Primary hyperparathyroidism

Parathyroid hormone (PTH)-mediated hypercalcemia is often an incidental finding on routine laboratory assessment. Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia and occurs in 1 in 1,000 persons in the United States. The incidence of PHPT peaks in the seventh decade of life. More than 80% of patients with PHPT are considered asymptomatic at the time of diagnosis.[1] Classic symptoms of the disease include nephrolithiasis and bone disease (osteoporosis, osteitis fibrosa cystica). Other symptoms of PHPT are often vague, nonspecific, and may overlap with common complaints among elderly patients. These include easy fatigability, myalgias, bone pain, depressed affect, abdominal cramping or constipation, weakness, headaches, irritability, forgetfulness, difficulty rising from a chair. Laboratory findings in PHPT universally include hypercalcemia as well as inappropriately normal or high serum PTH levels. Additional studies may show low serum phosphate, hypercalciuria, high levels of renal cyclic adenosine monophosphate (cAMP), and enhanced markers of bone resorption.

Patients with confirmed PHPT who are symptomatic should undergo parathyroidectomy. Unfortunately, the distinction between symptomatic and asymptomatic patients is rarely well defined. A careful history for onset of symptoms compared to trajectory of serum calcium may be helpful in challenging cases. If a patient is not clearly symptomatic, guidelines should be followed to determine management.[2] Specifically, parathyroidectomy is indicated in asymptomatic patients with PHPT who meet any one of the following conditions: (1) serum calcium concentration of 1.0 mg/dL or more above the upper limit of normal; (2) creatinine clearance that is reduced to <60 mL/min; (3) bone density at the hip, lumbar spine, or distal radius that is more than 2.5 standard deviations below peak bone mass (T score ≤–2.5) and/or previous fragility fracture; (4) age less than 50 years.

The type of surgical intervention is dictated by the number of parathyroid glands involved. PHPT is most often caused by a single adenoma (80%–85%) or four-gland hyperplasia (10%–15%).[1] It is rarely part of hereditary syndromes such as multiple endocrine neoplasia types 1 and 2A. Neck imaging is not necessary for diagnosis of PHPT, but it should be ordered if surgery is indicated. Localization of the overactive gland(s) can decrease the invasiveness and morbidity of surgery. Both sestamibi scan and neck ultrasound are useful for localization.[3] Parathyroidectomy should be performed by an experienced surgeon who uses intraoperative PTH monitoring. Surgery is associated with a cure rate of 95%–98%. There is a low rate (1%–3%) of complications, including laryngeal-nerve palsy and postoperative hypocalcemia, particularly when vitamin D is not replete prior to surgery. Successful parathyroidectomy is followed by a prompt normalization of the PTH level, serum and urinary calcium levels, and gradual increases in bone mineral density (up to 10% over the course of several years).

In elderly patients who are asymptomatic and have serum calcium concentrations <1.0 mg/dL above the upper limit of normal, parathyroidectomy can be deferred. Surveillance should include monitoring with yearly measurement of serum creatinine, calcium, and bone mineral density. Although counterintuitive, calcium intake through dietary sources or supplements should reach 1,000 mg daily for skeletal protection. Vitamin D deficiency often coexists with PHPT and should be actively managed to prevent additional bone loss and superimposed secondary hyperparathyroidism. Vitamin D should be repleted to levels ≥20 ng/mL both prior to surgery and with conservative management. In elderly patients who meet criteria for parathyroidectomy but are medically unfit for surgery or do not wish to have surgery, medical management with cinacalcet may be effective. Unfortunately, cinacalcet does not improve bone mineral density, and there is no data on its effects on nephrolithiasis. In patients with PHPT who are medically unfit for surgery and have low bone mineral density, bisphosphonates may have a dual benefit of improving bone density and lowering calcium levels.[5]

Vitamin D deficiency

Vitamin D is predictive of a wide variety of clinical outcomes related to mortality, cardiovascular health, cognitive function, muscle and bone health, and multiple sclerosis. The prevalence of vitamin D deficiency in persons over the age of 65 has been estimated at 50%, although this is highly variable and dependent on geographic location and socioeconomic, clinical, and other factors.[6] Further complicating this statistic is the lack of consensus regarding the definition of “deficiency.” Although the Institute of Medicine defines sufficient as serum 25-hydroxy vitamin D above 20 ng/mL (50 nmol/L), many organizations – including the Endocrine Society, National Osteoporosis Foundation, and American Geriatric Society – recommend that the elderly maintain a minimum serum level of 30 ng/mL (75 nmol/L) to reduce the risk of falls and fracture.[7–9] Elderly and institutionalized patients are at risk for vitamin D deficiency due to age-related decline in renal function and skin structure modifications that affect vitamin D production. Low sunlight exposure, female sex, dark skin pigmentation, malnutrition, and obesity are also risk factors for vitamin D deficiency.[10]

A 2005 Cochrane review concluded that calcium and vitamin D treatment in frail elderly people who are confined to institutions reduces hip and vertebral fractures.[11] A meta-analysis of randomized controlled trials investigating oral vitamin D with or without calcium concluded that vitamin D 700 IU–800 IU per day reduces the risk of hip and nonvertebral fractures in ambulatory or institutionalized elderly individuals, whereas 400 IU per day was insufficient for fracture protection. For individuals with vitamin D deficiency on lab testing, high-dose repletion in the form of weekly ergocalciferol 50,000 IU may be necessary for several weeks. In some, ergocalciferol every other week standing has been shown to effectively maintain serum levels. Vitamin D deficiency has been implicated as a cause of bone pain, weakness, impaired cognition, low mood, and fatigue. Repletion may improve these symptoms, although data have not been definitive.

Secondary and tertiary hyperparathyroidism

Secondary hyperparathyroidism is diagnosed in the setting of elevated PTH with concurrent normo- or hypocalcemia. The most common causes of secondary hyperparathyroidism in the elderly are vitamin D deficiency and chronic kidney disease (CKD). PTH increases in CKD as an adaptive response to declining glomerular filtration rate (GFR). Produced in the kidney, circulating 1,25-dihydroxyvitamin D levels begin to decrease in stage 2 CKD and continue to fall with ongoing renal insufficiency. As GFR decreases below 60 mL/min/1.73m², phosphate is retained in the kidney and stimulates synthesis and secretion of PTH. Hypocalcemia develops as the GFR decreases below 50 mL/min/1.73 m², further stimulating release of PTH.

Chronic secondary hyperparathyroidism of any cause can result in bone loss and fractures, cardiovascular disease, and increased mortality. Elderly patients with secondary hyperparathyroidism due to CKD should be followed by a nephrologist and/or endocrinologist for implementation of calcium, vitamin D, and cinacalcet and/or calcitriol therapy to lower PTH levels.[12] If left untreated, secondary hyperparathyroidism may evolve into tertiary disease in which parathyroid glands begin to function autonomously. This phenomenon is most commonly observed in those with longstanding renal disease or hemodialysis patients. Laboratory studies in tertiary hyperparathyroidism mimic those of primary disease with elevations in serum calcium and PTH levels. If pharmacotherapy is not effective in controlling serum calcium and PTH levels, subtotal parathyroidectomy may be necessary.

Hypercalcemia of malignancy

In the elderly population, hypercalcemia in the presence of a low or suppressed PTH level should always prompt screening for occult malignancy. Parathyroid hormone–related protein (PTHrP) has been identified as the most common cause of hypercalcemia in patients with nonmetastatic solid tumors. PTHrP elevations are seen most commonly in squamous cell carcinoma (lung, head, neck), breast, prostate, renal, and bladder cancers.[13] Patients with non-Hodgkin’s lymphoma, chronic myeloid leukemia, and adult T-cell leukemia may also have elevated PTHrP levels. The two other major mechanisms of hypercalcemia of malignancy are (1) osteolytic metastases with local release of cytokines (including osteoclast-activating factors), and (2) tumor production of 1,25-dihydroxyvitamin D (calcitriol). Osteolytic metastases account for approximately one-fifth of cases of hypercalcemia of malignancy due to bone destruction by osteoclasts and occur in solid tumors with bone metastases and multiple myeloma. In lymphoma, hypercalcemia may be due to increased and PTH-independent production of 1,25-dihydroxyvitamin D (calcitriol), increased intestinal calcium absorption, and bone resorption. In most cases, treatment of the underlying malignancy improves serum calcium levels; occasionally, antiresorptive medications or steroids are also needed.

Hypoparathyroidism

Congenital hypoparathyroidism is usually part of a genetic syndrome detected early in life. In elderly patients, new onset hypoparathyroidism is more likely to be iatrogenic. Acquired hypoparathyroidism is often due to inadvertent removal of the parathyroid glands or irreversible damage to their blood supply during thyroidectomy, parathyroidectomy, or neck dissection surgery. Patients may present with perioral numbness and tingling, tetany, hypotension, and arrhythmias, depending on the acuity of serum calcium declines. In the outpatient setting, these patients are treated with high-dose calcium and/or and calcitriol, with the goal albumin-corrected calcium level at the lower end of normal range (8.0 mg/dL–8.5 mg/dL) to prevent nephrolithiasis.

Hypothyroidism

The most common form of hypothyroidism is due to autoimmune disease (Hashimoto’s) in which circulating thyroid antibodies damage the thyroid gland over time, impairing its ability to make thyroid hormone. Hypothyroidism may also result from surgical removal of the thyroid or radiation therapy. The symptoms of hypothyroidism can be nebulous and similar to those occurring in natural aging. These include fatigue, cold intolerance, constipation, dry skin and hair, weight gain, and impaired concentration. It is important to consider depression and anemia in these patients as well, since all three conditions share the same symptoms and are commonly diagnosed in the elderly.[14] Measurement of serum thyrotropin (TSH) should be used to screen for an underactive thyroid gland. The anterior pituitary releases TSH in response to decreased circulating levels of free thyroxine (FT4) and free tri-iodothyronine (FT3) inadequately produced by the thyroid gland. Overt hypothyroidism is defined by elevated TSH with frankly low FT4 levels. There has been some debate as to whether the reference range for normal TSH should be adjusted for age. It is well known that TSH increases with each decade of life despite maintenance of circulating thyroid hormone. Some studies have shown that elderly individuals with high TSH and lower FT4 have a prolonged survival, suggestive that changes in thyroid function are adaptive mechanisms to conserve energy expenditure with age.[15]

Overt hypothyroidism requires treatment with thyroid hormone to alleviate symptoms and prevent progression to myxedema, an endocrine emergency characterized by undetectable thyroid hormone levels, obtundation, hypothermia, and decreased cardiac output that can progress to heart failure.[16] Patients with established hypothyroidism should be treated with synthetic L-thyroxine (T4), which is peripherally converted in peripheral tissues to FT3, the active form of thyroid hormone. L-thyroxine is typically administered as a once-daily dose of 1.6 ug/kg. A recent clinical trial demonstrated that starting with full-dose L-thyroxine is safe and effective in asymptomatic patients with hypothyroidism, including the elderly.[17] TSH levels should be monitored six weeks after initiation of L-thyroxine and at six-week intervals after any dose adjustments. After dose stabilization, TSH levels can be monitored annually. The most common complications of L-thyroxine therapy in the elderly are myocardial ischemia, arrhythmias (usually atrial fibrillation), and bone loss. The risk of these complications can be minimized by avoiding TSH suppression below the normal range.

Subclinical hypothyroidism

Subclinical hypothyroidism is defined by elevated TSH with normal FT4 levels. This condition can occur with the progression of autoimmune disease or temporarily in the setting of thyroiditis. In contrast to overt hypothyroidism, there are no clearly established indications for treatment of subclinical hypothyroidism in the elderly. Possible, although contentious, reasons to treat subclinical hypothyroidism may include alleviating hypothyroid symptoms, preventing progression to overt hypothyroidism if antibodies are present, and possibly reducing the risk of cardiovascular and all-cause mortality.[18] The majority of trials of L-thyroxine in elderly patients with subclinical hypothyroidism showed no improvement in symptoms. In patients with subclinical hypothyroidism, the combination of TSH >10 uIU/mL and thyroid antibody positivity has been linked to increased risk of progression to overt hypothyroidism. There is insufficient evidence to suggest that treatment of subclinical hypothyroidism reduces cardiovascular complications in the elderly.[19, 20] A very small number of trials in patients with subclinical hypothyroidism have shown increased risk of congestive heart failure, cardiovascular mortality, and all-cause mortality.

Given limited data supporting the treatment of subclinical disease, current guidelines recommend L-thyroxine therapy (LT4) only when serum TSH concentrations are >10 uIU/mL in the setting of normal FT4.[21] Treatment should be considered in patients with serum TSH concentrations above a laboratory’s normal reference range but below 10 uIU/mL on the basis of individual factors, including symptoms, thyroid antibody positivity, or evidence of atherosclerotic cardiovascular disease. Treatment of subclinical hypothyroidism usually requires only 50 ug–75 ug of L-thyroxine daily; TSH levels should be monitored six weeks after initiating therapy. Elderly patients with cardiovascular disease should start with even lower doses, LT4 12.5 ug–25 ug daily.

Hyperthyroidism

Hyperthyroidism is defined by low TSH levels and frankly elevated FT4 and/or T3 levels. Elderly patients with hyperthyroidism are more likely to present with cardiovascular symptoms (tachycardia, atrial fibrillation), dyspnea, edema, weakness, and weight loss and are less likely to present with tremor or nervousness. Hyperthyroidism in the elderly is often termed “apathetic,” as the classic hyperactive symptoms are often absent. Overt hyperthyroidism is associated with increased cardiovascular risk, osteoporosis, and mortality in the elderly. Compared to younger patients, a higher proportion of elderly patients with hyperthyroidism have toxic multinodular goiter. Thyrotoxicosis can also be due to autoimmune stimulation of the thyroid gland (Graves’ disease), thyroiditis, or iodine-containing medications (namely amiodarone).[22] Given the broad differential of hyperthyroidism, neck examination is a key component of the physical exam. Multiple thyroid nodules may suggest toxic multinodular goiter, whereas a single thyroid nodule could be an autonomous toxic nodule. Presence of a diffuse goiter may suggest Graves’ disease, although many elderly patients with Graves’ disease may have a nonpalpable thyroid gland. A tender thyroid gland suggests subacute (granulomatous) thyroiditis.

Neck ultrasound and radioactive iodine (RAI) uptake and scan should be performed in patients with suppressed TSH and nodule(s) on examination. Toxic nodules that appear “hot” on nuclear medicine testing can be definitively treated with radioactive iodine, though thionamide treatment can be temporizing. Nodules seen on neck ultrasound but “cold” on scan should be biopsied to rule out thyroid cancer. If RAI scanning shows diminished radiotracer uptake and poor gland visibility, subacute or subclinical thyroiditis should be suspected. Subacute thyroiditis can occur transiently following an upper respiratory illness and is associated with neck pain. The condition can be treated with NSAIDs and/or a short course of prednisone. Subclinical, painless thyroiditis is thought to be autoimmune mediated and does not typically require therapy. Both subacute and subclinical thyroiditis can be associated with a hypothyroid phase that follows hyperthyroidism. In some cases, the hypothyroidism does not resolve and requires lifelong LT4 therapy. As such, TSH and free T4 should be monitored closely every six weeks.

Graves’ disease will show diffuse RAI uptake and increased vascularity on neck ultrasound. Graves’ disease can be initially treated with thionamides (methimazole, PTU), as remission can occur within the first year in 20%–30% of patients. Unless contraindicated, methimazole is preferred over PTU, given its once daily dosing. Starting dose depends on the severity of thyrotoxicosis, but is usually 10 mg–15 mg daily for mild Graves’ disease. Beta blockers are also recommended in Graves’ disease, if appropriate. Thyroid function tests with TSH, free T4, and total T3 should be monitored every six weeks in Graves’ patients, with adjustment of methimazole dose to achieve normal free T4 and total T3 levels and a TSH in the detectable range. If Graves’ does not go into remission with methimazole treatment for a year or becomes difficult to control, RAI treatment should be pursued. In cases where RAI is required to manage hyperthyroidism, resultant hypothyroidism should be anticipated and managed accordingly.[16]

Amiodarone is an iodine-containing anti-arrhythmic medication that can cause thyrotoxicosis in one of two ways: amiodarone-induced thyrotoxicosis (AIT) type 1 is iodine-induced and occurs in individuals with autoimmune thyroid disease or thyroid nodules; AIT type 2 is destructive thyroiditis caused by toxic effects of amiodarone on follicular thyroid cells. It is important to obtain a thyroid ultrasound in these patients to distinguish which type of AIT exists, as the treatment is different for the two conditions. AIT type 1 is treated with thionamides, radioactive iodine, or surgery, if necessary. AIT type 2 is treated with steroids. A baseline TSH should be checked in all patients prior to initiating amiodarone and monitored at least yearly.

Subclinical hyperthyroidism

Subclinical hyperthyroidism is defined by low TSH levels and normal FT4 and total T3 levels. It is important to distinguish this condition from nonthyroidal illness or “euthyroid sick syndrome,” which can be due to chronic or critical illness. Euthyroid sick syndrome is characterized by low or normal TSH, low or normal FT4, and low total T3 and FT3. This condition is common in the elderly and affects up to one-third of critically ill hospitalized patients.[23, 24] The failure of TSH to rise in response to low thyroid hormone levels in critical illness is due in part to central hypothyroidism from alterations in the hypothalamic-pituitary-thyroid axis. Euthyroid sick syndrome is usually transient and does not require treatment, as the laboratory findings normalize when the underlying illness has resolved.

Many studies have shown that subclinical hyperthyroidism has adverse effects on cardiovascular health and bone mass in patients >65 years. It has been linked to a threefold increased risk of atrial fibrillation in the elderly. For treatment purposes, a clinical consensus group with representatives from the Endocrine Society, American Thyroid Association, and American Association of Clinical Endocrinologists has recommended that elderly patients with TSH <0.1 uIU/mL undergo diagnostic testing and begin treatment for the causative condition. Elderly men and women with TSH in the 0.1–0.5 uIU/mL range should also be treated, as they are at increased risk of cardiac arrhythmia and bone loss.[25]

Thyroid nodules

Almost 50% of patients >65 years of age have thyroid nodules on ultrasound examination, the prevalence confirmed by autopsy studies. Greater than 95% of thyroid nodules are benign. Elderly patients with palpable thyroid nodules should be evaluated with thyroid ultrasound, as the incidence of thyroid cancer increases with age. Those with thyroid nodule(s) and suppressed TSH should have 24-hour radioactive iodine uptake and scan (as detailed earlier), to identify hyperfunctioning, “hot” nodule(s). Hyperfunctioning nodules rarely harbor malignancy, and cytologic evaluation is rarely necessary.

Elderly patients with thyroid nodules should be evaluated by an endocrinologist to determine if biopsy with fine-needle aspiration (FNA) is indicated. In general, nodules measuring 1.0 cm or larger with suspicious features (hypoechoic, microcalcifications, increased vascularity, infiltrating margins, etc.) should undergo biopsy. All patients with abnormal cervical lymph nodes detected on exam or ultrasound and thyroid nodule(s) should also undergo FNA. Spongiform and mixed cystic-solid nodules do not require FNA biopsy unless they are 2.0 cm or larger in size. If biopsy reveals a benign nodule or nodules, patients can be followed every one to two years with thyroid ultrasound for changes in size or character, in which case repeat biopsy or surgical removal may be warranted.[26]

Thyroid cancer

Differentiated thyroid carcinoma has a good prognosis if detected early and treated with thyroidectomy (and radioactive iodine, if indicated). However, patients older than 65 often have more aggressive disease with multiple, larger tumors and more advanced-stage disease, nonpapillary histology, and extrathyroidal extension. Anaplastic thyroid carcinoma, which carries the worst prognosis among thyroid cancers, presents almost exclusively after the age of 60 years. If biopsy of a thyroid nodule reveals thyroid cancer cells or findings suspicious for thyroid cancer, thyroidectomy should be performed. Total thyroidectomy is generally recommended if the primary thyroid carcinoma is >1 cm; there are contralateral thyroid nodules present, or regional or distant metastases are present, the patient has a personal history of radiation therapy to the head and neck, or the patient has first-degree family history of differentiated thyroid cancer. Older patients (age >45 years) should also undergo total thyroidectomy even with tumors <1 cm–1.5 cm, because of higher recurrence rates in this age group.[26] Age by itself is not a contraindication to thyroidectomy. Studies have shown no difference in complication rates (permanent hypoparathyroidism, recurrent laryngeal nerve palsy, etc.) between older and younger patients who undergo thyroidectomy for thyroid cancer.[27] Treatment decisions to include thyroidectomy, neck dissection, radioactive iodine remnant ablation, TSH suppression, and ongoing follow-up should be made by an experienced endocrinologist and thyroid surgeon.

Hypopituitarism

The incidence of hypopituitarism in the adult general population (mean age of diagnosis 50 years; range 18–79 years) has been estimated at 4.2 cases per 100,000.[28] Pituitary adenomas, particularly nonfunctional pituitary adenomas, are the most common cause of hypopituitarism in the elderly, with an incidence of 7%–9.9% in this population.[29–31] The incidence of pituitary adenomas in the elderly is increasing, likely related to the increasing frequency of neuroimaging in this population. Pituitary adenomas are nonfunctional in 65%–84% of cases, with the most common functional pituitary adenomas secreting growth hormone (GH, 17%), prolactin (4.5%–10%), and adrenocorticotropic hormone (ACTH, 0%–6%). Gonadotrophic adenomas, which are usually included in the non-functional pituitary adenoma group, tend to increase with age, particularly over the age of 50.[32] Other causes of hypopituitarism include nonadenomatous tumors such as craniopharyngiomas, meningiomas, gliomas, and metastases, as well as infiltrative lesions such as hemochromatosis, granulomatous diseases, histiocytosis and autoimmune lymphocytic hypophysitis. Pituitary apoplexy, surgery and radiation can result in hypopituitarism up to 10 years following therapy.[33]

Clinical manifestations of either partial or complete hypopituitarism may be nonspecific and attributed to the natural aging process or related comorbidities. Pituitary tumors are incidentally discovered on imaging in approximately 5%–15% of elderly patients. Due to the predominance of nonfunctioning pituitary adenomas, clinical symptoms are often associated with local mass effect on the optic chiasm resulting in visual impairment. Due to age-related decline in visual acuity, cataracts, and macular degeneration, the link between visual symptoms and pituitary pathology may be misdiagnosed in up to 20% of cases. Other manifestations of mass effect – including headaches, cranial nerve palsy due to cavernous sinus invasion or pituitary apoplexy, and opthalmoplegia – are less common.[34]

Symptoms of hormonal deficits are less commonly recognized as a presenting feature of pituitary tumors, largely due to their nonspecific nature and overlap with those related to aging and medical comorbidities. However, with thorough preoperative evaluations, rates of symptoms at presentation can be identified in up to 50% of individuals.[35] Hyponatremia, whether due to age-related changes in vasopressin secretion or adrenal insufficiency, can be a presenting feature of hypopituitarism in up to 9.5% of cases in the elderly.[36] Conversely, diabetes insipidus is unlikely to be due to a pituitary adenoma and is more commonly seen in cases of craniopharyngioma, lymphocytic hypophysitis, infiltrative disease, or pituitary metastases.[35]

Biochemical hormonal assessment with cortisol, IGF-1, free T4, and prolactin levels, as well as neuroradiological imaging with a pituitary-protocol MRI with baseline visual field testing are important components of the diagnosis of hypopituitarism at any age. However, the diagnosis of pituitary dysfunction in the elderly individual poses specific challenges. There are morphologic changes in the hypothalamus and pituitary in addition to age-related declines in GH, androgens, and estrogen that must be considered. Additional illnesses and medications may further confound assessment. Classically, acquired hypopituitarism progresses such that GH deficiency appears first, followed by hypogonadotrophic hypogonadism and subsequently thyroid and/or adrenal insufficiency.[35]

Growth hormone deficiency is diagnosed on the basis of subnormal serum insulin-like growth factor 1 (IGF-1) levels measured against gender and age-specific norms. GH deficiency is then confirmed with a glucagon stimulation test. In the setting of acromegaly, documentation of elevated IGF-1 levels should be followed by confirmatory oral glucose tolerance testing with measurement of growth hormone levels.[35] Assessment of central hypogonadism in the elderly man is made on the basis of 8 am testosterone levels in the setting of low LH and FSH levels. Prolactinomas typically present as macroadenomas (>2 cm) in the elderly. There may be associated hypogonadism in men as well as galactorrhea. Prolactin levels may be elevated as a side effect of several medications used commonly in the elderly, including antipsychotic agents. Nonfunctional pituitary adenomas may also result in modest elevations in prolactin levels due to stalk compression. The diagnosis of central hypothyroidism can be made on the basis of low plasma free T4 levels in the setting of thyroid stimulating hormone (TSH) levels in the low or inappropriate-normal range. Adrenal insufficiency is diagnosed based on low morning serum cortisol levels with confirmatory subnormal response to the 250 mcg ACTH stimulation test (<18 mcg/dL).

When selecting the appropriate treatment for pituitary tumors, whether surgical or medical, it is important to consider the impact of mass effect, hormonal deficits, and hormonal excess. Transsphenoidal surgery is regarded as both safe and successful in the elderly in the hands of an experienced neurosurgical team. Studies show no increase in perioperative morality or severe anesthesiologic complications in individuals aged 65 and older. The most frequent postoperative complications include diabetes insipidus and cerebrospinal fluid leak.[31, 37] Transsphenoidal surgery is also the treatment of choice for elderly patients with visual disturbances due to nonfunctioning pituitary adenomas. More than 70% of individuals will demonstrate postoperative visual improvement, although a small percentage may develop visual deterioration due to hemorrhagic or ischemic damage.[31] The indication for surgical intervention in nonfunctional sellar masses without visual impairment is less clear. Conservative interval monitoring with laboratory studies and imaging may be a reasonable option and should be considered in those at high surgical risk.[35]

Hormonal replacement in elderly patients with hypopituitarism can be complicated and requires addressing each of the impaired axes. For ACTH deficiency, cortisol replacement regimens must be tailored to achieve hemodynamic stability while avoiding overtreatment that could adversely impact bone health and metabolism. It is of paramount importance to ensure that individuals with ACTH deficiency wear a medical alert tag and are aware of the need to contact their physician for dose adjustments in acute illness or prior to invasive procedures. Thyroid hormone should be started at low dose and uptitrated gradually to a goal of 1.3 +/–0.2 mcg/kg/day.[38] In hypopituitarism, dosing is titrated to free T4 levels and not to TSH levels. Further, prior to initiating thyroid hormone replacement, central adrenal insufficiency should be identified and treated to avoid precipitating an adrenal crisis.

Indications for replacement of testosterone and growth hormone in cases of hypopituitarism are less well established, particularly in the elderly population. Testosterone replacement therapy has important implications for maintaining lean body mass, bone mineralization, erythropoiesis, and sense of well-being. However, recent studies have revealed a possible link between testosterone replacement and increased cardiovascular risk in older men. Testosterone initiations should take place after carefully assessing the risk–benefit ratio for the individual in question. Deficiency in growth hormone is associated with visceral obesity, insulin resistance with impaired glucose tolerance, and dyslipidemia. In the absence of contraindications such as malignancy or proliferative diabetic retinopathy, growth hormone replacement may be beneficial in select cases. Lower-dose therapy is typically required in the elderly, and IGF-1 levels should be closely monitored.[34, 35]