Endocrine dysfunction is an increasing cause of morbidity in patients with cancer. In the Childhood Cancer Survivor Study, 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 patients with cancer. Box 61-1 outlines the causes of endocrine dysfunction among patients with cancer. 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 endocrine complications of various cancer therapies. A brief section is also included on endocrine adverse effects from newer therapeutic agents. Tumors of endocrine origin and neuroendocrine tumors are discussed in relevant sections of this textbook.

Box 61-1 Causes of Endocrine Dysfunction in Patients with Cancer

• Direct product of hyperplastic/neoplastic endocrine tissue

• Iatrogenic

After surgery

After radiation

After chemotherapy

After use of biological 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 and was the first effective therapy for advanced breast or prostate cancers.² Response rates of 15% to 30% were reported after hypophysectomy or adrenalectomy in patients with advanced breast cancer.³ 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 agonists along with aromatase inhibitors (that inhibit adrenal steroidogenesis) to attain functional castration.⁴ Orchiectomy, whether surgical or medical, is a critical therapeutic option for men with advanced prostate cancer.⁵

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.

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. Box 61-2 lists factors that are known to be associated with a high risk of endocrine dysfunction after 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. The most accurate scale for grading radiation-induced effects on normal tissues, including to the hypothalamic-pituitary axis and thyroid, is LENT-SOMA (Late Effects on Normal Tissue—Subjective, Objective, Management and Analytic).⁷ These scales grade the radiation-induced adverse effects on organs exposed to irradiation by using criteria similar to the common toxicity criteria grading of adverse effects developed by the National Cancer Institute (http://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf).

Box 61-2 Risk Factors Associated with Increased Incidence of Radiation-Induced Endocrine Dysfunction

• Radiation dose >30 Gy

• Total body irradiation

• Cranial irradiation

• Age (children are more sensitive)

• Prior pituitary compromise by tumor/surgery

• Length of follow-up

Hypothalamic-Pituitary Axis

Anterior pituitary damage can result from irradiation of extracranial or primary brain tumors, especially those involving the pituitary. Total body irradiation as part of a bone marrow transplant preparative regimen and prophylactic cranial radiation in patients with acute lymphoblastic leukemia can also cause hypopituitarism.10–10 After curative irradiation for nasopharyngeal carcinoma, approximately 19% of patients have a deficiency in one or more anterior pituitary hormones as early as 2 years after therapy.¹⁰

Data indicate that the hypothalamus is more radiosensitive than the pituitary. Secondary pituitary atrophy evolves with time as a result of impaired secretion of hypothalamic regulatory factors or direct radiation-induced damage, which 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.

Somatotrophs (cells that secrete growth hormone) are the most vulnerable to radiation damage; hence growth hormone deficiency (GHD) is the endocrine abnormality most commonly seen after cranial irradiation. GHD may occur in isolation after irradiation of the hypothalamic-pituitary axis even with doses less than 30 Gy. The clinical manifestations of GHD of reduction in growth velocity and short stature are most evident in the growing child.¹⁰ 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 the onset of GHD. In postpuberal individuals, GHD is associated with a decrease in muscle mass along with an increase in adiposity.

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. Higher dose irradiation (>30 Gy) is associated with delayed sexual maturation because of gonadotropin deficiency from damage to GnRH secretory neurons.¹¹ Lower doses (<30 Gy) can result in precocious puberty equally in both sexes with a radiation dose of 30 to 50 Gy. Radiation-induced precocious puberty might be caused by damage to inhibitory GABAergic neurons, leading to disinhibition and premature activation of GnRH neurons.¹¹

Deficiency in other pituitary hormones is less common. Littley and colleagues ¹² described 251 patients who had been treated for pituitary disease with external radiotherapy. Five years after completion of treatment, these investigators noted a 9% dose-related incidence of thyroid-stimulating hormone (TSH) deficiency at 20 Gy, which increased to 52% at 42 to 45 Gy. A similar trend in frequency of adrenocorticotrophic hormone (ACTH) deficiency was seen. Hyperprolactinemia related to damage to inhibitory neurons that control prolactin secretion can be seen after high-dose radiotherapy (>40 Gy); it has been described in both sexes and all age groups but is most common in young women. Hyperprolactinemia occurs with a described frequency ranging from 20% to 50% of patients with nasopharyngeal and brain irradiation.¹⁰ Hyperprolactinemia can cause delayed puberty in children, galactorrhea or amenorrhea in adult women, and decreased libido and impotence in men.

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

Thyroid

Irradiation of the thyroid may produce hypothyroidism, Graves disease, silent thyroiditis, benign nodules, and thyroid cancers.¹³ Hancock and colleagues described a series of patients with thyroid dysfunction among patients treated with irradiation with or without chemotherapy for Hodgkin disease at Stanford University.¹⁴ 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 healthy subjects. The risk of thyroid cancer was 15.6 times the expected risk for healthy subjects. These data remind clinicians to monitor 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 Hodgkin disease survivors (including 959 males). Among patients with Hodgkin disease, a 50% risk of hypothyroidism was found 20 years from the time of diagnosis in persons treated with 45 Gy or more.¹⁵ The total dose of irradiation received has been shown to correlate with the incidence of hypothyroidism in many studies.^15–15 However, controversy exists regarding the effect of age and gender at the time of irradiation.^15–15

Radiation-induced thyroid dysfunction is thought to be caused by damage to small thyroid vessels and to the glandular capsule. Histomorphologic features that are described in such patients include focal and irregular follicular hyperplasia, hyalinization, and fibrosis beneath the vascular endothelium; lymphocytic infiltration; single and multiple adenomas; and thyroid carcinomas.13,14

A rare complication of neck irradiation is acute radiation thyroiditis, which is more commonly associated with therapeutic doses of radioiodine for thyroid diseases. Patients typically have symptoms of 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 disease.¹⁴ The incidence is uncertain because of 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 that seen in persons with classic Graves disease.

Parathyroid Glands

Several studies link prior head and neck irradiation and hyperparathyroidism. Cohen and colleagues ¹⁶ followed a cohort of patients who were treated with radiation to the tonsils before the age of 16 years. Among the 2923 patients, 32 were found to have clinical hyperparathyroidism—a 2.5- to 2.9-fold increase compared with the general population in the same age group. A long latency period (>25 years) occurs between exposure and the onset of hyperparathyroidism. Parathyroid adenomas were found in most of the patients in whom this complication develops.¹⁷ Clinical presentations vary from asymptomatic increases in serum parathormone levels and hypercalcemia to disabling metabolic bone disease or nephrolithiasis. Persons with a history of head and neck radiation should be monitored with calcium levels periodically (every 1 to 2 years) and indefinitely.

Role of Systemic Therapy

Effects of systemic chemotherapy on ovarian and testicular function are discussed in Chapter 60.

Hypothalamic-Pituitary Axis

In children, chemotherapeutic agents without any cranial irradiation may disrupt growth hormone (GH) secretion. Roman and colleagues ¹⁸ studied growth and GH secretion in 60 children who were in complete remission after treatment with chemotherapy and surgery for solid tumors. They observed GH deficiency in 45% of those studied and found that the GHD group had received significantly higher doses of actinomycin D compared with the non-GHD group (P < .05). These investigators found no correlation with duration of treatment, length of follow-up, tumor type, sex, or age. Depending on the intensity of chemotherapy, significant height loss was detected in 40% to 70% of patients at 6-year follow-up. Adjuvant chemotherapy can also aggravate growth failure in children with brain tumors who receive craniospinal radiation.¹⁹ Rose and colleagues²⁰ reported hypothalamic dysfunction in patients with non–central nervous system tumors who received chemotherapy but did not receive cranial irradiation and had no history of traumatic brain injury. Of 31 identified patients, GHD was identified in 15 (48%), central hypothyroidism was identified in 16 (52%), and pubertal abnormalities was identified in 10 (32%). GHD and hypothyroidism were coexistent in eight patients (26%). Overall, 81% had GHD, hypothyroidism, precocious puberty, or gonadotropin deficiency.

The syndrome of inappropriate antidiuretic hormone (SIADH) secretion is associated with various malignant tumors including certain primary brain tumors, hematologic malignancies, intrathoracic nonpulmonary cancers, skin tumors, gastrointestinal cancers, gynecologic cancer, breast and prostatic cancer, and sarcomas.²¹ SIADH 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,²² whereas alkylating agents enhance renal tubular sensitivity to ADH.²³ 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. Case reports also implicate platinum agents,²⁴ vinorelbine,²⁵ taxanes,²⁶ and methotrexate.²⁷ Clinically significant hyponatremia may occur with administration of these agents, and management requires fluid restriction and, at times, salt replacement.

Thyroid

Clinically evident thyroid dysfunction has rarely been 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, following use of preparation regimens that do not include radiation. Thyroid dysfunction has been reported in as many as 50% of allogeneic bone marrow transplant recipients treated with busulfan and cyclophosphamide.²⁸ Thyroid dysfunction may appear as low T3 syndrome (i.e., normal levels of free T4 and TSH and a below-normal level of free T3), chronic thyroiditis, and transient subclinical hyperthyroidism or hypothyroidism. Chemotherapy may potentiate radiation-induced damage to normal tissue.

Newer biological agents, tyrosine kinase inhibitors, and immune-based cancer treatments (e.g., ipilimumab, interferon-α, and interleukin-2) have been associated with various types of thyroid dysfunction.29, 30 Box 61-3 summarizes the well-described adverse effects of cancer therapies on thyroid function.

Hypothyroidism is a recognized complication of treatment with 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 ³¹ reported hypothyroidism in patients undergoing sunitinib therapy. One potential mechanism may be sunitinib-induced destructive thyroiditis through follicular cell apoptosis. However, there is no explanation for the apparent sensitivity of thyroid tissue compared with other endocrine organs. Sunitinib inhibits the RET tyrosine kinase that is involved in pathogenesis of medullary thyroid cancer; however, the relationship between specific tyrosine kinase inhibition and the development of hypothyroidism is unclear.

Imatinib, an inhibitor of the bcr-abl tyrosine kinase, interacts with thyroid hormone replacement and results in increased TSH levels in persons with hypothyroidism who are being treated with levothyroxine. However, it does not appear to have a direct effect on the thyroid but alters the levels of thyroxine-binding protein.³²

Aminoglutethimide, which now is infrequently used to disrupt adrenal and peripheral steroid hormone synthesis, inhibits cholesterol conversion to pregnenolone. It causes thyroid dysfunction after long-term use as a result of the blockade of iodination of tyrosine.³³ Chemotherapeutic agents can also interfere with circulating thyroid hormone, thereby altering free blood levels. The drug 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. 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 and free T4 levels. Transient hyperthyroidism after l-asparaginase therapy for acute lymphoblastic leukemia has also been observed. These thyroid abnormalities are mild and short-lived and generally do not require specific therapy.³⁰

In postmenopausal women, tamoxifen therapy is associated with changes in thyroid hormone concentrations, although patients may remain clinically euthyroid. Mamby and colleagues ³⁴ evaluated the effect of tamoxifen, 10 mg orally, twice daily on the thyroid in a placebo-controlled trial. Thyroid function was examined before and 3 months after initiation of therapy. Serum thyroid-binding globulin increased, as did T4 uptake and T4 levels in the tamoxifen-treated group compared with the group that received a placebo. TSH levels and the free thyroxine index remained unchanged; patients were clinically euthyroid and did not require treatment.

Adrenal

Medical ablation of adrenal function has been extensively evaluated. Aminoglutethimide and ketoconazole both suppress adrenal function. These drugs appear to have their effect through the inhibition of important cytochrome P-450 isozymes, which are necessary for adrenal steroid synthesis.33,35 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 glucocorticoid replacement 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 and has potent antiadrenal effects. It is used primarily to treat adrenal hyperfunction associated with adrenal carcinoma or ectopic production of corticotrophin.³⁶ Although its mechanism of action is incompletely understood, adrenal necrosis and permanent adrenal insufficiency can result, necessitating lifelong glucocorticoid administration.

Abiraterone acetate, a pregnenolone analog, is a small molecule that irreversibly inhibits CYP17, a rate-limiting enzyme in androgen biosynthesis. It is approved for treatment of metastatic, castration-resistant prostate cancer. Abiraterone administration decreases the production of cortisol by blocking the activity of 17α hydroxylase. This process leads to increased production of ACTH after diminished negative feedback, which, in turn, stimulates production of steroid precursors above the 17α hydroxylase level. One of these precursors is corticosterone, which is only a weak inhibitor of ACTH. The increased production of corticosterone leads to fluid retention, hypokalemia, and hypertension. These effects can be prevented by concomitant administration of low doses of prednisone, corticosterone, or dexamethasone.³⁷

Pancreas

Pancreatic exocrine or endocrine insufficiency attributable to chemotherapy is uncommon. Although rare, cases of diabetes mellitus have been associated with l-asparaginase therapy.³⁸ Hyperglycemia is usually transient and responds to intravenous fluids and drug discontinuation. A plausible although unproven mechanism underlying this phenomenon may be inhibition of protein synthesis by l-asparaginase, leading to interference with insulin production. High triglyceride levels have also been associated with l-asparaginase use, although these changes are not clearly associated with an increased incidence of pancreatitis in such patients. The occurrence of pancreatitis seems to be independent of the individual or cumulative asparaginase dose.

High-dose cytarabine therapy can result in pancreatitis. Siemers and colleagues ³⁹ described two patients with evidence of pancreatitis among 30 patients treated with high-dose cytarabine.³⁹ Streptozotocin is a nitrosourea that is used primarily for the treatment of pancreatic endocrine tumors. In preclinical models in many species, streptozotocin causes β-cell necrosis and insulin-dependent diabetes.⁴⁰ Mild glucose intolerance has been described in patients receiving this agent; however, frank diabetes requiring specific treatment is rare.

Androgen ablation therapy may also be associated with diabetes. Keating and colleagues ⁴¹ reported an increased incidence of diabetes in patients with prostate cancer who were treated with GnRH agonists. A potential mechanism is the increase in body fat mass associated with hypogonadism, which results in insulin resistance.

Phosphatidyl inositol 3 kinase (PI3K) inhibitors, which are presently in clinical trials with promising results in persons with breast cancer, have been recognized to cause hyperglycemia. This effect is related to decreased glucose uptake by cells rather than any effect on insulin or glucagon secretion. Mammalian target of rapamycin (mTOR) inhibitors also produce hyperglycemia.⁴²

Role of Biological Agents

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

Immune therapies may cause thyroid dysfunction. Interleukin-2 therapy is associated with both hypothyroidism and hyperthyroidism, although the former is more common. In the original report by Atkins and colleagues,⁴³ 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. All five symptomatic patients had borderline or elevated serum antimicrosomal antibody titers after treatment; two had serum antibodies to thyroglobulin. The proposed mechanism is autoimmune with development of antithyroid antibodies.

Ipilimumab (anti–CTLA-4 antibody) has been shown to induce hypophysitis and result in immune-mediated hypopituitarism. In a recent phase 3 trial, nine patients treated with ipilimumab (1.8%) experienced severe or life-threatening hypopituitarism. Several other endocrine adverse effects including hypothyroidism, adrenal insufficiency, or hypogonadism were also noted. Primary thyroid disease may present as hyperthyroidism with Graves disease or as hypothyroidism as a result of destructive thyroiditis. Secondary hypothyroidism may result from decreased production of TSH as a result of hypophysitis and panhypopituitarism. Immune-mediated pancreatitis was also noted in the study. The median time to onset of endocrine symptoms was 11 weeks; delayed symptoms were observed in some patients even after completion of the intended four courses. Some of the endocrine dysfunction is thought to be reversible with cessation of therapy with ipilimumab. Limited data are available on the long-term sequelae of ipilimumab therapy.²⁹ Patients treated with ipilimumab should be monitored for clinical signs or symptoms associated with pituitary, thyroid, or adrenal disease. Baseline monitoring of TSH, repeated with every cycle of treatment, is recommended to detect hypothyroidism. Evaluation and testing for other endocrinopathies should be guided by clinical symptoms. Treatment includes hormone replacement therapy, corticosteroids, and cessation of ipilimumab based on the severity of the complication.⁴⁴

Interferon-α therapy may increase ACTH, prolactin, growth hormone, and cortisol levels.⁴⁵ An assessment of interferon-α–induced endocrine stimulation in patients with myeloproliferative disorders demonstrated 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. The acute stimulatory effect of interferon-α on cortisol release appears to be mediated by the release of hypothalamic corticotropin-releasing hormone. Alterations in the levels of sex hormones during interferon therapy have been reported, and male sexual dysfunction has been noted.⁴⁵

Clinicians should keep in mind that data are limited regarding the effects of many new agents, and one must be alert to endocrine dysfunction in patients receiving any agent with which experience is limited.

Evaluation and Treatment of Common Endocrine Dysfunction

A detailed history, including treatment history and physical examination, should be performed for 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 61-1 provides a brief outline of the evaluation of common endocrine disorders.

Table 61-1

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	IGF1, 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