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V Popovic

Publications and source records attributed to V Popovic.

At least 37 records · Page 2Linked to original sources
PubMed2000

GH-releasing hormone and GH-releasing peptide-6 for diagnostic testing in GH-deficient adults.

BACKGROUND: The diagnosis of growth hormone (GH) deficiency in adults is based on provocative testing of GH secretion. The insulin tolerance test (ITT), currently the favoured test for this diagnosis, has been criticised for poor reproducibility and inconvenience. Since the combined administration of GH-releasing hormone (GHRH) plus GH-releasing peptide-6 (GHRP-6) is the most potent stimulus of GH secretion, we did a multicentre study comparing GH peaks elicited by ITT with those elicited by the GHRH/GHRP-6 test in healthy controls and GH-deficient individuals (cases). METHODS: 125 adult patients with organic pituitary disease and 125 healthy individuals were studied. All cases and controls were given GHRH 1 microg per kg bodyweight intravenously plus GHRP-6 1 microg per kg intravenously at 0 min and blood samples were obtained during a subsequent 120 min period. 27 controls and all cases had an ITT. Inclusion criteria were severe GH deficiency--ie, a GH peak after ITT of < or = 3 microg/L. Results of the GHRH/GHRP-6 test were analysed by receiver-operating characteristic curve methodology. FINDINGS: GH peaks seen after the GHRH/GHRP-6 test did not result in any side-effects and were not affected by age, sex, amount of adipose tissue, or by the GH assay system used. The GH mean peak after the GHRH/GHRP-6 test was 59.2 microg/L (SD 2.2) for controls and 4.1 microg/L (0.3) for cases, whereas after ITT the mean peak was 14.3 microg/L (1.7) and 0.5 microg/L (0.06), respectively. The differential peak responses of controls and cases was greater (p<0.001), for GHRH/GHRP-6 test than for ITT. When individually analysed GH peaks were a continuum, from 139.0 microg/L to 0.01 microg/L, with a cut-off point of 15.0 microg/L. The GHRH/GHRP-6 test performed well under the ROC curve analysis. For clinical utility, it is then proposed that values > or = 20.00 microg/L be considered normal and < or = 10.00 microg/L as GH deficient. INTERPRETATION: The GHRH/GHRP-6 test is a convenient, safe and reliable test for adult GH deficiency and is not confounded by clinical factors known to alter GH secretory patterns. An evoked GH concentration of > or = 15.0 microg/L accurately distinguishes between healthy and GH-deficient adults.

Adolescent↗
PubMed2000

Regulation of somatotroph cell function by the adipose tissue.

Obese subjects exhibit a marked decrease in plasma growth hormone (GH) levels. However, the mechanisms by which increased adiposity leads to an impairment of GH secretion are poorly understood. Recent evidence suggests that the adipose tissue can markedly influence GH secretion via two different signals, namely free fatty acids (FFA) and leptin. FFA appear to inhibit GH secretion mainly by acting directly at pituitary level. Interestingly, reduction in circulating FFA levels in obese subjects led to a marked increase in GH responses to different GH secretagogues. This indicates that FFA exert a tonic inhibitory effect that contributes to blunted GH secretion in obese subjects. Recent data have shown that leptin is a metabolic signal that regulates GH secretion, since the administration of leptin antiserum to adult rats led to a marked decrease in spontaneous GH secretion. However, leptin prevents,the inhibitory effect exerted by fasting on plasma GH levels. The effect of leptin in adult rats appears to be exerted at hypothalamic level by regulating growth hormone releasing hormone (GHRH), somatostatin and neuropeptide Y (NPY)-producing neurones. In addition, during fetal life or following the development of pituitary tumors, leptin can also act directly at the anterior pituitary.

Adipose Tissue↗
PubMed1999

Course of exfoliation and simplex glaucoma after primary trabeculectomy.

AIM: To study the course of exfoliation and simplex glaucoma with respect to intraocular pressure (IOP) regulation and visual field survival after primary trabeculectomy. METHODS: Postoperative IOP regulation and complications were analysed prospectively in 95 patients. Mean follow up was 46 months. Visual field survival was studied by high pass resolution perimetry (HRP) in a subsample of 28 patients. RESULTS: Medical treatment was reinstated in 42% of exfoliation and in 36% of simplex glaucoma. In these patients, mean medicine free survival time, last untreated IOP, and mean IOP at the end of follow up were similar for both glaucoma types. Among patients with controlled postoperative IOP without added medication, mean IOP at the end of follow up was significantly lower in exfoliation glaucoma. Visual field deterioration and the pattern of complications were similar for both glaucoma types. CONCLUSION: The effect of trabeculectomy on IOP regulation was good in both types of glaucoma, and somewhat better in exfoliation glaucoma. The magnitude of IOP lowering could not separate patients with continued visual field deterioration from those in whom visual fields remained stable. Visual field preservation was similar for both glaucoma types.

Aged↗
PubMed1999

Regulation of growth hormone secretion by signals produced by the adipose tissue.

The neuroregulation of growth hormone (GH) secretion and the state of the adipose tissue reserves are closely related. GH exerts lipolytic actions on the adipose tissue and low body weight enhances secretion of GH while obesity is associated with reduced levels of GH and blocked release of GH when challenged by all stimuli. The mediators of the regulation exerted by the adipose tissue on the GH/insulin-like growth factor-I axis are not fully understood, but in the last few years two relevant factors have emerged--free fatty acids (FFA) and the adipocyte-produced hormone leptin. FFA and GH integrate a classical feedback loop and a rise in FFA blocks GH secretion. This action is rapid, dose-related and exerted at the pituitary level with no evident hypothalamic participation. A pharmacological reduction in FFA enhances secretion of GH and eliminates the GH blockade of obesity and Cushing's syndrome. The discovery of leptin has expanded our knowledge of the way in which the adipose tissue participates in some neuroendocrine actions. Obesity is associated with elevated levels of serum leptin while undernutrition and fasting lead to low leptin. In fasted rats, the pattern of GH pulsatility is eliminated with a near absence of spontaneous peaks, but the administration of leptin by the intracerebroventricular (i.c.v.) route restores the altered pattern. When fed rats receive antileptin antibodies i.c.v the normal pattern is reversed to an absence of pulses, reminiscent of the fasting state. These results are the first demonstration that, at least in experimental animals, leptin is a relevant factor in GH regulation. Leptin has no direct pituitary action and its action at the hypothalamic level appears to be mediated by neuropeptide Y, being the final step in a reduction in the somatostatin tone. On the other hand, the action of GH on leptin levels seems to be tenuous in humans, but in the near future it will be possible to investigate the action of leptin on human GH. As the hypothalamic neuroregulation of GH secretion in humans is unlike that in the rat, a crucial point for elucidation will be the actions, if any, and the mechanisms by which leptin participates in GH regulation in humans, as well as its alterations in disease states.

Adipose Tissue↗
PubMed1998

Early choroidal detachment after trabeculectomy.

PURPOSE: To estimate the occurrence of choroidal detachment (CD) in 17 patients operated on with trabeculectomy. METHODS: Ultrasonography was used to assess the occurrence of CD and pachymetry was used to estimate the depth of the anterior chamber (AC). Mean follow-up was 19 months. RESULTS: Twelve (71%) patients suffered from marked hypotony (IOP < or =5 mm Hg) and 9 (53%) patients suffered from shallowing of the AC some period early after operation. CD was diagnosed in 10 (59%) patients. Ophthalmoscopy was not sufficient to diagnose CD in 3 (18%) patients. None of the eyes without CD showed more than 10% reduction of the AC. Four of these eyes were markedly hypotonic. On the other hand, all markedly hypotonic eyes with more than 10% reduction of the AC developed CD. CONCLUSION: No postoperative IOP level alone could separate patients at risk for CD development from patients without any such risk. However, concomitant marked hypotony and more than 10% reduction of the AC were found in 2/3 of the CD eyes.

Aged↗
PubMed1998

Growth hormone secretion elicited by GHRH, GHRP-6 or GHRH plus GHRP-6 in patients with microprolactinoma and macroprolactinoma before and after bromocriptine therapy.

OBJECTIVE: Growth hormone-releasing peptides (GHRPs) are potent GH releasers which act at both pituitary and hypothalamic levels through specific G-protein coupled receptors, recently cloned. A synergistic effect from the simultaneous administration of GHRH + GHRP-6 on GH release is observed in normal subjects, while it is absent in patients with hypothalamo-pituitary disconnection. We studied the effects of GHRH, GHRP-6 and both secretagogues on GH release in patients harbouring pituitary tumours that may be reduced in size by medical treatment. DESIGN: Analysis of peak GH response to GHRH, GHRP-6 and GHRH plus GHRP-6 in patients with micro- and macroprolactinomas. Integrated GH response over 2 hours calculated as AUG-GH mU/l x 120 min. Analysis of delta PRL above the basal level in response to the same GH releasers. PATIENTS: Eleven patients with macroprolactinomas aged 41.2 +/- 4.8 years (range 24-75), nine patients with microprolactinomas aged 31.5 +/- 3.4 (range 22-53) and 13 healthy subjects aged 42.1 +/- 4.7 years (range 22-64) were studied. Prolactinoma patients were then treated with bromocriptine (15-20 mg orally) for 6-24 months. Tests were repeated when there was evidence of tumour shrinkage and normalized plasma prolactin concentrations. RESULTS: Peak GH response before treatment in macroprolactinoma patients was 4.9 +/- 0.9 mu/l after GHRH, 8 +/- 4 mU/l after GHRP-6 and 18 +/- 5 mU/l after GHRH + GHRP-6. Synergism was absent. AUC were 390 +/- 90; 500 +/- 100 and 1100 +/- 300 mU/l x 120 min respectively. These values were all significantly different (P < 0.05) from normal subjects and patients with microprolactinomas with peak GH 16.8 +/- 0.9 mU/l after GHRH; 43 +/- 6 mU/l after GHRP-6 and 130 +/- 10 mU/l after GHRH + GHRP-6. AUC-GH was 1200 +/- 400 after GHRH, 2200 +/- 400 after GHRP-6 and 9000 +/- 1000 mU/l x 120 min after GHRH + GHRP-6. As in normal subjects, synergism was preserved in patients with microprolactinoma (P > 0.05). After treatment with bromocriptine peak GH in patients with macroprolactinoma was 8 +/- 4 mU/l after GHRH, 22 +/- 5 mU/l after GHRP-6 and 70 +/- 20 mU/l after GHRH + GHRP-6. AUC-GH was 800 +/- 300, 1100 +/- 300 and 3500 +/- 800 mU/l x 120 min, respectively. The response of GH after GHRP-6 and GHRH + GHRP-6 improved significantly (P < 0.05) in treated patients with macroprolactinoma. There was no significant change in GH response in microprolactinoma patients after treatment with bromocriptine. Peak GH after GHRH was 30 +/- 20 mU/l, after GHRP-6 it was 75 +/- 8 mU/l and after GHRH + GHRP-6 it was 200 +/- 30 mU/l. AUC-GH was 1500 +/- 700 after GHRH, 4500 +/- 500 after GHRP-6 and 15,100 +/- 600 mU/l x 120 min. Delta prolactin after GHRP-6 did not change before and after bromocriptine treatment in patients with macroprolactinoma or microprolactinoma. CONCLUSION: GH release after GHRP-6 or GHRH + GHRP-6 is fully preserved in patients with microprolactinomas and does not differ before and after treatment with bromocriptine. Patients with macroprolactinoma have blunted responses of GH after GHRH and GHRP-6 and synergism is severely compromised. GH responsiveness to and synergistic interaction between GHRH and GHRP-6 recovers after shrinkage of macroprolactinoma with bromocriptine. Prolactin release stimulated by intravenous administration of GHRP-6 in healthy subjects was not seen in patients with micro- or macroprolactinomas.

Adult↗
PubMed1998

Increased incidence of neoplasia in patients with pituitary adenomas. The Pituitary Study Group.

OBJECTIVE: The goal of our study was to determine the rate of neoplasms in patients with other pituitary adenomas (non-functioning and prolactinomas) in comparison with acromegaly which is known to favour the development of neoplasia. DESIGN AND PATIENTS: We reviewed clinical records for 220 patients with acromegaly, 151 patients with non-functioning pituitary adenoma (NF) and 98 patients with prolactinomas. Incidence rates of cancer for patients with pituitary tumours were calculated per person-years of follow-up study. These rates were then compared with sex and age adjusted incidence rates reported by National Tumour Registry. An internal control group of 163 subjects with a non-neoplastic condition, i.e. Graves' disease followed chronically in the same clinic was also studied. The ratios observed to expected were expressed as standardized incidence rates (SIR). The only significant difference between the acromegalic and other pituitary tumours patients was in hypopituitarism, present in 18.2% (acromegaly) 47% (NF) and 18.6% (prolactinomas). RESULTS: Twenty-three malignant tumours were registered in 19 acromegalics (1 Hodgkin disease, 1 myelogenous leukaemia, 1 lymphocytic leukaemia, 3 papillary thyroid carcinomas, 1 ovarian carcinoma, 2 colorectal carcinoma, 1 renal cell carcinoma, 4 cervical carcinoma, 2 skin cancers, 2 pancreatic carcinoma, 4 breast carcinoma, 1 bladder carcinoma). Three acromegalics harboured two malignancies. Patients with acromegaly had a 3.39-fold increased rate of malignant tumours compared with the general population and a 3.21-fold increased rate compared with our internal control group. Eleven malignant tumours were found in patients with NF-pituitary adenomas and 2 in prolactinoma patients (1 lymphoma, 1 multiple myeloma, 1 colonic cancer, 1 renal cell cancer, 1 stomach cancer, 2 lung cancers, 1 cervix carcinoma, 1 breast cancer, 1 testicular carcinoma and 3 melanoma). Patients with NF pituitary adenomas had a 3.91-fold increased rate of malignant tumours compared with the general population and 4.07-fold increase compared with the internal control group. Patients harbouring prolactinomas did not have an increased incidence rate of malignancy compared with the general population or our internal controls. Female patients with acromegaly and male patients with NF-pituitary adenoma had higher incidences of neoplasia. CONCLUSION: We have demonstrated that the overall incidence of malignant tumours in patients with non-functioning pituitary adenomas and acromegaly is significantly higher than expected for general population and for our internal control group.

Acromegaly↗
PubMed1998

The effect of thyrotropin-releasing hormone on gonadotropin and free alpha-subunit secretion in patients with acromegaly and functionless pituitary tumors.

UNLABELLED: Paradoxical response of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and alpha-subunits (alpha-SU) to thyrotropin-releasing hormone (TRH) have previously been reported in individuals with clinically nonfunctioning pituitary tumors (NFT). In the present study, we assessed the in vivo responses of LH, FSH, alpha-SU to TRH in 34 patients with NFT and 29 patients with agromegaly. Twenty-three clinically NFT were postoperatively analyzed by immunocytochemistry and 21 stained positive for beta-FSH and/or beta-LH. Two patients with NFT had elevated basal circulating levels of FSH (41.5 IU/L) and thus were characterized as FSH-secreting adenomas. TRH in these patients increased LH from basal 1.6 IU/L to 32.6 IU/L. In other patients with NFT, circulating levels of glycoprotein peptides were not elevated. TRH induced significant rise of LH in 8 (23.5%), FSH in 5 (14.7%), and alpha-SU in 10 (29.4%) patients with NFT. Thus, a bolus dose of TRH elicited a notable increment in FSH, LH or alpha-SU in 23 of 34 patients with NFT. Among 29 patients with acromegaly, LH rose in 6 (20.7%), FSH in 5 (17.2%), and alpha-SU in 3 (10.3%) patients. IN CONCLUSION: (1) We confirm that most NFTs are capable of synthesizing gonadotropin hormones and subunits (beta-FSH, beta-LH). (2) Most patients in our study responded by either FSH, LH or alpha-SU secretion after TRH, independent of basal hormone levels. Furthermore, recent studies show that by measurement of TRH stimulated beta-FSH and beta-LH one might further improve the diagnostic tools. (3) Gonadotropin response and possibly alpha-SU to TRH are also found in some patients with acromegaly. This could be a marker of a plurihormonal pituitary tumor.

Acromegaly↗
PubMed1998

The pathophysiology of circulating corticotropin-releasing hormone-binding protein levels in the human.

To establish the factors that modulate circulating CRH-binding protein (CRH-BP) levels, we measured plasma CRH-BP in patients with a variety of endocrine and systemic disorders. CRH-BP was measured by RIA. Young women have higher plasma levels of CRH-BP than young men [females (n = 18), mean +/- SEM, 145 +/- 7; males (n = 20), 99 +/- 6 ng/mL; P < 0.0001], but levels do not fall with the menopause or vary during the menstrual cycle and are unaffected by estrogen replacement therapy. Levels were lower in patients with liver disease than in healthy men (26 +/- 3 vs. 99 +/- 6; P < 0.0001) and were elevated in chronic renal failure compared to those in healthy women (211 +/- 11.2 vs. 145 +/- 7; P < 0.01). Levels were unaffected by fasting in men or women (male fasted, 97 +/- 11; male fed, 97 +/- 8; female fasted, 136 +/- 9; female fed, 152 +/- 10). Dexamethasone treatment lowered CRH-BP in all subjects (129 +/- 8 vs. 111 +/- 9; P < 0.003). Similarly, CRH-BP levels were lower in patients with Cushing's syndrome (all female) than in healthy female controls (median, 82; range, 53-106; vs. median, 142; range, 101-190; P < 0.0001). In Cushing's patients, an i.v. bolus of 100 micrograms human CRH further lowered plasma CRH-BP at 15 min (81 +/- 5 vs. 50 +/- 4; P < 0.0003). Plasma levels of CRH-BP are higher in women than men, but this is unrelated to circulating estrogen levels. The low levels in liver disease and the high levels in renal failure support its hepatic origin and the kidneys as the route of clearance from plasma. The ability of glucocorticoids and exogenous CRH to lower plasma CRH-BP levels and of CRH-BP to modulate the bioactivity of circulating CRH suggest that the protein may be an important regulator of circulating CRH or related ligands.

Adult↗
PubMed1998

Preserved growth hormone (GH) secretion in aged and very old subjects after testing with the combined stimulus GH-releasing hormone plus GH-releasing hexapeptide-6.

Either spontaneous or pharmacological stimulated GH secretion is reduced with advanced age. This observation is an added difficulty for the biochemical diagnosis of GH deficiency in adults. Furthermore, the combined administration of saturating doses of GH-releasing hormone (GHRH) plus GH-releasing hexapeptide (GHRP)-6 is nowadays the most effective GH-releasing stimulus tested in a variety of settings related to altered somatotroph function. To understand whether the GH discharge elicited by the combined stimulus declines with age, 26 normal subjects of both sexes, divided into 3 age groups [adults 19-40 yr; aged 46-65 yr; and very old (75-96 yr) subjects] were studied. They were administered i.v., as bolus and in combination, 90 micrograms GHRH plus 90 micrograms GHRP-6. In the three groups, the combined administration of GHRH plus GHRP-6 elicited a GH area under the curve (microgram/L per 120 min) of 3,127 +/- 262, 3,409 +/- 573, and 4,655 +/- 737 for adults, aged, and very old subjects, respectively (nonsignificant differences). The mean GH peak was 47.5 +/- 4.5 micrograms/L for adults, 52.9 +/- 8.4 micrograms/L for aged subjects, and 76.0 +/- 11.7 for very old subjects (nonsignificant differences). Individually examined, there were no nonresponders to the combined stimulus, and all subjects (independently of age) showed a GH peak over 25 micrograms/L (the lowest peak was 27.3 micrograms/L, and the highest peak was 119.2 micrograms/L). In conclusion, the GHRH plus GHRP-6-induced GH release is well preserved in aged and very old subjects, which suggests that the GH secretory capability of the combined test is not reduced by age. This combined test may be useful for the diagnosis of GH-deficient states in adults.

Adult↗
PubMed1998

Serum leptin and insulin concentrations in patients with insulinoma before and after surgery.

Inferential studies suggest that circulating insulin concentrations positively regulate leptin secretion by adipocytes. In humans, however, insulin requires prolonged periods of time, and relatively artificial set-ups before a relationship with leptin can be observed. In the present work, serum leptin concentrations were measured in five patients with insulinoma before and one month after surgery and in five control subjects matched by sex and body mass index (BMI). The control subjects presented a mean serum leptin concentration of 6.7+/-1.5 microg/l and a BMI of 24.9+/-1.1. The mean serum leptin concentration in patients with insulinoma was 11.8+/-3.1 microg/l (P < 0.05 vs controls), with a BMI of 26.3+/-1.9. After surgery, there was a non-significant reduction in BMI (25.8+/-1.7), and a clear reduction in serum leptin concentration (5.6+/-2.4 microg/l, P < 0.05 vs pre surgical values and no difference vs control subjects). The fasting area under the curve (AUC) of insulin concentration (in mU/l per 120 min) before surgery was 14421+/-4981 and after surgery was 1306-/+171 (P < 0.05). Before surgery, serum leptin concentrations significantly correlated with BMI (r = 0.71) and AUC of insulin (r = 0.82), a correlation that was lost after surgery. In conclusion, serum leptin concentrations are significantly elevated in patients with chronically high insulin levels due to insulinoma. After surgical treatment and normalization of insulin values, leptin levels return to normal.

Adult↗
PubMed1997

Serum immunoreactive leptin concentrations in patients with anorexia nervosa before and after partial weight recovery.

Leptin, the product of the ob gene, is a recently discovered hormone secreted by adipocytes. Serum leptin concentrations increase in correlation with the percentage of body fat, but besides that little is known about the physiological actions of leptin in humans. In order to understand the role of leptin in severe malnutrition, in the present work 10 patients recently diagnosed with anorexia nervosa were studied both before and 2 months later, after partial weight recovery, and were compared with 18 normal-weight women as controls. Leptin was measured by a newly developed radioimmunoassay and both IGF-I and IGFBP-3 were measured by commercial radioimmunoassays. The mean (+/-SE) serum leptin concentrations (in microgram/liter) were 18.1 +/- 2.0 in control women with BMI of 21.1 +/- 0.3, significantly higher (P < 0.01) than that in the anorexia nervosa patients at diagnosis (2.2 +/- 0.1, BMI 15.3 +/- 0.6). These differences were also observed in IGF-I values (microgram/liter) that were 228.0 +/- 14.6 in controls and 157.4 +/- 28.7 in anorexia nervosa patients (P < 0.02). No differences were observed in IGF-BP3. After treatment, patients with anorexia nervosa experienced an increase in BMI (17.1 +/- 0.5, P < 0.0001 vs before) although they were still underweight. The partial recovery in weight led to a complete normalization of IGF-I levels (214.0 +/- 21.0 micrograms/liter) and to an enhancement in leptin levels (3.3 +/- 0.5 micrograms/liter; P < 0.03 vs before treatment), though still lower than those in normal-weight women (P < 0.05). Individually analyzed, a large dispersion was observed in control subjects, with leptin levels ranging from 5.5 to 38.7 micrograms/liter, while in all anorexia nervosa patients leptin levels were under 3 micrograms/liter. A treatment-induced increase in body weight led to an increase in leptin levels in 7 out of the 10 anorexia nervosa patients studied and the 3 patients with no increase in leptin were all initially under the 14.5 BMI. In conclusion, leptin levels are severely reduced in anorexia nervosa patients with severe malnutrition, and a significant rise occurred after partial weight recovery. There seems to be a level of BMI below which leptin levels do not drop further but also do not increase despite weight gain. While IGF-I reflects the energy intake of the previous few weeks, the serum leptin concentration reflects the true status of the adipose stores, a fact that has useful clinical implications.

Adult↗
PubMed1997

Absence of desensitization by hexarelin to subsequent GH releasing hormone-mediated GH secretion in patients with anorexia nervosa.

OBJECTIVE: Both the basal levels and the neuroregulation of GH secretion are perturbed in patients with anorexia nervosa. It is unknown if these alterations are due to severe undernutrition or if they reflect basic neurotransmitter alterations of the patient's neural pathways. On the other hand, prior administration of the GH secretagogue hexarelin in normal subjects blocks the GH-releasing capability of GH releasing hormone (GHRH) administered 2 hours later. In the present work a sequential test was performed using the administration of hexarelin as first stimulus followed 120 minutes later by GHRH. The two aims of the study were: (a) to evaluate the interaction of GHRH and hexarelin, and (b) to further understand the alterations in GH neuroregulation in patients with anorexia nervosa. DESIGN: The GH stimuli used were hexarelin (1 micrograms/kg i.v.), a GH stimulus whose main action is hypothalamic, followed 120 minutes later by GHRH (1 micrograms/kg i.v.) as a pituitary stimulus. Each woman was tested once. PATIENTS: Thirty-two woman matched for age participated in the study: six normal-weight women as controls, 14 women with anorexia nervosa, seven women with secondary amenorrhoea due to voluntary weight loss for aesthetic reasons, and five normal-weight women after 72 hours of a controlled hypocaloric diet (800 cal/day). MEASUREMENTS: Plasma GH levels were measured by time-resolved fluoroimmunosasay, each value shown is the mean +/- SE in mU/l. RESULTS: The administration of hexarelin to the normal-weight women induced a clear-cut GH secretion (expressed as mean +/- SE of GH peak in mU/l of 77.5 +/- 21.8, but blocked the GH-releasing capability of GHRH administered 120 minutes later (6.6 +/- 2.8, P < 0.05). In contrast, the women with anorexia nervosa showed a normal GH response after the two stimuli: hexarelin 64.8 +/- 9.2. GHRH 71.1 +/- 14.2. The absence of heterologous desensitization was specific to anorexia nervosa, because the women with amenorrhoea due to voluntary weight loss but with a normal energy intake showed a pattern similar to the controls (GH after hexarelin 60.3 +/- 9.5 and to GHRH 120 minutes later 6.2 +/- 1.0 (P < 0.05)). Similarly, the women after the short-term hypocaloric diet showed a hexarelin-mediated GH secretion of 99.6 +/- 17.8, which blunted the subsequent administration of GHRH (GH mean peak of 9.9 +/- 2.9, P < 0.05 vs hexarelin). CONCLUSIONS: In the normal subjects, the administration of hexarelin induced clear-cut GH secretion, but inhibited the action of GHRH when administered 120 min later, while this heterologous desensitization was not observed in the patients with anorexia nervosa. This sequentially delayed test may be of some value in the clinical setting for assessing the status of patients with anorexia nervosa.

Adult↗
PubMed1997

Neuropharmacological assessment of growth hormone secretion.

The biochemical diagnosis of individuals who are either deficient in growth hormone (GH) or who have alterations in the normal pattern of GH secretion is difficult. The uncertainty surrounding diagnosis reflects the lack of a thorough understanding of the physiology of GH secretion and of the hypothalamic hormones involved. At least three hormones are implicated: GH-releasing hormone (GHRH), somatostatin and the endogenous ligand of the GH secretagogue receptor, although the role that each plays in the release of GH is not clear from the available experimental evidence. In such a situation, most of the dynamic tests of GH secretory capacity in humans need to undergo a 'trial and error' process before being validated. The search for the 'gold standard' test of GH secretion is ongoing, and the combination of GHRH plus GH secretagogues will probably play an important role in future clinical diagnosis.

Growth Hormone↗
PubMed1997

Growth hormone secretagogues in pathological states: diagnostic implications.

The identification and cloning of the receptor for synthetic growth hormone (GH) secretagogues, even before the endogenous ligand has been identified or its precise physiological role established, suggests that there is a novel target of action for this class of drug. In an attempt to select patients who will benefit from GH treatment, GH secretagogues are being evaluated for their usefulness in diagnosing GH deficiency. The effects of GH-releasing peptides (GHRPs) on GH release as a function of age and metabolic status, and in different neuroendocrine pathologies, are described, as are the different mechanisms of action, potency and reproducibility of the response to GHRPs compared with GH-releasing hormone (GHRH). GHRPs offer the advantage over GHRH in natural models of deranged GH secretion in that, in various metabolic states (e.g. obesity, anorexia nervosa and non-insulin-dependent diabetes mellitus), the GH response to GHRH is more impaired than it is to GHRPs. However, in some neuroendocrine pathologies, the reverse is true. Thus, both secretagogues provide separate information on the physiological status of somatotrophs.

Anorexia Nervosa↗
PubMed1996

The sequential administration of growth hormone-releasing hormone followed 120 minutes later by hexarelin, as an effective test to assess the pituitary GH reserve in man.

OBJECTIVE: GH deficiency, either in children or in adults, is a clinically relevant problem. The diagnosis is based on dynamic tests of GH secretion, which are clear cut on a group basis but highly problematic for individual diagnosis. The controversy surrounding the diagnosis of GH deficiency reflects the absence of a gold standard dynamic test. The synthetic hexapeptide hexarelin and GHRH stimulate GH secretion using different mechanisms. A sequential test has been devised using the administration of GHRH as first stimulus followed 120 minutes later by hexarelin. The two aims of the study were (a) to evaluate the interaction of GHRH and hexarelin, and (b) to devise a sequential test of GH reserve. DESIGN: The GH stimuli used were GHRH (1 microgram/kg i.v.) as a pituitary stimulus, and hexarelin (1 microgram/kg i.v.) as a GH stimulus whose main action is hypothalamic. Each subject was tested twice in order to serve as his own control. Three different studies, each with two duplicate tests, were performed on separate groups of individuals: (a) GHRH followed 120 minutes later by hexarelin and on the second day hexarelin followed 120 minutes later by GHRH; (b) GHRH followed 120 minutes later by GHRH and on the other day hexarelin followed 120 minutes later by hexarelin; (c) GH 0.5 IU i.v. followed 120 minutes later by GHRH and on the other day, the same dose of GH followed 120 minutes later by hexarelin. PATIENTS: Eighteen normal volunteers (12 women, 6 men) after giving informed consent. MEASUREMENTS: Plasma GH levels were measured by time-resolved fluoroimmunoassay; each value shown is the mean +/- SEM of n = 6. RESULTS: GHRH followed 120 minutes later by hexarelin induced two episodes of GH secretion (expressed as mean GH peak, mU/l). The GHRH-mediated GH release showed a mean GH peak of 38.2 +/- 13.6 mU/l and after hexarelin 120 minutes later of 56.7 +/- 18.0 mU/l. The contrary sequence blocked the second stimulus, i.e. the hexarelin-stimulated GH mean peak was 54.7 +/- 18.4, and the GH release 120 minutes later after GHRH was 4.8 +/- 1.9 (P < 0.05 vs GHRH used as first stimulus). In the two sequential tests using the same stimulus, the second GH peak was reduced. In fact, GHRH induced a GH mean peak of 63.8 +/- 21.1 mU/l as first stimulus, greater (P < 0.05) than when GHRH was administered again 120 minutes later (22.0 +/- 5.9 mU/l). Similar results were obtained with hexarelin, with a first mean peak of 70.6 +/- 10.3 mU/l, and a second one 120 minutes later of 13.4 +/- 4.6 mU/l (P < 0.05). The blockade of the second stimulus was not due to the feed-back action of the GH released by the first stimulus. In fact, the i.v. administration of exogenous GH induced a mean GH peak of 168.0 +/- 89.7 and reduced the action of GHRH administered 120 minutes later (26.1 +/- 8.1). The previous administration of GH (mean peak 115.5 +/- 42.0) did not alter the action of hexarelin injected 120 minutes later, showing a mean peak of 71.9 +/- 11.2. The large variability in the stimulatory action of GHRH contrasted vividly with the reproducibility of hexarelin. Furthermore, individually analysed, only one of the 12 subjects tested first with hexarelin, compared to 4 out of 12 tested with GHRH as first stimulus, presented a blunted response (< 13 mU/l). After the sequential stimulus there were no false negatives. CONCLUSION: The sequential administration of GHRH in normal subjects and of hexarelin 120 minutes later provides separate information regarding pituitary GH reserve, of both secretagogues without mutual interference. There were not false negative results to the combined test. This sequentially delayed test may be of some value in the clinical setting for assessing pituitary GH reserve.

Adult↗
PubMed1996

Effect of sodium valproate on luteinizing hormone secretion in pre- and postmenopausal women and its modulation by naloxone infusion.

The synchronized activity of the GnRH neurons can be modulated through both excitatory and inhibitory circuits: one such inhibitory modulator is gamma-aminobutyric acid (GABA), but this has been little studied in humans. The aim of this study was to examine whether acute or chronic modulation of the GABA-ergic system with the drug sodium valproate (VPA) affects gonadotropin secretory frequency and/or amplitude in a steroid-dependent manner, and whether any such modulation might interact with endogenous opioids. Sixty postmenopausal women (age range 50-60 yr, group I), 50 postmenopausal women who had been on estrogen replacement therapy (group II), and 30 women in the luteal phase of their regular menstrual cycle (age range 25-40 yr, group III) were studied. VPA was administered acutely using doses of 300, 600, and 1200 mg orally. Samples for serum gonadotropins were taken at intervals over 24 h. Each dose of VPA caused significant LH suppression in group I. The maximum degree of suppressibility was the same with the three doses of VPA (14-20%). However, no dose had any effect on gonadotropin levels in group II. In group III, the single high dose of 1200 mg VPA significantly suppressed serum LH levels. The efficacy of chronic VPA administration in the three groups studied was assessed by measuring LH pulsatility (10-min samples) over 6 h, before and after 1 month's treatment with VPA. No change in either mean basal LH or in the LH pulsatility parameters was found. Naloxone infusion (1.6 mg/h for 6 h) had no effect on LH pulsatility in group I. When 1200 mg of VPA was administered before naloxone infusion, the level of LH suppression was 18% and was associated with a significant decrease in LH pulse frequency (P < 0.01). Naloxone infusion alone significantly increased mean serum LH and LH pulse frequency in group II patients (P < 0.01), and this elevation was antagonized by VPA pretreatment. Naloxone infusion alone significantly increased mean LH levels and LH pulse frequency in patients in group III, and this was also blocked by VPA pretreatment. These results suggest that an acute increase in GABA-ergic tone may inhibit gonadotropin secretion in the estrogen-deprived state, or when endogenous opioid inhibition is blocked in postmenopausal women on estrogens, as well as during the luteal phase of the menstrual cycle. It is possible that GABA-ergic pathways interact with opioids in the inhibitory modulation of gonadotropins in the human female.

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