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ENDOCRINOLOGY..........Updated July 2018 David A. Gruenewald, MD; Alvin M. Matsumoto, MD

KEY POINTS

  • Thyroid-stimulating hormone (TSH), or thyrotropin, levels may normalize within 1–2 years in up to half of older adults with a single mildly increased TSH level; therefore, hypothyroidism should be confirmed by the combination of a persistently increased TSH concentration and a decreased free T4 level.

  • In older adults with mild subclinical hypothyroidism, levothyroxine supplementation has not been shown to be beneficial for relief of symptoms, or to reduce the risk of cognitive dysfunction or cardiovascular events. Individuals with more marked symptoms and TSH levels of at least 10 mIU/L are more likely to experience symptomatic improvement with levothyroxine.

  • Chronic adrenal insufficiency presents with nonspecific symptoms such as anorexia, nausea, weight loss, abdominal pain, weakness, hypotension, and impaired function. It should be considered as a cause of unexplained cachexia, loss of mobility, and hypotension, even in the absence of hyponatremia and hyperkalemia.

  • Vitamin D deficiency is common and not only contributes to bone loss due to osteoporosis and osteomalacia but also has been associated with muscle weakness and falls. In meta-analyses of randomized, controlled trials (RCTs), reduced hip fracture and mortality risk with vitamin D supplementation in older adults living in institutions has been reported, but reduced risk of falls or fractures in community-dwelling older adults has not been consistently found.

  • The most common causes of hypercalcemia are primary hyperparathyroidism in outpatients, and malignant hypercalcemia (eg, caused by squamous cell cancers, breast cancer, myeloma, and lymphoma) in the inpatient setting.

  • There is little evidence of long-term clinical benefit from supplementation with dehydroepiandrosterone (DHEA) or testosterone in older adults.

Impaired homeostatic regulation, a hallmark of aging, occurs in many endocrine systems but may become manifest only during stress. For example, fasting blood glucose concentrations change little with normal aging, increasing 1–2 mg/dL per decade of life. In contrast, glucose concentrations after glucose challenge (eg, postprandially) increase much more in healthy older adults than in young adults. In some cases, a loss of function in one aspect of endocrine function can result in a compensatory change in endocrine regulation and be associated with changes in catabolism to maintain homeostasis. For example, decreased testosterone production by the testes, which is seen in many older men, may be partially compensated for by an increase in secretion of pituitary luteinizing hormone and offset by a decrease in metabolism of testosterone. In other instances, compensatory changes or changes in hormone catabolism do not fully offset age-related impairment in endocrine functions, as illustrated by the age-related decline in basal serum aldosterone concentrations. In this case, a decline in aldosterone clearance fails to offset the decrease in aldosterone secretion.

As with diseases in other organ systems, endocrine disorders in older adults often display nonspecific, muted, or atypical symptoms and signs. Some of these presentations are well-defined syndromes that are seen almost exclusively in older adults, such as apathetic thyrotoxicosis or hyperosmolar nonketotic state in patients with type 2 diabetes mellitus. However, more commonly, endocrine disorders present with subtle, nonspecific symptoms, such as cognitive impairment or reduced functional status; some patients may have no complaints. Indeed, the diagnosis of endocrinopathies such as primary hyperparathyroidism, type 2 diabetes mellitus, hypothyroidism, and hyperthyroidism in older adults commonly results from abnormalities found on routine laboratory testing. Finally, nodules are more common with aging in all glands and are often detected incidentally on imaging studies. The presence of a nodule per se is not necessarily an indication of a disease needing treatment in older adults.

Laboratory evaluation of older adults for endocrine disorders can be complicated by coexisting medical illnesses and medications. For example, the presence of serious acute or chronic nonthyroidal illness can lead to the mistaken impression of a thyroid disorder because of an increase or decrease in T4 concentrations and sometimes increased or decreased TSH concentrations in sick but euthyroid older adults. As a result of biological and assay variability, hormone concentrations may vary considerably in the short term. Therefore, abnormal hormone measurements should always be repeated to confirm endocrine dysfunction, and a stimulatory or suppression test may be required to firmly establish a diagnosis of endocrine hypofunction or hyperfunction, respectively. Furthermore, ranges of normal laboratory values for endocrine testing are commonly established in younger adults, and even age-adjusted norms for laboratory tests may be confounded by the inclusion of older adults who are ill. Consequently, normal ranges for healthy older adults are not available for many laboratory tests.

THYROID DISORDERS

With aging, a decrease in T4 secretion is balanced by a decrease in T4 clearance, resulting in unchanged circulating T4 concentrations (Table 1). T3 concentrations are unchanged until extreme old age, when they decrease slightly, possibly reflecting a decrease in 5ʹ-deiodinase activity with aging. T3 concentrations are also commonly decreased in nonthyroidal illness because of decreased peripheral conversion of T4 to T3. The distribution of TSH concentrations shifts toward a higher level with increasing age, with the 97.5th percentile of TSH distribution of 6.3–7.5 mIU/L in adults ≥80 years old, contributing to the higher prevalence of biochemical hypothyroidism. This shift toward higher TSH concentrations with age appears also to apply to extremely long-lived individuals. Nonspecific, atypical, or asymptomatic presentations of thyroid disease are common in older adults. Laboratory testing in stable outpatients using TSH measurements is the most reliable way to identify hypothyroidism or hyperthyroidism in older adults who are not acutely ill. There is no consensus regarding screening asymptomatic older adults for hypo- and hyperthyroidism. However, the prevalence of hypothyroidism and hyperthyroidism is sufficiently high to warrant TSH testing in all older adults with a recent decline in clinical, cognitive, or functional status, or on admission to a nursing home. However, the results of thyroid function testing can be confusing in euthyroid patients with significant concurrent illnesses (discussed below).

Table 1—Circulating Hormone Levels in Normal Aging, Hypothyroidism, and Hyperthyroidism

Circulating Hormone Level
Normal Aging
Subclinical Primary Hypothyroidism
Overt Primary Hypothyroidism
Secondary Hypothyroidism
Subclinical Hyperthyroidism
Overt Hyperthyroidism
T4
NL
NL
NL
­ ↑ (may be NL in T3 toxicosis)
T3
↓ or NL
Not useful to measure*
Not useful to measure*
NL
NL or ­↑(­↑in T3 toxicosis)
TSH
NL or ­↑
­
­
NL or ↓
T4=thyroxine, T3=triiodothyronine, TSH=thyroid-stimulating hormone
↓ = decreased, ­ ↑ = increased, NL = within normal limits
* T3 is within normal limits in about 1/3 of overtly hypothyroid patients and does not fall below normal range until free T4 is already low.

Hypothyroidism

Most prevalence estimates of hypothyroidism in older adults range from 0.5% to 5% for overt disease, depending on the population studied. As in younger people, most cases of hypothyroidism in older adults are due to chronic autoimmune thyroiditis (Hashimoto disease). Symptoms of hypothyroidism are often atypical in older adults. Some clinical features of hypothyroidism (eg, dry skin, decreased skin turgor, slowed mentation, weakness, constipation, anemia, hyponatremia, arthritis, paresthesias, peripheral neuropathy, gait disturbances, edema, and increased myocardial fraction of creatine kinase) can misleadingly suggest other diseases. Furthermore, these symptoms usually have an insidious onset and a slow rate of progression. Consequently, the diagnosis of hypothyroidism is rarely made based on clinical examination in older adults, and laboratory testing for a serum TSH level is necessary to detect most cases of hypothyroidism in this population. In addition, older adults with mild hypothyroidism who develop serious nonthyroidal illness may rapidly become severely hypothyroid, a situation that increases susceptibility to myxedema coma. Demented older adults with hypothyroidism rarely recover normal cognitive function with thyroid replacement, but cognition, functional status, and mood may improve with treatment of the hypothyroidism.

Subclinical hypothyroidism is characterized by increased serum TSH (>4.5 mIU/L) and normal free T4 concentrations and is defined biochemically without regard to the presence or absence of clinical symptoms (Table 1). Subclinical hypothyroidism has been reported in up to 15% of people ≥65 years old and is more common in women. However, up to 70% of these individuals have values within their age-specific 97.5th percentile limits, and those with exceptional longevity have higher TSH levels than those 70 years old. Furthermore, TSH levels increased over a 13-year longitudinal follow-up of an aging cohort (mean age 85 years at final assessment). These findings suggest that using an age-specific TSH reference range would reduce the risk of mislabeling many older adults as having subclinical hypothyroidism. Epidemiologic studies in older adults have not found a consistent association between subclinical hypothyroidism and risk of coronary heart disease mortality or total mortality. Overall, meta-analyses in patients with subclinical hypothyroidism have reported a clearer association between increased risk of cardiovascular disease events in persons younger than 65 years of age and in older adults with TSH levels ≥10 mIU/L.

In observational studies of patients with subclinical hypothyroidism, a lower risk of ischemic heart disease and heart failure events has been reported, as well as all-cause mortality, in patients treated with levothyroxine than in untreated patients. However, the lower risk of ischemic heart disease events associated with treatment over a 7.6-year period occurred only in patients <70 years old, not in patients ≥70 years old. In randomized controlled trials (RCTs) of T4 supplementation in older adults, those with subclinical hypothyroidism did not show a consistent improvement in symptoms, although those with TSH concentrations >10–12 mIU/L and those with greater symptom burden may derive symptomatic benefit. Other studies found that levothyroxine may improve surrogate markers of cardiovascular risk (eg, serum cholesterol levels) and lessen the effects of some comorbidities in older adults, eg, reduced rate of decline in renal function with levothyroxine treatment in patients with chronic kidney disease (mean age 63.2 years, mean TSH 8.86 mIU/L, in study participants).

Potentially confusing scenarios in the diagnosis of hypothyroidism may occur in nonthyroidal illness. By itself, an increased TSH concentration is usually due to primary hypothyroidism, but TSH levels may be low during acute nonthyroidal illness and then transiently increase during the recovery phase. Importantly, TSH levels normalize within 12 months in up to 50% of older adults with a single increased TSH level >5.5 mIU/L. Therefore, the diagnosis of hypothyroidism should be confirmed by the combination of a persistently increased TSH concentration and a decreased free T4 level. The most common alteration in thyroid hormone levels in nonthyroidal illness is a decrease in serum T3 levels (low T3 syndrome) with normal TSH levels, occurring even in mild nonthyroidal illnesses. In severe nonthyroidal illnesses, circulating total T4 levels decrease (low T4 syndrome) without increased TSH concentrations. Free T4 concentrations are usually normal in the low T4 syndrome. Thyroid hormone supplementation has not been shown to be beneficial in these patients, and it may be harmful. An inappropriately normal or low TSH concentration found in conjunction with a low free T4 concentration suggests secondary hypothyroidism, which is also characterized by the presence of hypopituitarism (deficiencies in other pituitary hormones) (Table 1). To minimize confusion between thyroid disease and the nonthyroidal illness syndrome, thyroid function testing in seriously ill patients should be performed only if thyroid dysfunction is strongly suspected, with repeat testing performed after recovery from acute illnesses. Endocrinology referral is indicated to guide testing and management in many of these situations.

T4 replacement is usually started at a low dosage in older adults (eg, 25 mcg/d, or 50 mcg/d in those without evidence of coronary heart disease), increasing the dosage every 4–6 weeks until TSH concentrations reach the normal range. However, in patients with severe cardiac disease, it may be prudent to begin replacement therapy at even lower dosages (eg, 12.5 mcg/d) if patients have minimal symptoms of hypothyroidism (SOE=D). In these patients, thyroid replacement should not be withheld for fear of exacerbating cardiac disease; instead, the goal is to reduce or eliminate symptoms of hypothyroidism while minimizing the potential for exacerbating cardiac symptoms, such as angina. Adverse effects may occur more commonly in patients taking thyroid extract than with levothyroxine, and there is insufficient information about the safety and benefits of free triiodothyronine surges occurring shortly after ingestion of thyroid extracts; therefore, the use of thyroid extract cannot be recommended. Furthermore, combination therapy with levothyroxine plus L-triiodothyronine is not recommended in older adults because of an increased risk of cardiovascular complications.

Older adults who are severely hypothyroid at presentation should receive higher initial T4 replacement doses of 50–100 mcg orally, or as high as 200 mcg IV followed by 100 mcg IV daily until oral intake is possible for those with myxedema stupor or coma, even if there is preexisting heart disease (SOE=D). Older adults with severe hypothyroidism or myxedema stupor or coma should also be tested to exclude concomitant adrenal insufficiency and should be given stress doses of glucocorticoids before T4 to avoid precipitating an adrenal crisis with T4 replacement.

Thyroid hormone requirements decrease with age because of a decreased clearance rate; T4 replacement dosages are as much as a third lower in older than in younger adults. The average T4 replacement dosage in older adults is approximately 110 mcg/d. However, in many older hypothyroid patients, low T4 doses (25–50 mcg/d) are sufficient to normalize serum TSH levels. Thyroid hormone is best taken fasting to avoid reduced absorption related to food and other medications (eg, calcium, iron, or soy). The target TSH level should be higher in older than in younger adults (4–7 mIU/L [SOE=D]). Over-replacement of thyroid hormone should be avoided, because osteopenia and exacerbation of heart disease may occur. With correction of the hypothyroid state, the clearance rate of medications such as antiepileptics, digoxin, and opioid analgesic agents may be affected, necessitating dosage adjustments.

Hyperthyroidism

Hyperthyroidism develops in 0.5%–2.3% of older adults, and 15%–25% of all cases of thyrotoxicosis are in adults ≥60 years old. In the United States, most cases in older adults are due to Graves disease, but toxic multinodular goiter and autonomously functioning adenomas are more common in older than in younger adults, especially in populations with low iodine intake.

Hyperthyroidism often presents with vague, atypical, or nonspecific symptoms in frail older adults. Many findings that are common in younger adults (eg, tremor, hyperkinesis, heat intolerance, tachycardia, frequent bowel movements, ophthalmopathy, increased perspiration, goiter, brisk reflexes) are less common or absent in older adults, whereas other manifestations, such as atrial fibrillation, heart failure, weight loss, muscle atrophy, and weakness, are more common in older adults. Older adults more often present with a paucity of symptoms than young adults, which may lead to delays in treatment and poorer outcomes. Older adults can present with apathetic thyrotoxicosis, a well-known clinical presentation of hyperthyroidism that is rarely seen in younger adults, in which the usual hyperkinetic presentation is replaced by depression, inactivity, lethargy, or withdrawn behavior, often in association with symptoms such as anorexia, weight loss, constipation, muscle weakness, or cardiac symptoms. A low TSH concentration is associated with a 3-fold higher risk of developing atrial fibrillation within 10 years, and hyperthyroidism is present in 13%–30% of older adults with atrial fibrillation. Hyperthyroidism is a cause of secondary osteoporosis and should be considered in the evaluation of patients with decreased bone mass.

A highly sensitive TSH test is adequate as an initial test for hyperthyroidism in relatively healthy older adults, but the diagnosis should be confirmed with free T4 and T3 tests (Table 1). Most asymptomatic older adults with low serum TSH concentrations are clinically euthyroid; they have normal T4 and T3 concentrations, and normal TSH on repeat testing 4–6 weeks later. T3 toxicosis, with increased T3 but normal T4 concentrations (Table 1), is seen in a minority of hyperthyroid patients, but it is more common with aging, especially in older adults with toxic adenomas or toxic multinodular goiter. T4 toxicosis, with a low serum TSH level together with high serum T4 and normal to low T3 levels, may be seen in hyperthyroid older patients with decreased conversion of T4 to T3 associated with aging and concomitant nonthyroidal illness. Diagnostic confusion can occasionally occur in euthyroid patients with nonthyroidal illness or medications causing increased T4 concentrations (high T4 syndrome). Finally, serum TSH levels may be low in euthyroid patients with severe nonthyroidal illnesses (eg, associated with glucocorticoid and dopamine treatment and prolonged fasting).

Radioactive iodine (RAI) uptake and scanning may be useful in determining the etiology of hyperthyroidism. Increased RAI uptake in one or more nodules may occur in toxic multinodular goiter or toxic adenomas, whereas diffusely increased uptake may be seen in Graves disease. Decreased RAI uptake is consistent with thyroiditis, exogenous thyroid supplementation, or iodine-induced hyperthyroidism. Endocrinology consultation may be helpful to assist in the interpretation of thyroid function tests.

Subclinical hyperthyroidism is defined biochemically as a low or undetectable serum TSH level with normal free T4 and T3 levels (Table 1), with or without signs and symptoms (despite the “subclinical” label) consistent with thyroid hormone excess. Its prevalence increases with age, ranging from <1% to as high as 10%, depending on the population studied. However, exogenous subclinical hyperthyroidism is present in 20%–40% of older patients on levothyroxine supplementation. Overt hyperthyroidism (Table 1) develops in 1%–2% of patients per year with a TSH concentration of <0.1 mIU/L but is uncommon in those with TSH concentrations of 0.1–0.45 mIU/L. TSH concentrations normalize over time in many of these patients, although in those with undetectable TSH levels, persistence of subclinical hyperthyroidism is the most common outcome.

There is good evidence for an association between subclinical hyperthyroidism and atrial fibrillation in those with TSH concentrations <0.45 mIU/L, especially when concentrations are <0.1 mIU/L. Furthermore, a meta-analysis of individual level data from 10 prospective cohort studies concluded that there is an increased risk of cardiovascular (HR 1.29; 95% CI, 1.02–1.62) and total mortality (HR 1.24; 95% CI, 1.06–1.46) in patients with subclinical hyperthyroidism. The risk of cardiovascular mortality was higher in those with TSH levels <0.1 mIU/L than in those with levels of 0.1–0.45 mIU/L. Observational data strongly suggest that subclinical hyperthyroidism accelerates bone mineral density (BMD) loss and increases fracture risk, especially in people with a TSH concentration <0.1 mIU/L, but even thyroid function within the high-normal range is associated with reduced BMD and increased risk of hip and other nonvertebral fractures. In postmenopausal women, ongoing bone losses associated with TSH concentrations <0.1–0.2 mIU/L are stabilized by treating the hyperthyroidism. Data on the association between subclinical hyperthyroidism and cognitive impairment and the development of dementia are conflicting.

Treatment of hyperthyroidism should be strongly considered (and endocrinology consultation is strongly advised) in all adults >60 years old with persistently low TSH concentrations <0.1 mIU/L, based on the increased risk of atrial fibrillation, congestive heart failure, osteoporosis, and evidence of progressively increased mortality risk with age in these individuals (SOE=C). Current guidelines suggest treatment of older adults with milder subclinical hyperthyroidism (persistently suppressed TSH levels 0.1–0.4 mIU/L); the presence of symptoms or comorbidities, including heart disease and osteoporosis, may weigh in favor of treatment. Of note, a prospective observational study in women >65 years old found that symptoms, incidence of atrial fibrillation, BMD, and bone turnover markers were similar in people with TSH levels between 0.1–0.4 mIU/L compared to age-matched euthyroid controls. While the duration of mild subclinical hyperthyroidism in these participants was unknown and adverse skeletal and cardiac effects are possible during long-term follow-up, these findings suggest that immediate treatment of mild subclinical hyperthyroidism may be unwarranted in some older adults (eg, those without skeletal and heart comorbidities). In such cases, it may be appropriate to consider treatment if these problems arise during follow-up.

RAI therapy under the supervision of an endocrinologist is the treatment of choice for most older adults with hyperthyroidism caused by Graves disease or toxic nodular thyroid disease, although antithyroid thiourea drugs (methimazole or propylthiouracil) are commonly used as well. RAI treatment is usually curative in patients with toxic adenoma, but higher or repeated doses are often necessary for patients with toxic multinodular goiter. Thiourea treatment should be considered before RAI (SOE=B), but some experts believe the risk of exacerbating thyrotoxicosis is sufficiently low that the risks of these drugs may outweigh the anticipated benefit. β-Blocking agents are helpful to manage symptoms such as tachycardia, tremor, and anxietyOL (SOE=B), and should be considered even in asymptomatic older patients to lessen the increased risk of complications due to worsening of hyperthyroidism (SOE=C). Patients receiving β-blocking agents should be monitored for changes in cardiopulmonary function. Older adults with thyrotoxicosis may also require treatment of coexisting congestive heart failure, myocardial ischemia, and atrial arrhythmias, including atrial fibrillation. Treatment with β-blocking agents may be sufficient to manage cardiovascular morbidity due to subclinical hyperthyroidism, notably atrial fibrillation.

After RAI therapy, patients should be monitored by serial measurements of TSH concentration for eventual development of hypothyroidism and for persistent or recurrent hyperthyroidism. With resolution of hyperthyroidism, the clearance rate of other medications may decrease, necessitating dosage adjustments to avoid excessive drug concentrations.

Nodular Thyroid Disease and Thyroid Cancer

The incidence of multinodular goiter increases with age. Multinodular goiters often have autonomously functioning areas, and administration of exogenous thyroid hormone to suppress these goiters can cause iatrogenic hyperthyroidism. Older adults with multinodular goiter can develop iodine-induced thyrotoxicosis after receiving radiocontrast or amiodarone.

Approximately 90% of women ≥70 years old and 60% of men ≥80 years old have thyroid nodules. Most of these nodules are nonpalpable and are detected incidentally on highly sensitive ultrasound or imaging studies done for other reasons (eg, carotid duplex ultrasound). Thyroid cancer is present in 4%–6.5% of thyroid nodules, and the prevalence of cancer is higher in adults >60 years old with nodules, especially men. Incidentally discovered nonpalpable nodules are as likely to be malignant as palpable nodules. The reported incidence of thyroid cancer has increased markedly in recent decades while thyroid cancer mortality rates have remained stable, reflecting increased detection of low-risk cases of papillary thyroid cancer. In 2017, the U.S. Preventive Services Task Force (USPSTF) recommended against screening for thyroid cancer after determining that the harms exceed the benefits. Of note, studies reviewed by the USPSTF involved primarily younger and middle-aged adults, and the increase in thyroid cancer incidence is much less evident in older than in middle-aged adults. Although the incidence of differentiated thyroid cancers is similar in older and younger adults, thyroid lymphomas are more common in older adults and anaplastic thyroid carcinomas are found almost exclusively in this population. Additionally, even well-differentiated papillary and follicular carcinomas are more aggressive and are associated with increased mortality in older adults. Based on the foregoing, the risk of thyroid cancer over-diagnosis and over-treatment may be higher in younger and middle-aged people than in older adults.

Ultrasound of the thyroid is the most sensitive test to detect thyroid nodules. Screening ultrasonography of the thyroid is not indicated in the general population, but ultrasonography and a serum TSH level are indicated in all older adults with known or suspected thyroid nodules or multinodular goiter (SOE=A) (Table 2). Autonomously functioning thyroid nodules are rarely malignant, so no further evaluation for cancer is generally required in patients with low TSH concentrations and a “hot” (increased RAI uptake) nodule on radionuclide thyroid scanning that corresponds to a palpable nodule. Radionuclide thyroid scanning is not indicated in individuals with normal or increased TSH levels; these scans cannot conclusively distinguish whether a “cold” (nonfunctioning) nodule is benign or malignant, and fine-needle aspiration (FNA) is needed to exclude malignancy (SOE=A). Endocrinology referral is generally indicated for further diagnostic evaluation and management.

Table 2—Indications for Thyroid Ultrasonography
Screening
  • History of head and neck irradiation
  • Multiple endocrine neoplasia type 2
  • Family history of thyroid cancer*
Diagnosis
  • Unexplained cervical lymphadenopathy
  • All patients with known or suspected thyroid nodules or multinodular goiter
  • Selection of thyroid nodule(s) for biopsy
  • Guidance for fine-needle aspiration of single or multiple thyroid nodules
  • Identification of nodular characteristics suspicious for cancer
  • Thyroid nodule discovered incidentally on CT, MRI, or PET scanning
* Current guidelines do not recommend for or against screening ultrasonography in people with familial follicular cell–derived differentiated thyroid cancer because of lack of evidence that this would lead to reduced morbidity or mortality.

In current guidelines, risk stratification and decisions to pursue FNA are based both on ultrasound characteristics and size of the nodule. In general, in people without known thyroid cancer risk factors, only nodules >1 cm require evaluation for malignancy because of their potential to be clinically significant cancers. Nodules that are purely cystic do not require FNA. Benign thyroid nodules on FNA should be followed with ultrasonography within 12 to ≥24 months after the initial procedure, as determined by risk stratification based on ultrasonography pattern (SOE=D). FNA should be repeated when the results are nondiagnostic. If FNA cytology is diagnostic of or suspicious for a malignancy, surgery should be performed (SOE=A). Lobectomy may be considered for some low-risk differentiated thyroid cancers (DTC), eg, lesions <4 cm. Molecular testing may help to reduce the number of diagnostic thyroid surgeries in patients ultimately found to have benign thyroid nodules. Postoperative RAI should be administered to patients with high-risk DTC and some with intermediate-risk DTC but not to low-risk patients (SOE=B). Levothyroxine suppressive therapy may be indicated to reduce the risk of cancer recurrence and mortality for patients with thyroid cancer after near-total or total thyroidectomy, but adverse cardiac effects and osteoporosis can occur with long-term thyroid suppression. Current guidelines propose ongoing risk stratification to determine the degree of optimal TSH suppression (SOE=C). β-Blocking agentsOL and bone antiresorptive agentsOL can help minimize these untoward effects (SOE=D).

Importantly, in a nomenclature revision, encapsulated papillary neoplasms now known as noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) behave in a highly indolent fashion and are no longer considered malignant. Although thyroid lobectomy is still required to diagnose NIFTP, more extensive completion thyroidectomy and postoperative RAI are not indicated for this condition.

DISORDERS OF PARATHYROID AND CALCIUM METABOLISM

Important changes occur with aging in several systems that regulate calcium homeostasis, ultimately leading to decreased bone mass and, in some cases, osteoporosis in older adults (Table 3). The net effect of these changes is to increase circulating concentrations of parathyroid hormone (PTH), which increases 30% between 30 and 80 years of age. Serum calcium concentrations remain normal with the increase in PTH, but the balance between bone resorption and bone formation is changed in favor of resorption, resulting in decreased bone mass and increased risk of osteoporosis with aging.

Table 3—Causes of Age-Related Changes in Calcium Homeostasis

Decreased concentrations of 25(OH)D and 1,25(OH)2D
Decreased renal 1α-hydroxylase activity
Decreased vitamin D synthesis by the skin
Decreased sunlight exposure (housebound and institutionalized older adults)
Decreased intestinal absorption of dietary calcium
Inadequate dietary calcium and vitamin D intake
Decreased intestinal responsiveness to 1,25(OH)2D
Decreased gastric acid secretion
Lactase deficiency (causing avoidance of dairy products)
Increase in serum parathyroid hormone concentrations
Slight decrease in serum calcium concentrations
Decreased renal clearance of parathyroid hormone
Decreased parathyroid hormone responsiveness

Vitamin D Deficiency

Vitamin D deficiency, defined as a circulating 25(OH)D level <20 ng/mL, is very common. In the National Health and Nutrition Examination Survey (NHANES) 2000–2004, 26.6% of men and 33.6% of women of all races >70 years old had serum 25(OH)D levels <20 ng/mL. Increased bone turnover and bone loss, especially of cortical bone, is a major consequence of the secondary hyperparathyroidism that arises in vitamin D–deficient older adults. Beyond its skeletal effects, vitamin D deficiency is associated with muscle weakness and can contribute to fall risk in some individuals.

Patients with severe vitamin D deficiency (25[OH]D levels <10 ng/mL) are commonly treated with 50,000 IU/week of vitamin D2 or D3 orally for 8–12 weeks followed by vitamin D3 at 800 IU/d thereafter, but the comparative efficacy of this practice versus other dosing regimens is unknown. The dose above which vitamin D becomes toxic is unclear, but high-dose vitamin D supplementation, eg, doses well above the IOM-recommended safe upper limit of 4,000 IU/d for prolonged periods, may cause vitamin D intoxication with hypercalciuria (the initial manifestation of toxicity), hypercalcemia, impaired kidney function, and bone loss. Exceptions include individuals with malabsorption (eg, celiac disease) or severe obesity, who may require vitamin D supplementation in very large doses to maintain vitamin D sufficiency.

Although current data are insufficient to determine the optimal dose, a dose adequate to maintain 25(OH)D levels >30 ng/mL is prudent and safe. Maintaining adequate calcium intake (1,000–1,500 mg/d from the diet and supplements) is also important for bone health and prevention of secondary hyperparathyroidism. Daily dietary intake of calcium (mainly in dairy products) should be factored in, which in some people may obviate the need for calcium supplements. Obese people are at high risk of vitamin D deficiency, likely because vitamin D is fat soluble and sequestered in body fat. Consequently, the increment in 25(OH)D levels after either sunlight exposure or oral vitamin D supplementation is less in obese adults than in nonobese adults, and longer periods of vitamin D supplementation may be required to normalize 25(OH)D levels in obese vitamin D–deficient individuals. Obese individuals (BMI >30 kg/m2), people taking medications that accelerate vitamin D metabolism such as phenytoin and phenobarbital, and those with malabsorption syndromes who are vitamin D–deficient often require vitamin D dosages much higher than 1,000 IU/d to normalize 25(OH)D levels.

The main form of vitamin D in circulation, 25(OH)D, is measured in serum to evaluate vitamin D status. Measurement of 1,25(OH)2D3, the active metabolite of vitamin D, is not useful to assess in most individuals, because levels are normal or increased in vitamin D–deficient individuals with secondary hyperparathyroidism. Levels of 1,25(OH)2D3 are mostly used clinically in patients with late-stage chronic kidney disease.

Importantly, despite having lower total 25(OH)D levels, black Americans have higher BMD and lower fracture risk than white Americans; the concentration of bioavailable 25(OH)D may in fact be similar to that of white Americans when vitamin D–binding protein is considered. Black Americans have higher intestinal calcium absorption efficiency and lower urinary calcium excretion than white Americans and may have skeletal resistance to secondary hyperparathyroidism. Consequently, modestly low 25(OH)D levels in black Americans may not necessarily indicate true vitamin D deficiency, and vitamin D deficiency may be overdiagnosed in this population.

Hypercalcemia

Primary hyperparathyroidism (PHPT) and malignancy are the most common causes of hypercalcemia in older adults. The annual incidence of PHPT is approximately 1 per 1,000, and the disease is 3-fold more prevalent in women than in men. Most patients with PHPT are asymptomatic, and the diagnosis is made after an incidental finding of hypercalcemia on a chemistry battery. When the disease is symptomatic, older adults are more likely than younger adults to present with neuropsychiatric symptoms that may be subtle, such as depression and cognitive impairment, or with neuromuscular problems such as proximal muscle weakness and osteoporosis. Typical laboratory findings in PHPT and other common causes of hypercalcemia are shown in Table 4. The diagnosis of PHPT is confirmed with an increased or high normal PTH concentration, using an assay for intact PTH, in the presence of hypercalcemia. A low 24-hour urinary calcium excretion distinguishes familial hypocalciuric hypercalcemia from PHPT. Familial hypocalciuric hypercalcemia is associated with longstanding mild hypercalcemia, does not respond to parathyroidectomy, and is generally not associated with complications. Normocalcemic PHPT may be identified during the evaluation of older adults with reduced BMD. Causes of secondary hyperparathyroidism should be excluded in these patients, including renal failure, vitamin D deficiency, calcium malabsorption (eg, from celiac disease), and urinary calcium loss due to the use of loop diuretics.

Table 4—Typical Laboratory Results in the Differential Diagnosis of Hypercalcemia

Laboratory Test
Primary Hyperparathyroidism
Humoral Hypercalcemia of Malignancy
Local Osteolytic Hypercalcemia
Serum calcium
↑ or ↑↑
↑ or ↑↑
Serum phosphate
↓ or low-normal
Urine calcium
Parathyroid hormone
↓↓
↓↓
Parathyroid hormone-related peptide
0
0
NOTE: The diagnosis of malignancy-related hypercalcemia is normally straightforward, and extensive diagnostic testing is rarely required.
↑ = increased, ↑↑ = markedly increased, ↓ = decreased, ↓↓ = markedly decreased, 0 = undetectable

Indications for parathyroid surgery are shown in Table 5. In RCTs evaluating parathyroidectomy in patients with mild, apparently asymptomatic disease, BMD and other measures that may be relevant to quality of life improved after parathyroidectomy. Asymptomatic patients can safely be followed without surgery at least for several years; many of these patients remain stable without deterioration of biochemical indices or BMD for up to 10 years. However, after 8–10 years, about 25% of these patients develop progressive disease, including worsening hypercalcemia, hypercalciuria, and reductions in BMD. Bone density eventually declines in most patients after 10–15 years, especially at cortical sites such as the femoral neck or forearm. Parathyroidectomy can be performed safely in older adults, even those >80 years old, who may experience improvements in symptoms comparable to those in younger adults, as well as improvements in function (SOE=B). Although most people with PHPT are older adults, only 1 in 4 patients >70 years old who meet surgical criteria undergo parathyroidectomy. In general, surgery should be offered to all older adults meeting criteria who have minimal perioperative risk and sufficient life expectancy. The best outcomes are achieved by surgeons who have extensive experience with the procedure.

Table 5—Indications for Parathyroid Surgery in Primary Hyperparathyroidism

Symptomatic primary hyperparathyroidism
Asymptomatic primary hyperparathyroidism in the following situations:
  • Total serum calcium concentrations >1 mg/dL above the normal range
  • Creatinine clearance <60 mL/min
  • Markedly decreased BMD (T score below −2.5 at lumbar spine, hip, or distal ⅓ of radius on bone densitometry)
  • Vertebral fracture
  • Nephrolithiasis or nephrocalcinosis on imaging
  • 24-hour urine calcium >400 mg/d, together with increased stone risk by biochemical stone risk analysis
  • Neurocognitive and neuropsychiatric symptoms attributable to primary hyperparathyroidism (endorsed by some but not all guidelines)
  • Consider in some patients with cardiovascular disease on a case-by-case basis to mitigate cardiovascular sequelae (endorsed by some but not all guidelines)*
BMD=bone mineral density
* Available data linking primary hyperparathyroidism and cardiovascular disease are observational.

Asymptomatic patients who are managed conservatively should avoid lithium carbonate, thiazide diuretics, volume depletion, and immobilization. Baseline assessment in these patients should include blood pressure; serum calcium, phosphate, and creatinine; creatinine clearance; and bone densitometry. Follow-up assessments should include serum calcium and creatinine every 12 months and bone densitometry (at 3 sites) every 12–24 months (SOE=C). Some manifestations of PHPT such as reduced BMD and fracture risk are exacerbated by vitamin D deficiency and improve with vitamin D repletion. Moderate calcium (eg, 1,200 mg/d [SOE=C]) and vitamin D supplementation (eg, starting dose of 600–1,000 IU/d with a goal of 25(OH)D level ≥20–30 ng/mL [SOE=C]) should be maintained. In addition, these patients should be followed clinically for development of nephrolithiasis, fractures caused by minimal trauma, and neuropsychiatric or neuromuscular symptoms.

Medical management of PHPT may be appropriate in nonsurgical candidates when it is desirable to lower the serum calcium level, increase BMD, or both. Options for patients with low BMD include the bisphosphonate alendronateOL, which improves BMD in patients with PHPT without consistently affecting calcium or PTH concentrations (SOE=A). However, it is unknown whether alendronate or other bisphosphonates reduce fracture risk in these patients. Cinacalcet, a calcimimetic agent that inhibits parathyroid cell function, reduces or normalizes serum calcium concentrations and reduces PTH concentrations during long-term treatment of PHPT, but BMD is not increased. Accordingly, the role of cinacalcet is limited to management of symptomatic or severe hypercalcemia in patients who cannot undergo parathyroid surgery (SOE=C). Limited data suggest that combined therapy with cinacalcet and a bisphosphonate may accomplish both calcium lowering and improvement in BMD in people who have both low BMD and severe hypercalcemia (SOE=B). Estrogen–progestin therapy increases BMD in postmenopausal women with PHPT but without consistent effects on serum calcium or PTH levels. Estrogen–progestin therapy may be a useful option for women who are not surgical candidates, especially those with menopausal symptoms, but the benefits and risks must be considered in light of contraindications to this therapy.

In hospitalized patients, the most common cause of hypercalcemia is a malignancy that produces PTH-related peptide (PTHrp) (Table 4), often referred to as humoral hypercalcemia of malignancy, with hypercalcemia resulting primarily from increased net bone resorption. The presence of an underlying cancer is usually evident on examination and routine diagnostic testing. These patients are often managed primarily by consulting oncologists, and treatment of the underlying cancer may improve and prevent recurrence of hypercalcemia. Squamous cell cancers of the lung or head and neck are common causes of hypercalcemia due to PTHrp production. Other common malignancies associated with hypercalcemia include breast cancer, lymphoma, and myeloma, although the mechanisms of the hypercalcemia associated with these malignancies are usually not PTHrp-mediated and may be responsive to glucocorticoid treatment. Acute treatment for hypercalcemia of malignancy includes volume replacement with intravenous saline. A parenteral bisphosphonate such as pamidronate or zoledronic acid should be given, along with treatment for the underlying malignancy, if possible. In addition to their usefulness in treatment of hypercalcemia, high-potency bisphosphonates such as zoledronic acid may decrease bone pain and the risk of pathologic fractures in patients with osteolytic bone metastases from a variety of cancers (SOE=A). Potential nephrotoxicity associated with these agents may be minimized by adhering to recommended dosages and infusion times, but these agents should be used cautiously, if at all, in people with a creatinine clearance of ≤30 mL/min. Cancer patients receiving repetitive dosing of parenteral bisphosphonates who have had recent dental extractions, dental implants, poorly fitting dentures, or preexisting mandibular disease, or receiving high-dosage glucocorticoid treatment are at increased risk of osteonecrosis of the jaw. Denosumab is an approved alternative to bisphosphonates for treatment of hypercalcemia of malignancy refractory to bisphosphonates. It may also prevent skeletal-related events (eg, fractures, pain from bone metastases) in people with bone metastases from solid tumors but not for patients with multiple myeloma, and it may be useful for patients in whom bisphosphonates are contraindicated because of severe renal impairment. Hypercalcemic patients with vitamin D deficiency may become hypocalcemic after receiving bisphosphonates or denosumab.

Paget Disease of Bone

Paget disease is characterized by localized areas of increased bone remodeling, resulting in a change in bone architecture and an increased tendency to deformity and fracture. Its prevalence increases with aging, affecting 2%–5% of people ≥50 years old. Paget disease is usually asymptomatic and localized and is often diagnosed as an incidental finding on radiographs or during evaluation for an unexplained increase in serum alkaline phosphatase. The most commonly affected sites are the pelvis, spine, femur, tibia, and skull. When Paget disease is symptomatic, pain is the most common presenting symptom, either localized to the affected bones or resulting from secondary osteoarthritic changes, often in the hips, knees, and vertebrae. When bone deformities occur, the long bones of the legs are usually affected, often with bowing. Skull involvement may result in sensorineural hearing loss, thought to be due to cochlear damage rather than to compression of the eighth cranial nerve. Paraplegia or quadriplegia occurs rarely as a consequence of spinal stenosis from vertebral involvement or as vascular steal from spinal cord adjacent to vascular pagetic bone; it may be reversible with timely treatment. The most devastating complication of Paget disease is malignant transformation of affected bone, particularly osteosarcoma.

When Paget disease is suspected, plain radiographs should be obtained of areas of suspected involvement. After the diagnosis is made, a radionuclide bone scan is useful to determine the extent of the disease, along with serum alkaline phosphatase (SAP) or bone-specific alkaline phosphatase (BSAP) to determine the level of metabolic activity. The primary indication for treatment in asymptomatic patients is active disease in areas where complications may occur, including the skull, weight-bearing bones, and bone adjacent to major joints, which may increase the risk of secondary osteoarthritis (SOE=C). Bisphosphonates suppress the accelerated bone turnover and bone remodeling characteristic of Paget disease and are the treatment of choice for most patients with active disease who are at risk of complications (SOE=A). Increasing evidence indicates that a single dose of zoledronic acid 5 mg IV is superior to other bisphosphonates for patients without contraindications (such as glomerular filtration rate <35 mL/min). Zoledronic acid is more likely to achieve a complete and sustained response to therapy, including improved pain and quality of life, than other bisphosphonates (SOE=A). Bisphosphonates may help to prevent or slow the development of hearing loss and osteoarthritis in joints adjacent to those affected with Paget disease (SOE=C), although joint replacement may be necessary in some individuals to restore function and relieve joint pain. Pretreatment with an aminobisphosphonate (eg, zoledronic acid or alendronate) may be advisable 1–4 months before elective total joint replacement to minimize the risks of intraoperative bleeding due to increased blood flow to pagetic bone and postoperative loosening of the prosthesis (SOE=B).

Calcium and vitamin D should be administered concomitantly with bisphosphonates to prevent hypocalcemiaOL. NSAIDs may be useful in treating secondary osteoarthritis for short periods (eg, several weeks), although even short courses of treatment with NSAIDs expose older adults to known risks, including increased risk of GI bleeding, renal dysfunction, heart attack and stroke, and other adverse effects. During treatment, patients should be monitored clinically for changes in bone pain, joint function, and neurologic status. SAP or BSAP levels should be monitored to assess the initial and ongoing response to bisphosphonate therapy.

DISORDERS OF THE ANTERIOR PITUITARY

Secondary hypothyroidism results from undersecretion of TSH by the anterior pituitary. Patients with suspected secondary hypothyroidism (Table 1) require neuroimaging of the hypothalamus and pituitary as well as measurement of other pituitary hormones, with special attention to exclude secondary adrenal insufficiency before T4 administration that could result in adrenal crisis.

For major hormones produced by the anterior pituitary and the factors influencing their secretion or action, see Table 6. Hypothalamic-pituitary-adrenal (HPA) axis function changes little with age. Basal adrenocorticotropic hormone (ACTH) levels are unchanged in later life, but the effects of aging on the ACTH response to stress can vary, depending on the stressor. Increases in cortisol and ACTH levels in response to metyrapone, ovine corticotropin-releasing hormone (CRH), and insulin-induced hypoglycemia are normal or slightly prolonged with aging. Inhibition of ACTH secretion by cortisol is unchanged with aging, indicating that feedback sensitivity to cortisol is unchanged. The dose-dependent suppression of CRH-induced ACTH release by dexamethasone is blunted with aging.

Table 6—Regulation of Anterior Pituitary Hormones

Synthetic Cells in Anterior Pituitary
Hormone
Factors Promoting Secretion
Factors Inhibiting Secretion
Comments
Somatotrophs
Growth hormone
GHRH
Somatostatin, IGF-1
GHRH and somatostatin are produced by the hypothalamus, IGF-1 primarily by the liver.
Mammotrophs
Prolactin
TRH
Dopamine
TRH and dopamine are produced by the hypothalamus. Antipsychotic and opiate drugs inhibit dopamine activity.
Thyrotrophs
TSH
TRH
Dopamine
TRH and dopamine are produced by the hypothalamus. Antipsychotic and opiate drugs inhibit dopamine activity.
Corticotrophs
ACTH
Corticotropin-releasing hormone
Cortisol
Systemic corticosteroid drugs inhibit ACTH release.
Gonadotrophs
LH, FSH
GnRH
Estradiol, testosterone
GnRH is produced by the hypothalamus. Prolactin and opiate drugs inhibit GnRH release.
GHRH=growth hormone–releasing hormone, TRH=thyrotropin-releasing hormone, TSH=thyroid-stimulating hormone, ACTH=adrenocorticotropic-releasing hormone, LH=leutinizing hormone, FSH=follicle-stimulating hormone, GnRH=gonadotropin-releasing hormone

Hyperprolactinemia and Pituitary Adenomas

Some older adults develop mild hyperprolactinemia due to causes such as renal failure, primary hypothyroidism, hypothalamic diseases that interfere with synthesis of dopamine (prolactin-inhibitory factor), and medications that inhibit dopamine activity (eg, antipsychotics, opioids, and metoclopramide). The clinical manifestations of hyperprolactinemia often go unrecognized in older adults and are usually subtle, including sexual dysfunction, gynecomastia, and rarely galactorrhea. Hyperprolactinemia should be considered in evaluation of secondary causes of osteoporosis in older men, because the antigonadotropic actions of prolactin may cause hypogonadism and accelerated bone loss.

Endocrinology consultation may help to ensure appropriate diagnosis and management of patients with hyperprolactinemia and pituitary tumors. When hyperprolactinemia is detected in asymptomatic patients, macroprolactinemia due to less bioactive dimeric and polymeric forms of prolactin should be excluded to avoid further unnecessary evaluation and management in these patients. In patients with true hyperprolactinemia, treatment of underlying secondary causes of hyperprolactinemia or discontinuation of medications such as antipsychotics often resolve the problem. MRI of the hypothalamus and pituitary is generally indicated to exclude a tumor or other lesion after investigation of secondary causes of hyperprolactinemia. Nonfunctioning pituitary adenomas can cause hyperprolactinemia by compressing the pituitary stalk or hypothalamus, thereby interfering with dopamine inhibition of prolactin secretion. Failure to recognize this possibility may lead to a misdiagnosis of prolactinoma and ineffective treatment with dopamine agonists rather than surgical treatment for tumors other than prolactinomas. However, prolactin levels >200 ng/mL nearly always indicate the presence of a prolactinoma, with higher prolactin levels predicting larger tumor mass.

Hyperprolactinemia due to a pituitary microprolactinoma (defined as <10 mm in size) may be managed with observation if the patient is asymptomatic, or with a dopamine agonist if secondary osteoporosis or symptoms such as sexual dysfunction are present. Dopamine agonists are first-line treatment for hyperprolactinemia from any cause and are effective in reducing prolactin concentrations. Older adults are at risk of adverse effects of these agents, including hallucinations and GI symptoms, so dopamine agonists should be started at low doses and the dose increased slowly. Cabergoline is the preferred dopamine agonist for its efficacy in decreasing prolactin levels, the size of pituitary macroadenomas (ie, ≥10 mm), and the likelihood of causing adverse effects. Compulsive behaviors, including hypersexuality and excessive gambling, may occur with dopamine agonists. Dosing should be titrated to normalize prolactin levels, with MRI repeated in 1 year or sooner if hyperprolactinemia or symptoms worsen despite treatment. Serial visual field testing is indicated for patients with macroadenomas near the optic chiasm. Trans-sphenoidal surgery or radiation therapy is occasionally necessary in patients with macroprolactinomas and persistent visual field defects or in those who cannot tolerate dopamine agonists.

Although the incidence of pituitary adenomas increases with age, most of these tumors remain asymptomatic. The majority of pituitary adenomas are nonfunctioning, followed by smaller numbers of prolactinomas and GH-secreting tumors. Nonsecreting and gonadotropin- or α-subunit-secreting adenomas are typically large at the time of diagnosis because of the absence of symptoms associated with hormone excess. Symptoms in these patients are generally due to mass effect, eg, headache, visual field abnormalities due to pressure on the optic chiasm, and panhypopituitarism.

Increasingly, pituitary incidentalomas are found on imaging studies ordered to evaluate comorbid illnesses in older adults. When these lesions are identified, careful clinical evaluation and measurement of pituitary and end-organ hormones should be performed to exclude hypopituitarism and hormone hypersecretion. A visual field examination is required when the tumor is adjacent to the optic chiasm or optic nerves. Pituitary microadenomas may be managed expectantly. Patients with macroadenomas other than prolactinomas should be referred for trans-sphenoidal surgery if there are visual field abnormalities due to compression of the optic chiasm or optic nerves; if there is hypersecretion of TSH, ACTH, or GH; or if other neurologic symptoms are present. Hypopituitarism (if present) may persist after pituitary adenomas are surgically removed, so hypopituitarism by itself is not an indication for surgery. The risks of trans-sphenoidal surgery have been reported to increase with age, but postoperative hypopituitarism and other complications are less likely and outcomes are similar to those in younger adults when these surgeries are performed at specialized centers by surgeons with extensive experience.

Hypopituitarism and the Empty Sella Syndrome

Hypopituitarism has been reported to develop in ⅓ to ½ of older adults with diagnosed pituitary tumors. Other causes of hypopituitarism in older adults include traumatic brain injury (TBI), infections such as tuberculosis, metastatic cancer, prior irradiation or surgery for pituitary tumors, and vascular disorders such as pituitary infarction or carotid artery aneurysms. An increasing number of cases of hypophysitis with impaired anterior pituitary function have been reported in melanoma patients treated with ipilimumab; older men appear especially at risk. Manifestations of panhypopituitarism include fatigue, hypogonadism and loss of libido, hypotension, weight loss, hypoglycemia, and hyponatremia. When the diagnosis is suspected, concurrent measurement of hormone levels in the pituitary and target organ(s) is indicated to determine whether hormonal axis responses are appropriate, typically with endocrinology referral. Dynamic testing of the HPA axis with ACTH stimulation testing is also indicated to evaluate for secondary adrenal insufficiency.

After even minor falls or trauma with head injury, acute hypopituitarism occurs commonly in older adults. In the acute phase (first 7–10 days), potentially life-threatening glucocorticoid insufficiency may develop, and serial morning cortisol measurements should be obtained, especially when hypotension, hypoglycemia, or hyponatremia are present. Acute diabetes insipidus may also occur. Evaluation of GH, thyroid, and gonadal axis function is unnecessary in the acute phase. After the acute phase of TBI, some hormonal deficiencies that were manifest initially may resolve and others may develop. Although the natural history of hypopituitarism after TBI is not well described, it is appropriate (in consultation with an endocrinologist) to monitor for signs and symptoms and to obtain hormone measurements 3–6 months and at 1 year after the TBI, and to reevaluate hormonal status whenever concerning symptoms develop.

Cases of empty sella syndrome are increasingly being detected as neuroimaging procedures performed for other indications have increased. Pituitary height and volume tend to diminish with aging in healthy adults, and empty sella has been observed in 19% of older study participants. Most cases of primary empty sella syndrome (ie, not associated with pituitary tumors or their treatment) occur in obese, middle-aged women with hypertension. In contrast to men, most women with this condition do not have significant pituitary hormone hypofunction. It is unknown whether an incidental finding of empty sella in otherwise healthy older adults has any functional significance. These patients are typically managed with visual field testing and pituitary and target organ hormone measurements to detect abnormalities in pituitary hormones.

DISORDERS OF THE ADRENAL CORTEX

Basal serum cortisol concentrations do not change with aging, because decreased cortisol secretion is balanced by a decrease in clearance. Clinically, acute cortisol responses to stress may be higher and more prolonged in older than in younger adults, possibly because cortisol clearance is reduced. Accordingly, in nonemergent situations, adrenal function testing should be deferred at least 48 hours after major stressors, such as surgery or trauma. In older adults with a normal ACTH stimulation test in whom adrenal insufficiency is suspected, endocrinology consultation is recommended to assist with further testing.

Hypoadrenocorticoidism

Chronic glucocorticoid therapy is the most common cause of adrenal failure in older adults because of chronic suppression of adrenal function. Recovery of adrenal axis function is variable and may take several months to a year. Autoimmune-mediated adrenal failure is less common in older than in younger adults; in contrast, tuberculosis, adrenal metastases, and adrenal hemorrhage in anticoagulated patients are more common. Additionally, prolonged use of megestrol acetate (eg, as an appetite stimulant) may cause ACTH suppression and hypoadrenocorticoidism.

Older adults with chronic adrenal insufficiency may present with nonspecific symptoms such as anorexia, nausea, weight loss, abdominal pain, weakness, hypotension, or impaired functional status, and hyponatremia and hyperkalemia may not always be present. Accordingly, a high index of suspicion is required to make the diagnosis. When adrenocortical insufficiency is suspected, the ACTH stimulation test should be performed (SOE=A), and therapy initiated (SOE=B). A normal serum cortisol (basal or 30–60 minutes after administration of 250 mcg of ACTH [cosyntropin]) is ≥18-20 mcg/dL. A serum ACTH concentration should be obtained before administration of cosyntropin to distinguish secondary adrenal insufficiency (decreased pituitary ACTH secretion), which is characterized by a low or normal ACTH concentration, from primary adrenal insufficiency (PAI), which is associated with a high ACTH concentration. Patients with suspected PAI should have simultaneous measurements of plasma renin and aldosterone to detect mineralocorticoid deficiency. In older adults instructed to stop chronic glucocorticoid therapy, the drug should be tapered gradually (SOE=D), and stress dose coverage given for major surgery and other acute physiologic stresses until adrenocortical function has returned to normal (SOE=D). Recovery of the HPA axis may take >9 months.

Acute adrenal insufficiency is a potentially life-threatening emergency. Patients in suspected adrenal crisis should, after blood draw for diagnosis, receive IV hydrocortisone at stress doses (hydrocortisone 100–200 mg over 24 hours continuously or in divided doses every 6 hours [SOE=A]) without waiting for laboratory confirmation, along with intravenous volume resuscitation with careful monitoring of volume status and electrolytes. The underlying cause of the adrenal crisis (eg, infection) should be determined and treated. Hydrocortisone replacement may provide sufficient mineralocorticoid activity in PAI, unless mineralocorticoid deficiency is severe. In chronic adrenal insufficiency, older adults should receive the minimum glucocorticoid and, in PAI, mineralocorticoid replacement doses needed to relieve symptoms and to avoid long-term complications of glucocorticoid excess, volume overload, hypertension, and electrolyte disturbances. Typical replacement doses of glucocorticoid are hydrocortisone 15–25 mg daily in two or three divided doses (SOE=B), or prednisone or prednisolone 3–5 mg daily in one or two divided doses (SOE=D). Mineralocorticoid replacement in PAI is fludrocortisone 50–100 mcg daily (SOE=A). During minor illnesses, patients should take 2–3 times the usual maintenance dose of glucocorticoid for 3 days (SOE=B). These patients should wear a medical alert bracelet or necklace indicating adrenal insufficiency and should be given parenteral stress dose glucocorticoids in the event of major illnesses, trauma, or major surgery (SOE=D).

Hyperadrenocorticoidism

Exogenous glucocorticoids are the most common cause of hyperadrenocorticoidism in older adults, often causing adverse events, including psychiatric and cognitive symptoms, osteoporosis, myopathy, and glucose intolerance. Notably, the use of 10 mg/d of prednisone continuously for >90 days is associated with a 7-fold increase in hip fractures and a 17-fold increased risk of vertebral fractures. For patients beginning long-term glucocorticoid therapy, baseline and follow-up bone densitometry measurements are indicated; and calcium and vitamin D (SOE=B) and antiresorptive agents, such as bisphosphonates, should be started as appropriate in patients at high risk of fractures for prevention or treatment of glucocorticoid-induced osteoporosis (SOE=A or B, depending on risk group). Teriparatide may be used in cases of severe bone loss (SOE=A). To counteract corticosteroid-induced suppression of sex hormones, hormone replacement therapy may also be appropriate in some cases.

Adrenal Neoplasms

In radiographic studies, the prevalence of clinically inapparent adrenal masses (adrenal incidentalomas) is estimated to be 3%–4% in middle-aged adults, rising to ≥10% in older adults. Most of these are benign adrenocortical adenomas, although pheochromocytomas and adrenocortical carcinomas are also found. When an incidentaloma is discovered, it is important to exclude pheochromocytoma, because these are not uncommon and potentially life threatening.

The goals of assessment are to determine whether the tumor is functional (hormone-secreting) (Table 7) and malignant. Endocrinology referral is appropriate when evidence of hormone excess is present. Many adrenocortical adenomas have a degree of functional autonomy, and subclinical glucocorticoid hypersecretion is present in 5%–24% of cases of adrenal incidentalomas. An overnight low-dose (1 mg) dexamethasone suppression test together with measurement of a morning serum ACTH level are appropriate to exclude subclinical Cushing syndrome. Although some of these patients may be at increased risk of new vertebral fractures, hypertension, insulin resistance, and other metabolic derangements, it is unclear whether the long-term outcomes of adrenalectomy are superior to those of medical management. Moreover, screening all older adults with adrenal incidentalomas for glucocorticoid hypersecretion would yield a high proportion of false-positive results. Accordingly, it may be best to limit testing for hyperadrenocorticoidism to younger individuals, those with a symptom complex suggesting hyperadrenocorticoidism, and patients scheduled for major surgery who are at risk of postoperative adrenal crisis due to diminished HPA axis reserve from chronic glucocorticoid excess (SOE=D). Similarly, the merits of screening for primary aldosteronism (PA) in hypertensive older adults are uncertain, and the long-term outcomes of medical versus surgical management of PA are unclear. The risks and benefits of unilateral adrenalectomy for hypertensive older patients with PA due to unilateral adenoma or adrenal hyperplasia should be assessed on a case-by-case basis. Older patients with PA who are unable or unwilling to undergo surgery, or who have bilateral adrenal disease, should be treated with a mineralocorticoid receptor antagonist (SOE=B).

Table 7—Diagnostic Evaluation of Hormone Hypersecretion in Patients with Adrenal Incidentalomas

Indications
Test and Result Supporting Diagnosis
Diagnosis
All patients with incidentaloma
1-mg overnight dexamethasone suppression test showing failure to suppress cortisol
Functional adrenocortical adenoma
Cushing syndrome manifestations, before major surgery 24-hour urine free cortisol ↑
All patients with incidentaloma
24-hour urine for fractionated metanephrines ↑ or plasma-free metanephrines ↑
Pheochromocytoma
Before major surgery Plasma-free metanephrines ↑ Pheochromocytoma
Hypertension with or without hypokalemia
Ratio of morning plasma aldosterone concentration to plasma renin activity ↑
Primary aldosteronism

The most helpful indicator in initial assessment of malignancy risk in patients with adrenal incidentaloma is the attenuation coefficient in Hounsfield units (HU) on noncontrast CT imaging. Lesions with attenuation values of ≤10 HU are probably benign. Adrenal masses with values >10 HU but smaller than 4 cm are also likely to be benign adenomas. Interdisciplinary case review and consideration of surgical resection may be appropriate for masses ≥4 cm, especially for lesions >6 cm, and with imaging characteristics suggesting malignancy, such as irregular shape, unilaterality, tumor calcification, and rapid growth rate (SOE=B). In patients with masses >2 cm without clearly benign features who are followed expectantly, imaging should be repeated in 6–12 months to identify rapidly growing tumors, because they are more likely to be malignant (SOE=B).

Adrenal Androgens

Adrenal production of dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) is the main source of androgens in women; in men the adrenals contribute little to overall androgen production. DHEA and DHEA-S are prohormones that are converted to more active androgens and estrogens in the adrenal glands and peripheral tissues. While trials of oral DHEA have not shown health benefits in postmenopausal women, vaginal low-dose DHEA administration is an approved treatment for the genitourinary syndrome of menopause (see Estrogen Therapy, below). In the vagina, DHEA is converted locally into estrogens and androgens, and daily vaginal administration of DHEA 6.5 mg was found to improve menopausal vaginal atrophy without changing serum levels of estrogenic or androgenic metabolites.

Oral DHEA is available in the United States only as a dietary supplement. The potency and purity of these preparations is unreliable, and the long-term safety of oral DHEA supplementation has not been established.

TESTOSTERONE

Total and free testosterone (T) levels gradually and progressively decline with age and are lower in healthy older men than in younger men; older men commonly have T levels below the normal range for young men. Aging may be associated with nonspecific complaints, such as decreased libido and potency, reduced energy, depressed mood, weakness, decreased muscle mass, osteopenia, and memory loss. Because these manifestations are also consistent with those of T deficiency, the possibility arises that declining T with aging might contribute to their development, and that T treatment might prevent or treat them. Whether declining T levels in older men are simply a biomarker of poor health or a deficiency state in need of treatment is not yet known.

Older men may exhibit varying degrees of combined primary and secondary testicular dysfunction. In advanced old age, testicular production of T decreases, associated with increased gonadotropin levels (primary hypogonadism). Comorbidities and medications may also lead to suppression of gonadotropin levels so that they are not increased but inappropriately normal (secondary hypogonadism). Overt secondary testicular failure is common in chronically ill and debilitated older men and in men receiving chronic opioids or glucocorticoids. These men have severely low T levels and manifestations suggesting T deficiency, such as decreased libido, hair loss, and muscle weakness. T replacement therapy may be warranted in these severely clinically and biochemically T-deficient patients, as it is in hypogonadal young men, but adequate studies of the benefits and risks of T treatment in these patient populations have not been performed.

In the United States, the use of T supplementation by older men has increased nearly 10-fold in the past two decades, driven at least in part by direct-to-consumer advertising campaigns and the availability of transdermal T gel and patch formulations. Many men who are started on T supplementation have not had recent measurement of serum T concentrations, indicating that inappropriate prescribing is common.

Until recently, trials of T treatment in older men have had methodologic limitations. The most consistent findings in early studies were increased muscle mass and decreased fat mass. Effects on physical performance, BMD, sexual function, and energy were inconsistent.

The carefully designed Testosterone Trials (TTrials) were a group of 7 coordinated double-blind, placebo-controlled trials in men ≥65 years old with symptoms and objective evidence of low libido, low vitality, and walking difficulty, and with morning total T levels <275 ng/dL on two occasions. Men were treated with testosterone gel for 1 year at dosages adjusted to maintain normal T levels. Outcomes thought to be related to T deficiency, including sexual function, vitality, physical function, cognitive function, anemia, BMD, and cardiovascular health were assessed. Results showed modest improvements in sexual function; small improvements in walking distance, mood, and depression symptoms; and no change in vitality. BMD increased in amounts comparable to those achieved with standard osteoporosis therapies, and estimated bone strength improved. However, BMD was not low in study participants, and the study was not designed to assess changes in fracture risk. T treatment did not improve memory or other cognitive functions in men with age-associated memory impairment but did increase hemoglobin levels in men with anemia as well as those without. In a cardiovascular sub-study using CT to measure coronary artery plaque volume, compared with placebo, T treatment was associated with a greater increase in total and noncalcified plaque volume but not in calcified plaque or in the number of cardiovascular events.

The TEAAM Trial was a randomized, controlled trial of T supplementation for 3 years in healthy men ≥60 years old with total T levels of 100–400 ng/dL or free T levels <50 pg/mL. Modest improvements in stair-climbing power, muscle mass, and power were found in the group receiving supplement, but the clinical significance of these findings is uncertain. Results of ultrasonography and CT did not show an effect of T on the rates of change in coronary artery calcium or common carotid artery intima-media thickness. Meta-analyses of trials of T treatment have reported conflicting results of the risk of cardiovascular events in participants receiving T. Taken together, the TTrials and the TEAAM Trial provide evidence only for short-term benefits of T treatment but do not allay concerns about possible long-term risks of cardiovascular, prostate, or other adverse events.

Men with clinical manifestations of T deficiency should be evaluated initially with a morning, preferably fasting, serum total T level using an accurate and reliable assay. The diagnosis should be confirmed with a repeat morning total T, or, ideally, with a morning serum free T level, measured by equilibrium dialysis or calculated from measurements of total T and sex hormone–binding globulin (SHBG). Alternatively, a bioavailable (non–sex hormone–binding globulin-bound) T level may be determined. Direct “analogue” immunoassays for free T are widely used but are inaccurate and not recommended. If abnormally low T levels are confirmed, luteinizing hormone and follicle-stimulating hormone levels should be obtained to determine whether low T is due to a disorder of the testes (primary hypogonadism) or a hypothalamic-pituitary disorder (secondary hypogonadism). Medications that can suppress gonadotropins (eg, glucocorticoids, opioids, and other medications with CNS activity) should be discontinued if possible, and a prolactin level obtained if gonadotropins are low or inappropriately normal in the presence of low T levels. High prolactin concentrations inhibit gonadotropin secretion and could be due to a pituitary adenoma, a hypothalamic disorder, or medications. Further studies (eg, MRI of the pituitary fossa, assessment of other pituitary functions) may be warranted in such patients with guidance from an endocrinologist. Baseline BMD measurements should be obtained in older men with decreased T levels to exclude osteoporosis.

T supplementation should be considered only after potentially reversible functional causes of hypogonadism are addressed. Based on the uncertainties described above, the FDA cautions that T replacement therapy may be associated with increased cardiovascular risk. Accordingly, caution is suggested when using T treatment in frail older men with established cardiovascular disease or cardiovascular risk factors. After explicit discussion of the uncertain risks and benefits of T therapy, including potential increased cardiovascular and prostate cancer risk, a trial of T supplementation may be appropriate in older men with unequivocally and repeatedly severely low serum total and free (or bioavailable) T levels (eg, <200 ng/dL), and clinical features suggesting hypogonadism (eg, loss of libido, muscle wasting or weakness, osteoporosis or mild anemia of unclear cause)OL (SOE=C). Clinicians should aim to achieve total T levels in the lower part of the normal range for young men (eg, 400–500 ng/dL). Androgen replacement therapy is inappropriate in asymptomatic older men with low-normal total and free T levels who do not have clinical manifestations consistent with T deficiency. Older men with mildly reduced T levels and nonspecific symptoms will benefit most from other approaches, including lifestyle interventions, for problems such as obesity, muscle weakness, erectile dysfunction, depression, and osteoporosis. T administration is contraindicated in patients with prostate cancer and breast cancer and should be avoided in men with the following: undiagnosed prostate nodule or induration on digital rectal examination, consistently increased prostate-specific antigen (PSA) levels, erythrocytosis, severe lower urinary tract symptoms due to benign prostatic hyperplasia, or uncontrolled severe heart failure (SOE=C). For available preparations of T, see Table 8.

Table 8—Testosterone Preparations Available in the United States for Hypogonadal Older Men
Preparation
Initial Treatment Dosage
Testosterone enanthate or cypionate
75 mg IM every week, or 150 mg IM every 2 weeks
Testosterone undecanoate
750 mg IM initially, followed by 750 mg IM 4 weeks later, then 750 mg every 10 weeks thereafter
Nonscrotal transdermal patch
2 or 4 mg transdermal every night
Gel
1% gel: 25–100 mg transdermal every day
1.62% gel: 20.25–81 mg every day
2% gel: 10–70 mg every day
Solution
30–120 mg applied to axilla once daily
Intranasal gel
5.5 mg (1 actuation) each nostril 3 times daily
Buccal tablet
30 mg applied to buccal mucosa every 12 hours
Testosterone pellets
150–450 mg SC every 3–6 months

Men should be monitored closely for efficacy as well as for adverse events of T treatment, including new or worsening snoring, observed apnea during sleep, or excessive daytime sleepiness that may suggest obstructive sleep apnea. Routine monitoring for efficacy and potential adverse effects should be performed within the first year after initiation and then annually thereafter (SOE=C). Monitoring should include measurement of serum hematocrit to check for erythrocytosis, and inquiry about lower urinary tract symptoms and gynecomastia at 3–6 months after starting T treatment. Prostate cancer screening should be offered with a discussion of risks and benefits of screening to men with a remaining life expectancy of >10 years, particularly in men at high risk for prostate cancer (black Americans or men who have a first-degree relative with prostate cancer). If desired by the patient, serum PSA and digital rectal examination should be performed before and 3–12 months after starting T treatment (to detect the presence of prostate cancer at baseline or shortly after starting therapy). Serum T levels should be monitored to assess the adequacy of delivery, especially in men receiving transdermal T formulations (patch or gel). After T treatment has begun, a PSA concentration >4 ng/mL (or >3 ng/mLin men with a high risk of prostate cancer), or a palpable prostate nodule or induration, can indicate the presence of previously undetected prostate cancer. In these circumstances, T treatment should be discontinued until the prostate has been fully evaluated by a urologist (SOE=C). Despite this guidance, there is as yet no direct evidence that T treatment increases risk of prostate cancer or symptomatic benign prostatic hyperplasia.

RESOURCES

American Geriatrics Society Workgroup on Vitamin D Supplementation for Older Adults. Recommendations abstracted from the American Geriatrics Society Consensus Statement on Vitamin D for Prevention of Falls and Their Consequences. J Am Geriatr Soc. 2014;62(1):147–162.

This consensus statement provides clinical guidance regarding use of vitamin D supplements to prevent falls and fractures in older adults. Its focus is to maximize the likelihood of benefit in this population without risk of toxicity. The Workgroup concluded that routine measurement of serum 25(OH)D concentrations is not necessary for older adults in the absence of underlying conditions that increase hypercalcemia risk. The referenced article is a summary; the complete document is available at https://geriatricscareonline.org/ProductAbstract/american-geriatrics-society-consensus-statement-vitamin-d-for-prevention-of-falls-and-their-consequences-in-older-adults/CL009.

Snyder PJ, Bhasin S, Cunningham GR, et al. Lessons From the Testosterone Trials. Endocr Rev. 2018;39(3):369–386.

The landmark Testosterone Trials (TTrials) are 7 independent multicenter, double-blind, placebo-controlled, randomized controlled trials (RCTs) sponsored by the National Institutes of Health. The trials' findings suggest potentially beneficial effects of testosterone on some clinical measures of well-being in older men, but do not provide sufficient evidence to supoort testosterone replacement therapy in most older men wiht mildly decreased testosterone levels and symptoms that could be due to low testosterone. Larger and longer duration studies are needed to determine the long-term effects of testosterone treatment, including its effects on prostate and cardiovascular outcomes.

The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24(7):728–753.

The NAMS position statement offers guidance endorsed by a broad range of other societies, including the Academy of Women’s Health, American Association of Clinical Endocrinologists, and American Society for Reproductive Medicine. The statement notes that estrogen therapy (ET, either estrogen alone or estrogen + progestogen) is the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM). The benefit-risk ratio of ET is favorable for healthy women with VMS or at risk of osteoporosis and fractures who are <60 years old or within 10 years of menopause onset and have no contraindications to ET. However, the benefit-risk ratio becomes less favorable in women starting ET after age 60 or more than 10 years after menopause onset; these women have increased risk of coronary heart disease, stroke, dementia, and venous thromboembolism with ET. Low-dose vaginal ET is recommended for bothersome symptoms of GSM in women who do not have an indication for systemic ET, but women with breast cancer should consult with their oncologists before deciding to use it.

Ross DS, Burch HB, Cooper DS, et al; 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid. 2016;26(10):1343–1421.

This comprehensive guideline offers updated evidence-based recommendations for the care of patients with thyrotoxicosis. The following two recommendations are relevant to older adults. 1) Radioactive iodine can cause a transient exacerbation of hyperthyroidism; therefore, b-adrenergic blockade should be considered in older patients receiving radioactive iodine treatment of toxic multinodular goiter or toxic adenoma. 2) Treatment of subclinical hyperthyroidism is recommended in all adults ≥65 years old who have serum thyrotropin levels persistently <0.1 mIU/L and should be considered in those ≥65 years old with thyrotropin levels persistently between 0.1 and 4.5 mIU/L.

Stott DJ, Rodondi N, Kearney PM, et al; TRUST Study Group. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017;376(26):2534–2544.

The TRUST trial, a large, double-blind, placebo-controlled randomized controlled trial (RCT) evaluated the effects of levothyroxine treatment in 737 participants >65 years old with subclinical hypothyroidism, with the aim of determining whether levothyroxine improves symptoms in subclinical hypothyroidism. Participants were started on 50 mcg/day of levothyroxine (25 mcg/d for those with coronary heart disease or body weight <50 kg), with dose adjustments to achieve thyrotropin levels of 0.4–4.59 mIU/L, or matching dose-adjusted placebo. In line with the findings of smaller scale RCTs, this trial found no benefit of levothyroxine on symptoms, mood, or quality of life. However, participants were not very symptomatic before treatment, and thyrotropin levels were only mildly increased (mean 6.4 mIU/L). The trial was inadequately powered to determine the effect of levothyroxine on cognitive function and cardiovascular events, and additional RCTs are needed to evaluate the effects of levothyroxine on these outcomes in older adults with subclinical hypothyroidism.