Mecanism Of Centripetal Lipid Accumulation Supraclavicular Fat And Face

NEUROENDOCRINOLOGY

Sandeep Kunwar

The pituitary gland is often considered the "master gland," regulating most of the body's hormonal balance. The gland itself is regulated by the hypothalamus through stimulatory and inhibitory hormones that travel through the infundibulum and pituitary stalk. The adult pituitary gland measures 12 x 6 x 9 mm and weighs 0.6 g. It enlarges during pregnancy, when it may weigh 1 g or more. The gland is situated near the sella turcica ("Turkish saddle") formed by the sphenoid bone and is completely covered by dura and the sellar diaphragm above. The pituitary stalk enters the sella turcica through a hole in the sellar diaphragm. Laterally, the pituitary fossa is bounded by the cavernous sinuses containing the carotid artery and the third, fourth, fifth, and sixth cranial nerves. Superiorly, the optic nerves and chiasm traverse 4 to 6 mm above the sellar diaphragm. The human pituitary gland is divided into two parts: the adenohypophysis and the neurohypophysis.

The adenohypophysis is derived from the invagination of the hypophyseal-pharyngeal duct known as Rathke's pouch. The adenohypophysis constitutes approximately 80% of the entire pituitary and is divided into the pars distalis (anterior lobe), pars intermedia (intermediate lobe), and the pars tuber-alis (pars infundibularis). The pars distalis is the largest and the functional part of the adenohypophysis. The pars intermedia in the human pituitary is a poorly developed, rudimentary structure lying between the anterior and posterior lobes. It often degenerates into a pars intermedia cyst (less than 5 mm) filled with colloid material. The pars tuberalis is an upward extension of the anterior lobe along the pituitary stalk and may be a source of suprasellar anterior-lobe pathology. The anterior lobe is the source of prolactin (PRL), growth hormone (GH), thyroid-stimulating hormone (TSH), gonadotropic hormones (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), and adrenocorticotropic hormone (ACTH).

The neurohypophysis is derived from the ventral outgrowth of the neuroectoderm. This is a funnel-shaped structure, with the base forming the tuber cinereum, median eminence, infundibulum, and infundibular process (pituitary stalk) and ending in the posterior lobe within the pituitary fossa. The posterior lobe is made up of axonal end bulbs containing neurosecretory vesicles (storing oxytocin and antidiuretic hormone) and pituicytes. These axons originate from the magnocellular neurons of the hypothalamus (in the supraoptic, paraventricu-lar, and accessory nuclei), where the hormones are produced.

The pituitary receives its blood supply from the superior and inferior hypophysial arteries. Some data indicate that 70% to 80% of the anterior lobe blood comes from the large portal vessels that arise from the median eminence and traverse down the infundibulum, and the remainder of the pituitary blood supply comes from the short portal system. The communication between the hypothalamus and anterior lobe is through the blood via the portal circulation.

PITUITARY PHYSIOLOGY AND PATHOPHYSIOLOGY

Growth Hormone

Somatotrophs are GH-producing cells constituting approximately 50% of the anterior lobe, primarily located in the lateral wings. GH is a 191-amino acid polypeptide. GH-releasing hormone (GHRH) secreted by the hypothalamus induces transcription of the GH gene and stimulates secretion of GH. Somatostatin (somatotrophin release-inhibiting factor [SRIF]), also released by the hypothalamus, inhibits GH secretion, and is primarily responsible for the pulsatile secretion of GH.12 As the name implies, GH's major function is growth promotion. Most of GH's effect occurs through stimulation of insulin-like growth factor 1 (IGF-1) or somatomedin C, primarily produced by the liver. IGF-1 causes growth of muscle, bone, and cartilage; protein synthesis and amino acid transportation; and DNA and

RNA synthesis and cell proliferation.4 IGF-1 also suppresses the production of GH as part of a negative-feedback loop.

Hyposecretion of GH can occur as a result of a variety of pathologies, in isolation or as part of panhypopituitarism. Somatotrophic cells are very sensitive to trauma, radiation, and compression. Isolated GH deficiency has been reported after closed head injury,6 and GH is one of the first hormones to be depressed by compression of the pituitary gland from a mass lesion. GH deficiency is most clinically relevant in children, resulting in short stature and delay in puberty, and is the most common presenting symptom in children with pituitary lesions.7 Recently, GH-deficiency syndrome in adults has been recognized, although the diagnosis remains controversial. Symptoms include decreased energy and a feeling of social isolation. In addition, changes in body composition, with an increase in fat and decrease in lean body mass, are reported. Synthetic GH has improved treatment of GH deficiency. There is no orally bioavailable form, and replacement therapy currently requires daily injections. In children GH replacement is critical for growth and development; however, in adults replacement therapy has been controversial. For patients with normal IGF-1 levels, there may not be any benefit from GH therapy.8 For patients with diminished IGF-1, GH can be titrated to normalize IGF-1 to determine if any benefit in energy or muscle mass is noted. Initial therapy can cause muscu-loskeletal pain that resolves with time or reductions in dose.

Hypersecretion of GH is related to a somatotroph adenoma in 98% of cases. Approximately 20% of GH-secreting adenomas also secrete PRL. Other causes include excess GHRH from a hypothalamic hamartoma or choristoma, or from ectopic production (i.e., bronchial carcinoid, pancreatic islet cell tumor, or small-cell lung cancer). Hypersecretion of GH leads to the clinical syndrome of acromegaly in adults and gigantism in children. Acromegaly is characterized by an enlarged protruding jaw (macrognathia) with associated overbite; enlarged tongue (macroglossia); enlarged, swollen hands and feet resulting in increased shoe and ring size; coarse facial features with enlargement of the nose and frontal bones; and spreading of the teeth (Table 6-1). Musculoskeletal symptoms are a leading cause of morbidity and include arthralgias leading to severe debilitating arthritic features. Skin tags; hyperhidrosis (in up to 50% of patients), often associated with body odor; hirsutism; deepening of the voice; neuropathies; and paresthesias (e.g., carpal tunnel syndrome) from nerve entrapment are common. Cardiovascular disease is accelerated with cardiomyopathy (left ventricular hypertrophy) and hypertension. GH is a potent antagonist of insulin action, and diabetes is a major determinant of mortality. The combination of macroglossia, mandible deformation, and mucosal hypertrophy can lead to airway obstruction, snoring, and sleep apnea in a majority of patients. Acromegaly is associated with a significant increased risk of colonic polyps and gastrointestinal cancer. The overall mortality rate in acromegaly is approximately two to four times that of the general population.1,14

The primary goal for treatment of acromegaly is normalization of GH levels; in particular, life-table analysis showed that GH levels less than 2.5 ng/mL were associated with survival rates equal to those of the general population.1 The principal treatment for somatotroph adenomas is surgical resection of the tumor; however, because the symptoms of acromegaly are insidious in onset, tumors are often large at time of presentation and have invaded surrounding structures. In cases

Table 6-1

Clinical Manifestations of Acromegaly

Local Tumor Effects

Visual field defects

Cranial nerve palsy (diplopia)

Headache

Somatic

Acral enlargement

Thickening of soft tissue of the hands and feet (increased ring and shoe size)

Musculoskeletal

Prognathism Malocclusion Arthralgias

Carpal tunnel syndrome Frontal bossing

Skin

Hyperhidrosis Skin tags

Colon

Polyps

Cardiovascular

Left ventricular hypertrophy Hypertension Congestive heart failure

Sleep Disturbances

Sleep apnea Narcolepsy

Visceral

Macroglossia Hepatomegaly Splenomegaly Thyroid enlargement

Sexual Function

Menstrual abnormalities Galactorrhea (hyperprolactinemia) Decreased libido

Carbohydrate

Impaired glucose tolerance Insulin resistance Hyperinsulinemia Diabetes mellitus

Lipids

Hypertriglyceridemia where residual tumor remains, radiation therapy or medical management with somatostatin analogues may be necessary. Octreotide binds selectively to somatostatin receptor 2 (SSTR2) and inhibits GH release. Long-term treatment can result in normalized levels of GH and IGF-1 in more than 50% of patients, with amelioration of symptoms. Dopamine agonists have also been used, although GH normalization occurs in fewer than 15% of patients.

Prolactin

Lactotrophs are PRL-producing cells constituting 20% to 30% of the anterior lobe. They are scattered throughout the pars distalis with some accumulation within the posterolateral region. A sharp increase in the number of PRL cells (hyperplasia) occurs during pregnancy and lactation. PRL is a 198-amino acid peptide primarily known for its lactogenic properties. It is unique among pituitary hormones in that its secretion is spontaneous in the absence of any stimulation from the hypothalamus. The primary mechanism controlling PRL secretion is tonic inhibition by hypothalamic dopamine secretion. In addition, PRL secretion can be inhibited by somatostatin. PRL-releasing factors (PRFs), including thy-rotropin-releasing hormone (TRH), estrogen, vasoactive intestinal peptide (VIP), and oxytocin, stimulate PRL. Serum levels range from 4 to 20 mg/L and are 20% to 30% lower in men. During the third trimester of pregnancy, the PRL levels increase up to 200 to 300 mg/L. PRL levels fall rapidly after delivery and return to resting levels within 2 to 3 weeks if breast-feeding does not occur. Surges in serum PRL levels are associated with suckling and can remain elevated 2 to 6 months after delivery if breast-feeding is continued.

PRL causes extensive proliferation of the lobuloalveolar epithelium, causing breast enlargement and breast milk production. PRL also inhibits gonadal activity by its influence on the hypothalamus, decreasing the release of gonadotropin-releasing hormone (GnRH) and subsequently LH. In women, this can result in infertility (lactational infertility is one consequence of high PRL values associated with breast-feeding), oligomenorrhea, and amenorrhea. In men hyperprolactinemia can result in loss of libido and impotence. PRL is also a brain-regulating hormone and is believed to be involved in maternal behavior patterns. The effects on the brain may also include stimulation of appetite, analgesia (through an opioid pathway), and increases in rapid-eye movement (REM) sleep activity.

Hypoprolactinemia occurs in the presence of panhypopituitarism. Rare cases of isolated PRL deficiency have been described and can be seen in patients on dopamine agonist therapy. Isolated PRL deficiency can result in lactational failure and reproductive difficulty, but no other obvious problems have been reported.5

Hyperprolactinemia is among the most common of pituitary disorders and may be seen in a variety of medical conditions and through different mechanisms (Table 6-2). Physiologic hyperprolactinemia is seen with both physical and emotional stress, pregnancy, nipple stimulation, and after sexual orgasm. Many medications can elevate PRL secretion, including certain antiemetics, antidepressants, antipsychotics, and narcotics, by antagonizing dopamine action. Medications that work primarily to diminish dopamine secretion (e.g., reser-pine) or are dopamine receptor antagonists (e.g., phenothiazides, haldol) can often cause hyperprolactinemia. Pathologic hyper-

Table 6-2

Causes of Hyperprolactinemia

Hypothalamic Tumors Sarcoid

Radiation therapy Pituitary

Hormonally active tumors Prolactinomas Somatotroph adenomas TSH adenomas Stalk effect Nonfunctioning adenomas Rathke's cleft cyst Parasellar tumors Stalk transection Drugs

Dopamine receptor antagonist Inhibitors of dopamine synthesis and release Estrogens Neurogenic Chest wall/spinal cord lesions Breast stimulation Suckling Physical stress Others Primary hypothyroidism Renal failure Pregnancy Idiopathic prolactinemia can be seen with lesions in the sella and the parasellar region. PRL-secreting adenomas (prolactinomas) account for 40% to 60% of all pituitary adenomas. In prolactinomas PRL secretion is unregulated and directly proportional to tumor size. Hyperprolactinemia can also result from excessive glandular secretion as a result of distortion of the pituitary stalk or increased pressure within the gland causing disruption of the tonic dopamine inhibition of PRL secretion (stalk effect), resulting in PRL levels up to 150 mg/L. Thus large adenomas (macroadenomas) that do not secrete PRL, parasellar tumors that distort the pituitary stalk (i.e., tuberculum sellar meningioma), and pathology involving the hypothalamus (i.e., hypothalamic glioma, germinoma) can result in hyperpro-lactinemia from stalk effect. Moderate hyperprolactinemia can also be seen in approximately 20% of patients with hypothy-roidism that results in elevated TRH secretion, which stimulates PRL release, or in thyrotropic hyperplasia of the gland and subsequent "stalk effect."

The clinical findings of hyperprolactinemia in women of reproductive age include amenorrhea, galactorrhea, and infertility. In most cases, changes in the menstrual cycle result in early evaluation and diagnosis of hyperprolactinemia, and thus most premenopausal women present with microprolactinomas (<1 cm). Hypoestrogenemia associated with hyperprolactine-mia can result in dyspareunia and loss of libido, and long-

lasting effects include osteopenia. Seborrhea and hirsutism may be present. In men the most common clinical manifestation of hyperprolactinemia is the progressive loss of libido and impo-tency. Oligospermia and other physical signs of hypogonadism (i.e., muscular hypotrophy, increased abdominal fat) are commonly reported. Galactorrhea or gynecomastia is present in 15% to 30% of male patients.2 Prolactinomas among men and postmenopausal women are often macroadenomas (>1 cm), because changes in libido are not detected early. Hyperpro-lactinemia in both sexes can also be associated with anxiety, depression, fatigue, emotional instability, and hostility.10,11

Treatment of hyperprolactinemia depends on the cause. Normalization of PRL levels results in immediate restoration of menstrual function and fertility in women and libido and potency in men, assuming the residual normal gland remains functional. In cases of drug-induced hyperprolactinemia, cessation of the offending drug is often sufficient to return PRL levels to normal. In patients with psychosis, administration of antipsychotics that do not induce hyperprolactinemia should be instituted. For hypothyroid-related hyperprolactinemia, treatment of the hypothyroidism with thyroxine will result in normalization of PRL. In patients with a tumor or mass lesion, primary treatment should focus on the appropriate treatment for the tumor. For microprolactinomas, treatment options include surgical resection of the tumor or medical therapy with dopamine agonists. Surgical resection of microadenomas in experienced hands results in high cure rates with minimal mor-bidity.13 Medical therapy (i.e., bromocriptine, cabergoline) is very effective in controlling the hyperprolactinemia and tumor growth for prolactinomas but requires life-long treatment. Dopamine agonists inhibit production and secretion of PRL from lactotroph adenomas and result in the shrinkage of the cell size with a decrease in secretory vesicles, which results in shrinkage of the overall tumor size. Dopamine agonists also prevent tumor cells from replicating, thus causing growth arrest. Discussion with both an endocrinologist and neurosurgeon with specialization in this therapy is required to determine the most appropriate treatment. For macroprolactinomas, because the local invasiveness results in lower surgical cure rates, surgery is reserved for patients desiring pregnancy (which requires cessation of medical therapy for at least the first trimester), those with visual deterioration, and those who are intolerant of or unresponsive to medical therapy. In idiopathic cases of hyperprolactinemia, correction of the PRL level with dopamine agonist or replacement of the sex hormones will correct the hypogonadal state.

Thyrotropin

Thyrotrophs, or TSH-producing cells, constitute approximately 5% of the anterior lobe. Thyrotrophs may undergo hyperplasia as a result of primary hypothyroidism that regresses after appropriate thyroxine therapy. TSH is composed of two sub-units, a and p. The a-subunit is common to LH, FSH, and human chorionic gonadotrophin (HCG). The production and secretion of TSH is regulated by hypothalamic TRH. TRH is synthesized in the paraventricular nucleus of the hypothalamus and released into the portal capillary plexus. The main function of TRH is to stimulate TSH release, although TRH can also cause PRL secretion. TSH leads to increased formation and secretion of tetraiodothyronine (T4) and to a lesser degree tri-iodothyronine (T3). T4 results in inhibition of both TRH and

TSH release as part of a negative-feedback loop. T4 is the major hormone secreted by the thyroid gland. It is converted to T3, the metabolically active hormone, by target tissues. Thyroid hormone is critical in the development of the brain in children and in regulating tissue metabolism in adults.

Hypothyroidism is considered primary when increased TSH levels accompany low T3 and T4 levels, suggesting thyroid pathology. In secondary or central hypothyroidism, low T3 and T4 are associated with low TSH and suggest pituitary insufficiency. Thyroid hormone deficiency causes mental retardation in infants, growth delay in children, and myxedema in adults. Symptoms of thyroid hormone insufficiency include cold intolerance, weight gain, memory loss, dry skin, hair loss, brittle nails, constipation, increased sleep demand, and fatigue. Severe, untreated hypothyroidism can lead to coma and even death. Hypothyroidism from TSH or TRH deficiency can result from hypothalamic or pituitary destruction (neoplastic, inflammatory, granulomatous, vascular, traumatic, autoimmune, or from radiation necrosis). In the presence of an expanding pituitary mass (i.e., pituitary adenoma), loss of TSH secretion is typically associated with other hormonal abnormalities because there is a step-wise loss of pituitary function starting with growth hormone, gonadotropins, and then thyrotropin (lastly ACTH). Treatment of most types of hypothyroidism is successful with replacement therapy using thyroxine, which is adjusted until normal serum hormone levels are achieved.

Hyperthyroidism, or thyrotoxicosis, is most commonly caused by thyroid gland pathology (Graves' disease, toxic multinodular goiter, and toxic adenoma), which is associated with low or undetectable TSH levels. TSH-secreting (thy-rotroph) adenomas are rare and account for less than 1% of all pituitary adenomas. They are associated with long-standing hypothyroidism (characterized by high TSH and low T4), or they can have high levels of TSH associated with high T4 levels. In the former case, thyrotroph hyperplasia as a result of primary hypothyroidism must be ruled out. The symptoms of either primary or central cause of hyperthyroidism include tachycardia, heat intolerance, weight loss, diarrhea, tremor, osteoporosis, polyuria, and emotional lability. TSH-secreting adenomas can co-secrete other hormones, including GH, PRL, and gonadotropins, and tend to have more invasive features. Surgery is the primary treatment for thyrotroph adenomas. Successful resection depends on the extension and size of the tumor. Incompletely resected tumors will require radiation therapy or a trial of medical therapy with a dopamine agonist.

Adrenocorticotropic Hormone

Corticotroph cells produce ACTH and constitute 10% to 20% of the anterior lobe. Corticotrophs are concentrated in the central third of the gland but are also found in the lateral wings of the adenohypophysis and in the pars intermedia. Cortisol secretion is regulated by the hypothalamic-pituitary-adrenal axis. Corticotropin-releasing hormone (CRH) made by the par-aventricular neurons in the hypothalamus stimulate the release of ACTH. ACTH is synthesized as part of the precursor proopiomelanocortin (POMC), which is cleaved into pro-ACTH and b-lipotropin (PLPH). Further processing of pro-ACTH yields ACTH, corticotrophin-like intermediate lobe peptide (CLIP), endorphin, lipotropin, and melanocyte-stimulating hormone (MSH). The major role of ACTH is to stimulate steroidogenesis in the adrenal cortex, which results in the syn thesis and release of cortisol. Cortisol exerts negative feedback at the pituitary and the hypothalamus. Regulation of cortisol by the brain is through CRH release and involves a complex integration of neural inputs into the hypothalamus. Cholinergic and serotonergic input stimulate CRH secretion, whereas adrener-gic pathways constitute an inhibitory pathway, all of which mediate stress-induced and circadian ACTH secretion. Peak levels of ACTH, and subsequently cortisol, are reached at 6 am, decline during the day to 4 PM, and then further decline to a nadir between 11 pm and 3 am.

The effects of ACTH pathology are primarily caused by cortisol dysregulation. Cortisol is a steroid hormone that does not bind to cellular receptors as in peptide hormones. Cortisol crosses the cell membrane and binds to cytosolic or nuclear receptors resulting in alteration of gene transcription and subsequent levels of protein synthesis of targeted genes. Cortisol is important in metabolic homeostasis and has a wide range of effects, including stimulation of protein breakdown for gluco-neogenesis (catabolism) and anti-inflammatory effects.

Hypocortisolemia can be primary, in which there is a defect intrinsic to the adrenal gland, or secondary, when pituitary or hypothalamic dysfunction causes decreased secretion of CRH or ACTH. Primary adrenal insufficiency was described by Thomas Addison in 1855 and is most commonly associated with destruction of the adrenal glands, either by tuberculosis, acquired immunodeficiency syndrome (AIDS), autoimmune disorder, adrenal hemorrhage, or tumor. In such cases, ACTH levels are high in response to the low plasma levels of gluco-corticoids. Secondary adrenal insufficiency is most often caused by suppression of the hypothalamic-pituitary axis by exogenous glucocorticoid therapy. Endogenous causes are a result of pituitary destruction by large tumors, apoplexy (hemorrhage into a pituitary adenoma), pituitary infarction (Sheehan's syndrome), inflammatory process (lymphocytic hypophysitis, Langerhans cell histiocytosis), or granulomatous disease (sarcoidosis). In almost all cases, loss of ACTH function is associated with panhypopituitarism. One exception is hypothalamic-pituitary suppression from long-standing Cushing's syndrome (described later), which results in impaired CRH and ACTH response up to 6 to 12 months after resolution of Cushing's syndrome. Clinically, hypocortisolism is associated with weakness, fatigue, anorexia, nausea and vomiting, diarrhea, and postural hypotension. The mineralo-corticoid insufficiency that may accompany glucocorticoid insufficiency can lead to hyponatremia and hyperkalemia. In patients with primary adrenal insufficiency, hyperpigmentation can be detected (secondary to the elevated ACTH and associated MSH secretion). Adrenal insufficiency is typically diagnosed by detecting either a low early morning serum cortisol or an inadequate cortisol response (less than 18 mg/dL) to ACTH administration (Cortrosyn stimulation test). Treatment involves two to three doses throughout the day of cortisol replacement (e.g., 15 mg hydrocortisone at 8:00 AM and 10 mg at 3:00 pm). Patients with adrenal insufficiency should wear a medic alert indicator to avoid adrenal crisis at times of physical stress (severe illness, trauma, planned surgery), when stress dose steroids (e.g., hydrocortisone, 100 mg intravenously) should be initiated and maintained during the period of stress.

Hypercortisolemia leads to a syndrome first described by Harvey Cushing in 1912.3 Cushing's syndrome is the eponym for the general clinical syndrome produced by chronic hyper-cortisolism. The most common cause of Cushing's syndrome is exogenous steroid use (e.g., in the treatment of arthritis, cerebral edema). Hypercortisolism resulting from excess ACTH secretion from the pituitary is termed Cushing's disease. Nearly all organ systems are affected by hypercortisolism (Table 6-3). Centripetal fat deposition is the most common manifestation of glucocorticoid excess and often the initial symptom. Fat accumulates in the face and the supraclavicular and dorsocervical fat pads, leading to the typical moon facies and buffalo-hump, often accompanied by facial plethora. The mechanisms that determine fat redistribution probably lie in the differential sensitivity of central and peripheral adipocytes to the opposite lipolytic and lipogenic actions of cortisol excess versus secondary hyperinsulinism. Other clinical features are related to the protein-wasting effect of cortisol, including skin thinning caused by the atrophy of the epidermis and connective tissue, purple to red striae, muscle wasting leading to fatigability, and large-muscle atrophy resulting in difficulty in getting up from

Table 6-3

Clinical Features of Cushing's Syndrome

Fat Distribution

Centripetal obesity Generalized obesity Moon facies "Buffalo hump" Supraclavicular fat pad

Skin Manifestations

Stria (red or purple)

Plethora

Hirsutism

Acne

Bruising

Pigmentation

Musculoskeletal

Osteopenia (pathological fractures) Proximal muscle weakness

Sexual Function

Menstrual disorder Decreased libido Impotence

Metabolic/Cardiovascular

Glucose intolerance Diabetes mellitus Poor wound healing Hypertension Cardiac hypertrophy Congestive heart failure

Mental Changes

Irritability Psychosis Emotional lability Depression a chair. Osteopenia with increased risk for pathologic fractures and compression fractures of the vertebral bodies may be presenting symptoms. Chronic hypercortisolism also results in impaired defense mechanisms against infections, hypertension-inducing cardiac hypertrophy and eventually congestive heart failure, and hirsutism caused by excess adrenocortical andro-gens. Psychic disturbances are extremely common and include anxiety, increased emotional lability and irritability, euphoria, and depression. Diagnosis involves a two-step process, first establishing that hypercortisolism or Cushing's syndrome exists and then identifying its cause. Plasma morning cortisol values can be easily measured; however, 50% of patients with Cushing's syndrome will have normal levels. Because patients with Cushing's syndrome usually lack a normal circadian rhythm, an evening serum or salivary cortisol level may be helpful. A 24-hour urine free-cortisol level is the most ideal measure of the cortisolic state. The most reliable means to confirm or rule out the diagnosis of Cushing's syndrome is the low-dose dex-amethasone suppression test, which assesses the normal negative-feedback loop in the hypothalamic-pituitary-adrenal axis. Between 10 and 11 pm, 1 mg of dexamethasone is administered orally and plasma cortisol is measured the next morning at 8:00 am. In normal patients, plasma cortisol values will be suppressed below a certain threshold depending on the assay used (typically less than 2 mg/dL). Although this test has very high sensitivity to Cushing's disease, the specificity is lower, with as many as 13% of obese patients lacking normal suppression.

When the diagnosis of Cushing's syndrome has been made, the cause is investigated. Plasma ACTH levels can be helpful in differentiating adrenocortical tumors (in which ACTH levels will be low), Cushing's disease (in which ACTH levels will be slightly above normal or normal), and ectopic ACTH tumors (in which ACTH levels are markedly elevated). The high-dose dexamethasone suppression test determines the pituitary dependency of the hypercortisolic state. The classic test requires 2 mg of dexamethasone given every 6 hours for 2 days. A 24-hour urine free-cortisol level is measured on the second day. Suppression of steroid levels of greater than 50% is seen in nearly all patients with Cushing's disease. No significant reduction of steroid levels is noted in patients with adrenal tumors. Similar results are seen with the use of a single 8-mg dose of dexamethasone at 11 pm and a plasma cortisol level at 8 am. Patients with Cushing's disease have plasma cortisol decrease to 50% or less of the baseline value. An additional test is the metyrapone test, in which 750 mg of metyrapone are given every 4 hours for six doses, resulting in cortisol deprivation. Urine (24 hour) steroid levels are measured. In normal patients, the levels can rise twofold; however, in Cushing's disease (and in ectopic ACTH tumors) there is an explosive increase in urinary steroid levels after metyrapone in up to 98% of patients. If Cushing's disease is suspected, magnetic resonance imaging (MRI) is necessary to identify the corticotroph adenoma. If MRI is negative, suggesting a pituitary tumor too small to visualize or an ectopic ACTH tumor, bilateral inferior petrosal sinus (IPS) sampling (IPSS) is performed. ACTH measurements are made simultaneously from blood within the IPS from both sides and from a peripheral source. A central-to-peripheral ACTH gradient of greater than 2:1 is consistent with Cushing's disease. In patients with an ectopic ACTH tumor, this gradient is almost always lower than 1.7:1. Bilateral IPSS also can help to identify the location of a pituitary tumor. If the side-to-side gradient is greater than 1.5:1, and taking into account anomalous venous drainage, the tumor is most likely located within the side of the gland with the higher ACTH level. The use of CRH stimulation increases the sensitivity of IPSS.9 Treatment of Cushing's disease entails selective adenomec-tomy through a transsphenoidal operation. Because these tumors are often very small and invasive, surgical exploration should be performed by surgeons with significant experience with Cushing's disease. In certain cases, removal of half of the pituitary gland (hemihypophysectomy) guided by the IPSS can lead to cure in up to 80% of patients.9

Patients with long-standing hypercortisolemia have isolated hypothalamic-pituitary corticotropic suppression. Following successful treatment of Cushing's syndrome, patients will require replacement cortisol therapy for 6 to 12 months, until CRH and ACTH responses return to baseline. Total bilateral adrenalectomy is considered one of the last treatment options in patients with persistent or recurrent Cushing's disease not responding to other therapies. In such a case, the drastic cortisol deprivation induced by the hypocortisolism can trigger a boost in the growth and secretory activity of the cor-ticotroph adenoma. This is associated with increased plasma ACTH levels and clinical hyperpigmentation with an expanding sellar mass, defining Nelson's syndrome.

Follicle-Stimulating Hormone and Luteinizing Hormone

Gonadotrophs produce both gonadotropic hormones (FSH and LH) and constitute 15% of the adenohypophysis. Both hormones share the same a-subunit, which is a 116-amino acid peptide that includes a 24-amino acid signal peptide. The b-subunit confers on each hormone its unique immunologic and biologic properties. The hypothalamus regulates gonadotrope release through GnRH. GnRH is a decapeptide released by neurons in the preoptic and arcuate nucleus within the hypothalamus. The relative amounts of LH and FSH secreted by gonadotroph cells in response to GnRH is a function of the frequency and concentration of administration of GnRH. The pulsatile release of LH and FSH is related to the pulsatile release of GnRH. In males, LH binds to receptors on Lyedig cells and stimulates testosterone production. The role of FSH remains uncertain in males but may work with testosterone for normal qualitative and quantitative spermatogenesis. In females, LH is a major regulator of ovarian steroid synthesis and oocyte maturation. FSH plays a critical role in follicle growth and in regulating estrogen production in the ovary.

Hypogonadism is separated into primary (dysfunction of the testis or ovary) or central (pituitary or hypothalamic). Clinical manifestations of hypogonadism in prepubertal children cause no symptoms, whereas in adolescents hypogonadism leads to delayed or absent pubertal development. In adult women, hypogonadism causes amenorrhea, infertility, loss of libido, vaginal dryness, and hot flashes. In men, hypogonadism leads to loss of libido, erectile dysfunction, and infertility. Causes of primary hypogonadism include genetic disposition, menopause, autoimmune reactions, viruses, radiation, and chemotherapeutic agents. Central hypogonadism is most often caused by pituitary adenomas. Through compression of the gland, these tumors can cause destruction of pituitary tissue or interference with GnRH input from the hypothalamus. Gonadotropin dysfunction is the second most common hor monal disorder from compression of the pituitary gland after GH suppression. Hypothalamic disorders, such as those associated with tumors or radiation therapy, and hypothalamic amenorrhea can lead to hypogonadism. Fasting, weight loss, anorexia nervosa, bulimia, excessive exercise, or stressful conditions result in defects in pulsatile GnRH secretion ("hypothalamic amenorrhea"). Elevated PRL levels can also suppress GnRH pulses and lead to hypothalamic hypogonadism. Diagnosis requires measurement of LH, FSH, and testosterone or estrogen with reference to age-adjusted normal values. Treatment of hypogonadism in men and premenopausal women is effectively accomplished by replacement hormonal therapy.

Overproduction of gonadotropins is a result of pituitary adenomas. Most of the previously classified "nonfunctioning" adenomas are in fact gonadotropin-producing. The abnormally high levels of a-subunit, FSH, or, rarely, LH does not produce any clinical syndrome, however. Furthermore, many of these tumors are inefficient in hormonal secretion or release improperly processed gonadotropins. Treatment of gonadotroph adenomas is surgical resection, most often through a transsphe-noidal approach.

Antidiuretic Hormone

Antidiuretic hormone (ADH), or vasopressin, is a nonapeptide synthesized as a prohormone in the magnocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus. Neurosecretory granules are transported down axons that extend to the posterior pituitary, where the hormones are stored. Secretion of ADH is highly sensitive to osmotic regulation. Osmotic receptors located in the anterior aspect of the hypothalamus can be stimulated with as little as 1% change in plasma osmolality, causing release of ADH. Volume regulation of ADH secretion is less sensitive. These receptors are located in the aorta, carotid sinus, and left atrium and send their signal through the vagal and glossopharyngeal nerves to the brain-stem. A 10% to 15% reduction in blood pressure is needed to stimulate release of ADH. Once secreted, ADH causes water retention in the kidneys. The hormone binds to receptors of the renal collecting ducts and stimulates free-water absorption from the distal convoluted tubules and collecting ducts.

Diabetes insipidus (DI) is the excretion of dilute urine related to hyposecretion of vasopressin (hypothalamic DI). Most patients with DI who are alert have a normal thirst mechanism and are able to drink sufficient water to maintain a relatively normal state of metabolic balance. These patients have secondary polydipsia and polyuria and nocturia. Because the posterior lobe is a storage depot for ADH, damage to the posterior lobe of the pituitary or the lower stalk seldom causes permanent DI. However, upper pituitary stalk and hypothalamic damage (e.g., germ cell tumors, craniopharyngioma, lympho-cytic hypophysitis) is more likely to result in permanent DI, whereas pituitary adenomas are rarely associated with DI. Surgical pituitary stalk section can result in a triphasic response. An initial period of DI caused by shock to the posterior lobe is followed by excessive ADH secretion as the neurohypophyseal cells die off and release the stored ADH. Permanent DI eventually follows. Synthetic ADH (DDAVP, or desmopressin) can be used to treat patients who are unable to maintain adequate oral fluids (with resultant hypernatremia) or who display severe polyuria and nocturia. Transient DI may require therapy when urine specific gravity is below 1.005, urine output is greater than 200 mL/hr for at least 2 hours, and the patient has hyper-natremia, suggesting that the patient is unable to keep up oral intake with urinary output.

Hypersecretion of ADH represents the syndrome of inappropriate secretion of ADH (SIADH). SIADH is defined as continued secretion of ADH despite a low serum osmolality. The diagnosis of SIADH can be made only when there is a normal state of hydration; there is normal renal, thyroid, and adrenal function; and the patient is not taking diuretics. In all cases, the patient is hyponatremic and has urine that is less than maximally dilute. Possible causes of SIADH include ADH secretion from malignant systemic tumors (e.g., small-cell lung carcinoma, lymphoma, pancreatic tumors), chronic obstructive pulmonary disease (COPD), or drugs (e.g., induced by phe-nothiazine, tricyclic antidepressants, carbamazepine, lithium). Central nervous system disorders can be associated with SIADH, perhaps through loss of chronic inhibition of the brain on the magnacellular neurons. The clinical manifestations of hyponatremia are dependent on the onset and include confusion, stupor, coma, and seizures. Generally, symptoms do not develop in a normal individual until sodium levels fall below 125 mmol/L. The clinical manifestation probably represents brain edema caused by the osmotic water shifts into the brain because of the decreased plasma osmolality. Treatment of SIADH commonly involves restricting water intake to 600 to 800 mL per day, resulting in a gradual rise in sodium over 2 to 3 days. If patients are hyponatremic for a prolonged period, rapid sodium correction can lead to central pontine myelinoly-sis with quadriparesis and bulbar palsies. If patients rapidly develop hyponatremia and are very symptomatic, correction of the sodium level can occur with hypertonic (3%) saline in addition to fluid restriction.

Oxytocin

Oxytocin (OT) is the only other hormone stored within the posterior lobe. It is also a nonapeptide and is the most potent hormone to cause uterine contraction. Its effects have been utilized for the induction and augmentation of labor, as well as for prevention and treatment of postpartum hemorrhage. OT is also involved in lactation, causing milk ejection from the breast.

Panhypopituitarism

Pituitary dysfunction can involve selected hormones or complete loss of all pituitary function (panhypopituitarism). Loss of pituitary function from direct compression from a macroade-noma or from radiation therapy typically occurs in a stepwise fashion, with loss of GH secretion followed by loss of gonadotropin, thyrotropin, and finally corticotropic function. This graded loss of function relates to the sensitivity of pituitary cells to external trauma. Pituitary adenomas can cause symptoms related to hypersecretion of a hormone (hormonally active adenomas) or through progressive compression of the normal pituitary gland. In the latter case and in cases of Rathke's cleft cysts, the first hormonal symptoms typically include loss of libido in men and postmenopausal women and amenorrhea in premenopausal women. This can be caused by direct loss of gonadotropic function or because of hyperpro-lactinemia from stalk effect and subsequent GnRH suppression. Later, as the tumor or cyst enlarges, thyroid function and finally adrenal regulation can be affected, resulting in more pro nounced symptoms. Often, signs and symptoms from local mass effect, causing headaches or pressure on the optic chiasm that result in a bitemporal hemianopsia, lead to the diagnosis. In patients who have diabetes insipidus or panhypopituitarism in the absence of symptoms of mass effect, nonadenoma sellar pathology should be considered. This pathology includes infection, sarcoidosis, lymphocytic hypophysitis, craniopharyngioma, glioma, germ cell tumor, lymphoma, Langerhans cell histiocytosis, or metastases. Acute pituitary failure can occur, with pituitary apoplexy caused by hemorrhage into a pituitary adenoma or infarction of the gland (Sheehan's syndrome). Radiation therapy involving the pituitary gland and, in particular, the pituitary stalk can result in pituitary failure in up to 50% of patients at 3 to 5 years. The clinical manifestations of hypopituitarism are detailed within the sections regarding individual hormones above.

References

1. Abosch A, Tyrrell JB, Lamborn KR, et al: Transsphenoidal microsurgery for growth hormone-secreting pituitary adenomas: initial outcome and long-term results. J Clin Endocrinol Metab 83:34113418, 1998.

2. Carter JN, Tyson JE, Tolis G, et al: Prolactin-screening tumors and hypogonadism in 22 men. N Engl J Med 299:847-852, 1978.

3. Cushing H: Medical Classic. The functions of the pituitary body: Harvey Cushing. Am J Med Sci 281:70-78, 1981.

4. Jones JI, Clemmons DR: Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16:3-34, 1995.

5. Kauppila A: Isolated prolactin deficiency. Curr Ther Endocrinol Metab 5:29-31, 1994.

6. Kelly DF, Gonzalo IT, Cohan P, et al: Hypopituitarism following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a preliminary report. J Neurosurg 93:743-752, 2000.

7. Kunwar S, Wilson CB: Pediatric pituitary adenomas. J Clin Endocrinol Metab 84:4385-4389, 1999.

8. Monson JP: Long-term experience with GH replacement therapy: efficacy and safety. Eur J Endocrinol 148 Suppl 2:S009-S014, 2003.

9. Oldfield EH, Doppman JL, Nieman LK, et al: Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing's syndrome. N Engl J Med 325:897-905, 1991.

10. Reavley A, Fisher AD, Owen D, et al: Psychological distress in patients with hyperprolactinaemia. Clin Endocrinol (Oxf) 47:343-348, 1997.

11. Sobrinho LG: The psychogenic effects of prolactin. Acta Endocrinol (Copenh) 129(suppl 1):38-40, 1993.

12. Thorner MO, Vance ML: Growth hormone. J Clin Invest 82:745-747, 1988.

13. Tyrrell JB, Lamborn KR, Hannegan LT, et al: Transsphenoidal microsurgical therapy of prolactinomas: initial outcomes and long-term results. Neurosurgery 44:254-261; discussion 261263, 1999.

14. Wright AD, Hill DM, Lowy C, et al: Mortality in acromegaly. Q J Med 39:1-16, 1970.

CHAPTER

NEUROTOLOGY

William H. Slattery III and Marian R. Hansen

Benign lesions of the lateral skull base and cerebellopontine angle (CPA) often produce neurotologic symptoms such as hearing loss, dizziness, imbalance, facial weakness, and facial hypesthesia. Clinicians who manage patients with skull base lesions should have a working understanding of the clinical evaluation of these symptoms. This chapter focuses on the neurotologic evaluation of patients with benign lesions of the lateral skull base and CPA. We begin with a brief description of the more common surgical approaches to these regions from the neurotologic perspective. We then focus on key elements of the neurotologic examination and clinical testing that assist in establishing the diagnosis and selecting the most appropriate clinical management.

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