Immunological signatures and predictive biomarkers for first-generation somatostatin receptor ligand resistance in Acromegaly.

PURPOSE: Predicting resistance to first-generation Somatostatin Receptor Ligands (fg-SRL) in Acromegaly patients remains an ongong challenge. Tumor-associated immune components participate in various pathological processes, including drug-resistance. We aimed to identify the immune components involved in resistance of fg-SRL, and to investigate biomarkers that can be targeted to treat those drug-resistant Acromegaly. METHODS: We conducted a retrospective study involving 35 Acromegaly patients with somatotropinomas treated postoperatively with fg-SRL. Gathering clinicopathological data, SSTR2 expression, and immunological profiles, we utilized univariate, binary logistic regression, and ROC analyses to assess their predictive roles in fg-SRL resistance. Spearman correlation analysis further examined interactions among interested characteristics. RESULTS: 19 patients (54.29%) exhibited resistance to postoperative fg-SRL. GH level at diagnosis, preoperative tumor volume, T2WI-MRI intensity, granularity, PD-L1, SSTR2, and CD8 + T cell infiltration showed association with clinical outcomes of fg-SRL. Notably, T2WI-MRI hyperintensity, PD-L1-IRS > 7, CD8 + T cell infiltration < 14.8/HPF, and SSTR2-IRS < 5.4 emerged as reliable predictors for fg-SRL resistance. Correlation analysis highlighted a negative relationship between PD-L1 expression and CD8 + T cell infiltration, while showcasing a positive correlation with preoperative tumor volume of somatotropinomas. Additionally, 5 patients with fg-SRL resistance underwent re-operation were involved. Following fg-SRL treatment, significant increases in PD-L1 and SSTR5 expression were observed, while SSTR2 expression decreased in somatotropinoma. CONCLUSION: PD-L1 expression and CD8 + T cell infiltration, either independently or combined with SSTR2 expression and T2WI-MRI intensity, could form a predictive model guiding clinical decisions on fg-SRL employment. Furthermore, targeting PD-L1 through immunotherapy and embracing second-generations of SRL with higher affinity to SSTR5 represent promising strategies to tackle fg-SRL resistance in somatotropinomas.

Acromegaly, inflammation and cardiovascular disease: a review.

Acromegaly is characterized by Growth Hormone (GH) and Insulin-like Growth Factor 1 (IGF-1) excess. Uncontrolled acromegaly is associated with a strongly increased risk of cardiovascular disease (CVD), and numerous cardiovascular risk factors remain present after remission. GH and IGF-1 have numerous effects on the immune and cardiovascular system. Since endothelial damage and systemic inflammation are strongly linked to the development of CVD, and have been suggested to be present in both controlled as uncontrolled acromegaly, they may explain the presence of both micro- and macrovascular dysfunction in these patients. In addition, these changes seem to be only partially reversible after remission, as illustrated by the often reported presence of endothelial dysfunction and microvascular damage in controlled acromegaly. Previous studies suggest that insulin resistance, oxidative stress, and endothelial dysfunction are involved in the development of CVD in acromegaly. Not surprisingly, these processes are associated with systemic inflammation and respond to GH/IGF-1 normalizing treatment.

Co-Occurrence of ANCA-Associated Vasculitis and Sjögren's Syndrome in a Patient With Acromegaly: A Case Report and Retrospective Single-Center Review of Acromegaly Patients.

Background: ANCA-associated vasculitis (AAV) and Sjögren's syndrome (SS) are uncommon autoimmune diseases. The co-occurrence in the same patient has been rarely described. Acromegaly has been associated with autoimmune thyroiditis, but the prevalence of other autoimmune disorders such as AAV and SS has not been evaluated in acromegaly. Methods: Characterization of a patient with acromegaly and two rare autoimmune diseases-SS and AAV (microscopic polyangiitis (MPA))-by autoantibody-array and whole exome sequencing (WES). Single-center retrospective review of medical records of acromegaly patients to explore the prevalence of diagnosed autoimmune diseases. Results: We report a Caucasian woman in her 50's with a serologically (anti-SSA/Ro, anti-MPO-ANCA antibodies) and histologically confirmed diagnosis of symptomatic SS and MPA. SS with MPO-ANCA positivity preceded MPA. An exploratory autoantigen array detected a broad spectrum of autoantibodies. WES revealed heterozygous carrier status of the PTPN22 mutation R620W, which is associated with an increased risk for autoimmunity. A similar combination of positive anti-SSA/Ro autoantibodies and ANCA was only present in 5/1184 (0.42%) other patients tested for both antibodies in our clinic over six years. Amongst 85 acromegaly patients seen at our clinic in a 20-year period, 12% had a clinically relevant associated immunological disease. Conclusion: We present a rare case of SS and AAV in a patient with acromegaly and multiple autoantibody specificities. Patients with SS and ANCA should be closely monitored for the development of (subclinical) AAV. Whether acromegaly represents a risk for autoimmunity should be further investigated in prospective acromegaly cohorts.

Overcoming Hurdles in Nanoparticle Clinical Translation: The Influence of Experimental Design and Surface Modification.

Nanoparticles are becoming an increasingly popular tool for biomedical imaging and drug delivery. While the prevalence of nanoparticle drug-delivery systems reported in the literature increases yearly, relatively little translation from the bench to the bedside has occurred. It is crucial for the scientific community to recognize this shortcoming and re-evaluate standard practices in the field, to increase clinical translatability. Currently, nanoparticle drug-delivery systems are designed to increase circulation, target disease states, enhance retention in diseased tissues, and provide targeted payload release. To manage these demands, the surface of the particle is often modified with a variety of chemical and biological moieties, including PEG, tumor targeting peptides, and environmentally responsive linkers. Regardless of the surface modifications, the nano-bio interface, which is mediated by opsonization and the protein corona, often remains problematic. While fabrication and assessment techniques for nanoparticles have seen continued advances, a thorough evaluation of the particle's interaction with the immune system has lagged behind, seemingly taking a backseat to particle characterization. This review explores current limitations in the evaluation of surface-modified nanoparticle biocompatibility and in vivo model selection, suggesting a promising standardized pathway to clinical translation.

Plasma thrombin-activatable fibrinolysis inhibitor (TAFI) antigen levels in acromegaly patients in remission

Background/aim: Acromegaly is associated with increased morbidity andmortality, mostly due to cardiovascular complications.Plasma thrombin-activatable fibrinolysis inhibitor (TAFI) antigen levels are associated with coagulation/fibrinolysis and inflammation. Plasma TAFI may play a role in arterial thrombosis in cardiovascular diseases. In this study, it was aimed to evaluate the thrombin-activatable fibrinolysis inhibitor (TAFI) antigen and homocysteine levels in patients with acromegaly and healthy control subjects. Materials and methods: Plasma TAFI antigen and homocysteine levels in 29 consecutive patients with acromegaly and 26 age-matched healthy control subjects were measured. All patients included in the study were in remission. The TAFIa/ai antigen in the plasma samples was measured using a commercially available ELISA kit. Results: Routine biochemical parameters, fasting blood glucose, prolactin, thyroid stimulating hormone, total-cholesterol, low density lipoprotein cholesterol, triglyceride, and homocysteine levels were similar in the 2 groups (P > 0.05), whereas the plasma TAFI antigen levels were significantly elevated in the acromegalic patients (154.7 ± 94.0%) when compared with the control subjects (107.2 ± 61.6%) (P = 0.033). No significant correlation was identified by Pearson's correlation test between the plasma TAFI antigen and homocysteine levels (r = 0.320, P = 0.250). Conclusion: A significant alteration in the plasma TAFI antigen levels was detected in acromegaly. Increased plasma TAFI antigen levels might aggravate prothrombotic and thrombotic events in patients with acromegaly.

Evaluation of blood neutrophil to lymphocyte and platelet to lymphocyte ratios according to plasma glucose status and serum insulin-like growth factor 1 levels in patients with acromegaly.

INTRODUCTION: Cardiovascular, respiratory, and cerebrovascular diseases and malignancies are responsible for morbidity and mortality in acromegaly. Also these diseases are associated with chronic inflammation. The neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are currently gaining interest as new markers of inflammation. Moreover, increased morbidity and mortality are positively correlated with the presence of diabetes and levels of insulin-like growth factor 1 (IGF-1) in acromegaly. The objective of the present study was to investigate the relationship between these markers and acromegaly according to plasma glucose status and serum IGF-1 levels. MATERIALS AND METHODS: We retrospectively analyzed data from 61 acromegaly patients who were in a newly diagnosed period (35 male, 26 female; mean age 38.13 ± 13.98). Patients with normal plasma glucose (n = 27), impaired fasting glucose (n = 18), and diabetes mellitus (n = 16) were categorized into three different groups. NLR and PLR were compared between the study groups and were evaluated according to IGF-1 levels. RESULTS: There were no statistically significant differences in NLR and PLR measurements among the study groups (p > 0.05). However, there were significant positive correlations between NLR and IGF-1 levels and between PLR and IGF-1 levels when all patients were evaluated (r = 0.334, p = 0.011 and r = 0.277, p = 0.035, respectively). CONCLUSIONS: This is the first report studying the relationship of NLR and PLR with glucose status and IGF-1 levels in acromegaly patients. Our study results suggest that subclinical inflammation may play a role in increased incidence of mortality and morbidity, which depends on uncontrolled IGF-1 levels in patients with acromegaly.

Thyroid autoimmune disorders in patients with acromegaly.

PURPOSE: Disorders of the hypothalamic-pituitary-thyroid axis are common in patients with acromegaly and thyroid enlargement is present in the majority of them. The exact prevalence of goiter in patients with acromegaly remains uncertain and the presence of thyroid autoimmunity has not been extensively evaluated so far. METHODS: We retrospectively evaluated thyroid biochemical and morphological findings in 116 acromegalic patients who attended our hospital. Serum TSH, total thyroxine levels and anti-thyroid peroxidase (ATPO) antibodies were measured by standard ultrasensitive techniques in all the patients. Thyroid ultrasound was performed in 75 out of them. The antibody control group was composed by healthy Argentinean individuals who attended the blood bank of our hospital in whom ATPO antibodies were measured. RESULTS: Twenty-nine out of the 116 acromegalic patients (25 %) showed elevated titers of thyroid antibodies (79 % were women and 21 % men). The control group had a 10 % prevalence of thyroid autoimmunity. The prevalence of goiter by ultrasound was 36 %, being more common in females (41 %) than in males (28 %). Thirty-five percent of patients who presented thyroid nodules and 44 % of patients with ultrasound diagnosed goiters had positive thyroid autoimmunity. There was no significant correlation between the presence of nodules and IGF-1 levels, duration of disease or age. CONCLUSION: We found a high prevalence of thyroid autoimmunity in our patients with acromegaly as compared to the normal population. Thyroid autoimmunity seems to be an additional mechanism for the development of thyroid disorders in acromegaly.

Inflammatory adipokines contribute to insulin resistance in active acromegaly and respond differently to different treatment modalities.

BACKGROUND: Active acromegaly is associated with insulin resistance, but it is uncertain whether inflammation in adipose tissue is a contributing factor. AIM: To test if GH/IGF1 promotes inflammation in adipocytes, and if this is relevant for systemic insulin resistance in acromegaly. Furthermore, to investigate the effect of treatment modalities (transsphenoidal surgery (TS), somatostatin analogs (SAs), and pegvisomant (PGV)) on glucose metabolism and inflammatory biomarkers in acromegaly. METHODS: The in vitro effects of GH/IGF1 on gene expression of adipokines in human adipocytes were investigated. Body composition, glucose metabolism, and circulating adipokines (adiponectin (AD), high-molecular weight AD (HMWAD), leptin, vascular endothelial growth factor-A (VEGF-A), monocyte chemotactic protein 1 (MCP1), and thioredoxin (TRX)) were measured in 37 patients with active acromegaly before and after treatment. RESULTS: In vitro GH, but not IGF1, increased VEGF and MCP1 in human adipocytes. In all treatment groups, body fat increased and IGF1 decreased to the same extent. Fasting glucose decreased in the TS (P=0.016) and PGV (P=0.042) groups, but tended to increase in the SA group (P=0.078). Insulin and HOMA-IR decreased in both TS and SA groups, while the PGV group showed no changes. Serum VEGF and MCP1 decreased significantly in the TS group only (P=0.010, P=0.002), while HMWAD increased with PGV treatment only (P=0.018). A multivariate analysis model identified the changes in GH and VEGF as predictors of improvement in HOMA-IR after treatment (R²=0.39, P=0.002). CONCLUSIONS: i) GH directly promotes inflammation of human adipocytes by increasing VEGF and MCP1 levels; ii) glucose metabolism and inflammation (VEGF and MCP1) improve to some extent after treatment, despite an increase in adipose tissue mass; and iii) the decrease in insulin resistance after therapy in acromegaly depends, to some extent, on treatment modalities.

Adipocytes as a source of increased circulating levels of nicotinamide phosphoribosyltransferase/visfatin in active acromegaly.

BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT)/visfatin is a widely expressed protein with various effects on glucose and lipid metabolism, cell survival, and inflammation. AIM: We hypothesized that NAMPT was related to metabolic disturbances in active acromegaly. METHODS: Body composition, glucose metabolism, and NAMPT levels were measured in 47 patients with active, untreated acromegaly and 24 age-, sex-, and body mass index-matched controls. The in vitro effects of GH/IGF-I on NAMPT expression in human sc adipocytes (SCA), visceral adipocytes, osteoblasts, and hepatocytes were studied. The effects of overnight incubation with the highly specific NAMPT inhibitor FK866 on the GH-stimulated monocyte chemotactic protein-1 and IL-6 expression in mature SCA were evaluated. RESULTS: NAMPT was increased in active acromegaly (P = 0.004) and correlated negatively with limb (arms + legs) fat percentage (% fat, r = -0.32; P = 0.032). After adjusting for age, gender, leptin, and GH, the circulating NAMPT correlated negatively with limb and total body fat percentage (% fat limbs, r = -0.43, P = 0.006; % fat total body, r = -0.36, P = 0.022) and correlated positively with limb and total body lean percentage (% lean limbs, r = 0.31, P = 0.047; % lean total body, r = 0.33, P = 0.034). No correlation between NAMPT and glucose metabolic parameters was found. In vitro studies revealed that GH increased NAMPT expression in adipocytes. The inhibition of NAMPT enzymatic activity attenuated GH-induced monocyte chemotactic protein-1 expression in SCA. CONCLUSIONS: NAMPT is increased in active acromegaly and may be an inflammatory mediator that causes monocyte infiltration in adipose tissue.

Prevalence of antipituitary antibodies in acromegaly.

Acromegaly is a rare disorder due to an excessive production of growth hormone (GH), typically caused by a GH-secreting pituitary adenoma. Anti-pituitary antibodies (APAs) are often seen in patients with different kinds of pituitary pathologies. Because GH has been proposed as a possible antigen recognized by such antibodies, the prevalence of APAs may be higher in conditions characterized by excessive GH secretion. The primary aim of this study was to compare the prevalence of APAs in patients with acromegaly and in controls with other types of pituitary tumors and healthy subjects. Secondary aim was to characterize the pituitary cells targeted by the APAs. Thirty eight acromegaly patients and 215 controls, including 38 patients with prolactinomas, 64 with non-functioning pituitary adenomas (NFPA), and 113 healthy subjects were enrolled in the study. All subjects were tested for APAs using indirect immunofluorescence. Target cells recognized by APAs were identified by double staining immunofluorescence. APAs were significantly more prevalent in acromegaly cases than in healthy controls (10.5% vs. 1.8%, P < 0.05). This prevalence was similar to that found in patients with prolactinomas (7.9%) and NFPA (12.5%). Among APAs-positive subjects, antibodies recognizing somatotrope cells were more common in acromegaly cases than in healthy controls (3/4 vs. 0/113, P < 0.0001), but had similar frequencies in NFPA (2/8) and prolactinomas (1/3). APAs are more frequently found in patients with pituitary adenomas than healthy subjects, with no significant difference among the tumor types studied. GH-secreting cells could represent a target of the autoimmune response.

Does Apolipoprotein E genotype affect cardiovascular risk in subjects with acromegaly?

Acromegaly is a syndrome that results when the pituitary gland produces excess growth hormone after epiphyseal closure at puberty. Usually, subjects with acromegaly exhibit a 2- to 3-fold higher mortality rate from diseases that are associated with cardiovascular complications when compared to the normal population. In this study, we therefore aimed to evaluate whether a well-established cardiovascular risk factor, the Apolipoprotein E (Apo E) genotype, contributes to increased risk of cardiovascular complications in subjects with acromegaly. A total of 102 unrelated acromegaly subjects were prospectively included into this case-control association study and constituted our study group. The study group was comparable by age and gender with 200 unrelated healthy subjects constituting our control group. Genomic DNA was isolated from the peripheral blood leukocytes of all subjects and Apo E genotype (codon 112/158) was assessed by melting temperature analyses after using a real-time PCR protocol. The Apolipoprotein E4 allele was found at a significantly higher frequency in the study group when compared with the control group (P = 0.032). Subjects with the E2 allele, on the other hand, had significantly increased values in body mass index (P = 0.004), waist circumference (P = 0.001), C-reactive protein (CRP) (P < 0.001), and left-side carotid intima media thickness (P = 0.025). The Apolipoprotein E2 genotype might contribute to increased risk of cardiovascular complications in subjects with acromegaly since it is concurrently present with other cardiovascular risk factors such as the left-side carotid intima media thickness and CRP.

Micronucleus evaluation in mitogen-stimulated lymphocytes of patients with acromegaly.

Acromegaly is a syndrome characterized by a sustained elevation of circulating growth hormone and insulin-like growth factor-1 (IGF-1). Insulin-like growth factor-1 is a potent mitogen and has a role in the transformation of normal cells to malignant cells. This study aims to evaluate the spontaneous micronucleus (MN) frequency by using the cytokinesis-block MN assay to determine genetic damage in the lymphocytes of patients with acromegaly. The study was carried out in 20 patients who had active acromegaly and in 20 age- and sex-matched healthy controls. The MN values were measured in binucleated cells obtained from mitogen-stimulated lymphocytes of patients and control subjects. The distribution of binucleated cells with 1, 2, 3, or more MNs was also measured. We found significantly higher MN frequency values in the lymphocytes of acromegalic patients than in those of the control subjects (2.23 ± 0.68 vs 1.03 ± 0.54, P = .001). The MN frequency increased with increasing IGF-1 levels of acromegalic patients (P = .036, R = 0.47). We observed that the number of binucleated cells with 2 MNs was higher for the majority of patients with acromegaly than for control subjects. Furthermore, the receiver operating characteristic curve (area under the curve = 0.914, P < .0001) was calculated to assess the discriminative power of the MN frequency. Our results indicate that increased MN frequency in the lymphocytes of patients with acromegaly may reflect genomic instability and this increased MN frequency may be associated with elevated levels of circulating growth hormone and IGF-1.

Familial acromegaly: a familial report and review of the literature.

Familial acromegaly without features of multiple endocrine neoplasie type 1 (MEN 1) is an exceptional clinical entity. We report in this article three cases of acromegaly due to pituitary macroadenomas without any other endocrinopathy in a family. A 31-year-old woman (subject A) and her 34-year-old sister (subject B) with elevated basal rolactin (PRL) levels, elevated growth hormone (GH) levels during the oral glucose tolerance test (OGTT) and a pituitary adenoma in Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) were diagnosed as acromegaly. Subject A was treated only with radiotherapy and Lysuride. Subject B underwent transsphenoidal microsurgical extirpation 15 years ago. 11 years later her 24-year-old son (subject C) also presented with typical signs of acromegaly, elevated basal PRL level and elevated GH levels during OGTT. A pituitary macroadenoma was identified by MRI and he also underwent transsphenoidal adenomectomy. Pathology reports confirmed the diagnosis of GH-secreting pituitary adenoma in subject B and C. Immunocytochemistry revealed that tumours of subject B (> 20% of tumour cells) and C (> 50% of tumour cells) were positive for GH. Tumours of subject B (> 10% of tumour cells) and C (> 50% of tumour cells) also exhibited immunoreactivity for PRL. On investigation of histocompatibility antigens, it was observed that the subject A, B, and C shared the same haplotypes [HLA A24(9), HLA B13(6), HLA B35, HLA DQ7(3), HLA DR13(6)] and so it is very possible that investigation of HLA antigens in patients with pituitary tumour, contributes to better identification of its familial nature and frequency. Here we describe an acromegaly family and the distributions of HLA antigens.

[Estimation of efficacy of the octreotide LAR administration in the patients with somatotropinoma]. / Ocena skutecznosci stosowania oktreotydu LAR u pacjentów z guzami przysadki typu somatotropinoma.

Acromegaly is caused by excessive secretion of growth hormone by a hypophyseal adenoma type of somatotropinoma. IGF-I is formed in the liver and mediates most biological actions of GH. Treatment of adenomas, which secrete GH, involves pharmacotherapy followed by surgery. Modern pharmacotherapy leaning is based on somatostatin analogues (factor restrictive secretion GH): octreotide, octreotide LAR and lanreotide. The aim of our study was estimation of efficiency of octreotide LAR in the patients with somatotropinoma prepared to neurosurgery intervention. We examined 16 patients (10 of women and 6 men) with the features of active acromegaly. In all cases the increased concentration of HGH and IGF-I were observed. The presence of pituitary adenoma in all patients was confirmed by MRI. The patients were treated with octreotide LAR monthly in dose 20 mg and 30 mg respectively. Before and after application of somatostatin analogues the concentration HGH, IGF-I, PRL in serum were marked. The concentration of GH before octreotide LAR therapy in all patients increased remarkable and ranged from 15.6 to 78.6 ng/ml, mean: 31.20 +/- 16.84 (norm: 0-10 ng/ml), also, in all cases the serum IGF-I level was increased and ranged from 451 to 1107.6 ng/ml, mean: 801.75 +/- 207.82 (norm: 100-400 ng/ml). The prolactin concentration ranged from 7.4 to 49.9 ng/ml, mean: 22.8 +/- 13.7 (norm: 2-20 ng/ml) and in 8 (50%) cases the increased of PRL concentration in serum was observed. After the administration of octreotide LAR the level of: GH [mean: 12.99 +/- 17.16 ng/ml (p < 0.001)], of IGF-I [mean 422.8 +/- 229 ng ml (p < 0.01)] statistical important decreased and prolactin in 8 with increased concentration [mean: 12.45 +/- 5.57 (p < 0.01)] were observed. Long acting somatostatin analogues--octreotide LAR is particular efficient in lowering of growth hormone and IGF-I in patients with somatotropinoma and shows efficiency in normalization of increased prolactin concentration. Because of extreme effectiveness of octreotide LAR, it should be used the routine treatment at the patients suffering from active acromegaly and preparing to neurosurgical treatment.

Increased prevalence of colonic polyps and altered lymphocyte subset pattern in the colonic lamina propria in acromegaly.

OBJECTIVE: The balance of evidence suggests that acromegaly is a risk factor for colonic neoplasia. We have evaluated the prevalence of colonic polyps in acromegalics from Southern Italy and characterized the lymphocyte subsets in the colonic lamina propria in order to analyze differences in the colonic immunological environment. DESIGN: All the patients and controls were submitted to pancolonoscopy. Ten per-endoscopic biopsies of the intestinal mucosa surrounding polyps were carried out to evaluate lymphocyte subsets. PATIENTS: Fifty acromegalics and 318 sex- and age-matched controls entered this study. Colonic lamina propria lymphocyte subsets were studied in 34 patients and 34 controls. RESULTS: Colonic polyps were resected in 23 acromegalics (46%) and 42 controls (13.2%; P < 0.0001); hyperplastic polyps were found in 24% and 6.3%, adenomatous polyps in 22 and 6.9%, (P < 0.01), adenocarcinoma in 2 and 1.2% while synchronous polyps occurred in 18% and 2.5% (P < 0.01), respectively. The number of polyps was significantly correlated with age both in acromegalics (r = 0.422, P < 0.005) and in controls (r = 0.865, P < 0.001). However, polyp prevalence was greater in patients aged below 40 yrs (r.r = 1.9) and in patients with two or more skin tags (r.r = 1.2). A significant decrease of CD20, CD19, CD16, gamma/delta, CD4@leu8- and increase of CD3 and CD4+/leu8+ was found in the lamina propria lymphocyte subsets. CONCLUSIONS: The results of this study confirm that acromegalics are at increased risk of colonic polyps compared to the healthy population. The increased prevalence of premalignant polyps, namely the adenomatous type, suggests that acromegalics should undergo a careful screening and follow-up by pancolonoscopy. An impairment of mucosal immune surveillance seems to exist in acromegaly although a causal effect in the polyp formation cannot be ruled out.

Bioactive GH-like immunoglobulins G in active acromegaly: response to long-term treatment with bromocriptine.

In acromegaly, certain forms of circulating immunoreactive hGH are not true GH but IgGs which possess GH biological activity (bioactive GH-like IgGs). In this study, we tested the effect of bromocriptine on circulating bioactive GH-like IgGs in an acromegalic woman. Increasing doses of oral bromocriptine (2.5, 5.0 and 7.5 mg/day) were administered (for 2, 8 and 6 months respectively). TRH tests were performed before treatment and at the end of treatment with each dose. The patient was without detectable pituitary or extra-pituitary tumour by magnetic resonance imaging. Her serum contained bioactive GH-like IgGs equivalent to 240 mU/l of hGH and elevated insulin-like growth factor I (IGF-I; 9500 U/l). Basal hGH was 12.8 mU/l and increased to 220 mU/l 15 min after TRH (200 micrograms, i.v.). In addition, in the basal samples of each test we measured total IgGs (radial immunodiffusion), bioactive GH-like IgGs (isolated by Sephadex and protein A affinity chromatography and assayed using the Nb2 cell assay) and IGF-I(RIA). Bromocriptine treatment gradually reduced serum levels of bioactive GH-like IgGs and IGF-I, with significant falls observed first at 10 months of treatment. Bioactive GH-like IgGs were 240, 240, 36.0 and < 0.124 mU/l and IGF-I levels were 9500, 8700, 4000 and 3100 U/l at 0, 2, 10 and 16 months of treatment, respectively. In contrast, IR-hGH response to TRH decreased after 2 months of treatment to 89 mU/l and to 49.2 mU/l at the end of the study while basal IR-hGH remained between 13 and 8.4 mU/l. Basal PRL fell to almost undetectable levels. Bromocriptine treatment decreased the GH response to TRH and the serum concentration of bioactive GH-like IgGs and IGF-I. The striking similarity between the pattern of decrease of serum bioactive GH-like IgGs and IGF-I supports the presence of an immuno component in our patient's acromegaly.

Effect of elevated growth hormone concentrations on the phenotype and functions of human lymphocytes and natural killer cells.

Over the past decades, strong evidence has accumulated that growth hormone (GH) has immunostimulatory properties. Therefore, an investigation was conducted on 10 acromegalic patients and 9 age- and sex-matched healthy controls to determine whether plasma GH concentrations correlate with changes in several immune parameters, including serum concentrations of immunoglobulins, lymphocyte subsets, lymphocyte transformation with phytohemagglutinin (PHA), natural killer (NK) cell activity as well as phagocytic and metabolic burst activity. While NK cell activity, serum concentrations of immunoglobulins (IgG, IgM, IgA) and metabolic burst activity were within the normal range in both groups, a significantly enhanced phagocytic activity was observed in the acromegalic patients. Surface markers on T lymphocytes (CD3, CD4, CD8), B lymphocytes (CD19) and NK cells (CD16/56) were normal in both groups; however, in the acromegalic subjects, CD4+ and CD8+ cells showed a significant higher expression of transferrin receptors (CD71), indicating enhanced T-cell activity. The lymphocyte transformation response to PHA at the highest concentration tested showed a tendency to be elevated in acromegalics; however, the difference failed to be significant. Long-lasting and pronounced elevation of GH in acromegaly induces significantly enhanced phagocytic activity, but only negligible changes in most patients in lymphocyte phenotype and in the lymphocyte response to PHA.

[The CD2, CD4 and CD8 mRNA expression of T lymphocytes in patients with acromegaly and hyperprolactinemia].

The CD2, CD4 and CD8 mRNA expression of human peripheral blood lymphocytes (HPBL) from 49 female patients with acromegaly and hyperprolactinemia and 15 healthy women were studied by dot blotting assay using corresponding CD2, CD4 and CD8 antisense RNA probes. It was found that CD2 mRNA expression increased in women with growth hormone over-expression and the ratio of CD4 and CD8 mRNA declined significantly in the women with prolactin over-expression. These suggested that the mRNA expression of these cluster differentiation antigens in peripheral T lymphocytes was affected by the pituitary hormones. The significance of these findings relevant to the study of the neuroendocrine and immune network was discussed.

Protease-induced alteration of insulin-like growth factor binding protein-3 as detected by radioimmunoassay. Agreement with ligand blotting data.

Structural alteration of insulin-like growth factor binding protein-3 (IGFBP-3) resulting from limited proteolysis by one or more serine proteases in vivo was first described in the serum of pregnant women and in certain pathological conditions. Western immunoblotting has since been employed to detect the phenomenon in normal serum, using a polyclonal antibody raised against recombinant human IGFBP-3 and a highly sensitive technique of visualization by chemiluminescence. The major proteolytic fragment of 30 kDa, which fails to be detected in native serum by ligand blotting owing to its weak affinity for IGFs, has proved clearly visible in all serum samples tested, sometimes accompanied by smaller fragments of 20 and 16 kDa. Among the serum samples analysed, increasing proportions of proteolysed IGFBP-3 were found in the following order: acromegalic patients, normal subjects, GH-deficient patients, pregnant women. In RIAs done with the same antibody, many of the serum samples yielded dose-response curves which were not parallel with standard curves, with lower gradients. In the samples where measurements were possible, apparent IGFBP-3 levels proved lower in pregnant women (2.28 +/- 0.23 mg/l, mean +/- SEM) than in normal adults (4.26 +/- 0.33 mg/l, P < 0.001). These observations, which contradict earlier reports of higher levels in pregnant women, suggest that the 30 kDa proteolytic fragment has a weaker affinity for the antibody than the intact IGFBP-3 (which in ligand- and immunoblotting appears as a characteristic 42-39 kDa doublet and which is barely or not detectable in pregnancy serum).(ABSTRACT TRUNCATED AT 250 WORDS)