Serum GH Levels Research Articles

Antiphase signalling in the neuroendocrine-immune system in healthy humans

Background Any quantity varying in the spatial-temporal dimension may be considered as a signal. Human lymphocyte cell surface molecules and subsets present circadian variation and this variation may represent a kind of signalling in the neuroendocrine-immune system. We have analyzed the dynamics of variation of specific lymphocyte subsets in healthy humans. Subjects and methods In our study, lymphocyte subpopulation analyses were performed and cortisol, melatonin, GH and TSH serum levels were measured on blood samples collected every 4 h for 24 hours from eleven healthy men, ages 35–53 years (mean = 44 ± 6 SD). Results A clear circadian rhythm was validated for CD8 and cortisol with acrophase during the day and for CD3, CD4, melatonin, GH and TSH with acrophase at night. Cross-correlation showed that CD3 correlated positively with CD4 ( ρ = 0.67, P < 0.05) and negatively with CD8 ( ρ = −0.41, P < 0.05), CD4 correlated positively with melatonin ( ρ = 0.90, P < 0.05), GH ( ρ = 0.92, P < 0.05) and TSH ( ρ = 0.71, P < 0.05), negatively with CD8 ( ρ = −0.90, P < 0.05) and cortisol ( ρ = −0.18, P < 0.05), CD8 correlated positively with cortisol ( ρ = 0.38, P < 0.05). Discussion The different profiles of nyctohemeral changes of lymphocyte cell surface molecules and specific lymphocyte subsets realize different relationships with the neuroendocrine hormones and might represent a way of signal transmission among the multiple components of the neuroendocrine-immune system.

The GH/IGF-I Axis and Cognitive Changes across a 4-Year Period in Healthy Adults

After the age of 40, the amount of growth hormone in humans decreases. The reduced activity of the GH-IGF axis may play a role in age-related cognitive impairments. In the present study, mood and cognition of 30 healthy subjects (7 males, 23 females, aged 41–76 yr, mean age 60.9 ± 9.0) were examined twice. At baseline, we determined fasting blood levels of GH and IGF-I. Mood and cognitive status were assessed at baseline and after, on the average, 3 years and 9 months of followup. Working memory performance decreased over the years in the low IGF-group (P = .007), but not the high IGF-I group. Higher levels of GH were related with a better working memory at the second test (r = 0.42, P = .01) while higher levels of IGF-I tended to be related with a better working memory (r = 0.3, P = .06). The results suggest that higher serum levels of GH and IGF-I preserve the quality of working memory functions over the years.

Colonic neoplasia in acromegaly: increased proliferation or deceased apoptosis?

Patients with acromegaly have higher prevalence of colorectal neoplasms. The pathogenetic mechanism is still unclear and may be related to sustained increase in serum GH-IGF1. We aimed to evaluate the proliferative and apoptotic markers in samples of colonic mucosa obtained during screening colonoscopic biopsy from patients with acromegaly and study their relationship to serum IGF-1 and GH levels. The study subjects included 32 patients with acromegaly (4 female), 10 healthy controls (irritable bowel syndrome) and 10 positive controls (non-acromegalic colonic adenocarcinoma). Patients with acromegaly were divided into two groups, active disease (AD) and disease in remission (AR). Two biopsies each were obtained during colonoscopy from the right colon, transverse colon and rectosigmoid region. All the polyps were biopsied and subjected to histopathological examination. Immunohistochemistry for proliferation marker (Ki-67) and apoptotic markers (caspase-3 and TdT-Mediated dUTP Nick-End Labeling (TUNEL) was carried out in the histopathological samples. Indices of proliferation were significantly different in patients with acromegaly as compared to healthy controls. The mean Ki-67 positivity was 45.1 ± 17.7% in AD and 45.6 ± 23.1% in AR, as compared to 10 ± 5% in healthy controls. While none of the healthy controls had Ki-67 positivity beyond the lower third of crypts, among patients with acromegaly 12/32 (37.5%) had mid-third positivity (P = 0.000) and 15/32 (46.8%) had full length of crypt positively (P = 0.00). Immunostaining for caspase-3 was negative in patients with acromegaly and healthy controls. TUNEL was strongly positive in patients with colonic adenocarcinoma but not in healthy controls and patients with acromegaly. IGF-1 levels were higher in those with Ki-67 positivity in the superficial mucosa. Patients with acromegaly have increased proliferation of colonic epithelial cells. Elevated levels of serum IGF1 are associated with increase proliferation in the superficial crypt cells.

Klinefelter syndrome and short stature: an unusual combination

Klinefelter syndrome is not easy to diagnose in childhood because of the absence of significant manifestations before puberty. Three main clinical signs should suggest the diagnosis in a child: small testes, tall stature, and mental retardation or learning problems. We present a patient with Klinefelter syndrome and short stature due to growth hormone deficiency. His height was below the third percentile for age and his bone age delayed. Maximal serum GH levels after insulin-induced hypoglycemia and clonidine were low, demonstrating GH deficiency. He received growth hormone treatment with good response. The diagnosis of Klinefelter syndrome was made at puberty, because the patient did not present a normal progression of testicular development and puberty. At that moment, a karyotype was made confirming the suspected diagnosis. We wish to emphasize the rare association between Klinefelter syndrome and growth hormone deficiency.

Naloxone decreases the inhibitory effect of somatostatin on GH release induced by cigarette smoking in man

To establish whether somatostatin (SRIH) exerts its inhibitory effect on the nicotine-induced release of GH by interacting with an opioid pathway, normal volunteers were treated with naloxone during (2 no-filter) cigarettes smoking and with SRIH. Nicotine significantly increased serum GH levels about 3.5 fold. Naloxone alone did not change GH rise induced by cigarette smoking. The stimulatory effect of GH by nicotine was completely blocked by SRIH. In the presence of both SRIH and naloxone, GH levels rose 1.5 fold in response to nicotine. Since naloxone only partially reversed the inhibiting action of SRIH, only a partial involvement of opioid peptides in SRIH action might be supposed. Alternatively, SRIH and naloxone-sensitive opiates might produce this inhibiting effect on GH rise in response to cigarette smoking through independent pathways.

Effects of high-dose octreotide LAR on glucose metabolism in patients with acromegaly inadequately controlled by conventional somatostatin analog therapy

In this study, the effect of high-dose octreotide LAR on glucose metabolism in patients with acromegaly was investigated. A post-hoc analysis of a clinical trial enrolling 26 patients with acromegaly not controlled by standard maximal somatostatin analog (SSAs) dose and randomized to receive high-dose (60 mg/28 days) or high-frequency (30 mg/21 days) octreotide i.m. injection (octreotide LAR) for 6 months. Glucose metabolic status was defined as worsened when a progression from normoglycemia to impaired fasting glucose (IFG) or from IFG to diabetes occurred or when an increase of HbAlc by at least 0.5% was demonstrated. An improvement of glucose metabolism was defined in the presence of a regression from IFG to normoglycemia and/or when HbAlc decreased by at least 0.5%. Glucose metabolic status remained unchanged in a majority of patients (16/26 patients, 65.3%), worsened in six patients, and improved in four patients. Pre-existing metabolic status did not predict worsening of glucose metabolism, which, conversely, was significantly related to persistent biochemical activity of the disease. In fact, patients with worsened glucose metabolism exhibited a less frequent decrease in serum GH and IGF1 levels, compared with patients with improved or unchanged glucose metabolism (2/6 vs 18/20; P=0.01). An increase in octreotide LAR dose or frequency did not impact on glucose metabolism in most patients. Worsening of glucose metabolic status occurred in close relation with persistently uncontrolled acromegaly.

Age-related changes of GH-IGF1 axis function

Background There is a reduction in the GH-IGF1 axis activity with increasing age, but there is evidence that the pool of GH available for release is not diminished in elderly subjects. We investigated whether there are differences among healthy young-middle aged and old aged subjects in the 24 hour secretory profiles of GH and IGF1. Methods The study was carried out on 15 healthy young-middle aged subjects (age range 36–55 years) and 15 healthy old aged subjects (age range 67–79 years). GH, IGF1, melatonin and cortisol serum levels were measured on blood samples collected every four hours for 24 hours. The fractional variation between single time point GH and IGF1 serum levels, mean photoperiod (06:00h–10:00h–14:00 h) and scotoperiod (18:00h–22:00h–02:00 h) values and the presence of circadian rhythmicity were evaluated. Results A normal circadian rhythmicity was recognizable for GH, melatonin and cortisol secretion in young-middle aged and old aged subjects, MESOR of cortisol was higher in the elderly ( P = 0.002) and the acrophase of cortisol was advanced in the group of old aged subjects ( P = 0.03), whereas the amplitude of IGF1 was higher in the group of young-middle-aged subjects ( P < 0.01). Old aged subjects presented higher mean GH levels in the photoperiod ( P = 0.01), but lack of variability of GH and IGF1 fractional variations, whereas young-middle aged subjects presented significant variability of GH and IGF1 factional variations ( P = 0.05 and P = 0.003, respectively) and increased fractional variation of nocturnal GH and IGF1 serum levels in respect to older subjects ( P = 0.03 and P = 0.05, respectively). There was no statistically significant difference between mean melatonin serum levels in the photoperiod ( P = 0.937) and in the scotoperiod (P = 0.494). There was no statistically significant difference between mean cortisol serum levels in the photoperiod (P = 0.235), whereas mean cortisol serum levels were higher in old aged subjects in the scotoperiod (P = 0.04). Linear regression evidenced a statistically significant negative trend between age and the 24 h mean of GH (P < 0.01) and a statistically significant positive trend between age and the 24 h mean of cortisol (P < 0.001). Conclusions Aging is associated with an altered pattern of GH secretion and IGF1 production.

ACTH response to desmopressin in a patient with acromegaly; Expression of corticotropin-releasing factor, urocortins and vasopressin V1b receptor in GH-producing pituitary adenoma

GH-producing pituitary adenomas frequently co-produce other certain anterior pituitary hormones, such as prolactin (PRL). In contrast, GH-producing adenomas which express all of corticotropin-releasing factor (CRF), urocorin1 (Ucn1) and urocortin3 (Ucn3) have not been reported. A 39-year-old woman was admitted for evaluation of the pituitary tumor. The diagnosis of acromegaly was confirmed by elevated serum GH and IGF-I levels, and the absence of GH suppression by oral glucose tolerance test. ACTH response to desmopressin (DDAVP) was observed (plasma ACTH levels increased from 13.9 to 50.4 pg/ml at 90 min). Although it is known that ACTH response to DDAVP is considerably useful for the diagnosis of ACTH-dependent Cushing's syndrome, the diagnosis of Cushing's disease was not supported by the criteria. The patient underwent transsphenoidal resection of the pituitary tumor. Immunohistological examination confirmed a GH- and PRL-producing adenoma, whereas ACTH was negative. ACTH response to DDAVP disappeared after tumor removal. To determine the cause of preoperative ACTH response to DDAVP, we examined expression of CRF family peptides and vasopressin V1b receptor in the pituitary adenoma by immunohistochemistry. Immunohistochemistry revealed positive immunostaining for CRF, Ucn1, Ucn3 and vasopressin V1b receptor in the adenoma. These observations raised the possibility that DDAVP caused an ACTH response, perhaps via the paracrine effects of tumor-derived CRF and Ucn1. When ACTH response to DDAVP is observed in patients with pituitary tumor, not only the direct effect of DDAVP on ACTH secretion, but also a possible involvement of CRF and/or urocortins expressed in the pituitary adenoma, should be considered.

Neuroendocrine axes function in healthy aging: Evaluation of predictive and manipulable blood serum indexes

Aging is characterized by alteration of neuroendocrine axes function. We evaluated possible predictive and manipulable blood serum indexes of function of these axes in healthy elderly. The study was carried out on 15 healthy young-middle aged subjects (age range 36–55 years) and 15 healthy old-aged subjects (age range 67–79 years). Melatonin, cortisol, TRH, TSH, FT4, GH and IGF1 serum levels were measured on blood samples collected every four hours for 24 hours. The presence of circadian rhythmicity, the differences in MESOR, amplitude and acrophases, the differences in the mean of 06:00–10:00–14:00 h values and the mean of 18:00–22:00–02:00 h values hormone serum levels and ratios (melatonin/cortisol ratio, TRH/TSH ratio and GH/IGF1 ratio) between the two groups were evaluated. A normal circadian rhythmicity was recognizable for melatonin, cortisol, TRH, TSH and GH secretion in young-middle aged subjects and for melatonin, cortisol TSH and GH in old-aged subjects, that showed higher cortisol MESOR value (P = 0.001 ) and lower TSH MESOR value (P = 0.002 ). Old-aged subjects presented higher GH/IGF1 ratio in the photoperiod (P = 0.02 ), and higher TRH/TSH ratio in the scotoperiod (P = 0.001 ). There was no statistically significant difference in melatonin/cortisol ratio between young-middle aged and old-aged subjects. Aging is associated with alteration of some neuroendocrine axes function, but melatonin/cortisol ratio is a valuable predictive and manipulable blood serum index of normal function in healthy aging.

Stage dependent destructuration of neuro-endocrine-immune system components in lung cancer patients

Background Close relationships among the nervous, endocrine and immune system components maintain body homeostasis. Alteration of time-related prophile of variation of system components and loss of integrated function may favour the developing of cancer and may be aggravated in the presence of neoplastic disease. The aim of our study was to evaluate the prophiles of time-related variation of neuro-endocrine-immune system components in lung cancer patients. Methods Peripheral blood samples were collected at intervals of 4 hours for 24 hours from 11 healthy subjects (age range 35–53 years, mean age ± s.e. 43.6 ± 1.7) and nine patients suffering from nonsmall cell lung cancer (age range 43–63 years, mean age ± s.e. 51.0 ± 2.4). In each blood sample, lymphocyte subpopulations (CD3, CD4, CD8, HLA-DR, CD16, CD20, CD25, γδTcR) were analyzed and melatonin, cortisol, TRH, TSH, free thyroxine, GH, IGF1 and interleukin IL2 on serum were measured. Results In our I–II stage lung cancer patients CD8+ lymphocytes ( P = 0.01), and in particular the T suppressor subset ( P < 0.0001), CD20+ cells ( P = 0.05), γδTCR expressing cells ( P < 0.01) and IGF1 ( P = 0.004) were diminished, whereas CD16+ cells ( P < 0.0001), CD25+ cells ( P = 0.03), free thyroxine ( P = 0.001) and GH ( P < 0.0001) were increased in respect of healthy subjects. In our III–IV stage lung cancer patients CD8+ lymphocytes ( P = 0.003) and in particular the T suppressor subset ( P < 0.0001), CD20+ cells ( P = 0.05), γδTCR expressing cells ( P = 0.01), melatonin ( P = 0.03), TSH ( P = 0.006) and IGF1 ( P < 0.0001) were diminished, whereas CD4+ cells ( P = 0.002), CD16+ cells ( P < 0.0001), CD25+ cells ( P = 0.002), cortisol ( P = 0.003), TRH ( P = 0.004), free thyroxine ( P = 0.001), GH ( P < 0.0001) and IL2 ( P = 0.0002) were increased in respect of healthy subjects. A statistically significant difference was evidenced between the two groups of cancer patients for the values of CD16+ cells ( P < 0.0001), free thyroxine ( P = 0.001) and IGF1 ( P < 0.0001) higher in I–II stage lung cancer patients and for the values of CD4+ cells ( P < 0.0001), γδTCR expressing cells ( P = 0.002), TRH ( P = 0.002) and IL2 ( P = 0.01) higher in III–IV stage lung cancer patients. Lung cancer patients showed alteration of the pattern of circadian variation of CD3+, CD8+, CD8+ dim, CD16+, CD20+ and γδTCR expressing cells and of cortisol, TSH and GH serum levels. Pair-wise comparisons showed severe and stage dependent alterations in lung cancer patients. Conclusions The prophiles of time-related variation of neuro-endocrine-immune system components are altered in a stage dependent manner in lung cancer patients and this alteration may impair the customary integrated system function.

Hypothesis: Extra-hepatic acromegaly: a new paradigm?

Medical treatment of acromegaly with long-acting somatostatin analogs (LA-SMSA) and the GH receptor antagonist, pegvisomant (PEGV), has made it possible to achieve normal serum IGF1 concentrations in a majority of patients with acromegaly. These two compounds, however, impact the GH-IGF1 axis differently, which challenges the traditional biochemical assessment of the therapeutic response. We postulate that LA-SMSA in certain patients normalizes serum IGF1 levels in the presence of elevated GH actions in extra-hepatic tissues. This may result in persistent disease activity for which we propose the term extra-hepatic acromegaly. PEGV, on the other hand, blocks systemic GH actions, which are not necessarily reliably reflected by serum IGF1 levels, and this treatment causes a further elevation of serum GH levels. Medical treatment is therefore difficult to monitor with the traditional biomarkers. Moreover, the different modes of actions of LA-SMSA and PEGV make it attractive to use the two drugs in combination. We believe that it is time to challenge the existing concepts of treatment and monitoring of patients with acromegaly.

The actions of in ovo cortisol on egg fertility, embryo development and the expression of growth‐related genes in rainbow trout embryos, and the growth performance of juveniles

Rainbow trout (Oncorhynchus mykiss) oocytes were incubated for 3 hr in ovarian fluid alone (CC), or cortisol-enriched ovarian fluid [100 or 1,000 ng ml(-1) (CL and CH, respectively)], after which they were fertilized; the growth and development of the embryos reared from these oocytes was monitored until first feed, and the juveniles were monitored for 9 months. The hatching rates of the CH group were significantly reduced, but the overall survival as measured at 40-week post-fertilization was similar in the three treatment groups. In addition, significant apparently biphasic changes relative to the CC group were found in the expression of some key growth-related genes in the CL and CH treatment groups, particularly IGF-1, IGF-2, GH1, GH2, GH receptors, and thyroid hormone receptors (TRα and TRβ). Moreover, the juveniles of the CL (but not the CH treatment group) exhibited enhanced growth; the enhanced growth could not be explained on the basis of increased feed conversion efficiency or changes in serum GH levels at the juvenile stage. Additionally, relative growth rates from the three treatment groups were similar, suggesting that the biphasic growth-enhancing effects of cortisol occurred very early in embryogenesis.

Growth hormone and lactate responses induced by maximal isometric voluntary contractions and whole-body vibrations in healthy subjects

In contrast with maximal voluntary resistance exercise, which is allegedly considered a potent GH stimulus in young subjects, evaluation of GH response to whole-body vibrations (WBV) has yielded conflicting results. The acute effects of WBV alone (test A), maximal voluntary isometric contractions (MVC) (test B), and combination of WBV and MVC (test C) on serum GH and blood lactate (LA) levels were studied in 9 healthy adult males. Muscle soreness was assessed 24 and 48 h after exercise by a visual analogue scale. GH responses were significantly higher after tests B and C than after test A (GH peaks: 18.8 ± 9.5 ng/ml or 20.8 ± 13.7 ng/ml, respectively, vs 4.3 ± 3.5 ng/ml; p<0.05), with no difference between tests B and C. LA concentrations significantly increased after tests A, B, and C, being significantly higher after tests B and C than after test A (LA peaks: 2.0 ± 0.5 mmol/l or 6.7 ± 2.3 mmol/l, respectively, vs 7.6 ± 0.9 mmol/l; p<0.05). Peak LA values were significantly correlated to GH peaks in the 3 tests (r=0.48; p<0.05). Muscle soreness was significantly higher 24-48 h after tests B and C than after test A, no significant differences being present between tests B and C. WBV stimulates GH secretion and LA production, with no additive effect when combined with repeated isometric voluntary contractions. Optimization of protocols based on WBV seems important to maximize the positive effects of this intervention on the somatotropic function.

N-terminal pro-brain natriuretic peptide in newly diagnosed acromegaly

The mechanisms of acromegalic cardiomyopathy are not clearly understood. Brain natriuretic peptide (BNP) and N-terminal fragment of its pro-hormone (NT-proBNP) are released by the cardiac ventricles and increase in heart failure. In the present study, we aimed to evaluate serum NT-proBNP levels in acromegalic patients and determine a relationship between NT-proBNP levels and echocardiographic parameters. Twenty-two newly diagnosed acromegalic patients [mean age 38.85 ± 11.06 yr; body mass index (BMI): 28.51 ± 3.48 kg/m2] and 26 age- and BMI-matched healthy control subjects (mean age 32.9 ± 12.6 yr; BMI: 26.2 ± 5.3 kg/m2) were included in the study. Standard oral glucose tolerance test (OGTT) was performed. Serum NT-proBNP and GH were measured at the beginning of the OGTT (0 min). Body fat analyses were measured by bioelectrical impedance. Echocardiography was used in cardiac evaluations. The mean NT-proBNP level in the acromegalic group was not significantly different from the control subjects (55.89 ± 46.64 pg/ml in acromegaly vs 28.76 ± 22.13 pg/ml in control subjects). There were no correlations between the serum NTproBNP, GH, and IGF-I levels. Echocardiography revealed significantly increased left ventricular end-diastolic diameter (p=0.008), interventricular septum thickness (p=0.009), left atrium (p=0.029), and right ventricle diameter (p=0.027) in the acromegalic group. NT-proBNP levels were found to be slightly higher in acromegalic patients as an indicator of heart failure, but the increase was not statistically significant. Although these cardiac structural changes in newly diagnosed acromegalic patients are present, the normal level of NT-proBNP shows that NT-proBNP may not be a good indicator in acromegaly.

Neuroendocrine axes function in healthy aging: Evaluation of predictive and manipulable blood serum indexes

Aging is characterized by alteration of neuroendocrine axes function. We evaluated possible predictive and manipulable blood serum indexes of function of these axes in healthy elderly. The study was carried out on 15 healthy young-middle aged subjects (age range 36–55 years) and 15 healthy old-aged subjects (age range 67–79 years). Melatonin, cortisol, TRH, TSH, FT4, GH and IGF1 serum levels were measured on blood samples collected every four hours for 24 hours. The presence of circadian rhythmicity, the differences in MESOR, amplitude and acrophases, the differences in the mean of 06:00–10:00–14:00 h values and the mean of 18:00–22:00–02:00 h values hormone serum levels and ratios (melatonin/cortisol ratio, TRH/TSH ratio and GH/IGF1 ratio) between the two groups were evaluated. A normal circadian rhythmicity was recognizable for melatonin, cortisol, TRH, TSH and GH secretion in young-middle aged subjects and for melatonin, cortisol TSH and GH in old-aged subjects, that showed higher cortisol MESOR value (P = 0.001 ) and lower TSH MESOR value (P = 0.002 ). Old-aged subjects presented higher GH/IGF1 ratio in the photoperiod (P = 0.02 ), and higher TRH/TSH ratio in the scotoperiod (P = 0.001 ). There was no statistically significant difference in melatonin/cortisol ratio between young-middle aged and old-aged subjects. Aging is associated with alteration of some neuroendocrine axes function, but melatonin/cortisol ratio is a valuable predictive and manipulable blood serum index of normal function in healthy aging.

Short- and Long-Term Efficacy of Combined Cabergoline and Octreotide Treatment in Controlling IGF-I Levels in Acromegaly

Objective: Nearly 40% of acromegalic patients fail to control GH/IGF-I levels with somatostatin analogues (SA). Dopaminergic agonists (DA) are even less effective, but combination therapy with SA and DA normalizes IGF-I levels in 33–56% of patients not controlled by octreotide alone in short-term studies. This study was designed to evaluate short- and long-term efficacy of cabergoline in controlling IGF-I levels in acromegalic patients receiving octreotide. Design: Open-label, single arm, prospective trial. Nineteen patients (14 females, 29–78 years of age) with high IGF-I on octreotide-LAR (30 mg/month IM) for ≧6 months were enrolled. Study I: Cabergoline (PO) was started at 1.0, increased to 2.0 and 3.5 mg/week, and withdrawn at 6-week intervals. IGF-I, GH, and PRL were measured at baseline and at 6-week intervals. Study II: Responder patients (IGF-I ≤1 ULN) resumed cabergoline at individual lowest effective doses and were evaluated at 6-month intervals for ≧12 months. Study III: Responders were withdrawn from octreotide and hormonally evaluated at 3-month intervals. Methods: Serum IGF-I (IRMA), GH (ICMA) and PRL (ICMA) levels were determined by commercially available kits. Results: Addition of cabergoline to octreotide-LAR normalized IGF-I levels in 7 of 19 patients (37%) during both short- and long-term follow-up (12–27 months, mean: 18 months). Octreotide withdrawal increased IGF-I levels in only 2 of 6 responder patients. Normalization of IGF-I levels by cabergoline was strongly associated with IGF-I ≤2.2 ULNR and/or GH ≤4.0 ng/ml under octreotide treatment. Conclusion: Addition of cabergoline to octreotide was effective in both short- and long-term control of IGF-I in acromegaly, especially in patients with mild/moderately elevated GH/IGF-I levels during octreotide.

Effectofrosiglitazoneonserum IGF-I concentrations in uncontrolled acromegalic patients under conventional medical therapy: Results froma pilot phase 2 study

Current therapies for acromegaly are unsatisfactory for some patients. High-dose thiazolidinediones have been reported to reduce serum GH levels in animal models of acromegaly. The objective of the study was to evaluate the effect of increasing doses of rosiglitazone on serum GH and IGF-I concentrations in acromegalic patients. Phase 2 clinical trial. Five consecutive patients with active and uncontrolled acromegaly under conventional medical therapies were treated with increasing doses of rosiglitazone [4 mg/day every month, starting from 8 up to 20 mg/day] added to previous medical therapies for acromegaly. Mean serum IGF-I concentrations decreased from 547 ± 91 to 265 ± 126 μg/l (p<0,001) during rosiglitazone treatment: 4 patients had normal serum IGF-I concentrations, and a patient had lowered serum IGF-I values, although still abnormal, at the end of the study. On the contrary, serum GH concentrations did not significantly changed during rosiglitazone therapy as well as other pituitary hormones. No relevant side effects of rosiglitazone were observed during the study period. Quantitative real time PCR and Western blotting showed that rosiglitazone lowered GH-dependent hepatic generation of IGF-I in HepG2 cell line. Rosiglitazone reduces serum IGF-I concentrations in patients with uncontrolled acromegaly under conventional medical therapies, likely acting on the GH-dependent hepatic synthesis of IGF-I. Large studies are necessary to confirm the role of rosiglitazone as an adjunctive therapy for uncontrolled acromegalic patients under conventional medical therapies.

Altered time structure of neuro-endocrine-immune system function in lung cancer patients

BackgroundThe onset and the development of neoplastic disease may be influenced by many physiological, biological and immunological factors. The nervous, endocrine and immune system might act as an integrated unit to mantain body defense against this pathological process and reciprocal influences have been evidenced among hypothalamus, pituitary, thyroid, adrenal, pineal gland and immune system. In this study we evaluated differences among healthy subjects and subjects suffering from lung cancer in the 24-hour secretory profile of melatonin, cortisol, TRH, TSH, FT4, GH, IGF-1 and IL-2 and circadian variations of lymphocyte subpopulations. MethodsIn ten healthy male volunteers (age range 45-66) and ten male patients with untreated non small cell lung cancer (age range 46-65) we measured melatonin, cortisol, TRH, TSH, FT4, GH, IGF-1 and IL-2 serum levels and percentages of lymphocyte subpopulations on blood samples collected every four hours for 24 hours. One-way ANOVA between the timepoints for each variable and each group was performed to look for a time-effect, the presence of circadian rhythmicity was evaluated, MESOR, amplitude and acrophase values, mean diurnal levels and mean nocturnal levels were compared.ResultsA clear circadian rhythm was validated in the control group for hormone serum level and for lymphocyte subsets variation. Melatonin, TRH, TSH, GH, CD3, CD4, HLA-DR, CD20 and CD25 expressing cells presented circadian rhythmicity with acrophase during the night. Cortisol, CD8, CD8bright, CD8dim, CD16, TcRδ1 and δTcS1 presented circadian rhythmicity with acrophase in the morning/at noon. FT4, IGF-1 and IL-2 variation did not show circadian rhythmicity. In lung cancer patients cortisol, TRH, TSH and GH serum level and all the lymphocyte subsubsets variation (except for CD4) showed loss of circadian rhythmicity. MESOR of cortisol, TRH, GH, IL-2 and CD16 was increased, whereas MESOR of TSH, IGF-1, CD8, CD8bright, TcRδ1 and δTcS1 was decreased in cancer patients. The melatonin/cortisol mean nocturnal level ratio was decreased in cancer patients.ConclusionThe altered secretion and loss of circadian rhythmicity of many studied factors observed in the subjects suffering from neoplastic disease may be expression of gradual alteration of the integrated function of the neuro-immune-endocrine system

Effect of ghrelin and metoclopramide on prolactin secretion in normal women

Administration of ghrelin to women stimulates the secretion of PRL but the mechanism is not known. The aim of the study was to investigate the effect of the dopamine receptor blocker, metoclopramide, on ghrelin-induced PRL release. Ten healthy normally cycling women were studied in the midluteal phase of 4 menstrual cycles. A single dose of normal saline (cycle 1), ghrelin (1 μg/kg) (cycle 2), metoclopramide (20 mg) (cycle 3), and ghrelin plus metoclopramide (cycle 4) was given to the women iv. Blood samples in relation to the iv injection (time 0) were taken at -15, 0, 15, 30, 45, 60, 75, 90, and 120 min. The response of PRL and GH was assessed. Following ghrelin administration (cycles 2 and 4), plasma ghrelin and serum PRL and GH levels increased rapidly, peaking at 30 min (p<0.001). PRL was also increased after the injection of metoclopramide (p<0.001, cycle 3), but the increase was much greater than after the administration of ghrelin. The combination of ghrelin and metoclopramide stimulated PRL secretion to the same extent with metoclopramide alone. No changes in GH and PRL levels were seen after saline injection. These results demonstrate that the stimulating effect of ghrelin on PRL secretion is not additive with that of metoclopramide, although a dose range study might provide further information.

Arginine and Ornithine Supplementation Increases Growth Hormone and Insulin-Like Growth Factor-1 Serum Levels After Heavy-Resistance Exercise in Strength-Trained Athletes

This placebo-controlled double-blind study was designed to investigate the effect of arginine and ornithine (arg and orn) supplementation during 3-week heavy-resistance training on serum growth hormone/insulin-like growth factor-1/insulin-like growth factor-binding protein 3 (GH/IGF-1/IGFBP-3), testosterone, cortisol, and insulin levels in experienced strength-trained athletes. The subjects were randomly divided between a placebo group (n = 8) and the l-Arg/l-Orn-supplemented group (n = 9), and performed pre and posttraining standard exercise tests with the same absolute load, which consisted of the same exercise schedule as that applied in the training process. Fasting blood samples were obtained at rest, 2 minutes after the cessation of the strength exercise protocol, and after 1 hour of recovery. The resting concentrations of the investigated hormones and IGFBP-3 did not differ significantly between the study groups. In response to exercise test, all the hormones were elevated (p < 0.05) at both time points. Significant increases (p < 0.05) were observed in both GH and IGF-1 serum levels after arg and orn supplementation at both time points, whereas a significant decrease was seen in IGFBP-3 protein during the recovery period. Because there was no between-group difference in the remaining hormone levels, it appears that the GH/IGF-1/IGFBP-3 complex may be the major player in muscle tissue response to short-term resistance training after arg and orn supplementation.