Idiopathic Hypogonadotropic Hypogonadism Patients Research Articles

Clinical and molecular features of 40 Chinese patients with idiopathic hypogonadotropic hypogonadism.

Male idiopathic hypogonadotropic hypogonadism (IHH) is a heterogeneous clinical rare genetic disorder that can be divided into two forms: Kallmann syndrome (KS) and olfactory normal IHH (nIHH). Nearly half of unknown pathogenic genes and related pathogenic mechanisms have yet to be explored. Clinical data of 40 IHH patients (22 KS and 18 nIHH) were retrospectively recorded. All patients were diagnosed at the Department of Endocrinology of Jinling Hospital, Jiangsu Provincial People's Hospital, and the First Affiliated Hospital of the University of Science and Technology of China from 2014 to 2021. The proband genomic DNA (gDNA) was confirmed by whole exome sequencing (WES) and Sanger sequencing. Ten new genetic mutations related to IHH in four families and eight sporadic unrelated IHH patients were identified. The total positive detection rate of 40 patients was 30% (nIHH 8/18 + KS 4/22), and the FGFR1 mutation rate accounted for 7.5% (3/40). Mutation rates of ANOS1, CHD7, and KISS1R were 5% (2/40), respectively. The mutation rates of SEMA3E, PROKR2, and SOX10 were 2.5% (1/40), respectively. After analysis by SIFT and PolyPhen-2 software, all missense mutation sites, such as SEMA3E (p.P323S), CHD7 (p.W1785C), PROKR2 (p.Y223D and p.R298C), were harmful; all nonsense mutation sites, such as FGFR1 (p.R661X) and KISS1R (p.R331X, p.Y103X), analyzed were pathogenic by Mutation Taster software. The comparison of MEGA5 software showed that all the variants had extremely high homology among different species and were extremely conservative in evolution. The study aims to expand the genotype mutation spectrum of IHH and provide evidence for the follow-up clinical treatment and genetic counseling of the disease.

Clinical Manifestations, Genetic Variants and Therapeutic Evaluation in Sporadic Chinese Patients with Idiopathic Hypogonadotropic Hypogonadism.

Genetic factors account for a large proportion of idiopathic hypogonadotropic hypogonadism (IHH) etiologies, although not necessarily a complete genetic basis. This study aimed to characterize the clinical presentations, genetic variants, and therapeutic outcomes of patients with sporadic IHH, which may be helpful for genetic counseling and treatment decisions. Eleven Chinese patients with IHH were retrospectively analyzed. Rare genetic variants were evaluated using whole-exome sequencing and bioinformatics analysis and were further classified according to the ACMG-AMP guidelines. The therapeutic responses of patients were further evaluated. Six heterozygous variants of SOX10, WDR11, PROKR2, CHD7 and FGF17 were detected in five Kallmann syndrome (KS) patients, whereas two heterozygous variants of CHD7 and PROKR2 were detected in two normosmic IHH (nIHH) patients. Among these variants, a novel likely pathogenic variant in the SOX10 (c.429-1G>C) was considered to cause the KS phenotype in patient 02, and two potential variants of uncertain significance (VUS) in CHD7 (c.3344G>A and c.7391A>G) possibly contributed to the KS phenotype in patient 05 and the nIHH phenotype in patient 07, which need to be confirmed by further evidence. Additionally, long-term testosterone or estradiol replacement treatment effectively improved the development of sexual characteristics in patients with IHH. Next-generation sequencing is a powerful tool for identifying the molecular etiology and early diagnosis of IHH. Efficient therapeutic outcomes strongly indicate a need for timely treatment.

POU6F2 mutation in humans with pubertal failure alters GnRH transcript expression.

Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by the absence of pubertal development and subsequent impaired fertility often due to gonadotropin-releasing hormone (GnRH) deficits. Exome sequencing of two independent cohorts of IHH patients identified 12 rare missense variants in POU6F2 in 15 patients. POU6F2 encodes two distinct isoforms. In the adult mouse, expression of both isoform1 and isoform2 was detected in the brain, pituitary, and gonads. However, only isoform1 was detected in mouse primary GnRH cells and three immortalized GnRH cell lines, two mouse and one human. To date, the function of isoform2 has been verified as a transcription factor, while the function of isoform1 has been unknown. In the present report, bioinformatics and cell assays on a human-derived GnRH cell line reveal a novel function for isoform1, demonstrating it can act as a transcriptional regulator, decreasing GNRH1 expression. In addition, the impact of the two most prevalent POU6F2 variants, identified in five IHH patients, that were located at/or close to the DNA-binding domain was examined. Notably, one of these mutations prevented the repression of GnRH transcripts by isoform1. Normally, GnRH transcription increases as GnRH cells mature as they near migrate into the brain. Augmentation earlier during development can disrupt normal GnRH cell migration, consistent with some POU6F2 variants contributing to the IHH pathogenesis.

Clinical and Biochemical Characteristics of Male Idiopathic Hypogonadotropic Hypogonadism Patients: A Retrospective Cross Sectional Study.

Idiopathic hypogonadotropic hypogonadism (IHH) is a medical condition where there is a deficiency or insensitivity of gonadotropin-releasing hormone (GnRH) without a known cause. Not only are the sexual characteristics of a person affected by this condition but also are the psychological and physical development, thus necessitating its early recognition and treatment. This research was carried out to identify the laboratory parameters and to present symptoms of the patients with complaints of IHH. This retrospective, center, single-center, cross-sectional study was carried out in Aga Khan University from December 2000 until December 2020 on the patients that presented to the clinic with IHH. The patients included in the study were those that presented with hypogonadism, a low concentration of sex steroid hormone, and an abnormal gonadotropin level without any expansive pituitary or hypothalamic lesion. Seventy nine patients presenting with IHH were included with their mean age of 24.2 ± 7.5 years. Of these, 64 (81.0%) had genital atrophy, 50 (63.6%) showed an absence of secondary sexual characteristics, 53 (67.1%) complained of infertility, 44 (55.7%) had not shown signs of puberty, 52 (65.8%) had erectile dysfunction, 46 (58.2%) had a decrease in libido, 11(13.9%) had a previous familial history, 24 (30.3%) had gynecomastia, 9 (11.4%) had non-descended testes, and 6 (7.6%) had anosmia. These patients had serum testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels of 26.3 ± 60, 1.3 ± 2.4, and 2.7 ± 5.0 (IU/L), respectively. Thus, it can be stated that small genitalia is the most common complaint among patients with IHH, followed by infertility and lack of secondary sexual characteristics. The testosterone level in serum is also found to be low among these patients.

Relations Between Body Fat Mass and Insulin Resistance in Non-Obese Patients with Idiopathic Hypogonadotropic Hypogonadism and Normal Glucose Tolerance.

The purpose of this study was to investigate the relationship between body fat mass and insulin resistance in non-obese patients with idiopathic hypogonadotropic hypogonadism (IHH) and normal glucose tolerance. A total of 42 patients with IHH and normal glucose tolerance, and BMI lower than 28 kg/m2 were recruited. Patients were required to have a normal glucose tolerance test for inclusion in the study. Ten Healthy subjects were recruited as control group. Laboratory studies included fasting insulin, testosterone, and lipids. Waist circumference (WC), weight, and body fat mass were measured, and waist-to-hip ratio (WHR), body mass index (BMI), HOMA-IR, and logHOMA-B were calculated. Data were compared between groups, and linear regression was used to determine relations. Blood pressure, fasting glucose, BMI, WHR, and lipids were similar between the groups. Fasting insulin levels (15.61±7.66 mIU/l vs. 7.60±3.84 mIU/l), logHOMA-B (2.39±0.29 vs. 2.03±0.21), HOMA-IR (3.38±1.71 vs. 1.64±0.91), and body fat mass (30.49±9.46% vs. 21.11±4.31%) were significantly greater in the IHH group compared with those in control group (all p<0.05). Multivariable linear regression showed that in IHH patients body fat mass was an independent predictor of fasting insulin level (β=0.71, p<0.01), logHOMA-B (β=0.02, p<0.05), and HOMA-IR (β=0.14, p<0.05). Body fat mass is an independent predictor of insulin resistance in non-obese IHH patients with normal glucose tolerance.

Reversal of idiopathic hypogonadotropic hypogonadism in a Chinese male cohort.

Idiopathic hypogonadotropic hypogonadism (IHH) is a rare genetically heterogeneous disease and characterized by incomplete or absent puberty and infertility. It is worth noting that partial IHH patients could recover reproductive endocrine function following treatment, which is termed reversal. This study aimed to investigate clinical and genetic characteristics of IHH reversal patients. A total of 141 IHH male patients were enrolled and followed up regularly. Their clinical and genetic features were collected and analysed to discover something in common in reversal cases. These IHH patients with a median age of 21 years (interquartile range: 18-24) were divided into reversal group (n=13) and non-reversal group (n=128). IL17RD, ERBB4, DLX5, EGFR, SEMA4D, B3GNT1 and CCKAR RSVs were demonstrated in reversal cases for the first time. Pathogenic/likely pathogenic (P/LP) RSVs consisted of 3 RSVs (one each patient, including PROKR2 p.W178S, EGFR p.G630R and CCKAR p.S291del) in reversal group. Reversal of IHH could not be ignored in clinical follow-up. Patients with high levels of basal LH and T may harbour more possibility of reversal and worthy extra attention to identify whether reversal occurs or not. Relapse after reversal also needs to be monitored.

Analysis of PROKR2 gene mutation in patients with hypogonadotropic hypogonadism

To investigate the clinical and genetic characteristics of patients with idiopathic hypogonadotropic hypogonadism (IHH), the clinical data of 23 patients with IHH were retrospectively analyzed. Gene analyses were accomplished with whole-exome sequencing (WES) and Sanger sequencing. Functional prediction of mutation sites was conducted using two bioinformatics platforms, SIFT and Polyphen. Among the 23 patients with IHH, 9 patients carried prokinin 2 (PROKR2) gene mutations including 4 missense mutations (p.W178S, p.Y113H, p.A103V, p.R164Q), and 1 frameshift mutation (p.D42delinsDED), the remaining 14 cases were found negative in gene sequencing. Functional prediction showed that the above mutations may affect protein function suggestive of a pathogenic role of PROKR2 mutation in the patients. There were no significant differences in the levels of follicle-stimulating hormone, luteinizing hormone, testosterone, and estradiol between the IHH patients with PROKR2 gene mutation and those without. PROKR2 gene mutation might associated with IHH, and the mutations reported in the present study could enrich the pathogenic spectrum of genes.

A novel compound variant in GNRHR causing congenital idiopathic hypogonadotropic hypogonadism in a young male Korean patient.

Idiopathic hypogonadotropic hypogonadism (IHH) is a disease that shows symptoms of no or incomplete sexual maturation after 18 years old. The mutation of gonadotropin releasing hormone receptor gene (GNRHR) has been reported as the cause in 16% of total IHH patients. An 18-year-old adolescent was referred to endocrinology department for hypogonadism. He was born with cryptorchidism, had small testes at the age of 7 years, and showed low testosterone levels. Management of his hypogonadism was delayed due to his uncontrolled nephrotic syndrome. There were no abnormal findings on the brain MRI; atrophied testes discovered on his pelvis MRI; low levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone were observed. In the HCG simulation test, testosterone levels showed no significant increase, rising from 1.11 to 1.15 ng/dL. The patient harbored a novel compound heterozygous variant of c.514G>A (p.Gly172Arg) and c.113G>A (p.Arg38Gln) in the GNRHR gene. Here, we report a case of new GNRHR compound variant c.514G>A (p.Gly172Arg) and c.113G>A (p.Arg38Gln) in a Korean adolescent for hypogonadotropic hypogonadism.

Analysis of CHD7 gene variants in 22 patients with idiopathic hypogonadotropic hypogonadism

To explore clinical evaluation and genetic analysis of patients with idiopathic hypogonadotropic hypogonadism (IHH). The clinical data and phenotypes of 22 patients with IHH diagnosed and treated in our department were reviewed and analyzed. Whole-exome sequencing (WES) and Sanger method were used for variant analysis and verification. Among the 22 cases of IHH probands, 12 cases of Kalman syndrome (KS) and 10 cases of IHH (nIHH) with normal sense of smell. On physical examination, males showed short penis, small testicles, small or inconspicuous laryngeal knots, and a sharp voice. Mammary gland development, mammary gland dysplasia, primary amenorrhea, etc. in women. Sex hormone examination: Follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), estradiol (E2) levels are reduced or at the lower limit of normal. There were nine missense variants of CHD7 gene in 8 patients. Based on the American College of Medical Genetics and Genomics guidelines, the c.307T>A(p.Ser103Thr), c.3143G>A(p.Gly1048Glu), c.6956G>T (p.Arg2319Leu) and c.3145A>T (p.Ser1049Cys) variants of CHD7 gene were predicted to be likely pathogenic (PS1+PP1+PM2, PM2+PM6+PP2+PP3, PM2+PM5+PM6+PP2+PP3 and PM2+PM6+PP2+PP3), the remaining 14 cases of IHH patients had negative genetic screening. CHD7 gene variants may be related to IHH disease.

1383-P: Relationship between Body Fat Mass and Insulin Resistance in Nonobese Patients with Idiopathic Hypogonadotropic Hypogonadism and Normal Glucose Tolerance

Objective: The purpose of this study was to investigate the relations between body fat mass and insulin resistance in non-obese patients with idiopathic hypogonadotropic hypogonadism (IHH) and normal glucose tolerance. Methods: A total of 42 patients with IHH and BMI lower than 28 kg/m2 from January 2013 to October 2017 were recruited. Patients were required to have a normal glucose tolerance test for inclusion in the study. Ten Healthy subjects having a routine physical examination and a normal glucose tolerance test were also recruited as control group. Laboratory studies included fasting insulin, testosterone, and lipids. Waist circumference (WC) , weight, and body fat mass were measured, and waist-to-hip ratio (WHR) , body mass index (BMI) , HOMA-IR, and LogHOMA-B were calculated. Data were compared between groups, and linear regression was used to determine relations. Results: Blood pressure, fasting glucose, BMI, WHR, and lipids were similar between the groups. Fasting insulin levels (15.61 ± 7.66 mIU/L vs. 7.60 ± 3.84 mIU/L) , logHOMA-B (2.39 ± 0.29 vs. 2.03 ± 0.21) , HOMA-IR (3.38 ± 1.71 vs. 1.64 ± 0.91) , and body fat mass (30.49 ± 9.46% vs. 21.± 4.31%) were significantly greater in the IHH group compared with those in control group (all, P &amp;lt; 0.05) . Multivariable linear regression showed that in IHH patients body fat mass was an independent predictor of fasting insulin level (β = 0.71, 95% confidence interval [CI]: 0.54, 0.88, P &amp;lt; 0.01) , LogHOMA-B (β = 0.02, 95% CI: 0.001, 0.032, P &amp;lt; 0.05) , and HOMA-IR (β = 0.14, 95% CI: 0.09, 0.18, P &amp;lt; 0.05) . Conclusion: Body fat mass is an independent predictor of insulin resistance in IHH patients with normal glucose tolerance. Disclosure H.Xu: None. X.Chen: None. X.Yang: None. W.Xu: None. Funding This study was supported by Natural Science Foundation of Guangdong Province [2018A030313915]; Medical Scientific Research Foundation of Guangdong Province of China [A2018286].

Unilaterally disrupted structural and functional connectivity of the fronto-limbic system in idiopathic hypogonadotropic hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) is rare and can either be associated with normal or defective olfactory sensation, classified as normosmic IHH (nIHH) or Kallmann syndrome (KS). We do not yet understand the central processing pathways in the olfactory system. We aimed to compare the resting-state structural and functional connectivity (FC) of olfactory neural pathways in patients with IHH. We hypotheses that alterations of structuralconnectivity and FC may exist in the olfactory cortex pathways in IHH patients. STRUCTURAL AND FUNCTIONAL CONNECTIVITY DATA RESULTS BETWEEN TWO GROUPS WERE ANALYZED: Patients: Twenty-five IHH patients (13 nIHH patients and 12 KS patients) were recruited from the Department of Endocrinology and were assessed. A total of 25 age-matched healthy male controls were recruited from the community. All subjects underwent diffusion tensor imaging and functional magnetic resonance imaging (fMRI) scans. Structural and functional connectivity data analyses were then performed. Pearson's correlation analyses were performed to investigate the correlations between the fractional anisotropy (FA) value and FC strength, showing significant differences among the three groups separately. Compared with the HC group, FA value in the right uncinate fasciculus (UF) decreased significantly in the IHH group. The olfactory cortex FC values of the right gyrus rectus, orbitofrontal cortex (OFC) and right middle temporal gyrus in the IHH group were decreased compared with those in the HC group. Moreover, there were significant negative correlations between right UF FA and olfactory cortex-FC to both the gyrus rectus and OFC within the HC group (p &lt; .05). Our findings suggest that alterations of structural and FC support the presence of neurobiological disruptions in IHH patients, particularly a specific structural-functional asymmetry disruption may exist in the olfactory cortex pathways in IHH patients.

PLXNB1 mutations in the etiology of idiopathic hypogonadotropic hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) comprises a group of rare genetic disorders characterized by pubertal failure caused by gonadotropin-releasing hormone (GnRH) deficiency. Genetic factors involved in semaphorin/plexin signaling have been identified in patients with IHH. PlexinB1, a member of the plexin family receptors, serves as the receptor for semaphorin 4D (Sema4D). In mice, perturbations in Sema4D/PlexinB1 signaling leads to improper GnRH development, highlighting the importance of investigating PlexinB1 mutations in IHH families. In total, 336 IHH patients (normosmic IHH, n=293 and Kallmann syndrome, n=43) from 290 independent families were included in the present study. Six PLXNB1 rare sequence variants (p.N361S, p.V608A, p.R636C, p.V672A, p.R1031H, and p.C1318R) are described in eight normosmic IHH patients from seven independent families. These variants were examined using bioinformatic modeling and compared to mutants reported in PLXNA1. Based on these analyses, the variant p.R1031H was assayed for alterations in cell morphology, PlexinB1 expression, and migration using a GnRH cell line and Boyden chambers. Experiments showed reduced membrane expression and impaired migration in cells expressing this variant compared to the wild-type. Our results provide clinical, genetic, molecular/cellular, and modeling evidence to implicate variants in PLXNB1 in the etiology of IHH.

SLIT2 Rare Sequencing Variants Identified in Idiopathic Hypogonadotropic Hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) is a rare reproductive disorder resulting from gonadotropin-releasing hormone (GnRH) deficiency. However, in only approximately half of patients with IHH is it possible to identify a likely molecular diagnosis. Mice lacking Slit2 have a reduced number or altered patterning of GnRH neurons in the brain. In order to assess the contribution of SLIT2 to IHH, we carried out a candidate gene burden test analysis. A total of 196 IHH probands and 2,362 ethic-matched controls were recruited for this study. The IHH probands and controls were subjected to whole-exome sequencing. In the IHH patients with SLIT2 variants and their available family members, detailed phenotyping and segregation analysis were performed. Nine heterozygous SLIT2 rare sequencing variants (RSVs) were identified in 13 probands, with a prevalence of 6.6%. Furthermore, we identified an increased mutational burden for SLIT2 in this cohort (odds ratio = 2.2, p = 0.021). The segregation analysis of available IHH families revealed that the majority of SLIT2 RSVs were inherited from unaffected or partially affected parents. Our study suggests SLIT2 as a new IHH-associated gene and expands the clinical and genetic spectrum of IHH. Furthermore, SLIT2 alone does not appear to be sufficient to cause the disorder, and it may interact with other IHH-associated genes to induce a clinical phenotype.

Male Idiopathic Hypogonadotropic Hypogonadism: Serum Insulin-like Growth Factor-1 and Oestradiol Levels.

Idiopathic hypogonadotropic hypogonadism (IHH) is a form of male infertility caused by a congenital defect in the secretion or action of gonadotropin-releasing hormone from the hypothalamus. Oestradiol emerged as the main sex steroid in the regulation of the hypothalamic-pituitary-testicular axis, reproductive function and growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis in men. Moreover, GH/IGF-1 axis has been suggested to play a role in IHH. This study evaluated serum IGF-1 in IHH men and controls. Furthermore, we evaluated the association between serum total oestradiol (TE2) and IGF-1 levels in patients and controls. Parameters including age, body mass index and fertility history were analysed. This prospective study was conducted at the Royan institute. In 20 men with IHH and 20 controls, serum IGF-1 levels were estimated using chemiluminescence immunoassay and serum E2 levels were assessed by means of the electrochemiluminescence method. Kolmogorov-Smirnov test, parametric t-test or the Mann-Whitney and the Pearson correlation coefficient were performed. SPSS version 22 was used for the analysis of data. There was a significant decrease in serum IGF-1 levels in IHH patients compared with controls (145.1 ± 8.9 ng/ml vs. 229.6 ± 7.3 ng/ml P < 0.001, respectively). Furthermore, a significant decrease was observed in TE2 levels in IHH male patients (12.3 ± 2.5 pg/ml) compared with controls (31.9 ± 5.3 pg/ml P < 0.001). A positive correlation was observed between serum IGF-1 and TE2 levels in the total number of participants, suggesting that E2 deficiency in IHH cases can explain the lower levels of serum IGF-1. These findings suggest that the reduction in IGF-1 levels may be associated with the influence of E2 on the GH/IGF-1 axis, and may confirm the role of the GH/IGF-1 axis in IHH. Further investigations will be required to determine the exact mechanisms by which E2 and IGF-1 affect the reproductive neuroendocrine function.

DLG2 Mutations in the Etiology of Pubertal Delay and Idiopathic Hypogonadotropic Hypogonadism

Introduction: Idiopathic hypogonadotropic hypogonadism (IHH) is caused by dysfunction of the hypothalamic-pituitary-gonadal axis. DLG2 was recently implicated as a gene associated with delayed puberty and which may also contribute to IHH. The confirmation of the candidate puberty genes in independent IHH cohorts has become crucial due to the lack of proper genotype-phenotype segregations in reported pedigrees. Therefore, we aimed to screen DLG2 in patient variants in a large cohort of IHH patients. Methods: The present study included a total of 336 IHH patients from 290 independent families. The coding and flanking regions of DLG2 were screened for potentially important variants in the WES data. Candidate variants were evaluated in the ­gnomAD and GME databases according to their allele frequencies, and only those with a frequency <0.0001 were considered rare. Detected variants were classified according to the ACMG/AMP criteria. Results: We found 1 homozygous and 2 heterozygous missense variants in 3 independent pedigrees. Identified variants were found extremely rare or not reported in gnomAD. Two variants were categorized as “uncertain significance,” and the other one was “likely pathogenic” according to the ACMG criteria. All patients were normosmic, and in 2 of the 3 families, there were no causal variants in other IHH-related genes. Conclusion: We detected 3 rare sequencing variants in DLG2 in 5 patients with IHH or delayed puberty in a large IHH cohort. Our results support the contention that the DLG2 mutations are associated with IHH in human puberty.

Discovery of a Novel Variant of SEMA3A in a Chinese Patient with Isolated Hypogonadotropic Hypogonadism.

Semaphorin (SEMA) has an important role in nerve development, organ formation, immune response, angiogenesis, and tumor growth. SEMA can regulate the growth and branching of axons, the morphology of dendrites, and the migration of neurons. The loss-of-function in SEMA and its receptors PLXNs and NRP affect the migration of GnRH neurons, leading to idiopathic hypogonadotropic hypogonadism (IHH). As a member of the SEMA family, SEMA3A has an important role in axonal rejection, dendritic branching, synaptic formation, and neuronal migration. There are more and more SEMA3A variants identified in IHH patients. In this study, we identified a novel SEMA3A variant (c.1369A > G (p.T457A)) in a male nIHH patient. Functional studies indicated that the T457A SEMA3A variant led to the defect of FAK phosphorylation and GN11 cell migration, which strongly argued in favor of its pathogenic effect in the nIHH patient. Our findings substantiated that the 435–457 position of SEMA3A might be very important for the secretion of SEMA3A. Haploin-sufficiency of SEMA3A in humans was sufficient to cause the IHH phenotype. SEMA3A variants might have a role in modifying the IHH phenotype, according to the variants at different positions of SEMA3A. SEMAs and its receptors formed a complex network, and other members of the SEMA-signaling pathway might also be involved in the pathogenesis of IHH.

Abstract #1001080: Characteristics of Male Idiopathic Hypogonadotropic Hypogonadism (IHH) Patients; an Experience from a Developing Country

Idiopathic Hypogonadotropic Hypogonadism (IHH) is a condition caused by deficiency or insensitivity to gonadotropin-releasing hormone where the pathology behind the mechanism is unknown and no secondary causes of hypogonadotropic hypogonadism are present. The condition not only affects sexual characteristic but can affect the physical and psychosocial development of a patient, therefore, making its prompt diagnoses and treatment necessary. The purpose of this study was to determine the clinical symptoms and laboratory parameters of the male IHH patients presenting in a tertiary setting.

Increased Bone Mineral Density in Male Patients With Idiopathic Hypogonadotropic Hypogonadism Who Undergo Sex Hormone Therapy: Findings From Cross-Sectional and Longitudinal Studies

ObjectiveThis retrospective observational study assessed the long-term impact of pulsatile gonadotropin-releasing hormone, combined gonadotropin, or testosterone replacement therapy on total hip, femoral, and lumbar bone mineral density (BMD) and Z-scores in adult men with idiopathic hypogonadotropic hypogonadism (IHH). MethodsIn the cross-sectional study, 69 patients were allocated to untreated (n = 42) and treated (n = 27) groups. The untreated group included IHH patients without hormone therapy history, while the treated group included age- and body mass index-matched patients who had received hormone therapy for at least 5 years. The longitudinal study included 53 IHH patients, and their hip and lumbar BMDs were measured several times during hormone therapy. We then evaluated the changes in their BMD. ResultsOur cross-sectional study showed that the treated group had a significantly higher BMD and Z-score for total hip, femoral neck, and lumbar spine (P < 0.001 for all) than the untreated group, and the average bone mass even reached the age-matched normal range. The prevalence of low BMD was 80.95% and 11.11% in untreated and treated groups, respectively. In the longitudinal study (N = 53), the total hip, femoral neck, and lumbar spine BMD gradually increased during treatment. The lumbar spine showed a greater increment in BMD compared with the total hip and femoral neck (P < 0.05). ConclusionSex hormone therapy improved hip and lumbar spine BMD and Z-scores in patients with IHH. The lumbar spine showed a greater improvement in BMD compared with the total hip and femoral neck.

A partial loss-of-function variant in GNRNR gene in a Chinese cohort with idiopathic hypogonadotropic hypogonadism.

BackgroundIdiopathic hypogonadotropic hypogonadism (IHH) is a rare genetic disease attributed to the disorder of hypothalamic-pituitary-gonadal axis. Mutations in the GNRHR gene are one of the most common genetic causes of IHH. Herein, we aimed to investigate GNRHR variants in a Chinese cohort with IHH, and to characterize them at the molecular level.MethodsA total of 153 IHH patients were recruited, and variants were detected using a tailored next-generation sequencing panel. GNRHR rare sequencing variant (RSV) was verified using Sanger sequencing. Phenotypic features and therapeutic outcomes of patients were followed up. In order to examine the pathogenicity of the GNRHR RSV, we performed conservative analysis, crystal structure prediction, expression analysis as well as the assessment of ERK1/2 activation and IP3/Ca2+ response.ResultsThe same heterozygous RSV (p.R240Q) in GNRHR was identified in four sporadic IHH patients. These patients exhibited different severity of testicular development and hormone profile. hCG treatment was effective in improving gonadal development, serum testosterone, and semen quality. The GNRHR RSV has no effect on the expression of mRNA and protein, whereas damaged ERK1/2 activation and inositol triphosphate/calcium signaling.ConclusionsThe study expands GNRHR mutation spectrum in IHH patients, and reveals that the GNRHR RSV is a partial loss-of-function mutation. Although this heterozygous RSV may not have a significant influence on the pathogenesis of IHH, but its homozygous/ compound status should be paid attention in this research field.

Cell adhesion molecule L1 like plays a role in the pathogenesis of idiopathic hypogonadotropic hypogonadism.

The pathogenesis of idiopathic hypogonadotropic hypogonadism (IHH) is genetically complex. The aims of this study were to investigate the genetic profile and clinical manifestation of IHH in a Chinese pedigree and to discover new IHH-associated genes. The first step was to follow up the clinical phenotype and therapeutic outcomes of the pedigree in university hospital. The second step was that mutation screening was performed in this pedigree and 100 healthy controls. The third step was to further verify the pathogenicity of the discovered rare sequencing variant (RSV) by functional experiments. Whole exome sequencing, Sanger sequencing, testicular volume (TV), semen analysis, assessment of cell migration and necroptosis were performed. One heterozygous RSV (p.G517E) in CHL1 was identified in two male IHH patients and their mother in the pedigree, but not in healthy controls. All the three individuals exhibited olfactory impairment. hCG/hMG treatment significantly improved TV, serum testosterone and/or semen parameters of the two male patients. Functional analysis indicated that CHL1 significantly regulated GnRH neuronal cell line (GN11 cells) migration and necroptosis, with alteration of ERK1/2 activation, calcium loading, and transcription of RIPK3 and MLKL. However, the above processes were negatively influenced by the CHL1 RSV. Our study reports the genetic relevance of CHL1 in IHH, and characterizes the phenotypic and therapeutic profiles in patients carrying the CHL1 RSV. CHL1 may act as a new IHH-associated gene, and should be taken into consideration in future investigations for this field.