RESUMO
CONTEXT: Concern exists in the literature that the long-term use of ergot-derived dopamine agonist drugs for the treatment of hyperprolactinemia may be associated with clinically significant valvular heart disease. OBJECTIVE: The aim of the study was to determine the prevalence of valvular heart abnormalities in patients taking dopamine agonists as treatment for lactotrope pituitary tumors and to explore any associations with the cumulative dose of drug used. DESIGN: A cross-sectional echocardiographic study was performed in a large group of patients who were receiving dopamine agonist therapy for hyperprolactinemia. Studies were performed in accordance with the British Society of Echocardiography minimum dataset for a standard adult transthoracic echocardiogram. Poisson regression was used to calculate relative risks according to quartiles of dopamine agonist cumulative dose using the lowest cumulative dose quartile as the reference group. SETTING: Twenty-eight centers of secondary/tertiary endocrine care across the United Kingdom participated in the study. RESULTS: Data from 747 patients (251 males; median age, 42 y; interquartile range [IQR], 34-52 y) were collected. A total of 601 patients had taken cabergoline alone; 36 had been treated with bromocriptine alone; and 110 had received both drugs at some stage. The median cumulative dose for cabergoline was 152 mg (IQR, 50-348 mg), and for bromocriptine it was 7815 mg (IQR, 1764-20 477 mg). A total of 28 cases of moderate valvular stenosis or regurgitation were observed in 24 (3.2%) patients. No associations were observed between cumulative doses of dopamine agonist used and the age-corrected prevalence of any valvular abnormality. CONCLUSION: This large UK cross-sectional study does not support a clinically concerning association between the use of dopamine agonists for the treatment of hyperprolactinemia and cardiac valvulopathy.
Assuntos
Agonistas de Dopamina/uso terapêutico , Alcaloides de Claviceps/uso terapêutico , Doenças das Valvas Cardíacas/epidemiologia , Hiperprolactinemia/tratamento farmacológico , Hiperprolactinemia/epidemiologia , Adulto , Cabergolina , Estudos Transversais , Ecocardiografia , Ergolinas/uso terapêutico , Feminino , Doenças das Valvas Cardíacas/induzido quimicamente , Doenças das Valvas Cardíacas/diagnóstico por imagem , Humanos , Hiperprolactinemia/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Prevalência , Reino Unido/epidemiologiaRESUMO
This report highlights a case of severe hyponatraemia secondary to excessive sweating and salt [corrected] poor fluid consumption and low salt diet in hot conditions. The case was complicated by the presence of marked hypokalaemia caused by secondary hyperaldosteronism confirmed, for the first time, by the presence of grossly elevated serum renin and aldosterone concentrations. With the rise in global temperature affecting even temperate climates doctors, especially in acute and general medicine, may be faced with this condition more often.
Assuntos
Hiponatremia/diagnóstico , Hiponatremia/terapia , Desidratação/complicações , Desidratação/diagnóstico , Desidratação/terapia , Dieta Hipossódica/efeitos adversos , Temperatura Alta/efeitos adversos , Humanos , Hiperaldosteronismo/complicações , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/terapia , Hipopotassemia/complicações , Hipopotassemia/diagnóstico , Hipopotassemia/terapia , Hiponatremia/etiologia , Masculino , Adulto JovemRESUMO
Cranial radiation is routinely used to manage pituitary tumours, craniopharyngiomas, primary brain tumours, tumours of the head and neck and, in the past, for the prophylaxis of intracranial disease in patients with acute lymphoblastic leukaemia. If the hypothalamic-pituitary axis falls within the radiation fields, the patient is at risk of developing hypopituitarism. The effect of radiation is determined by the dose and the time that has elapsed since treatment. Classically, growth hormone (GH) is the most sensitive of the anterior pituitary hormones to irradiation, followed by gonadotrophins, adrenocorticotrophic hormone (ACTH) and thyroid-stimulating hormone (TSH). Low-dose irradiation in prepubertal children can initially cause early or precocious puberty and subsequently gonadotrophin deficiency. Higher doses may cause gonadotrophin deficiency and pubertal delay. The ACTH and TSH axes are relatively resistant to the effects of irradiation, but minor abnormalities may occur. Patients who receive cranial irradiation that affects the hypothalamic-pituitary axis remain at risk of developing multiple hormone deficiencies for many years and require long-term follow-up by an endocrinologist.
Assuntos
Irradiação Craniana/efeitos adversos , Hormônio do Crescimento Humano/deficiência , Hipopituitarismo/etiologia , Hormônio Adrenocorticotrópico/metabolismo , Neoplasias Encefálicas/radioterapia , Gonadotropinas/deficiência , Humanos , Hipotálamo/fisiopatologia , Hipotálamo/efeitos da radiação , Hipófise/fisiopatologia , Hipófise/efeitos da radiação , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Puberdade/efeitos da radiação , Lesões por Radiação/etiologia , Tireotropina/metabolismoRESUMO
OBJECTIVE: Circulating insulin-like growth factor (IGF)-II and IGF binding protein-2 (IGFBP-2) are frequently altered, often in parallel, in numerous pathologies including neoplastic disease but little is known about their normal regulation. This study compared serum IGF-II and IGFBP-2 distributions between acromegalics and a large normal adult population to explore possible determinants. PATIENTS: Sixty acromegalic patients undergoing screening colonoscopy (age range 25-81 years); normative data from 306 healthy adults (age range 20-89 years). MEASUREMENTS: Serum IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were measured in healthy adults and acromegalics. Mean growth hormone (GH) levels were obtained for acromegalic patients. Differences were compared using t-tests (unadjusted) and multiple regression models (adjusted for age and gender). Correlations were expressed as Pearson's coefficient (r). RESULTS: For acromegalic patients, GH was significantly correlated with IGF-I (r = 0.50; P < 0.001) and IGFBP-3 (r = 0.29; P = 0.03) but not IGF-II or IGFBP-2. Contrary to expectations, mean IGF-II and IGFBP-2 levels were significantly raised in the acromegalics compared with normals [adjusted mean difference (95% CI) = 226 (181, 271) microg/l and 305 (200, 410) microg/l, respectively]. Ten acromegalic patients had colorectal neoplasia but their presence did not contribute to the elevations in serum IGF-II and IGFBP-2. The (IGF-I + IGF-II)/IGFBP-3 molar ratios were remarkably constant in both healthy adults and acromegalics, but the relationships of the ligands individually with IGFBP-3 were not linear: as IGFBP-3 increased, IGF-I also increased whereas IGF-II initially increased but then decreased. IGFBP-2 did not correlate with IGF-II, but molar concentration significantly correlated with the IGF-II/IGFBP-3 molar ratio (r = 0.40; P = 0.001). CONCLUSIONS: Serum IGF-II and IGFBP-2 levels were paradoxically elevated in acromegalics, independent of the presence of colorectal neoplasia. The (IGF-I + IGF-II)/IGFBP-3 molar ratio appears to be pivotal in determining IGF-II values, which, in turn, expressed as a ratio of IGFBP-3, is related to IGFBP-2. These observations offer new insights into the regulation of these peptides.
Assuntos
Acromegalia/sangue , Neoplasias Colorretais/sangue , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like II/análise , Acromegalia/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Estudos de Casos e Controles , Neoplasias Colorretais/complicações , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Pessoa de Meia-Idade , Análise de RegressãoRESUMO
In patients with treated acromegaly, improved survival is associated with serum GH concentrations below 2 microgram/L (5 mU/L). A principal aim of therapy in acromegaly is to achieve a GH level less than 2 microgram/L, as such levels are thought to be "safe." However, such GH levels do not always equate with normalization of plasma insulin-like growth factor I (IGF-I), although epidemiological data linking survival or morbidity to IGF-I levels are at present lacking. The aims of this study were 1) to further define the nature of GH release in those acromegalic patients who achieve mean GH concentrations below 2 microgram/L post therapy, 2) to examine the effect of different therapeutic interventions on the 24-h GH profile (surgery alone or radiotherapy), and 3) to determine the relationship between the various characteristics of the 24-h GH profile and IGF-I production in acromegalic subjects who have achieved GH below 2 microgram/L. Spontaneous 24-h GH secretion was measured using both a conventional immunoradiometric assay (limit of detection, 0.4 microgram/L) and an ultrasensitive assay (limit of detection, 0.002 microgram/L). The GH data have been analyzed by several methods: 1) the pulse detection algorithm Cluster, 2) a distribution method for detection of peak [the observed concentration 95%, i.e. the threshold at or below which GH concentrations are assessed to be 95% of the time, as calculated by probability analysis (OC 95%)] and trough (OC, 5%) GH activity, 3) deconvolution analysis, and 4) approximate entropy analysis. GH was sampled every 20 min for 24 h, along with basal IGF-I and IGF-binding protein-3, in 21 treated acromegalic patients with a mean GH below 2 microgram/L [ACR; 9 women and 12 men; median age (range), 49 (31-76) yr] and 16 healthy controls [C; 6 women and 10 men; age, 50 (30-75) yr]. Mean 24-h serum GH concentrations were [median (range)]: ACR, 1.1 (0.04-1.5) microgram/L; C, 0.4 (0.02-3.3) microgram/L (P = 0.28). GH pulse frequency was: ACR, 11 (1-14)/24 h; C, 10 (8-18)/24 h (P = 0.41). In the GH profiles the mean heights of the GH peaks were: ACR, 1.2 (0.05-2.8) microgram/L; C, 0.8 (0.02-5.1) microgram/L (P = 0.91), and the mean GH valley nadirs were: ACR, 0.65 (0.03-1.1) microgram/L; C, 0.09 (0.01-1.8) microgram/L (P < 0.02). The OC 95% was: ACR, 1.0 (0.04-3.8) microgram/L; C, 1.0 (0.02-10) microgram/L (P = 0.65), and the OC 5% was: ACR, 0.09 (0.01-0.6) microgram/L; C, 0.01 (0.001-0.4) microgram/L (P < 0.001). The median IGF-I was: ACR, 227 (100-853) microgram/L; C, 156 (89-342) microgram/L (P < 0.005). Approximate entrophy values were: ACR, 1.06 (0.35-1.45); and C, 0.57 (0.27-1.19); P < 0.05. In the acromegaly group a significant positive correlation was found between IGF-I and the calculated GH secretory burst amplitude in the radiotherapy subset (r = 0.85; P < 0.0005) as well as between IGF-I and both the mean GH valley nadir (r = 0.60; P < 0.004) and the trough (OC 5%) GH activity for the acromegalic patients as a whole (r = 0.55; P < 0.02). We conclude that in treated acromegaly (GH, <2 microgram/L), 1) IGF-I (by approximately 50%) and basal GH secretion (by 5-fold) remain significantly elevated compared with control values despite similar mean 24-h GH concentrations; 2) the calculated GH secretory pulse amplitude, mean GH valley nadir, and OC 5% correlate positively with IGF-I; 3) the greater mean GH valley nadir and OC 5% in acromegalic patients compared with controls may account for the raised IGF-I; and 4) radiotherapy is unlikely to normalize the GH secretory pattern, which underlies the persisting elevated IGF-I levels.
Assuntos
Acromegalia/metabolismo , Acromegalia/terapia , Ritmo Circadiano , Hormônio do Crescimento Humano/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Acromegalia/radioterapia , Acromegalia/cirurgia , Adulto , Idoso , Feminino , Humanos , Ensaio Imunorradiométrico , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Medições Luminescentes , Masculino , Pessoa de Meia-IdadeRESUMO
Due to persistent qualitative abnormalities in GH secretion following treatment, and lack of a sensitive marker of GHD in mid-adult life it is extremely difficult to diagnose GHD in treated acromegalic patients. The diagnosis of GHD in patients with pituitary disease relies on provocative tests of GH reserve. Arginine releases GH by reducing somatostatin inhibition of GH release, whereas GH secretagogues (GHS) affect GH release by direct stimulation of the GHS receptor, though an intact GH releasing hormone (GHRH) axis is a prerequisite. The peak GH response to insulin-induced hypoglycaemia and arginine in acromegalic patients, in whom basal serum GH levels of less than 5 mU/l have been achieved, is greatly diminished in those treated by hypothalamo-pituitary irradiation. We aimed to study the response of successfully treated acromegalic patients to the growth hormone secretagogue hexarelin in view of its different putative mechanism of action, and in addition, to determine whether it has any value in the diagnosis of GH deficiency in this subset of patients. Nineteen acromegalic patients, in whom mean serum GH levels below 5 mU/l have been achieved through treatment, were recruited. Eight of the patients had been treated by surgery alone (Group A) and 11 had received primary or postoperative irradiation (Group B). All patients underwent 20 min blood sampling to provide a 24-h GH profile. Serum IGF-I was measured from a sample drawn between 0900 h and 1000 h. On a second visit arginine 20 g/m2 was infused over 30 min, blood samples were taken before commencing the infusion and at 30-min intervals thereafter for 180 min. At the final visit hexarelin 1.5 mcg/kg was administered as an intravenous bolus at t = 0. Blood was drawn at 15-min intervals from - 30 to 180 min. All patients in group A showed an increment in serum GH following hexarelin (DeltaGHHEX) > 20 mU/l, a normal response to arginine, and a mean 24-h GH > 0.5 mU/l. In group B only 4/11 achieved a DeltaGHHEX > 20 mU/l, 5/11 producing a response of < 2 mU/l. Four of the five patients with a DeltaGHHEX < 2 mU/l were also demonstrated to have a mean 24-h GH of < 0.5 mU/l and serum IGF-I SDS < + 0.5. All four patients in Group B who achieved a DeltaGHHEX > 20 mU/l, were observed to show an absent or minimal GH response to arginine. Despite loss of the GH response to arginine, the DeltaGHHEX is retained in a proportion of those patients in whom "safe" GH levels were achieved following irradiation. From the putative mechanisms of action of these provocative agents a plausible explanation would be that the GHRH axis is more resilient than endogenous somatostatin-secreting neurones to radiation-induced damage. Furthermore, GH secretagogues may have a role, in combination with serum IGF-I levels, in the diagnosis of GH deficiency in treated acromegaly.
Assuntos
Acromegalia/sangue , Acromegalia/cirurgia , Hormônio do Crescimento/deficiência , Acromegalia/diagnóstico por imagem , Adulto , Idoso , Arginina , Feminino , Hormônio do Crescimento/sangue , Hormônio Liberador de Hormônio do Crescimento/análogos & derivados , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Oligopeptídeos , Radiografia , Estatísticas não Paramétricas , Estimulação QuímicaRESUMO
In peripheral tissues, corticosteroid hormone action is determined, in part, through the activity of 11beta-hydroxysteroid dehydrogenases (11beta-HSD), two isozymes of which interconvert hormonally active cortisol (F) and inactive cortisone (E). 11beta-HSD type 2 (11beta-HSD2) inactivates F to E in the kidney, whilst 11beta-HSD type 1 (11beta-HSD1) principally performs the reverse reaction activating F from E in the liver and adipose tissue. Alteration in expression of these 11beta-HSD isozymes in peripheral tissues modifies corticosteroid action: loss of 11beta-HSD2 activity in the kidney results in cortisol-induced mineralocorticoid excess, and loss of hepatic 11beta-HSD1 activity improves insulin sensitivity through a reduction in cortisol-induced gluconeogenesis and hepatic glucose output. Conversely, overexpression of 11beta-HSD1 in omental adipose tissue can stimulate glucocorticoid-induced adipocyte differentiation which may lead to central obesity. Patients with hypopituitarism have many clinical features in common with patients with Cushing's syndrome--notably visceral obesity, insulin resistance, osteoporosis and increased vascular mortality. Our hypothesis was that many of these features may be explained by an effect of growth hormone (GH) on the 11beta-HSD isozymes. As assessed by urinary free cortisol/urinary free cortisone ratios and endorsed through in vitro studies, neither GH nor insulin-like growth factor (IGF)-I affect 11beta-HSD2 activity. Patients with acromegaly show a reduction in hepatic-derived metabolites of cortisol/cortisone - levels return to normal when GH concentrations are normalized. Conversely, patients with GH deficiency in the setting of hypopituitarism demonstrate an increased cortisol/cortisone metabolite ratio and reduction in circulating cortisol concentrations in patients on hydrocortisone replacement. Treatment with low-dose GH replacement reverses these abnormalities. These clinical data suggest that GH (and/or IGF-I) inhibits 11beta-HSD1 (i.e. E to F conversion) (parallel in vitro studies suggest that IGF-I and not GH inhibits 11beta-HSD1). These findings have important clinical ramifications. Firstly, the GH-mediated increase in cortisol metabolism (mediated via reduced E to F conversion) may precipitate adrenal insufficiency in hypopituitary patients with partial adrenocorticotropic hormone deficiency commencing GH therapy. Secondly, many of the phenotypic features of hypopituitarism can be explained by an alteration in 11beta-HSD1 activity: GH deficiency effectively increases cortisol production in key target tissues including liver and adipose tissue, promoting insulin resistance and visceral adiposity. Thirdly, the reported beneficial effects of GH on cardiovascular risk factors in patients with hypopituitarism may be an indirect effect via alterations in cortisol metabolism. Finally, the GH/IGF-I modulation of cortisol metabolism may underpin the pathogenesis of common diseases such as central obesity and idiopathic osteoporosis. Patients with central obesity but with no evidence of hypopituitarism have relative GH deficiency and it is exciting to speculate that low-dose GH treatment in this group, by inhibiting cortisol generation within omental fat, may offer a novel therapeutic approach.
Assuntos
Cortisona/metabolismo , Hormônio do Crescimento/fisiologia , Hidrocortisona/metabolismo , Fator de Crescimento Insulin-Like I/fisiologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2 , 11-beta-Hidroxiesteroide Desidrogenases , Animais , Hormônio do Crescimento/deficiência , Hormônio do Crescimento/uso terapêutico , Humanos , Hidrocortisona/uso terapêutico , Hidroxiesteroide Desidrogenases/fisiologia , Hipopituitarismo/tratamento farmacológico , Hipopituitarismo/metabolismo , Obesidade/etiologia , Obesidade/metabolismoAssuntos
Hormônio do Crescimento/metabolismo , Hormônios Peptídicos , Peptídeos/fisiologia , Receptores Acoplados a Proteínas G , Animais , Caprilatos/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/fisiologia , Mucosa Gástrica/metabolismo , Grelina , Humanos , Hipotálamo/metabolismo , Mucosa Intestinal/metabolismo , Peptídeos/farmacologia , Hipófise/metabolismo , Ratos , Receptores de Superfície Celular/metabolismo , Receptores de GrelinaRESUMO
Pulsatile growth hormone (GH) secretion is regulated by three hypothalamic factors, growth hormone-releasing hormone (GHRH), somatostatin and the natural ligand for the GH secretagogue receptor (Ghrelin). These factors and their effects are, in turn, affected by short loop feedback of GH itself. To test the hypothesis that hypothalamic GH receptors are involved in the ultradian rhythmicity of pituitary GH secretion, the rat GH receptor antagonist (G118R) was administered to adult male rats by intracerebroventricular (i.c. v.) injection and the effects on spontaneous GH secretion were studied. Normal saline was administered i.c.v. to eight control rats. Mean GH concentrations increased significantly in the rat treated with G118R compared to rats that received normal saline. The pulse amplitude rose by a mean of 33.3 ng/ml and the total area under the curve increased by a mean of 15 061 ng/ml x min. The number of GH peaks did not change significantly following G118R. These data suggest that GH regulates its own secretion by acting directly on hypothalamic GH receptors.
Assuntos
Hormônio do Crescimento/metabolismo , Receptores da Somatotropina/antagonistas & inibidores , Receptores da Somatotropina/metabolismo , Animais , Área Sob a Curva , Retroalimentação/efeitos dos fármacos , Retroalimentação/fisiologia , Hipotálamo/química , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Injeções Intraventriculares , Masculino , Fluxo Pulsátil , Ratos , Ratos Sprague-DawleyRESUMO
11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) functions as a net reductase converting cortisone to cortisol. GH inhibits 11beta-HSD1, resulting in a shift in cortisol metabolism favoring cortisone, an observation that may have significance in patients with ACTH deficiency who are unable to compensate for such changes. We have studied the effect of three doses of GH replacement (0.17, 0.33, and 0.5 mg each given for 12 weeks in ascending order) on cortisol metabolism in nine patients, aged 62-70 yr, with hypopituitarism who were receiving fixed doses of oral hydrocortisone. Serum insulin-like growth factor I levels rose in a dose-dependent manner over the course of the study. Fat mass decreased significantly at 24 weeks (P = 0.02), a change that was maintained at 36 weeks. Fasting serum insulin levels did not change significantly over the course of the study. The ratio of urine cortisol to cortisone metabolites (Fm/Em) fell significantly at 12 weeks (GH dose, 0.17 mg/day) from 1.32 (0.91-2.20) at baseline to 1.08 (0.89-2.11) (P < 0.05). Although it did not fall further as the dose of GH was increased, the reduction in the Fm/Em ratio persisted at 24 weeks (GH dose, 0.33 mg/day), 1.09 (0.8-2.11) (P < 0.05 vs. baseline), and 36 weeks (GH dose, 0.5 mg/day), 1.19 (0.82-2.31) (P < 0.05 vs. baseline). The Fm/Em ratio did not correlate with serum insulin-like growth factor I, fat mass, or fasting insulin levels at any time during the study. This study confirms the inhibitory effect of GH on 11beta-HSD1 but has shown that the effect occurs maximally at very low GH doses and is not mediated indirectly by change in circulating insulin. Patients with partial or total ACTH deficiency, in whom cortisol replacement is suboptimal, may be at risk of the clinical manifestations of cortisol deficiency when they are commenced on GH therapy.
Assuntos
Hormônio do Crescimento Humano/administração & dosagem , Hidrocortisona/urina , Hipopituitarismo/tratamento farmacológico , Hipopituitarismo/metabolismo , 11-beta-Hidroxiesteroide Desidrogenases , Tecido Adiposo , Hormônio Adrenocorticotrópico/deficiência , Composição Corporal , Cortisona/urina , Jejum , Feminino , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Hidrocortisona/uso terapêutico , Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: The net interconversion of inactive cortisone to active cortisol by 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) may determine hepatic and adipose tissue exposure to glucocorticoid action. Cortisol metabolism exhibits a sexual dimorphism with an apparently lower activity of 11betaHSD1 in females that, in an animal model, has been attributed to the effects of oestrogen. The aim of this study is to determine whether the sexual dimorphism of cortisol metabolism persists between post-menopausal, oestrogen-deficient women and elderly men. PATIENTS: Fifteen healthy men, aged 60.8-82.0 years, and 7 healthy women, aged 62.4-87.5 years, were studied. None of the subjects was receiving steroid medication at the time of the study. All the women were post-menopausal and none was receiving sex steroid replacement therapy. MEASUREMENTS: 24-h urine collections were taken from each patient and assayed for steroid metabolites by gas chromatography. Body composition was determined by dual energy X-ray absorptiometry. Blood was drawn, after an overnight fast, for the determination of serum IGF-I and IGFBP1 levels. RESULTS: The ratio of 11-hydroxy cortisol metabolites to 11-oxo cortisol metabolites (Fm/Em) was significantly higher in men than in women, 0.80 (0.55-1.86) vs. 0.67 (0.46-0.98) (P < 0.02), as was the ratio of allo-tetrahydrocortisol (5alpha-THF) + tetrahydrocortisol (THF)/tetrahydrocortisone (THE), 0.74 (0.37-2.08) vs. 0.40 (0.22-1.10) (P < 0.047). In the group as a whole there was a negative correlation between Fm/Em and percent body fat, r = - 0. 43 (P < 0.05), and the negative relationship between cortisol and cortisone metabolite (Fm/Em) and total fat mass approached significance, r = - 0.39 (P = 0.07). These relationships were not apparent in the women when considered alone. Among the men there were negative relationships between Fm/Em and total fat mass, r = - 0.48, and Fm/Em and trunk fat mass, r = - 0.48 which approached significance (both P = 0.07). Serum IGFBP-1 levels were not significantly different between the two sexes. There was a significant correlation between IGFBP-1 and Fm/Em in the men, r = 0. 84 (P < 0.0001) which persisted when total body fat mass, r = 0.85 (P < 0.0001) and trunk fat mass, r = 0.83 (P < 0.0001), were controlled for. This relationship was not evident among the women. CONCLUSION: This study demonstrates that the previously described sexual dimorphism in cortisol metabolism is not dependent on oestrogen, although the possibility that oestrogen exerts a permanent modifying effect on 11beta-HSD1 gene expression during the pre-menopausal period cannot be excluded. The findings confirm the primary importance of body fat as a determinant of cortisol-cortisone conversion.
Assuntos
Composição Corporal , Cortisona/metabolismo , Estrogênios/metabolismo , Hidrocortisona/metabolismo , Caracteres Sexuais , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Tetra-Hidrocortisol/análogos & derivados , Tetra-Hidrocortisol/urinaRESUMO
Lipoprotein(a) [Lp(a)], an independent risk factor for cardiovascular disease, has previously been reported to increase, decrease or show no change in growth hormone (GH)-deficient individuals receiving GH replacement. To assess whether these inconsistencies could be attributed to differences in immunoassay methods, Lp(a) was measured by six commercial kits at 0, 3, 6 and 9 months in nine GH-deficient individuals (median age 68.3 years, six male) during 9 months GH therapy. There was a significant rise in Lp(a) with the INCStar immunoturbidimetric (IT) method and the Mercodia enzyme linked immunosorbent assay (ELISA) (P=0.05, two-tailed Wilcoxon signed rank test), a non-significant rise with the Pharmacia immuno-radiometric assay and the Biopool ELISA methods (P =0.06), and no change with the Immuno ELISA and WAKO IT kits. There was also considerable variation in the values reported within each individual. These results suggest that the previously reported inconsistencies may in part be due to methodological differences, and that the effect of GH on Lp(a) remains unknown. This study highlights the need for a more common approach to the standardization of Lp(a) methods and the selection of antibodies used in them. Better performing methods may allow a more reliable interpretation of the effects of GH on Lp(a)
Assuntos
Análise Química do Sangue/métodos , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Lipoproteína(a)/sangue , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores de TempoRESUMO
In human studies, the principal determinant of serum leptin concentrations is fat mass (FM), but lean mass (LM) also has a significant negative influence. GH treatment in GH deficiency (GHD) alters body composition, increasing LM and decreasing FM, and thus would be expected to alter leptin concentrations. We have therefore examined the acute and chronic effects of GH on serum leptin in 12 elderly GHD subjects (ages 62-85 yr; 3 women and 9 men). FM (kilograms) and LM (kilograms) were determined by dual energy x-ray absortiometry. Leptin, insulin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 were measured by specific immunoassays. Leptin, insulin, and IGFBP-1 concentrations were log10 transformed, and data were expressed as the geometric mean (-1, +1 tolerance factor). All other data are presented as the mean +/- SD. In the acute study, patients received a single bolus dose of GH (0.1 mg/kg BW) at time zero, with blood samples drawn at 0, 12, 24, 48, and 72 h and 1 and 2 weeks. There was a significant rise in leptin, insulin, and IGF-I at a median time of 24 h, followed by a significant fall, and nadir concentrations were reached at a median time of 1.5 weeks (leptin) or 2 weeks (insulin and IGF-I). IGFBP-3 concentrations were also significantly increased, but peak concentrations were not achieved until 48 h. IGF-II, IGFBP-1, and IGFBP-2 exhibited transient decreases before returning to baseline levels. There was no relationship between increased leptin concentrations and either insulin or IGF-I concentrations. In the chronic study, patients received daily GH treatment at doses of 0.17, 0.33, and 0.5 mg/day, each for 3 months (total time on GH, 9 months), and were then followed off GH for a further 3 months. Dual energy x-ray absortiometry was undertaken at 0, 3, 6, 9, and 12 months, and blood samples were drawn at these time points. Over 9 months on GH there was a significant fall in FM and a significant rise in LM, but no change in leptin. There were also significant increments in insulin, IGF-I, and IGFBP-3, whereas IGF-II, IGFBP-1, and IGFBP-2 did not change over 9 months of GH treatment. After 3 months off GH, there was a significant rise in FM and leptin. High dose single bolus GH led to an increase in serum leptin within 24 h apparently independent of changes in insulin or IGF-I. Despite the changes in body composition during chronic GH treatment, there was no change in leptin. However, discontinuation of GH led to a rapid reversal of the favorable body composition and a rise in serum leptin.
Assuntos
Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/deficiência , Proteínas/análise , Idoso , Idoso de 80 Anos ou mais , Composição Corporal/efeitos dos fármacos , Feminino , Humanos , Insulina/sangue , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Leptina , Masculino , Pessoa de Meia-IdadeRESUMO
Adults over the age of 60 yr with organic disease of the hypothalamic-pituitary axis have a 90% reduction in GH secretion. This is distinct from the hyposomatotropism associated with increasing age and results in a significant reduction in serum insulin-like growth factor I (IGF-I), an increase in fat mass, abnormal bone turnover, and an adverse lipid profile compared with those in healthy subjects of the same age. These findings suggest that the elderly with organic GH deficiency might benefit from GH replacement therapy. However, the dose of GH required to maintain serum IGF-I levels in the normal range while minimizing side-effects in this group of patients is unknown. We have studied 12 patients with organic GH deficiency, aged 62.4-85.2 (median, 67.9 yr), each treated with three doses of GH (0.167, 0.33, and 0.5 mg/day). Each dose was administered for 12 weeks. The serum IGF-I level rose in a dose-related manner over the course of the study (P < 0.0001). From a baseline median (range) IGF-I concentration of 101 (49-148) microg/L to 149 (49-227) microg/L at 12 weeks (P = 0.003 vs. baseline), 200 (70-453) microg/L at 24 weeks (P = 0.002 vs. baseline; P = 0.04 vs. 12 weeks), and 239 (122-502) microg/L at 36 weeks (P = 0.002 vs. baseline; P = 0.07 vs. 24 weeks). The age-specific IGF-I SD score exceeded normal in two subjects taking 0.33 mg/day and in six subjects taking 0.5 mg/day. Serum IGF-binding protein-3 also rose over the course of the study (P < 0.001); however, the greatest increase occurred during the first 12 weeks, after which the IGFBP-3 level plateaued. Body composition changed significantly during the study, with a fall in fat mass (P = 0.0003) and an increase in lean body mass (P = 0.0001). GH was well tolerated in this elderly group, all of whom completed the study. Three patients developed side-effects while taking 0.5 mg/day; two developed headaches, and one developed arthralgia. This study has demonstrated that the GH replacement dose in elderly subjects is considerably lower than that required by younger adults with GH deficiency. In 50% of the subjects a dose of 0.5 mg/day was excessive, whereas 83% maintained their serum IGF-I within normal limits while taking 0.33 mg/day. No patient exhibited a supranormal IGF-I level on 0.17 mg/day.
Assuntos
Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Composição Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Qualidade de VidaRESUMO
We present the case of an adult patient with growth hormone (GH) insufficiency and hereditary motor and sensory neuropathy type 1. Stopping GH replacement at the attainment of final height was associated with a marked reduction in power and mobility, resulting in the patient becoming wheelchair bound. GH replacement was assessed in a double-blind placebo-controlled trial. During the GH replacement arm of the trial, the patient's mobility and independence returned to previous levels. We suggest that the indications for GH replacement in adults should take account of other medical problems, in particular neuromuscular disorders, as well as the degree of GH deficiency.
Assuntos
Doença de Charcot-Marie-Tooth/tratamento farmacológico , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Adolescente , Doença de Charcot-Marie-Tooth/fisiopatologia , Método Duplo-Cego , Humanos , Masculino , Debilidade Muscular/tratamento farmacológico , Músculo Esquelético/fisiopatologiaRESUMO
OBJECTIVE: Adults over the age of 60 years with organic disease of the hypothalamic-pituitary axis may be deficient in growth hormone (GH) to a degree that is distinct from the age-related decline in GH secretion and sufficient to cause perturbations of body composition, serum lipid profile and bone metabolism. In order to determine the best method for detecting GH deficiency in this age group we have compared spontaneous GH secretion, a provocative test of GH secretion, the arginine stimulation test (AST), and basal estimates of circulating insulin-like growth factors (IGF) and IGF-binding proteins (IGFBP). DESIGN: Twenty-four patients (16 male) with organic hypothalamic-pituitary disease and 24 controls (17 male) were studied. The groups were matched for BMI but the patients were slightly younger than the controls, 66.0 (61.0-85.7) vs. 70.6 (60.8-87.5) years (P = 0.04). All subjects underwent a 24-h GH profile (20-minute sampling), measurement of serum IGF-I, IGF-II, IGFBP3, IGFBP2 and growth hormone binding protein (GHBP) and, after an overnight fast, an AST (intravenous arginine 20 g/m2 over 30 minutes). GH concentrations were measured using an ultrasensitive chemiluminescence assay (sensitivity 0.002 microgram/l). Normative data for serum IGF-I, IGF-II, IGFBP3 and IGFBP2 were obtained from 125 subjects aged 60-87 years. RESULTS: None of the parameters studied was able to distinguish between all the GH deficient patients and the healthy controls. The median (range) area under the GH profile (AUCGH) and peak GH response to arginine were lower in the patients than in the controls, 310.05 (18.90-2193.36) vs. 2518.20 (526.76-12024.97) min mU/l (P < 0.00001), 1.07 (0.08-17.90) vs. 23.06 (4.60-109.98) mU/l (P < 0.00001), respectively. There was a significant relationship between AUCGH and peak GH response to arginine in the patients (r = 0.89, P < 0.0001) and in the controls (r = 0.56, P = 0.005). Serum IGF-I, IGFBP2, and IGFBP3 levels were significantly lower in the patients compared with the normal range, 102 (14-162) vs. 142 (59-298) micrograms/l (P < 0.0001), 415 (122-1868) vs. 640 (140-2585) micrograms/l (P = 0.0007) and 2.29 (0.81-3.75) vs. 2.59 (1.00-3.52) mg/l (P = 0.009), respectively. The degree of overlap between the two groups, however, was too great to make these measurements useful diagnostically. Serum IGF-II and GHBP concentrations in the patients were not significantly different from the normal range. The patients were divided into groups determined by the number of anterior pituitary hormone deficits present. There was a significant downward trend in the peak GH response to arginine with increasing severity of hypopituitarism (J = -3.04, P = 0.0012). Ninety per cent of patients with two or three additional pituitary deficiencies had a peak GH response less than 2.0 mU/l. CONCLUSIONS: Of the indices studied the arginine stimulation test is more effective than GH markers, such as IGF-I or IGFBP3, or measurement of spontaneous GH secretion for diagnosing GH deficiency in adults over the age of 60 years. By relating the peak GH response to the degree of hypopituitarism, a GH response less than 2.0 mU/l is suggestive of severe GH deficiency in this age group under the appropriate clinical circumstances.
Assuntos
Arginina , Hormônio do Crescimento/deficiência , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/sangue , Doenças da Hipófise/sangue , Somatomedinas/análise , Idoso , Idoso de 80 Anos ou mais , Proteínas de Transporte/sangue , Feminino , Hormônio do Crescimento/sangue , Hormônio do Crescimento/metabolismo , Humanos , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like II/análise , Masculino , Pessoa de Meia-Idade , Estimulação QuímicaRESUMO
The diagnosis of GH deficiency (GHD) in the elderly is based at present on the peak GH concentration during a stimulation test. We have now evaluated the performance of urinary GH (uGH), urinary insulin-like growth factor I (uIGF-I), and urinary IGF-binding protein-3 (uIGFBP-3) in the diagnosis of GHD in this group. Twenty GHD elderly patients with a history of pituitary disease and a peak GH response to arginine stimulation of less than 3 ng/mL (15 men and 5 women; age, 61.1-83.4 yr) and 19 controls (12 men and 7 women; age, 60.8-87.5 yr) were studied. GH secretion was assessed by 24-h profile and expressed as the area under the curve (AUCGH). Serum (s) IGF-I and sIGFBP-3 were measured in a single morning, fasted sample. Urinary GH, uIGF-I, and uIGFBP-3 were measured in a 24-h urine sample collected over the same interval as the GH profile, and results were expressed as total amount excreted in 24 h (tuGH24, nanograms; tuIGF-I24, nanograms; tuIGFBP-3(24), micrograms). Data are presented as the mean +/- SD, except for AUCGH, tuGH24, and tuIGFBP-3(24), which are presented as the geometric mean (-1, +1 tolerance factor). AUCGH, sIGF-I, and sIGFBP-3 were significantly lower in GHD subjects than in controls. Total uGH24 was lower in GHD subjects, but tuIGF-I24 and tuIGFBP-3(24) excretion were not different in the two groups. AUCGH provided the best separation between GHD and control subjects, whereas there was substantial overlap for sIGF-I, sIGFBP-3, and tuGH24. In both groups sIGF-I was correlated to sIGFBP-3 (GHD, r = 0.75; controls, r = 0.65; both P < 0.01), whereas tuIGF-I24 was not correlated to tuIGFBP-3(24) in either group. Moreover, tuIGF-I24 and tuIGFBP-3(24) were not related to their respective serum concentrations in either group. Total uGH24 was correlated with AUCGH only in controls (r = 0.54; P < 0.05). These data demonstrate that urinary GH and urinary and serum IGF-I and IGFBP-3 are not suitable diagnostic markers for GHD in elderly subjects.
Assuntos
Hormônio do Crescimento Humano/fisiologia , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/urina , Fator de Crescimento Insulin-Like I/metabolismo , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/urina , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/urina , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Caracteres SexuaisRESUMO
The current definition of cure after treatment for acromegaly stipulates a reduction in GH levels to less than 2 ng/mL (< 5 mU/L), as such GH concentrations are believed to be associated with normalization of long term survival. We sought to further define the nature of the cure in such patients, when cure has been achieved by alternative therapeutic modalities, in the expectation that hypothalamic neuroregulatory control of GH secretion might be affected differently by radiotherapy or surgery. In particular we wished to determine the effect of therapy modality on endogenous somatostatin (SMS) tone, using the GH response to i.v. arginine as a paradigm. We studied 20 patients with cured acromegaly (mean 24-h GH concentration, < 2 ng/mL). Eight patients had been cured by surgery only (S; 4 women and 4 men; mean +/- SEM age, 52 +/- 5 yr), and 12 patients had been cured by radiotherapy (R; 4 women and 8 men; age, 52 +/- 3 yr). Sixteen healthy subjects were studied as a control group (C; 6 women and 10 men; age 53 +/- 3]. The median (range) GH during 24-h profiles was similar in each group: S, 1.3 (0.7-1.8) ng/mL; R, 0.6 (0.4-1.8) ng/mL; and C, 0.7 (0.4-3.2) ng/mL (P = 0.57). The median incremental GH responses to arginine were significantly lower in the R group compared with those in the S and C groups: S, 6.4 (2.1-16.6) ng/mL; R, 0.1 (0-1.7) ng/mL; and C, 9.2 (0-16.1) ng/mL (P = 0.0002; S vs. R, P < 0.01; S vs. C, P > 0.05; R vs. C, P < 0.001). We conclude that in acromegalic patients deemed to be cured (GH, < 2 ng/mL), the mode of therapy has considerable influence on the remaining hypothalamic-somatotroph function. In view of the putative mechanism by which arginine releases GH, we suggest that radiotherapy leads to a reduction or complete loss of endogenous SMS tone. This may have implications for the treatment of those acromegalic patients who are not cured (GH, > 2 ng/mL) and who require SMS analog therapy.
Assuntos
Acromegalia/radioterapia , Acromegalia/cirurgia , Doenças Hipotalâmicas/etiologia , Hipotálamo/fisiopatologia , Radioterapia/efeitos adversos , Acromegalia/fisiopatologia , Adulto , Idoso , Arginina , Feminino , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/metabolismo , Humanos , Doenças Hipotalâmicas/fisiopatologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Somatostatina/fisiologiaRESUMO
Secretion of growth hormone (GH) falls with increasing age, and early studies of GH secretion in elderly patients suggested that secretion may cease in a proportion of adults aged over 60 years. In order to determine whether organic disease of the hypothalamic-pituitary axis in adults aged over 60 years results in GH deficiency distinct from the age-related decline in GH secretion, studies were performed in subjects aged 61-88 years. GH secretion in patients with GH deficiency was reduced by 90% compared with controls. Serum insulin-like growth factor-I levels in patients with organic GH deficiency were significantly reduced compared with normal data, but only 17% had concentrations below the lower limit of the normal range. Although levels of IGF binding protein-3 in patients were lower when compared with normal data, all were within the normal range. There was a significant increase in fat mass in patients with GH deficiency compared with healthy controls. Unlike younger adults with GH deficiency, no significant reduction in lean mass was demonstrated in adults with GH deficiency aged over 60 years. Serum osteocalcin and deoxypyridinoline excretion were significantly reduced in patients with GH deficiency, suggesting a reduction in bone turnover. Despite this, total body bone mineral content and bone mineral density in the hip and spine were not reduced compared with controls. In conclusion, organic disease of the hypothalamic-pituitary axis in adults aged over 60 years results in GH deficiency distinct from the age-related decline in GH secretion.
Assuntos
Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/metabolismo , Tecido Adiposo , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Aminoácidos/sangue , Densidade Óssea , Estudos de Casos e Controles , Feminino , Hormônio do Crescimento Humano/deficiência , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Osteocalcina/sangue , RadioimunoensaioRESUMO
Organic growth hormone (GH) deficiency in adults results in many adverse changes similar to the changes which occur in humans with increasing age. The secretion of GH from the anterior pituitary declines with increasing age. This observation, together with the changes in body composition associated with organic GH deficiency in adults, has led to the suggestion that the elderly without hypothalamic-pituitary disease are GH deficient and may benefit from GH therapy. The impact of organic disease of the hypothalamic-pituitary axis in the elderly may result in a reduction in GH secretion of up to 90%. This reduction in GH secretion is sufficient to cause a fall in the serum insulin-like growth factor-1 (IGF-1) concentration, abnormal body composition and abnormal bone turnover, although bone mineral density is unaffected. These changes are distinct from those associated with the hyposomatotropism of the elderly, but are less severe than those seen in younger adults with organic GH deficiency. In this chapter we discuss the effects of organic GH deficiency in elderly subjects and the potential effects of GH replacement therapy. We also examine the potential for GH therapy to correct some of the detrimental effects of the ageing process.