GH deficiency (GHD) is the most common, and often the only, anterior pituitary hormone deficit following radiotherapy that includes the HPA in the radiation field. In a recent study of 748 long-term adult survivors of childhood cancer treated with cranial radiotherapy (including survivors of acute lymphoblastic leukemia and CNS tumors), the prevalence estimate of GHD was 46.5% (95%CI, 42.9–50.2%) (Chemaitilly et al. 2015a). The risk of GHD is even higher in cohorts of brain tumor survivors (Laughton et al. 2008). Based on the results of one study in 192 pediatric patients with localized brain tumors, a cumulative radiation dose of 16.1 Gy to the hypothalamus was determined to be the mean dose required to achieve a 50% risk of GHD at 5 years (Merchant et al. 2011).

Despite being common, however, GHD is not the only contributor to poor linear growth during childhood, especially during active cancer therapy when confounding factors such as poor nutrition and the use of glucocorticoids may also be present. Years after radiation therapy, concomitant endocrinopathies such as hypothyroidism and pubertal disorders may also affect height and growth velocity. Furthermore, final adult height in children with GHD may be negatively impacted by having received concomitant spine radiotherapy, which can directly damage the vertebral epiphyses and lead to disproportionate growth (upper/lower segment ratio < 0.9; arm span more than 5 cm > height; sitting height standard deviation < standing height standard deviation) (Fig. 31.2) (Diller et al. 2009; Shalet et al. 1987; Clayton and Shalet 1991; Edgar et al. 2009; Meacham 2003).

The clinical presentation and diagnosis of GHD is reviewed in more detail elsewhere and is primarily based on auxological criteria (Growth Hormone Research Society 2000; Stanley 2012). In general, GHD classically manifests as a subnormal growth velocity (normal is >5 cm/year in prepubertal children) associated with a crossing of height percentiles. The bone age X-ray (plain radiograph of the left arm and wrist that assesses skeletal maturity via a comparison of the epiphyses with age-matched standards) is typically delayed for the child’s chronologic age, and the insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGF-BP3) are characteristically low for age and pubertal status. GH provocative testing is frequently utilized to confirm a diagnosis of GHD, and in fact is often required by third-party payors despite issues with reliability and reproducibility.

There are some notable exceptions regarding the presentation of GHD in the child who has received irradiation. First is that plasma IGF-1 and IGF-BP3 levels are not always reliable screening tests for GHD in children exposed to CNS radiation as they may be normal in individuals with a diagnosis proven by provocative testing (Weinzimer et al. 1999). Second, GHD may occur concomitantly with premature sexual maturation in a large number of pediatric cancer survivors (Figs. 31.1 and 31.2) (Sklar and Constine 1995), and therefore the bone age may not be delayed or may even be advanced; obesity and previous chemotherapy exposure (e.g., treatment with retinoic acid) may also influence the bone age in this fashion (Hobbie et al. 2011; Russell et al. 2001). Third, growth velocity may be normal in the child with profound GHD and concomitant CPP or obesity (Edgar et al. 2009). Finally, GHD may be partial and may be manifested only by a diminished pubertal growth spurt (Meacham 2003).

The treatment of GHD in childhood generally involves the use of daily subcutaneous injections of recombinant human GH, which in turn can improve final height outcome (Diller et al. 2009; Gleeson et al. 2003; Ciaccio et al. 2010), although children treated with radiotherapy may never fully achieve their genetic height potential (Beckers et al. 2010). Given the proliferative and pro-mitogenic properties of GH and IGF-1, the safety of GH therapy in individuals with a history of cancer has been an area of concern. Recent studies have not identified a clear risk from GH therapy, specifically as relates to the development of second CNS neoplasms (Patterson et al. 2014), and current understanding is that it is safe to prescribe GH to the pediatric cancer survivor as early as 1 year after cancer therapy is complete (Raman et al. 2015).

Puberty is characterized by the development of sex-specific secondary sexual characteristics, accelerated growth, and ultimately fusion of the growth plates and cessation of linear growth. In girls, breast development is the first sign of puberty whereas in boys, it is testicular enlargement with the possible and notable exception of those concurrently exposed to gonadotoxic therapies. CPP, commonly defined as pubertal onset before age 8 in girls and 9 in boys, arises from the premature activation of the hypothalamic-pituitary-gonadal axis and, if untreated, may cause a final adult height significant shorter than is genetically predetermined. LH and FSH deficiencies become apparent when the child has delayed entrance into puberty (>age 13 in girls or >age 14 in boys), delayed menarche (>age 16 in girls), or develops hypogonadotropic hypogonadism (amenorrhea in girls, low testosterone levels in boys with inappropriately low or normal LH/FSH levels) after puberty has begun. The diagnosis and treatment of pubertal disorders is more comprehensively reviewed elsewhere (Chen and Eugster 2015; Palmert and Dunkel 2012).

Cranial radiation is a significant risk factor for dysfunctional gonadotropin secretion (Diller et al. 2009; Laughton et al. 2008; Gleeson and Shalet 2004; Gan et al. 2015; Edgar et al. 2009; Meacham 2003; Stephen et al. 2011; Oberfield et al. 1996; Armstrong et al. 2009a). CPP may occur following treatment with a wide range of cranial radiotherapy doses, especially >20–25 Gy (Gleeson and Shalet 2004; Muller 2002; Ogilvy-Stuart et al. 1994), with younger age at radiotherapy conferring the highest risk of CPP (Oberfield et al. 1996; Ogilvy-Stuart et al. 1994; Lannering et al. 1997). Patients who develop CPP following radiation doses exceeding 30 Gy have a significant risk of ultimately developing LH/FSH deficiencies (Constine et al. 1993; Toogood 2004; Brauner et al. 1984) (Fig. 31.1). The timing of menarche can also be impacted by irradiation, especially when treatment is received at ages younger than age 5, and both early and late menarche can occur (Armstrong et al. 2009b; Chow et al. 2008).

In pediatric cancer survivors, the clinical presentation of CPP can pose distinct challenges. As mentioned above, CPP can mask co-occurring GHD by inducing seemingly normal growth rates at the expense of rapid bone age advancement, leading to reduced adult height (Figs. 31.1 and 31.2). Importantly, increasing testicular volume, which is the hallmark of pubertal entrance in boys, may not be reliable in the identification of pubertal onset in male childhood cancer survivors who received cytotoxic chemotherapy or direct testicular radiation; thus a high index of suspicion and measurement of LH/FSH and testosterone levels supplement the physical exam (Armstrong et al. 2009a; Quigley et al. 1989). Plasma estradiol and gonadotropin levels and/or uterine length measurements using pelvic ultrasound may likewise be helpful in determining the pubertal status of a subset of girls.

Deficiency of TSH secretion results in insufficient stimulation of thyroid follicular cells and resultant low circulating thyroxine levels, which can cause typical signs and symptoms of hypothyroidism in children, including decreased growth velocity, delayed skeletal maturation, constipation, skin dryness, and constitutional symptoms such fatigue and cold intolerance. The main risk factor associated with TSH deficiency is HPA exposure to radiation doses ≥30 Gy (Chemaitilly et al. 2015a; Laughton et al. 2008; Rose et al. 1999). As there is no widely available provocative testing, the diagnosis of central hypothyroidism is made by documenting a serum-free thyroxine level below the lab-specific normal range in the presence of a low, inappropriately normal, or minimally elevated serum TSH level. The evolution of TSH deficiency can be prolonged and the diagnosis difficult to make; often, the downward trend in thyroxine levels can help to alert the clinician to the diagnosis (Darzy 2009).

The hypothalamic-pituitary-adrenal axis, although more resilient, can also be damaged by the effects of irradiation. ACTH deficiency causes low serum cortisol levels through gradual atrophy of the adrenal cortex, and central adrenal insufficiency can present with symptoms of anorexia/nausea, weakness, fatigue, and unintentional weight loss. Aldosterone production is not under the direct control of ACTH and so hyperkalemia and salt wasting are not components of ACTH deficiency although symptomatic hypotension can occur during episodes of acute physiological stress when the compensatory secretion of cortisol fails to occur. The main risk factor for central adrenal insufficiency is HPA exposure to radiation doses exceeding 30–40 Gy (Chemaitilly et al. 2015a; Laughton et al. 2008; Rose et al. 2005; Patterson et al. 2009). The diagnosis of ACTH deficiency is usually made after cosyntropin stimulation (Chrousos et al. 2009), as random morning plasma ACTH and cortisol levels may be unreliable (Patterson et al. 2009). ACTH deficiency can also be partial, and some patients may require only stress steroid coverage instead of commencing daily glucocorticoid replacement (Darzy 2009). Although one of the least common endocrine sequelae of CNS irradiation, central adrenal insufficiency is nonetheless an important entity to recognize given the potential life-threatening consequences of untreated cortisol deficiency, especially during acute illness.