PATHOPHYSIOLOGYOF ENDOCRINE DISEASES

Endocrine diseases can occur on a congenital, often genetic, basis or can be acquired. Many of the congenital abnormalities are from mutations that result in structural abnormalities, defects in hormone biosynthesis, or abnormalities in hormone-receptor structure or postreceptor signaling mechanisms. Tables 1 and 2 provide examples of identified mutations that result in over-and underexpression of hormone action. Most endocrine diseases are acquired and fit broadly into the categories of neoplasia, destruction or impairment of function of the endocrine gland through infection, infiltrative processes, vascular disorders, trauma, or immune-mediated injury, as well as functional aberrations owing to multiorgan dysfunction, metabolic abnormalities, or drugs.

These processes may disrupt the biosynthesis of protein hormones through interference with transcription, mRNA processing, translation, posttranslational protein modifications, protein storage, degradation, or secretion. Abnormalities in steroid hormone, thyroid

Table 1

Examples of Mutations That Cause Endocrine Hyperfunction

Disorder


Type of mutation

Membrane receptor

•  TSH receptor constitutive activation

•  LH/hCG receptor constitutive activation

•  Calcium-sensing receptor defect Signal pathway

•  Pituitary Gsa activation

•  Thyroid Gsa activation

•  Generalized Gsa activation

•  Temperature-sensitive Gsa activation

•  Thyroid p53

•  Ret protooncogene

•  Cyclin D1 fusion to PTH promoter (PRAD-1) activation

•  (PRAD-1) activation

•  Gja (gip oncogene in adrenal and ovaries)

•  MENIN gene

Enzyme

•  Aldosterone synthase-jjp-hydroxylase chimera

Thyroid adenoma; hyperthyroidism

Familial male precocious puberty (testotoxicosis)

Familial hypocalciuric hypocalcemia; neonatal hyperparathyroidism

Acromegaly

Thyroid adenoma; hyperthyroidism McCune-Albright syndrome Testotoxicosis and pseudohypoparathyroidism Neoplasia MEN 2a

Parathyroid adenoma

Adrenocortical and ovarian tumors MEN 1

Glucocorticoid-remediable hypertension

Hormone, and calcitriol production may result from loss of the orderly enzymatic conversion of precursor molecules into active hormones. Many disease states as well as medications may alter the transport and metabolism of hormones. Finally, there is a multitude of lesions that can affect hormone-receptor interaction, as well as postreceptor signal pathways. From a functional standpoint, clinical endocrine disease can be broadly classified into diseases of the endocrine glands that are not associated with hormonal dysfunction, diseases from overexpression of hormone action, and diseases characterized by underexpression of hormone action (Table 3). Occasionally, situations exist in which endocrine testing with immunoassays detects elevated hormones, but no clinical endocrine syndrome is apparent. An example of this is so-called idiopathic hyperprolactinemia, in which prolactin (PRL) is bound by a circulating immunoglobulin or the PRL protein is modified by glycation resulting in delayed degradation and excretion of often biologically inactive PRL. Endocrine diseases without hormonal aberrations are generally nonfunctional neoplasms such as thyroid carcinoma or the frequently found incidental pituitary and adrenal adenomas. These neoplasms generally cause symptoms through their anatomic effects on the surrounding structures or, in the case of some malignant neoplasms, through their metastases.

2.1. Overexpression of Hormone

Most endocrine disorders that result in overexpression of hormone action do so through excessive produc-

Table 3

Pathophysiology of Endocrine Diseases

Neoplastic growth of endocrine glands without hyper-or hypofunction.

Overexpression of hormone action

•  Excessive production of hormones

¦  Eutopic

¦  Autonomous

¦  Excessive physiologic stimulation

¦  Altered regulatory feedback set point

¦  Ectopic

¦  Direct secretion by tumor

¦  Indirect

¦  Dysregulation

•  Excessive activation of hormone receptors

Constitutively activated receptors Hormone mimicry Receptor crossreactivity

•  Postreceptor activation of hormone action

•  Altered metabolism of hormones Underexpression of hormone action

•  Aplasia or hypoplasia of hormone source

•  Acquired destruction of source of hormone

•  Congenital absence of hormone

•  Production of inactive forms of hormone

•  Substrate insufficiency

•  Destruction of target organ

•  Enzyme defects in hormone production

•  Antihormone antibodies

•  Hormone resistance Absent or altered receptor

•  Receptor occupancy

•  Downregulation of normal receptors

•  Postreceptor defects Altered metabolism of hormones

Table 2

Examples of Mutations That Cause Endocrine Hypofunction

T-ype of mutation

Disorder

Hormone/hormone precursor • GH gene deletion

Growth retardation

• TSH P-subunit gene

Hypothyroidism

• LH P-subunit gene

Hypogonadism

• Neurophysin/ADH processing

Central diabetes insipidus

• PTH processing

Hypoparathyroidism

• Proinsulin processing

Diabetes mellitus

• Insulin gene

Diabetes mellitus

• Thyroglobulin

Hypothyroidism with goiter

Membrane receptor • GH

Laron dwarfism

• TSH

Hypothyroidism

• LH/hCG

Resistant testes syndrome

• FSH

Resistant ovary syndrome

• ACTH

Familial glucocorticoid deficiency

• Vasopressin V2

NDI

• PTH

Pseudohypoparathyroidism

• Insulin

Insulin resistance

• P3-adrenergic

Obesity

Nuclear receptor • Thyroid hormone

Thyroid hormone resistance syndrome (generalized or pituitary)

• Glucocorticoid

Glucocorticoid resistance syndrome

• Androgen

Androgen insensitivity syndromes

• Estrogen

Delayed epiphyseal closure, osteoporosis

• Mineralocorticoid

Generalized pseudohypoaldosteronism

• Progesterone

Progesterone resistance

• Vitamin D

Vitamin D-resistant rickets

• DAX-1, SF-1

X-linked adrenal hypoplasia congenital

Signal pathway • Gsa inactivation

Albright hereditary osteodystrophy

Transcription factors • SRY translocation

(pseudohypoparathyroidism with resistance to PTH, TSH, gonadotropins) XX male

• SRY mutation

XY female

• HESX1

Variable degree of hypopituitarism

• PROP1, Pit1 mutation

Growth retardation and hypothyroidism (GH, TSH, and PRL deficiencies)

• RIEG

Occasional GH deficiency

Enzymes • Thyroid —Peroxidase

Hypothyroidism with goiter

—Iodotyrosine deiodinase

Goiter + hypothyroidism

• Adrenal and testes

—Cholesterol side-chain cleavage

CAH with hypogonadism (20,22-desmolase)

—3 P-Hydroxysteroid dehydrogenase

CAH with ambiguous genitalia

—17 a-Hydroxylase

CAH with androgen deficiency and hypertension

• Adrenal

—11 P-Hydroxylase

CAH, androgen excess, hypertension

—21 a-Hydroxylase

CAH with androgen excess + salt wasting

• Testes

—17,20-Desmolase

Hypogonadism

—17-Ketosteroid reductase

Hypogonadism

• Pancreas and Liver —Glucokinase gene

Maturity onset diabetes of the young

• Multiple tissues —Aromatase

Estrogen deficiency with virilization, delayed epiphyseal closure, tall stature

—5 a-Reductase

Male pseudohermaphroditism

—PC1, PC2

ACTH deficiency, hypopigmentation, diabetes mellitus

Other

• KAL protein deficiency

Kallmann syndrome

• AQP-2 water channel

NDI

Tion of hormones. Such production may be eutopic, in which the normal physiologic source of the hormone secretes excessive quantities of that hormone, or ectopic, in which a neoplasm or other pathology involving a tissue, that is not the known physiologic source of the hormone produces excessive quantities of the hormone. Eutopic hypersecretion may be due to autonomous production of the hormone with loss of normal target organ product feedback regulation. This is found in many hormone-secreting benign and malignant neoplasms.

An example would be a cortisol-secreting adrenal cortical adenoma that continues to secrete cortisol despite the suppression of endogenous adrenocorticotropic hormone (ACTH) levels. Dysfunction of endocrine glands leading to hyperplasia may be found in situations when there is excessive physiologic stimulation such as occurs in secondary hyperaldosteronism owing to cirrhosis or congestive heart failure, in which there is decreased effective vascular volume, resulting in stimulation of aldosterone secretion through the renin-angiotensin system. Alterations in the normal feedback set point also cause dysfunction of the endocrine gland, as is seen in the hypercalcemia found in patients with familial hypocalciuric hypercalcemia or in hypercalce-mic patients receiving lithium. In both situations, there are alterations in the calcium-sensing mechanism in parathyroid cells, which require higher serum calcium concentrations than normal to suppress parahormone production. The concept of an altered set point for feedback regulation also forms the basis for the low - and high-dose dexamethasone suppression tests in patients with pituitary-dependent Cushing disease. In such patients, ACTH and cortisol production is not suppressed normally following low-dose dexamethasone, but generally it is suppressed following administration ofto a high-dose ofdexamethasone. A wide variety of hormones have been found to be secreted ectopically by tumors, especially solid tumors of the lung, kidney, liver, and head and neck region. These tumors may directly secrete excessive quantities of a prohormone or active hormone or, in some instances, may secrete releasing factors, which, in turn, stimulates the release of hormone from the normal endocrine glands. Thus, the ectopic ACTH syndrome may be found in patients with oat cell carcinoma of the lung owing to ectopic production of ACTH by the tumor, and it may also be found in patients with bronchial carcinoid tumors that secrete corticotropin-releasing factor, which, in turn, stimulates the pituitary to secrete ACTH. Another form of ectopic hormone production is found with some benign and malignant diseases in which there is dysregulation of metabolic pathways. Patients with sarcoidosis or other granulomatous processes, as well as patients with some forms of lymphoma, may develop hypercalcemia owing to excessive quantities of 1,25-(OH)2-vitamin D produced from normal circulating quantities of 25-(OH)-vitamin D because of dysregulation of macrophage 1a-hydroxylase in the lesions.

A second broad mechanism responsible for overexpression of hormone action is through excessive activation of hormone receptors. Constitutive activation of thyroid-stimulating hormone (TSH) receptors owing to point mutations is found in some patients with toxic thyroid adenomas, and several families with constitutive activation of the luteinizing hormone (LH) receptor in the testes who present with familial male precocious puberty (testotoxicosis) have been described. Hormone receptors may also be activated by hormones that share close homology with the hormone for which the receptor is the primary target. Thus, human chorionic gonadotropin (hCG) when present in high concentrations, as occurs in some women with large hydatidiform moles, may stimulate the TSH receptor, resulting in hyperthyroidism. Other examples of receptor crossreaction include insulin binding to the insulinlike growth factor-1 receptor (IGF-1R) in the ovary, thereby stimulating androgen production, and growth hormone (GH) interaction with the PRL receptor, resulting in galactorrhea in some patients with acromegaly. Some nonhormonal substances can mimic hormone action through interraction with the hormone receptor. The thyroid-stimulating immunoglobulins present in the sera of patients with Graves disease and the hypoglycemia found in some patients with type B insulin resistance with insulin receptor autoantibodies are examples of this phenomenon.

On binding its receptor, a hormone induces a conformational change in the hormone/receptor complex, which, in turn, activates a variety of intracellular signaling pathways to mediate hormone action and regulate cellular function. There are several intracellular signaling pathways that regulate hormone function. Among these are the adenylyl cyclase-cyclic adenosine monophosphate (cAMP) system, tyrosine kinase, guanylyl cyclase, and activation of phospholipase C. Many of these regulatory processes involve the guanylyl nucleotide-binding proteins (G proteins). Some activating mutations of the G protein subunits “turn on” these signaling pathways, which results in the hyperfunction of an endocrine cell. In some situations, the activating G protein subunit mutation is confined to a single cell type, as in the case of ~40% of pituitary somatotroph tumors associated with acromegaly or in a minority of thyroid follicular adenomas associated with neonatal hyperthyroidism. In inherited conditions, such as McCune-

Albright syndrome, G protein subunit mutations are found in multiple tissues, resulting in polyendocrine overactivity including acromegaly and LH-releasing hormone (GnRH) - independent sexual precocity, as well as nonendocrine manifestations. In both cases, G protein subunit mutation results in constitutive activation of the G protein subunit-stimulated cAMP, regardless of the presence or absence of ligand, and the cAMP intracellular signaling pathway is permanently “turned on”This occurs in some somatotrophs associated with acromegaly or thyroid follicular cells associated neonatal hyperthyroidism. This also occurs in the endocrine target cells, which when activated through a G protein mutation function as if they were exposed to excessive quantities of the hormone. This mechanism is responsible for the precocious puberty and other clinical manifestations of the McCune-Albright syndrome (Table 1).

Hormone metabolism may be altered by disease states and medications. Hyperthyroidism, obesity, liver disease, and spironolactone increase the aromati-zation of testosterone and androstenedione, leading to enhanced production of estradiol and estrone, respectively, which can cause gynecomastia in affected individuals. Clinicians caring for patients with type 1 diabetes mellitus have long known that the unexpected onset of frequent hypoglycemic reactions necessitating the reduction in insulin dosages may herald the onset of renal insufficiency with loss of the ability of the kidneys to metabolize the exogenous insulin.

Multiple mechanisms also exist resulting in the underexpression of hormone action. Certainly, congenital aplasia or hypoplasia of endocrine tissue will prevent the normal synthesis or secretion of hormones by that tissue. Anencephaly, which is associated with an absence or maldevelopment of the hypothalamus, leads to a loss of hypothalamic-releasing hormones, which in turn, leads to profound panhypopituitarism. Other examples of abnormal hypothalamic development are holoprosencephaly, owing to chromosomal-medi-ated abnormalities of the transcription factor pituitary adenylate cyclase-activating polypeptide (PACAP) or PACAP receptor, resulting in abnormal midline forebrain development and hypothalamic insufficiency, and Kallman syndrome, owing to mutations in the KAL gene, which encodes the KAL adhesion protein, called anosmin, responsible for the coordinated migration of the gonadotropin-releasing hormone (GnRH)-secreting neurons from the olfactory placode into the hypothalamus.

Another example of an abnormal development of at least a portion of the hypothalamus is X-chromosome-linked Kallmann’s syndrome. Loss of this normal migration results in inadequate production and secretion of

GnRH, leading to a hypogonadotropic hypogonadism. In addition to congenital structural defects, destruction of endocrine organs can occur from replacement by tumor or involvement with one of the many processes listed earlier. Congenital absence of a hormone owing to a gene deletion is rare and has been described for GH. More commonly, point mutations in the genes encoding a hormone or a hormone subunit may result in a biologically inactive form of the hormone, which may or may not retain its immunologic activity. Other mechanisms may result in hormone deficiency. Substrate required for hormone production may be limited, as occurs in individuals with vitamin D deficiency owing to inadequate intake, lack of sun exposure, or the presence of malabsorption. Without an appropriate amount of native vitamin D, insufficient quantities of 25(OH)-vitamin D and 1,25(OH)2-vitamin D may be produced. Because many hormones are produced in a prohormone form, some point mutations may result in a defect that preventsthe normal processing of the biologically inactive prohormone to the biologically active hormone (Table 2).

Although antibodies that bind circulating hormone do not usually impair do not cause a major interference in hormone action, however, some antibodies may sufficiently interfere with hormone action to result in hormone deficiency. insufficiency state. Examples include the high-titer, high-affinity antibodies against insulin that occasionally cause insulin resistance, gonadotropin antibodies that occasionally form in individuals with hypogonadotropic hypogonadism receiving exogenous gonadotropins, and the extremely rare GH inactivating antibody found in some GH-deficient children receiving exogenous GH. Spontaneous antihormone antibodies are occasionally seen in patients with autoimmune diseases but rarely cause clinical manifestations. In addition, the target organ may not appropriately respond to hormonal stimulation because of structural defects in the hormone receptor; acquired disease; or in the case of thyroid hormones, steroid hormones, and vitamin D, congenital or acquired defects in the enzymes responsible for conversion of the hormone into its final active form (Table 2).

Another mechanism for the underexpression of hormone action is hormone resistance at the target organ level due to receptor or postreceptor abnormalities. A number of inactivating mutations in both membrane and nuclear hormone receptors have been described (Table 2). In addition, the receptors may be occupied by autoantibodies, which prevent the normal hormone-receptor interaction from taking place. In contrast to the stimulatory effects of thyroid-stimulating Igs in patients with Graves disease, blocking of autoantibodies to the TSH receptor is a cause of goitrous hypothyroidism. Similarly, anti-insulin receptor antibodies may block the effect of insulin in some patients, whereas in others the antibodies may mimic the effect of insulin and cause hypoglycemia. Normal receptors exposed to large quantities of its complementary hormone may be downregulated. Therapeutically, this is the mechanism by which long-largeacting analogs of GnRH lead to a loss of responsiveness by the gona-dotropes to endogenous GnRH, which, in turn, leads to a lowering of LH and follicle-stimulating hormone (FSH) concentrations. Finally, hormone resistance may occur because of postreceptor defects involving the signal pathway. Albright hereditary osteodystrophy, which is manifest by resistance to parathyroid hormone (PTH), TSH, and gonadotropins, results from inactivation of Gsaa in a variety of tissues. Another type of postreceptor defect is homologous desensitization, which refers to the inability of a hormone to stimulate the signaling pathway after extensive interaction with its receptor at a time when other factors are able to continue to stimulate that pathway. Such homologous desensitization is seen in the corpus luteum during early pregnancy when hCG has completely occupied its receptors. Although early in pregnancy hCG is able to stimulate adenylyl cyclase activity after interaction with the hCG/LH receptor in the corpus luteum, once the receptors are occupied, adenylyl cyclase activity decreases, but it is still able to be stimulated by forskolin and phorbal esters, which act on the signaling mechanism at the postreceptor sites. Certain disease states, drugs, and medications are known to alter the metabolism of hormones and may result in overerexpression of hormone action. Alcohol enhances the A-ring metabolism of testosterone, increasing its metabolism. Phenobarbital decreases the production of 25-(OH)-vitamin D from its precursors, by stimulating the formation of more polar metabolites by the liver.

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