SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Parathyroid function was assessed in six acromegalic subjects by measurement of serum levels of parathyroid hormone (PTH). Only one patient had increased PTH levels. These findings suggest that hyperparathyroidism does not uniformly occur in acromegaly.
Sera of 7 patients with active acromegaly were fractionated by Sephadex G-100 chromatography and the effects of bromocriptine on the concentrations of total growth hormone (hGH) and its different molecular forms studied. Three immunoreactive peaks were observed, corresponding to molecular weights of about 20,000 ('little hGH'), 40,000 ('big hGH'), and more than 100,000 ('big big hGH') Following bromocriptine administration, there was significantly more reduction of 'little hGH' than of 'big big hGH'. Careful interpretation of these changes is required in view of the possible influences of sample storage and handling on hGH heterogeneity. We suggest that either bromocriptine acts differentially on the release of 'little' and 'big big hGH', or that these components differ in their metabolic half-life. However, even the suppression of 'little hGH' is insufficient to explain the clinical response of the disease to bromocriptine.
The effect of a long-acting analogue of Met-enkephalin (Damme) and naloxone on anterior pituitary hormone secretion has been investigated in 14 acromegalic patients. Damme produced a progressive fall in circulating LH and cortisol and stimulated prolactin release in normoprolactinaemic patients. Naloxone infusion significantly stimulated gonadotrophin and cortisol secretion without modifying basal prolactin release both in normo-and hyperprolactinamic patients. GH levels remained unchanged during naloxone and Damme infusion. The data suggest that endogenous opiate receptors do not play a major role in modulating GH hypersecretion in acromegaly.
In untreated acromegalic patients, mean serum level of insulin-like growth factor (IGF) is two times higher than in controls, and all patients have IGF values above the mean + 2 SD of the controls, while some of these patients have normal GH values. After treatment, clinical status correlates better with IGF than with GH. Thus, measurements of serum IGF can be helpful in the diagnosis of acromegaly and in assessment of the efficiency of therapy.
A 36-year-old man is described having McCune-Albright syndrome, acromegaly likely due to somatotroph hyperplasia and hyperthyroidism due to adenomatous goiter. Sexual precocity was not noted. The sella was narrow in size and no mass was seen. The decline of elevated GH by hyperglycemia and increase by GHRH-44(NH2) may support somatotroph hyperplasia, but plasma GHRH-44(NH2) levels were not elevated. A mass in the right lobe and enlargement of the left lobe of the thyroid were noted. Thyroid hormone levels in serum and thyroidal radioiodine uptake values were elevated, while TSH measurements in serum were low. The radioiodine scan showed a cold nodule in the right lobe and a hot area in the left of the thyroid. Thyroidal radioiodine was not suppressed following T3 given orally. These findings are compatible with functioning glands autonomously as the mechanism for the endocrinopathies associated with the McCune-Albright syndrome.
Patients with active acromegaly were treated with octreotide (SMS 201-995, Sandostatin; Sandoz Pharmaceuticals) given in high dosage by continuous subcutaneous administration (CSI). Serum growth hormone (GH) and insulin-like growth factor 1 (IGF-1) concentrations were rapidly and consistently reduced to the normal range and maintained for up to 14 weeks of study. Maximal inhibition of GH and IGF-1 secretion was obtained at a dose of 600 micrograms/24 h; all except 1 of the 7 patients were able to tolerate a higher dose of 1,600 micrograms/24 h. A single patient failed to show GH suppression at any dosage of octreotide. Computed tomographic evidence of tumour shrinkage was not demonstrated in these 7 patients, although in 2 patients subsequently studied by us definite tumour shrinkage was observed. These data show that the administration of octreotide by CSI is a highly satisfactory method for persistently lowering GH and IGF-1 concentrations in acromegalic patients sensitive to this drug.
The aim of this study was to evaluate plasma thyrotropin (TSH), prolactin (PRL) and growth hormone (GH) responses to the TSH-releasing hormone (TRH) test and to a combined arginine-TRH test (ATT-TRH) in 10 normal subjects and in 15 acromegalic patients. In controls, TSH responsiveness to TRH was enhanced by ATT (p less than 0.001). When considering the 15 acromegalic patients as a whole, no significant difference in TSH responses was detected during the two tests. However, patients without suppression of plasma GH levels after oral glucose load showed an increased TSH responsiveness to the ATT-TRH test if compared to TRH alone (p less than 0.025), while patients with partial suppression of plasma GH levels after glucose ingestion showed a decreased TSH responsiveness to ATT-TRH (p less than 0.05). No difference was recorded in PRL and GH responses, evaluated as area under the curve, during TRH or ATT-TRH tests in controls and in acromegalics. In conclusion, (1) normal subjects have an enhanced TSH response to the ATT-TRH test and (2) acromegalic patients without suppression of GH levels after oral glucose load show a TSH responsiveness to the ATT-TRH test similar to that of controls, while acromegalics with partial GH suppression after oral glucose load have a decreased TSH responsiveness to the ATT-TRH test. These data suggest that acromegaly is a heterogeneous disease as far as the somatostatinergic tone is concerned.
We investigated the relationship between urinary growth hormone (u-GH) and spontaneous 24-hour plasma GH secretion in 15 acromegalic patients. To measure u-GH, we have developed a method based on concentrating the sample by centrifugal ultrafiltration and then performing an immunoradiometric assay using commercially available reagents. u-GH correlated well with the integrated concentration of plasma GH (r = 0.66, p < 0.02). Additionally, u-GH excretion in acromegalic patients was significantly higher than in the control group (190 +/- 100 vs. 3.89 +/- 0.56 pg/min, mean +/- SEM, p < 0.001). Immunoreactive u-GH showed the same elution pattern in Sephadex G-75 as standard or labeled hGH, proving that the substance measured in urine is authentic GH. In conclusion, u-GH appears to be a simple, noninvasive and inexpensive test for evaluating GH secretion in active acromegaly.
In four acromegalic patients, estrogen therapy did not significantly alter the mean values of basal radioimmunoassayable plasma growth hormone. In two patients, estrogen therapy did not qualitatively alter the lack of reduction of plasma growth hormone levels after oral administration of glucose, nor did it reduce in these patients the response of plasma growth hormone to insulin-induced hypoglycemia. In one of the patients, insulin sensitivity with respect to glucose and the hypoglycemia-induced growth hormone rise seemed greater during estrogen therapy. Despite the absence of demonstrable reductions inplasma growth hormone level under varying experimental circumstances, the administration of estrogen resulted in reduction of urinary calcium and hydroxyproline excretion, in reduction of radiocalcium bone accretion rates and exchangeable pools, in reduction of serum phosphorus, and in more negative nitrogen balances. The experimental data therefore suggest that estrogen may be a peripheral antagonist of the effects of excessive growth hormone secretion in acromegaly.
Growth hormone (GH)-releasing activity has been detected in extracts of carcinoid and pancreatic islet tumors from three patients with GH-secreting pituitary tumors and acromegaly. Bioactivity was demonstrated in 2 N acetic acid extracts of the tumors using dispersed rat adenohypophyseal cells in primary monolayer culture and a rat anterior pituitary perifusion system. The GH-releasing effect was dose responsive and the greatest activity was present in the pancreatic islet tumor. Small amounts of activity were also found in two other tumors (carcinoid and small cell carcinoma of lung) unassociated with GH hypersecretion. Each of the tumors contained somatostatin-like immunoreactivity but the levels did not correlate with the net biologic expression of the tumor. Sephadex G-75 gel filtration indicated the GH-releasing activity to have an apparent molecular size of slightly greater than 6,000 daltons. The GH-releasing activity was adsorbed onto DEAE-cellulose at neutral pH and low ionic strength, from which it could be eluted by increasing ionic strength. The GH-releasing activity was further purified by high pressure liquid chromatography using an acetonitrile gradient on a cyanopropyl column to yield a preparation that was active at 40 ng protein/ml. Partially purified GH-releasing activity, from which most of the bioactive somatostatin had been removed, increased GH release by pituitary monolayer cultures to five times base line. Enzymatic hydrolysis studies revealed that the GH-releasing activity was resistant to carboxypeptidase, leucine-aminopeptidase, and pyroglutamate-amino-peptidase but was destroyed by trypsin and chymotrypsin, indicating that internal lysine and/or arginine and aromatic amino acid residues are required for biologic activity and that the NH2-terminus and CO9H-terminus are either blocked or not essential. The results provide an explanation for the presence of GH-secreting tumors in some patients with the multiple endocrine neoplasia syndrome, type I, and warrant the addition of GH-releasing activity to the growing list of hormones secreted by tumors of amine precursor uptake and decarboxylation cell types.
We measured plasma growth hormone concentrations by three different two-site immunometric assays (Pharmacia hGH RIA, IDS Gamma-BCT and Delfia 22 kDa hGH) to determine whether there are GH isoforms secreted by acromegalic patients that are under-recognized by some assays. There was a fairly good agreement between assays with the IDS Gamma-BCT and Delfia 22 kDa assays giving lower results than the Pharmacia IRMA. GH was measured on stored plasma samples from 24 patients with proven acromegaly. There was a consistent difference between the three assays of approximately 20% of the mean value for each patient.
Increase in lung size has been described in acromegalic patients, but data on respiratory muscle function and control of breathing are relatively scarce. Lung volumes, arterial blood gas tensions, and respiratory muscle strength and activation during chemical stimulation were investigated in a group of 10 patients with acromegaly, and compared with age- and sex-matched normal controls. Inspiratory muscle force was evaluated by measuring pleural (Ppl,sn) and transdiaphragmatic (Pdi,sn) pressures during maximal sniffs. Dynamic pleural pressure swing (Ppl,sw) was expressed both as absolute value and as percentage of Ppl,sn. Expiratory muscle force was assessed in terms of maximal expiratory pressure (MEP). In 8 of the 10 patients, ventilatory and respiratory muscle responses to hyperoxic progressive hypercapnia and to isocapnic progressive hypoxia were also evaluated. Large lungs, defined as total lung capacity (TLC) greater than predicted (above 95% confidence limits), were found in five patients. Inspiratory or expiratory muscle force was below normal limits in all but three patients. During unstimulated tidal breathing, respiratory frequency (fR) and mean inspiratory flow (tidal volume/inspiratory time (VT/tI)) were greater, while inspiratory time (tI) was shorter than in controls. Minute ventilation (V'E) and mean inspiratory flow response slopes to hypercapnia were normal In contrast, four patients had reduced delta(VT/tI)/arterial oxygen saturation (Sa,O2) and three had reduced deltaV'E/Sa,O2. Ppl,sw(%Ppl,sn) response slopes to increasing end-tidal carbon dioxide tension (PET,CO2) and decreasing Sa,O2 did not differ from the responses of the normal subjects, suggesting normal central chemoresponsiveness. At a PET,CO2 of 8 kPa or an Sa,O2 of 80%, patients had greater fR and lower tI compared with controls. Pdi,sn and Ppl,sn related both to deltaV'E/deltaSa,O2 (r=0.729 and r=0.776, respectively) and delta(VT/tI)/deltaSa,O2 (r=0.860 and r=0.90, respectively). Pdi,sn also related both to deltaV'E/deltaPET,CO2 (r=0.8) and delta(VT/tI)/deltaPET,CO2 (r=0.76). In conclusion, the data suggest the relative independence of pneumomegaly and respiratory muscle strength. Peripheral (muscular) factors appear to modulate a normal central motor output to give a more rapid pattern of breathing.
Transgenic mice overexpressing the human GH-releasing hormone (hGHRH) gene, an animal model of acromegaly, were used to investigate the effects of potent GHRH antagonists MZ-4-71 and MZ-5-156 on the excessive GH and insulin-like growth factor I (IGF-I) secretion caused by overproduction of hGHRH. Because metallothionein (MT)-GHRH mice express the hGHRH transgene in various tissues, including the pituitary and hypothalamus, initial experiments focused on the effectiveness of the GHRH antagonists in blocking basal and stimulated GH secretion from pituitary cells in vitro. Both MZ-4-71 and MZ-5-156 suppressed basal release of GH from superfused MT-GHRH pituitary cells, apparently by blocking the action of endogenously produced hGHRH. In addition, these antagonists effectively eliminated the response to stimulatory action of exogenous hGHRH(1-29)NH2 (30 and 100 nM). To ascertain whether MZ-4-71 and MZ-5-156 could antagonize the effect of hGHRH hyperstimulation in vivo, each antagonist was administered to MT-GHRH transgenic mice in a single iv dose of 10-200 microg. Both compounds decreased serum GH levels in transgenic mice by 39-72% at 1 h after injection. The inhibitory effect of 50 microg MZ-5-156 was maintained for 5 h. Twice daily ip administration of 100 microg MZ-5-156 for 3 days suppressed the highly elevated serum GH and IGF-I concentrations in transgenic mice by 56.8% and 39.0%, respectively. This treatment also reduced IGF-I messenger RNA levels in the liver by 21.8% but did not affect the level of GH messenger RNA in the pituitary. Our results demonstrate that GHRH antagonists MZ-4-71 and MZ-5-156 can inhibit elevated GH levels caused by overproduction of hGHRH. The suppression of circulating GH concentrations induced by the antagonists seems to be physiologically relevant, because both IGF-I secretion and synthesis also were reduced. Our findings, showing the suppression of GH and IGF-I secretion with GHRH antagonists, suggest that this class of analogs could be used for the diagnosis and therapy of disorders characterized by excessive GHRH secretion.
Two different dwarf rat models with primary (dw/dw, DW) or secondary (transgenic growth retarded, WF/Tgr) GH deficiency and contrasting hypothalamic GH-releasing hormone (GHRH) and somatostatin (SRIH) expression were implanted sc with GC cells. These form encapsulated rat GH-secreting tumors that maintain high plasma rat GH levels for several weeks. In both strains, GC cell tumors stimulated growth and raised GHBP levels, without affecting pituitary GH content. In DW rats, GC cell implants increased SRIH expression in the periventricular nucleus (PeV), but not in the arcuate nucleus (ARC), whereas their high GHRH expression in ARC was decreased by GC cells. In contrast, GC cell implants in WF/Tgr rats had little effect on the already high SRIH expression in PeV or low GHRH expression in ARC, although they reduced SRIH expression in ARC. GC cell implants also reduced GH receptor expression in both ARC and PeV in the WF/Tgr dwarves. Thus, chronic GH overexposure stimulates rapid growth in both dwarf strains, but has differential hypothalamic effects in these models. This experimental approach now makes it possible to study the effects of pathophysiological concentrations of GH ranging from dwarfism to acromegaly in the same animal model.
Depot somatostatin analogs are now increasingly being prescribed as adjuvant and primary therapy for the treatment of acromegaly. Previous studies have shown them to be both effective and safe, suppressing GH levels to less than 2 micro g/liter in 50-65% of cases and normalizing serum IGF-I levels in 65%. However, published data on their long-term efficacy and safety is scanty. We analyzed data from 22 patients (16 female and 6 male) treated with Sandostatin LAR or Lanreotide for an average of 41 months (range 12-89). Three patients had previously been treated with surgery, two with radiotherapy, and seven with both. Ten patients had received primary medical therapy. Mean pretreatment GH levels were 13.1 +/- 3.4 micro g/liter, and IGF-I levels were 592.9 +/- 53.9 micro g/liter. Results after 12 months of therapy indicated reduction in GH (3.2 +/- 0.7 micro g/liter; P < 0.0001) and IGF-I (321.9 +/- 33.9 micro g/liter; P < 0.001) concentrations, and this was sustained at latest follow-up. Using GH criteria (serum GH < 2 micro g/liter), 46% of subjects achieved a cure at 12 months, and 36% achieved a cure long-term. Fifty-two percent achieved normal IGF-I values at 12 months, and 67% long-term. Mean fasting and 2-h plasma glucose concentrations were similar at latest follow-up and at 12 months to baseline values. Three patients developed impaired glucose tolerance within 12 months of treatment, one going on to develop frank diabetes mellitus. However, glucose tolerance improved in five patients. Five patients developed gallstones while on treatment. In summary, this study reports the long-term efficacy of the depot somatostatin analogs as either adjuvant or primary therapy. Although overall glucose tolerance did not change, the development of impaired glucose tolerance in three patients at a time when GH levels were not changing highlights the ongoing need to monitor the long-term safety of these preparations.
Studies of acromegaly have shown a doubling of mortality compared with the general population. With the development of new modalities of treatment, it has become important to identify prognostic factors relating to mortality. Between 1964 and 2000, 208 acromegalic patients were followed for a mean of 13 yr at Auckland Hospital. Treatment was by surgery or radionuclide pituitary implantation, and all except 27 patients received pituitary radiation. Over the duration of the study, 72 patients died at a mean age of 61 +/- 12.8 yr. Those dying were significantly older at diagnosis, had a higher prevalence of hypertension and diabetes, and were more likely to have hypopituitarism. The observed to expected mortality ratio (O/E ratio) fell from 2.6 (95% confidence interval, 1.9-3.6) in those with last follow-up GH greater than 5 microg/liter to 2.5 (1.6-3.8), 1.6 (0.9-3), and 1.1 (0.5-2.1) for those with GH less than 5, less than 2, and less than 1 microg/liter, respectively (P < 0.001). Serum IGF-I, expressed as an SD score, was significantly associated with mortality, with O/E mortality ratios of 3.5 (95% confidence interval, 2.8-4.2) for those with an SD score greater than 2, 1.6 (0.6-2.6) for those with an SD score less than 2 (normal or low levels), and 1.0 (0.1-3) for those with an SD score less than zero. When assessed by multivariate analysis, last serum GH (P < 0.001), age, duration of symptoms before diagnosis (P < 0.03), and hypertension (P < 0.04) were independent predictors of survival. If IGF-I was substituted for GH, then survival was independently related to last IGF-I SD score (P < 0.02), indicating that GH and IGF-I act equivalently as predictors of mortality. These findings indicate that reduction of GH to less than 1 microg/liter or normalization of serum IGF-I reduces mortality to expected levels.
We evaluated survival after optimal treatment for acromegaly and assessed the predictive effects of different remission criteria for survival in 164 consecutive acromegalic patients, treated by transsphenoidal surgery and adjuvant therapy between 1977 and 2002. The goal of treatment was a mean GH less than 5 mU/liter, a normal glucose-suppressed GH, and a normal IGF-I for age in all patients. Surgery initially cured 108 patients (66%). Adjuvant therapy for persistent disease was given to 49 patients. At the end of follow-up (mean, 12.3 yr), remission rates for surgery and multimodality treatment were 54% and 90%, respectively. In 2033 person-years of follow-up, 28 of 164 patients died, resulting in an observed:expected mortality ratio of 1.3 (confidence interval, 0.87-1.87). Significant predictors for survival were the duration of disease and the postoperative glucose-suppressed GH. The effects of these predictors became less significant with increasing follow-up duration. A time-dependent effect on survival was observed for serial IGF-I concentrations, but not for serial GH concentrations. Of the three remission criteria, IGF-I was the only one to be significantly associated with survival in this study, with a relative risk of 4.78 for an elevated as opposed to a normal IGF-I concentration.
Somatostatin analogs are the mainstay of medical therapy for acromegaly. Suppression of GH hypersecretion, lowering of IGF-I production, and control of symptoms are established benefits of therapy. In addition, clinically significant tumor shrinkage has been seen in a number of studies, particularly in patients undergoing primary medical therapy. This review summarizes current knowledge of the effects of somatostatin analogs on tumor size and cellular morphology and examines the available data on predictors of tumor shrinkage.