INTRODUCTION	Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: The diagnosis of hypopituitarism is easily overlooked as the symptoms and signs are frequently protean and nonspecific, including alterations in electrolyte levels, mental status, glucose levels, body temperature, and heart rate. The setting is not uncommon in which an emergency physician is evaluating a patient with complaints of weakness, fatigue, or altered mental status without a clear diagnosis. Subtle, but still abnormal vital signs, such as slightly reduced blood pressure or heart rate may be the only initial clues to suggest a pituitary deficiency rather than a relatively benign etiology.

Awareness and clinical recognition of the diagnosis is vital, given that emergency physicians frequently provide care to patients at risk of developing hypopituitarism such those with traumatic brain injury (TBI), cocaine snorting, subarachnoid hemorrhage, and postpartum hypotension (Sheehan syndrome).

The physician must be vigilant to consider hypopituitarism as the cause for otherwise unexplained abnormal laboratory values and vital signs.

The pituitary gland was first called "hypophysis" by Thomas Soemmering in 1778. Hypophysis is a Greek term that describes how the pituitary appears to "grow beneath the brain."

The pituitary gland carries the respectable sobriquet "master gland" because it produces hormones that regulate growth, development, and reproduction.

Despite its vital role, the pituitary gland is merely the size of a small pea. It is located in the middle cranial fossa within a recess of the sphenoid bone called the sella turcica ("Turks saddle").

The gland has two parts: the anterior pituitary (adenohypophysis) and the posterior pituitary (neurohypophysis).

The anterior pituitary receives signals from the hypothalamus that either stimulate or inhibit secretion of pituitary hormones. These hormones are secreted directly into the systemic circulation, where they act upon specific organs.

The actions of the pituitary gland can be modulated at many stages. The pituitary hormones, or target organ hormones, can influence both the hypothalamus and the pituitary to decrease or increase pituitary hormone secretion through long and short feedback loops. Hormones secreted by the anterior pituitary include the following:

• Thyrotropin, or thyroid-stimulating hormone (TSH)

• Gonadotropins, or follicle-stimulating hormone (FSH) and luteinizing hormone (LH)

• Growth hormone (GH)

• Corticotropin, or adrenocorticotropic hormone (ACTH)

• Prolactin hormone (PRL)

The posterior pituitary does not produce its own hormones. The hypothalamus produces two hormones, vasopressin (VP) and oxytocin (OXT), that are secreted into the capillary beds that supply the posterior pituitary, where they are ultimately released into circulation.

Vasopressin primarily acts on the V₂ receptors of the distal tubules of the kidney to reabsorb water, which increases total body water and urine osmolality. Vasopressin also acts as a pressor on the V₁ receptors of vascular smooth muscle. Oxytocin induces labor in pregnant women, causing contraction of uterine smooth muscle; the hormone also initiates the mechanics of breastfeeding.

Pathophysiology: Common causes of pituitary insufficiency include pituitary adenomas or other intrasellar and parasellar tumors, inflammatory destruction, surgical removal, radiation-induced destruction of pituitary tissue, traumatic brain injury (TBI), subarachnoid hemorrhage, and postpartum pituitary necrosis (Sheehan syndrome).

Pituitary tumors, or adenomas, are the most common cause of hypopituitarism in adults. Depletion of pituitary function by tumors occurs via the following 3 mechanisms:

• In primary pituitary destruction (intrinsic pituitary destruction), the hormone-secreting cells of the anterior pituitary are destroyed. This condition can involve some or all pituitary hormones.

• Intrinsic hypothalamic disease involves compression or destruction of the hypothalamus. This condition causes a deficiency or loss of hypothalamic regulatory hormones and impairs anterior pituitary hormone secretion.

• Extrinsic diseases destroy the hypothalamus, the pituitary stalk, or the anterior pituitary gland.

Pituitary tumors, or adenomas, can be secretory or nonsecretory. Approximately 30% of all macroadenomas larger than 10 mm will produce at least one hormone.

Frequency:

• In the US: Although the prevalence of pituitary adenomas is strikingly high (10-20%) in autopsy and MRI studies, the actual presence of clinical disease is quite uncommon. Approximately 2-8 in 100,000 persons per year present with symptoms attributed to pituitary tumors.

Mortality/Morbidity: The systemic effects of pituitary hormone deficiencies vary depending on the extent of pituitary involvement. Given that the pituitary acts on numerous endocrine sites, the consequences of pituitary dysfunction range from mild single-system disease to panhypopituitarism.

• Missed or delayed diagnosis could potentially lead to permanent disability or death.

• Female patients with hypopituitarism receiving controlled thyroid and steroid hormone substitution, but without growth hormone replacement, have more than a 2-fold increase in cardiovascular mortality compared with the general population.

• Cardiovascular disease is significantly higher among hypopituitary patients (incidence ratio, 3.7; 95% confidence interval, 1.2–11.3).

• Hypopituitary patients have lower high-density lipoprotein cholesterol (P = 0.002) and higher low-density/high-density lipoprotein ratio (P = 0.009).

Sex:

• The most frequent etiologies of hypopituitarism do not demonstrate a significant disparity in incidence between genders. Postpartum pituitary necrosis (Sheehan syndrome) is clearly only seen among female patients.

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History: Symptom presence and severity depend on the amount of and rapidity of hormone depletion. Clinical manifestations closely match those of primary deficiency or hypofunctioning of target glands. Hypopituitarism is usually a combination of several hormonal deficiencies and rarely involves all pituitary hormones. End-organ hormonal insufficiencies are referred to as secondary deficiencies of the target organ (eg, hypothyroidism caused by a decrease in TSH will be termed secondary hypothyroidism).

The presence of an antecedent closed head injury may be elicited. Patients with traumatic brain injury can have some degree of hypopituitarism as soon as 3 months and typically by 12 months following the injury. Nearly all patients with resultant pituitary deficiency will have experienced loss of consciousness following the trauma, and approximately half have a skull fracture.

• The onset of hypopituitarism is often gradual over a period of years, but in some conditions, rapid onset is seen. The insidious decline in health is often attributed to other medical conditions prior to recognition.

• Adrenocorticotropic hormone deficiency

• Deficiency in corticotropin is characterized by a decrease in adrenal androgens and production of cortisol.

• Acute loss of adrenal function is a medical emergency and may lead to hypotension and death if not treated.

• Signs and symptoms of ACTH deficiency may be profound and potentially fatal and include myalgias, arthralgias, fatigue, headache, weight loss, anorexia, nausea, vomiting, abdominal pain, altered mentation or altered consciousness, dry wrinkled skin, decreased axillary and pubic hair, anemia of chronic disease, dilutional hyponatremia, hypoglycemia, hypotension, and shock.

• Symptoms are nearly identical to those of primary adrenal insufficiency but can be differentiated by lack of hyperpigmentation. Hyperpigmentation occurs in a long feedback loop in which a cortisol deficiency results in increased production of ACTH by the pituitary. The ACTH precursor coupled to melanocyte-stimulating hormone is not produced in those with pituitary disease, and therefore hyperpigmentation does not take place.

• Patients with secondary adrenal sufficiency usually are eukalemic. This differs from primary adrenal insufficiency, in which patients develop hyponatremia and hyperkalemia.

• Aldosterone secretion is not affected, as it does not depend on corticotropin but instead on the renin-angiotensin axis.

• Thyrotropin deficiency

• Secondary thyrotropin deficiency (ie, hypothyroidism) due to decreased TSH exhibits identical symptoms to primary thyroid disease, only typically less severe.

• Signs and symptoms of secondary hypothyroidism include fatigue, weakness, weight gain, thickened subcutaneous tissues, constipation, cold intolerance, altered mental status, impaired memory, and anemia.

• Physical examination may reveal bradycardia, delayed relaxation of the deep tendon reflexes, and periorbital edema.

• Gonadotropin deficiency

• Low FSH and LH levels increase risk of osteoporosis due to decreased bone density and result in hypogonadism in both men and women.

• In men, symptoms include decreased libido, varying degrees of erectile dysfunction, decreased ejaculate, muscle weakness, and fatigue.

• Men with long-standing hypogonadism have decreased hair growth, soft testes, and gynecomastia.

• Patients may be anemic due to decreased erythropoietin production, which causes a normochromic, normocytic anemia.

• Premenopausal women present with altered menstrual function, ranging from regular anovulatory periods to amenorrhea, hot flashes, decreased libido, breast atrophy, vaginal dryness, and dyspareunia.

• Pubic and axillary hair growth is usually normal unless a concomitant ACTH deficiency exists.

• Postmenopausal women usually present with headache or visual abnormalities due to other hormonal deficiencies or mass lesions.

• In children, FSH and LH deficiency can cause eunuchoidism and lack of sexual development.
  • FSH and LH have an indirect effect on bone growth by causing closure of the epiphysis.

  • Characteristics of eunuchoidism are due to delay in closure of the epiphysis, resulting in long extremities.

• Growth hormone deficiency

• In children, GH deficiency presents as growth retardation and delayed sexual maturation.

• Patients may present with fasting hypoglycemia due to loss of the gluconeogenic effect of GH, which counteracts the effect of insulin.

• In adults, GH deficiency presents as weakness, poor wound healing, decreased exercise tolerance, and decreased social functioning.

• Prolactin deficiency

• Tumor growth that decreases PRL production affects the process of lactation; these tumors become evident only in the postpartum state.

• PRL deficiency is very rare; any process that affects the hypothalamus and the pituitary stalk decreases the normal inhibitory effect of dopamine from the hypothalamus on the pituitary, causing a rebound increase in PRL.

• Antidiuretic hormone deficiency

• Antidiuretic hormone (ADH) deficiency causes polyuria and polydipsia (diabetes insipidus).

• When deficient in ADH, the distal tubules of the kidney are unable to absorb water, producing very dilute urine and increasing serum osmolality.

• If water excretion exceeds oral intake, a patient may become hypotensive and hypovolemic with hypernatremia and elevated serum osmolality.

• If fluid intake matches fluid output, serum sodium and osmolality may remain normal.

• Central diabetes insipidus is caused by a decrease in ADH secretion, in contrast to nephrogenic diabetes insipidus, in which the kidney is ADH resistant.

• Oxytocin deficiency

• Deficiency in oxytocin is characterized by a decrease in milk ejection during lactation. Interestingly, women with known oxytocin deficiency undergo normal labor and delivery despite the lack of hormone.

• One of the initial clues to the presence of Sheehan syndrome should be the lack of lactation secondary to oxytocin deficiency.

Physical: A complete physical examination including thyroid palpation, genital inspection, and visual examination (particularly visual field testing) is essential in the setting of protean complaints, electrolyte abnormalities, a history of traumatic brain injury, lack of postpartum lactation and menstrual irregularity.

During both the neurologic and ophthalmic examinations, check specifically for visual acuity, extraocular movements, and bitemporal hemianopsia. (See the above discussion for signs that are consistent with each of the abnormal hormonal states.)

Causes:

• Hypopituitarism resulting from pituitary adenomas is due to impaired blood flow to the normal tissue, compression of normal tissue, or interference with the delivery of hypothalamic hormones via the hypothalamus-hypophysial portal system.

• Hypersecretion of the secretory pituitary tumor hormone is suggestive of an adenoma.

• Another indication of a pituitary adenoma is a deficiency in some pituitary hormones with concomitant hyperprolactinemia. Normally, dopamine, produced in the hypothalamus, inhibits prolactin secretion by the anterior pituitary. Compressing the pituitary stalk decreases the inhibitory effect of dopamine and increases prolactin levels.

• Another common intracranial tumor is craniopharyngioma, a squamous cell tumor that arises from remnants of the Rathke pouch. One third of these tumors extend into the sella, while approximately two thirds remain suprasellar.

• Sheehan syndrome occurs with large volume of postpartum hemorrhage.

• During pregnancy, the pituitary gland enlarges due to hyperplasia and hypertrophy of the lactotroph cells, which produce prolactin. The hypophyseal vessels, which supply the pituitary, constrict in response to decreasing blood volume, and subsequent vasospasm occurs, causing necrosis of the pituitary gland. The degree of necrosis correlates with the severity of the hemorrhage.

• As many as 30% of women experiencing postpartum hemorrhage with hemodynamic instability may develop some degree of hypopituitarism. These patients can develop adrenal insufficiency, hypothyroidism, amenorrhea, diabetes insipidus, and an inability to breastfeed.

• Pituitary apoplexy denotes the sudden destruction of the pituitary tissue resulting from infarction or hemorrhage into the pituitary.

• The most likely cause of the apoplexy is brain trauma; however, it can occur in patients with diabetes mellitus, pregnancy, sickle cell anemia, blood dyscrasias or anticoagulation, and increased intracranial pressure.

• Apoplexy usually spares the posterior pituitary and solely affects the anterior pituitary.

• Head trauma from a motor vehicle accident, a fall, or a projectile can cause hypopituitarism by direct damage to the pituitary or by injuring the pituitary stalk or the hypothalamus. Hypopituitarism may occur immediately, or it may develop months or years later. Recovery is uncommon.

• Other causes of hypopituitarism include empty sella syndrome and infiltrative diseases.

• Empty sella syndrome occurs when the arachnoid herniates into the sella turcica through an incompetent sellar diaphragm and flattens the pituitary against bone.

• Infiltrative diseases, such as Wegener granulomatosis and sarcoidosis, can cause destruction of the anterior pituitary.

• Physiologic or psychological states can influence the hypothalamic-pituitary stalk by impairing synthesis and secretion of regulating hormones.

• The degree of the deficiency varies greatly and depends on the extent of the process and its location.

• Some functional causes include emotional disorders, changes in body weight, habitual exercise, anorexia, bulimia, congestive heart failure (CHF), renal failure, and certain medications.