Pituitary damage and subsequent dysfunction can be seen with chronic infections such as tuberculosis, with opportunistic fungal infections associated with AIDS, and in tertiary syphilis. Other inflammatory processes, such as granulomas or sarcoidosis, may mimic the features of a pituitary adenoma. These lesions may cause extensive hypothalamic and pituitary damage, leading to trophic hormone deficiencies.
Cranial Irradiation
Cranial irradiation may result in long-term hypothalamic and pituitary dysfunction, especially in children and adolescents, as they are more susceptible to damage following whole-brain or head and neck therapeutic irradiation. The development of hormonal abnormalities correlates strongly with irradiation dosage and the time interval after completion of radiotherapy. Up to two-thirds of patients ultimately develop hormone insufficiency after a median dose of 50 Gy (5000 rad) directed at the skull base. The development of hypopituitarism occurs over 5–15 years and usually reflects hypothalamic damage rather than primary destruction of pituitary cells. Although the pattern of hormone loss is variable, GH deficiency is most common, followed by gonadotropin and ACTH deficiency. When deficiency of one or more hormones is documented, the possibility of diminished reserve of other hormones is likely. Accordingly, anterior pituitary function should be evaluated over the long term in previously irradiated patients, and replacement therapy instituted when appropriate (see below).
Lymphocytic Hypophysitis
This often occurs in postpartum women; it usually presents with hyperprolactinemia and MRI evidence of a prominent pituitary mass often resembling an adenoma, with mildly elevated PRL levels. Pituitary failure caused by diffuse lymphocytic infiltration may be transient or permanent but requires immediate evaluation and treatment. Rarely, isolated pituitary hormone deficiencies have been described, suggesting a selective autoimmune process targeted to specific cell types. Most patients manifest symptoms of progressive mass effects with headache and visual disturbance. The erythrocyte sedimentation rate is often elevated. As the MRI image may be indistinguishable from that of a pituitary adenoma, hypophysitis should be considered in a postpartum woman with a newly diagnosed pituitary mass before embarking on unnecessary surgical intervention. The inflammatory process often resolves after several months of glucocorticoid treatment, and pituitary function may be restored, depending on the extent of damage.
Pituitary Apoplexy
Acute intrapituitary hemorrhagic vascular events can cause substantial damage to the pituitary and surrounding sellar structures. Pituitary apoplexy may occur spontaneously in a preexisting adenoma; post-partum (Sheehan's syndrome); or in association with diabetes, hypertension, sickle cell anemia, or acute shock.The hyperplastic enlargement of the pituitary during pregnancy increases the risk for hemorrhage and infarction. Apoplexy is an endocrine emergency that may result in severe hypoglycemia, hypotension, central nervous system (CNS) hemorrhage, and death. Acute symptoms may include severe headache with signs of meningeal irritation, bilateral visual changes, ophthalmoplegia, and, in severe cases, cardiovascular collapse and loss of consciousness. Pituitary computed tomography (CT) or MRI may reveal signs of intratumoral or sellar hemorrhage, with deviation of the pituitary stalk and compression of pituitary tissue.
Empty Sella
A partial or apparently totally empty sella is often an incidental MRI finding. These patients usually have normal pituitary function, implying that the surrounding rim of pituitary tissue is fully functional. Hypopituitarism, however, may develop insidiously. Pituitary masses may undergo clinically silent infarction with development of a partial or totally empty sella by cerebrospinal fluid (CSF) filling the dural herniation. Rarely, small but functional pituitary adenomas may arise within the rim of pituitary tissue, and these are not always visible on MRI
For example, low free thyroxine in the setting of a low or inappropriately normal TSH level suggests secondary hypothyroidism. Similarly, a low testosterone level without elevation of gonadotropins suggests hypogonadotropic hypogonadism. Provocative tests may be required to assess pituitary reserve (Table 333-3). GH responses to insulin-induced hypoglycemia, arginine, L-dopa, growth hormone–releasing hormone (GHRH), or growth hormone–releasing peptides (GHRPs) can be used to assess GH reserve. Corticotropin-releasing hormone (CRH)
administration induces ACTH release, and administration of synthetic ACTH (cortrosyn) evokes adrenal cortisol release as an indirect indicator of pituitary ACTH reserve (Chap. 336). ACTH reserve is most reliably assessed during insulin-induced hypoglycemia. However, this test should be performed cautiously in patients with suspected adrenal insufficiency because of enhanced susceptibility to hypoglycemia and hypotension. Insulin-induced hypoglycemia is contraindicated in patients with active coronary artery disease or seizure disorders
Hormone production does not always correlate with tumor size. Small hormone-secreting adenomas may cause significant clinical perturbations, whereas larger adenomas that produce less hormone may be clinically silent and remain undiagnosed (if no central compressive effects occur). About one-third of all adenomas are clinically nonfunctioning and produce no distinct clinical hypersecretory syndrome.
For example, individuals with type 2 DM may return to the impaired glucose tolerance category with weight loss These values do not apply to the diagnosis of gestational DM. It is estimated that between 5 and 10% of individuals who develop DM after age 30 have type 1 DM. In 2005, the prevalence of DM in the United Sates was estimated to be 0.22% in those <20>20 years. In individuals >60 years, the prevalence of DM was 20.9%. The prevalence is similar in men and women throughout most age ranges (10.5% and 8.8% in individuals >20 years) but is slightly greater in men >60 years In 2005, the CDC estimated that the prevalence of DM in the United States (age > 20 years) was 13.3% in African Americans, 9.5% in Latinos, 15.1% in Native Americans (American Indians and Alaska natives), and 8.7% in non-Hispanic whites. Individuals belonging to Asian-American or Pacific-Islander ethnic groups in Hawaii are twice as likely to have diabetes compared to non-Hispanic whites. DM is defined as the level of glycemia at which diabetes-specific complications occur rather than on deviations from a population-based mean Criterios Dx de DM • Symptoms of diabetes plus random blood glucose concentration >11.1 mmol/L (200 mg/dL)aor • Fasting plasma glucose >7.0 mmol/L (126 mg/dL)bor • Two-hour plasma glucose >11.1 mmol/L (200 mg/dL) during an oral glucose tolerance testc Glucose tolerance is classified into three categories based on the FPG (Fig. 338-1): (1) FPG <>= 5.6–6.9 mmol/L (100–125 mg/dL) is defined as IFG; and (3) FPG >7.0 mmol/L (126 mg/dL) warrants the diagnosis of DM. Based on the OGTT, IGT is defined as plasma glucose levels between 7.8 and 11.1 mmol/L (140 and 199 mg/dL) and diabetes is defined as a glucose > 11.1 mmol/L (200 mg/dL) 2 h after a 75-g oral glucose load. Some individuals have both IFG and IGT. Individuals with IFG and/or IGT, recently designated pre-diabetes by the American Diabetes Association (ADA), are at substantial risk for developing type 2 DM (25–40% risk over the next 5 years) and have an increased risk of cardiovascular disease. The current criteria for the diagnosis of DM emphasize that the FPG is the most reliable and convenient test for identifying DM in asymptomatic individuals. A random plasma glucose concentration >11.1 mmol/L (200 mg/dL) accompanied by classic symptoms of DM (polyuria, polydipsia, weight loss) is sufficient for the diagnosis of DM (Table 338-2). Oral glucose tolerance testing, although still a valid means for diagnosing DM, is not recommended as part of routine care. the A1C is not currently recommended to diagnose diabetes. Screening: ADA recommends screening all individuals >45 years every 3 years and screening individuals at an earlier age if they are overweight [body mass index (BMI) > 25 km/m2] and have one additional risk factor for diabetes Risk factors (10) Family history of diabetes (i.e., parent or sibling with type 2 diabetes) Obesity (BMI >25 kg/m2) (sobrepeso) Habitual physical inactivity Race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) Previously identified IFG or IGT History of GDM or delivery of baby >4 kg (>9 lb) Hypertension (blood pressure >140/90 mmHg) HDL cholesterol level <35>250 mg/dL (2.82 mmol/L) Polycystic ovary syndrome or acanthosis nigricans History of vascular disease
Insuline: Insulin is produced in the beta cells of the pancreatic islets. It is initially synthesized as a single-chain 86-amino-acid precursor polypeptide, preproinsulin. Subsequent proteolytic processing removes the aminoterminal signal peptide, giving rise to proinsulin. Proinsulin is structurally related to insulin-like growth factors I and II, which bind weakly to the insulin receptor. Cleavage of an internal 31-residue fragment from proinsulin generates the C peptide and the A (21 amino acids) and B (30 amino acids) chains of insulin, which are connected by disulfide bonds. The mature insulin molecule and C peptide are stored together and cosecreted from secretory granules in the beta cells. Because the C peptide is cleared more slowly than insulin, it is a useful marker of insulin secretion and allows discrimination of endogenous and exogenous sources of insulin in the evaluation of hypoglycemia
Glut 2 secrecion insulin insulin estimula expression glut 4 Glucose phosphorylation by glucokinase is the rate-limiting step that controls glucose-regulated insulin secretion. Further metabolism of glucose-6-phosphate via glycolysis generates ATP, which inhibits the activity of an ATP-sensitive K+ cannel. Inhibition of this K+ channel induces beta cell membrane depolarization, which opens voltage-dependent calcium channels (leading to an influx of calcium), and stimulates insulin secretion. Glucagon-like peptide 1 (GLP-1), the most potent incretin, is released from L cells in the small intestine and stimulates insulin secretion only when the blood glucose is above the fasting level. Incretin analogues, such as exena-tide, are being used to enhance endogenous insulin secretion. Once insulin is secreted into the portal venous system, ~50% is degraded by the liver. Descrito hace más de 40 años, se debe a la acción de 2 hormonas gastrointestinales conocidas como GLP-1 (glucagon-like peptide-1,) y GIP (glucose-dependent insulinotropic polypeptide). GLP-1 es secretado por la células L situadas a nivel del íleon y colon, mientras que GIP es liberado a partir de las células K localizadas en el duodeno y yeyuno. Las incretinas, especialmente el GLP-1, tienen un efecto dual al incrementar la secreción de insulina y suprimir la secreción de glucagón de forma glucosa dependiente. Este efecto se halla presente en la diabetes tipo 2, aunque disminuido. Ambas hormonas, GLP-1 y GIP son inactivadas rápidamente (2-3 min) por la enzima dipeptidil peptidasa-4 (DPP-IV), presente en la circulación (forma soluble) y en diversos tejidos. La infusión iv. continua de GLP-1 disminuye la concentración plasmática de glucosa en ayunas y tras la ingesta. Para aumentar el efecto de GLP-1 en pacientes con diabetes tipo 2 se han utilizado dos estrategias distintas: (1) utilizar análogos de GLP-1 (incretín-miméticos), como exenatide (Byetta®, comercializado en EEUU) o liraglutide, resistentes a la acción de GLP-1, que se administran 1-2 veces/día por vía sc., o (2) inhibir la enzima DPP-IV para incrementar los niveles de GLP-1 de forma fisiológica (potenciadores del efecto incretina, PEI). DM1: In the majority, immunologic markers appear after the triggering event but before diabetes becomes clinically overt. Features of diabetes do not become evident until a majority of beta cells are destroyed (~80%. Most individuals with type 1 DM have the HLA DR3 and/or DR4 haplotype. Refinements in genotyping of HLA loci have shown that the haplotypes DQA1*0301, DQB1*0302, and DQB1*0201 are most strongly associated with type 1 DM. Hence, most individuals with type 1 DM do not have a first-degree relative with this disorder. Pathologically, the pancreatic islets are infiltrated with lymphocytes (in a process termed insulitis). The islet destruction is mediated by T lymphocytes rather than islet autoantibodies.
Islet cell autoantibodies (ICAs) are a composite of several different antibodies directed at pancreatic islet molecules such as GAD glutamic acid decarboxylase (GAD, the biosynthetic enzyme for the neurotransmitter GABA),, insulin, and IA-2/ICA-512 homology with tyrosine phosphatases )and serve as a marker of the autoimmune process of type 1 DM. ICA’s In combination with impaired insulin secretion after IV glucose tolerance testing, they predict a >50% risk of developing type 1 DM within 5 years. Putative environmental triggers include viruses (coxsackie and rubella most prominently), bovine milk proteins, and nitrosourea compounds. The Diabetes Prevention Trial—type 1 concluded that administering insulin (IV or PO) to individuals at high risk for developing type 1 DM did not prevent type 1 DM.
DM2: The concordance of type 2 DM in identical twins is between 70 and 90%. As insulin resistance and compensatory hyperinsulinemia progress, the pancreatic islets in certain individuals are unable to sustain the hyperinsulinemic state. IGT, characterized by elevations in postprandial glucose, then develops. A further decline in insulin secretion and an increase in hepatic glucose production lead to overt diabetes with fasting hyperglycemia. Ultimately, beta cell failure may ensue. Insulin resistance impairs glucose utilization by insulin-sensitive tissues and increases hepatic glucose output; both effects contribute to the hyperglycemia. Increased hepatic glucose output predominantly accounts for increased FPG levels, whereas decreased peripheral glucose usage results in postprandial hyperglycemia. For example, adipocytes secrete a number of biologic products (nonesterified free fatty acids, retinol-binding protein 4, leptin, TNF-, resistin, and adiponectin). In addition to regulating body weight, appetite, and energy expenditure, adipokines also modulate insulin sensitivity. The increased production of free fatty acids and some adipokines may cause insulin resistance in skeletal muscle and liver This lipid storage or steatosis in the liver may lead to nonalcoholic fatty liver disease (Chap. 303) and abnormal liver function tests. This is also responsible for the dyslipidemia found in type 2 DM [elevated triglycerides, reduced high-density lipoprotein (HDL), and increased small dense low-density lipoprotein (LDL) particles
Metabolic syndrome: Two distinct syndromes of severe insulin resistance have been described in adults: (1) type A, which affects young women and is characterized by severe hyperinsulinemia, obesity, and features of hyperandrogenism; and (2) type B, which affects middle-aged women and is characterized by severe hyperinsulinemia, features of hyperandrogenism, and autoimmune disorders
demonstrated that intensive changes in lifestyle (diet and exercise for 30 min/day five times/week) in individuals with IGT prevented or delayed the development of type 2 DM by 58% compared to placebo. metformin prevented or delayed diabetes by 31% compared to placebo. acarbose, metformin, thiazolidinediones, and orlistat prevent or delay type 2 DM but are not approved for this purpose. A recent ADA Consensus panel concluded that metformin, but not other medications, could be considered in individuals with both IFG and IGT who are at very high risk for progression to diabetes.
Six different variants of MODY, caused by mutations in genes encoding islet-enriched transcription factors or glucokinase (Fig. 338-4), are transmitted as autosomal dominant disorders. MODY 1, MODY 3, and MODY 5 are caused by mutations in the hepatocyte nuclear transcription factor (HNF) 4, HNF-1, and HNF-1, respectively. Studies of populations with type 2 DM suggest that mutations in MODY-associated genes are rare (<5%) causes of type 2 DM
C19 steroids have predominantly androgenic activity. The C21 steroids have either glucocorticoid or mineralocorticoid properties.
GlomerularàALDO
Fasiculataà Cortisol
ReticularàAndrogenos DHEA
Normally, <5% style=""> One is a high-affinity, low-capacity 2-globulin termed transcortin or cortisol-binding globulin (CBG), and the other is a low-affinity, high-capacity protein, albumin. CBG is increased in high-estrogen states (e.g., pregnancy, oral contraceptive administration). The rise in CBG is accompanied by a parallel rise in protein-bound cortisol, with the result that the total plasma cortisol concentration is elevated. However, the free cortisol level probably remains normal, and manifestations of glucocorticoid excess are absent. Aldosterone is bound to proteins to a smaller extent than cortisol, and an ultrafiltrate of plasma contains as much as 50% of circulating aldosterone.
The daily secretion of cortisol ranges between 40 and 80 mol (15 and 30 mg; 8–10 mg/m2), with a pronounced circadian cycle. In individuals with normal salt intake, the average daily secretion of aldosterone ranges between 0.1 and 0.7 mol (50 and 250 microg). During a single passage through the liver, >75% of circulating aldosterone is normally inactivated by conjugation with glucuronic acid.
The major androgen secreted by the adrenal is dehydroepiandrosterone (DHEA) and its sulfuric acid ester (DHEAS). Approximately 15–30 mg of these compounds is secreted daily. Glucocorticoids and mineralocorticoids bind with nearly equal affinity to the mineralocorticoid receptor (MR). However, only glucocorticoids bind to the glucocorticoid receptor (GR). Because cortisol binds to the MR with the same affinity as aldosterone, mineralocorticoid specificity is achieved by local metabolism of cortisol to the inactive compound cortisone. glucocorticoid effects of other steroids, such as high-dose progesterone, correlate with their relative binding affinities for the GR.
ACTH physiology: Some related peptides such as -lipotropin (-LPT) are released in equimolar concentrations with ACTH, suggesting that they are cleaved enzymatically from the parent POMC before or during the secretory process. However, -endorphin levels may or may not correlate with circulating levels of ACTH, depending on the nature of the stimulus. adrenergic agonists and -aminobutyric acid (GABA) probably inhibit CRH release.The opioid peptides -endorphin and enkephalin inhibit, and vasopressin and angiotensin II augment, the secretion of CRH and ACTH. Plasma ACTH varies during the day as a result of its pulsatile secretion and follows a circadian pattern, with a peak just prior to waking and a nadir before sleeping. AVP release acts synergistically with CRH to amplify ACTH secretion. For example, inflammatory cytokines [tumor necrosis factor (TNF), interleukin (IL) 1, IL-1, and IL-6] produced by monocytes increase ACTH release by stimulating secretion of CRH and/or AVP. Cortisol decreases the responsiveness of pituitary corticotropic cells to CRH; the response of the POMC mRNA to CRH is also inhibited by glucocorticoids. The biologic half-life of ACTH in the circulation is <10>. The action of ACTH is also rapid; within minutes of its release, the concentration of steroids in the adrenal venous blood increases.
Renine-AT: In addition, angiotensin II stimulates production of aldosterone by the zona glomerulosa of the adrenal cortex. Most of the effects of angiotensins II and III are mediated by the AT1 receptor.
C. yuxtaglomerularesàaumentan renina
Macula densaàdisminuye renina y libera adenosina
High intake of Postassiumàdisminuye renina
control of renin release involves both intrarenal (pressor receptor and macula densa) and extrarenal (sympathetic nervous system, potassium, angiotensin, etc.) mechanisms.
GC: The descriptive term glucocorticoid is used for adrenal steroids whose predominant action is on intermediary metabolism. The actions on protein metabolism are mainly catabolic, resulting in an increase in protein breakdown and nitrogen excretion. Hyperaminoacidemia also facilitates gluconeogenesis by stimulating glucagon secretion.
Glucocorticoids cause a leukocytosis that reflects release from the bone marrow of mature cells as well as inhibition of their egress through the capillary wall. Glucocorticoids produce a depletion of circulating eosinophils and lymphoid tissue, specifically T cells, by causing a redistribution from the circulation into other compartments. Thus, cortisol impairs cell-mediated immunity. Glucocorticoids reduce prostaglandin and leukotriene production by inhibiting the activity of phospholipase A2, thus blocking release of arachidonic acid from phospholipids.
Cortisol has major effects on body water. It helps regulate the ECFV by retarding the migration of water into cells and by promoting renal water excretion. The consequence is to prevent water intoxication by increasing solute-free water clearance. Glucocorticoids can also influence behavior; emotional disorders may occur with either an excess or a deficit of cortisol. Finally, cortisol suppresses the secretion of pituitary POMC and its derivative peptides (ACTH, -endorphin, and -LPT) and the secretion of hypothalamic CRH and vasopressin.
Efectos en epitelio: Aldosterone stimulates all three of these processes by increasing gene expression directly (for the sodium pump and the potassium channels) or via a complex process (for epithelial sodium channels) to increase both the number and activity of the sodium channels. When normal individuals are given aldosterone, an initial period of sodium retention is followed by natriuresis, and sodium balance is reestablished after 3–5 days. As a result, edema does not develop. This process is referred to as the escape phenomenon, signifying an "escape" by the renal tubules from the sodium-retaining action of aldosterone. While renal hemodynamic factors may play a role in the escape, the level of atrial natriuretic peptide also increases. However, it is important to realize that there is no escape from the potassium-losing effects of mineralocorticoids.
1.Efx en no epiteliales: They do not modify sodium-potassium homeostasis.
2.The groups of regulated genes differ, although only a few are known; for example, in nonepithelial cells, aldosterone modifies the expression of several collagen genes controlling tissue growth factors, e.g., transforming growth factor (TGF), plasminogen activator inhibitor, type 1 (PAI-1), adiponectin, and leptin.
3.In some of these tissues (e.g., myocardium and brain), the MR is not protected by the 11-HSD 2 enzyme.
4.Efx no genomicos y genomicos. In the intact organism, some, if not all, of both nongenomic and genomic effects are mediated via an interaction between the MR, aldosterone, and proteins in specialized areas in the target cell's surface membrane termed caveolae . However, caveolin proteins are not always required as aldosterone still produces adverse cardiovascular effects in caveolin-knockout animals.
Na, DAàdecrease ALDO
K, serotonine, ACTHàincrease ALDO
Potassium ion directly stimulates aldosterone secretion, independent of the circulating renin-angiotensin system, which it suppresses. An increase in serum potassium of as little as 0.1 mmol/L increases plasma aldosterone levels under certain circumstances. Oral potassium loading therefore increases aldosterone secretion, plasma levels, and excretion.
Physiologic amounts of ACTH stimulate aldosterone secretion acutely, but this action is not sustained unless ACTH is administered in a pulsatile fashion. Most studies relegate ACTH to a minor role in the control of aldosterone.
Androgenos: Androgens regulate male secondary sexual characteristics and can cause virilizing symptoms in women (Chap. 50). Adrenal androgens have a minimal effect in males whose sexual characteristics are predominately determined by gonadal steroids (testosterone).
A basic assumption is that measurements of the plasma or urinary level of a given steroid reflect the rate of adrenal secretion of that steroid. However, urine excretion values may not truly reflect the secretion rate because of improper collection or altered metabolism. Plasma levels reflect the level of secretion only at the time of measurement. The plasma level (PL) depends on two factors: the secretion rate (SR) of the hormone and the rate at which it is metabolized, i.e., its metabolic clearance rate (MCR).
The plasma levels of ACTH and angiotensin II can be measured by immunoassay techniques. Both upright posture and sodium restriction elevate angiotensin II levels. PRA plasma rennin activity and active renin correlate very well on low-sodium diets but less well on high-sodium diets.
Measurement of the sulfate conjugate of DHEA may be a useful index of adrenal androgen secretion, as little DHEA sulfate is formed in the gonads and because the half-life of DHEA sulfate is 7–9 h. However, DHEA sulfate levels reflect both DHEA production and sulfatase activity.
Urine:Elevated levels of urinary free cortisol correlate with states of hypercortisolism, reflecting changes in the levels of unbound, physiologically active circulating cortisol. Urinary 17-ketosteroids originate in either the adrenal gland or the gonad. In normal women, 90% of urinary 17-ketosteroids is derived from the adrenal, and in men 60–70% is of adrenal origin.
Stimulation tests:
GCàA screening test (the so-called rapid ACTH stimulation test) involves the administration of 25 units (0.25 mg) of cosyntropin IV or IM and measurement of plasma cortisol levels before administration and 30 and 60 min after administration; the test can be performed at any time of the day. The most clear-cut criterion for a normal response is a stimulated cortisol level of >500 nmol/L (>18 microg/dL), and the minimal stimulated normal increment of cortisol is >200 nmol/L (>7 microg/dL) above baseline. Severely ill patients with elevated basal cortisol levels may show no further increases following acute ACTH administration.
MC: Stimulation tests use protocols designed to create a programmed volume depletion, such as sodium restriction, diuretic administration, or upright posture. A simple, potent test consists of severe sodium restriction and upright posture. After 3–5 days of a 10-mmol/d sodium intake, rates of aldosterone secretion or excretion should increase two- to threefold over the control values. Supine morning plasma aldosterone levels are usually increased three- to sixfold, and they increase a further two- to fourfold in response to 2–3 h of upright posture.
Suppression Tests
Suppression tests to document hypersecretion of adrenal hormones involve measurement of the target hormone response after standardized suppression of its tropic hormone. The best screening procedure is the overnight dexamethasone suppression test. This involves the measurement of plasma cortisol levels at 8 A.M. following the oral administration of 1 mg dexamethasone the previous midnight. The 8 A.M. value for plasma cortisol in normal individuals should be <140>).
The definitive test of adrenal suppressibility (Liddle) involves administering 0.5 mg dexamethasone every 6 h for two successive days while collecting urine over a 24-h period for determination of creatinine and free cortisol and/or measuring plasma cortisol levels. In a patient with a normal hypothalamic-pituitary ACTH release mechanism, a fall in the urine free cortisol to <25>.
A normal response to either suppression test implies that the glucocorticoid regulation of ACTH and its control of the adrenal glands is physiologically normal. However, an isolated abnormal result, particularly to the overnight suppression test, does not in itself demonstrate pituitary and/or adrenal disease.
MC: These tests rely on an expansion of ECFV, which should decrease circulating plasma renin activity and decrease the secretion and/or excretion of aldosterone. Various tests differ in the rate at which ECFV is expanded. One convenient suppression test involves the IV infusion of 500 mL/h of normal saline solution for 4 h, which normally suppresses plasma aldosterone levels to <220>. Alternatively, a high-sodium diet can be administered for 3 days with 0.2 mg fludrocortisone twice daily. Aldosterone excretion is measured on the third day and should be <28 style="background: yellow none repeat scroll 0% 0%; -moz-background-clip: -moz-initial; -moz-background-origin: -moz-initial; -moz-background-inline-policy: -moz-initial;">These tests should not be performed in potassium-depleted individuals since they carry a risk of precipitating hypokalemia.
Respuesta pituitario-adrenal: Stimuli such as insulin-induced hypoglycemia, AVP, and pyrogens induce the release of ACTH from the pituitary by an action on higher neural centers or on the pituitary itself. Insulin-induced hypoglycemia is particularly useful, because it stimulates the release of both growth hormone and ACTH. In this test, regular insulin (0.05–0.1 U/kg body weight) is given intravenously as a bolus to reduce the fasting glucose level to at least 50% below basal. The normal cortisol response is a rise to >500 nmol/L (18 microg/dL). Glucose levels must be monitored during insulin-induced hypoglycemia, and it should be terminated by feeding or IV glucose, if subjects develop symptoms of hypoglycemia. This test is contraindicated in individuals with coronary artery disease or a seizure disorder.
Metyrapone inhibits 11a-hydroxylase in the adrenal. As a result, the conversion of 11-deoxycortisol (compound S) to cortisol is impaired, causing 11-deoxycortisol to accumulate in the blood and the blood level of cortisol to decrease (Fig. 336-2). The hypothalamic-pituitary axis responds to the declining cortisol blood levels by releasing more ACTH. Note that assessment of the response depends on both an intact hypothalamic-pituitary axis and an intact adrenal gland. Although modifications of the original metyrapone test have been described, a commonly used protocol involves administering 750 mg of the drug by mouth every 4 h over a 24-h period and comparing the control and postmetyrapone plasma levels of 11-deoxycortisol, cortisol, and ACTH. In normal individuals, plasma 11-deoxycortisol levels should be >210 nmol/L (7 microg/dL) and ACTH levels should be >17 pmol/L (75 pg/mL) following metyrapone administration.
The rapid ACTH test can often distinguish between primary and secondary adrenal insufficiency, because aldosterone secretion is preserved in secondary adrenal failure by the renin-angiotensin system and potassium. Cosyntropin (25 units) is given IV or IM, and plasma cortisol and aldosterone levels are measured before and at 30 and 60 min after administration. The cortisol response is abnormal in both groups, but patients with secondary insufficiency show an increase in aldosterone levels of at least 140 pmol/L (5 ng/dL). No aldosterone response is seen in patients in whom the adrenal cortex is destroyed.
Cushing
In most cases, the cause is bilateral adrenal hyperplasia due to hypersecretion of pituitary ACTH or ectopic production of ACTH by a nonpituitary source. The incidence of pituitary-dependent adrenal hyperplasia is three times greater in women than in men, and the most frequent age of onset is the third or fourth decade. Most evidence indicates that the primary defect is the de novo development of a pituitary adenoma, as tumors are found in >90% of patients with pituitary-dependent adrenal hiperplasia. In surgical series, most individuals with hypersecretion of pituitary ACTH are found to have a microadenoma. , only an individual who has an ACTH-producing pituitary tumor is defined as having Cushing's disease, whereas Cushing's syndrome refers to all causes of excess cortisol: exogenous ACTH tumor, adrenal tumor, pituitary ACTH-secreting tumor, or excessive glucocorticoid treatment. The typical signs and symptoms of Cushing's syndrome may be absent or minimal with ectopic ACTH production, and hypokalemic alkalosis is a prominent manifestation. onset of Cushing's syndrome may be sudden, particularly in patients with carcinoma of the lung, and this feature accounts in part for the failure of these patients to exhibit the classic manifestations. On the other hand, patients with carcinoid tumors or pheochromocytomas have longer clinical courses and usually exhibit the typical cushingoid features.
The most common cause of Cushing's syndrome is iatrogenic administration of steroids for a variety of reasons.
Some signs and symptoms in patients with hypercortisolism—i.e., obesity, hypertension, osteoporosis, weakness and fatigability, and diabetes—are nonspecific and therefore are less helpful in diagnosing the condition. On the other hand, easy bruising, violaceus striae, proximal myopathy, and virilizing signs (like, amenorrea, hirsutism and acne; although less frequent) are, if present, more suggestive of Cushing's síndrome. Hypercortisolism promotes the deposition of adipose tissue in characteristic sites, notably the upper face (producing the typical "moon" facies), the interscapular area (producing the "buffalo hump"), supraclavicular fat pads, and the mesenteric bed (producing "truncal" obesity).
Dx: For initial screening, the overnight dexamethasone suppression test is recommended (see above). In difficult cases (e.g., in obese or depressed patients), measurement of a 24-h urine free cortisol can also be used as a screening test. A level >140 nmol/d (50 microg/d) is suggestive of Cushing's syndrome. The definitive diagnosis is then established by failure of urinary cortisol to fall to <25>). Plasma ACTH levels can be useful in distinguishing the various causes of Cushing's syndrome, particularly in separating ACTH-dependent from ACTH-independent causes.
When the diagnosis of Cushing's syndrome is clear-cut on the basis of baseline urinary and plasma assays, the high-dose dexamethasone suppression test may be used without performing the preliminary low-dose suppression test. high-dose suppression test provides close to 100% specificity if the criterion used is suppression of urinary free cortisol by >90%. Failure of low- and high-dose dexamethasone administration to suppress cortisol production (Table 336-4) can occur in patients with adrenal hyperplasia secondary to an ACTH-secreting pituitary macroadenoma or an ACTH-producing tumor of nonendocrine origin and in those with adrenal neoplasms. , most patients with pituitary-hypothalamic dysfunction and/or a microadenoma have an increase in steroid or ACTH secretion in response to metyrapone or CRH administration, whereas most patients with ectopic ACTH-producing tumors do not.
The main diagnostic dilemma in Cushing's syndrome is to distinguish those instances due to microadenomas of the pituitary from those due to ectopic sources (e.g., carcinoids or pheochromocytoma) that produce CRH and/or ACTH. The clinical manifestations are similar unless the ectopic tumor produces other symptoms, such as diarrhea and flushing from a carcinoid tumor or episodic hypertension from a pheochromocytoma. Sometimes, one can distinguish between ectopic and pituitary ACTH production by using metyrapone or CRH tests, as noted above.
The diagnosis of a cortisol-producing adrenal adenoma is suggested by low ACTH and disproportionate elevations in baseline urine free cortisol levels with only modest changes in urinary 17-ketosteroids or plasma DHEA sulfate. Adrenal androgen secretion is usually reduced in these patients owing to the cortisol-induced suppression of ACTH and subsequent involution of the androgen-producing zona reticularis
The diagnosis of adrenal carcinoma is suggested by a palpable abdominal mass and by markedly elevated baseline values of both urine 17-ketosteroids and plasma DHEA sulfate. Plasma and urine cortisol levels are variably elevated. Adrenal carcinoma is usually resistant to both ACTH stimulation and dexamethasone suppression. Elevated adrenal androgen secretion often leads to virilization in the female.
Pseudocushing: Patients with chronic alcoholism and those with depression share similar abnormalities in steroid output: modestly elevated urine cortisol, blunted circadian rhythm of cortisol levels, and resistance to suppression using the overnight dexamethasone test. Iatrogenic:The distinction can be made, however, by measuring blood or urine cortisol levels in a basal state; in the iatrogenic syndrome these levels are low secondary to suppression of the pituitary-adrenal axis. The severity of iatrogenic Cushing's syndrome is related to the total steroid dose, the biologic half-life of the steroid, and the duration of therapy. Also, individuals taking afternoon and evening doses of glucocorticoids develop Cushing's syndrome more readily and with a smaller total daily dose than do patients taking morning doses only.
This is not surprising since ~6% of adult/elderly subjects at autopsy have adrenocortical adenomas. However, the prevalence of incidental adenomas is age-dependent, i.e., cortical adenomas are very uncommon in individuals <30>. The next step is to determine whether the tumor is functioning, although the great majority (70–80%) are nonsecretory. All patients with incidentally discovered masses should be screened for pheochromocytoma. the probability of ACC is very low (<0.01%),>
Primary Aldosteronism with an Adrenal Tumor
In the original descriptions of excessive and inappropriate aldosterone production, the disease was the result of an aldosterone-producing adrenal adenoma (Conn's syndrome).Most cases involve a unilateral adenoma, which is usually small and may occur on either side. Rarely, primary aldosteronism is due to an adrenal carcinoma. Aldosteronism is twice as common in women as in men, usually occurs between the ages of 30 and 50, and is present in ~1% of unselected hypertensive patients
Without tumor
In many patients with clinical and biochemical features of primary aldosteronism, a solitary adenoma is not found at surgery. Instead, these patients have bilateral cortical nodular hyperplasia. In the literature, this disease is also termed idiopathic hyperaldosteronism, and/or nodular hiperplasia. In contrast to patients with an aldosteronoma, those with bilateral hyperplasia are unlikely to have hypokalemia and usually have lower levels of aldosterone and less radiologic evidence for adrenal pathology. They constitute perhaps as many as 80% of patients with primary aldosteronism.
Signs: Hypersecretion of aldosterone increases the renal distal tubular exchange of intratubular sodium for secreted potassium and hydrogen ions, with progressive depletion of body potassium and development of hypokalemia. Most patients have diastolic hypertension, which may be very severe, and headaches(cramps, paresthesias, muscular weakness, renal insipid diabetes, arrhythmyas and secondary DM). some individuals with mild disease, particularly most with the bilateral hyperplasia type, may have potassium levels in the low normal range and therefore have no symptoms associated with hypokalemia. edema is characteristically absent(Patients with primary aldosteronism characteristically do not have edema, since they exhibit an "escape" phenomenon from the sodium-retaining aspects of mineralocorticoids). However, structural damage to the cerebral circulation, retinal vasculature, and kidney occurs more frequently than would be predicted based on the level and duration of the hypertension.
Hypokalemia may be severe (<3>300 mmol. In mild forms of primary aldosteronism, potassium levels may be normal. Hypernatremia is infrequent but may be caused by sodium retention, concomitant water loss from polyuria, and resetting of the osmostat. Metabolic alkalosis and elevation of serum bicarbonate are caused by hydrogen ion loss into the urine and migration into potassium-depleted cells. The alkalosis is perpetuated by potassium deficiency, which increases the capacity of the proximal convoluted tubule to reabsorb filtered bicarbonate. If hypokalemia is severe, serum magnesium levels are also reduced
Dx: The criteria for the diagnosis of primary aldosteronism are (1) diastolic hypertension without edema, (2) hyposecretion of renin (as judged by low plasma renin activity levels) that fails to increase appropriately during volume depletion (upright posture, sodium depletion), and (3) hypersecretion of aldosterone that does not suppress appropriately in response to volume expansion. Ultimately, it is necessary to demonstrate a lack of aldosterone suppression to diagnose primary aldosteronism.
A useful maneuver to distinguish between these conditions is the measurement of plasma renin activity. Secondary hyperaldosteronism in patients with accelerated hypertension is due to elevated plasma renin levels; in contrast, patients with primary aldosteronism have suppressed plasma renin levels. Indeed, in patients with a serum potassium concentration <>. The most common problem is to distinguish between hyperaldosteronism due to an adenoma and that due to idiopathic bilateral nodular hyperplasia. This distinction is important because hypertension associated with idiopathic hyperplasia does not usually benefit from bilateral adrenalectomy, whereas hypertension associated with aldosterone-producing tumors is usually improved or cured by removal of the adenoma. A definitive diagnosis is best made by radiographic studies, including bilateral adrenal vein catheterization.
Primary aldosteronism due to an adenoma is usually treated by surgical excision of the adenoma. Where possible, a laparoscopic approach is favored. However, dietary sodium restriction and the administration of an aldosterone antagonist—e.g., spironolactone—are effective in many cases. When idiopathic bilateral hyperplasia is suspected, surgery is indicated only when significant, symptomatic hypokalemia cannot be controlled with medical therapy, i.e., by spironolactone, eplerenone, triamterene, or amiloride. Hypertension associated with idiopathic hyperplasia is usually not benefited by bilateral adrenalectomy.
2ª HiperALDO: Secondary aldosteronism refers to an appropriately increased production of aldosterone in response to activation of the renin-angiotensin system (Fig. 336-11). The production rate of aldosterone is often higher in patients with secondary aldosteronism than in those with primary aldosteronism. Secondary hypersecretion of renin can be due to a narrowing of one or both of the major renal arteries by atherosclerosis or by fibromuscular hiperplasia. The secondary aldosteronism is characterized by hypokalemic alkalosis, moderate to severe increases in plasma renin activity, and moderate to marked increases in aldosterone levels. Secondary aldosteronism with hypertension can also be caused by rare renin-producing tumors (primary reninism). 2º HyperALDO is also present in edemas of renal, heart or liver origin.
FunnyNote: Several clinical trials support these experimental results. In the RALES trial, patients with class II/IV heart failure were randomized to standard care or a low dose of the MR antagonist, spironolactone. There was a 30% reduction in all-cause mortality and cardiovascular mortality and hospitalizations after 36 months.
ADISSON
Acquired forms of primary insufficiency are relatively rare, may occur at any age, and affect both sexes equally. Because of the common therapeutic use of steroids, secondary adrenal insufficiency is relatively common. In early series, tuberculosis was responsible for 70–90% of cases, but the most frequent cause now is idiopathic atrophy, and an autoimmune mechanism is probably responsable. Some patients also have antibodies to thyroid, parathyroid, and/or gonadal tissue (Chap. 345). There is also an increased incidence of chronic lymphocytic thyroiditis, premature ovarian failure, type 1 diabetes mellitus, and hypo- or hyperthyroidism. The presence of two or more of these autoimmune endocrine disorders in the same person defines the polyglandular autoimmune syndrome type II. The combination of parathyroid and adrenal insufficiency and chronic mucocutaneous candidiasis constitutes type I polyglandular autoimmune síndrome.
Clinical suspicion of adrenal insufficiency should be high in patients with AIDS (Chap. 182). CMV regularly involves the adrenal glands (so-called CMV necrotizing adrenalitis), and involvement with Mycobacterium avium-intracellulare, Cryptococcus, and Kaposi's sarcoma has been reported.
Clinic: Adrenocortical insufficiency caused by gradual adrenal destruction is characterized by an insidious onset of fatigability, weakness, anorexia, nausea and vomiting, weight loss, cutaneous and mucosal pigmentation, hypotension, and occasionally hypoglycemia. Hyperpigmentation may be striking or absent. It commonly appears as a diffuse brown, tan, or bronze darkening of parts such as the elbows or creases of the hand and of areas that normally are pigmented such as the areolae about the nipples. Bluish-black patches may appear on the mucous membranes. Some patients develop dark freckles, and irregular areas of vitiligo may paradoxically be present. As an early sign, tanning following sun exposure may be persistent.
Arterial hypotension with postural accentuation is frequent, and blood pressure may be in the range of 80/50 or less.
Abnormalities of gastrointestinal function are often the presenting complaint. Symptoms vary from mild anorexia with weight loss to fulminating nausea, vomiting, diarrhea, and ill-defined abdominal pain, which may be so severe as to be confused with an acute abdomen. Patients may have personality changes, usually consisting of excessive irritability and restlessness. Enhancement of the sensory modalities of taste, olfaction, and hearing is reversible with therapy. Axillary and pubic hair may be decreased in women due to loss of adrenal androgens
Basal levels of cortisol and aldosterone are subnormal and fail to increase following ACTH administration. In brief, the best screening test is the cortisol response 60 min after 250 g of cosyntropin given IM or IV. Cortisol levels should be >495 nmol/L (18 microg/dL). If the response is abnormal, then primary and secondary adrenal insufficiency can be distinguished by measuring aldosterone levels from the same blood samples. In secondary, but not primary, adrenal insufficiency, the aldosterone increment will be normal [150 pmol/L (5 ng/dL)]. Furthermore, in primary adrenal insufficiency, plasma ACTH and associated peptides (-LPT) are elevated because of loss of the usual cortisol-hypothalamic-pituitary feedback relationship, whereas in secondary adrenal insufficiency, plasma ACTH values are low or "inappropriately" normal.
Racial pigmentation may be a confounding feature, but a recent and progressive increase in pigmentation is usually reported by the patient with gradual adrenal destruction.
Treatment: Hydrocortisone (cortisol) is the mainstay of treatment. The dose for most adults (depending on size) is 20–30 mg/d. Patients are advised to take glucocorticoids with meals or, if that is impractical, with milk or an antacid, because the drugs may increase gastric acidity and exert direct toxic effects on the gastric mucosa. To simulate the normal diurnal adrenal rhythm, two-thirds of the dose is taken in the morning, and the remaining one-third is taken in the late afternoon. MC effect: This is accomplished by the administration of 0.05–0.1 mg fludrocortisone per day PO. Patients should also be instructed to maintain an ample intake of sodium (3–4 g/d). In female patients with adrenal insufficiency, androgen levels are also low. Thus, some physicians believe that daily replacement with 25–50 mg of DHEA PO may improve quality of life and bone mineral density.
During periods of intercurrent illness, especially in the setting of fever, the dose of hydrocortisone should be doubled. With severe illness it should be increased to 75–150 mg/d. When oral administration is not possible, parenteral routes should be employed.
2º AI: Patients with secondary adrenocortical hypofunction have many symptoms and signs in common with those having primary disease but are not hyperpigmented. Patients with total pituitary insufficiency have manifestations of multiple hormone deficiencies. An additional feature distinguishing primary adrenocortical insufficiency is the near-normal level of aldosterone secretion seen in pituitary and/or isolated ACTH deficiencies. Patients receiving long-term steroid therapy, despite physical findings of Cushing's syndrome, may develop adrenal insufficiency because of prolonged pituitary-hypothalamic suppression and adrenal atrophy secondary to the loss of endogenous ACTH. These patients have two deficits, a loss of adrenal responsiveness to ACTH and a failure of pituitary ACTH release.
Acute adrenocortical insufficiency may result from several processes. On the one hand, adrenal crisis may be a rapid and overwhelming intensification of chronic adrenal insufficiency, usually precipitated by sepsis or surgical stress. Alternatively, acute hemorrhagic destruction of both adrenal glands can occur in previously well individuals. In children, this event is usually associated with septicemia with Pseudomonas or meningococcemia (Waterhouse-Friderichsen syndrome). The third and most frequent cause of acute insufficiency is the rapid withdrawal of steroids from patients with adrenal atrophy owing to chronic steroid administration
