Factors determining the long-term outcome of surgery for acromegaly

Seventy-nine patients with acromegaly were investigated before and after transsphenoidal adenomectomy, to determine the immediate and late outcome, the pre-operative features associated with a good result, and the accuracy of post-operative testing in predicting outcome. Pre-operative evaluation included basal growth hormone (GH), GH response to oral glucose tolerance test (OGTT), GH response to thyrotrophin-releasing hormone (TRH), tests of pituitary reserve, and pituitary scanning to assess tumour size. A few weeks after surgery, these tests were repeated. The patients were recalled for late assessment 1-13 years (median 86 months) after the operation. At the immediate postoperative testing, minimum GH after oral glucose was < or = 2 mU/l in 48.7%, < 5 mU/l in 76.3% and < 10 mU/l in 84.2%. Only 12 patients had GH > 10 mU/l. Basal GH was < or = 2 mU/l in 21%, < 5 in 59.2%, < 10 in 73.6% and < 20 in 90.8%. A minimum GH of < or = 2 mU/l during an OGTT was achieved in 67.4% of patients with intrasellar tumours, compared with 27.3% with extrasellar tumours. Basal GH and post-glucose GH correlated with the late outcome. GH response to TRH showed no correlation with outcome. IGF-1, which could not be assessed in detail, correlated with GH but was not a reliable indicator of outcome. Transsphenoidal adenomectomy is thus a very satisfactory treatment for acromegaly. Postoperative levels of basal growth hormone < 5 mU/l and post-glucose GH < or = 2 mU/l can be regarded as a biochemical cure. Postoperative radiotherapy is not required in patients who achieve a good result. The preoperative factors which significantly influenced the final outcome were basal GH, post-glucose minimum GH, tumour size and impaired pituitary reserve.     

The effect of a new slow-release, long-acting somatostatin analogue, lanreotide, in acromegaly

OBJECTIVE: Previous studies have shown that somatostatin analogues such as octreotide and lanreotide are effective in suppressing GH and IGF-I levels in acromegaly, but the mode of administration and the frequency of injections were inconvenient for the patients. We have evaluated the effects of a new slow-release (SR), long-acting formulation of lanreotide, a somatostatin analogue, on clinical, biochemical and safety responses in acromegaly. DESIGN: We studied the effects of SR-lanreotide 30 mg administered intramuscularly twice or three times monthly for 6 months. Ten patients were studied, in whom acromegaly was confirmed by clinical features,mean GH > 5 mU/l, and failure to suppress GH to < 2 mU/l after a 75-g oral glucose load. MEASUREMENTS: Subjective improvement in clinical symptoms of acromegaly was graded and recorded. Any adverse reactions were noted. Plasma GH levels were measured every 10 min for one hour from 08300930h; fasting IGF-I levels were determined at 0830h; GH, glucose and insulin responses to oral glucose loading were measured at 0,30,60,90 and 120 minutes from 0930 to 1130h. Baseline measurements were carried out and repeated at 3 and 6 months. Biliary ultrasonography was performed at baseline and 6 months. RESULTS: GH levels in the 10 patients decreased from 26.8 12.0 (mean SEM) to 12.7 7.0 mU/l at 3 months (P = 0.04) and 9.8 5.0 mU/l at 6 months (P = 0.06). Fasting IGF-I levels decreased from 123.2 27.0 to 73.5 13.0 nmol/l at 3 months (P = 0.01), and increased slightly to 97.4 31.0 nmol/l (P = 0.05) but remained below baseline levels at 6 months. Five patients achieved good control (GH < 5 mU/l) at 3 months. In the remaining 5 patients the dose frequency was increased to every 10 days and one achieved good control. IGF-I levels normalized in 3 and 5 patients at 3 and 6 months, respectively. Fasting insulin levels and peak insulin after an oral glucose load did not change significantly at 3 months but decreased from 11.7 2.0 to 7.8 3.3 mU/l (P = 0.05) and 106.2 24.6 to 53.3 14.3 mU/l (P = 0.04) at 6 months, respectively. There was no significant change in fasting glucose at 3 or 6 months. Most patients reported clinical improvement in acromegalic symptoms. No major adverse events were reported, but mild to moderate gastrointestinal symptoms were recorded after the initial injections. One patient developed asymptomatic gallstones at 6 months. CONCLUSIONS: This slow-release formulation of lanreotide given either twice or thrice monthly was well tolerated, more convenient for patients, effective in controlling and alleviating the symptoms of acromegaly, as well as suppressing GH and IGF-I levels, and had no detrimental effects on carbohydrate tolerance in acromegaly.     

"Born from the flank"--discussion concerning "cesarean section" in animals in the Talmud

We determined growth hormone (GH) and insulin-like growth factor I (IGF-I) levels after a 3 h infusion of escalating doses of growth hormone-releasing hormone (GHRH(1-29)) followed by a bolus injection in hypopituitary patients with marked differences in pituitary features at magnetic resonance imaging (MRI) in order to evaluate further the contribution of MRI in the definition of pituitary GH reserve in GH-deficient patients. Twenty-nine patients (mean age 14.5 +/- 4.0 years) were studied. Group I comprised 13 patients: seven with isolated GH deficiency (IGHD) (group Ia) and six with multiple pituitary hormone deficiency (MPHD) (group Ib) who had anterior pituitary hypoplasia, unidentified pituitary stalk and ectopic posterior pituitary at MRI, Group II consisted of eight patients with IGHD and small anterior pituitary/empty sella, while in group III eight had IGHD and normal morphology of the pituitary gland. Growth hormone and IGF-I levels were measured during saline infusion at 08.30-09.00 h, as well as after infusion of GHRH (1-29) at escalating doses for 3h: 0.2 micrograms/kg at 09.00-10.00 h, 0.4 micrograms/kg at 10.00-11.00 h, 0.6 micrograms/kg at 11.00-12.00 h and an intravenous bolus of 2 micrograms/ kg at 12.00 h. In the group I patients, the peak GH response to GHRH(1-29) was delayed (135-180 min) and extremely low (median 2mU/l). In group II it was delayed (135-180 min), high (median 34.8 mU/l) and persistent (median 37.4 mU/l at 185-210 min). In group III the peak response was high (median 30.8 mU/l) and relatively early (75-120 min) but it declined rapidly (median 14.4 mU/l at 185-210 min). In one group I patient, GH response increased to 34.6 mU/l. The mean basal value of IGF-I levels was significantly lower in group I (0.23 +/- 0.05 U/ml) than in groups II (0.39 +/- 0.13U/ ml, p < 0.01) and III (1.54 +/- 0.46 U/ml, p < 0.001) and did not vary significantly during the GHRH(1-29) infusion. The present study demonstrates that the impaired GH response to 3 h of continuous infusion of escalating doses of GHRH(1-29) was strikingly indicative for pituitary stalk abnormality, strengthening the case for use of GHRH in the differential diagnosis of GH deficiency. The low GH response, more severe in MPHD patients, might be dependent on the residual somatotrope cells, while the better response (34.6 mU/l) in the group Ia patients might suggest that prolonged GHRH infusion could help in evaluating the amount of residual GH pituitary tissue. Pituitary GH reserve, given the GH response to GHRH infusion in GH-deficient patients with small anterior pituitary/empty sella, seems to be maintained.     

Evaluation of disease status with sensitive measures of growth hormone secretion in 60 postoperative patients with acromegaly

Traditionally, suppression of GH measured by polyclonal RIA to less than 2.0 microg/L after oral glucose was accepted as evidence of remission after transsphenoidal surgery for acromegaly. Recently, with newer, more sensitive GH assays, a cut-off of less than 1.0 microg/L has been suggested. With the development of accurate insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) assays, additional tools are now available for assessing postoperative GH secretion. There has, however, never been a systematic comparison of sensitive GH, IGF-I, and IGFBP-3 assays in defining disease status in a large cohort of postoperative patients with acromegaly. Therefore, we evaluated how the use of modern assays impacts on our assessment of disease activity in these patients. Sixty postoperative subjects with acromegaly and 25 age-matched healthy subjects were evaluated with nadir GH levels after 100 g oral glucose as well as baseline IGF-I and IGFBP-3 levels. GH was assayed by polyclonal RIA, sensitive immunoradiometric assay (IRMA), and highly sensitive enzyme-linked immunosorbent assay. The mean nadir GH determined by IRMA was 0.09 +/- 0.004 microg/L in the healthy subjects, with the upper limit of the normal nadir being 0.14 microg/L (mean + 2 SD). Subjects with acromegaly were divided into those with active disease (n = 22), defined by elevated IGF-I levels, and those in remission (n = 38), defined by normal IGF-I levels. GH determined by IRMA failed to suppress into the normal range defined by our healthy subjects in all patients with active disease; nadir GH determined by IRMA ranged from 0.33-5.0 microg/L in this group. In 50% of the active group, nadir GH levels determined by IRMA were less than 1.0 microg/L, a GH nadir previously considered normal by strict criteria. When nadir GH levels in the subjects with active disease were measured by polyclonal RIA, there was overlap with the range of RIA values in the healthy subjects. Thus, the IRMA was superior to the RIA in that the overlap between these two groups was eliminated. Subjects with acromegaly in remission included those with normal GH suppression (n = 23; mean nadir GH by IRMA, 0.10 +/- 0.006 microg/L) and others with abnormal GH suppression by IRMA (n = 15; mean nadir GH by IRMA, 0.35 +/- 0.07 microg/L). The latter group may have persistent GH dysregulation detected by the sensitive IRMA. GH levels measured by enzyme-linked immunosorbent assay confirmed the IRMA results. IGFBP-3 levels were significantly higher in subjects with active acromegaly (4940 +/- 301 microg/L) vs. those in healthy subjects (2887 +/- 153 microg/L; P < 0.0001) and those in the subjects in remission (2966 microg/L; P < 0.0001). IGFBP-3 levels correlated overall with IGF-I levels (r = 0.765; P < 0.0001), but IGFBP-3 levels were not predictive of disease status because 32% of the subjects with active acromegaly had normal IGFBP-3 levels. In addition, failure of GH to suppress adequately was not associated with a higher IGFBP-3 level among the subjects in remission. These data indicate that the IRMA is superior to the RIA in distinguishing between patients with active disease (defined by elevated IGF-I levels) and healthy subjects. We also show that GH levels after oral glucose measured with highly sensitive GH assays can be much lower in subjects with active disease than previously believed; values less than 1.0 microg/L may be found in up to 50% of patients. In addition, in 39% of patients in apparent remission with normal IGF-I levels, GH determined by highly sensitive assays fails to suppress normally; it remains to be determined whether these patients are at higher risk for recurrence of active disease.     

Hypothalamic dysfunction in "cured" acromegaly is treatment modality dependent

The current definition of cure after treatment for acromegaly stipulates a reduction in GH levels to less than 2 ng/mL (< 5 mU/L), as such GH concentrations are believed to be associated with normalization of long term survival. We sought to further define the nature of the cure in such patients, when cure has been achieved by alternative therapeutic modalities, in the expectation that hypothalamic neuroregulatory control of GH secretion might be affected differently by radiotherapy or surgery. In particular we wished to determine the effect of therapy modality on endogenous somatostatin (SMS) tone, using the GH response to i.v. arginine as a paradigm. We studied 20 patients with cured acromegaly (mean 24-h GH concentration, < 2 ng/mL). Eight patients had been cured by surgery only (S; 4 women and 4 men; mean +/- SEM age, 52 +/- 5 yr), and 12 patients had been cured by radiotherapy (R; 4 women and 8 men; age, 52 +/- 3 yr). Sixteen healthy subjects were studied as a control group (C; 6 women and 10 men; age 53 +/- 3]. The median (range) GH during 24-h profiles was similar in each group: S, 1.3 (0.7-1.8) ng/mL; R, 0.6 (0.4-1.8) ng/mL; and C, 0.7 (0.4-3.2) ng/mL (P = 0.57). The median incremental GH responses to arginine were significantly lower in the R group compared with those in the S and C groups: S, 6.4 (2.1-16.6) ng/mL; R, 0.1 (0-1.7) ng/mL; and C, 9.2 (0-16.1) ng/mL (P = 0.0002; S vs. R, P < 0.01; S vs. C, P > 0.05; R vs. C, P < 0.001). We conclude that in acromegalic patients deemed to be cured (GH, < 2 ng/mL), the mode of therapy has considerable influence on the remaining hypothalamic-somatotroph function. In view of the putative mechanism by which arginine releases GH, we suggest that radiotherapy leads to a reduction or complete loss of endogenous SMS tone. This may have implications for the treatment of those acromegalic patients who are not cured (GH, > 2 ng/mL) and who require SMS analog therapy.     

Use of an AC induction motor system for producing finger movements in human subjects

Cushing's disease appears as a functionally heterogeneous disease, but criteria that are able to distinguish between different clinical forms remain elusive. We compared two subgroups of patients with proven Cushing's disease according to the size of the pituitary adenoma, evaluated by computed tomography or magnetic resonance imaging. Our series comprised 11 patients with a microadenoma and 10 with a macroadenoma (median volumes (range): 173 (13-270) and 3022 (500-10312) mm3 respectively; P < 0.0001). The clinical presentation was similar in the two groups, but the time elapsed before diagnosis was longer, and visual impairment was less frequent in the patients with a microadenoma (1.5+/-0.8 years and 0%) than in those with a macroadenoma (0.7+/-0.6 years and 40%; P < 0.05). Morning and evening peripheral concentrations of ACTH were greater in patients with macroadenoma (134+/-78 and 130+/-7 ng/l respectively) than in those with microadenoma (52+/-28 and 56+/-19 ng/l, P < 0.05). Hypokalaemia and lymphopenia were also more pronounced in patients with macroadenoma (3.4+/-0.3 mmol/l and 1273+/-401 lymphocytes/mm3) than in those with microadenoma (3.8+/-0.3 mmol/l and 1852+/-668 lymphocytes/mm3 P < 0.05), although morning and evening plasma cortisol concentrations were similar in both groups. In patients with macroadenoma, there was less relative nycthemeral variation of ACTH concentrations (28+/-24%, compared with 62+/-39% in those with microadenoma; P < 0.05), less suppression of plasma cortisol by high doses of dexamethasone (-30+/-14%, compared with -61+/-25%; P < 0.05), and a reduced concentration ratio of mean basal cortisol to ACTH (7+/-3, compared with 12+/-5; P < 0.05). Plasma IGF-I concentration and the TSH peak response to TRH were significantly lower in patients with macroadenoma than in those with microadenoma (0.4+/-0.2 x 10(3) IU/I and 2.3+/-1.8 mIU/I, compared with 1.8+/-0.6 x 10(3) IU/I and 5.2+/-1.6 mUI/l; P < 0.05). Thus, in comparison with microadenomas, corticotroph macroadenomas are characterized by a greater and more autonomous ACTH secretion, inducing more pronounced biological signs of hypercorticism, and are more often accompanied by visual field defects and impairment of other pituitary hormonal secretions.     

A hairpin-loop conformation in tandem repeat sequence of the ice nucleation protein revealed by NMR spectroscopy

We report two cases of acromegaly due to pituitary adenoma without any other endocrinopathy in a family. The patients had high plasma GH and were improved by transsphenoidal adenomectomy. Acromegaly is usually a clinical syndrome of sporadic nonfamilial occurrence. The familial occurrence of acromegaly not associated with multiple endocrine neoplasia is very rare. Our patients are unlikely to be associated with the multiple endocrine neoplasia type 1 syndrome. Here we describe two patients with acromegaly, a father and his daughter, and review familial cases reported.     

Remission of acromegaly caused by pituitary carcinoma after surgical excision of growth hormone-secreting metastasis detected by 111-indium pentetreotide scan

GH-secreting carcinomas of the pituitary are extremely rare. We describe a 37-yr-old woman with refractory acromegaly 15 yr after transphenoidal surgery and radiotherapy, with no evidence of a recurrent pituitary mass. Scanning with 111-indium pentetreotide revealed an area of intense activity in the left neck. A 3.5 x 2.5-cm mass was excised from the neck after demonstrating an arterio-venous GH gradient of 7:1. GH levels (50 ng/mL) dropped to 0.8 ng/mL 3 h after surgery and remained normal. GH gene expression was demonstrated in the metastasis by Northern and Western blot analyses and by positive immunocytochemistry and immunoelectron microscopy. In vitro cultured cells responded to GHRH and TRH by increasing GH levels (P < 0.01). Medium GH was identical to authentic pituitary GH, as demonstrated by high pressure liquid chromatography. RT-PCR of hypothalamic hormone receptor messenger RNA in the mass revealed somatostatin receptor subtypes 2, 3, and 5 and GHRH, TRH, and dopamine receptor expression. No GH gene amplification, rearrangement, or gsp mutation was found. RB gene deletion and H-ras mutations, previously reported in PRL- and ACTH-secreting carcinomas, were not detected. In conclusion, clinical and molecular features of a GH-secreting pituitary carcinoma are presented. This metastatic lesion synthesized GH and expressed functional hypothalamic hormone receptors.     

Increasing required neural response to expose abnormal brain function in mild versus moderate or severe Alzheimer''s disease: PET study using parametric visual stimulation

OBJECTIVES: Glycaemic control often deteriorates during puberty in girls with insulin dependent diabetes mellitus (IDDM). This may be due in part to the normal psychosocial changes associated with adolescence. Puberty is, however, also characterized by rapid somatic development, orchestrated by hormonal changes. Some of these hormones play a major role in glucose homeostasis. We have examined the insulin-GH-IGF-I axis in 11 adolescent girls with poorly controlled insulin dependent diabetes and compared the data with those of 10 non-diabetic girls matched for age, pubertal stage and body mass index (BMI). METHODS: Serum profiles of glucose, insulin, GH and IGF binding protein 1 (IGFBP1) were analysed in addition to IGF-I in serum and nocturnal urinary excretion of GH. MEASUREMENTS: Serum glucose, insulin and IGFBP1 were measured every hour for 24 h, whereas GH in serum was measured every 30 minutes during the same period. Nocturnal urinary GH was analysed as a mean of three consecutive nights. RESULTS: The insulin profiles of the IDDM patients were flat with low post-prandial peaks, corresponding to only one-third of the peaks of the non-diabetic girls. The integrated insulin levels, both during 24-h sampling and during daytime, were significantly lower in the diabetic group. There were no differences during night-time. The diabetic patients had elevated mean baseline levels of serum GH (IDDM 2.8 +/- 0.5 mU/l, controls 0.7 +/- 0.2; P < 0.001), a higher 24-h mean serum GH level (9.8 +/- 1.7 mU/l vs. 4.4 +/- 0.7; P < 0.001), significantly more peaks and a urinary GH excretion twice as high as in the non-diabetic group. An interesting observation was the finding of marked differences in daytime GH concentrations between the groups, both regarding overall integrated levels (GH AUC 103 +/- 15.8 and 35.9 +/- 7.1 mU/l x 12 h, respectively; P < 0.005) as well as baseline levels (3.8 +/- 0.6 mU/l vs. 0.7 +/- 0.2; P < 0.001). In contrast, during night-time only the mean basal levels of GH differed. The level of IGF-I was reduced in the diabetic group compared with the healthy controls (IDDM 233 +/- 19 micrograms/l vs. controls 327 +/- 21; P < 0.005). In addition, the IDDM patients had significantly increased concentrations of IGFBP 1, but kept a normal diurnal rhythm with a pronounced night peak. CONCLUSION: Hypoinsulinaemia in adolescent IDDM patients, particularly in the portal hepatic circulation, results in decreased IGF-I and increased IGFBP 1 production in the liver. High levels of IGFBP 1 may, in turn, reduce the bioactivity of IGF-I even further. Low levels of IGF-I will lead to increased GH secretion. Earlier studies on the relationship between GH and diabetic control have focused on elevated GH levels during the night. In this study we have observed markedly elevated levels of GH also during daytime in adolescent IDDM patients. This indicates increased insulin resistance and insulin demand also during the day in diabetic subjects. The increased insulin resistance may result in hyperglycaemia leading to additional insulin resistance. A vicious circle may thus be induced, accelerating metabolic impairment in poorly controlled adolescent IDDM girls.     

Medical management after pituitary surgery

Although the majority of patients with pituitary tumor, undergoing transsphenoidal microsurgery, have a low incidence of hormonal deficiency after surgery, the endocrinological evaluations should be carefully done before and after surgery. Glucocorticoid replacement is necessary in patients with Cushing's disease during and after surgery as well as those with adrenal insufficiency. Repeated CRF test is useful to assess the secondary adrenal insufficiency of Cushing's disease after surgery. Patients with impaired secretion of both ACTH and TSH should receive glucocorticoid replacement before thyroid hormone replacement in order to avoid adrenal crisis. A combination of CRF, GRF, TRH and GnRH is a safer and more reliable test to evaluate pituitary function than the conventional triple test consisting of insulin, TRH and GnRH, especially in patients predicted to have pituitary-adrenal insufficiency. Diabetes insipidus(DI), immediately after pituitary surgery, should be treated with subcutaneous injection of Pitressin. Even if patients seem to have recovered from DI several days after surgery, they must be monitored closely because of the incidence of triphasic DI. Less attention has been given to replacement for GH deficiency in adults. Recent reports revealed that GH replacement in adults with GH deficiency decreases visceral fat tissue and increases plasma calcium, phosphorus, osteocalcin and procollagen III levels. GH replacement will become more popular even in adults. Many options and technological advantages in the diagnosis and treatment of pituitary tumors have developed in a decade. In the near future, post-operative patients with pituitary tumors must be cared for in view of the "quality of life".     

Effect of octreotide pretreatment on surgical outcome in acromegaly

Pretreatment with octreotide (OCT) in acromegaly has been reported to improve surgical outcome. The objective of this study was to analyze retrospectively the effects of a 3- to 6-month presurgical treatment with OCT in acromegalics focusing on electrocardiographic (ECG) records, blood pressure levels, glucose and lipid profile, tumor size and consistency, easy tumor removal at surgery, and morphological findings at pathology. Fifty-nine patients with acromegaly who were undergoing surgical treatment were studied randomly before surgery; 37 patients were untreated, and 22 were treated with OCT at doses ranging 150-600 micrograms/day for 3-6 months. At study entry, untreated and OCT-treated patients had similar circulating GH and insulin-like growth factor I (IGF-I), glucose, and cholesterol levels as well as prevalence of overt diabetes mellitus, hypertension, and ECG abnormalities. In untreated and OCT-treated patients, respectively, radiological imaging documented microadenoma in 0 and 1, intrasellar macroadenoma in 10 and 6, intra- and suprasellar macroadenoma in 18 and 11, invasive macroadenoma in 9 and 4 patients. Before surgery, serum GH and IGF-I levels significantly decreased in the 22 OCT-treated acromegalics, and in 5 of them, a significant shrinkage was documented. ECG abnormalities disappeared in 7 of 11 (63.6%) OCT-treated patients. In 3 of the 7 patients with diabetes mellitus, treatment with OCT together with low carbohydrate intake normalized blood glucose levels, whereas in 2 patients, insulin could be replaced by oral antidiabetics, and in 2 patients, the insulin dose was reduced. Presurgical blood glucose, total cholesterol and triglyceride levels, as well as systolic (145.2 +/- 3.4 vs. 132.9 +/- 2.5 mm Hg; P < 0.01) and diastolic (94.3 +/- 1.7 vs. 84.3 +/- 1.6 mm Hg; P < 0.001) blood pressure levels were significantly higher in untreated than in OCT-treated patients. Two weeks after surgery, circulating GH and IGF-I levels were normalized in 11 untreated (29.7%) and 12 OCT-treated (54.5%) patients (P < 0.005, by chi 2 test). Macroscopically, no difference was found between untreated and OCT-treated adenomas, whereas at pathology, a significant increases in cellular atypia (31.6% vs. 19.2%; P < 0.05) was found in OCT-treated adenomas. One patients in the untreated group died from cardiorespiratory arrest during the early postoperative period. Finally, the average duration of hospitalization after operation was longer in untreated than in OCT-treated patients (8.6 +/- 0.7 vs. 5.6 +/- 0.5 days). We conclude that a 3- to 6-month treatment with OCT before surgery for GH-secreting adenoma improved clinical conditions and surgical outcome and reduced the duration of hospitalization after operation.     

TNF-alpha-induced corticosterone elevation but not serum protein or corticosteroid binding globulin reduction is vagally mediated

OBJECTIVE: Growth deficiency is commonly seen in polytransfused beta-thalassaemia patients, especially in adolescence. It is not completely dependent on the lack of their pubertal growth spurt. GH impairment at different levels (hypothalamic or pituitary) and/or a reduced IGF-1 synthesis have been suggested the main causes of stunted growth in these patients. We evaluated the relationship between GH reserve and growth in short beta-thalassaemia patients. PATIENTS: Twenty-nine short patients (height < -1.8 SDS for chronological age) were divided into two groups (low and normal responders) on the basis of their GH peak during insulin and clonidine tests (< or = and > 20 mU/l, respectively). All but one low responders underwent the GHRH test to exclude the impairment of somatotroph function and in eight of them an IGF-1 generation test was also performed. The two groups were compared with each other with respect to growth (height deficiency, height velocity, bone age and bone delay), haematological characteristics (serum ferritin levels, age at the start both of low (subcutaneous) s.c. infusion of desferrioxamine and of transfusional therapy) and serum IGF-1 and IGF-1 binding protein 3 levels. RESULTS: Thirteen patients (45%) (11 males, two females) were low responders, all but two having serum IGF-1 < 5th centile (< 0.1 centile in 42%); the GHRH test excluded the impairment of somatotroph function in 8/12. Height deficiency, serum ferritin levels, and age at the start of s.c. chelating therapy did not differ in low compared to normal responders. Height was negatively correlated both with the age at the start of s.c. chelating therapy and with serum ferritin levels. CONCLUSION: The reduction of GH reserve, more frequently due to a hypothalamic than to a pituitary dysfunction, is frequent in polytransfused beta-thalassaemia patients, especially in males. The height function is not related to the GH reserve, given the current methods for testing GH reserve. Late start of s.c. chelating therapy as well as haemosiderosis seem to play a role in the height deficiency, but not in GH reserve. Impairment of GH secretory reserve, therefore, cannot be considered the main cause of height deficiency in these patients.     

In vivo responsiveness of morphological variants of growth hormone-producing pituitary adenomas to octreotide

The somatostatin analog, octreotide, is an inhibitor of growth hormone (GH) secretion that has been used to treat patients with GH-producing pituitary tumors. In this study we investigated the in vivo responsiveness to treatment with this analog in patients harboring different morphological types of GH-producing pituitary adenomas. Both GH and insulin-like growth factor I (IGF-I) plasma levels in 30 patients treated with octreotide (300 micrograms/day) for 4 months preoperatively were compared with those from 30 patients who did not receive treatment preoperatively. Tissue samples were studied using ultrastructural and immunohistochemical techniques. Amongst patients harboring densely granulated (DG) adenomas, mean GH levels were reduced to 32 +/- 9% by octreotide, to 30 +/- 7% by surgery and to 26 +/- 9% of baseline by both interventions. Surgery was equally as effective in lowering GH levels in patients with sparsely granulated (SG) adenomas as it was in those with DG adenomas; in patients with SG adenomas, GH levels were reduced by surgery alone to 37 +/- 16% and to 24 +/- 15% when performed following octreotide pretreatment. In contrast, treatment with octreotide alone in patients harbouring SG adenomas reduced GH levels to only 70 +/- 13% of baseline (p < 0.02 compared to surgery alone, or surgery and octreotide). We conclude that the GH inhibitory effects of octreotide are significantly better in patients harboring DG somatotroph adenomas compared with those harboring SG adenomas.     

A new heat shock protein that binds nucleic acids

Familial acromegaly/gigantism occurring in the absence of multiple endocrine neoplasia type I (MEN-1) or the Carney complex has been reported in 18 families since the biochemical diagnosis of GH excess became available, and the genetic defect is unknown. In the present study we examined 2 unrelated families with isolated acromegaly/gigantism. In family A, 3 of 4 siblings were affected, with ages at diagnosis of 19, 21, and 23 yr. In family B, 5 of 13 siblings exhibited the phenotype and were diagnosed at 13, 15, 17, 17, and 24 yr of age. All 8 affected patients had elevated basal GH levels associated with high insulin-like growth factor I levels and/or nonsuppressible serum GH levels during an oral glucose tolerance test. GHRH levels were normal in affected members of family A. An invasive macroadenoma was found in 6 subjects, and a microadenoma was found in 1 subject from family B. The sequence of the GHRH receptor complementary DNA in 1 tumor from family A was normal. There was no history of consanguinity in either family, and the past medical history and laboratory results excluded MEN-1 and the Carney complex in all affected and unaffected screened subjects. Five of 8 subjects have undergone pituitary surgery to date, and paraffin-embedded pituitary blocks were available for analysis. Loss of heterozygosity on chromosome 11q13 was studied by comparing microsatellite polymorphisms of leukocyte and tumor DNA using PYGM (centromeric) and D11S527 (telomeric), markers closely linked to the MEN-1 tumor suppressor gene. All tumors exhibited a loss of heterozygosity at both markers. Sequencing of the MEN-1 gene revealed no germline mutations in either family, nor was a somatic mutation found in tumor DNA from one subject in family A. The integrity of the MEN-1 gene in this subject was further supported by demonstration of the presence of MEN-1 messenger ribonucleic acid, as assessed by RT-PCR. These data indicate that loss of heterozygosity in these affected family members appears independent of MEN-1 gene changes and suggest that a novel (tissue-specific?) tumor suppressor gene(s) linked to the PYGM marker and expressed in the pituitary is essential for regulation of somatotrope proliferation.     

Glycoprotein hormone alpha-subunit secretion in non-functioning pituitary adenomas

The aim of the present study was to investigate the prevalence of elevated free glycoprotein hormone alpha-subunit in different pituitary adenomas, to establish the diagnostic value of the basal and stimulated free alpha-subunit secretion in non-functioning adenomas. Serum basal levels of alpha-subunit were increased in 1 of 22 untreated, in 1 of 16 operated patients with non-functioning adenoma, in 6 of 28 untreated, in 1 of 7 operated patients with acromegaly, in 0 of 5 untreated prolactinomas and in 0 of 1 untreated gonadotrop adenoma. Overall free alpha-subunit levels were increased in 9 of 79 cases (11.4%). In 6 of 9 patients with untreated non-functioning adenoma thyrotrop hormone releasing hormone caused an abnormal--paradox--elevation of serum alpha-subunit. These data indicate that measurement of basal and stimulated alpha-subunit is of relatively poor value in the diagnosis of non-functioning pituitary adenomas. The transsphenoidal surgery did not resulted in a change of alpha-subunit secretion neither in patients with non-functioning adenoma nor with acromegaly. The present data confirm the view that non-functioning pituitary adenomas are not homogeneous since this subset of tumors includes adenomas that either do not secrete measurable amounts of free alpha-subunit or produce normal or supranormal amounts of subunits as consequence of still undefined biosynthetic abnormalities.     

The influence of sleep breathing disorder on growth hormone secretion in children with tonsil hypertrophy

INTRODUCTION: Recently it has been revealed that Obstructive Sleep Apnea Syndrome has an influence on the endocrine system, especially to the secretion of growth hormone (GH). It was previously reported that secretion of GH has a circadian rhythm along with a correlation with slow wave sleep. Normally in a pediatric patient, after 90 min of sleep the brain wave shows patterns of deep sleep, and a matching peak in GH secretion is observed. We have studied the effect of GH secretion in sleep breathing disorder of pediatric patients by observing the pre- and post-operative difference in GH secretion in children with tonsillar hypertrophy who had tonsillectomies. MATERIAL AND METHODS: Ten pediatric patients who complained of sleep apnea or hypopnea, and were highly suspected of having sleep breathing disorders due to tonsil hypertrophy and underwent surgery were chosen. Pre and post-operative blood somatomedin C and urinary growth hormone levels were measured. In 6 of the 10 patients blood GH levels were measured after overnight collection of blood every 30 min through a catheter placed in the vein. METHOD OF ANALYSIS: Integral blood GH calculated from GH levels of the blood samples taken every 30 min was used to express the efficacy of GH secretion during sleep, and was compared with blood somatomedin C and urinary GH levels. Pre- and post-operative somatomedin C and urinary GH measurements were compared. RESULT: 1) In 6 of the 10 patients, there was a positive correlation with integral GH and urinary GH, and no correlation with integral GH or somatomedin C. 2) Post-operatively, 7 of the 10 patients had increased urinary GH levels, 1 showed no change and 2 had decreased levels. There was a significant increase in the mean urinary GH levels from 18.6 +/- 16.1 pg/ml pre-operatively to 35.8 +/- 19.6 pg/ml post-operatively (P < 0.05). 3) Eight of the 10 patients had a post-operative increase in somatomedin C levels, 1 showed no change and the other patient had a decreased level. There was a significant increase in mean somatomedin C levels from 175.9 +/- 124.8 ng/ml pre-operatively to 226.6 +/- 134.3 ng/ml post-operatively (P < 0.01). CASE: An 8-year-old-boy was diagnosed as having habitual tonsillitis and suspected sleep breathing disorder, and was admitted to our hospital for a tonsillectomy. Apnea and hypopnea were observed during sleep in the hospital. After receiving his parents' consent, GH secretion was evaluated before and after the tonsillectomy. Integrated GH measurements, somatomedin C and urinary GH increased significantly after the operation. CONCLUSION: In this study, the improvement of sleep breathing disorder by surgery was associated with a positive effect to the GH secretion. GH secretion is important for growth of a child. Wen the cause of sleep breathing disorder is evident in the upper airway system, active treatment and cure by surgery is advised. Measurement of urinary GH in the morning is useful and simple for evaluating the ability to secrete GH.     

Reassessment of the role of radiation therapy in the treatment of endocrine-inactive pituitary macroadenomas

OBJECTIVE: This prospective clinical trial was undertaken to assess the rate of tumor recurrence in patients with endocrine-inactive pituitary macroadenomas who underwent gross total surgical resection of their tumors and did not receive adjuvant radiotherapy. METHODS: Between December 1987 and July 1994, 45 patients with endocrine-inactive pituitary macroadenomas underwent transsphenoidal surgery. In 38 (84%) of these patients, gross total surgical resection was achieved and was confirmed by postoperative magnetic resonance imaging (n = 37) or computed tomography (n = 1). After receiving counseling from the neurosurgeon concerning the risks and benefits of radiation therapy, 32 of the 38 patients elected not to receive adjuvant radiotherapy. Patients were followed through March 1998 with radiographic imaging obtained every 6 months for the first 2 years, annually for postoperative Years 3 and 4, and then every 2 to 3 years thereafter. The study end point was defined as radiographic tumor recurrence or patient death. RESULTS: The mean follow-up duration for the study group was 5.5 years. During that time, 2 of 32 (6%) patients developed recurrence, at 18 and 24 months, respectively, after initial surgery. Both were successfully treated using radiation therapy, with one requiring additional surgery. Three additional patients died as a result of unrelated causes 9, 12, and 49 months, respectively, after initial surgery. Immunocytochemical analysis revealed 66% of the tumors to be weak gonadotroph cell adenomas, 22% to be null cell adenomas, 9% to be silent prolactinomas, and 3% to be silent corticotroph cell adenomas. CONCLUSION: This study demonstrates a 6% 5-year recurrence rate in patients with endocrine-inactive pituitary macroadenomas treated using gross total surgical resection alone. Reserving radiation therapy for the infrequent patient with recurrence and sparing the majority of patients the associated risks inherent in its use seems reasonable.     

Indium-111 pentetreotide single-photon emission tomography in patients with TSH-secreting pituitary adenomas: correlation with the effect of a single administration of octreotide on serum TSH levels

Few data are available on the visualization of somatostatin receptors in vivo in patients with thyrotropin (TSH)-secreting adenoma. We studied five patients with TSH-secreting adenomas using single-photon emission tomography (SPET) after administration of indium-111 pentetreotide. The intensity of 111In-pentetreotide uptake by the tumours was correlated with the degree of TSH suppression after a single administration of 100 microg octreotide s. c. Five patients (three women and two men) aged 27-46 years were investigated. Except for one patient with acromegaly, all had pure TSH-secreting tumours. One patient was previously untreated, while two had received octreotide, one antithyroid drugs, and one radioiodine. In all patients SPET demonstrated increased uptake of 111In-pentetreotide by the pituitary adenoma. The target to non-target ratio (T/nT) of 111In-pentetreotide uptake was higher than 10 in three patients. Administration of 100 microg octreotide s. c. caused a significant reduction in TSH levels from 4.8+/-1.4 mU/l to a nadir of 3.1+/-1.1 mU/l after 6 h (P<0.001 by ANOVA). Suppression of TSH secretion ranged from 30% to 60% of the baseline value. The T/nT ratio showed a trend toward a direct relationship with the degree of TSH inhibition after acute octreotide administration (r=0.67; P=NS). Our study showed that 111In-pentetreotide scan visualized somatostatin receptors in all five of the patients with TSH-secreting pituitary adenomas, confirming the frequent presence of somatostatin receptors in these rare tumours, even though the correlation with the TSH inhibition after a single administration of octreotide did not reach significance.     

Bomocriptine treatment of patients with acromegaly resistant to conventional therapy

Eleven patients with active acromegaly resistant to conventional therapy were treated with bromocriptine for 15 (12--22) months by increasing the daily dose stepwise from 5 to 10--60 mg. A satisfactory response was achieved in all but one of the eight patients, in whom the mean diurnal level of serum GH was less than 50 ng/ml, whereas patients with grossly elevated serum GH levels responded poorly. In the longterm, no overall effects on glucose tolerance or plasma insulin (IRI) levels were observed but the chemical diabetes of three patients ameliorated in two. On the other hand, a dose-dependent acute suppressive effect of bromocriptine on plasma IRI response to oral glucose was observed, suggesting a direct effect of bromocriptine on the release of insulin from beta cells. Bromocriptine seems to be a good alternative in the treatment of patients with acromegaly who have not responded to conventional therapy.     

Multiple pituitary hormone deficiencies in a patient with spinocerebellar ataxia: magnetic resonance imaging and hormonal studies

Degenerative spinocerebellar ataxia has a rare association with hypogonadotropic hypogonadism. In this report we present the results of the detailed endocrine evaluation and magnetic resonance imaging in one such patient. A 20-year-old male with progressive cerebellar ataxia, hypogonadism, and short stature was investigated. Basal testing revealed hypogonadotropic hypogonadism (LH < 5 mU/L, FSH < 5 mU/L, testosterone 2.5 nM/L). There was no rise in LH after stimulation with LHRH, peak LH level being < 5 mU/L. Insulin hypoglycemia testing was consistent with GH deficiency, with peak GH being 3.2 mU/L. On TRH stimulation, there was no significant rise in prolactin, though the TSH response was normal. Magnetic resonance imaging revealed cerebellar atrophy. The anterior pituitary was atrophic, with a height of 1.4 mm. The posterior pituitary and the pituitary stalk were normal in size and position. This patient with degenerative spinocerebellar ataxia had multiple pituitary hormone deficiencies. The results of our endocrine evaluation and MR imaging lead us to believe that these deficits may result from a lesion at the level of the pituitary gland.