Hypothalamic–Pituitary and Growth Disorders in Survivors of Childhood Cancer

An Endocrine Society Clinical Practice Guideline

Charles A. Sklar; Zoltan Antal; Wassim Chemaitilly; Laurie E. Cohen; Cecilia Follin; Lillian R. Meacham; M. Hassan Murad

Disclosures

J Clin Endocrinol Metab. 2018;103(8):2761-2784. 

In This Article

Central Hypothyroidism–TSH Deficiency in Childhood Cancer Survivors

Epidemiology, Morbidity, and Mortality

The diagnosis of central hypothyroidism or TSH deficiency (TSHD) is complicated, and there is no uniform definition by which to make the diagnosis. Most endocrinologists diagnose TSHD in a patient recognized to be at risk for hypothalamic damage based on a low-normal or below-normal free T4 (fT4) level with a TSH level in the normal, below normal, or mildly elevated range.[146] The diagnosis is more likely when based on progressively declining fT4 levels over time.[147,148] In the context of this broad definition, studies have reported that the prevalence of TSHD in childhood cancer survivors who have CNS tumors or were treated with HP axis RT is 2.6% to 14.9%.[47,111,149–157] Symptoms are subtle, often delaying diagnosis.

Etiology

TSHD and ACTH deficiency (ACTHD) are among the least common anterior pituitary hormone deficits. TSHD is most often present after high-dose HP RT;[47,151] however, neither TSHD nor ACTHD is commonly present with doses <24 Gy or after TBI. A study of adult survivors of childhood cancer reported TSHD in 7.5% of participants with HP RT dose ≥30 Gy as an independent risk factor.[47] Clinicians should evaluate patients with tumors in the HP region for TSHD if they have had suprasellar surgery or other hypothalamic deficiencies.

Factors associated with TSHD include hypothalamic involvement, radiation site and dose, and time elapsed since radiation exposure.[111,150,152,156] In general, chemotherapeutic agents have not been associated with TSHD.[150,155]

Diagnosis of Central Hypothyroidism in Childhood Cancer Survivors

   5.1 We recommend lifelong annual screening for TSHD in childhood cancer survivors treated for tumors in the region of the HP axis and those exposed to ≥30 Gy HP radiation. (1∣⊕⊕⊕O)

   5.2 We advise using the same biochemical tests to screen for TSHD in childhood cancer survivors as are used in the noncancer population (Table 2). (Ungraded Good Practice Statement)

   5.3 We recommend against using serum triiodothyronine, TSH surge analysis, or thyrotropin-releasing hormone stimulation to diagnose TSHD. (1∣⊕⊕OO)

Evidence. Clinicians should obtain fT4 and TSH levels at least annually.[47,147,149,151,152] An fT4 level at the lower limits of normal or below the reference range in conjunction with a low, normal, or mildly elevated TSH level that does not appear appropriate for the fT4 level in the setting of disruption to the hypothalamus or pituitary is evidence of TSHD. The case for TSHD is made stronger with progressively decreasing fT4 levels.[148] TSHD can develop many years after radiation exposure, and for this reason we recommend lifelong surveillance.[158]

Previous data indicated that hidden central hypothyroidism was an early, subtle hypothalamic abnormality that clinicians could detect via the TSH surge pattern or TSH response to stimulation testing.[159] Subsequent research indicated that the abnormalities of TSH dynamics uncovered by TSH surge analysis and thyrotropin-releasing hormone stimulation testing represent subtle variations that are not indicative or predictive of TSHD.[160]

Treatment of TSHD in Childhood Cancer Survivors

   5.4 We advise using the same approach to treat TSHD in childhood cancer survivors as is used in the noncancer population (Table 2). (Ungraded Good Practice Statement)

Evidence. The treatment of central hypothyroidism in childhood cancer survivors is no different than in other children/adolescents with TSHD. The thyroid axis is one of the more resilient axes, and there is an increased risk of damage to other HP endocrine axes, which should be addressed. Clinicians should therefore perform regular, careful surveillance for GHD, full and partial ACTHD, and abnormalities of LH/FSH secretion in childhood cancer survivors who had RT, tumors, or surgery in the area around the hypothalamus and pituitary and who are diagnosed with TSHD.[13,147,149] Clinicians should confirm the existence of an intact adrenal axis before beginning thyroid hormone replacement, recheck fT4 levels 4 to 6 weeks after dose adjustment or starting GH replacement, and maintain fT4 levels in the middle to upper half of the normal range. TSH levels are not useful in monitoring the adequacy of thyroid hormone replacement in subjects with TSHD.[79,161] Many survivors at risk for TSHD are also at risk for seizures, and treatment with antiepileptic medications such as phenytoin, carbamazepine, oxcarbazepine, and topiramate can accelerate the metabolism of thyroid hormones. Consequently, clinicians should monitor thyroid hormone levels after starting or changing the dose of antiepileptics.[145,162] Commonly used fT4 assays, which use competitive binding methods, may give artifactually low fT4 levels in patients who are treated with antiepileptics (e.g., phenytoin, carbamazepine, oxcarbazepine) due to displacement of thyroid hormone from binding proteins.[163] Confirmation of the low fT4 level by a direct method, such as equilibrium dialysis or ultrafiltration, may be indicated in these patients.

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