Radiation-induced hypopituitarism.

PURPOSE OF REVIEW: Progressive and irreversible neuro-endocrine dysfunction following radiation-induced damage to the hypothalamic-pituitary (h-p) axis is the most common complication in cancer survivors with a history of cranial radiotherapy involving the h-p axis and in patients with a history of conventional or stereotactic pituitary radiotherapy for pituitary tumours. This review examines the controversy about the site and pathophysiology of radiation damage while providing an epidemiological perspective on the frequency and pattern of radiation-induced hypopituitarism. RECENT FINDINGS: Contrary to the previously held belief that h-p axis irradiation with doses less than 40 Gy result in a predominant hypothalamic damage with time-dependent secondary pituitary atrophy, recent evidence in survivors of nonpituitary brain tumours suggests that cranial radiation causes direct pituitary damage with compensatory increase in hypothalamic release activity. Sparing the hypothalamus from significant irradiation with sterteotactic radiotherapy for pituitary tumours does not appear to reduce the long-term risk of hypopituitarism. SUMMARY: Radiation-induced h-p dysfunction may occur in up to 80% of patients followed long term and is often associated with an adverse impact on growth, body image, skeletal health, fertility, sexual function and physical and psychological health. A detailed understanding of pathophysiological and epidemiological aspects of radiation-induced h-p axis dysfunction is important to provide targeted and reliable long-term surveillance to those at risk so that timely diagnosis and hormone-replacement therapy can be provided.

Hypopituitarism following Radiotherapy Revisited.

Neuroendocrine disturbances in anterior pituitary hormone secretion are common following radiation damage to the hypothalamic-pituitary (H-P) axis, the severity and frequency of which correlate with the total radiation dose delivered to the H-P axis and the length of follow-up. The somatotropic axis is the most vulnerable to radiation damage and GH deficiency remains the most frequently seen endocrinopathy. Compensatory hyperstimulation of a partially damaged somatotropic axis may restore normality of spontaneous GH secretion in the context of reduced but normal stimulated responses in adults. At its extreme, endogenous hyperstimulation may limit further stimulation by insulin-induced hypoglycaemia resulting in subnormal GH responses despite the normality of spontaneous GH secretion. In children, failure of the hyper-stimulated partially damaged H-P axis to meet the increased demands for GH during growth and puberty may explain what has previously been described as radiation-induced GH neurosecretory dysfunction and, unlike in adults, the insulin tolerance test remains the gold standard for assessing H-P functional reserve. With low radiation doses (<30 Gy) GH deficiency usually occurs in isolation in about 30% of patients, while with radiation doses of 30-50 Gy, the incidence of GH deficiency can reach 50-100% and long-term gonadotropin, TSH and ACTH deficiencies occur in 20-30, 3-9 and 3-6% of patients, respectively. With higher dose cranial irradiation (>60 Gy) or following conventional irradiation for pituitary tumours (30-50 Gy), multiple hormonal deficiencies occur in 30-60% after 10 years of follow-up. Precocious puberty can occur after radiation doses of <30 Gy in girls only, and in both sexes equally with a radiation dose of 30-50 Gy. Hyperprolactinaemia, due to hypothalamic damage is mostly seen in young women after high dose cranial irradiation and is usually subclinical. H-P dysfunction is progressive and irreversible and can have an adverse impact on growth, body image, sexual function and quality of life. Regular testing is advised to ensure timely diagnosis and early hormone replacement therapy.

Radiation-induced hypopituitarism after cancer therapy: who, how and when to test.

Subtle to frank abnormalities in hypothalamic-pituitary axis function are frequently seen in cancer survivors who have received prophylactic or therapeutic cranial irradiation. The growth hormone (GH) axis is the most vulnerable to radiation damage, and isolated GH deficiency can occur after doses as low as 18 Gy. Furthermore, the frequency of GH deficiency can reach 50-100% within 3-5 years of cranial irradiation with doses of 30-50 Gy. TSH and adrenocorticotropic hormone deficiency occur in 3-6% of patients after conventional irradiation (30-50 Gy). Abnormalities in gonadotropin secretion are dose-dependent: gonadotropin deficiency is seen only after doses of 30 Gy or more, whereas lower doses usually lead to precocious puberty. Hyperprolactinemia predominantly occurs in young women after intensive irradiation and is usually subclinical. The frequencies of gonadotropin, adrenocorticotropic hormone and TSH deficiencies substantially increase with intensive irradiation (greater than 60 Gy) and after conventional irradiation for pituitary tumors, with a cumulative incidence of 30-60% after 10 years. The irreversible and progressive nature of radiation-induced anterior-pituitary hormone deficiencies and their adverse effect on body image, growth, sexual function, skeletal health and quality of life makes it essential that cancer survivors are tested regularly to ensure appropriate diagnosis and timely hormone replacement therapy.

Cranially irradiated adult cancer survivors may have normal spontaneous GH secretion in the presence of discordant peak GH responses to stimulation tests (compensated GH deficiency).

CONTEXT: We have previously demonstrated that spontaneous (physiological) GH secretion was entirely normal in cranially irradiated patients who had normal individual peak GH responses to the insulin tolerance test (ITT) but reduced maximal somatotroph reserve as indicated by substantially reduced group GH responses to the GHRH + arginine stimulation test (AST). The normality of spontaneous GH secretion was attributed to a compensatory increase in hypothalamic stimulatory input within a partially damaged hypothalamic-pituitary (h-p) axis. It is unknown, however, if such compensatory stimulation can also maintain normality of GH secretion in those who fail the ITT but pass the GHRH + AST. STUDY SUBJECTS AND DESIGN: We studied 24-h spontaneous GH secretion by 20-min sampling both in the fed state (n = 11) and in the last 24 h of a 33-h fast (n = 9) in adult cancer survivors with subnormal peak GH responses to the ITT but either normal or relatively less attenuated peak GH responses to the GHRH + AST. The study was conducted 8.3 +/- 1.8 (range 2-23) years after cranial irradiation for nonpituitary brain tumours (n = 9) or leukaemia/lymphoma (n = 2) in comparison with 30 normal controls (fasting, 14). RESULTS: Previously published diagnostic thresholds for the ITT, GHRH + AST and spontaneous GH secretion were used to characterize GH secretion. Four of the 11 patients with impaired stimulated responses to both tests showed only minor discordancies between stimulated and spontaneous GH secretion. Two of the remaining seven patients had subnormal spontaneous GH secretion. However, spontaneous GH secretion, both individually and as a group, was entirely normal in the remaining five patients who had impaired GH responses to the ITT but normal individual responses to the GHRH + AST; in these five patients, IGF-I standard deviation scores (SDS; -2.7 to -0.8) were significantly reduced to a moderate degree compared with normals. CONCLUSIONS: In cranially irradiated adult cancer survivors, it cannot be assumed that failure to pass the ITT in isolation reflects severe GH deficiency (GHD). It appears that in some patients near-maximal compensatory overdrive of the partially damaged somatotroph axis may result in near-normal quantitative restoration of spontaneous GH secretion, thus limiting further stimulation with the ITT to the extent that impaired GH responses can be seen even before spontaneous GH secretion starts to decline in adults. However, IGF-I status continues to provide useful information about the adequacy of the compensatory process and therefore the degree of normality of GH secretion.

Hypopituitarism following radiotherapy.

Deficiencies in anterior pituitary hormones secretion ranging from subtle to complete occur following radiation damage to the hypothalamic-pituitary (h-p) axis, the severity and frequency of which correlate with the total radiation dose delivered to the h-p axis and the length of follow up. Selective radiosensitivity of the neuroendocrine axes, with the GH axis being the most vulnerable, accounts for the high frequency of GH deficiency, which usually occurs in isolation following irradiation of the h-p axis with doses less than 30 Gy. With higher radiation doses (30-50 Gy), however, the frequency of GH insufficiency substantially increases and can be as high as 50-100%. Compensatory hyperstimulation of a partially damaged h-p axis may restore normality of spontaneous GH secretion in the context of reduced but normal stimulated responses; at its extreme, endogenous hyperstimulation may limit further stimulation by insulin-induced hypoglycaemia resulting in subnormal GH responses despite normality of spontaneous GH secretion in adults. In children, failure of the hyperstimulated partially damaged h-p axis to meet the increased demands for GH during growth and puberty may explain what has previously been described as radiation-induced GH neurosecretory dysfunction and, unlike in adults, the ITT remains the gold standard for assessing h-p functional reserve. Thyroid-stimulating hormone (TSH) and ACTH deficiency occur after intensive irradiation only (>50 Gy) with a long-term cumulative frequency of 3-6%. Abnormalities in gonadotrophin secretion are dose-dependent; precocious puberty can occur after radiation dose less than 30 Gy in girls only, and in both sexes equally with a radiation dose of 30-50 Gy. Gonadotrophin deficiency occurs infrequently and is usually a long-term complication following a minimum radiation dose of 30 Gy. Hyperprolactinemia, due to hypothalamic damage leading to reduced dopamine release, has been described in both sexes and all ages but is mostly seen in young women after intensive irradiation and is usually subclinical. A much higher incidence of gonadotrophin, ACTH and TSH deficiencies (30-60% after 10 years) occur after more intensive irradiation (>60 Gy) used for nasopharyngeal carcinomas and tumors of the skull base, and following conventional irradiation (30-50 Gy) for pituitary tumors. The frequency of hypopituitarism following stereotactic radiotherapy for pituitary tumors is mostly seen after long-term follow up and is similar to that following conventional irradiation. Radiation-induced anterior pituitary hormone deficiencies are irreversible and progressive. Regular testing is mandatory to ensure timely diagnosis and early hormone replacement therapy.

Cranial irradiation and growth hormone neurosecretory dysfunction: a critical appraisal.

CONTEXT: It has been suggested that radiation-induced GH neurosecretory dysfunction exists in children; however, the pathophysiology is poorly understood, and it is unknown if such a phenomenon exists in adult life. STUDY SUBJECTS: Twenty-four-hour spontaneous GH secretion was studied by 20-min sampling both in the fed state (n = 16; six women) and the last 24 h of 33-h fast (n = 10; three women) in adult cancer survivors of normal GH status defined by two GH provocative tests, 13.1 +/- 1.6 (range, 3-28) yr after cranial irradiation (18-40 Gy) for nonpituitary brain tumors (n = 12) or leukemia (n = 4) in comparison with 30 (nine women) age- and body mass index-matched normal controls (fasting, 11 men and three women). RESULTS: Using previously published diagnostic thresholds, all patients had stimulated peak GH responses in the normal range to both the insulin tolerance test and the combined GHRH plus arginine stimulation test, as well as normal individual mean profile GH levels during the fed and fasting states. However, gender-specific comparisons revealed marked reduction (by 40%) in the overall peak GH responses to both provocative tests but similar GH secretory profiles; no differences were seen in the pulsatile attributes of GH secretion (cluster analysis) or the profile absolute and mean GH levels in the fed state or when the hypothalamic-pituitary axis was stimulated by fasting. CONCLUSIONS: Radiation-induced GH neurosecretory dysfunction either does not exist or is a very rare phenomenon in irradiated adult cancer survivors. The normality of physiological GH secretion in the context of reduced maximum somatotroph reserve suggests compensatory overdrive of the partially damaged somatotroph axis and constitutes a relative argument against somatotroph dysfunction being explained purely by hypothalamic damage with secondary atrophy due to GHRH deficiency. It is therefore possible that radiation in doses less than 40 Gy causes dual damage to both the pituitary and the hypothalamus.

Pathophysiology of radiation-induced growth hormone deficiency: efficacy and safety of GH replacement.

Radiation-induced growth hormone deficiency (GHD) is primarily due to hypothalamic damage. GH secretion by the pituitary may be affected either secondary to some degree of quantitative deprivation of hypothalamic input or, if the radiation dose is high enough, by direct pituitary damage. As a consequence, the neurosecretory profile of GH secretion in an irradiated patient remains pulsatile and qualitatively intact. The frequency of pulse generation is unaffected, but the amplitude of the GH pulses is markedly reduced. Over the last 25 years, the final heights achieved by children receiving GH replacement for radiation-induced GHD have improved; these improvements are attributable to refinements in GH dosing schedules, increased use of GnRH analogues for radiation-induced precocious puberty, and a reduced time interval between completion of irradiation and initiation of GH therapy. When retested at the completion of growth, 80-90% of these teenagers are likely to prove severely GH deficient and, therefore, will potentially benefit from GH replacement in adult life. Such long-term GH treatment in patients treated previously for a brain tumor means that critical and continuous surveillance must be devoted to the risk of tumor recurrence and the possibility of second neoplasms.

The impact of short-term fasting on the dynamics of 24-hour growth hormone (GH) secretion in patients with severe radiation-induced GH deficiency.

CONTEXT: In patients with severe radiation-induced GH deficiency, we previously demonstrated that pulsatile GH secretion and diurnal rhythm are maintained in the fed state, albeit with great attenuation of the pulse amplitude. However, it remained unclear whether stressing the hypothalamic-pituitary axis could unmask neurosecretory dysregulation that is not seen under basal conditions. In addition, the impact of fasting on GH pulsatility and diurnal variation in GH-deficient patients has not been studied in detail before. STUDY SUBJECTS AND DESIGN: Twenty-four-hour GH profiles at 20-min intervals were undertaken in the fed state and in the last 24 h of a 33-h fast in eight young adult cancer survivors (two women) with severe GH deficiency after cranial irradiation for nonpituitary brain tumors in childhood and 14 matched normal controls (three women). A sensitive chemiluminescence GH assay was used with cluster analysis. RESULTS: Fasting induced a significant (P < 0.05) rise in all amplitude-dependent measures (absolute GH peak and nadir, profile mean GH, and mean pulse amplitude and area) in both groups. Pulse frequency was nonsignificantly increased (by 10%) in normals but significantly increased (by 20%) in the patients. The average increase in the individual fasting profile mean GH concentration was 3.7-fold (range 1.5-8.3) in normals, compared with 2.7-fold (range 1-4.7) in the patients (P > 0.05). Fasting amplified amplitude-related differences between patients and controls, and thus, unlike in the fed state, the day (0900-2040 h) mean GH completely demarcated patients from normals. An absolute GH peak level of 2 and 4 microg/liter and a profile mean GH level of 0.25 and 0.65 microg/liter completely separated patients from normals in the fed and the fasting states, respectively. Overall, fasting seems to induce a feminized pattern of GH secretion with relatively higher interpeak levels, preserved but diminished diurnal variation, and increased secretory disorderliness (increased approximate entropy scores). CONCLUSION: The overall pulsatile pattern of GH secretion during fasting in patients with radiation-induced GH deficiency and the relative augmentation in GH release are similar to that seen in normals emphasizing that GH neuroregulation is preserved in these patients even when the hypothalamic-pituitary axis is under physiological stress.

Circadian and stimulated thyrotropin secretion in cranially irradiated adult cancer survivors.

CONTEXT: It has been claimed that with the use of the TRH test and knowledge of the nocturnal TSH surge, the diagnosis of so-called hidden central hypothyroidism might be uncovered in a substantial proportion of euthyroid cranially irradiated children. STUDY SUBJECTS: We conducted 24-h TSH profiles and TRH tests in 37 euthyroid adult cancer survivors 2-29 yr (median, 11.5) after irradiation (18-64 Gy) and in 33 matched normal controls. RESULTS: Basal and stimulated TSH levels (during the TRH test) were significantly (P < 0.05) higher in the patients who had received craniospinal irradiation, more so in those with severe GH deficiency. Six patients (16%) had a hypothalamic TSH response to TRH. The maximum TSH surge calculated from the highest peak (average of the highest three sequential samples) and the smallest nadir (average of the smallest three sequential samples) in the whole 24-h profile period was above the cutoff value of 50% in all except one control subject and two patients. However, the nocturnal TSH surge was greatly reduced or absent in eight normal subjects (24%) and six patients (16%), not due to a genuine loss of diurnal rhythm, but simply to a shift in the timing of the peak TSH and/or the nadir TSH to outside the recommended sampling times (for the nocturnal surge) of 2200-0400 and 1400-1800 h, respectively; thereby potentially leading to an erroneous diagnosis of hidden central hypothyroidism. Overall, the maximum TSH surge was significantly (P = 0.01) reduced only in the GH-deficient patients (100.7 +/- 11%) compared with normal subjects (154.9 +/- 18.2%). Free T4 levels did not correlate with TSH surge results. CONCLUSIONS: The normality of free T4 levels and the wide discrepancy between the high rate of these TSH abnormalities and the very low rate of overt secondary hypothyroidism (3-6%) after prolonged periods of postirradiation follow-up strongly suggest that in the vast majority of patients, these abnormalities in TSH dynamics represent subtle functional disturbances in the hypothalamic-pituitary axis rather than genuine pathology that may progress with time. We suggest that in this context, use of the term hidden central hypothyroidism is inappropriate, because these subtle changes may not have any clinical significance.

Absence of adrenocorticotropin (ACTH) neurosecretory dysfunction but increased cortisol concentrations and production rates in ACTH-replete adult cancer survivors after cranial irradiation for nonpituitary brain tumors.

CONTEXT: For the first time, physiological cortisol secretion has been studied in ACTH-replete adult cancer survivors to explore any discrepancy between stimulated (during insulin-induced hypoglycemia) and spontaneous cortisol secretion and, in particular, the possible existence of ACTH neurosecretory dysfunction that might explain the excessive fatigue suffered by some cancer survivors. STUDY SUBJECTS: Cortisol profiling at 20-min intervals over 24 h during the fed state was undertaken in 34 patients (10 females), aged 17-53.7 yr (median, 21.5 yr), 2-29 yr (median, 11.5 yr) after receiving conventional cranial irradiation for nonpituitary brain tumors or leukemia (n = 5) and in 33 age-, gender-, and body mass index-matched normal controls, of whom 23 patients and 17 controls were also profiled in the last 24 h of a 33-h fast. RESULTS: The fed profile mean cortisol concentration (mean +/- sem) was significantly increased (by 14%) in the patients compared with that in normal subjects (213 +/- 6.9 vs. 187 +/- 6.7 nmol/liter; P = 0.009), with all individual values above the lowest seen in normal subjects. Multiparameter deconvolution analysis revealed a parallel increase (by 20%) in cortisol secretion rates (1.8 +/- 0.09 vs. 1.5 +/- 0.08 nmol/liter.min; P = 0.03) due to selective augmentation of the cortisol mass released per burst with no changes in burst frequency (12/24 h) or half-life. No significant differences were observed between males and females, after short-term fasting, or between female patients and normal females. Thus, in the light of total group comparisons, male patients had even higher values than normal males, and more so during fasting (mean cortisol and cortisol secretion increased by 20 and 29% in the fed state and by 41 and 32% in the fasting state, respectively; P < 0.05). CONCLUSIONS: This study has demonstrated that radiation-induced ACTH neurosecretory dysfunction does not exist and, thus, resolved the clinical dilemma as to whether cortisol replacement should be considered in those patients with excessive fatigue and normal stimulated cortisol responses. On the contrary, cranial irradiation causes activation of the corticotrope-adrenal axis, and in the absence of ACTH deficiency, this activation is manifested by parallel increases in circulating cortisol levels and cortisol production rates without any change in cortisol half-life. The lack of cortisol increase in female patients may be attributed to the adverse effect of their higher body mass index on cortisol secretion or may reflect a genuine gender dichotomy.

The dynamics of growth hormone (GH) secretion in adult cancer survivors with severe GH deficiency acquired after brain irradiation in childhood for nonpituitary brain tumors: evidence for preserved pulsatility and diurnal variation with increased secretory disorderliness.

Dynamics of GH secretion in patients with GH deficiency due to radiation damage of the hypothalamic-pituitary (h-p) axis acquired in childhood has rarely been studied. Thus, we used a sensitive chemiluminescence GH assay to analyze 24-h GH profiles (20-min sampling) from 10 adult cancer survivors with severe GH deficiency acquired after brain irradiation in childhood for nonpituitary brain tumors. An age- and sex-matched control group of 30 normal healthy volunteers, eight of whom were matched for body mass index with the patients, were also studied. Cluster analysis with gender-specific comparisons revealed a significant reduction (P < 0.05) in all amplitude-related measurements [profile mean GH levels or area under curve for GH, absolute (maximum) GH peak height, mean peak height, and mean pulse area] in patients. No differences were observed in frequency-related measurements (pulse frequency, pulse duration, and interpulse interval). Pulsatile secretion was relatively more attenuated than basal secretion in patients, and approximate entropy (ApEn) scores were significantly (P < 0.05) elevated, suggesting more disordered GH secretion. Radiation inflicts quantitative damage to the h-p axis, leading to amplitude-dependent dampening of GH secretion with relative preservation of nonpulsatile secretion. Qualitative perturbation in hypothalamic control of GH release is evident by the increase in ApEn values reflecting more disordered GH secretion. The integrity of the h-p axis and GH neuroregulation is fundamentally preserved in irradiated GH-deficient patients with a GH secretory pattern similar to that observed in normal subjects and those with GH deficiency due to other etiologies.

Hypopituitarism as a consequence of brain tumours and radiotherapy.

Radiation-induced damage to the hypothalamic-pituitary (h-p) axis is associated with a wide spectrum of subtle and frank abnormalities in anterior pituitary hormones secretion. The frequency, rapidity of onset and the severity of these abnormalities correlate with the total radiation dose delivered to the h-p axis, as well as the fraction size, younger age at irradiation, prior pituitary compromise by tumour and/or surgery and the length of follow up. Whilst, the hypothalamus is the primary site of radiation-induced damage, secondary pituitary atrophy evolves with time due to impaired secretion of hypothalamic trophic factors and/or time-dependent direct radiation-induced damage. Selective radiosensitivity in the neuroendocrine axes with the GH axis being the most vulnerable to radiation damage accounts for the high frequency of GH deficiency, which usually occurs in isolation following irradiation of the h-p axis with doses less than 30 Gy. With higher radiation doses (30-50 Gy), however, the frequency of GH insufficiency substantially increases and can be as high as 50-100%, and TSH and ACTH deficiency start to occur with a long-term cumulative frequency of 3-6%. Abnormalities in gonadotrophin secretion are dose-dependent; precocious puberty can occur after radiation dose less than 30 Gy in girls only, and in both sexes equally with a radiation dose of 30-50 Gy. Gonadotrophin deficiency occurs infrequently and is usually a long-term complication following a minimum radiation dose of 30 Gy. Hyperprolactinemia, due to hypothalamic damage leading to reduced dopamine release, has been described in both sexes and all ages but is mostly seen in young women after intensive irradiation and is usually subclinical. A much higher incidence of gonadotrophin, ACTH and TSH deficiencies (30-60% after 10 years) occur after more intensive irradiation (>70 Gy) used for nasopharyngeal carcinomas and tumours of the skull base and following conventional irradiation (30-50 Gy) for pituitary tumours. Radiation-induced anterior pituitary hormone deficiencies are irreversible and progressive. Regular testing is mandatory to ensure timely diagnosis and early hormone replacement therapy to improve linear growth and prevent short stature in children cured from cancer, and in adults preserve sexual function, prevent ill health and osteoporosis and improve the quality of life.