**2.2 Growth Hormone (GH) deficiency**

#### **2.2.1 Epidemiology and pathophysiology**

GH deficiency is the earliest manifestation of neuro-endocrine injury following cranial irradiation. With intensive irradiation used for NPC, the cumulative frequency of GH deficiency is well above 60% after 5 years (Lam et al., 1991). Higher incidence of severe GH deficiency is seen with longer follow up periods reaching well above 80% (Samaan et al., 1987). Given the higher radiosensitivity of the GH axis, GH deficiency is almost always present if deficiencies of one or more of the other anterior pituitary hormones are confirmed. Studies of stimulated GH secretion in children treated for brain tumours indicate that almost all children treated with doses in excess of 35 Gy will have blunted GH secretion within 2-5 years of treatment (Clayton & Shalet, 1991). With the more intensive radiation used for NPC, all children treated for this condition will undoubtedly manifest features of severe GH deficiency soon after irradiation.

Apart from the higher radiosensitivity of the GH axis in children, the higher frequency of severe GH deficiency in children may be explained by the much higher threshold of peak GH response to stimulation used to diagnose GH deficiency in this age group. Children who have been categorised as having severe GH deficiency may in fact be categorised as having normal GH status when retested in adult life. This apparent discrepancy is not related to recovery of the GH axis, but can be attributed to the use of more strict thresholds for the diagnosis of GH deficiency in adults (Shalet et al., 1998).

GH is secreted in a pulsatile manner with a diurnal variation. The latter is characterised by nocturnal increase in GH secretion. This complex pattern of secretion is under hypothalamic control. Recent pathophysiological studies by the author et al of stimulated and spontaneous GH secretion in a cohort of adult cancer survivors irradiated for brain tumours with doses of less than 50 Gy, suggested that hypothalamic regulation of GH secretion in patients with severe GH deficiency is maintained with preserved pulsatility and diurnal variation (Darzy et al., 2005, 2006). The reduction in GH levels appears to be related to a predominant quantitative damage to the pituitary somatotrophs leading to reduced GH pulse amplitude but not frequency. Another study by the author et al (Darzy et al., 2007) has suggested the presence of a compensatory increase in hypothalamic GHRH release to maintain a normal spontaneous GH secretion in patients with reduced pituitary somatotrophs reserve indicated by reduced peak GH responses to direct stimulation with the most potent GHRH and Arginine stimulation test. There has also been a suggestion for the presence of 'compensated GH deficiency' in some patients who would otherwise have been diagnosed with GH deficiency due to impaired peak GH responses to insulin-induced

Endocrine Complications Following Radiotherapy

clinical context, i.e. previous irradiation.

**2.2.3 Clinical impact and treatment** 

Boer et al., 1995).

3- Osteopenia and Osteoporosis

9- Reduced quality of life (QoL) A- Reduced vitality B- Reduced energy C- Depressed mood D-Increased anxiety

E- Increased social isolation

5- Glucose intolerance and insulin resistance 6- Impaired fibrinolysis and nitric oxide generation

8- Reduced exercise capacity and muscle strength

F- Impaired emotional and self-control

Table 1. Features of the adult growth hormone deficiency syndrome.

7- Altered cardiac function and structure

and Chemotherapy for Nasopharyngeal Carcinoma 139

In addition to biochemical tests, auxological measurements of the irradiated child at regular intervals may provide invaluable information about the GH status. Growth in children is a sensitive marker of GH status. Thus, in the absence of other aetiologies for growth retardation, the presence of significant growth deviation over a one year period, that is, growth velocity below the 25th centile or a drop in height of ≥ 1 standard deviation (SD) is highly suggestive of clinically significant GH deficiency, particularly in the appropriate

GH deficiency is an important cause for impaired linear growth in irradiated children cured from cancer. Ample evidence from studies in brain tumour survivors suggests that GH therapy in those patients prevent further height loss and maintain their initial height centile to adulthood (Clayton et al., 1988; Sulmont et al., 1990) while those who do not receive treatment show further deterioration in their height centiles with a tendency for extreme short stature (Brauner et al., 1989; Clarson & Del Maestro, 1999). In addition, those patients may also need GH replacement therapy in the transition to adulthood to maximize bone density and prevent osteoporosis, which is a frequent finding in the irradiated cancer

In adults, GH deficiency may be associated with symptoms and signs of the well described adult GH deficiency syndrome (Table 1), in particular impaired quality of life (QoL) (de

GH replacement therapy in the irradiated adult cancer survivors may improve QoL, as in those with GH deficiency due to pituitary tumours (Murray et al., 2002). Thus, it is important that a robust diagnosis of radiation-induced GH deficiency is made so that appropriate GH replacement therapy can be introduced at the right time. Despite the numerous and proven benefits of GH replacement therapy in adults (Table 2), this is currently only recommended to primarily improve QoL. It is given on a trial basis with

survivors (Brennan et al., 2005; Murray et al., 1999; Shalet & Rosenfeld, 1998).

1- Increased fat mass (especially truncal) and increased waist/hip ratio 2- Reduced lean body mass (reduced muscle bulk and strength)

4- Adverse lipid profile (increased LDL and reduced HDL)

hypoglycaemia (Darzy et al., 2009). It is unknown if the dynamics of GH secretion in patients with GH deficiency following intensive irradiation for NPC, with high probability of hypothalamic damage, are similar to what has been described by the author in patients with history of less intensive irradiation.

#### **2.2.2 Diagnosis**

Given the pulsatile nature of GH secretion, a single estimation of GH level is meaningless for the biochemical confirmation of a suspected GH deficiency. Physiological tests of GH secretion, such 24-hour or nocturnal GH profiling are rarely used in routine clinical practice. In current clinical practice, the diagnosis of GH deficiency relies on demonstrating a subnormal peak GH response to pharmacological tests that provoke GH release due to direct stimulation of the pituitary somatotrophs or indirectly through stimulation of the hypothalamus. Various dynamic tests are used in clinical practice; the choice is largely influenced by the experience of the endocrine centre and to some extent by patient's requirement. The insulin tolerance test (ITT) remains the gold standard, especially in the irradiated patients (Lissett et al., 2001), unless contraindicated due to epilepsy or heart disease. Other tests that are commonly used in clinical practice include Glucagon stimulation test, Arginine stimulation test (AST), L-Dopa test, GHRH test and the GHRH+AST.

The cut-off peak GH threshold used to define GH status following various stimuli is arbitrarily defined (Hoffman et al., 1994; Shalet et al., 1998). In children, the peak GH response to the ITT or equipotent tests (Glucagon, AST, L-Dopa or GHRH) below which a child is considered to be suffering from GH deficiency has been gradually increased and currently most GH therapy would be considered, in the appropriate clinical context, if that child failed to achieve a peak GH response above 20mU/L (7g/L) (Shalet et al., 1998). In adults, however, severe GH deficiency for which GH replacement therapy may be considered is defined as a peak response to ITT or equipotent tests of less than 9mU/L (3g/L) (Growth Hormone Research Society, 1998) and less than 9g/L for the GHRH+AST (Aimaretti et al., 1998).

Additional support for diagnosing GH deficiency may be obtained from measuring GHdependent markers including insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3). It is to be noted, however, that age and gender-corrected IGF-I and/or IGFBP-3 levels are frequently normal in patients with documented radiation-induced GH deficiency defined by physiological and/or pharmacological tests (Achermann et al., 1998; Cicognani et al., 1999; Tillmann et al., 1998). Thus, it had been thought that neither of these markers can be used as a reliable index of the development of radiation-induced GH deficiency. In general, a reduction in age- and gender-corrected IGF-I levels by 2 standard deviation (SD) is supportive of a diagnosis of GH deficiency providing other causes that reduce IGF-I production have been excluded, such as malnutrition, hypothyroidism, renal failure, liver disease, or diabetes mellitus (Shalet et al., 1998). In patients with panhypoptuitarism, the diagnosis of GH deficiency is almost certain especially if IGF-I levels are significantly reduced and biochemical confirmation can almost always be achieved accurately with a single test.

hypoglycaemia (Darzy et al., 2009). It is unknown if the dynamics of GH secretion in patients with GH deficiency following intensive irradiation for NPC, with high probability of hypothalamic damage, are similar to what has been described by the author in patients

Given the pulsatile nature of GH secretion, a single estimation of GH level is meaningless for the biochemical confirmation of a suspected GH deficiency. Physiological tests of GH secretion, such 24-hour or nocturnal GH profiling are rarely used in routine clinical practice. In current clinical practice, the diagnosis of GH deficiency relies on demonstrating a subnormal peak GH response to pharmacological tests that provoke GH release due to direct stimulation of the pituitary somatotrophs or indirectly through stimulation of the hypothalamus. Various dynamic tests are used in clinical practice; the choice is largely influenced by the experience of the endocrine centre and to some extent by patient's requirement. The insulin tolerance test (ITT) remains the gold standard, especially in the irradiated patients (Lissett et al., 2001), unless contraindicated due to epilepsy or heart disease. Other tests that are commonly used in clinical practice include Glucagon stimulation test, Arginine stimulation test (AST), L-Dopa test, GHRH test and the

The cut-off peak GH threshold used to define GH status following various stimuli is arbitrarily defined (Hoffman et al., 1994; Shalet et al., 1998). In children, the peak GH response to the ITT or equipotent tests (Glucagon, AST, L-Dopa or GHRH) below which a child is considered to be suffering from GH deficiency has been gradually increased and currently most GH therapy would be considered, in the appropriate clinical context, if that child failed to achieve a peak GH response above 20mU/L (7g/L) (Shalet et al., 1998). In adults, however, severe GH deficiency for which GH replacement therapy may be considered is defined as a peak response to ITT or equipotent tests of less than 9mU/L (3g/L) (Growth Hormone Research Society, 1998) and less than 9g/L for the GHRH+AST

Additional support for diagnosing GH deficiency may be obtained from measuring GHdependent markers including insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3). It is to be noted, however, that age and gender-corrected IGF-I and/or IGFBP-3 levels are frequently normal in patients with documented radiation-induced GH deficiency defined by physiological and/or pharmacological tests (Achermann et al., 1998; Cicognani et al., 1999; Tillmann et al., 1998). Thus, it had been thought that neither of these markers can be used as a reliable index of the development of radiation-induced GH deficiency. In general, a reduction in age- and gender-corrected IGF-I levels by 2 standard deviation (SD) is supportive of a diagnosis of GH deficiency providing other causes that reduce IGF-I production have been excluded, such as malnutrition, hypothyroidism, renal failure, liver disease, or diabetes mellitus (Shalet et al., 1998). In patients with panhypoptuitarism, the diagnosis of GH deficiency is almost certain especially if IGF-I levels are significantly reduced and biochemical confirmation can almost always be achieved accurately with a

with history of less intensive irradiation.

**2.2.2 Diagnosis** 

GHRH+AST.

(Aimaretti et al., 1998).

single test.

In addition to biochemical tests, auxological measurements of the irradiated child at regular intervals may provide invaluable information about the GH status. Growth in children is a sensitive marker of GH status. Thus, in the absence of other aetiologies for growth retardation, the presence of significant growth deviation over a one year period, that is, growth velocity below the 25th centile or a drop in height of ≥ 1 standard deviation (SD) is highly suggestive of clinically significant GH deficiency, particularly in the appropriate clinical context, i.e. previous irradiation.
