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CHAPTER 50 ENDOCRINE DISORDERS

CHAPTER 50 ENDOCRINE DISORDERS
Practice of Geriatrics
CHAPTER 50 ENDOCRINE DISORDERS
Paul J. Davis, M.D., and Faith B. Davis, M.D.
Pituitary-Thyroid Function
Pituitary-Adrenal Function
Catecholamines
Parathyroid Gland and Vitamin D
Antidiuretic Hormone (Arginine Vasopressin)
Atrial Natriuretic Peptide
Growth Hormone
Prolactin
Gonadal Function
Carbohydrate Metabolism and Diabetes Mellitus
The generalist who manages endocrine problems in elderly patients must distinguish among three clinical states: (1) endocrine function that is altered relative to younger subjects but is an expected consequence of normal aging, (2) altered endocrine function that is secondary to coincident nonendocrine disease but is of no pathologic significance, and (3) authentic endocrinopathy. The patterns of change in endocrine function in the course of normal aging are summarized in Table 50-1. Certain of these changes can affect diagnostic evaluations in important ways—for example, the relative nonresponsiveness of the renin-aldosterone axis in the normal elderly, the increased incidence of the uncomplicated empty sella turcica syndrome in older subjects, and alterations in carbohydrate tolerance. These changes create an impression of endocrine disease and are discussed in subsequent sections of this chapter. There is no unifying physiologic mechanism that explains the alterations in endocrine function that accompany normal aging. Some of the changes represent decreased organ function, and others reflect enhanced sensitivity of one or more aspects of an endocrine axis (Table 50-1).

TABLE 50-1 PATTERNS OF CHANGE IN ENDOCRINE FUNCTION WITH NORMAL AGINGa

The impact of substantial nonendocrine disease on endocrine physiology in subjects of all ages can also lead to a misimpression of the presence of endocrinopathy. Examples of the effects of nonendocrine disease are the reductions in serum 3,5,3′-L-triiodothyronine (T3) and thyrotropin (TSH) concentrations in both sexes and the fall in serum testosterone levels in men who have serious systemic diseases such as cancer or heart failure. In elderly patients with multisystem disease, caution must be used in interpreting the results of laboratory tests of endocrine function.
Finally, bona fide endocrinopathies in older patients need not present with the conventional findings observed in younger patients. For example, the presentation of hyperthyroidism or hyperparathyroidism in the elderly may be muted or may be obscured by the coincident presence of unrelated heart, lung, or nervous system disorders whose life-threatening consequences divert the attention of the clinician from the possible presence of endocrine disease.
The epidemiology of the various endocrinopathies is also different in the older patient population (Fig. 50-1). For example, in older subjects, diabetes mellitus is of the noninsulin-dependent or type II variety, and adrenocortical disease is rare. The aggressiveness of endocrine tumors, notably thyroid cancer, is different in elderly patients than in younger ones despite identical histologic findings. The treatment of endocrinopathies may also require modification in the older patient population.

Figure 50-1 Percentage of patients with selected endocrinopathies who are 60 years of age or more.

PITUITARY-THYROID FUNCTION
Physiology
Thyroid hormone is a principal regulator of cell and higher organism respiration, and its actions affect virtually all body systems. To understand thyroid function and tests of thyroid function in the healthy elderly and to diagnose thyroid disease in aged subjects, it is important to understand the physiology of the pituitary-thyroid gland complex during the life span.
Thyroid hormone circulates in blood as L-thyroxine (T4, tetraiodothyronine) and 3,5,3′-L-triiodothyronine (T3). T4 is released by the thyroid gland under the direction of normal levels of pituitary thyrotropin (TSH), and T4 in turn regulates TSH secretion by a negative feedback inhibition loop at the pituitary gland. T3 is derived from T4 by deiodination (activity of iodothyronine 5′-monodeiodinase) in various organs (e.g., liver and kidney), but it is also released by the thyroid gland when plasma TSH levels increase. T3 is biologically ten times more active than T4. Because of its biologic activity, particularly in the elderly, T3 is not desirable as hormone replacement in hypothyroid patients, and T4 is prescribed.
When the 5-iodine rather than the 5′-iodine in various organs is removed from T4, a hormone analog called reverse T3 (rT3) is formed; this is a relatively inactive form of the hormone. Intrapituitary conversion of T4 to T3 controls TSH secretion by the negative feedback loop. Circulating T4 and T3 are bound to plasma proteins, the most important of which is thyroxine-binding globulin (TBG). Less than 0.01% of T4 is unbound by TBG and other proteins, and less than 0.1% of T3 is unbound; these unbound species of hormone are free T4 and free T3 and are the metabolically active forms of the hormone.
Regardless of a patient’s age, conventional forms of hyperthyroidism (which is due to excessive production of hormone by the thyroid gland) suppress endogenous TSH levels. Conventional forms of hypothyroidism (which is due to primary failure of the thyroid gland) are associated with increased circulating levels of TSH. In the course of normal aging, serum levels of T4 and free T4 do not change, T3 and free T3 concentrations decline modestly, and TSH levels remain stable.1 One can conclude from these observations that the function of the pituitary-thyroid complex is preserved over the life span and that the great majority of healthy elderly, up to centenarian status, have normal results on serum thyroid function tests (concentrations of total and free T4, total and free T3, and TSH). However, a few healthy older subjects appear to have an increased sensitivity of the negative feedback loop in that they have somewhat low free T4 levels, but the serum TSH concentrations do not increase as a result.
The most important feature of thyroid hormone metabolism in the evaluation of elderly patients is the impact of nonthyroidal illness (NTI) on thyroid function.1 Many studies of “healthy elderly” in the literature have not rigorously excluded NTI and, as a result, have confused changes due to disease states with those due to normal aging. NTI impairs T4 to T3 conversion, leading to very low serum T3 and free T3 levels. At the same time, in most clinical situations in which NTI occurs (with the exception of end-stage renal disease), rT3 formation is enhanced. NTI can promote degradation of TBG and decrease its secretion by the liver, leading to low serum total T4 concentrations. NTI can be associated with low or high free hormone levels, and pituitary TSH secretion may be suppressed. The suppression can suggest either hyperthyroidism or decreased pituitary function (hypopituitarism). Despite these alterations, most patients with NTI are eumetabolic. It is important to note that significantly reduced caloric intake acutely reproduces some of the changes of NTI (decreased T3 and increased rT3; low serum T4, if the condition is chronic, may result from decreased hepatic synthesis of TBG). Finally, during recovery from NTI, patients may show modest elevations of serum TSH that are consistent with early hypothyroidism but actually represent recovery of the pituitary-thyroid axis from the impact of NTI. The effort to document bona fide thyroid disease in the presence of NTI is thus a complex issue, and the presence or absence of thyroid disease is sometimes documented by laboratory tests only when NTI has resolved.
There is no evidence currently that a decrease in thyroid function contributes to the aging process. There is suggestive evidence that certain tissues, such as the heart and perhaps the pituitary gland, may acquire in some patients heightened sensitivity to thyroid hormone during the life span. The latter statement is based on the appearance of single-organ hyperthyroidism (monosystemic hyperthyroidism) in occasional patients (e.g., those who may present only with myocardial symptoms and signs of thyroid hyperfunction).
It should also be noted that behavioral changes associated with normal aging, such as decreased physical activity and altered bowel function, may be accentuated or mimicked by thyroid disorders. Because thyroid disorders are common, the physician must consider the possible contribution of these diseases in every patient in whom behavioral changes “consistent with normal aging” have occurred.
Clinical Assessment
HYPERTHYROIDISM
The prevalence of hyperthyroidism in the ambulatory urban elderly population is as high as 0.7%. The clinical symptoms and signs found in hyperthyroid older patients are summarized in Table 50-2. The majority of older patients with thyrotoxicosis have classic findings.2 About 25% of elderly hyperthyroid patients have subtle symptoms or present with authentic thyrotoxicosis in the presence of severe nonthyroidal illness, such as congestive heart failure, systemic infection, or cerebrovascular disease. In such patients, hyperthyroidism may be readily overlooked (“masked” hyperthyroidism). Alternatively, the older subject with thyrotoxicosis may have symptoms and signs limited to a single organ system such as the heart, or may present with phlegmatic or apathetic mien rather than in the hyperkinetic state.

TABLE 50-2 CLINICAL FEATURES OF HYPERTHYROIDISM IN THE ELDERLY

Crescendo angina pectoris may herald the presence of hyperthyroidism, but acute myocardial infarction has occurred relatively infrequently in patients with thyroid hyperfunction and coronary artery disease. Older hyperthyroid patients may experience anorexia rather than increased appetite, and the constellation of anorexia, weight loss, and constipation occurs in as many as 15% of elderly thyrotoxic subjects. New-onset hypertension or exacerbation of previously well-controlled hypertension may occur. The impressively widened pulse pressure observed in younger hyperthyroid patients is less frequently seen in the elderly because the diastolic pressure may not fall in older patients who become thyrotoxic. Demineralizing bone disease may be a presenting sign in elderly patients with hyperthyroidism.
Atrial fibrillation is eight times more frequent in hyperthyroidism in the elderly than in young patients. This arrhythmia usually reverts to a sinus mechanism in the course of treatment of hyperthyroidism in younger people but does so in only 50% of older thyrotoxic patients. Atrial fibrillation may be associated with a slow ventricular response in elderly hyperthyroid patients (ventricular rate of 50 to 60 beats/minute). This atrioventricular conduction block is related to the concomitant presence of atherosclerotic or other disease such as amyloidosis in the cardiac conducting system or to the use of digitalis, or both. The risk of stroke is increased in patients with atrial fibrillation associated with thyrotoxicosis despite the fact that the left atrium may be small and blood flow through the heart may be increased.
Goiter is absent in 40% of older patients with hyperthyroidism.2 Insistence by the physician on the presence of goiter before obtaining tests of thyroid function will therefore lead to underdiagnosis of hyperthyroidism in the elderly. Hyperthyroidism due to a single thyroid nodule or to multinodular goiter is more common in older subjects than in younger patients, but a third or more of thyrotoxic elderly who have thyroid enlargement have diffusely enlarged (non-nodular) thyroid glands.
Serious endocrine ophthalmopathy is infrequent in older patients. Stare and lid-lag are common in both old and young hyperthyroid subjects. These signs are less specific than proptosis for thyroid disease because they may occur in the presence of chronic congestive heart failure, chronic obstructive pulmonary disease, or renal or liver failure.
In the great majority of older patients with hyperthyroidism, the laboratory profile includes elevations of traditional parameters of thyroid function: serum T4 and free T4 concentrations and thyroidal uptake of radioactive iodine. The sensitive sandwich radioimmunoassay (RIA) for TSH in serum—the lower limit of normal of which is 0.2 µU/mL or less—distinguishes between suppressed TSH (characteristic of hyperthyroidism) and low normal levels of the hormone and may be used to screen both young and elderly subjects for the presence of hyperthyroidism. Low normal serum TSH levels do not imply the presence of imminent thyrotoxicosis, but undetectable (suppressed) serum TSH levels are consistent with subclinical hyperthyroidism (see later discussion). Measurement of serum total T4 and free T4 by RIA is an alternative method and should be compared within the institution for cost effectiveness relative to TSH assay. Low serum concentrations of TBG due to chronic nonthyroidal illness are associated with low serum T4 levels. Constitutional (X-linked) increases in TBG are associated with increased circulating concentrations of T4 in patients without hyperthyroidism. In these states in which TBG is abnormal, serum free T4 and TSH measurements are within the normal range.
As many as 10% of older patients with thyrotoxicosis have standard thyroid function test results that are misleadingly normal. Some of these patients have T3 toxicosis, a syndrome in which only serum T3, measured by radioimmunoassay, is elevated. Serum T4 and free T4 concentrations are normal. A few patients may have free T3 toxicosis with normal results in the remaining serum tests of thyroid function. Finally, an interesting group of patients 65 years of age or older have suppressed serum TSH concentrations but otherwise normal or high normal thyroid function test results (subclinical hyperthyroidism). Some of these patients have chronic or paroxysmal atrial fibrillation3 or unexplained weight loss and appear to have emerging hyperthyroidism, characterized by a single symptom or a limited number of clinical findings. As mentioned earlier, these patients have hyperthyroidism that appears to represent a condition of heightened sensitivity of a hormone target organ (myocardium) to apparently normal levels of circulating T4 and T3. Rarely, younger patients may have hyperthyroidism due to pituitary secretion of excessive amounts of TSH. It is not yet clear whether there is an appreciable risk of this syndrome in elderly patient populations.
No accurate cost-effective tests are available to measure the action of thyroid hormone on its target tissues, such as the heart or nervous system. Measurements of serum cholesterol concentration, alkaline phosphatase activity, and calcium concentration may be abnormal in thyrotoxic patients of any age, but they are not useful in establishing the diagnosis of hyperthyroidism or for monitoring the effects of treatment.
Therapeutic alternatives in the acute management of hyperthyroidism in elderly patients are shown in Table 50-3. Acute management involves control of symptoms of thyroid dysfunction, anticipation of possibly life-endangering complications of thyrotoxicosis, and preparation of the patient for definitive long-term therapy. The latter usually consists of ablation of the thyroid gland with radioactive iodide (Na131I).

TABLE 50-3 MEDICAL THERAPEUTIC ALTERNATIVES FOR HYPERTHYROIDISM IN THE ELDERLY

Thioamide-related suppression of bone marrow granulocyte production is more likely to develop in patients over the age of 40 years than in younger subjects when conventional doses of methimazole (30 mg/day) are exceeded; thus, propylthiouracil is recommended in older patients when a thioamide is required. Patients with subclinical hyperthyroidism who develop atrial fibrillation are candidates for radioablation of the thyroid gland or for a trial of PTU to reduce circulating T4 and T3 levels sufficiently to result in detectable serum TSH levels and to determine whether the cardiac findings then subside. Ablative treatment may then be used, and hypothyroidism should be anticipated.
Many of the symptoms of hyperthyroidism in the elderly can be controlled by cautious administration of a beta-adrenergic blocking agent. As little as 40 mg of propranolol daily in four doses of 10 mg each can be effective in controlling tachycardia in the older thyrotoxic patient, although total daily doses of 80 to 120 mg (1.2 mg/kg body weight/day) are more commonly required. It is critical to recognize that as the patient is rendered euthyroid by the use of radioactive iodide or by thioamide drugs, the dose of beta-blocker that was formerly therapeutic can become toxic. Symptomatic sinus bradycardia may emerge as thyrotoxicosis subsides if relatively high doses of propranolol are continued. Although the most substantial experience with beta-blockade has been accumulated with propranolol, other beta-blockers are effective as well.
It is widely acknowledged that beta-adrenergic blockade may exacerbate congestive heart failure in patients with hyperthyroidism. However, cautious slowing of tachycardia with small doses of a beta-blocker may improve the symptoms of heart failure in hyperthyroid patients by increasing diastolic filling time. We recommend a careful trial of a short-acting beta-blocking agent in elderly patients with hyperthyroidism and ventricular response rates of more than 140 beats/minute. Titration is carried out to achieve a heart rate of 100 to 110 beats/minute. In patients with hyperthyroidism and heart failure who have ventricular rates of less than 140 beats/minute, the authors avoid beta-blockade.
The life-threatening phase of hyperthyroidism—“thyroid storm”—does occur in the elderly. This state is imprecisely defined as “exaggerated symptoms of hyperthyroidism” in association with fever and tachycardia. Sometimes “apathetic thyroid storm” is encountered; this may proceed to coma and death with the manifestation of few signs of thyrotoxicosis except for tachycardia or fever or both. The authors look upon elderly thyrotoxic patients with heart rates of 120 beats/minute or greater, those with a previous history of congestive heart failure unrelated to thyroid disease, and those with significant fever (core temperature higher than 100.6°F) as “pre-storm” patients who should be aggressively managed with nonradioactive iodide administration, thioamide, and propranolol, reserving use of the latter for those with (1) a heart rate greater than 140 beats/minute, or (2) sensorial changes that accompany fever and heart rate greater than 120 beats/minute in patients with suspected or established hyperthyroidism.
The definitive treatment of hyperthyroidism is thyroid gland ablation with 131I-. Ablative radioactive iodide therapy should be administered under cover of low-dose beta-blockade or after achievement of eumetabolism with thioamide treatment. This conservative approach—rendering the elderly patient relatively euthyroid with beta-blockade or PTU—minimizes the risk of thyroid storm occurring 7 to 14 days after administration of 131I-. The incidence of storm after 131I- is low even without prior conversion of patients to the euthyroid state, but the desirability of avoiding the complication is extraordinarily high. Elderly patients can be treated long-term with PTU should they reject the concept of ablative 131I- therapy. Thyroidectomy is rarely used in older patients for management of hyperthyroidism.
HYPOTHYROIDISM
The prevalence of hypothyroidism in ambulatory urban elderly populations as well as in referral center hospitals is as high as 6%. Because younger patients do not tolerate the major symptom complex of hypothyroidism—lassitude, constipation, ambient cold temperature intolerance, and dry skin—without consulting a physician, moderately advanced and severe hypothyroid states are found almost exclusively in the elderly. Myxedema stupor and coma are rare in patients under the age of 50 years. The subtlety of early hypothyroidism in elderly subjects is easily confused with the progression of “normal aging,” and a low diagnostic threshold for the possibility of hypothyroidism should be maintained by the physician in evaluating this age group.
The classic features of hypothyroidism are well known. Several of these should be emphasized as herald findings of the disease. As many as one third of hypothyroid patients are hypertensive, and one third of these patients can normalize their blood pressure with thyroid hormone replacement therapy alone. Gait disorders, apparently due to cerebellar dysfunction, occur in hypothyroidism, as does a striated muscle myopathy, usually in a proximal muscle distribution. Asymmetrical hypertrophy of the myocardial ventricular septum is an occasional feature of hypothyroidism, and remission of this sign may occur with hormone replacement.
Primary destruction of the thyroid gland, due either to Hashimoto’s thyroiditis or to iatrogenic ablation of the previously overactive gland by radioiodide, accounts for 95% of cases of hypothyroidism. The remainder of the hypothyroid patient population have pituitary or hypothalamic-pituitary disease (secondary hypothyroidism). Distinguishing between primary and secondary hypothyroidism is important clinically, as will be discussed in the section on treatment of hypothyroidism. Patients with marginal hypofunction of the thyroid may be acutely hypothyroid when acute systemic nonthyroidal illness supervenes. Unexplained medical deterioration in the condition of elderly patients with appropriately treated severe nonthyroidal illness should cause the physician to consider the possibility that concomitant unappreciated hypothyroidism is present. Reversible sleep apnea syndrome may also be a feature of hypothyroidism.
The diagnosis of primary hypothyroidism in patients of any age is secured with the finding of an elevated serum TSH level and a low serum T4 concentration. Measurement of the T4 concentration alone may be misleading because the occurrence of low serum TBG levels is relatively frequent. The free T4 level has reduced usefulness in patients with hypothyroidism because it is sometimes low normal rather than low. The possibility that TBG content may be contributing to a low serum T4 level must always be considered and can be excluded by the measurement of serum free T4 concentration or radioimmunoassay for TBG. Patients with early or subclinical primary hypothyroidism may have an elevated serum TSH and a low normal or even mid-range T4 level. Excessive stimulation of the thyroid gland in such patients by administration of endogenous TSH is required to maintain the neareuthyroid state. The patient with a low serum T4 concentration and a low serum TSH level has either hypopituitary (secondary) hypothyroidism or nonthyroidal illness, as discussed earlier under Physiology.
There is no indication for the measurement of serum antithyroid antibody titers in elderly patients with spontaneous hypothyroidism. Although hypothyroidism is presumably autoimmune in origin (end-stage Hashimoto’s thyroiditis), antibody levels are infrequently elevated by the time the thyroid gland has been destroyed. The possibility of hypopituitarism can be evaluated by measuring the circulating levels of cortisol and radiographic assessment (by computer-assisted tomography [CT] or magnetic resonance imaging [MRI]) of the sella turcica to look for evidence of a pituitary tumor or the empty sella syndrome. Because the incidence of the empty sella syndrome is appreciable in the elderly, it should be understood that the finding of an enlarged sella does not necessarily imply the presence of a pituitary tumor.
A number of nonthyroidal laboratory test abnormalities can accompany hypothyroidism. These include macrocytic anemia, due either to concomitant pernicious anemia or to erythroid maturation arrest of unknown cause, elevated serum creatine phosphokinase (CPK) activity, hyponatremia, and hyperuricemia. Patients with moderate to severe hypothyroidism may also hypoventilate and retain carbon dioxide. When present, elevated serum CPK activity usually originates in the skeletal muscle (MM isoenzyme), and it tends to be elevated consistently until thyroid hormone replacement therapy is instituted. Increased serum CPK activity in patients with hypothyroidism occasionally includes the myocardial isoenzyme (MB) in the absence of other evidence of myocardial necrosis. Hyponatremia in the hypothyroid population usually reflects decreased renal free water clearance resulting from excessive antidiuretic hormone (ADH, arginine vasopressin [AVP]) of central origin. Thyroid hormone replacement normalizes serum sodium concentration.
Initiation of treatment of primary hypothyroidism in older patients involves oral L-thyroxine (T4) replacement in graded doses. In many elderly subjects, the concomitant presence of heart disease (usually atherosclerotic disease but occasionally cardiomyopathic on a hypothyroid basis) mandates a conservative incremental approach to hormone replacement. The presence of clinically significant heart disease associated with hypothyroidism is defined as any one or more of the following: cardiomegaly, congestive heart failure, angina pectoris, or a prior history of myocardial infarction or cardiac arrhythmia. Initial hormone therapy in such patients consists of 0.025 mg of T4 daily. After 2 to 4 weeks, the dose is increased to 0.050 mg of T4/day, and thereafter the daily dose is raised at 2- to 6-week intervals by 0.025-mg increments until a total daily dose of between 0.075 and 0.150 mg lowers the serum TSH into the normal range.4 It is important to avoid full suppression of TSH, since the latter state risks the promotion of metabolic bone disease (osteoporosis) and exacerbation of underlying heart disease.
Metabolic equilibration at a given dose of thyroid hormone may be incomplete for 2 months. Thus, the graded dosage regimen described here is a general recommendation. Once an appropriate reduction in serum TSH level has been achieved, however, adjustments in hormone replacement dose can be considered if symptoms suggestive of hyperthyroidism develop months after an apparently stable dose of T4 has been achieved. There is no role for the use of T3 or mixtures of T4 and T3 in the management of hypothyroidism in the elderly. A few patients have primary hypothyroidism and primary adrenocortical failure (Schmidt’s syndrome) and require chronic replacement therapy for both diseases. It is very rare for hypothyroid elderly patients undergoing oral T4 replacement therapy to develop relative adrenocortical insufficiency, a syndrome of hypotension and mild hyponatremia that requires transient corticosteroid support.
Substantial attention has been focused on the cohort of patients who have minimally elevated or even high normal serum TSH levels, a normal serum T4 concentration, and few or no symptoms suggestive of hypothyroidism. Hypercholesterolemia may or may not be present. This state has been termed “subclinical hypothyroidism.” Patients with these findings are presumed to have mild thyroiditis and defective hormonogenesis that will support normal levels of circulating T4 when slight increases in endogenous TSH occur compensatorily. Some authorities advocate hormone replacement therapy for patients with this laboratory test profile because subjective improvement may occur in such patients when they are treated. Some cognitive dysfunction in patients in this situation has also been thought to be reversed with hormone replacement. Lowdensity lipoprotein cholesterol levels may decline. It should be noted that exposure of untreated patients with subclinical hypothyroidism to iodine loads, such as those encountered with amiodarone, radiographic contrast media, or kelp, may precipitate acute hypothyroidism.
The authors view the following findings to be secure indications for T4 therapy in patients with subclinical hypothyroidism: (1) the presence of goiter; (2) decline of serum T4 concentration into the lower quartile of the normal range in the context of mildly elevated serum TSH content; or (3) elevated serum antithyroid antibody titers. (Although measurement of antibody titers is not cost-effective in patients with established hypothyroidism, such titers may be useful in subjects with incipient hypothyroidism.) Patients with substantial evidence of heart disease and subclinical hypothyroidism are not candidates for T4 replacement because the risks outweigh the possible benefits of treatment. If the physician elects not to treat the patient with subclinical hypothyroidism, regular evaluation is indicated to detect the emergence of symptomatic hypothyroidism.
Severe hypothyroidism—myxedema stupor or coma—is a medical emergency and requires treatment with parenteral T4. The diagnosis is considered when a profound alteration of sensorium is complicated by hypothermia (core body temperature of less than 95°F) or hypotension in a patient with already established or presumptively diagnosed but undertreated primary hypothyroidism. These patients may also have an elevated arterial P CO2 and hypoxemia. Specific management of such patients is beyond the scope of this text but is carried out in the intensive care unit and involves intravenous administration of relatively large doses of T4 and stress level corticosteroids.
PITUITARY-ADRENAL FUNCTION
Physiology
Basal levels of serum cortisol and the response of cortisol secretion by the adrenal cortex to exogenous adrenocorticotropic hormone (ACTH) are unaffected by normal aging in humans.5 The provocative stimulus of insulin-induced hypoglycemia and the attendant release of endogenous ACTH by the pituitary gland are also undiminished during the life span. There is an advance in phase in the cortisol circadian rhythm in the elderly (i.e., earlier nadir and peak in diurnal cortisol secretion), but this is thought to be behavioral, reflecting the inverse relationship between age and customary bedtime.
In contrast to cortisol secretion, the sensitivity of aldosterone secretion to the conventional stimuli of sodium restriction and prolonged assumption of the upright posture is diminished in normal elderly subjects. Response of plasma renin levels to the same stimuli is also decreased with normal aging. The physiologic significance, if any, of these changes in control of aldosterone secretion in the course of aging is not clear, although it has been suggested that essential hypertension in the elderly may be associated with retention of the responsiveness of the renin-aldosterone axis observed in younger subjects. Whether the stimulation by hyperkalemia of aldosterone release is also diminished in healthy elderly people has not been determined. The diagnosis of hyporeninemic hypoaldosteronism as a cause of hyperkalemia should be applied very cautiously in elderly patients because of the diminished sensitivity of the renin-aldosterone axis in the normal elderly population.
Clinical Assessment
HYPOADRENOCORTICISM
The clinical syndrome of adrenocortical hypofunction is unaltered by aging. Because asthenia and easy fatigability may be associated with the stereotype of “normal aging,” these symptoms as heralds of hypoadrenocorticism may attract insufficient medical attention in the elderly. Hyponatremic and hyperkalemic syndromes of various causes are relatively common in the older patient. In the majority of elderly patients with hyponatremia, however, euvolemia is present, and hyponatremia reflects impaired free water clearance (syndrome of inappropriate secretion of antidiuretic hormone, SIADH). The situations in which renal free water clearance is decreased include tumoral secretion of arginine vasopressin (AVP, ADH) and administration of a variety of drugs, including diuretics, carbamazepine, chlorpropamide, and antipsychotic medications.
In addition to hypoadrenocorticism, hyperkalemic syndromes in older patients may be related to decreased renal function, excessive use of potassium-sparing diuretics (particularly when oral potassium intake is high, as it is with use of a salt substitute), administration of angiotensin-converting enzyme (ACE) inhibitors, and hypoaldosteronism. The last is rarely encountered as an isolated biochemical abnormality in the adrenal cortex; more commonly it is due to inadequate renin production by the kidney (hyporeninemic hypoaldosteronism). The frequency of hyporeninemic hypoaldosteronism is increased in patients with non-insulin-dependent diabetes mellitus (NIDDM) when modest decreases in glomerular filtration rate have supervened. As pointed out previously, the diagnosis of hyporeninemic hypoaldosteronism is difficult to establish in the elderly because of the physiologic changes in the renin-aldosterone axis that occur in the course of normal aging.

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