Endocrine disorders can result from dysfunction originating in the peripheral endocrine gland itself (primary disorders) or from understimulation or overstimulation by the pituitary (secondary disorders). The disorders can result in hormone overproduction (hyperfunction) or underproduction (hypofunction). Rarely, endocrine disorders (usually hypofunction) occur because of abnormal tissue responses to hormones. Clinical manifestations of hypofunction disorders are often insidious and nonspecific.
Hyperfunction:
Hyperfunction of endocrine glands may result from overstimulation by the pituitary but is most commonly due to hyperplasia or neoplasia of the gland itself. In some cases, cancers from other tissues can produce hormones (ectopic hormone production). Hormone excess also can result from exogenous hormone administration. In some cases, patients take hormones without telling the physician (factitious disease). Tissue hypersensitivity to hormones can occur. Antibodies can stimulate peripheral endocrine glands, as occurs in hyperthyroidism of Graves' disease. Destruction of a peripheral endocrine gland can rapidly release stored hormone (eg, thyroid hormones in thyroiditis). Enzyme defects in the synthesis of a peripheral endocrine hormone can result in overproduction of hormones proximal to the block. Finally, overproduction of a hormone can occur as an appropriate response to a disease state.
Hypofunction:
Hypofunction of an endocrine gland can result from understimulation by the pituitary. Hypofunction originating within the peripheral gland itself can result from congenital or acquired disorders (including autoimmune disorders, tumors, infections, vascular disorders, and toxins). Genetic disorders causing hypofunction can result from deletion of a gene or by
production
of an abnormal hormone. A decrease in hormone production by the peripheral endocrine gland with a resulting increase in production of pituitary regulating hormone can lead to peripheral endocrine gland hyperplasia. For example, if synthesis of thyroid hormone is defective, thyroid-stimulating hormone (TSH) is produced in excessive amounts, causing goiter.
Several hormones require conversion to an active form after secretion from the peripheral endocrine gland. Certain disorders can block this step (eg, renal disease can inhibit production of the active form of vitamin D). Antibodies to the circulating hormone or its receptor can block the ability of the hormone to bind to its receptor. Disease or drugs can cause increased rate of clearance of hormones. Circulating substances may also block the function of hormones. Abnormalities of the receptor or elsewhere in the peripheral endocrine tissue can also cause hypofunction.
Laboratory Testing
Because symptoms of endocrine disorders can begin insidiously and may be nonspecific, clinical recognition is often delayed for months or years. For this reason, biochemical diagnosis is usually essential; it typically requires measuring levels of the peripheral endocrine hormone, the pituitary hormone, or both in the blood.
Free or bioavailable hormone (ie, hormone not bound to a specific binding hormone) is generally believed to be the active form. Free or bioavailable hormones are measured using equilibrium dialysis, ultrafiltration, or a solvent-extraction method to separate the free and albumin-bound hormone from the binding globulin. These methods can be expensive and time-consuming. Analog and competitive free hormone assays, although often used commercially, are not always accurate and should not be used.
Free hormone levels can also be estimated indirectly by assessing levels of the binding protein and using them to adjust levels of the total serum hormone. However, indirect methods are inaccurate if the binding capacity of the hormone-binding protein has been altered (eg, by a disorder).
Because most hormones have circadian rhythms, measurements need to be made at a prescribed time of day. Hormones that vary over short periods (eg, luteinizing hormone) necessitate obtaining 3 or 4 values over 1 or 2 h or using a pooled blood sample. Hormones with week-to-week variation (eg, testosterone) necessitate obtaining separate values a week apart.
In some cases, indirect estimates are used. For example, because growth hormone (GH) has a short serum half-life and is difficult to detect in serum, serum insulin-like growth factor 1 (IGF-1), which is produced in response to GH, is often measured as an index of GH activity. Sometimes, urine (eg, free cortisol when testing for Cushing disease) or salivary hormone levels may be used. Whether measurement of circulating hormone metabolites indicates the amount of bioavailable hormone is under investigation.
In many cases, a dynamic test is necessary. Thus, in the case of hypofunctioning organs, a stimulating test can be used. In hyperfunction, a suppressive test can be used.
Treatment
Hypofunction disorders are usually treated by replacement of the peripheral endocrine hormone regardless of whether the defect is primary or secondary (an exception is GH replacement for pituitary dwarfism). If resistance to the hormone exists, drugs that reduce resistance can be used (eg,metformin
or thiazolidinediones for type 2 diabetes mellitus). Occasionally, a hormone-stimulating drug is used.
Radiation therapy, surgery, and drugs that suppress hormone production are used to treat hyperfunction disorders. In some cases, a receptor antagonist is used.
Aging and Endocrinology
Hormones undergo many changes as a person ages. Most hormone levels decrease. Some remain normal, including TSH, ACTH (basal), thyroxine, cortisol (basal), 1,25-dihydroxycholecalciferol, insulin (sometimes increases), and estradiol (in men). Hormones that increase, including ACTH (increased response to corticotropin-releasing hormone), follicle-stimulating hormone, sex-hormone binding globulin, and activin (in men), gonadotropins (in women), epinephrine (in the oldest old), parathyroid hormone, norepinephrine, cholecystokinin, vasoactive intestinal peptide and ADH (also loss of circadian rhythm), and atrial natriuretic factor, are associated with either receptor defects or postreceptor defects, resulting in hypofunction. Many age-related changes are similar to those in patients with hormone deficiency, leading to the hypothesis of a hormonal fountain of youth (ie, speculation that some changes associated with aging can be reversed by the replacement of one or more deficient hormones). Some evidence suggests that replacing certain hormones in the elderly can improve functional outcomes (eg, muscle strength, bone mineral density), but little evidence exists regarding effects on mortality. In some cases, replacing hormones may be harmful, as in estrogen replacement in most older women.
A competing theory is that the age-related decline in hormone levels represents a protective slowing down of cellular metabolism. This concept is based on the rate of living theory of aging (ie, the faster the metabolic rate of an organism, the quicker it dies). This concept is seemingly supported by studies on the effects of dietary restriction. Restriction decreases levels of hormones that stimulate metabolism, thereby slowing metabolic rate; this prolongs life in rodents.
Dehydroepiandrosterone (DHEA) and its sulfate levels decline dramatically with age. Despite optimism for the role of DHEA supplementation in older people, most controlled trials failed to show any major benefits.
Pregnenolone is the precursor of all known steroid hormones. As with DHEA, its levels decline with age. Studies in the 1940s showed its safety and benefits in people with arthritis, but additional studies failed to show any beneficial effects on memory and muscle strength.
Levels of GH and its peripheral endocrine hormone (IGF-1) decline with age. GH replacement in older people sometimes increases muscle mass but does not increase muscle strength (although it may in malnourished people). Adverse effects (eg, carpal tunnel syndrome, arthralgias, water retention) are very common. GH may have a role in the short-term treatment of some undernourished older patients, but in critically ill undernourished patients GH increases mortality. Secretagogues that stimulate GH production in a more physiologic pattern may improve benefit and decrease risk.
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