Idiopathic Hypogonadotropic Hypogonadism Research Articles

Successful testicular descent induced by gonadotropin replacement therapy in young men with congenital hypogonadotropic hypogonadism

Successful testicular descent induced by gonadotropin replacement therapy in young men with congenital hypogonadotropic hypogonadism

Genetic diagnosis of endocrine disorders in Cyprus through the Cyprus Institute of Neurology and Genetics: an ENDO-ERN Reference Center

The report covers the current and past activities of the department Molecular Genetics-Function and Therapy (MGFT) at the Cyprus Institute of Neurology and Genetics (CING), an affiliated Reference Center for the European Reference Network on Rare Endocrine Conditions (Endo-ERN).The presented data is the outcome of > 15 years long standing collaboration between MGFT and endocrine specialists from the local government hospitals and the private sector. Up-to-date > 2000 genetic tests have been performed for the diagnosis of inherited rare endocrine disorders. The major clinical entities included Congenital Adrenal Hyperplasia (CAH) due to pathogenic variants in CYP21A2 gene and Multiple Endocrine Neoplasia (MEN) type 2 due to pathogenic variants in the RET proto-oncogene. Other rare and novel pathogenic variants in ANOS1, WDR11, FGFR1, RNF216, and CHD7 genes were also found in patients with Congenital Hypogonadotropic Hypogonadism. Interestingly, a few patients with Disorders of Sexual Differentiation (DSD) shared rare pathogenic variants in the SRD5A2, HSD17B3 and HSD3B2 while patients with Glucose and Insulin Homeostasis carried theirs in GCK and HNF1A genes. Lastly, MGFT over the last few years has established an esteemed diagnostic and research program on premature puberty with emphasis on the implication of MKRN3 gene on the onset of the disease and the identification of other prognosis biomarkers.As an Endo-ERN member MGFT department belongs to this large European network and holds the same humanistic ideals which aim toward the improvements of health care for patients with rare endocrine conditions in respect to improved and faster diagnosis.

Reversibility of congenital hypogonadotropic hypogonadism: lessons from a rare disease.

Reversibility of congenital hypogonadotropic hypogonadism: lessons from a rare disease.

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

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. To determine whether common genetic variants that influence pubertal timing contribute to CDP and IHH. Case-control study. 80 individuals with CDP; 301 with normosmic IHH, and 348 with Kallmann syndrome; control genotyping data from unrelated studies. Polygenic scores (PGS) based on genome-wide association studies for timing of male pubertal hallmarks and age at menarche (AAM). 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). 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.

Mini-Puberty, Physiological and Disordered: Consequences, and Potential for Therapeutic Replacement.

There are 3 physiological waves of central hypothalamic-pituitary-gonadal (HPG) axis activity over the lifetime. The first occurs during fetal life, the second-termed "mini-puberty"-in the first months after birth, and the third at puberty. After adolescence, the axis remains active all through adulthood. Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by a deficiency in hypothalamic gonadotropin-releasing hormone (GnRH) secretion or action. In cases of severe CHH, all 3 waves of GnRH pulsatility are absent. The absence of fetal HPG axis activation manifests in around 50% of male newborns with micropenis and/or undescended testes (cryptorchidism). In these boys, the lack of the mini-puberty phase accentuates testicular immaturity. This is characterized by a low number of Sertoli cells, which are important for future reproductive capacity. Thus, absent mini-puberty will have detrimental effects on later fertility in these males. The diagnosis of CHH is often missed in infants, and even if recognized, there is no consensus on optimal therapeutic management. Here we review physiological mini-puberty and consequences of central HPG axis disorders; provide a diagnostic approach to allow for early identification of these conditions; and review current treatment options for replacement of mini-puberty in male infants with CHH. There is evidence from small case series that replacement with gonadotropins to mimic "mini-puberty" in males could have beneficial outcomes not only regarding testis descent, but also normalization of testis and penile sizes. Moreover, such therapeutic replacement regimens in disordered mini-puberty could address both reproductive and nonreproductive implications.

Classes and predictors of reversal in male patients with congenital hypogonadotropic hypogonadism: a cross-sectional study of six international referral centres

Although some male patients with congenital hypogonadotropic hypogonadism (CHH) undergo spontaneous reversal following treatment, predictors of reversal remain elusive. We aimed to assemble the largest cohort of male patients with CHH reversal to date and identify distinct classes of reversal. This multicentre cross-sectional study was conducted in six international CHH referral centres in Brazil, Finland, France, Italy, the UK, and the USA. Adult men with CHH (ie, absent or incomplete spontaneous puberty by age 18 years, low serum testosterone concentrations, and no identifiable cause of hypothalamic-pituitary-gonadal [HPG] axis dysfunction) were eligible for inclusion. CHH reversal was defined as spontaneous recovery of HPG axis function off treatment. Centres provided common data elements on patient phenotype, clinical assessment, and genetics using a structured, harmonised data collection form developed by COST Action BM1105. Latent class mixture modelling (LCMM) was applied to establish whether at least two distinct classes of reversal could be identified and differentially predicted, and results were compared with a cohort of patients without CHH reversal to identify potential predictors of reversal. The primary outcome was the presence of at least two distinct classes of reversal. A total of 87 male patients with CHH reversal and 108 without CHH reversal were included in the analyses. LCMM identified two distinct reversal classes (75 [86%] in class 1 and 12 [14%] in class 2) on the basis of mean testicular volume, micropenis, and serum follicle-stimulating hormone (FSH) concentration. Classification probabilities were robust (0·998 for class 1 and 0·838 for class 2) and modelling uncertainty was low (entropy 0·90). Compared with class 1, patients in class 2 had significantly larger testicular volume (p<0·0001), no micropenis, and higher serum FSH concentrations (p=0·041), consistent with the Pasqualini syndrome (fertile eunuch) subtype of CHH. Patients without CHH reversal were more likely to have anosmia (p=0·016), cryptorchidism (p=0·0012), complete absence of puberty (testicular volume <4 cm³; p=0·0016), and two or more rare genetic variants (ie, oligogenicity; p=0·0001). Among patients who underwent genetic testing, no patients (of 75) with CHH reversal had a rare pathogenic ANOS1 variant compared with ten (11%) of 95 patients without CHH reversal. Individuals with CHH reversal had a significantly higher rate of rare variants in GNRHR than did those without reversal (nine [12%] of 75 vs three [3%] of 95; p=0·025). Applying LCMM to a large cohort of male patients with CHH reversal uncovered two distinct classes of reversal. Genetic investigation combined with careful clinical phenotyping could help surveillance of reversal after withdrawing treatment, representing the first tailored management approach for male patients with this rare endocrine disorder. National Institutes of Health National Center for Advancing Translational Sciences; Ministry of Health, Rome, Italy; Ministry of University, Rome, Italy; National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development; and the Josiah Macy Jr Foundation. For the Italian translation of the abstract see Supplementary Materials section.

"Results of Genetic Studies of Adolescents with Idiopathic Hypogonadotropic Hypogonadism"

"Results of Genetic Studies of Adolescents with Idiopathic Hypogonadotropic Hypogonadism"

"The significance of the GNRH 1 gene polymorphism (rs 6185, rs1812594) in the development of idiopathic hypogonadotropic hypogonadism."

The purpose of the study is to study the significance of the GNRH 1 gene polymorphism (rs 6185, rs1812594) in the development of idiopathic hypogonadotropic hypogonadism in boys and girls.

Bleeding per rectum as a rare presentation of obsessivecompulsive disorder in a patient with Kallmann syndrome: A case report

Kallmann syndrome is also called idiopathic hypogonadotropic hypogonadism with anosmia, a genetic disorder with rare occurrence in humans characterized by delay/absence of signs of puberty with an absent/impaired sense of smell. Hypothalamic dysfunction is suggested to be aetiologically involved [1].

Heavy Metal Levels in Males With Idiopathic Hypogonadotropic Hypogonadism.

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. 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. 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). 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.

Clinical manifestations and spermatogenesis outcomes in Chinese patients with congenital hypogonadotropic hypogonadism caused by inherited or de novo FGFR1 mutations.

Fibroblast growth factor receptor 1 ( FGFR1 ) mutations are associated with congenital hypogonadotropic hypogonadism (CHH) through inheritance or spontaneous occurrence. We detected FGFR1 mutations in a Chinese cohort of 210 CHH patients at Peking Union Medical College Hospital (Beijing, China) using next-generation and Sanger sequencing. We assessed missense variant pathogenicity using six bioinformatics tools and compared clinical features and treatment outcomes between inherited and de novo mutation groups. Among 19 patients with FGFR1 mutations, three were recurrent, and 16 were novel variants. Sixteen of the novel mutations were likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines, with the prevalent P366L variant. The majority of FGFR1 mutations was inherited (57.9%), with frameshift mutations exclusive to the de novo mutation group. The inherited mutation group had a lower incidence of cryptorchidism, short stature, and skeletal deformities. In the inherited mutation group, luteinizing hormone (LH) levels were 0.5 IU l -1 , follicle-stimulating hormone (FSH) levels were 1.0 IU l -1 , and testosterone levels were 1.3 nmol l -1 . In contrast, the de novo group had LH levels of 0.2 IU l -1 , FSH levels of 0.5 IU l -1 , and testosterone levels of 0.9 nmol l -1 , indicating milder hypothalamus-pituitary-gonadal axis (HPGA) functional deficiency in the inherited group. The inherited mutation group showed a tendency toward higher spermatogenesis rates. In conclusion, this study underscores the predominance of inherited FGFR1 mutations and their association with milder HPGA dysfunction compared to de novo mutations, contributing to our understanding of the genetic and clinical aspects of FGFR1 mutations.

Evaluating Sperm Recovery Time and Efficacy of Monotherapy vs. Combination Therapies in Men with Congenital Hypogonadotropic Hypogonadism: A Systematic Review and Meta-Analysis.

There is a lack of pooled data exploring the time and rates for human chorionic gonadotropin (hCG) monotherapy vs. combination therapies (hCG+human menopausal gonadotropin or recombinant human follicle-stimulating hormone) to restore spermatogenesis in azoospermic men with congenital hypogonadotropic hypogonadism (CHH). We aimed to investigate the time and rates to recover spermatogenesis among azoospermic CHH men receiving monotherapy vs. combination therapy. We conducted a systematic review and meta-analysis following the PRISMA guidelines. The search was performed on PubMed, EMBASE, Web of Science, and Scopus databases up to November 2023. Forrest plots were generated to visually present the pooled effect sizes for time to recover spermatogenesis, specifically employing the standardized mean difference (SMD). Publication bias was assessed utilizing funnel plots. PROSPERO ID: CRD42023473615. The search identified 720 studies meeting inclusion criteria. Our meta-analysis of 1,240 men with CHH revealed significant differences in the time to recover spermatogenesis between combination therapies and monotherapy. The weighted mean recovery time was significantly shorter for combination therapies (10 months) compared to monotherapy (33 months). The SMD under the common effect model was 8.8 for combination therapies and 24.98 for monotherapy, indicating a more rapid recovery with combination therapies, p<0.01. The rates of sperm recovery were 66.76% for combination therapies and 51.9% for monotherapy, p=0.03. Significant heterogeneity was observed in both groups (I²=86% for combination therapies and I²=68% for monotherapy), suggesting considerable variation in individual responses. The present meta-analysis reveals that in men with CHH, combination therapies expedite spermatogenesis recovery more than monotherapy. Additionally, combination therapies yield a higher rate of sperm appearing in the ejaculate as compared to hCG monotherapy. The significant heterogeneity observed in both groups underscores the variability in individual responses, warranting further investigation and caution in interpreting these results.

Gene-environment interaction in functional hypothalamic amenorrhea.

Functional hypothalamic amenorrhea (FHA) is a common cause of amenorrhea and chronic anovulation in adolescent girls and young women, diagnosed after excluding other organic causes. It is commonly associated with calorie restriction, excessive physical exercise, and psychosocial stress. These stressors alter the pulsatile secretion of gonadotropin-releasing hormone, leading to a chronic condition of hypoestrogenism and significant health consequences. Recent evidence has highlighted a genetic predisposition to FHA that could explain interindividual variability in stress response. Indeed, not all women experience FHA in response to stress. Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism have been identified in women with FHA, suggesting that these mutations may contribute to an increased susceptibility of women to the trigger of stress exposure. FHA appears today as a complex disease resulting from the combination of genetic predisposition, environmental factors, and epigenetic changes. Furthermore, the genetic background of FHA allows for the hypothesis of a male counterpart. Despite the paucity of data, preliminary findings indicate that an equivalent condition of FHA exists in men, warranting further investigation. This narrative review aims to summarize the recent genetic evidence contributing to the pathophysiology of FHA and to raise awareness on a possible male counterpart.

The role of KNDy neurons in human reproductive health.

In the early 2000s, metastin, an endogenous ligand for G protein-coupled receptor 54 (GPR54), was discovered in human placental extracts. In 2003, GPR54 receptor mutations were found in a family with congenital hypogonadotropic hypogonadism. Metastin was subsequently renamed kisspeptin after its coding gene, Kiss1. Since then, studies in mice and other animals have revealed that kisspeptin is located at the apex of the hypothalamic-pituitary-gonadal axis and regulates reproductive functions by modulating gonadotropin-releasing hormone (GnRH). In rodents, kisspeptin (Kiss1) neurons localize to two regions, the hypothalamic arcuate nucleus (ARC) and the anteroventral periventricular nucleus (AVPV). ARC Kiss1 neurons co-express neurokinin B (NKB) and dynorphin and are thus termed KNDy neurons. Kiss1 neurons in humans are concentrated in the infundibular nucleus (equivalent to the ARC), with few Kiss1 neurons localized to the preoptic area (equivalent to the AVPV), and the mechanisms underlying GnRH surge secretion in humans are poorly understood. However, peripheral administration of kisspeptin to humans promotes gonadotropin secretion, and administration of kisspeptin to patients with hypothalamic amenorrhea or congenital hypogonadotropic hypogonadism restores the pulsatile secretion of GnRH/luteinizing hormone. Thus, kisspeptin undoubtedly plays an important role in reproductive function in humans. Studies are currently underway to develop kisspeptin receptor agonists or antagonists for clinical application. Modification of KNDy neurons by NKB agonists/antagonists is also being attempted to develop therapeutic agents for various menstrual abnormalities, including polycystic ovary syndrome and menopausal hot flashes. Here, we review the role of kisspeptin in humans and its clinical applications.

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

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). 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). 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. 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. 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.

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

ObjectivesCHARGE 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. MethodsThis 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. ResultsWES 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. ConclusionsWe 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.

Role of Inhibin B, AMH, GnRHa Test and HCG Stimulation Test to Distinguish Isolated Hypogonadotropic Hypogonadism (IHH) from Constitutional Delay in Growth and Puberty (CDGP).

This study aimed to distinguish isolated hypogonadotropic hypogonadism (IHH) from constitutional delay in growth and puberty (CDGP) by various hormonal tests in both sexes. Boys with testicular volume (TV) <4 ml (14-18 years) and girls with breast B1 stage (13-18 years) were enrolled in this study. A detailed history, clinical examination and hormonal analysis including basal luteinising hormone (LH), follicle-stimulating hormone (FSH), inhibin B, anti-Mullerian hormone (AMH), testosterone (boys), oestradiol (girls), triptorelin stimulation test and 3-day human chorionic gonadotropin (HCG) stimulation test (boys) were performed. All patients were followed for 1.5 years or till 18 years of age. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-offs with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for various hormones to distinguish IHH from CDGP. Of 34 children (male: 22 and female: 12), CDGP and IHH were diagnosed in 21 and 13 children, respectively. 4 hours post-triptorelin LH had the highest sensitivity (100%) and specificity (100%) for identifying IHH in both sexes. Basal inhibin B had good sensitivity (male: 85.7% and female: 83.8%) and specificity (male: 93.3% and female: 100%) for diagnosing IHH. 24 hours post-triptorelin testosterone (<34.5 ng/dl), day 4 post-HCG testosterone (<99.7 ng/dl) and 24 hours post-triptorelin oestradiol (<31.63 pg/ml) had reasonable sensitivity and specificity for identifying IHH. Basal LH, FSH and AMH were poor discriminators for IHH in both sexes. The best indicator was post-triptorelin 4-hour LH followed by inhibin B, which had a reasonable diagnostic utility to distinguish IHH from CDGP in both boys and girls.

Analysis of genotype and phenotype in congenital hypogonadotropic hypogonadism with reversible gonadotropin deficiency: A case report

The case involved a 32-year-old male patient who experienced delayed puberty until the age of 18. He exhibited low levels of LH, FSH, and testosterone. Chromosome karyotyping revealed a 46XY genotype, while whole exon sequencing identified a missense mutation (c.337T&gt;C) in the PROKR2 gene. Pituitary MRI did not indicate the presence of any masses, leading to a clinical diagnosis of Congenital Hypogonadotropic Hypogonadism (CHH). The patient underwent hormone replacement therapy with HCG for 3 years, followed by long-term testosterone treatment. Interestingly, the patient demonstrated spontaneous sperm production without the need for gonadotropin therapy. His wife conceived naturally on four occasions, resulting in two miscarriages and two successful deliveries, indicating a reversal of the patient’s gonadal function. Bioinformatics analysis and analysis based on the guidelines provided by the American College of Medical Genetics and Genomics (ACMG) confirmed that the missense mutation c.337T&gt;C in the PROKR2 gene was a potential pathogenic variant. However, our study indicated that this specific mutation in the PROKR2 gene could not solely account for the observed reversal of gonadal function in this patient.

Gonadotropin-Releasing Hormone Receptor (GnRHR) and Hypogonadotropic Hypogonadism

Human sexual and reproductive development is regulated by the hypothalamic-pituitary-gonadal (HPG) axis, which is primarily controlled by the gonadotropin-releasing hormone (GnRH) acting on its receptor (GnRHR). Dysregulation of the axis leads to conditions such as congenital hypogonadotropic hypogonadism (CHH) and delayed puberty. The pathophysiology of GnRHR makes it a potential target for treatments in several reproductive diseases and in congenital adrenal hyperplasia. GnRHR belongs to the G protein-coupled receptor family and its GnRH ligand, when bound, activates several complex and tissue-specific signaling pathways. In the pituitary gonadotrope cells, it triggers the G protein subunit dissociation and initiates a cascade of events that lead to the production and secretion of the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) accompanied with the phospholipase C, inositol phosphate production, and protein kinase C activation. Pharmacologically, GnRHR can be modulated by synthetic analogues. Such analogues include the agonists, antagonists, and the pharmacoperones. The agonists stimulate the gonadotropin release and lead to receptor desensitization with prolonged use while the antagonists directly block the GnRHR and rapidly reduce the sex hormone production. Pharmacoperones include the most recent GnRHR therapeutic approaches that directly correct the misfolded GnRHRs, which are caused by genetic mutations and hold serious promise for CHH treatment. Understanding of the GnRHR’s genomic and protein structure is crucial for the most appropriate assessing of the mutation impact. Such mutations in the GNRHR are linked to normosmic hypogonadotropic hypogonadism and lead to various clinical symptoms, including delayed puberty, infertility, and impaired sexual development. These mutations vary regarding their mode of inheritance and can be found in the homozygous, compound heterozygous, or in the digenic state. GnRHR expression extends beyond the pituitary gland, and is found in reproductive tissues such as ovaries, uterus, and prostate and non-reproductive tissues such as heart, muscles, liver and melanoma cells. This comprehensive review explores GnRHR’s multifaceted role in human reproduction and its clinical implications for reproductive disorders.

Can clinical, biochemical and genetic parameters help distinguish congenital hypogonadotrophic hypogonadism from self-limited delayed puberty?

Can clinical, biochemical and genetic parameters help distinguish congenital hypogonadotrophic hypogonadism from self-limited delayed puberty?