Response of acromegaly to long term bromocriptine therapy: a biochemical and clinical assessment.

The long term effects of bromocriptine in 12 acromegalics treated for a mean duration of 10.2 months are reported. Seven showed a significant (P less than 0.05) and sustained fall in serum immunoreactive growth hormone (GH) levels throughout 24 h, 6 of whom had a 50% or greater reduction in mean circulating GH during glucose tolerance testing. Only one patient had mean serum GH levels throughout the day suppressed to normal (less than 5 mIU/l) but 3 had suppression of mean serum GH during GTT to normal or very near normal (less than 10 mIU/l). The effective dose was 20 mg daily. Only 4 patients reported any improvement in soft tissue swelling and acral features, which was unrelated to the GH response. Possible reasons for the discrepancy between clinical and biochemical responses are discussed. In 9 of the 12 patients bromocriptine was discontinued and pituitary ablative therapy offered. Three out of 4 patients who underwent trans-sphenoidal hypophysectomy had mean GH levels during GTT reduced to less than 7 mIU/l. In the three who continued bromocriptine treatment GH suppression was maintained at less than 10 mIU/l for up to 3 years but with little change in acral features. Although bromocriptine is safe and was well tolerated it is not as effective as existing forms of pituitary ablative therapy and should be reserved for those cases where ablation is contraindicated or unsuccessful.     

Long-term effect of 90Y pituitary implantation in acromegaly

This report examines the long-term trends in GH levels and pituitary function in a group of 38 acromegalic patients who were selected insofar as we were able to follow them up for more than 10 years after a single dose of 90Y interstitial pituitary irradiation as the sole treatment. Mean serum GH had fallen from 106 to 24 mIU/l within 3-6 months and then slowly declined to 4 mIU/l after 10 years. GH levels of less than or equal to 5 mIU/l during a 50 g oral glucose tolerance test were obtained in 8% of patients at 3-6 months and in 18% at 1 year, the cumulative percentage increasing to 53% at 10, and 76% at 14 years. The percentage of patients requiring hormone replacement therapy rose from nil pre-implant to 16% by 3-6 months, and then slowly increased to 39% by 14 years. Serial coned radiographs of the pituitary fossa were available for 32 patients. By 10 years, 16 showed thickening of the dorsum sellae and/or reduction of at least one diameter by 3 mm. Concerning symptoms, all 29 patients whose GH level fell to less than or equal to 5 mIU/l showed improvements, 22 becoming asymptomatic. Seven patients with lesser falls in GH levels (from a mean of 193 to a mean of 15 mIU/l) all improved, one becoming asymptomatic. Two showed no variation. These results show that 90Y pituitary implants have a cumulative effect over the years in inducing remission and hypopituitarism in acromegalic patients, the early decline in GH levels being swifter than from other forms of irradiation.     

Conventional pituitary irradiation is effective in normalising plasma IGF-I in patients with acromegaly

OBJECTIVE: For patients in whom acromegaly persists despite pituitary surgery, conventional pituitary irradiation represents an additional treatment option. A 30-60% cure rate is described in the literature, but these studies did not utilise strict rules of remission, such as "safe" GH levels <2.5 microg/l, and age-adjusted normal IGF-I levels. DESIGN AND METHODS: We report the outcome of 41 patients with acromegaly who received pituitary conventional external irradiation. The median follow-up time was 12.8 years (3.7-43.4 years) post-radiotherapy. RESULTS: The median pre-irradiation GH level was 31.0 microg/l (7.0-210 microg/l). Information on IGF-I levels was only available for 6 patients prior to therapy. Utilising strict rules of remission, one-third (14/41) of our patients had normal biochemical parameters, i.e. "safe" GH (0.5 microg/l (range 0.2-1.6 microg/l)) and normal age-adjusted IGF-I levels (multiple of upper limit of normal range (xULN); 0.45 (0.2-1.0)) at the end of the follow-up period. An additional 9 patients achieved normal levels with adjunctive drug therapy. Furthermore, disease activity was reduced in a considerable proportion of the 18 patients who did not achieve normal biochemical levels (GH: 3.6 microg/l (1.9-15.7 microg/l); xULN of IGF-I: 1.6 (0.9-2.6)). In retrospect, remission is unlikely in patients who had a GH level greater than 52 microg/l (mean+2 s.d. of cured patients) prior to radiotherapy. In addition to the 12 patients with pre-irradiation pituitary functional deficiency, another 11 patients developed symptoms of panhypopituitarism during the 3-year period following irradiation. Within a 6-year period, partial pituitary insufficiency was observed in a further 7 patients, thus necessitating hormone substitution treatment. CONCLUSION: Using strict rules of remission, in our cohort we found both a normalisation of IGF-I and safe GH levels in 34% of patients treated for acromegaly with conventional irradiation therapy.     

Postoperative radiotherapy in acromegaly is effective in reducing GH concentration to safe levels

OBJECTIVE: Several studies have established that in treated acromegaly mortality is only normalized in patients achieving a serum GH concentration below 5 mU/l. Few studies however, have addressed results of radiotherapy using this strict criterion. The aim of our study was to assess the efficacy of postoperative radiotherapy in reducing serum GH concentration below 5 mU/l. PATIENTS AND METHODS: Forty acromegalic patients who underwent radiotherapy for postoperative persistent disease after transsphenoidal surgery were studied. Mean time of follow-up after radiotherapy was 123+/-11.1 months. A serum GH concentration of <5 mU/l was used to define remission. RESULTS: Following surgery mean GH concentration decreased from 120.8+/-21 mU/l to 24.4+/-5.2 mU/l and mean GH concentration prior to radiotherapy, administered after a mean of 8.2+/-2.7 (0.5-96) months postoperatively was 26.0+/-5.1 mU/l. Using individual regression plots, GH was reduced to 50% by radiotherapy after a mean of 27+/-5 months (range 3-105 months). The observed mean GH concentration as measured at follow-up visits was reduced by 55% (-36-95%) after the first year, by 65% (-29-97.3%) after 2 years and by 78% (-29-99%) after 5 years. We could not demonstrate a significant correlation between a normalized GH concentration on the one hand and tumour size, preradiotherapy GH concentration or duration of follow-up on the other hand. During follow-up, GH-suppressive medical therapy was used in 11 patients, five of whom were still using medication at the end of follow-up. Eight patients had a follow-up of less than 5 years and three of them had a serum GH concentration of <5 mU/l at their latest follow-up visit (38%). At 5 years of follow-up after radiotherapy, 24 out of 32 patients had a GH level of <5 mU/l without medication (75%). At 10 years following irradiation, 16 of 21 patients (76%) had a GH level of <5 mU/l without medical treatment. At 15 years follow-up, a serum GH concentration of <5 mU/l was observed in 13 out of 15 patients (87%) without GH suppressive medication. At the latest follow-up visit, serum GH concentration below 5 mU/l was present in 75% of patients (30 out of 40) without medical therapy after a mean of 10.4+/-0.9 years, but five patients required octreotide up to the end of follow-up. Twenty-seven out of 37 patients with available IGF-I data had normal IGF-I at the end of follow-up (73%). Fifty percent of patients needed substitution therapy for (partial) hypopituitarism after 10 years and 75% after 15 years of radiotherapy. CONCLUSION: In our group of patients who were incompletely cured by surgery, but had a significant postoperative decrease of serum GH concentrations, radiotherapy was able to achieve 'safe' serum GH concentrations in the majority in the long term.     

Effectiveness of adding dopamine agonist therapy to long-acting somatostatin analogues in the management of acromegaly

BACKGROUND: The excess mortality and morbidity associated with acromegaly are secondary to prolonged elevation of GH and IGF-I. Vigorous control of these biochemical parameters results in improved morbidity and mortality. Somatostatin analogues (SAs) allow adequate control of GH and IGF-I in approximately 65% of subjects, leaving a significant cohort uncontrolled. Dopamine agonists (DAs), a cheap alternative to SAs, allow control of GH and IGF-I in less than 20% of patients with acromegaly. AIMS: To assess the effectiveness of adding DA therapy to SA in the biochemical control of acromegaly. SUBJECTS: One hundred and twenty cases from the Sheffield Acromegaly Register were reviewed; 24 (20%) did not require medical treatment following pituitary surgery alone; 16 (13%) had safe GH levels following surgery and radiotherapy; and 58 (48%) required medical treatment despite having had surgery, radiotherapy or both. The remaining 22 (18%) received only medical treatment. METHODS: In nine subjects a DA (three bromocriptine, six cabergoline) was added to an SA to control active disease. GH day curves and IGF-I levels were compared before and after the addition of a DA to existing SA treatment. All were on stable maximum-dose treatment with an SA, with inadequate biochemical control prior to addition of DA therapy. Mean duration of treatment on a DA before biochemical assessments were made was 10.3 months. Six subjects had previously been treated with either transsphenoidal surgery, radiotherapy or both. In three subjects SA was the primary therapy. RESULTS: All subjects exhibited a fall in median GH and IGF-I levels. Introduction of a DA resulted in a 36.1% reduction in median GH levels (8.3 vs 5.3 mIU/l; P = 0.008) on a GH day curve and a 35.2% reduction in IGF-I levels (387.2 vs 251.0 microg/l; P = 0.018). Only four subjects had elevated prolactin levels prior to the addition of a DA (>368 mIU/l). CONCLUSION: Addition of DAs to SAs is of benefit in the biochemical control of acromegaly and should be considered in those inadequately controlled. Furthermore, the beneficial effects of DAs occur even when pre-treatment prolactin levels are within the normal range.     

The outcome of surgery for acromegaly: the need for a specialist pituitary surgeon for all types of growth hormone (GH) secreting adenoma

OBJECTIVE: Acromegaly is associated with reduced life expectancy, while therapeutic 'cure' (defined by achievement of GH levels < 5 mU/l) is associated with normalization of life expectancy. Surgery remains the treatment of choice but in those in whom operative 'cure' is not achieved, radiotherapy and/or medical treatment are valuable treatment modalities. The chance of subsequent 'cure' with radiotherapy or somatostatin analogue therapy is increased if the post-operative GH level is reduced below 30 mU/l. Using strict criteria for cure and a single dedicated pituitary surgeon, two large European studies reported 'cure' rates of 42% and 56%. In the Manchester region, surgery for these patients has been performed by a number of neurosurgeons, with no specific designated pituitary surgeon dominating the picture. We wished to examine the impact of this surgical strategy on cure rates and the incidence of a post-operative GH level below 30 mU/l. DESIGN: We reviewed the GH results between 1974 and 1997 for every acromegalic who had been referred to the endocrine departments of the two Manchester hospitals responsible for the majority of pituitary disease referrals in Manchester and who had been subsequently referred for pituitary surgery. PATIENTS AND MEASUREMENTS: Seventy-three (33 male) patients had had GH status assessed before and after surgery by an OGTT or GH profile. The patients were aged between 19 and 70 (mean 43) years at surgery. Seventy-one underwent transsphenoidal and 2 transfrontal surgery. Nine surgeons performed operations. RESULTS: Eighteen (24.7%) had microadenomas and 51 (69.9%) macroadenomas. In 4 patients (5.5%) insufficient data were available to size the adenoma. 17.8% of patients were cured by surgery, 38.8% with microadenomas and 11.8% with macroadenomas. In addition, of 52 patients whose GH levels were > 30 mU/l before surgery, only 27 (51.9%) had GH levels below 30 mU/l post-operatively (81.8% of microadenomas, 43.2% of macroadenomas). CONCLUSION: In comparison with other series, the cure rate in this study is significantly lower. The success in reducing GH levels below 30 mU/l post-operatively is difficult to compare with previously published studies, as few groups have analysed their data in this manner. Nonetheless, of our acromegalic patients with a pretreatment GH level in excess of 30 mU/l, nearly 50% have similar GH status postoperatively, thereby rendering them less amenable to cure by alternative therapeutic modalities. This highlights the importance of a specialist pituitary surgeon, not only for GH secreting microadenomas but also for GH secreting macroadenomas. If these patients are not 'cured', the cost of continuing therapy becomes a significant burden on health-care costs. In addition, if the postoperative GH levels remain above 30 mU/l the chances of achieving adequate control of GH levels are greatly reduced, thereby increasing mortality rates as well as morbidity in these patients.     

EFFECTIVE LONG-TERM TREATMENT OF ACROMEGALY WITH A LONG-ACTING SOMATOSTATIN ANALOGUE (SMS 201–995)

Nine acromegalic patients, six previously untreated, were studied before and after 3-15 months of treatment with a long-acting somatostatin analogue (SMS 201-995; 100 micrograms injected s.c. three times daily). During treatment, the mean (+/- SEM) 24-h GH concentration fell from 82 +/- 22 mIU/l to 33 +/- 7 mIU/l (P less than 0.001), and eight of the 9 patients showed a reduction of at least 50% in GH levels in the fasting state and/or during a glucose tolerance test. There was a significant 30% fall in serum concentrations of insulin-like growth factor (IGF-1) with SMS. All patients showed rapid clinical improvement, with diminished sweating and headaches, and reduction in skinfold thickness, hand volumes and finger size. Computer tomographic scanning of the pituitary in eight patients showed no change in the size of the pituitary tumour during treatment. The only side-effects of SMS noted were transient abdominal discomfort and loose stools in two patients on initiating therapy. Although fasting plasma glucose concentration did not change during treatment (5.4 +/- 0.3 vs 5.5 +/- 0.3 mmol/l), mean 24-h plasma glucose concentration was higher with SMS (6.6 +/- 0.5 mmol/l vs 6.0 +/- 0.4 mmol/l; P less than 0.02). Mean 24-h plasma insulin concentration fell from 87 +/- 11 mIU/l before treatment to 39 +/- 6 mIU/l during treatment (P less than 0.005). No change in other anterior pituitary hormones was observed. SMS appears to be a safe, rapidly effective, long-term treatment for certain patients with acromegaly.     

Gender and age influence the relationship between serum GH and IGF-I in patients with acromegaly

BACKGROUND: In patients with acromegaly serum IGF-I is increasingly used as a marker of disease activity. As a result, the relationship between serum GH and IGF-I is of profound interest. Healthy females secrete three times more GH than males but have broadly similar serum IGF-I levels, and women with GH deficiency require 30-50% more exogenous GH to maintain the same serum IGF-I as GH-deficient men. In a selected cohort of patients with active acromegaly, studied off medical therapy using a single fasting serum GH and IGF-I measurement, we have reported previously that, for a given GH level, women have significantly lower circulating IGF-I. OBJECTIVE: To evaluate the influence of age and gender on the relationship between serum GH and IGF-I in an unselected cohort of patients with acromegaly independent of disease control and medical therapy. METHODS: Sixty (34 male) unselected patients with acromegaly (median age 51 years (range 24-81 years) attending a colonoscopy screening programme were studied. Forty-five had previously received pituitary radiotherapy. Patients had varying degrees of disease control and received medical therapy where appropriate. Mean serum GH was calculated from an eight-point day profile (n = 45) and values obtained during a 75-g oral glucose tolerance test (n = 15). Serum IGF-I, IGFBP-3 and acid-labile subunit were measured and the dependency of these factors on covariates such as log10 mean serum GH, sex, age and prior radiotherapy was assessed using regression techniques. RESULTS: The median calculated GH value was 4.7 mU/l (range 1-104). A significant linear association was observed between serum IGF-I and log10 mean serum GH for the cohort (R = 0.5, P < 0.0001). After simultaneous adjustment of the above covariates a significant difference in the relationship between mean serum GH and IGF-I was observed for males and females. On average, women had serum IGF-I levels 11.44 nmol/l lower than men with the same mean serum GH (P = 0.03, 95% CI 1.33-21.4 nmol/l). Age significantly influenced the relationship and for a given serum GH, IGF-I was estimated to fall by 0.37 nmol/l per year (P = 0.04, 95% CI 0.015-0.72). CONCLUSIONS: In keeping with previous observations of relative GH resistance in normal and GH-deficient females we have observed lower serum IGF-I levels for equivalent mean serum GH levels in females patients with acromegaly. This gender-dependent difference is independent of disease activity and the use of concomitant medical therapy. Additionally, we have demonstrated that for a given serum GH level, age significantly influences IGF-I concentrations in patients with acromegaly. These data have important implications for the use of serum IGF-I and GH as markers of disease activity in acromegaly.     

HOW EFFECTIVE IS EXTERNAL PITUITARY IRRADIATION FOR GROWTH HORMONE-SECRETING PITUITARY TUMOURS?

Forty-six patients with GH-secreting pituitary tumours were treated with conventional external pituitary irradiation through two opposed fields to a total dose of 3750 cGy over 15 fractions. Thirty-patients received external radiotherapy as primary treatment and 16 received radiotherapy combined with pituitary surgery. The mean (+/- SD) serum GH in the former group was 74.3 +/- 74.8 mU/l before treatment, falling by 28% per year over 0-5 years and by 16% per year over 0-20 years. The mean (+/- SD) serum GH in the latter group was 265.4 +/- 209.3 mU/l before treatment, falling by 76% in the first year--a direct result of surgical removal of tumour--then by 30% per year over 1-5 years and 16% per year over 1-20 years. Progressive failure of normal anterior pituitary function developed by 10 years, with variable loss of gonadotrophin, corticotrophin and thyrotrophin function. The respective figures for patients treated with radiotherapy alone were 47.4, 29.6 and 16.0% and for the combined group were 70.2, 53.9 and 38.1%. Whilst external pituitary irradiation appears to reduce serum GH concentrations in patients with GH-secreting pituitary tumours the major disadvantages of this form of treatment are the time taken to achieve a cure and the high incidence of hypopituitarism. Nevertheless there did not appear to be any other serious side effects.     

LONG-TERM EFFECTS OF MEGAVOLTAGE RADIOTHERAPY IN ACROMEGALY

The progress of 41 Chinese patients with acromegaly treated with megavoltage radiotherapy was reviewed after a mean follow-up of 4.5 (one-ten) years. Nine received prior surgery. Radiotherapy was delivered by a 3-field technique to a total of 4000–5000 cGy in 25 fractions. By life table analysis successful treatment of growth hormone (GH) hypersecretion, as defined by a mean GH concentration of 10 mu/L, could be expected in 6, 11, 26, 64 and 67% of the patients after one, two, five, eight and ten years respectively. Median intervals before achieving a mean GH level of 10 mu/L were 6.6 and 8.6 years following radiotherapy with the higher (4500–5000 cGy) and lower (4000 cGy) doses respectively, suggesting a tendency towards earlier response following radiotherapy with the higher dose. The prevalence of acquired hypopituitarism in patients followed up for over five years was 40% for gonadotrophins, 30% for TSH and 20% for ACTH deficiency respectively. In the majority of patients, acquired hypopituitarism was not apparent within five years after radiotherapy. No mortality or major side effects were noted following radiotherapy. In 34 patients on long-term bromocriptine treatment, mean GH concentrations were normalised in 26.5% of patients. We conclude that with judicious selection of patients and use of adjunctive medical therapy, megavoltage radiotherapy remains a safe and satisfactory form of treatment for acromegaly especially if expert transphenoidal surgery is not readily available.     

Growth hormone status following treatment for Cushing''s syndrome

OBJECTIVE: Both pituitary surgery and radiotherapy for Cushing's disease can lead to growth hormone (GH) deficiency. Studies to date have, however, described the incidence of impaired GH secretion and not the incidence of severe GH deficiency following treatment of Cushing's disease. Furthermore, following cure of Cushing's disease and resolution of hypercortisolaemia, recovery of GH secretory status is seen, thus creating uncertainty as to the persistence of any documented GH deficiency. This study has two aims; to determine the incidence of severe persistent GH deficiency following treatment of Cushing's disease and to assess the time scale of any recovery of GH secretory status following surgical cure of Cushing's disease. DESIGN AND PATIENTS: The case notes of 37 patients either cured or in clinical and biochemical remission following treatment for Cushing's syndrome were reviewed to determine the incidence of severe GH deficiency. Of 34 patients with Cushing's disease, 20 were treated by pituitary surgery, and 14 with radiotherapy. Three patients with adrenal adenomas underwent unilateral adrenalectomy. MEASUREMENTS: GH secretory status was assessed by provocative testing using an insulin tolerance test (ITT, 85% of all tests), glucagon stimulation test (GST) or arginine stimulation test (AST). RESULTS: Thirty-six percent (5/14) of radiotherapy treated patients demonstrated severe GH deficiency at a mean time of 99 months following remission. Fifty-nine percent (10/17) of surgically treated patients assessed in the two years following remission demonstrated severe GH deficiency, whilst only 22% (2/9) of patients assessed beyond two years following remission demonstrated severe GH deficiency. This latter cohort is biased, with patients in whom severe GH deficiency had been demonstrated on earlier tests being over-represented. It is more accurate to estimate the incidence of persistent severe GH deficiency following surgically induced remission of Cushing's disease by incorporating data from patients in whom original testing demonstrated adequate GH reserve. Collating such data, 13% (2/15) of patients had persistent severe GH deficiency. Across all time periods five surgically treated patients demonstrated recovery of GH secretory status over a median time course of 19 months. In the surgically treated cohort, seven (35%) patients had anterior pituitary hormone deficits other than GH deficiency: 14% (2/14) of patients with normal GH secretory status at the last assessment, 83% (5/6) of patients with severe GHD at the last assessment. Of the 5 patients who demonstrated recovery of GH secretory status 40% (2) had additional anterior pituitary hormone deficits. Within the radiotherapy treated cohort 14% (2/14) of patients demonstrated additional anterior pituitary hormone deficits: 11% (1/9) of patients with normal GH secretory status and 20% (1/5) of patients with severe GH deficiency. None of the patients with adrenal adenomas treated by unilateral adrenalectomy demonstrated any abnormality of GH secretory status CONCLUSIONS: The incidence of severe persistent GH deficiency following surgically induced or radiotherapy induced remission of Cushing's disease is lower than has been suggested by previous studies, although these latter studies have assessed GH insufficiency and not severe GH deficiency. In the presence of additional pituitary hormone deficits severe GHD is common and is likely to be persistent. Recovery of GH secretory status is seen in a high proportion of patients reassessed, at a median time of 19 months following surgically induced remission of Cushing's disease. Thus, we recommend that definitive assessment of GH secretory status is delayed for at least two years following surgical cure of Cushing's disease. This has important implications for patients in whom GH replacement therapy is being considered.     

The evolution of radiation-induced growth hormone deficiency in adults is determined by the baseline growth hormone status

OBJECTIVE Recent studies of GH replacement have suggested several beneficial effects for GH deficient adults. It would therefore be helpful to predict the time of onset of GH deficiency after external pituitary irradiation. We have studied the evolution of GH deficiency with time In patients irradiated for pituitary adenomas and other hypothalamic pituitary tumours. DESIGN Analysis of serial peak GH responses to Insulin hypoglycemia following external irradiation to the hypothalamlc-pitultary axis using statistical models which allowed for age, sex, previous surgery and the pre-radiotherapy GH peak response. PATIENTS Eighty-five non-acromegalic adults (48 male), 75 of whom had either a pituitary adenoma or a craniopharyngioma and 10 who had other tumours in the hypothalamic-pituitary region. All the patients had received a radiation dose between 37.5 and 45 Gy divided into 15 fractions given over 21 days. MEASUREMENTS The GH responses to an insulin tolerance test (ITT) performed as part of the regular endocrine follow-up In patients who received Irradiation to the hypothalamic-pituitary region. RESULTS Three hundred and forty-five ITTs were performed over a period of 10 years following radiotherapy. There was a decline In the modelled mean peak GH response to an ITT over the first 5 years which then appeared to plateau. Using an extended model, women had higher GH peak responses than men and this difference was maintained throughout the ten-year period. The magnitude of the post-radiotherapy peak GH response at any given time was dependent on the baseline peak GH response, but the rate of the decrease was not affected (P= 0.66). To develop severe GH deficiency (peak GH response less than 5mU/l) after radiotherapy it took patients with baseline GH peaks of 30, 20 and 10mU/l approximately 4 years, 3 years and 1 year respectively. Those patients with a baseline GH peak of greater than 50mU/l are unlikely to develop severe GH deficiency within the first 5 years following radiotherapy. CONCLUSION These results provide an insight into the pattern of the decline In GH secretion following radiotherapy in patients with pituitary disease and the factors affecting It. This Information will help the clinician predict the frequency and timing of GH deficiency in patients irradiated for pituitary disease and the potential need for GH replacement therapy.     

Hepatitis-C patients have reduced growth hormone (GH) secretion which improves during long-term therapy with pegylated interferon-alpha

OBJECTIVES: In vitro and in vivo data indicate multiple, but contradictory effects of interferon on pituitary hormone secretion. We therefore investigated prospectively basal and stimulated pituitary hormone secretion in 21 patients with chronic hepatitis C virus (HCV) infection before and during antiviral therapy. METHODS: Twenty-one patients received pegylated interferon-alpha plus either ribavirin or levovirin. Baseline and stimulated growth hormone (GH), cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), and thyroid-stimulating hormone (TSH) responses were measured using standard pituitary function tests, before therapy in all and during therapy in 17 out of the 21 patients. RESULTS: Before therapy 17 patients (81%) had severe GH insufficiency and 9 of these had low insulin-like growth factor-1 (IGF-1) concentrations. Basal and stimulated GH concentrations increased significantly during therapy, reducing the number of patients with severe GH insufficiency to four, but IGF-1 remained low. Basal PRL and TSH concentrations were normal before and during therapy, while thyroid-releasing hormone (TRH)-stimulated concentrations increased significantly during therapy. The adrenocorticotropic hormone (ACTH)/cortisol axis, basal and stimulated gonadotropin, and testosterone concentrations were normal throughout. Neither the HCV RNA level nor transaminases correlated with hormone concentrations before or during therapy. CONCLUSIONS: GH insufficiency is common in patients with chronic HCV infection. While GH secretion improves during antiviral therapy, IGF-1 remains low, indicating persistent GH resistance of hepatocytes. Whether improvement in GH secretion during treatment is due to a direct drug effect or related to the suppression of viral load could not be differentiated, as most patients demonstrated a positive virologic response.     

An account of the quality of life of patients after treatment for non-functioning pituitary tumours

OBJECTIVE Studies assessing quality of life in GH-deficient adults have shown varying results. This may be due to a number of factors including varying causes of GH deficiency, the use of radiotherapy in treatment and patient selection. We aimed to assess whether anterior pituitary hormone deficiency or external pituitary radiotherapy influenced the quality of life of patients with non-functioning pituitary tumours. PATIENTS We studied 48 patients treated and under follow up for non-functioning pituitary tumours on standard hormone replacement therapy excluding GH. There were 21 females and 27 males with a mean age of 59±12 years. We also studied 42 control patients who had undergone mastoid surgery and were followed at least annually. There were 17 females and 25 males with a mean age of 61±14 years. DESIGN All patients attended a research clinic and completed the Short Form 36 (SF36) and General Well Being Schedule (GWBS) to assess quality of life. Thyroid function tests, IGF1 and IGFBP3 were measured on all patients. Gonadotrophin and cortisol measurements were made on the patients with pituitary disease where appropriate. RESULTS IGF1 and IGFBP3 levels were lower in the pituitary patients compared with controls: 104±98 vs 143±37 μg/l (P<0.0001) and 2.9±0.75 vs 3.3±0.52 mg/l (P<0.004). There were no significant differences in the quality of life scores between the pituitary patients and the control subjects. There was also no difference in quality of life between pituitary patients with two or more hormone deficiencies (n=29) compared with controls. Patients who had received radiotherapy (n=18), when compared with controls, had a decreased mental health score using the SF36 71±21 vs 81±17 (P<0.05) and decreased total GWBS score 70±20 vs 82±17 (P<0.05). Subscore analysis of GWBS showed this to be due to depression and decreased control of emotions. CONCLUSIONS We found that the quality of life of patients treated and under follow up for non-functioning pituitary tumours was similar to that of patients treated by mastoid surgery and under similar follow up. The pituitary patients deficient in two hormones and thus most likely to be GH deficient were also similar to the controls. These results suggest that adding GH replacement in this patient group may not be routinely indicated for improvement in quality of life and needs careful assessment. Patients who had received radiotherapy were more depressed and anxious than controls. Further investigation into the psychological and psychomotor effects of radiotherapy in this group of patients is required.     

GH deficiency in patients irradiated for acromegaly: significance of GH stimulatory tests in relation to the 24 h GH secretion

BACKGROUND: Radiotherapy for pituitary adenomas frequently leads to GH deficiency (GHD). The characteristics of GH secretion in GHD induced by postoperative radiotherapy for acromegaly are not known. HYPOTHESIS: In the long term, stimulated and spontaneous GH release is not different between patients with GHD treated by postoperative radiotherapy for acromegaly or for other pituitary adenomas. DESIGN/SUBJECTS: We compared the characteristics of basal and stimulated GH secretion in patients with GHD, who had previously received adjunct radiotherapy after surgery for GH-producing adenomas (n=10) vs for other pituitary adenomas (n=10). All patients had a maximal GH concentration by insulin tolerance test (ITT) of 3 microg/l or less, compatible with severe GHD. Mean time after radiation was 17 and 18.7 years, respectively. Stimulated GH release was also evaluated by infusion of growth hormone-releasing hormone (GHRH), GHRH-arginine and arginine, and spontaneous GH by 10 min blood sampling for 24 h. Pulse analyses were performed by Cluster and approximate entropy. OUTCOMES: There were no differences between both patient groups in stimulated GH concentrations in any test. Spontaneous GH secretion was not different between both patient groups, including basal GH release, pulsatility and regularity. Pulsatile secretion was lost in two acromegalic and three non-acromegalic patients. Insulin-like growth factor-I (IGF-I) was below -2 s.d. score in nine patients in each group. CONCLUSION: Acromegalic patients treated by surgery and postoperative radiotherapy with an impaired response to the ITT do not differ, in the long term, in GH secretory characteristics from patients treated similarly for other pituitary tumors with an impaired response to the ITT. The ITT (or the GHRH-arginine test) is therefore reliable in establishing the diagnosis of GHD in patients treated for acromegaly by surgery and radiotherapy.     

Gamma knife stereotactic radiosurgery for acromegaly

BACKGROUND: Gamma knife radiosurgery (GKR) is an adjuvant treatment for acromegaly if surgery fails to normalize GH hypersecretion. OBJECTIVE: To examine the effect of GKR on tumor growth and hypersecretion, and to characterize the adverse effect of this treatment. DESIGN: Cross-sectional follow-up study. First, retrospective data pre- and post-GKR were collected. Patients then underwent a predefined survey including radiological, endocrinological, ophthalmological, and neurosurgical evaluation. Setting: Norwegian National Center for gamma knife treatment. Patients: Sixty-one patients treated with GKR for acromegaly. Out of 55, 53 living patients underwent a detailed survey. The mean follow-up was 5.5 years. No patient was lost to follow-up. RESULTS: Tumor growth was stopped in all patients. At 3, 5, and 10 years after GKR, 45, 58, and 86% of patients had normal IGF-I levels. Consecutive hormone value analysis showed that patients receiving GH-suppressive medication had a more rapid decline in hypersecretion than those who did not receive such medication. Evaluated by survey baseline values alone, non-elevated IGF-I and GH levels below 5 mIU/l were found in 38%. GH-suppressive medication was terminated in 16 out of 40 patients following GKR. Nine out of 53 surveyed patients (17%) had normal IGF-I and GH nadir below 2.6 mIU/l at glucose tolerance tests, while not on hormone-suppressive medication. Two patients developed minor visual field defects. Eight patients started hormone substitution therapy during the follow-up period. CONCLUSION: GKR is an effective adjuvant treatment for residual acromegaly, carrying few side effects.     

LONG-TERM RESULTS OF TRANSSPHENOIDAL PITUITARY MICROSURGERY IN 60 ACROMEGALIC PATIENTS

Sixty patients with clinically and biochemically active acromegaly were treated by transsphenoidal surgery. All patients underwent a full assessment of pituitary function both preoperatively and postoperatively; these studies were repeated 6 months after surgery and every year, when possible. The mean follow-up period was 3.3 years (range 0.5-7 years). The GH level normalized in 62% of patients after surgery. A paradoxical reaction of GH to TRH was present in 35 patients before surgery and had normalized in 17 after surgery. Large tumours were associated with higher GH levels than smaller tumours. A prognostic factor in terms of normalization of both the GH level and an eventual paradoxical reaction to TRH or a glucose challenge was a low preoperative GH level. Three out of seven patients with either a positive postoperative TRH test but a normal GH level, or a slightly elevated GH level suffered a biochemical and clinical recurrence and two of them underwent reoperation. In contrast, when the TRH test had normalized (always in association with normal GH levels) no recurrence was found. The impact of surgery on the other pituitary functions was generally slight and the numbers of patients with preoperative and postoperative impairment were about equal. Postsurgical radiation therapy was administered to patients with an elevated GH level, a non-normalized TRH test irrespective of whether the GH level had normalized, or local invasion of the tumour. In 11 out of 17 patients with elevated GH levels after surgery, normalization was achieved by radiation therapy after a mean period of 2.7 years. The incidence of pituitary failure after irradiation appeared to be high; gonadal function in men and the GH reserve function were especially vulnerable. From this study we conclude that in many cases the adenoma can be removed effectively, without compromising the other pituitary functions. However, a substantial number of the patients require additional radiation therapy, leading to an inevitable loss of other pituitary functions.     

GROWTH HORMONE DEFICIENCY AND THE MEASUREMENT OF SOMATOMEDIN C/IGF-I: THE INFLUENCE OF SEXUAL MATURATION

Fifty-nine short children 2–19 years, 25 females and 34 males, were studied for clinical and biochemical evidence of growth hormone deficiency (GHD). Group 1 ( n = 32), mean height SDS — 3.26 ± 1.5, mean retardation of bone age 2 years, had a mean peak GH of 6.1 ± 3.7 mIU/l during tests of GH release, and were classified as GHD. Group 2 ( n = 27), had a mean height SDS of - 2.65 ± 1, mean bone age retardation of 1.7 years and had a mean peak GH during provocation tests of 24.3 ± 11.1 mIU/l and were classified as non-GHD. Basal IGF-I concentrations were correlated with height and bone age, for both groups and for GHD children, with pubertal score. Neither peak GH values nor integrated GH concentrations in a provocative test were correlated with IGF-I values. The minimum IGF-I concentrations occurred at a bone age of 8 years, the reference point that was taken as the average expected time of maturational change. IGF-I concentrations rose in five GHD children when their bone age exceeded 8 years and when their free testosterone was greater than 10 pmol/l. Eighty-nine per cent of the GHD children with a bone age at or below 8 years were identified as GHD from their basal IGF-I values, but for, all bone ages this fell to 62.5%. Basal IGF-I values appear to be less discriminatory for identification of GHD as sexual maturity and bone age advance.     

How many tests are required to diagnose growth hormone (GH) deficiency in adults?

OBJECTIVE: The diagnosis of GH deficiency in adults relies on the results of GH provocative testing. Whilst in some patients the testing strategy is clear, this is not the case in all patients. The objective of this study was to further examine the concordance between the GH responses to two different provocative stimuli, to correlate this with the number of additional pituitary hormone deficits, and to produce guidelines as to which patients require two GH provocative tests and which require only one. STUDY DESIGN AND PATIENTS: The results of GH provocative tests were reviewed in 103 patients (mean age 28 years, 48 male), with documented or potential hypothalamic-pituitary disease and 35 normal volunteers (mean age 21 years, 18 male). All patients and normal volunteers underwent an insulin tolerance test (ITT) and an arginine stimulation test (AST). Severe GH deficiency was defined as a GH response to an ITT of < 5 mU/l and a GH response to an AST of < 2 mU/l, utilizing data from previous studies in this unit. Patients were divided into four groups according to the number of anterior pituitary hormone deficits present other than possible GH deficiency: no other pituitary hormone deficits (GHD0) or one, two or three other hormone deficits (GHD1, GHD2 or GHD3). RESULTS: The 103 patients were divided between the four groups as follows: 69 (67%) in GHD0, 15 (14. 6%) in GHD1, six (5.8%) in GHD2, and 13 (12.6%) in GHD3. There was a significant decline in the median GH peak to both the ITT and the AST with increasing numbers of other pituitary hormone deficits (P < 0.0001). If the magnitude of the difference between each individual's GH response to the ITT and AST is plotted against the mean GH value a clear trend is seen (Spearmans rank correlation = 0. 88, P < 0.0001) indicating that the magnitude of the difference between the GH responses to an ITT and AST increases with the underlying mean GH value. These data allow the estimation of the median ITT/AST ratio as 1.17 (CI 0.98, 1.39). None of the control subjects and 14.1% (10), 26.7% (four), 83% (five) and 92.3% (12) of groups GHD0, 1, 2 and 3, respectively, had severe GHD. The concordance between the AST and ITT (percent of patients in whom both tests confirmed or refuted the biochemical diagnosis of severe GHD) was 100%, 76.8%, 66.6%, 83.3%, and 92.3% in the controls, GHD0, 1, 2, and 3, respectively. Thus, 16/69 GHD0, 5/15 GHD1, 1/6 GHD2 and 1/13 GHD3 patients were misclassified by one or other test. CONCLUSION: We have demonstrated that a constant ratio links the GH response to an ITT and AST in an individual, rather than a constant difference, and that the difference between the GH responses to two provocative stimuli is greater in those patients with milder degrees of GH deficiency or insufficiency. These patients tend to have one or no additional pituitary hormone deficits and may be misclassified if a single GH provocative test is performed. We suggest that whilst a single GH provocative test can be used with confidence in patients with two or three additional pituitary hormone deficits, in patients with suspected isolated GH deficiency or with only one additional pituitary hormone deficit, two GH provocative tests should be performed.     

The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism

OBJECTIVE A number of studies of the effect of GH replacement therapy in adult patients with GH deficlency have been published, but the definition of GH deficiency has varied considerably. In order to define severe GH deficiency more critically we have determined GH status in the context of gonadotrophin, ACTH and TSH secretion in adult patients with pituitary disease. DESIGN Analysis of peak GH response to an insulin tolerance test performed during comprehensive assessment of pituitary function. PATIENTS One hundred and ninety non-acromegalic patients (96 male) with pituitary disease whose ages ranged from 16 to 72 (mean 39·4) years. MEASUREMENTS The patients were divided into four groups according to the number of anterior pituitary hormone deficiencies demonstrated; isolated GH deficiency (GHD0), or GH deficiency plus an additional one, two or three pituitary hormone deficits (GHD1, GHD2, GHD3). RESULTS The four groups were matched for age and blood glucose nadir during the ITT. The median (interquartile range) GH peaks were GHD0, 10·0 (5·4–16); GHD1, 4·0 (2·7–7·7); GHD2, 2·0 (1–2·9); GHDB, 1·8 (1–3·2) mU/l. There was a Significant downward trend in the medians (P < 0·0001). The differences between GHD0 and GHD1, and GHD1 and GHD2, were highly significant (P < 0·0001); however, there was no difference between GHD2 and GHD3. Ninety-one per cent of patients in combined groups GHD2 and GHD3, 55% in GHD1 and 24% in GHD0 had a peak GH < 5 mU/l. CONCLUSIONS Our study has shown that GH deficiency is variable according to the degree of hypopltuitarism present and that the greater the number of pituituary hormone deficits the more severe the GH deficiency. These observations will help to clarify the diagnosis of GH deficiency In adult life.