The effect of growth hormone replacement on cortisol metabolism and glucocorticoid sensitivity in hypopituitary adults

OBJECTIVE: Growth hormone (GH) replacement therapy in hypopituitary adults is associated with sodium and water retention. The underlying mechanisms are incompletely understood and a possible contribution of altered cortisol metabolism or action has not been evaluated. We have investigated the effect of GH replacement therapy on cortisol metabolism, cortisol binding globulin and in-vitro glucocorticoid sensitivity in a group of adult hypopituitary patients. DESIGN AND PATIENTS: We studied 19 adult hypopituitary patients (18 adult onset, M:F, 6:13), who were receiving conventional hydrocortisone (16 patients), thyroxine (14 patients), triiodothyronine (1 patient), sex steroid (9 patients), human chorionic gonadotrophin (1 patient) or desmopressin (6 patients) replacement during a 6-month, double blind controlled trial of GH therapy (active:placebo, 8:11) followed by a 6-month open phase of GH (mean dose: 0.2 IU/kg/week, range 0.051-0.27) and after a 6-week washout phase following discontinuation of GH therapy. MEASUREMENTS: Twenty-four-hour urine free cortisol, cortisol metabolites (CoM), ratio 11-hydroxy/11-oxo CoM (F/E) and ratio 5 alpha/beta tetrahydrocortisol were measured at 6 months, 12 months and after the 6 week washout phase. Serum cortisol binding globulin was measured basally, at 6 months, 12 months and after washout. Glucocorticoid sensitivity was determined in lymphocyte preparations from 8 patients, during GH therapy and after washout, using an in-vitro technique dependent on dexamethasone suppression of phytohaemagglutinin-stimulated thymidine incorporation into DNA. Plasma renin activity and aldosterone were measured after 6-12 months GH therapy and after washout. RESULTS: After 6 months of GH, in patients on hydrocortisone (n = 9), there were significant decreases in CoM (mean decrement 21%, P < 0.01), F/E (mean decreased from 1.27 to 1.0, P = 0.04; reference range 0.33-1.29) and 5 alpha/5 beta tetrahydrocortisol (mean decreased from 0.67 to 0.48, P = 0.01) and a subsequent increase after washout. Patients not on hydrocortisone (n = 2) demonstrated a normal basal F/E falling by 25% on GH therapy but no change in CoM. During 12 months of GH therapy, patients on hydrocortisone (n = 7) demonstrated a further trend to decrement in CoM (P = 0.09) which reversed after washout (P = 0.04). Urine free cortisol tended to fall during GH therapy and increased significantly following washout after 12 months treatment (P < 0.02). Serum cortisol binding globulin decreased by 20% (P < 0.05) during 12 months GH treatment but remained within the reference range. In-vitro studies demonstrated a trend to reduced glucocorticoid sensitivity on GH therapy; the maximum inhibition of phytohaemagglutinin by dexamethasone tended to be less on GH therapy (P = 0.052) and was also lower than in 29 normal volunteers (P < 0.05). There were no significant changes in plasma renin but there was a small increment in aldosterone in recumbent patients (P = 0.04) during the open phase of GH therapy in the placebo arm. CONCLUSIONS: GH therapy in hypopituitary adults is associated with an apparent reduction in availability of administered hydrocortisone as measured by urine cortisol metabolites and urine free cortisol. This effect is unlikely to be clinically significant except possibly in ACTH deficient subjects on suboptimal hydrocortisone replacement. The changes in F/E suggest that GH may directly or indirectly modulate the activity of 11 beta-hydroxysteroid dehydrogenase. The apparent decrease in glucocorticoid sensitivity during GH therapy, demonstrated in vitro, merits further investigation.     

Incidental finding of occult hydronephrosis after blunt abdominal trauma

Occult congenital and acquired renal lesions are often discovered during evaluation of patients with haematuria after minor blunt torso trauma. This relatively 'minor trauma', can precipitate severe haematuria and hypovolemic shock. This group of patients frequently presents a difficult diagnostic and therapeutic challenge. We discuss the significance of occult hydronephrosis and minor blunt trauma in one patient.     

Synthesis and antiplatelet, antiinflammatory, and antiallergic activities of substituted 3-chloro-5,8-dimethoxy-1,4-naphthoquinone and related compounds

2-Amino (6), 2-alkylamino (7-8), 2-methoxy (9), 2-acetamido (10), and 5,8-diacetoxy (11) derivatives of the lead compound 2,3-dichloro-5,8-dimethoxy-1,4-naphthoquinone (4) were synthesized, together with 6,7-dichloro-5,8dimethoxy-1,4-naphthoquinone (5), a positional isomer of 4. Antiplatelet, antiinflammatory, and antiallergic activities were evaluated, and most compounds were quite potent in all assays. Compounds 5 and 9-11 were especially active; however, 5 was ineffective against neutrophil superoxide formation, and 10 was ineffective against mast cell degranulation.     

Lack of sensitization to the effects of d-amphetamine and apomorphine on sensorimotor gating in rats

Haemolytic-uremic syndrome (HUS) is the leading cause of acute renal failure in the childhood. It is characterised by microangiopathic hemolytic anemia, thrombocytopenia, acute renal failure and injury of the renal microvascular endothelium. In HUS the condition of proteolytic kallikrein-kinin system is unknown. The renal KKS seems to participate in the regulation of blood pressure, control of sodium and water excretion, renal vascular resistance and renin release. In this study the role kallikrein in the developing HUS was studied. The general activity of kallikrein in plasma and urine was determined by trypsin-like peptidohydrolase activity (TP), which was measured using substrate Z-D-Ala-Leu-Arg-pNa. Chymotrypsin-like protease activity (ChP) was measured using substrate Glp-Ala-Ala-Leu-pNa. Clinical data were analysed on 60 pediatric patients with HUS, 29 girls and 31 boys, ranging in the age from 3 months to 11 years. TP and ChP levels were determined in different periods of HUS (anuria, diuresis beginning, polyuria, recovery) in serum and urine. In acute phase TP and ChP activities increased significantly. In diuresis recovery serum TP activity was higher, but urine TP level became normal. In dynamic serum and urine ChP levels had tendency to decrease. The present work showed that TP and ChP levels demonstrated activity of pathological renal process and condition of glomerules.     

The perinatal mortality rate as an indicator of quality of care in international comparisons

Priming and recollection are expressions of human memory mediated by different brain events. These brain events were monitored while people discriminated words from nonwords. Mean response latencies were shorter for words that appeared in an earlier study phase than for new words. This priming effect was reduced when the letters of words in study-phase presentations were presented individually in succession as opposed to together as complete words. Based on this outcome, visual word-form priming was linked to a brain potential recorded from the scalp over the occipital lobe about 450 ms after word onset. This potential differed from another potential previously associated with recollection, suggesting that distinct operations associated with these two types of memory can be monitored at the precise time that they occur in the human brain.     

Pore functioning of outer membrane protein PhoE of Escherichia coli: mutagenesis of the constriction loop L3

Each monomer of the trimeric outer membrane porin PhoE of Escherichia coli consists of a 16-stranded beta-barrel with short turns at the periplasmic side and large loops at the cell surface. One of these loops, L3, is folded inside the beta-barrel and forms a constriction within the channel. Therefore, it is assumed to play an important role in the permeability properties of this general diffusion pore. Several site-directed mutations were introduced in loop L3 to investigate its function. The loop L3 contains a short alpha-helix and, at the tip of the loop, a highly conserved PEFGG sequence. The alpha-helix was deleted and the two glycines in the PEFGG sequence were either replaced by alanines or deleted. A serine residue, supposed to play an indirect role in the anion selectivity of the pore, was removed. The mutant porins were analysed both in vitro and in vivo. The results suggest that flexibility of the third loop is important for solute passage and that this flexibility is determined by the two glycine residues in the PEFGG sequence. Furthermore, the alpha-helix is probably important for the folding of the protein. The supposed involvement of Ser115 (Ser121A in OmpF nomenclature) in anion selectivity was confirmed.      

5-HT4 receptor antagonism does not affect motor and reward mechanisms in the rat

5-HT4 receptors are concentrated in areas of the brain which are rich in dopamine neuronal markers, which may suggest that they influence motor and reward processes. We tested this hypothesis by examining the effects of a 5-HT4 receptor antagonist, 8-amino-7-chloro-(N-butyl-4-piperidyl)methylbenzo-1,4-dioxan-5-car boxylate hydrochloride (SB-204070-A) on amphetamine- and nicotine-induced locomotor stimulation in intact rats. In rats with unilateral 6-hydroxydopamine-induced lesions of the ascending nigrostriatal dopaminergic projection, SB-204070-A was tested for its effects on amphetamine-induced rotation. SB-204070-A was also tested for its effects on rewarded behaviour maintained by intracranial self-stimulation. SB-204070-A did not alter behaviour under any of these conditions, suggesting a lack of involvement of the 5-HT4 receptor in motor and reward processes.