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Endocrine diseases can be divided into three major types of conditions: (1) hormone excess, (2) hormone deficiency, and (3) hormone resistance (Table 1-1).
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CAUSES OF HORMONE EXCESS
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Syndromes of hormone excess can be caused by neoplastic growth of endocrine cells, autoimmune disorders, and excess hormone administration. Benign endocrine tumors, including parathyroid, pituitary, and adrenal adenomas, often retain the capacity to produce hormones, perhaps reflecting the fact that these tumors are relatively well differentiated. Many endocrine tumors exhibit subtle defects in their “set points” for feedback regulation. For example, in Cushing’s disease, impaired feedback inhibition of adrenocorticotropic hormone (ACTH) secretion is associated with autonomous function. However, the tumor cells are not completely resistant to feedback, as evidenced by ACTH suppression by higher doses of dexamethasone (e.g., high-dose dexamethasone test) (Chap. 8). Similar set point defects are also typical of parathyroid adenomas and autonomously functioning thyroid nodules.
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The molecular basis of some endocrine tumors, such as the multiple endocrine neoplasia (MEN) syndromes (MEN 1, 2A, 2B), have provided important insights into tumorigenesis (Chap. 29). MEN 1 is characterized primarily by the triad of parathyroid, pancreatic islet, and pituitary tumors. MEN 2 predisposes to medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. The MEN1 gene, located on chromosome 11q13, encodes a putative tumor-suppressor gene, menin. Analogous to the paradigm first described for retinoblastoma, the affected individual inherits a mutant copy of the MEN1 gene, and tumorigenesis ensues after a somatic “second hit” leads to loss of function of the normal MEN1 gene (through deletion or point mutations).
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In contrast to inactivation of a tumor-suppressor gene, as occurs in MEN 1 and most other inherited cancer syndromes, MEN 2 is caused by activating mutations in a single allele. In this case, activating mutations of the RET protooncogene, which encodes a receptor tyrosine kinase, leads to thyroid C cell hyperplasia in childhood before the development of medullary thyroid carcinoma. Elucidation of this pathogenic mechanism has allowed early genetic screening for RET mutations in individuals at risk for MEN 2, permitting identification of those who may benefit from prophylactic thyroidectomy and biochemical screening for pheochromocytoma and hyperparathyroidism.
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Mutations that activate hormone receptor signaling have been identified in several GPCRs. For example, activating mutations of the luteinizing hormone (LH) receptor cause a dominantly transmitted form of male-limited precocious puberty, reflecting premature stimulation of testosterone synthesis in Leydig cells (Chap. 11). Activating mutations in these GPCRs are located predominantly in the transmembrane domains and induce receptor coupling to Gsα even in the absence of hormone. Consequently, adenylate cyclase is activated, and cyclic adenosine monophosphate (AMP) levels increase in a manner that mimics hormone action. A similar phenomenon results from activating mutations in Gsα. When these mutations occur early in development, they cause McCune-Albright syndrome. When they occur only in somatotropes, the activating Gsα mutations cause GH-secreting tumors and acromegaly (Chap. 5).
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In autoimmune Graves’ disease, antibody interactions with the thyroid-stimulating hormone (TSH) receptor mimic TSH action, leading to hormone overproduction (Chap. 7). Analogous to the effects of activating mutations of the TSH receptor, these stimulating autoantibodies induce conformational changes that release the receptor from a constrained state, thereby triggering receptor coupling to G proteins.
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CAUSES OF HORMONE DEFICIENCY
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Most examples of hormone deficiency states can be attributed to glandular destruction caused by autoimmunity, surgery, infection, inflammation, infarction, hemorrhage, or tumor infiltration (Table 1-1). Autoimmune damage to the thyroid gland (Hashimoto’s thyroiditis) and pancreatic islet β cells (type 1 diabetes mellitus) is a prevalent cause of endocrine disease. Mutations in a number of hormones, hormone receptors, transcription factors, enzymes, and channels can also lead to hormone deficiencies.
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Most severe hormone resistance syndromes are due to inherited defects in membrane receptors, nuclear receptors, or the pathways that transduce receptor signals. These disorders are characterized by defective hormone action despite the presence of increased hormone levels. In complete androgen resistance, for example, mutations in the androgen receptor result in a female phenotypic appearance in genetic (XY) males, even though LH and testosterone levels are increased (Chap. 29). In addition to these relatively rare genetic disorders, more common acquired forms of functional hormone resistance include insulin resistance in type 2 diabetes mellitus, leptin resistance in obesity, and GH resistance in catabolic states. The pathogenesis of functional resistance involves receptor downregulation and postreceptor desensitization of signaling pathways; functional forms of resistance are generally reversible.
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CLINICAL EVALUATION OF ENDOCRINE DISORDERS
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Because most glands are relatively inaccessible, the physical examination usually focuses on the manifestations of hormone excess or deficiency as well as direct examination of palpable glands, such as the thyroid and gonads. For these reasons, it is important to evaluate patients in the context of their presenting symptoms, review of systems, family and social history, and exposure to medications that may affect the endocrine system. Astute clinical skills are required to detect subtle symptoms and signs suggestive of underlying endocrine disease. For example, a patient with Cushing’s syndrome may manifest specific findings, such as central fat redistribution, striae, and proximal muscle weakness, in addition to features seen commonly in the general population, such as obesity, plethora, hypertension, and glucose intolerance. Similarly, the insidious onset of hypothyroidism—with mental slowing, fatigue, dry skin, and other features—can be difficult to distinguish from similar, nonspecific findings in the general population. Clinical judgment that is based on knowledge of disease prevalence and pathophysiology is required to decide when to embark on more extensive evaluation of these disorders. Laboratory testing plays an essential role in endocrinology by allowing quantitative assessment of hormone levels and dynamics. Radiologic imaging tests such as computed tomography (CT) scan, magnetic resonance imaging (MRI), thyroid scan, and ultrasound are also used for the diagnosis of endocrine disorders. However, these tests generally are employed only after a hormonal abnormality has been established by biochemical testing.
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HORMONE MEASUREMENTS AND ENDOCRINE TESTING
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Immunoassays are the most important diagnostic tool in endocrinology, as they allow sensitive, specific, and quantitative determination of steady-state and dynamic changes in hormone concentrations. Immunoassays use antibodies to detect specific hormones. For many peptide hormones, these measurements are now configured to use two different antibodies to increase binding affinity and specificity. There are many variations of these assays; a common format involves using one antibody to capture the antigen (hormone) onto an immobilized surface and a second antibody, coupled to a chemiluminescent (immunochemiluminescent assay [ICMA]) or radioactive (immunoradiometric assay [IRMA]) signal, to detect the antigen. These assays are sensitive enough to detect plasma hormone concentrations in the picomolar to nanomolar range, and they can readily distinguish structurally related proteins, such as PTH from PTH-related peptide (PTHrP). A variety of other techniques are used to measure specific hormones, including mass spectroscopy, various forms of chromatography, and enzymatic methods; bioassays are now rarely used.
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Most hormone measurements are based on plasma or serum samples. However, urinary hormone determinations remain useful for the evaluation of some conditions. Urinary collections over 24 h provide an integrated assessment of the production of a hormone or metabolite, many of which vary during the day. It is important to assure complete collections of 24-h urine samples; simultaneous measurement of creatinine provides an internal control for the adequacy of collection and can be used to normalize some hormone measurements. A 24-h urine free cortisol measurement largely reflects the amount of unbound cortisol, thus providing a reasonable index of biologically available hormone. Other commonly used urine determinations include 17-hydroxycorticosteroids, 17-ketosteroids, vanillylmandelic acid, metanephrine, catecholamines, 5-hydroxyindoleacetic acid, and calcium.
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The value of quantitative hormone measurements lies in their correct interpretation in a clinical context. The normal range for most hormones is relatively broad, often varying by a factor of two- to tenfold. The normal ranges for many hormones are sex- and age-specific. Thus, using the correct normative database is an essential part of interpreting hormone tests. The pulsatile nature of hormones and factors that can affect their secretion, such as sleep, meals, and medications, must also be considered. Cortisol values increase fivefold between midnight and dawn; reproductive hormone levels vary dramatically during the female menstrual cycle.
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For many endocrine systems, much information can be gained from basal hormone testing, particularly when different components of an endocrine axis are assessed simultaneously. For example, low testosterone and elevated LH levels suggest a primary gonadal problem, whereas a hypothalamic-pituitary disorder is likely if both LH and testosterone are low. Because TSH is a sensitive indicator of thyroid function, it is generally recommended as a first-line test for thyroid disorders. An elevated TSH level is almost always the result of primary hypothyroidism, whereas a low TSH is most often caused by thyrotoxicosis. These predictions can be confirmed by determining the free thyroxine level. In the less common circumstance when free thyroxine and TSH are both low, it is important to consider secondary hypopituitarism caused by hypothalamic-pituitary disease. Elevated calcium and PTH levels suggest hyperparathyroidism, whereas PTH is suppressed in hypercalcemia caused by malignancy or granulomatous diseases. A suppressed ACTH in the setting of hypercortisolemia, or increased urine free cortisol, is seen with hyperfunctioning adrenal adenomas.
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It is not uncommon, however, for baseline hormone levels associated with pathologic endocrine conditions to overlap with the normal range. In this circumstance, dynamic testing is useful to separate the two groups further. There are a multitude of dynamic endocrine tests, but all are based on principles of feedback regulation, and most responses can be rationalized based on principles that govern the regulation of endocrine axes. Suppression tests are used in the setting of suspected endocrine hyperfunction. An example is the dexamethasone suppression test used to evaluate Cushing’s syndrome (Chaps. 5 and 8). Stimulation tests generally are used to assess endocrine hypofunction. The ACTH stimulation test, for example, is used to assess the adrenal gland response in patients with suspected adrenal insufficiency. Other stimulation tests use hypothalamic-releasing factors such as corticotropin-releasing hormone (CRH) and growth hormone–releasing hormone (GHRH) to evaluate pituitary hormone reserve (Chap. 5). Insulin-induced hypoglycemia also evokes pituitary ACTH and GH responses. Stimulation tests based on reduction or inhibition of endogenous hormones are now used infrequently. Examples include metyrapone inhibition of cortisol synthesis and clomiphene inhibition of estrogen feedback.
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SCREENING AND ASSESSMENT OF COMMON ENDOCRINE DISORDERS
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Many endocrine disorders are prevalent in the adult population (Table 1-2) and can be diagnosed and managed by general internists, family practitioners, or other primary health care providers. The high prevalence and clinical impact of certain endocrine diseases justifies vigilance for features of these disorders during routine physical examinations; laboratory screening is indicated in selected high-risk populations.
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