William E. Clutter
EVALUATION OF THYROID FUNCTION
Thyroid-Stimulating Hormone
· Plasma thyroid-stimulating hormone (TSH) assay is the initial test of choice in most patients with suspected thyroid disease.
· TSH levels are elevated in even mild primary hypothyroidism and can be suppressed to <0.1 μU/mL in subclinical hyperthyroidism (i.e., thyroid hormone excess too mild to cause symptoms). A normal TSH level excludes hyperthyroidism and primary hypothyroidism.
· TSH levels usually are within the reference range in secondary hypothyroidism and are not useful for detection of this rare form of hypothyroidism.
· Abnormal TSH levels are not specific for clinically important thyroid disease, which should usually be confirmed by plasma thyroid hormone measurement.
· TSH is mildly elevated (up to 20 μU/mL) in some euthyroid patients with nonthyroidal illnesses and in subclinical hypothyroidism.
· TSH levels may be suppressed to <0.1 μU/mL in nonthyroidal illness, in subclinical hyperthyroidism, and during treatment with dopamine or high doses of glucocorticoids.
· TSH levels remain <0.1 μU/mL for some time after hyperthyroidism is corrected.
Free Thyroxine
· Measurement of free T4 confirms the diagnosis of clinical hypothyroidism in patients with elevated plasma TSH and confirms the diagnosis and assesses the severity of hyperthyroidism when plasma TSH is <0.1 μU/mL.
· It is also used to diagnose secondary hypothyroidism and adjust thyroxine therapy in patients with pituitary disease.
· Measurement of total plasma T4 alone is not adequate, because thyroxine-binding globulin (TBG) levels are altered in many circumstances.
Effect of Nonthyroidal Illness
· Many illnesses alter thyroid tests without causing true thyroid dysfunction. These changes must be recognized to avoid mistaken diagnosis and therapy.
· The low T3 syndrome occurs in many illnesses, during starvation, and after trauma or surgery. Conversion of T4 to T3 is decreased, and plasma T3 levels are low. It may be an adaptive response to illness, and thyroid hormone therapy is not beneficial.
· The low T4 syndrome occurs in severe illness. It may be due to decreased TBG levels, inhibition of T4 binding to TBG, or suppressed TSH secretion.
· TSH levels decrease early in severe illness, sometimes to <0.1 μU/mL. During recovery, they rise, sometimes to levels higher than the normal range (but rarely higher than 20 μU/mL).
Effects of Drugs
· Iodine-containing drugs (e.g., amiodarone, radiographic contrast media) may cause hyperthyroidism or hypothyroidism in susceptible patients.
· Many drugs alter thyroid function tests, especially plasma T4, without causing true thyroid dysfunction (Table 21-1).
· In general, plasma TSH levels are a reliable guide to determining whether true hyperthyroidism or hypothyroidism is present.
TABLE 21-1 Effects of Drugs on Thyroid Function Tests
T3, triiodothyronine; T4, thyroxine; TBG, thyroxine-binding globulin; TSH, thyroid-stimulating hormone.
Hypothyroidism
GENERAL PRINCIPLES
· Primary hypothyroidism (due to disease of the thyroid itself) accounts for >90% of cases.1
· Hypothyroidism is readily treatable and should be suspected in any patient with compatible symptoms, especially in the presence of a goiter or a history of radioactive iodine (RAI) therapy or thyroid surgery.
· Chronic lymphocytic thyroiditis (Hashimoto disease) is the most common cause and may be associated with Addison disease and other endocrine deficits. Its prevalence is greatest in women and increases with age.
· Iatrogenic hypothyroidism due to thyroidectomy and RAI therapy is also a common cause.
· Transient hypothyroidism occurs in postpartum thyroiditis and subacute thyroiditis, usually after a period of hyperthyroidism.
· Drugs that may cause hypothyroidism include iodine and iodine-containing drugs like amiodarone, lithium, α- and β-interferon, interleukin-2, thalidomide, sunitinib, and bexarotene.
· Secondary hypothyroidism due to TSH deficiency is uncommon but may occur in any disorder of the pituitary or hypothalamus. It rarely occurs without other evidence of pituitary disease.
DIAGNOSIS
Clinical Presentation
· Most symptoms of hypothyroidism are nonspecific and develop gradually. They include cold intolerance, fatigue, somnolence, poor memory, constipation, menorrhagia, myalgias, and hoarseness.
· Mild weight gain may occur, but hypothyroidism does not cause obesity.
· Signs include slow deep tendon reflex relaxation, bradycardia, facial and periorbital edema, dry skin, and nonpitting edema (myxedema).
· Rare manifestations include hypoventilation, pericardial or pleural effusions, deafness, and carpal tunnel syndrome.
Diagnostic Testing
· Laboratory findings may include hyponatremia and elevated plasma levels of cholesterol, triglycerides, and creatine kinase.
· The ECG may show low-voltage and T-wave abnormalities.
· Thyroid imaging with ultrasound or radionuclide scan is not useful in diagnosis of hypothyroidism.
· In suspected primary hypothyroidism, TSH is the best initial diagnostic test. A normal value excludes primary hypothyroidism, and a markedly elevated value (>20 μU/mL) confirms the diagnosis. If plasma TSH is elevated moderately (5 to 20 μU/mL), plasma free T4 should be measured. A low free T4 confirms clinical hypothyroidism.
· A clearly normal free T4 with an elevated plasma TSH indicates subclinical hypothyroidism, in which thyroid function is impaired but increased secretion of TSH maintains plasma T4 levels within the reference range. These patients may have nonspecific symptoms that are compatible with hypothyroidism as well as a mild increase in serum cholesterol and low-density lipoprotein cholesterol levels. They develop clinical hypothyroidism at a rate of 2.5% per year.
· If secondary hypothyroidism is suspected because of evidence of pituitary disease, plasma free T4 should be measured. Plasma TSH levels are usually within the reference range in secondary hypothyroidism and cannot be used alone to make this diagnosis. Patients with secondary hypothyroidism should be evaluated for other pituitary hormone deficits and for a mass lesion of the pituitary or hypothalamus.
· In severe nonthyroidal illness, the diagnosis of hypothyroidism may be difficult. Plasma free T4 measured by routine assays may be low. Plasma TSH is still the best initial diagnostic test. Marked elevation of plasma TSH (>20 μU/mL) establishes the diagnosis of primary hypothyroidism. A normal TSH value is strong evidence that the patient is euthyroid, except when there is evidence of pituitary or hypothalamic disease, in which case free T4should be measured. Moderate elevations of plasma TSH (<20 μU/mL) may occur in euthyroid patients with nonthyroidal illness and are not specific for hypothyroidism.
TREATMENT
Thyroid Hormone Replacement
· Levothyroxine (T4) is the drug of choice.1 The average replacement dose is 1.6 μg/kg PO qd, and most patients require doses between 75 and 150 μg qd. Young and middle-aged patients should be started on 100 μg daily. In otherwise healthy elderly patients, the initial dose should be 50 μg daily. Patients with heart disease should be started on 25 μg daily and monitored carefully for exacerbation of cardiac symptoms.
· The need for lifelong treatment should be emphasized.
· Thyroxine should be taken 30 minutes before a meal, since dietary fiber interferes with its absorption, and should not be taken with medications such as calcium or iron supplements that affect its absorption.
Follow-Up and Dose Adjustment
· In primary hypothyroidism, the goal of therapy is to maintain plasma TSH within the normal range. After 6 to 8 weeks, plasma TSH should be measured. The dose of T4 then should be adjusted in 12- to 25-μg increments at intervals of 6 to 8 weeks until plasma TSH is normal. Thereafter, annual TSH measurement is adequate to monitor therapy.
· Overtreatment, indicated by a plasma TSH below the normal range, should be avoided, as it increases the risk of osteoporosis and atrial fibrillation.
· In secondary hypothyroidism, plasma TSH cannot be used to adjust therapy. The goal of therapy is to maintain plasma free T4 near the middle of the reference range. The dose of T4 should be adjusted at 6- to 8-week intervals until this goal is achieved. Thereafter, annual measurement of plasma free T4 is adequate to monitor therapy.
· Coronary artery disease may be exacerbated by treatment of hypothyroidism. The dose should be increased slowly, with careful attention to worsening angina, heart failure, or arrhythmias.
Difficult-to-Control Hypothyroidism
· Difficulty in controlling hypothyroidism is most often due to poor compliance with therapy. Observed therapy may be necessary in some cases.
· Other causes of increasing T4 requirements include the following:
o Malabsorption due to intestinal disease
o Drugs that interfere with T4 absorption (e.g., calcium carbonate, ferrous sulfate, colesevelam, cholestyramine, sucralfate, aluminum hydroxide)
o Other drug interactions that increase T4 clearance (e.g., rifampin, carbamazepine, phenytoin, estrogen) or block conversion of T4 to T3 (amiodarone)
o Pregnancy, in which T4 requirement increases in the first trimester
o Gradual failure of remaining endogenous thyroid function after treatment of hyperthyroidism
Subclinical Hypothyroidism
· Subclinical hypothyroidism should be treated with T4 if any of the following is present: symptoms compatible with hypothyroidism, goiter, hypercholesterolemia that warrants treatment, and plasma TSH >10 μU/mL.2Untreated patients should be monitored annually, and T4 should be started if symptoms develop or serum TSH increases to >10 μU/mL.
Pregnancy
· Thyroxine dose increases by an average of 50% in the first half of pregnancy.3 In women with primary hypothyroidism, plasma TSH should be measured as soon as pregnancy is confirmed and monthly thereafter through the second trimester.
· The thyroxine dose should be increased as needed to maintain plasma TSH within the lower half of the normal range. After delivery, the prepregnancy dose should be resumed.
Urgent Therapy
· Urgent therapy is rarely necessary for hypothyroidism.
· Most patients with hypothyroidism and concomitant illness can be treated in the usual manner; however, hypothyroidism may impair survival in critical illness by contributing to hypoventilation, hypotension, hypothermia, bradycardia, or hyponatremia. Such patients should be admitted to the hospital for therapy of hypothyroidism and the concomitant illness.
· Confirmatory tests should be obtained before thyroid hormone therapy is started in a severely ill patient, including serum TSH and free T4.
· T4, 50 to 100 μg IV, can be given every 6 to 8 hours for 24 hours, followed by 75 to 100 μg IV daily until oral intake is possible.
· Such rapid correction is warranted only in extremely ill patients.
· Vital signs and cardiac rhythm should be monitored carefully to detect early signs of exacerbation of heart disease.
· Hydrocortisone, 50 mg IV every 8 hours, usually is recommended during rapid treatment with thyroid hormone on the grounds that replacement of thyroid hormone may precipitate adrenal failure.
Hyperthyroidism
GENERAL PRINCIPLES
· Hyperthyroidism should be suspected in any patient with compatible symptoms, as it is a readily treatable disorder that may become highly debilitating.4
· Graves disease causes most cases of hyperthyroidism, especially in young patients. This autoimmune disorder may also cause two signs that are not found in other causes of hyperthyroidism: proptosis (exophthalmos) and pretibial myxedema.
· Toxic multinodular goiter (MNG) is a common cause in older patients.
· Unusual causes include iodine-induced hyperthyroidism, usually precipitated by drugs (e.g., amiodarone or radiographic contrast media), thyroid adenomas (which present as a single nodule), subacute thyroiditis (painful tender goiter with transient hyperthyroidism), painless thyroiditis (nontender goiter with transient hyperthyroidism, often postpartum), and surreptitious ingestion of thyroid hormone.
· TSH-induced hyperthyroidism is extremely rare.
DIAGNOSIS
Clinical Presentation
· Symptoms include heat intolerance, weight loss, weakness, palpitations, oligomenorrhea, and anxiety.
· Signs include brisk deep tendon reflexes, fine tremor, proximal weakness, stare, and eyelid lag.
· Cardiac abnormalities may be prominent, including sinus tachycardia, atrial fibrillation, and exacerbation of coronary artery disease or heart failure. In the elderly, hyperthyroidism may present with only atrial fibrillation, heart failure, weakness, or weight loss, and a high index of suspicion is needed to make the diagnosis.
· Presence of proptosis or pretibial myxedema indicates Graves disease (although many patients with Graves disease lack these signs).
· Palpation of the thyroid can determine whether a diffuse or nodular goiter is present; most hyperthyroid patients with a diffuse nontender goiter have Graves disease.
· History of recent pregnancy, neck pain, or iodine administration suggests causes other than Graves disease.
· The differential diagnosis is presented in Table 21-2.
TABLE 21-2 Differential Diagnosis of Hyperthyroidism
Diagnostic Testing
· Plasma TSH is the best initial diagnostic test.
o If plasma TSH is <0.1 μU/mL, plasma free T4 should be measured to determine the severity of hyperthyroidism and as a baseline for therapy.
o If plasma free T4 is elevated, the diagnosis of clinical hyperthyroidism is established.
o If plasma TSH is <0.1 μU/mL but free T4 is normal, the patient may have clinical hyperthyroidism due to elevation of plasma T3 alone; in this case, plasma T3 should be measured. This combination of test results may also be due to suppression of TSH by nonthyroidal illness.
· Subclinical hyperthyroidism may lower TSH to <0.1 μU/mL, and therefore, suppression of TSH alone does not confirm that symptoms are due to hyperthyroidism. Subclinical hyperthyroidism is present when the plasma TSH is suppressed to <0.1 μU/mL, but the patient has no symptoms that are definitely caused by hyperthyroidism and plasma levels of T4 and T3 are normal.5
· In rare cases, 24-hour RAI uptake (RAIU) is needed to distinguish Graves disease or toxic MNG (in which RAIU is elevated) from postpartum thyroiditis, iodine-induced hyperthyroidism, or factitious hyperthyroidism (in which RAIU is very low).
TREATMENT
· Some forms of hyperthyroidism (subacute or postpartum thyroiditis) are transient and require only symptomatic therapy.
· Three methods are available for definitive therapy: RAI, thionamides, and subtotal thyroidectomy, none of which controls hyperthyroidism rapidly.
· During treatment, patients are followed by clinical evaluation and measurement of plasma free T4. Plasma TSH is useless in assessing the initial response to therapy, as it remains suppressed until after the patient becomes euthyroid.
· Regardless of the therapy used, all patients with Graves disease require lifelong follow-up for recurrent hyperthyroidism or development of hypothyroidism.
Symptomatic Therapy
· β-Adrenergic antagonists are used to relieve such symptoms as palpitations, tremor, and anxiety until hyperthyroidism is controlled by definitive therapy or until transient forms of hyperthyroidism subside. The initial dose of atenolol, 25 to 50 mg daily, is adjusted to alleviate symptoms and tachycardia. β-Adrenergic antagonist therapy should be reduced gradually, then stopped as hyperthyroidism is controlled.
· Verapamil at an initial dose of 40 to 80 mg tid can be used to control tachycardia in patients with contraindications to β-adrenergic antagonists.
Thionamides
· Methimazole and propylthiouracil (PTU) inhibit thyroid hormone synthesis.4 PTU also inhibits extrathyroidal conversion of T4 to T3. These drugs have no permanent effect on thyroid function. Because of a better safety profile, methimazole should be used rather than PTU except in specific situations.
· Once thyroid hormone stores are depleted (after several weeks to months), T4 levels decrease.
· In the majority of patients with Graves disease, hyperthyroidism recurs within 6 months after therapy is stopped. Spontaneous remission of Graves disease occurs in approximately one-third of patients during thionamide therapy, and, in this minority, no other treatment may be needed. Remission is more likely to occur in mild, recent-onset hyperthyroidism and with a small goiter.
· Before starting therapy, patients must be warned of side effects and precautions. Usual starting doses are methimazole, 10 to 40 mg PO daily, or PTU, 100 to 200 mg PO tid; higher initial doses can be used in severe hyperthyroidism.
· Restoration of euthyroidism takes up to several months. Patients are evaluated at 4-week intervals with assessment of clinical findings and plasma free T4. If plasma free T4 levels do not fall after 4 to 8 weeks, the dose should be increased. Doses as high as methimazole, 60 mg PO daily, or PTU, 300 mg PO qid, may be required. Once the plasma free T4 level falls to normal, the dose is adjusted to maintain plasma free T4 within the normal range.
· No consensus exists on the optimal duration of therapy, but periods of 6 months to 2 years are used most commonly. Regardless of the duration of therapy, patients must be monitored carefully for recurrence of hyperthyroidism after the drug is stopped.
· Side effects are most likely to occur within the first few months of therapy.
o Minor side effects include rash, urticaria, fever, arthralgias, and transient leukopenia. Agranulocytosis occurs in 0.3% of patients who are treated with thionamides. Other life-threatening side effects include hepatitis, vasculitis, and drug-induced lupus erythematosus. Complications usually resolve if the drug is stopped promptly.
o Patients must be warned to stop the drug immediately if jaundice or symptoms suggestive of agranulocytosis (e.g., fever, chills, sore throat) develop and to contact their physician promptly for evaluation.
o Routine monitoring of the white blood cell count is not useful for detecting agranulocytosis, which develops suddenly.
o Methimazole has been associated with congenital abnormalities and should not be used in early pregnancy or in women attempting pregnancy.
Radioactive Iodine Therapy
· A single dose permanently controls hyperthyroidism in about 90% of patients, and further doses can be given if necessary.4 Usually, 24-hour RAIU is measured and used to calculate the dose.
· A pregnancy test is done immediately before therapy in potentially fertile women, since RAI is contraindicated in pregnancy.
· Thionamides interfere with RAI therapy and should be stopped 3 days before treatment. If iodine treatment has been given, it should be stopped at least 2 weeks before RAI therapy.
· Most patients with Graves disease are treated with 10 to 12 mCi, although treatment of toxic MNG requires higher doses.
· Several months are usually needed to restore euthyroidism. Patients are evaluated at 4- to 6-week intervals, with assessment of clinical findings and plasma free T4. If thyroid function stabilizes within the normal range, the interval between follow-up visits is increased gradually to annual intervals.
· T4 therapy is started if hypothyroidism develops, indicated by a low or low-normal FT4. TSH may remain suppressed for several weeks after hypothyroidism develops and is not a reliable indicator in early hypothyroidism.
· If symptomatic hyperthyroidism persists after 6 months, RAI treatment is repeated.
· Side effects:
o Hypothyroidism occurs in most patients within the first year and continues to develop at a rate of approximately 3% per year thereafter.
o A slight rise in plasma T4 may occur in the first 2 weeks after therapy, owing to release of stored hormone. This is clinically important only in patients with severe cardiac disease, which may worsen as a result. Such patients should be treated with thionamides to restore euthyroidism and to deplete stored hormone before treatment with RAI.
o No convincing evidence has been found that RAI has a clinically important effect on the course of Graves eye disease.
o RAI does not increase the risk of malignancy.
o There is no increase in congenital abnormalities in the offspring of women who conceive after RAI therapy.
Subtotal Thyroidectomy
· This procedure provides long-term control of hyperthyroidism in most patients.4
· Surgery may trigger a perioperative exacerbation of hyperthyroidism, and patients should be prepared for surgery by one of two methods.
o A thionamide is given until the patient is nearly euthyroid. Supersaturated potassium iodide (SSKI), 40 to 80 mg (1 to 2 drops) PO bid, is then added, and surgery is scheduled 1 to 2 weeks later. Both drugs are stopped postoperatively.
o Atenolol, 50 to 100 mg daily, and SSKI, 1 to 2 drops PO bid, are started 1 to 2 weeks before surgery is scheduled. The dose of atenolol is increased, if necessary, to reduce the resting heart rate below 90 beats/minute. Atenolol, but not SSKI, is continued for 5 to 7 days after surgery.
· Patients should be evaluated 4 to 6 weeks after surgery, with assessment of clinical findings and plasma free T4 and TSH. If thyroid function is normal, the patient is seen at 3 and 6 months and then annually. If hypothyroidism develops, T4 therapy is started. Hyperthyroidism persists or recurs in 3% to 7% of patients.
· Complications of thyroidectomy include hypothyroidism in 30% to 50% of patients and hypoparathyroidism in 3%. Rare complications include permanent vocal cord paralysis due to recurrent laryngeal nerve injury and perioperative death. The complication rate appears to depend on the experience of the surgeon.
Choice of Definitive Therapy
· In Graves disease, RAI therapy is the treatment of choice for almost all patients. It is simple, is highly effective and causes no life-threatening complications.
· RAI cannot be used in pregnancy. PTU should be used to treat hyperthyroidism in the first trimester of pregnancy, with consideration of then changing to methimazole. Thionamides provide long-term control of hyperthyroidism in fewer than one-half of patients and carry a small risk of life-threatening side effects.
· Thyroidectomy should be used only in patients who refuse RAI therapy and who relapse or develop side effects with thionamide therapy.
Other Causes of Hyperthyroidism
· Toxic MNG and toxic adenoma should be treated with RAI (except in pregnancy).
· Transient forms of hyperthyroidism due to thyroiditis should be treated symptomatically with atenolol.
· Iodine-induced hyperthyroidism is treated with methimazole and atenolol.
· Although treatment of some patients with amiodarone-induced hyperthyroidism with glucocorticoids has been advocated, nearly all patients with amiodarone-induced hyperthyroidism respond well to methimazole.6
· Subclinical hyperthyroidism increases the risk of atrial fibrillation in the elderly and predisposes to osteoporosis in postmenopausal women and should be treated in these groups of patients.5Asymptomatic young patients can be observed for spontaneous remission or worsening hyperthyroidism that warrants therapy.
Urgent Therapy
· Urgent therapy is warranted when hyperthyroidism exacerbates heart failure or coronary artery disease and in rare patients with severe hyperthyroidism complicated by fever and delirium. Such patients should be admitted to the hospital for therapy.
· PTU, 300 mg PO every 6 hours, should be started immediately.
· Iodide (SSKI, 1 to 2 drops PO every 12 hours) should be started 2 hours after the first dose of PTU to inhibit thyroid hormone secretion rapidly.
· Propranolol, 40 mg PO every 6 hours (or an equivalent dose of a parenteral β-adrenergic antagonist), should be given to patients with angina or myocardial infarction, and the dose should be adjusted to prevent tachycardia. Propranolol may benefit some patients with heart failure and marked tachycardia but can further impair left ventricular function. In patients with clinical heart failure, it should be given only with careful monitoring of left ventricular function.
· Plasma free T4 is measured every 4 to 6 days, and treatment with iodine is discontinued when free T4 approaches the normal range.
· RAI therapy should be scheduled 2 weeks after iodine is stopped.
Hyperthyroidism in Pregnancy
· RAI is contraindicated in pregnancy, and therefore patients should be treated with PTU, with consideration of changing to methimazole after the first trimester.3 The dose should be adjusted to maintain the plasma free T4near the upper limit of the normal range to avoid fetal hypothyroidism. The dose required often decreases in the later stages of pregnancy.
· Atenolol, 25 to 50 mg PO daily, can be used to relieve symptoms while awaiting the effects of PTU.
· The fetus and neonate should be monitored carefully for hyperthyroidism.
Euthyroid Goiter
· The diagnosis of euthyroid goiter is based on palpation of the thyroid and on evaluation of thyroid function. If the thyroid is enlarged, the examiner should determine whether the enlargement is diffuse or multinodular or whether a single nodule is present. All three forms of euthyroid goiter are common, especially in women.
· Imaging studies, such as thyroid scans or ultrasonography, provide no useful additional information about goiters that are diffuse or multinodular by palpation and should not be performed in these patients. Furthermore, 30% to 50% of people have nonpalpable thyroid nodules that are detectable by ultrasound. These nodules rarely have any clinical importance, but their incidental discovery may lead to unnecessary diagnostic testing and treatment.7
· Almost all euthyroid diffuse goiters in the United States are due to chronic lymphocytic thyroiditis (Hashimoto thyroiditis). As Hashimoto disease may also cause hypothyroidism, plasma TSH should be measured even in patients who are clinically euthyroid. Small diffuse goiters usually are asymptomatic, and therapy is seldom required. The patient should be monitored regularly for the development of hypothyroidism.
· MNG is common in older patients, especially women. Most patients are asymptomatic and require no treatment. In a few patients, hyperthyroidism (toxic MNG) develops.
o In rare patients, the gland compresses the trachea or esophagus, causing dyspnea or dysphagia, and treatment is required. Thyroxine treatment has little or no effect on the size of MNGs and is not indicated. RAI therapy reduces gland size and relieves symptoms in most patients.8 Subtotal thyroidectomy can also be used to relieve compressive symptoms.
o The risk of malignancy in MNG is low and is comparable to the frequency of incidental thyroid carcinoma in clinically normal glands. Evaluation for thyroid carcinoma with needle biopsy is warranted only if one nodule is disproportionately enlarged.
Single Thyroid Nodules
· Single thyroid nodules are usually benign, but about 5% are thyroid carcinomas.9
· Clinical findings that increase the likelihood of carcinoma include the presence of cervical lymphadenopathy, a history of radiation to the head or neck in childhood, and a family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndromes type 2A or 2B. A hard fixed nodule, recent nodule growth, or hoarseness due to vocal cord paralysis also suggests malignancy. However, most patients with thyroid carcinomas have none of these risk factors, and nearly all palpable single thyroid nodules should be evaluated with needle aspiration biopsy. Patients with thyroid carcinoma should be managed in consultation with an endocrinologist.
· Nodules with benign cytology should be reevaluated periodically by palpation and biopsied again if they enlarge.
· T4 therapy has little or no effect on the size of single thyroid nodules and is not indicated.
· Imaging studies cannot distinguish benign from malignant nodules and are not necessary for the evaluation of a palpable thyroid nodule.
· The management of nonpalpable thyroid nodules discovered incidentally by ultrasound is controversial.7
Adrenal Failure
GENERAL PRINCIPLES
· Adrenal failure may be due to disease of the adrenal glands (primary adrenal failure, Addison disease), with deficiency of cortisol and aldosterone and elevated plasma adrenocorticotropic hormone (ACTH) or due to ACTH deficiency caused by disorders of the pituitary or hypothalamus (secondary adrenal failure) with deficiency of cortisol alone.
· Findings in adrenal failure are nonspecific and, without a high index of suspicion, the diagnosis of this potentially lethal but readily treatable disease is easily missed.
· Adrenal failure should be suspected in patients with hypotension (including orthostatic hypotension), persistent nausea, weight loss, hyponatremia, or hyperkalemia.
· Primary adrenal failure:
o Often due to autoimmune adrenalitis, which may be associated with other endocrine deficits (e.g., hypothyroidism).
o Infections of the adrenal gland such as tuberculosis and histoplasmosis may cause adrenal failure.
o Hemorrhagic adrenal infarction may occur in the postoperative period, in coagulation disorders and hypercoagulable states, and in sepsis (i.e., Waterhouse-Friderichsen syndrome). Adrenal hemorrhage often causes abdominal or flank pain and fever; CT scan of the abdomen reveals high-density bilateral adrenal masses.
o Adrenoleukodystrophy causes adrenal failure in young males.
o In patients with AIDS, adrenal failure may develop because of disseminated cytomegalovirus, mycobacterial or fungal infection, or adrenal lymphoma, or treatment with ketoconazole, which inhibits steroid hormone synthesis.
· Secondary adrenal failure is most often due to glucocorticoid therapy; ACTH suppression may persist for a year after therapy is stopped. Any disorder of the pituitary or hypothalamus can cause ACTH deficiency, but usually other evidence of these disorders can be seen.
DIAGNOSIS
Clinical Presentation
· Symptoms include anorexia, nausea, vomiting, weight loss, weakness, and fatigue.
· Orthostatic hypotension and hyponatremia are common.
· Usually symptoms are chronic, but shock that is fatal unless treated promptly may develop suddenly. Often, this adrenal crisis is triggered by illness, injury, or surgery.
· Hyperpigmentation (due to marked ACTH excess), hyperkalemia, and volume depletion (due to aldosterone deficiency) occur only in primary adrenal failure.
Diagnostic Testing
· The short cosyntropin stimulation test is used for diagnosis.
o Cosyntropin, 250 μg, is given IV or IM, and plasma cortisol is measured 30 minutes later. The normal response is a stimulated plasma cortisol >20 μg/dL.
o This test detects primary and secondary adrenal failure, except within a few weeks of onset of pituitary dysfunction (e.g., shortly after pituitary surgery).
· The distinction between primary and secondary adrenal failure usually is clear.
o Hyperkalemia, hyperpigmentation, or other autoimmune endocrine deficits indicate primary adrenal failure, whereas deficits of other pituitary hormones, symptoms of a pituitary mass (e.g., headache, visual field loss), or known pituitary or hypothalamic disease indicate secondary adrenal failure.
o If the cause is unclear, the plasma ACTH level distinguishes primary adrenal failure (in which it is markedly elevated) from secondary adrenal failure.
o Evidence of adrenal enlargement or calcification on abdominal CT indicates that the cause is infection or hemorrhage.
o Patients with secondary adrenal failure should be tested for other pituitary hormone deficiencies and should be evaluated for a pituitary or hypothalamic tumor.
TREATMENT
Adrenal Crisis
· Adrenal crisis with hypotension must be treated immediately. These patients should be admitted to the hospital for therapy and be evaluated for an underlying illness that precipitated the crisis.
· If the diagnosis of adrenal failure is known, hydrocortisone, 100 mg IV every 8 hours, should be given, and 0.9% saline with 5% dextrose should be infused rapidly until hypotension is corrected.
o The dose of hydrocortisone is decreased gradually over several days as symptoms and precipitating illness resolve and then is changed to oral maintenance therapy.
o Mineralocorticoid replacement is not needed until the dose of hydrocortisone is <100 mg/day.
· If the diagnosis of adrenal failure has not been established, a single dose of dexamethasone, 10 mg IV, should be given, and a rapid infusion of 0.9% saline with 5% dextrose should be started.
o A cosyntropin stimulation test should be performed.
o Dexamethasone is used because it does not interfere with subsequent measurements of cortisol.
o After the 30-minute plasma cortisol measurement, hydrocortisone, 100 mg IV every 8 hours, should be given until the test result is known.
Outpatient Maintenance Therapy
· All patients with adrenal failure require cortisol replacement with prednisone. Most patients with primary adrenal failure also require replacement of aldosterone with fludrocortisone.
· Prednisone, 5 mg PO every morning, should be started.
o Patients should initially be evaluated every 1 to 2 months.
o The dose of prednisone is adjusted to eliminate symptoms and signs of cortisol deficiency or excess, with most patients requiring between 4 mg every morning to as much as 5 mg every morning and 2.5 mg every evening.
o The goal of therapy is the lowest dose of prednisone that relieves symptoms, to avoid the possibility of producing signs of Cushing syndrome.
o Eventually, annual follow-up is adequate unless an acute illness develops.
o Concomitant therapy with rifampin, phenytoin, or phenobarbital accelerates glucocorticoid metabolism and increases the dose requirement.
· During illness, injury, or the perioperative period, the dose of glucocorticoid must be increased.
o For minor illnesses, the patient should double the dose of prednisone for 3 days. If the illness resolves, maintenance dose is resumed. Vomiting requires immediate medical attention, with IV glucocorticoid therapy and IV fluid. Patients can be given a 4-mg vial of dexamethasone, to be self-administered IM for vomiting or severe illness if medical care is not immediately available.
o For severe illness or injury, hydrocortisone, 50 mg IV every 8 hours, should be given, with the dose tapered as severity of illness wanes. The same regimen is used in patients who are undergoing surgery, with the first dose of hydrocortisone given preoperatively. Usually, the dose can be reduced to maintenance therapy 2 to 3 days after uncomplicated surgery.
· In primary adrenal failure, fludrocortisone, 0.1 mg PO qd, should be given. During follow-up visits, supine and standing blood pressure and serum potassium should be monitored.
· The dose of fludrocortisone is adjusted to maintain blood pressure and serum potassium within the normal range; the usual dose is 0.05 to 0.2 mg PO qd.
· Patients should be educated in management of their disease, including adjustment of prednisone dose during illness. They should wear a medical identification tag or bracelet.
Cushing Syndrome
GENERAL PRINCIPLES
· Cushing syndrome (the clinical effects of increased glucocorticoid hormone) is most often iatrogenic due to therapy with glucocorticoid drugs.
· ACTH-secreting pituitary microadenomas (Cushing disease) account for approximately 80% of cases of endogenous Cushing syndrome. Adrenal tumors and ectopic ACTH secretion account for the remainder.
DIAGNOSIS
Clinical Presentation
· Clinical features include truncal obesity, rounded face, fat deposits in the supraclavicular fossae and over the posterior neck, hypertension, hirsutism, amenorrhea, and depression.
· More specific findings include thin skin, easy bruising, reddish striae, proximal muscle weakness, and osteoporosis.
· Diabetes mellitus develops in some patients.
· Hyperpigmentation or hypokalemic alkalosis suggests Cushing syndrome because of ectopic ACTH secretion.
Diagnostic Testing
· The diagnosis is based on increased cortisol excretion, lack of normal feedback inhibition of ACTH and cortisol secretion, or loss of the normal diurnal rhythm of cortisol secretion.10
· Overnight dexamethasone suppression test can be done as a screening test. 1-mg dexamethasone given PO at 11:00 PM; plasma cortisol measured at 8:00 AM the next day; normal plasma cortisol level <2 μg/dL. Salivary cortisol may be measured at home during the nadir of normal plasma cortisol at 11:00 PM.
· If the overnight dexamethasone suppression test or 11 PM salivary cortisol is abnormal, 24-hour urine cortisol should be measured. Twenty-four–hour urine cortisol measurement can also be done as a screening test. A normal value virtually excludes the diagnosis.
· If the 24-hour urine cortisol is more than four times the upper limit of the reference range in a patient with compatible symptoms, the diagnosis of Cushing syndrome is established.
· In patients with milder elevations of urine cortisol, a low-dose dexamethasone suppression test should be performed. Dexamethasone, 0.5 mg PO every 6 hours, is given for 48 hours, starting at 8:00 AM. Urine cortisol is measured during the last 24 hours, and plasma cortisol is measured 6 hours after the last dose of dexamethasone. Failure to suppress plasma cortisol to <2 μg/dL and urine cortisol to less than the normal reference range is diagnostic of Cushing syndrome.
· Testing should not be done during severe illness or depression, which may cause false-positive results.
· Phenytoin therapy also causes false-positive dexamethasone suppression test results by accelerating metabolism of dexamethasone.
· Random plasma cortisol levels are not useful for diagnosis, because the wide range of normal values overlaps that of Cushing syndrome.
· After the diagnosis of Cushing syndrome is made, tests to determine the cause should be done in consultation with an endocrinologist.
TREATMENT
The treatment of hypercortisolism is dependent on its cause, and a complete discussion of management is beyond the scope of this chapter. Stopping exogenous glucocorticoids when possible is clearly indicated. Other treatments usually require the assistance of an endocrinologist or neurosurgeon.
Incidental Adrenal Nodules
GENERAL PRINCIPLES
Adrenal nodules are a common incidental finding on abdominal imaging studies. Most incidentally discovered nodules are benign adrenocortical tumors that do not secrete excess hormone, but the differential diagnosis includes adrenal adenomas that cause Cushing syndrome or primary hyperaldosteronism, pheochromocytoma, adrenocortical carcinoma, and metastatic cancer.11
DIAGNOSIS
Clinical Presentation
The patient should be evaluated for symptoms and signs of Cushing syndrome. Hypertension suggests the possibility of primary hyperaldosteronism or pheochromocytoma. Episodes of headache, palpitations, and sweating suggest pheochromocytoma. Hirsutism suggests the possibility of an adrenocortical carcinoma.
Diagnostic Testing
· The imaging characteristics of the nodule may suggest a diagnosis (e.g., benign adrenocortical nodule) but are not specific enough to obviate further evaluation.
· Patients who have potentially resectable cancer elsewhere and in whom an adrenal metastasis must be excluded may require positron emission tomography.
· In other patients, the diagnostic issue is whether a syndrome of hormone excess or an adrenocortical carcinoma is present.
· Plasma potassium, fractionated metanephrines, and dehydroepiandrosterone sulfate should be measured, and an overnight dexamethasone suppression test should be performed.
· Patients with hypertension and hypokalemia should be evaluated for primary hyperaldosteronism by measuring the ratio of plasma aldosterone (in ng/dL) to plasma renin activity (in ng/mL/hour) in a single blood sample.
o This sample can be obtained from an ambulatory patient without special preparation.
o If the ratio is <20, the diagnosis of primary hyperaldosteronism is excluded, whereas a ratio of >50 makes the diagnosis very likely.
o Patients with an intermediate ratio should be further evaluated in consultation with an endocrinologist.
· An abnormal overnight dexamethasone suppression test should be evaluated further (see Cushing Syndrome).
· Elevation of plasma dehydroepiandrosterone sulfate or a large nodule suggests adrenocortical carcinoma.
TREATMENT
· If there is clinical or biochemical evidence of a pheochromocytoma, the nodule should be resected after appropriate α-adrenergic blockade with phenoxybenzamine.
· Most incidental nodules are <4 cm in diameter, do not produce excess hormone, and do not require therapy. One repeat imaging procedure 3 to 6 months later is recommended to ensure that the nodule is not enlarging rapidly (which would suggest an adrenal carcinoma).
· A policy of resecting all nodules >4 cm in diameter appropriately treats the great majority of adrenal carcinomas while minimizing the number of benign nodules removed unnecessarily.
Hypercalcemia
GENERAL PRINCIPLES
· Approximately 50% of serum calcium is ionized (free), and the remainder is complexed, primarily to albumin. Changes in serum albumin alter total calcium concentration without affecting the clinically relevant ionized calcium level, and if serum albumin is abnormal, clinical decisions should be based on albumin-corrected or ionized calcium levels.
· Parathyroid hormone (PTH) increases serum calcium by stimulating bone resorption, increasing renal calcium reabsorption, and promoting renal conversion of vitamin D to its active metabolite calcitriol (1,25-dihydroxyvitamin D [1,25(OH)2D]). Serum calcium regulates PTH secretion by a negative feedback mechanism; hypercalcemia suppresses PTH release.
· Vitamin D is converted by the liver to 25-hydroxyvitamin D [25(OH)D], which in turn is converted by the kidney to 1,25(OH)2D. The latter metabolite increases serum calcium by promoting intestinal calcium absorption and plays a role in bone formation and resorption.
· Other factors that raise serum calcium include PTH-related peptide, which acts on PTH receptors, and some cytokines produced by plasma cells and lymphocytes.
· The major causes of hypercalcemia are listed in Table 21-3. >95% of cases are due to primary hyperparathyroidism or malignancy.
· Primary hyperparathyroidism:
o Causes most cases of mild hypercalcemia in ambulatory patients.
o It is a common disorder, especially in elderly women. Approximately 85% of cases are due to an adenoma of a single gland, 15% to enlargement of all four glands, and 1% to parathyroid carcinoma.
o Familial syndromes that include primary hyperparathyroidism (e.g., the multiple endocrine neoplasia syndromes) cause enlargement of all four glands.
· Malignancy causes most severe, symptomatic hypercalcemia. Common causes of malignant hypercalcemia include the following:
o Breast carcinoma (which is usually metastatic to bone when hypercalcemia occurs).
o Squamous carcinoma of the lung, head and neck, or esophagus (which may produce humoral hypercalcemia without extensive bone metastases).
o Multiple myeloma.
o Most malignant hypercalcemia is due to secretion of PTH-related peptide by the tumor, except for myeloma, in which hypercalcemia is mediated by cytokines.
· Other causes of hypercalcemia are uncommon and are almost always suggested by the history or physical examination.12
o Thiazide diuretics cause persistent hypercalcemia only in patients with increased bone turnover, for example, due to mild primary hyperparathyroidism.
o Sarcoidosis and other granulomatous disorders may cause hypercalcemia by excessive synthesis of 1,25(OH)2D.
o Familial benign hypercalciuric hypercalcemia is a rare autosomal dominant disorder that causes asymptomatic hypercalcemia from birth. It is due to a genetic defect in the calcium-sensing receptor on parathyroid cells and should be suspected if there is a family history of asymptomatic hypercalcemia.
TABLE 21-3 Major Causes of Hypercalcemia
DIAGNOSIS
Clinical Presentation
· Most symptoms of hypercalcemia are present only if serum calcium is above 12 mg/dL.
· In the majority of patients, mild, asymptomatic hypercalcemia is found incidentally.
· Severe symptomatic hypercalcemia is usually due to malignancy and the cancer is almost always clinically apparent.
· The history and physical examination should focus on duration of hypercalcemia (if >6 months without obvious cause, primary hyperparathyroidism is almost certain), history of renal stones, symptoms and signs of malignancy, evidence for any of the unusual causes of hypercalcemia (e.g., calcium supplements, vitamin D, or lithium), and family history of hypercalcemia or other components of multiple endocrine neoplasia syndromes.
· Mild hypercalcemia causes polyuria. Polyuria combined with nausea and vomiting may cause marked dehydration, which impairs calcium excretion and may cause rapidly worsening hypercalcemia.
· Severe hypercalcemia may cause renal failure, and chronic hypercalcemia may cause nephrolithiasis (not seen in hypercalcemia of malignancy).
· Gastrointestinal symptoms include anorexia, nausea, vomiting, and constipation.
· Neurologic findings of severe hypercalcemia include weakness, fatigue, confusion, stupor, and coma.
· Decreased bone density (and rarely a specific bone disorder, osteitis fibrosa) can result from chronic hyperparathyroidism.
Diagnostic Testing
· Mildly elevated serum calcium levels should be repeated with serum albumin to allow for correction, and ionized calcium should be measured to determine whether hypercalcemia is actually present.
· The serum intact PTH level should be measured.
o If serum PTH is elevated in a patient with hypercalcemia, the diagnosis of primary hyperparathyroidism is confirmed.
o Intact PTH is suppressed to below the reference range or to the lower part of the reference range in all other causes of hypercalcemia except familial benign hypercalcemia.
o If the PTH level is suppressed, evaluation for other causes of hypercalcemia should be directed by clinical findings and may include a chest radiography, bone scan, and serum and urine protein electrophoresis.
· Vitamin D intoxication can be confirmed by measurement of elevated serum levels of 25(OH)D. The diagnosis of sarcoidosis as the cause of hypercalcemia is supported by elevated serum levels of 1,25(OH)2D.
· In rare cases in which the diagnosis remains unclear, measurement of serum levels of PTH-related peptide may help confirm or exclude malignancy.
· ECG manifestations include a shortened QT interval.
TREATMENT
· Patients with symptoms of hypercalcemia or serum calcium levels >13 mg/dL should be admitted to the hospital for evaluation and therapy. Treatment of severe hypercalcemia includes measures that increase calcium excretion and decrease resorption of calcium from bone. The purpose is to relieve symptoms, while the cause of hypercalcemia is found and treated.
· Severely hypercalcemic patients are almost always dehydrated, and the first step in therapy is extracellular fluid (ECF) volume repletion with 0.9% saline to restore the glomerular filtration rate and promote calcium excretion. At least 3 to 4 L should be given in the first 24 hours, and a positive fluid balance of at least 2 L should be achieved.
· After ECF volume is restored, infusion of 0.9% saline (100 to 200 mL/hour) promotes calcium excretion. Serum electrolytes, calcium, and magnesium should be measured every 6 to 12 hours. Furosemide adds little to the effect of saline diuresis and may prevent adequate restoration of ECF volume. It should not be given unless clinical evidence of heart failure develops.
Zoledronic Acid
· Zoledronic acid is a bisphosphonate that inhibits bone resorption and should be used if symptoms persist or the serum calcium continues to be >12 mg/dL after initial volume repletion.
· A dose of 4 mg in 100 mL 0.9% saline is infused over 15 minutes.
· Serum calcium should be measured daily.
· Hypercalcemia abates gradually over several days and remains suppressed for 1 to 2 weeks.
· Treatment can be repeated when hypercalcemia recurs.
· Side effects include asymptomatic hypocalcemia, hypomagnesemia, hypophosphatemia, and transient low-grade fever.
Glucocorticoids
· Steroids are effective in hypercalcemia due to myeloma, sarcoidosis, and vitamin D intoxication.
· The initial dose is prednisone, 20 to 50 mg PO bid or its equivalent.
· It may take 5 to 10 days for serum calcium to fall.
· After serum calcium stabilizes, the dose should be gradually reduced to the minimum needed to control symptoms of hypercalcemia.
Management of Primary Hyperparathyroidism
· The most effective therapy for primary hyperparathyroidisim is parathyroidectomy.
· However, in the asymptomatic majority of patients, surgery may not be indicated. The natural history of asymptomatic hyperparathyroidism is not fully known, but in many patients, the disorder has a benign course, with little change in clinical findings or serum calcium for years. The major concern in these patients is the possibility of progressive loss of bone mass and increased risk of fracture. Deterioration of renal function is also possible but unlikely in the absence of nephrolithiasis. Currently, it is impossible to predict the patients in whom problems will develop.
· Indications for parathyroidectomy include the following:13
o Symptoms due to hypercalcemia
o Nephrolithiasis
o Hip or spine bone mass by dual-energy radiography >2.5 standard deviations below the gender-specific mean peak bone mass (a T score < −2.5)
o Serum calcium >1 mg/dL above the upper end of the reference range
o Age <50 years
o Infeasibility of long-term follow-up
· Surgery is a reasonable choice in otherwise healthy patients even if they do not meet these criteria, because experienced surgeons have a success rate of 90% to 95% with low perioperative morbidity and correction of hyperparathyroidism is followed by an increase in bone mass and a decrease in the risk of fracture.
· Preoperative localization of an adenoma by sestamibi scan may permit a limited neck dissection, which further decreases the risk of complications.
· Asymptomatic patients who do not meet criteria for parathyroidectomy or who refuse surgery can be followed by assessing clinical status, serum calcium and creatinine levels, and bone mass at 1- to 2-year intervals.13 Surgery should be recommended if any of the above criteria develop or if there is progressive decline in bone mass or renal function.
Hyperprolactinemia
GENERAL PRINCIPLES
· The major causes of hyperprolactinemia are presented in Table 21-4.14
· In women, the most common causes of pathologic hyperprolactinemia are prolactin-secreting pituitary microadenoma (i.e., an adenoma with a diameter of <1 cm) and idiopathic hyperprolactinemia.
· In men, the most common cause is prolactin-secreting macroadenoma.
· Hypothalamic or pituitary lesions that cause deficiency of other pituitary hormones often cause hyperprolactinemia by compressing the pituitary stalk.
· In women, hyperprolactinemia causes amenorrhea or irregular menses and infertility. Only one-half of these women have galactorrhea. Prolonged estrogen deficiency increases the risk of osteoporosis.
· In men, hyperprolactinemia causes androgen deficiency and infertility but not gynecomastia. Mass effects of a large pituitary tumor (e.g., headaches, visual field loss) and hypopituitarism are common in men with hyperprolactinemia.
TABLE 21-4 Major Causes of Hyperprolactinemia
DIAGNOSIS
· The history and physical should include symptoms and signs of prolactin excess, pituitary mass effect, and hypothyroidism. A careful medication history should be obtained.
· Hyperprolactinemia is common in young women, and plasma prolactin should be measured in women with amenorrhea, whether or not galactorrhea is present. Mild elevations should be confirmed by repeat measurements. Laboratory evaluation should include plasma TSH and a pregnancy test.
· Prolactin levels >200 ng/mL occur only in prolactinomas, and levels between 100 and 200 ng/mL strongly suggest this diagnosis.
· Levels <100 ng/mL may be due to any cause except prolactin-secreting macroadenoma, and such levels in a patient with a large pituitary mass indicate that it is not a prolactinoma.
· Testing for hypopituitarism is needed only in patients with a macroadenoma or hypothalamic lesion and should include measurement of plasma free T4, a cosyntropin stimulation test (see Adrenal Failuresection, above), and measurement of plasma testosterone in men.
· Magnetic resonance imaging (MRI) of the pituitary should be performed in most cases, as nonfunctional pituitary or hypothalamic tumors may present with mild hyperprolactinemia.
TREATMENT
Microadenomas and Idiopathic Hyperprolactinemia
· Most patients are treated because of infertility or to prevent estrogen deficiency and osteoporosis.14
· Some women may be observed without therapy by periodic follow-up of prolactin levels and symptoms. In most patients, hyperprolactinemia does not worsen and prolactin levels sometimes return to normal. Enlargement of microadenomas is rare.
· Dopamine agonists suppress plasma prolactin and restore normal menses and fertility in most women.
o Initial doses are bromocriptine, 1.25 to 2.5 mg PO at bedtime with a snack, or cabergoline, 0.25 mg PO twice per week.
o Doses are adjusted by measurement of plasma prolactin at 2- to 4-week intervals to the lowest dose that suppresses prolactin to the normal range. Maximally effective doses are 2.5 mg bromocriptine tid and 1.5 mg cabergoline twice per week.
o Initially, patients should use barrier contraception, as fertility may be restored quickly.
o Side effects include nausea and orthostatic hypotension, which can be minimized by increasing the dose gradually and usually resolve with continued therapy. Side effects are less severe with cabergoline.
· Women who want to become pregnant should be managed in consultation with an endocrinologist.
· Women who do not want to become pregnant should be followed with clinical evaluation and plasma prolactin every 6 to 12 months.
o Every 2 years, plasma prolactin should be measured after bromocriptine has been withdrawn for several weeks to determine whether the drug still is needed.
o Follow-up imaging studies are not warranted unless prolactin levels increase substantially.
o Transsphenoidal resection of prolactin-secreting microadenomas is used only in the rare patients who do not respond to or cannot tolerate bromocriptine. Prolactin levels usually return to normal, but up to one-half of patients relapse.
Prolactin-Secreting Macroadenomas
· These tumors should be treated with a dopamine agonist, which usually suppresses prolactin levels to normal, reduces tumor size, and improves or corrects abnormal visual fields in about 90% of cases.14
· The dose is adjusted as described as above, except that if mass effects are present, the dose should be increased to maximally effective levels over a period of several weeks.
· Visual field tests, if initially abnormal, should be repeated 4 to 6 weeks after therapy is started. Pituitary imaging should be repeated 3 to 4 months after initiation of therapy. The full effect on tumor size may take >6 months. If tumor shrinkage and correction of visual abnormalities are satisfactory, therapy can be continued indefinitely, with periodic monitoring of plasma prolactin.
· Further imaging is generally not warranted unless prolactin levels rise despite therapy.
· Transsphenoidal surgery is indicated to relieve mass effects and to prevent further tumor growth if the tumor does not shrink or if visual field abnormalities persist during dopamine agonist therapy. However, the likelihood of surgical cure of a prolactin-secreting macroadenoma is low, and most patients require further therapy with a dopamine agonist.
· Women with prolactin-secreting macroadenomas should not become pregnant unless the tumor has been resected surgically or has decreased markedly in size on dopamine agonist therapy, as the risk of symptomatic enlargement during pregnancy is 15% to 35%. Contraception is essential during dopamine agonist treatment.
Male Hypogonadism
GENERAL PRINCIPLES
· The testes have two distinct but related roles:
o Secretion of testosterone (the major androgen) by the Leydig cells, which produce and maintain sexual characteristics
o Production of spermatozoa by the seminiferous tubules, a process that requires high local concentrations of testosterone
· The testes are regulated by the pituitary gland, which secretes the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Gonadotropin secretion is regulated by the hypothalamus via secretion of LH-releasing hormone and by negative feedback by gonadal hormones.
· Hypogonadism due to disease of the testes results in diminished feedback on the pituitary and increased secretion of gonadotropins. If hypogonadism is due to disorders of the pituitary or hypothalamus, serum gonadotropin levels are within or below the reference range.
· Male hypogonadism may present with androgen deficiency or infertility because of oligospermia (low sperm count). Androgen deficiency is always associated with infertility, but oligospermia often occurs in men with normal testosterone levels.
Etiology
· Male hypogonadism may be due to disorders of the testes or due to dysfunction of the pituitary or hypothalamus (Table 21-5). Cirrhosis and chronic renal failure also impair gonadotropin secretion and testicular function.
· Testicular disorders
o Klinefelter syndrome (47, XXY karyotype) occurs in approximately 1 in 1,000 male births. Seminiferous tubules fail to develop normally, and because of this, the testes are small and firm with no spermatogenesis. The degree of androgen deficiency ranges from mild to severe. Klinefelter syndrome usually presents as delayed puberty or persistent gynecomastia after puberty.
o Viral orchitis in adults, most often due to mumps, can cause testicular atrophy. It usually causes infertility alone, but androgen deficiency occurs in severe cases.
o Alcohol causes testicular dysfunction directly and indirectly via hepatic cirrhosis.
o Drugs that impair androgen synthesis or action include ketoconazole, cimetidine, and spironolactone.
o Infertility without androgen deficiency is usually idiopathic but may be due to milder forms of the disorders that cause androgen deficiency or due to cryptorchidism that was not corrected early in childhood.
o Azoospermia (complete absence of sperm in the ejaculate) with normal testosterone levels may be due to obstruction or absence of the vas deferens.
· Hypothalamic-pituitary dysfunction
o Any disorder of the hypothalamus or pituitary may cause androgen deficiency alone or combined with other pituitary hormone deficiencies.
o Hyperprolactinemia in men is usually due to a prolactin-secreting pituitary macroadenoma.
o Kallmann syndrome (congenital deficiency of LH-releasing hormone) presents as failure of puberty. Other pituitary hormones are usually intact. Most patients have anosmia (lack of sense of smell).
TABLE 21-5 Major Causes of Androgen Deficiency
DIAGNOSIS
Clinical Presentation
· The history should include the age at onset of puberty, libido, potency and frequency of intercourse, frequency of shaving, testicular injury or infection, past fertility, medications, and chronic illnesses.
· Physical signs may include testicular atrophy (testes <15 mL in volume or <4 cm in greatest diameter), decreased facial and body hair, gynecomastia, and lack of sense of smell.
· Impotence (erectile dysfunction) with a normal libido is usually due to neurologic or vascular disorders or drugs rather than due to androgen deficiency.
Diagnostic Testing
· Androgen deficiency is confirmed by measurement of plasma testosterone.15 If testosterone is low, plasma LH should be measured.
o Low testosterone levels should be confirmed with repeat testing in the morning.
o An elevated LH indicates a testicular cause of androgen deficiency.
o If LH is not elevated, hypothalamic or pituitary dysfunction is responsible, and serum prolactin should be measured, secretion of other pituitary hormones should be assessed, and the pituitary and the hypothalamus should be imaged.
· Men with infertility but normal serum testosterone levels should be evaluated by semen analysis.
o The most important characteristic is sperm concentration, with the normal range considered to be >20 million/mL.
o Interpretation is complicated by variability of the sperm count in normal men.
o Oligospermia should be confirmed by at least two semen analyses.
TREATMENT
· Androgen deficiency can be treated by injected or topical testosterone.15 Treatment is appropriate only for those with repeatedly and clearly low testosterone levels and symptoms of hypogonadism.
o Testosterone ester (testosterone enanthate or cypionate) can be given at a dose of 150 to 250 mg IM every 2 weeks. In most men, a dose of 200 mg is satisfactory.
o Testosterone gel can be applied topically. The starting dose is 5 g once daily.
o Side effects of androgens include acne, gynecomastia, erythrocytosis, benign prostatic hypertrophy, progression of prostate cancer, and cardiovascular disease.
o Men older than age 50 years should undergo appropriate screening for prostate cancer.
o Patients should be followed at 6- to 12-month intervals, with assessment of their clinical response.
o Measurement of serum testosterone is necessary only if there is an inadequate clinical response to therapy.
· Infertility due to testicular disorders such as idiopathic oligospermia is correctable only by assisted reproduction techniques.
o Patients with azoospermia and normal levels of testosterone and gonadotropins should be evaluated for obstruction of the vas deferens in consultation with a urologist.
o Patients with hypogonadism due to pituitary or hypothalamic disorders who desire fertility should be referred to an endocrinologist for treatment.
Hirsutism
GENERAL PRINCIPLES
· Hirsutism is the male pattern growth of dark terminal hair in a woman.16 It is a common complaint and may indicate androgen excess. However, there is a broad range of hair growth in normal women, and many patients with hirsutism have no evidence of androgen excess.
· Even slight increases in androgen production can cause noticeable hair growth in women. More severe androgen excess causes virilization (including deepening of the voice and male pattern baldness).
· The major issue in evaluating hirsutism is to exclude the possibility that a woman is one of the small minority with a serious cause (such as Cushing syndrome or an ovarian or adrenal tumor).
· Androgen excess can originate from the ovaries or adrenals. Exogenous androgens can also cause hirsutism.
· By far, the most common cause is the polycystic ovary syndrome, which includes hirsutism, infertility, and amenorrhea or irregular menses that are not due to another identifiable disorder.
o Hirsutism and menstrual irregularity usually begin at puberty.
o A wide range of abnormality is found in this syndrome, from mild hirsutism alone (sometimes called idiopathic hirsutism) to amenorrhea with enlarged ovaries.
o These women are resistant to insulin, and the resulting high insulin levels play a role in stimulating ovarian androgen production.
· Rare ovarian tumors may produce hirsutism. Adrenal causes of hirsutism include Cushing disease, congenital adrenal hyperplasia, and, rarely, adrenal carcinoma.
DIAGNOSIS
· The history should include the age at onset of hirsutism, symptoms of virilization, any abnormality of menses, and fertility.
· The physical examination should include the extent of hair growth, signs of Cushing syndrome or virilization, and palpation for ovarian enlargement. Signs of virilization like frontal and temporal balding, laryngeal enlargement and deepening of the voice, increased muscle mass, and clitoral enlargement are common features of virilization and suggest a serious underlying cause.
· Serum total and free testosterone should be measured.16
· Testing for Cushing syndrome should be performed if there are any symptoms or signs to suggest this disorder.
· Multiple ovarian cysts are a common finding in women with normal menses and no hirsutism; ultrasound of the ovaries should not be performed unless an ovarian tumor is suspected.
· Almost all patients with no evidence of virilization and mild elevation of free testosterone have a disorder that falls within the spectrum of polycystic ovary syndrome. They can be treated for this without further evaluation.
· Patients with evidence of virilization or with serum total testosterone levels >200 ng/dL may have an ovarian or adrenal tumor and should be further evaluated in consultation with an endocrinologist.
TREATMENT
· Patients with mild hirsutism may not require medical therapy if cosmetic measures such as plucking or shaving produce a satisfactory result.
· The response of hair growth to drug therapy is slow and often incomplete.
· Oral contraceptives suppress ovarian androgen production and may improve hirsutism.
· In women with the polycystic ovary syndrome, drugs that improve insulin resistance may reduce androgen production and improve menstrual abnormalities and fertility.16
o Metformin, 500 to 1,000 mg bid, can be used in patients with normal renal function.16 It should be started at a dose of 500 mg daily, and the dose gradually increased over a several-week period.
o Side effects include diarrhea, nausea, and abdominal cramps.
o Patients should be followed at 6-month intervals, with assessment of hair growth, menstrual regularity, and serum-free testosterone.
· Spironolactone, 25 to 100 mg bid, is an androgen and aldosterone antagonist that can reduce excess hair growth.16
o Side effects include irregular menses, nausea, and hyperkalemia.
o It should not be used in patients with renal dysfunction since they are more prone to hyperkalemia. It should not be used by women desiring fertility, and women must use contraception.
o Combination therapy with an oral contraceptive may be more effective and allows regular menses.
o Patients should be followed at 6-month intervals, with assessment of hair growth, menstrual regularity, and serum potassium.
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