Growth hormone deficiency in the adult

Growth hormone deficiency (GHD) in adults may be of either adult or childhood onset and may occur as isolated GHD or as multiple hormone deficiencies. Adult-onset GHD (AoGHD) usually results from damage to the pituitary gland or hypothalamus. GH is frequently undetectable in normal subjects and thus GHD cannot be distinguished from the normal state using a single random GH measurement. In general, a stimulation test is required to recognize GHD. Insulin tolerance test (ITT) has been considered the gold standard by the most important scientific societies, although alternative tests, in particular GHRH plus arginine have been proposed as valuable alternative to ITT. The clinical syndrome associated with AoGHD is characterized by a wide array of symptoms and important chronic complications, such as cardiovascular complications, which may be responsible for an increased mortality. The rationale for GH replacement in adults GHD patients is justified by the beneficial effects on some clinical end-points, such as quality of life (QoL) and cardiovascular risk factors, whereas the effects on mortality risk are still controversial. Over the recent years, guidelines on the use of rhGH as a substitution treatment in adult hypopituitarism have been issued by international (Growth hormone research society-GRS, Endocrine Society) and relevant national (National Institute of Clinical Excellence-UK, NICE) institutions. The aim of the paper is to review and discuss these guidelines.     

Serum IGF-I levels in the diagnosis and monitoring of acromegaly

Insulin-Like Growth Factor-I (IGF-I) is a reliable marker of disease activity and growth hormone (GH) status in acromegaly, but its clinical utility has been hampered over the years by various issues including a lack of robust reference range data and variability in assay sensitivity and specificity. In acromegaly IGF-I correlates well with GH activity and nadir GH on oral glucose tolerance test (OGTT) and is the most sensitive and specific test in diagnosis, where serum IGF-I is persistently seen to be elevated to a range that is distinct from that in healthy individuals. However it should not be relied on exclusively for diagnosis or used as the sole indication of disease severity and GH burden. Successful medical or surgical treatment of acromegaly is usually associated with normalisation of serum IGF-I but there is discordance between GH and IGF-I in some patients. Patients with a normal IGF-I but an abnormal GH suppression to OGTT are at risk of relapse and therefore it should not be used alone to establish disease remission. In contrast to the diagnosis of acromegaly, there is also considerable overlap in serum IGF-I with normality after primary treatment of disease, even in the presence of persisting GH excess. Gender, age and prior radiotherapy alters the relationship between GH and IGF-I and reliance on one marker of disease activity such as IGF-I is particularly precarious in certain disease states. However an elevated serum IGF-I has been shown to be associated with excess mortality and normalising IGF-I normalises mortality making it a useful marker. The tightening up of the assays means that establishing absolute concentrations as well as standard deviation scores are essential to allow cross-study comparisons. This becomes especially important in the use of Pegvisomant, where IGF-I becomes the sole biochemical marker of disease activity.     

成人生长激素缺乏症的诊断和治疗

成人生长激素缺乏症(AGHD)是一组临床表现多样的综合征,可表现为身体组分的改变,糖、脂、骨代谢异常,心血管疾病及骨折风险增加,生活质量下降等.诊断主要依据临床病史特征以及生长激素激发试验.重组人生长激素( rhGH)替代治疗可以明显改善患者的身体组分、异常代谢状态,降低心血管风险因素,提高其生活质量.     

Serum adiponectin is reduced in acromegaly and normalized after correction of growth hormone excess

Adiponectin, an adipocyte-derived hormone, possesses insulin-sensitizing, antiinflammatory, and antiatherogenic properties. We hypothesized that hypoadiponectinemia was present in acromegaly, as in other conditions with increased insulin resistance and cardiovascular risk. Using an in-house RIA, serum adiponectin was determined in 35 patients with active acromegaly and 35 age-, sex-, and body mass index-matched healthy controls. Twenty-five patients were restudied after GH-lowering therapies. Serum adiponectin was significantly reduced in the acromegalic patients (4.3 +/- 1.8 vs. 6.7 +/- 1.8 microg/ml in controls; P < 0.001), but was increased after treatment with Sandostatin LAR, a long-acting somatostatin analog (5.8 +/- 2.6 vs. 3.8 +/- 1.6 microg/ml pretreatment; P < 0.001; n = 15) or transsphenoidal surgery (6.5 +/- 2.7 vs. 3.9 +/- 1.5 microg/ml preoperation; P < 0.01; n = 10). Fasting insulin was an independent determinant of serum adiponectin levels (P < 0.01) in control subjects, contributing to 11.7% of the variance in circulating adiponectin. In cultured 3T3-L1 adipocytes, adiponectin mRNA levels were decreased by insulin (1.5 microm; P < 0.005) or IGF-I (1 microg/ml; P < 0.05), but not by GH (1 microm) or somatostatin (1 microm). In conclusion, hypoadiponectinemia is present in active acromegaly, probably secondary to the inhibitory effect of high circulating insulin levels. Hypoadiponectinemia, reversible with GH-lowering therapies, may contribute to the increased insulin resistance and cardiovascular risk in patients with acromegaly.     

Effect of pituitary ultrasonic treatment on plasma human growth hormone levels in diabetic retinopathy and acromegaly

Summary Sixteen diabetic patients presenting advanced retinopathy and 6 patients with acromegaly underwent ultrasonic treatment (UST) of the pituitary, according to Arslan’s method. In the diabetic retinopathy patients, circadian variations of plasma human growth hormone (HGH) levels were studied as well as the response to insulin stimulation, previous to and 7 days after the operation. Five patients were also studied 3 months post-ultrasonic treatment. Preoperative HGH plasma levels were normal and no reduction was observed following operation. Acromegalic patients were rested for oral glucose tolerance and insulin response, before and 7 days after operation. High pre-operatory HGH levels fell appreciably after operation, but the reduction was not significant. Our data demonstrate that high plasma levels of HGH are not always found in diabetes and that even after UST of the pituitary, there does not seem to be a relationship between degree of pituitary inhibition and clinical results. On the other hand, ultrasonic treatment of the pituitary in acromegalic patients determines partial hypophyseal inhibition. Research carried out with C.N.R. funds, Contract No. 73.00507.04.     

Efficacy and safety of long-acting growth hormone in adult growth hormone deficiency: A systematic review and meta-analysis

Background & aimsNo meta-analysis has analysed efficacy and safety of long-acting growth hormone (GH) therapy in adult GH deficiency. We undertook this meta-analysis to address this gap in knowledgeMethodsElectronic databases were searched for RCTs involving adult GH deficiency patients receiving weekly long-acting GH as compared to daily GH/placebo controls. Primary outcome was to evaluate changes in body-composition parameters. Secondary outcomes were to evaluate alterations in glycaemia and adverse-events.ResultsData from 5 studies involving 648 patients were analysed (4 studies having daily GH as active controls; 1 study having placebo as passive controls). Over 24–34 weeks clinical use, patients receiving long-acting GH had comparable change in lean mass [MD-0.28 kg (95%CI: 0.94 – 0.38); P = 0.41; I² = 29% (low heterogeneity)] and fat mass [MD-0.10 kg (95%CI: 1.97–1.78); P = 0.92; I² = 77%(considerable heterogeneity)] as compared to daily GH injections. Long-acting GH use was associated with significantly lower visceral adipose tissue [MD-1.75 cm²(95%CI: 2.14 to ?1.35); P < 0.01; I² = 0% (low heterogeneity)] and higher gynoid fat-mass [MD 0.14 kg(95%CI:0.02–0.26); P = 0.03] compared to daily GH injections. Total adverse events [Risk ratio (RR) 1.65 (95% CI: 0.83–3.29); P = 0.15; I² = 68%] and severe adverse events [RR 0.60 (95% CI: 0.30–1.19); P = 0.14; I² = 0%] were not significantly different in long-acting GH group compared to controls. Occurrence of headache, arthralgia, nasopharyngitis, new onset diabetes, anti-GH antibodies were comparable among groups. Long-acting GH users had significantly higher treatment adherence compared to controls [OR 4.80 (95%CI:3.58–6.02); P < 0.01; I² = 0%].ConclusionLong-acting GH has comparable beneficial impact on body composition parameters in adult GH deficiency, is well tolerated without any increased adverse events.     

IGF-I measurements in the diagnosis of adult growth hormone deficiency

Although serum insulin-like growth factor I (IGF-I) concentrations have utility as a screening test for growth hormone (GH) deficiency in children and young adults, they are less accurate for screening in adults over 40 years of age. There are two main limitations in the clinical use of IGF-I levels as a marker of GH secretion. First, IGF-I synthesis is not only regulated by GH but also by nutrient supply and by other hormones; second, low IGF-I levels in the presence of normal or increased GH secretion may reflect a peripheral resistance to GH action. Although serum IGF-I cannot be used as a stand-alone test for the diagnosis of adult GH deficiency, very low IGF-I levels in the context of documented hypothalamic or pituitary disease may be helpful in identifying patients with a high probability of GH deficiency. In the presence of two or more additional pituitary hormone deficiencies, an IGF-I level <84 μg/l (assayed by Esoterix Endocrinology, Inc. Calabasas Hills, CA, USA) indicates a 99% probability of GH deficiency. As this cut-off value has not been validated for other IGF-I assays, an IGF-I standard deviation score (SDS) of <-3 may be considered in adults over age 28; an even lower IGF-I SDS is needed for diagnosis in younger adults. In clinical practice, other causes of low serum IGF-I such as malnutrition, diabetes, hypothyroidism, liver disease, etc., should be excluded before applying these diagnostic criteria.     

阻塞性睡眠呼吸暂停低通气综合征患者血清脂联素水平的研究

目的 探讨血清脂联素在阻塞性睡眠呼吸暂停低通气综合征(OSAHS)患者体内的变化。方法 选择伴有肥胖的OSAHS患者71例(肥胖OSAHS组)、不伴肥胖的OSAHS患者21例(非肥胖OSAHS组)、单纯性肥胖者26例(单纯性肥胖组)和健康成人22例(正常对照组)。其中肥胖OSAHS组和单纯性肥胖组的体重指数(BMI)均大于25,两组间BMI差异无显著性。肥胖OSAHS组又进一步分为轻度(26例)、中度(22例)和重度(23例)。均接受多导睡眠仪监测和放射免疫法测定血清脂联素水平。结果 正常对照组血清脂联素水平[(8.9±0.6)mg/L]显著高于单纯性肥胖组[(7.1±1.3)mg/L](P<0.05)、非肥胖OSAHS组[(5.4±0.6)mg/L,P<0.01]和肥胖OSAHS组[(5.0±1.0)mg/L,P<01]。与单纯性肥胖组的血清脂联素水平相比,无论肥胖OSAHS组或非肥胖OSAHS组均显著降低,差异有显著性(P<0.05)。肥胖OSAHS组与非肥胖OSAHS组的血清脂联素水平相比,差异无显著性(P>0.05)。肥胖OSAHS组与单纯性肥胖组的分析显示:血清脂联素水平与呼吸暂停低通气指数(AHI)(r=-0.78,P<0.01)、BMI(r=-0.21,P<0.05)、腰围(r=-O.36,P<0.01)和颈围呈负相关(r=-0.42,P<0.01),与最低脉搏血氧饱和度呈正相关(r=0.48,P<0.01)。结论 OSAHS患者中血清脂联素水平较正常对照和单纯肥胖者更低,除了腰围和颈围的因素     

非酒精性脂肪性肝病患者血清脂联素和瘦素水平变化

目的研究血清脂联素和瘦素水平与非酒精性脂肪性肝病(NAFLD)的关系。方法应用放射免疫分析法检测56例NAFLD患者和42例健康人血清脂联素、瘦素、总胆固醇、甘油三酯、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、载脂蛋白ApoA、ApoB、胰岛素、胰岛素抵抗指数、体质量指数。结果对照组和NAFLD患者血清脂联素分别为12.4±3.2mg/L和6.1±1.9mg/L(P<0.01),高密度脂蛋白胆固醇为1.2±0.3mmol/L和1.0±0.3mmol/L(P<0.05),瘦素为5.3±1.4μg/L和9.2±2.1μg/L(P<0.01),胰岛素为9.4±4.2IU/L和18.5±7.8IU/L(P<0.01),甘油三酯为1.0±0.5mmol/L和2.4±1.2mmol/L(P<0.01),低密度脂蛋白胆固醇为2.2±0.6mmol/L和2.8±0.7mmol/L(P<0.05),体质量指数为21.5±2.1kg/m2和28.3±3.2kg/m(2P<0.01),胰岛素抵抗为1.1±0.4IU/mmol和3.8±2.21u/mmo(lP<0.01);脂联素水平与瘦素、体质量指数和胰岛素抵抗呈负相关(r=-0.552,-0.497,-0.513,P均<0.01)。结论 NAFLD患者血清脂联素水平下降,瘦素水平升高,且与胰岛素抵抗相关。     

Serum insulin in acromegaly

Summary The response of serum insulin to 100 g of glucose by mouth was determined in 23 acromegalics simultaneously by radioïmmunoassay and by assay on adipose tissue and muscle. The values obtained were compared with those of a normal group. 8 patients suffered from active acromegaly, and 15 were in an inactive phase of the disease. The method used by us for the determination of insulin-like activity on mouse-diaphragm in vivo is described. 1. After an oral glucose load, the changes in the concentrations of serum insulin, determined by radioimmunoassay, and of insulin-like activities, estimated by assay on adipose tissue and muscle, were largely parallel. — 2. At all interval serum insulin levels were higher in the acromegalic group than in the normal one. — 3. Patients with active acromegaly showed significantly higher 1 and 2 h values than the group with inactive acromegaly. — 4. No significant differences of insulin concentrations were found between the acromegalic groups with and without impairment of carbohydrate tolerance. — 5. In four patients investigated before and after irradiation or operation of the pituitary, there was a significant drop of serum insulin 1 and 2 h after oral glucose. — 6. Comparing the various insulin levels in the subgroups with different degrees of activity of acromegaly and in the patients seen before and after therapy, we found a parallel change of the Insulinogenic Index (Seltzer). — There is good agreement between the response of serum insulin as determined by radioimmunoassay and that of the insulin-like activity measured on fat and muscle tissue, in acromegaly. Each of the three methods used permits the assessment of the degree of activity of an acromegaly and the success of an intervention.We wish to express our gratitude to the Deutsche Forschungsgemeinschaft and the Landesamt für Forschung of Nordrhein-Westfalen for grants which made this work possible.     

Quality of life in growth hormone deficiency and acromegaly.

Quality of life (QoL) has emerged as an end point in the evaluation of adults with growth hormone deficiency and acromegaly. QoL is measured with questionnaires designed to be used in general population or any kind of disease (generic) or aimed at the specific dimensions affected in a determined condition; these latter ones are more likely to identify the impairments caused by the underlying disease and the benefits of treatment. QoL, which is severely impaired in adults with growth hormone deficiency, improves and normalizes after growth hormone replacement therapy and this effect is maintained over several years. Acromegalic patients also exhibit severe impairment of QoL, which despite improvement after successful therapy still remains below the reference values of normal population. QoL in these chronic endocrine diseases can be used as an measure for clinical and therapeutic evaluation.     

Skin morphological changes in growth hormone deficiency and acromegaly.

OBJECTIVE: To evaluate the histomorphology of skin and its appendages, especially eccrine sweat glands, in patients with GH disorders, because reduced sweating ability in patients with growth hormone deficiency (GHD) is associated with increased risk of hyperthermia under stressed conditions. DESIGN AND METHODS: A skin biopsy was obtained from 17 patients with GHD treated with GH, five patients with untreated GHD, 10 patients with active acromegaly and 13 healthy controls. RESULTS: The sweat secretion rate (SSR) was significantly decreased in both the untreated (median 41 mg/30 min, range 9-79 mg/30 min) and the GH-treated (median 98 mg/30 min, range 28-147 mg/30 min) patients with GHD compared with that in controls (median 119 mg/30 min, range 90-189 mg/30 min; P=0.001 and 0.01 respectively). Epidermal thickness was significantly decreased in both untreated (median 39 microm, range 28-55 microm) and GH-treated patients with GHD (median 53 microm, range 37-100 microm), compared with that in controls (median 66 microm, range 40-111 microm; P<0.02). A statistically non-significant tendency towards thinner epidermis (median 59 microm, range 33-83 microm) was recorded in acromegalic patients (P=0.08) compared with controls. There was no significant difference in the area of the sebaceous glands in the biopsies between the three groups and the controls. The area of eccrine sweat gland glomeruli was significantly decreased in the untreated patients with GHD (median 16407 microm2, range 12758-43976 microm2) compared with that in controls (median 29446 microm2, range 13511-128661 microm2; P=0.03), but there was no significant difference between the GH-treated patients with GHD and controls. CONCLUSIONS: We conclude that GH, either directly or via IGF-I, may have both a structural and a functional effect on human skin and its appendages, and that patients with GHD have histomorphological changes in skin compared with controls. Importantly, these changes are not fully reversed despite long-term and adequate GH treatment in patients with childhood onset GHD.     

Growth hormone measurements in the diagnosis and monitoring of acromegaly

Before the availability of immunoassays for IGF-I, growth hormone (GH) measurement was the sole method used in the biochemical assessment of acromegaly. IGF-I has since been established as the most reliable biochemical indicator of acromegaly. The last 25 years has seen important advances in the understanding of the neuroregulation and in the characterization of GH secretion in acromegaly. The availability of supersensitive GH has changed many aspects of the interpretation of GH-value in the management of acromegaly. Hypersecretion and abnormal neuroregulation characterize GH secretion in acromegaly. GH can be measured in many ways: as a single random sample, as multiple samples, either spontaneously or as an integral part of a dynamic test. These approaches give useful information on diagnosis, therapy, and prognosis. There is a place for measuring GH in the management of acromegaly although it complements that of IGF-I.     

高血压病患者血清脂联素水平的研究

目的 探讨在高血压病患者中脂联素水平及其与血压、肿瘤坏死因子-α、瘦素之间的关系。方法 45例高血压病患者和43例健康对照者常规测量血压、体重、身高,计算体重指数,抽取空腹静脉血检测其血糖、血脂、空腹胰岛素、甲状腺激素、肿瘤坏死因子-α、瘦素、脂联素以及服糖后2h血糖。结果 高血压病患者与健康对照者比较,脂联素水平下降[(4.15±1.99)μg/ml比(7.04±3.13)μg/ml,P=0.000],健康对照组脂联素与体重指数(r=-0.274,P=0.038)、总胆固醇(r=-0.257,P=0.048)呈负相关;高血压病组中脂联素与收缩压(r=-0.356,P=0.016)、甘油三酯(r=-0.367,P=0.013)、肿瘤坏死因子-α(r=-0.298,P=0.047)、三碘甲状腺原氨酸(r=-0.317,P=0.034)呈负相关。多元线性回归提示,在健康对照组中,体重指数是影响脂联素水平的独立因素;而在高血压病组中,收缩压、肿瘤坏死因子-α则是影响脂联素水平的独立因素。结论 在高血压病患者中,脂联素水平下降并与血压之间存在一定的相关性。     

高脂血症患者血尿酸、瘦素、脂联素水平的变化

目的观察不同临床类型的高脂血症患者血尿酸（uA）、瘦素、脂联素水平,探讨其在高脂血症发病中的作用。方法选择不同临床类型的高脂血症患者336例,分为高胆固醇血症组（高TC组）、高甘油三酯血症组（高TG组）、混合型高脂血症组（混合组）和低高密度脂蛋白血症组（低HDL—C组）组;另选择正常对照组204人。检测各组患者的血尿酸、血清瘦素和脂联素水平,并分析其在脂代谢中的作用。结果与正常对照组相比,高TG组、混合组及低HDL—C组UA水平有不同程度的升高（P〈0．05）,其中高TG组uA水平升高最明显。与正常对照组比较,除低HDL—C组脂联素水平明显升高外（P〈0．05）,其余各高脂血症组无论是血清瘦素水平,还是脂联素水平差异均无统计学意义（P〉0．05）。高脂血症各组之间两两比较,高TG组瘦素水平低于低HDL—C组（P〈0．05）,高TC组脂联素水平低于低HDL—C组（P〈0．05）。结论高脂血症患者存在尿酸代谢紊乱,可能与血清瘦素、脂联素共同参与有关。血清瘦素、脂联素将来有可能成为判定代谢综合征的严重程度及预后的指标。     

Alterations of haemostatic and fibrinolytic markers in adult patients with growth hormone deficiency and with acromegaly.

Alterations of coagulation and fibrinolytic systems might contribute to the increased cardiovascular and cerebrovascular mortality observed in patients with both chronic growth hormone (GH) excess (acromegaly) and deficiency (GHD). However, contrasting results have been so far reported. To assess the importance of GH in modulating haemostatic system, several haemostatic variables in patients with GHD and acromegaly were measured. Twenty-four adult patients with GHD (8 childhood- and 16 adult-onset; age: 41+/-12 years, insulin like growth factor-I, IGF-I: 6.7+/-4 nmol/L), 10 non-diabetic acromegalic patients (age: 39+/-15 years; IGF-I: 109+/-37 nmol/L) and 64 healthy volunteers age- and sex-matched with cases were studied. The plasma levels of tissue-type plasminogen activator antigen (t-PA), prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) were measured by ELISA. Plasminogen activator inhibitor type I (PAI-1) was measured by an immunoactivity assay and fibrinogen by von Clauss method. GH levels were measured by IFMA and IGF-I by RIA. GHD patients had higher PAI-1 (12.7+/-16.7 vs 4.8+/-5.3 U/ml, p<0.01), fibrinogen (363+/-104 vs 291+/-71 mg/dL, p< 0.05) and TAT levels (6.8+/-9 vs 3.6+/-2.8 ng/ml, p<0.05) than controls. Taking the 95th pecentile of the normal distribution in the control group as the cut-off point for normal plasma levels of the haemostatic variables, high PAI levels were found in 25% of patients with GHD (P<0.01), while high fibrinogen and TAT levels were observed in 21% (P<0.05). The alterations were mostly present in patients with adult-onset GHD, with the exception of hyperfibrinogenaemia which was equally present in adult- and childhood-onset patients. Acromegalic patients had higher mean fibrinogen levels than controls (398+/-111 vs 291+/-71 mg/dL, p< 0.05), 40% having hyperfibrinogenaemia (P<0.01, vs controls). They also had t-PA levels lower than controls and GHD. No correlations between hormonal and haemostatic variables were found. Body mass index and waist to hip ratio correlated positively with PAI-1 levels in GHD patients only. In conclusion, this study shows that several abnormalities of coagulation variables (increased PAI-1. fibrinogen and TAT levels) are present in patients with GHD, while only hyperfibrinogenaemia is found in patients with acromegaly. These changes do not appear to be directly related to IGF-I levels or to the degree of GH deficiency/excess. However, these abnormalities may be an additional trigger for the development of coronary heart disease and thromboembolic complications mostly in patients with GHD.     

Galanin decreases circulating growth hormone levels in acromegaly.

Galanin is able to elicit GH secretion in normal man. In acromegaly, circulating GH levels are elevated, and GH secretory dynamics are usually abnormal. The aim of our study was to investigate the effects of galanin on GH secretion in acromegalic subjects. Six acromegalic patients (four males and two females) and seven healthy adult subjects (five males and two females) underwent in randomized order: 1) iv infusion of 100 mL saline from 0-45 min, and 2) iv infusion of synthetic porcine galanin (0.5 mg in 100 mL saline) from 0-45 min. In normal subjects, peak GH levels after porcine galanin administration (8.2 +/- 1.9 micrograms/L) were significantly higher than after saline infusion (1.3 +/- 0.1 micrograms/L; P less than 0.05). In acromegalic patients, GH values fell from baseline (32.5 +/- 12 micrograms/L) to a mean nadir of 24.5 +/- 12.7 micrograms/L after galanin infusion. The mean change in GH values from baseline after galanin treatment in these subjects significantly differed from that observed after saline infusion from 15-90 min. Serum PRL levels were not significantly affected by galanin in either normal or acromegalic patients. Our results give the first evidence that the same dose of galanin, acting as a GH secretagogue in normal man, is, on the contrary, able to significantly inhibit GH in acromegalic patients. The cause of this paradoxical GH fall after galanin treatment in acromegaly remains to be explained. It can be hypothesized that galanin may interact at the pituitary level with its own receptors expressed by GH-secreting adenomatous cells.