Endocrine Complications

Hypothalamic-Pituitary Axis

Anterior pituitary damage can result from irradiation of extracranial or intracranial 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. 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.

Data indicate that the hypothalamus is more radiosensitive to ionizing radiation than the pituitary. Damage to the hypothalamus leads to secondary pituitary atrophy that develops as a result of impaired secretion of hypothalamic trophic and regulatory factors; of course, direct injury to the pituitary may also occur. This risk 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 [GH]) are the pituitary cells most vulnerable to radiation damage, and growth hormone deficiency (GHD) is the endocrine abnormality most commonly seen after cranial irradiation. GHD may occur in isolation after hypothalamic-pituitary axis irradiation, even with doses lower than 30 Gy. Reduction in growth velocity and short stature are the clinical manifestations of GHD most evident in the growing child. Although poor linear growth is very common in children with GHD, it is not universal or immediately apparent. Several studies have suggested that the slowing of growth might not occur for the first year or two after the onset of GHD. In postpubertal individuals, GHD is associated with a decrease in muscle mass along with an increase in adiposity.

Hypothalamic neurons secrete gonadotropin-releasing hormone (GnRH) in pulses, and such pulses are necessary for normal secretion of gonadotropins from the pituitary. The extent of disruption of GnRH pulses is related to the dose of irradiation administered. A dose greater than 30 Gy is associated with delayed sexual maturation because of gonadotropin deficiency from damage to GnRH secretory neurons. Doses as low as 12 Gy are reported to impair GH or gonadotrophin release. Merchant and colleagues have reported that GHD is likely to result within 36 months in patients receiving 20-Gy or higher doses of irradiation. Precocious puberty may result in both males and females after doses lower than 30 Gy, though is more commonly seen in females. At higher doses (between 30 and 50 Gy) delayed puberty and short stature is more likely in both genders. Radiation-induced precocious puberty is hypothesized to result from damage to inhibitory γ-aminobutyric acid–producing (GABAergic) neurons, leading to disinhibition and premature activation of GnRH neurons. Deficiency in other pituitary hormones is less common than disruption of GH or GnRH secretion. Littley and colleagues described 251 patients who had been treated for pituitary disease with external radiotherapy. Five years after completion of treatment, they noted a 9% dose-related incidence of thyroid-stimulating hormone (TSH) deficiency at 20 Gy; this rate increased to 52% at 42 to 45 Gy. A similar trend in frequency of adrenocorticotropic 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 at a frequency ranging from 20% to 50% among patients receiving nasopharyngeal and brain irradiation. 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, or silent thyroiditis and can lead to benign thyroid nodules or thyroid cancer. 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. Of 1787 patients, 1677 received irradiation to the thyroid. At 26 years of follow-up, the actuarial risk of thyroid disease was 67%. Hypothyroidism was the most common manifestation of thyroid dysfunction in these patients. 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, 50% had hypothyroidism 20 years after completion of therapy in persons treated with 45 Gy or more. The total dose of irradiation received has been shown to correlate with the incidence of hypothyroidism in many studies. However, controversy exists regarding the effect of age and gender at the time of irradiation.

Radiation-induced thyroid dysfunction is thought to be caused by damage to small thyroid vessels and to the glandular capsule. Histologic abnormalities 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.

A rare complication of neck irradiation is acute radiation thyroiditis. This is more commonly associated with therapeutic doses of radioiodine for thyroid diseases. Patients typically have fever, pain in the anterior neck, and transient hyperthyroidism. Hyperthyroidism with a clinical picture that resembles Graves disease may be seen after neck irradiation for Hodgkin disease. 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 the formation of autoantibodies, as is the case in persons with classic Graves disease.

Parathyroid Glands

Several studies link prior head and neck irradiation and hyperparathyroidism. Cohen and colleagues 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 (up to 25 years) may occur between exposure and the onset of hyperparathyroidism. Parathyroid adenomas were found in most of the patients in whom this complication developed. Clinical presentations vary from asymptomatic increases in serum parathormone levels to the development of hypercalcemia, disabling metabolic bone disease, and/or nephrolithiasis. Persons with a history of head and neck radiation should be monitored with calcium levels every 1 to 2 years, indefinitely.

Hypothalamic-Pituitary Axis

In children, chemotherapeutic agents alone may disrupt GH secretion. 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.

They found 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 occurred 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. Rose and colleagues 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 were 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 lung or nonpulmonary cancers, skin tumors, gastrointestinal cancers, gynecologic cancers, breast and prostatic cancers, and sarcomas. 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 stimulate the central release of ADH from the neurohypophyseal system, whereas alkylating agents enhance renal tubular sensitivity to ADH. Regardless of the pathway to disrupted control of ADH function, 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, vinorelbine, taxanes, and methotrexate. Management requires fluid restriction and, at times, salt replacement and diuretic-induced diuresis. Recent development of vasopressin antagonists provides an additional treatment option; tolvaptan is a nonpeptide, arginine vasopressin V2 receptor antagonist that has proven effective and safe in the treatment of patients with SIADH that is refractory to standard measures. Demeclocycline is a tetracycline antibiotic that interferes with renal tubular adenylyl cyclase activation and hence also counteracts the effect of ADH on the renal tubule. No comparative studies of tolvaptan and demeclocycline are available. In small series, both are safe and effective in refractory SIADH.

Thyroid

Historically, significant 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. Even more striking is the increasing frequency with which thyroid dysfunction is seen after the use of immune potentiating agents, interleukin-2 (IL-2), programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors such as pembrolizumab and nivolumab, and, especially, antagonists of cytotoxic T-cell antigen 4 (CTLA4 antagonists). These agents may induce a wide range of endocrine abnormalities, with most appearing to be associated with the induction of antibodies that induce inflammation, initial hyperfunction of the affected gland, or destruction and reduced function. These processes may affect the pituitary and thyroid glands, and more rarely the adrenals or endocrine pancreas. Although adrenal and pancreatic dysfunction are rare, thyroid and pituitary changes with anti-CTLA4 antibodies have been described in as many as 5% to 15% of patients receiving these agents.

Thyroid dysfunction may appear as low triiodothyronine (T ₃ ) syndrome (i.e., normal levels of free levothyroxine [T ₄ ] and TSH and a below-normal level of free T ₃ ), chronic thyroiditis, and transient subclinical hyperthyroidism or hypothyroidism. Chemotherapy may potentiate radiation-induced damage to normal tissue; Box 46.3 summarizes the well-described adverse effects of cancer therapies on thyroid function. Hypothyroidism is a recognized complication of treatment with tyrosine kinase inhibitors such as sunitinib maleate, an inhibitor approved for the treatment of gastrointestinal stromal tumors and renal cell carcinoma. Desai and colleagues 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, increases the levels of T ₄ -binding protein and in patients with hypothyroidism receiving T ₄ replacement therapy may result in reduced levels of free thyroid hormone and increased TSH levels. However, it does not appear to have a direct effect on the thyroid. 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. Chemotherapeutic agents can also interfere with circulating thyroid hormone, thereby altering free blood levels. The drug 5-fluorouracil increases total T ₃ and T ₄ levels, but free T ₄ index and TSH remain normal, indicating increased levels of T ₄ -binding globulin or enhanced binding capacity. l -Asparaginase causes transient T ₄ -binding globulin deficiency by diminishing hepatic synthesis and also inhibits TSH secretion from the pituitary, resulting in decreased total T ₄ and free T ₄ 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. In postmenopausal women, tamoxifen therapy is associated with changes in thyroid hormone concentrations, although patients may remain clinically euthyroid. Mamby and colleagues 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 T ₄ uptake and T ₄ levels in the tamoxifen-treated group compared with the group that received a placebo. TSH levels and the free T ₄ index remained unchanged; patients were clinically euthyroid and did not require treatment.