The pituitary gland is one of the control centers of the endocrine system. It is composed of an anterior and posterior lobe. In some animals, but not humans, there is a distinct intermediate lobe. The anterior lobe develops by week 4 to 5 gestational age. It begins as an evagination of the ectoderm of the oropharynx known as Rathke’s pouch. Eventually, the pouch is pinched off and is separated from the pharynx by the sphenoid bone. It is often referred to as the adenohypophysis. The residue of Rathke’s pouch demarcates the separation between the anterior and posterior lobes. The most superior part of the pouch surrounds the neural stalk and is called the pars tuberalis. Occasionally, cells of Rathke’s pouch are left behind and may form a craniopharyngioma.

The posterior lobe begins as an evagination of the floor of the third ventricle. The lumen walls eventually fuse to form the neural stalk. A small invagination in the floor of the third ventricle is also formed and is known as the median eminence. The median eminence, neural stalk, and posterior lobe form what is referred to as the neurohypophysis. Approximately 100,000 neurons of the hypothalamus project down through the neural stalk forming the hypophyseal tract. Their nerve terminals form the posterior lobe of the pituitary. In response to appropriate stimuli, these cells secrete antidiuretic hormone (ADH), also known as vasopressin, or oxytocin.

The anterior lobe cells are 50% somatotrophs secreting growth hormone (GH), 10% to 25% lactotrophs secreting prolactin, 15% to 20% corticotrophs secreting adrenocorticotropic hormone (ACTH), 10% to 15% gonadotrophs secreting luteinizing hormone (LH) or follicle-stimulating hormone (FSH), and 3% to 5% thyrotrophs secreting thyroid-stimulating hormone (TSH).

Blood supply to the pituitary is via the inferior and superior hypophyseal arteries. The capillaries of the inferior artery supplying the posterior lobe form a plexus that drains into the dural sinus. A small portion of them form the short hypophyseal portal veins that drain into the anterior lobe of the pituitary. The anterior lobe is supplied by the superior hypophyseal artery via the long hypophyseal portal veins formed by its capillaries. These veins surround the cells of the median eminence from whence neurohormones are secreted. A second plexus of fenestrated capillaries forms around the anterior lobe of the pituitary to enhance delivery of hormones to this part of the pituitary. Veins draining the anterior lobe drain into the cavernous sinus and eventually to the jugular veins.

The developed pituitary sits in a bony pouch called the sella turcica. The anterior wall is called the tuberculum sella, the posterior wall the dorsum sella. They are flanked by the anterior and posterior clinoid processes, respectively. These clinoid processes are connected by a reflection of the dura mater called the diaphragma sella. Thus, the entire sella is surrounded by dura. It is outside the arachnoid and cerebrospinal fluid and so is outside the blood-brain barrier. An important anatomical relationship is the optic chiasm, which is approximately 5 mm above the diaphragma sella and anterior to the stalk of the pituitary. Laterally, it is flanked by the cavernous sinus.

GH is a 19-amino acid polypeptide with two disulfide bridges and a four helical structure. It has several forms but in general has a half-life of about 20 minutes. It is considered an anabolic hormone. Its effects are mediated via insulin-like growth factors 1 and 2 (IGF1 and 2) produced by the liver and other target tissues. Cartilage growth at epiphyseal growth plates is stimulated resulting in an increase in bone mass. IGF 1 and 2 also have lipolytic effects resulting in increased lean body mass. An increase in organ size and function is also seen. GH also antagonizes insulin action resulting in insulin resistance. Its synthesis and secretion are stimulated by the release of growth hormone-releasing hormone (GHRH) from the arcuate nucleus of the hypothalamus into the hypophyseal portal system. Its secretion but not its synthesis is inhibited by somatostatin released by the periventricular nuclei of the hypothalamus. It is also inhibited via an IGF feedback loop at the level of the hypothalamus and pituitary. Ghrelin produced in the hypothalamus and by neuroendocrine cells of the gastric mucosa binds to the growth hormone secretagogue receptor stimulating GH release (1).

GH is secreted in pulsatile fashion with typically five pulses over 24 hours. The largest pulse occurs at the onset of sleep (2). Peak levels of GH occur during puberty with a general decline with age from that point. GH resistance in childhood results in Laron dwarfism, manifested by central facial dysmorphism and obesity. GH excess results in gigantism if present during development and in acromegaly if occurring in adulthood. Greater than 99% of these cases result from pituitary adenomas, usually macroadenomas. Gigantism results from hormone excess prior to epiphyseal plate closure. Acromegaly, which occurs in about 50/million population, results in increased IGF1 and subsequent proliferation of bone, cartilage, and soft tissue. Presenting symptoms include carpal tunnel syndrome, hyperinsulinemia and glucose intolerance, and hypogonadism due to decreased gonadotropin secretion. Excess GH levels may be seen in McCune-Albright syndrome (polyostotic fibrous dysplasia, precocious puberty, hyperthyroidism, hypercortisolism, and hyperprolactinemia) even though an adenoma is not present. It can also be associated with pituitary adenomas in multiple endocrine neoplasia type 1 (MEN-1). GH deficiency can be treated with hormone replacement therapy. GH excess associated with pituitary adenoma is typically treated with surgery plus or minus radiation therapy. Medical therapy can include somatostatin analogues.

Prolactin is a single-chain protein made of 199 amino acids with 3 disulfide bridges. It is very similar in structure to GH. Its main actions are the stimulation of breast development and milk production. It has many lesser understood functions and inhibits GHRH release. Its release is stimulated by thyrotropin-releasing hormone produced by the hypothalamus. Galanin, produced by the hypothalamus and pituitary, can also stimulate prolactin release. Inhibition occurs mainly through dopamine release by the tuberoinfundibular cells of the hypothalamus into the hypophyseal portal system. There is a negative feedback loop with prolactin stimulating tyrosine kinase activity in the tuberoinfundibular cells and subsequent release of dopamine.

Secretion of prolactin follows diurnal patterns with sleep-related increases in prolactin levels. Lactotroph hyperplasia is seen during pregnancy and lactation but usually normalizes within months of delivery. Excess prolactin occurs most commonly with dopamine antagonist drugs and primary hypothyroidism but can also be the result of other pituitary adenomas compressing the pituitary stalk. Up to 30% to 40% of pituitary adenomas are prolactinomas. Symptoms include infertility, menstrual irregularities or amenorrhea, and galactorrhea in females. Males experience a decrease in testosterone levels, decreased sperm production, and gynecomastia. Treatment of prolactin excess caused by pituitary adenomas is medical using dopamine agonists including bromocriptine and cabergoline (3). Surgery and radiation therapy are reserved for patients unresponsive to medical therapy.

ACTH is derived from a large precursor, pro-opiomelanocortin, which is cleaved by enzymatic action. Cleavage of the precursor also gives rise to melanocyte-stimulating hormone and opioid peptides. The main action of ACTH is on the renal cortex, stimulating release of glucocorticoids and androgens. Release of ACTH is stimulated by corticotropin-releasing hormone (CRH) release by hypothalamic CRH-producing cells in the median eminence. The action of CRH is potentiated by ADH. Inhibition of ACTH release is via a negative feedback loop where glucocorticoids detected at the level of the hypothalamus inhibit CRH release. Changes in osmolality and blood volume induced by ADH also have an inhibitory effect on CRH release. Secretory patterns follow a circadian rhythm with a nadir in the evening and a peak in the early morning. Secretion is pulsatile with up to 40 pulses per day. Amplitude rather than frequency of pulses determines the circadian rhythm. There is, however, a significant reserve in the system that can be mobilized in response to stress including infection, inflammation, and trauma.

Excess glucocorticoid production results in Cushingoid symptoms. Most commonly, Cushing’s is a result of exogenous glucocorticoids but rarely can be caused by a pituitary adenoma. Up to 15% of pituitary adenomas are corticotroph adenomas. Some release excess ACTH resulting in Cushing’s disease. However, a number of these are silent corticotroph adenomas, usually macroadenomas
with hemorrhage and mass effects including bone erosion (4). Treatment for these tumors is surgical with or without radiation therapy.

LH and FSH are homologous peptides that are released by the same cells of the anterior pituitary. They also share significant homology with TSH and bHCG. Each has a common alpha and distinct beta subunit. Posttranslational processing of carbohydrate side chains is also critical to hormonal signaling. The action of LH and FSH differs in males and females.

In females, LH stimulates cholesterol production for steroidogenesis in luteal cells of the ovary. It also enhances cytochrome P450-linked enzyme activity to synthesize pregnenolone and induces 3b-hydroxysteroid dehydrogenase, 17a hydroxylase, and 17,20 lyase activity. FSH regulates ovarian estrogen synthesis by inducing 17b hydroxysteroid dehydrogenase and aromatase. It also induces follicular growth, oocyte maturation, and androgen production. In males, Leydig cell LH receptors induce testicular testosterone production in response to LH. FSH may have a role in spermatozoa development.

Gonadotropin-releasing hormone release from the hypothalamus is pulsatile. The frequency and amplitude of the pulse determines the effect on LH and FSH secretion. The amplitude of the response is greater for LH than FSH. Generally, a decrease in pulse frequency induces LH secretion; an increase in pulse frequency induces a decrease in LH secretion. Inhibition is via a feedback mechanism. Testosterone inhibits LH and FSH release at both the hypothalamus and pituitary level. In fact, castration leads to an increase in gonadotropin levels. Gonadotropin release is also regulated by gonadal peptides inhibin A and B.

A deficiency in gonadotropins causes hypogonadism with decreased sex steroid production. If during childhood it is complete, there is a failure of male sexual development. In females it leads to amenorrhea. If partial, in males it leads to decreased libido, impotence, decreased fertility, and obesity. In females, partial deficiency leads to oligomenorrhea, vaginal dryness, hot flushes, decreased bone density, decreased breast tissue, and infertility.

Pituitary tumors of gonadotropin origin comprise about 15% of pituitary adenomas. Treatment is usually surgical but may be reserved for complications or impending complications since growth is variable. Stereotactic radiation may have a role for tumor control.

Thyrotrophs comprise approximately 5% of anterior pituitary cells. THS is a glycoprotein heterodimer composed of an alpha and beta subunit noncovalently linked. The beta subunit confers the specific action of TSH. The half-life of TSH is approximately 50 minutes. Its action is to stimulate thyroid follicle cells to synthesize and release thyroid hormone.

Stimulatory control occurs via thyroid-releasing hormone (TRH) released from the hypothalamus. Peak TSH levels occur approximately 30 minutes after TRH release. TRH stimulates both alpha and beta subunit transcription. Inhibition occurs through T3 feedback. T3 inhibits both alpha and beta subunit transcription. TSH release is also inhibited by dopamine, glucocorticoids, somatostatin, and some anti-inflammatory medications.

Thyrotroph cells of the anterior pituitary are developed by 12 weeks gestational age. TSH levels rise immediately after birth and remain elevated for about 5 days before reaching adult levels. TSH secretion also follows a circadian rhythm with a peak levels at 11 pm and 5 am.

Deficiency of TSH in childhood leads to mental and growth retardation. In adults, it leads to hypothermia and fluid retention, along with voice, hair, and skin changes. Excess leads to palpitations, arrhythmias, weight loss, tremor, and nervousness.

Tumors of thyrotroph origin are rare and compose less than 1% of all pituitary adenomas. When they do occur, they are usually macroadenomas and often show bony erosion on presentation. Surgery is the primary treatment for these tumors. Radiation may be used as adjuvant therapy. Medical therapy is occasionally used and often involves octreotide, a somatostatin analogue. This is usually combined with symptomatic management that may include propylthiouracil (PTU), propranolol, and occasionally total thyroidectomy.

ADH, also known as vasopressin, is a nonapeptide with a six-amino acid chain connected by a cysteine-cysteine bridge to a three-amino acid tail. It is well conserved across mammalian species. Stimulation of the cell body in the hypothalamus leads to an action potential propagated along the axon to the nerve terminal in the posterior pituitary. This causes an influx of calcium and subsequent extravasation of neurosecretory granules. At any time, there is a 30- to 50-day basal supply stored in the neurosecretory granules. Its half-life is approximately 15 minutes.

ADH plays a critical role in water homeostasis and osmolality of body fluids. It plays a lesser role in blood pressure/volume control, which is controlled to a greater degree by the renin-angiotensin system. V1 receptors for ADH are found in blood vessel walls, V2 in renal collecting duct epithelium, and V3 receptors play a role in factor VIII production. High pressure/volume receptors in the carotid sinus and aortic arch along with low pressure/volume receptors in the atria and pulmonary venous system send afferent signals via cranial nerves IX and X to the
brain stem. Vagotomy results in increased ADH activity. ADH interaction with the V1 receptor leads to arterial and venous constriction. Interaction with the V2 receptor leads to water reabsorption resulting in decreased urine volume and increased urine concentration. Together, these effects lead to an increase in blood volume/pressure. Generally, decreased blood pressure/volume leads to ADH release, and increased blood pressure/volume inhibits ADH release.

Osmotic receptors in the hypothalamus respond to changes in blood osmolality. Osmolality is mainly a function of sodium concentration and is tightly controlled maintaining a range from 280 to 295 mOsm/kg H2O. Basal ADH levels are 0.5 pg/mL. A 1% change in plasma osmolality will lead to a rapid release of ADH from secretory granules. There is a linear relationship between serum ADH levels and osmolality up to ADH levels of 6 pg/mL when maximum urine concentration is occurring.

Diabetes insipidus (DI) is defined by large volume, hypotonic dilute urine. The term insipidus means tasteless, as opposed to mellitus, which means sweet. There are three mechanisms that result in DI, so defined: (a) an inability to synthesize or secrete ADH, (b) nephrogenic—an inappropriate renal response to ADH—and (c) transient DI of pregnancy due to accelerated metabolism of ADH. A similar presentation can occur with excess water ingestion. This can be differentiated from an inability to synthesize or secrete ADH using serum sodium levels, which will be increased with hypothalamic DI and decreased in primary polydipsia. Hypothalamic DI may occur immediately after surgery in the region of the pituitary or hypothalamus (5). Patients ask for cold liquids and have large volume urine. More rarely, DI can be associated with craniopharyngiomas, pinealomas, and suprasellar germinomas. About 50% of DI is idiopathic.

Oxytocin is the other hormone released from nerve terminals of the posterior pituitary. Release of oxytocin stimulates myometrial contraction at parturition. It also stimulates smooth muscle activity in the breast, promoting milk letdown with nursing. Release is mediated via mechanical and tactile receptors stimulated by suckling, leading to an afferent stimulus of the supraventricular and supraoptic nuclei. This causes a pulsatile release of oxytocin. At the end of pregnancy, parturition leads to a 200-fold increase in the responsiveness of myometrial cells to oxytocin.

The parathyroid glands are derivatives of the third and fourth branchial pouches. The third pouch contains the primordia of the thymus and inferior parathyroid glands. The inferior parathyroids descend in the neck with the thymus typically reaching their destination in the anterior mediastinum at about the level of the inferior poles of their respective thyroid lobes. The fourth pouch gives rise to the superior parathyroid glands, which descend to their orthotopic position near the upper pole of the respective thyroid lobe. The fascia enveloping the thyroid gland can envelope the superior parathyroid glands as well. Even when the parathyroid glands are in their usual positions, the superior glands tend to be more posteromedial in position than the inferior glands. Supernumerary glands are not uncommon with up to 2.5% of the population having six glands. The normal adult weight for a parathyroid gland is 30 to 50 mg.

Ectopic locations for the parathyroid glands are not uncommon and reflect the direction and extent of descent during development. Superior glands can be found in the retro- or paraesophageal space and can be found in the posterior superior mediastinum. They can also be intrathyroidal (6). Inferior gland position is slightly more variable. Descent with the thymus leads to ectopic glands in the anterior superior mediastinum and even within the thymus. Up to one of three missed parathyroid adenomas will be found in the anterior mediastinum.

Blood supply to the parathyroid glands is usually via the inferior thyroid artery, but there are often multiple collaterals in the area. More rarely, the superior glands are supplied by the superior thyroid artery and the inferior gland by the inferior thyroid artery. Even more rarely, both glands are supplied by the superior thyroid artery. Venous drainage parallels arterial supply.

Parathyroid hormone (PTH) is an 84aa peptide cleaved from a larger precursor called pre-PTH. Its amino-terminal is the active portion of the hormone. It binds to receptors in bone and the kidney affecting an increase in serum calcium levels. In the kidney, receptor activation leads to an increase in 1,25(OH)₂D3, the active form of vitamin D. In turn, vitamin D augments calcium absorption in the intestine as well as increasing the influx of calcium from bone and kidney. There is a small direct effect of PTH that causes an increase in calcium absorption in the cortical ascending loop of Henle but a more pronounced effect promoting calcium reabsorption from the distal convoluted tubule and the connecting tubule. Phosphate reabsorption in the proximal and distal tubules is strongly inhibited by PTH. In the bone, PTH has direct effects on osteoblasts and preosteoblasts. Osteoblast production of collagen is inhibited and maturation of preosteoblasts is inhibited. Effects on osteoclasts, or bone resorbing cells, are indirect via preosteoblasts and osteoblasts, which send cell signals to osteoclasts to mature, resorb bone, and inhibit apoptosis. Interestingly, constitutive PTH leads to bone resorption, but intermittent PTH favors an increase in bone mass. This has been used clinically. Teriparatide, an amino-terminal segment of PTH administered subcutaneously, is an FDA-approved treatment for severe osteoporosis.

Secretion of PTH is stimulated by a decrease in serum ionized calcium levels. Not only does PTH secretion vary inversely with ionized calcium levels but the PTH response for a given level of hypocalcemia is more dramatic if the rate of fall of ionized calcium is greater. Inactivation of the receptor for calcium through mutation is seen in familial hypocalciuric hypercalcemia. Chronic calcium receptor activation is also seen with genetic mutations and causes hypoparathyroidism with hypocalciuria. 1,25(OH)₂D3 does not affect secretion of PTH. However, it does suppress PTH gene transcription. Increased phosphate levels stimulate PTH secretion indirectly by decreasing blood calcium and 1,25(OH)₂D3 levels. Beyond the increased transcription and secretion of PTH, parathyroid cell number increases in the setting of hypocalcemia, low levels of 1,25(OH)₂D3, hyperphosphatemia, and uremia. This is a slower response, and even if the underlying cause for the increased cell replication is no longer present, the resulting hyperparathyroidism can persist. This represents tertiary hyperparathyroidism.

Primary hyperparathyroidism is defined by the inappropriate hypersecretion of PTH. Seventy-five to eighty percent is caused by one or more adenoma, 20% by diffuse hyperplasia and <1% to 2% by parathyroid carcinoma. Carcinomas are usually associated with very high PTH levels and can be part of hyperparathyroidism-jaw tumor syndrome (parathyroid carcinoma and fibrous jaw tumors). Primary hyperparathyroidism is characterized by increased renal calcium absorption, phosphaturia, increased 1,25(OH)₂D3, and increased bone resorption. The prevalence is thought to be approximately 0.04/1,000 population, but because many of those with primary hyperparathyroidism are asymptomatic, the numbers may be higher. DNA mutations including those of protooncogenes PRAD-1 and cyclin D1 have been implicated (7). There is some evidence that a remote history of neck irradiation may increase the risk. These mutations cause not only an increase in cell numbers but a decreased response of those cells to serum calcium levels. Parathyroid hyperplasia is seen in the MEN syndromes type 1 and 2a. In type 1 MEN, hypercalcemia is seen in 95% of patients and usually present in the second or third decade of life. In type 2a MEN, only 5% to 20% of patients manifest symptoms of hyperparathyroidism.

The natural history of asymptomatic primary hyperparathyroidism is uncertain, although there is evidence of increased fracture risk (8). Current indications for surgery are controversial but include those (a) <50 years of age, (b) who cannot participate in appropriate follow-up, (c) with a serum calcium level >1.0 mg/dL above the normal range, (d) with urinary calcium >400 mg/24 h, (e) with a 30% decrease in renal function, or (f) with complications of primary hyperparathyroidism, including nephrocalcinosis, osteoporosis (T-score <2.5 SD at the lumbar spine, hip, or wrist), or a severe psychoneurologic disorder (9). Medical management for the remaining asymptomatic hyperparathyroid patients includes semiannual clinical evaluations, avoidance of diuretics and immobility, maintenance of adequate hydration, and limiting oral calcium to 800 mg/day. Symptomatic patients have combinations of decreased cortical bone, hypercalciuria associated with nephrolithiasis, and even renal failure, flank pain, polyuria/polydipsia, conjunctival calcifications, GI symptoms, and pathology that may include pancreatitis, neuropsychiatric problems, and neuromuscular complaints. Although symptoms can sometimes be difficult to directly attribute to hyperparathyroidism, the recommendation for symptomatic patients is for surgery unless it is otherwise contraindicated. In those patients that cannot undergo surgery, bisphosphonates like alendronate can improve bone density but have minimal effects on serum calcium and PTH. Calcimimetics like cinacalcet can lower serum calcium and PTH but do not affect bone density.

Secondary hyperparathyroidism is defined by the appropriate hypersecretion of PTH. It can be seen with decreased serum calcium levels secondary to excess urinary loss, or inadequate intake, hypophosphaturia due to aluminum poisoning, kidney disease and decrease calcium levels, and decreased 1,25(OH)₂D3 levels secondary to decreased sunlight exposure or malnutrition. Treatment is directed by the underlying cause.

Calcitonin is a 32aa polypeptide with a disulfide bridge. Although it is an important component of calcium metabolism in many species, its importance in humans remains uncertain. It is secreted by intrathyroidal C-cells of neural crest origin. It is incorporated into the thyroid gland as the ultimobranchial bodies (the primordia of the C-cells) merge with the developing thyroid. In other species, calcitonin causes a decrease in tubular resorption of calcium in the kidneys and decreases osteoclast-mediated bone resorption. However, in humans, thyroidectomy has no significant effect on bone density and even high-dose exogenous calcitonin has minimal long-term effects (10).

Secretion of calcitonin is closely related to serum calcium levels. C-cells have the same calcium receptor as parathyroid chief cells, and increased calcium levels cause an increase in calcitonin secretion. There are a number of gastrointestinal hormones that stimulate calcitonin secretion as well. Their role in calcium regulation is uncertain. Inhibition is through somatostatin via an autocrine secretion. Transcription for calcitonin in C-cells is inhibited by 1,25(OH)₂D3.

With sun exposure (UV radiation), the cutaneous precursor of vitamin D, 1,7dehydrocholesterol, undergoes cleavage to form a thermally labile product that subsequently undergoes a rearrangement to form vitamin D. Excess sun
exposure leads to alternative rearrangement leading to biologically inert products. Subsequently, the precursor product undergoes a 25 hydroxylation, which occurs in the liver. This is followed by 1-alpha hydroxylation in the proximal convoluted tubule of the kidney. 1-Alpha hydroxylase activity is stimulated by PTH and hypophosphatemia. The product of this hydroxylation has an inhibitory effect on 1-alpha hydroxylase. The final product 1,25(OH)₂D3 has a half-life of 6 to 8 hours. Vitamin D is also obtained through the diet. Fortified dairy products and cereal, egg yolks, and fish oil are major sources.

Vitamin D binds to nuclear receptors found in most tissues. Vitamin D precursors have an affinity but a much lesser affinity for the same receptors. Although present in most tissues, receptor binding has its greatest effect in the intestine. Receptors in the jejunum and duodenum, when bound, induce calcium channels important for intestinal absorption of calcium. A normal diet contains 700 to 900 mg of calcium. Typically, 30% to 35% is absorbed. Vitamin D effects on bone include increased differentiation of osteoclasts and osteoclast-mediated bone resorption.

There are many conditions that can cause hypercalcemia. The two most common etiologies are primary hyperparathyroidism and malignancy. Together, they account for about 90% of all cases. In the hospital setting, malignancy is often the underlying culprit in hypercalcemia. In the outpatient clinic, primary hyperparathyroidism is the dominant etiology for chronic asymptomatic hypercalcemia. Hypercalcemic crises are the result of severely elevated calcium levels due to any cause, malignancy being the most common, and are associated with a significant mortality rate. Calcium levels between 13 and 15 mg/dL require aggressive treatment, while levels above 15 mg/dL can be life threatening and demand emergent therapy. The severity of symptoms is related to not only the absolute calcium level but also the rate of calcium level elevation. Hypercalcemia due to malignancy carries a poor prognosis as life expectancy is generally less than 6 months when hypercalcemia develops. Patients often present with acute mental status changes, confusion, bone or muscle pain, constipation, and fatigue. On examination, they appear to be dehydrated, with varying degree of mental status change. Laboratory evaluation invariably demonstrates elevated calcium levels with low, normal, or elevated PTH levels depending on the etiology. Hypercalcemia may be accompanied by acute renal insufficiency.

The pathogenesis of hypercalcemia is mediated through 3 different mechanisms. It can be due to elevated PTH, which activates osteoclasts and bone resorption, increases calcium absorption from the gastrointestinal tract, as well as reducing calcium excretion in the urine. This is the underlying mechanism of hypercalcemia occurring in primary hyperparathyroidism. Hypercalcemia can also be due to elevated parathyroid hormone-like protein (PTHrP) in patients with squamous cell carcinoma of the lung, head and neck, cervix, esophagus, vulva, and skin, as well as breast cancer, renal cell, and bladder cancer. PTHrP has similar functions to PTH and occupies the same receptors, but its secretion is not regulated by calcium level. The third mechanism is through lymphokines or cytokines such as TNF-beta, IL-1, lymphotoxin, or 1,25 (OH)₂D released locally by tumor cells. These factors act on osteoblasts to stimulate bone resorption and cause hypercalcemia. This occurs often in patients with breast cancer or any cancer with metastasis to the bone or hematogenous tumors such as multiple myeloma, leukemia, and lymphoma.

The treatment of hypercalcemia includes aggressive IV hydration, judicious use of diuretics, bisphosphonates, calcitonin, and steroids. This combination approach can decrease serum calcium by 3 to 9 mg/dL within 24 to 48 hours in most patients, enough to relieve acute symptoms, prevent death from hypercalcemic crisis, and permit diagnostic evaluation. In a patient with hypercalcemic crisis, the critical first step in treatment is hydration. Patients are invariably dehydrated due to vomiting, poor intake, and a decreased ability to concentrate the urine induced by hypercalcemia. Rehydration with IV normal saline should be given as a bolus of 1 to 2 L initially, then at 200 mL/h for the first 24 hours in patients without a history of congestive heart failure. Subsequently, IV normal saline can be given at 100 mL/h until fluid status is replete. Care should be taken to prevent magnesium and potassium depletion. Loop diuretics such as furosemide can be given to patients to hasten calcium excretion only in the setting of adequate rehydration. Diuretics given too early in a dehydrated hypercalcemic patient may worsen hypercalcemia and renal insufficiency.

Calcitonin inhibits osteoclast action through receptors on the osteoclast. It also increases renal calcium excretion by inhibiting renal tubular calcium reabsorption. Therefore, it is a very effective agent within the first 24 hours of treatment of hypercalcemia as it can reduce calcium level within hours. However, its effect is short lasting secondary to tachyphylaxis, and it should not be used beyond the first 48 hours of treatment. The other benefit of calcitonin is that it has anesthetic effects, which can relieve the severe bone pain associated with hypercalcemia.

Bisphosphonates are the mainstay of treatment to lower calcium levels. Bisphosphonates are analogues of pyrophosphate, with a high affinity for bone, and reduce calcium levels by inhibiting osteoclast action, therefore suppressing bone resorption. This effect, however, takes 3 to 6 days to become effective and therefore cannot acutely lower calcium levels. Either pamidronate 30 to 90 mg or zoledronic acid 1 to 4 mg can be given intravenously to patient with hypercalcemia. Dose reduction is generally recommended in the setting of renal insufficiency. Repeat therapy as frequently as every month is necessary in patients with recurrent hypercalcemia due to malignancy.

Glucocorticoids can be helpful in hypercalcemia due to some malignancies. They increase urinary calcium excretion and decrease intestinal calcium absorption when given in pharmacologic doses. They are especially useful in those osteolytic malignancies such as multiple myeloma, leukemia, Hodgkin disease, other lymphomas, and carcinoma of the breast. They are also effective in treating hypercalcemia due to vitamin D intoxication and granulomatous disease such as sarcoidosis.

Other agents such as gallium nitrate and plicamycin are not used often nowadays, given their toxicity and better alternative therapies. Occasionally, dialysis may be needed in patients who have renal failure and hypercalcemia.