Pituitary Part 5

Diagnosis

Two clinical clues suggest vasopressin deficiency: sudden onset of polyuria and a preference for iced beverages. However, neurogenic diabetes insipidus must be distinguished from primary polydipsia, because overdrinking also results in polyuria and suppressed vasopressin secretion.

Neurogenic and nephrogenic diabetes insipidus can usually be differentiated by means of clinical testing. After confirmation that the blood glucose level is normal, the patient is deprived of water until 3% to 5% of body weight is lost and the serum tonicity is higher than 295 mOsm/kg. If polyuria disappears and the urine concentration rises above 500 mOsm/kg, vasopressin secretion is adequate. If polyuria and dilute urine (< 300 mOsm/kg) persist, then 20 mg desmopressin acetate (DDAVP), a synthetic vasopressin analogue, is given in-tranasally; alternatively, 300 |oU of DDAVP can be administered intravenously. If urine flow decreases and urine concentration rises, vasopressin deficiency can be inferred. If, however, the serum becomes concentrated and the urine remains dilute despite administration of DDAVP, the patient has nephrogenic diabetes insipidus.

Some cautions should be kept in mind when conducting dehydration tests. First, the term partial diabetes insipidus describes a patient who, when deprived of water, achieves a urine concentration greater than the serum osmolality but less than that obtained after administration of vasopressin. Functional testing can be misleading in patients with neurogenic or nephro-genic partial diabetes insipidus. In such patients, who have a urine concentration between 300 and 500 mOsm/kg, measurement of the serum vasopressin level can be extremely helpful. A high vasopressin level in the presence of concentrated serum and relatively dilute urine points to nephrogenic diabetes insipidus; a low value points to hormone deficiency. Conversely, partial resistance to vasopressin can result from chronic overdrinking, with secondary dilution of the medullary concentration in the kidney. If such patients control their excess water intake, they recover a normal renal medullary concentration and, at the same rate, a normal response to vasopressin. Finally, water deprivation appears to produce less thirst in older men than in younger men. Men older than 80 years must be watched carefully after testing to ensure that they resume appropriate water intake.

Granulomas, trauma, infection, and other infiltrations can all produce diabetes insipidus. Metastatic tumor seldom produces insufficiency in other endocrine glands, but secondary tumors arising from lung, breast, and other organs can all produce insufficiency in the posterior pituitary. The sensitivity of MRI has considerably refined the approach to the diagnosis of diabetes insipidus.

Diabetes insipidus can develop suddenly after neurosurgery or external trauma. Cases that develop after neurosurgery may be marked by a triphasic sequence of vasopressin deficiency, va-sopressin excess, and vasopressin deficiency. In postoperative or posttraumatic diabetes insipidus, a dilute polyuria with a serum sodium level greater than 145 mEq/L allows a presumptive diagnosis, and parenteral DDAVP should be given immediately. Conversely, hyponatremia from increased vasopressin secretion after transsphenoidal surgery should also be anticipated by following serum sodium levels. Explosive and fatal central diabetes mellitus and diabetes insipidus have been reported in young women with postoperative hyponatremia that was not aggressively treated. The pathogenesis of the disorder is not understood, but the pathologic sequence included cerebral edema and herniation, compression of the third cranial nerve, hypoxic infarction of the pituitary and hypothalamus, respiratory arrest, and coma. The rapidity of deterioration in these patients indicates that the hyponatremia in such cases should be promptly corrected, even though fixed pupillary dilatation, secondary to compression of the oculomotor nerve, may suggest brain death.

Treatment

There are several approaches to the treatment of diabetes in-sipidus. If the polyuria is mild and does not interfere with sleep, no treatment may be needed. Chlorpropamide potentiates the effect of vasopressin on renal concentrating ability and can be used to treat partial diabetes insipidus. It is given in a dosage of 250 to 375 mg once a day and usually does not produce hypo-glycemia in normal persons. However, if patients do not eat regularly or if they have unsuspected anterior pituitary insufficiency, chlorpropamide can be hazardous.

For patients with severe diabetes insipidus, intranasal or oral DDAVP provides excellent control of polyuria and polydipsia. Intranasal DDAVP is effective, nontoxic, and nonirritating. Tablets of DDAVP are given in a dose of 0.1 or 0.2 mg, taken one to three times daily. All patients with diabetes insipidus should be warned that in circumstances of extreme water loss or unconsciousness, they are exposed to added risk unless they are under the care of a physician who is aware of the diagnosis.

Pituitary Failure

Attenuated pituitary secretory reserve can develop as a result of impingement and compression of an expanding mass on adjacent functioning pituitary cells or because of acquired or inherited pituitary cell damage.34 Tropic hormone failure associated with pituitary compression or destruction usually occurs sequentially, with GH; then FSH, LH, and TSH; and finally ACTH. In childhood, growth retardation is often the presenting feature; in adults, hypogonadism is the earliest symptom. Pressure effects may impair synthesis or secretion of hypothalamic hormones, with pituitary failure [see Table 10].

Developmental pituitary dysfunction

Developmental pituitary dysfunction occurs with aplastic, hypoplastic, or ectopic pituitary gland development. Midline craniofacial disorders may be associated with structural pituitary dysplasia. Birth trauma—including cranial hemorrhage, asphyxia, and breech delivery—can cause acquired pituitary failure in the newborn.

Transcription Factor Mutations

Tissue-specific transcription factors, including Pit-1 and PROP-1, determine tissue-specific development and expression of pituitary hormones and are critical for maintaining anterior pituitary cell function. Hereditary transcription factor mutations may result in disruption of pituitary function, which may manifest during infancy, childhood, puberty, or early adulthood. Autosomal dominant or recessive Pit-1 mutations result in combined deficiency of GH, PRL, and TSH. Pituitary imaging may reveal a normal or hypoplastic gland. PROP-1 is an early transcription factor that appears to be necessary for Pit-1 function. PROP-1 mutations result in combined deficiency of GH, TSH, gonadotropins, and sometimes ACTH. Most afflicted patients have growth retardation and do not enter puberty spontaneously. By adulthood, most patients are deficient in TSH and gonadotropins, and some have an enlarged pituitary gland. T-Pit mutations result in isolated ACTH deficiency.

Dysgenesis of the septum pellucidum or corpus callosum may lead to hypothalamic dysfunction and hypopituitarism, with manifestations that include diabetes insipidus, GH deficiency, and, occasionally, TSH deficiency. Affected children harbor a mutation in the HESX-1 gene. Clinical features include cleft palate, syndactyly, ear deformities, and hypertelorism.

Table 10 Causes of Pituitary Failure³⁹

Development/ structural	Transcription factor defect
	Pituitary dysplasia/aplasia
	Congenital central nervous system masses, encephalocele
	Primary empty sella
	Congenital hypothalamic disorders (e.g., septo-optic dysplasia, Prader-Willi syndrome, Laurence-Moon-Biedl syndrome, Kallmann syndrome)
Traumatic	Surgical resection
	Radiation damage
	Accidental
Neoplastic	Pituitary adenoma
	Parasellar mass (meningioma, germinoma, ependymoma, glioma)
	Rathke cyst
	Craniopharyngioma
	Hypothalamic hamartoma, gangliocytoma
	Pituitary metastases
	Lymphoma and leukemia
	Meningioma
Infiltrative/ inflammatory	Lymphocytic hypophysitis
	Sarcoidosis
	Histiocytosis X
	Hemochromatosis
	Granulomatous hypophysitis
Vascular	Pituitary apoplexy
	Pregnancy-related infarction
	Sickle cell disease
	Arteritis
Infections	Fungal (histoplasmosis)
	Parasitic (toxoplasmosis)
	Tuberculosis
	Pneumocystis carinii

Acquired pituitary failure

Rarely, infiltration of the hypothalamus by diseases such as sarcoidosis, histiocytosis X, amyloidosis, or hemochromatosis may disrupt hypothalamic and pituitary function.35 This hypo-thalamic infiltration may result in diabetes insipidus and, if GH attenuation occurs before pubertal bone closure, in growth retardation. Hypogonadotropic hypogonadism and, rarely, hy-perprolactinemia occur with disrupted gonadotropin secretion. Pituitary damage may be directly caused by accidental or neuro-surgical trauma; pituitary or hypothalamic neoplasms, including pituitary adenomas, craniopharyngioma, Rathke cysts, chor-domas, or metastatic deposits; inflammatory disease, such as lymphocytic hypophysitis; or pituitary irradiation. Tuberculosis, opportunistic fungal infections associated with HIV infection, and tertiary syphilis may destroy pituitary tissue.

Cranial Irradiation

Cranial irradiation results in long-term compromise of hypo-thalamic and pituitary function. Children and adolescents who have undergone therapeutic irradiation of the brain or head and neck are at especially high risk. The resulting hormonal abnormalities correlate strongly with radiation dosage, as well as the time elapsed since completion of radiotherapy. By 10 to 15 years after therapy, GH deficiency invariably occurs, whereas central hypo-gonadism and ACTH deficiency less commonly occur. Anterior pituitary function should be tested in previously irradiated patients, and replacement therapy instituted when required.

Lymphocytic Hypophysitis

Lymphocytic hypophysitis usually occurs in pregnant or post-partum women. It presents as hyperprolactinemia and a pituitary mass resembling an adenoma on MRI; PRL levels are often mildly elevated.36 Transient pituitary failure and symptoms of progressive sellar compression, such as headache and visual disturbance, may occur, and the erythrocyte sedimentation rate may be elevated. Because its appearance on MRI may be indistinguishable from that of a pituitary adenoma, lymphocytic hypophysitis should be excluded in a postpartum woman with a newly diagnosed pituitary mass. Pituitary surgery is unnecessary in such cases: glucocorticoid treatment usually restores pituitary function within 6 months, and the mass invariably resolves.

Pituitary Apoplexy

Acute intrapituitary hemorrhage may result in catastrophic vascular compression of parasellar structures.37 Hemorrhage may occur in a preexisting adenoma, often in association with diabetes or hypertension, or in the postpartum period (Sheehan syndrome). During pregnancy, swelling of the pituitary increases the risk of intrapituitary hemorrhage and infarction. Hypo-glycemia, hypotension, shock, apoplexy, and death may follow. Severe headache with signs of meningeal irritation, visual loss, dynamically changing ophthalmoplegia, cardiovascular collapse, and loss of consciousness portend acutely progressive in-trasellar bleeding. Pituitary imaging may reveal signs of intratu-moral or sellar hemorrhage, with deviation of vital structures, including compression of noninvolved pituitary tissue. If vision is intact and consciousness is unimpaired, patients can be treated conservatively with observation and high-dose steroid infusions. Visual loss or decreased consciousness is an indication for urgent surgical decompression. Subsequent pituitary hormone replacement will be required for the inevitable pituitary damage.

Empty Sella Syndrome

Clinically silent pituitary mass infarction may result in development of a partially or totally empty sella. CSF fills the dural herniation. Pituitary function often remains intact, because the surrounding tissue is fully functional. Hypopituitarism may develop insidiously, however. A partially or apparently totally empty sella is usually an incidental MRI finding. Rarely, small functional pituitary adenomas may arise within the rim.

Diagnosis

Pituitary failure is characterized by the clinical impact of single or multiple tropic hormone loss. Growth disorders and abnormal body composition result from GH loss in children and adults, respectively; menstrual disorders and infertility in women and decreased sexual function, infertility, and loss of secondary sexual characteristics in men are caused by go-nadotropin deficits; hypothyroidism is caused by TSH loss; hypocortisolism with hypoglycemia is caused by ACTH loss; and failed lactation is caused by PRL loss. Polyuria and poly-dipsia reflect loss of ADH secretion.

Table 11 Replacement Therapy for Hypopituitarism in Adults

Tropic Hormone Deficit	Hormone Replacement
ACTH	Hydrocortisone, 10-15 mg q. A.M., 5 mg q. P.M. Cortisone acetate, 25 mg q. A.M., 12.5 mg q. P.M.
TSH	Levothyroxine, 0.075-0.15 mg daily
	Males
	Testosterone enanthate, 200 mg I.M. q. 2 wk
	Testosterone skin patch, 5-7.5 mg/day
	Females
FSH/LH	Conjugated estrogen, 0.65-1.25 mg daily for 25 days
	Ethinyl estradiol, 0.02-0.05 mg
	Progesterone on days 16-25 to facilitate uterine shedding
	Estradiol skin patch, 4-8 mg, twice weekly
GH	Somatotropin, 0.15-1.0 mg S.C. daily
Vasopressin	Desmopressin
	Intranasal: 5-20 ^g, b.i.d.
	Oral: 300-600 ^g, q.d.

Note: Doses should be individualized and should be reassessed during stress, surgery, or pregnancy. Treatment for infertility (gonadotropins or gonadotropin-releasing hormone) should be individualized.

ACTH—adrenocorticotropic hormone

FSH—follicle-stimulating hormone

GH—growth hormone

LH—luteinizing hormone

TSH—thyroid-stimulating hormone

These features may occur selectively or may be sequential and ultimately result in panhy-popituitarism. Enhanced mortality in patients with long-standing pituitary damage is caused mainly by increased cardiovascular and cerebrovascular disease.38

On laboratory tests, patients with pituitary insufficiency demonstrate lack of normal hormonal feedback responses, with low tropic hormone levels in conjunction with low target hormone concentrations. Provocative tests confirm lack of pituitary hormone reserve.

Rreatment

Replacement of pituitary hormones or their respective target hormones usually results in clinical homeostasis with few side effects [see Table 11]. Hormone replacement therapy for pituitary failure includes glucocorticoids, thyroid hormone, sex steroids, GH, and vasopressin. Rational replacement regimens ensure a normal and safe quality of life. Patients receiving glucocorticoid replacement require dose increases during stressful events, including dental procedures, trauma, and hospitalizations for acute illness.