Kisspeptin-54 accurately identifies hypothalamic GnRH neuronal dysfunction in men with congenital hypogonadotropic hypogonadism

2020 ◽  
Author(s):  
Ali Abbara ◽  
Pei Chia Eng ◽  
Maria Phylactou ◽  
Sophie A. Clarke ◽  
Edouard Mills ◽  
...  
Keyword(s):  
Neuronal Migration ◽  
Hypogonadotropic Hypogonadism ◽  
Neuronal Function ◽  
Specific Test ◽  
Healthy Men ◽  
Pituitary Dysfunction ◽  
Pathogenic Variants ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Gnrh Release ◽  
Hypothalamic Function

Background: Hypogonadotropic hypogonadism is hypogonadism due to either hypothalamic or pituitary dysfunction. Whilst gonadotropin releasing hormone (GnRH) can directly test pituitary function, no specific test of hypothalamic function exists. Kisspeptin-54 (KP54) is a neuropeptide that directly stimulates hypothalamic GnRH-release and thus could be used to specifically interrogate hypothalamic function. Congenital Hypogonadotropic Hypogonadism (CHH) is typically due to variants in genes that control hypothalamic GnRH neuronal migration of function. Thus, we investigated whether KP54 could accurately identify hypothalamic dysfunction in men with CHH. Methods: Men with CHH (n=21) and healthy eugonadal men (n=21) received an intravenous bolus of either GnRH (100mcg), or KP54 (6.4nmol/kg), on two occasions, and were monitored for 6hrs after administration of each neuropeptide. Results: Maximal LH-rise after KP54 was significantly greater in healthy men (12.5 iU/L) than in men with CHH (0.4 iU/L; P<0.0001). KP54 more accurately differentiated CHH men from healthy men than GnRH (auROC curve KP54: 1.0, 95%CI 1.0-1.0; GnRH: 0.88, 95%CI 0.76-0.99). Indeed, all CHH men had an LH-rise <2.0 iU/L following KP54, whereas all healthy men had an LH-rise >4.0 iU/L. Anosmic men with CHH (i.e. Kallmann syndrome) had even lower LH-rises after KP54 than did normosmic men with CHH (P=0.017). Likewise, men identified to have pathogenic/likely pathogenic variants in CHH genes had even lower LH-rises after KP54 than other men with CHH (P=0.035). Conclusion: KP54 fully discriminated men with CHH from healthy men. Thus, KP54 could be used to specifically interrogate hypothalamic GnRH neuronal function in patients with congenital hypogonadotropic hypogonadism.

scholarly journals New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism

2019 ◽  
Vol 181 (2) ◽  
pp. 103-119 ◽  
Author(s):  
Lorena Guimaraes Lima Amato ◽  
Luciana Ribeiro Montenegro ◽  
Antonio Marcondes Lerario ◽  
Alexander Augusto Lima Jorge ◽  
Gil Guerra Junior ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Rare Variants ◽  
Hypogonadotropic Hypogonadism ◽  
Splice Site Mutation ◽  
Rare Condition ◽  
Large Cohort ◽  
Site Mutation ◽  
Clinical Genetic ◽  
Pathogenic Variants ◽  
Congenital Hypogonadotropic Hypogonadism

Context Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. Several genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. The advent of next-generation sequencing (NGS) has allowed the simultaneous genotyping of several regions, faster, making possible the extension of the genetic knowledge of CHH. Objective Genetic characterization of a large cohort of Brazilian CHH patients. Design and patients A cohort of 130 unrelated patients (91 males, 39 females) with CHH (75 normosmic CHH, 55 Kallmann syndrome) was studied using a panel containing 36 CHH-associated genes. Results Potential pathogenic or probably pathogenic variants were identified in 43 (33%) CHH patients. The genes ANOS1, FGFR1 and GNRHR were the most frequently affected. A novel homozygous splice site mutation was identified in the GNRH1 gene and a deletion of the entire coding sequence was identified in SOX10. Deleterious variants in the IGSF10 gene were identified in two patients with reversible normosmic CHH. Notably, 6.9% of the patients had rare variants in more than one gene. Rare variants were also identified in SPRY4, IL17RD, FGF17, IGSF1 and FLRT3 genes. Conclusions This is a large study of the molecular genetics of CHH providing new genetic findings for this complex and heterogeneous genetic condition. NGS has been shown to be a fast, reliable and effective tool in the molecular diagnosis of congenital CHH and being able to targeting clinical genetic testing in the future.

scholarly journals NDNF variants are rare in patients with congenital hypogonadotropic hypogonadism

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Satoshi Tamaoka ◽  
Erina Suzuki ◽  
Atsushi Hattori ◽  
Tsutomu Ogata ◽  
Maki Fukami ◽  
...  
Keyword(s):  
Splice Site ◽  
Genetic Heterogeneity ◽  
Hypogonadotropic Hypogonadism ◽  
Causative Gene ◽  
Synonymous Substitutions ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Site Recognition

AbstractAlthough NDNF was recently reported as a novel causative gene for congenital hypogonadotropic hypogonadism (CHH), this conclusion has yet to be validated. In this study, we sequenced NDNF in 61 Japanese CHH patients. No variants, except for nine synonymous substitutions that appear to have no effect on splice-site recognition, were identified in NDNF coding exons or flanking intronic sequences. These results indicate the rarity of NDNF variants in CHH patients and highlight the genetic heterogeneity of CHH.

scholarly journals Neuron-Derived Neurotrophic Factor Is Mutated in Congenital Hypogonadotropic Hypogonadism

2020 ◽  
Vol 106 (1) ◽  
pp. 58-70 ◽  
Author(s):  
Andrea Messina ◽  
Kristiina Pulli ◽  
Sara Santini ◽  
James Acierno ◽  
Johanna Känsäkoski ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
Hypogonadotropic Hypogonadism ◽  
Congenital Hypogonadotropic Hypogonadism

scholarly journals Endocrine Dysfunction in Prader-Willi Syndrome: A Review with Special Reference to GH

2001 ◽  
Vol 22 (6) ◽  
pp. 787-799 ◽  
Author(s):  
Pia Burman ◽  
E. Martin Ritzén ◽  
Ann Christin Lindgren
Keyword(s):  
Replacement Therapy ◽  
Lean Body Mass ◽  
Body Mass ◽  
Genetic Disorder ◽  
Hormone Replacement ◽  
Hypogonadotropic Hypogonadism ◽  
Endocrine Disorders ◽  
Prader Willi Syndrome ◽  
Gh Treatment ◽  
Pituitary Dysfunction

Abstract Prader-Willi syndrome is a genetic disorder occurring in 1 in 10,000–16,000 live-born infants. In the general population, approximately 60 people in every 1,000,000 are affected. The condition is characterized by short stature, low lean body mass, muscular hypotonia, mental retardation, behavioral abnormalities, dysmorphic features, and excessive appetite with progressive obesity. Furthermore, morbidity and mortality are high, probably as a result of gross obesity. Most patients have reduced GH secretory capacity and hypogonadotropic hypogonadism, suggesting hypothalamic-pituitary dysfunction. Replacement of GH and/or sex hormones may therefore be beneficial in Prader-Willi syndrome, and several clinical trials have now evaluated GH replacement therapy in affected children. Results of GH treatment have been encouraging: improved growth, increased lean body mass, and reduced fat mass. There was also some evidence of improvements in respiratory function and physical activity. The long-term benefits of GH treatment are, however, still to be established. Similarly, the role of sex hormone replacement therapy needs to be clarified as few data exist on its efficacy and potential benefits. In summary, Prader-Willi syndrome is a disabling condition associated with GH deficiency and hypogonadism. More active treatment of these endocrine disorders is likely to benefit affected individuals.

Compromised Volumetric Bone Density and Microarchitecture in men with Congenital Hypogonadotropic Hypogonadism

2021 ◽  
Author(s):  
Agnès Ostertag ◽  
Georgios E Papadakis ◽  
Corinne Collet ◽  
Severine Trabado ◽  
Luigi Maione ◽  
...  
Keyword(s):  
Bone Markers ◽  
Bone Structure ◽  
Hypogonadotropic Hypogonadism ◽  
Quantitative Computed Tomography ◽  
Hormonal Treatment ◽  
Mineral Density ◽  
Trabecular Microarchitecture ◽  
Trabecular Thickness ◽  
Congenital Hypogonadotropic Hypogonadism

Abstract Context Men with Congenital Hypogonadotropic Hypogonadism (CHH) and Kallmann syndrome (KS) have both low circulating testosterone and estradiol levels. Whether bone structure is affected remains unknown. Objective To characterize bone geometry, volumetric density and microarchitecture in CHH/KS. Design Cross-sectional study. Setting One tertiary academic French center. Patients and Controls 51 genotyped CHH/KS patients and 40 healthy volunteers were included. Ninety-eight percent of CHH/KS men had received testosterone and/or combined gonadotropins. Intervention(s) High-resolution Peripheral Quantitative Computed Tomography (HR-pQCT), Dual X-ray absorptiometry (DXA) and measurement of serum bone markers. Main Outcome Volumetric bone mineral density (vBMD), cortical and trabecular microarchitecture. Results CHH and controls did not differ for age, BMI, vitamin D and PTH levels. Despite long-term hormonal treatment (10.8 ± 6.8 years), DXA showed lower areal BMD in CHH/KS at lumbar spine, total hip, femoral neck and distal radius. Consistent with persistently higher serum bone markers, HR-pQCT revealed lower cortical and trabecular vBMD as well as cortical thickness at the tibia and the radius. CHH/KS men had altered trabecular microarchitecture with a predominant decrease of trabecular thickness. Moreover, CHH/KS men exhibited lower cortical bone area, whereas total and trabecular areas were higher only at the tibia. Earlier treatment onset (before the age of 19 years) conferred a significant advantage for trabecular bone volume/tissue volume and trabecular vBMD at the tibia. Conclusion Both vBMD and bone microarchitecture remain impaired in CHH/KS men despite long-term hormonal treatment. Treatment initiation during adolescence is associated with enhanced trabecular outcomes, highlighting the importance of early diagnosis.

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