Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section G – Complications of Therapy

Chapter 65 – Endocrine Complications

Manpreet K. Chadha,Donald L. Trump

SUMMARY OF KEY POINTS

Introduction

  

   

Endocrine dysfunction may directly result from cancer or as a consequence of cancer therapy (surgery, radiation, chemotherapy, biologic agents, and hormone therapy). Endocrine dysfunction may be an intentional consequence or an adverse effect of antineoplastic therapy.

  

   

Hypopituitarism with clinically significant deficiencies of growth hormone, thyrotropin, gonadotropin, and corticotrophin may result from radiation (cranial or total body irradiation), surgery, or chemotherapy.

  

   

Thyroid dysfunction from neck irradiation, immune therapy (interleukin-2), and small molecule inhibitors such as sunitinib may result in either hyperthyroidism or hypothyroidism.

  

   

Gonadal dysfunction following surgery, radiotherapy, or chemotherapy results in disruption of puberty, infertility, and premature menopause.

  

   

Adrenal dysfunction from chemotherapy (ketoconazole, aminoglutethimide) may result in glucocorticoid or mineralocorticoid deficiency.

  

   

Pancreatitis and occasionally pancreatic exocrine or endocrine deficiencies may result from chemotherapy (L-asparaginase and streptozotocin).

Diagnostic Considerations

  

   

A detailed history along with a complete physical examination is the key to the diagnosis. Locations of primary as well as metastatic tumor along with past and current therapies are necessary elements of evaluation.

  

   

Signs and symptoms such as delayed or precocious puberty, fatigue, weight loss or gain, amenorrhea, orthostatic hypotension, hyperpigmentation, or electrolyte abnormalities should prompt consideration of unrecognized endocrine dysfunction.

  

   

When one hormonal deficiency is identified, others should be sought.

Evaluation and Treatment

Hypothalamic-Pituitary Axis

  

   

Basal serum hormone concentrations are usually sufficient; however, dynamic testing might be required to diagnose partial deficiencies.

  

   

Patients often have multiple, concurrent hormone deficiencies. Replacement therapy should be started as soon as possible.

Thyroid

  

   

Primary hypothyroidism is characterized by low free thyroxine (T4) level and elevated thyroid-stimulating hormone (TSH), while central hypothyroidism is associated with low free T4 and inappropriately normal or low TSH levels. Replacement with levothyroxine is indicated and highly effective.

  

   

Hyperthyroidism is caused by increased T4 and/or T3 (tri-iodothyronine) levels with a low serum TSH level. Treatment options include surgery, radioiodine ablation or antithyroid medications (propylthiouracil). Rarely, hyperthyroidism may be associated with production of TSH-like substances by germ cell or choriocarcinoma. Management in these instances involves thyroid suppression and treatment of the primary tumor.

Adrenal

  

   

Low- or high-dose corticotrophin test can distinguish between central and primary causes of adrenal insufficiency. Acute adrenal insufficiency is a medical emergency and should be treated by immediate parenteral glucocorticoid replacement and supportive care. Chronic insufficiency is treated by oral glucocorticoid supplement with or without mineralocorticoid.

Syndrome of Inappropriate Antidiuretic Hormone Secretion

  

   

Hyponatremia is classically associated with cyclophosphamide and vinca alkaloids. Measurement of serum and urine osmolality, renal function tests, and assessment of volume status of a patient are the key to diagnosis. Treatment involves fluid restriction and increased salt intake. Refractory cases might need loop diuretics, doxycycline, or newer vasopressin receptor blockers.

INTRODUCTION

Endocrine dysfunction is an increasing cause of morbidity in cancer patients. Improved cancer therapies and new agents with endocrine side effects are primarily responsible for the increase. For example, the Childhood Cancer Survivor Study showed that one or more endocrine conditions were reported in 43% of childhood brain tumor survivors.[1] Timely recognition and management of endocrine dysfunction are essential to prevent further morbidity and impairment of quality of life in cancer patients. Table 65-1 outlines the causes of endocrine dysfunction in this population. Appropriate evaluation and treatment of common endocrinopathies are discussed in the latter sections of this chapter. A special section is included on surveillance of childhood cancer survivors for detection of late endocrinecomplications of various cancer therapies. Tumors of endocrine origin and neuroendocrine tumors are discussed in relevant sections of this textbook.


Table 65-1   -- Causes of Endocrine Dysfunction in Patients with Cancer

  

   

Direct product of hyperplastic/neoplastic endocrine tissue

  

   

Iatrogenic

  

 

Postsurgical

  

 

Postradiation

  

 

Postchemotherapy

  

 

Postbiologic agents

  

 

Intentional hormone ablation therapy (e.g., for breast and prostate cancer)

 

 

ROLE OF SURGICAL THERAPY

Historically, surgery has been used as a means of disrupting normal endocrine function with therapeutic intent.[2] Response rates of 15% to 30% were reported after hypophysectomy or adrenalectomy in advanced breast cancer. [3] [4] However, these procedures resulted in significant morbidity, including hypoadrenalism and hypopituitarism, requiring lifelong replacement therapy. For premenopausal women, ovarian ablation by surgical oophorectomy remains a therapeutic option in metastatic and adjuvant settings. These surgical procedures have been largely supplanted by pharmacologic agents such as luteinizing hormone-releasing hormone agonists along with aromatase inhibitors (inhibit adrenal steroidogenesis) to attain functional castration. [5] [6] Orchiectomy is considered a therapeutic option for men with metastatic prostate cancer.[7]

Normal pituitary function may be altered by surgical resection of a pituitary tumor or by injury to the pituitary stalk disrupting the hypothalamic-pituitary axis. In the former case, anterior pituitary hormones are primarily affected; in the latter case, both the anterior and posterior pituitary hormones are affected.

Similarly, resection of a tumor involving other endocrine glands may result in deficiencies of hormones secreted from these glands: thyroid (hypothyroidism), parathyroids (hypoparathyroidism), pancreas (diabetes mellitus), ovaries (hypogonadism), testes (hypogonadism), or adrenals (hypoadrenalism). Unilateral gland resection rarely results in noticeable hormone deficiencies. Extensive neck surgery and irradiation for advanced head and neck cancers may result in parathyroid hormone deficiency. This might be due to interference with the vascular supply of the parathyroids. Permanent hypoparathyroidism can result inadvertently from total thyroidectomy; the reported incidence is up to 40%.[8] Subtotal removal of parathyroid glands as a part of therapy for parathyroid hyperplasia can also cause hypoparathyroidism. It is often possible to preserve parathyroid function by careful surgical technique and/or by autotransplanting the parathyroid tissue to another part of body.

ROLE OF RADIATION THERAPY

Endocrine organs may be intentionally or unavoidably exposed to ionizing radiation during treatment for malignancy, and high-dose radiation may result in endocrine dysfunction. Table 65-2 lists factors that are known to be associated with a high risk of endocrine dysfunction following radiation. Assessment of late effects of radiation may be difficult and subjective. Various groups have attempted to develop a scoring system to standardize toxicity reporting and description. An example is the LENT-SOMA (Late Effects on Normal Tissue–Subjective, Objective, Management and Analytic) to grade radiation-induced toxicity to the hypothalamic-pituitary axis and thyroid.[9] These scales grade the radiation-induced side effects on these organs exposed to irradiation in a manner similar to common toxicity criteria grading of adverse effects. Newer scales have been designed by the European Organization Treatment of Cancer and Radiation Therapy Oncology Group to grade toxicities related to radiation.[10] The late toxicity assessment of a treatment might depend on the toxicity scale used. The LENT-SOMA scale seems to be the most accurate scale so far. [11] [12]


Table 65-2   -- Risk Factors Associated with Increased Incidence of Radiation-Induced Endocrine Dysfunction

Radiation dose >30 Gy

Total body irradiation

Cranial irradiation

Age (children more sensitive)

Prior pituitary compromise by tumor/surgery

Length of follow-up

 

 

Hypothalamic-Pituitary Axis

Anterior pituitary dysfunction can result from irradiation of nasopharyngeal, extracranial, or primary brain tumors, especially those involving the pituitary. Total body irradiation as part of a bone marrow transplant preparative regimen[13] and prophylactic cranial radiation in patients with acute lymphoblastic leukemia can also cause hypopituitarism.[14] Approximately 19% of patients have a deficiency in one or more anterior pituitary hormones as early as 2 years after cranial irradiation for nasopharyngeal carcinoma.[15]

Data indicate that the hypothalamus is more radiosensitive and is damaged by lower doses of cranial radiation than is the pituitary.[16] Secondary pituitary atrophy evolves with time owing to impaired secretion of hypothalamic regulatory factors or direct radiation-induced damage. This necessitates prolonged follow-up and yearly testing of pituitary function in patients who have received cranial irradiation. The frequency, rapidity of onset, and severity of endocrine abnormalities correlate with the total radiation dose delivered to the hypothalamic-pituitary axis, the fraction size, younger age at irradiation, prior pituitary compromise by tumor and/or surgery, and the length of follow-up.[17]

Somatotrophes (cells that secrete growth hormone) are the most vulnerable to radiation damage; hence, growth hormone deficiency (GHD) is the most commonly seen endocrine dysfunction, following cranial irradiation. GHD may occur in isolation following irradiation of the hypothalamic-pituitary axis with doses less than 30 Gy. The clinical manifestations of GHD are most evident in the growing child: reduction in growth velocity and short stature. Some data suggest that children are more sensitive to radiation effects than are adults.[18] Although poor linear growth is very common in children with GHD, it is not universal or immediately apparent. Several studies suggest that the slowing of growth might not occur for the first year or two after onset of GHD. In postpubertal individuals, GHD is associated with a decrease in muscle mass along with an increase in adiposity.[19]

The hypothalamic neurons secrete gonadotropin-releasing hormone (GnRH) in pulses that are necessary for normal secretion of gonadotropins from the pituitary. This GnRH-pulse generation is affected differentially by the dose of radiation that is received. Abnormalities in gonadotrophin secretion are dose-dependent. Precocious puberty can occur after a radiation dose less than 30 Gy in girls and in both sexes equally with a radiation dose of 30 to 50 Gy. [20] [21] Radiation-induced precocious puberty might be caused by damage to inhibitory GABAergic neurons, leading to disinhibition and premature activation of GnRH neurons.[22] Higher-dose irradiation (>30 Gy) is associated with delayed sexual maturation due to gonadotropin deficiency from damage to GnRH secretory neurons.[23]

Deficiency in other pituitary hormones is less common. Five years after treatment, a study of 251 patients who had been treated for pituitary disease with external radiotherapy described an incidence of thyroid-stimulating hormone (TSH) deficiency of 9% at 20 Gy, increasing to 52% at 42 to 45 Gy.[24] A similar trend for incidence of adrenocorticotrophic hormone (ACTH) deficiency relation was seen. Hyperprolactinemia can be seen after high-dose radiotherapy (>40 Gy) and has been described in both sexes and all age groups but is most common in young women.[25] Constine and associates[26]described a 50% frequency of hyperprolactinemia in 32 patients who were treated with radiation for brain tumor with doses ranging from 39.6 to 70.2 Gy. Other investigators reported rates of 20% after treatment for nasopharyngeal carcinoma. Hyperprolactinemia can cause pubertal delay or arrest in children, galactorrhea and/or amenorrhea in women, and decreased libido and impotence in adult males.

Radiation-induced anterior pituitary hormone deficiencies are irreversible and progressive but are treatable with appropriate hormone replacement therapy. Careful surveillance and close follow-up with an endocrinologist are warranted.

Thyroid

Irradiation of the thyroid may produce hypothyroidism, Graves disease, silent thyroiditis, benign nodules, and thyroid cancers.[27] Hancock and colleagues described their experience with thyroid disease among patients treated with irradiation with or without chemotherapy for Hodgkin's disease at Stanford University.[28] Of 1787 patients, 1677 received irradiation to the thyroid. At 26 years of follow-up, the actuarial risk of thyroid disease was 67%. Hypothyroidism developed in the majority of the patients (47%). The risk of Graves disease was 7 to 20 times higher than that for normal subjects. The risk of thyroid cancer was noted to be 15.6 times the expected risk for normal subjects. The association between thyroid cancer and radiation is discussed in further detail in Chapter 75 . These data remind clinicians to follow thyroid function closely in patients who have been treated with upper mantle or cervical irradiation. Similar results were noted in the Childhood Cancer Survivor Study with an evaluable cohort of 1791 (959 males) Hodgkin's disease survivors. Among patients with Hodgkin's disease, the risk of hypothyroidism at 20 years from the time of diagnosis in those treated with 45 Gy or more was 50%.[29] Total dose of irradiation received has been shown to correlate with the incidence of hypothyroidism in many studies. [27] [28] [29] [30] There is controversy regarding the effect of age at the time of irradiation, gender, and association with the prior use of lymphangiograms. [27] [29]

Radiation-induced thyroid dysfunction is thought to be caused by damage to small thyroid vessels and to the glandular capsule. Focal and irregular follicular hyperplasia, hyalinization, and fibrosis beneath the vascular endothelium, lymphocytic infiltration, single and multiple adenomas, and thyroid carcinomas are histomorphologic features that are described in such patients. [27] [28]

A rare complication of external neck irradiation is acute radiation thyroiditis.[30] It is more commonly associated with therapeutic doses of radioiodine for thyroid diseases. Patients typically present with fever, pain in the anterior cervical region, and transient hyperthyroidism. Hyperthyroidism with a clinical picture that resembles Graves disease may be seen after neck irradiation for Hodgkin's disease.[31]The incidence is uncertain owing to the small number of cases reported. The clinical picture is characterized by diffuse thyroid enlargement, suppressed TSH, high levels of thyroid hormones, and development of thyroid autoantibodies. Ophthalmopathy, with or without overt hyperthyroidism, may be seen and is thought to be related to autoantibodies, similar to Graves disease.[32]

Parathyroid Glands

There are several studies that link prior head and neck irradiation and hyperparathyroidism. [33] [34] Cohen and colleagues[35] followed a cohort of patients who were treated with radiation to the tonsils before the age of 16 years. Among the 2923 patients, 32 patients were found to have clinical hyperparathyroidism. This is a 2.5-fold to 2.9-fold increase compared with the general population in the same age group. There is a long latency period (>25 years) between exposure and onset of hyperparathyroidism. Clinical presentations vary from asymptomatic increases in serum parathormone levels and hypercalcemia to disabling metabolic bone disease or nephrolithiasis. Individuals with a history of head and neck radiation should be monitored with calcium levels periodically (every 1 to 2 years) and indefinitely.[36]

ROLE OF SYSTEMIC THERAPY

Chemotherapy is not widely recognized to contribute to endocrine dysfunction; however, many data indicate to the contrary. Effects of systemic chemotherapy on ovarian and testicular function are discussed in Chapter 64 .

Hypothalamic-Pituitary Axis

In children, chemotherapeutic agents alone may disrupt growth hormone (GH) secretion even in the absence of cranial radiation. Roman and colleagues studied growth and GH secretion in 60 children who were in complete remission after treatment with chemotherapy and surgery for solid tumors.[37] They observed growth hormone deficiency in 45% of those studied and found that these children were more likely to have received high doses of chemotherapy (actinomycin D), but they could find no correlation with the duration of treatment, length of follow-up, tumor type, sex, or age. Depending on the intensity of chemotherapy, significant height loss can be detected in 40% to 70% of patients at 6-year follow-up.[38] Adjuvant chemotherapy can also aggravate growth failure in children with brain tumors receiving craniospinal radiation.[39]

Rose and colleagues reported hypothalamic dysfunction in patients with non–central nervous system tumors who received chemotherapy but did not receive cranial irradiation or traumatic brain injury.[40]Of 31 identified patients, GHD was identified in 15 (48%), central hypothyroidism in 16 (52%), and pubertal abnormalities in 10 (32%) patients. GHD and hypothyroidism were coexistent in eight patients (26%). Overall, 81% (n = 25) had GHD, hypothyroidism, precocious puberty, or gonadotropin deficiency.

The syndrome of inappropriate antidiuretic hormone (SIADH) secretion may result from the effects of many chemotherapeutic agents, either by potentiation of antidiuretic hormone (ADH) effect or by increased ADH secretion. The most commonly implicated agents are vinca alkaloids and cyclophosphamide. The vinca alkaloids are reported to stimulate the central release of ADH from the neurohypophyseal system,[41] whereas alkylating agents enhance renal tubular sensitivity to ADH.[42] Regardless of the mechanism, the result is an increase in water reabsorption by the distal tubules of the kidney, leading to volume expansion and dilutional hyponatremia. Many case reports also implicate platinum agents,[43] vinorelbine,[44] taxanes,[45] and methotrexate.[46] Clinically significant hyponatremia may occur with administration of these agents. Management requires fluid restriction and, at times, salt replacement.

Thyroid

Clinically evident thyroid dysfunction is rarely associated with the use of standard chemotherapy agents. However, a growing body of literature points to the increased prevalence of endocrine dysfunction after bone marrow transplantation, which may be seen following high doses of chemotherapy in absence of any radiation. There are reports of thyroid dysfunction in nearly 50% of allogeneic bone marrow transplant recipients treated with busulphan and cyclophosphamide alone.[47] Thyroid dysfunction may present as low T3 syndrome (free T4 normal, TSH normal, and free T3 below normal), chronic thyroiditis, and transient subclinical hyperthyroidism or hypothyroidism. Chemotherapy may potentiate radiation-induced damage to normal tissue. Among 32 patients treated for medulloblastoma in childhood, Paulino found that 18 patients developed hypothyroidism after a median time of 41 months after irradiation. Hypothyroidism was reported in 10 of the 12 patients (83%) who received 23.4 Gy plus chemotherapy (vincristine, N-[2-chloroethyl]-N′-cyclohexyl-N-nitrosourea [CCNU], cisplatin, or cyclophosphamide) and 6 of 10 (60%) of those who received 36 Gy plus chemotherapy (vincristine, CCNU, prednisone) versus only 2 of the 10 (20%) of those who received 36 GY radiation alone.[48]

Aminogluthemide, now an infrequently used drug to disrupt adrenal and peripheral steroid hormone synthesis, inhibits cholesterol conversion to pregnenolone. It causes thyroid dysfunction after long-term use due to blockade of iodination of tyrosine.[49] Figg and associates reported that 9 of 29 men who were treated with aminogluthemide for metastatic prostate cancer had clinical and biochemical evidence of hypothyroidism.[50]

Chemotherapeutic agents can also interfere with circulating thyroid hormones, thereby altering their free blood levels. 5-Fluorouracil increases total T3 and T4 levels, but free T4 index and TSH remain normal, indicating increased levels of thyroxine-binding globulin or enhanced binding capacity.[51] L-asparaginase causes transient thyroxine-binding globulin deficiency by diminishing hepatic synthesis and also inhibits TSH secretion from the pituitary, resulting in decreased total T4 as well as free T4 levels.[52] Transient hyperthyroidism after L-asparaginase therapy for acute lymphoblastic leukemia has also been observed.[53] These thyroid function abnormalities are mild and short-lived and generally do not require specific therapy.

In postmenopausal women, tamoxifen therapy is associated with changes in thyroid hormone concentrations, though patients may remain clinically euthyroid.[54] Mamby and colleagues undertook a randomized, placebo-controlled trial with tamoxifen 10 mg orally, twice daily, with 14 patients in each group.[55] Thyroid function test assessment before and 3 months after initiation of therapy was done. Serum thyroid-binding globulin increased, as did T4 uptake and T4 levels in the tamoxifen-treated group compared to placebo. TSH levels and free thyroxine index remained unchanged; patients were clinically euthyroid and did not require treatment.

Adrenal

A method of medically ablating or reducing adrenal function was sought for a number of years as an alternative to surgical resection of the adrenal glands. Surgical adrenalectomy was used primarily for the treatment of advanced breast cancer. Aminoglutethimide and ketoconazole both suppress adrenal function. These drugs appear to have their effect through their ability to inhibit important cytochrome P-450 isozymes, which are necessary for adrenal steroid synthesis. [56] [57] Aminoglutethimide, at doses of 1000 to 1500 mg/day, and ketoconazole, at doses of 800 to 1200 mg/day, produce adrenal insufficiency in 30% to 40% of patients. Although standard glucocorticoid treatment is generally required in these patients during treatment, mineralocorticoid replacement is usually not required. The antiadrenal effects of ketoconazole and aminoglutethimide are reversible with treatment discontinuation. Full recovery within 1 to 2 weeks is usual.

Mitotane (1-dichloro-2-[o-chlorophenyl]-2-[p-chlorophenyl]-ethane), is an oral chemotherapeutic agent that is used to treat adrenal carcinoma based on its potent antiadrenal effects.[58] It is used primarily to treat adrenal hyperfunction associated with adrenal carcinoma or ectopic production of corticotrophin. It has been reported to result in sustained remission for some patients with metastatic adrenal carcinoma with long-term administration.[59] Although the mechanism of action is incompletely understood, adrenal necrosis and permanent adrenal insufficiency can result, necessitating lifelong glucocorticoid administration.

Pancreas

Pancreatic exocrine or endocrine insufficiency attributable to chemotherapy is uncommon. Acute pancreatitis has been described as a complication of L-asparaginase therapy and can be fatal.[60] Although rare, several cases of diabetes mellitus have been associated with L-asparaginase therapy.[61] Hyperglycemia is usually transient and responds to intravenous fluids and drug discontinuation. A plausible mechanism may be inhibition of protein synthesis by L-asparaginase leading to interference with insulin production.[62] High triglyceride levels have been associated with L-asparaginase use, though it is not clearly associated with incidence of pancreatitis in these patients. Knoderer and colleagues retrospectively described 33 patients (13%) with asparaginase-associated pancreatitis in a cohort of 254 patients over a 5-year period.[63] Twelve cases were noted after Escherichia coli asparaginase, and 20 cases were noted after PEG-asparaginase therapy. The incidence of pancreatitis was found to be independent of the individual or cumulative asparaginase dose. The interval to pancreatitis diagnosis was longer for PEG-asparaginase than for E. coli asparaginase (P = 0.02). Patients who received prednisone (P = 0.02) and daunomycin (P = 0.006) were more likely to develop pancreatitis than were those who received dexamethasone (P = 0.04). Use of other chemotherapy agents was not observed to have a significant effect on the incidence of pancreatitis.

High-dose cytarabine can rarely result in pancreatitis. Siemers and colleagues described two patients with evidence of pancreatitis among 30 patients treated with cytarabine.[64] Prior therapy with L-asparaginase was found in another small series of patients who received cytarabine and developed pancreatitis.[65]

Streptozotocin is a nitrosurea that is used primarily for the treatment of pancreatic endocrine tumors. In preclinical models, streptozotocin causes beta cell necrosis and insulin-dependent diabetes in many species.[66] Mild glucose intolerance has been described in patients receiving this agent; however, specific treatment is rarely required.[67]

Androgen ablation therapy may also be associated with diabetes. Keating and colleagues showed an increased incidence of diabetes in prostate cancer patients receiving GnRH agonist. A potential mechanism is the increase in body fat mass associated with hypogonadism, which results in insulin resistance.[68]

ROLE OF BIOLOGIC AGENTS

Biologic agents are increasingly important in cancer treatment, and various endocrine complications are being recognized with the use of these agents.

Immune therapies may cause thyroid dysfunction. Atkins and colleagues[69] were the first to describe an association between therapy with recombinant interleukin-2 and thyroid abnormalities. Interleukin-2 therapy is known to be associated with both hypothyroidism and hyperthyroidism, though the former is more common.[70] In Atkins and colleagues’ original report, seven patients (21%) had laboratory evidence of hypothyroidism, a decline in the serum thyroxine concentration and serum free thyroxine index, and an increase in the serum TSH concentration 6 to 11 weeks after treatment.[69] All five symptomatic patients had borderline or elevated serum antimicrosomal antibody titers after treatment; two had serum antibodies to thyroglobulin. Five of the seven patients with hypothyroidism (71%) but only 5 of the 27 euthyroid patients (19%) had evidence of tumor regression (P < 0.02). Fifteen patients (47%) became hypothyroid with high serum TSH levels within 60 to 120 days after the start of treatment. The proposed mechanism is autoimmune with development of antithyroid antibodies. Proposed mechanisms are that either the interleukin-2 treatment itself triggers autoreactive B-cell clones or cellular and/or cytokine-mediated thyroid destruction leads to activation of autoreactive B-cell clones.

Hypothyroidism is a recognized complication of tyrosine kinase inhibitors. Sunitinib maleate is an oral tyrosine kinase inhibitor that was recently approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Desai and colleagues reported hypothyroidism in patients undergoing sunitinib therapy.[71] One potential mechanism may be sunitinib-induced destructive thyroiditis through follicular cell apoptosis. Sunitinib is also a RET/PTC tyrosine kinase inhibitor that is involved in pathogenesis of papillary thyroid cancer and perhaps affects normal thyroid function as well.

Imatinib also interacts with thyroid hormone replacement and results in increased TSH levels in hypothyroid individuals who are on levothyroxine therapy. However, it does not appear to have a direct effect on the thyroid but alters the levels of thyroxine binding protein.[72] Berman and colleagues reported hypophosphatemia and associated changes in bone mineral metabolism in patients taking imatinib for either chronic myelogenous leukemia or gastrointestinal stromal tumors.[73] Patients were found to have high levels of urinary phosphate and markedly decreased serum levels of osteocalcin and N-telopeptide, indicative of reduced bone turnover. Imatinib inhibits platelet-derived growth factor receptor, which in a rat model has been demonstrated to have a critical role in skeleton development.

Interferon-beta (IFN-β) and interferon-alpha (IFN-α) may both increase ACTH, prolactin, growth hormone, and cortisol levels in patients.[74] An assessment of IFN-α-induced endocrine stimulation in patients with myeloproliferative disorders revealed that on day 1 of therapy, a significant stimulation of the hypothalamic-pituitary axis was apparent, an effect that disappeared by the third week of therapy.[75] The acute stimulatory effect of IFN-α on cortisol release appears to be mediated by the release of hypothalamic corticotropin-releasing hormone. There are reports of alterations in the levels of sex hormones during IFN therapy, and male sexual dysfunction has been noted.[76]

Clinicians should keep in mind that there are limited data regarding the effects of many new agents and one must be alert to endocrine dysfunction in patients receiving such drugs.

EVALUATION AND TREATMENT OF COMMON ENDOCRINE DYSFUNCTION

A detailed history, including treatment history and physical examination, should be done in any patient who is suspected of having endocrine dysfunction. Evaluation should be directed by this information and the location and type of tumor. The initial approach to the diagnostic workup is outlined in the following sections. Endocrinology consultation should be sought for more complex and multisystem involvement. Table 65-3 shows a brief outline of evaluation of common endocrine disorders. The workup for gonadotropin deficiency and hormone replacement is discussed in detail in Chapter 64 .


Table 65-3   -- Diagnostic Evaluation of Common Endocrine Disorders

Disease

History

Signs

Screening

Confirmatory Tests

GH deficiency

Fatigue, poor stamina, hypoglycemia

Slow growth velocity, delayed puberty, truncal fat distribution

IGF-1, IGFBP-3, and bone maturation

Insulin hypoglycemia test, arginine, L-dopa, clonidine

Hypothyroidism (primary or secondary)

Fatigue, cold intolerance, weight gain, cognitive dysfunction, mental retardation, constipation, growth failure, dry skin, depression, menstrual disturbances

Slow movement and slow speech, delayed relaxation of tendon reflexes, bradycardia, coarse skin, periorbital edema, macroglossia

Free T4, TSH, and bone maturation

TSH surge

Hyperthyroidism

Hyperactivity, tremors, diarrhea, sweating, weight loss, heat intolerance

Atrial fibrillation, lid lag, proptosis, goiter

Free T4, T3, and TSH

Radioiodine uptake scan

Adrenal insufficiency (primary or secondary)

Dehydration, hyperpigmentation, weakness, fatigue

Electrolyte disturbance, hypotension, nausea, vomiting

Early morning serum cortisol level

Low- or high-dose ACTH stimulation test

 

 

Hypothalamic-Pituitary Axis Disorders

Growth Hormone Deficiency

EVALUATION.

The assessment of pituitary GH production is difficult because GH secretion is pulsatile and serum GH levels are often low between the pulses. Therefore, measurement of a single serum GH level is of limited use in diagnosing GHD. Serum insulin-like growth factor (IGF-1) and IGF binding protein-3 (IGFBP-3) concentrations may be measured as a surrogate marker for GH production, and further evaluation is indicated if these results are below the mean for normal children of the same age. An IGF-1 level below 84 ng/mL using the Esoterix assay reportedly is highly indicative of GHD.[77]Confirmation can be done by GH secretion provocative tests.

According to the consensus guidelines for the diagnosis and treatment of adults with GH deficiency, the insulin hypoglycemia test is the gold-standard GH provocative test.[78] According to the Food and Drug Administration, GHD is diagnosed if the maximum stimulated serum GH concentration is less than 5.1 μg/L (polyclonal radioimmunoassay) or less than 2.5 μg/mL (immunochemiluminescent assay).[79] Even though reliable, this test requires strict monitoring. The insulin hypoglycemia test is contraindicated in debilitated patients, those with cardiovascular or cerebrovascular disease, and those with a history of seizure, abnormal electroencephalogram (EEG), or history of brain surgery. [77] [78] [79] In these patients, the combined arginine/GHRH stimulation test may be used. The arginine stimulation test involves intravenous infusion of 0.5 g/kg body weight (to a maximum of 30 g) of arginine given over 30 minutes and measuring serum growth hormone level at 0, 30, 60, 90, and 120 minutes. Though historically the insulin hypoglycemia test was considered the gold standard for GHD, the arginine-GHRH test is much safer, is 95% sensitive and 91% specific (at a cutoff of 4.1 μg/L), and has essentially replaced the former.[80]

The diagnosis of GHD in childhood is a complex process that requires clinical and growth assessment combined with biochemical tests and radiologic evaluation. GHD may be an isolated finding or a component of multiple pituitary hormone deficiency. In a child with clinical criteria for GHD, a peak GH concentration less than 10 μg/L has traditionally been used to support the diagnosis after a provocative GH test.[81] Supportive evidence is indicated by very short height (more than 2.5 standard deviations below the mean height for normal children of the same age), delayed bone age, poor growth velocity (less than twenty-fifth percentile), and a predicted adult height substantially below the mean parental height.[77] IGF-I/IGFBP-3 levels and GH provocation tests should be done after hypothyroidism has been excluded as a cause of slow growth. Great care should be taken in using insulin or glucagon provocative tests in a young child, and testing should be monitored by an experienced team.

TREATMENT.

Children with proven GHD should receive GH therapy as soon as possible after diagnosis. The goal of therapy is to maximize height attained before puberty. The usual starting dose of GH is 25 to 50 μg/kg/day, administered subcutaneously in the evening. [72] [73] Each dose produces a pharmacologic level of GH for approximately 12 hours. Evaluation of the growth response and adjustment of GH dose should occur every 4 to 6 months, and assessment should include measurement of height, weight, and arm span. GH dose is increased as weight gain occurs to maintain a stable dose per kilogram of body weight. Serum IGF-1 measurements are recommended yearly. If IGF-1 increases above the upper limits of normal for age and gender, the GH dose should be decreased.

GH therapy in adults is approved by the Food and Drug Administration only if there is evidence of hypothalamic or pituitary disease and a subnormal serum GH response to a provocative test. The goal of the therapy is to improve muscle and cardiac function, restore normal body composition, and improve serum lipids. The usual starting dose for adults between 30 to 60 years of age is 300 μg/day; the dose is increased every 1 to 2 months by 100 to 200 μg/day, guided by clinical response and measurement of serum GH levels. [77] [78]

Hyperprolactinemia

EVALUATION.

The presenting symptoms of hyperprolactinemia include amenorrhea, galactorrhea, impotence, and infertility. The diagnosis of hyperprolactinemia is made by a random serum prolactin level measurement. Dynamic testing of the lactotrophin reserve with thyrotropin-releasing hormone is not useful because it does not differentiate between the different causes of hyperprolactinemia.[82] Hypothyroidism must also be ruled out as a cause of clinical findings, and careful review of medications should be done to rule out drug-induced hyperprolactinemia.

TREATMENT.

Dopamine released from hypothalamic nerve endings acts as a prolactin inhibitory factor, and dopaminergic agonists are useful in the treatment of hyperprolactinemia. Commonly used agents include bromocriptine and cabergoline. The most common side effects of these drugs are nausea, postural hypotension, and mental fogginess. Less common side effects include nasal stuffiness, depression, Raynaud phenomenon, alcohol intolerance, and constipation. The usual starting dose is 0.25 mg of cabergoline twice a week or 1.25 mg of bromocriptine once a day. The doses can be increased on the basis of serum prolactin level and the side effect profile.

Thyroid Disorders

EVALUATION.

Primary hypothyroidism is characterized by a high serum TSH (normal range: 0.5 to 5 mU/L) concentration and a low serum free T4 concentration (normal range- 0.8 to 1.8 ng/dL). Secondary hypothyroidism is characterized by a low serum T4 concentration and a serum TSH concentration that is not appropriately elevated.[83] To distinguish between pituitary and hypothalamic causes of hypothyroidism, thyrotropin-releasing hormone stimulation test and/or imaging studies of the sellar and suprasellar region should be done. Patients who are diagnosed with central hypothyroidism should also be evaluated for coexistent adrenocortical, gonadal, posterior pituitary, and, in children, growth hormone function. As was noted previously, patients with cranial irradiation or traumatic brain injury are at high risk for panhypopituitarism.

Primary hyperthyroidism is associated with low TSH and high free T4. Graves disease is associated with uniformly high 24-hour radioiodine uptake, while toxic adenoma is associated with focal high uptake. If free T4 and T3 are high with a normal or high TSH in a clinically hyperthyroid patient, pituitary magnetic resonance imaging should be done to look for a pituitary mass (TSH-secreting adenoma).

TREATMENT.

Thyroid hormone replacement with levothyroxine (T4) is usually sufficient. The goal of therapy is to attain normal TSH (in primary hypothyroidism) and free T4 levels (in secondary hypothyroidism). The average replacement dose of T4 in adults is approximately 1.6 μg/kg body weight per day. Treatment with liothyronine (T3) may be required in patients with no response to levothyroxine therapy or in patients with myxedema coma.

Thyroid ablation with surgery, radioiodine, or pharmacologic agents (propylthiouracil, methimazole) should be considered in patients with hyperthyroidism. Beta blocker therapy is used as a clinical adjunct in most patients. The goal of therapy is to keep the TSH and T3 and T4 in the normal range. Surgery is indicated primarily in patients who have large or obstructive goiter.

Syndrome of Inappropriate Antidiuretic Hormone

EVALUATION.

SIADH is characterized by hyponatremia, a low plasma osmolality, an inappropriately elevated urine osmolality (above 100 mosmol/kg), and a high urinary sodium concentration (usually above 40 mEq/L). Other supportive findings include low BUN and serum uric acid concentration, normal plasma creatinine concentration, normal acid-base and potassium balance, and normal adrenal and thyroid function.[84]

TREATMENT.

Water restriction is the mainstay of therapy in asymptomatic hyponatremia and in chronic SIADH. Severe, symptomatic, or resistant hyponatremia requires the administration of salt tablets or hypertonic saline administration. A loop diuretic (such as furosemide once or twice a day) may be used to enhance the effect of fluid reduction, since it directly interferes with the countercurrent concentrating mechanism by decreasing sodium and chloride reabsorption in the medullary portion of the loop of Henle.[85] In patients who remain refractory, demeclocycline (300 to 600 mg twice a day) or lithium may be used.[86] These drugs act on the collecting tubule cell to diminish its responsiveness to ADH, thereby increasing water excretion. ADH receptor antagonists are being evaluated that are selective for the V2 (antidiuretic) receptor and may thus reverse the hyponatremia. Conivaptan blocks V2 and V1a receptors and is available in parenteral form.[87]

Hyperparathyroidism

EVALUATION.

Primary hyperparathyroidism is characterized by elevated parathormone level and hypercalcemia. Supportive findings include low serum phosphate level, an increase in 24-hour urinary calcium excretion, a decrease in serum calcitriol and 25(OH) cholecalciferol, and an increase in biochemical markers of bone turnover (collagen cross-links, osteocalcin, bone-specific alkaline phosphatase). Patients may present with classic symptoms of the disease (nephrolithiasis or bone disease), or they may have nonspecific symptoms such as fatigue, weakness, mild depression, vague abdominal pain, and constipation.

TREATMENT.

Patients should be advised to avoid factors that can aggravate hypercalcemia, including thiazide diuretic and lithium carbonate therapy, volume depletion, prolonged bed rest or inactivity, and a high-calcium diet (>1000 mg/day). Daily vitamin D intake of 400 to 600 IU daily should be maintained, as vitamin D deficiency stimulates parathormone secretion and bone resorption and therefore is deleterious in patients with primary hyperparathyroidism. Surgical removal of the parathyroid glands remains the mainstay of therapy in most patients. Medical therapy involves estrogen plus progestin, bisphosphonates, or raloxifene. These drugs inhibit bone resorption and increase bone density and possibly lower serum calcium concentrations in patients with hyperparathyroidism. Calcimimetics and vitamin D analogs act by suppressing parathyroid hormone release and counteract the effects of hyperparathyroidism at the level of the parathormone receptor. Calcimimetics are currently being studied for primary and secondary hyperparathyroidism.[88]

Adrenal Disorders

EVALUATION.

There is controversy about the optimal biochemical approach to diagnosis of corticotropin deficiency. In moderate to severe corticotropin deficiency, the early morning serum cortisol levels are consistently less than 250 nM. A corticotropin stimulation test may be used to confirm the diagnosis. Both low-dose (1 μg) and high-dose (250 μg) corticotropin stimulation tests are useful to distinguish primary from pituitary (secondary) causes of adrenal insufficiency. Serum cortisol levels are measured at 0, 30, and 60 minutes after intravenous administration of corticotropin. If corticotropin and adrenal secretion are normal, the serum cortisol levels should increase to 20 μg/dL or higher. In patients with severe corticotropin deficiency, the serum cortisol response will be lower or absent as a result of adrenal atrophy. Primary adrenal insufficiency is characterized by low response to both low-dose and high-dose corticotropin stimulation tests. Acute adrenal crisis is an oncologic emergency. Electrolyte disturbances such as hyponatremia, hyperkalemia, azotemia, hypercalcemia, and hypoglycemia are common.

TREATMENT.

Adrenal insufficiency requires glucocorticoid supplementation and at times mineralocorticoid supplementation. Pituitary or isolated ACTH deficiency is not characterized by mineralocorticoid deficiency. Patients with symptomatic adrenal insufficiency should be treated with hydrocortisone or cortisone in the early morning and afternoon. The usual initial oral dose is 25 mg of hydrocortisone (15 mg in the morning and 10 mg in the afternoon). This may be decreased over time, with the goal of using the minimal effective dose to prevent weight gain and osteoporosis.[89] Patients with primary adrenal insufficiency require mineralocorticoid replacement with fludrocortisone (0.05 to 2 mg orally each day). During periods of stress, patients with adrenal insufficiency require higher-than-usual doses of hydrocortisone, and in severe illness, they might require intravenous high-dose hydrocortisone therapy due to acute adrenal crisis. Box 65-1 outlines a treatment algorithm for acute adrenal crisis, which should be treated as an oncologic emergency.

Box 65-1 

TREATMENT OF ACUTE ADRENAL CRISIS

  

1.   

Check airway, breathing and circulation, and baseline vital signs. Establish intravenous access with a large-gauge needle.

  

2.   

Assess serum electrolytes, glucose, and random plasma cortisol and ACTH levels.

  

3.   

Replace intravascular volume with isotonic saline (at least 2 to 3 liters), and maintain hydration.

  

4.   

Intravenous corticosteroid administration preferably with dexamethasone (4 mg intravenous every 8 hrs) intravenously. Hydrocortisone 100 mg IV every 6 hours may be used but can interfere with ACTH stimulation test.

  

5.   

Treat underlying causes of the adrenal crisis (e.g., infection).

  

6.   

Perform a short ACTH stimulation test to confi rm the diagnosis of adrenal insuffi ciency if the patient does not have known adrenal insuffi ciency.

  

7.   

Begin mineralocorticoid replacement with fl udrocortisone (0.1 mg by mouth daily) after volume replacement.

SURVEILLANCE OF CHILDHOOD CANCER SURVIVORS

With improved therapy for most childhood cancers, there is an increasing population of childhood cancer survivors.[90] Such individuals are at risk for long-term endocrine complications related to the tumor and/or the treatment received. The risk of a particular endocrinopathy depends on the tumor location and the dose and duration of radiotherapy and chemotherapy received. Box 65-2 depicts a summary of recommended yearly surveillance in childhood cancer survivors for endocrine complications.[91] Close follow-up should be performed every 4 to 6 months if the initial tests are normal but the child remains symptomatic.

Box 65-2 

YEARLY SURVEILLANCE FOR ENDOCRINE DISORDERS IN CHILDHOOD CANCER SURVIVORS

  

1.   

Detailed history and physical examination, including accurate height and weight measurements (arm span measurement if unable to assess height)

  

2.   

Determination of bone age (radiograph of left hand and wrist) in children who are growing too fast or too slowly

  

3.   

Ascertainment of Tanner stage of pubertal development and interpretation of whether the pubertal status and rate of progression are appropriate for chronologic age

  

4.   

Measurement of IGF-I and IGFBP-3 levels in children who are growing too slowly (to assess for GHD)

  

5.   

Measurement of serum LH, FSH, and sex hormone levels (testosterone or estradiol) in children with delayed or interrupted progression of puberty

  

6.   

Measurement of free T4 and TSH levels

Children typically exhibit catch-up growth and weight gain after completion of therapy. Some children transiently develop breast buds corresponding to this period of newly improved nutrition. These children should be examined every 3 to 6 months to evaluate for precocious puberty. Assessment of Tanner stage of pubertal development is useful to assess for precocious or delayed puberty. Further testing should be guided by the physical findings.

Surveillance for adrenocortical deficiency is indicated primarily for high-risk patients such as those who received cranial irradiation in excess of 40 Gy. There is controversy regarding how long the surveillance should be carried out. The surveillance is guided largely by the pattern of growth and development. If normal growth and pubertal development are attained, the surveillance can be stopped.

CONCLUSION

Endocrine disorders are common in patients with cancer and are related primarily to cancer therapy. Careful clinical examination and yearly surveillance should be done in cancer survivors. A high degree of clinical suspicion is necessary in patients who are on newer therapies with which there is limited experience. Most endocrine disorders are readily treatable, and an accurate diagnosis should be pursued aggressively.

REFERENCES

  1. Gurney JG, Kadan-Lottick NS, Packer RJ, et al: Endocrine and cardiovascular late effects among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study.  Cancer2003; 97:663-673.
  2. Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma: suggestions for new methods of treatment.  Lancet1896; 2:104-107.162–165
  3. Schwarz M, Tindall GT, Nixon DW: Transsphenoidal hypophysectomy in disseminated breast cancer.  South Med J1981; 74:315-317.
  4. Silverstein MJ, Byron RL, Yonemoto RH: Bilateral adrenalectomy for advanced breast cancer.  Surgery1975; 77:825-832.
  5. Buzdar A: Endocrine therapy in the treatment of metastatic breast cancer.  Semin Oncol2001; 28:291-304.
  6. Dees EC, Davidson NE: Ovarian ablation as adjuvant therapy for breast cancer.  Semin Oncol2001; 28:322-331.
  7. Samson DJ, Seidenfeld J, Schmitt B, et al: System-atic review and meta-analysis of monotherapy compared with androgen blockage for patients with advanced prostate carcinoma.  Cancer2002; 95:361-376.
  8. Lo CY: Parathyroid autotransplantation during thryoidectomy.  Aust N Z J Surg2002; 72:902-907.
  9. LENT SOMA tables.  Radiother Oncol1995; 3:17-60.
  10. Hoeller U, Tribius S, Kuhlmey A, et al: Increasing the rate of late toxicity by changing the score? A comparison of RTOG/EORTC and LENT/SOMA scores.  Int J Radiat Oncol Biol Phys2003; 55:1013-1018.
  11. Dennis F, Garaud P, Bardet E, et al: Late toxicity results of the GORTEC 94-01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems.  Int J Radiat Oncol Biol Phys2003; 55:93-98.
  12. Anacak Y, Yalman D, Ozsaran Z, Haydaroglu A: Late radiation effects to the rectum and bladder in gynecologic cancer patients: the comparison of LENT/SOMA and RTOG/EORTC late-effects scoring systems.  Int J Radiat Oncol Biol Phys2001; 50:1107-1112.
  13. Mills W, Chatterjee R, McGarrigle HH, et al: Partial hypopituitarism following total body irradiation in adult patients with hematological malignancy.  Bone Marrow Transplant1994; 14:471-473.
  14. Hata M, Ogino I, Aida N, et al: Prophylactic cranial irradiation of acute lymphoblastic leukemia in childhood: outcomes of late effects on pituitary function and growth in long term survivors.  Int J Cancer2001; 96:117-124.
  15. Lam KS, Tse VK, Wang C, et al: Early effects of cranial irradiation on hypothalamic-pituitary function.  J Clin Endocrinol Metab1987; 64:418-424.
  16. Spoudeas HA, Hindmarsh PC, Matthews DR, Brook CG: Evolution of growth hormone neurosecretory disturbance after cranial irradiation for childhood brain tumours: a prospective study.  Journal of Endocrinology1996; 150:329-342.
  17. Darzy KH, Shalet SM: Hypopituitarism as a consequence of brain tumours and radiotherapy.  Pituitary2005; 8:203-211.
  18. Brennan B, Shalet S: Endocrine late effects after bone marrow transplant.  Br J Haematol2002; 118:58-66.
  19. Salamon F, Cuneo R, Hesp R, et al: The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency.  N Engl J Med1989; 321:1797-1803.
  20. Didcock E, Davies HA, Didi M, et al: Pubertal growth in young adults survivors of childhood leukemia.  J Clin Oncol1995; 13:2503-2507.
  21. Darzy KH, Shalet SM: Hypopituitarism as a consequence of brain tumours and radiotherapy.  Pituitary2005; 8:203-211.
  22. Roth C, Schmidberger H, Schaper O, et al: Cranial irradiation of female rats causes dose-dependent and age-dependent activation or inhibition of pubertal development.  Pediatr Res2000; 47:586-591.
  23. Muller J: Disturbance of pubertal development after cancer treatment.  Best Pract Res Clin Endocrinol Metab2002; 16:91-103.
  24. Littley MD, Shalet S, Morgasnstern G, et al: Radiation-induced hypopituitarism is dose-dependent.  Clin Endocrinol (Oxf)1989; 31:363-373.
  25. Sklar CA, Constine LS: Chronic neuroendocrinological sequelae of radiation therapy.  Int J Radiat Oncol Biol Phys1995; 31:1113.
  26. Constine LS, Woolf PD, Cann D, et al: Hypothalamic-pituitary dysfunction after radiation for brain tumors.  N Engl J Med1993; 328:87-94.
  27. Hancock SL, McDougall IR: Thyroid abnormalities after therapeutic external radiation.  Int J Radiat Oncol Biol Phys1995; 31:1165-1170.
  28. Hancock SL, Cox RS, McDougall IR: Thyroid diseases after treatment of Hodgkin's disease.  N Engl J Med1991; 325:599-605.
  29. Sklar C, Whitton J, Mertens A, et al: Abnormalities of the thyroid in survivors of Hodgkin's disease: data from the Childhood Cancer Survivor Study.  J Clin Endocrinol Metab2000; 85:3227-3232.
  30. Jereczek-Fossa BA, Alterio D, Jassem J, et al: Radiotherapy-induced thyroid disorders.  Cancer Treat Rev2004; 30:369-384.
  31. Loeffler JS, Tarbell NJ, Garber JR, et al: The development of Graves' disease following radiotherapy for Hodgkin's disease.  Int J Radiat Oncol Biol Phys1988; 14:175-178.
  32. Jacobson DR, Fleming BJ: Graves' disease with ophthalmopathy following radiotherapy for Hodgkin disease.  Am J Med Sci1984; 288:217-220.
  33. Christmas TJ, Chapple CR, Noble JG, et al: Hyperparathyroidism after neck irradiation.  Br J Surg1988; 75:873-874.
  34. Ron E, Saftlas AF: Head and neck radiation carcinogensis: epidemiologic evidence.  Otolaryngol Head Neck Surg1996; 115:403-408.
  35. Cohen J, Gierlowski TC, Schneider AB: A prospective study of hyperparathyroidism in individuals exposed to radiation in childhood.  JAMA1990; 264:581-584.
  36. Schneider AB, Gierlowski TC, Shore-Freedman E, et al: Dose-response relationships for radiation-induced hyperparathyroidism.  J Clin Endocrinol Metab1995; 80:254-257.
  37. Roman J, Vilaaizan CJ, Garcia-Foncillas J, et al: Growth and growth hormone secretion in children with cancer treated with chemotherapy.  J Pediatr1997; 131:105-112.
  38. Spoudeas H: Growth and endocrine function after chemotherapy and radiotherapy in childhood.  Eur J Cancer2002; 38:1748-1759.
  39. Olshan JS, Gubernick J, Packer J, et al: The effects of adjuvant chemotherapy on growth in children with medulloblastoma.  Cancer1992; 70:2013-2017.
  40. Rose SR, Schreiber RE, Kearney NS, et al: Hypothalamic dysfunction after chemotherapy.  J Pediatr Endocrinol Metab2004; 17:55-66.
  41. Antony A, Robinson WA, Roy C, et al: Inappropriate antidiuretic hormone secretion after high dose vinblastine.  J Urol1980; 123:783-784.
  42. Campbell DM, Atkinson A, Gillis D, et al: Cyclophosphamide and water retention: mechanism revisited.  J Pediatr Endocrinol Metab2000; 13:673-675.
  43. Ishii K, Aoki Y, Sasaki M, et al: Syndrome of inappropriate secretion of antidiuretic hormone induced by intraarterial cisplatin chemotherapy.  Gynecol Oncol2002; 87:150-151.
  44. Garrett CA, Simpson Jr TA: Syndrome of inappropriate secretion of antidiuretic hormone associated with vinorelbine therapy.  Ann Pharmacother1998; 32:1306-1309.
  45. Langer-Nitsche C, Luck HJ, Heilmann M: Severe syndrome of inappropriate antidiuretic hormone secretion with docetaxel treatment in metastatic breast cancer.  Acta Oncol2000; 39:1001.
  46. Frahm H, von Hulst M: Increased secretion of vasopressin and edema formation in high dosage methotrexate therapy.  Z Gesamante Int Med1988; 43:411-414.
  47. Tauchmanova L, Selleri C, Rosa GD: High prevalence of endocrine dysfunction in long-term survivors after allogeneic bone marrow transplantation for hematologic diseases.  Cancer2002; 95:1076-1084.
  48. Paulino AC: Hypothyroidism in children with medulloblastoma: a comparison of 3600 and 2340 cGy craniospinal radiotherapy.  Int J Radiat Oncol Biol Phys2002; 53:543-547.
  49. Cytadren (aminoglutethimide).  Product information,  East Hanover, NJ, Novartis Pharmaceuticals Corporation, 2000.
  50. Figg WD, Thibault A, Sartor AO, et al: Hypothyroidism associated with aminoglutethimide in patients with prostate cancer.  Arch Intern Med1994; 154:1023-1025.
  51. Shalet SM: Endocrine sequelae of cancer therapy.  Eur J Endocrinol1996; 135:135-143.
  52. Garnick MB, Larsen PR: Acute deficiency of thyroxine binding globulin during L-asparaginase therapy.  N Engl J Med1979; 301:252-253.
  53. Heidemann PH, Stubbe P, Beck W: Transient secondary hypothyroidism and thyroxine binding globulin deficiency in leukemic children during polychemotherapy: An effect of L-asparaginase.  Eur J Pediatr1981; 136:291-295.
  54. Kostoglou-Athanassiou I, Ntalles K, Markopoulous G, et al: Thyroid function in postmenopausal women with breast cancer on tamoxifen.  Eur J Gynaecol Oncol1998; 19:150-154.
  55. Mamby CC, Love RR, Lee KE: Thyroid function test changes with adjuvant tamoxifen therapy in postmenopausal women with breast cancer.  J Clin Oncol1995; 13:854-857.
  56. Santen RJ, Samojlik E, Lipton A: Kinetic, hormonal and clinical studies with aminoglutethimide in breast cancer.  Cancer1977; 39:2948-2958.
  57. Trump DL, Havlin KH, Messing EM: High dose ketoconazole in advanced hormone-refractory prostate cancer: endocrinologic and clinical effects.  J Clin Oncol1989; 7:1093-1098.
  58. Lubitz JA, Freeman L, Ikun R: Mitotane in inoperable adrenal cortical carcinoma.  JAMA1973; 223:1109-1112.
  59. Ilias I, Alevizaki M, Philippou G, et al: Sustained remission of metastatic adrenal carcinoma during long-term administration of low-dose mitotane.  J Endocrinol Invest2001; 24:532-535.
  60. Lamelas RG, Chapchap P, Magalhaes AC, et al: Successful management of a child with asparaginase-induced hemorrhagic pancreatitis.  Med Pediatr Oncol1999; 32:316.
  61. Jaffe N: Diabetes mellitus secondary to L-asparaginase therapy.  J Pediatr1972; 81:1270.
  62. Ettinger LJ, Ettinger AG, Aiavaramis VI, et al: Acute lymphoblastic leukemia: a guide to asparaginase and pegasparase therapy.  BioDrugs1997; 7:30-39.
  63. Knoderer HM, Robarge J, Flockhart JA: Predicting asparaginase-associated pancreatitis.  Pediatr Blood Cancer2007; 49:634-639.
  64. Siemers RF, Freidenberg RF, Norfleet RG: High-dose cytosine arabinoside-associated pancreatitis.  Cancer1985; 56:1940-1942.
  65. Altman AJ, Dindorf P, Quinn JJ: Acute pancreatitis in association with cytosine arabinoside therapy.  Cancer1982; 49:1384-1386.
  66. Yang H, Wright J: Human (beta) cells are exceedingly resistant to streptozocin in vivo.  Endocrinology2002; 143:2491-2495.
  67. Broder LE, Carter SK: Pancreatic islet cell carcinoma: results of treatment with streptozocin in 52 patients.  Ann Intern Med1973; 79:108-118.
  68. Keating NL, O'Malley AJ, Smith MR, et al: Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer.  J Clin Oncol2006; 24:4448-4456.
  69. Atkins MB, Mier JW, Parkinson DR: Hypothyroidism after treatment with interleukin-2 and lymphokine activated killer cells.  N Engl J Med1988; 318:1557-1563.
  70. Weijl NI, Van der Harst D, Brand A, et al: Hypothyroidism during immunotherapy with interleukin-2 is associated with antithyroid antibodies and response to treatment.  J Clin Oncol1993; 11:1376-1383.
  71. Desai J, Yassa L, Margusse E, et al: Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors.  Ann Intern Med2006; 145:660.
  72. De Groot JW, Zonnenberg BA, Plukker JT, et al: Imatinib induces hypothyroidism in patients receiving levothyroxine.  Clin Pharmacol Ther2005; 78:433-438.
  73. Berman E, Nicolaides M, Maki RG, et al: Altered bone and mineral metabolism in patients receiving imatinib mesylate.  N Engl J Med2006; 354:2006-2013.
  74. Nolten WE, Goldstein D, Lindstrom M, et al: Effects of cytokines on the pituitary-adrenal axis in cancer patients.  J Interferon Res1993; 13:349-357.
  75. Gisslinger H, Svoboda T, Clodi M, et al: Interferon-alpha stimulates the hypothalamic-pituitary-adrenal axis in vivo and in vitro.  Neuroendocrinology1993; 57:489-495.
  76. Jones TH, Wadler S, Hupart KH: Endocrine-mediated mechanisms of fatigue during treatment with interferon-alpha.  Semin Oncol1998; 25(suppl 1):54-63.
  77. Hartman ML, Crowe BJ, Biller BM, et al: Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency?.  J Clin Endocrinol Metab2002; 87:477-485.
  78. Molitch ME, Clemmons DR, Malozowski S, et al: Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline.  J Clin Endocrinol Metab2006; 91:1621-1634.
  79. Vance ML, Mauras N: Growth hormone therapy in adults and children.  N Engl J Med1999; 341:1206.
  80. Biller BM, Samuels MH, Zagar A, et al: Sensitivity and specificity of six tests for the diagnosis of adult growth hormone deficiency.  J Clin Endocrinol Metab2002; 87:2067-2079.
  81. GH Research Society : Consensus guidelines for the diagnosis and treatment of growth hormone deficiency in childhood and adolescence: summary statement of the GH research society.  J Clin Endocrinol Metab2000; 85:3990-3993.
  82. Suliman AM, al-Saber F, Hayes F: Hyperprolactinemia: analysis of presentation, diagnosis and treatment in the endocrine service of a general hospital.  Ir Med J2000; 93:74-76.
  83. Dayan CM: Interpretation of thyroid function tests.  Lancet2001; 357:619-624.
  84. Clayton JA, Le Jeune IR, Hall IP: Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome.  QJM2006; 99:505-511.
  85. Decaux G, Waterlot Y, Genette F, Mockel J: Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with furosemide.  N Engl J Med1981; 304:329-330.
  86. Forrest Jr JN, Cox M, Hong C, et al: Superiority of demeclocycline over lithium in the treatment of chronic syndrome of inappropriate secretion of antidiuretic hormone.  N Engl J Med1978; 298:173-177.
  87. Chen S, Jalandhara N, Battle D: Evaluation and management of hyponatremia: an emerging role for vasopressin receptor antagonists.  Nat Clin Pract Nephrol2007; 3:82-95.
  88. Dong BJ: Cinacalcet: an oral calcimimetic agent for the management of hyperparathyroidism.  Clin Ther2005; 27:1725-1751.
  89. Arlt W, Allolio B: Adrenal insufficiency.  Lancet2003; 361:1881-1893.
  90. Aziz NM, Oeffinger KC, Brooks S, Turoff AJ: Comprehensive long-term follow-up programs for pediatric cancer survivors.  Cancer2006; 107:841-848.
  91. Landier W, Bhatia S, Eshelman DA, et al: Development of risk-based guidelines for pediatric cancer survivors: the Children's Oncology Group long-term follow-up guidelines from the Children's Oncology Group Late Effects Committee and Nursing Discipline.  J Clin Oncol2004; 22:4979-4990.