NOTE:

*Numbers within parentheses indicate the number of amino acids in the protein or peptide(s).

    Diagnostically, if an endocrinologist suspects that a hormone is inappropriately low, he or she will try to stimulate it; if high, he or she will try to suppress it (table 56.2). Failure to rise or fall normally indicates either failure of the gland or unregulated hyperfunction. It is often possible to measure the level of the upstream hormone to determine the location (central [pituitary] or peripheral) of the problem. By going through this process, we capitalize on the presence of feedback loops. Similarly, treatments for endocrine disorders aim to replace the hormone in deficiency states (e.g., hypothyroidism) or to interfere with production in excess states (e.g., prolactinoma).

PITUITARY TUMORS

Pituitary tumors account for approximately 15% of all primary intracranial neoplasms. Proliferation of cells within the pituitary can cause hormonal excess syndromes, or compress the pituitary resulting in hormonal deficiency. Pituitary tumors can expand and interfere with local anatomic structures such as the optic chiasm and cavernous sinuses.

PROLACTINOMA

Prolactin-secreting tumors account for the majority of functional pituitary tumors. More than 90% are small (<1 cm) benign tumors that do not increase in size.

Clinical Features

Hyperprolactinemia leads to galactorrhea in approximately 80% of affected women. High levels of prolactin interfere with the secretion of gonadotropin-releasing hormone from the hypothalamus, resulting in amenorrhea/oligomenorrhea and infertility in women and hypogonadism in men. Both men and women develop osteoporosis if hyperprolactinemia is left chronically untreated. Macroprolactinomas can enlarge by one-third or more during pregnancy.

Evaluation

Dopamine tonically inhibits prolactin release, so medications that interfere with dopamine are often associated with hyperprolactinemia. Phenothiazines, butyrophenones, metoclopramide, risperidone, monoamine oxidase inhibitors, tricyclic antidepressants, verapamil, and serotonin-reuptake inhibitors can all increase prolactin levels. Large pituitary tumors can compress the pituitary stalk and impair normal dopamine signaling, resulting in hyperprolactinemia. Chronic renal failure and severe primary hypothyroidism are also associated with hyperprolactinemia. Magnetic resonance imaging (MRI) of the pituitary is recommended when a patient has elevated prolactin levels and other causes of hyperprolactinemia have been excluded.

Treatment

Both cabergoline (which is typically given twice weekly) and bromocriptine (given twice daily) are effective in decreasing prolactin levels and reducing tumor size in >80% of patients. The goal of treatment in microadenomas is symptomatic relief in patients with galactorrhea, and restoration of eugonadism and bone density. Both micro- and macroprolactinomas can be managed medically; surgery is required only rarely. Treatment is continued for at least 2 years in patients with microadenomas, and generally given indefinitely in patients with macroadenomas. Macroadenomas that extend beyond the sella in women should generally be debulked surgically before pregnancy is attempted; pregnant women with macroprolactinomas are generally managed with bromocriptine throughout their pregnancy.

ACROMEGALY

Acromegaly is rare and develops when somatotropes proliferate and oversecrete growth hormone. These tumors tend to grow slowly and insidiously and are rarely associated with plurihormonal polysecretion (such as coproduction of prolactin and growth hormone). Most of these tumors are >1 cm (i.e., are macroadenomas) at the time of presentation.

Clinical Features

The features of acromegaly are diverse and are generally related to somatic growth (acral enlargement, malocclusion, carpal tunnel syndrome), tissue enlargement (macroglossia, prostatic hypertrophy, left ventricular hypertrophy, sleep apnea, goiter), and metabolic interference (diabetes mellitus, hypertriglyceridemia, hypogonadism).

Evaluation

The biochemical diagnosis of acromegaly is made by confirming autonomous secretion of growth hormone during a 2-hour 75-g oral glucose tolerance test. Nadir growth hormone levels in excess of 1 µg/L are consistent with the diagnosis, especially if the patient also has an elevated level of insulin-like growth factor-1 (IGF-1).

Treatment

Neurosurgical resection is the treatment of choice for most resectable pituitary tumors associated with acromegaly. Complications such as hypopituitarism and recurrence risk correlate with the size of the tumor. Medical treatments for acromegaly include somatostatin receptor ligands (octreotide and lanreotide), which suppress pituitary release of growth hormone; dopamine antagonists (cabergoline and bromocriptine are minimally effective); and use of a growth hormone receptor antagonist (pegvisomant). Radiotherapy is used for unresponsive tumors but it is associated with high risk of panhypopituitarism. Levels of IGF-1 are used to monitor treatment efficacy.

OTHER PITUITARY DISORDERS

DIABETES INSIPIDUS

Central diabetes insipidus is a heterogeneous condition characterized by polyuria and polydipsia due to a deficiency of arginine vasopressin. In many patients it is caused by the destruction or degeneration of the neurons that originate in the supraoptic and paraventricular nuclei of the hypothalamus. The three main causes of diabetes insipidus (trauma/surgery, tumors, and idiopathic) account for approximately equal fractions of cases.

Clinical Features

Diminished or absent arginine vasopressin causes polyuria or polydipsia by diminishing the patient’s ability to concentrate urine. These patients generally have severe nocturia and consume 3–20 liters of liquid daily. Nephrogenic diabetes insipidus is characterized by a decrease in the ability to concentrate urine due to a resistance to arginine vasopressin action in the kidney.

Evaluation

Diabetes insipidus is diagnosed when urine is inappropriately dilute (urine specific gravity of <1.005 and a urine osmolality <200 mOsm/kg) in a patient with a high serum osmolality (generally >287 mOsm/kg). Because many patients can maintain a normal osmolality with access to water, a water-deprivation test is often necessary to document the abnormality and exclude primary polydipsia. A vasopressin analogue can be given to patients at the end of a water deprivation test to exclude nephrogenic diabetes insipidus. Patients with central diabetes insipidus should undergo pituitary imaging with an MRI.

Treatment

Diabetes insipidus is treated with vasopressin analogues, administered subcutaneously, nasally, or orally, coupled with ready access to water.

LYMPHOCYTIC HYPOPHYSITIS

Lymphocytic hypophysitis is an uncommon autoimmune disease in which the pituitary gland is infiltrated by lymphocytes, plasma cells, and macrophages, usually causing impaired function. Lymphocytic hypophysitis is mainly associated with late pregnancy or the postpartum period, although it can occur in nonpregnant women (some of whom may be postmenopausal) and in men. This disorder may have an autoimmune origin, and it is associated with other autoimmune disorders, especially autoimmune thyroiditis. Tests for antinuclear antibodies and rheumatoid factor are often positive, and the erythrocyte sedimentation rate may be elevated. Headache, visual field impairment, and, more rarely, diplopia are due to extrasellar pituitary enlargement with optic chiasma compression and/or to invasion of cavernous sinuses. Deficiency of adrenocorticotropic hormone (ACTH) (resulting in secondary hypoadrenalism) is the earliest and most frequent endocrine manifestation. MRI usually demonstrates extrasellar symmetrical pituitary enlargement and loss of the posterior pituitary bright spot. Treatment is symptomatic, with compressive effects reduced through treatment with high-dose corticosteroids (20–60 mg/day of prednisone) and/or surgical decompression. The prognosis for hormonal recovery is poor.

HYPOTHYROIDISM

Presentation of Hypothyroidism

Hypothyroidism affects about 2% of adult women and about 0.2% of adult men; subclinical hypothyroidism is substantially more common. Primary hypothyroidism refers to intrinsic thyroid failure and accounts for 99% of cases; secondary hypothyroidism refers to hypothyroidism that results from pituitary dysfunction. The most common cause of primary hypothyroidism in iodine-sufficient areas is chronic autoimmune (Hashimoto) thyroiditis; this is most common among older women and is generally permanent. Thyroidectomy, radioiodine treatment, and external radiation therapy are other frequent causes of hypothyroidism. Both iodine deficiency and excess can cause hypothyroidism. Iodine deficiency is a type of hypothyroidism associated with goiter. It is the most common cause of hypothyroidism worldwide, but is quite uncommon in the United States where iodine is added to salt. Acute administration of iodine suppresses thyroxine synthesis; however patients recover their thyroid function after just a few days of treatment. Other drugs that cause hypothyroidism include antithyroid drugs (e.g., methimazole, propylthiouracil), amiodarone, lithium, and interferon-α.

    Hypothyroidism can be transient when related to thyroiditis. Inflammation of the thyroid gland can be painful or entirely painless. Hypothyroidism occurring postpartum is one of the most common presentations of thyroiditis. Transient hypothyroidism lasts up to as long as 6 months, but the hypothyroidism will have resolved in a significant majority within 3 months.

Clinical Features

Patients with hypothyroidism can present with a variety of nonspecific symptoms. Some of the most common features include dry skin, cold intolerance, weight gain, constipation, menorrhagia, and fatigue. The clinical picture of hypothyroidism is now a good deal milder since screening became more common. The most common signs in patients with moderate to severe hypothyroidism include bradycardia, delayed ankle reflexes, periorbital puffiness, and coarse hair. The term myxedema refers to the appearance of the skin and subcutaneous tissues in a patient who is severely hypothyroid.

Evaluation

Patients with primary thyroid failure will have an elevated thyroid-stimulating hormone (TSH) level and low thyroxine concentration. Central hypothyroidism should be suspected if the TSH is normal or low and the thyroxine level is low.

Treatment

Patients with an elevated TSH level should be treated with replacement thyroxine, with a target TSH of between 1 and 2. Levothyroxine has a long half life, and once-daily treatment results in a nearly constant serum thyroxine level. As a result of variations in the thyroxine content of individual formulations, reassessment of the adequacy of replacement is indicated if the formulation is changed. The mean replacement dose of thyroxine is 1.6 µg/kg (generally 75–112 µg/day in women and 125–200 µg/day in men). A lower dose (such as 50 μg daily) should be initiated in the elderly and titrated upward as needed. Obese patients require doses that are approximately 20% higher. Drugs that interfere with the absorption of levothyroxine include cholestyramine, calcium carbonate, and ferrous sulfate. Patients receiving estrogen replacement also require a higher dose of levothyroxine.

    Combination replacement of liothyronine and levothyroxine is requested by some patients but it is not supported by the balance of clinical trial data. If instituted, 25 µg of levothyroxine can be replaced with 5 µg of liothyronine. Desiccated thyroid, liothyronine alone, and other thyroid preparations are not recommended.

    Transient hypothyroidism can be difficult to distinguish from Hashimoto thyroiditis. It is reasonable to attempt to reduce the dose of levothyroxine by 50% after approximately 3 months in patients who are suspected to have had transient hypothyroidism: if the TSH measured 6 weeks later rises, then the initial dose is reinstated; if the TSH is stable, then thyroxine can be withdrawn, and the TSH checked again.

    Patients with an elevated TSH and a normal thyroxine level are most likely to have subclinical hypothyroidism. Testing for the presence of thyroid peroxidase antibody can be helpful in such patients, as it predicts the progression to permanent hypothyroidism. These patients should be monitored for the development of more severe hypothyroidism, or levothyroxine can be initiated at the outset.

    Patients with central hypothyroidism should have their thyroxine dose titrated to the level of free thyroxine.

Hypothyroidism During Pregnancy

Levothyroxine requirements increase as early as the fifth week of gestation. Given the importance of maternal euthyroidism for normal fetal cognitive development, women with hypothyroidism should have their levothyroxine dose increased by approximately 30% as soon as pregnancy is confirmed. Thereafter, serum thyrotropin levels should be monitored and the levothyroxine dose adjusted accordingly. The goal of thyroxine replacement is to maintain the TSH in the trimester-specific reference range (below 2.5 mU/L in the first trimester and below 3 mU/L in the second and third trimesters) using measurements drawn every 4–6 weeks.

HYPERTHYROIDISM

Hyperthyroidism can be caused by an increased production of thyroid hormone (as in Graves disease or an autonomous nodule) or increased release of preformed thyroid hormone (as in thyroiditis). Hyperthyroidism can also be caused by overreplacement with exogenous thyroid hormone, ectopic hyperthyroidism, or by unregulated stimulation of the TSH receptor (as in trophoblastic disease or a TSH-secreting pituitary adenoma).

Clinical Features

The presentation of hyperthyroidism can be highly variable, especially in older people. Characteristic symptoms include anxiety, tremor, palpitations, heat intolerance, insomnia, oligomenorrhea, and weight loss despite an increased appetite. Typical signs include tachycardia, systolic hypertension, tremor, lid retraction, lid lag, warm skin, and hyperreflexia. The presence of a goiter will depend on the cause of the hyperthyroidism. A single palpable nodule or multiple nodules suggests an autonomous thyroid adenoma or a multinodular goiter as the source, respectively; a painful tender thyroid gland suggests granulomatous thyroiditis. Signs that are suggestive of Graves disease include goiter, thyroid bruit, exophthalmos, periorbital edema, and pretibial myxedema.

Evaluation

The diagnosis of hyperthyroidism is confirmed using biochemical testing of the thyroxine and TSH levels. An increased thyroxine level with a suppressed TSH characterizes overt hyperthyroidism. Patients with subclinical hyperthyroidism may have a normal thyroxine level and a suppressed TSH. Occasional patients demonstrate T3-toxicosis with a normal thyroxine level and an elevated level of triiodothyronine. TSH-induced hyperthyroidism and thyroid hormone resistance, each characterized by an increased level of TSH, are very rare. An elevated thyroxine with a normal TSH level is usually attributed to abnormalities in thyroid binding proteins in patients who are clinically euthyroid.

    When the etiology of the hyperthyroidism is unclear, a thyroid radioiodine uptake study can be performed. Graves disease is characterized by a high uptake, while thyroiditis is associated with a low uptake.

Treatment

Methimazole is the preferred antithyroid drug in the United States. Use of propylthiouracil is limited to pregnant women. These agents are actively concentrated by the thyroid gland, and their primary effect is to inhibit thyroid hormone synthesis by interfering with thyroid peroxidase–mediated iodination of tyrosine residues in thyroglobulin, a critical step in the synthesis of thyroxine and triiodothyronine. Propylthiouracil also blocks the conversion of thyroxine to triiodothyronine within the thyroid and peripheral tissues, although the clinical importance of this function is uncertain. No dose adjustment is needed in patients with renal or liver failure, among children, or the elderly.

    The usual starting dose of methimazole is 20 mg/day as a single daily dose, and the usual starting dose of propylthiouracil is 100 mg given three times a day. Following initial dosing, follow-up testing of thyroid function is suggested approximately every 6 weeks until the thyroid function tests normalize. Many patients can ultimately be controlled at a low dose. Testing frequency can be reduced to every 6 months over time. Following a discussion about the risk of relapse, antithyroid drugs can be withdrawn after 12–18 months to determine if ongoing treatment is required.

    Cutaneous reactions to antithyroid drugs are quite common and usually mild. The drug should be discontinued in patients complaining of arthralgias, as this may be a presentation of a transient migratory polyarthritis associated with antithyroid drug use. The most feared side-effect of antithyroid drugs are agranulocytosis (especially with methimazole, seen in 1 of every 270 treated patients) and liver failure (especially with propylthiouracil). The drug should be discontinued if the granulocyte count is <1000/mm³.

    Current treatments for Graves disease include antithyroid drugs, radioiodine, and surgery. Initial treatment usually includes an antithyroid drug such as methimazole 20 mg taken once daily. Beta-blockers may provide symptomatic relief. For patients with more severe hyperthyroidism, iodine treatment can provide rapid relief of symptoms. A typical approach would be to prescribe 3 drops of saturated solution of potassium iodide three times daily for up to 10 days. Radioiodine can be given as primary treatment for patients with Graves’ hyperthyroidism, although many clinicians will wait until the first relapse before offering this approach. Hyperthyroidism can be exacerbated for a short time by radioiodine treatment. In patients with cardiac disease or in the elderly in whom such an exacerbation would be risky, pretreatment with antithyroid drugs can be useful. Surgery is usually reserved for patients with an obstructing goiter.

    Hyperthyroidism associated with toxic thyroid adenomas can be treated with antithyroid drugs and a beta-blocker. As these autonomous nodules do not resolve spontaneously, more definitive treatment is usually indicated after the initial symptoms have been controlled. Radioiodine is preferred over surgery for most patients (since it tends to target only the overactive tissue, resulting in low long-term risk of hypothyroidism), but this is less likely to be effective in patients with large or multiple nodules.

Hyperthyroidism During Pregnancy

Women who develop hyperthyroidism while pregnant are at increased risk of spontaneous abortion, premature labor, stillbirth, and preeclampsia. Changes in thyroid hormone–binding globulin (usually doubles), levels of human chorionic gonadotropin (that can mimic the actions of TSH), and endogenous physiology (altered TSH responsiveness) can complicate the biochemical assessment of thyroid function in pregnancy. As radioiodine is absolutely contraindicated during pregnancy, antithyroid drugs are the preferred treatment for pregnant women with hyperthyroidism. Propylthiouracil remains the preferred treatment for hyperthyroidism occurring during pregnancy. The dose should be minimized to prevent fetal hypothyroidism, as the drug does cross the placenta. Methimazole may be associated with congenital anomalies including aplasia cutis and choanal or esophageal atresia. Generally treatment is given to a point where mild hyperthyroidism is allowed to persist. Low thyroid function at birth is found in approximately half of neonates whose mothers received an antithyroid drug— ultimate intelligence appears to be normal. Both methimazole and propylthiouracil are approved for nursing mothers by the American Academy of Pediatrics, although they do appear in breast milk in minute quantities.

THYROID NODULES

In the United States, between 4% and 7% of the adult population have a palpable thyroid nodule. Only 5% of these are malignant. Other causes of nodules include thyroid cyst, a colloid nodule, a focal area of thyroiditis, and benign follicular neoplasms. Nodules can be solitary or multiple. The risk of cancer is not lower when nodules are multiple.

Evaluation

The history can provide useful prognostic information. Rapid growth, or the presence of a family history of thyroid carcinoma, or multiple endocrine neoplasia (MEN) increases the risk that a nodule is cancerous. Risk increases more moderately if age is <20 years or >70 years, if the patient is male, if there is a history of head and neck irradiation, the nodule is >4 cm, or if there are local symptoms such as dysphagia, hoarseness, or cough. High-risk signs include a hard nodule, the presence of regional lymphadenopathy, or hoarseness.

    A suppressed TSH level suggests a benign hyperfunctioning nodule. Hyperfunctioning nodules are so rarely malignant that if the TSH is suppressed, fine needle aspiration (FNA) can be deferred. A normal or high TSH level does not obviate the need for further investigation. Ultrasonography can be performed in the office and increases the sensitivity and specificity of the FNA result. Ultrasonography can detect high-risk features such as hypoechogenicity, microcalcifications, irregular margins, increased vascularity by Doppler, and evidence of local lymphadenopathy.

    Patients undergoing FNA do not typically need to stop aspirin or anticoagulants. The procedure is safe and well tolerated. Each lesion >1cm in size should be sampled with two to four passes of the needle.

    Cystic nodules can be drained after any solid portion has been aspirated, although most recur; use of sclerosants such as ethanol and tetracycline has been disappointing.

    Radionucleotide scanning uses ¹²³iodine, ¹³¹iodine, or ⁹⁹mtechnetium-pertechnetate to detect whether a nodule is functioning. A scan can also determine whether a nodule is dominant within a multinodular or retrosternal gland. A scan cannot accurately determine the size of a thyroid nodule.

Treatment

Benign nodules can remain in situ. Repeat ultrasonography after 9–12 months to ensure that there has been no significant change in size is suggested. Levothyroxine suppression is rarely recommended, as TSH must be suppressed to <0.1 mU/L to effectively suppress nodular growth or formation, and suppression to this level is associated with an increased risk of bone loss and atrial fibrillation.

    Follicular neoplasm may be benign or malignant, and cellular aspirates cannot distinguish these two. If the patient prefers, or if the nodule is cold on radionucleotide scanning, then excision is recommended.

    Malignant nodules should be excised with a total thyroidectomy and usually require postoperative thyroid ablation with ¹³¹iodine. Disease recurrence can be screened for using thyroglobulin measurements.

    Nondiagnostic aspirates occur about 10% of the time. If a second sample is again nondiagnostic, then referral for surgical excision is appropriate.

THYROID CANCER

Papillary and follicular thyroid cancers account for approximately 75% and 10% of all cancers in the thyroid gland, respectively. Metastases and medullary and anaplastic cancers make up the balance of cases. The 10-year survivals are very different for these tumors, ranging from 98% for papillary, 92% for follicular, and 13% for anaplastic carcinoma.

Clinical Features

Most tumors are detected incidentally, or a nodule is palpated. High-risk features of a nodule include rapid growth, a family history of thyroid carcinoma or multiple endocrine neoplasia, age <20 years or >70 years, male gender, and if there is a history of head and neck irradiation. Local symptoms such as dysphagia, hoarseness, or cough are worrisome.

Evaluation

Thyroid cancers are almost always diagnosed by FNA. Differentiated cancers are staged according to the TNM classification. In this classification, all patients aged <45 years of age are stage 1 unless they have distant metastases (stage 2). For older patients, stage depends on size, presence and laterality of lymph node involvement, and whether distant metastases have been detected.

Treatment

Total thyroidectomy is the primary therapy for differentiated thyroid cancer, although unilateral lobectomy can be considered for tumors <1 cm. Regional neck dissection is indicated if a preoperative neck ultrasound shows evidence of adenopathy. Following surgery, most patients undergo radioiodine treatment to ablate any thyroid remnant so that serum thyroglobulin can be used as a tumor marker. High-risk patients undergo radioiodine scans (after withdrawal of replacement thyroxine and dietary iodine restriction or by administering synthetic TSH) to determine the extent of any metastatic disease, and the uptake of iodine in these scans is used to dose therapeutic radioiodine. All patients are treated with levothyroxine to prevent symptomatic hypothyroidism and reduce potential thyrotropin stimulation of tumor growth. The target thyrotropin level is generally below or in the bottom half of the normal range; lower targets are used for advanced disease. Adjuvant external-beam radiotherapy and some chemotherapy are occasionally used for refractory cases.

    Anaplastic thyroid cancer is almost always fatal. The cancer is generally treated surgically. If unresectable, some of these tumors respond to paclitaxel and external beam radiotherapy for local control.

OSTEOPOROSIS

Osteoporosis is a common problem ultimately afflicting half of all postmenopausal women and about a quarter of men. It is characterized by low bone mass and an increased risk of fracture. Fractures occur because of qualitative and quantitative deterioration in the trabecular and cortical skeleton. Bone quality cannot be measured clinically, but bone mineral density can be measured easily using bone densitometry.

Clinical Features

Osteoporosis is asymptomatic until fracture occurs. Vertebral fracture is the most common, and the majority are asymptomatic. Hip fracture and radial fractures are common.

Evaluation

Most fractures of the hip, wrist, and vertebral body with no occurrence of trauma are indicative of osteoporosis. On densitometry, osteopenia is defined as bone mass that is between 1 and 2.5 standard deviations below the mean peak bone mass of control population. Osteoporosis is defined as a bone mass value >2.5 standard deviations below the peak bone mass of a control population. Generally the hip and spine are imaged. In postmenopausal white women, the relative risk of fracture is increased by a factor of 1.5 to 3 for each decrease of 1.0 in the T score. Densitometry also provides the deviation of bone mass from age-matched controls and reports this as a Z score. The Z score determines whether any bone loss is substantially greater than expected for age. A basic evaluation with low bone density comprises a biochemical profile, liver enzymes, alkaline phosphatase, 25-hydroxyvitamin D, and a complete blood count. Patients with low Z scores should have evaluation for secondary causes of bone loss such as hyperparathyroidism, hyperthyroidism, myeloma, and malabsorption. Markers of bone turnover (such as urinary N-terminal telopeptide or serum C-terminal telopeptide) can be useful in determining the need for treatment in equivocal cases.

Treatment

An optimal initial strategy for patients with low bone mass includes supplemental calcium (1000–1200 mg elemental) and vitamin D (400–800 IU daily) when appropriate, weightbearing physical activity (30 min at least 3 times per week), and smoking cessation counseling if needed. Patients with any of the following four criteria qualify for pharmacologic intervention:

• History of hip or vertebral fracture

• Osteoporosis by densitometry

• Any fracture and osteopenia by densitometry

• Osteopenia by densitometry with a 10-year risk of a major osteoporotic fracture that is more than 20% or of hip fracture more than 3% (risk calculator at http://www.shef.ac.uk/FRAX/)

Bisphosphonates are the recommended first-line treatment for patients with osteoporosis. Alendronate (70 mg orally once weekly) and risedronate (35 mg once weekly or 150 mg once a month) are given orally. Ibandronate (150 mg once monthly by mouth) has more limited data regarding its efficacy. Zolendronate 5 mg is given intravenously once a year. All have been shown to reduce hip and spine fracture risk.

    Gastrointestinal adverse effects of oral bisphosphonates are rare if administration instructions are followed. Intravenous bisphosphonates lead to short-term flu-like symptoms. Hypocalcemia can complicate bisphosphonate treatment if vitamin D levels are not sufficient. Osteonecrosis of the jaw is a rare complication of bisphosphonate use, occurring once per 10,000 to 100,000 patient-years. Although most cases have been in cancer patients or in patients with cancers treated with intravenous bisphosphonates, rare cases have been noted in patients with postmenopausal osteoporosis taking oral bisphosphonates.

    Synthetic parathyroid hormone (PTH: teriparatide) is available for daily subcutaneous use and increases bone mineral density and reduces fracture risk. It is generally reserved for patients with severe osteoporosis; treatment is limited to 24 months. Denosumab is an injectable medication used to manage patients who cannot tolerate or be treated with bisphosphonates, or who have severe osteoporosis. Monitoring densitometry should generally be performed no more frequently than every 2 years.

HYPERCALCEMIA

Clinical Features

Patients with mild hypercalcemia (10.5–12 mg/dL) are often asymptomatic. Patients with more severe hypercalcemia can present with nonspecific symptoms that include nausea, anorexia, constipation, abdominal pain, bone pain, fatigue, polydipsia, and confusion. Calcium levels higher than 14 mg/dL are dangerous and can be lethal. Signs of hypercalcemia include dysrhythmias, hypertension, and a shortened QT-interval on an electrocardiogram.

Evaluation

The two most common causes of hypercalcemia are primary hyperparathyroidism and neoplastic disease, accounting for more than 90% of cases, and these can be discriminated on the basis of the serum parathyroid hormone level. Primary hyperparathyroidism has a relatively benign course. Osteoporosis and renal impairment are two important long-term consequences that drive early intervention. Parathyroidectomy is recommended for patients with an elevated parathyroid hormone and hypercalcemia who are aged <50 years, if the calcium is >12.5 mg/dL, if there are renal stones, evidence of renal insufficiency, the Z score on bone densitometry is <2, or urinary calcium excretion is particularly high. A preoperative parathyroid sestamibi scan can assist the endocrine surgeon and limit the extent of surgery. Intraoperative parathyroid hormone levels allow the surgeon to be confident of the procedure’s success before surgical closure. Chronic renal failure generally causes hypocalcemia. If untreated, prolonged high phosphate and low vitamin D levels can lead to increased PTH secretion and subsequent hypercalcemia. This is termed tertiary hyperparathyroidism and can be managed surgically or medically.

    Hypercalcemia of malignancy is usually symptomatic and can be severe. Solid tumors induce hypercalcemia by releasing parathyroid-hormone related protein (PTHrp), which mimics the action of endogenous parathyroid hormone. Bone destruction by metastatic disease or myeloma can also induce hypercalcemia, often in association with an elevated alkaline phosphatase level.

    Vitamin D can induce hypercalcemia if taken in overdose, or if there is excessive action of the 1-alpha hydroxylase that creates the active form of vitamin D. This enzyme is hyperactive in patients with granulomatous disease such as sarcoidosis and responds well to treatment with glucocorticoids while the underlying disease is being treated. Consumption of large amounts of calcium or vitamin A can rarely lead to hypercalcemia.

    Familial hypocalciuric hypercalcemia is an autosomal dominant condition caused by a mutation in the gene for the calcium-receptor. Patients have an innocuous course characterized by mild to moderate hypercalcemia, normal or slightly elevated parathyroid hormone levels, and low urinary calcium excretion. These patients do not benefit from parathyroidectomy.

Treatment

Treatment of severe hypercalcemia includes emergent fluid repletion with saline and intravenous administration of bisphosphonates. Initially saline is given at 200–300 ml/hour and adjusted to maintain the urine output to 100–150 mL/hour. A loop diuretic can be added but is not always necessary and can lead to hypokalemia and hypomagnesemia. In the United States, pamidronate and zoledronate are bisphosphonates licensed for use in this indication. Zolendronate is preferred, as it can be given over a shorter time (15 minutes as compared to 2 hours for pamidronate) and is more potent. Hypocalcemia occurs in up to 50% of patients treated with bisphosphonates for hypercalcemia of malignancy, although symptomatic hypocalcemia is rare. Calcitonin is characterized by good tolerability but poor efficacy in normalizing the serum calcium level. However, a major advantage of calcitonin is the acute onset of the hypocalcemic effect (reduction of 1–2 mg/dL within 6 hours), which contrasts with the delayed (approximately 2–4 days) but more pronounced effect of bisphosphonates. It is administered intramuscularly or subcutaneously every 12 hours at a dose of 4 IU/kg (nasal calcitonin is not effective for this purpose).

HYPOPARATHYROIDISM

Hypocalcemia results from inadequate parathyroid hormone, an insufficient supply of vitamin D, abnormal magnesium levels, or during metabolic circumstances such as sepsis or pancreatitis. Hypoparathyroidism is diagnosed when the parathyroid hormone level is inappropriately low in a patient with hypocalcemia and a normal magnesium level.

Clinical Features

Neuromuscular symptoms such as muscle cramping, circumoral numbness and tingling, and muscle twitching are the most typical presenting features of hypocalcemia. As calcium levels drop further, seizures, heart failure, bronchospasm, and laryngospasm can occur. Chronic hypocalcemia can lead to cataracts, basal ganglial calcification and has been associated with pseudotumor cerebri.

    Hypoparathyroidism typically results from surgical intervention in the neck and occurs in up to 5% of total thyroidectomy surgeries. Parathyroid sufficiency generally requires a single remaining parathyroid gland. Parathyroid failure may also occur if the parathyroids accumulate iron (e.g., hemochromatosis) or copper (Wilson disease). Autoimmune destruction of the parathyroid glands is generally associated with the autoimmune polyendocrine syndrome type 1 (which incorporates at least two of the triad of Addison disease, hypoparathyroidism, and chronic mucocutaneous candidiasis). Early-onset hypoparathyroidism accompanying immunodeficiency characterizes the DiGeorge syndrome. Magnesium is essential for parathyroid hormone secretion, and both hyper- and hypomagnesemia can lead to hypocalcemia.

Evaluation

The corrected total calcium should be calculated (measured total calcium in mg/dL + 0.8 [4- serum albumin in g/dL]) or ionized calcium measured. The laboratory evaluation should include measures of intact parathyroid hormone, 25-hydroxy vitamin D, phosphate and magnesium.

Treatment

Patients with severe symptoms of hypocalcemia should be treated with intravenous calcium gluconate. Long-term management requires patients to receive calcium salts and a vitamin D metabolite such as calcitriol. Each are titrated to obtain normal levels. Thiazides can be used to reduce hypercalciuria and prevent nephrolithiasis, particularly if the 24-hour urinary calcium level exceeds 250 mg. Parathyroid hormone repletion is not yet approved for the treatment of hypoparathyroidism but early data are promising.

ADRENAL FAILURE

Addison disease refers to chronic adrenocortical insufficiency due to dysfunction of the entire adrenal cortex (incorporating glucocorticoid, mineralocorticoid, and sex steroid deficiency). Acute adrenal failure can also result from surgery, hemorrhage, tumor invasion, antifungal medications, acquired immunodeficiency syndrome. or infection that affects both adrenal glands. Adrenal failure becomes symptomatic when approximately 90% of adrenal function has been lost.

Clinical Features

Patients in acute adrenal crisis present with nausea, vomiting, and hypotension. Abdominal or flank pain and fever may be present. Chronic adrenal failure presents insidiously with weakness, fatigue, anorexia, nausea, and weight loss. Examination may reveal both hyperpigmentation (resulting from the stimulant effect of adrenocorticotropin on melanocytes), and vitiligo (autoimmune destruction of melanocytes). Other examination features include decreased body hair owing to loss of adrenal androgens, a feature that is especially apparent in women.

Evaluation

Patients with acute adrenal failure will generally be hypotensive. Hyperkalemia and hyponatremia are indicators of mineralocorticoid deficiency. Eosinophilia and hypoglycemia may accompany adrenal crisis. A random cortisol level may be inappropriately low for a stressed patient.

    An adrenocorticotropin stimulation test generally comprises measurement of cortisol and aldosterone at baseline, intravenous injection of 250 µg of adrenocorticotropin, with aldosterone levels drawn at 30 minutes and cortisol levels drawn at 60 minutes. An aldosterone level that fails to increase by 5 ng/dL is indicative of abnormal mineralocorticoid function. The cortisol level should rise to more than 20 µg/dL, and increase by at least 7 µg/dL from baseline to establish normal glucocorticoid function. Thyrotropin and thyroxine levels should be measured. Adrenal autoantibodies can be helpful to establish risk of other autoimmune conditions.

Treatment

Acute treatment comprises 50–100 mg of hydrocortisone administered intravenously. Clinical improvement should follow within 6 hours. Glucocorticoid repletion generally comprises hydrocortisone 15–25 mg daily in two to three divided doses, titrated to symptoms. Mineralocorticoid repletion should be initiated with fludrocortisone, generally 0.05–0.2 mg/day, titrated to blood pressure, potassium, and morning plasma renin activity. Patients should be provided with injectable glucocorticoids for emergency use such as during vomiting, diarrhea, trauma, and wear an emergency identification bracelet or necklace.

ADRENAL NODULES AND TUMORS

Adrenal masses are detected in approximately 3% of all abdominal computed tomography scans and in approximately 10% of all autopsies. When evaluating adrenal masses the clinician should consider whether the mass is malignant and whether it is hormonally active. The adrenal cortex can produce a variety of hormones and syndromes including cortisol (Cushing syndrome), aldosterone (Conn syndrome), androgens (virilization), and estrogens (feminization); the adrenal medulla generates catecholamines (pheochromocytoma).

Evaluation

Imaging features can help to determine the malignancy risk. High-risk features include irregular shape, diameter greater than 4 cm, high CT attenuation value (>10 Hounsfield units [HU]), and inhomogenous enhancement after intravenous contrast. Metastatic disease from another source tends to cause bilateral disease, have a similar attenuation as the liver on T1 imaging, and a high T2 signal intensity. Benign nodules (that may be functional) tend to be round, homogenous, and smaller (<4 cm) with low CT attenuation (<10 HU), and isointense with the liver on T1- and T2- weighted MRI imaging. Adrenal cysts, myelolipoma, and adrenal hemorrhage are usually readily distinguishable by their unique imaging characteristics.

Clinical Features

Pheochromocytoma can be suggested by the presence of hypertension (can be chronic or paroxysmal), a history of “spells,” headache, palpitations, or pallor. Even in the absence of any symptoms, pheochromocytoma should always be excluded before proceeding to surgery, as intraoperative risks of an unrecognized pheochromocytoma are high. Serum metanephrines are specific and sensitive providing the patient has not consumed acetaminophen (Tylenol) in the prior 72 hours. Two consecutive 24-hour urinary collections for total metanephrines and catecholamines provide confirmatory evidence.

    Primary aldosteronism is suggested by refractory hypertension and occasionally hypokalemia. An aldosterone to renin ratio of >30 when the aldosterone is at least 10 ng/dL is suggestive. To obtain an interpretable result, patients must not be taking aldosterone receptor antagonists (such as spironolactone, eplerenone). A suppressed renin in a patient taking an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker is highly suggestive of hyperaldosteronism.

    Measures of androgens and estrogens are not routinely performed in the absence of suggestive symptoms or signs. Virilization is suggested by male-pattern baldness, deepening of the voice, and clitoromegaly in women. Feminization in men is suggested by gynecomastia, decreased libido, and loss of muscle strength.

PRIMARY ALDOSTERONISM

Primary aldosteronism resulting from an adrenal adenoma is a reversible cause of hypertension; it accounts for at least 10% of causes of resistant hypertension. These tumors are usually <2 cm in size and are benign; most adenomas are unilateral.

Clinical Features

Most patients are asymptomatic or have minimal symptoms. Headache may accompany severe hypertension. Polyuria, nocturia, and muscle cramps may accompany hypokalemia.

Evaluation

Spontaneous hypokalemia with metabolic alkalosis and a serum sodium level at the high end of the normal range or hypernatremia is common. Plasma renin activity is suppressed in almost all patients with untreated primary aldosteronism, and plasma aldosterone levels are elevated. A plasma aldosterone to plasma renin ratio of >30 with a plasma aldosterone of >20 ng/dL usually indicates primary aldosteronism. Aldosterone concentrations are uninterpretable in a patient on spironolactone. Diuretics, ACE inhibitors, and angiotensin receptor blockers can falsely elevate the plasma renin activity, leading to a lower aldosterone to plasma renin activity ratio; therefore, the presence of suppressed plasma renin activity in a patient treated with a diuretic or, especially, an ACE inhibitor or angiotensin receptor blocker, is a strong predictor for primary hyperaldosteronism. The most definitive test in diagnosing primary aldosteronism is a nonsuppressed 24-hour urinary aldosterone excretion rate during a salt load (of at least 1 teaspoon of salt daily for 3 days). Patients over the age of 40 generally require adrenal vein sampling to avoid resecting an innocuous cortical adenoma.

Treatment

Patients with biochemical evidence of primary hyperaldosteronism and a unilateral adenoma on tomography can proceed to unilateral adrenalectomy. Patients with bilateral adrenal hyperplasia, and patients who either refuse or are not surgical candidates, can be managed with spironolactone or eplerenone with a program of salt restriction and regular aerobic activity.

PHEOCHROMOCYTOMA

Catecholamine-secreting tumors can result in a dramatic and life-threatening clinical syndrome. Most of these tumors arise from the adrenal medulla. Tumors arising outside of the adrenal gland are termed paraganglionomas. These tumors are rare, accounting for fewer than 1 per 1000 cases of hypertension.

Clinical Features

The classic triad includes episodic headache, palpitation, and diaphoresis. Spells may occur as infrequently as monthly or multiple times daily. Anxiety, nausea, tremor, chest and epigastric pain, and weight loss are other reported features. Patients with pheochromocytoma are typically hypertensive; approximately half of the patients will have episodic hypertension.

Evaluation

Because pheochromocytomas can occur in association with the multiple endocrine neoplasia type 2 syndrome and in von Hippel Lindau syndrome, indications of these diagnoses should be sought.

    Patients at low risk for pheochromocytoma can have the diagnosis excluded by measuring catecholamines and metanephrines in a 24-hour urine collection, a test with high specificity. High-risk patients can be screened with plasma metanephrines. Most patients with pheochromocytomas have urinary or plasma levels that are at least three to four times the upper limit of normal. Tricyclic antidepressants, levodopa, labetalol, ethanol, sotalol, amphetamines, buspirone, benzodiazepines, methyldopa, and chlorpromazine all increase catecholamines and should be avoided.

    If the diagnosis is biochemically confirmed, imaging of the adrenals with MRI is recommended; these lesions are usually at least 3 cm in size and pheochromocytomas are uniquely hyperintense on T2-weighted images. Nuclear medicine scanning with ¹²³I-metaiodobenzylguanidine or positron-emission tomography can be performed if MR/CT imaging is negative.

Treatment

Patients with pheochromocytoma should be managed by experienced hypertension specialists. Surgery is the treatment of choice and can be a high-risk procedure. Preoperative preparation generally combines alpha-blockade (such as phenoxybenzamine, titrated to postural hypotension) with calcium-channel or beta-blockers as needed. Some clinicians recommend metyrosine, but there is limited experience with this inhibitor of catecholamine synthesis. Perioperative crises are managed with nitroprusside. Surgical resection is prudent for malignant pheochromocytomas, although long-term survival is poor.

CUSHING SYNDROME

Chronically elevated glucocorticoid levels result in protean symptoms and signs that are common (such as obesity, hyperglycemia and hypertension) and nonspecific (weakness, acne, edema, striae, headache, plethora). These features make the diagnosis of Cushing syndrome challenging. The hypercortisolemia of Cushing syndrome can originate in the adrenal or result from a pituitary adenoma or other tumor-secreting adrenocorticotropin.

Clinical Features

The most common presenting feature is obesity of the face, neck, and abdomen that spares the extremities. Facial fat deposition can result in a rounded face, exacerbated by deposition of fat in the supraclavicular fat pads, which makes the neck appear shortened. These patients develop skin thinning, atrophy, and easy bruising. Striae typical of Cushing syndrome are typically purple in color, wide, and multiple, factors that help distinguish them from stretch marks associated with obesity. Women with Cushing disease may have signs of hyperandrogenism such as hirsutism. Proximal myopathy (usually described as difficulty rising from a seated position), psychiatric change (emotional lability, depression, and mild paranoia are common), and hypertension are often present at presentation. Other features associated with longer-standing or more severe hypercortisolemia include glucose intolerance, glaucoma, and osteopenia.

Evaluation

The first step in evaluating whether a patient may have Cushing syndrome is to elucidate any history of exposure to corticosteroids, including potent inhaled, injected or topical steroids, or medroxyprogesterone acetate—a progestin with intrinsic steroid activity. Factitious Cushing syndrome accounts for <1% of all cases and is suggested by erratic and inconsistent results. In such cases, synthetic glucocorticoids can be assayed directly in the urine.

    To establish hypercortisolemia, at least two 24-hour urine samples for free cortisol (and creatinine) should be obtained. Patients whose levels are greater than three times higher than the upper reference range can be assumed to have Cushing syndrome. Patients with equivocal values should be retested after a few weeks or be evaluated with further testing according to the clinical suspicion.

    An overnight dexamethasone suppression test is also used as a screening test to diagnose hypercortisolemia. In this test, an 8 a.m. serum cortisol level is drawn after a 1 mg dexamethasone dose at 11 p.m. to midnight. Most normal patients should suppress their endogenous cortisol level to <2 μg/dL. A screening strategy that uses three consecutive late-evening salivary cortisols may ultimately replace these aforementioned tests. These can be performed by an ambulatory patient with minimal instruction. Reference ranges are laboratory-specific.

    Once the diagnosis of Cushing syndrome is secure, a source for the hypercortisolemia should be sought. Determining whether Cushing’s syndrome is ACTH- dependent or adrenal in origin requires accurate measurement of ACTH levels. Cortisol secretion can be deemed to be ACTH-independent if the ACTH is <5 pg/mL when the cortisol level is >15 μg/dL. Under the same circumstances, the syndrome is very likely to be ACTH-dependent (Cushing disease) if the ACTH level is >15 pg/mL when the cortisol is at least 15 μg/dL; ACTH levels of between 5 and 15 pg/mL are less specific but usually indicate ACTH-dependency. Patients with equivocal values should be reinvestigated.

    Patients with ACTH-independent hypercortisolemia should undergo thin-slice CT of the adrenal glands to identify the responsible adenoma, carcinoma, or nodules.

    Patients with ACTH-dependent hypercortisolemia should undergo further testing to discriminate between Cushing disease related to a pituitary adenoma and that related to ectopic ACTH secretion. Tumors recognized to secrete ACTH include small-cell cancer of the lung and bronchial and thymic carcinoids. Clinicians should resist the temptation to image the pituitary because 10% of the population have a structurally abnormal pituitary. Patients should instead undergo a high-dose dexamethasone suppression test, where 2 mg of dexamethasone is given every 6 hours for 2 days. This test capitalizes on the fact that ACTH-secreting pituitary adenomas retain some feedback responsiveness and often suppress their ACTH production when ambient glucocorticoid levels are high. Cortisol levels are reduced by >90% among 70% of those with Cushing disease. In the same study, by contradistinction, no patients with ectopically derived ACTH suppressed cortisol below 90% in response to this high-dose suppression test.

    Petrosal sinus sampling using corticotropin-releasing hormone (CRH) stimulation is a final approach to confirming that ACTH is derived from the pituitary. Criteria for confirming the pituitary as the source of the ACTH include a ratio of ACTH between one side of the petrosal sinus and the peripheral plasma of >2, or a ratio >3 during infusion of CRH as compared with the level before infusion is begun. If one side has an ACTH level that is a multiple of 1.4 times or more the level on the opposite side, then the adenoma is highly likely to reside on that side. Patients with suspected ectopic ACTH should have an octreotide imaging performed with chest plain and tomographic images obtained as indicated.

Treatment

The goal of treatment of Cushing syndrome is the eradication of any tumor, suppression of cortisol levels to as low as possible, and avoidance of permanent hormone dependency. The treatment of choice for Cushing disease is transsphenoidal pituitary resection, irrespective of the size of the pituitary tumor. The more extensive the resection, the greater is the risk of permanent hypopituitarism. This may have particular implications for younger patients who have yet to start a family. Pituitary radiation can be provided to patients with unresectable or residual tumors, although this is associated with a high rate of hypopituitarism.

    Adrenal tumors causing hypercortisolemia are best resected. Medical management of unresectable tumors, or patients with metastatic hormonally active adrenal cancer, is challenging because these malignancies are poorly responsive to adjuvant therapies. Patients may benefit from the use of mitotane, an adrenal poison. These patients must be given supplemental glucocorticoids in replacement doses to ensure they do not develop adrenal insufficiency during treatment. Patients with uncontrollable hypercortisolemia can benefit from adrenal steroid enzyme inhibitors such as ketoconazole or metyrapone. Experimental chemoradiotherapy or additional agents may be available as part of a clinical trial.

HIRSUTISM

Hirsutism refers to the appearance of excessive terminal hair that appears in a male pattern in women. Approximately 5% of women are hirsute. Hirsutism results from an interaction between the androgen level and the sensitivity of the hair follicle to androgen; as a result, androgen levels do not correlate well with the degree of hirsutism. Approximately one half of women with hirsutism have the idiopathic condition.

Clinical Features

Clinical features that suggest one of the rare or more serious causes of hirsutism include abrupt onset, a presentation later in life, and progressive worsening. Symptoms and signs of virilization include frontal balding, acne, clitoromegaly, and deepening of the voice. Hair growth on the upper lip, chin, chest, abdomen, back, pubis, and legs should be assessed. Hirsutism should be distinguished from hypertrichosis, the appearance of generalized excessive hair growth that is genetically determined or follows treatment with glucocorticoids, phenytoin, or cyclosporine.

Evaluation

If hirsutism is moderate or severe, the plasma testosterone and free testosterone should be measured in the early morning (ideally on days 4–10 of the menstrual cycle in cycling women).

    Hyperandrogenism is most frequently related to the polycystic ovary syndrome, one of the most common hormonal disorders affecting women. The syndrome is diagnosed when the patient has at least two of chronic hyperandrogenism, oligo- or anovulation, and polycystic ovaries, and other diagnoses are excluded. These patients often have menstrual irregularity, obesity, and evidence of insulin resistance (e.g., acanthosis nigricans). A pelvic ultrasound is not required for diagnosis. Additional testing may include a pregnancy test if the patient has amenorrhea. These patients should be evaluated for glucose intolerance and sleep apnea and often respond well to insulin sensitizers such as metformin or a thiazolidinedione. Spironolactone and oral contraceptives are frequently used to manage hirsutism in these patients.

    Other causes of hyperandrogenism are unusual. Virilizing congenital adrenal hyperplasia is suggested by the premature growth of pubic hair and clitoromegaly and can be excluded by measuring the morning 17-alpha-hydroxyprogesterone level.

    Cushing syndrome is suggested by the development of truncal obesity, moon face, buffalo hump, purple striae, or proximal muscle weakness. (See Chapter 49 on Adrenal Disorders.) Hyperprolactinemia is suggested by the presence of galactorrhea and an elevated prolactin level. Acromegaly is suggested by the coarsening of facial features or by hand enlargement and confirmed by an elevated IGF-1 level.

    Androgen-secreting tumors are very rare but they should be considered among women with an acute presentation or who have very high levels of testosterone (>200 ng/dL). Such women should be evaluated with a level of dehydroepiandrosterone sulfate and an abdominal and pelvic ultrasound.

    Idiopathic hirsutism is the most common diagnosis after these other disorders have been excluded by clinical or laboratory features.

Treatment

Hirsutism can be managed with cosmetic and hormonal therapy. It is useful to complete an objective assessment of the degree of hirsutism in advance of initiating treatment. The Ferriman-Gallwey score is one such scoring system.

    Cosmetic approaches include bleaching, shaving, waxing, electrolysis, laser treatment, and the use of depilatory agents. Eflornithine hydrochloride cream can be used for facial hirsutism but must be used approximately 8 weeks before its efficacy can be determined.

    Estrogen-progestin contraceptives suppress plasma testosterone levels and can reduce the need for shaving and slow the progression of hirsutism. Contraceptives with nonandrogenic progestins are preferred. Antiandrogens can be offered when hirsutism is moderate to severe. Spironolactone at high dose (50–100 mg twice a day) is effective in reducing hirsutism. Patients must be informed that spironolactone may be teratogenic and is generally not prescribed to women who are sexually active without concomitant use of an oral contraceptive. Hyperkalemia is rarely associated with spironolactone among women with normal renal function. Flutamide is an antiandrogen that is associated with hepatotoxicity and is not generally recommended for managing hirsutism. Cyproterone acetate is an antiandrogen that is available in Canada, Mexico, and Europe but not in the United States.

MALE HYPOGONADISM

Testosterone deficiency can result from disease of the testes or from pituitary or hypothalamic dysfunction. These causes can be distinguished by measuring the gonadotropins, luteinizing hormone, and follicle-stimulating hormone.

Clinical Features

Intrauterine testosterone deficiency can result in micropenis and cryptorchidism, and, when it occurs before puberty, testosterone deficiency will result in incomplete maturation, a eunuchoid habitus, and reduced peak bone mass. When testosterone deficiency occurs after puberty, a decrease in libido and erectile function occur, with loss of sexual hair, muscle mass, and bone mineral density. Gynecomastia can be present.

Evaluation

Causes of low testosterone should be sought from the history, including indications of opiate use, sleep apnea, hemochromatosis, testicular trauma, orchitis, and obesity. The normal adult testis is approximately 4–6 cm in length or 20–25 mL in volume. The lower body segment (sole to pubis) should normally be no more than 2 cm longer than the upper segment (pubis to crown). Breast enlargement, small testes, and behavioral abnormalities suggest Klinefelter syndrome. Anosmia suggests Kallman syndrome.

    Total testosterone and sex-hormone binding globulin concentrations should be measured in a morning sample with luteinizing hormone and follicle-stimulating hormone. Free testosterone measurements are generally unreliable. Semen analysis is appropriate if infertility is a primary concern.

Treatment

Testosterone treatment should be reserved for men with clinical symptoms and signs of hypogonadism accompanied by a subnormal testosterone concentration who have a normal prostate specific antigen level. Testosterone esters can be given by intramuscular injection weekly or biweekly. Transdermal testosterone gels are available in sachets and a metered dose pump and are administered daily after showering; patients should be cautious about skin-to-skin transmission to a bed-partner. Testosterone patches are available but cause local irritation. The dose is titrated to a morning total testosterone level, drawn before the next dose. Clinicians should monitor for symptoms of benign prostatic hypertrophy, sleep apnea, and acne, and monitor prostate-specific antigen and hematocrit for erythrocytosis.

DIABETES MELLITUS

The prevalence of diabetes mellitus is increasing exponentially around the globe. The disease affects approximately 18 million Americans. Type 2 diabetes accounts for approximately 95% of all cases and is characterized by insulin resistance and hyperglycemia. Hyperinsulinemia occurs early in the disease but is not maintained indefinitely. Many patients ultimately require insulin to maintain glucose in the normal range. Because almost 80% of all patients with diabetes will die from cardiovascular complications, cardiovascular risk reduction is the primary target.

Clinical Features

Diabetes is diagnosed if there are symptoms of diabetes (polyuria, polydipsia, unexplained weight loss), and a random glucose of >200 mg/dL. A fasting glucose >126 mg/dL or a glucose of >200 mg/dL 2 hours after a 75g glucose load are also diagnostic. A hemoglobin A1c (HbA1c) of at least 6.5% is also diagnostic. Screening every 3 years for diabetes is recommended for all patients who are overweight with risk factors, and in everyone beginning at age 45.

    Hyperglycemia, to meet the diagnostic criteria for diabetes (prediabetes), is indicated by a HbA1c of between 5.7% and 6.5% and is categorized as either impaired fasting glucose (fasting glucose 100–125 mg/dL) or impaired glucose tolerance (glucose 140–199 mg/dL 2 hours after a 75g glucose load). The incidence of diabetes can be reduced by over 50% in patients with prediabetes if patients lose weight and embark on an exercise program comprising at least 30 minutes of exercise five times weekly. Metformin reduces the incidence of diabetes in these high-risk patients by approximately 25%.

Evaluation

Secondary causes of diabetes should be considered when evaluating any patient with newly diagnosed hyperglycemia. Drugs that are associated with hyperglycemia such as glucocorticoids, antipsychotics, and some antiretrovirals should be reevaluated to determine if an alternative agent can be substituted safely. Genetic causes of diabetes should be excluded if a strong family history of diabetes is present or a typical phenotype (e.g., Down syndrome Turner syndrome, or Klinefelter syndrome) is noted. Endocrinopathies such as Cushing syndrome, acromegaly, pheochromocytoma, hyperthyroidism, and others should be sought from the history and examination. Patients with diseases that affect the exocrine pancreas such as hemochromatosis, chronic pancreatitis, pancreatic malignancy, or cystic fibrosis are at high risk for diabetes; treatment of the underlying disease is often critical to reduce the rate of progression to insulin deficiency and to manage the hyperglycemia.

Treatment

Patients who are newly diagnosed with type 2 diabetes should be provided with a glucometer and testing instructions and referred for diabetes education and medical nutrition therapy. The optimal frequency of fingerstick glucose testing has not been determined. Smoking cessation and the benefits of exercise and weight loss should be emphasized. Targets of treatment are listed in table 56.3.

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