Hypopituitarism Following External Radiotherapy for Pituitary Tumours in Adults

SUMMARY The development of anterior pituitary hormone deficiencies hasbeen studied in a group of 165 patients who underwent externalradiotherapy for tumours of the pituitary or closely relatedanatomical sites, and who have been observed for up to 10 years.One hundred and forty had undergone pituitary surgery beforeradiotherapy. All patients received external radiotherapy bya three-field technique, giving 3750–4250 cGy in 15 or16 fractions over 20–22 days. A combined test of anteriorpituitary function using insulin hypoglycaemia or glucagon stimulationin conjunction with thyrotrophin and gonadotrophin releasinghormone tests and basal estimations of prolactin, thyroid hormonesand testosterone or oestradiol was performed before radiotherapy.This was repeated six and 12 months later and subsequently annually.Before radiotherapy, 18 per cent of patients had normal growthhormone secretion, 21 per cent had normal gonadotrophin secretion,57 per cent had normal corticotrophin reserve and 80 per centhad normal thyrotrophin secretion. Life table analysis demonstratedincreasing incidences of all anterior pituitary hormone deficiencieswith time: by five years all patients were growth hormone deficient,91 per cent were gonadotrophin deficient, 77 per cent were corticotrophindeficient and 42 per cent were thyrotrophin deficient. At eightyears, respective incidences of deficiencies were 100, 96, 84and 49 per cent. Radiation-induced hyperprolactinaemia was seenin 73 patients; mean serum prolactin concentration rose from227±11 mU/1 to a peak of 369±60 mU/1 at two yearsand subsequently declined towards the basal value. The primarydiagnosis, patient age, sex, irradiated tissue volume and previoussurgery were examined as variables that might influence therate of development of anterior pituitary hormone deficiencies,but none of these factors had a significant effect. The radiationinduced hyperprolactinaemia was however more marked in femalepatients. Although anterior pituitary hormone deficiencies mostcommonly developed in the order growth hormone, gonadotrophin,corticotrophin, thyrotrophin (61 per cent of patients), othersequences were evident. Most notably corticotrophin deficiencyoccurred before gonadotrophin deficiency. There is a high incidence of anterior pituitary hormone deficienciesin patients treated surgically for pituitary tumours and theincidence increases after external radiotherapy. Deficienciesmay occur in an unpredictable sequence and endocrine testingis recommended on an annual basis.     

RADIATION-INDUCED HYPOPITUITARISM IS DOSE-DEPENDENT

Radiation-induced hypopituitarism has been studied prospectively for up to 12 years in 251 adult patients treated for pituitary disease with external radiotherapy, ranging in dose from 20 Gy in eight fractions over 11 days to 45 Gy in 15 fractions over 21 days. Ten further patients were studied 2-4 years after whole-body irradiation for haematological malignancies using 12 Gy in six fractions over 3 days and seven patients were studied 3-11 years after whole-brain radiotherapy for a primary brain tumour (30 Gy, eight fractions, 11 days). Five years after treatment, patients who received 20 Gy had an incidence of TSH deficiency of 9% and in patients treated with 35-37 Gy, 40 Gy and 42-45 Gy, the incidence of TSH deficiency (22, 35 and 52% respectively) increased significantly (P less than 0.001) with increasing dose. A similar relationship was observed for both ACTH and gonadotrophin deficiencies when the 20 Gy group was compared to patients treated with 35-45 Gy (P less than 0.01 and P less than 0.05 respectively). Growth hormone deficiency was universal by 5 years over the dose range 35-45 Gy. In seven patients who were treated with 30 Gy in eight fractions over 11 days, deficiencies were observed at a similar frequency to the 40 Gy group (15 fractions, 21 days). No evidence of pituitary dysfunction was detected in the ten patients who received 12 Gy (six fractions, 3 days). Both total radiation dose and fractionation schedule may determine the incidence of pituitary hormone deficiencies. The dose below which deficiencies do not occur is probably irrelevant to therapeutic irradiation of pituitary and other intracranial neoplasms.     

The Effect of External Pituitary Irradiation on Elevated Serum Prolactin Levels in Patients with Pituitary Macroadenomas

The response of serum prolactin to external radiotherapy wasstudied in 58 patients (32 women) with pituitary tumours, agedbetween 16 and 75 years. Forty-four patients underwent pituitarysurgery before radiotherapy. Six Patients were irradiated witha regimen of 20 Gy in eight fractions over 10–11 daysand the remainder received 35–42.5 Gy in 15 fractionsover 20–22 days. Following radiotherapy, 44 patients receivedadditional treatment with dopaminergic agonists. Prolactin levelsranged from 1078 to 491000 mU/I (median 11750 mU/I) before radiotherapyand all but three patients showed a fall in serum prolactin(measured 4 weeks after stopping bromocriptine in those on dopamineagonist therapy) during observation over periods of up to 154months. All patients had evidence of pituitary fossa erosionor expansion at presentation and large tumours (Hardy-VezinaGrade 3–4) were more common in male patients (²=10.08,p<0.01). The rate of fall of serum prolaetin levels was greaterin patients with true prolactin-secreting tumours when comparedwith those who had stalk or hypothalamic damage (p< 0.005).The rate of decline of serum prolactin was also significantlyrelated to the pre-radiotherapy value (p=0.519, p<0.01).A serum prolactin level. <500 mU/I was achieved in 31 outof 44 patients treated with radiotherapy and dopaminergic agonistbut only nine remained normoprolactinaemic when medication wasdiscontinued for 4 weeks or more. The serum prolactin levelfell permanently to <500 mU/I in two of 14 patients treatedwith radiotherapy only. Actuarial analysis of data from allpatients indicated a 50 per cent probability that prolactinwould be reduced to <500 mU/I by 10 years; this increasedto 58 per cent for patients with smaller tumours (Hardy-Vezinagrade 2). Fourteen of 19 women of premenopausal age were amenorrhoeicbefore radiotherapy, but despite bromocriptine, menstruationwas restored in only five. A separate group of nine patientswith primary suprasellar, non-prolactin-secreting tumours andelevated prolactin levels was also studied. Prolactin concentrationsranged between 1016 and >4600 mU/I intially and were reducedby radiotherapy at a rate indistinguishable from that of patientswith pituitary adenomas associated with disconnection hyperprolactinaemia.None achieved permanent reduction of serum prolactin to <500mU/I. External radiotherapy is effective in reducing serum prolactinlevels in patients with pituitary macroadenomas, particularlywhere the hyperprolactinaemia is due to true tumour hypersecretion,but normal levels may take over 10 years to achieve. Radiation-inducedhypothalamic damage probably contributes to the hyperprolactinaemiapersisting after therapy and together with tumour-associatedor radiation-induced hypopituitarism accounts for the poor prospectsfor fertility in female patients.     

LOW-DOSE PITUITARY IRRADIATION FOR ACROMEGALY

External radiotherapy has been used as primary treatment for acromegaly in 29 patients and in combination with surgery in 41 patients in whom growth hormone levels remained elevated postoperatively. Fourteen further patients who did not receive radiotherapy have also been studied, four of whom had undergone surgical treatment. Radiotherapy schedules consisted of 20 Gy in eight fractions over 11 days (n = 23) or 35-40 Gy in 15 fractions over 21 days (n = 47). Growth hormone hypersecretion was either unchanged or increased with time in non-irradiated patients. In those patients who underwent radiotherapy, the likelihood of the mean GH level during GTT falling to less than 5 mU/l was unaffected by the total dose of radiation administered. However, patients with a pre-radiotherapy GH level of less than 30 mU/l showed a significantly increased probability of achieving a post- radiotherapy GH level less than 5 mU/l (P = 0.002). Previous surgery, initial serum prolactin and the age or sex of the patient did not predict the successful outcome of radiotherapy. In view of the known dose dependency of radiation-induced hypopituitarism, lower radiation dose schedules (20 Gy; eight fractions in 11 days) can be used in acromegaly with some benefit, especially in younger patients. However, all patients should undergo operative removal of as much GH-secreting tissue as possible, in order to lower GH levels and increase the probability of achieving a cure following radiotherapy.     

COMPARISON OF THE ACTH AND CORTISOL RESPONSES TO PROVOCATIVE TESTING WITH GLUCAGON AND INSULIN HYPOGLYCAEMIA IN NORMAL SUBJECTS

The glucagon stimulation test (GST) is often used to assess pituitary ACTH reserve, particularly when other tests are contra-indicated. In a preliminary investigation, in patients with pituitary disease, we failed to demonstrate the ACTH dependence of the cortisol response. We have therefore compared the ACTH, cortisol and glucose responses to glucagon (1 mg s.c.), insulin (0.2 U/kg i.v., ITT) and placebo in six healthy male volunteers, sampling every 10 min for 6 h. During the GST, mean +/- SD serum cortisol rose from 256 +/- 80 nmol/l to a peak of 481 +/- 164 nmol/l (range 289-717 nmol/l, P less than 0.01) in comparison with 280 +/- 81 nmol/l to 602 +/- 110 nmol/l (range 493-742 nmol/l) during the ITT (P less than 0.002). The mean peak cortisol levels achieved in the two tests did not differ significantly. In the GST, plasma ACTH rose from a mean basal value of 10.9 +/- 16.6 ng/l to a mean peak level of 123 +/- 76 ng/l (P less than 0.02) (ACTH ng/l x 0.225 = pmol/l). The corresponding values in the ITT were 7.1 +/- 16.2 ng/l and 263 +/- 91 ng/l (P less than 0.001). The mean peak ACTH level was significantly greater during the ITT (P less than 0.05). Thus the cortisol response was ACTH dependent in both the GST and the ITT in normal subjects. Furthermore, the ACTH response was of sufficient duration to be detected by the usual procedure of sampling every 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)