RESUMEN
We describe a patient affected by PD with a rapid progression of cognitive decline. This case could suggest the coexistence of many neurodegenerative diseases, which is a common condition in older patients. We propose an hypothetical trajectory of the cognitive impairment usually associated with motor symptoms in the later phase of Parkinsonian patients. The trajectory is almost linear in classical Parkinson's disease dementia (PDD), while a constant acceleration of the cognitive decline with a subsequent change of the slope of the direction could suggest the coexistence of PD with other neurodegenerative disease. Finally, if the cognitive decline in PD is comparable to a "stepped" decline, vascular lesions could be the cause of the change of the slope. This case could suggest to request an autopsy in all cases of unexplained PDD, for better understanding the mixture of non-motor symptoms in PD.
Asunto(s)
Encéfalo/patología , Enfermedad de Parkinson/patología , Anciano , Anciano de 80 o más Años , Autopsia , Trastornos del Conocimiento/patología , Demencia/patología , Femenino , Humanos , MasculinoRESUMEN
Classic male hypogonadism is associated with known adverse effects including decreased libido, erectile dysfunction, osteoporosis, and changes in body composition. Recently, we have come to appreciate that reduction in serum testosterone (T) levels resulting from aging or chronic disease or androgen deprivation therapy (ADT) have consequences similar to those seen in classic male hypogonadism which include increased fat mass, decreased lean body mass, decreased muscle strength, and sexual dysfunction. These data suggest that low T levels may represent a newly recognized cardiometabolic risk factor. Therefore, we carried out a careful review of the literature, focusing on major turning points of research and studies which gave more important and controversial contribution to the cardiovascular role of T. Observational studies and clinical trials investigating the relationship between T levels and cardiovascular disease and mortality were identified byMedline search. The results were synthesized, tabulated, and interpreted. The aim of this review is to discuss the association between low T levels and adverse metabolic profile such as insulin resistance, metabolic syndrome, and diabetes. We will also investigate the potential mechanisms by which male hypogonadism, especially age related or induced by ADT, may increase cardio-metabolic risk. Finally we will detail the emerging relationship between low T and mortality in men addressing also the reverse hypothesis that low T has a protective role by turning off T-dependent functions.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/mortalidad , Hipogonadismo/complicaciones , Testosterona/deficiencia , Adulto , Enfermedades Cardiovasculares/diagnóstico , Humanos , Hipogonadismo/sangre , Masculino , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Optimal nutritional and hormonal statuses are determinants of successful ageing. The age associated decline in anabolic hormones such as testosterone and insulin-like growth factor 1 (IGF-1) is a strong predictor of metabolic syndrome, diabetes and mortality in older men. Studies have shown that magnesium intake affects the secretion of total IGF-1 and increase testosterone bioactivity. This observation suggests that magnesium can be a modulator of the anabolic/catabolic equilibrium disrupted in the elderly people. However, the relationship between magnesium and anabolic hormones in men has not been investigated. We evaluated 399 ≥65-year-old men of CHIANTI in a study population representative of two municipalities of Tuscany (Italy) with complete data on testosterone, total IGF-1, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEAS) and serum magnesium levels. Linear regression models were used to test the relationship between magnesium and testosterone and IGF-1. Mean age of the population was 74.18 ± 6.43 (years ± SD, age range 65.2-92.4). After adjusting for age, magnesium was positively associated with total testosterone (ß ± SE, 34.9 ± 10.3; p = 0.001) and with total IGF-1 (ß ± SE, 15.9 ± 4.8; p = 0.001). After further adjustment for body mass index (BMI), log (IL-6), log (DHEAS), log (SHBG), log (insulin), total IGF-1, grip strength, Parkinson's disease and chronic heart failure, the relationship between magnesium and total testosterone remained strong and highly significant (ß ± SE, 48.72 ± 12.61; p = 0.001). In the multivariate analysis adjusted for age, BMI, log (IL-6), liver function, energy intake, log (insulin), log (DHEAS), selenium, magnesium levels were also still significantly associated with IGF-1 (ß ± SE, 16.43 ± 4.90; p = 0.001) and remained significant after adjusting for total testosterone (ß ± SE, 14.4 ± 4.9; p = 0.01). In a cohort of older men, magnesium levels are strongly and independently associated with the anabolic hormones testosterone and IGF-1.
Asunto(s)
Anabolizantes/sangre , Hormonas Esteroides Gonadales/sangre , Magnesio/sangre , Anciano , Humanos , Italia , MasculinoRESUMEN
SHBG is a major carrier of androgens. In men, SHBG levels increase with age, while in women data are scant. There is evidence that body mass index (BMI) and fasting insulin influence SHBG concentration. Since low SHBG levels are predictors of insulin resistance and diabetes, understanding the relationship of SHBG with age, insulin, and BMI is important to gain insight into the role of SHBG as a cardiovascular risk factor in women. Differences in SHBG across adult life span and their relationship with insulin and BMI were evaluated in a representative cohort of 616 Italian women free of diabetes and not on hormone replacement therapy enrolled in the InCHIANTI Study. The relationship of SHBG with age, BMI, and fasting insulin levels was analyzed using linear regression and by loess smoother. Serum SHBG levels showed a U-shaped trajectory with age, declining from the 2nd to the 6th decade of life and increasing after the 6th decade (p<0.0001). Age-related trends for BMI and fasting insulin mirrored the trend observed for SHBG. After adjusting for fasting insulin, the relationship between log (SHBG) and age square was attenuated (beta coefficient from 0.00044 to 0.00039) and was further reduced after adjustment for BMI (from 0.00039 to 0.00028). SHBG levels show an age-related U-shaped trajectory. These changes mirror the age-related changes in BMI and fasting insulin, suggesting that BMI and insulin negatively influence SHBG concentration.
Asunto(s)
Envejecimiento/fisiología , Índice de Masa Corporal , Insulina/sangre , Globulina de Unión a Hormona Sexual/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Ayuno , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , Adulto JovenRESUMEN
PURPOSE OF THE STUDY: In a population-based sample of older persons, we studied the relationship between tibial bone density and geometry and factors potentially affecting osteoporosis. METHODS: Of the 1260 participants aged 65 years or older eligible for the InCHIANTI study, 1155 received an interview and 915 (79.2%) had complete data on tibial QCT scans and other variables used in the analysis presented here. The final study population included 807 persons (372 men and 435 women, age range 65-96 years) after exclusion of participants affected by bone diseases or treated with drugs that interfere with bone metabolism. RESULTS: In both sexes, calf cross-sectional muscle area (CSMA) was significantly and independently associated with total bone cross-sectional area (tCSA) and cortical bone cross-sectional area (cCSA) but not with trabecular or cortical volumetric bone mineral density (vBMD). Bioavailable testosterone (Bio-T) was independently associated with both trabecular and cortical vBMD in both sexes. In women, independently of confounders, 25(OH)-vitamin D was positively associated with tCSA and cortical vBMD, while PTH was negatively associated with cortical vBMD. IL-1 beta was negatively correlated with cortical vBMD in women, while TNF-alpha was associated with enhanced bone geometrical adaptation in men. CONCLUSIONS: Physiological parameters that are generically considered risk factors for osteoporosis were associated with specific bone parameters assessed by tibial QCT. Factors known to be associated with increased bone reabsorption, such as 25(OH)-vitamin D, PTH and Bio-T, affected mainly volumetric BMD, while factors associated with bone mechanical stimulation, such as CSMA, affected primarily bone geometry. Our results also suggested that pro-inflammatory cytokines might be considered as markers of bone resorption.
Asunto(s)
Densidad Ósea/fisiología , Tibia/patología , Anciano , Anciano de 80 o más Años , Fenómenos Biomecánicos , Resorción Ósea/sangre , Resorción Ósea/patología , Resorción Ósea/fisiopatología , Calcifediol/sangre , Registros de Dieta , Femenino , Humanos , Interleucina-1beta/sangre , Interleucina-6/sangre , Masculino , Osteoporosis/sangre , Osteoporosis/patología , Osteoporosis/fisiopatología , Factores de Riesgo , Factores Sexuales , Encuestas y Cuestionarios , Tibia/metabolismo , Tibia/fisiopatología , Tomografía Computarizada por Rayos X/métodos , Factor de Necrosis Tumoral alfa/sangreRESUMEN
The ability of ovine corticotropin-releasing factor (CRF) to stimulate both ACTH release and intracellular cAMP accumulation is rapidly and reversibly desensitized when rat anterior pituitary cells are cultured in the absence of added glucocorticoids. Since this desensitization has not been readily apparent in vivo, where initial CRF exposure results in high levels of ambient glucocorticoids, we examined the effect of glucocorticoids on the desensitization process in vitro. Rat anterior pituitary cells were cultured for 3-5 days in the absence of added steroid hormones. Dexamethasone was then added to some culture wells 24 h before the desensitization experiment began. Desensitization of CRF was achieved by preincubating the cells for 4 h with varying concentrations (10(-11)-10(-7) M) of ovine CRF, washing the cells with medium alone, and then reexposing the cells to CRF. In the absence of glucocorticoid, the ED50 for CRF desensitization (the preincubation dose causing 50% desensitization of subsequent ACTH release) was 3 X 10(-10) M, but cells that had been preexposed to dexamethasone desensitized less readily. With concentrations of dexamethasone of 10(-8) M or greater, no desensitization occurred. When cells were incubated in the absence of added glucocorticoids, CRF-stimulated intracellular cAMP accumulation was diminished by prior exposure to CRF. No decrease in intracellular cAMP accumulation was seen in those cells that had been preincubated with dexamethasone, however. Similar changes in CRF desensitization of ACTH release were observed when cells were incubated with corticosterone, but not with 10(-8) M testosterone, progesterone, aldosterone, or estradiol. These data demonstrate that glucocorticoids profoundly alter the development of CRF desensitization in vitro and suggest that high ambient glucocorticoid concentrations prevent the development of substantial CRF desensitization in vivo.
Asunto(s)
Hormona Liberadora de Corticotropina/farmacología , Dexametasona/farmacología , Adenohipófisis/metabolismo , Hormona Adrenocorticotrópica/metabolismo , Animales , Células Cultivadas , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos , Masculino , Adenohipófisis/efectos de los fármacos , Ratas , Ratas EndogámicasRESUMEN
Preincubation of rat pituitary cells in primary culture with rat GH-releasing factor (rGRF) resulted in substantial desensitization to subsequent GRF stimulation. rGRF-directed GH release and intracellular cAMP accumulation decreased in the desensitized cells. Whereas prior treatment of rat pituitary cells caused partial depletion of intracellular GH levels, diminished cellular reserves could not entirely account for the decreased GH release. Cells that had been preexposed to 10 nM rGRF for 4 h demonstrated at 30-50% depletion of intracellular GH; subsequent stimulation of those cells with 10 nM rGRF elicited GH release which was only 5% of that seen in cells that were not desensitized [control, 112 +/- 3.2 ng/well (+/- SEM); GRF-stimulated, 435 +/- 32 ng/well; GRF-pretreated, control, 63 +/- 3 ng/well, GRF-pretreated, GRF-stimulated, 73 +/- 3.4 ng/well]. Despite the marked depletion of cellular GH stores and the greatly diminished rGRF-stimulated GH release in cells that had been preexposed to rGRF, both forskolin and (Bu)2cAMP were able to induce a 2-fold stimulation of GH release. Incubation of the rGRF-pretreated cells with fresh medium which lacked rGRF resulted in gradual recovery of the ability of rGRF to stimulate GH release without complete reconstitution of the intracellular GH stores. These results indicate that exposure of rat pituitary cells to rGRF results in 1) partial depletion of intracellular GH stores; 2) a diminished ability of a subsequent rGRF challenge to elicit GH secretion and intracellular cAMP accumulation, and 3) a sustained ability of forskolin and (Bu)2cAMP to stimulate GH release, indicating that rGRF desensitization occurs in vitro.
Asunto(s)
Hormona Liberadora de Hormona del Crecimiento/fisiología , Adenohipófisis/fisiología , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Hormona del Crecimiento/metabolismo , Hormona Liberadora de Hormona del Crecimiento/farmacología , Masculino , Adenohipófisis/citología , Adenohipófisis/efectos de los fármacos , Ratas , Ratas Endogámicas , Factores de TiempoRESUMEN
The pattern of GH secretion undergoes substantial changes in the aging rat, resulting in decreased daily secretion of GH. In this study, the pituitary responsiveness to GH-releasing factor (GRF) was examined in young (2- to 5-month old) and aging (14- to 18-month old) male rats. In vivo studies were performed under sodium pentobarbital anesthesia. After injection of 250 ng GRF/100 g BW, young rats experienced more GH secretion [peak level, 544.5 +/- 209.5 (+/- SEM) ng/ml] than did 18-month-old rats (89.3 +/- 13.7 ng/ml). To investigate the locus of this insensitivity to GRF, anterior pituitary cells from young and aging rats were dispersed and placed in primary culture. While basal GH secretion from the cultured pituitary cells was similar in the two groups (49.7 +/- 3.5 vs. 47.8 +/- 2.7 ng/ml X 4 h for the 2- and 18-month old rats, respectively), the GH-releasing ability of GRF was partially but significantly impaired in cells derived from both 14- and 18-month old rats; 100 nM GRF stimulated the release of 96.7 +/- 1.8 ng/ml X 4 h in the 18-month old rats as opposed to 115.0 +/- 6.0 (P less than 0.05) ng/ml X 4 h in the 2-month-old rats. Since GRF stimulates GH release through the activation of adenylate cyclase, intracellular cAMP levels were measured in the cultured pituitary cells. GRF stimulated 65% less intracellular cAMP accumulation in the 18-month-old rats. In 14-month-old rats, the ability of forskolin and (Bu)2 cAMP to release GH was impaired, while phorbol ester-elicited GH secretion was unchanged. In conclusion, the GH response to GRF is blunted in aging rats. While much of the insensitivity to GRF may be mediated by the increased somatostatin tone reported in aging rats, a diminished pituitary cAMP response to GRF may also be an important etiological factor in the hyposomatotropinemia of the aging male rat.
Asunto(s)
Envejecimiento , Hormona Liberadora de Hormona del Crecimiento/farmacología , Hormona del Crecimiento/metabolismo , Adenohipófisis/metabolismo , Animales , Bucladesina/farmacología , Células Cultivadas , Colforsina/farmacología , AMP Cíclico/metabolismo , AMP Cíclico/farmacología , Cinética , Masculino , Adenohipófisis/efectos de los fármacos , Proteína Quinasa C/metabolismo , Ratas , Ratas Endogámicas , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
Hypothalamic-pituitary-end-organ axes are frequently controlled by long loop negative feedback homeostatic mechanisms. Insulin-like growth factor I (IGF-I), IGF-II, and insulin receptors have recently been described in normal and neoplastic rat and acromegalic human pituitary cells, a finding which suggests the possibility that somatomedins might exert feedback at the level of the anterior pituitary. To study the kinetics of this feedback response, we used perifused dispersed rat anterior pituitary cells to learn if somatomedins or insulin could inhibit GH-releasing hormone (GHRH)-stimulated GH secretion. Cells were exposed to hourly boluses of 1 nM GHRH with or without varying doses of IGF or insulin. IGF-I inhibited GHRH-elicited GH release with an IC50 of 6.5 nM; maximal inhibition (approximately 67%) was achieved with 10 nM IGF-I. IGF-II was a less potent hormone, with 10 nM inhibiting about 30% of GHRH-stimulated GH release. Slight inhibition of stimulated GH release (less than 15%) was seen when cells were treated with insulin, but only when doses of insulin of 10 nM or more were used. In conclusion, nanomolar concentrations of IGF-I and IGF-II inhibited GHRH-elicited GH release from perifused rat pituitary cells in a dose-dependent manner; and insulin was not an effective inhibitor of stimulated GH release at physiological peptide concentrations. In conjunction with our previous findings that the concentrations of IGF-I and IGF-II receptors greatly exceed that of insulin receptors on normal rat pituitary cells, we hypothesize that the GH-inhibiting action of high dose insulin is mediated through an IGF receptor.
Asunto(s)
Hormona Liberadora de Hormona del Crecimiento/farmacología , Hormona del Crecimiento/metabolismo , Factor II del Crecimiento Similar a la Insulina/farmacología , Factor I del Crecimiento Similar a la Insulina/farmacología , Adenohipófisis/metabolismo , Somatomedinas/farmacología , Animales , Retroalimentación , Insulina/farmacología , Masculino , Perfusión , Adenohipófisis/efectos de los fármacos , Ratas , Ratas EndogámicasRESUMEN
Rat pituitary GH3 tumor cells express GH and insulin-like growth factor-I (IGF-I) mRNAs and possess specific IGF-I and IGF-II receptors which mediate the inhibitory effect of IGF on GH secretion. T3 increases the rate of cell replication and GH gene transcription, and causes an increase in IGF-I binding to cell membranes. Since the IGFs circulate in association with specific binding proteins (IGFBPs) that appear to modulate the access of IGFs to their receptors, we have investigated the effect of T3 treatment on the expression of IGFBPs in GH3 cells. Cells were grown in serum-free defined medium, and IGFBP secretion was determined by Western ligand blotting of conditioned medium after the addition of T3 and/or various peptides for 48-72 h. The conditioned medium of GH3 cells revealed a complex of bands migrating at 40-45 Mr, a pattern typical of rat (r) IGFBP-3. T3 treatment resulted in an increase in rIGFBP-3. IGF-I, IGF-II, and insulin did not alter rIGFBP-3 levels. After concentrating (10-fold) conditioned medium samples, two additional bands at 24K and 28K mol wt were also seen. These bands corresponded in size to rIGFBP-4 (24K) and its glycosylated form (28K). The mRNAs for both rIGFBP-3 and rIGFBP-4 were present in GH3 cells; T3 treatment increased steady state levels of rIGFBP-3 mRNA, but did not affect BP-4 mRNA levels. To learn whether the increased expression of IGFBPs could be responsible for the increased IGF-I binding seen after T3 treatment, [125I]IGF-I was cross-linked to GH3 membranes, and the proteins were separated on a 5-15% gradient sodium dodecyl sulfate-polyacrylamide gel under reducing conditions. T3 treatment induced a large increase in the intensity of bands migrating at 135K and 280K, representing the alpha-subunit of the IGF-I receptor and an incompletely reduced alpha-alpha-dimer, respectively. No membrane-associated IGFBPs were detected. In conclusion, GH3 cells express two IGFBPs, rIGFBP-3 and rIGFBP-4, which are differentially regulated by T3. The increased binding of IGF-I to GH3 cell membranes after T3 treatment indicates that thyroid hormone induces an up-regulation of IGF-I receptors and that the increased IGF-I binding to GH3 membranes is not due to increased expression of membrane-associated IGFBPs.
Asunto(s)
Proteínas Portadoras/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patología , Hormonas Tiroideas/farmacología , Animales , Northern Blotting , Proteínas Portadoras/análisis , Densitometría , Electroforesis en Gel de Poliacrilamida , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina , Neoplasias Hipofisarias/química , ARN Mensajero/análisis , ARN Mensajero/genética , Ratas , Triyodotironina/farmacología , Células Tumorales Cultivadas/química , Células Tumorales Cultivadas/patología , Células Tumorales Cultivadas/ultraestructuraRESUMEN
The isolation and hormonal regulation of two low molecular weight insulin-like growth factor binding proteins (IGFBPs) present in the conditioned medium (CM) of the rat neuroblastoma cell line B104 cells has been performed. IGFBPs were purified by ZnSO4 precipitation, insulin-like growth factor-I 1IGF-I) affinity chromatography, and reverse phase HPLC. Final isolation and N-terminal analysis was accomplished by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, electroblotting to polyvinylidene difluoride membranes, and sequencing of the bound proteins. Two IGFBPs, with apparent Mr of 28K and 24K were coisolated and sequenced. Both proteins had identical N-terminal sequences and appear to be two forms of IGFBP-4. Treatment of the IGFBPs with endoglycosidase-F caused a shift in the apparent Mr of the 28K IGFBP to 24K. However, there was no change in the apparent Mr of the 24K IGFBP. The data from this study suggest that the IGFBP-4 exists as both a glycosylated and nonglycosylated protein. Treatment of B104 cells with IGF-I increased the expression of both the 24K and 28K IGFBPs and also resulted in the appearance of IGFBP-3 and an unknown IGFBP at 29K. When added to subconfluent cells, IGF-I was also mitogenic in B104 cells. Similar to IGF-I, IGF-II treatment increased cell number and resulted in the appearance of IGFBP-3 and the 29K IGFBP. However, IGF-II treatment resulted in a significant decrease (approximately 50%) in the 24K IGFBP and also decreased the 28K IGFBP. This decrease in the expression of the 24K and 28K IGFBPs was dose-dependent and was blocked by addition of IGF-I to the cells. When an IGF-II receptor antibody was added to the cells it mimicked the effects of IGF-II on B104 cells, suggesting that the inhibitory effects of IGF-II are mediated through the type II IGF receptor. Although both IGF-I and IGF-II affected the amount of the 24K IGFBP in the CM, neither peptide affected the expression of the messenger RNA for the 24K IGFBP. In conclusion, we have isolated two IGFBPs from the CM of B104 cells. Both the 24K and 28K IGFBPs appear to be isoforms of the same protein, and sequence data suggest these proteins are two forms of IGFBP-4. IGF-I increases the expression of both of these IGFBPs, whereas IGF-II decreases their expression.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Proteínas Portadoras/metabolismo , Factor II del Crecimiento Similar a la Insulina/farmacología , Factor I del Crecimiento Similar a la Insulina/farmacología , Neuroblastoma/metabolismo , Secuencia de Aminoácidos , Animales , Western Blotting , Proteínas Portadoras/aislamiento & purificación , Medios de Cultivo , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina , Ligandos , Datos de Secuencia Molecular , Neuroblastoma/patología , Somatomedinas/metabolismo , Células Tumorales CultivadasRESUMEN
GH secretion is stimulated by hypothalamic GH-releasing factor (GHRH) and inhibited by somatostatin. Since GH induces the production of insulin-like growth factors (IGF) in liver and other tissues, it is of interest to learn whether IGF alters GH release through long loop feedback inhibition. Pituitary adenomas which had been removed from six acromegalic patients were processed for dispersed cell cultures and/or cell membrane preparations. Binding studies using 125I-labeled IGF-I, IGF-II, and insulin revealed specific hormone binding for each ligand to cell membranes derived from four somatotropinomas. A partially purified somatomedin preparation inhibited basal and/or GHRH-stimulated GH release from cultured pituitary cells derived from three of four adenomas; there was no effect of somatomedin in one tumor. In a single tumor, insulin also partially inhibited GHRH-stimulated GH release. Additionally, in one nonadenomatous pituitary removed from a patient with diabetes mellitus, insulin and somatomedin inhibited GHRH-stimulated GH release, and insulin inhibited basal GH secretion. These results indicate that specific cell membrane receptors for somatomedin peptides and insulin may be found on cell membranes from GH-secreting tumors, and that somatomedins and insulin can inhibit GH release in cultured human somatotropinoma cells. Thus, these data suggest that somatomedins may exert feedback inhibition of GH secretion in some patients with acromegaly.
Asunto(s)
Adenoma/metabolismo , Hormona del Crecimiento/metabolismo , Neoplasias Hipofisarias/metabolismo , Acromegalia/metabolismo , Sitios de Unión , Células Cultivadas , Retinopatía Diabética/metabolismo , Humanos , Insulina/farmacología , Péptidos/farmacología , Receptor de Insulina/metabolismo , Somatomedinas/farmacologíaRESUMEN
To evaluate GH pituitary responsivity to nonphysiological stimuli in insulin-dependent (type I) diabetes, a TRH test (200-micrograms iv bolus) was carried out in 31 type I diabetics (16 females and 15 males). TRH was capable of inducing GH responses in most of the studied patients, with a striking difference between the sexes; responses were documented in 7 of 15 males and in 13 of 16 females. Linear regression analyses of the results showed a positive correlation between basal values and peak levels of GH and a negative correlation between GH peaks and the ages of the patients. No correlation was found between GH values (basal and peak levels) and blood glucose levels or duration of disease. In conclusion, our results support the observation that GH secretion in diabetes is abnormal. TRH induces GH secretory responses, especially when GH basal values are elevated and in female patients. Pituitary GH responsiveness to TRH shows a progressive decline with advancing age unrelated to the duration of the disease or the presence of retinopathy.
Asunto(s)
Diabetes Mellitus Tipo 1/fisiopatología , Hormona del Crecimiento/sangre , Hipófisis/fisiopatología , Hormona Liberadora de Tirotropina , Adolescente , Adulto , Factores de Edad , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Factores de TiempoRESUMEN
The activity of the hypothalamic-GH-insulin-like growth factor (IGF) network declines with age. It has recently been shown that increased cardiovascular mortality occurs in adults with GH deficiency. As hypercholesterolemia is common in GH-deficient adults, and because there is experimental evidence that GH may play a role in regulating plasma cholesterol, we decided to investigate the activity of the GH-IGF axis in an elderly population by measuring serum IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) levels and to study their relationship with blood lipid levels. One hundred and thirty-two elderly subjects, 52 men and 80 women, were studied (age range, 60-91 yr). Men had significantly lower levels of IGFBP-3, high density lipoprotein cholesterol (HDL-C) and apoprotein A1 (ApoA1) compared to the women, whereas IGF-I and IGF-II were only slightly lower. Using linear regression analysis, we observed an inverse relationship of age with IGF-I (r = -0.35; P < 0.001), IGF-II (r = 0.40; P < 0.001), IGFBP-3 (r = 0.52; P < 0.001), body mass index, and lipid levels. Univariate regression analysis showed a strong and positive correlation of both IGF-I and IGFBP-3 with HDL-C and ApoA1. Partial correlation analysis, after adjustment for age and body mass index, showed that IGFBP-3 and IGF-II were still significantly and positively related to HDL-C and ApoA1. Furthermore, a strong association was documented among IGF-I, IGF-II, and IGFBP-3. These data demonstrate that even in an elderly population, further aging is accompanied by a progressive decline in circulating IGF-I, IGF-II, and IGFBP-3, suggesting a continuing diminution of the GH-IGF axis throughout aging. Moreover, the strong correlation between HDL-C and an index of GH secretion, such as IGFBP-3, suggests that GH might play an important role in lipid metabolism in healthy elderly subjects.
Asunto(s)
Envejecimiento/sangre , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor II del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Lípidos/sangre , Anciano , Anciano de 80 o más Años , Apolipoproteína A-I/metabolismo , Índice de Masa Corporal , HDL-Colesterol/sangre , Femenino , Hormona de Crecimiento Humana/fisiología , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , Caracteres Sexuales , Triglicéridos/sangreRESUMEN
A young woman with acromegaly and Zollinger-Ellison syndrome associated with a GH-releasing factor (GRF)- and gastrin-secreting metastatic islet cell carcinoma was studied by means of specific antisera which recognize various regions of the GRF molecule. Using specific immunohistochemical techniques, the tumor cells were shown to contain GRF, gastrin, and gastrin-releasing peptide, but not GH. During a 4-h period, plasma GRF levels averaged 5.6 +/- 1.4 ng/ml (+/- SD), while GH levels averaged 148 +/- 71 ng/ml. GH secretion was pulsatile and increased after TRH administration. GRF RIAs may be useful in establishing the diagnosis of acromegaly secondary to the ectopic secretion of GRF.
Asunto(s)
Acromegalia/etiología , Adenoma de Células de los Islotes Pancreáticos/complicaciones , Hormona Liberadora de Hormona del Crecimiento/análisis , Neoplasias Pancreáticas/complicaciones , Síndromes Paraneoplásicos Endocrinos/etiología , Síndrome de Zollinger-Ellison/etiología , Acromegalia/metabolismo , Adenoma de Células de los Islotes Pancreáticos/metabolismo , Adulto , Femenino , Gastrinas/metabolismo , Hormona del Crecimiento/metabolismo , Hormona Liberadora de Hormona del Crecimiento/sangre , Humanos , Neoplasias Pancreáticas/metabolismo , Síndromes Paraneoplásicos Endocrinos/metabolismo , Síndrome de Zollinger-Ellison/metabolismoRESUMEN
The function of the growth hormone-insulin-like growth factor I (GH-IGF-I) axis is reduced in aging, although the secretory capacity of somatotrope cells is preserved. Previous studies have suggested that continuous administration of GH-releasing peptides (GHRPs) results in homologous desensitization to the GH-releasing effect of the peptides. In the present study we have studied whether healthy elderly subjects would remain responsive to short-term, intermittent treatment with Hexarelin (HEX), a GHRP, and whether this treatment would result in an increase in serum IGF-I. In study I, the effect of an 8-day treatment with intranasal administration of 1.25 mg (about 18 micrograms/kg) t.i.d. HEX on the acute GH response to the hexapeptide and on serum IGF-I, IGF binding protein 3 (IGFBP-3), prolactin and cortisol levels was studied in seven elderly subjects (four males and three females, aged 67-80 years). In study II, the same parameters were studied before and after a 15-day treatment with oral administration of 20 mg (about 300 micrograms/kg) t.i.d. HEX in seven elderly women (aged 63-80 years). The GH response to the intranasal HEX administration was not significantly higher than that induced by 1 microgram/kg iv GHRH (229.4 +/- 35.9 vs 145.8 +/- 26.9 micrograms.l-1.h-1) and was maintained with a trend towards increase after an 8-day treatment with the peptide (342.5 +/- 199.3 micrograms.l-1.h-1). On the other hand, HEX treatment did not significantly modify IGF-I (138.7 +/- 11.1 vs 122.4 +/- 14.1 micrograms/l) but increased IGFBP-3 levels (2.4 +/- 0.2 vs 1.6 +/- 0.2 mg/l, p < 0.02). The GH response to the oral HEX administration was also not significantly higher than that to iv GHRH (257.6 +/- 72.0 vs 179.0 +/- 42.8 micrograms.l-1.h-1) and did not change after a 15-day treatment with the peptide (237.8 +/- 42.8 micrograms.l-1.h-1). Both IGF-I and IGFBP-3 levels were slightly but significantly increased by oral HEX treatment (156.0 +/- 10.7 vs 141.6 +/- 13.6 micrograms/l, p < 0.03, 3.4 +/- 0.2 vs 3.1 +/- 0.2 mg/l, p < 0.03, respectively). Neither intranasal nor oral HEX treatment modified PRL or cortisol levels and did not induce any side effect. In conclusion, these results indicate that chronic but intermittent treatment with HEX, administered either by intranasal or oral route, does not desensitize the GH response to the peptide. Moreover, after HEX treatment a trend towards increase was shown for IGF-I and IGFBP-3 levels. Thus, our findings strengthen the hypothesis that prolonged treatment with HEX may restore the reduced GH release in aging.
Asunto(s)
Envejecimiento/fisiología , Hormona de Crecimiento Humana/fisiología , Oligopéptidos/administración & dosificación , Administración Intranasal , Administración Oral , Anciano , Anciano de 80 o más Años , Femenino , Hormona de Crecimiento Humana/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , Oligopéptidos/farmacología , Factores de TiempoRESUMEN
It is well known that both spontaneous and growth hormone-releasing hormone (GHRH)-stimulated GH secretion undergo an age-related decrease; in addition, there is supportive evidence that the GH hyposecretory state of aging is of hypothalamic origin. The aims of the study in 35 normal elderly subjects (20 males and 15 females aged 65-89 years) were to verify whether the low somatotrope responsiveness to GHRH (1 microgram/kg) can be primed by a daily GHRH treatment and whether the potentiating effect of both high intravenous (0.5 g/kg) and low oral (8 g) doses of arginine (ARG) on GH response to GHRH is maintained with time. In group A (N = 14) the GH response to GHRH on day 1 (AUC: 373.5 +/- 78.5 micrograms.l-1.h-1) was unchanged after 7 (3720 +/- 38 micrograms.l-1.h-1) and 15 days (377.9 +/- 63.8 micrograms.l-1.h-1) of daily GHRH administration. In group B (N = 6) the GH response to GHRH co-administered with iv ARG on day 1 (1614.2 +/- 146.2 micrograms.l-1.h-1) was higher (p < 0.05) than that of GHRH alone (group A) and persisted unchanged after 7 (1514.7 +/- 366.5 micrograms.l-1.h-1) and 15 days (1631.7 +/- 379.1 micrograms.l-1.h-1) of treatment. In group C (N = 15) the GH response to GHRH co-administered with oral ARG on day 1 (950.6 +/- 219.4 micrograms.l-1.h-1) was higher (p < 0.03) than that of GHRH alone (group A) but lower (p < 0.05) than that to GHRH plus iv ARG (group B).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Envejecimiento/metabolismo , Arginina/farmacología , Hormona Liberadora de Hormona del Crecimiento/farmacología , Hormona del Crecimiento/metabolismo , Administración Oral , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Hormona del Crecimiento/sangre , Hormona Liberadora de Hormona del Crecimiento/efectos adversos , Humanos , Inyecciones Intravenosas , Masculino , Valores de Referencia , Factores de TiempoRESUMEN
Growth hormone (GH) secretion declines during normal aging, resulting in lower serum insulin-like growth factor (IGF)-I levels. It has been proposed that many of the catabolic changes seen in normal aging, including osteoporosis and muscle atrophy, are in part caused by the decreased action of the GH-IGF-I axis. In addition, patients with GH deficiency have increased overall cardiovascular mortality. Several investigators have initiated GH treatment for elderly patients with relative hyposomatotropinemia. Initial reports suggest that GH can increase muscle mass, improve exercise tolerance, increase REM sleep and cause an enhanced sense of well-being. The basis for neuropsychiatric changes during GH therapy may be due to a direct CNS action of GH itself, to the increased IGF-I secretion which GH elicits, or to enhanced functioning of peripheral organ systems. Long-term studies will determine whether GH or IGF-I can exert a neurotrophic action in the aging brain.
Asunto(s)
Envejecimiento/efectos de los fármacos , Encéfalo/efectos de los fármacos , Hormona del Crecimiento/uso terapéutico , Adulto , Anciano , Envejecimiento/fisiología , Composición Corporal/efectos de los fármacos , Composición Corporal/fisiología , Encéfalo/fisiología , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Hormona del Crecimiento/efectos adversos , Hormona del Crecimiento/fisiología , Humanos , Factor I del Crecimiento Similar a la Insulina/fisiología , Persona de Mediana EdadRESUMEN
The insulin-like growth factors (IGF)-I and IGF-II are peptides with structural homology to insulin and potent mitogenic and anabolic actions in vitro and in vivo. IGF-I levels are growth hormone (GH)-dependent and vary strikingly with age. IGF-I levels are typically low in infancy and childhood, increase dramatically during puberty, and then gradually decline with advancing age. Whether age-associated changes in GH production or sex steroid secretion, or other unknown factors, cause diminished IGF production in the elderly remains to be determined. In the brain, IGF-II appears to be the most prevalent IGF, but a truncated form of IGF-I also has been recognized. IGF actions are mediated by binding to a family of receptors, which includes the insulin receptor, the structurally homologous type I IGF receptor, and the IGF-II/M-6P receptor, all of which are found in the central nervous system. Additionally, the IGFs bind with high affinity to a family of IGF-binding proteins (IGFBPs). Of the six known IGFBPs, IGFBP-2 appears to be the major one in the mammalian brain and is a major component of CSF. Immunoreactive IGFBP-2 has been identified in astrocytes, and its mRNA has been identified in fetal and adult brain and choroid plexus. The IGFBPs transport the IGFs in serum and other body fluids and appear to regulate IGF access to receptors. In vivo regulation of IGFBPs includes tissue-specific proteases, which cleave specific IGFBPs, altering their affinities for IGF peptides.(ABSTRACT TRUNCATED AT 250 WORDS)