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The pituitary gland controls the function of multiple other glands in the human body, including the thyroid, adrenals, ovaries and testes. It regulates growth, lactation, uterine contractions in labor as well as osmolality and intravascular fluid volume v ia
resorption of water in the k idneys. It secretes eight peptide hormones; six from the anterior lobe and two from the posterior lobe (Table 1).
The Pituitary Gland
Assessment of Pituitary Function CARRIE R. MUH, MD, MS; NELSON M. OYESIKU, MD, PhD, FACS Emory University Hospital, Department of Neurological Surgery
Key words: pituitary gland, pituitary function, hypothalamic-pituitary-adrenal (HPA) ax is, pituitary dysfunction workup
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Table 1 Summary of Pituitary Function. (Copied from Oyesiku N: Assessment of Pituitary Function, Rengachary S, Ellenbogen R (eds): Principles of Neurosurgery . New York, Elsev ier Mosby, 2005)(30)
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The pituitary lies in the sella turcica, a concav ity in the sphenoid bone. Its stalk, which contains the pituitary portal veins and neuronal processes, passes through the diaphragma sella, just above which pass the optic nerves (Figure 1). The cavernous sinuses form the lateral borders of the sella, and contain w ithin them the internal carotid arteries, cranial nerves III, IV and VI, and the ophthalmic and max illary div isions of cranial nerve V.
Because of its diverse array of functions as well as the multiple structures in close prox imity to the gland, tumors or abnormalities of pituitary function can present in many different ways. Disorders can lead to an excess or def iciency of pituitary hormones, mass effect from tumors can lead to compression of the pituitary stalk or ad jacent structures,
and lesions may cause a blockage of the blood supply to the gland. Therefore, a thoroughassessment of the pituitary requires clinical examination for signs of hormonal abnormalities, endocrine evaluation of pituitary and related target-organ hormones, and ophthalmologic evaluation to assess for damage to the ad jacent cranial nerves. These evaluations not only help to def ine the pathology prior to treatment, but they can be used to assess the effects of surgery, radiation or medical treatment. Here, we w ill discuss details the endocrine evaluations needed to determine pituitary function.
Anterior Pituitary Hormones Six hormones are produced in the anterior pituitary by f ive distinct cell types.
Lactotroph cells make prolactin (PRL), somatotroph cells produce growth hormone (GH), corticotrophs secrete adrenocorticotrophic hormone (ACTH), thyrotrophs make thyroid-stimulating hormone (TSH), and gonadotrophs produce follicle-stimulating
Assessment of Pituitary Function 195
Fig . 1 Anatomic relationships of the pituitary gland. A coronal v iew through the sella turcica shows the pituitary gland, its stalk and the relationship to
surrounding structures including the cavernous sinuses, carotid arteries and cranial nerves II, III, IV, V1, V2 and VI. (Figure from Oyesiku N: Assessment of Pituitary Function, in Rengachary S, Ellenbogen R (eds) : Principles of Neurosurgery . New York, Elsev ier Mosby, 2005, pp 559-591)(30)
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hormone (FSH) and luteinizing hormone (LH). The secretion of these hormones is regulated by complex feedback controls from the hypothalamus and target glands (Figure 2).
PRL release is largely determined by dopamine release from the hypothalamus. Corticotropin-releasing factor (CRH), thyrotropin-releasing factor (TRH) and gonadotropin-releasing hormone (GnRH) are secreted by the hypothalamus to stimulate the release of ACTH, TSH and the gonadotropins, respectively . Both excitatory and inhibitory signals are sent from the hypothalamus to the pituitary to control hormone
production; for instance, growth hormone-releasing hormone (GHRH) and somatostatinalternately increase and decrease growth hormone secretion. Target gland hormones generally cause a negative feedback loop, inhibiting further production of the hormone that stimulated their release.
Prolactin The lactotrophs that secrete PRL are unique in that they can proliferate during
adulthood. PRL production is inhibited by dopamine, also known as prolactin-inhibiting factor (23). Dopamine travels along the portal circulation from nerves that originate in the hypothalamic arcuate nucleus. PRL production is stimulated by sleep, vasoactive peptide (VIP), GnRH, peptide histidine methionine (PHM), opiates and estrogen. Exogenous TRH leads to a rapid release of PRL, though the normal physiologic role of this interaction is unclear.
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Fig . 2 Hypothalamic control and feedback regulat ion. The neural processes of the hypothalamic nuclei terminate on the portal venous system in the median eminence. The portal veins carry releasing and inhibiting factors to the anterior lobe of the pituitary, where they regulate the release of hormones. The production and secretion of these hormones is inhibited by the hormonal products of the target organs v ia negative feedback . The neural processes of the hypothalamic neurons of the supraoptic and paraventricular nuclei carry ADH and oxytocin which are released from nerve terminals in the posterior pituitary . (Figure from Oyesiku N: Assessment of Pituitary
Function, Rengachary S, Ellenbogen R (eds): Principles of Neurosurgery . New York, Elsev ier Mosby, 2005)(30)
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PRL is secreted episodically, peak ing 13-14 times per day, w ith an interpulse interval of about 90 minutes. Small post-prandial rises can be seen, secondary to central stimulation from the amino acids in food (9). During pregnancy, estrogen stimulates lactotroph hyperplasia, leading to hyperprolactinemia. The effects of PRL on the breasts are blocked until after delivery, at which time PRL initiates lactation. Within 4-6 months after delivery, basal PRL levels return to normal (35).
Prolactin Deficiency Hypopituitarism leads to a decrease in PRL release. A blunted PRL response in a TRH-
stimulation test, w ith a less than 2-fold increase over basal levels, is ev idence of inadequate lactotroph reserve which may occur w ith hypopituitarism. Insuff icient PRL can lead to a failure of lactation. This may be an early indication of peripartum pituitary necrosis, or Sheehan's syndrome. Lymphocytic hypophysitis is an autoimmune disorder which usually occurs during or immediately follow ing pregnancy .
Transient hyperprolactinemia occurs during its active phase, followed by hypopituitarism and hypoprolactinemia.
Prolactin Excess Multiple causes can lead to the over-stimulation of prolactin release and elevated serum
PRL levels. Hyperprolactinemia may be due to: 1. excess autonomous production, such as from a pituitary prolactinoma; 2. decreased hypothalamic production of dopamine or blockage of delivery of dopamine to the pituitary, such as from a hypothalamic tumor, drugs that inhibit dopamine production, interruption of the
portal venous system in the stalk from a pituitary tumor or aneurysm, or follow ing pituitary irradiation; 3. inhibition of dopamine activ ity on lactotrophs, such as from phenothiazines that block the interaction of dopamine from its receptors; or 4. over- stimulation of PRL by estrogens or opiates. Non-hypothalamic-pituitary causes may be responsible as well, including pregnancy, polycystic ovarian syndrome or primary hypothyroidism. Physiologic, transient hyperprolactinemia occurs w ith exercise, stress, nipple stimulation, sexual intercourse, and breast-feeding.
Women w ith hyperprolactinemia generally present w ith amenorrhea, galactorrhea, diminished libido and infertility . Gonadal def iciency and decreased estrogen secretion can
lead to osteoporosis. Hyperprolactinemia in men generally manifests as decreasedlibido, impotence and decreased sperm count leading to infertility .
Workup Laboratory tests for suspected hypo- or hyperprolactinemia include serial
measurements of basal, resting serum PRL levels by radioimmunoassay . Normal values are gender-specif ic, and peak values occur during the late hours of sleep (37). PRL is secreted episodically, so random levels may be above or below normally-accepted limits. Because of this variability, minimally elevated levels should be conf irmed from several samples, or from a pooled sample. In normal sub jects, serum PRL levels range from 5-20 ng/mL.
PRL def iciency of <2 ng/mL is generally associated w ith severe hypopituitarism, though may be due to PRL-lowering medications. A PRL level of more than 200 ng/mL
Assessment of Pituitary Function 197 Assessment of Pituitary Function 357
is nearly diagnostic of a prolactinoma (33). Prolactinomas are the most common type of hormone-secreting pituitary tumor, comprising almost 30% of all pituitary tumors. Pregnancy must be excluded, however, as PRL levels reach 100-250 ng/mL by the third trimester (34).
An intermediate degree of PRL elevation, 20-200 ng/mL, can result from a number of different conditions. Medications can cause PRL levels of more than 100 ng/mL. Compression of the pituitary stalk from a pituitary tumor rarely causes PRL to rise above 100 ng/mL, but elevations to more than 200 ng/mL can occur. This increase in PRL due to compression of the stalk is known as the “stalk effect”. Stimulation of PRL secretion w ith a TRH-stimulation test can suggest the presence of a prolactinoma. In normal sub jects, intravenous (IV) administration of 200-500 µg of TRH should lead to a 3 to 5- fold increase in serum PRL level w ithin an hour. Patients w ith a prolactinoma w ill often have a blunted response of less than a 2-fold increase, due to their limited lactotroph reserve.
Prolactin levels may be falsely low on laboratory testing due to the “hook effect”. If the serum PRL level is extremely high, the amount of PRL antigen may saturate the capture antibody in the radioimmunoassay, leading to a falsely low PRL value. If a prolactinoma is suspected, the PRL level should be tested again w ith serial dilutions in order to determine the true PRL level.
There is considerable heterogeneity in circulating PRL due to posttranslational modif ication. 80-90% of PRL in serum is monomeric, while 8-20% is dimeric, and 1-5% is polymeric (41). Larger polymeric variants have decreased bioactiv ity . Some patients w ith elevated levels of basal PRL but normal reproductive function have elevated
proportions of polymeric PRL that result in decreased PRL bioactiv ity (41). Dynamic tests of PRL secretion, using TRH, hypoglycemia, chlorpromazine, or L-dopa,
prov ide useful information about the mechanism of control of PRL secretion but have a limited value in the differential diagnosis of hyperprolactinemia. The patient's medical history, physical examination, blood chemistries, thyroid function tests and pregnancy test should be rev iewed to assess for non-hypothalamic-pituitary causes.
Growth Hormone GH is required for normal human growth; it plays little role in the f irst year of life, but
becomes very important during puberty . It is secreted in bursts by the somatotroph cells,and its release is controlled by GHRH and somatostatin which stimulate and inhibit its release, respectively . GH, in turn, stimulates the liver's production of somatomedin-C, also known as insulin-like growth factor 1 (IGF-1). IGF-1 mediates many of the effects of GH, including stimulating somatostatin release at the hypothalamus and inhibiting GH release at the pituitary .
Sleep, stress, exercise and hypoglycemia increase the release of GH, while obesity, hyperglycemia and excess glucocorticoids decrease it. GH increases the uptake of amino acids into tissue, and an increase in amino acids increases GH release in a healthy indiv idual. GH and IGF-1 levels are highest in children and young adults, then decrease w ith age in normal sub jects. In normal sub jects, serum GH levels are very low or undetectable for most of the day . GH has a half life of 20-30 minutes and is secreted in short pulses, w ith 2-7 peaks per day . Some of these bursts are associated w ith meals, while
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others occur during the early stages of sleep. The half life of IGF-1, on the other hand, is 2-18 hours, and serum levels are relatively stable throughout the day .
GH def iciency in children leads to dwarf ism. In adults, however, it is clinically silent. Because of its short half life and the variations in GH levels throughout the day, serum GH levels are not very useful in diagnosing GH def iciency . Serum IGF-1 levels are more useful; however these levels must be interpreted tak ing age-related variations into account. The diagnosis of GH def iciency, therefore, generally is accomplished using a dynamic stimulation test. Dynamic stimulation tests include an insulin tolerance test (ITT), a glucagon test, an arginine (ARG) stimulation test, an L-Dopa test, or a combination of ARG and GHRH. A subnormal rise in serum GH after one or more of these tests can diagnose GH def iciency .
The insulin tolerance test is generally considered the gold-standard for the biochemical diagnosis of GH def iciency, as it is the most commonly used and well validated of these dynamic studies. 0.15 units of insulin per kg body weight are given as an IV bolus (32). The ITT is relatively contraindicated in patients w ith epilepsy or vascular disease, and a pre-test potassium level, cortisol level and EKG should be performed prior to the test. The Growth Hormone Research Society has def ined severe GH def iciency in adults as a peak response to insulin-induced hypoglycemia of <3 µg/L (<9 mU/L) (2, 19). Normal indiv iduals should reach a peak GH response of 7-15 ng/mL w ith this test.
A 2002 study determined the sensitiv ity and specif icity of multiple diagnostic tests (7).
The ITT had 96% sensitiv ity and 92% specif icity using a cut off of 5.1 ng/mL. This was followed closely by the ARG plus GHRH test w ith 95% sensitiv ity and 91% specif icity w ith a cut off of 4.1 ng/mL; the latter test also scored a higher patient preference w ith fewer side effects. Side effects of the ITT included sweating, vasodilation, hunger, palpitations, dizziness and syncope; for the ARG plus GHRH test, side effects included vasodilation, paresthesias and nausea. Other dynamic tests, using ARG alone, L-Dopa, or ARG plus L-Dopa, showed signif icant overlap between healthy sub jects and GH def icient sub jects, and adequate specif icity levels were diff icult to achieve. This same study showed that measurement of the IGF-1 level was less sensitive than any of the dynamic
tests for diagnosing GH def iciency (7). IGF-1 levels are also less useful in older patients,as normal GH and IGF-1 levels decline w ith age. Other studies that can be used to diagnose GH def iciency are the stimulation of GH
secretion w ith 20 minutes of brisk exercise, w ith GH levels checked at 0, 20 and 40 minutes; or clonidine, w ith GH levels checked at 0, 60 and 90 minutes. These tests can stimulate GH levels to >7 ng/mL in normal sub jects, but w ill be signif icantly lower in those w ith GH def iciency .
Growth Hormone Excess An overproduction of GH results in excess growth of soft tissue as well as bony
changes. Adults develop acromegaly while children affected before epiphyseal closure w ill suffer gigantism. Signs and symptoms of acromegaly include coarse facial features w ith prognathism and malocclusion of the teeth, enlargement of the paranasal sinuses w ith
Growth Hormone Deficiency and Workup
frontal bossing, deepening of the voice, organomegaly, hyperhidrosis, acanthosis nigricans, enlargement of the hands and feet leading to an increase in ring, glove and shoe size, and headache. Insulin resistance can lead to diabetes mellitus. Enlargement of the tongue can lead to sleep apnea. Excess soft issue in the hands leads to a “doughy ” handshake, and excess soft tissue in the feet can lead to a noticeable increase in heel-pad thickness on radiographs. Acromegalic patients may also suffer from prox imal myopathy and weakness, osteoarthritis, carpal tunnel syndrome, cardiomegaly and hypertension. Accelerated atherosclerosis and metabolic changes lead to a shortened life span, w ith death generally from cardiovascular, cerebrovascular or respiratory events.
GH excess w ith acromegaly or gigantism is usually due to a GH-secreting pituitary adenoma. The average acromegalic patient has symptoms for eight to ten years before being diagnosed, so these tumors are generally quite large on presentation. Many of these lesions w ill compress the optic apparatus and lead to a decrease in v isual acuity or bitemporal hemianopia before the tumor is recognized.
Workup When acromegaly or gigantism are suspected, a thorough endocrine evaluation
should include measurement of basal GH and IGF-1 levels as well as test ing to assess for suppression of GH secretion w ith hyperglycemia. Exercise and stress can stimulate GH production, so serum GH levels should be obtained early in the morning, before the patient arises from bed, or 2 hours after a meal, when GH levels should be suppressed. There is some heterogeneity in serum GH due to post-translational modif ication and differential splicing (6, 13, 24). Two main forms of GH are found in the circulation; the
22K form accounts for 90% of serum GH, while the 20K form makes up 5% (24). This heterogeneity may account for differences between radioimmunoassay values and actual biological activ ity . Although GH binding proteins ex ist in circulation, it is unclear whether they affect GH activ ity physiologically .
In healthy sub jects, basal GH levels are usually <5 ng/mL while more than 90% of acromegalic patients have levels >10 ng/mL. Levels vary w idely, however, so some acromegalic patients have normal GH levels. In acromegalic patients, the normal pulsatile GH secretory pattern is replaced by a more consistent elevation throughout the day (4). Due to the short half life and pulsatile secretion, random GH levels are of
limited value and single determinations of GH correlate poorly w ith severity of disease.Serum GH levels may be elevated in other conditions as well, including uncontrolled diabetes mellitus, malnutrition, renal failure, and during physical or emotional stress (11).
To conf irm a diagnosis of acromegaly, a glucose suppression test can be performed. In a normal glucose suppression test, GH w ill suppress to <2 ng/mL after glucose loading, while in an acromegalic patient, this suppression w ill fail to occur (22).
Because serum levels of IGF-1 are more stable than those of GH, measurement of IGF- 1 can be used to prov ide a reliable indicator of the overall exposure of GH on the body . IGF-1 is increased in nearly all patients w ith acromegaly, even in those whose serum GH levels are w ithin the range of normal. Normal levels of IGF-1 range from 0.45-2.2 U/mL in women and from 0.34-2.0 U/mL in men (11). IGF-1 is not directly affected by stress or exercise, and it is bound to carrier proteins that regulate its function and stabilize its levels. There are at least four different IGF-binding proteins (IGFBPs), the
levels of two of which can be measured to assist in the diagnosis of acromegaly . The serum level of IGFBP-1 is correlated inversely w ith the amount of GH, while the level of IGFBP-3 w ill correlate directly w ith GH. IGF-1 is also a reliable parameter for post- treatment follow-up of acromegaly, since it reflects GH secretion over the prior 24 hours (25).
Additional testing may be needed to conf irm the diagnosis of excessive GH production. Thyrotropin releasing hormone (TRH) stimulation does not cause a signif icant change in GH levels in normal sub jects, but w ill lead to a 50% rise in GH in untreated acromegalics. Though this f inding also occurs in patients w ith liver disease, renal failure or depression, it can be highly suggestive of acromegaly in the correct clinical setting. This test may prov ide useful therapeutic information as well, as patients who have a positive response to TRH-stimulation may respond to bromocriptine therapy . TRH-stimulation may also be used to identify those patients who, despite a normal GH level after surgery, have residual GH-secreting tumor and are therefore at risk of tumor recurrence (12, 36).
An L-Dopa test may also be performed. Administration of oral L-Dopa to a normal fasting sub ject w ill stimulate GH secretion, while it w ill paradox ically lower GH levels in a fasting patient w ith acromegaly (8). Likew ise, Bromocriptine, a dopamine agonist that binds D2 receptors, w ill raise GH levels in a normal sub ject, but lower them in acromegalic patients. Other dynamic tests include the arginine-stimulation test, somatostatin-stimulation test, LH-releasing hormone stimulation test, and insulin- induced hypoglycemia stimulation. Each of these tests may also prov ide additional information in cases of acromegaly .
As GH-producing pituitary lesions are often large at the time of diagnosis, patients
should undergo formal v isual-f ield testing and endocrine testing for hypopituitarism, in addition to an MRI w ith thin cuts through the sella.
Those rare patients who have acromegaly, but no pituitary lesion on MRI, should undergo a workup to f ind another site of a GHRH-secreting tumor. GHRH levels can be useful in this workup. Ectopic acromegaly, due to non-central nervous system causes such as a pancreatic islet cell tumor or a bronchial carcinoid, w ill result in a signif icantly elevated level of circulating serum GHRH, whereas GHRH is barely detectable in acromegaly due to a pituitary lesion (5).
Hypothalamic-Pituitary-Adrenal AxisCortisol is necessary for the homeostatic biochemical and physiologic responses to stress, and the hormone is essential for life. Cortisol secretion is regulated by the hypothalamic-pituitary-adrenal (HPA) ax is. Psychological and physical stress and signals from the brain to produce the diurnal rhythm of plasma cortisol levels stimulate the hypothalamus to secrete corticotrophin releasing factor (CRH) which then stimulates pituitary ACTH production. ACTH is produced by the corticotrophs while they are producing pro-opiomelanocortin. The adrenal glands then secrete cortisol in response to ACTH. This HPA ax is is regulated by the balance between stimuli that encourage secretion of CRH and ACTH, and the negative feedback inhibition from cortisol on production of CRH and ACTH (Figure 3).
Both ACTH and cortisol have pulsatile secretion patterns. In a normal sub ject, ACTH peaks in the early morning, then declines to a nadir around midnight (32). Circadian rhythms affect ACTH secretion, so levels are affected by light and change in time-zone. Physical trauma, surgery, fever, hypoglycemia and other stressors lead to an increase in ACTH and cortisol secretion. The half life of bioactive ACTH is only 4-8 minutes, while its immunoreactive half life is quite variable.
Glucocorticoids increase gluconeogenesis and prevent glucose uptake into peripheral tissues. With extended exposure to glucocorticoids, lipolysis is enhanced and body fat
redistribution occurs. Glucocorticoids suppress inflammatory responses, lower peripherallymphocyte counts and raise granulocyte counts. They lead to an increase in osteoclasts and a decrease in osteoblasts, and thereby diminish new bone formation. Linear growth is suppressed in children. The catabolic effects of glucocorticoids cause the destruction of muscle proteins and lead to myopathy . Fibroblast proliferation and function are inhibited, as are some extracellular matrix proteins, leading to impaired wound healing. Glucocorticoids can also have psychological and behav ioral effects, causing altered mood, sleep and cognition.
Cortisol Deficiency Adrenocortical insuff iciency leads to nausea and emesis, abdominal pain, anorex ia,
weight loss, generalized weakness, hypotension, hyponatremia, and the inability to respond to stressful stimuli. Primary adrenocortical insuff iciency, or Addison's disease,
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Fig . 3 Regulat ion of cortisol secretion . Th e hypothalamus releases CRH to st imulate corticotrophs to produce ACTH. This ACTH then stimulates the adrenal cortex to secrete cortisol. A negative feedback loop occurs as cortisol inhibits further CRH and ACTH release . (F igure from Oyesiku N: Assessment of Pitu itary Function, Rengachary S, Ellenbogen R (eds): Principles of Neurosurgery . New York, Elsev ier Mosby, 2005)(30)
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is due to a disorder of the adrenal glands, while secondary adrenocortical insuff iciency is due to a disorder of the hypothalamic-pituitary ax is. Primary adrenal disorders generally produce more severe and life-threatening symptoms and may lead to hyponatremia, hyperkalemia and hypovolemia due to lack of aldosterone secretion. Tuberculous infection was the leading cause of Addison's disease in the past; however, today it is more often due to autoimmune disease, adrenal hemorrhage from severe stress, or surgical removal of the adrenal glands.
Secondary adrenocortical insuff iciency w ill occur w ith pan-hypopituitarism. Isolated ACTH insuff iciency is uncommon, though, as ACTH secretion is the most resistant of the pituitary hormones to loss. Prolonged exposure to exogenous glucocorticoids or to the excessive endogenous production of glucocorticoids w ith Cushing's syndrome, however, can lead to isolated ACTH def iciency . This chronic hypercortisolism w ill suppress hypothalamic CRH secretion and pituitary ACTH secretion such that, even after the excess exposure to glucocorticoids is eliminated, it may take 6-24 months before the
HPA-ax is resumes normal function.
Workup Cortisol is a more stable hormone than ACTH, and cortisol levels should be measured
in any evaluation of the HPA ax is. Basal levels should be drawn between 8:00 and 9:00AM as production is highest at this time. Random serum levels at other times of day are less useful. Patients w ith severe adrenal insuff iciency w ill often have a low 24 hour urine free-cortisol level as well as a basal serum cortisol level of <100 nmol/L. A basal level of >450 nmol/L demonstrates that the patient likely has normal adrenal function (32).
Patients w ith moderate hypoadrenalism may have basal cortisol levels in the low- normal range.
Medications may affect cortisol secretion or may interfere w ith the radioimmunoassay used to measure cortisol levels. Hydrocortisone and prednisolone w ill interfere w ith the results, and should be stopped at least 24 hours prior to testing (16). Oral estrogens may increase cortisol levels for several weeks after administration, due to an increase in the production of cortisol binding globulin. The specif ic immunoassay used w ill affect the result as well, as a w ide variation in results occurs w ith different assays (10). The levels measured should therefore be assessed in each patient's specif ic clinical context rather
than rely ing on set cut-off points, and dynamic-stimulation tests are needed to conf irmadrenal insuff iciency . The adrenal cortex atrophies in the absence of ACTH stimulation, so the response to
ACTH is suppressed in both primary and secondary adrenal insuff iciency, The short ACTH stimulation test in jects 25 units (0.25 mg) of cosyntropin, synthetic short ACTH which retains the biologic activ ity of ACTH, intravenously (IV) or intramuscularly (IM), and measures plasma cortisol levels immediately before, 30 minutes after and 60 minutes after in jection. In normal sub jects, an increase in cortisol of at least 7 µg/dL over the basal level, or a peak cortisol of at least 20 µg/dL is expected. Patients w ith chronic ACTH def iciency have a blunted response, while those w ith primary adrenal insuff iciency generally have no response to the cosyntropin.
Once a diagnosis of adrenal insuff iciency is conf irmed, measurements of basal plasma ACTH levels and a CRH stimulation tests are performed to determine the etiology of the
disorder (16). In primary adrenal disease, diminished cortisol production prov ides decreased negative feedback inhibition on the pituitary corticotrophs, so basal ACTH levels should be high. Conversely, in patients w ith pituitary disease or those w ith prolonged glucocorticoid exposure, basal ACTH levels are low and are unable to respond normally to CRH stimulation.
The insulin tolerance test (ITT) and glucagon stimulation test (GST) can be used to determine how the HPA ax is responds to stress. The ITT, as discussed earlier, is considered by many to be the 'gold-standard' for measuring both GH and ACTH reserves (1, 29). A bolus of insulin, 0.15 units/kg, is given IV, to induce hypoglycemia. A normal response is a cortisol increase of 200 nmol/L, reaching a peak level of at least 500 nmol/L (32).
A glucagon-stimulation test is not as w idely used as the ITT, but may be useful in those patients for whom an ITT would be contraindicated. An IM in jection of 1 mg glucagon is given, then ACTH and GH levels are measured six times, starting at 90 minutes
post-in jection and continuing every 30 minutes thereafter. Normal cortisol response is delayed but otherw ise similar to that for the ITT.
Cortisol Excess; Cushing's Syndrome Longstanding exposure to excess cortisol leads to Cushing's syndrome. Multiple
processes can lead to this syndrome, and determining the exact cause in a particular patient may be diff icult. Generally, late evening plasma levels are elevated over the normal values of f ive to 25 ng/mL and the usual diurnal variation in levels is lost, leading to an elevated mean cortisol level. This chronic hypercortisolemia suppresses
hypothalamic CRH and pituitary ACTH secretion, and the pituitary corticotrophs atrophy .
Approx imately 75% of patients w ith Cushing's syndrome, endogenous adrenocortical hyperfunction, have Cushing's disease, excess ACTH secretion from a pituitary corticotroph tumor. Many of these ACTH-secreting adenomas are microadenomas which may not be v isible even on high quality sellar MRI. Cushing's syndrome patients may also have an ectopic, non-pituitary, source of excess ACTH production. This is most often due to small cell lung carcinoma, but may also be attributable to bronchial carcinoid, thymic carcinoid, pancreatic carcinoid, pancreatic islet cell tumor,
pheochromocytoma, medullary thyroid carcinoma or another neuroendocrine tumor.There are also rare CRH-secreting tumors, generally bronchial carcinoids. Other patients w ith Cushing's syndrome have adrenal tumors that secrete cortisol rather than ACTH. These may be benign adenomas or malignant carcinomas, and the syndrome can be clinically indistinguishable from that of Cushing's disease or ectopic ACTH-secreting tumors. Therefore, endocrine testing to determine the etiology of Cushing's syndrome is very important.
Symptoms associated w ith Cushing's syndrome include central weight gain, often accompanied by a buffalo hump; moon facies, due to thickening of facial fat; hypertension; hyperglycemia or diabetes mellitus; hirsutism; acne; purple striae; facial telangiectasias ; amenorrhea or hypogonadism ; muscle wasting ; osteoporosis; hyperpigmentation; and depression. Patients w ith Cushing's syndrome lose the normal diurnal cortisol variation. In Cushing's disease, the HPA ax is maintains its homeostatic
responses, but is altered to respond only to higher than normal glucocorticoid levels. Cushing's syndrome from an ectopic ACTH-secreting tumor, on the other hand, w ill exhibit autonomous cortisol production and fail to demonstrate any feedback inhibition. Cushing's disease is diagnosed if a patient has 1. increased basal cortisol levels, 2. relative resistance to negative feedback from glucocorticoids, 3. ACTH response to decreased cortisol, 4. ACTH response to CRH or vasopressin, 5. cortisol response to exogenous ACTH, and 6. a pituitary source of the excess ACTH.
Workup When Cushing's syndrome is suspected, one must f irst establish that there is indeed
excess secretion of cortisol. This may be accomplished v ia tests that 1. directly or indirectly measure cortisol production over 24 hours, such as v ia 24-hour urine collection for free cortisol and 17-hydroxyglucocorticoid excretion and 2. assess the presence of normal sensitiv ity of the hypothalamic-pituitary-adrenal ax is to negative
feedback by glucocorticoids, for instance, by using a low-dose glucocorticoid tests including the overnight test or the low-dose portion of the 6-day dexamethasone suppression test.
Serum free cortisol f ilters into saliva and urine, and cortisol urinary excretion products are elevated. 24 hour urine free cortisol (UFC) is 20-90 µg in a normal sub ject, but increases to >150 µg in Cushing's syndrome. Some of the metabolites of cortisol, including 17-hydroxysteroids (17-OHCS), and some of its precursors, including 17- ketosteroids and DHEAS, are elevated as well. The saliva and urine free cortisol levels are more accurate indicators of increased cortisol secretion than is urinary 17-OHCS, as they
increase more rapidly after plasma cortisol exceeds the binding capacity of transcortin. Salivary cortisol is easy to use in an outpatient setting and allows for repeated sampling. An 11:00PM salivary free cortisol >3.6 nmol/L is highly suggestive of Cushing's syndrome.
Once it is determined that a patient has Cushing's syndrome, then the next step is to determine the source of the excess hormone production. The differential diagnosis includes ACTH-dependent processes which lead to Cushing's syndrome by excess ACTH secretion, and ACTH-independent processes which lead to the syndrome by excess cortisol secretion. ACTH-dependent lesions include ACTH-secreting pituitary tumors,
ectopic ACTH-secreting tumors such as small cell lung carcinoma, diffuse corticotrophhyperplasia, and ectopic CRH secretion, while ACTH-independent processes include cortisol-secreting primary adrenal disease (Table 2).
Table 2 Etiology of Cushing's Syndrome. (Copied from Oyesiku N: Assessment of Pituitary Function, Rengachary S, Ellenbogen R (eds): Principles of Neurosurgery . New York, Elsev ier Mosby, 2005)(30)
Normal ACTH is <10 pg/mL (2 pmol/L). Patients w ith ACTH-dependent disease have excess cortisol due to excess ACTH, so they w ill have plasma ACTH levels which are inappropriately elevated for the level of cortisol present. Conversely, the hypothalamic and pituitary portions of the HPA ax is are relatively normal in primary adrenal disease, so hypercortisolemia w ill suppress pituitary ACTH secretion in these patients, and their serum ACTH levels w ill be undetectable or very low . A simultaneous serum cortisol level must be drawn to properly evaluate the plasma ACTH level.
Patients in whom ACTH-independent Cushing's syndrome is suspected should undergo MRI or CT adrenal imaging. Nearly 100% of these patients w ill have an adrenal tumor, most of which can be v isualized radiographically . When ACTH- dependent Cushing's syndrome is suspected, the differential is a bit larger. Most ACTH- secreting pituitary and ectopic tumors are very small and are not easily recognized on radiographic imaging. Basic endocrinologic principles can assist in mak ing the diagnosis. ACTH-secreting pituitary adenomas are well-differentiated tumors that originate from
pituitary corticotrophs. They are therefore more likely to respond to glucocorticoids and to CRH stimulation than are ectopic ACTH-secreting tumors, which arise from tissues that are not supposed to secrete ACTH, respond to glucocorticoids or contain receptors for CRH. Therefore a dexamethasone suppression test (DST) or CRH-stimulation test may be useful.
In the overnight DST, 0.5-1 mg of dexamethasone is given orally at midnight, and serum cortisol is checked at 8:00AM the next morning, while in the two day low-dose DST, 0.5 mg of dexamethasone is given orally every 6 hours for 8 doses. In normal sub jects, these doses are enough to suppress the HPA ax is, leading to serum cortisol levels
<140 nmol (5 µg/dl), urinary 17-OHCS <6.9 µmol (2.5 mg) in 24 hours, and urinary free cortisol <55 nmol (20 µg) in 24 hours. Patients w ith Cushing's syndrome, on the other hand, w ill not have this HPA ax is suppression.
The high dose DST gives patients 2 mg dexamethasone. Patients w ith Cushing's disease w ill generally suppress their levels to 50% of their baseline w ith this test, while patients w ith ectopic ACTH tumors or adrenal tumors w ill not have any signif icant suppression w ith either the high or low dose tests.
The CRH or AVP suppression tests can also help differentiate Cushing's disease from ectopic lesions. CRH and AVP are physiologic secretagogues to which most
pituitary microadenomas w ill respond. In Cushing's disease, either compound w illlead to a signif icant increase in ACTH, while in cases of ectopic ACTH secretion, ACTH levels w ill not respond.
The metyrapone test is a less common test that can also be used to d istinguish between a pituitary and an ectopic ACTH source. Metyrapone is a compound that inhibits cortisol synthesis at several steps, including at the conversion of 11-deoxycortisol to cortisol. As plasma cortisol levels fall, corticotrophs respond by increasing production of ACTH, which can be measured v ia increased urinary 17-OHCS. For patients w ith ectopic ACTH production, the hypothalamic and pituitary ax is is chronically suppressed and is not reactivated w ith metyrapone.
Another test which can help to differentiate between pituitary and non-pituitary disease processes is the high dose 6 day dexamethasone suppression test known as the Liddle test. In this test, a patient undergoes 2 days of baseline urinary 17-hyrdroxysteroid
measurements, then is given 2 days of low dose dexamethasone, 0.5 mg orally every 6 hours, lastly he is given 2 days of high dose dexamethasone, 2 mg orally every 6 hours. Liddle f irst observed in 1960 that the ma jority of patients w ith a pituitary source of excess ACTH, Cushing's disease, had a more than 50% decrease in 17-OHCS excretion on the second day of high-dose glucocorticoid administration, while this response was not seen in patients w ith adrenal tumors (15).
Once Cushing's disease is suspected, the location of the tumor must be established. When radiographic imaging does not demonstrate a lesion, inferior petrosal sinus sampling (IPSS) can assist w ith this. The petrosal sinuses drain the pituitary gland. Bilateral catheters are placed v ia the femoral veins and fed up the internal jugular veins to the inferior petrosal sinuses. ACTH levels are measured in the peripheral circulation and each sinus both before and after IV in jection of CRH to stimulate ACTH secretion. Bilateral catheterization allows for simultaneous sampling of the right and left sinuses so that the ACTH concentrations can be compared. A gradient between the sinuses can
lateralize the tumor w ithin the pituitary . As spontaneous ACTH release is episodic in nature, CRH stimulation helps to ensure secretion at the time of sampling. An inferior petrosal sinus to peripheral blood (ISP:P) ratio >2.0 in basal samples has up to 95% sensitiv ity and 100% specif icity, while a peak IPS:P ratio >3.0 after CRH administration has been reported to have 100% sensitiv ity and 100% specif icity (14, 28, 38). An inter- sinus gradient >1.4 predicts the location of the lesion in up to 75% of patients. Cavernous sinus sampling is less commonly used, but can prov ide slightly more accurate localization (Table 3).
Mild hyperprolactinemia is present in about one quarter of patients w ith Cushing's disease. Some of these tumors contain PRL-secreting cells (42). PRL levels can also be
Table 3 Clinical Approach to Patients w ith Suspected Cushing's Syndrome. (Copied from Oyesiku N: Assessment of Pituitary Function, Rengachary S, Ellenbogen R (eds): Principles of Neurosurgery . New York, Elsev ier Mosby, 2005)(30)
measured as part of the IPSS to assist in localizing the tumor. Most patients undergo a combination of these tests. It is important to establish that the
patient does indeed have Cushing's syndrome before proceeding w ith tests to determine if the diagnosis is Cushing's disease or an ectopic source. In sub jects w ithout Cushing's syndrome, pituitary ACTH secretion is suppressed by dexamethasone and responds to CRH. This can therefore be erroneously attributed to Cushing's disease, causing a normal patient to undergo unnecessary pituitary surgery .
Glycoprotein Hormones The glycoprotein pituitary hormones are thyroid-stimulating hormone (TSH),
follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Each of these is composed of 2 glycopeptide chains: an alpha chain and a unique beta chain. These chains are synthesized indiv idually, and there is generally a slight excess of the alpha chain which can be detected w ith radioimmunoassay .
Pituitary-Thyroid Axis Hypothalamic secretion of TRH to the portal venous complex regulates the production
and secretion of thyrox ine (T4) and triiodothyronine (T3). When thyrotrophs sense TRH, they release TSH, which acts on the thyroid gland to release T3 and T4. T3 and T4, in turn, inhibit hypothalamic TRH release and pituitary TSH release. Somatostatin, glucocorticoids and dopamine also suppress both TRH release and the pituitary response to TRH.
Hypothyroidism Signs and symptoms of hypothyroidism include fatigue, dry sk in, cold intolerance,
alopecia, and, in severe cases, myxedema coma. Most patients w ith hypothyroidism have primary hypothyroidism due to a disorder of the thyroid gland. Autoimmune Hashimoto's thyroiditis, thyroid destruction after 131I therapy and surgery for hyperthyroidism are the most common causes of this condition . In primary hypothyroidism, absence of the feedback inhibition of the thyroid hormones on the pituitary and hypothalamus results in elevated TRH and TSH levels. When patients are untreated, the increased TRH secretion stimulates thyrotroph hyperplasia and may
lead to pituitary enlargement. As TRH also stimulates PRL secretion, these patients may be misdiagnosed w ith a PRL-secreting or TSH-secreting tumor. TSH def iciency causes secondary hypothyroidism and results from pituitary or
hypothalamic disease. It frequently accompanies pan-pituitary def iciency from a large pituitary adenoma or suprasellar mass.
Workup The mean TSH concentration in euthyroid adults is 1.4-2.0 U/ml. These levels do not
differ signif icantly w ith gender or w ith age between adolescence and about 60 years. TSH levels rise to a peak between midnight and the early morning and drop to a nadir in the late afternoon (26, 31). Increased TSH levels are seen in hypothyroidism, TSH-secreting tumors, and w ith some drugs, including iodine and dopamine antagonists. Decreased TSH levels occur w ith hyperthyroidism, severe illnesses, chronic renal failure, pan-
hypopituitarism, pituitary tumors or hypophysitis, sarcoid, hypothalamic tumors or trauma, or drugs such as glucocorticoids, oral contraceptives or dopamine agonists.
In both primary and secondary hypothyroidism, the serum level of free thyrox ine (free T4) is low . Free T4 can be measured by direct radioimmunoassay from a serum sample or may be estimated by the free thyrox ine index (FTI = total T4 x T3 resin uptake). Though it is generally reliable, the FTI can be misleading in patients in whom prolonged illness causes a low FTI despite clinical euthyroidism and normal serum levels of free T4. When serum free T4 is low, measurement of plasma TSH can distinguish primary from secondary hypothyroidism: an elevated TSH is a sign of primary disease, while a low TSH is a sign of secondary disease (Table 4). Non-thyroid illnesses, such as hepatic failure or sepsis, can also alter TSH levels, however.
A TRH stimulation test w ill further differentiate primary and secondary hypothyroidism, and in secondary hypothyroidism may distinguish between pituitary and hypothalamic disorders. 200-500 µg TRH is given IV over 30 minutes, and serum TSH levels are obtained at -5, 0, 15, 30 and 60 minutes. Patients w ith primary hypothyroidism w ill have elevated basal TSH levels and w ill respond rapidly and excessively to TRH stimulation. Patients w ith pituitary lesions that damage the thyrotrophs w ill have no TSH response to TRH, while patients w ith hypothalamic disorders w ill have a delayed TSH response which peaks at 60 minutes. Normal sub jects w ill have a serum TSH peak at 15 minutes after stimulation as well as an increase of at least 6 µU/mL over their basal value.
Hyperthyroidism Symptoms of hyperthyroidism include tremulousness, anx iety, heat intolerance,
diarrhea and changes in mental status. The ma jority of hyperthyroid patients have a circulating thyroid-stimulating antibody, a thyroid adenoma, or thyroiditis. Hypersecretion of TSH by a pituitary adenoma is quite rare, occurring in less than 1% of hypothyroid patients. These TSH-secreting tumors may also secrete GH or PRL. Since primary hyperthyroidism is relatively common and TSH-secreting tumors are rare, many patients w ith TSH-secreting pituitary adenomas are initially misdiagnosed and receive ablative therapy of the thyroid gland. Thus, they may no longer have hyperthyroidism when the pituitary tumor is recognized, mak ing it more diff icult to diagnose. Because of the common delay in diagnosis, TSH-secreting pituitary adenomas are often large, invasive tumors at the time that they are recognized.
Table 4 Thyroid Screening Tests. (Copied from Oyesiku N: Assessment of Pituitary Function, Rengachary S, Ellenbogen R (eds):
Principles of Neurosurgery . New York, Elsev ier Mosby, 2005)(30)
Workup As w ith the evaluation of hypothyroidism, TSH levels should be measured, but they
may not prov ide the full picture. Patients w ith hyperthyroidism due to primary thyroid disease w ill have elevated serum levels of free T4, w ith a low plasma TSH. A TRH stimulation test may be useful in the assessment of mild thyroid dysfunction and in the functional evaluation of the hypothalamic-pituitary-thyroid ax is. Serum TSH levels are measured at baseline and again after the administration of TRH. A dose-response relationship between TRH and TSH levels is observed (18). In primary hyperthyroidism, the excess thyroid hormones w ill inhibit the pituitary thyrotrophs, so the pituitary TSH response to TRH stimulation w ill be suppressed.
Secondary hypothyroidism, from a pituitary or hypothalamic disorder, w ill generally demonstrate low levels of T4 in combination w ith lower than expected levels of TSH. Serum TSH levels are not always useful, however, as they may appear normal if the patient secretes a form of TSH which is detectable on radioimmunoassay but biologically
inactive. In TSH-secreting tumors, the production of alpha and beta subunits is imbalanced
such that excess alpha subunit is secreted, which produces a ratio of serum alpha subunit to serum TSH of >1. In a patient w ith hyperthyroidism, or a patient w ith a pituitary tumor who has been prev iously treated for hyperthyroidism, an elevated TSH level combined w ith an elevated ratio of alpha-subunit to TSH, indicates a TSH- secreting pituitary adenoma.
In patients who have had ablative thyroid treatments for misdiagnosed TSH-secreting pituitary tumors, elevated plasma TSH levels do not fully suppress when the patient is
given thyroid hormone, and the pituitary TSH response to TRH is blunted.
Gonadotropins FSH and LH are produced and released by the gonadotrophs of the adenohypophysis
to regulate ovarian and testicular function. In women, FSH stimulates growth of the granulosa cells of the ovarian follicle and controls their estrogen secretion. At the midpoint of the menstrual cycle, the increasing level of estradiol stimulates a surge of LH secretion, which then triggers ovulation. After ovulation, LH supports the formation of the corpus luteum. Exposure of the ovary to FSH is required for expression of the LH
receptors. In men, LH is responsible for the production of testosterone by Leydig cells inthe testes. The combined effects of FSH and testosterone on the seminiferous tubule stimulate sperm production.
FSH and LH secretion occur in a pulsatile fashion in response to pulses of secretion of GnRH from the hypothalamus. GnRH is also known as LH-releasing hormone (LHRH) because of its potent stimulation of LH secretion. Levels of FSH and LH are regulated by a balance of GnRH stimulation, negative feedback regulation from the inhibin peptide secreted by the ovaries and the testes, and the effect of the sex steroids on the pituitary and the hypothalamus. Appropriate concentrations of FSH and LH are required for normal sexual development and reproductive function in both women and men. LH and FSH circulate in blood predominantly in the monomeric form found in the pituitary . FSH has a half life of 3-5 hours, so serum levels are more stable than are those of LH, which has a half life of 30-60 minutes.
GnRH stimulates gonadotropin secretion from the pituitary for the f irst few months of life, then the pituitary becomes unresponsive to GnRH until puberty, when pulsatile secretion of FSH and LH occur in response to pulses of GnRH. At menopause, when gonadal failure occurs, the negative feedback prov ided by the hormonal products of the gonads is eliminated so serum levels of FSH and LH increase.
Gonadotropin Deficiency and Workup Hypogonadism presents in women as amenorrhea and loss of libido associated w ith
uterine and vaginal atrophy . In men, low testosterone results in loss of libido, impotence, decreased beard growth and body hair, and testicular softening.
When hypogonadism is suspected, endocrine evaluation should include measurement of plasma FSH, LH and sex hormones estradiol in women and testosterone in men. FSH and LH are measured by immunoassay . In men above the age of puberty, these levels are w ithin a fairly narrow range. In women, however, the pulsatile nature of LH and FSH,
and their marked fluctuation during the menstrual cycle, pregnancy and menopause have to be considered in the interpretation of these lab results. In adolescents and women, isolated and random FSH and LH levels are of little diagnostic use alone, and must be correlated w ith the results of simultaneous levels of estradiol or testosterone and the results of dynamic testing.
Estradiol binds to sex-hormone binding globulin which w ill have elevated levels in women who are tak ing oral contraceptive pills or hormone replacement therapy . Testosterone in men has a signif icant diurnal variation, and should be assessed between 8:00am and 9:00am.
Primary hypogonadism is associated w ith low levels of sex steroids and high levels of FSH and LH. This may be due to primary ovarian failure such as w ith ovarian dysgenesis, oophorectomy or premature ovarian failure, or primary testicular failure such as w ith Klinefelter's syndrome or orchiectomy . Decreased levels of FSH and LH may also be found in hypothalamic disease including tumors such as craniopharyngiomas or hypothalamic region meningiomas, germinomas, gliomas or hamartomas, as well as other hypothalamic inf iltrative or infectious pathology such as sarcoidosis, eosinophilic granuloma, tuberculosis, fungal infections or syphilis. Hypothalamic trauma, vascular disease and radiation therapy can also be the cause.
If FSH and LH are inappropriately low and are associated w ith a decreased level of estradiol or testosterone, then hypogonadotropic hypogonadism can be diagnosed. This may be a primary result of congenital causes, as w ith Kallman's syndrome, in which GnRH def iciency is associated w ith anosmia and defective development of the midline structures of the brain. More commonly however, hypogonadotropic hypogonadism is a secondary, acquired defect of GnRH production associated w ith hypothalamic dysfunction, as occurs w ith destruction of the pituitary gonadotrophs or interruption of pituitary stalk function from a sellar mass or apoplexy, or from surgery or radiation to treat a sellar tumor, or as a result of stress, system ic disease, anorex ia nervosa or bulimia, or sometimes seen in very athletic women.
GnRH stimulation testing is rarely used today, but at times may be useful to determine the presence of adequate gonadotroph reserve. If a detectable elevation of FSH and LH levels occurs after GnRH administration, functional gonadotropic cells are still present.
This response to GnRH may require priming of the gonadotrophs w ith repeated in jections of GnRH.
Gonadotropin Excess and Workup Elevated FSH and LH may be seen w ith polycystic ovary syndrome, paraneoplastic
gonadotropin secretion, precocious puberty and gonadotrope-secreting adenomas. Though FSH-secreting and LH-secreting pituitary adenomas are rarely observed clinically, approx imately 5% of pituitary adenomas have immunohistochemical staining for the gonadotropins or their subunits. Nearly all of these tumors are clinically nonfunctioning pituitary macroadenomas that cause symptoms because of their mass effect on sellar or parasellar structures, as there is no characteristic hypersecretory endocrinopathy, as occurs w ith other hormone secreting tumors. About 20% of these tumors secrete the alpha-subunit rather than a complete gonadotropin.
Precocious puberty is often associated w ith hypothalamic hamartomas in children.
These tumors interrupt the normal suppression of pituitary gonadotropin function by higher neural centers, leading to pulsatile secretion of GnRH and, in turn, secretion of FSH and LH, estrogen, and testosterone and premature sexual development. Sustained, non-pulsatile exposure to GnRH desensitizes the gonadotrophs to GnRH and inhibits FSH and LH release. A long-acting analogue of GnRH is used to suppress pituitary gonadotropin secretion and reverse sexual development in children w ith idiopathic precocious puberty or precocious puberty due to a hypothalamic hamartoma. Ectopic production of gonadotropin, usually of human chorionic gonadotropin which has LH- like activ ity, by germinomas, lung carcinomas and other tumors may also lead to
precocious puberty .
Posterior Pituitary Hormones The neurohypophysis is the posterior lobe of the pituitary . This lobe secretes
antidiuretic hormone (ADH) and oxytocin, which are produced by hypothalamic neurons but are stored in secretory granules in the nerve terminals of the neurohypophysis and are released from there in response to various stimuli.
If the posterior pituitary is selectively damaged but the median eminence and hypothalamus remain intact, these hormones can be secreted from the median eminence.
Antidiuretic Hormone ADH conserves water by reducing the rate of urine output. This antidiuretic effect is
achieved by promoting the reabsorption of solute-free water in the distal collecting tubules of the k idney . Though this hormone is also known as vasopressin, it has little to no cardiac pressor effect in healthy humans. Through the action of ADH, serum sodium concentrations and serum osmolality are maintained w ithin a narrow range, despite large daily variations in sodium intake and water loss. Derangements in ADH secretion can lead to severe, life-threatening disturbances in serum osmolality and volume.
Though multiple hypothalamic signals influence ADH secretion, the primary stimuli for ADH release are an increase in plasma osmolality or a decrease in plasma volume. Even a 2% increase in plasma osmolality caused by an impermeable solute, such as NaCl, causes shrinkage of hypothalamic osmoreceptor cells, stimulating ADH release as well as
thirst. This osmoregulatory mechanism is differentially sensitive to various plasma solutes. Sodium and its anions, which normally contribute >95% of the osmotic pressure in plasma, are the most potent stimulators of ADH release. Sugars, such as sucrose and mannitol, are nearly as powerful. Decreased intravascular volume is also a potent stimulator of ADH secretion. Small decreases in volume activate stretch receptors in the left atrium which lead to ADH release, while decreases in volume of about 10% stimulate ADH release v ia baroreceptors in the carotid arteries and the aortic arch (Figure 4).
Higher neural centers also influence ADH levels. Beta-adrenergic and cholinergic agonists stimulate ADH secretion, while alpha-adrenergic agonists and atropine inhibit it. Psychological factors, pain, and stress can therefore increase ADH release. Nausea is an instantaneous and extremely potent stimulus for ADH secretion in humans. Other stimuli for ADH release include hypoglycemia, angiotensin, nicotine, morphine, and barbiturates, while inhibitors of ADH release include alcohol, phenytoin, and narcotic antagonists.
Fig . 4 Regulation of ADH secretion. The main stimulators of ADH release by the posterior pituitary are an increase in plasma osmolality or a decrease in intravascular volume. Osmolality is detected by hypothalamic osmoreceptor cells, while volume changes are detected by atrial stretch receptors and carotid and aortic baroreceptors. (Figure from Oyesiku N: Assessment of Pituitary
Function, Rengachary S, Ellenbogen R (eds):Principles of Neurosurgery . New York, Elsev ier Mosby, 2005)(30)
Deficient ADH; Diabetes Insipidus The typical clinical manifestations of diabetes insipidus (DI) include polyuria, polydipsia, excessive thirst and nocturia. Polyuria may be def ined as the excretion of more than 2.5 L of urine per 24 hours on at least 2 consecutive days, prov ided that patients are allowed free access to and drink water ad libitum. The severity of diabetes insipidus varies w idely, w ith urine volumes ranging up to 20 L per day . If access to water is restricted, dehydration can rapidly become severe and result in altered mentation, fever, hypotension, and death.
Central DI is def icient ADH secretion from the neurohypophysis in response to normal osmotic stimulation. This disorder is also known as hypothalamic DI, cranial DI or neurogenic DI. These patients generally have normal thirst sensation though they have insuff icient circulating antidiuretic activ ity . Diabetes insipidus secondary to renal tubular insensitiv ity to the antidiuretic effect of ADH is usually called nephrogenic diabetes insipidus. These patients generally have a normal of high level of circulating
ADH. Primary polydipsia is a third mechanism leading to diabetes insipidus. This is the ingestion of excessive volumes of water, resulting in suppression of vasopressin release and consequent polyuria.
Causes of central DI include sellar and parasellar tumors, especially craniopharyngiomas, large non-functional pituitary adenomas, germinomas, and metastatic tumors; hypothalamic tumors or inf iltrative processes such as sarcoidosis and histiocytosis-X ; pituitary or hypothalamic in jury or surgery ; head trauma; subarachnoid hemorrhage from ruptured intracranial aneurysms; and idiopathic causes. DI is rarely a presenting feature in patients w ith pituitary adenomas, but is more common in patients
w ith craniopharyngioma or hypothalamic lesions. DI from head trauma or damage to the pituitary stalk or hypothalamus generally presents w ith 24 hours of in jury . In about 50% of cases of posttraumatic diabetes insipidus, the condition resolves spontaneously w ithin a few days. Permanent diabetes insipidus develops in another 30-40% of these patients, and the remainder exhibit a triphasic response to in jury . In this last group, the onset of polyuria is abrupt but lasts only a few days. It is followed by a period of anti- diuresis similar to SIADH that lasts 2-14 days before permanent DI develops . This triple response to in jury is believed to be attributable to release of the stored ADH w ithin the neurohypophysis (27, 40).
Glucocorticoid def iciency or thyroid hormone def iciency can lead to impairment of the k idney 's ability to excrete a water load and to dilute urine max imally . This impairment of anterior pituitary function can therefore mask central DI, which becomes apparent only when the hypopituitarism is treated.
Workup Patients w ith DI w ill demonstrate persistent urine osmolality of less than 300
mOsm/kg H2O associated w ith urine specif ic grav ity of 1.005 or less and plasma osmolality greater than the normal 287 mOsm/kg H2O. To conf irm the diagnosis, patients are tested to document that there is inadequate release of ADH to an osmotic stimulus. The safest and most w idely used test to raise plasma osmolality is the water deprivation test. In this test, baseline body weight, urine and plasma osmolality, and v ital signs are measured, then all oral intake is stopped. Water deprivation begins the night
before the test in patients w ith mild polyuria, and early on the day of the test in patients w ith severe polyuria. It is important that the test only be performed while the patient is under constant superv ision, to prevent severe dehydration. For patients w ith DI this test can be dangerous. Hourly measurements of urine osmolality and weight are obtained. Dehydration continues until either two sequential urine osmolalities vary by <30 mOsm/kg H2O, more than 3% of body weight is lost, or orthostatic hypotension and postural tachycardia appear. Sub jects then receive 5 units of aqueous vasopressin subcutaneously and a f inal urine osmolality is measured 1 hour later. In normal sub jects, endogenous ADH secretion concentrates the urine and preserves normal plasma osmolality . Thus, urine osmolality normally exceeds 500 mOsm/kg H2O and plateaus, while plasma osmolality remains below 300 mOsm/kg H2O before vasopressin in jection, and urine osmolality rises less than 5% after in jection. By contrast, in patients w ith central DI, urine osmolality plateaus at 300-500 mOsm/kg H2O, plasma osmolality may exceed 300 mOsm/kg H2O, and urine osmolality rises >9% after vasopressin in jection.
This test not only establishes whether or not diabetes insipidus is present, it also distinguishes central DI from other causes of polyuria. In patients w ith polyuria from renal disease or nephrogenic DI, the rise in urine osmolality w ith dehydration is limited and does not increase after vasopressin administration. In patients w ith primary polydipsia, water deprivation is prolonged before urine osmolality plateaus, and urine osmolality does not increase after the in jection of vasopressin.
The measurement of plasma ADH concentration under basal conditions can be used as an ad junct to the water deprivation test, but this radioimmunoassay test is not routinely available and is rarely affords diagnostic benef it.
Excess ADH; Syndrome of Inappropriate ADH Secretion The syndrome of inappropriate antidiuretic hormone (SIADH) is the most common
cause of euvolemic hypo-osmolality . It is also the most prevalent cause of hypo- osmolality of all etiologies encountered in current clinical practice, occurring in 30-40% of all hypo-osmolar patients (21). SIADH results from excess ADH secretion, either from the hypothalamus or from an ectopic source. This excess ADH stimulates excessive retention of free water and leads to the inability to excrete dilute urine. This results in hyponatremia and serum hypotonicity . When a patient has hyponatremia and low
serum osmolality, then continued ADH release, w ith the osmolality of urine higher thanthat of plasma, is inappropriate. The etiology of SIADH is diverse. Causes include ectopic production of ADH by
tumors, classically oat cell carcinoma; by lung tissue during inflammatory diseases such as tuberculosis; excessive neuro-hypophyseal release of ADH caused by intracranial disorders, including head trauma, subarachnoid hemorrhage, subdural hematoma, pituitary apoplexy, pituitary stalk damage, intracranial surgery, encephalitis, meningitis, intracranial abscess, or hydrocephalus; Guillain-Barré syndrome; delirium tremens; acute psychosis; or by drugs that stimulate ADH release such as chlorpropamide, carbamazepine or tricyclic antidepressants (20, 21).
The clinical features of SIADH include weight gain, weakness, lethargy, and mental confusion. As serum sodium drops below 120 mEq/L seizures and coma can occur. Hypo-osmolality is associated w ith a broad spectrum of neurologic manifestations. In the
most severe cases, death can result from respiratory arrest after tentorial cerebral herniation and brainstem compression. This process has been termed hyponatremic encephalopathy and primarily reflects brain edema resulting from osmotic water shifts into the brain due to decreased plasma osmolality (3, 17). Signif icant symptoms generally do not occur until plasma sodium concentration falls below 123 mEq/L, and the severity of symptoms can be roughly correlated w ith the degree of hypo-osmolality (3).
The period over which hypo-osmolality develops also greatly affects the severity of symptoms. Rapid development of hypo-osmolality w ill cause marked neurologic symptoms, whereas gradual development over several days or weeks often presents w ith only mild symptomatology despite profound degrees of hypo-osmolality . If given suff icient time, the brain can counteract osmotic swelling by excreting intracellular solutes such as potassium and organic osmolytes, an adaptive process known as volume regulation (17, 39). Rapid development of hypo-osmolality may cause brain edema before
this adaptation can occur. Underly ing neurologic disease also affects the level of hypo-osmolality at which CNS
symptoms appear. Moderate hypo-osmolality that would be of little concern in an otherw ise healthy patient can cause morbidity in a patient w ith an underly ing seizure disorder. Non-neurologic metabolic disorders such as hypox ia, hypercapnia, acidosis and hypercalcemia, can similarly affect the level of serum osmolality at which CNS symptoms occur.
Workup
Laboratory f indings in SIADH include hyponatremia, serum hypotonicity, urine osmolality that exceeds that of plasma, and elevated urinary sodium concentration. Plasma osmolality is generally >275 mOsm/kg H2O, urine osmolality is >100 mOsm/kg H2O w ith normal renal function, and urine sodium w ill generally be greater than or equal to 20 mEq/L, though this may be lower in patients who are chronically sodium depleted of sodium. The SIADH patient w ill be euvolemic, w ithout clinical signs of hypovolemia such as orthostatic hypotension or tachycardia, or signs of hypervolemia such as ascites. The diagnosis of SIADH is made when these features are present and after adrenal, thyroid, renal, and hepatic dysfunction and diuretic use have been excluded.
Measurement of a plasma ADH level that is inappropriately elevated relative toplasma osmolality conf irms, but is not essential for, the diagnosis. An abnormal water load test can also conf irm SIADH. A patient is given a 20 ml/kg water bolus and excretion and urine osmolality are measured. Inability to excrete at least 90% of the water load w ithin 4 hours and/or failure to dilute urine osmolality to <100 mOsm/hg H2O demonstrate an abnormal test.
Once true hypo-osmolality is verif ied, the patient's extra-cellular fluid volume status should be assessed by careful clinical examination. If the patient has SIADH and is truly euvolemic, then he w ill experience no signif icant correction of osmolality w ith volume expansion but w ill have improvement after fluid restriction. If fluid retention is present, the treatment of the underly ing disease should take precedence over the correction of plasma osmolality . If hypovolemia is present, the patient must be considered to have depletion-induced hypo-osmolality, in which case volume repletion w ith isotonic saline
at a rate appropriate for the estimated volume depletion should be immediately initiated. If diuretics have been used, the isotonic saline should be supplemented w ith 30-40 mEq/L potassium even if serum potassium concentrations are normal, because of the high incidence of total body potassium depletion in these patients.
Oxytocin Oxytocin stimulates uterine contractions at parturition and facilitates nursing through
stimulating contraction of the myoepithelial cells in the lactating mammary gland; it works to expel milk from the secretory tissue of the breast to the nipple during suckling. There is no signif icant clinical hypo- or hypersecretory syndrome, and oxytocin is not routinely assayed in the assessment of pituitary function.
Non-endocrine Studies In addition to the multiple endocrine studies discussed above, any patient w ith
suspected pituitary disease should be evaluated for ophthalmologic dysfunction as well. Because of the prox imity of the optic structures to the pituitary gland, full v isual f ields should be documented and any in jury to the optic nerves should be assessed. Magnetic resonance imaging (MRI) w ith gadolinium should also be obtained w ith thin cuts through the sella in order to evaluate for any pituitary mass or other lesion. The assistance of the neuro-ophthalmology and neuro-radiology serv ices in addition to the endocrinology serv ice w ill be invaluable in the assessment of these patients.
In a Nutshell
• The pituitary secretes 8 peptide hormones: 6 from the anterior lobe and 2 from the posterior lobe.
• A PRL level of <2 ng/mL is associated w ith severe hypopituitarism; a PRL level of >200 ng/mL is nearly diagnostic of prolactinoma.
• The insulin tolerance test is the gold-standard for the biochemical diagnosis of GH def iciency ; IGF-1 levels are more accurate that GH levels in the diagnosis of acromegaly .
• For a diagnosis of Cushing's disease, a patient must have an increased basal cortisol level, resistance to negative feedback from glucocorticoids, ACTH
response to decreased cortisol or to CRH, cortisol response to exogenous ACTH,and a pituitary source of the excess ACTH. • SIADH causes euvolemic hypo-osmolality, while DI leads to low urine osmolality
w ith an elevated plasma osmolality .
Multiple Choice Questions 1. In acromegalic patients:
a. random GH levels are the easiest and most accurate diagnostic test. b. a glucose suppression test w ill not suppress GH to <2ng/mL as it w ill in normal
sub jects. c. basal GH levels are usually 2-8ng/mL. d. due to its short half life, pulsatile secretion and w idely variable daily levels, random
IGF-1 levels are not an accurate indicator of overall GH levels.
2. A TRH stimulation test (200-500 µg IV TRH): a. w ill lead to a 3-5 fold increase in PRL level in normal sub jects, and can help
differentiate between primary and secondary hypothyroidism. b. does not prov ide any information for prolactin level workup, but w ill lead to a rapid
decrease in TSH levels in normal sub jects. c. w ill lead to a rapid 2-6 fold decrease in PRL in normal sub jects, but has no role to
play in a hypothyroid workup. d. w ill lead to a less than 2-fold increase in PRL in normal sub jects, and a rapid
increase in TSH levels in secondary hypothyroid patients. 3. Which is false regarding DI?
a. Typical symptoms of DI include polyuria, polydipsia, excessive thirst and nocturia. b. Patients w ith DI have urine osmolality <300 mOsm/kg H2O, urine specif ic grav ity
<1.005 and plasma osmolality >287 mOsm/kg H2O. c. The water deprivation test is the safest and easiest test to diagnose DI as it can be
given to the patient to complete on his own and does not require medical superv ision.
d. In central DI, there is def icient ADH secretion in response to normal osmotic stimulation; these patients often have normal thirst but insuff icient circulating antidiuretic activ ity .
4. Signs of SIADH include: a. low serum sodium, high serum tonicity, low urine osmolality, low urine sodium and
tachycardia. b. high serum sodium, high serum tonicity, low urine osmolality, low urine sodium
and bradycardia. c. low serum sodium, low serum tonicity, high urine osmolality, high urine sodium
and euvolemia. d. high serum sodium, low serum tonicity, high urine osmolality, high urine sodium
and orthostatic hypotension.
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