The role of endogenous growth hormone-releasing hormone in acromegaly

CONTEXT: Some indirect evidence suggests hypothalamic control of GH secretion in acromegaly. OBJECTIVE: The objective of the study is to examine whether GH secretion in acromegaly is dependent on endogenous GHRH. PATIENTS AND STUDY DESIGN: We studied eight patients with untreated acromegaly due to a GH-producing pituitary tumor. All patients received an iv infusion of normal saline for 24 h and GHRH-antagonist (GHRH-ant) at 50 microg/kg x h for 7 d. GH was measured every 10 min for 24 h during the normal saline infusion and on the last day of the GHRH-ant infusion. A group of nine different patients with untreated acromegaly served as the control group and underwent blood sampling for GH every 10 min for two 24-h periods to assess the day-to-day variability of GH secretion. SETTING: The study was set in a university referral center. MAIN OUTCOME MEASURE: Twenty-four-hour mean GH was the main outcome measured. RESULTS: In six of eight subjects treated with GHRH-ant, 24-h mean GH decreased by 5.8-30.0% during iv GHRH-ant and, in three subjects, the change in the 24-h mean GH was greater than the upper limit of the 95% confidence interval of the spontaneous day-to-day variability of the mean GH in patients with acromegaly. Based on the binomial distribution, the probability of this magnitude of change to occur in three of eight subjects by chance alone is 0.0008. CONCLUSION: In some patients with acromegaly due to a pituitary adenoma, GH secretion is under partial control by endogenous GHRH.     

The prevalence of growth hormone deficiency in survivors of subarachnoid haemorrhage: results from a large single centre study

Objective

The variation in reported prevalence of growth hormone deficiency (GHD) post subarachnoid haemorrhage (SAH) is mainly due to methodological heterogeneity. We report on the prevalence of GHD in a large cohort of patients following SAH, when dynamic and confirmatory pituitary hormone testing methods are systematically employed.

Design

In this cross-sectional study, pituitary function was assessed in 100 patients following SAH. Baseline pituitary hormonal profile measurement and glucagon stimulation testing (GST) was carried out in all patients. Isolated GHD was confirmed with an Arginine stimulation test and ACTH deficiency was confirmed with a short synacthen test.

Results

The prevalence of hypopituitarism in our cohort was 19% and the prevalence of GHD was 14%. There was no association between GHD and the clinical or radiological severity of SAH at presentation, treatment modality, age, or occurrence of vasospasm. There were statistically significant differences in terms of Glasgow Outcome Scale (GOS; p?=?0.03) between patients diagnosed with GHD and those without. Significant inverse correlations between GH peak on GST with body mass index (BMI) and waist hip ratio (WHR) was also noted (p?<?0.0001 and p?<?0.0001 respectively).

Conclusion

Using the current testing protocol, the prevalence of GHD detected in our cohort was 14%. It is unclear if the BMI and WHR difference observed is truly due to GHD or confounded by the endocrine tests used in this protocol. There is possibly an association between the development of GHD and worse GOS score. Routine endocrine screening of all SAH survivors with dynamic tests is time consuming and may subject many patients to unnecessary side-effects. Furthermore the degree of clinical benefit derived from growth hormone replacement in this patient group, remains unclear. Increased understanding of the most appropriate testing methodology in this patient group and more importantly which SAH survivors would derive most benefit from GHD screening is required.

     

Psychosocial morbidity in acromegaly: a study from India

To study the psychosocial profile of patients of acromegaly in a developing country setting. Seventeen patients with acromegaly underwent a cross-sectional assessment regarding their socio-demographic and clinical profile, life events, social support, coping, dysfunction, quality of life and psychiatric morbidity. Seventeen demographically matched healthy participants (free from psychological morbidity) acted as the control group. The acromegaly group had predominance of urban married males (64.7%) with mean age 36.05 +/- 17.06 years (range = 15-61), and mean duration of illness of 36.05 +/- 42.5 (range = 4-240) months. Six subjects (i.e., GHQ-positive group) scored positive (indicating presence of psychiatric morbidity) on the General Health Questionnaire-12 giving a psychiatric morbidity rate of 33.33%, with five fulfilling an ICD-10 diagnosis. Compared to the GHQ-negative group, the GHQ-positive group had more number of life events in the entire lifetime, used significantly more number of emotional coping strategies, had more dysfunction, and poorer quality of life (in domains of physical health, social relationship, and general well-being). Psychiatric morbidity occurs in a significant percentage of patients with acromegaly. Presence of psychiatric morbidity is associated with dysfunction and poorer quality of life.     

Electronic control device exposure: a review of morbidity and mortality

The use of electronic control devices has expanded worldwide during the last few years, the most widely used model being the Taser. However, the scientific knowledge about electronic control devices remains limited. We reviewed the medical literature to examine the potential implications of electronic devices in terms of morbidity and mortality, and to identify and evaluate all the existing experimental human studies. A single exposure of an electronic control device on healthy individuals can be assumed to be generally safe, according to 23 prospective human experimental studies and numerous volunteer exposures. In case series, however, electronic control devices could have deleterious effects when used in the field, in particular if persons receive multiple exposures, are intoxicated, show signs of "excited delirium," or present with medical comorbidities. As the use of electronic control devices continues to increase, the controversy about its safety, notably in potentially high-risk individuals, is still a matter of debate. The complications of electronic control device exposure are numerous but often recognizable, usually resulting from barbed dart injuries or from falls. Persons exposed to electronic control devices should therefore be fully examined, and traumatic lesions must be ruled out.     

Outcome of surgical treatment for acromegaly performed by a single neurosurgeon and cumulative meta-analysis

The aim of this retrospective study was to evaluate the results of transsphenoidal surgery in a group of patients with acromegaly who were operated by the same neurosurgeon. Our results were compared to those from a cumulative meta-analysis of 10 series (1,632 patients) published between 1992 and 2005. We followed 28 patients (17M/11F; 44.1 +/- 12.7 yr; 27 with macroadenomas; 86% being invasive) during 21.4 +/- 17.6 months after treatment. Patients were classified according to disease activity as follows: 1) controlled (CD): basal or mean GH < 2.5 ng/ml or nadir GH (OGTT) < 1 ng/ml and normal IGF-1; 2) uncontrolled (UCD): basal or mean GH > 2.5 ng/ml or nadir GH > 1 ng/ml and elevated IGF-1; 3) inadequately controlled (ICD): normal GH and elevated IGF-1 or elevated GH and normal IGF-1. After surgery, GH levels decreased from 61.7 +/- 101.1 ng/ml to 7.2 +/- 13.7 ng/ml (p< 0.001) and mean IGF-1 from 673.1 +/- 257.7 ng/ml to 471.2 +/- 285 ng/ml (p= 0.01). Biochemical remission rate was 57% [10 (35.5%) patients with CD and 6 (21.5%) with ICD], similar to the mean remission rate observed in the meta-analysis of surgical outcome of macroadenomas. Seven of 28 patients were submitted to surgical re-intervention (4 had been previously operated elsewhere and 3 by our neurosurgeon), with CD observed in 5 (71.5%) on follow-up. Cavernous sinuses invasion was more prevalent in UCD and ICD, whereas infundibular stalk deviation occurred only in patients with UCD. Remission rate was significantly higher in series where all surgical procedures were performed by the same surgeon (66% vs. 49%; p< 0.05). Thus, the surgeon's experience significantly improves the surgical outcome in acromegaly, especially in patients harboring large and invasive tumors, and re-intervention performed by an experienced surgeon should be considered in the algorithms for clinical management of this disease.     

The growth hormone responses to L-dopa and TRH in acromegaly

The GH responses to TRH and L-dopa were investigated in 14 Indian and African patients with untreated acromegaly. A positive response to L-dopa (greater than 50% change from basal) was obtained in 6 of the 14 patients tested while a positive response to TRH (greater than 100% change from basal) was found in 5 of 12 patients tested. While 9 patients responded to at least one agent, only 2 had a positive response to both agents. Positive responders appeared to be hyper-prolactinemic and have evidence of abnormal glucose tolerance as compared to nonresponders.     

The role of prolactin in the inhibitory action of bromocriptine on growth hormone secretion in acromegaly

Bromocriptine treatment results in clinical improvement and inhibition of plasma GH levels in only part of the acromegalic patients. The possible role of the simultaneous presence of Prl and GH in GH-secreting pituitary adenomas was investigated with regard to the inhibitory action of bromocriptine on GH secretion and the paradoxical increase of GH release in reaction to TRH. Surgically obtained pituitary tumour tissue from 35 consecutive acromegalic patients was studied immunohistochemically. In 21 patients no Prl was present in the tumour tissue. These patients had normal plasma Prl levels. In the other 14 patients Prl was present in the tumour tissue. Hyperprolactinaemia was found in 10 of these 14 patient. Plasma GH levels from 2 till 10 h after the administration of 2.5 mg bromocriptine measured before operation were significantly more suppressed in the patients with mixed GH/Prl-containing than in those with pure GH-containing pituitary adenomas, being 38 +/- 4% and 65 +/- 4% of basal values, respectively (P less than 0.01). The response of GH to TRH, however, did not differ significantly between the two groups. Conclusions: 1. In about 70% of patients with 'mixed' GH/Prl containing adenomas, hyperprolactinaemia is present. 2. The simultaneous presence of Prl and GH in a GH-secreting pituitary tumour increases the sensitivity of GH secretion to bromocriptine. 3. The plasma Prl level is of value to predict which patients with acromegaly are likely to respond to bromocriptine with an inhibition of GH secretion.     

The role of growth hormone in determining birth size and early postnatal growth, using congenital growth hormone deficiency (GHD) as a model

OBJECTIVE: The role of GH in early human growth is unclear. Congenital GH deficiency (CGHD) provides a useful tool to explore this putative role. We have assessed the effects of CGHD on birth size and early postnatal growth, and the further impact of the presence of additional pituitary hormone deficiencies and midline brain defects on these parameters. DESIGN, PATIENTS AND MEASUREMENTS: Weight, length and BMI expressed as standard deviation scores (SDS), over the first two years of life, were retrospectively compared in 44 GH-deficient children (M:F 26 : 18). Thirty-eight of 44 patients underwent GH provocation testing and all patients had neuro-imaging of the brain. The patients were divided into three groups of increasing phenotypic complexity {group A [n = 12, isolated GHD, no midline defects], group B [n = 10, combined pituitary hormone deficiency (CPHD); no midline defects], group C (n = 22, CPHD with midline defects)}. RESULTS: Mean birth weight, length and BMI SDS were -0.4, -0.9 and +0.1 SDS, respectively. The differences were significant for weight (P = 0.03) and BMI (P = 0.003), but not length (P = 0.3) SDS, between groups A and C. Of the three groups, group A had a lower weight and BMI SDS than group C. The prevalence of postnatal complications (n = 25) was significantly different in the three groups [group A (8%), group B (80%), group C (73%); P < 0.001] and particularly between patients with isolated GH deficiency (IGHD) (group A) and CPHD (groups B and C; P < 0.0001). No patients in group A presented with neonatal hypoglycaemia as compared with 70% of those in group B and 59% in group C (P = 0.001). A reduced length SDS was observed in all patients within 6 months of birth and the reduction was greatest in group B (P = 0.03). Group C remained significantly (P < 0.05) heavier at 12, 18 and 24 months compared to group A. BMI SDS was significantly (P < 0.05) greater at all study points in CPHD patients (groups B and C) as compared with IGHD. Serum GH concentrations at testing did not correlate significantly with birth length (r = -0.08, P = 0.7), birth weight (r = -0.08, P = 0.6) or the age at induction of GH treatment (r = 0.12, P = 0.5). There were no significant differences between peak serum GH concentrations in patients in groups A (7.8 +/- 6.3 mU/l), B (3.9 +/- 4.8 mU/l) or C (8.7 +/- 5.4 mU/l). CONCLUSIONS: Length, weight and BMI data from our study groups suggest that GH per se has a minimal effect on intrauterine growth but a significant effect during the infancy period. Early growth may also be influenced by the complexity of the hypopituitary phenotype reflected by the presence of additional pituitary hormone deficiencies and midline forebrain defects.     

Acute effects of a single administration of dexamethasone on basal and growth hormone-releasing hormone stimulated GH secretion in acromegaly

A single administration of dexamethasone causes both an early stimulatory and a late inhibitory effect on GH secretion in normal subjects. OBJECTIVE We investigated the effects of a single administration of dexamethasone on basal and GH-releasing hormone-stimulated GH secretion in eight patients with active acromegaly. DESIGN On three different days the patients received 4 mg i.v. dexamethasone, 1 μg/kg body weight GH-releasing hormone 1-29, or matched placebos in different order. PATIENTS Eight subjects with active acromegaly, five of whom had not been treated previously, while the other three had received octreotide therapy which was stopped at least 7 days before testing. MEASUREMENTS Serum GH levels were measured in duplicate by a commercially available RIA kit. RESULTS Dexamethasone administration caused a significant decline of mean ± SE GH levels from 51.8 ± 13.8 to 30.0 ± 9.2 mU/l at 180 minutes, that was not influenced by placebo administration at 180 minutes. On the contrary, when GH-releasing hormone substituted placebo administration, GH levels increased from 34.0 ± 9.8 mU/l at 180 minutes to 56.0 ± 15.6 mU/l at 195 minutes. The GH increase was higher when GH-releasing hormone was given without dexamethasone pretreatment (from 52.4 ± 13.0 mU/l at 180 minutes to 86.4 ± 25.4 mU/l at 195 minutes). Analysis of the GH area under the curve confirmed the significant inhibition of GH secretion after dexamethasone administration and the significant reduction of the GH response to GH-releasing hormone in the study with dexamethasone pretreatment. CONCLUSIONS At variance with data in normal subjects, acute i.v. administration of dexamethasone inhibits basal GH secretion and partially suppresses the GH response to GH-releasing hormone in acromegaly. Both alterations in the regulatory mechanism of adenomatous cells and perturbations of hypothalamic regulatory influences, induced by the state of chronic GH hypersecretion, are likely explanations of the different response to dexamethasone.     

The effect of minisomatostatin on anomalous growth hormone responses in acromegaly

Twelve patients with active acromegaly were treated with the long-acting somatostatin analogue SMS 201-995 at a dose of 50 micrograms sc twice daily in the first 2 weeks of treatment and 100 micrograms twice daily thereafter. Four hours after the first injection of SMS, GH levels became normal in 8 of the 12 patients. The GH response after hpGRF administration was strongly suppressed by SMS. Paradoxical GH responses to TRH disappeared in 6 out of 7 patients during SMS. Paradoxical GH responses to LHR, however, persisted in 4 out of 4 patients. Paradoxical responses of GH after glucose loading disappeared in 2 out of 2 patients. We conclude that SMS normalizes most anomalous growth hormone kinetics in acromegaly. This drug offers a new tool in the treatment of this disease.     

Evidence of a circulating growth hormone stimulating factor other than growth hormone releasing hormone in a patient with pituitary tumour and acromegaly

This study is a report on the growth hormone (GH) stimulatory effect of serum and plasma from a patient with notably active acromegaly due to a GH producing pituitary adenoma. Pituitary adenomatous tissue from 7 patients with GH producing adenomas, one with a prolactin (Prl) producing adenoma, one with a TSH producing adenoma, and one with a non-secreting adenoma, were cultured in vitro for 8-10 days. Media were changed every 48-72 h and contained Neumann Tytell buffer with the addition of 1) foetal calf serum, 2) patients' own serum or plasma, 3) serum or plasma from the patient with notably active acromegaly. GH release expressed as microgram GH/1/48-72 h between day 6 and 8 in culture did not differ when adenomatous tissue was cultured in buffer, foetal calf serum or the patients' own serum or plasma. In contrast, GH release was increased in 9/10 patients, when media contained serum or plasma from the patient with notably active acromegaly. This GH stimulatory effect was demonstrated in vitro in human pituitary adenomatous tissue from patients with pathological as well as normal GH secretion in vivo. Furthermore, this GH releasing plasma in a concentration of 10% increased GH release in cultures of dispersed rat anterior pituitary cells. In the same system, synthetic growth hormone-releasing hormone (GRF)-44 stimulated the release of GH in a dose-dependent manner. However, at all dose levels including maximally stimulating doses of GRF, an additive effect on GH release was seen with 10% of the GH releasing plasma.(ABSTRACT TRUNCATED AT 250 WORDS)     

The size of growth hormone granules in pituitary adenomas producing acromegaly

Measurements of the diameters of large numbers of granules in electron micrographs of pituitary adenomas in cases of acromegaly do not show that a typical size exists which allows of the retrospective diagnosis of the hormone secreted by the tumour. The granule diameters found in single cases show a normal distribution. The average values determined in 19 unselected cases of acromegaly range between 160 and 342 nm. They are also normally distributed about the mean for the entire group which is 238 nm. With histo-immunological electron microscopic techniques h GH can be demonstrated in small, medium and large granules. The size of hormone granules is determined by functional factors such as the speed of hormone synthesis and hormone release but not by the type of hormone secreted.