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Table of Contents

Published July 19, 2002

Amir
Hamrahian, MD

Department of
Endocrinology

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Anatomy and Physiology of the Pituitary Gland

     Definition and      Prevalence

     Pathophysiology

     Signs and
     Symptoms

     Diagnosis

     Therapy

     Outcomes

     National
     Guidelines

The pituitary gland weighs about 0.5 to 1 gram and is divided into an anterior and a posterior lobe. It sits in the sella turcica immediately behind the sphenoid sinus. Cavernous sinuses are located laterally on each side of the sella, and include the internal carotid artery and cranial nerves III, IV, V₁, V₂, and VI. Magnetic resonance imaging (MRI) is the best method for visualizing the hypothalamic-pituitary anatomy, since the optic chiasm, vascular structures, and any tumor extension to cavernous sinuses can be well visualized compared with other imaging techniques (Figure 1).

Anterior pituitary hormones are regulated by hypothalamic releasing and inhibitory hormones and the negative feedback action of the target glandular hormones at both pituitary and hypothalamic levels (Table 1). Among pituitary hormones, only the secretion of prolactin is increased in the absence of hypothalamic influence, since it is mainly under tonic suppression through the prolactin inhibitory factor.¹ All anterior pituitary hormones are secreted in a pulsatile fashion and tend to follow a diurnal pattern.

Antidiuretic hormone (ADH; vasopressin) is produced by the supraoptic and paraventricular nuclei of hypothalamus and travels in the axons through the pituitary stalk to the posterior pituitary gland. The chief physiologic stimulus of ADH secretion is an increase in serum osmolality and a decrease in plasma volume, resulting in water reabsorption at the level of distal and collecting ducts of the kidney. Small increments in serum osmolality above 290 mOsm/kg lead to prompt secretion of ADH.

Disorders of the pituitary gland include pituitary tumors, pituitary incidentalomas (incidentally found masses without clinical signs or symptoms), lymphocytic hypophysitis, empty sella, pituitary apoplexy, and diabetes insipidus.

Pituitary adenomas arise from adenohypophyseal cells. The true incidence and prevalence of pituitary adenomas is difficult to establish, but epidemiologic studies suggest a prevalence of about 20 cases per 100,000 population and an incidence of 0.5 to 7.4 per 100,000 population.² An apparent increase in the incidence of pituitary tumors in the last two decades may be related to the introduction of computed tomography (CT), MRI, and a variety of radioimmunoassay techniques for pituitary hormones.

Pituitary adenomas are usually slow-growing and invariably benign (Table 2). They are arbitrarily designated as microadenomas (< 10 mm in diameter) and macroadenomas (>10 mm in diameter). Functional tumors are more common at younger ages, whereas nonfunctional tumors are seen mostly at older ages. Most nonfunctional pituitary adenomas on morphologic examination reveal secretory granules suggestive of hormonal synthesis, but they fail to secrete functional hormones. Pituitary adenomas are rarely associated with parathyroid and pancreatic hyperplasia or neoplasia as part of the multiple endocrine neoplasia type I syndrome. Pituitary carcinomas are rare, but metastases from other solid malignancies (mainly breast and lung) can occur.

Recent advances in molecular biology have confirmed that most pituitary adenomas are monoclonal in origin. Some possible underlying mechanisms include overexpression of a pituitary tumor-transforming gene, inactivation of tumor-suppressor genes, hypersecretion of hypothalamic-releasing hormones, and/or hyposecretion of inhibitory hormones.

Pituitary tumors may present with signs and symptoms related to hypofunction or hyperfunction, and/or to a mass effect (Table 3). Impingement on the chiasm or its branches by pituitary tumor may result in visual field defects, the most common being bitemporal hemianopia. Lateral extension of the pituitary mass to the cavernous sinuses may result in diplopia, ptosis, or altered facial sensation. Among the cranial nerves, the third nerve is the most commonly affected. There is no specific headache pattern, and a headache may be unrelated to pituitary adenoma.

Glycoprotein-producing or nonfunctional pituitary adenomas may present by their mass effect, symptoms related to varying degrees of hypopituitarism, or as incidental findings during imaging studies of the head for reasons not related to pituitary disorders (Figure 2). Rarely, a follicle-stimulating hormone (FSH) adenoma may cause amenorrhea in a woman, or a luteinizing hormone (LH) adenoma may lead to precocious puberty in a boy.

Hypopituitarism:

Pituitary adenomas are the most common cause of hypopituitarism, but other causes include parasellar diseases, pituitary surgery, radiation therapy, and head injury. The classic sequential loss of pituitary hormones secondary to a mass effect is in the following order: growth hormone (GH), gonadotropins (LH, FSH), adrenocorticotropic hormone (ACTH) and thyroid-stimulating hormone (TSH).¹ The underlying etiology for typical earlier loss of GH and gonadotropins is not known. Isolated deficiencies of various anterior pituitary hormones can also occur. Diabetes insipidus is almost never seen in patients with microadenoma, but it rarely occurs in those with larger tumors extending superiorly, affecting the synthesis of ADH.

Growth Hormone Deficiency
The symptoms of GH deficiency in adults are subtle, consisting of decreased muscle strength and exercise tolerance and a reduced sense of well-being (eg, diminished libido, social isolation). Patients with GH deficiency have increased body fat, particularly intra-abdominally, and decreased lean body mass compared with normal adults. Some patients have decreased bone mineral density, which may improve with GH replacement.

Gonadotropin Deficiency
In women, gonadotropin deficiency causes infertility and oligomenorrhea or amenorrhea. It is often associated with lack of libido, hot flashes, and dyspareunia. In men, hypogonadism is diagnosed less often, since decreased libido and impotence may be considered a function of aging. Hypogonadism is often diagnosed retrospectively in men and postmenopausal women when patients present with mass effect. Osteopenia is a consequence of long-standing hypogonadism and should respond to hormone replacement therapy.

Adrenocorticotropic Hormone Deficiency
Patients with ACTH deficiency maintain their mineralocorticoid secretion. The symptoms usually include chronic malaise, fatigue, anorexia, and hypoglycemia. Severe hypotension, hyperkalemia, and hyperpigmentation are not present although an acute severe illness may precipitate vascular collapse, since cortisol is necessary for maintenance of peripheral vascular tone. Both forms of primary and secondary adrenal insufficiency may lead to hyponatremia. This is secondary to inappropriate ADH secretion, which is caused by cortisol deficiency.

Thyrotropin (TSH) Deficiency
This is a relatively late finding in patients with pituitary disorders. The symptoms are similar to those of primary hypothyroidism, including malaise, leg cramps, fatigue, dry skin, and cold intolerance. The degree of hypothyroidism depends on the duration of thyrotropin deficiency.

Pituitary Excess Hormone Secretion:

Prolactinoma
Women of reproductive age present mainly with oligomenorrhea, amenorrhea, galactorrhea, or infertility. Men and postmenopausal women usually come to medical attention because of mass effect such as headaches and visual field defects. Many men with hyperprolactinemia do not report any sexual dysfunction, but once treated effectively for hyperprolactinemia, most of them realize the presence of problems that include impotence and decreased libido. Osteopenia affects trabecular bone more than cortical bone, and is seen in hyperprolactinemic, hypogonadal women as well as men. Restoration of normal gonadal function halts bone loss and increases bone mineral density.

Acromegaly
The clinical picture of acromegaly progresses insidiously (Table 4). Patients with full-blown acromegalic features are not difficult to diagnose, but only experienced physicians will be sensitive to early changes occurring in this disease (Figure 3). Cardiac diastolic function is impaired, secondary to ventricular muscle hypertrophy. Sleep apnea is frequent, and it is often of central rather than peripheral origin. Patients may develop peripheral neuropathy of motor and sensory nerves with muscular atrophy, neuropathic joints, and other sequelae of nerve dysfunction. Acromegalic patients probably carry an increased risk of malignancy, although published data vary greatly in their findings. Among different malignancies, colon cancer is the most likely associated type.

Cushing's Disease
The clinical picture can vary greatly among patients depending on duration and severity of disease. None of the clinical features is pathognomonic, but central obesity, proximal myopathy, spontaneous ecchymoses, wide (>1 cm) purplish striae, skin atrophy, osteoporosis, and hypokalemia are suggestive of the disease (Figure 4). Supraclavicular and dorsocervical fat pads are not specific and are present in most obese patients.

Thyroid-stimulating-hormone-secreting Adenoma
Symptoms secondary to hyperthyroidism and goiter are the initial complaints in most patients, followed by pituitary mass effect if the disease remains undiagnosed. Most patients at the time of presentation have undergone therapy aimed at their thyroid gland, including thyroidectomy and radioactive iodine ablation.

There is usually a delay in diagnosis of pituitary tumors since many of the patient's symptoms, including headache, decreased energy, low libido, and weight gain may be attributed to stress, depression, or aging. Pituitary MRI is the preferred diagnostic imaging technique in patients with visual loss or hypopituitarism suggestive of a pituitary tumor (Figure 2). Once a pituitary adenoma is found, it is necessary to find the type of adenoma (secretory or nonsecretory), pituitary function (hypo- or hyperfunction), and if there is any visual field defect (Tables 5 and 6).
Diagnosis of glycoprotein-producing and nonfunctional pituitary adenomas may be confirmed by measurement of either intact glycoprotein hormones or their α- and ß-subunits. Levels of the a-subunit tend to be inappropriately elevated compared with those of the intact hormone itself.

Hypopituitarism:

GH Deficiency
GH deficiency is best evaluated with dynamic testing, including the insulin tolerance test and the GH-RH/arginine test. Patients with multiple pituitary axis deficiency (>2) and a low sex- and age-matched insulin-like growth factor (IGF)-1 level are considered GH-deficient and do not need any dynamic testing.

Gonadotropin Deficiency
Gonadotropin deficiency is evaluated through sexual history and simultaneous measurements of prolactin, FSH, LH, and estradiol (free and total testosterone in men). The presence of normal menstruation is the best indicator of the integrity of the gonadotropin axis in women of reproductive age. An FSH level <25 mU/mL in a postmenopausal woman who has a normal prolactin level suggests secondary gonadotropin deficiency.

ACTH Deficiency
ACTH deficiency is evaluated by measurement of morning cortisol level and a low-dose (1 µg) or standard-dose (250 µg) cosyntropin (Cortrosyn) test, with the low-dose cosyntropin test being more sensitive for detecting partial secondary adrenal insufficiency. A morning cortisol level <5 µg/dL is highly suggestive of adrenal insufficiency, and a level >15 µg/dL makes the diagnosis unlikely. The insulin tolerance test is considered the gold standard for evaluation of secondary adrenal insufficiency, but it needs to be done only by experienced clinicians.

Thyrotropin (TSH) Deficiency
Thyrotropin (TSH) deficiency cannot be evaluated through measurement of TSH only, since such patients may have a normal TSH. For this reason, if secondary hypothyroidism is clinically suspected, TSH and a free T₄ index (or free T₄) should be measured together. Typically, patients will have a low or normal TSH with a low free T₄ level.

Pituitary Excess Hormone Secretion:

Prolactinoma
Hyperprolactinemia can be physiologic or pathologic (Table 7; Figure 5). Drug history is a very important part of the initial evaluation, since some medications are associated with hyperprolactinemia and their discontinuation (if possible) will avoid any further, often expensive, workup. A high prolactin level should be repeated at least once before proceeding with further diagnostic evaluation and treatment. The prolactin level usually correlates with the size of the prolactinoma. Almost all patients with prolactin level >200 ng/mL harbor a prolactinoma. A serum prolactin level <200 µg/L in the presence of a large pituitary adenoma suggests stalk compression.

Acromegaly
Due to the pulsating nature of GH secretion, random GH levels can overlap in acromegalic patients and normal individuals. Therefore, a single GH level is usually inadequate to establish the diagnosis. IGF-1 has a longer plasma half-life than GH, and is an excellent initial screening test for those suspected of having acromegaly (Figure 6). The oral glucose tolerance test remains the gold standard test to confirm the diagnosis of acromegaly. Normal individuals suppress their GH level to less than 1 µg/L (using chemiluminescent or radioimmunometric assays) within 2 hours after ingestion of a 75-gram oral glucose solution.

Cushing's Disease
Twenty-four-hour urinary free cortisol measurement is the single best test for diagnosis of Cushing's disease (Figure 7). Because of the significant overlap between normal individuals and those with Cushing, random serum cortisol has no role in the diagnosis of Cushing's disease. An overnight 1-mg dexamethasone suppression test with a cortisol cutoff of 1.8 mg/dL is an excellent test for ruling out the disease, but it has up to 40% false-positive rate. A combination of the low-dose dexamethasone suppression test and the corticotropin-releasing hormone stimulation test has been shown to be particularly helpful in differentiating patients with true Cushing from those with pseudo-Cushing syndrome (sever depression, alcoholism), who may have elevated 24-hour urinary free cortisol.

TSH-secreting Adenoma
The most important biochemical feature is elevation of serum thyroid hormones T₄ and T₃, with an inappropriately normal or increased TSH level. For this reason, any patient presenting with endogenous hyperthyroidism and an elevated or normal TSH should be further evaluated for the presence of a TSH-secreting pituitary adenoma.

The goals for treatment of a pituitary tumor include reduction or complete removal of tumor, elimination of mass effect if present, normalization of hormone hypersecretion, and restoration of normal pituitary function. Some patients, especially those with large tumors, may require several therapeutic modalities including medical, surgical, and radiation therapy. The most important factor in pituitary surgery is availability of a good neurosurgeon. The referring physician has the responsibility of referring the patient to an experienced neurosurgeon, who may be available only in a neuroendocrine (pituitary) center. Radiation therapy is used primarily as an adjunctive therapy when surgical or medical therapy is not successful.

Hypopituitarism:

Growth Hormone Deficiency
Growth hormone deficiency is now recognized as a pathologic state, and more patients with GH deficiency undergo GH replacement. GH deficiency may contribute to increased mortality in patients with hypopituitarism, with cardiovascular disease being the most common cause. A trial of GH replacement is recommended in adults with documented GH deficiency and symptoms or metabolic abnormalities suggestive of GH deficiency. The most common side effects of GH therapy include fluid retention, arthralgia, and carpal tunnel syndrome. These side effects are usually dose-related and improve with dose reduction.

ACTH Deficiency
The suggested replacement regimen is hydrocortisone 15 to 20 mg/day, which is usually given in two to three divided doses. The largest portion of replacement should be taken on awakening. Patients should be instructed to double their replacement dosage for 2 to 3 days in the case of an acute event, and should be covered by stress doses of hydrocortisone if undergoing surgery. Mineralocorticoid replacement is unnecessary in patients with pituitary disease since aldosterone secretion is regulated primarily by renin-angiotensin system and serum potassium concentration.

Gonadotropin Deficiency
Testosterone may be replaced by intramuscular injection or transdermally through patch or gel. Oral testosterone is not recommended because of the potential risk for liver toxicity. Transdermal preparations provide more physiologic and consistent testosterone concentration but at a higher cost than intramuscular testosterone injection. Serum prostate-specific antigen, hematocrit, and lipid profile should be monitored during therapy. Estrogen replacement is necessary in hypogonadal women to prevent osteoporosis and to treat hot flashes, decreased libido, and vaginal dryness.

Thyrotropin Deficiency
Treatment of patients with thyrotropin deficiency is similar to that for primary hypothyroidism. The levothyroxine replacement dose should be adjusted according to the patient's clinical status and the free T₄ level, but not TSH. It is very important to evaluate the corticotropin axis before initiating levothyroxine replacement, since therapy in those with underlying ACTH deficiency may result in an adrenocortical crisis secondary to an increase in metabolic demand.

Pituitary Excess Hormone Secretion:

Prolactinoma
Medical therapy with dopamine agonists is considered the first-line treatment, since it is effective in decreasing adenoma size and restoration of a normal prolactin level. Bromocriptine (Parlodel), and cabergoline (Dostinex) are potent inhibitors of PRL secretion and often result in tumor shrinkage. Dopamine agonists should be initiated slowly, since side effects often occur at the beginning of treatment. The most common side effects of dopamine agonists include nausea, headache, dizziness, nasal congestion, and constipation. Although some patients with microprolactinoma may be observed without therapy, all patients with macroprolactinoma should be treated. Surgery is reserved for patients who are intolerant of or refractory to medical therapy. Radiation therapy may be considered for patients who tolerate dopamine agonists poorly and are not likely to be cured by surgery (eg, tumor invasion of cavernous sinuses).

Acromegaly
The surgical approach is the treatment of choice in patients presenting with pituitary microadenoma or when tumor is confined to the sella, with a cure rate up to 90%. Radiation therapy almost always induces a decrease in the size of tumor and GH level, but long-term results have been less satisfactory when strict cure criteria including normalization of IGF-1 is used.³ Radiosurgery (gamma knife) seems to be superior to conventional radiation therapy, but large studies with strict cure criteria, including normalization of IGF-1 and long-term safety profiles, are awaited.

Medical treatment of acromegaly has gained significance since the limitations of radiation and surgical therapy have become evident. Octreotide (Sandostatin and long-acting Sandostatin LAR Depot) result in normalization of IGF-1 in about 70% of patients. The most common side effects are gastrointestinal, including diarrhea, abdominal pain, and nausea. The most serious side effect of octreotide is cholelithiasis, seen in up to 25% of patients on chronic therapy. A GH-receptor antagonist (B2036-PEG) has been recently developed and is expected to be released to market soon. It is more effective than octreotide in normalization of IGF-1, which is achieved in more than 90% of patients.

Cushing's Disease
Surgical (trans-sphenoidal) removal of ACTH-secreting pituitary tumor is the treatment of choice, with an 80% to 90% remission rate following surgery. Availability of an experienced neurosurgeon is crucial. An undetectable cortisol level postoperatively with the patient off steroids is considered to be a good marker for long-term cure. For those not cured by the surgery, other options include a second operation and radiation therapy. Medical therapy for Cushing's has limited value because of the associated toxicity, and is used mainly for short-term symptomatic control.

Nonfunctional/gonadotropin-secreting Adenoma
The standard treatment is surgery, mainly through a trans-sphenoidal approach, especially if there is impaired vision or cranial nerve palsy. Radiotherapy is indicated in those patients with residual pituitary tumor following surgical debulking. The efficacy of medical therapy in these patients is not established.

TSH-secreting Adenoma
Surgery is the primary therapeutic approach. Radiation is generally used for those with residual tumor. Octreotide may be effective for control of excess TSH production, leading to improvement in hyperthyroidism and possibly to a decrease in tumor size.

The prognosis for recovery and cure of a pituitary tumor depends on the type and size of the adenoma. Although surgery is effective in reducing the size of large pituitary tumors, it is usually unsuccessful in their cure. The availability of an experienced neurosurgeon is a very important factor in surgical outcome and reduction of surgical complications. A decrease in excess GH or ACTH probably does reduce the premature mortality rate, although outcome data in Cushing's disease are lacking. Recurrence of a secretory tumor is diagnosed by following the initially elevated hormone level, such as IGF-1 in acromegaly. There is always a risk for tumor recurrence even if the tumor is thought to have been completely resected. For this reason, close follow-up of such cases is very important.

There have been a few consensus guidelines published for diagnosis and management of acromegaly and at least one for prolactinomas. Unfortunately, there are no consensus statements for other pituitary disorders. Generally, once a patient has been diagnosed with a pituitary tumor, lifelong medical follow-up is necessary to detect early recurrence, to monitor hormone replacement, and to treat any complication related to the tumor.

A consensus guideline for the diagnosis and treatment of hyperprolactinemia was published after a symposium held in Boston in July 1999.⁴ We favor a similar approach, which has been summarized above with few exceptions. While frequent repeat of pituitary MRI in those with microprolactinomas and normal prolactin level was not recommended in the consensus, we do not repeat MRI unless there is a rise in prolactin level, the patient develops symptoms suggestive of mass effect, or a plan has been made for discontinuation of dopamine agonist therapy. Considering the significantly shorter half-life of bromocriptine compared with cabergoline, the need for more than once-daily dosing in some patients and published data indicating higher side effects, we rarely use bromocriptine unless a dopamine agonist is needed during pregnancy.

A consensus guideline discussing the diagnosis and cure criteria for acromegaly was published in 1999 as a result of a workshop held in Italy.⁵ The consensus recommended measurement of IGF-1 and GH as screening tools for patients suspected of having acromegaly. The failure of GH suppression to <1 µg/L during the oral glucose tolerance test in the appropriate clinical context was recommended for establishing the diagnosis. We do not use random GH as a screening tool in acromegaly, since there are spontaneous fluctuations in GH level. IGF-1 has a longer half-life and gives excellent information about integrated GH secretion.

The proceedings of a Scandinavian workshop, discussing different therapeutic modalities for acromegaly, were published in 2001.⁶ The surgical approach was recommended as first-line therapy. Medical therapy, including octreotide analogues and dopamine agonists, was indicated for those patients not eligible for surgery or with persistent disease after surgery. We do recommend a surgical approach as the treatment of choice in patients with somatotrope adenoma confined to the sella; however, in those with invasive tumor, we favor a trial of medical therapy prior to surgery. This may result in improved surgical outcome, but this is an area of debate, with randomized clinical studies being awaited. It should be emphasized that with the near-future availability of GH-receptor antagonists, medical therapy will be more effective and attractive in acromegaly, although surgical cure will likely remain the most cost-effective approach.

A pituitary incidentaloma is defined as a pituitary adenoma discovered by CT or MRI examination in the absence of any symptoms or clinical findings suggestive of a pituitary-dependent disease. Pituitary incidentalomas are discussed separately here because of their usual asymptomatic nature and since they are a common cause for patient referral to endocrinologists. Adenomas <10 mm have been reported in 1.5% to 27% of pituitary autopsy series in those without suspected pituitary disease. The prevalence of pituitary incidentalomas found by MRI imaging is about 10%. Almost 99.5% of them were microadenomas.

Incidentally found pituitary adenomas may result in significant anxiety in patients because of the fear for future problems, including tumor growth. Some subclinical hypersecretory pituitary adenomas may be associated with increased morbidity. For instance, subclinical Cushing's disease may contribute to poor control of blood sugar and blood pressure levels. Pituitary microadenomas do not generally cause any disruption of normal pituitary function, but patients with incidental macroadenomas may have hypopituitarism and/or visual field defects. Careful physical and biochemical evaluation is necessary in such patients, especially in older populations.

For patients with microadenoma, the major clinical issue is to rule out a subclinical pituitary hormone hypersecretion. The initial workup should be limited and include serum prolactin and IGF-1 levels.⁷ The 24-hour urinary free cortisol has a very low yield in the absence of any clinical features suggestive of Cushing's disease.

Patients with hormonally inactive pituitary microadenoma do not need any therapy. The size of the pituitary adenoma should be followed yearly by MRI, increasing the duration between two imaging studies after 2 to 3 years if no change in size is noted. Patients with pituitary macroadenomas and no visual field defect or pituitary hypo- or hyperfunction should be closely monitored for any increase in the size of their adenoma.

Lymphocytic hypophysitis is a rare inflammatory lesion of the pituitary gland, commonly affecting young women during late pregnancy or in the postpartum period. This disorder is believed to have an autoimmune pathogenesis, with increased association with other autoimmune disorders, mainly Hashimoto's thyroiditis and Addison's disease. The clinical manifestations are mainly secondary to mass effects such as headaches and visual field abnormality or partial and total hypopituitarism.⁸ The corticotropin axis is the most frequently affected axis. The chronologic association with pregnancy or the postpartum period and isolated ACTH deficiency may be clues to its diagnosis. Trans-sphenoidal surgery is the therapy of choice in those with pituitary mass effect. Corticosteroids have been advocated to reduce inflammation and have been effective in some patients. Most experts in this field agree on the necessity for close monitoring of patients with this condition, with periodic biochemical evaluation of those with variable degrees of hypopituitarism, since some patients may have partial or full recovery of their pituitary axes.

Diabetes insipidus (DI) is a syndrome characterized by the chronic excretion of an abnormally large volume (>50 mL/kg) of dilute urine. The true prevalence of DI is not known, but it is usually underdiagnosed, since the symptoms and signs are benign and many patients either ignore them or are unaware of them. Central DI is secondary to inadequate ADH secretion that is insufficient to concentrate the urine. It results from destruction of ADH, producing magnocellular neurons of the neurohypophysis. It may be caused by a variety of pituitary/hypothalamic lesions (Table 9).

DI by itself is usually well tolerated and results in few symptoms. The polyuria results in nonspecific symptoms of urinary frequency or incontinence. Nocturia is often the primary reason for which patients seek medical attention. DI in most patients is not associated with any abnormality on physical examination or routine laboratory evaluation except for a low urine osmolality. Overt disturbances in fluid and electrolytes are uncommon unless some other factors, such as loss of consciousness, interfere with the normal compensatory mechanism of polydipsia.

A patient with polydipsia and polyuria should be initially evaluated for uncontrolled diabetes mellitus. If it is absent, then the patient should have a 24-hour urinary volume measured during ad libitum fluid intake. DI is diagnosed in those with abnormally high urinary output (>50 mL/kg/day), low urinary osmolality (<300 mOsm/kg), and appropriate creatinine level (15-20 mg/kg body weight). Once the diagnosis has been established, the next step is to differentiate the type of DI.¹¹ These include central and nephrogenic DI, primary polydipsia and gestational DI.

Patients with DI who are conscious usually have sufficient thirst to maintain normal serum sodium in spite of polyuria. In this situation, a standard water deprivation test should be performed by an experienced endocrinologist, since severe water deficit with hypernatremia may occur in a short period in those with full DI. The posterior pituitary enhances on MRI with gadolinium and is a good assay for ADH reserve, keeping in mind that up to 20% of normal individuals do not have a bright spot (Figure 10).

The therapy of choice for central DI is administration of the ADH analogue desmopressin (DDAVP). The drug is available in subcutaneous, oral, and nasal spray formulations. The spray or oral form of desmopressin is usually started at bedtime and should be gradually titrated for the desired antidiuretic effect. The duration of response should be determined in each person, since there is considerable individual variation. The therapy for patients with central DI should be initiated and adjusted by an experienced clinician, since overtreatment may result in severe water intoxication.

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