Mother and daughter with Kenny-Caffey syndrome: the adult phenotype.

Kenny-Caffey Syndrome (KCS) is a genetic syndrome characterized by growth retardation with short stature, cortical thickening and medullary stenosis of long bones, and hypoparathyroidism with hypocalcemia. KCS and the related but more severe condition osteocraniostenosis are determined by monoallelic variants in the FAM111A gene. Here we describe the KCS phenotype resulting from the monoallelic FAM111A variant p.Y511H in a 31-year-old woman and in her 56-year-old mother, who is one of the oldest affected individuals known so far. To our knowledge, it is also one of the few molecularly confirmed cases of a mother-to-child transmission of KCS.

Prevalence of child malnutrition at a university hospital using the World Health Organization criteria and bioelectrical impedance data

Malnutrition constitutes a major public health concern worldwide and serves as an indicator of hospitalized patients’ prognosis. Although various methods with which to conduct nutritional assessments exist, large hospitals seldom employ them to diagnose malnutrition. The aim of this study was to understand the prevalence of child malnutrition at the University Hospital of the Ribeirão Preto Medical School, University of São, Brazil. A cross-sectional descriptive study was conducted to compare the nutritional status of 292 hospitalized children with that of a healthy control group (n=234). Information regarding patients’ weight, height, and bioelectrical impedance (i.e., bioelectrical impedance vector analysis) was obtained, and the phase angle was calculated. Using the World Health Organization (WHO) criteria, 35.27% of the patients presented with malnutrition; specifically, 16.10% had undernutrition and 19.17% were overweight. Classification according to the bioelectrical impedance results of nutritional status was more sensitive than the WHO criteria: of the 55.45% of patients with malnutrition, 51.25% exhibited undernutrition and 4.20% were overweight. After applying the WHO criteria in the unpaired control group (n=234), we observed that 100.00% of the subjects were eutrophic; however, 23.34% of the controls were malnourished according to impedance analysis. The phase angle was significantly lower in the hospitalized group than in the control group (P<0.05). Therefore, this study suggests that a protocol to obtain patients’ weight and height must be followed, and bioimpedance data must be examined upon hospital admission of all children.

Prevalence of child malnutrition at a university hospital using the World Health Organization criteria and bioelectrical impedance data.

Malnutrition constitutes a major public health concern worldwide and serves as an indicator of hospitalized patients' prognosis. Although various methods with which to conduct nutritional assessments exist, large hospitals seldom employ them to diagnose malnutrition. The aim of this study was to understand the prevalence of child malnutrition at the University Hospital of the Ribeirão Preto Medical School, University of São, Brazil. A cross-sectional descriptive study was conducted to compare the nutritional status of 292 hospitalized children with that of a healthy control group (n=234). Information regarding patients' weight, height, and bioelectrical impedance (i.e., bioelectrical impedance vector analysis) was obtained, and the phase angle was calculated. Using the World Health Organization (WHO) criteria, 35.27% of the patients presented with malnutrition; specifically, 16.10% had undernutrition and 19.17% were overweight. Classification according to the bioelectrical impedance results of nutritional status was more sensitive than the WHO criteria: of the 55.45% of patients with malnutrition, 51.25% exhibited undernutrition and 4.20% were overweight. After applying the WHO criteria in the unpaired control group (n=234), we observed that 100.00% of the subjects were eutrophic; however, 23.34% of the controls were malnourished according to impedance analysis. The phase angle was significantly lower in the hospitalized group than in the control group (P<0.05). Therefore, this study suggests that a protocol to obtain patients' weight and height must be followed, and bioimpedance data must be examined upon hospital admission of all children.

Successful domino liver transplantation in maple syrup urine disease using a related living donor

Maple syrup urine disease (MSUD) is an autosomal recessive disease associated with high levels of branched-chain amino acids. Children with MSUD can present severe neurological damage, but liver transplantation (LT) allows the patient to resume a normal diet and avoid further neurological damage. The use of living related donors has been controversial because parents are obligatory heterozygotes. We report a case of a 2-year-old child with MSUD who underwent a living donor LT. The donor was the patient's mother, and his liver was then used as a domino graft. The postoperative course was uneventful in all three subjects. DNA analysis performed after the transplantation (sequencing of the coding regions of BCKDHA, BCKDHB, and DBT genes) showed that the MSUD patient was heterozygous for a pathogenic mutation in the BCKDHB gene. This mutation was not found in his mother, who is an obligatory carrier for MSUD according to the family history and, as expected, presented both normal clinical phenotype and levels of branched-chain amino acids. In conclusion, our data suggest that the use of a related donor in LT for MSUD was effective, and the liver of the MSUD patient was successfully used in domino transplantation. Routine donor genotyping may not be feasible, because the test is not widely available, and, most importantly, the disease is associated with both the presence of allelic and locus heterogeneity. Further studies with this population of patients are required to expand the use of related donors in MSUD.

Successful domino liver transplantation in maple syrup urine disease using a related living donor.

Maple syrup urine disease (MSUD) is an autosomal recessive disease associated with high levels of branched-chain amino acids. Children with MSUD can present severe neurological damage, but liver transplantation (LT) allows the patient to resume a normal diet and avoid further neurological damage. The use of living related donors has been controversial because parents are obligatory heterozygotes. We report a case of a 2-year-old child with MSUD who underwent a living donor LT. The donor was the patient's mother, and his liver was then used as a domino graft. The postoperative course was uneventful in all three subjects. DNA analysis performed after the transplantation (sequencing of the coding regions of BCKDHA, BCKDHB, and DBT genes) showed that the MSUD patient was heterozygous for a pathogenic mutation in the BCKDHB gene. This mutation was not found in his mother, who is an obligatory carrier for MSUD according to the family history and, as expected, presented both normal clinical phenotype and levels of branched-chain amino acids. In conclusion, our data suggest that the use of a related donor in LT for MSUD was effective, and the liver of the MSUD patient was successfully used in domino transplantation. Routine donor genotyping may not be feasible, because the test is not widely available, and, most importantly, the disease is associated with both the presence of allelic and locus heterogeneity. Further studies with this population of patients are required to expand the use of related donors in MSUD.

Dopamine receptor subtype 2 and somatostatin receptor subtype 5 expression influences somatostatin analogs effects on human somatotroph pituitary adenomas in vitro.

Dopamine (DA) and somatostatin (SRIF) receptor agonists inhibit growth hormone (GH) secretion by pituitary adenomas. We investigated DA subtype 2 receptor (DR2) and SRIF receptor (sst) subtypes 2 and 5 expression in 25 GH-secreting pituitary adenomas and tested in primary culture the effects on GH and prolactin (PRL) secretion of sst agonists selectively interacting with sst2 (BIM-23120), sst5 (BIM-23206), and sst2 and sst5 (BIM-23244). All adenomas expressed sst2; eight adenomas expressed both sst5 and DR2, eight sst5 but not DR2, and eight DR2 but not sst5. One tissue lacked expression of DR2 and sst5. GH secretion was inhibited by BIM-23120 in all samples, while it was reduced by BIM-23206 only in adenomas not expressing DR2. BIM-23120's inhibitory effects correlated with sst2 and DR2 expression, whereas DR2 expression correlated inversely with BIM-23206 inhibitory effects on GH secretion. In seven mixed GH-/PRL-secreting pituitary adenomas, PRL secretion was inhibited in sst5-expressing tumors by BIM-23206, but not by BIM-23120. BIM-23244 reduced PRL secretion only in adenomas expressing sst2, sst5 and DR2. sst5 and DR2 expression correlated directly with BIM23206 inhibitory effects on PRL secretion. Our results suggest that adenomas expressing DR2 are less likely to respond to clinically available SRIF analogs in terms of GH secretion inhibition. Therefore, drugs interacting also with DR2 might better control secretion of pituitary adenomas.

Maternal plasma calcitonin gene-related peptide levels do not change during labor and are not influenced by delivery route.

OBJECTIVE: Calcitonin gene-related peptide (CGRP) circulates in maternal circulation throughout pregnancy, and specific receptors for CGRP (CGRPrs) are expressed by human myometrium. Because CGRP induces a dose-dependent relaxation of human myometrium, we examined a role for CGRP in modulation of myometrial smooth muscle contractility during pregnancy and labor. The aim of the present study was to evaluate the changes of maternal serum CGRP levels during parturition, according to the mode of delivery and in relation to cervical dilatation. METHODS: Circulating CGRP levels were measured in the following groups of healthy women: nonpregnant women, during the follicular phase of the menstrual cycle (n = 19); at term pregnancy (39-40 weeks; n = 24); after elective cesarean delivery (39-40 weeks; n = 20); and at spontaneous vaginal delivery (39-40 weeks; n = 16). In a subgroup of women, blood samples were collected longitudinally throughout labor at various cervical dilatations in the progress of labor (n = 8). RESULTS: Pregnant women at term not in labor had significantly higher CGRP levels than nonpregnant women (P =.021). No significant difference was found between women who delivered vaginally and those who had elective cesarean, and there were no correlations between CGRP plasma levels and cervical dilatation. CONCLUSIONS: Parturition is characterized by no significant changes in maternal serum CGRP levels, and no significant correlation exists between plasma CGRP levels and cervical dilatation during labor.

Blood growth hormone-binding protein levels in premenopausal and postmenopausal women: roles of body weight and estrogen levels.

A substantial proportion of GH circulates bound to high affinity GH-binding protein (GHBP), which corresponds to the extracellular domain of the GH receptor. Current evidence indicates that nutritional status has an important role in regulating plasma GHBP levels in humans. In the present study the relationship among plasma GHBP levels, body composition [by bioelectrical impedance analysis (BIA) and dual energy x-ray absorptiometry (DEXA)] and serum estradiol (E(2)) was evaluated in premenopausal (n = 92) and postmenopausal (n = 118) healthy women with different body weight [three groups according to body mass index (BMI): normal, 18.5-24.99; overweight, 25-29.99; obese, 30-39.99 kg/m(2)]. Plasma GHBP levels were measured by high pressure liquid chromatography gel filtration. GH and insulin-like growth factor I levels were determined by immunoradiometric assay and RIA, respectively. GHBP levels were significantly higher in premenopausal women with BMI above 25 kg/m(2) (overweight, 3.789 +/- 0.306 nmol/L; obese, 4.372 +/- 0.431 nmol/L) than those observed in postmenopausal women (overweight, 1.425 +/- 0.09 nmol/L; obese, 1.506 +/- 0.177 nmol/L). No significant differences were found between normal weight premenopausal (1.741 +/- 0.104 nmol/L) and postmenopausal (1.524 +/- 0.202 nmol/L) women. In premenopausal women GHBP levels correlated positively with BMI (r = 0.675; P < 0.001), fat mass (FM; r = 0.782; P < 0.001; by BIA; r = 0.776; P < 0.001; by DEXA), truncal fat (TF; r = 0.682; P < 0.001), waist to hip circumference ratio (WHR; r = 0.551; P < 0.001), and E(2) (r = 0.298; P < 0.05), whereas no significant correlation was found in postmenopausal women between GHBP levels and BMI, FM, TF, WHR, or E(2). In normal weight pre- and postmenopausal women GHBP levels did not change between the ages of 20 and 69 yr. No statistically significant correlation was found between GHBP and age for all groups studied. Moreover, in two distinct subgroups of pre- and postmenopausal women, aged 40-49 yr, the direct relationship between GHBP levels and all indexes of adiposity were only observed in premenopausal women [BMI: r = 0.836; P < 0.001; FM: r = 0.745 (BIA) and r = 0.832 (DEXA); P < 0.001; TF: r = 0.782; P < 0.001; WHR: r = 0.551; P < 0.05], but not in postmenopausal women. In conclusion, the present data indicate a strong direct correlation between GHBP and body fat in premenopausal, but not in postmenopausal women, whereas they failed to detect a relationship between GHBP and age. Therefore, these results suggest that endogenous estrogen status may be an important determinant of the changes in GHBP levels in women with different body weights.

Diurnal rhythm of plasma catecholamines in acromegaly.

We investigated the 24-h profiles of the circulating levels of norepinephrine (NE) and epinephrine (E), blood pressure (BP), and heart rate in 14 acromegalic patients, before (A) and 3-6 months after transsphenoidal surgery (C-A, cured; A-A, active), and in 8 age-matched normal subjects (N). In addition, the responses of NE, E, PRA, and aldosterone to upright posture were investigated. No significant differences in the mean 24-h plasma NE and E levels were observed between either group of acromegalics and the N subjects. Analysis of the 24-h profiles indicated a statistically significant 24-h rhythm of both NE and E in N subjects. No evidence of a 24-h rhythm of plasma NE and E and BP was found in A patients. After surgery, a statistically significant 24-h rhythm of NE was detected in the patients with acrophase (13.54 and 13.45 h in C-A and A-A patients, respectively) and mesor (1019.8+/-45.1 and 1017.8+/-54.7 pmol/L in C-A and A-A patients, respectively) similar to those observed in N subjects (acrophase, 13.21 h; mesor, 942.3+/-42.5 pmol/L). After surgery, the plasma concentration of E clearly fluctuated throughout the 24 h in both C-A and A-A patients, even if cosinor analysis failed to reveal a 24-h significant rhythm. A statistically significant 24-h rhythm of BP was restored only in C-A patients. The mean 24-h heart rate was slightly, but significantly (P<0.05), higher in A than in N subjects and decreased after surgery. No significant differences in upright-stimulated NE, E, and plasma aldosterone levels were observed between each group of acromegalics and N subjects. However, basal and upright-stimulated PRA levels were significantly (P<0.001) lower in A patients. In conclusion, our study demonstrates the lack of a clear circadian variation in catecholamine levels and BP in active acromegaly and the return of a significant 24-h rhythm of NE and BP after pituitary surgery, concomitant with the reduction in GH and insulin-like growth factor I serum levels.

Unexpected activation of pituitary-adrenal axis in healthy young and elderly subjects during somatostatin infusion.

In this study we explored, in man, the effect of acute attenuation of growth hormone (GH) release induced by somatostatin (SRIH) on ACTH and cortisol plasma levels. Sixteen young (8 women, aged 23-32 years, and 8 men, aged 18-27 years) and 14 elderly (8 women, aged 65-82 years, and 6 men, aged 65-70 years) healthy subjects volunteered to participate in this investigation. Each subject was tested on two separate occasions by: (1) a 90-min i.v. infusion of SRIH given in 50 ml 0.9% saline delivered at a rate of 9 microg/kg/h, and (2) a 90-min i.v. infusion of isovolumetric amounts of 0.9% saline. Plasma GH, ACTH, cortisol and glucose concentrations were determined prior and up to 180 min after SRIH or saline infusion. SRIH induced a significant (p < 0.05) decrease in plasma GH levels from basal values of 0.6 +/- 0.15 and 0.5 +/- 0.15 microg/l to nadir values 0.25 +/- 0.1 and 0.2 +/- 0.1 microg/l in young and elderly subjects, respectively. The administration of SRIH was associated with a clear-cut increase in plasma ACTH levels both in young (peak, 10.6 +/- 1.6 pmol/l; AUC, 558.6 +/- 147.5 pmol/l/h) and in elderly (peak, 21.3 +/- 5.6 pmol/l; AUC, 841.9 +/- 153.8 pmol/l/h) subjects with a significant (p < 0.01) difference as compared to saline infusion. Consistent with these results, SRIH infusion resulted in an unequivocal rise in plasma cortisol levels both in young (peak, 394.8 +/- 36.4 nmol/l; AUC, 18,591.62 +/- 1,372.45 nmol/l/h) and in elderly (peak, 585.6 +/- 51.5 nmol/l; AUC, 24,871.05 +/- 1,837.03 nmol/l/h) subjects. The ACTH and cortisol responses to SRIH were significantly (p < 0.05 and p < 0.01) higher in elderly than in young subjects. No sex-related differences occurred in the SRIH-induced activation of hypothalamic-pituitary-adrenocortical (HPA) axis. We conclude that (1) infusion of SRIH, at a dose that inhibited basal GH secretion, was associated with an activation of HPA axis, and (2) this response was higher in elderly individuals compared with younger adults. The reason for this novel and unexpected SRIH effect is presently unclear; however, the latter may be mediated, at least in part, by some central nervous system ACTH-releasing mechanisms activated by SRIH-induced decrease in GH secretion.

Hypothalamic amenorrhea and cardiovascular hormones: changes of plasma calcitonin gene-related peptide and atrial natriuretic peptide levels.

Typical modifications of cardiovascular activity and water and salt homeostasis throughout female reproductive life are well known. Differences in plasma levels of calcitonin gene-related peptide (CGRP) and atrial natriuretic peptide (ANP) have been observed in conditions characterized by different estrogenic levels, suggesting a correlation between female reproductive function and these cardiovascular hormones. The aim of our study was to investigate in hypothalamic amenorrhea the relationship between estrogen deficiency and plasma ANP and CGRP response to adaptive tests (saline infusion test and upright posture test, respectively). Women with hypothalamic amenorrhea (aged 18-28 years) (n = 6) and age-matched healthy controls (n = 6) underwent both functional tests. Plasma CGRP and ANP levels were measured by specific radioimmunoassays before and in course of the tests. Basal plasma CGRP levels of amenorrheic patients did not significantly differ from those of normal women, while basal plasma ANP levels were significantly higher compared to controls (p < 0.01). In amenorrheic women, plasma CGRP levels showed a significant increase in response to upright posture test, though lower than the increase observed in normal women. In contrast, saline infusion test determined a significant increase in plasma ANP levels only in control subjects. In women with hypothalamic amenorrhea, the altered response of CGRP and ANP to adaptive stimuli indicates a partial derangement in the control of the secretion of these cardiovascular hormones. Nevertheless, the differences between such modifications and those observed in other conditions of altered estrogenic levels, suggest that in amenorrheic women hypogonadism is not the major factor influencing CGRP and ANP response to adaptive stimuli.

Defective hypothalamic growth hormone (GH)-releasing hormone activity may contribute to declining GH secretion with age in man.

There is evidence that withdrawal of SRIH infusion in man promotes a rebound GH response that allegedly has been proposed to be related to the function of GHRH-producing neurons. In the present study we have evaluated whether a reduction in endogenous GHRH activity contributes to the decreased GH secretion of the elderly. Sixteen young (8 women, aged 23-32 yr, and 8 men, aged 18-27 yr) and 13 elderly (8 women, aged 65-82 yr, and 5 men, aged 65-70 yr) healthy subjects volunteered to participate in this investigation. Each subject was tested on 2 separate occasions: 1) a 90-min iv infusion of SRIH was given in 50 mL 0.9% saline delivered at a rate of 9 micrograms/kg.h; and 2) a 90-min iv infusion of isovolumetric amounts of 0.9% saline was given. Plasma GH levels were determined before and up to 180 min after SRIH or saline infusion, whereas plasma insulin-like growth factor I, estradiol, and testosterone levels were measured in basal samples. In elderly women, the mean maximum (delta) GH peak (2 +/- 0.7 micrograms/L) after withdrawal of SRIH infusion was significantly (P < 0.02) lower than that in young women (7.3 +/- 2 micrograms/L). In elderly men, the mean delta GH peak (2.9 +/- 0.6 micrograms/L) after withdrawal of SRIH infusion was lower than that in young men (6.3 +/- 1.6 micrograms/L), although the difference failed to achieve statistical significance. Baseline insulin-like growth factor I levels were significantly lower in elderly compared to young subjects in both men and in women. In women, both age and basal plasma estradiol and testosterone levels significantly correlated with delta GH peak after SRIH withdrawal (r = -0.61, r = 0.61, and r = 0.66, respectively), whereas in men they did not. These findings are compatible with the view that an age-related decrease in endogenous GHRH function may contribute to the defective GH secretion of the elderly. Alterations in plasma concentrations of sex steroids may have important implications in the observed changes.

Hormonal replacement therapy affects calcitonin gene-related peptide and atrial natriuretic peptide secretion in postmenopausal women.

OBJECTIVE: Menopause is associated with critical changes in the cardiovascular system, and the possible effect of hormonal replacement therapy (HRT) on these changes is under investigation. The aim of our study was to evaluate in postmenopausal women the effects of HRT and clonidine on the response of plasma calcitonin gene-related peptide (CGRP) and plasma atrial natriuretic peptide (ANP) to the upright posture test and the saline infusion test respectively. METHODS: CGRP and ANP levels were measured with specific radioimmunological assays and expressed in pmol/l (means +/- S.E.M). DESIGN: Postmenopausal women (age 46-53 years) (n = 18) were studied before and after 3 months of HRT (n = 13) or clonidine treatment (n = 5). RESULTS: After HRT or clonidine treatment plasma CGRP levels (14.9 +/- 1.6 and 15.9 +/- 3.8 pmol/l) were significantly higher than before (9.8 +/- 0.6 and 10.5 +/- 1.6 pmol/l) (P < 0.01). The assumption of upright posture caused no change in plasma CGRP levels before treatment, while after HRT, but not after clonidine treatment, an increase in plasma CGRP levels was observed (P < 0.01 at 5 and 20 min). Basal plasma ANP levels significantly decreased after both HRT and clonidine treatment (P < 0.01). In untreated women the saline infusion test did not induce any change in plasma ANP levels; a significant response to the test was restored after HRT but not after clonidine treatment (P < 0.01 at 90 and 120 min). CONCLUSIONS: The results show that some of the adaptive responses modified by menopausal changes are restored by HRT but not clonidine treatment, suggesting a modulatory role for sex steroid hormones in cardiovascular function and salt and water balance.

Acute administration of human galanin in normal subjects reduces the potentiating effect of pyridostigmine-induced cholinergic enhancement on release of norepinephrine and pancreatic polypeptide.

The neuropeptide galanin (GAL) is widely distributed in the central and peripheral nervous systems where it often coexists with catecholamines and acetylcholine. Recently we have reported that human GAL (hGAL) in man depresses the release of norepinephrine (NE) and the responses to both assumption of upright posture and insulin-induced hypoglycemia. To gain an insight into the action of hGAL on sympathetic nervous system activity in man, we investigated the effects of a 60-min infusion (80 pmol/kg/min) of hGAL or saline on the release of NE, epinephrine (E) and pancreatic polypeptide (PP) induced by an acetylcholinesterase inhibitor, pyridostigmine bromide (PD), in nine healthy volunteers. PD (120 mg orally) induced a significant rise in plasma concentrations of NE (1.6 +/- 0.04 vs. 1.08 +/- 0.06 nmol/l), E (0.34 +/ 0.05 vs. 0.12 +/- 0.04 nmol/l) and PP (178.06 +/- 33 vs. 37.57 +/- 7.35 pmol/l), whilst it significantly reduced heart rate (HR; 61 +/- 2 vs. 71 +/- 4 beats/min). Changes in plasma levels of PP were determined as an indirect measure of amplification of endogenous cholinergic activity produced by PD. Administration of hGAL blunted the release of NE and PP evoked by PD. The mean (+/- SEM) area under the curve produced by PD of NE (50.05 +/- 3.97 nmol/l.90 min) and PP (8,692.87 +/- 1,724 pmol/l.90 min) was significantly (p < 0.001) reduced by hGAL infusion (2.65 +/- 1.57 nmol/l.90 min and 248.1 +/- 148 pmol/l.90 min, for NE and PP, respectively). hGAL failed to affect significantly the E release evoked by PD. hGAL was able to enhance HR significantly (104 +/- 5 vs. 69 +/- 3 beats/min), and completely prevented the PD-induced slowing of HR. Both PD and hGAL did not alter supine systolic and diastolic blood pressure. We conclude that hGAL significantly reduces the release of NE and PP stimulated by PD-induced enhancement of cholinergic activity. These findings are consistent with a functional interrelationship between GAL and the cholinergic system in man, and may suggest the participation of a cholinergic pathway in the galaninergic modulation of the autonomic nervous system.

Changes of plasma calcitonin gene-related peptide levels in postmenopausal women.

OBJECTIVE: Our purpose was to investigate whether the secretion of a cardiovascular hormone, calcitonin gene-related peptide, is modified in climateric women according to cardiovascular adaptive responses. STUDY DESIGN: Plasma calcitonin gene-related peptide levels were measured in climateric women in a basal condition (n = 15), in response to an upright position (n = 8), and during hot flushes (n = 12). The effect of hormonal replacement therapy on plasma calcitonin gene-related peptide was also studied (n = 9). Plasma calcitonin gene-related peptide levels were measured by a specific radioimmunoassay after an acidic extraction. RESULTS: Plasma calcitonin gene-related peptide levels in postmenopausal women were significantly lower than in the control group (p < 0.01). After the women assumed an upright posture, a lack of plasma calcitonin gene-related peptide increase was observed in control fertile women, who showed the typical significant hormonal increase (p < 0.01). In all patients the occurrence of hot flushes was associated with a significant and rapid increase of plasma calcitonin gene-related peptide levels. After 3 months of hormonal replacement therapy basal plasma calcitonin gene-related peptide levels returned to the range of healthy fertile women. CONCLUSIONS: The current data show that the secretion of plasma calcitonin gene-related peptide is lower in postmenopausal women and its response to postural stimulus is impaired. Vasomotor changes are associated with an increase of plasma levels of this cardiovascular hormone. An effect of hormonal replacement therapy on calcitonin gene-related peptide secretion has been shown.

Function of the GH/IGF-1 axis in healthy middle-aged male runners.

In an attempt to examine the effect of prolonged physical activity on the function of the GH/IGF-1 axis during the aging process in man, we have evaluated basal and GHRH (GHRH-29: 1 microgram/kg i.v. as a bolus) stimulated GH secretion as well as basal plasma IGF-1 levels in a group of 25 healthy runners (50-60 years, mean age 55.5 +/- 0.6) and 24 age-matched relatively sedentary normal controls (mean age 55.8 +/- 0.7). The runners had a minimum distance in kilometers of 26 km/week for at least 15 years, and competed in distances ranging from 16 km to the marathon. In runners, GHRH induced an increase of GH which was significantly higher (p < 0.001) than that observed in the age-matched controls. Baseline IGF-1 levels were significantly higher (p < 0.001) in trained runners (171 +/- 8.4 micrograms/1) compared to the controls (91.1 +/- 5.5 micrograms/1). These data show that in middle-age prolonged physical activity increases the function of the GH/IGF-1 axis. To clarify the possible mechanisms underlying the GH/IGF-1 secretory pattern in the runners, the GH responses to both single and combined administration of GHRH and arginine (ARG: 30 g infused over 30 min), a GH secretagogue likely acting via inhibition of hypothalamic somatostatin release, were investigated in 6 runners (mean age 55 +/- 1.9 years) and 6 controls (mean age 55 +/- 0.9 years). ARG clearly increased the GH response to GHRH in the controls, whereas it was unable to further potentiate the GH-releasing effect of GHRH in runners, thus suggesting that the increased GH responsiveness to GHRH might be due to an exercise-related decrease in endogenous hypothalamic somatostatinergic activity.

Interrelationships between calcitonin gene-related peptide and sympathoadrenomedullary system: effects of administration of epinephrine and norepinephrine in healthy man.

To investigate the influence of the sympathoadrenomedullary system on the modulation of the circulating levels of calcitonin gene-related peptide (CGRP), the effects of epinephrine (E) and norepinephrine (NE) were studied in 8 normal subjects (4 females and 4 males). The mean basal levels of CGRP in normal subjects were 10.2 +/- 1 pmol/l. After the infusion of E (20 ng/kg per min for 30 min), a significant rise (P < 0.005) in plasma CGRP levels was observed with the expected increases in systolic blood pressure (BP), heart rate (HR) and plasma renin activity (PRA), and decrease in diastolic BP, whereas plasma aldosterone (PA) levels did not significantly change. The infusion of NE (40 ng/kg per min for 30 min) induced an increase in systolic and diastolic BPs, whereas it failed to modify CGRP, HR, PA and PRA. Our data demonstrate that the sympathoadrenomedullary system may modulate CGRP release in man perhaps via the beta-adrenergic pathway. It is likely that the modifications of plasma CGRP levels may be part of the acute vasal response to E.

Effect of human galanin on the response of circulating catecholamines to hypoglycemia in man.

Human galanin (hGAL) is a neuropeptide with 30 amino acid residues that has been found in the peripheral and central nervous system, where it often co-exists with catecholamines. In order to clarify the possible role of hGAL in the regulation of sympathoadrenomedullary function, the effect of a 60-min infusion of hGAL (80 pmol.kg-1.min-1) on plasma epinephrine and norepinephrine responses to insulin-induced hypoglycemia in nine healthy subjects was investigated. Human GAL administration significantly reduced both the release of basal norepinephrine and the response to insulin-induced hypoglycemia, whereas it attenuated the epinephrine response by 26%, with the hGAL-induced decrease in epinephrine release failing to achieve statistical significance. Human GAL significantly increased the heart rate in resting conditions and clearly exaggerated the heart rate response to insulin-induced hypoglycemia, whereas it had no effect on the blood pressure. We conclude that GAL receptor stimulation exerts an inhibitory effect on basal and insulin-induced hypoglycemia-stimulated release of norepinephrine. These findings provide further evidence that GAL may modulate sympathetic nerve activity in man but that it does not play an important role in the regulation of adrenal medullary function.

Differential effects of deltorphin on arginine and galanin-induced growth hormone secretion in healthy man.

Recently we demonstrated the inhibitory action on Growth Hormone (GH) secretion of an opioid heptapeptide, deltorphin (DT), that is highly selective in binding delta-opioid receptors. To investigate the possible mechanism leading to the decrease in GH secretion by specific activation of delta-opioidergic pathway in man, we compared, in normal subjects, the effect of DT on GH secretion responses to two different GH secretagogues, namely arginine (ARG) and galanin (GAL). DT completely blunted the GH response to ARG, whereas it attenuated the GH response to GAL, but not at a statistically significant level. We suggest that the specific activation of delta-opioid receptors in man may exert an inhibitory influence on GH secretion principally by modulating endogenous hypothalamic somatostatin (SRIH) release.

Human galanin reduces plasma norepinephrine levels in man.

The neuropeptide galanin (GAL) is widely distributed in the peripheral and central nervous systems, where it often coexists with catecholamines. To gain insight into the action of human GAL on sympathetic nervous system activity in man, we investigated the effects of a 60-min infusion of human (h) GAL (80 pmol/kg.min) or saline on peripheral norepinephrine (NE) and epinephrine concentrations, heart rate (HR), and systolic and diastolic blood pressure (BP) in the supine position as well as after assumption of the upright posture (UP) in eight healthy male volunteers. hGAL depressed supine plasma NE (0.84 +/- 0.06 vs. 0.33 +/- 0.02 nmol/L) and blunted the NE response to assumption of the UP (1.68 +/- 0.03 vs. 0.44 +/- 0.03 nmol/L), but caused a significant enhancement of the epinephrine response to assumption of the UP (0.22 +/- 0.02 vs. 0.65 +/- 0.06 nmol/L). hGAL significantly increased supine HR (70 +/- 2 vs. 99 +/- 4 beats/min) and potentiated the HR response to assumption of the UP (82 +/- 3 vs. 107 +/- 4 beats/min). hGAL did not alter supine systolic and diastolic BP, but caused a significant decrease in the systolic (121 +/- 3 vs. 98 +/- 2 mm Hg) and diastolic (74 +/- 2 vs. 62 +/- 2 mm Hg) BP responses to assumption of the UP. Our data show that hGAL decreases supine position- and UP-stimulated release of NE, suggesting an inhibitory modulation of hGAL on sympathetic outflow in man. The finding that hGAL induces an increase in HR, both in the supine position and after UP, and an inhibition of the systolic and diastolic BP response to UP provides further support for an involvement of hGAL in regulation of the cardiovascular and autonomic nervous systems in man.