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.     

重组人生长激素治疗青春期前生长激素缺乏症的临床观察

目的探讨重组人生长激素（ｒｈＧＨ）对青春期前特发性生长激素缺乏症（ＩＧＨＤ）患者的疗效。方法对３家医院的６３例ＩＧＨＤ以ｒｈＧＨ进行治疗,每晚临睡前皮下注射０．１ＩＵ／ｋｇ共６个月。结果６３例患儿身高平均增加（７．０±１．６）厘米,年生长速度由治疗前的（２．９±０．９）厘米／年,增加到（１４．０±３．２）厘米／年,身高标准差计分（ＳＤＳ）由治疗前的（－４．８±１．７）变为（－３．９±１．６）;体重也明显增加,但对骨龄无明显促进作用。治疗期间有３９．７％的患儿出现亚临床甲状腺功能低减,２２．４％的患儿于注射局部曾出现短暂的红肿或痒等,７．９％的患儿出现血清ＡＬＴ轻度升高,但所有这些现象均未影响患儿体格的线性增长。结论ｒｈＧＨ是治疗ＩＧＨＤ的一种安全、有效的促生长药物。     

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.     

生长激素缺乏症的诊断和治疗

生长激素缺乏症(GHD)在儿童主要以身材矮小、生长障碍为主要表现,成人患者表现多无特异性,可有身体组分改变、血脂紊乱、骨密度降低、运动耐力下降、胰岛素抵抗、心血管风险增加、生活质量下降等.临床一般需要结合病史、发育状况、症状、体征、影像学资料、生长激素(GH)-胰岛素样生长因子(IGF)轴相关生化指标及GH激发试验来作...     

Isolated growth hormone deficiency

Isolated growth hormone deficiency (IGHD) represents conditions of GH deficiency that are not necessarily associated with other pituitary hormone deficiencies or with an organic lesion. Three sub-categories of IGHD have been clinically identified (IGHD types 1–3), and IGHD type 1 has been further separated into IGHD types 1a and b. However, this clinical sub-categorization of IGHD may need reconsideration due to the recent identification of molecular heterogeneity within each sub-type of IGHD. In a small number of children with IGHD, defects in the GH, GH-releasing hormone receptor (GHRH-R), and GH1 genes have been identified. In most cases, no cause for IGHD can be identified; however, the proportion of idiopathic IGHD cases may be decreasing due to identification of causative factors. The phenotype of IGHD is variable depending in part on the underlying genetic disorders in the affected individuals. Several studies have focused on the usefulness of MRI findings in patients with GHD but anatomic abnormalities of the pituitary gland are variable. We review current studies and the clinical, biochemical, and molecular features described for different groups of affected individuals with IGHD.     

单纯促性腺激素释放激素类似物或联合重组人生长激素治疗青春期矮小患儿的疗效分析

目的 比较分析单纯促性腺激素释放激素类似物(GnRHa)或联合重组人生长激素(rhGH)治疗青春期非生长激素缺乏矮小(NGHDSS)患儿的助长疗效,探讨科学有效的青春期助长治疗方案.方法 42例青春期NGHDSS患儿(男性14,女性28),采用GnRHa联合rhGH治疗者(联合组)30例,单独GnRHa 治疗者(单治组)12例.GnRHa初始剂量100ug·kg-1·d-1(28 d),维持剂量60-80μg·kg-1·d-1(28d);rhGH初始剂量0.15 IU·ks-1·d-1(28 d),维持剂量0.10～0.15 IU·ks-1·d-1(28 d),疗程均为1-2年.主要观察各组年生长速率(GV)、对年龄的身高标准差分值(HtSDSCA)、对骨龄的身高标准差分值(HtSDSBA)、预测身高标准差分值(PAHSDS)的动态变化.结果 (1)1年疗效:联合组治疗前后比较,GV、HtSDSCA、HtSDSBA、PAHSDS变化均有统计学意义(均P<0.05).单治组患儿治疗前后比较,GV、HtSDSCA、HtSDSBA、PAHSDS变化均无统计学意义(均P>0.05).2组间比较,GV、HtSDSBA、PAHSDS均有显著性差异(均P<0.05).(2)2年疗效:联合组治疗前后比较,GV、HtSDSCA、HtSDSBA、PAHSDS变化均有统计学意义(均P<0.05).单治组治疗前后比较,GV、HtSDSCA、HtSDSBA、PAHSDS变化均无统计学意义(均P>0.05).2组间比较,GV、HtSDSBA、HtSDSCA、PAHSDS均有显著性差异(均P<0.05).结论 采用GnRHa联合rhGH治疗青春发育初期的NGHDSS患儿能有效促进近期生长速率,其疗效明显优于单独GnRHa治疗,但对成年终身的贡献尚待研究.

Abstract：

Objective To assess the efficacy of gonadotropin-releasing hormone analogue(GnRHa)with or without recombinant human growth hormone(rhGH)treatment in Chinese short pubertal children with non-growth hormone deficiency.Methods Of 42 short pubertal children(14 males,28 females)without growth hormone deftcieney,the average age was(11.6±0.8)year.30 children were treated with slow release GnRHa with initial dose (100μg·kg-1·d-1,28d)and maintenance dose(60-80μg·kg-1·d-1,28d)labd rgGH with initial dose(0.15IU·kg-1·d-1)and maintenance dose(0.10-0.15IU·kg-1·d-1)for at least 1year.16 of them were still ongoing till the end of the second year.12 children were treated with GnRHa alone by initial dose(100μg·kg-1·d-1,28d)and maintenance dose (60-80μg·kg-1·d-1,28d),and 7 of them remained on it for 2 years.Dynamic changes including annual growth velocity(GV),bone age(BA)/chronologic age(CA)ratio,Tanner stage,height SDS for CA (HtSDSCA),height SDS for BA(HtSDSBA),and predicted adult height (PAHSDS)were observed.Results By the end of the first year tretment with combination therapy,the following parameters:GV,HtSDSCA,HtSDSBA,and PAHSDS all increased significantly(all P<0.05).Treatment with GnRHa alone did not yield significant changes in GV,HtSDSCA,HtSDSBA,and PAHSDS(all P>0.05).Changes in GV,HtSDSBA,and PAHSDS between these two groups were statistically significant(all P<0.05).By the end of the second year treatment,in the combination group,GV slowed from 6.7 to 5.5 cm/year(P<0.05).HtSDSCA,HtSDSBA,PAHSDS increased(all P<0.05).In the group with GnRHa treatment alone,GV slowed from 4.0 to 3.6 cm/year(P>0.05).HtSDSCA,HtSDSBA,PAHSDS increased(all P>0.05).Changes in GV,HtSDSCA,HtSDSBA,and PAHSDS between these 2 groups were statistically significant respectively(all P<0.05).Conclusion This combined treatment regimen significantly impreved the growth by increasing growth rate and delaying bone matumtion in pubertal chidren without growth hormone deficiency.Further study is needed to verify beneficial effects on the final height gain.     

重组人生长激素治疗单纯性生长激素缺乏症和特发性矮小症患儿血清C型利钠肽氨基末端浓度与生长速率的变化

目的 探讨单纯性生长激素缺乏症(isolated growth hormone deficiency,IGHD)以及特发性矮小症(idiopathic short stature,ISS)患儿经重组人生长激素(recombinant human growth hormone,rhGH)治疗后,血清C型利钠肽氨基末端(NTproCNP)浓度的变化及其与生长速率(growth velocity,GV)的关系.方法 共有48例青春期前的患儿纳入研究(IGHD 25例,ISS 23例),并给予rhGH治疗1年.治疗前及治疗后6个月分别测血清胰岛素样生长因子-Ⅰ (IGF-Ⅰ)和NTproCNP的浓度.治疗1年后,计算所有患儿的GV、身高Z积分(HTSDS)以及身高Z积分的变化值(△HTSDS).结果 IGHD组中,治疗前后IGF-I Z积分的变化值(△IGF-ISDS)、NTproCNP浓度的变化值(△NTproCNP)与治疗1年中GV呈正相关(r=0.407,P=0.044;r=0.490,P=0.013);治疗前生长激素(CH)峰值也与治疗前IGF-ISDS、NTproCNP浓度(r=0.558,P=0.004;r=0.630,P=0.001)以及治疗后△IGF-ISDS与△NTproCNP呈正相关(r=0.466,P=0.019).而在ISS患儿中,治疗1年中GV只与治疗后△NTproCNP相关(r=0.845,P＜0.01).结论 在IGHD和ISS患儿应用rhGH的促生长治疗中,NTproCNP水平随着生长速率的增加而增加.因此除了IGF-I,NTproCNP作为一种新的生化标记物,也可用于评估和预测这两类患儿在rhGH治疗后的GV变化.     

生长激素缺乏但持续增高:垂体柄中断合并垂体多激素缺乏一例报告及文献复习

报道一例垂体柄中断合并垂体多激素缺乏、包括经低血糖刺激试验发现生长激素缺乏、但表现为持续增高的病例.结合文献复习发现,此种非生长激素依赖的身高生长一般有垂体其他激素尤其是促性腺激素缺乏、骨骺未闭合为基础条件.     

重组人生长激素治疗不同生长激素分泌状态青春前期矮小患儿追赶性生长模式分析

目的 比较不同生长激素(GH)分泌状态矮小患儿重组人生长激素(rhGH)治疗后的初始追赶性生长模式,初步探讨其机制.方法 回顾性分析62例青春前期不同GH分泌状态矮小患儿对rhGH治疗1年半的追赶性生长模式并定期监测体格指标、促生长素轴的血清指标和骨龄.结果 各组在初始追赶性生长的幅度相似,特发性矮小(ISS)组比完全性生长激素缺乏症(GHD)组更早出现生长减速,并与生长激素结合蛋白(GHBP)水平降低和胰岛素样生长因子结合蛋白3的标准差分数(SDS)增值较小显著相关.GH激发峰值(Ghmax)>7μg/L的部分性GHD组与ISS组有类同的生长追赶的模式.结论 GH受体的降调节和受体后效应的降低可能是ISS组较早出现生长减速的机制.以Ghmaxμg/L作为GHD诊断的界值并相应选择rhGH治疗剂量有更充分的依据和临床意义.     

Efficacy and safety of recombinant growth hormone treatment in children with growth retardation related to long-term glucocorticosteroid therapy

ObjectiveTo evaluate safety and efficacy of recombinant human growth hormone treatment in children on long-term glucocorticoid therapy.MethodsA 5-year prospective open-label study included children on glucocorticoid therapy with either standard deviation score (SDS) < −2 for height for chronological age (CA) if naïve to growth hormone treatment, or annual growth rate ≥ 0 SDS for CA if currently receiving growth hormone.ResultsNinety-eight patients began treatment, 63 discontinued; 59 were analyzed for safety and 58 for efficacy. There was male predominance (78.0%). Median age was 13.0 years. Median height screening was 136.0 cm (range, 95.1–159.7 cm). Mean SDS for height for CA in the efficacy analysis set was −2.91 ± 1.19 (range, −7.49 to −0.96). Mean growth hormone dose was 0.4, 0.4, 0.4 and 0.3 mg/kg/week at month 0, M12, M24, and M36, respectively. Primary analysis of change in SDS for height for CA from baseline to M36 showed a significant increase of 0.80 ± 1.03. Twenty patients in the safety analysis set had ≥ 1 treatment-emergent adverse event (TEAE) related to study treatment. Two patients experienced serious treatment-related TEAEs: 1 case of poor compliance, and 1 of mild hyperglycemia, both already observed under growth hormone treatment.ConclusionThis study suggests that growth hormone treatment could be effective in increasing height in children on long-term glucocorticoid treatment with a safety profile comparable to that in approved rhGH treatment indications.Clinical trial registrationNCT00163189.     

生长激素治疗扩张性心肌病前后心电图及激素水平变化

目的进一步探讨重组人生长激素(r-GH)治疗扩张性心肌病(DCM)心力衰竭前后的心电图、超声心动图(UCG)改变以及r-GH和胰岛素生长因子(IGF-1)、肿瘤坏死因子(TNF)水平的变化,探讨其相互之间的关系。方法住院确诊DCM者46例,在常规治疗心力衰竭的基础上分为常规治疗心力衰竭组(A组)与r-GH治疗组(B组),用r-GH4u皮下注射三个月后,测定治疗前后的P-R间期、心率、ST段、QRS波群间期及血清GH、IGF-1、TNF水平、左室舒张末径(LVEDd)、左室收缩末径(LVESd)心胸比例。结果①心电图在A组与B组的ST段、心率及P-R间期在组内比较有显著性差异(P<0.05)。②TNF在正常组与心力衰竭组,A组与B组内及组间比较都有显著性差异(P<0.05)。③r-GH、IGF-1在A组与B组内及组间比较无显著性差异。④心胸比例、LVEDd、LVESd在治疗前后的组内与组间比较有显著差异性(P<0.05)。结论小剂量的(r-GH)治疗DCM能够使心功能改善,短期内治疗效果良好。     

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成人生长激素缺乏症(GHD)最常见于下丘脑和(或)垂体结构破坏或功能损害,临床上主要根据一系列非特异性临床表现及相应的生化指标来确诊。由于生长激素(GH)的脉冲式分泌及正常人群随机GH测定值的波动,GHD患者不能仅依据随机GH结果与正常人群相鉴别。目前国际上公认的成人GHD诊断金标准是胰岛素低血糖试验(ITT),近年来认为生长激素释放激素(GHRH)+精氨酸试验,GH-RH+生长激素释放肽(GHRP)及胰高血糖素兴奋试验的诊断价值与ITT相当。成人GHD常合并多种并发症,其中慢性心血管系统并发症可能是导致该类患者病死率增加的主要原因。而重组人生长激素(rh-GH)替代治疗可以改善这部分患者的许多临床终点事件,包括生活质量的提高及心血管风险的降低等。     

Increased melatonin concentrations in children with growth hormone deficiency

A relationship between melatonin and growth hormone (GH) is poorly understood. We compare circadian melatonin rhythms in short children with normal and decreased GH secretion. The analysis included 22 children (20 boys and 2 girls) aged 11.1-16.9 yr (mean +/- S.E.M. = 14.1 +/- 0.3 yr) with short stature (height SDS below -2.0). Based on the GH peak in stimulation tests patients were divided into two groups: idiopathic short stature (ISS, n = 11; GH peak > or = 10 ng/mL) and GH deficiency (GHD, n = 11; GH peak < 10 ng/mL). In all patients the circadian melatonin rhythm was assessed on the basis of nine blood samples, collected in 4-hr intervals during the daytime and 2-hr intervals at night, with dark period lasting from 22:00 to 06:00 hr. Magnetic resonance imaging examination excluded organic abnormalities in central nervous system in all patients. Melatonin concentration at 24:00, 02:00 and 04:00 hr as well as the area under curve of melatonin concentrations (AUC) were significantly higher in the patients with GHD than in individuals with ISS. Significant correlations between GH secretion and melatonin concentrations at 24:00, 02:00 and 04:00 hr, and AUC were also observed. On the basis of these data it seems that the assessment of nocturnal melatonin secretion might be a valuable diagnostic tool used for the improvement of the difficult diagnosis of short stature in children.     

Growth hormone deficiency in children

The foundation for the diagnosis of growth hormone (GH) deficiency in childhood must be auxology, that is, the comparison of the child’s growth pattern to that of established norms for gender and ethnicity. It is only in those growing considerably more slowly than average that testing for GHD makes sense. Assessment of laboratory tests, whether static, for example, the measurement of growth factors or their binding proteins, or dynamic, for example, secretagogue-stimulated GH secretion is confirmatory. One must be cognizant of the assay used to determine GH, for there may be a 3-fold difference in the concentration of GH among commercially-available assays. Controversy still exists concerning the measurement of spontaneous GH release and whether sex-steroid priming is appropriate in prepubertal children. Imaging analysis may prove helpful in some children with congenital GHD or to detect a space-occupying lesion in the area of the hypothalamus and pituitary. The final diagnosis is based on multiple parameters and occasionally on a therapeutic trial of GH therapy to determine if there is a significant acceleration of growth velocity.     

Low hemoglobin levels in children with in idiopathic growth hormone deficiency

Multiple lines of evidence have implicated the growth hormone (GH) axis in the regulation of erythropoiesis. To test the hypothesis that GH deficiency is associated with hematologic abnormalities, we analyzed pretreatment hemoglobin levels in 100 children with GH deficiency. Hemoglobin levels were decreased in children with GH deficiency compared with age-corrected norms.     

Long-term therapy with recombinant human growth hormone (Saizen) in children with idiopathic and organic growth hormone deficiency

In an open-label study, 69 children with organic or idiopathic growth hormone deficiency (GHD) were treated with recombinant human growth hormone (Saizen) for an average of 64.4 mo, with treatment periods as long as 140.9 mo. Auxologic measurements, including height velocity, height standard deviation score, and bone age, were made on a regular basis. The data suggest that long-term treatment with Saizen in children with GHD results in a positive catch-up growth response and proportionate changes in bone age vs height age during treatment. In addition, long-term Saizen therapy was well tolerated, with the majority of adverse events related to common childhood disorders or existing baseline medical conditions and not to study treatment. There were no significant changes in laboratory safety data or vital signs, and no positive antibody tests for Saizen.     

Growth hormone levels in the diagnosis of growth hormone deficiency in adulthood

Current guidelines for the diagnosis of adult growth hormone deficiency (GHD) state that the diagnosis must be proven biochemically by provocative testing that is done within the appropriate clinical context. The need for reliance on provocative testing is based on evidence that the evaluation of spontaneous growth hormone (GH) secretion over 24 h and the measurement of IGF-I and IGFBP-3 levels do not distinguish between normal and GHD subjects. Regarding IGF-I, it has been demonstrated that very low levels in patients highly suspected for GHD (i.e., patients with childhood-onset, severe GHD, or with multiple hypopituitarism acquired in adulthood) may be considered definitive evidence for severe GHD obviating the need for provocative tests. However, normal IGF-I levels do not rule out severe GHD and therefore adults suspected for GHD and with normal IGF-I levels must undergo a provocative test of GH secretion. The insulin tolerance test (ITT) is the test of choice, with severe GHD being defined by a GH peak less than 3 microg/l, the cut-off that distinguishes normal from GHD adults. The ITT is contraindicated in the presence of ischemic heart disease, seizure disorders, and in the elderly. Other tests are as reliable as the ITT, provided they are used with appropriate cut-off limits. Glucagon stimulation, a classical test, and especially new maximal tests such as GHRH in combination with arginine or GHS (i.e., GHRP-6) have well-defined cut-off limits, are reproducible, are independent of age and gender, and are able to distinguish between normal and GHD subjects. The confounding effect of overweight or obesity on the interpretation of the GH response to provocative tests needs to be considered as the somatotropic response to all stimuli is negatively correlated with body mass index. Appropriate cut-offs for lean, overweight, and obese subjects must be used in order to avoid false-positive diagnoses of severe GHD in obese adults.