Prolactin-lowering effect of luteinizing hormone-releasing hormone agonist administration in prolactinoma patients.

We studied the effect of LHRH agonist administration on serum PRL levels in five women with microprolactinomas and two women and a man with intrasellar macroprolactinomas. Each patient received either D-Trp6-LHRH or buserelin for 90 days. Serum PRL levels decreased significantly in the patients with microprolactinomas by 65%, from 156 +/- 93 (+/- SD) to 54 +/- 49 micrograms/L on day 90 (P = 0.011), but it did not decrease in the macroprolactinoma patients. Mean serum LH and FSH decreased by 43% and 62.5%, respectively, in all eight patients. There was no statistically significant correlation between the serum PRL and LH or FSH levels in the microprolactinoma patients. We conclude that LHRH agonists can counteract the hyperprolactinemia produced by microprolactinomas and that the effect probably is not exerted by an action on the gonadotrophs.

Cholinergic mediation of growth hormone secretion elicited by arginine, clonidine, and physical exercise in man.

The role of acetylcholine in human GH secretion was studied with atropine, which selectively blocks cholinergic muscarinic receptors and crosses the blood-brain barrier. Paired tests were performed in 22 normal subjects divided into 4 groups. The stimuli employed were arginine (30 g/30 min, iv), clonidine (300 micrograms, orally), physical exercise for 20 min, and saline. In the second test, atropine (1 mg, im) was administered before GH stimulation. Arginine elicited a GH secretory peak of 16.6 +/- 5 ng/ml (mean +/- SEM), which was completely blocked when atropine was administered with arginine (0.9 +/- 0.1 ng/ml). Atropine did not, however, modify the PRL secretory response; peak levels after arginine and atropine plus arginine were 16.3 +/- 3.1 and 16.8 +/- 2.5 ng/ml, respectively. Clonidine elicited a GH secretory peak (11.8 +/- 2.7 ng/ml) which also was blocked by pretreatment with atropine (1.2 +/- 0.2 ng/ml). Neither clonidine nor clonidine plus atropine altered PRL secretion. GH levels also were sharply increased after physical exercise, with a peak level of 19.4 +/- 4.9 ng/ml. Atropine completely blocked exercise-induced GH secretion (2 +/- 0.9 ng/ml). Atropine alone did not modify GH or PRL values compared with saline administration. The potency of the atropine-induced suppression of GH secretion by three different stimuli, each with presumably different mechanisms of action, suggests that acetylcholine plays an important role in the regulation of GH secretion.

Atropine blockade of growth hormone (GH)-releasing hormone-induced GH secretion in man is not exerted at pituitary level.

The role of acetylcholine (Ach) in the regulation of human GH secretion was assessed using atropine, which selectively blocks cholinergic muscarinic receptors. Paired tests were performed in seven normal subjects using GH-releasing hormone (GHRH) 1-44 (1 microgram/kg iv), with and without atropine pretreatment (1 mg im). The GHRH 1-44-induced GH secretory peak [20.7 +/- 4.5 (SEM) ng/ml] was completely blocked by atropine administration (2.3 +/- 0.6 ng/ml) (P less than 0.01). To determine whether this atropine blockade was at the pituitary level, a series of in vitro studies were conducted using monolayer cultures of cells from bovine anterior pituitary glands. GHRH 1-44 (10(-8) M) stimulated bovine GH release (11.1 +/- 1.5 micrograms/ml) as compared to control values (5.1 +/- 0.4 microgram/ml) (P less than 0.01). This response was not altered by 10(-6) M atropine (14.9 +/- 0.9 microgram/ml). Similar results were obtained with GHRH, 10(-9) M, with or without atropine, 10(-7) M. Addition of 10(-6) M Ach to the incubation medium significantly increased bovine GH release (12.7 +/- 1.2 microgram/ml) and the effect of 10(-6) M Ach and 10(-8) M GHRH was additive (20.9 +/- 2.1 micrograms/ml) (P less than 0.01). Similar results were obtained with Ach, 10(-5) M, and GHRH, 10(-9) M. Atropine or eserine alone did not alter basal GH secretion, and atropine blocked Ach-stimulating activity. In conclusion, atropine blockade of GHRH-induced GH secretion appears to be exerted at a site other than pituitary.

Free fatty acids block growth hormone (GH) releasing hormone-stimulated GH secretion in man directly at the pituitary.

Increases in plasma FFA levels inhibit GH responses to a variety of pharmacological and physiological stimuli. To gain further insight into the mechanism by which FFA exert their effect, we studied the plasma GH responses to GHRH-(1-44) (1 microgram/kg, iv) in normal subjects in whom plasma FFA levels were raised by a lipid-heparin infusion (250 mL 10% Intralipid plus 2500 U heparin). Paired tests were performed in 10 normal subjects, with and without lipid-heparin pretreatment. Lipid-heparin infusion from -30 to 120 min increased mean FFA levels from 0.41 +/- 0.03 (+/- SEM) to 3.12 +/- 0.40 mmol/L at 120 min. The mean plasma GH levels after GHRH administration were lower at all times; however, the values were significantly different (P less than 0.05) only at the later times (45, 60, and 90 min). When considered individually, an all or none pattern was observed; 5 subjects had no plasma GH response to GHRH, and 5 had no reduction. To investigate the time relationships between the FFA peak and subsequent GH blockade, a different protocol of paired tests was performed with GHRH with or without a different lipid-heparin infusion protocol. Lipid-heparin was infused from -90 to 0 min, with an additional heparin pulse at -15 min, to obtain a higher and earlier (0 min) FFA increase. FFA increased from 1.06 +/- 0.19 to 11.61 +/- 0.83 mmol/L at zero time. The GHRH-induced GH secretory peak (15.8 +/- 3.5 ng/ml) at 15 min was completely blocked (0.9 +/- 0.2 ng/ml), and the mean plasma GH levels were also lower at 30, 45, and 60 min. To determine whether the FFA-induced blockade of GH secretion was exerted in the pituitary, a series of in vitro studies was conducted using monolayer cultures of rat anterior pituitary glands, with GHRH concentrations of both 10(-10) and 10(-8) M and 10(-5) M forskolin to stimulate GH release. Both caprylic and oleic acid inhibited basal GH release and GHRH- or forskolin-induced GH release. PRL release was not altered, nor were toxic actions noted on the cells. In conclusion, FFA are able to block GH secretion directly at the pituitary level.

D-Trp6-luteinizing hormone-releasing hormone inhibits sulpiride-induced hyperprolactinemia in normal men.

The effect of a potent agonistic analog of LHRH, D-Trp6-LHRH, on hyperprolactinemia induced by sulpiride was studied in normal men. Six men received sulpiride (100 mg, twice daily, orally) for 44 days. D-Trp6-LHRH was given sc during the last 2 weeks of sulpiride administration; the dose was 500 micrograms on the first day and 100 micrograms daily for the subsequent 14 days. All men had high serum PRL levels before D-Trp6-LHRH administration (mean +/- SEM, 56 +/- 9 ng/mL), which decreased significantly after the first dose of the analog (45 +/- 5 ng/mL; P = 0.031) and also after 15 days of analog administration (41 +/- 6 ng/mL; P = 0.016). These data demonstrate that administration of LHRH agonist can inhibit the hyperprolactinemic effect of sulpiride, suggesting a direct action of the analog on the pituitary gland to modulate PRL secretion.

Clinical response and plasma haloperidol levels in chronic and subchronic schizophrenia.

Levels of haloperidol were determined by radioimmunoassay (RIA) in 30 schizophrenic patients (diagnosed according to the criteria of DSM-III), who were treated with fixed doses of this neuroleptic for a period of 21 days. An inverted U-shaped relationship was found between the percent improvement observed in the BPRS global score and the steady state of haloperidol. The interval of effective concentration of haloperidol was set between 12.0 and 35.5 ng/ml. However, the limits of such an interval found in the subchronic schizophrenic subgroup (SS) ranged from 7.4 to 24.9 ng/ml, whereas in the chronic schizophrenic subgroup (CS), it ranged from 14.8 to 38.5 ng/ml. This finding suggests that the interval of effective concentrations may vary as a function of the number of years of evolution of the subjects' illness. This may be compatible with the development of tolerance in the mesolimbic and/or mesocortical dopaminergic systems as a response to prolonged neuroleptic treatments.

Differential effects of direct and indirectly acting cholinergic agonists on growth hormone release in man, and lack of effect on cortisol secretion.

Abstract Acetylcholine plays a key role in the modulation of growth hormone secretion. In fact, growth hormone release after provocative stimuli is blocked by muscarinic cholinergic antagonists, and conversely, indirect cholinergic agonists potentiate growth hormone secretion. To further understand the mechanism by which cholinergic pathways exert their effects, we have compared the growth hormone and cortisol secretion elicited on normal volunteers by pyridostigmine and by RS-86 (2-ethyl-8-methyl-2,8-diazaspiro-((4,5))-decan-1,3-dion hydrobromide). The former acts by inhibiting acetylcholinesterase, thus being an indirect muscarinic agonist, while the latter is a muscarinic receptor agonist which binds directly to and stimulates cholinergic receptors. In six subjects, pyridostigmine (120 mg po) induced an increase of growth hormone of 11.0+/-2.4 mug/L at 90 min, significantly greater than following placebo administration (1.4 +/- 0.3 mug/L). In another group of five volunteers, RS-86 was administered in separate tests at a dose of 0.5, 1 and 2 mg po. Growth hormone levels were not altered by any RS-86 dose compared with placebo values. Neither pyridostigmine nor RS-86 altered cortisol values. These results suggest that the mechanism of action of the cholinergic agonists is of great importance for their growth hormone-releasing capabilities, and question the accepted view of a cholinergic regulation of cortisol secretion in man.

Lower serum osteocalcin levels in pregnant drug users and their newborns at the time of delivery.

Osteocalcin was evaluated by radioimmunoassay at the time of delivery in mothers and in the umbilical arteries of newborns in a group of pregnant drug users (eight heroin users and seven cocaine users) and compared with findings from a group of normal mothers and their newborns (N = 18). Drug users had lower osteocalcin values than did the normal women (1.3 +/- 0.7 versus 2.7 +/- 0.8 ng/mL, P less than .001); and infants of drug users had lower values than normal infants (14.1 +/- 3.8 versus 19.0 +/- 4.0 ng/mL, P less than .005). The birth weights of drug users' infants were smaller (3160 +/- 402 versus 3591 +/- 374 g, P less than .05) and there was a significant negative correlation (P less than .001) between osteocalcin and drug intake during pregnancy, but no changes in osteocalcin dependent on the type of drug used. These results suggest a toxic effect of these drugs on the osteoblast, which could account for the lower birth weights and skeletal alterations reported in the infants of drug users.

Somatomedin-C and growth hormone levels in anorexia nervosa in relation to the puberal or post puberal stages.

1. Plasma concentrations of somatomedin-C and GH were determined in 21 patients diagnosed as anorexia nervosa (AN) and in 44 controls. 2. Somatomedin-C concentrations were significantly lower in pubertal AN patients than in controls, but not in post pubertal patients. 3. GH was increased in both pubertal and post pubertal AN patients, although more in pubertal AN patients. 4. Our results suggest that the hormonal alterations that appear in AN constitute a mechanism of defense against starvation. The activation of these defense mechanisms and the degree of modification produced in normal hormonal patterns depend not only on caloric intake but also on metabolic requirements.

Determination of plasma haloperidol concentrations by radioreceptor assay in schizophrenia: clinical utility.

1. Haloperidol concentrations were determined by radioreceptor assay (RRA) and prolactin concentrations were measured in 20 patients diagnosed as schizophrenia (DSM-III). 2. The patients were treated with a fixed dose of haloperidol for 21 days. 3. Our results suggest the existence of a curvilinear relationship, in the form of an inverted U, between stable haloperidol levels and clinical improvement assessed by total BPRS score. 4. We also found a curvilinear relationship between the improvement observed in positive symptoms and state steady levels. 5. No relationship was seen between improvement in negative symptoms and state steady levels. 6. An interval of optimal haloperidol concentration was found: 8.1 ng/ml to 19.6 ng/ml. 7. No relation was found between the dose of haloperidol administered and plasmatic concentration, nor between haloperidol and prolactin levels. 8. Our findings suggest that haloperidol concentrations determined by RRA have clinical utility as predictors of response in schizophrenia.

The dexamethasone suppression test in delusional depression. Further findings.

The results of the overnight 1 mg dexamethasone suppression test (DST) administered to 26 unipolar delusional depressed patients and 47 unipolar non-delusional depressed controls are reported. There were no significant differences between the rates of abnormal responses in the two groups. However, there was a higher percentage of normal responses in the delusional depressive sample with mood incongruency. While 55% of the mood-congruent depressive patients were non-suppressors, only 12% of the depressed patients with mood-incongruent psychotic features had abnormal DST responses.

Effect of calcium pidolate on biochemical and hormonal parameters in involutional osteoporosis.

The purpose of this study was to determine the value of calcium pidolate in the treatment of involutional osteoporosis. This compound has been reported to be better absorbed than other calcium salts, to lower the levels of parathyroid hormone (PTH) and to raise those of growth hormone (GH). We accordingly treated one group of 10 women suffering from involutional osteoporosis with the equivalent of 1 g elemental calcium and administered a placebo to a second group of 10 osteoporotic women whose mean age and body surface area were comparable. Basal sequential multiple analysis (SMA-12) was performed in all subjects to determine calcium, phosphorus, alkaline phosphatase (ALP) and total protein levels, the same blood samples being used for the evaluation of mean PTH, GH and osteocalcin (BGP). Urinary 24-h calcium excretion was determined and the calcium/creatinine (Ca/Cr) and hydroxyproline/Cr (HP/Cr) ratios were measured in 12-h fasting urine samples, the results being corrected for glomerular filtrate. The same parameters were measured again following a month of uninterrupted treatment. After 30 days, we observed no differences in either group as regards calcaemia, phosphataemia, ALP, total proteins, PTH, GH, BGP or 24-hour calciuria. The only noteworthy changes seen were significant decreases (P less than 0.001) in the Ca/Cr and HP/Cr ratios in the group treated with calcium pidolate. These results show that calcium pidolate at the dose administered inhibits bone resorption but does not affect the levels of PTH, GH, BGP or ALP in the medium term. Our findings indicate that it has no influence on bone formation.

Reversion of the steroid-induced decrease of serum osteocalcin with sodium fluoride.

Osteopenia observed in corticotherapy is due, among other causes, to a decrease in bone formation as can be shown by a steroid-induced osteocalcin decrease. Although various treatments have been proposed there is no agreement as to which one is the best. Two such treatments, sodium fluoride and vitamin D administration increase osteocalcin levels. We treated a group of 12 patients under corticoid therapy (mean dose 16 mg per day) with 50 mg/day p.o. sodium fluoride, and determined osteocalcin levels before and two weeks after sodium fluoride treatment. Similarly, another group of 9 patients with a similar mean steroid dose was treated with 0.5 micrograms/day of 1 alpha (OH)2D3 in order to assess the effect of this vitamin on osteocalcin and to determine which was the best treatment. Both groups were compared with respective control groups. A significant osteocalcin increase was observed in the control groups (p less than 0.001); similar significance was observed in the sodium fluoride group, whereas a lower significance (p less than 0.01) was observed in the vitamin D group. These results suggest that sodium fluoride could be more effective than vitamin D in the treatment of steroid-induced osteopenia.

Osteopenia in rheumatoid arthritis: a biochemical, hormonal and histomorphometric study.

To determine whether the osteopenia of rheumatoid arthritis (RA) is due to reduction of trabecular bone mass (TBV) and/or cortical width (CW), we evaluated these parameters by bone histomorphometry; we also measured the calciotropic hormones parathormone(PTH) and calcitonin (CT), vitamin D [25(OH)D] and the biological markers of bone remodeling in a group of patients with RA. Study subjects were divided into Group C - premenopausal patients, and Group A - menopausal patients and men of the same ages. These groups were compared to two age-matched control groups, B and D. In both A vs. B and C vs. D, TBV and CW were significantly lower in patients. There were no differences in PTH or CT, but 25(OH)D was significantly reduced, and BGP, OHP/Cr and AP were raised in patients. Patients also exhibited TBV loss in more than 55% and CW loss in more than 98%. These changes suggest that the decline in bone mass, mainly cortical, but also trabecular, is due to increased bone turnover and enhanced resorption and seem to reflect intrinsic alterations of RA.

CHRNA7 haplotypes are associated with impaired attention in euthymic bipolar disorder.

BACKGROUND: Bipolar disorder (BD) patients show a deficit in sustained attention during euthymic periods. This deficit may be relevant for genetic studies in these patients. The α7 cholinergic receptor plays an important role in attentional deficit in humans and animal models. Moreover, there is evidence suggesting the role of the alpha 7 nicotinic cholinergic receptor subunit gene (CHRNA7) in BD susceptibility. The aim of the present study was to investigate the impact of CHRNA7 in sustained attention performance. METHODS: We studied the association of a promoter variant (-86C/T) and three intronic polymorphisms, rs883473, rs6494223 and rs904952, in the non-duplicated region of CHRNA7 with sustained attention in 143 euthymic BD patients (based on DSM-IV criteria) and 101 healthy subjects. Sustained attention was assessed by the degraded stimulus (DS-CPT) version of Continuous Performance Test. Age, gender, years of education and IQ (WAIS vocabulary subtest) were controlled in the analyses as potential confounders. RESULTS: Several candidate polymorphisms showed significant associations with different measures of the neuropsychological task for bipolar group. The CTCT haplotype was associated with an improvement in the attentional task performance in the BD group (p ≤ 0.025). On the other hand, different low frequency haplotypes showed influence in bipolar attentional performance (p ≤ 0.026). LIMITATIONS: A replication study using larger samples may be required for conclusive results. CONCLUSIONS: Our results point toward a slight association of CHRNA7 genotypes and haplotypes with sustained attention performance in euthymic patients with BD.