HIV-1 envelope protein gp120 triggers a Th2 response in mice that shifts to Th1 in the presence of human growth hormone

Immunization of mice with HIV-1-gp120 results in predominant activation of the Th2 lymphocyte subset, leading to enhanced IL-4 production. Administration of human growth hormone at the time of gp120 immunization provokes a change in the cytokine production pattern, with lower IL-4 and higher gamma-IFN and IL-2 synthesis levels, indicating a preferential switch in stimulation from Th2 to Th1 cells. A growth hormone would thus be of great use for pharmacological intervention in those cases in which an infectious microorganism evades immune defenses by provoking a Th2 response. In addition, the ability of growth hormone to induce a Th1-type response upon vaccination with an HIV-antigen should be examined in the development of new therapeutic strategies or in the design of novel vaccines against HIV infection.     

Xenon and nitrogen single-breath washout curves in patients with airway obstruction

In 25 diabetics and 8 controls the insulin hypoglycemia test was performed with subsequent determination of growth hormone secretion by the radioimmunoassay method. The rise of the growth hormone level began earlier and persisted longer in diabetics as compared with controls. Juvenile diabetes was associated with a rapid secretory response of the hormone while in maturity-type diabetes the release of growth hormone in response to stimulation was excessive but delayed. A somewhat lower secretory response was found in diabetes lasting over 5 years as compared with short-lasting diabetes. The observed phenomena were not related to the absolute blood glucose level. Although the phenomenon of growth hormone hypersecretion remains yet to be explained, it seems, however, to be secondary to carbohydrate metabolism disturbance and insulin disorders.     

Growth hormone and diabetes mellitus. A review of sixty-three years of medical research and a glimpse into the future?

The diabetogenic action of pituitary extracts containing growth hormone has been recognised for more than 60 years and the importance of growth hormone in the development and progression of diabetic retinopathy for more than 30 years. Hypophysectomy was the first effective treatment for retinopathy but was discontinued because of the risk of severe hypoglycaemia that it produced and the development of an alternative, less dangerous therapy--photocoagulation. The precise role and significance of growth hormone in diabetes care, however, remains to this day a mystery. The fact that modern, highly purified biosynthetic preparations of growth hormone still retain full diabetogenic potency and the fact that diabetes develops in up to 25% of patients with acromegaly indicate growth hormone's potential for involvement in the aetiology of diabetes mellitus, although most will agree that this is not likely to be an important factor in the large majority of 'idiopathic' cases. There is strong evidence to indicate a substantial hypersecretion of growth hormone in 'idiopathic' diabetes mellitus (particularly insulin-dependent cases and those with retinopathy), which appears to be more related to residual pancreatic insulin secretion than to metabolic control. Since the advent of biosynthetic growth hormone in sufficient quantity to perform trials in adults, we are more aware of growth hormone's considerable potency in the regulation of body composition, growth factor production and intermediary metabolism. In this article, we review the literature and, from this and our own work, propose a new hypothesis which links the hypersecretion of growth hormone to reduced hepatic secretion of insulin-like growth-factor I (IGF-I) as a direct result of reduced portal insulin levels in diabetes mellitus. The hypersecretion of growth hormone exposes peripheral organs such as the retina and kidney to conditions favouring the expression of growth-hormone-dependent growth factors such as IGF-I which may contribute to the development of diabetic microvascular disease by autocrine and/or paracrine effects. If this hypothesis proves to be true, it offers new opportunities for the prevention of diabetic microvascular complications through suppression of growth hormone secretion which in turn will increase insulin sensitivity and facilitate good glycaemic control.     

Maxillary sinus pneumocele

The aim of this study was to compare the growth response of 22 short pre-pubertal children without growth hormone deficiency, treated with a single daily growth hormone injection (group A), to the growth response of 27 similar children, treated with the same daily dose divided into 2 subcutaneous injections per day (group B), for 1 y, in a randomized study. GH treatment significantly promoted growth parameters, height standard deviation score and height velocity standard deviation score in both groups. Serum insulin-like growth factor I was also increased. There were no significant differences in growth response, serum IGF-I levels, or the advance in bone age between the two study groups after 1 y of GH therapy. We conclude that twice daily s.c. growth hormone injections provide no advantages over once daily injection of the same dose in promoting the linear growth of short children without growth hormone deficiency.     

Coping with stress: parallelism between the effects of septal lesions on growth hormone and corticosterone levels

In order to characterize the effects of a septal lesion on plasma growth hormone levels, blood samples were taken from normal and sham-operated rats and rats with a bilateral septal lesion under conditions of rest and following stressful stimulation. Nonlesioned control rats evidenced a significant base line diurnal rhythm in plasma growth hormone levels which was unaffected by a septal lesion. In response to stress, plasma growth hormone levels evidenced a significant drop. Minimum levels were reached 15 min after stimulation and remained depressed during 1 hr of observation after stimulation. Rats with a septal lesion evidenced the same pattern of growth hormone response to stressful stimulation as nonlesioned rats, however the magnitude of response was potentiated in septal rats. The present data were compared to the previously published corticosterone data from the same animals. A septal lesion has similar effects on boting 24-hour rhythm of either of these hormones but potentiated the response of both corticosterone and growth hormone to stress even though the direction of response is opposite. The results are interpreted as suggesting the septum is an element in some central coping mechanism which is involved when an organism reacts to environmental demands. Preliminary data further suggest that the same central coping mechanism is involved in both the behavioral and hormonal responses to stress.     

Transient diabetes mellitus in a neonate. Evaluation of insulin, glucagon, and growth hormone secretion and management with a continuous low-dose insulin infusion

This neonate developed marked hyperglycemia four days after birth and required insulin therapy for eight weeks. During the acute phase of the disease, immunoreactive insulin was undetectable in portal venous serum. Neither tolbutamide nor theophylline administration significantly triggered insulin secretion. Somatostatin infusion inhibited growth hormone release but had no effect on plasma glucagon or blood glucose concentrations. At 2 1/2 months, two weeks after insulin withdrawal, the infant was still intolerant to an oral glucose load, insulin response was markedly delayed, and growth hormone secretion was paradoxical. At five months, the insulin, glucagon, and growth hormone responses to glucose and to somatostatin were normalized. Thus, in this patient, insulin secretion was transiently deficient. Peculiarities of glucagon and growth hormone secretion were also present but are more characteristic of this age group than of diabetes. The hyperglycemic state was managed by intraportal infusion of 0.1 to 0.2 IU regular insulin/kg/hour. This mode of insulin administration proved efficient, secure, and easy to manage.     

Twenty-four hour growth hormone secretion in a patient with Werner's syndrome

OBJECTIVE: To assess the 24-h endogenous secretory growth hormone (GH) profile and serum insulin-like growth factor-I (IGF-I) response to exogenous recombinant human growth hormone (rhGH) in a patient with Werner's syndrome. DESIGN: Blood sampling every 20 min for 24 h followed by three daily injections of growth hormone. SETTING: General Clinical Research Center. PATIENTS: Single patient with Werner's syndrome. MEASUREMENTS: Serum GH and IGF-I. RESULTS: Growth hormone pulses were absent during the 24-h monitoring period. Likewise, integrated GH concentrations were very low at 0.25 mu min/mL, and no peaks occurred after sleep onset. Following single daily administration of rhGH, serum GH and IGF-I rose. CONCLUSIONS: Our findings support previous but less extensive studies suggesting patients with Werner's syndrome have reduced growth hormone levels. Preliminary investigations using rhGH in patients with Werner's syndrome should be considered.     

Growth hormone treatment of children with neural tube defects: results from 6 months to 6 years

OBJECTIVE: Patients with neural tube defects (myelomeningocele) have severe growth retardation, and treatment with recombinant human growth hormone (rHGH) for 6 months accelerates growth velocity. We examined patients treated for longer periods to determine whether accelerated growth persists, and whether patients demonstrated to be growth hormone deficient have a greater response to rHGH therapy. METHODS: We retrospectively evaluated the growth rate and length standard deviation score (SDS) of 22 patients in response to treatment with 0.3 mg/kg per week of rHGH for 7 to 72 months. Nine of 22 patients were growth hormone deficient (nocturnal and provocative growth hormone responses < 7 ng/ml). Treatment success was defined as an increase of length SDS of > 0.2 SD per year. RESULTS: Fourteen patients (64%) had treatment successes, and eight had treatment failures. Length SDS improved from a pretreatment value of -2.9 (+/- 1.2) to the most recent length SDS of -1.9 (+/- 1.4) (p < 0.001). The growth rate was significantly increased through year 4 of treatment. The annualized growth rate after 6 months of rHGH treatment was significantly different for the success and failure groups (11.0 +/- 2.6 cm/yr vs 5.1 +/- 3 cm/yr, p < 0.001). The annualized 6-month growth rate during treatment was related to the probability of treatment success. CONCLUSION: Treatment with rHGH significantly improves the growth rate and length SDS of children with neural tube defects. The 6-month annualized growth velocity during treatment was predictive of long-term treatment response. The effect on adult stature is unknown.     

Effect of selenium and lodine supplementation on growth rate and on thyroid and somatotropic function in dairy calves at pasture

The effects of Se and I supplementation on growth rate and on thyroid and somatotropic function were examined for heifer calves from two herds fed pasture. Supplementation of calves with intraruminal Se pellets increased the basal plasma concentration of 3,5,3'-triiodothyronine and reduced the basal plasma concentration of thyroxine for both herds. For one herd, supplementation with Se increased the triiodothyronine response to challenge with thyrotropin-releasing hormone, increased BW gain, and tended to increase the plasma concentration of IGF-I. The plasma concentration of growth hormone was unaffected by Se supplementation. Supplementation with I increased the response of thyroid hormones to thyrotropin-releasing hormone but did not increase BW gain. Interaction between Se and I treatment within the herds was not apparent for any outcome variable. These data suggest that the effects of Se deficiency in grazing calves may be mediated by alterations in thyroid hormone metabolism but apparently are not mediated through modulation of the peripheral concentration of growth hormone.     

Intracellular misrouting and abnormal secretion of adrenocorticotropin and growth hormone in cpefat mice associated with a carboxypeptidase E mutation

Cpefat mice carry a mutation in the carboxypeptidase E/H gene which encodes an exopeptidase that removes C-terminal basic residues from endoproteolytically cleaved hormone intermediates. These mice have endocrine disorders including obesity, infertility, and hyperproinsulinemia-diabetes syndrome, but the etiology remains an enigma. Because studies have identified membrane carboxypeptidase E as a sorting receptor for targeting prohormones to the regulated secretory pathway for processing and secretion, the intracellular routing and secretion of pro-opiomelanocortin/adrenocorticotropin and growth hormone from anterior pituitary cells were investigated in Cpefat mice. In Cpefat mice, pro-opiomelanocortin was accumulated 24-fold above normal animals in the pituitary and it was poorly processed to adrenocorticotropin. Furthermore, pro-opiomelanocortin was secreted constitutively at high levels, showing no response to stimulation by corticotropin-releasing hormone. Similarly, growth hormone release was constitutive and did not respond to high K+ stimulation. Both pro-opiomelanocortin and growth hormone levels were elevated in the circulation of Cpefat mice versus normal mice. These data provide evidence that the lack of carboxypeptidase E, the sorting receptor, results in the intracellular misrouting and secretion of pro-opiomelanocortin and growth hormone via the constitutive pathway in the pituitary of Cpefat mice.     

The role of dietary calcium in hypertensive disease: update and clinical implications

The pancreatic beta-cell response to stimulation with glucose and GIP, single and combined, was studied in acromegalics and in normal subjects. Acromegalics had higher IRI and GIP basal values with glucose levels and glucose disposal in the normal range. Further, acromegalics showed a greater IRI response to glucose, GIP and glucose combined with GIP. The results suggested that high growth hormone levels cause a greater activity of the entero-insular axis both in the basal state and after meal ingestion, as mimicked by GIP infusion. From these and previous observations, it can be assumed that growth hormone induces a facilitation of the IRI response to metabolite substrates and hormones.     

Disturbed release of growth hormone in mature dogs: a comparison with congenital growth hormone deficiency

An acquired defect in growth hormone secretion in mature dogs has been associated with some forms of generalised alopecia. In an attempt to elucidate the pathogenesis of the disturbance in growth hormone release, the plasma concentrations of growth hormone and insulin-like growth factor I (IGF-I) were measured in two seven-year-old poodles with alopecia and, for comparison, in two young German sheperd dogs with congenital hyposomatotropism (pituitary dwarfism). In the poodles the basal concentrations of growth hormone were low, although often above the detection limit of the assay. The concentrations of IGF-I were in the reference range for healthy poodles. No growth hormone could be detected in the plasma of the German sheperd dogs and the concentrations of IGF-I were very low. Stimulation with clonidine and growth hormone releasing hormone (GHRH) before and after repeated injections of GHRH did not result in significant increases in growth hormone concentrations in plasma. The concentrations of growth hormone in the poodles fluctuated at low levels during the test period. In the German sheperd dogs the levels of growth hormone remained unmeasurable during the stimulation tests. It was concluded that in the two poodles the basal concentrations of growth hormone were sufficient to maintain normal IGF-I concentrations, and thus the release of growth hormone was considered appropriate. Based upon measurements of urinary corticoids and a review of the literature it is suggested that the lack of a growth hormone response to stimulation was due to the enhanced release of somatostatin as a result of mild and fluctuating hyperadrenocorticism.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Oral administration of arginine enhances the growth hormone response to growth hormone releasing hormone in short children

We have evaluated the effect of oral administration of arginine chlorhydrate on the growth hormone response to growth hormone releasing hormone in a group of nine short prepubertal children (six boys and four girls). Arginine chlorhydrate 10 g, administered orally 60 min before an i.v. bolus injection of growth hormone releasing hormone 1-29, 1 microgram/kg, significantly enhanced the growth hormone response to the neuropeptide, confirming the results of previous studies which used the i.v. route. Furthermore, our data strengthen the view that the effects of arginine chlorhydrate on growth hormone secretion are mediated by inhibition of endogenous somatostatin release.     

Suppression of immunological response against a transgene product delivered from microencapsulated cells

A potential obstacle to successful gene therapy for some patients is the in vivo production of neutralizing antibodies against the recombinant therapeutic product delivered. To mimic this clinical situation, we implanted microencapsulated recombinant cells producing human growth hormone into C57B1/6 mice to provoke antihuman growth hormone antibody production. We then investigated the efficacy of different immunosuppressive treatments to inhibit the development of neutralizing antibodies. The experimental mice were treated with either an immunosuppressive drug (FK506 or cyclophosphamide), a cytokine (interferon-gamma [IFN-gamma] or interleukin-12 [IL-12], or a monoclonal antibody (anti-CD4, anti-gp39, or CTLA4-Ig). Serum human growth hormone and mouse anti-human growth hormone antibody levels were measured by enzyme-linked immunosorbent assay (ELISA) for 4 weeks. There were three patterns of response noted among the seven treatment groups. First, the mice receiving IFN-gamma, IL-12, anti-gp39, or CTLA4-Ig were similar to the untreated controls-no suppression of anti-hGH antibodies and no improvement in delivery of hGH. Next, the mice receiving FK506 or cyclosphosphamide showed > or = 90% suppression of antibodies but also no improvement in product delivery. Last, the mice receiving anti-CD4 showed almost complete antibody suppression over 1 month postimplantation. Furthermore, only anti-CD4 permitted a sustained level of human growth hormone delivery to day 28, in contrast to the controls whose human growth hormone delivery was undetectable by day 14 postimplantation. Hence, the use of anti-CD4 inhibited formation of neutralizing antibodies against a recombinant gene product delivered in vivo, and allowed prolonged delivery of a foreign protein. Its role as adjunct treatment for appropriate patients receiving gene therapy should be examined further.     

On the agglutinogens of red cells developed with proteolytic enzymes and neuraminidase

Four cases of slipped upper femoral epiphyses in patients with intracranial tumours causing hypopituitarism and chiasmal compression are presented. Detailed endocrine studies in three cases showed severe deficiencies of growth hormone as well as of gonadotrophin and sex hormones. The literature is reviewed and the aetiology is discussed with special reference to Harris's hypothesis that an increase in growth hormone relative to oestrogen predisposes to slipping of the upper femoral epiphysis in humans, which these cases do not seem to support. In all cases the slip was bilateral, and it is emphasised that surgical treatment can provide only temporary fixation because fusion is dependent on correct hormonal therapy.     

The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group

A combined anterior pituitary (CAP) function test was assessed in eight healthy male beagle dogs. The CAP test consisted of sequential 30-second intravenous administrations of four hypothalamic releasing hormones in the following order and doses: 1 microgram of corticotropin-releasing hormone (CRH)/kg, 1 microgram of growth hormone-releasing hormone (GHRH)/kg, 10 micrograms of gonadotropin-releasing hormone (GnRH)/kg, and 10 micrograms of thyrotropin-releasing hormone (TRH)/kg. Plasma samples were assayed for adrenocorticotropin, cortisol, GH, luteinizing hormone (LH), and prolactin (PRL) at multiple times for 120 min after injection. Each releasing hormone was also administered separately in the same dose to the same eight dogs in order to investigate any interactions between the releasing hormones in the combined function test. Compared with separate administration, the combined administration of these four hypothalamic releasing hormones caused no apparent inhibition or synergism with respect to the responses to CRH, GHRH, and TRH. The combined administration of these four hypothalamic releasing hormones caused a 50% attenuation in LH response compared with the LH response to single GnRH administration. The side effects of the combined test were confined to restlessness and nausea in three dogs, which disappeared within minutes after the administration of the releasing hormones. It is concluded that with the rapid sequential administration of four hypothalamic releasing hormones (CRH, GHRH, GnRH, and TRH), the adenohypophyseal responses are similar to those occurring with the single administration of these secretagogues, with the exception of the LH response, which is lower in the CAP test than after single GnRH administration.     

A risk-benefit assessment of growth hormone use in children

Growth hormone prepared by recombinant DNA technology (somatropin) has been commercially available for over 11 years. More than 38,000 children have been treated with different growth hormone products. While the best response to treatment occurs in children with severe growth hormone deficiency, therapy with growth hormone will increase the rate of statural growth in children with short stature of many different aetiologies. There are few studies of the effect of growth hormone treatment of final adult height, and the magnitude of this effect is harder to gauge, particularly in children with idiopathic short stature. Other benefits of growth hormone treatment in children include improvement in psychosocial functioning and physiological parameters, such as bone mineral density. Adverse effects associated with growth hormone treatment have been relatively uncommon. Most of the safety data on growth hormone have come from large postmarketing databases maintained by 2 pharmaceutical companies. The adverse event profile reported in children treated with growth hormone is different from that found in adults. Peripheral oedema and carpal tunnel syndrome, which are common in adults treated with growth hormone and frequently result in treatment discontinuation, are rare in children. Intracranial hypertension is rare, but can occur in children with growth hormone deficiency, Ullrich-Turner syndrome or renal insufficiency during the first 8 to 12 weeks after the start of growth hormone treatment; it has seldom been reported in adults with growth hormone deficiency. Children with growth hormone deficiency, Ullrich-Turner syndrome or renal insufficiency are prone to develop slipped capital femoral epiphyses both before and during growth hormone treatment. Therefore, limping and complaints of hip or knee pain should be carefully investigated.     

Effect of somatostatin on metabolic and hormonal changes induced by nicotinic acid in insulin-dependent diabetics

The study investigated the respective influences of nicotinic acid and somatostatin on plasma concentrations of blood glucose, free fatty acids, glucagon, growth hormone and cortisol in insulin-dependent diabetic subjects. After administration of nicotinic acid alone, marked depression of plasma FFA was accompanied by significant increases of plasma glucagon, growth hormone and cortisol. The glucagon and growth hormone responses to nicotinic acid were significantly reduced when plasma FFA were raised by intravenous administration of heparin and triglycerides. Somatostatin alone induced a significant decrease in blood glucose, plasma glucagon and growth hormone concentrations. Plasma FFA remained unchanged. Somatostatin did not modify the nicotinic acid-induced fall in plasma FFA, but completely blocked the corresponding increments in glucagon and growth hormone. The cortisol rise was not altered by somatostatin. Rebound of glucagon and growth hormone levels were seen upon discontinuation of the somatostatin administration. These results demonstrate that the plasma FFA concentration plays a role in the regulation of glucagon and growth hormone secretion in insulin-dependent diabetics. Furthermore, they indicate that somatostatin, previously shown to be capable of negating the stimulatory effect of various factors on glucagon and growth hormone secretion, also affects the response of these hormones to FFA depression.     

Production of alpha-subunit of glycoprotein hormones by pituitary somatotroph adenomas in vitro

Somatotroph adenomas of the pituitary secrete growth hormone in excess and are associated with acromegaly. Morphologically, they can be separated into two entities, densely and sparsely granulated variants. It has been shown that a number of somatotroph adenomas produce alpha-subunit of glycoprotein hormones; however, it is not clear whether alpha-subunit production correlates with tumor cell morphology. We studied 32 surgically removed pituitary somatotroph adenomas in tissue culture to determine structure-function correlations of growth hormone and alpha-subunit production. All tumors were classified on the basis of detailed histological, immunocytochemical and electron-microscopic studies. Fifteen tumors were densely granulated and 17 were sparsely granulated. In addition to growth hormone, all 15 densely granulated tumors released alpha-subunit in vitro, whereas of the 17 sparsely granulated tumors only 4 released alpha-subunit; moreover, the mean baseline levels of alpha-subunit were significantly higher in densely granulated adenomas than in sparsely granulated adenomas. Parallel response of release of both hormones was found during stimulation with growth hormone-releasing hormone or thyrotropin-releasing hormone and during suppression with somatostatin or bromocriptine in densely granulated tumors. alpha-subunit response to stimulation or suppression could not be determined with significance in sparsely granulated tumors because of low basal levels. The results indicate that alpha-subunit production and release is characteristic of densely granulated somatotroph adenomas and that alpha-subunit is coregulated with growth hormone by adenohypophysiotropic substances; in contrast, alpha-subunit production, by sparsely granulated somatotroph adenomas is rare and, when present, much lower in quantity.(ABSTRACT TRUNCATED AT 250 WORDS)