Anatomy, Neurohypophysis

Structure and Function

Etiology

Several etiologies contribute to neurohypophyseal dysfunction. These factors disrupt hormone synthesis, transport, or release, leading to impaired posterior pituitary function.

Neoplastic causes include pituitary adenoma, hypothalamic glioma, craniopharyngioma, pituicytoma, granular cell tumors, and germ cell tumors. These lesions may compress or infiltrate the hypothalamic–neurohypophyseal axis, impairing hormone synthesis, transport, or release.

Traumatic brain injury (TBI) may disrupt hypothalamic or pituitary connections, leading to impaired neurohypophyseal function. Brain surgery represents an iatrogenic cause, with potential damage to the pituitary stalk or surrounding structures. Radiation exposure may similarly result in delayed injury to neuroendocrine tissues.

Inflammatory causes include sarcoidosis, multiple sclerosis, pituitary hypophysitis, Langerhans cell histiocytosis, and hemochromatosis. These conditions involve infiltration or immune-mediated damage to the hypothalamic–pituitary axis, resulting in hormonal dysregulation.

Infectious etiologies include meningitis, encephalitis, acquired immunodeficiency syndrome, abscess, septic shock, and subarachnoid hemorrhage. These processes may directly injure neurohypophyseal structures or disrupt vascular supply.

Hypoxic and vascular insults include Sheehan syndrome, pituitary apoplexy, cardiac arrest, and hydrocephalus. Reduced perfusion or increased intracranial pressure may impair posterior pituitary function. Anorexia may also contribute through metabolic and hypothalamic dysregulation. Aneurysm of the anterior communicating artery may compress adjacent neuroendocrine structures.

Congenital causes include pituitary stalk interruption syndrome, characterized by abnormal development of the hypothalamic–pituitary connection. Genetic disorders such as Prader–Willi syndrome and multiple endocrine neoplasia type 1 may involve hypothalamic or pituitary dysfunction through inherited mechanisms.

Pharmacologic etiologies include phenothiazines, carbamazepine, valproic acid, omeprazole, selective serotonin reuptake inhibitors, morphine, 3,4-methylenedioxymethamphetamine (ecstasy), vincristine, amitriptyline, immune checkpoint inhibitors, opioids, and megestrol acetate. These agents may alter the secretion or action of neurohypophyseal hormones through central or peripheral mechanisms.

Epidemiology

Disorders of the neurohypophysis have variable etiologies that affect populations from a young age to late adulthood; the etiology influences the condition's frequency. The prevalence of hypopituitarism is 29 to 45 per 100,000, with an incidence of 4.2 new cases per 100,000 per person per year, with no gender predominance.[4] Most studies evaluate the dysfunction of the entire pituitary gland.

In AVP-D, the reported incidence after traumatic brain injury (TBI) is between 3 to 50%. Its frequency varies widely, as the diagnostic parameter used in each study may underestimate its true incidence. Hyponatremia affects 15% of hospitalized patients. The SIADH secretion causing hyponatremia has been reported as the most common abnormality following a TBI in children and adults.[5] SIADH secretion is responsible for 46% of the cases of hyponatremia, which is the most common electrolyte abnormality in outpatient practise. For some neurological conditions, the presentation of SIAD is more than 70%. In neurosurgical units, SIADH occurs in 5% to 10% of cases due to disorders of the posterior neurohypophysis.[6]

The neurohypophysis is a popular site for germinomas, which are most commonly found in the pineal region. Presentation in the neurohypophyseal/pineal region is common in germinomas. Half of the patients with a combined tumor at the pineal and pituitary gland are germinomas.[7]

Pituitary stalk interruption syndrome presents with a triad that consists of the ectopic posterior pituitary, thin or absent pituitary stalk, and anterior pituitary hypoplasia. AVP-D occurs in up to 10% of cases. It is more prevalent in males (2:1). In patients with hypopituitarism, it can be the etiology in 4-8% of cases.[8][9][10][11][12][13]

Granular cell tumors arise primarily in the neurohypophysis and have been discovered in 9% of routine neurohypophysis autopsy specimens.[14][15] They are considered to be unique neoplasms of the neurohypophysis and pituitary stalk; they have been suggested to derive from pituicytes. They occur more frequently in women than in men (2:1).[16][17] Granular cell tumors comprise 0.17 % of resected sellar lesions in major transsphenoidal series.[18]

Sheehan syndrome is more prevalent in developing countries and is estimated to occur in approximately 3.1% of parous women, with home delivery being more common. Sheehan syndrome causes 6-8% of all causes of hypopituitarism.

Pathophysiology

The neurohypophysis secretes two neurohormones: oxytocin, which increases uterine contractions, and vasopressin, which increases water reabsorption by the distal tubules of the kidney. These hormones are packaged in secretory vesicles and granules within magnocellular neurosecretory cells in the hypothalamus. They are released from the paraventricular and supraoptic nuclei of the hypothalamus and travel down axons of magnocellular cells to the neurohypophysis.[19] 

The hormones are then stored in the herring bodies of the neurohypophysis, which are the terminal ends of the axons. Upon release from the herring bodies, action potentials are produced, activating voltage-gated channels that allow calcium to enter and trigger the release of the hormone into the neurohypophyseal capillaries, which then transport the hormone into the systemic circulation. Predominantly, the paraventricular nucleus is related to oxytocin secretion, while the supraoptic nucleus is concerned with vasopressin secretion. Small amounts of each hormone are also produced at the other nuclei. The release of these hormones is triggered by afferent stimuli from neurons projecting to the magnocellular neurons of the hypothalamus.

The neurohypophysis receives its blood supply from the inferior hypophyseal artery, a branch of the cavernous internal carotid (ICA) artery. The cavernous ICA has a dorsal trunk, the meningohypophyseal trunk, which gives rise to 3 terminal branches: the inferior hypophyseal artery, the tentorial artery (artery of Bernasconi and Cassinari), and the dorsal meningeal artery. Venous drainage of the posterior pituitary gland is by the short portal and hypophyseal veins into the cavernous sinus.

Sheehan syndrome can develop AVP-D and hypernatremia due to ischemic necrosis damage to the posterior gland, causing impaired vasopressin secretion. Hyponatremia can also occur due to an increased ADH secretion as a response to hypotension and reduced cardiac output owing to glucocorticoid deficiency. Also, the cortisol deficit stimulated the secretion of corticotropin-releasing hormone, which further stimulates the ADH secretion.[20]

During septic shock, vasopressin secretion undergoes a biphasic pattern. Initially, there is an increased secretion to maintain homeostasis, but later, when hypotension is pronounced, there is an unexpected, significant decrease in the secretion. This decrease is thought to result from depletion of vasopressin stores in the neurohypophysis, autonomic dysfunction, and nitric oxide-mediated inhibition of secretion in the hypothalamus.[21]

In TBI, AVP-D is caused by direct damage to the neurohypophysis, pituitary stalk, hypothalamic nuclei, or the vascular supply, or by traumatic edema in the neurohypophysis or hypothalamus. These changes are usually reversible, but irreversible changes with gliosis can cause permanent DI.[22][23]

Histopathology

The neurohypophysis is made of the axons arising predominantly from magnocellular neurons of the supraoptic and paraventricular nuclei of the hypothalamus. They form the hypothalamohypophyseal tract, and these axons terminate near the sinusoids of the posterior lobe. The neurosecretory granules mostly contain oxytocin or vasopressin. The axon terminals are supported by pituicytes, which express the Thyroid transcription factor (TTF)-1 and demonstrate only patchy GFAP and S100 expression.[24]

Clinical Significance

History and Physical

For patients presenting with disorders of neurohypophysis, obtaining a detailed history, including previous medication, is prudent. It is essential to assess recent medical history for depression, psychosis, seizures, or cancer because some antidepressants, anticonvulsants, antipsychotic agents, and cytotoxic agents can cause SIADH secretion. Any previous history of stroke, malignancy, or trauma to the head should be obtained in detail. For patients who are unable to provide their history, questioning how the patient was immediately before the episode is essential. The most common presentation of SIAD is hyponatremia with euvolemic fluid status, with clinical features including normal blood pressure, regular heart rate, normal skin turgor, moist mucous membranes, absent jugular venous pulsations, no pitting edema, and normal central venous pressure if measured. Clinical manifestations include nausea, vomiting, restlessness, headache, lethargy, obtundation, seizures, coma, and respiratory arrest. These manifestations progress as the level of hyponatremia advances from mild to severe.

In a presentation of AVP-D due to neurohypophysis dysfunction, it is essential to rule out other acquired etiologies, as treatment should address the primary etiology causing the symptoms. Neurosurgery is the most common cause, and these patients should be closely monitored. There is a triphasic presentation in these cases post-surgery: AVP-D in the first 48 hours, SIAD from day 3 to 7, and permanent AVP-D.[25] The most common symptoms of AVP-D include polyuria and polydipsia, with patients complaining of increased thirst that, at first, can be controlled by increasing water intake to maintain normal serum osmolality and volume status. Some patients with altered neurological status will not recognize the thirst sensation and will not be able to drink water, developing free water deficiency with hyperosmolarity, hypernatremia, and signs of dehydration that can progress to hypertonic encephalopathy with irritability, confusion, disorientation, muscle twitching, seizures, coma, and death. Other symptoms include weakness, fatigue, and myalgias.

Some patients may develop acute kidney failure, hypotension, muscle damage, and even hepatic failure. There is an increased incidence of subarachnoid hemorrhage, strokes, and deep vein thrombosis in the setting of hyperosmolar states.[26] Adipsic AVP-D is a condition that is crucial to recognize because patients lack the sensation of thirst. It is caused by infarction of the anterior hypothalamus, where osmoreceptors are located, impairing their normal homeostatic thirst mechanism despite the symptoms of AVP-D.[27] Despite being dehydrated, the patient will not drink an adequate amount of water.

Evaluation

When a patient presents with a disorder of the neurohypophysis, its manifestation is most commonly related to a disorder of the antidiuretic hormone. Antidiuretic hormone acts on the distal collecting duct, increasing free water reabsorption and promoting indirect sodium excretion. Any disturbances related to this hormone can create sodium electrolyte abnormalities.

Brain magnetic resonance imaging, the gold standard for visualizing the anterior and posterior pituitary, should be ordered to identify or rule out possible etiologies that can cause neurohypophysis dysfunction.

AVP Deficiency

Serum and urine sodium and osmolality, hourly urine output, 24-hour urine volume, and specific gravity must be obtained. AVP-D must be distinguished from AVP-R(Arginine Vasopressin Resistance, formerly known as Nephrogenic DI). A water deprivation test can be used with or without desmopressin injection. In AVP-D, the vasopressin will correct urine osmolality, while in AVP-R, the correction will be suboptimal.[28][29]

Criteria for the diagnosis of AVP-D:

• Polyuria in two consecutive hours of > 300 ml/hr or 4 to 5 ml/kg/hr in two consecutive hours
• Polyuria > 3L/24 hours or > 2ml/kg/hr in 24 hours
• Serum osmolality > 295 mOsm/kg
• Urine osmolality < 300 mOsm/kg
• Urine/plasma osmolality <  1
• The specific gravity is <1.005
• Serum sodium: >145 mmol/L

SIAD

The first step is to assess the fluid status and obtain laboratory tests to evaluate serum and urine sodium, serum and urine osmolality, blood sugar, potassium levels, and liver function. When SIAD is suspected, it is important to order thyroid-stimulating hormone and thyroxine levels (TSH/T4) and serum cortisol to rule out thyroid and glucocorticoid hormone deficiency. The most common presentation in SIAD is hyponatremia with a euvolemic fluid status. Patients will have decreased plasma osmolality and increased sodium excretion.[30][31] Other causes of hyponatremia (adrenal insufficiency, hypothyroidism, cardiac failure, hepatic damage, renal disease, pituitary dysfunction, drugs) must be excluded.

Criteria for the diagnosis of SIADH secretion:

• Serum sodium < 135 mEq/L
• Serum osmolality < 275 mOsm/kg
• Urine osmolality  > 100 mOsm/kg
• Urine sodium  > 30 mEq/L
• Normal dietary and water intake 
• No recent use of diuretic agents
• Correction of the deficit with fluid restriction
• No signs of edema, heart failure, or renal dysfunction [32][33]

Treatment / Management

AVP-D

The medication recommended in the acute and chronic setting of AVP-D is desmopressin.[34][35] Desmopressin, D-amino D-arginine vasopressin (DDAVP), is given intranasally, orally, and intravenously with a half-life of 2 to 4 hours. It is crucial to establish the dose that improves the patient's polyuria and polydipsia without compromising plasma electrolytes. The water loss must be replaced. In acute DI after a TBI, it is mandatory to evaluate if the patient is conscious or unconscious. If the patient is conscious, encourage drinking. If the patient cannot drink, enforce fluid intake via nasogastric tube, guided by daily weight measurements. If the patient is unconscious, a 5% dextrose intravenous solution is administered. Treatment with DDAVP is administered at 10 mcg by nasal puff, or 0.4 to 4 mcg subcutaneously or intravenously. Maintenance is usually by 1 to 2 nasal puffs every 12 hours. Hypokalemia, if present, must be corrected. Urine volume, fluid balance, urine osmolality, plasma osmolality, and serum electrolytes must be monitored. The goal is to balance electrolytes and to have normal urine output. After desmopressin is given, it is essential to monitor sodium levels. In the management of hypernatremia in AVP-D, it is vital to use dextrose or nasogastric water at a rate that lowers plasma sodium concentration by 0.5 mEq/L/hr or less.

SIAD

Offending drugs or etiology should be treated first. Fluid restriction is the primary treatment for SIAD. Fluids should be reduced to 800 to 1000 mL/day. The correction should aim to reach a serum sodium of 130 mEq/L. If hyponatremia persists, patients could receive salt tablets and furosemide 20 mg twice a day. Isotonic fluids will not correct the deficit; therefore, 3% hypertonic (513 mOsm/kg) should be given for severe hypernatremia. A 100 mL bolus is given over 3 hours, and a repeat bolus may be given as needed based on serum electrolytes. In TBI, hypertonic saline will also help to reduce intracranial pressure. Correction should not be more than 8 mEq/L over 24 hours or 0.5 to 1 mEq/L per hour to prevent osmotic demyelination syndrome. The AVP receptor antagonists produce a selective water diuresis (aquaresis) without affecting sodium and potassium excretion. For persistent hyponatremia, oral tolvaptan or intravenous conivaptan, both vasopressin V2 receptor antagonists, are administered. Tolvaptan is hepatotoxic and can not be given to patients with liver disease. Demeclocycline, which is a tetracycline vasopressin inhibitor, can be given but can produce side effects of reversible azotemia, cirrhosis, and photosensitive skin rashes.[36] Urea has also been used to reduce natriuresis and has been comparable to vaptans in reversing hyponatremia in SIADH.

Differential Diagnosis

• Polydipsia
• Water intoxication
• Hypovolemia
• Arginine Vasopressin Resistance
• Congestive heart failure
• Cirrhosis
• Uncontrolled diabetes mellitus
• Chronic nausea/vomiting
• Cerebral salt wasting syndrome
• SIADH secretion
• Inappropriate intravenous therapy
• Glucocorticoid deficiency
• Hypothyroidism
• Pseudohyponatremia (hyperglycemic and hyperlipidemic patients)
• Drugs that affect ADH (carbamazepine, oxcarbazepine, chlorpropamide, cyclophosphamide, and selective serotonin reuptake inhibitors)
• Small-cell lung cancer 
• Non-pulmonary tumors secreting ADH-like substances
• Hypercalcemia
• Hypokalemia
• Histiocytosis

Prognosis

The prognosis for AVP-D is excellent after the primary cause is treated. Hypernatremia can lead to cerebral herniation due to an increase in intracranial pressure. When AVP-D has been diagnosed in trauma patients, the majority recover in 2 to 4 days, and the remaining few recover during a 6-month timeframe, which provides good patient outcomes. Permanent AVP-D after TBI has a prevalence of 6%. Acute onset of AVP-D in TBI increases the mortality rate.

For acute SIAD, the prognosis is related to the level of hyponatremia and its response to treatment. Hyponatremia is a major contributing factor to severe morbidity and mortality. The management of SIAD is complex, and water restriction does not always correct the hyponatremia, requiring further investigations and second-line treatments.

Complications

Potential complications include the following:

• Hyponatremia
• Hypernatremia
• Confusion
• Seizures
• Muscle twitching
• Lethargy
• Coma
• Death
• Lack of breastfeeding
• Poor uterine contraction
• Poor cervical dilatation
• Poor sexual response
• Depression

Deterrence and Patient Education

The management of a patient with disorders of the neurohypophysis can be challenging in the hospital setting. In certain situations, complications can be avoided with early recognition of symptoms and close monitoring. The presentation due to sodium abnormalities can be varied but can progress to coma and death if untreated. The patient must be aware of any changes in urine volume or an increase in thirst sensation. The patient needs to recognize polyuria, increased thirst sensation, muscle weakness, twitching, and confusion. In the presence of any of those symptoms, immediate contact with the primary physician is recommended for further assessment and evaluation.

Enhancing Healthcare Team Outcomes

Disorders of the neurohypophysis frequently present a diagnostic dilemma. Patients may exhibit non-specific signs and symptoms such as vomiting, nausea, hypernatremia, hyponatremia, and diuresis. The cause of neurohypophysis disorders can be multiple, including tumoral, traumatic, inflammatory, infectious, and metabolic etiologies. The etiology is difficult to determine without a thorough history and imaging studies.

The primary physician is usually responsible for the initial evaluation of the patient. The physician will determine whether it is an emergency or non-emergency situation, which depends on the presenting symptoms. Usually, an acute presentation is associated with more aggressive symptoms and treatment, while a chronic presentation can be managed more conservatively. The management will also depend on the type of neurohypophysis disorder.

While an endocrinologist is almost always involved in the care of patients with disorders of the neurohypophysis, it is essential to consult an interprofessional team of specialists, including a neurosurgeon and a neurologist. The nurses are also vital members of the interprofessional group, as they will monitor the patient's vital signs and assist with patient and family education. The pharmacist will provide analgesics, antiemetics, appropriate antibiotics, antiepileptics, and antidiuretic medications. The neuroradiologist can assist in determining the cause. Women of childbearing age presenting with disorders of the neurohypophysis can experience issues during labor and later with breastfeeding.

The outcomes of neurohypophyseal disorders depend on the cause. However, to improve outcomes, prompt consultation with an interprofessional group of specialists is recommended. The care provided to the patient must use an integrated care pathway, combined with an evidence-based approach to planning and evaluating activities.