重组人生长激素对生长激素缺乏症患儿成年身高的影响

目的观察重组人生长激素(rhGH)对生长激素缺乏症(GHD)患儿成年身高(FAH)的影响。方法对11例GHD患儿(男7,女4)应用rhGH治疗,每晚睡前皮下注射,剂量为0．7 IU·kg~(-1)·w~(-1),疗程1．1～7．3年。治疗结束后定期复诊,年生长速度＜1cm,或女性患儿骨龄(BA)≥14岁,男性患儿BA≥16岁时的身高视为近似成年身高或FAH。分析FAH和影响FAH的因素。结果FAH标准差分值(SDS)在男性患儿为(-1．47±0．37),女性患儿为(-1．07±0．60)。85．7%(6/7)男性患儿的FAH达到或超过遗传靶身高(THt)范围,50%(2/4)女性患儿的FAH达到或超过THt范围,男女患儿的FAHSDS与THtSDS比较差异无统计学意义(P＞0．05)。男性患儿的FAHSDS与治疗开始的年龄呈负相关,与治疗开始按年龄的身高SDS(HtSDS_(CA))、青春发育时HtSDS_(CA)和疗程呈正相关；逐步回归分析显示,青春发育时HtSDS_(CA)是影响男性患儿FAHSDS(F=32．58,P=0．002)的独立因素。而女性患儿的FAHSDS与上述因素不相关。孤立性GHD患儿的FAHSDS与由垂体病变引起的多激素缺乏症患儿相比差异无统计学意义(P＞0．05)。结论rhGH能改善GHD患儿的FAH。影响FAH的最主要因素是青春发育时的身高。因此,为达到满意的成年身高,对GHD患儿必须尽早诊断,尽早治疗,以使在青春发育前达到较理想的身高,而对于青春期开始治疗者,必须采用足够的剂量以获得较好FAH。     

人生长激素对垂体功能低下儿童头围的疗效

作者对两组生长激素缺乏的儿童应用人生长激素进行治疗。第一组14人(9男5女)为单纯缺乏生长激素(IGHD),第二组21人(13男8女)为多种垂体激素缺乏(MPHD)。治疗前,两组均有脑颅的生长延缓。IGHD 组较为显著,头围(两眉间至枕骨部最大直径)的平均值在同龄正常儿童平均值约2.5标准差以下。MPHD 组头围平均值虽低于正常,但多数仍在正常范围内。生长激素为间断治疗。开始治疗的实际年龄从9     

颅咽管瘤及其生长激素替代治疗

颅咽管瘤(CP)是一种起源于颅咽峡囊(Rathke囊)的先天性肿瘤,占颅内肿瘤总数的4%～6%,是儿童鞍区常见的先天性肿瘤之一。手术切除肿瘤仍是目前的主要治疗手段,但术后多数患儿下丘脑-垂体功能受到不同程度的影响,发生多项垂体激素分泌缺乏(MPHD)的症状。生长激素(GH)对儿童CP患者长期生存的意义重大,若长期的生长发育得不到充足的GH将影响患儿的正常生长发育,甚至心理成长。目前重组人生长激素(rhGH)治疗因生长激素缺乏(GHD)所致矮小疗效肯定,有效及时的替代治疗能使患儿整体呈现有效的快速生长追赶。总的来说rhGH的替代治疗安全性良好,既不增加新发恶性肿瘤的风险,也不增加中枢神经系统肿瘤的复发率,但仍有进一步研究的必要。     

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.     

生长激素治疗Turner综合征成年终身高的疗效及其影响因素分析

目的 观察重组人生长激素(rhGH)治疗Turner综合征(TS)的疗效并综合分析改善其成年终身高(FAH)相关的影响因素.方法 达FAH的TS患儿以往经rhGH治疗组30例、未治疗组16例,比较分析经治组与未治组、治疗前后的预测成年身高的标准差分值( PAHSDS)、按年龄的身高标准差分值( HtSDScA)、按骨龄的身高标准差分值(HtSDSBA)和生长速率(GV)等生长参数的变化,并分析影响FAH的因素.结果 rhGH治疗组较未治组FAH有明显改善[(149.5±6.3对142.4±5.2)cm,P＜0.01],相关性分析显示治疗组FAH与初诊时HtSDScA、HtSDSBA、初诊时的身高别年龄、rhGH治疗的疗程、性激素治疗前单纯rhGH治疗的疗程和初诊时PAHSDS( PAH.SDS)呈正相关;逐步回归显示性激素治疗前单纯rhGH治疗的疗程和PAHoSDS是影响治疗组患者FAH的独立因素(F分别为11.56和86.91,均P＜0.01);且单体型组(45,XO)和嵌和型组(46,XX/45,XO)TS患儿的FAH差异有统计学意义(P=0.038).结论 rhGH治疗能显著改善TS患儿的FAH,但疗效存在个体差异,以按性激素治疗前单纯rhGH治疗的疗程及PAHD SDS为FAH的最主要影响因素,核型也可能对FAH有所影响.故对于TS的患儿采用rhGH治疗起始年龄宜早,性激素启动青春发育前的rhGH疗程宜长,FAH才更获益.     

生长激素与小剂量司坦唑醇联合应用对Turner综合征女孩生长和成年身高的影响

40例Turner综合征(TS)女孩接受重组人生长激素(rhGH)与小剂量司坦唑醇治疗,开始治疗的年龄为(12.6±1.9)岁(8.8 ～16.2岁),观察年生长速率(GV)、参照健康中国女孩的身高标准差分值(HtSDSNor)和参照未治疗中国TS女孩的身高标准差分值(HtSDSTS)的动态变化.其中13例女孩疗程(2.9±1.2)年(2～5年),结束治疗后随诊至身高达最终成年身高(FAH)或接近FAH,开始雌激素替代年龄是(16.0±1.1)岁.40例TS女孩经治疗HtSDSNor逐年升高,治疗前为-4.2±1.0,治疗后的第1、2、3、4年和第5年分别为-3.4±1.0、-2.8±1.0、-2.4±0.8、-2.5±0.5和-2.3±0.3;HtSDSTs变化与HtSDSNor相似.其中13例TS女孩的FAH为(151.7±4.1)cm,显著高于治疗前预测成年身高(PAH,142.8±4.2)cm(P＜0.01),FAH改善了(8.9±2.8)cm;HtSDSNor从治疗前-3.8±0.8提高到-1.6±0.8.研究结果表明对于年龄接近及大于9岁的TS女孩,采用rhGH与小剂量司坦唑醇联合治疗能有效促进生长;在适当推迟雌激素诱导发育的情况下,促生长疗程≥2年能有效改善FAH.     

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.     

重组人生长激素治疗骨龄13～17岁的特发性生长激素缺乏性矮小症

目的　探讨重组人生长激素(rhGH)对骨龄13~17岁的特发性生长激素缺乏性(IGHD)矮小症患者的促身高增长疗效。方法　21例骨龄13~17岁的IGHD患者被分为两组, A组(骨龄13. 0 ~14. 9岁)和B组(骨龄15. 0~17. 0岁)。A组11例(男8,女3),B组10例(男6,女4),年龄分别为(17. 9±3. 2)岁, (18. 7±2. 1)岁;骨龄分别为(13. 5±0. 6)岁, (15. 2±0. 4)岁,其身高标准差计分分别为-4. 6±1. 6, -3. 3±0. 8,而治疗前生长速度分别为(2. 6±1. 1)和(2. 3±0. 9)cm /年。每晚睡前皮下注射rhGH0. 1IU/kg共6个月。结果　A,B两组IGHD患者的身高分别由治疗前(140. 3±9. 2)和(147. 5±5. 3)cm增至(145. 5±8. 6)和(151. 9±5. 9)cm,两组患儿治疗1~3个月时的生长速度明显增加,但B组治疗4~6个月时的生长速度明显减缓,并明显低于A组患儿4~6个月时生长速度(P<0. 05);而两组患儿的体重和骨龄均没有明显的变化。在骨龄为15~17岁的IGHD患者中,血清胰岛素样生长因子Ⅰ和骨钙素水平明显升高(均P<0. 05)。结论　rhGH治疗对骨龄为13~17岁的IGHD患儿身高的增长仍有促进作用。     

生长激素缺乏症生化检测综合分析

目的以临床诊断作为矮小症患儿(可疑GHD)诊断标准,评估生长激素激发试验、胰岛素样生长因子Ⅰ(IGFⅠ)及IGF结合蛋白3(IGFBP3)对GHD的诊断价值。方法放免方法检测84例可疑GHD患者及63例非GHD患者GH峰值、IGFⅠ及IGFBP3,运用ROC曲线方法选定各生化检测的最佳截定值,并计算各最佳截定值的敏感性(sensitivity,S)、特异性(specificity,Sp)及诊断有效率(diagnosticefficiency,DEf)。结果ROC曲线显示GH激发试验GH峰值7.65μg/L为最佳截定值,DEf达84.4%,S为75.9%,Sp达94.9%;IGFⅠSDS最佳截定值为-1.85,S为70.2%、Sp为83.1%、DEf为70.2%;IGFBP3SDS最佳截定值为-1.55,比传统-2SD高,DEf为64.3%,Sp较高(89.8%),但S仅为45.8%。联合使用上述3种测定有较佳的DEf(91.2%),S(89.3%)和Sp(93.7%)。结论GH激发试验如选取一个好的截定值(本研究为GH峰值7.65μg/L),则该试验对GHD具有较高诊断价值;单个IGFⅠ检测则逊于GH激发试验;IGFBP3单独诊断GHD价值不大。三者联合使用诊断率及准确率皆很高,最具诊断价值。     

成人生长激素缺乏症的诊断与治疗

1 成人生长激素缺乏症(GHD)的定义 1.1 除非有已知的基因突变、可引起多种激素分泌缺陷的胚胎病理损伤或不可逆的结构损伤/破坏,推荐儿童期发病的GHD,经生长激素(GH)治疗已获得成人身高的患者再次筛查GHD.1.2下丘脑/垂体有结构性病变、行外科手术或接受过放射线照射、头外伤或有其他垂体激素缺乏证据的成人患者,应接受评估以明确是否有获得性GHD.     

Isolated growth hormone (GH) deficiency in adult patients: baseline clinical characteristics and responses to GH replacement in comparison with hypopituitary patients. A sub-analysis of the KIMS database.

BACKGROUND: Isolated growth hormone deficiency (IGHD) provides the ideal model to characterize GHD without interference from other pituitary deficiencies or their treatment. No study has addressed the question whether adult patients with IGHD differ in clinical presentation or in responsiveness to GH replacement from adult patients with multiple pituitary hormone deficiencies (MPHD) receiving conventional replacement therapy. PATIENTS AND METHODS: Data were retrieved from the outcomes research database KIMS (Pfizer international metabolic database). Patients with IGHD accounted for 9.6% (274/2868) of all GHD patients. Patients were separated according to the timing of onset. In the adult-onset (AO) group, 167 patients with IGHD were compared to 1992 patients with MPHD. In the childhood-onset (CO) group, 107 patients with IGHD were compared to 602 patients with MPHD. To assess the effect of GH replacement after one year, a longitudinal sub-analysis in the AO group was performed comparing 89 IGHD patients to 1234 MPHD patients. The same study was done in the CO group comparing 66 IGHD patients to 386 MPHD patients. Because IGHD patients were significantly younger than MPHD patients, data analysis was also performed after adjustment for gender and age. RESULTS: In the AO group, non-functioning and secreting pituitary adenomas were the most common primary diagnoses in both IGHD and MPHD. Medical history revealed a high prevalence of hypertension and fractures in both subgroups, but also of non-insulin dependent diabetes mellitus. The prevalence of obesity was high and the waist circumference was elevated. The lipid profile was unfavourable in both IGHD and MPHD. IGF-I concentration and SDS were comparable in both subgroup. Quality of life assessed by QoL-AGHDA was equally poor in both IGHD and MPHD. GH replacement therapy induced favourable changes without distinction. In the CO group, the most common cause in both subgroups was idiopathic. Fracture rate was similarly prevalent in both IGHD and MPHD. Obesity was prominent in both subgroups, but BMI and waist circumference were lower in IGHD. Adverse lipid changes were similarly found in both IGHD and MPHD. IGF-I concentration and SDS were significantly higher in the IGHD subgroup compared to the MPHD subgroup. The QoL-AGHDA score was equally abnormal in both IGHD and MPHD. GH replacement achieved similar significant improvement in both subgroups. CONCLUSIONS: GHD patients with AO-IGHD and AO-MPHD present with a similar clinical expression and respond similarly to GH replacement. Patients with CO-IGHD are less severely affected by GHD than CO-MPHD patients, but, nevertheless, both groups show a comparable adverse lipid profile and poor quality of life and respond favourably to GH replacement. These findings support the concept that GH alone is responsible for most if not all metabolic aspects of hypopituitary patients receiving conventional replacement therapy, regardless of age of onset or aetiology. As a consequence, GH replacement therapy not only has potential benefit in GHD patients with additional hormonal deficits, but also the indication of treatment must be extended to patients with isolated GHD.     

Long-term follow-up evaluation of magnetic resonance imaging in the prognosis of permanent GH deficiency

OBJECTIVE: In patients with GH deficiency (GHD), magnetic resonance imaging (MRI) has revealed morphological abnormalities such as pituitary hypoplasia, pituitary stalk agenesis (PSA) and ectopia of the posterior pituitary (PPE). The MRI anomalies have been more frequently reported in patients with multiple pituitary hormone deficiency (MPHD) than in subjects with isolated GH deficiency (IGHD). The aim of this work was to define which MRI anatomical abnormalities of the hypothalamo-pituitary area can be considered as a prognostic marker of permanent GHD. DESIGN: To investigate the relationship between the neuroradiological images and endocrine findings, we clinically re-evaluated 93 out of the 121 GHD patients with IGHD and MPHD previously studied. RESULTS: No additional hormone deficiencies were observed in 55 out of 60 patients initially classified as having IGHD with a normal (15 cases) or reduced (40 cases) pituitary gland size, without other MRI abnormalities. The remaining five children, who had initially shown an apparently IGHD in spite of PSA and PPE, developed a MPHD over time. In 33 MPHD patients with (25 cases) or without (8 cases) MRI abnormalities, the associated hormone deficiencies were confirmed during follow-up. CONCLUSIONS: The IGHD patients showing PSA and PPE inevitably develop additional hormone deficiencies, while IGHD subjects having no MRI abnormalities maintain IGHD. Moreover, the anatomical abnormalities of the hypothalamo-pituitary area can be considered as a prognostic marker of permanent GHD.     

Effect of growth hormone (GH) treatment on the near-final height of 1258 patients with idiopathic GH deficiency: analysis of a large international database

CONTEXT: Treatment with GH has been used to correct the growth deficit in children with GH deficiency (GHD). Although successful in increasing height velocity, such treatment often falls short of helping patients achieve full genetic height potential. OBJECTIVE: This study set out to analyze near-final height (FH) data from a cohort of GH-treated children with idiopathic GHD. DESIGN, SETTING, AND PARTICIPANTS: Of 1258 evaluable patients in the Pfizer International Growth Database (KIGS) with GHD, 980 were of Caucasian origin, and 278 were of Japanese origin; 747 had isolated GHD (IGHD), and 511 had multiple pituitary hormone deficiencies (MPHD). MAIN OUTCOME MEASURES: Near-FH, relation to midparental height, and factors predictive of growth outcomes were the main outcome measures. RESULTS: Median height sd scores (SDS) at the start of treatment were -2.4 (IGHD) and -2.9 (MPHD) for Caucasian males and -2.6 (IGHD) and -3.4 (MPHD) for females, respectively; comparable starting heights were -2.9 (IGHD) and -3.6 (MPHD) for Japanese males and -3.3 (IGHD) and -4.0 (MPHD) for females, respectively. Corresponding near-adult height SDS after GH treatment were -0.8 (IGHD) and -0.7 (MPHD) for Caucasian males and -1.0 (IGHD) and -1.1 (MPHD) for females, respectively; and -1.6 (IGHD) and -1.9 (MPHD) for Japanese males and -2.1 (IGHD) and -1.8 (MPHD) for females, respectively. Differences between near-adult height and midparental height ranged between -0.6 and +0.2 SDS for the various groups, with the closest approximation to MPH occurring in Japanese males with MPHD. The first-year increase in height SDS and prepubertal height gain was highly correlated with total height gain, confirming the importance of treatment before pubertal onset. CONCLUSIONS: It is possible to achieve FH within the midparental height range in patients with idiopathic GHD treated from an early age with GH, but absolute height outcomes remain in the lower part of the normal range. Patients with MPHD generally had a slightly better long-term height outcome.     

Recombinant hGH replacement therapy and the hypothalamus–pituitary–thyroid axis in children with GH deficiency: when should we be concerned about the occurrence of central hypothyroidism?

OBJECTIVE: Recombinant hGH treatment may alter thyroid hormone metabolism and we have recently reported that 50% of patients with GH deficiency (GHD) due to organic lesions, previously not treated with thyroxine, developed hypothyroidism during treatment with recombinant human GH (rhGH). These results prompted us to evaluate the impact of rhGH treatment on thyroid function in children with GHD. DESIGN: Open study of GH treatment up to 12 months. Investigations were performed at baseline, and after 6 and 12 months of GH therapy. MEASUREMENT AND STUDY SUBJECTS: Serum TSH, FT4, FT3, AbTg and AbTPO, IGF-I, height and weight, were evaluated in 20 euthyroid children (group A) with idiopathic isolated GHD and in six children (group B) with multiple pituitary hormone deficiencies (MPHD) due to organic lesions. Among the latter, four already had central hypothyroidism and were on adequate LT4 replacement therapy, while two were euthyroid at the beginning of the study. RESULTS: Serum IGF-I levels normalized in all patients. In both groups, a significant reduction in FT4 levels (P < 0.01) occurred during rhGH therapy. No patient in group A had FT4 values into the hypothyroid range, while in four of six patients in group B, fell FT4 levels into the hypothyroid range during rhGH. In particular, the two euthyroid children developed central hypothyroidism during rhGH treatment, and their height velocities did not normalize until the achievement of euthyroidism through appropriate LT4 substitution. No variation in serum FT3 and TSH levels was recorded in either groups. CONCLUSION: Contrary to that observed in patients with MPHD, rhGH replacement therapy does not induce central hypothyroidism in children with idiopathic isolated GHD, further supporting the view that in children with MPHD, as in adults, GHD masks the presence of central hypothyroidism. Slow growth (in spite of adequate rhGH substitution and normal IGF-I levels) is an important clinical marker of central hypothyroidism, therefore a strict monitoring of thyroid function is mandatory in treated children with MPHD.     

Adult height in patients with permanent growth hormone deficiency with and without multiple pituitary hormone deficiencies

CONTEXT: It has been reported that patients with multiple pituitary hormone deficiencies (MPHDs) achieve a greater final height, compared with patients with isolated GH deficiency (IGHD). However, the outcome of patients with permanent GH deficiency (GHD) has not yet been reported. OBJECTIVES: The objectives of the study were to evaluate and compare adult height data and the effect of spontaneous or induced puberty after long-term treatment with GH in young adults with either permanent IGHD or MPHD. DESIGN AND SETTING: This was a retrospective multicenter study conducted in university research hospitals and a tertiary referral endocrine unit. PATIENTS AND METHODS: Thirty-nine patients with IGHD (26 males, 13 females) and 49 with MPHD (31 males, 18 females), diagnosed at a median age of 7.7 and 6.9 yr, respectively, were reevaluated for GH secretion after adult height achievement (median age 17.6 and 19.8 yr). The diagnosis of permanent GHD was based on peak GH levels less than 3 microg/liter after an insulin tolerance test or peak GH levels less than 5 microg/liter after two different tests. Fifteen subjects had idiopathic GHD and seventy-three had magnetic resonance imaging evidence of congenital hypothalamic-pituitary abnormalities. Height sd score (SDS) was analyzed at diagnosis, the onset of puberty (either spontaneous or induced), and the time of GH withdrawal. RESULTS: The subjects with IGHD entered puberty at a median age of 12.6 yr (females) and 13.4 yr (males). Puberty was induced at a median age of 13.5 and 14.0 yr, respectively, in males and females with MPHD. Median height SDS at the beginning of puberty was similar in the IGHD and MPHD subjects. Total pubertal height gain was similar between patients with IGHD or MPHD. Median adult height was also not significantly different between IGHD and MPHD patients (males, 168.5 vs. 170.3 cm; females, 160.0 vs. 157.3 cm). The adult height SDS of the IGHD subjects was positively correlated with height at the time of diagnosis and with total pubertal height gain. Conversely, the adult height SDS of the MPHD subjects was positively correlated with both the duration of GH treatment and height SDS at the time of GHD diagnosis. CONCLUSIONS: Adult height in patients with permanent IGHD and spontaneous puberty is similar to adult height in patients with MPHD and induced puberty.     

Role of magnetic resonance imaging in the diagnosis and prognosis of growth hormone deficiency

OBJECTIVE In patients with congenital GH deficiency (GHD), magnetic resonance Imaging (MRI) has revealed morphological abnormalities such as pituitary hypoplasia, absence of the stalk and ectopia of the posterior pituitary (PPE). Our study was aimed at investigating the possible relationship between neuroradioiogical Images and the presence of Isolated GH or multiple pituitary hormone deficiency. DESIGN We studied 121 patients, aged 0.3–25 years, with Isolated GHD (IGHD, 81 cases) or multiple pituitary hormone deficiency (MPHD, 40 cases). Of 81 IGHD patients, 50 were at prepubertal and 22 at pubertal age, while 9 had a delayed onset of puberty. Out of 40 MPHD patients, 25 were at prepubertal age and 15 at the age of puberty. RESULTS Pituitary hypoplasia, defined as a gland with a height of less than ?2 SD for age, was observed more frequently in prepubertal (66%) than pubertal (18%) IGHD patients. It was also found in the majority of MPHD patients of prepubertal (76%) and pubertal age (80%), and of IGHD patients with delayed onset of puberty (100%). Mean ± SEM pituitary height was significantly lower (P < 0.001) In both prepubertal IGHD (?2.70 ± 0.20 SD) and MPHD children (?3.10 ± 0.39 SD) than in IGHD patients with normal onset of puberty (?1.55 ± 0.2 SD). A significantly greater pituitary height was observed in IGHD patients with normal onset of puberty (?1.55 ± 0.20 SD) than In MPHD patients at the age of puberty (?4.38 ± 0.61 SD, P < 0.001) and in IGHD subjects with delayed onset of puberty (?4.06 ± 0.41 SD, P < 0.001). An Important Increase (P < 0.02) in the height of the pituitary gland was found in 6 of the 9 patients with delayed puberty when they were re-evaluated after completing their spontaneous pubertal development. The frequency of other MRI abnormalities (PPE, stalk transection) was significantly higher in MPHD patients than In IGHD patients (P < 0.001). CONCLUSION Our results confirm the usefulness of MRI In the evaluation of children affected by GH deficiency. The association of gland hypoplasia with other MR abnormalities could suggest the presence of multiple anterior pituitary deficiencies. Finally, puberty seems to play an important role in the increase of pituitary size in multiple pituitary hormone deficiency and isolated GH deficiency patients.     

Hypothalamic-pituitary dysfunction in growth hormone-deficient patients with pituitary abnormalities

Hypothalamic-pituitary function was studied in 45 patients with idiopathic GH deficiency (GHD), 33 of whom had pituitary abnormalities on magnetic resonance imaging: pituitary hypoplasia, undescended stalk and ectopia of the posterior lobe in 8 patients with isolated GHD (IGHD) (group I) and in 12 patients with multiple pituitary hormone deficiency (MPHD) (group II); isolated pituitary hypoplasia in 13 patients with IGHD (group III); no evidence of pituitary abnormalities in the remaining 12 patients with IGHD (group IV). Sellar and pituitary volumes were significantly lower in groups I, II, and III than in group IV (P less than 0.001). No significant differences were observed between group I and group II in the GH response to GHRH1-44 expressed both as peak serum GH and area under the curve. Mean GH peak in group III and IV was significantly higher than that in group I (P less than 0.005) and II (P less than 0.001), as were the mean AUC (P less than 0.005), suggesting hypothalamic defect. Delayed peak serum TSH after TRH was found in all patients of group II, and overt hypothyroidism in 11 of them. Furthermore, basal hyperprolactinemia was present in 6 patients and adrenal insufficiency in 7 cases of group II. Finally, a reduced response of FSH to GnRH was observed in all these patients (P less than 0.005 vs. each of the other groups), and clinical hypogonadism was present in all of them. We suggest that: 1) A high incidence of pituitary abnormalities seems to be present in idiopathic GHD patients; 2) Pituitary hormone deficiencies are more dependent on the type of the hypothalamic-pituitary abnormality than on the size of the pituitary per se: the association of pituitary hypoplasia, undescended stalk and ectopia of the posterior lobe should possibly be considered a distinct entity reflecting an early abnormality in hypothalamic development; 3) The majority of patients with IGHD or MPHD probably have a primary hypothalamic releasing hormone deficiency even if pituitary hypoplasia is associated; 4) Magnetic resonance imaging may have a role in the diagnosis and prognosis of patients with GHD through differentiation between patients who are at risk for developing MPHD vs. those who are candidates for having a persistently isolated GHD.     

MRI findings of the pituitary gland in short children born small for gestational age (SGA) in comparison with growth hormone-deficient (GHD) children and children with normal stature

BACKGROUND: Disturbances in the GH/IGF-I axis are reported in 25-60% of short children born small for gestational age (SGA). We hypothesized that these abnormalities might be related to abnormalities in the pituitary region. Therefore, the results of magnetic resonance imaging (MRI) of short SGA children were compared to MRI results of other groups of short children and to normal controls. PATIENTS AND METHODS: MRI was performed in four groups of short children: SGA children without GH deficiency (SGA group; n = 17), SGA children with isolated GH deficiency (SGA + IGHD group; n = 10), non-SGA children with isolated GH deficiency (IGHD group; n = 24) and non-SGA children with multiple pituitary hormone deficiencies (MPHD group; n = 15). MRI was also performed in children with normal stature (control group; n = 13). Pituitary height (PH) and thickness of the pituitary stalk (PS) were measured and their relationship with the maximum GH peak during a GH stimulation test, serum IGF-I and IGFBP-3 levels was evaluated. RESULTS: Short SGA children either with or without IGHD did not show major anatomical abnormalities in the hypothalamic-pituitary region in contrast to 58% of the non-SGA IGHD children and 87% of the MPHD children who had anatomical abnormalities. PH in SGA children without GHD was normal whereas it was significantly lower in SGA children with IGHD. The lowest PHs were measured in non-SGA children with MPHD. A moderate decrease in PH was associated with significantly lower maximum serum GH peaks and lower serum IGF-I and IGFBP-3 levels. CONCLUSION: Measuring PHs in children with less severe GHD, who underwent MRI as part of the diagnostic process, might support the diagnosis of GHD even in the absence of anatomical abnormalities. Our study demonstrates that there is no indication to perform MRI of the pituitary region in short children born SGA without GHD.     

Diagnosis of GH deficiency in the transition period: accuracy of insulin tolerance test and insulin-like growth factor-I measurement

OBJECTIVE: A consensus exists that severe growth hormone deficiency (GHD) in adults is defined by a peak GH response to insulin-induced hypoglycemia (insulin tolerance test, ITT) of less than 3 microg/l based on a cohort of subjects with a mean age of 45 years. DESIGN AND METHODS: By considering one of the following two criteria for the diagnosis of probable permanent GHD, i.e. the severity of GHD (suggested by the presence of multiple pituitary hormone deficiencies (MPHD)) or the magnetic resonance (MR) imaging identification of structural hypothalamic-pituitary abnormalities, 26 patients (17 males, 9 females, mean age 20.8 +/- 2.3 years, range 17-25 years) were selected for re-evaluation of the GH response to ITT and their IGF-I concentration. Eight subjects had isolated GHD (IGHD) and 18 had MPHD. Normative data for peak GH were obtained after ITT in 39 healthy subjects (mean age 21.2 +/- 4.4 years, range 15.1-30.0 years) and the reference range for IGF-I was calculated using normative data from 117 healthy individuals. RESULTS: Mean peak GH response to ITT was significantly lower in the 26 patients (1.8+/-2.0 microg/l, range 0.1-6.1 microg/l) compared with the 39 controls (18.5 +/- 15.5 microg/l, range 6.1-84.0 microg/l; P < 0.0001). One subject with septo-optic dysplasia had a peak GH response of 6.1 microg/l that overlapped the lowest peak GH response obtained in normal subjects. There was an overlap for IGF-I SDS between subjects with IGHD and MPHD, as well as with normal controls. The diagnostic accuracy of a peak GH response of 6.1 microg/l showed a 96% sensitivity with 100% specificity. The maximum diagnostic accuracy with IGF-I SDS was obtained with a cut-off of -1.7 SDS (sensitivity 77%, specificity 100%) while an IGF-I < or = - 2.0 SDS showed a sensitivity of 62%. CONCLUSION: Our data show that the cut-off value of the peak GH response to ITT of less than 3 microg/l or 5 microg/l and of IGF-I of less than -2.0 SDS are too restrictive for the diagnosis of permanent GH deficiency in the transition period. We suggest that permanent GHD could be investigated more accurately by means of an integrated analysis of clinical history, the presence of MPHD, IGF-I concentration and the MR imaging findings of structural hypothalamic-pituitary abnormalities.     

Evaluation of adult idiopathic growth hormone deficiency with other pituitary hormones deficiency

The type and percentage of multiple pituitary hormone deficiency (MPHD) were studied in 42 patients with idiopathic growth hormone deficiency (IGHD). It was found that the development of secondary sexual characteristics was poor or absent in 39 patients (93%) with gonadotropin deficiency (GnD). Mean serum testosterone (T), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the 39 patients were significantly less than those of normal adult males (P less than 0.01). Mean testicular volume in 36 patients with GnD was significantly less than that in 3 with normal T level. We also found that 24-hour urinary free cortisol level (24 hour UFC) was low in 24 (57.1%) of 42 patients, but it is important that none had obvious symptoms of hypoadrenocorticism such as hypoglycemia, hypotension etc and received adrenal-corticosteroid treatment. 22 (52.4%) of the 42 patients suffered from hypothyroidism, with serum thyroxine (T4) level lower than normal but thyrotrophin (TSH) within normal range. 6 patients with hypothyroidism had moderate symptoms such as cold intolerance, constipation, rough and dry skin, slowing down both mentally and physically. 17 patients have treated with thyroxine. From the results mentioned above, 14 of the 41 patients with MPHD had pan-pituitary hormones (LH, FSH, TSH, ACTH) deficiency, only one had isolated growth hormone deficiency. Among all the patients, 23 underwent breech delivery and 11 patients had birth asphyxia. We therefore conclude that: (1) most of the IGHD cases are complicated with other pituitary hormone deficiency; (2) most of the IGHD cases have with MPHD; (3) Breech delivery and birth asphyxia were important etiological factors of IGHD.