, non-adenomatous tumors, particularly craniopharyngiomas and dysgerminomas, were the most common causes. In adults, the predominant causes of hypopituitarism were pituitary macroadenomas or damage from medical treatment such as surgery, radiation, and chemotherapy.

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) because 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 (85; 83). 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.

In a study of 33 cases of pituitary abscess, symptoms were generally typical of an intrasellar mass, generally without any symptomatic evidence for infection (55). Diabetes insipidus, hypopituitarism, and headaches were the most salient features. MR imaging with and without gadolinium revealed an intrasellar mass with an enhancing rim. Thirty cases were treated with antibiotics and surgery (transsphenoidal evacuation), whereas three patients were treated with antibiotics only. Despite some recurrences, abscesses resolved in nearly all cases; however, protracted hypopituitarism remained protracted necessitated hormone replacement therapy.

Features of Oliver-McFarlane syndrome include chorioretinopathy, pituitary dysfunction with hypopituitarism, and trichomegaly-chorioretinopathy (80; 39). This condition may mimic choroideremia-hypopituitarism association (62). However, the latter condition is associated with a 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).

In cases of congenital hypopituitarism, pituitary stalk interruption is a well-known entity, but only rarely has a known genetic cause been assigned to these cases. PROKR2 variants in some cases suggest a potential role of the prokineticin pathway in pituitary development (77).

Hypopituitarism is a well-known manifestation among the multitude of neurologic abnormalities that occur with nonsyndromic mitochondrial disorders. A high index of suspicion is needed for diagnosis.

Diagnostic workup

Definitive diagnosis of hypopituitarism primarily depends on certain laboratory studies, particularly the measurement of basal anterior pituitary and target organ hormone levels. Usual tests include thyroid stimulating hormone, thyroxine, follicle-stimulating hormone, LH, estradiol in women or testosterone in men, prolactin, insulin-like growth factor 1, and morning (AM) cortisol (72).

If growth hormone deficiency is suspected, at least one 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 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 established by low basal serum free/total thyroxine levels with a normal to low thyroid stimulating hormone 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. A gonadotrophin releasing hormone (GnRH) provocation test has not been found to provide any additional information in adults (20).

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 with measurement of basal and hourly plasma and urine osmolalities, as well as urine volumes. After 8 hours, intramuscular desmopressin 2 mg is injected, and then blood and urine osmolalities are remeasured. 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 patients with 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 (72).

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 effects predominate, such as bitemporal hemianopsia, resulting from upward mass effect on the optic chiasm. Because the macula (and, therefore, central vision), is usually spared with mass lesions of the pituitary, 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 consequently 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 10 mm in diameter or more. Macroadenomas often produce enlargement of the sella turcica and may cause erosion of portions of it. There may also be extension into the suprasellar cistern, sphenoid sinus, or cavernous sinus (69).

In the 2016 systematic review and evidence-based guidelines, the Congress of Neurological Surgeons recommended high-resolution MRI (level II) as the standard for preoperative assessment of nonfunctioning pituitary adenomas, which may be supplemented with CT (level III) and fluoroscopy (level III) (21). On T1-weighted MR images, adenomas are hypo- to iso-intense and have poor uptake of gadolinium. On T2-weighted MR images, adenomas are isointense to white matter (69). 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). MRI findings associated with traumatic damage include pituitary-stalk deviation, signal inhomogeneity (attributable to hemorrhage or infarction), or an empty sella (17).

Not all sellar enhancing lesions causing hypopituitarism are pituitary adenomas as evidenced, for example, by anecdotal reports of giant aneurysms of the internal carotid artery causing hypopituitarism (53). Although symptoms are similar to those of pituitary adenomas, the presence of rim-like calcification around the intrasellar mass on CT and flow-related effects on T2-weighted MRI support the diagnosis of an aneurysm. Confirmation of an intrasellar cerebral aneurysm is obtained with a cerebral angiogram (52). The prevalence of intrasellar giant aneurysms is estimated at 0.2% (42).

A comparative study found that MR imaging findings were similar in patients with lymphocytic hypophysitis and those with pituitary adenomas; however, the presence of the parasellar T2 dark sign in lymphocytic hypophysitis was a specific finding that distinguished it from pituitary adenoma (67).

In the 2016 systematic review and evidence-based guideline, the Congress of Neurological Surgeons recommended preoperative ophthalmologic evaluation including both functional and anatomic assessment in the evaluation of patients with pituitary macroadenomas (68). The evaluation may provide prognostic factors for recovery and, when paired with postoperative evaluation, can document postoperative changes (68; 69). In addition to formal ophthalmologic examination, tests of value include automated static perimetry and optical coherence tomography. A normal retinal nerve fiber layer thickness demonstrated on optical coherence tomography supports an increased propensity for visual recovery, whereas those with a thin retinal nerve fiber layer show limited improvement over a longer time frame (months) (29). Older patients and patients with longer duration (more than 4 months) of vision loss should be counseled regarding the reduced chance of improvement in vision postoperatively (68).

Individuals presenting with optic nerve hypoplasia are at high risk for neuroradiologic and endocrine abnormalities (61). The neuroradiologic features are predictive of the presence and the type of hypopituitarism, though the etiology remains unidentified in the majority of cases.

Management

The goals of hormone replacement therapy in hypopituitarism are to achieve normal levels of the circulating hormones with minimal side effects (72). The treatment of hypopituitarism may require a multidisciplinary team of endocrinologists, neurosurgeons, neurologists, 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, may be amenable to treatment with dopamine agonists, but a recurrent ACTH producing pituitary neoplasm is likely to require a combination of surgical and nonsurgical treatments.

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 (19). 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, thyroid stimulating hormone 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 (72).

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 (73; 38). Estrogen is given for postmenopausal hormone replacement 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. 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 (98). 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 (16). Testosterone is currently available for administration by 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 is with 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 medical-alert 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 is 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 (50). Szerlip and colleagues report the use of iMRI for pituitary adenoma resection (89). 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 (94).

Symptomatic macroadenomas. Both fractionated radiotherapy and stereotactic radiosurgery can be effective treatment modalities for the control of tumor growth in patients with pituitary macroadenomas. In one study, single-dose radiosurgery promptly produced an effect on the hypersecretion of pituitary hormones and was recommended over fractionated radiotherapy for suitable patients (50).

Transsphenoidal surgery is the treatment of choice for Сushing disease, with an effectiveness ranging from 70 to 90% and recurrence after successful treatment of about 25% (97). If surgical treatment is unsuccessful or recurrence occurs, radiation treatment is the next therapeutic option, with about 90% effectiveness, but the hypopituitarism rate as a side effect of treatment is higher (97).

Surgical resection is recommended as the preferred primary intervention for symptomatic nonfunctioning pituitary macroadenomas. Hypopituitarism is present in 80% of patients with nonfunctioning pituitary macroadenomas, and about half achieve sustained improvement after surgical resection (02). Hyperprolactinemia at diagnosis and lower tumor dimensions are associated with favorable endocrine prognosis. These results support the option of early surgery in patients with nonfunctioning pituitary macroadenomas who have pituitary deficits, independent of the presence of visual disturbances.

In a 2016 systematic review and evidence-based guideline, the Congress of Neurological Surgeons found that multiple retrospective studies and some prospective studies had demonstrated consistent effectiveness of primary surgical resection of symptomatic nonfunctioning pituitary macroadenomas with acceptable morbidity rates (57). Surgery produces an immediate tumor volume reduction in nearly all patients and a residual tumor rate of 10% to 36% (57). One prospective, observational cohort study and multiple retrospective studies showed improved visual function (75% to 91% of surgically treated patients) and improved hypopituitarism (35% to 50% of surgically treated patients). Limited class II evidence showed inconsistent benefits for observation alone, primary radiation-based treatment, or primary medical treatment (ie, using somatostatin analogs, dopamine agonists, or combination therapy) for improving vision, headaches, hypopituitarism, or tumor volume. One retrospective study of observation alone showed tumor progression in half of the patients and a requirement for surgery in 21%. Studies reporting primary radiosurgery treatment of nonfunctioning pituitary macroadenomas showed decreased tumor size in 38% to 60% of patients. Although reports for alternative treatment strategies to primary surgical resection are limited and inconsistent, such modalities may play a valid role in patients who are not surgical candidates.

Posttreatment follow-up. In a 2016 systematic review and evidence-based guideline, the Congress of Neurological Surgeons made recommendations for the posttreatment follow-up evaluation of patients with nonfunctioning pituitary macroadenomas (99). The authors recommended long-term radiologic, endocrinologic, and ophthalmologic surveillance monitoring after surgical or radiation therapy treatment of nonfunctioning pituitary macroadenomas to evaluate for tumor recurrence or regrowth, and to monitor pituitary and visual status. The first radiologic study to evaluate the extent of resection of a nonfunctioning pituitary macroadenomas should be performed at least 3 months after surgical intervention (99).

Outcomes

Postoperative visual outcome following microscopic transsphenoidal surgery for pituitary adenomas is proportional to preoperative visual acuity (32). Although the visual outcomes are good in the long run, regardless of the duration of symptoms, the speed of recovery is proportional to the presurgical duration of visual deficits (32).

Hypopituitarism in patients presenting with a pituitary adenoma is generally considered to be permanent. However, pituitary function recovers after transsphenoidal adenomectomy in some patients, possibly due to normalization of intrasellar pressure and blood flow (94). In addition, approximately 50% of patients with pituitary adenomas and preoperative hypopituitarism recover pituitary function after endoscopic endonasal transsphenoidal resection, whereas 10% of patients with normal function develop new deficits (04). Patients with nonfunctioning pituitary adenomas with visual involvement and operated on in the first 4 years of the neurosurgeon's learning curve, and patients with functioning pituitary adenomas with presurgical visual impairment and tumor size larger than 3 cm, have a higher risk of postoperative hypopituitarism (04).

With appropriate hormonal replacement therapy, patients with hypopituitarism can lead reasonably normal lives. Some (79), but not all (14) studies have demonstrated increased mortality among compared patients with hypopituitarism to age-matched control groups with most of the increased risk attributable to death from cardiovascular diseases. The principal complications are those of inappropriately replaced hormones (either too high or too low). Acute adrenal insufficiency may develop 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 (81). Osmotic demyelination syndrome and generalized dystonia have been reported with rapid correction of hyponatremia in two patients with preoperative sellar region tumors associated with hypopituitarism and secondary adrenal insufficiency (87). Persistent hyponatremia has been reported with Sheehan syndrome (11).

Special considerations

Pregnancy

The first documentation of enlargement of the pituitary gland during pregnancy was recorded in a doctoral dissertation by the French physician Louis Comte (1870-?) in 1898 (24). 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 pituitary gland. Essential criteria for the diagnosis of Sheehan syndrome include severe postpartum uterine bleeding, deficiency of at least one pituitary hormone deficiency, or a partial or complete empty sella on MRI or CT imaging. Severe hypotension during delivery, postpartum amenorrhea, or postpartum agalactia are also strongly suggestive of Sheehan syndrome (31).

The hypogonadal state resulting from hypopituitarism makes it unlikely that future spontaneous pregnancy can occur without assisted reproductive techniques (08). If pregnancy occurs in a woman with hypopituitarism, some have suggested that only the thyroid hormone needs to be adjusted (increased by about 50% on average) (58). Others have advocated a more inclusive replacement of deficient hormones (ie, increased dosage of replacement treatment for thyroid stimulating hormone, ACTH, and antidiuretic hormone deficits and discontinuation of growth hormone) (08). 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. Pregnancy outcomes in women with panhypopituitarism are comparable to those of the general population (34), though with a high rate of excessive gestational weight gain and cesarean section (08).

In a large group of pregnancies associated with growth hormone deficiency and hypopituitarism identified from 85 outpatient clinics at medical centers in 15 countries, pregnancy outcomes and pregnancy complications were not related to growth hormone replacement therapy treatment patterns, method of conception, or number of additional pituitary deficiencies (95).

Anesthesia

The physiological stress response to surgery includes an increase in circulating cortisol. In a patient with hypopituitarism, this cortisol response must be pharmacologically created; 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.

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 (37).