Hypopituitarism is the inability of the pituitary gland to provide sufficient hormones adapted to the needs of organism [1] . It can be caused by either an inability of the pituitary gland itself or an insufficient supply of hypothalamic releasing hormone.

Pituitary irradiation is a well-known cause of hypopituitarism. Hypopituitarism has been found in patients treated with cranial irradiation for a number of intracranial pathologies, including pituitary adenomas, suprasellar tumors, primary tumors, nasopharyngeal carcinomas, head and neck tumors and bone tumors affecting the skull. It can also occur in patients who have received prophylactic cranial irradiation as part of the treatment schedule for acute lymphoblastic leukemia in childhood [2] .

Radiation induced toxicity depends on the total radiation dose, the fraction size and the time allowed between fractions for tissue repair [3] . The physical dose of radiation delivered to hypothalamus and pituitary during conventional external beam depends on whether they are included in the radiation field or whether they are located near the field, in which the radiation dose delivered will be less [3] . The severity of the hypopituitarism depends on the dose of radiation. Low radiation dose (<50 Gy) usually result in isolated growth hormone deficiency [2, 3] ; while higher doses (>60 Gy) for nasopharyngeal carcinoma lead to panhypopituitarism.

Irradiation of the hypothalamic-pituitary axis causes a characteristic pattern of hormone loss: growth hormone (GH) is usually affected first, followed by gonadotrophins, corticotrophin (ACTH) and thyroid-stimulating hormone (TSH) [4, 5] . The hypothalamic-pituitary dysfunction is progressive and evolves over many years. Studies have demonstrated that the number of pituitary hormone deficiencies increases with the length of time from irradiation [4, 5] . The rate at which the hormone deficiency develops depends on the dose of radiation used [2].

Age is another factor that has impact on development of hypopituitarism. Younger individuals are more vulnerable to radiation damage [3] . The progression of the hypopituitarism is also influenced by prior compromise of hypothalamic-pituitary neuronal integrity such as underlying pituitary tumor or previous surgery [2, 3] . Lam et al studied 28 patients undergoing radiotherapy for nasopharyngeal carcinoma with normal prior pituitary function [5] . At five years, GH, gonadotrophins, ACTH and TSH axes remained normal in 36.5%, 69%, 73% and 85% respectively.

Clinical features
The clinical manifestations of hypopituitarism are variable and often insidious in onset. They are also dependent on the degree of hormonal deficiency. It can be subclinical, indicated only by measurement of hormones, or its clinical onset might be acute or severe.

Table 1 Symptoms of hypopituitarism

Diagnostic Test
In principle, a combination of low peripheral and inappropriately low pituitary hormones indicates hypopituitarism. Thus, as an initial investigation, basal serum hormones should be measured. However, basal concentrations alone might not be distinctive owing to pulsatile, circadian or situational secretion of some hormones. Dynamic stimulation tests are indicated in equivocal basal hormone levels or to diagnose partial hormonal deficiencies. Every dynamic test has its specific limitations and the test of choice depends on the local experience and practical considerations.

ACTH deficiency
ACTH and cortisol secretion follow a diurnal rhythm, with highest levels in the early morning and lowest concentration around midnight. A morning cortisol value below 100 nmol/l is indicative of hypothalamic-pituitary-adrenal (HPA) axis insufficiency, whereas HPA insufficiency can be excluded if the morning serum cortisol is above 500nmol/l [6] .

Between 100 and 500 nmol/l, ACTH deficiency is not unequivocally excluded and a dynamic test is required. Hypoglycemia (blood glucose <2.2 mmol/l) induced by insulin tolerance test is a strong stressor and regarded as a gold standard for assessment of the hypothalamic-pituitary-adrenal axis [1] . A maximum response of 500nmol/l generally excludes HPA insufficiency although some advocate a higher cut-off level of 550 nmol/l [7] . However, this test has some unpleasant side effects, such as sweating, trembling, fatigue and hunger. It is potentially dangerous and thus requires the supervision of a physician. It is also contraindicated in patients with heart disease and epilepsy.

As sustained ACTH deficiency leads to adrenal atrophy and ACTH receptor down regulation [6] , standard ACTH stimulation rest (synacthen test) can be used to establish secondary adrenal insufficiency at least 4 weeks after the onset of the ACTH deficiency [1] . Stimulated cortisol level below 500nmol/l is indicative of adrenal insufficiency. However, there are some patients who pass the synacthen test but not the insulin tolerance test (ITT). There is also a debate as to whether a low dose 1 mcg synacthen stimulation test would represent a more physiological stimulus for maximal adrenal stimulation compared to the 250 mcg stimulation. A recent meta-analysis reported similar operating characteristic between the 2 doses [8] .

TSH deficiency
The diagnosis of TSH deficiency can be made by serial free T4 measurement. Concentrations of free thyroxine are decreased with TSH being low or normal [1, 7] . Dynamic testing is generally not necessary, as it does not add to diagnostic reliability. In some cases, TSH can be slightly raised due to secretion of biologically inactive TSH.

Lutenising hormone (LH) and follicle-stimulating hormone (FSH) deficiency
Hypogonadism in premenopausal women is easy to diagnose because of the menstrual disturbance. Presence of menstrual disturbance and an inappropriately low LH and FSH indicate secondary hypogonadism. Absence of typical postmenopausal rise in LH and FSH also indicates central hypogonadism. Similarly, in men, the presence of low testosterone and low or normal LH and FSH is indicative of central hypogonadism. Dynamic tests are of limited value and are seldom used [7] .

Growth Hormone deficiency
The diagnosis of growth hormone deficiency is established by clinical and biochemical criteria. Normal insulin-like growth factor-I (IGF-I) concentration does not exclude the diagnosis of GH deficiency [9] as one third of patients with GH deficiency have IGF-I in the normal range. Thus provocative tests are usually indicated [9] . Hartman et al, however, suggested that in patients with an appropriate clinical background of pituitary pathology or irradiation, GH provocative test may not be required. The presence of more than 2 pituitary hormones deficiencies or low IGF-I level is sufficient for diagnosis [10] .

Insulin tolerance test (ITT) is still the diagnostic test of choice [9] with peak of growth hormone below 9mU/l suggesting severe deficiency.

Other alternatives included glucagon stimulation tests, growth hormone-releasing hormone (GHRH) plus arginine test and more recently GHRH plus growth hormone-releasing peptide 6 test, are easier to do but unfortunately not available in our center. A point to note is that tests that stimulate the pituitary directly, as in GHRH plus arginine, may produce response that do not reflect the GH status [2, 11] as the hypothalamus is the immediate site of damage following irradiation. No test for assessment of growth axis is 100% reliable.

Prolactin
Prolactin can be mildly elevated after radiation due to hypothalamic dysfunction. This may not require treatment unless the level is very high and possibly contributing to central hypogonadism.

Conclusion
With more patients receiving cranial irradiation having a better chance of survival, more are now left with the prospect of pituitary dysfunction. The frequency and severity of developing hypopituitarism is both dose- and time-dependent. The onset of hypopituitarism is insidious and symptoms are often subtle and nonspecific. Hence, an index of suspicion should be present when reviewing patients with cranial irradiation. Periodic screening for signs and symptoms of hypopituitarism and basal hormonal tests should be considered when appropriate.

Dr Kek Peng Chin
Associate Consultant

Dr Loh Lih Ming
Consultant
Department of Endocrinology
Singapore General Hospital


Reference:

[1]	Schneider, H.J., et al., Hypopituitarism. Lancet, 2007. 369(9571): p. 1461-70.
[2]	Toogood, A.A., Endocrine consequences of brain irradiation. Growth Horm IGF Res, 2004. 14 Suppl A: p. S118-24.
[3]	Darzy, K.H. and S.M. Shalet, Hypopituitarism as a consequence of brain tumours and radiotherapy. Pituitary, 2005. 8(3-4): p. 203-11.
[4]	Littley, M.D., et al., Hypopituitarism following external radiotherapy for pituitary tumours in adults. Q J Med, 1989. 70(262): p. 145-60.
[5]	Lam, K.S., et al., Effects of cranial irradiation on hypothalamic-pituitary function--a 5-year longitudinal study in patients with nasopharyngeal carcinoma. Q J Med, 1991. 78(286): p. 165-76.
[6]	Arlt, W. and B. Allolio, Adrenal insufficiency. Lancet, 2003. 361(9372): p. 1881-93.
[7]	van Aken, M.O. and S.W. Lamberts, Diagnosis and treatment of hypopituitarism: an update. Pituitary, 2005. 8(3-4): p. 183-91.
[8]	Dorin, R.I., C.R. Qualls, and L.M. Crapo, Diagnosis of adrenal insufficiency. Ann Intern Med, 2003. 139(3): p. 194-204.
[9]	Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency. J Clin Endocrinol Metab, 1998. 83(2): p. 379-81.
[10]	Hartman, M.L., et al., Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency? J Clin Endocrinol Metab, 2002. 87(2): p. 477-85.
[11]	Darzy, K.H., et al., The usefulness of the combined growth hormone (GH)-releasing hormone and arginine stimulation test in the diagnosis of radiation-induced GH deficiency is dependent on the post-irradiation time interval. J Clin Endocrinol Metab, 2003. 88(1): p. 95-102.