RARE DISEASE
Isolated congenital hypogonadotropic hypogonadism
Isolated congenital hypogonadotropic hypogonadism
Isolated congenital hypogonadotropic hypogonadism
Synonyms: Gonadotropic deficiency, Isolated congenital gonadotropin deficiency, Isolated gonadotropin-releasing hormone deficiency
Synonyms: Gonadotropic deficiency, Isolated congenital gonadotropin deficiency, Isolated gonadotropin-releasing hormone deficiency
Synonyms: Gonadotropic deficiency, Isolated congenital gonadotropin deficiency, Isolated gonadotropin-releasing hormone deficiency
Drug discovery
1
drug
With orphan designation
Overview
Isolated congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by deficient gonadotropin-releasing hormone (GnRH) secretion or action, resulting in impaired puberty and infertility. It presents as normosmic CHH or Kallmann syndrome (with anosmia). Over 25 genetic causes have been identified, with variable penetrance and complex inheritance patterns. Diagnosis involves hormonal profiling (low sex steroids and gonadotropins) and exclusion of structural hypothalamic-pituitary lesions [1][2][6][12].
Burden
Physical: Osteoporosis, metabolic syndrome, and 20–30% treatment resistance in severe cases [3][12][18].
Psychological: Reduced quality of life due to delayed puberty, body image concerns, and infertility [8][18].
Genetic: Oligogenic inheritance in 15–30% of cases; lifelong monitoring for reversibility (~10% spontaneous recovery) [6][7][14].
Categories: rare endocrine diseases, rare genetic diseases, rare gynecological and obstetric diseases, rare infertility disorders
Research Papers
123 drug discovery papers about Isolated congenital hypogonadotropic hypogonadism, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
123 drug discovery papers about Isolated congenital hypogonadotropic hypogonadism, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-10-01 | Congenital Hypogonadotropic Hypogonadism in Saudi Arabia: A Single-Center Case Series and Literature Review Across Both Sexes
Background: Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder of absent or incomplete puberty due to deficient gonadotropin-releasing hormone action. The Kallmann variant is associated with anosmia or hyposmia. In Saudi Arabia, reports are limited to isolated familial cases, including a KISS1R mutation in a consanguineous family. Broader clinical and genetic data remain scarce. We present a multi-patient series to highlight phenotypic diversity, genetic findings, and treatment outcomes. Case Description: We reviewed nine patients (seven males and two females) presenting primarily in late adolescence or early adulthood. Anosmia or hyposmia was present in eight, cryptorchidism in five, and micropenis in two. Dysmorphic features included syndactyly, dental agenesis, and gynecomastia in select cases. Imaging revealed hypoplastic testes or uterus, with absent olfactory bulbs in one female. Baseline gonadotropins and sex steroids were consistently low (median LH: 0.2 IU/L, FSH: 0.2 IU/L, testosterone: 0.9 nmol/L). Genetic testing identified ANOS1 and FGFR1 variants most frequently, alongside CHD7, PROKR2, and GNRHR; one patient carried an Xp22 microdeletion encompassing ANOS1/STS. Pathogenic or likely pathogenic variants were confirmed in several patients, while others had variants of uncertain significance. Management strategies included testosterone replacement in males, gonadotropins (hCG ± recombinant FSH) for fertility induction, and stepwise estrogen induction in females. Eight of nine patients achieved partial or complete pubertal development, with improved virilization or feminization, normalized sex steroid levels, and better quality of life. Fertility outcomes remain pending, though early hormonal responses were promising. Conclusion: This case series provides the first multipatient description of CHH from Saudi Arabia. Patients exhibited typical features, genetic heterogeneity, and responded well to therapy. Pubertal induction was successful in most, but spermatogenesis and pregnancy were not achieved. These findings highlight both the benefits and persistent reproductive challenges in CHH, emphasizing the need for early recognition, sustained follow-up, and access to fertility care. Publication History Article published online: 29 December 2025 © 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
2024-12-14 | Gonadotropin Therapy for Mini-Puberty Induction in Male Infants With Hypogonadotropic Hypogonadism.
Congenital hypogonadotropic hypogonadism (CHH) is defined as an isolated deficiency of gonadotropin hormones. Mini-puberty, a transient postnatal activation of the hypothalamic-pituitary-gonadal axis in healthy infants, provides a window of opportunity to diagnose and treat CHH. Currently, in male infants with CHH, testosterone is used to increase phallus size. However, gonadotropin replacement could additionally promote testicular descent and development, particularly relating to Sertoli cells. We conducted a systematic review of the effectiveness of gonadotropin therapy in stimulating mini-puberty related outcomes in male infants with CHH. In line with PRISMA guidelines, a systematic review of 11 databases was carried out (August 2023). Evidence quality was assessed using the Cochrane Risk of Bias for Non-Randomised Studies of Interventions tool. Protocol registered on PROSPERO (CRD42023453080). After a double-consensus screen of 767 abstracts and 66 full texts, 11 studies were included from 7 countries. A total of 71 male infants were enrolled, 12 with Kallmann syndrome. Median age at treatment initiation was 4.2 months (range, 0.25-57 months) and follow-up ranged from 3 to 10 years. Gonadotropin therapy was administered using continuous subcutaneous infusion (n = 35) or subcutaneous injection (n = 36). Due to treatment variability, modalities were combined for data synthesis. Gonadotropins induced a statistically significant increase in penile length and inhibin B concentration (P = .0007) and led to partial or full testicular descent in 73% (n = 62) of patients. This systematic review provides unique evidence supporting the efficacy of gonadotropins for induction of mini-puberty. However, the reliability and generalizability are limited due to disparate data and treatment modality variation.
2024-10-10 | Kallmann syndrome: Diagnostics and management.
Kallmann syndrome is a genetic disorder characterized by delayed or absence of puberty and a reduced or absent sense of smell (anosmia). Kallmann syndrome is a form of hypogonadotropic hypogonadism due to lack of the production of sex hormones which is associated with development of secondary sexual characteristics. Kallmann Syndrome is a genetically heterogeneous disorder, characterized by the combination of hypogonadotropic hypogonadism (a deficiency in sex hormone production) and anosmia. Germline mutations in KAL1 gene causes deficiency in GnRH hormone followed by low level of circulating gonadotropin and testosterone which finally leads to the failure of puberty (development of secondary sexual characters). Kallmann Syndrome can be inherited in several manners including X-linked recessive (e.g., mutations within KAL1) and autosomal dominant and recessive forms. Germline mutation in KAL1 gene was identified among 8% of patients with Kallmann Syndrome. A review of the recent literature done reveals numerous clinical manifestations in Kallmann Syndrome patients with the KAL1 mutation, including microgenitalia, impotence, reduced libido, infertility, unilateral renal agenesis, and synkinesia. Genetic molecular diagnostics through prenatal diagnosis and preimplantation genetic testing are most significant way to reduce the risk of Kallmann syndrome in next generation. Complication associated with Kallmann syndrome can be prevented by early diagnosis, diet supplementation and medical therapy. Goal of therapeutic intervention is to the development of secondary sexual characteristics, build and sustain bone density as well as muscle mass and restore fertility. This review aims to explore the genetic diagnosis and management strategies for Kallmann Syndrome, particularly focusing on KAL1 gene mutations.
2024-05-15 | Foxp2 deficiency impairs reproduction by modulating the hypothalamic-pituitary-gonadal axis in zebrafish†.
FOXP2 was initially characterized as a transcription factor linked to speech and language disorders. Single-cell RNA sequencing reveals that Foxp2 is enriched in the gonadotrope cluster of the pituitary gland and colocalized with the hormones LHB and FSHB in chickens and mice, implying that FOXP2 might be associated with reproduction in vertebrates. Herein, we investigated the roles of foxp2 in reproduction in a Foxp2-deficient zebrafish model. The results indicated that the loss of Foxp2 inhibits courtship behavior in adult male zebrafish. Notably, Foxp2 deficiency disrupts gonad development, leading to retardation of follicle development and a decrease in oocytes in females at the full-growth stage, among other phenotypes. The transcriptome analysis (RNA-seq) also revealed that differentially expressed genes clustered into the estrogen signaling and ovarian steroidogenesis-related signaling pathways. In addition, we found that Foxp2 deficiency could modulate the hypothalamic-pituitary-gonadal axis, especially the regulation of lhb and fshb expression, in zebrafish. In contrast, the injection of human chorionic gonadotropin, a specific LH agonist, partially rescues Foxp2-impaired reproduction in zebrafish, suggesting that Foxp2 plays an important role in the regulation of reproduction via the hypothalamic-pituitary-gonadal axis in zebrafish. Thus, our findings reveal a new role for Foxp2 in the regulation of reproduction in vertebrates.
2024-04-17 | Fertility outcomes in male adults with congenital hypogonadotropic hypogonadism treated during puberty with human chorionic gonadotropin and recombinant follicle stimulating hormone.
Hormone replacement therapy with testosterone for pubertal induction in boys with congenital hypogonadotropic hypogonadism (CHH) achieves virilization but not spermatogenesis. By contrast, human chorionic gonadotropin (hCG) and recombinant follicle stimulating hormone (rFSH) provides both virilization and spermatogenesis. Fertility outcomes of boys treated with recombinant therapy during adolescence have been infrequently described. We report fertility induction and pregnancy outcomes in CHH patients treated with recombinant gonadotropins during puberty. Data of six subjects with CHH (n = 3 Kallmann syndrome & n = 3 Isolated hypogonadotropic hypogonadism) treated with hCG and FSH for pubertal induction were reviewed. Of these, five underwent subsequent fertility induction while one desired fertility at the end of pubertal induction. Partners of all subjects achieved pregnancies using hCG and rFSH, all with full term live births. All infants were clinically normal. This study provides early evidence of proof of concept of use of gonadotropin induction of puberty being beneficial in subsequent fertility outcome.
small molecules
2025-11-06 | Central SELENOT deficiency impairs gonadotrope axis function, sexual behavior, and fertility in male and female mice.
Reproductive disorders can result from a defective action of the neuropeptide gonadotropin-releasing hormone (GnRH), the master regulator of reproduction. We have previously shown that selenoprotein T (SELENOT), a newly described thioredoxin-like selenoprotein highly expressed in endocrine and neuroendocrine cells, plays a role in hormone secretion and neuroprotection. However, whether SELENOT is involved in neuroendocrine regulation in vivo is totally unknown. We found that SELENOT deficiency in the brain impaired sexual behavior, leading to a decline in fertility in both male and female mice. Biochemical and histological analyses of the gonadotrope axis of these mice revealed a higher expression of GnRH, which is associated with circulating luteinizing hormone (LH) excess, and elevated steroid hormones in males and a polycystic ovary syndrome-like phenotype in females. In addition, SELENOT deficiency impaired LH pulse secretion in both male and female mice. These changes were reverted after administration of a GnRH antagonist. Together, our data demonstrate for the first time to our knowledge the role of a selenoprotein in the central control of sexual behavior and reproduction, and identify a redox effector of GnRH neuron activity impacting both male and female reproductive function.
2025-05-08 | ‘’Benefit of Pulsatile GnRH Therapy in Treatment of Functional Hypothalamic Amenorrhea (FHA) and Congenital Hypogonadotropic Hypogonadism(CHH) in Infertile Patients Over Canonical Gonadotropins with IVF –A Short Communication’’
Normoprolactinemic hypogonadotropic hypogonadismis (HH) a germanely frequent etiology of anovulation. It originates from pituitary and /or suprapituitary structures. Besides hyperprolactinemia, ovulation induction by gonadotropins or pulsatile gonadotropin-releasing hormone (GnRH) delivery might be posited in women who want pregnancy. The choice of ovulation induction medications are based on the region of the gonadotropic axis impacted: pulsatiledelivery of GnRH might just be taken into account in suprapituitary etiologes, while injectable gonadotropins possess the capacity of getting utillized in both suprapituitary and pituitary etiologes. Hypothalamic anovulation is usually categorized into congenital and acquired etiologies .In case of acquired normoprolactinemic HH, organic etiologies are compared to functional hypothalamic amenorrhea (FHA). FHA takes place by diminished pulsatilityof GnRH leading to a diminished frequency and amplitude of luteinizing hormone (LH) pulses. Restriction of fat intake and/or increased physical activity is implicated in such diminished pulsatility. The phenotypic expression of suprapituitary congenital hypogonadotropic hypogonadism (CHH) might differ. An escalating number of genes are implicated in the migration of GnRH neurons at the time of intrauterine life in addition to / or in the homeostasis of the gonadotropic axis are isolated. Till now, practically 50%of corroborated cases of CHH continue to be idiopathic subsequent to genetic evaluation.No studies have contrasted the efficacy of pulsatile GnRH delivery as per the etiology of suprapituitary anovulation or tried to isolate prognostic factors for the success of this treatment. Recently in a retrospective cohort study at France, the ongoing pregnancy rate per initiated cycle amongst FHA and CHH patients was contrasted subsequent to treatment with pulsatile GnRH delivery aiming for monofollicular ovulation. Comparable outcome were seen in FHA and CHH, advocating its superiority over gonadotropins and IVF.
2025-03-26 | Neurokinin 3 receptor agonist senktide stimulates GnRH release in isolated hypogonadotropic hypogonadism mice.
Isolated hypogonadotropic hypogonadism (IHH) is caused by defective gonadotropin-releasing hormone (GnRH) secretion or action, resulting in absent or incomplete pubertal development and infertility. However, the pathogenesis mechanism of IHH is not fully understood. This study utilized PROK2/PROKR2 knockdown mice and GT1-7 cells to investigate the effects and potential mechanismsof the NK3R agonist senktide on GnRH deficiency and related syndromes. In this investigation, PROK2/PROKR2 knockdown resulted in a deficiency of GnRH neurons, reduced levels of LSH, FSH, and E2, and the inhibition of the MAPK/ERK and PI3K/AKT pathways in mice. However, this effect was reversed by senktide. Furthermore, the inhibition of MAPK/ERK or PI3K/AKT signaling pathways counteracted the remission of the GnRH insufficiency and associated syndrome by senktide in mice with PROK2/PROKR2 knockdown. In summary, NK3R agonist senktide alleviated the GnRH insufficiency and related syndromes caused by PROK2/PROKR2 knockdown via the MAPK/ERK pathway and the PI3K/AKT pathway.
2025-03-14 | An Effective Outcome Despite Delayed Treatment Initiation in a Female With Kallmann Syndrome: A Case Report.
Kallmann syndrome (KS) is an idiopathic hypogonadotropic hypogonadism with anosmia due to isolated gonadotropin-releasing hormone deficiency. In females, the diagnosis often occurs around age 15 due to primary amenorrhea, prompting hormone replacement therapy (HRT) initiation. However, limited data exists on the effectiveness of delayed HRT in females with KS. Here, we describe a case involving a female with KS who began treatment at the age of 27. Following HRT initiation, the patient showed increases in uterine size, bone mineral density, and growth of breasts over a two-year period. Delayed diagnosis of KS in females, as in this case, is extremely rare, and this case demonstrates two important clinical issues. First, HRT can still be effective in females with KS even if treatment initiation is delayed, and, second, therapeutic benefits become apparent within two years following initiation of treatment. These findings may be applicable to other patients with congenital hypogonadotropic hypogonadism whose treatment initiation was delayed.
2024-10-01 | 8138 Pituitary Stalk Interruption Syndrome (PSIS) in a patient with Isolated Hypogonadotropic Hypogonadism
Abstract Disclosure: A. Thomson: None. R. Osman: None. Pituitary Stalk Interruption Syndrome in a Patient with Isolated Hypogonadotropic Hypogonadism Pituitary Stalk Interruption syndrome (PSIS) is a rare cause of hypopituitarism, characterized by a radiologic constellation of thin or interrupted pituitary stalk, hypoplasia, or aplasia of the anterior lobe and with the presence of an ectopic posterior pituitary (EPP). It is most commonly associated with isolated growth hormone deficiency (IGHD) and is often diagnosed in childhood. We present one case of a patient with isolated hypogonadotropic hypogonadism in adulthood, subsequently found to have an PSIS on MRI. A 45 year old male patient presented to our clinic with hypogonadism. He gradually started developing decreasing libido, fatigue, and loss of erections. He had normal puberty and childhood growth, and has fathered one child. He denied history of anosmia or visual symptoms. Subsequent hormonal testing showed: morning Total Testosterone: 145 ng/dl (normal 264-916 ng/dl), Free testosterone 1.5 pg/ml (normal 6.8-21.5 pg/ml), LH 1.1 mIU/ml (normal 1.7-8.6 mIU/ml) and FSH of 3.6 mIU/ml (normal 1.5-12.4 mIU/ml). Prolactin was minimally elevated at 21 ng/ml (normal 4.0 - 15.2 ng/ml). Thyroid, IGF-1, cortisol, and ferritin levels were within normal limits. Repeat levels showed similar findings. He denied ever taking any form of exogenous testosterone. His pituitary MRI revealed a small volume of anterior pituitary tissue, measuring 0.2cm x 0.7cm x 0.7cm, without discrete pituitary adenoma, a hypoplastic midline stalk measuring 1.3 mm in AP diameter (nl 2-3 mm), with a T1 hyperintense nodularity measuring 0.6cm x 0.4cm along the posterior aspect of the sella turcica consistent with EPP. No additional structural abnormality or any mass lesions were identified. He was subsequently started on replacement testosterone therapy and his symptoms resolved. PSIS usually presents in childhood with IGHD. Patients may have other pituitary hormone deficiencies and congenital central nervous system defects, although panhypopituitarism is rare. There have been reports in children with delayed puberty and isolated hypogonadotropic hypogonadism who have been found to have PSIS. Only one othercase of an adult female patient exhibiting hypogonadotropic hypogonadism as the only manifestation of PSIS has been documented in the literature. Our case highlights the potential for an adult male to present later in life with hypogonadotropic hypogonadism as a manifestation of PSIS. The marginally elevated prolactin level may be due to lack of inhibition of hypothalamic dopamine on lactotroph cells within the pituitary caused by the EPP, although it is doubtful that this has clinical significance. This is a rare presentation of PSIS, clinicians should be mindful ofthis radiological constellation and the potential for isolated hypogonadotropic hypogonadism presenting unusually in the adulthood. Presentation: 6/3/2024
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.
proteins
2025-10-01 | Congenital Hypogonadotropic Hypogonadism in Saudi Arabia: A Single-Center Case Series and Literature Review Across Both Sexes
Background: Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder of absent or incomplete puberty due to deficient gonadotropin-releasing hormone action. The Kallmann variant is associated with anosmia or hyposmia. In Saudi Arabia, reports are limited to isolated familial cases, including a KISS1R mutation in a consanguineous family. Broader clinical and genetic data remain scarce. We present a multi-patient series to highlight phenotypic diversity, genetic findings, and treatment outcomes. Case Description: We reviewed nine patients (seven males and two females) presenting primarily in late adolescence or early adulthood. Anosmia or hyposmia was present in eight, cryptorchidism in five, and micropenis in two. Dysmorphic features included syndactyly, dental agenesis, and gynecomastia in select cases. Imaging revealed hypoplastic testes or uterus, with absent olfactory bulbs in one female. Baseline gonadotropins and sex steroids were consistently low (median LH: 0.2 IU/L, FSH: 0.2 IU/L, testosterone: 0.9 nmol/L). Genetic testing identified ANOS1 and FGFR1 variants most frequently, alongside CHD7, PROKR2, and GNRHR; one patient carried an Xp22 microdeletion encompassing ANOS1/STS. Pathogenic or likely pathogenic variants were confirmed in several patients, while others had variants of uncertain significance. Management strategies included testosterone replacement in males, gonadotropins (hCG ± recombinant FSH) for fertility induction, and stepwise estrogen induction in females. Eight of nine patients achieved partial or complete pubertal development, with improved virilization or feminization, normalized sex steroid levels, and better quality of life. Fertility outcomes remain pending, though early hormonal responses were promising. Conclusion: This case series provides the first multipatient description of CHH from Saudi Arabia. Patients exhibited typical features, genetic heterogeneity, and responded well to therapy. Pubertal induction was successful in most, but spermatogenesis and pregnancy were not achieved. These findings highlight both the benefits and persistent reproductive challenges in CHH, emphasizing the need for early recognition, sustained follow-up, and access to fertility care. Publication History Article published online: 29 December 2025 © 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
2024-12-14 | Gonadotropin Therapy for Mini-Puberty Induction in Male Infants With Hypogonadotropic Hypogonadism.
Congenital hypogonadotropic hypogonadism (CHH) is defined as an isolated deficiency of gonadotropin hormones. Mini-puberty, a transient postnatal activation of the hypothalamic-pituitary-gonadal axis in healthy infants, provides a window of opportunity to diagnose and treat CHH. Currently, in male infants with CHH, testosterone is used to increase phallus size. However, gonadotropin replacement could additionally promote testicular descent and development, particularly relating to Sertoli cells. We conducted a systematic review of the effectiveness of gonadotropin therapy in stimulating mini-puberty related outcomes in male infants with CHH. In line with PRISMA guidelines, a systematic review of 11 databases was carried out (August 2023). Evidence quality was assessed using the Cochrane Risk of Bias for Non-Randomised Studies of Interventions tool. Protocol registered on PROSPERO (CRD42023453080). After a double-consensus screen of 767 abstracts and 66 full texts, 11 studies were included from 7 countries. A total of 71 male infants were enrolled, 12 with Kallmann syndrome. Median age at treatment initiation was 4.2 months (range, 0.25-57 months) and follow-up ranged from 3 to 10 years. Gonadotropin therapy was administered using continuous subcutaneous infusion (n = 35) or subcutaneous injection (n = 36). Due to treatment variability, modalities were combined for data synthesis. Gonadotropins induced a statistically significant increase in penile length and inhibin B concentration (P = .0007) and led to partial or full testicular descent in 73% (n = 62) of patients. This systematic review provides unique evidence supporting the efficacy of gonadotropins for induction of mini-puberty. However, the reliability and generalizability are limited due to disparate data and treatment modality variation.
2024-10-10 | Kallmann syndrome: Diagnostics and management.
Kallmann syndrome is a genetic disorder characterized by delayed or absence of puberty and a reduced or absent sense of smell (anosmia). Kallmann syndrome is a form of hypogonadotropic hypogonadism due to lack of the production of sex hormones which is associated with development of secondary sexual characteristics. Kallmann Syndrome is a genetically heterogeneous disorder, characterized by the combination of hypogonadotropic hypogonadism (a deficiency in sex hormone production) and anosmia. Germline mutations in KAL1 gene causes deficiency in GnRH hormone followed by low level of circulating gonadotropin and testosterone which finally leads to the failure of puberty (development of secondary sexual characters). Kallmann Syndrome can be inherited in several manners including X-linked recessive (e.g., mutations within KAL1) and autosomal dominant and recessive forms. Germline mutation in KAL1 gene was identified among 8% of patients with Kallmann Syndrome. A review of the recent literature done reveals numerous clinical manifestations in Kallmann Syndrome patients with the KAL1 mutation, including microgenitalia, impotence, reduced libido, infertility, unilateral renal agenesis, and synkinesia. Genetic molecular diagnostics through prenatal diagnosis and preimplantation genetic testing are most significant way to reduce the risk of Kallmann syndrome in next generation. Complication associated with Kallmann syndrome can be prevented by early diagnosis, diet supplementation and medical therapy. Goal of therapeutic intervention is to the development of secondary sexual characteristics, build and sustain bone density as well as muscle mass and restore fertility. This review aims to explore the genetic diagnosis and management strategies for Kallmann Syndrome, particularly focusing on KAL1 gene mutations.
2024-05-15 | Foxp2 deficiency impairs reproduction by modulating the hypothalamic-pituitary-gonadal axis in zebrafish†.
FOXP2 was initially characterized as a transcription factor linked to speech and language disorders. Single-cell RNA sequencing reveals that Foxp2 is enriched in the gonadotrope cluster of the pituitary gland and colocalized with the hormones LHB and FSHB in chickens and mice, implying that FOXP2 might be associated with reproduction in vertebrates. Herein, we investigated the roles of foxp2 in reproduction in a Foxp2-deficient zebrafish model. The results indicated that the loss of Foxp2 inhibits courtship behavior in adult male zebrafish. Notably, Foxp2 deficiency disrupts gonad development, leading to retardation of follicle development and a decrease in oocytes in females at the full-growth stage, among other phenotypes. The transcriptome analysis (RNA-seq) also revealed that differentially expressed genes clustered into the estrogen signaling and ovarian steroidogenesis-related signaling pathways. In addition, we found that Foxp2 deficiency could modulate the hypothalamic-pituitary-gonadal axis, especially the regulation of lhb and fshb expression, in zebrafish. In contrast, the injection of human chorionic gonadotropin, a specific LH agonist, partially rescues Foxp2-impaired reproduction in zebrafish, suggesting that Foxp2 plays an important role in the regulation of reproduction via the hypothalamic-pituitary-gonadal axis in zebrafish. Thus, our findings reveal a new role for Foxp2 in the regulation of reproduction in vertebrates.
2024-04-17 | Fertility outcomes in male adults with congenital hypogonadotropic hypogonadism treated during puberty with human chorionic gonadotropin and recombinant follicle stimulating hormone.
Hormone replacement therapy with testosterone for pubertal induction in boys with congenital hypogonadotropic hypogonadism (CHH) achieves virilization but not spermatogenesis. By contrast, human chorionic gonadotropin (hCG) and recombinant follicle stimulating hormone (rFSH) provides both virilization and spermatogenesis. Fertility outcomes of boys treated with recombinant therapy during adolescence have been infrequently described. We report fertility induction and pregnancy outcomes in CHH patients treated with recombinant gonadotropins during puberty. Data of six subjects with CHH (n = 3 Kallmann syndrome & n = 3 Isolated hypogonadotropic hypogonadism) treated with hCG and FSH for pubertal induction were reviewed. Of these, five underwent subsequent fertility induction while one desired fertility at the end of pubertal induction. Partners of all subjects achieved pregnancies using hCG and rFSH, all with full term live births. All infants were clinically normal. This study provides early evidence of proof of concept of use of gonadotropin induction of puberty being beneficial in subsequent fertility outcome.
small molecules
2025-11-06 | Central SELENOT deficiency impairs gonadotrope axis function, sexual behavior, and fertility in male and female mice.
Reproductive disorders can result from a defective action of the neuropeptide gonadotropin-releasing hormone (GnRH), the master regulator of reproduction. We have previously shown that selenoprotein T (SELENOT), a newly described thioredoxin-like selenoprotein highly expressed in endocrine and neuroendocrine cells, plays a role in hormone secretion and neuroprotection. However, whether SELENOT is involved in neuroendocrine regulation in vivo is totally unknown. We found that SELENOT deficiency in the brain impaired sexual behavior, leading to a decline in fertility in both male and female mice. Biochemical and histological analyses of the gonadotrope axis of these mice revealed a higher expression of GnRH, which is associated with circulating luteinizing hormone (LH) excess, and elevated steroid hormones in males and a polycystic ovary syndrome-like phenotype in females. In addition, SELENOT deficiency impaired LH pulse secretion in both male and female mice. These changes were reverted after administration of a GnRH antagonist. Together, our data demonstrate for the first time to our knowledge the role of a selenoprotein in the central control of sexual behavior and reproduction, and identify a redox effector of GnRH neuron activity impacting both male and female reproductive function.
2025-05-08 | ‘’Benefit of Pulsatile GnRH Therapy in Treatment of Functional Hypothalamic Amenorrhea (FHA) and Congenital Hypogonadotropic Hypogonadism(CHH) in Infertile Patients Over Canonical Gonadotropins with IVF –A Short Communication’’
Normoprolactinemic hypogonadotropic hypogonadismis (HH) a germanely frequent etiology of anovulation. It originates from pituitary and /or suprapituitary structures. Besides hyperprolactinemia, ovulation induction by gonadotropins or pulsatile gonadotropin-releasing hormone (GnRH) delivery might be posited in women who want pregnancy. The choice of ovulation induction medications are based on the region of the gonadotropic axis impacted: pulsatiledelivery of GnRH might just be taken into account in suprapituitary etiologes, while injectable gonadotropins possess the capacity of getting utillized in both suprapituitary and pituitary etiologes. Hypothalamic anovulation is usually categorized into congenital and acquired etiologies .In case of acquired normoprolactinemic HH, organic etiologies are compared to functional hypothalamic amenorrhea (FHA). FHA takes place by diminished pulsatilityof GnRH leading to a diminished frequency and amplitude of luteinizing hormone (LH) pulses. Restriction of fat intake and/or increased physical activity is implicated in such diminished pulsatility. The phenotypic expression of suprapituitary congenital hypogonadotropic hypogonadism (CHH) might differ. An escalating number of genes are implicated in the migration of GnRH neurons at the time of intrauterine life in addition to / or in the homeostasis of the gonadotropic axis are isolated. Till now, practically 50%of corroborated cases of CHH continue to be idiopathic subsequent to genetic evaluation.No studies have contrasted the efficacy of pulsatile GnRH delivery as per the etiology of suprapituitary anovulation or tried to isolate prognostic factors for the success of this treatment. Recently in a retrospective cohort study at France, the ongoing pregnancy rate per initiated cycle amongst FHA and CHH patients was contrasted subsequent to treatment with pulsatile GnRH delivery aiming for monofollicular ovulation. Comparable outcome were seen in FHA and CHH, advocating its superiority over gonadotropins and IVF.
2025-03-26 | Neurokinin 3 receptor agonist senktide stimulates GnRH release in isolated hypogonadotropic hypogonadism mice.
Isolated hypogonadotropic hypogonadism (IHH) is caused by defective gonadotropin-releasing hormone (GnRH) secretion or action, resulting in absent or incomplete pubertal development and infertility. However, the pathogenesis mechanism of IHH is not fully understood. This study utilized PROK2/PROKR2 knockdown mice and GT1-7 cells to investigate the effects and potential mechanismsof the NK3R agonist senktide on GnRH deficiency and related syndromes. In this investigation, PROK2/PROKR2 knockdown resulted in a deficiency of GnRH neurons, reduced levels of LSH, FSH, and E2, and the inhibition of the MAPK/ERK and PI3K/AKT pathways in mice. However, this effect was reversed by senktide. Furthermore, the inhibition of MAPK/ERK or PI3K/AKT signaling pathways counteracted the remission of the GnRH insufficiency and associated syndrome by senktide in mice with PROK2/PROKR2 knockdown. In summary, NK3R agonist senktide alleviated the GnRH insufficiency and related syndromes caused by PROK2/PROKR2 knockdown via the MAPK/ERK pathway and the PI3K/AKT pathway.
2025-03-14 | An Effective Outcome Despite Delayed Treatment Initiation in a Female With Kallmann Syndrome: A Case Report.
Kallmann syndrome (KS) is an idiopathic hypogonadotropic hypogonadism with anosmia due to isolated gonadotropin-releasing hormone deficiency. In females, the diagnosis often occurs around age 15 due to primary amenorrhea, prompting hormone replacement therapy (HRT) initiation. However, limited data exists on the effectiveness of delayed HRT in females with KS. Here, we describe a case involving a female with KS who began treatment at the age of 27. Following HRT initiation, the patient showed increases in uterine size, bone mineral density, and growth of breasts over a two-year period. Delayed diagnosis of KS in females, as in this case, is extremely rare, and this case demonstrates two important clinical issues. First, HRT can still be effective in females with KS even if treatment initiation is delayed, and, second, therapeutic benefits become apparent within two years following initiation of treatment. These findings may be applicable to other patients with congenital hypogonadotropic hypogonadism whose treatment initiation was delayed.
2024-10-01 | 8138 Pituitary Stalk Interruption Syndrome (PSIS) in a patient with Isolated Hypogonadotropic Hypogonadism
Abstract Disclosure: A. Thomson: None. R. Osman: None. Pituitary Stalk Interruption Syndrome in a Patient with Isolated Hypogonadotropic Hypogonadism Pituitary Stalk Interruption syndrome (PSIS) is a rare cause of hypopituitarism, characterized by a radiologic constellation of thin or interrupted pituitary stalk, hypoplasia, or aplasia of the anterior lobe and with the presence of an ectopic posterior pituitary (EPP). It is most commonly associated with isolated growth hormone deficiency (IGHD) and is often diagnosed in childhood. We present one case of a patient with isolated hypogonadotropic hypogonadism in adulthood, subsequently found to have an PSIS on MRI. A 45 year old male patient presented to our clinic with hypogonadism. He gradually started developing decreasing libido, fatigue, and loss of erections. He had normal puberty and childhood growth, and has fathered one child. He denied history of anosmia or visual symptoms. Subsequent hormonal testing showed: morning Total Testosterone: 145 ng/dl (normal 264-916 ng/dl), Free testosterone 1.5 pg/ml (normal 6.8-21.5 pg/ml), LH 1.1 mIU/ml (normal 1.7-8.6 mIU/ml) and FSH of 3.6 mIU/ml (normal 1.5-12.4 mIU/ml). Prolactin was minimally elevated at 21 ng/ml (normal 4.0 - 15.2 ng/ml). Thyroid, IGF-1, cortisol, and ferritin levels were within normal limits. Repeat levels showed similar findings. He denied ever taking any form of exogenous testosterone. His pituitary MRI revealed a small volume of anterior pituitary tissue, measuring 0.2cm x 0.7cm x 0.7cm, without discrete pituitary adenoma, a hypoplastic midline stalk measuring 1.3 mm in AP diameter (nl 2-3 mm), with a T1 hyperintense nodularity measuring 0.6cm x 0.4cm along the posterior aspect of the sella turcica consistent with EPP. No additional structural abnormality or any mass lesions were identified. He was subsequently started on replacement testosterone therapy and his symptoms resolved. PSIS usually presents in childhood with IGHD. Patients may have other pituitary hormone deficiencies and congenital central nervous system defects, although panhypopituitarism is rare. There have been reports in children with delayed puberty and isolated hypogonadotropic hypogonadism who have been found to have PSIS. Only one othercase of an adult female patient exhibiting hypogonadotropic hypogonadism as the only manifestation of PSIS has been documented in the literature. Our case highlights the potential for an adult male to present later in life with hypogonadotropic hypogonadism as a manifestation of PSIS. The marginally elevated prolactin level may be due to lack of inhibition of hypothalamic dopamine on lactotroph cells within the pituitary caused by the EPP, although it is doubtful that this has clinical significance. This is a rare presentation of PSIS, clinicians should be mindful ofthis radiological constellation and the potential for isolated hypogonadotropic hypogonadism presenting unusually in the adulthood. Presentation: 6/3/2024
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.
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Drug Discovery Landscape
1 orphan drug designation for Isolated congenital hypogonadotropic hypogonadism, including 1 approved therapy.
1 orphan drug designation for Isolated congenital hypogonadotropic hypogonadism, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Gonadorelin acetate [Lutrepulse] | small molecules | FDA | 1987-04-22 | 1989-10-10 | Ferring Laboratories, Inc. |
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