RARE DISEASE
Congenital hypogonadotropic hypogonadism
Congenital hypogonadotropic hypogonadism
Congenital hypogonadotropic hypogonadism
Drug discovery
4
drugs
With orphan designations
Overview
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by insufficient gonadotropin-releasing hormone (GnRH) secretion or action, leading to absent/incomplete puberty and infertility. It manifests as low sex steroids with inappropriately low gonadotropins and may coexist with anosmia (Kallmann syndrome) or non-reproductive anomalies (e.g., cryptorchidism, cleft palate). Genetic mutations in over 30 genes contribute to its pathogenesis, though ~50% of cases remain genetically unresolved [1][4][15].
Therapies
Puberty induction: Gradual testosterone replacement (intramuscular or topical) [3][7].
Fertility restoration: Combined gonadotropin therapy (hCG + FSH) or pulsatile GnRH to stimulate spermatogenesis [3][7].
Infancy interventions: Short-term neonatal gonadotropin therapy to correct micropenis and promote testicular descent [1][7].
Categories: rare endocrine diseases, rare genetic diseases, rare gynecological and obstetric diseases, rare infertility disorders
Research Papers
487 drug discovery papers about Congenital hypogonadotropic hypogonadism, with 1 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
487 drug discovery papers about Congenital hypogonadotropic hypogonadism, with 1 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-07-24 | A Novel Hemizygous ANOS1 Variant in a Patient With Kallmann Syndrome and Type 2 Diabetes Mellitus: A Case Report.
Kallmann syndrome (KS), a rare genetic disorder, is characterized by congenital hypogonadotropic hypogonadism (CHH) and anosmia or hyposmia. We report a case of KS with type 2 diabetes mellitus (T2DM) associated with a novel hemizygous missense variant in ANOS1 (NM_000216.4; exon 4; c.505G >C;p.(Gly169Arg)). A 33-year-old male presented with persistent hyperglycemia, delayed pubertal development with absent secondary sexual characteristics, and lifelong anosmia. Olfactory testing, magnetic resonance imaging (MRI) of the pituitary region, and a gonadotropin-releasing hormone (GnRH) stimulation test supported a clinical diagnosis of KS. Trio-based exome sequencing (ES) revealed the aforementioned hemizygous variant in ANOS1. Notably, neither parent harbored this variant, supporting a de novo origin, which is consistent with the variant's potential pathogenicity. Multiple sequence alignment showed that Gly169 is highly conserved across species, suggesting it may be functionally important for the protein. Furthermore, a three-dimensional protein model generated using SWISS-MODEL predicted marked conformational changes in the protein attributable to this amino acid substitution at a highly conserved residue, suggesting a potential functional impact. Notably, emerging evidence has linked ANOS1 variants to dysregulated glucose metabolism, supporting a potential association with T2DM in this case. For treatment, insulin and oral hypoglycemic agents were used for glycemic control, and a GnRH pump was initiated. At the sixth follow-up visit, the patient had achieved satisfactory glycemic control; however, serum testosterone levels remained low despite GnRH pump therapy, so testosterone replacement therapy was subsequently initiated. ANOS1 variants are genetically diverse and may contribute to both KS pathogenesis and the development of comorbid T2DM, though further studies are needed to confirm this link. For KS patients, close monitoring of fasting glucose, glycated hemoglobin, and oral glucose tolerance test results is advisable to detect diabetes and prediabetes early.
2026-05-18 | Case Report: Homozygous KISS1R mutation associated with congenital hypogonadotropic hypogonadism in two siblings: pulsatile GnRH therapy restores pituitary architecture and induces pubertal development.
Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterized by deficient production, secretion, or action of gonadotropin-releasing hormone (GnRH), the central regulator of the reproductive axis. We report two siblings from a consanguineous family with CHH caused by a homozygous nonsense mutation (c.182C > A; p. Ser 61Ter) in exon 1 of KISS1R gene. The 15-years-old male proband presented with absent puberty, micropenis, and gynecomastia. Endocrine evaluation revealed low gonadotropin levels and brain magnetic resonance imaging (MRI) showed pituitary hypoplasia. His 12-years-old sister exhibited puberty delays, with absent breast development and pubic hair. The male patient received 1 year of pulsatile GnRH therapy, resulting in significant clinical improvements, including markedly increased testicular volume (from 0.9 to 5.6 mL), penile growth, and the resolution of gynecomastia. Notably, follow-up imaging demonstrated morphological recovery of the pituitary gland, with an increase in height from 3.5 to 4.5 mm, accompanied by the successful induction of spermatogenesis. This excellent response to GnRH underscores its efficacy in restoring fertility, particularly when initiated in early adolescence, and highlights the value of genetic diagnosis in consanguineous families.
2026-04-17 | Comparing the response of triple therapy and conventional treatment in male congenital hypogonadotropic hypogonadism: a randomized controlled trial.
This study investigated whether triple therapy with human chorionic gonadotropin (hCG), follicle-stimulating hormone(FSH) and testosterone(T) in congenital hypogonadotropic hypogonadism(CHH) promoted more timely virilization, aiding psychosocial development while reducing hCG requirements, offering a balanced approach to long-term management. An open-label randomized controlled trial (1:1:1) was conducted in adult males with CHH. Group A received triple therapy, Group B received combined hCG and FSH from the outset, and Group C received hCG monotherapy followed by combined FSH and hCG. Initial doses comprised hCG 2,000 IU twice weekly, FSH 75 IU thrice weekly and intramuscular testosterone(T) 100 mg every two weeks. Group A titrated hCG to achieve AMH of 7.4ng/ml; Groups B and C aimed for T normalization. Primary outcomes were hCG/FSH doses required for spermatogenesis induction and the time to spermatogenesis. Forty-five CHH males (mean age 25.8 ± 6.1years) were randomized. Spermatogenesis was achieved in 84.6% of group A participants compared with 69.2% and 75% in groups B and C, respectively(p=0.648). Median hCG dose at spermatogenesis was 7500IU/week in group A and 9000IU/week in groups B and C(p=0.016). The time to spermatogenesis was comparable (Groups A/B:12 months; Group C:15 months;p=0.345). Group A participants achieved an AMH of 3.5(2.31-5.38)ng/ml, comparable to the other groups(p=0.962). Predictors of spermatogenesis included USGmTV cut-off of 1.97ml (sensitivity-86.2%,specificity-62.5%), hCG dose of 9,000 IU/week (sensitivity-79.3%,specificity-87.5%) and an Inh B cut-off of 66.8 pg/ml(sensitivity-92.6%,specificity-100%). Triple therapy provided a better quality of life without compromising spermatogenesis. The AMH and Inh B provided an effective means of monitoring. www.ctri.nic.in, identifier CTRI/2022/05/042795.
2026-03-25 | Clinical Implications of Minipuberty.
Minipuberty refers to a specific period in early postnatal life with high activity of the hypothalamic-pituitary-gonadal (HPG) hormone axis. In infant boys 1 to 3 months of age, high concentrations of follicle-stimulating hormone and luteinizing hormone are released, which results in high levels of gonadal hormones from testicular Leydig cells (testosterone and insulin-like 3) and Sertoli cells (inhibin B and antimüllerian hormone). The HPG axis is also active in infant girls, who have adult levels of follicle-stimulating hormone and luteinizing hormone during this period. Immediately after minipuberty, the HPG axis is silenced for approximately 10 years and is reactivated only with the onset of puberty. Thus, minipuberty represents an early window for diagnosing disorders of sexual differentiation and rare endocrine disorders, such as congenital hypogonadotropic hypogonadism, and may help guide dosing of therapeutic interventions including gonadotropin therapy. Of note, minipuberty predicts adult reproductive capacity.
2026-02-20 | Management of infertility in women with hypothalamic hypogonadotropic hypogonadism: an expert opinion.
Hypothalamic gonadotropin-releasing hormone (GnRH) plays a central role in regulating the pituitary-gonadal axis. The pulsatility of GnRH release is critical for maintaining the function of GnRH receptors and the secretion pattern of gonadotropins, namely follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which regulate endocrine function and follicular growth and maturation. During the luteal phase, LH is crucial for supporting a functional corpus luteum and stimulating it to produce progesterone, estradiol and relaxin.Hypothalamic hypogonadotropic hypogonadism originates from a deficiency in GnRH secretion. Low circulating gonadotropin levels subsequently lead to reduced ovarian function and anovulation. This condition may be congenital or acquired, for example through functional hypothalamic amenorrhoea (FHA) or FHA combined with polycystic ovarian morphology (PCOM). Pulsatile GnRH therapy plays a pivotal role in restoring the physiological menstrual cycle and selecting a dominant follicle in these women, thereby inducing ovulation and achieving fertility. There is extensive literature accounting for a high ovulation rate and consequently high pregnancy and birth rates per cycle, with a lower risk of adverse outcomes. In this review, based on clinical evidence and published studies, we provide recommendations for the alternative treatment of infertility in women with congenital hypothalamic hypogonadotropic hypogonadism (CHH) and FHA (with or without PCOM), until pulsatile GnRH therapy becomes available again or in countries where this device is not marketed. Starting doses and adjustments should be made according to the aetiology of hypothalamic hypogonadotropic hypogonadism and other patient parameters. In all cases, luteal phase support is imperative and should ideally be provided by hCG injections to optimize corpus luteum functions. When pulsatile GnRH therapy is not available, and to ensure the effective treatment of female infertility due to FHA (with or without PCOS) or hypothalamic CHH, we advise physicians to optimise stimulation with exogenous gonadotropins according to the cause of hypothalamic hypogonadotropic hypogonadism. In all cases, providing luteal phase support by optimising corpus luteum function is mandatory.
small molecules
2026-06-26 | Reversible congenital hypogonadotropic hypogonadism: keys for clinical management.
Congenitalhypogonadotropic hypogonadism (CHH) is characterized by absent/incomplete puberty and a treatable form of male infertility resulting from deficient gonadotropin-releasing hormone (GnRH) secretion/action. Traditionally, CHH has been considered a permanent, lifelong condition. However, evidence indicates a subset men undergo reversal and recover reproductive axis function. We conducted a structured literature search (Medline, PubMed) using keywords to retrieve articles on CHH reversal (1975-2025). We synthesize the literature to provide a high-level overview of CHH and the reversal phenomenon in males. Particular focus is given to clinical aspects of CHH and reversal using a case vignette to highlight keys to management. Approximately 10-15% of males with CHH undergo reversal with sustained normalized testosterone levels and spermatogenesis off treatment. A key sign of reversal is testicular growth while on testosterone replacement therapy. Those men with some degree of spontaneous puberty (i.e., larger testicular volume), detectable follicle stimulating hormone levels , and/or pathogenic variants in GNRHR are more likely to undergo reversal. In contrast, severe GnRH deficiency, pathogenic ANOS1 and/or two or more combined pathogenic variants (oligogenicity) in CHH genes are less likely to recover reproductive axis function. Reversal is not lasting in all cases. The reversal phenomenon challenges the classical dogma that CHH is permanent and lifelong. Reversal cases highlight the plasticity of the neuroendocrine control of reproduction. Clinicians can tailor the approach to men with CHH using reversal predictors to guide supervise washout to identify reversal as well as long-term monitoring to assess potential relapse.
2026-02-25 | Congenital Hypogonadotropic Hypogonadism Caused by Prokineticin Receptor 2 Rare Sequence Variants: Molecular Genetics, Clinical Phenotypes and Therapeutic Outcomes From a Single-center Cohort.
Limited data are available regarding the fertility-inducing treatment outcomes and spermatogenic duration in congenital hypogonadotropic hypogonadism patients carrying prokineticin receptor 2 rare sequence variants. We aimed to delineate the rare sequence variant profiles of PROKR2 in a large Chinese cohort with congenital hypogonadotropic hypogonadism, and to characterize the associated clinical phenotypes and therapeutic outcomes. In addition, the reproductive phenotypes and therapeutic outcomes were compared between patients with congenital hypogonadotropic hypogonadism who harbored PROKR2 rare sequence variants and those without identified rare sequence variants in known congenital hypogonadotropic hypogonadism-associated genes. Seven unrelated congenital hypogonadotropic hypogonadism probands carrying PROKR2 rare sequence variants (four with Kallmann syndrome and three with normosmic congenital hypogonadotropic hypogonadism) were included. PROKR2 variants in these patients were identified using targeted next-generation sequencing and verified using Sanger sequencing. The pathogenicity of the identified PROKR2 rare sequence variants was assessed according to the American College of Medical Genetics and Genomics guidelines. Baseline clinical characteristics and therapeutic outcomes were retrospectively evaluated and compared between patients with PROKR2 rare sequence variants and those lacking the identified rare sequence variants in established congenital hypogonadotropic hypogonadism-associated genes. We identified a novel PROKR2 rare sequence variant (p.Y154*, a nonsense mutation). Four rare sequence variants were classified as likely pathogenic according to the American College of Medical Genetics and Genomics guidelines. Spermatogenesis was achieved in all six male patients with PROKR2 rare sequence variants who received gonadotropin therapy following an average of 1.28 years. No statistically significant differences were observed in the baseline clinical characteristics and spermatogenic outcomes between patients with PROKR2 rare sequence variants and those without identified rare sequence variants in known congenital hypogonadotropic hypogonadism-associated genes. We observed a lack of evidence for a significant difference in reproductive phenotype or spermatogenic outcomes between male patients with congenital hypogonadotropic hypogonadism and PROKR2 rare sequence variants and those without identified rare sequence variants in congenital hypogonadotropic hypogonadism-associated genes, but this finding is critically limited by the small number of PROKR2 rare sequence variant carriers in our treatment cohort. The identification of a novel PROKR2 rare sequence variant expands the PROKR2 variant spectrum in patients with congenital hypogonadotropic hypogonadism.
2026-02-19 | A rare case of Kallmann syndrome in a female with pulmonary valve stenosis: Coincidence or genetic link?
Kallmann De Morsier syndrome (KS) is a rare genetic disorder characterized by congenital gonadotropic deficiency alongside anosmia or hyposmia, with a lower prevalence in females. Diagnosis relies on clinical and biological assessment, confirmed through pituitary magnetic resonance imaging (MRI). Cardiac involvement in this syndrome is uncommon, with only a few cases documented in the literature. We reported the case of a 22-year-old female with a history of pulmonary valve stenosis for which she underwent balloon dilatation at the age of five years. She presented with primary amenorrhoea and a history of anosmia was noted. Hormonal investigations revealed hypogonadotropic hypogonadism and a hypothalamic-pituitary MRI identified complete agenesis of the olfactory bulbs. A diagnosis of KS was made. Genetic testing for the KAL1 gene was negative. The patient was put on hormone replacement therapy in order to achieve her puberty and promote general well-being Conclusion: This case represents the first reported association between KS and pulmonary valve stenosis, highlighting the need for further molecular biological research to explore other genes that may explain this connection.
2026-01-23 | Micropenis in Children and Adolescents: A Narrative Review.
To summarize current evidence on the etiology, diagnostic approach, management strategies, and outcomes of micropenis in children and adolescents. A narrative review was performed using PubMed/MEDLINE (October 2025) with the search terms (Micropenis OR Microphallus OR "Small Penis") AND (Children OR Youth OR Adolescents). From 707 records screened, 36 studies were selected based on methodological quality and relevance to clinical practice. Micropenis is a clinical sign frequently associated with underlying endocrinopathies, particularly Congenital Hypogonadotropic Hypogonadism (CHH). Accurate diagnosis relies on standardized Stretched Penile Length (SPL) assessment, recently optimized by the Stretched Penile Length INdicator Technique (SPLINT). Use of population-specific SPL nomograms is critical for diagnostic reliability. Testosterone therapy remains the primary treatment modality and demonstrates greatest efficacy in early infancy, promoting significant penile growth and generally favorable functional outcomes. Spontaneous catch-up growth during puberty has been reported in select cases. Current evidence supporting surgical interventions in children and adolescents is limited, heterogeneous, and associated with inconsistent long-term results; thus, surgery should not be considered first-line therapy. High-quality long-term outcome data and randomized placebo-controlled trials are lacking. Standardized SPL measurement and appropriate nomogram use are essential for accurate diagnosis. Early hormonal therapy, especially in CHH-associated micropenis, appears to yield optimal functional and psychosocial outcomes. Expectant management may be appropriate in selected clinical scenarios. Surgical techniques remain controversial, with insufficient evidence to recommend routine use. Further well-designed prospective studies, including randomized placebo-controlled trials, are needed to define long-term outcomes and guide clinical decision-making.
2026-01-01 | Kallmann Syndrome: Review of Two Cases in Brothers
Background: Kallmann syndrome is a rare genetic disorder characterized by congenital hypogonadotropic hypogonadism associated with anosmia. We report two cases of Kallmann syndrome in two brothers followed at the University Mother and Child Hospital of N’Djamena. Case Presentation: An 18-year-old young man presented with micropenis (40 mm), bilateral cryptorchidism, anosmia, and severe growth retardation (height 146 cm, −4 SD). Biological investigations revealed hypogonadotropic hypogonadism (FSH: 0.42 IU/ml, LH 2). After 5 injections, significant clinical improvement was observed: increase in penile length to 70 mm and 65 mm respectively, with regular erections, ejaculation, and testicular descent. Conclusion: Kallmann syndrome, although rare, warrants systematic consideration in adolescents presenting with delayed puberty, anosmia, and micropenis.
cell therapies
2022-09-08 | A Molecular Analysis of Neural Olfactory Placode Differentiation in Human Pluripotent Stem Cells.
During embryonic development, the olfactory sensory neurons (OSNs) and the gonadotropic-releasing hormone neurons (GNRHNs) migrate from the early nasal cavity, known as the olfactory placode, to the brain. Defects in the development of OSNs and GNRHNs result in neurodevelopmental disorders such as anosmia and congenital hypogonadotropic hypogonadism, respectively. Treatments do not restore the defective neurons in these disorders, and as a result, patients have a diminished sense of smell or a gonadotropin hormone deficiency. Human pluripotent stem cells (hPSCs) can produce any cell type in the body; therefore, they are an invaluable tool for cell replacement therapies. Transplantation of olfactory placode progenitors, derived from hPSCs, is a promising therapeutic to replace OSNs and GNRHNs and restore tissue function. Protocols to generate olfactory placode progenitors are limited, and thus, we describe, in this study, a novel in vitro model for olfactory placode differentiation in hPSCs, which is capable of producing both OSNs and GNRHNs. Our study investigates the major developmental signaling factors that recapitulate the embryonic development of the olfactory tissue. We demonstrate that induction of olfactory placode in hPSCs requires bone morphogenetic protein inhibition, wingless/integrated protein inhibition, retinoic acid inhibition, transforming growth factor alpha activation, and fibroblast growth factor 8 activation. We further show that the protocol transitions hPSCs through the anterior pan-placode ectoderm and neural ectoderm regions in early development while preventing neural crest and non-neural ectoderm regions. Finally, we demonstrate production of OSNs and GNRHNs by day 30 of differentiation. Our study is the first to report on OSN differentiation in hPSCs.
2020-10-27 | Novel therapeutic approaches of tissue engineering in male infertility.
Male reproductive organ plays an important role in sperm production, maintenance and entry to the female reproductive tract, as well as generation and secretion of male sex hormones responsible for the health of male reproductive system. The purpose of this paper is to discuss the experimental and clinical evidence on the utilization of tissue engineering techniques in treating male infertility. Tissue engineering (TE) and regenerative medicine have developed new approaches to treat patients with reproductive disorders such as iatrogenic injuries, congenital abnormalities, and trauma. In some cases, including congenital defects and undescended testis or hypogonadism, the sperm samples are not retrieved. This makes TE a possible future strategy for restoration of male fertility. Here, we have summarized the recent advances in experimental and clinical application of cell-, tissue-, and organ-based regenerative medicine in male reproductive disorders.
2016-12-09 | An updated view of hypothalamic–vascular–pituitary unit function and plasticity
The discoveries of novel functional adaptations of the hypothalamus and anterior pituitary gland for physiological regulation have transformed our understanding of their interaction. The activity of a small proportion of hypothalamic neurons can control complex hormonal signalling, which is disconnected from a simple stimulus and the subsequent hormone secretion relationship and is dependent on physiological status. The interrelationship of the terminals of hypothalamic neurons and pituitary cells with the vasculature has an important role in determining the pattern of neurohormone exposure. Cells in the pituitary gland form networks with distinct organizational motifs that are related to the duration and pattern of output, and modifications of these networks occur in different physiological states, can persist after cessation of demand and result in enhanced function. Consequently, the hypothalamus and pituitary can no longer be considered as having a simple stratified relationship: with the vasculature they form a tripartite system, which must function in concert for appropriate hypothalamic regulation of physiological processes, such as reproduction. An improved understanding of the mechanisms underlying these regulatory features has implications for current and future therapies that correct defects in hypothalamic-pituitary axes. In addition, recapitulating proper network organization will be an important challenge for regenerative stem cell treatment.
2016-08-01 | Development of Gonadotropin-Releasing Hormone-Secreting Neurons from Human Pluripotent Stem Cells
Gonadotropin-releasing hormone (GnRH) neurons regulate human puberty and reproduction. Modeling their development and function in vitro would be of interest for both basic research and clinical translation. Here, we report a three-step protocol to differentiate human pluripotent stem cells (hPSCs) into GnRH-secreting neurons. Firstly, hPSCs were differentiated to FOXG1, EMX2, and PAX6 expressing anterior neural progenitor cells (NPCs) by dual SMAD inhibition. Secondly, NPCs were treated for 10 days with FGF8, which is a key ligand implicated in GnRH neuron ontogeny, and finally, the cells were matured with Notch inhibitor to bipolar TUJ1-positive neurons that robustly expressed GNRH1 and secreted GnRH decapeptide into the culture medium. The protocol was reproducible both in human embryonic stem cells and induced pluripotent stem cells, and thus provides a translational tool for investigating the mechanisms of human puberty and its disorders.
2015-07-24 | Zebrafish adult-derived hypothalamic neurospheres generate gonadotropin-releasing hormone (GnRH) neurons
Gonadotropin-releasing hormone (GnRH) is a hypothalamic decapeptide essential for fertility in vertebrates. Human male patients lacking GnRH and treated with hormone therapy can remain fertile after cessation of treatment suggesting that new GnRH neurons can be generated during adult life. We used zebrafish to investigate the neurogenic potential of the adult hypothalamus. Previously we have characterized the development of GnRH cells in the zebrafish linking genetic pathways to the differentiation of neuromodulatory and endocrine GnRH cells in specific regions of the brain. Here, we developed a new method to obtain neural progenitors from the adult hypothalamus in vitro. Using this system, we show that neurospheres derived from the adult hypothalamus can be maintained in culture and subsequently differentiate glia and neurons. Importantly, the adult derived progenitors differentiate into neurons containing GnRH and the number of cells is increased through exposure to either testosterone or GnRH, hormones used in therapeutic treatment in humans. Finally, we show in vivo that a neurogenic niche in the hypothalamus contains GnRH positive neurons. Thus, we demonstrated for the first time that neurospheres can be derived from the hypothalamus of the adult zebrafish and that these neural progenitors are capable of producing GnRH containing neurons.
gene therapies
2025-10-01 | SAT-160 Functional study of a novel variant of FGFR1 detected in an adult patient with Kallmann syndrome on the gonadal steroidogenesis
Abstract Disclosure: F. Otsuka: None. Y. Soejima: None. N. Iwata: None. K. Yamamoto: None. A. Suyama: None. Y. Nakano: None. Kallmann syndrome (KS) is a congenital developmental disorder characterized by hypogonadotropic hypogonadism and anosmia, which results from incomplete embryonic migration of gonadotropin-releasing hormone (GnRH)-synthesizing neurons and olfactory neurons. KS is often accompanied by cryptorchidism, testicular atrophy, micropenis, orofacial clefts and/or tooth agenesis, renal anomalies, bimanual synkinesis, and hearing loss. KS exhibits different inheritance patterns and genetic heterogeneity including X-linked recessive, ANOS1; autosomal recessive, PROK2 and PROKR2; and autosomal dominant, FGFR1, FGF8, and CHD7. Fibroblast growth factor receptor 1 (FGFR1) was the first gene to be identified as an autosomal dominant form of KS, and more than 140 FGFR1 variants have so far been reported. FGFR1, also known as KAL2, is a tyrosine kinase receptor for FGF and it regulates cell proliferation, differentiation and migration. FGFR1 gene is expressed mainly in Rathke’s pouch and the ventral diencephalon during the embryonic period. It has been reported that variants of FGFR1 cause KS and variants have been detected in 10% of KS cases. We here report an adult case of KS with a novel variant of FGFR1. A middle-aged male was refereed for a compression fracture of a lumbar vertebra. It was shown that he had severe osteoporosis, anosmia, gynecomastia, and a past history of operations for cryptorchidism. Endocrine workup by pituitary and gonadal stimulation tests revealed the presence of both primary and central hypogonadism. Genetic testing revealed a novel variant of FGFR1 (c.2197_2199dup, p.Met733dup). To identify the pathogenicity of the novel variant and the clinical significance for the gonads, we investigated the effects of the FGFR1 variant on downstream signaling of FGFR1 and gonadal steroidogenesis by using human steroidogenic granulosa KGN cells. It was revealed that transfection of the variant gene significantly impaired FGFR1 signaling, detected by downregulation of SPRY2, compared with that in the case of forced expression of wild-type FGFR1, and that the forced expression of the variant gene apparently altered the expression levels of key steroidogenic factors including StAR and aromatase in the gonad. Collectively, the results suggested that the novel variant of FGFR1 detected in a patient with KS was linked to impairment of FGFR1 signaling as well as alteration of gonadal steroidogenesis, leading to the pathogenesis of latent primary hypogonadism. Presentation: Saturday, July 12, 2025
2025-03-24 | Evaluation of the potential roles of kisspeptin and neurokinin genes in puberty treatment
Objective: Kisspeptin (KP) and neurokinin (NK) are neuropeptides that govern the reproductive endocrine axis through regulating hypothalamic neuronal activity and pulsatile.Their critical role in reproductive health was first described by the demonstration of congenital hypogonadotropic hypogonadism and pubertal developmental anomalies following loss of function due to mutations in genes encoding the KP or NK signaling.This study aimed to investigate the efficacy of KP and NK, in mesenchymal stem cell (MSC)-based treatment of different origin, and examine the relationship of the expression of these genes with the passage number.Methods: Three adult rats (Rattus norvegicus) were used in our study.MSCs were obtained from bone marrow and adipose tissue of rats.The MSCs were analysed by flow cytometry using surface markers and RNA (ribonucleic acid) isolation was performed.Gene expressions of KP, NK and their receptors were investigated by real-time Makale Dili "Trke"/
2024-03-25 | 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.
2023-01-04 | CRISPR/Cas9-editing of KISS1 to generate pigs with hypogonadotropic hypogonadism as a castration free trait
Introduction: Most male pigs are surgically castrated to avoid puberty-derived boar taint and aggressiveness. However, this surgical intervention represents a welfare concern in swine production. Disrupting porcine KISS1 is hypothesized to delay or abolish puberty by inducing variable hypogonadotropism and thus preventing the need for castration. Methods: To test this hypothesis, we generated the first KISS1-edited large animal using CRISPR/Cas9-ribonucleoproteins and single-stranded donor oligonucleotides. The targeted region preceded the sequence encoding a conserved core motif of kisspeptin. Genome editors were intracytoplasmically injected into 684 swine zygotes and transferred to 19 hormonally synchronized surrogate sows. In nine litters, 49 American Yorkshire and 20 Duroc liveborn piglets were naturally farrowed. Results: Thirty-five of these pigs bore KISS1-disruptive alleles ranging in frequency from 5% to 97% and did not phenotypically differ from their wild-type counterparts. In contrast, four KISS1-edited pigs (two boars and two gilts) with disruptive allele frequencies of 96% and 100% demonstrated full hypogonadotropism, infantile reproductive tracts, and failed to reach sexual maturity. Change in body weight during development was unaffected by editing KISS1. Founder pigs partially carrying KISS1-disruptive alleles were bred resulting in a total of 53 KISS1+/+, 60 KISS1+/-, and 34 KISS1-/- F1 liveborn piglets, confirming germline transmission. Discussion: Results demonstrate that a high proportion of KISS1 alleles in pigs must be disrupted before variation in gonadotropin secretion is observed, suggesting that even a small amount of kisspeptin ligand is sufficient to confer proper sexual development and puberty in pigs. Follow-on studies will evaluate fertility restoration in KISS1 KO breeding stock to fully realize the potential of KISS1 gene edits to eliminate the need for surgical castration.
2019-01-21 | Evidence for a Common Genetic Origin of Classic and Milder Adult-Onset Forms of Isolated Hypogonadotropic Hypogonadism
Multiple metabolic and inflammatory mechanisms are considered the determinants of acquired functional isolated hypogonadotropic hypogonadism (IHH) in males, whereas classic IHH is a rare congenital condition with a strong genetic background. Since we recently uncovered a frequent familiarity for classic IHH among patients with mild adult-onset hypogonadism (AO-IHH), here we performed a genetic characterization by next generation sequencing of 160 males with classic or "functional" forms. The prevalence of rare variants in 28 candidate genes was significantly higher than in controls in all IHH patients, independently of the age of IHH onset, degree of hypogonadism or presence of obesity. In fact, it did not differ among patients with classic or milder forms of IHH, however particular genes appear to be more specifically associated with one or the other category of IHH. ROC curves showed that Total Testosterone <6.05 nmol/L and an age of onset <41 years are sensitive cutoffs to identify patients with significantly higher chances of harboring rare IHH gene variants. In conclusion, rare IHH genes variants can frequently predispose to AO-IHH with acquired mild hormonal deficiencies. The identification of a genetic predisposition can improve the familial and individual management of AO-IHH and explain the heritability of congenital IHH.
other
2022-08-09 | Dicer ablation in Kiss1 neurons impairs puberty and fertility preferentially in female mice
Abstract Kiss1 neurons, producing kisspeptins, are essential for puberty and fertility, but their molecular regulatory mechanisms remain unfolded. Here, we report that congenital ablation of the microRNA-synthesizing enzyme, Dicer, in Kiss1 cells, causes late-onset hypogonadotropic hypogonadism in both sexes, but is compatible with pubertal initiation and preserved Kiss1 neuronal populations at the infantile/juvenile period. Yet, failure to complete puberty and attain fertility is observed only in females. Kiss1-specific ablation of Dicer evokes disparate changes of Kiss1-cell numbers and Kiss1 /kisspeptin expression between hypothalamic subpopulations during the pubertal-transition, with a predominant decline in arcuate-nucleus Kiss1 levels, linked to enhanced expression of its repressors, Mkrn3, Cbx7 and Eap1. Our data unveil that miRNA-biosynthesis in Kiss1 neurons is essential for pubertal completion and fertility, especially in females, but dispensable for initial reproductive maturation and neuronal survival in both sexes. Our results disclose a predominant miRNA-mediated inhibitory program of repressive signals that is key for precise regulation of Kiss1 expression and, thereby, reproductive function.
2018-04-01 | Reproductive role of miRNA in the hypothalamic-pituitary axis
The hypothalamic-pituitary-gonadal (HPG) axis plays a critical role in regulating reproductive function. Gonadotropin-releasing hormone (GnRH), which is secreted by the hypothalamus, acts on pituitary gonadotrophs to stimulate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) synthesis and secretion, ultimately affecting the animal's fertility. MicroRNAs are small, non-coding RNAs that are widely expressed throughout the brain and can fine-tune gene expression post-transcriptionally. Recently, growing evidence has unveiled the central position of miRNAs within a key regulatory process involving GnRH secretion and subsequent activation in the pituitary. Although transcriptional regulation of reproduction has been well studied, the post-transcriptional processes are less well understood. In this review, we elaborate comprehensively on the critical role of miRNAs in the reproductive process, including both temporal and spatial aspects. A better understanding of how miRNAs impact the neuroendocrine system may improve our knowledge of reproduction and provide novel targets for therapeutic development.
2017-02-19 | Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility
MicroRNAs (miRNAs) are negative modulators of gene expression that fine-tune numerous biological processes. miRNA loss-of-function rarely results in highly penetrant phenotypes, but rather, influences cellular responses to physiologic and pathophysiologic stresses. Here, we have reported that a single member of the evolutionarily conserved miR-7 family, miR-7a2, is essential for normal pituitary development and hypothalamic-pituitary-gonadal (HPG) function in adulthood. Genetic deletion of mir-7a2 causes infertility, with low levels of gonadotropic and sex steroid hormones, small testes or ovaries, impaired spermatogenesis, and lack of ovulation in male and female mice, respectively. We found that miR-7a2 is highly expressed in the pituitary, where it suppresses golgi glycoprotein 1 (GLG1) expression and downstream bone morphogenetic protein 4 (BMP4) signaling and also reduces expression of the prostaglandin F2a receptor negative regulator (PTGFRN), an inhibitor of prostaglandin signaling and follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion. Our results reveal that miR-7a2 critically regulates sexual maturation and reproductive function by interconnecting miR-7 genomic circuits that regulate FSH and LH synthesis and secretion through their effects on pituitary prostaglandin and BMP4 signaling.
proteins
2026-07-24 | A Novel Hemizygous ANOS1 Variant in a Patient With Kallmann Syndrome and Type 2 Diabetes Mellitus: A Case Report.
Kallmann syndrome (KS), a rare genetic disorder, is characterized by congenital hypogonadotropic hypogonadism (CHH) and anosmia or hyposmia. We report a case of KS with type 2 diabetes mellitus (T2DM) associated with a novel hemizygous missense variant in ANOS1 (NM_000216.4; exon 4; c.505G >C;p.(Gly169Arg)). A 33-year-old male presented with persistent hyperglycemia, delayed pubertal development with absent secondary sexual characteristics, and lifelong anosmia. Olfactory testing, magnetic resonance imaging (MRI) of the pituitary region, and a gonadotropin-releasing hormone (GnRH) stimulation test supported a clinical diagnosis of KS. Trio-based exome sequencing (ES) revealed the aforementioned hemizygous variant in ANOS1. Notably, neither parent harbored this variant, supporting a de novo origin, which is consistent with the variant's potential pathogenicity. Multiple sequence alignment showed that Gly169 is highly conserved across species, suggesting it may be functionally important for the protein. Furthermore, a three-dimensional protein model generated using SWISS-MODEL predicted marked conformational changes in the protein attributable to this amino acid substitution at a highly conserved residue, suggesting a potential functional impact. Notably, emerging evidence has linked ANOS1 variants to dysregulated glucose metabolism, supporting a potential association with T2DM in this case. For treatment, insulin and oral hypoglycemic agents were used for glycemic control, and a GnRH pump was initiated. At the sixth follow-up visit, the patient had achieved satisfactory glycemic control; however, serum testosterone levels remained low despite GnRH pump therapy, so testosterone replacement therapy was subsequently initiated. ANOS1 variants are genetically diverse and may contribute to both KS pathogenesis and the development of comorbid T2DM, though further studies are needed to confirm this link. For KS patients, close monitoring of fasting glucose, glycated hemoglobin, and oral glucose tolerance test results is advisable to detect diabetes and prediabetes early.
2026-05-18 | Case Report: Homozygous KISS1R mutation associated with congenital hypogonadotropic hypogonadism in two siblings: pulsatile GnRH therapy restores pituitary architecture and induces pubertal development.
Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterized by deficient production, secretion, or action of gonadotropin-releasing hormone (GnRH), the central regulator of the reproductive axis. We report two siblings from a consanguineous family with CHH caused by a homozygous nonsense mutation (c.182C > A; p. Ser 61Ter) in exon 1 of KISS1R gene. The 15-years-old male proband presented with absent puberty, micropenis, and gynecomastia. Endocrine evaluation revealed low gonadotropin levels and brain magnetic resonance imaging (MRI) showed pituitary hypoplasia. His 12-years-old sister exhibited puberty delays, with absent breast development and pubic hair. The male patient received 1 year of pulsatile GnRH therapy, resulting in significant clinical improvements, including markedly increased testicular volume (from 0.9 to 5.6 mL), penile growth, and the resolution of gynecomastia. Notably, follow-up imaging demonstrated morphological recovery of the pituitary gland, with an increase in height from 3.5 to 4.5 mm, accompanied by the successful induction of spermatogenesis. This excellent response to GnRH underscores its efficacy in restoring fertility, particularly when initiated in early adolescence, and highlights the value of genetic diagnosis in consanguineous families.
2026-04-17 | Comparing the response of triple therapy and conventional treatment in male congenital hypogonadotropic hypogonadism: a randomized controlled trial.
This study investigated whether triple therapy with human chorionic gonadotropin (hCG), follicle-stimulating hormone(FSH) and testosterone(T) in congenital hypogonadotropic hypogonadism(CHH) promoted more timely virilization, aiding psychosocial development while reducing hCG requirements, offering a balanced approach to long-term management. An open-label randomized controlled trial (1:1:1) was conducted in adult males with CHH. Group A received triple therapy, Group B received combined hCG and FSH from the outset, and Group C received hCG monotherapy followed by combined FSH and hCG. Initial doses comprised hCG 2,000 IU twice weekly, FSH 75 IU thrice weekly and intramuscular testosterone(T) 100 mg every two weeks. Group A titrated hCG to achieve AMH of 7.4ng/ml; Groups B and C aimed for T normalization. Primary outcomes were hCG/FSH doses required for spermatogenesis induction and the time to spermatogenesis. Forty-five CHH males (mean age 25.8 ± 6.1years) were randomized. Spermatogenesis was achieved in 84.6% of group A participants compared with 69.2% and 75% in groups B and C, respectively(p=0.648). Median hCG dose at spermatogenesis was 7500IU/week in group A and 9000IU/week in groups B and C(p=0.016). The time to spermatogenesis was comparable (Groups A/B:12 months; Group C:15 months;p=0.345). Group A participants achieved an AMH of 3.5(2.31-5.38)ng/ml, comparable to the other groups(p=0.962). Predictors of spermatogenesis included USGmTV cut-off of 1.97ml (sensitivity-86.2%,specificity-62.5%), hCG dose of 9,000 IU/week (sensitivity-79.3%,specificity-87.5%) and an Inh B cut-off of 66.8 pg/ml(sensitivity-92.6%,specificity-100%). Triple therapy provided a better quality of life without compromising spermatogenesis. The AMH and Inh B provided an effective means of monitoring. www.ctri.nic.in, identifier CTRI/2022/05/042795.
2026-03-25 | Clinical Implications of Minipuberty.
Minipuberty refers to a specific period in early postnatal life with high activity of the hypothalamic-pituitary-gonadal (HPG) hormone axis. In infant boys 1 to 3 months of age, high concentrations of follicle-stimulating hormone and luteinizing hormone are released, which results in high levels of gonadal hormones from testicular Leydig cells (testosterone and insulin-like 3) and Sertoli cells (inhibin B and antimüllerian hormone). The HPG axis is also active in infant girls, who have adult levels of follicle-stimulating hormone and luteinizing hormone during this period. Immediately after minipuberty, the HPG axis is silenced for approximately 10 years and is reactivated only with the onset of puberty. Thus, minipuberty represents an early window for diagnosing disorders of sexual differentiation and rare endocrine disorders, such as congenital hypogonadotropic hypogonadism, and may help guide dosing of therapeutic interventions including gonadotropin therapy. Of note, minipuberty predicts adult reproductive capacity.
2026-02-20 | Management of infertility in women with hypothalamic hypogonadotropic hypogonadism: an expert opinion.
Hypothalamic gonadotropin-releasing hormone (GnRH) plays a central role in regulating the pituitary-gonadal axis. The pulsatility of GnRH release is critical for maintaining the function of GnRH receptors and the secretion pattern of gonadotropins, namely follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which regulate endocrine function and follicular growth and maturation. During the luteal phase, LH is crucial for supporting a functional corpus luteum and stimulating it to produce progesterone, estradiol and relaxin.Hypothalamic hypogonadotropic hypogonadism originates from a deficiency in GnRH secretion. Low circulating gonadotropin levels subsequently lead to reduced ovarian function and anovulation. This condition may be congenital or acquired, for example through functional hypothalamic amenorrhoea (FHA) or FHA combined with polycystic ovarian morphology (PCOM). Pulsatile GnRH therapy plays a pivotal role in restoring the physiological menstrual cycle and selecting a dominant follicle in these women, thereby inducing ovulation and achieving fertility. There is extensive literature accounting for a high ovulation rate and consequently high pregnancy and birth rates per cycle, with a lower risk of adverse outcomes. In this review, based on clinical evidence and published studies, we provide recommendations for the alternative treatment of infertility in women with congenital hypothalamic hypogonadotropic hypogonadism (CHH) and FHA (with or without PCOM), until pulsatile GnRH therapy becomes available again or in countries where this device is not marketed. Starting doses and adjustments should be made according to the aetiology of hypothalamic hypogonadotropic hypogonadism and other patient parameters. In all cases, luteal phase support is imperative and should ideally be provided by hCG injections to optimize corpus luteum functions. When pulsatile GnRH therapy is not available, and to ensure the effective treatment of female infertility due to FHA (with or without PCOS) or hypothalamic CHH, we advise physicians to optimise stimulation with exogenous gonadotropins according to the cause of hypothalamic hypogonadotropic hypogonadism. In all cases, providing luteal phase support by optimising corpus luteum function is mandatory.
small molecules
2026-06-26 | Reversible congenital hypogonadotropic hypogonadism: keys for clinical management.
Congenitalhypogonadotropic hypogonadism (CHH) is characterized by absent/incomplete puberty and a treatable form of male infertility resulting from deficient gonadotropin-releasing hormone (GnRH) secretion/action. Traditionally, CHH has been considered a permanent, lifelong condition. However, evidence indicates a subset men undergo reversal and recover reproductive axis function. We conducted a structured literature search (Medline, PubMed) using keywords to retrieve articles on CHH reversal (1975-2025). We synthesize the literature to provide a high-level overview of CHH and the reversal phenomenon in males. Particular focus is given to clinical aspects of CHH and reversal using a case vignette to highlight keys to management. Approximately 10-15% of males with CHH undergo reversal with sustained normalized testosterone levels and spermatogenesis off treatment. A key sign of reversal is testicular growth while on testosterone replacement therapy. Those men with some degree of spontaneous puberty (i.e., larger testicular volume), detectable follicle stimulating hormone levels , and/or pathogenic variants in GNRHR are more likely to undergo reversal. In contrast, severe GnRH deficiency, pathogenic ANOS1 and/or two or more combined pathogenic variants (oligogenicity) in CHH genes are less likely to recover reproductive axis function. Reversal is not lasting in all cases. The reversal phenomenon challenges the classical dogma that CHH is permanent and lifelong. Reversal cases highlight the plasticity of the neuroendocrine control of reproduction. Clinicians can tailor the approach to men with CHH using reversal predictors to guide supervise washout to identify reversal as well as long-term monitoring to assess potential relapse.
2026-02-25 | Congenital Hypogonadotropic Hypogonadism Caused by Prokineticin Receptor 2 Rare Sequence Variants: Molecular Genetics, Clinical Phenotypes and Therapeutic Outcomes From a Single-center Cohort.
Limited data are available regarding the fertility-inducing treatment outcomes and spermatogenic duration in congenital hypogonadotropic hypogonadism patients carrying prokineticin receptor 2 rare sequence variants. We aimed to delineate the rare sequence variant profiles of PROKR2 in a large Chinese cohort with congenital hypogonadotropic hypogonadism, and to characterize the associated clinical phenotypes and therapeutic outcomes. In addition, the reproductive phenotypes and therapeutic outcomes were compared between patients with congenital hypogonadotropic hypogonadism who harbored PROKR2 rare sequence variants and those without identified rare sequence variants in known congenital hypogonadotropic hypogonadism-associated genes. Seven unrelated congenital hypogonadotropic hypogonadism probands carrying PROKR2 rare sequence variants (four with Kallmann syndrome and three with normosmic congenital hypogonadotropic hypogonadism) were included. PROKR2 variants in these patients were identified using targeted next-generation sequencing and verified using Sanger sequencing. The pathogenicity of the identified PROKR2 rare sequence variants was assessed according to the American College of Medical Genetics and Genomics guidelines. Baseline clinical characteristics and therapeutic outcomes were retrospectively evaluated and compared between patients with PROKR2 rare sequence variants and those lacking the identified rare sequence variants in established congenital hypogonadotropic hypogonadism-associated genes. We identified a novel PROKR2 rare sequence variant (p.Y154*, a nonsense mutation). Four rare sequence variants were classified as likely pathogenic according to the American College of Medical Genetics and Genomics guidelines. Spermatogenesis was achieved in all six male patients with PROKR2 rare sequence variants who received gonadotropin therapy following an average of 1.28 years. No statistically significant differences were observed in the baseline clinical characteristics and spermatogenic outcomes between patients with PROKR2 rare sequence variants and those without identified rare sequence variants in known congenital hypogonadotropic hypogonadism-associated genes. We observed a lack of evidence for a significant difference in reproductive phenotype or spermatogenic outcomes between male patients with congenital hypogonadotropic hypogonadism and PROKR2 rare sequence variants and those without identified rare sequence variants in congenital hypogonadotropic hypogonadism-associated genes, but this finding is critically limited by the small number of PROKR2 rare sequence variant carriers in our treatment cohort. The identification of a novel PROKR2 rare sequence variant expands the PROKR2 variant spectrum in patients with congenital hypogonadotropic hypogonadism.
2026-02-19 | A rare case of Kallmann syndrome in a female with pulmonary valve stenosis: Coincidence or genetic link?
Kallmann De Morsier syndrome (KS) is a rare genetic disorder characterized by congenital gonadotropic deficiency alongside anosmia or hyposmia, with a lower prevalence in females. Diagnosis relies on clinical and biological assessment, confirmed through pituitary magnetic resonance imaging (MRI). Cardiac involvement in this syndrome is uncommon, with only a few cases documented in the literature. We reported the case of a 22-year-old female with a history of pulmonary valve stenosis for which she underwent balloon dilatation at the age of five years. She presented with primary amenorrhoea and a history of anosmia was noted. Hormonal investigations revealed hypogonadotropic hypogonadism and a hypothalamic-pituitary MRI identified complete agenesis of the olfactory bulbs. A diagnosis of KS was made. Genetic testing for the KAL1 gene was negative. The patient was put on hormone replacement therapy in order to achieve her puberty and promote general well-being Conclusion: This case represents the first reported association between KS and pulmonary valve stenosis, highlighting the need for further molecular biological research to explore other genes that may explain this connection.
2026-01-23 | Micropenis in Children and Adolescents: A Narrative Review.
To summarize current evidence on the etiology, diagnostic approach, management strategies, and outcomes of micropenis in children and adolescents. A narrative review was performed using PubMed/MEDLINE (October 2025) with the search terms (Micropenis OR Microphallus OR "Small Penis") AND (Children OR Youth OR Adolescents). From 707 records screened, 36 studies were selected based on methodological quality and relevance to clinical practice. Micropenis is a clinical sign frequently associated with underlying endocrinopathies, particularly Congenital Hypogonadotropic Hypogonadism (CHH). Accurate diagnosis relies on standardized Stretched Penile Length (SPL) assessment, recently optimized by the Stretched Penile Length INdicator Technique (SPLINT). Use of population-specific SPL nomograms is critical for diagnostic reliability. Testosterone therapy remains the primary treatment modality and demonstrates greatest efficacy in early infancy, promoting significant penile growth and generally favorable functional outcomes. Spontaneous catch-up growth during puberty has been reported in select cases. Current evidence supporting surgical interventions in children and adolescents is limited, heterogeneous, and associated with inconsistent long-term results; thus, surgery should not be considered first-line therapy. High-quality long-term outcome data and randomized placebo-controlled trials are lacking. Standardized SPL measurement and appropriate nomogram use are essential for accurate diagnosis. Early hormonal therapy, especially in CHH-associated micropenis, appears to yield optimal functional and psychosocial outcomes. Expectant management may be appropriate in selected clinical scenarios. Surgical techniques remain controversial, with insufficient evidence to recommend routine use. Further well-designed prospective studies, including randomized placebo-controlled trials, are needed to define long-term outcomes and guide clinical decision-making.
2026-01-01 | Kallmann Syndrome: Review of Two Cases in Brothers
Background: Kallmann syndrome is a rare genetic disorder characterized by congenital hypogonadotropic hypogonadism associated with anosmia. We report two cases of Kallmann syndrome in two brothers followed at the University Mother and Child Hospital of N’Djamena. Case Presentation: An 18-year-old young man presented with micropenis (40 mm), bilateral cryptorchidism, anosmia, and severe growth retardation (height 146 cm, −4 SD). Biological investigations revealed hypogonadotropic hypogonadism (FSH: 0.42 IU/ml, LH 2). After 5 injections, significant clinical improvement was observed: increase in penile length to 70 mm and 65 mm respectively, with regular erections, ejaculation, and testicular descent. Conclusion: Kallmann syndrome, although rare, warrants systematic consideration in adolescents presenting with delayed puberty, anosmia, and micropenis.
cell therapies
2022-09-08 | A Molecular Analysis of Neural Olfactory Placode Differentiation in Human Pluripotent Stem Cells.
During embryonic development, the olfactory sensory neurons (OSNs) and the gonadotropic-releasing hormone neurons (GNRHNs) migrate from the early nasal cavity, known as the olfactory placode, to the brain. Defects in the development of OSNs and GNRHNs result in neurodevelopmental disorders such as anosmia and congenital hypogonadotropic hypogonadism, respectively. Treatments do not restore the defective neurons in these disorders, and as a result, patients have a diminished sense of smell or a gonadotropin hormone deficiency. Human pluripotent stem cells (hPSCs) can produce any cell type in the body; therefore, they are an invaluable tool for cell replacement therapies. Transplantation of olfactory placode progenitors, derived from hPSCs, is a promising therapeutic to replace OSNs and GNRHNs and restore tissue function. Protocols to generate olfactory placode progenitors are limited, and thus, we describe, in this study, a novel in vitro model for olfactory placode differentiation in hPSCs, which is capable of producing both OSNs and GNRHNs. Our study investigates the major developmental signaling factors that recapitulate the embryonic development of the olfactory tissue. We demonstrate that induction of olfactory placode in hPSCs requires bone morphogenetic protein inhibition, wingless/integrated protein inhibition, retinoic acid inhibition, transforming growth factor alpha activation, and fibroblast growth factor 8 activation. We further show that the protocol transitions hPSCs through the anterior pan-placode ectoderm and neural ectoderm regions in early development while preventing neural crest and non-neural ectoderm regions. Finally, we demonstrate production of OSNs and GNRHNs by day 30 of differentiation. Our study is the first to report on OSN differentiation in hPSCs.
2020-10-27 | Novel therapeutic approaches of tissue engineering in male infertility.
Male reproductive organ plays an important role in sperm production, maintenance and entry to the female reproductive tract, as well as generation and secretion of male sex hormones responsible for the health of male reproductive system. The purpose of this paper is to discuss the experimental and clinical evidence on the utilization of tissue engineering techniques in treating male infertility. Tissue engineering (TE) and regenerative medicine have developed new approaches to treat patients with reproductive disorders such as iatrogenic injuries, congenital abnormalities, and trauma. In some cases, including congenital defects and undescended testis or hypogonadism, the sperm samples are not retrieved. This makes TE a possible future strategy for restoration of male fertility. Here, we have summarized the recent advances in experimental and clinical application of cell-, tissue-, and organ-based regenerative medicine in male reproductive disorders.
2016-12-09 | An updated view of hypothalamic–vascular–pituitary unit function and plasticity
The discoveries of novel functional adaptations of the hypothalamus and anterior pituitary gland for physiological regulation have transformed our understanding of their interaction. The activity of a small proportion of hypothalamic neurons can control complex hormonal signalling, which is disconnected from a simple stimulus and the subsequent hormone secretion relationship and is dependent on physiological status. The interrelationship of the terminals of hypothalamic neurons and pituitary cells with the vasculature has an important role in determining the pattern of neurohormone exposure. Cells in the pituitary gland form networks with distinct organizational motifs that are related to the duration and pattern of output, and modifications of these networks occur in different physiological states, can persist after cessation of demand and result in enhanced function. Consequently, the hypothalamus and pituitary can no longer be considered as having a simple stratified relationship: with the vasculature they form a tripartite system, which must function in concert for appropriate hypothalamic regulation of physiological processes, such as reproduction. An improved understanding of the mechanisms underlying these regulatory features has implications for current and future therapies that correct defects in hypothalamic-pituitary axes. In addition, recapitulating proper network organization will be an important challenge for regenerative stem cell treatment.
2016-08-01 | Development of Gonadotropin-Releasing Hormone-Secreting Neurons from Human Pluripotent Stem Cells
Gonadotropin-releasing hormone (GnRH) neurons regulate human puberty and reproduction. Modeling their development and function in vitro would be of interest for both basic research and clinical translation. Here, we report a three-step protocol to differentiate human pluripotent stem cells (hPSCs) into GnRH-secreting neurons. Firstly, hPSCs were differentiated to FOXG1, EMX2, and PAX6 expressing anterior neural progenitor cells (NPCs) by dual SMAD inhibition. Secondly, NPCs were treated for 10 days with FGF8, which is a key ligand implicated in GnRH neuron ontogeny, and finally, the cells were matured with Notch inhibitor to bipolar TUJ1-positive neurons that robustly expressed GNRH1 and secreted GnRH decapeptide into the culture medium. The protocol was reproducible both in human embryonic stem cells and induced pluripotent stem cells, and thus provides a translational tool for investigating the mechanisms of human puberty and its disorders.
2015-07-24 | Zebrafish adult-derived hypothalamic neurospheres generate gonadotropin-releasing hormone (GnRH) neurons
Gonadotropin-releasing hormone (GnRH) is a hypothalamic decapeptide essential for fertility in vertebrates. Human male patients lacking GnRH and treated with hormone therapy can remain fertile after cessation of treatment suggesting that new GnRH neurons can be generated during adult life. We used zebrafish to investigate the neurogenic potential of the adult hypothalamus. Previously we have characterized the development of GnRH cells in the zebrafish linking genetic pathways to the differentiation of neuromodulatory and endocrine GnRH cells in specific regions of the brain. Here, we developed a new method to obtain neural progenitors from the adult hypothalamus in vitro. Using this system, we show that neurospheres derived from the adult hypothalamus can be maintained in culture and subsequently differentiate glia and neurons. Importantly, the adult derived progenitors differentiate into neurons containing GnRH and the number of cells is increased through exposure to either testosterone or GnRH, hormones used in therapeutic treatment in humans. Finally, we show in vivo that a neurogenic niche in the hypothalamus contains GnRH positive neurons. Thus, we demonstrated for the first time that neurospheres can be derived from the hypothalamus of the adult zebrafish and that these neural progenitors are capable of producing GnRH containing neurons.
gene therapies
2025-10-01 | SAT-160 Functional study of a novel variant of FGFR1 detected in an adult patient with Kallmann syndrome on the gonadal steroidogenesis
Abstract Disclosure: F. Otsuka: None. Y. Soejima: None. N. Iwata: None. K. Yamamoto: None. A. Suyama: None. Y. Nakano: None. Kallmann syndrome (KS) is a congenital developmental disorder characterized by hypogonadotropic hypogonadism and anosmia, which results from incomplete embryonic migration of gonadotropin-releasing hormone (GnRH)-synthesizing neurons and olfactory neurons. KS is often accompanied by cryptorchidism, testicular atrophy, micropenis, orofacial clefts and/or tooth agenesis, renal anomalies, bimanual synkinesis, and hearing loss. KS exhibits different inheritance patterns and genetic heterogeneity including X-linked recessive, ANOS1; autosomal recessive, PROK2 and PROKR2; and autosomal dominant, FGFR1, FGF8, and CHD7. Fibroblast growth factor receptor 1 (FGFR1) was the first gene to be identified as an autosomal dominant form of KS, and more than 140 FGFR1 variants have so far been reported. FGFR1, also known as KAL2, is a tyrosine kinase receptor for FGF and it regulates cell proliferation, differentiation and migration. FGFR1 gene is expressed mainly in Rathke’s pouch and the ventral diencephalon during the embryonic period. It has been reported that variants of FGFR1 cause KS and variants have been detected in 10% of KS cases. We here report an adult case of KS with a novel variant of FGFR1. A middle-aged male was refereed for a compression fracture of a lumbar vertebra. It was shown that he had severe osteoporosis, anosmia, gynecomastia, and a past history of operations for cryptorchidism. Endocrine workup by pituitary and gonadal stimulation tests revealed the presence of both primary and central hypogonadism. Genetic testing revealed a novel variant of FGFR1 (c.2197_2199dup, p.Met733dup). To identify the pathogenicity of the novel variant and the clinical significance for the gonads, we investigated the effects of the FGFR1 variant on downstream signaling of FGFR1 and gonadal steroidogenesis by using human steroidogenic granulosa KGN cells. It was revealed that transfection of the variant gene significantly impaired FGFR1 signaling, detected by downregulation of SPRY2, compared with that in the case of forced expression of wild-type FGFR1, and that the forced expression of the variant gene apparently altered the expression levels of key steroidogenic factors including StAR and aromatase in the gonad. Collectively, the results suggested that the novel variant of FGFR1 detected in a patient with KS was linked to impairment of FGFR1 signaling as well as alteration of gonadal steroidogenesis, leading to the pathogenesis of latent primary hypogonadism. Presentation: Saturday, July 12, 2025
2025-03-24 | Evaluation of the potential roles of kisspeptin and neurokinin genes in puberty treatment
Objective: Kisspeptin (KP) and neurokinin (NK) are neuropeptides that govern the reproductive endocrine axis through regulating hypothalamic neuronal activity and pulsatile.Their critical role in reproductive health was first described by the demonstration of congenital hypogonadotropic hypogonadism and pubertal developmental anomalies following loss of function due to mutations in genes encoding the KP or NK signaling.This study aimed to investigate the efficacy of KP and NK, in mesenchymal stem cell (MSC)-based treatment of different origin, and examine the relationship of the expression of these genes with the passage number.Methods: Three adult rats (Rattus norvegicus) were used in our study.MSCs were obtained from bone marrow and adipose tissue of rats.The MSCs were analysed by flow cytometry using surface markers and RNA (ribonucleic acid) isolation was performed.Gene expressions of KP, NK and their receptors were investigated by real-time Makale Dili "Trke"/
2024-03-25 | 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.
2023-01-04 | CRISPR/Cas9-editing of KISS1 to generate pigs with hypogonadotropic hypogonadism as a castration free trait
Introduction: Most male pigs are surgically castrated to avoid puberty-derived boar taint and aggressiveness. However, this surgical intervention represents a welfare concern in swine production. Disrupting porcine KISS1 is hypothesized to delay or abolish puberty by inducing variable hypogonadotropism and thus preventing the need for castration. Methods: To test this hypothesis, we generated the first KISS1-edited large animal using CRISPR/Cas9-ribonucleoproteins and single-stranded donor oligonucleotides. The targeted region preceded the sequence encoding a conserved core motif of kisspeptin. Genome editors were intracytoplasmically injected into 684 swine zygotes and transferred to 19 hormonally synchronized surrogate sows. In nine litters, 49 American Yorkshire and 20 Duroc liveborn piglets were naturally farrowed. Results: Thirty-five of these pigs bore KISS1-disruptive alleles ranging in frequency from 5% to 97% and did not phenotypically differ from their wild-type counterparts. In contrast, four KISS1-edited pigs (two boars and two gilts) with disruptive allele frequencies of 96% and 100% demonstrated full hypogonadotropism, infantile reproductive tracts, and failed to reach sexual maturity. Change in body weight during development was unaffected by editing KISS1. Founder pigs partially carrying KISS1-disruptive alleles were bred resulting in a total of 53 KISS1+/+, 60 KISS1+/-, and 34 KISS1-/- F1 liveborn piglets, confirming germline transmission. Discussion: Results demonstrate that a high proportion of KISS1 alleles in pigs must be disrupted before variation in gonadotropin secretion is observed, suggesting that even a small amount of kisspeptin ligand is sufficient to confer proper sexual development and puberty in pigs. Follow-on studies will evaluate fertility restoration in KISS1 KO breeding stock to fully realize the potential of KISS1 gene edits to eliminate the need for surgical castration.
2019-01-21 | Evidence for a Common Genetic Origin of Classic and Milder Adult-Onset Forms of Isolated Hypogonadotropic Hypogonadism
Multiple metabolic and inflammatory mechanisms are considered the determinants of acquired functional isolated hypogonadotropic hypogonadism (IHH) in males, whereas classic IHH is a rare congenital condition with a strong genetic background. Since we recently uncovered a frequent familiarity for classic IHH among patients with mild adult-onset hypogonadism (AO-IHH), here we performed a genetic characterization by next generation sequencing of 160 males with classic or "functional" forms. The prevalence of rare variants in 28 candidate genes was significantly higher than in controls in all IHH patients, independently of the age of IHH onset, degree of hypogonadism or presence of obesity. In fact, it did not differ among patients with classic or milder forms of IHH, however particular genes appear to be more specifically associated with one or the other category of IHH. ROC curves showed that Total Testosterone <6.05 nmol/L and an age of onset <41 years are sensitive cutoffs to identify patients with significantly higher chances of harboring rare IHH gene variants. In conclusion, rare IHH genes variants can frequently predispose to AO-IHH with acquired mild hormonal deficiencies. The identification of a genetic predisposition can improve the familial and individual management of AO-IHH and explain the heritability of congenital IHH.
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2022-08-09 | Dicer ablation in Kiss1 neurons impairs puberty and fertility preferentially in female mice
Abstract Kiss1 neurons, producing kisspeptins, are essential for puberty and fertility, but their molecular regulatory mechanisms remain unfolded. Here, we report that congenital ablation of the microRNA-synthesizing enzyme, Dicer, in Kiss1 cells, causes late-onset hypogonadotropic hypogonadism in both sexes, but is compatible with pubertal initiation and preserved Kiss1 neuronal populations at the infantile/juvenile period. Yet, failure to complete puberty and attain fertility is observed only in females. Kiss1-specific ablation of Dicer evokes disparate changes of Kiss1-cell numbers and Kiss1 /kisspeptin expression between hypothalamic subpopulations during the pubertal-transition, with a predominant decline in arcuate-nucleus Kiss1 levels, linked to enhanced expression of its repressors, Mkrn3, Cbx7 and Eap1. Our data unveil that miRNA-biosynthesis in Kiss1 neurons is essential for pubertal completion and fertility, especially in females, but dispensable for initial reproductive maturation and neuronal survival in both sexes. Our results disclose a predominant miRNA-mediated inhibitory program of repressive signals that is key for precise regulation of Kiss1 expression and, thereby, reproductive function.
2018-04-01 | Reproductive role of miRNA in the hypothalamic-pituitary axis
The hypothalamic-pituitary-gonadal (HPG) axis plays a critical role in regulating reproductive function. Gonadotropin-releasing hormone (GnRH), which is secreted by the hypothalamus, acts on pituitary gonadotrophs to stimulate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) synthesis and secretion, ultimately affecting the animal's fertility. MicroRNAs are small, non-coding RNAs that are widely expressed throughout the brain and can fine-tune gene expression post-transcriptionally. Recently, growing evidence has unveiled the central position of miRNAs within a key regulatory process involving GnRH secretion and subsequent activation in the pituitary. Although transcriptional regulation of reproduction has been well studied, the post-transcriptional processes are less well understood. In this review, we elaborate comprehensively on the critical role of miRNAs in the reproductive process, including both temporal and spatial aspects. A better understanding of how miRNAs impact the neuroendocrine system may improve our knowledge of reproduction and provide novel targets for therapeutic development.
2017-02-19 | Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility
MicroRNAs (miRNAs) are negative modulators of gene expression that fine-tune numerous biological processes. miRNA loss-of-function rarely results in highly penetrant phenotypes, but rather, influences cellular responses to physiologic and pathophysiologic stresses. Here, we have reported that a single member of the evolutionarily conserved miR-7 family, miR-7a2, is essential for normal pituitary development and hypothalamic-pituitary-gonadal (HPG) function in adulthood. Genetic deletion of mir-7a2 causes infertility, with low levels of gonadotropic and sex steroid hormones, small testes or ovaries, impaired spermatogenesis, and lack of ovulation in male and female mice, respectively. We found that miR-7a2 is highly expressed in the pituitary, where it suppresses golgi glycoprotein 1 (GLG1) expression and downstream bone morphogenetic protein 4 (BMP4) signaling and also reduces expression of the prostaglandin F2a receptor negative regulator (PTGFRN), an inhibitor of prostaglandin signaling and follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion. Our results reveal that miR-7a2 critically regulates sexual maturation and reproductive function by interconnecting miR-7 genomic circuits that regulate FSH and LH synthesis and secretion through their effects on pituitary prostaglandin and BMP4 signaling.
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Drug Discovery Landscape
4 orphan drug designations for Congenital hypogonadotropic hypogonadism, including 1 approved therapy.
4 orphan drug designations for Congenital hypogonadotropic hypogonadism, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Leuprorelin acetate | small molecules | EMA | 2017-01-12 | — | Stichting Centre for Human Drug Research (CHDR) |
Follitropin alfa, recombinant [Gonal-F] | proteins | FDA | 1998-12-21 | 2000-05-24 | EMD Serono, Inc. |
Urofollitropin | proteins | FDA | 1997-12-05 | — | EMD Serono, Inc. |
Somatropin | proteins | FDA | 1987-09-01 | — | Novo Nordisk Pharmaceuticals |
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