Injury of the Hypothalamic Pituitary Axis in Patients with Cancer

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The hypothalamic-pituitary axis (HPA) is vulnerable to damage by certain tumors, surgical trauma, irradiation, and chemotherapy [11, 60]. A summary of common risk factors for HPA disorders that develop after cancer treatment is presented in Table 5.2. Patients with tumors in the area of the HPA (e.g. craniopharyngioma or hypothalamic/chiasmatic tumor) are at particular risk for neuroendocrinopathy [15, 33]. Many HPA injuries are attributable to damage caused by radiation therapy (see section 5.1.1.3). However, the incidence of pre-RT neuroendocrino-pathies in pediatric patients with brain tumors is high. For example, out of 68 pediatric patients in one study [32], 45 (66%) showed evidence of neuro-endocrinopathy before RT,including 15 of 32 patients with tumors in the posterior fossa not adjacent to the HPA. Seventeen of the 45 patients (38%) revealed abnormalities in GH, 19 (43%) in TSH and 10 (22%) in ACTH. Six patients (13%) had aberrations in

Table 5.2. Risk factors,diagnostic studies,and treatment options

Disorder

Highest risk

Diagnostic studies

Treatment options

GH deficiency

> 18 Gy CRT Pre-transplant CRT TBI

Young age Tumor near HPA Hydrocephalus

IGF-1, IGFBP-3 GH stimulation tests

Recombinant GH GHRH

GnRH agonist (if pubertal maturity too advanced for height)

Gonadotropin deficiency

> 30 Gy CRT Tumor near HPA

LH,FSH,estradiol,or testosterone (4 to 8 AM) Bone age

GnRH stimulation test

Estrogen / progestin (women) Testosterone (men)

Precocious puberty

18-24 Gy CRT Female Young age Tumor near HPA

LH, FSH, estradiol or testosterone (4 to 8 AM) Bone age radiograph Pelvic ultrasound (female) +/- GnRH stimulation test +/- GH stimulation test

GnRH agonist

Tumor near HPA Hydrocephalus

Free T4,TSH (8 AM) Nocturnal TSH surge TRH stimulation test

L-thyroxine

ACTH deficiency

> 30 Gy CRT Tumor near HPA Hydrocephalus

Cortisol (8 AM) Adrenal stimulation test

Hydrocortisone

Hyper-prolactinemia

> 50 Gy CRT Tumor near HPA

Prolactin

Dopamine agonists

Diabetes insipidus

Histiocytosis Germinomas Tumor or tumor-related cysts near HPA

Simultaneous serum and urine osmolarity after 8-12 hours without fluid intake

Desmopressin

Osteopenia

Low GH,TSH, or LH/FSH High prolactin

DEXA or quantitative CT

Calcium + vitamin D +/-bisphosphonates

Hypothalamic obesity

Young age (<6 years) > 50 Gy (hypothalamus) Tumor near HPA

Fasting insulin and glucose Oral glucose tolerance test with insulin levels

Diet and exercise Ritalin or Dexedrine Metformin (monitor for hypoglycemia) Octreotide

GH, growth hormone; CRT, cranial radiation therapy;TBI, total body irradiation; HPA, hypothalamic-pituitary axis; IGF-1, insulinlike growth factor 1; IGFBP3, IGF binding protein 3;GHRH,growth hormone-releasing hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; T4, thyroxine; TSH, thyroid-stimulating hormone; TRH, thyrotropin-releasing hormone; ACTH, adrenocorticotrophin gonadotropin. In addition to these dysfunctions, patients who receive chemotherapy alone (with no history of RT or CNS tumor) may be at risk for neu-roendocrinopathy. Of the 31 patients evaluated in one study for altered growth and development, 48 % had GH deficiency, 52 % had central hypothyroidism, and 32% had pubertal abnormalities [57].

GH deficiency is commonly believed to be the first hypothalamic-pituitary deficiency to emerge after injury to the HPA, followed by deficiencies of gonadotropin, ACTH and TSH [60,65]; however, these deficiencies can occur in any order [11,21,35,54,67]. Although the most common neuroendocrinologic abnormality in survivors of childhood cancer is GH deficiency, hypothyroidism is at least as prevalent when sensitive testing methods are used [54]. The next most common alteration is in pubertal timing (precocious, rapid, delayed, or absent). ACTH deficiency, although less common than the other disorders, has more serious consequences if it is not detected. Osteopenia may result from hypothalamic-pituitary deficiency, particularly GH deficiency, hypothyroidism and hypogonadism. Hypothalamic injury resulting from tumor, surgery, or irradiation can result in unrelenting weight gain, termed "hypothalamic obesity."

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