Recovery from paradoxical growth hormone responses in acromegaly after transphenoidal selective adenomectomy

A patient with acromegaly was studied before and after treatment by transphenoidal removal of a pituitary adenoma. "Paradoxical" GH responses to the dopamine agonists L-DOPA and ampomorphine disappeared after surgery, with reversion of GH responsiveness to normal. TSH-releasing hormone (TRH)-induced GH release observed pre-operatively did not occur after surgery. The findings suggest that in certain cases, acromegaly is due to pituitary dysfunction alone.     

Treatment of vancomycin-resistant Enterococcus faecium infections with an investigational streptogramin antibiotic (quinupristin/dalfopristin): a report of fifteen cases

OBJECTIVE: Previous studies of surgical treatment for acromegaly have used varied criteria for 'cure', but elevated GH levels are considered to be associated with continuing disease activity. We wished to analyse the results of transsphenoidal pituitary surgery for acromegaly and assess the longer-term outcome for patients not offered further treatment when post-operative levels of GH < 5 mU/l were achieved. DESIGN: We studied a retrospective group of patients who underwent transsphenoidal surgery for acromegaly at St Bartholomew's Hospital between 1985 and 1993. PATIENTS: One hundred consecutive patients (53 male, mean age 46 years, range 18-68 years) undergoing transsphenoidal surgery for acromegaly were assessed. The patients were followed for a mean of 3.8 years (range 0.5-8 years) after operation. MEASUREMENTS: GH levels are represented as a mean value from a four-point day curve taken at 0830, 1300, 1700 and 1900 h. ACTH reserve was assessed basally and, if this was normal, with the insulin tolerance or glucagon tests. TSH, T4, PRL, LH, FSH, testosterone or oestradiol and plasma and urine osmolality were also measured. RESULTS: Post-operatively, 42% of patients achieved a mean GH level of < 5 mU/l. The success of surgery was related to the preoperative GH level; 65% of the patients with preoperative GH levels < 20 mU/l but only 18% of the patients with GH levels > 100 mU/l achieved post-operative GH values < 5 mU/l. In addition, tumour size influenced the outcome of surgery with 61% of patients with a microadenoma but only 23% of patients with a macroadenoma achieving post-operative GH levels of < 5 mU/l. Of the 42 patients considered in remission post-operatively (mean GH < 5 mU/l), 32 were available for long-term follow-up and were not offered any further treatment: only one of these has shown evidence of mild biochemical recurrence after a mean follow-up of 3.8 years (range 0.5-8). There were no peri-operative deaths. Two patients required surgical repair for CSF leaks and there were eight documented cases of meningitis. Permanent diabetes insipidus was noted in eight patients post-operatively. New anterior pituitary deficiency occurred in 21% of patients following surgery; 73% had unaltered pituitary function and in 6% recovery of partial hypopituitarism was noted. CONCLUSIONS: The stated outcome of surgery depends on the criteria adopted. Safe GH levels (mean levels < 5 mU/l) can be achieved in 42% of an unselected series of patients with acromegaly and if the tumour is a microadenoma this figure rises to 61%. Based on the current evidence it is safe not to offer further treatment to those patients in whom post-operative GH < 5 mU/l are achieved.     

Effect of human C-reactive protein on chemokine and chemotactic factor-induced neutrophil chemotaxis and signaling

C-reactive protein (CRP) is a unique serum pentraxin and the prototype acute phase reactant. CRP is a ligand for specific receptors on phagocytic leukocytes, and mediates activation reactions of monocytes/macrophages, but inhibits the respiratory burst of neutrophils (PMN). Since CRP selectively accumulates at inflammatory sites in which IL-8 is also produced, we tested the effects of CRP on the responsiveness of PMN to IL-8 and the bacterial chemotactic peptide, FMLP-phenylalanine (FMLPP). Purified human CRP inhibited the chemotactic response of PMN to IL-8 and FMLPP. A mouse IgM mAb that was generated against the leukocyte CRP receptor (CRP-R) also inhibited the chemotactic response. Incubation of purified CRP with activated PMN generated CRP-derived peptides that also inhibited chemotaxis. A synthetic CRP peptide (residues 27-38) that binds to the CRP-R had weak chemotactic activity, whereas two other CRP synthetic peptides (residues 174-185 and 191-205) inhibited chemotaxis of PMNs to both IL-8 and FMLPP. CRP did not alter receptor-specific binding of IL-8, but exerted its effect at the level of signaling. CRP augmented both IL-8- and FMLPP-induced mitogen-activated protein kinase (extracellular signal-regulated kinase-2) activity. CRP at acute phase levels increased both agonist-induced and noninduced phosphatidylinositol-3 kinase activity. The results suggest a role for CRP as a regulator of leukocyte infiltration at inflammatory sites.     

Differential presentation of cortical and trabecular peripheral bone mineral density in acromegaly

Growth hormone (GH) has been suggested as a therapeutic tool for the treatment of osteopenia. To assess the differential influence of growth hormone on cortical and trabecular bone, bone mineral densities (BMD) of the ultradistal radius were determined in 18 men and 19 women with clinically and biochemically confirmed acromegaly using peripheral computed tomography and a specialized scanner (Stratec XCT 900). The results were expressed in equivalents to hydroxyl-apatite (mg/ccm) and compared with the BMD of healthy controls (17 men, 34 women). Cortical bone mineral density was significantly higher in acromegalic women (295.2 +/- 18.4, X +/- SEM) and men (339.4 +/- 21.2) compared to healthy women (243.0 +/- 12.8) and men (272.2 +/- 15.9). In contrast, trabecular BMD did not differ between acromegalic patients (men: 161.0 +/- 16.1; women: 116.5 +/- 10.5) and controls (men: 158.0 +/- 12.2; women: 134.1 +/- 6.3). Acromegalic women showed a significant correlation between insulin-like growth factor (IGF-I) expression and cortical BMD, whereas in acromegalic men GH levels correlated significantly with cortical BMD. Greatly increased serum osteocalcin levels in both, acromegalic men (15.5 +/- 3.3 ng/ml) and women (12.9 +/- 1.8) compared to controls (men: 6.7 +/- 1.7; women: 7.7 +/- 1.0) indicates the activation of osteoblastic bone formation. This study revealed an increase in cortical BMD at the forearm; in acromegalic patients; though trabecular BMD did not differ from controls. The differential mineralization of cortical and trabecular bone in acromegaly may be indicative of the detrimental effect accompanying pituitary insufficiency can have on trabecular bone, despite substitution therapy, but could also be due to different reactivity of cortical and trabecular bone to GH and/or IGF I. The observable increase of bone mineral density in acromegaly suggests a potential use for GH in treating osteoporosis.     

Stimulation by urocortin of growth hormone (GH) secretion in GH-producing human pituitary adenoma cells

Urocortin (Ucn) possesses high homology with CRH and is considered to be a ligand to type-2 CRH receptor. We investigated the effect of Ucn on hormone release from cultured GH-producing human pituitary adenoma cells in vitro. GH-producing human pituitary adenoma cells were superfused on a Sephadex G-25 column. Both Ucn (10 nM) and CRH (10 nM) elicited an increase in GH release from the pituitary adenoma cells in one patient with acromegaly. In contrast, GH release from the pituitary adenoma cells was stimulated by Ucn but not by CRH in the other patient with acromegaly. These preliminary findings suggest that type-2 CRH receptors are expressed in some population of GH-producing human pituitary adenoma cells and that Ucn might be involved in GH secretion from tumorous tissues in patients with acromegaly.     

An evaluation of antiseptics used for hand disinfection in wards

The diurnal rhythm of plasma aldosterone concentration (PA), plasma renin activity (PRA), plasma cortisol (PC) and serum growth hormone (GH) were examined in 5 cases of normotensive acromegaly and the results were compared with the observations in normal subjects. Moreover, the response of PA to angiotensin-II infusion was studied in 6 cases of normotensive acromegaly. A normal diurnal rhythm with the lowest values in the evening or midnight and the highest values in the morning was observed in 3 of 5 cases in PA and 3 of 4 cases in PC. On the other hand, no apparent rhythm of GH was observed in any cases and that of PRA in 4 of 5 cases. Although there was a significant positive correlation between PA and PC, no significant correlation was demonstrated between PA and PRA. The response of PA to angiotensin-II fusion was significantly suppressed in normotensive acromegaly as compared to the normal subjects in spite of normal levels of PRA except for 1 case. The above observations were interpreted to suggest that the aldosterone regulation system is slightly altered in a certain number of patients with normotensive acromegaly in contrast to the normal subjects in which PRA is the main contributing factor. The low PA and suppressed response of PA toangiotensin-II infusion may suggest the defective action of angiotensin-II infusion on the adrenal gland.     

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.     

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.     

Adherent neutrophils activate endothelial myosin light chain kinase: role in transendothelial migration

Increased vascular endothelial cell (EC) permeability and neutrophilic leukocyte (PMN) diapedesis through paracellular gaps are cardinal features of acute inflammation. Activation of the EC contractile apparatus is necessary and sufficient to increase vascular permeability in specific models of EC barrier dysfunction. However, it is unknown whether EC contraction with subsequent paracellular gap formation is required for PMN transendothelial migration in response to chemotactic factors. To test this possibility, we assessed migration of human PMNs across confluent bovine pulmonary arterial EC monolayers. Transendothelial PMN migration in the absence of a chemotactic gradient was minimal, whereas abluminal addition of leukotriene B4 (LTB4; 5 microM) resulted in significantly increased PMN migration. Reductions in EC myosin light chain kinase (MLCK) activity by EC monolayer pretreatment with specific MLCK inhibitors (KT-5926 or ML-7) or by increases in cAMP-protein kinase A activity (cholera toxin) significantly reduced PMN transmigration (30-70% inhibition). In contrast, pretreatment with the myosin-associated phosphatase inhibitor calyculin resulted in the accumulation of phosphorylated myosin light chains, EC contraction, and significantly enhanced PMN migration. Finally, the interaction of PMNs with 32P-labeled EC monolayers was shown to directly increase EC myosin phosphorylation in a time-dependent fashion. Taken together, these results are consistent with the hypothesis that the phosphorylation status of EC myosin regulates PMN migration and further indicate that EC MLCK is activated by chemoattractant-stimulated PMNs. Neutrophil-dependent activation of the EC contractile apparatus with subsequent paracellular gap formation may be a key determinant of transendothelial PMN migration responses to chemotactic agents.     

Mammosomatotroph adenoma cells secrete both growth hormone and prolactin

Pituitary adenoma cells from a mammosomatotroph adenoma obtained from a 21-year-old female presenting with acromegaly and amenorrhea were investigated by sandwich cell immunoblot assay, immunohistochemistry, and electron microscopy. The new, simple technique of sandwich cell immunoblot assay could detect two hormones secreted in the same one cell, and found that 89% of mammosomatotrophs secreted both growth hormone (GH) and prolactin (PRL). Immunohistochemistry showed that the tumor cells were positive for both GH and PRL. Electron microscopy showed cells contained granules ranging in size form 150 to 500 nm. This is the first demonstration of both GH and PRL in the same mammosomatotroph cell. Sandwich cell immunoblot assay can measure the amount of secreted hormone, allowing a new approach to the investigation of mammosomatotroph adenomas.     

Somatuline LA: a new treatment for acromegaly

Somatostatin analogues have become well established as treatment for acromegaly. However, to ensure growth hormone (GH) levels are sufficiently suppressed, thrice daily subcutaneous injections are required. The introduction of Somatuline LA, a long acting formulation which controls plasma GH levels for up to 14 days and improves acromegaly symptoms, is likely to improve patient compliance and quality of life.     

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.     

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.     

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In 1985, Losa et al reported that an i.v. bolus injection of GH-releasing hormone (GHRH) was able to paradoxically stimulate PRL secretion in more than half of their acromegalic patients. However, this observation was not generally accepted since several other investigators have concluded that such an anomalous PRL response to GHRH was an extremely rare phenomenon in acromegaly. Therefore, in this study we examined a large number (51 patients) of active acromegalics in order to obtain more reliable data on the incidence of the paradoxical PRL response to GHRH in this disorder. Each patient underwent i.v. bolus injections of GHRH (100 micrograms) and thyrotropin-releasing hormone (TRH, 500 micrograms) on separate days, and plasma levels of GH and PRL were measured. The plasma PRL response to GHRH was considered positive (a paradoxical increase) when an increase over baseline of at least 50% occurred. We found that only 6 patients (12%) showed a positive PRL response to GHRH. These PRL-responders to GHRH had higher GH responses to this peptide than PRL-non-responders to GHRH. Although PRL-responders and non-responders to GHRH had a similar PRL responsiveness to TRH, the GH response to TRH was lower in PRL-responders to GHRH than PRL-non-responders to this peptide. In addition, PRL-non-responders to GHRH had lower basal GH and higher basal PRL levels than PRL-responders to GHRH.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Chemotactic migration of leucocytes through corneal layers: an in vitro study

The ability of polymorphonuclear leucocytes (PMNs) to migrate into the different corneal layers in the presence or absence of a chemotactic stimulus was investigated in rabbits. The epithelial and/or endothelial surfaces were damaged in some corneas and in others they were intact. One side of the cornea was kept in contact with a viable population of rabbit PMNs and the other side with a chemotactic agent (zymosan activated human serum). The migration of PMNs into the cornea was traced histologically. The PMNs could not penetrate intact epithelium and Descemet's membrane even under the influence of a chemotactic stimulus. The stroma allowed PMN migration only when the chemotactic agent was present. The endothelium offered no resistance to PMN invasion whether the chemotactic stimulus was present or not.     

Low serum somatomedin activity in celiac disease. A misleading aspect in growth failure from asymptomatic celiac disease

In 4 children with celiac disease, aged 7 months to 11 years, serum somatomedin activities (SMA) were consistently low: less than 0.40 U/ml (N greater than 0.50 U/ml). Basal plasma growth hormone (GH) levels were not elevated and increased normally under arginine-insulin stimulation in 3 patients. Human GH administration at a dosage which usually determines an increase of serum SMA in children with GH deficiency (4 mg/day/2 days) did not modify significantly the low serum SMA. However, in 1 child a clear-cut increase of serum SMA (0.22-0.82 U/ml) was noted under a higher dosage of human GH (8 mg/day/2 days). In 3 patients serum SMA was studied 3 weeks to 4 months after starting the gluten-free diet and was found to be normal. A limitation of the somatomedin generation unrelated to a deficit in GH secretion and probably resistant to GH appears therefore to be present in celiac disease. The rapid normalization of serum SMA under gluten-free diet suggests that the low serum SMA is induced through some unknown hormonal or metabolic signal by the protein malabsorption and/or the nutritional deficiency present in celiac disease.     

Stimulation of DNA synthesis in isolated chondrocytes by somatomedin. II. Validation of the assay for clinical use and comparison with stimulation of protein synthesis

The effects of GH on cartilage may be mediated by a variety of serum factors (somatomedins; SM). We have reported (Endocrinology 90: 1086, 1972) stimulation of thymidine incorporation in isolated chicken embryo chondrocytes by normal human serum. This was greater than that caused by serum from patients with hypopituitarism. We have now compared the stimulatory activity estimated by [3H]thymidine incorporation (SMT) with that estimated by [3H]leucine incorporation in 46 sera from children with GH deficiency; with short stature, but normal GH responsiveness; or with normal stature and normal GH responsiveness. These activities were also measured in sera from 9 normal adults and 12 acromegalics. Sera from GH deficient children had reduced SMT activity (.54 +/- .04; (mean +/- SE) P less than .01) compared to normal children (.83 +/- .08) whereas the sera from children with short stature and normal GH responsiveness had higher levels than normal (1.19 +/- .10: P less than .02). Acromegalic adults averaged higher SMT activity than normal adults (1.62 +/- .15 vs. 1.17 +/- .11; P less than .05). In sharp contrast, the leucine incorporation was essentially the same in the different groups of children. These studies have validated the use of the incorporation of thymidine into isolated chicken embryo chondrocytes as an adjunct in the evaluation of children with short stature (82.6% of the samples from children gave results that were consistent with their status as determined by provocative tests for GH). The disparity between the results with thymidine incorporation and those with leucine incorporation is as yet unexplained.     

Use of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 in the diagnosis of acromegaly and growth hormone deficiency in adults

The goal of our study was to compare the clinical usefulness of plasma insulin-like growth factor-I (IGF-I) (with and without binding protein extraction) and IGF binding protein-3 (IGFBP-3) measurements in the diagnosis of growth hormone (GH) disorders in adults. IGF-I and IGFBP-3 concentrations were measured in 25 acromegalic and 25 GH-deficient adult (GHDA) subjects (20-76 years) by comparison to a control population (n = 81) after age and sex stratification. In untreated acromegaly, IGF-I and IGFBP-3 were clearly increased (10 times the mean of controls for unextracted IGF-I, 4 times for extracted IGF-I and 2 times for IGFBP-3). Using the mean + 2SD of the control population as the cut-off point, the sensitivity of IGF-I for the diagnosis of acromegaly was higher than that of IGFBP-3 (unextracted IGF-I: 96% and extracted IGF-I: 100% vs IGFBP-3: 76%). In GHDAs, IGF-I and IGFBP-3 were decreased (34% of the mean of controls for unextracted IGF-I, 37% for extracted IGF-I and 70% for IGFBP-3). Using the mean - 2SD of the control population as the cut-off point, the sensitivity of IGF-I measurement for the diagnosis of GHDA was relatively low, but better for unextracted (68%) than for extracted IGF-I (52%). The sensitivity of IGFBP-3 was much lower (36%), thus invalidating this parameter for the diagnosis of GHDA. Our observations demonstrate that IGF-I measurement is a more powerful tool than IGFBP-3 measurement for the diagnosis of GH disorders in adults. Both IGF-I and IGFBP-3 are very useful for the diagnosis of acromegaly, but they are less reliable for diagnosing GHDA, as normal IGF-I or IGFBP-3 values do not rule out GH deficiency.     

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.