Prevalence of pathogenic variants and digenic disease in patients diagnosed with normosmic hypogonadotropic hypogonadism/Kallmann Syndrome.

BACKGROUND: Hypogonadotropic hypogonadism (HH) is due to impaired gonadotropin releasing hormone (GnRH) action resulting in absent puberty and infertility. At least 44 genes have been identified to possess genetic variants in 40-50% of nHH/KS, and 2-20% have presumed digenic disease, but not all variants have been characterized in vitro. HYPOTHESIS: The prevalence of pathogenic (P)/likely pathogenic (LP) variants in monogenic and digenic nHH/KS is lower than reported. DESIGN: Cross-sectional study. SETTING: University Research Laboratory. SUBJECTS: 158 patients with nHH/KS. METHODS: Exome sequencing (ES) was performed and variants were filtered for 44 known genes using Varsome and confirmed by Sanger Sequencing. MAIN OUTCOME MEASURES: P/LP variants in nHH/KS genes. RESULTS: ES resulted in >370,000 variants, from which variants in 44 genes were filtered. Thirty-one confirmed P/LP variants in 10 genes (ANOS1, CHD7, DUSP6, FGFR1, HS6ST1, KISS1, PROKR2, SEMA3A, SEMA3E, TACR3), sufficient to cause disease, were identified in 30/158 (19%) patients. Only 2/158 (1.2%) patients had digenic variant combinations: a male with hemizygous ANOS1 and heterozygous TACR3 variants and a male with heterozygous SEMA3A and SEMA3E variants. Two patients (1.2%) had compound heterozygous GNRHR (autosomal recessive) variants-one P and one variant of uncertain significance (VUS). Five patients (3.2%) had heterozygous P/LP variants in either GNRHR or TACR3 (both autosomal recessive), but no second variant. CONCLUSION: Our prevalence of P/LP variants in nHH/KS was 19%, and digenicity was observed in 1.2%. These findings are less than those previously reported, and probably represent a more accurate estimation since VUS are not included.

Contributions of common genetic variants to constitutional delay of puberty and idiopathic hypogonadotropic hypogonadism.

CONTEXT: Constitutional delay of puberty (CDP) is highly heritable, but the genetic basis for CDP is largely unknown. Idiopathic hypogonadotropic hypogonadism (IHH) can be caused by rare genetic variants, but in about half of cases, no rare-variant cause is found. OBJECTIVE: To determine whether common genetic variants that influence pubertal timing contribute to CDP and IHH. DESIGN: Case-control study. PARTICIPANTS: 80 individuals with CDP; 301 with normosmic IHH, and 348 with Kallmann syndrome; control genotyping data from unrelated studies. MAIN OUTCOME MEASURES: Polygenic scores (PGS) based on genome-wide association studies for timing of male pubertal hallmarks and age at menarche (AAM). RESULTS: The CDP cohort had higher PGS for male pubertal hallmarks and for AAM compared to controls (for male hallmarks, Cohen's d = 0.85, p = 1 × 10-16; for AAM, d = 0.67, p = 1 × 10-10). The normosmic IHH cohort also had higher PGS for male hallmarks compared to controls, but the difference was smaller (male hallmarks d = 0.20, p = 0.003; AAM d = 0.10, p = 0.055). No differences were seen for the KS cohort compared to controls (male hallmarks d = 0.04, p = 0.45; AAM d = -0.03, p = 0.86). CONCLUSIONS: Common genetic variants that influence pubertal timing in the general population contribute strongly to the genetics of CDP, weakly to normosmic IHH, and potentially not at all to KS. These findings demonstrate that the common-variant genetics of CDP and normosmic IHH are largely but not entirely distinct.

Heavy Metal Levels in Males With Idiopathic Hypogonadotropic Hypogonadism.

INTRODUCTION: The toxic effects of heavy metals on biological systems are being investigated with increasing interest day by day. Our purpose was to investigate heavy metals such as aluminum (Al), cadmium (Cd), arsenic (As), lead (Pb), and nickel (Ni) in males with idiopathic hypogonadotropic hypogonadism (IHH) and to determine whether there is a relationship between heavy metals and testosterone levels. METHODS: Twenty-six male patients with IHH aged 18-50 and 22 healthy males aged 21-50 admitted to the Outpatient Department of Endocrinology for follow-up were enrolled. BMIs were calculated by measuring the height and weight of all participants. Al, Cd, As, Pb, and Ni levels were measured and compared between groups. Testosterone levels were measured to investigate whether there was a correlation with heavy metal levels. RESULTS: Al, Cd, As, Pb, and Ni levels were statistically higher in the patient group compared to the control group (p<0.001). A moderately strong significant negative correlation was detected between the patients' testosterone and As levels (p=0.001, r=-0.609, R2=0.371). Decreased As and Cd levels were observed as the patients' ages increased (p=0.013, r=-0.471). CONCLUSION: Heavy metals might play potential roles in IHH. We hope that investigating heavy metal levels in IHH and adding toxicity-preventive treatments to hormonal therapies will be beneficial in the multifaceted management of the disease in clinical practice.

High Population Frequency of GNRHR p.Q106R in Malta: An Evaluation of Fertility and Hormone Profiles in Heterozygotes.

Context: The gonadotropin-releasing hormone receptor variant GNRHR p.Q106R (rs104893836) in homozygosity, compound heterozygosity, or single heterozygosity is often reported as the causative variant in idiopathic hypogonadotropic hypogonadism (IHH) patients with GnRH deficiency. Genotyping of a Maltese newborn cord-blood collection yielded a minor allele frequency (MAF) 10 times higher (MAF = 0.029; n = 493) than that of the global population (MAF = 0.003). Objective: To determine whether GNRHR p.Q106R in heterozygosity influences profiles of endogenous hormones belonging to the hypothalamic-pituitary axis and the onset of puberty and fertility in adult men (n = 739) and women (n = 239). Design Setting and Participants: Analysis of questionnaire data relating to puberty and fertility, genotyping of the GNRHR p.Q106R variant, and hormone profiling of a highly phenotyped Maltese adult cohort from the Maltese Acute Myocardial Infarction Study. Main Outcome and Results: Out of 978 adults, 43 GNRHR p.Q106R heterozygotes (26 men and 17 women) were identified. Hormone levels and fertility for all heterozygotes are within normal parameters except for TSH, which was lower in men 50 years or older. Conclusion: Hormone data and baseline fertility characteristics of GNRHR p.Q106R heterozygotes are comparable to those of homozygous wild-type individuals who have no reproductive problems. The heterozygous genotype alone does not impair the levels of investigated gonadotropins and sex steroid hormones or affect fertility. GNRHR p.Q106R heterozygotes who exhibit IHH characteristics must have at least another variant, probably in a different IHH gene, that drives pathogenicity. We also conclude that GNRHR p.Q106R is likely a founder variant due to its overrepresentation and prevalence in the island population of Malta.

Whole-Exome Sequencing Analysis of Idiopathic Hypogonadotropic Hypogonadism: Comparison of Varicocele and Nonobstructive Azoospermia.

As a rare disease leading to male infertility, idiopathic hypogonadotropic hypogonadism (IHH) has strong heterogeneity of clinical phenotype and gene mutation. At present, there is no effective diagnosis and treatment method for this disease. This study is to explore the possible new pathogenic gene of idiopathic hypogonadotrophic hypogonadism and the pathological mechanism affecting its occurrence. We performed a whole-exome sequencing on 9 patients with normosmic idiopathic hypogonadotropic hypogonadism (nIHH), 19 varicocele patients with asthenospermia, oligospermia, or azoospermia, 5 patients with simple nonobstructive azoospermia, and 13 normal healthy adult males and carried out comparative analysis, channel analysis, etc. After preliminary sequencing screening, 309-431 genes harbouring variants, including SNPs and indels, were predicted to be harmful per single patient in each group. In genetic variations of nIHH patients' analysis, variants were detected in 10 loci and nine genes in nine patients. And in co-analysis of the three patient groups, nine nIHH patients, 19 VC patients, and five SN patients shared 116 variants, with 28 variant-harbouring genes detected in five or more patients. We found that the NEFH, CCDC177, and PCLO genes and the Gene Ontology pathways GO:0051301: cell division and GO:0090066: regulation of anatomical structure size may be key factors in the pathogenic mechanism of IHH. Our results suggest that the pathogenic mechanism of IHH is not limited to the central nervous system effects of GnRH but may involve other heterogeneous pathogenic genetic variants that affect peripheral organs.

Digenic CHD7 and SMCHD1 inheritance Unveils phenotypic variability in a family mainly presenting with hypogonadotropic hypogonadism.

Objectives: CHARGE syndrome is a congenital hereditary condition involving multiple systems. Patients are easily misdiagnosed with idiopathic hypogonadotropic hypogonadism (IHH) due to the overlap of clinical manifestations. An accurate clinical diagnosis remains challenging when the predominant clinical manifestation resembles hypogonadotropic hypogonadism. Methods: This original research is conducted based on the genetic finding and analysis of clinical cases. Whole-exome sequencing (WES) and in-silico analyse were performed on two sisters to investigate the pathogenesis in this family. Homology modelling was conducted to evaluate structural changes in the variants. Results: WES and Sanger sequencing revealed two siblings carrying a nonsense mutation (NM_017780.4: c.115C > T) in exon 2 of CHD7 inherited from a mildly affected mother and a missense mutation (NM_015295.3: c.2582T > C) in exon 20 of SMCHD1 inherited from an asymptomatic father. The nonsense mutation in CHD7 was predicted to generate nonsense-mediated decay, whereas the missense mutation in SMCHD1 decreased protein stability. Conclusions: We identified digenic CHD7 and SMCHD1 mutations in IHH-associated diseases for the first time and verified the synergistic role of oligogenic inheritance. It was also determined that WES is an effective tool for distinguishing diseases with overlapping features and establishing a molecular diagnosis for cases with digenic or oligogenic hereditary disorders, which is beneficial for timely treatment, and family genetic counseling.

Idiopathic hypogonadotropic hypogonadism caused by compound heterozygosity for two novel mutations in the GNRH1 gene: a case report.

BACKGROUND: Idiopathic hypogonadotropic hypogonadism (IHH) is a rare congenital or acquired genetic disorder caused by gonadotropin-releasing hormone (GnRH) deficiency. IHH patients are divided into two major groups, hyposmic or anosmic IHH (Kallmann syndrome) and normosmic IHH (nIHH), according to whether their sense of smell is intact. Here we report a case of novel compound heterozygous mutations in the GNRH1 gene in a 15-year-old male with nIHH. CASE PRESENTATION: The patient presented typical clinical symptoms of delayed testicular development, with testosterone < 3.5 mmol/L and reduced gonadotropin (follicle-stimulating hormone, luteinizing hormone) levels. Two heterozygous variants of the GNRH1 gene were detected, nonsense variant 1: c.85G > T:p.G29* and variant 2: c.1A > G:p.M1V, which disrupted the start codon. CONCLUSIONS: Two GNRH1 mutations responsible for nIHH are identified in this study. Our findings extend the mutational spectrum of GNRH1 by revealing novel causative mutations of nIHH.

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

Purpose: 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. Patients and Methods: 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. Results: 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. Conclusion: 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.

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

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

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.

The p190 RhoGAPs, ARHGAP35, and ARHGAP5 are implicated in GnRH neuronal development: Evidence from patients with idiopathic hypogonadotropic hypogonadism, zebrafish, and in vitro GAP activity assay.

PURPOSE: The study aimed to identify novel genes for idiopathic hypogonadotropic hypogonadism (IHH). METHODS: A cohort of 1387 probands with IHH underwent exome sequencing and de novo, familial, and cohort-wide investigations. Functional studies were performed on 2 p190 Rho GTPase-activating proteins (p190 RhoGAP), ARHGAP35 and ARHGAP5, which involved in vivo modeling in larval zebrafish and an in vitro p190A-GAP activity assay. RESULTS: Rare protein-truncating variants (PTVs; n = 5) and missense variants in the RhoGAP domain (n = 7) in ARHGAP35 were identified in IHH cases (rare variant enrichment: PTV [unadjusted P = 3.1E-06] and missense [adjusted P = 4.9E-03] vs controls). Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a, the predominant ARHGAP35 paralog in the zebrafish brain, display decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant [ARHGAP35 p.(Arg1284Trp)] had decreased GAP activity. Rare PTVs (n = 2) also were discovered in ARHGAP5, a paralog of ARHGAP35; however, arhgap5 zebrafish mutants did not display significant GnRH3-GFP+ abnormalities. CONCLUSION: This study identified ARHGAP35 as a new autosomal dominant genetic driver for IHH and ARHGAP5 as a candidate gene for IHH. These observations suggest a novel role for the p190 RhoGAP proteins in GnRH neuronal development and integrity.

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.

SLIT2 Rare Sequencing Variants Identified in Idiopathic Hypogonadotropic Hypogonadism.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The evaluation of ovarian function in normosmic idiopathic hypogonadotropic hypogonadism with a fibroblast growth factor receptor 1 mutation: a case report.

Normosmic idiopathic hypogonadotropic hypogonadism (nIHH) is a rare disorder with pubertal delay, normal sense of smell. nIHH with a fibroblast growth factor receptor 1 mutation is much more common in adult males but is rarely reported in females. In addition, the assessment and monitoring of ovarian function in nIHH females has often been ignored. We report a 24-year-old nIHH female with the complaint of primary amenorrhea and delayed secondary sexual traits development. Whole-Exome Sequencing analysis revealed a novel mutation in the third exon of fibroblast growth factor receptor 1 gene (c.289 G > A), which resulted in the replacement of glycine acid with serine. Then the patient was recommended to start with the hormone therapy (HT). After several months of estrogen combined with progesterone replacement, the patient had regular menstruation. The breast development and genital development gradually became Tanner stage 5. Anti-Müllerian hormones (AMHs) were also evaluated and the serum AMH level keeps fluctuating within the normal reference range. We highlight the great variability of fibroblast growth factor receptor 1 mutation phenotypes and the evaluation of ovarian reserve in nIHH, and the hormone replacement therapy is necessary to improve secondary sexual development for patients with nIHH.

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

OBJECTIVE: 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 structural connectivity and FC may exist in the olfactory cortex pathways in IHH patients. DESIGN: 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. MEASUREMENTS: 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. RESULTS: 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 < .05). CONCLUSION: 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.

Clinical, hormonal, and genetic characteristics of 25 Chinese patients with idiopathic hypogonadotropic hypogonadism.

BACKGROUND: Idiopathic hypogonadotropic hypogonadism (IHH) is a type of congenital disease caused by a variety of gene variants leading to dysfunction in the secretion of hypothalamic gonadotropin-releasing hormones (GnRHs). Clinically, IHH can be divided into Kallmann syndrome (KS) with dysosmia and normosmic idiopathic hypogonadotropic hypogonadism (nIHH) according to the presence or absence of an olfactory disorder. METHODS: We retrospectively evaluated 25 IHH patients (8 KS and 17 nIHH) who were diagnosed at the Department of Endocrinology of Shanghai Children's Hospital from 2015 to 2021. We analysed the patients' clinical data, including their hormone levels and gene sequences. RESULTS: All male patients exhibited small phalli, and 35% of them exhibited cryptorchidism. A significant difference was observed in the levels of dihydrotestosterone (DHT) after human chorionic gonadotropin (HCG) stimulation (P = 0.028) between the KS group and the nIHH group. Missense variants were the major cause of IHH, and the main pathogenic genes were FGFR1, PROKR2/PROK2, and KAl1. Nine reported and 13 novel variants of six genes were identified. De novo variants were detected in 16 IHH patients; eight patients inherited the variants from their mothers, while only three patients inherited variants from their fathers. One patient had both KAl1 and PROKR2 gene variants, and another patient had two different PROKR2 gene variants. These two patients both had the hot spot variant c.533G > C (p. Trp178Ser) of the PROKR2 gene. CONCLUSION: IHH should be highly suspected in patients with a small phallus and cryptorchidism. Compared with nIHH patients, KS patients exhibited a higher level of DHT after HCG stimulation. Missense variants were the major cause of IHH, and most of the inherited variants were from their mothers who exhibited no obvious clinical symptoms. We identified 9 reported variants and 13 novel variants that led to IHH. A small proportion of patients were at risk of inheriting either the oligogenic variant or the compound heterozygous variant. The hot spot variant c.533G > C (p. Trp178Ser) of PROKR2 might be involved in oligogenic inheritance and compound heterozygous inheritance. These findings provide deeper insight into the diagnosis and classification of IHH and will contribute to its clinical assessment.

New and Consolidated Therapeutic Options for Pubertal Induction in Hypogonadism: In-depth Review of the Literature.

Delayed puberty (DP) defines a retardation of onset/progression of sexual maturation beyond the expected age from either a lack/delay of the hypothalamo-pituitary-gonadal axis activation or a gonadal failure. DP usually gives rise to concern and uncertainty in patients and their families, potentially affecting their immediate psychosocial well-being and also creating longer term psychosexual sequelae. The most frequent form of DP in younger teenagers is self-limiting and may not need any intervention. Conversely, DP from hypogonadism requires prompt and specific treatment that we summarize in this review. Hormone therapy primarily targets genital maturation, development of secondary sexual characteristics, and the achievement of target height in line with genetic potential, but other key standards of care include body composition and bone mass. Finally, pubertal induction should promote psychosexual development and mitigate both short- and long-term impairments comprising low self-esteem, social withdrawal, depression, and psychosexual difficulties. Different therapeutic options for pubertal induction have been described for both males and females, but we lack the necessary larger randomized trials to define the best approaches for both sexes. We provide an in-depth and updated literature review regarding therapeutic options for inducing puberty in males and females, particularly focusing on recent therapeutic refinements that better encompass the heterogeneity of this population, and underlining key differences in therapeutic timing and goals. We also highlight persistent shortcomings in clinical practice, wherein strategies directed at "the child with delayed puberty of uncertain etiology" risk being misapplied to older adolescents likely to have permanent hypogonadism.

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

Background: 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. Aims: 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. Settings and Design: This prospective study was conducted at the Royan institute. Materials and Methods: 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. Statistical Analysis Used: 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. Results: 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. Conclusions: 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.

Clinical and molecular features of idiopathic hypogonadotropic hypogonadism in Taiwan: A single center experience.

BACKGROUND: Idiopathic (isolated) hypogonadotropic hypogonadism (IHH) is a rare disease that can be classified as Kallmann syndrome (KS) or normosmic IHH (nIHH). This study investigated the phenotype and genotype of IHH in Taiwanese patients. METHODS: Twenty-six unrelated IHH patients were included in this study and their clinical, hormonal, and radiological findings were analyzed retrospectively. Whole exome sequencing (WES) was performed to identify the etiology. RESULTS: The 26 patients (M:F = 19:7) were divided into a KS group (n = 11) and a nIHH group (n = 15). The diagnosis was earlier in boys than in girls. Fifteen patients were found to have pathogenic/likely pathogenic (P/LP) variants of IHH-associated genes, and the mutation detection rate was 58%. CHD7, FGFR1, and ANOS1 were the most common genetic etiologies identified in this group. Two patients with nIHH were found to have de novo SOX11 mutations and Coffin-Siris syndrome features. After treatment, the height outcomes and secondary sexual characteristics were significantly improved. There were no obvious differences between the genetically resolved (GR), variants of uncertain significance (VUS) and genetically unresolved groups (GUR). CONCLUSION: Whole exome sequencing is useful in patients with IHH, and we identified the SOX11 gene as a causal factor in this study. We described the clinical, hormonal, and molecular characteristics, and the treatment outcomes, of Taiwanese patients with IHH, which should aid therapeutic planning and further research.

Hormonal therapy is effective and safe for cryptorchidism caused by idiopathic hypogonadotropic hypogonadism in adult males.

Background: Hormonal therapy is a reasonable treatment for cryptorchidism caused by idiopathic hypogonadotropic hypogonadism (IHH). However, the clinical evidence on whether it is effective and safe for the treatment of cryptorchidism caused by IHH is lacking. Aim: To evaluate the effect of hormonal therapy in testicular descent, puberty development, and spermatogenesis in adult males with cryptorchidism caused by IHH. Methods: This retrospective study included 51 patients with cryptorchidism caused by IHH from the Andrology Clinic of University affiliated teaching hospital. Patients were divided into two groups: group A patients received hormonal therapy; group B patients received surgical treatment for cryptorchidism followed by hormonal therapy. Results: The rate of successful testicular descent following hormonal therapy (19/32 in group A) or surgical treatment (11/19 in group B) shows no statistically significant difference. There was also no statistically significant difference in penile length, Tanner stage of pubic hair, testicular volume, and success rate of spermatogenesis between the two groups. Testicular atrophy was seen in a single patient in group B. Conclusions: Hormone therapy in adult males with cryptorchidism caused by IHH is effective and safe regarding testicular descent, puberty development, and spermatogenesis. This study provides new insight into the treatment of cryptorchidism caused by IHH and highlights that hormonal therapy could be an effective, safe, and economic treatment option for cryptorchidism in males caused by IHH.