The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism.
The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism.
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DOI：
10.1210/jcem.87.1.8131
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发表时间：
2002
期刊：
影响因子：
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通讯作者：
Nelly Pitteloud;Frances J. Hayes;P. Boepple;Suzzunne DeCruz;S. Seminara;D. Maclaughlin;William F. Crowley
中科院分区：
文献类型：
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作者：
Nelly Pitteloud;Frances J. Hayes;P. Boepple;Suzzunne DeCruz;S. Seminara;D. Maclaughlin;William F. Crowley
随着我们对特发性低促性腺激素性性腺功能减退症 (IHH) 分子机制了解的不断深入，定义 IHH 表型谱变得越来越重要。在这项研究中，我们检查了 78 名 IHH 男性的历史、临床、生化、组织学和遗传特征，以进一步了解该综合征的表型异质性。我们假设至少某些表型谱可以通过将该疾病置于发育和遗传背景中来解释。 38% 的人口患有卡尔曼综合征（KS；IHH 伴嗅觉丧失），54% 的人患有正常嗅觉 IHH，8% 的人在青春期完成后获得 IHH。从表型上看，KS 代表最严重的亚型（87% 完全没有任何自发性青春期发育的病史或体征），正常性 IHH 显示出最大的异质性（41% 有一些自发性青春期的证据），青春期完成后获得的 IHH 集中在最温和的末端（均具有完全青春期）。基于先前青春期发育的历史或临床证据而不是嗅觉的存在或不存在的分类有助于在其他临床和生化特征方面更清楚地区分人群。根据先前青春期发育的缺失（68%）或存在（24%）来比较 IHH 患者，发现睾丸大小（3.3 +/- 0.2 与 11.8 +/- 1.2 ml；P < 0.001）、隐睾发生率（40% 与 5%；P < 0.05）、小阴茎（21% 与 0%；P < 0.05）存在显着差异。 0.05）、抑制素 B 水平（45 +/- 4 与 144 +/- 20 pg/ml；P < 0.0001）和苗勒管抑制物质水平（9.8 +/- 1.4 与 2 +/- 0.5 ng/ml）。大多数家族性病例没有青春期发育（95% vs. 5%；P < 0.001）； KAL 基因突变的男性表现出最严重的表型。缺乏促性腺激素的患者之间，平均促性腺激素水平（LH，1.8 +/- 0.1 vs. 2.9 +/- 0.4 IU/升；FSH，2.2 +/- 0.2 vs. 3.3 +/- 0.3 IU/升；P < 0.05）和基于频繁采样的搏动性 LH 分泌发现（80% vs. 55%；P < 0.05）之间存在统计学差异。以及表现出部分青春期发育的人，但重叠范围广泛。利用临床参数（是否存在青春期发育、隐睾和小阴茎的一些证据）、睾丸生长和分化的生化标志物（抑制素 B 和苗勒管抑制物质）以及遗传证据，可以深入了解 GnRH 缺乏的发病时间和严重程度。在 IHH 的发育、遗传和生化复杂性的完整背景下观察 IHH，可以最深入地了解其表型变异性。
As our knowledge of the molecular mechanisms underlying idiopathic hypogonadotropic hypogonadism (IHH) expands, it becomes increasingly important to define the phenotypic spectrum of IHH. In this study we examined historical, clinical, biochemical, histological, and genetic features in 78 men with IHH to gain further insight into the phenotypic heterogeneity of the syndrome. We hypothesized that at least some of the spectrum of phenotypes could be explained by placing the disorder into a developmental and genetic context. Thirty-eight percent of the population had Kallmann syndrome (KS; IHH with anosmia), 54% had normosmic IHH, and 8% had acquired IHH after completion of puberty. Phenotypically, KS represented the most severe subtype (87% with complete absence of any history or signs of spontaneous pubertal development), normosmic IHH displayed the most heterogeneity (41% with some evidence of spontaneous puberty), and acquired IHH after completion of puberty clustered at the mildest end (all had complete puberty). Classification based on historical or clinical evidence of prior pubertal development, rather than the presence or absence of sense of smell, served to distinguish the population more clearly with respect to other clinical and biochemical features. Comparing IHH patients according to the absence (68%) or presence (24%) of some prior pubertal development revealed significant differences in testicular size (3.3 +/- 0.2 vs. 11.8 +/- 1.2 ml; P < 0.001), incidence of cryptorchidism (40% vs. 5%; P < 0.05), microphallus (21% vs. 0%; P < 0.05), inhibin B levels (45 +/- 4 vs. 144 +/- 20 pg/ml; P < 0.0001), and Mullerian inhibitory substance levels (9.8 +/- 1.4 vs. 2 +/- 0.5 ng/ml). Most familial cases had no pubertal development (95% vs. 5%; P < 0.001); males with mutations in the KAL gene displayed the most severe phenotype. Mean gonadotropins levels (LH, 1.8 +/- 0.1 vs. 2.9 +/- 0.4 IU/liter; FSH, 2.2 +/- 0.2 vs. 3.3 +/- 0.3 IU/liter; P < 0.05) and the finding of apulsatile LH secretion based on frequent sampling (80% vs. 55%; P < 0.05) were statistically different between patients lacking and those exhibiting partial pubertal development, but the overlap was extensive. The use of clinical parameters (presence or absence of some evidence of prior pubertal development, cryptorchidism, and microphallus), biochemical markers of testicular growth and differentiation (inhibin B and Mullerian inhibitory substance), and genetic evidence provides insight into the time of onset and the severity of GnRH deficiency. Viewing IHH in the full context of its developmental, genetic, and biochemical complexity permits greatest insight into its phenotypic variability.