SOURCE: Grand Rounds Presentation, UTMB, Dept. of Otolaryngology
DATE: December 15, 1999
RESIDENT PHYSICIAN: Edward D. Buckingham, M.D.
FACULTY PHYSICIAN: Francis B. Quinn, M.D.
SERIES EDITOR: Francis B. Quinn, Jr., M.D.
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The pituitary gland consists of two embryologically distinct parts. The posterior pituitary or neurohypophysis is derived from the neural ectoderm of the floor of the midbrain near the 3rd ventricle. It is connected to the hypothalamus via two nervous tracts, the tuberohypophysial tract and the supra-optico-hypophysial tract. The anterior pituitary or adenohypophysis is derived from a pouchlike recess in the ectoderm of the stomodeum, the pouch of Rathke. The gland comes to lie in a bony cradle called the sella tercica of the sphenoid bone with the sphenoid sinus lying anteriorly and the clivus posteriorly. The soft tissue boundaries of the pituitary include the lamina dura forming the floor of the sella, the cavernous sinus laterally, the optic chiasm superiorly, and the diaphragma sellae forming the dural roof. The arterial supply to the pituitary is from the superior and inferior hypophysial arteries from the internal carotid artery. The venous drainage is via the cavernous sinus. The neurohypophysis secretes the octapeptides oxytocin and vasopressin, or anti-diuretic hormone (ADH). The adenohypophysis is regulated by the hypophyseal-portal system and secretes the chemicals adrenocorticotropin hormone (ACTH), thryoid stimulating hormone (TSH), growth hormone (GH), prolactin (PRL), follicle stimulating hormone (FSH), and lutinizing hormone (LH).
Two main systems interact to regulate the release of ADH, the osmotic and the nonosmotic pathways. The osmotic pathway is centered on the supraoptic and paraventricular nuclei of the hypothalamus. These centers are sensitive to minor changes in serum osmolality, as little as 2% of plasma osmolality above 280mOsm/kg. When there is an increase in plasma osmolality the osmoreceptors shrink and trigger a release of ADH; conversely when there is a decrease they swell and suppress the release. The nonosmotic pathway consists of volume receptors in the left atrium, and baroreceptors in the carotid sinus, and aortic arch mediated by cranial nerves IX and X. An increase in volume or pressure will stimulate the glossopharyngeal or vagus nerve and inhibit the release of ADH, while a decrease in these factors will stimulate its release. The action of ADH is to increase the permeability of the distal convoluted tubule and the collecting ducts to water, thus promoting urinary concentration.
Adrenocorticotropic hormone (ACTH), which is secreted by the corticotropes of the adenohypophysis, is derived from the prohormone, proopiomelanocortin. The lipotropins, melanotropins, and endorphins are all derived from this precursor molecule. ACTH is secreted from the pituitary in a circadian rhythm, which peaks in the morning between 6 am and 8 am and troughs between 10 pm and 3 am. Trophic stimuli from above and negative feedback from glucocorticoids regulate ACTH secretion. The trophic factor stimulating ACTH release is corticotropin-releasing factor (CRF) from the hypothalamus. CRF release is initiated by several factors, the most notable being stress and hypoglycemia. CRF secretion is inhibited by the level of glucocorticoids in the circulation as well as increasing levels of ACTH. The main action of ACTH is to stimulate the adrenal cortex to secrete glucocorticoids. ACTH also stimulates the secretion of aldosterone, but to a lesser extent and secondary to the renin-angiotensin-aldosterone system.
Thyrotropin (TSH) is a glycoprotein consisting of two peptide chains. The alpha subunit is identical to that of LH, FSH, and HCG. The beta subunit confers hormonal specificity. Unlike ACTH the blood level of TSH is constant, and ranges from 0.5 to 8 microunits/mL. TSH release is stimulated by thyrotropin-releasing hormone, TRH, from the hypothalamus and suppressed by the level of circulating thyroid hormones, primarily free T3. The action of TSH is to stimulate thyroid function through the cAMP mechanism. The acute effects of TSH are to increase the formation of colloid, uptake of iodine, and formation of thyroid hormones. The late effects are related to growth of the gland, resulting in increased volume and number of cells.
Growth hormone (GH) release is mediated by a number of factors. Factors that stimulate the release include; hypoglycemia, L-Dopa, arginine, sleep, serotonin, exercise, stress, and morphine. Factors that suppress release include somatostatin, glucose, alpha-blockade, and corticosteroids. The main action of growth hormone is to stimulate longitudinal growth. The action of GH is mediated through peptides called somatomedins. These peptides influence leucine incorporation into protein, uridine incorporation into RNA, and thymidine incorporation into DNA. Overall, GH is anabolic to protein metabolism, lipolytic, stimulatory to insulin release, and suppressive to peripheral tissue utilization of glucose.
Prolactin acts on mammary tissue which has been prepared by estrogen and progesterone secretion to initiate and maintain lactation.
FSH and LH are responsible for leydig cell production of testosterone and spermatogenesis in the male and for endometrial cycles and ovulation in the female . The feedback is complex and differs among the sexes. It will not be discussed here. Kallmann’s syndrome, due to the maldevelopment of the olfactory lobes and related hypothalamic lesions, is characterized by hyposmia or anosmia and an isolated Gn-RH deficiency with associated gonadal dysfunctions.
Diabetes insipidus, (DI), is a condition characterized by the passing of extremely large quantities of dilute urine. The basic defect is of the renal tubules to concentrate urine. When the condition is due to decreased production of vasopressin the condition is termed central DI; if it results from the renal tubule’s resistance to vasopressin it is termed nephrogenic DI. The condition to be discussed here is of the central variety. The most frequently encountered cause for central DI is trauma, especially surgical trauma. Transient DI is extremely common following pituitary surgery because of removal of the neurohypophysis. Permanent DI develops only when the pituitary stalk is damaged above the median eminence. The etiology of central DI includes the following:
From Kannan, Essential Endocrinology
The two salient features of DI of any cause are polydipsia and polyuria. The polyuria can be anywhere from 3-15 L/day, however 4-5 L/day is more common. The urine specific gravity is usually less than 1.005 with urine osmolality < 200 mOsm/kg. Plasma osmolality is usually greater than 287 mOsm/kg. The polydipsia is a compensatory mechanism to fluid loss. If tumor has destroyed the adjacent hypothalamic thirst center the result can be rapid and disastrous. The diagnosis can be confirmed by depriving the patient of water and monitoring the urine for increased osmolality. Following this the patient is given 5 units of aqueous vasopressin. The normal subject will begin concentrating urine within hours of water deprivation. The DI patient will continue to exhibit dilute urine. In central DI the patient will respond rapidly to vasopressin, while the nephrogenic DI patient will fail to respond to the vasopressin. Associated features to observe for include visual field loss, optic atrophy, papilledema, and other pituitary hormone abnormalities. The treatement for DI with dehydration is liberal fluid replacement coupled with short acting aqueous vasopressin. For chronic DI the treatment is dDAVP intranasally BID.
The syndrome of inappropriate ADH secretion is defined as a metabolic disorder characterized by continued secretion of antidiuretic hormone despite hypotonicity. The ADH may be secreted by the hypothalamus or by an ectopic source.
The response to hypotonic plasma in the normal state and in SIADH are compared in Table 24. The etiology of SIADH is diverse and demonstrated in table 25.
From Kannan Essential Endocrinology From Kannan Essential Endocrinology
The clinical symptoms of SIADH include fatigue, muscle weakness, and dizziness which then progresses to behavioral changes and drowsiness. When the serum sodium level falls below 120, stupor, convulsions, and coma result. The criteria for the diagnosis of SIADH are 1) hypotonicity of plasma, 2) hyponatremia, 3) less than maximally dilute urine, 4) natriuresis despite hyponatremia, and 5) exclusion of hepatic, renal, thyroid, and adrenal dysfunction. The treatment for SIADH consists of water restriction limited to 600-800 ml/day. With this intake the patient should soon develop a negative fluid balance due to insensible losses. Demeclocycline given in doses of 900 to 1200 mg/day blocks the action of vasopressin at the level of the distal and collecting tubules. The occasional side effects of this treatment include renal failure and bacterial superinfection. The use of hypertonic saline may be considered when the serum sodium is below 115 mEq/L, however the rapid correction of hyponatremia may result in the development of central pontine myelinolysis, a serious complication.
The parathyroid glands begin development during the 5th week of gestation. They form from the ectoderm of the 3rd and 4th pharyngeal pouches. The 3rd pouch also forms the thymus gland. As the 3rd pouch migrates inferiorly it brings the parathyroid with it and comes to lie near the inferior pole of the thyroid gland. The 4th pouch does not migrate and therefore forms the superior parathyroid. Aberrant parathyroid from the third and fourth pouches occurs in 15-20% of patients. The parathyroid tissue has been found from the internal carotid artery to the aortopulmonary window, anterior or posterior to the aortic arch. Knowledge of the derivatives of the third and fourth pouches will assist in identifying possible locations of aberrant tissue. The glands usually number four, however, there may be six or more on rare occasions, 2-4%. The blood supply is from the inferior and superior parathyroid arteries, which are usually branches of the inferior thyroid artery. Rarely, the superior artery arises from the superior thyroid artery.
The actions of parathyroid hormone, PTH, are that it 1) increases serum calcium level, 2) increases urinary phosphate and thus decreases serum phosphate level, 3) increases bone osteoclast and osteoblast activity and thus bone remodeling, 4) increases bicarbonate excretion by the kidney 5) increases the gastrointestinal absorption of calcium by enhancing vitamin D synthesis, and 6) increases the rate of conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 in the kidney. Calcitonin, a hormone secreted by the parafollicular cells of the thyroid gland, is an antihypercalcemic hormone. It inhibits bone resorption and increases phosphate excretion by the kidneys. Vitamin D, another important element in calcium metabolism, is absorbed through the skin or gastrointestinal tract and is converted by the liver to 25- hydroxycholecalciferol. 1a -hydroxylase, in the kidneys, then converts 25-hydroxycholecalciferol to its active form, 1,25-dihydroxycholecalciferol. Vitamin D promotes calcium and phosphate absorption in the GI tract and retention by the kidneys.
The causes of hypercalcemia are listed in Table 14-3:
From Bailey H&N Surgery Otolaryngolgy
Primary hyperthyroidism is caused by a single adenoma in 85% of cases, hyperplastic glands in 12%, and by multiple adenomas in 3% of cases. Secondary hyperparathyroidism is due to malfunction of another organ system usually renal failure. Tertiary hyperparathyroidism is similar to secondary, however PTH production is now autonomous from the underlying condition. This is seen occasionally after renal transplant when hyperparathyroidism persists despite correction of the renal function. Primary hyperparathyroidism is the most common cause in individuals under 50 years of age. Malignancy-related hypercalcemia is the most common cause in individuals over the age of 50. The malignant hypercalcemia may be by two mechanisms: 1) bone destruction secondary to metastasis or 2) secretion of a variety of humoral mediators that stimulate bone resorption.
Hyperparathyroidism is associated with many conditions and complications including: 1) renal disease (nephrolithiasis, nephrocalcinosis); 2) hypertension; 3) gout, pseudogout, hyperuricemia, chondrocalcinosis; 4) peptic ulcer disease; 5) pancreatitis; 6) MEN, type 1 (Wermer’s syndrome) parathyroid hyperplasia or multiple adenomas, pancreatic tumors (insulinomas, gastriomas), pituitary tumors, miscellaneous tumors; 7) MEN type 2 (Sipple syndrome), 2a-medullary thyroid carcinoma and C-cell hyperplasia, parathyroid hyperplasia, pheochromocytomas; 2b- medullary thyroid carcinoma, pheochromocytomas, ganglioneuromatosis, mucosal neuromas, marfanoid habitus; and 8) other disorders- sarcoidoisis, ankylosing spondylitis, diabetes mellitus, myeloma, hyperthyroidism. The clinical manifestations of hyperparathyroidism are numerous and include constitutional symptoms of weight loss and anorexia, renal colic, hematuria, back pain, polyuria, nocturia, bone pain, joint pain, proximal weakness, dyspepsia, constipation, nausea, emesis, pancreatitis, memory loss, lack of energy, headache, insomnia, neurosis, psychosis, hypertension, heart block, pruritus, brittle nails, and band keratopathy. The laboratory examination for hyperparathyroidism is summarized in Table 7-3:
From Clark Endocrine Surgery
The treatment for primary, secondary and tertiary hyperparathyroidism often requires surgery. However, many patients with hypercalcemia are discovered early and are asymptomatic. Do these patients benefit from surgery? The Mayo clinic followed 147 patients with minimal primary hyperparathyroidism for 10 years. 26% of the original 147 patients required surgery because they developed some complication from the disease. 35 people died over the course of the study (50% from vascular complications and 20% form hypertension) from causes known to be associated with hyperparathyroidism. Of the 74 unoperated patients who were alive, 38 had persistent disease, 13 were indeterminate, and 23 were lost to follow-up. Kaplan questioned whether patients with asymptomatic hyperparathyroidism received any metabolic benefits from parathyroidectomy. They compared the metabolic effects of hyperparathyroidism in six patients with asymptomatic hyperparathyroidism and in seven patients with symptomatic hyperparathyroidism before and after parathyroidectomy. The authors looked at hypercalciuria, bone density, creatinine clearance, and many other variables. The authors concluded that patients with asymptomatic hyperparathyroidism received the same metabolic benefits as patients with symptomatic hyperparathyroidism. Other issues supporting surgery include disease in post-menopausal women at risk for osteoporosis, studies by Cogan demonstrating psychological benefit, avoiding hypercalcemia in illness and dehydration, and parathyroidectomy has shown to be cost effective. In summary, parathyroidectomy from hyperparathyroidism is indicated in patients with hypertension, mildly reduced creatinine clearance, increased urine calcium, decreased bone density, or clinical symptoms.
The thyroid gland develops from the pharyngeal floor in the region of the foramen cecum. It is joined in its decent by the parathyroids from the 3rd and 4th pharyngeal pouches. Laterally, the gland extends to the tracheoesophageal groove, where it is in close association with the recurrent laryngeal nerve. The gland may rest in an ectopic location anywhere from the base of tongue to the mediastinum. Remnants of the thyroglossal tract may present as midline cysts. The arterial supply to the thyroid is from the superior thyroid artery branch of the external carotid artery and from the inferior thyroid artery branch of the thyrocervical trunk. The venous outflow is via the superior and middle thyroid veins, which drain into the internal jugular vein, and the inferior thyroid vein, which drains into the brachiocephalic vein. The lymphatic drainage is to the pretracheal and paratracheal lymph node group of level VI.
Hormonogenesis in the thyroid begins with the trapping of iodine, which is then immediately oxidized. The iodine is then incorporated into tyrosyl residues by a process called organification. The tyrosyl is provided by thyroglobulin, a large-molecular weight protein contained within the colloid. The iodination of thyroglubulin then produces monoidotyrosine (MIT). A series of coupling reactions results in the formation of diiodotyrosine (DIT), which then couples with MIT or DIT to form triiodothyronine (T3) or tetraiodothyronine (T4). After synthesis, the next step is secretion. The thyroid hormones circulate in the blood as both bound and free hormones. Approximately 95.5% is bound and 0.5% is free, biologically active hormone. Thyroid binding globulin is the primary binding protein, but also to a lesser extent prealbumin and albumin. The major fate of T4 is deiodination to T3, which occurs primarily in the liver and kidney. Approximately 80% of T3 in the circulation is derived in this manner. Renal or hepatic disease; acute or chronic illness; or drugs including, propylthiouracil, glucocorticoids, propranolol, iopanoic acid inhibit this process. Whenever this process is inhibited, regardless of the cause, the thyroxine in the blood is converted instead into reverse T3, a metabolically inert isomer. The regulation of hormone production is primarily by the feedback of free T3 on the hypothalamus and pituitary. The end action of thyroxine is increased metabolic rate and thermogenisis.
Many laboratory examinations are available to test thyroid function. T4 radioimmunoassay measures both the bound and unbound hormone. T3 resin uptake test is used to measure the level of TBG capacity. The test is conducted by giving radiolabled T3. This binds to the open sites on the TBG. A resin is then given to which a portion of the radiolabled T3 will bind to, normally 25-35%. If more than the usual 25 to 35% binds to the resin this indicates a decrease in the TBG capacity, and converse if less binds. Once the TBG capacity and T4 level have been determined the free thyroxine index can be calculated by taking the product of the T3RU and the T4 immunoassay. The FTI is a good indication of whether a patient is truly hyper or hypothyroid, and not just euthyroid with an alteration in the TBG level. The T3 radioimmunoassay reflects the peripheral metabolism of thyroxin more than thyroid function since 80% of T3 is produced by peripheral conversion. This test is useful to determine T3 thyrotoxicosis in a patient who has a normal FTI, but is still symptomatic. Thyroid stimulating hormone is measured by ultra- sensitive assays. The indication to obtain a TSH level is; to establish the etiology of hypothyroidism, to follow therapy with levothyroxine, and to evaluate euthyroid goiters. Compensated thyroid function can account for euthyroidism and goiter at the expense of an elevated TSH. It should be noted that TSH is seldom indicated in the evaluation of hyperthyroidism unless unusual disorders are suspected.
Thyroid scanning employs radioactive isotopes of iodine. It is of interest that iodinated contrast agents used in imaging take one month to clear before thyroid scanning may take place. The indication for thyroid scanning includes determining a hot from cold nodule, evaluating for metastatic thyroid cancer, ectopic thyroid, and identifying hypofunctioning areas in Hashimoto’s that may be lymphoma. The use of ultrasonography is primarily to determine solid from cystic nodules, for guiding fine needle aspiration in non-palpable nodules, and following non-palpable nodules response to thyroid suppression. The etiology and symptoms of hyperthyroidism are listed in tables 32 and 33.
From Kannan Essential Endocrinology From Kannan Essential Endocrinology
Likewise the etiology and symptoms of hypothyroidism are listed in tables 40 and 41.
From Kannan Essential Endocrinology From Kannan Essential Endocrinology
The adrenal gland consists of the outer cortex and the inner medulla. The cortex consists of three layers; the zona glomerulosa, which secretes the mineralocorticoid aldosterone, the zona fasciculata, which secretes the glucocorticoid cortisol, and the zona reticularis, which secretes the androgens. The medulla secretes catacholamines, norepinephrine and epineprine.
The production of aldosterone from the zona glomerulosa is primarily under the control of the renin-angiotesin-aldosterone system. Renin is secreted from the JG cell of the kidney in response to hyponatremia or hypovolemia. The renin converts angiotensinogen to angiotensin I which is then converted to angiotensin II by angiotensin converting enzyme. Angiotensin II is a potent pressor and is responsible for stimulating the adrenal gland to secrete aldosterone. Additionally, hyperkalemia stimulates and hypokalemia suppresses aldosterone secretion. ACTH to a much lesser extent also stimulates aldosterone secretion. Aldosterone’s major site of action is on the distal tubule of the kidney, however it also acts on the sweat glands, salivary glands, and GI tract. Aldosterone facilitates the exchange of sodium for potassium and hydrogen ions. The retention of sodium and water acts to increase the extracellular fluid and blood volume.
The zona fasciculata is under the control of ACTH as discussed in the pituitary section. Cortisol acts on many different systems. In general they are catabolic hormones causing muscle wasting, increased gluconeogenesis, and glucose output, which leads to insulin output and eventually islet cell exhaustion and diabetes. The excess fat is deposited centrally. Cortisol also leads to increased bone resorption and renal calcium loss, sodium retention and potassium loss. Initially there is an increase in antibody production, but eventually a decrease. Cortisol also acts as an anti-inflammatory and anti-allergic agent.
The zona reticularis is also under the control of ACTH, however there is no feedback between the androgens and ACTH. The adrenal androgens are important in adrenarche and the production of hormones in postmenopausal women.
Hyperadrenocorticism carries the name of the Boston neurosurgeon, Harvey Cushing, who first described its signs and symptoms. The disease presents in the 3rd to 6th decade of life and is more prominent in females 4 to 1. The causes include pharmocologic, pituitary adenoma, (true Cushing’s disease), adrenal adenoma, or carcinoma, or ectopic production of ACTH. The signs and symptoms include red cheeks, moon face, buffalo hump, thin skin, ecchymoses, high blood pressure, red abdominal striae, central obesity, thin arms and legs, and poor wound healing. The treatment of the disease is based on the cause.
Adrenocortical insufficiency may be due to primary causes, ie. Addison’s disease, including autoimmune disease, tumors, infection, hemorrhage, metabolic failure. Secondary causes include hypopituitarism and suppression by exogenous steroids. The signs and symptoms include fatigability, weakness, anorexia, nausea, weight loss, hyperpigmentation, hypotension, and loss of axillary and pubic hair in women. The condition can lead to severe volume depletion and shock. The treatment is with glucocorticoid and mineralocorticoid replacement as indicated and volume replacement in acute conditions.
Primary overproduction of aldosterone, or Conn’s disease, is usually caused by adenoma or nodular hyperplasia of the zona glomerulosa. Secondary causes of increased aldosterone include cirrhosis, ascites, nephrotic syndrome, diuretic use. The signs and symptoms include headache, hypokalemia causing muscle weakness, nocturnal polyuria, and hand cramping. Treatment is surgical for adenoma or medical for hyperplasia with spironolactone.
The endocrine pancreas consists primarily of alpha cells, which secrete glucagon, and the beta cells, which secrete insulin. Glucose, amino acids, glucagon, GI hormones, and vagal impulses stimulate insulin secretion. B-blockers, sympathomimetics, and somatostatin inhibit insulin release.
Table 91 demonstrates the characteristics of the two main types of diabetes.
From Kannan Essentials Endocrinology
Surgical care of the diabetic patient includes attempting to keep glucose levels between 120 and 250 mg/dL. The BGL should be check every 1-2 hours intraoperatively. Three grams/kg/day of glucose prevents catabolism and lipolysis. This equates to about 5% dextrose at 100 cc/hr. Ketoacidosis occurs in type I diabetes when inadequate insulin leads to lipolysis, free fatty acids, and the accumulation of ketone bodies. This leads to a metabolic acidosis, with volume depletion and electrolyte abnormalities. The condition should be treated with IV insulin, 12-20 unit bolus, followed by infusion of insulin at .05 to 0.1 u/kg/hr. 0.9 NS IVF bolus and maintenance based on fluid deficit should be given adding glucose when the blood sugar decreases to around 200. A potassium deficiency is invariably present and will worsen as the insulin drives potassium intracellularly, rehydration dilutes serum K+, correction of acidosis enhances the intracellular entry of K+, and volume expansion leads to more Na+ delivery to the distal tubule, which is under influence of high aldosterone level leading to kaliurisis. Replace electrolytes as needed and monitor the anion gap for the endpoint of successful therapy. Hyperosmolar nonketotic coma is similar to DKA, however lack of lypolysis prevents ketoacidosis. However, severe polyuria leads to loss of electrolytes and free water leading to severe dehydration and electrolyte imbalances. Treat similar to DKA, however disagreement exists on whether to use isotonic or hypotonic saline for resuscitation.
Barrs, David M., Perioperative Management Issues, In B.J. Bailey (ed.): Head and Neck Surgery-Otolaryngology Second Edition, Lippincott-Ravin, 1998, p. 247.
Clark, Orlo H. Endocrine Surgery of the Thyroid and Parthyroid Glands, Mosby 1985.
Coffey, Amy R., Petti, George H., Endocrinology, In B.J. Bailey (ed.): Head and Neck Surgery-Otolaryngology Second Edition, Lippincott-Ravin, 1998, pp. 163-177.
Hadley, Mac E., Endocrinology Fourth Edition, Prntice-Hall, Simon & schuster, 1996.
Kannan, C.R., Essential Endocrinology, A Primer for Nonspecialists, Plenum Publishing, 1986.
Netter, Frank H, The Ciba Collection of Medical Illustrations Vol 4, Endocrine System and Selected Metabolic Diseases, Ciba Pharmaceutical, 1965.