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(facing page). Neuroendocrine Profile and Serum Testosterone before and after Reversal of Idiopathic Hypogonadotropic Hypogonadism. Overnight sampling studies (every 10 minutes for 12 hours) depicting endogenous luteinizing hormone (LH) secretion are shown. Inverted triangles denote LH pulses. The shaded regions show the normal range of serum LH in men. To convert testosterone (T) values to nanomoles per liter, multiply by 0.03467.
Source publication
Idiopathic hypogonadotropic hypogonadism, which may be associated with anosmia (the Kallmann syndrome) or with a normal sense of smell, is a treatable form of male infertility caused by a congenital defect in the secretion or action of gonadotropin-releasing hormone (GnRH). Patients have absent or incomplete sexual maturation by the age of 18. Idio...
Similar publications
X-linked Kallmann's syndrome (KS) is a genetic disease characterized by anosmia and hypogonadism due to impairment in the development of olfactory axons and in the migration of gonadotropin-releasing hormone (GnRH)-producing neurons. Deletions or point mutations of a gene located at Xp22.3 (KAL1) are responsible for the disease. This gene encodes f...
Kallmann syndrome is defined by the association of hypogonadotropic hypogonadism and anosmia. The KAL1 gene is responsible for the X-linked form of Kallmann syndrome. In this study we describe monozygotic twins with Kallmann syndrome due to the same mutation in the KAL1 gene.
We studied male monozygotic twins with Kallmann syndrome.
We analyzed the...
Citations
... Among them, 28 male patients were eligible according to our inclusive criteria (poor response to HCG/HMG therapy) and were enrolled in this retrospective clinical trial. CHH was diagnosed according to the criteria reported previously (14). The inclusion criteria were as follows: (1) patient had experienced HCG/HMG therapy for ≥ 6 months and azoospermia during HCG/HMG therapy; ...
Objective
Both pulsatile gonadotropin-releasing hormone (GnRH) and combined gonadotropin therapy are effective to induce spermatogenesis in men with congenital hypogonadotropic hypogonadism (CHH). This study aimed to evaluate the effect of pulsatile GnRH therapy on spermatogenesis in male patients with CHH who had poor response to combined gonadotropin therapy.
Materials and methods
Patients who had poor response to combined gonadotropin therapy ≥ 6 months were recruited and shifted to pulsatile GnRH therapy. The rate of successful spermatogenesis, the median time to achieve spermatogenesis, serum gonadotropins, testosterone, and testicular volume were used for data analysis.
Results
A total of 28 CHH patients who had poor response to combined gonadotropin (HCG/HMG) therapy for 12.5 (6.0, 17.75) months were recruited and switched to pulsatile GnRH therapy for 10.0 (7.25, 16.0) months. Sperm was detected in 17/28 patients (60.7%). The mean time for the appearance of sperm in semen was 12.0 (7.5, 17.5) months. Compared to those who could not achieve spermatogenesis during pulsatile GnRH therapy, the successful group had a higher level of LH60min (4.32 vs. 1.10 IU/L, P = 0.043) and FSH60min (4.28 vs. 1.90 IU/L, P = 0.021). Testicular size increased during pulsatile GnRH therapy, compared to previous HCG/HMG therapy (P < 0.05).
Conclusion
For CHH patients with prior poor response to one year of HCG/HMG therapy, switching to pulsatile GnRH therapy may induce spermatogenesis.
Keywords
Congenital hypogonadotropic hypogonadism; gonadotropin therapy; pulsatile gonadotropin-releasing hormone therapy; spermatogenesis
... However, approximately 10-15% of individuals with CHH, including individuals with pathogenic rare variants, undergo a spontaneous reversal with normalised concentrations of serum testosterone, pulsatile secretion of luteinising hormone (LH), and spermatogenesis. [7][8][9][10] Spontaneous reversal rarely occurs before an individual has testosterone concentrations typically seen in an adult male, with at least 6-12 months on treatment. Since the 2007 prospective study showing reversal in a subset of male patients with CHH from a single centre in the USA, 7 as of time of writing, 19 subsequent publications have reported a total of 110 men with evidence of CHH reversal globally (appendix 2 pp 2-3). ...
... [7][8][9][10] Spontaneous reversal rarely occurs before an individual has testosterone concentrations typically seen in an adult male, with at least 6-12 months on treatment. Since the 2007 prospective study showing reversal in a subset of male patients with CHH from a single centre in the USA, 7 as of time of writing, 19 subsequent publications have reported a total of 110 men with evidence of CHH reversal globally (appendix 2 pp 2-3). CHH reversal can occur following several treatment modalities, including exoge nous replacement of testosterone, gonadotropin therapy, or treatment with pulsatile GnRH. ...
... These concentrations were measured during frequent sampling neuroendocrine evaluation (blood sampling every 10 min for 12 h) to assess the secretion pattern of endogenous LH, serum testosterone concentration, and FSH con centration as previously described. 7 Data following treatment washout were obtained from 87 patients from the six referral centres (by use of non-standardised protocols). In total, 85 (98%) of 87 patients with CHH reversal had undergone treatment washout after age 18 years. ...
... The accepted tentative diagnostic criteria for IHH have been age ≥ 18 years, incomplete or absent puberty, serum testosterone levels < 100 ng/dl (3.5 nmol/L), normal pituitary function, and normal hypothalamic-pituitary imaging features [19]. Based on these criteria, GnRH-agonist and HCG stimulation tests can be used to identify IHH and CDGP [20]. ...
Background
Idiopathic hypogonadotropic hypogonadism (IHH) is a rare congenital or acquired genetic disorder caused by gonadotropin-releasing hormone (GnRH) deficiency. IHH patients are divided into two major groups, hyposmic or anosmic IHH (Kallmann syndrome) and normosmic IHH (nIHH), according to whether their sense of smell is intact. Here we report a case of novel compound heterozygous mutations in the GNRH1 gene in a 15-year-old male with nIHH.
Case presentation
The patient presented typical clinical symptoms of delayed testicular development, with testosterone < 3.5 mmol/L and reduced gonadotropin (follicle-stimulating hormone, luteinizing hormone) levels. Two heterozygous variants of the GNRH1 gene were detected, nonsense variant 1: c.85G > T:p.G29* and variant 2: c.1A > G:p.M1V, which disrupted the start codon.
Conclusions
Two GNRH1 mutations responsible for nIHH are identified in this study. Our findings extend the mutational spectrum of GNRH1 by revealing novel causative mutations of nIHH.
... Six male showed low basal LH level (< 0.11 mIU/mL), low testosterone level (< 1.53 ng/mL) and small testicular volume (< 2.0 mL), which seems to consistent with previous reports that higher basal LH and stimulated LH levels as well as larger testicle size are favorite parameters for reversal. 11,19 Currently, pulsatile GnRH pump treatment, testosterone/estradiol treatment and human chorionic gonadotropin (hCG)/human menopausal gonadotropin (hMG) combination treatment are three main treatment options for KS or nIHH, wherein testosterone/estradiol only improve sexual characteristics and GnRH pump is restricted to hospital grade and high cost, by contrast, hCG/hMG https://doi.org/10.2147/IJGM.S430904 ...
Purpose
Genetic factors account for a large proportion of idiopathic hypogonadotropic hypogonadism (IHH) etiologies, although not necessarily a complete genetic basis. This study aimed to characterize the clinical presentations, genetic variants, and therapeutic outcomes of patients with sporadic IHH, which may be helpful for genetic counseling and treatment decisions.
Patients and Methods
Eleven Chinese patients with IHH were retrospectively analyzed. Rare genetic variants were evaluated using whole-exome sequencing and bioinformatics analysis and were further classified according to the ACMG-AMP guidelines. The therapeutic responses of patients were further evaluated.
Results
Six heterozygous variants of SOX10, WDR11, PROKR2, CHD7 and FGF17 were detected in five Kallmann syndrome (KS) patients, whereas two heterozygous variants of CHD7 and PROKR2 were detected in two normosmic IHH (nIHH) patients. Among these variants, a novel likely pathogenic variant in the SOX10 (c.429–1G>C) was considered to cause the KS phenotype in patient 02, and two potential variants of uncertain significance (VUS) in CHD7 (c.3344G>A and c.7391A>G) possibly contributed to the KS phenotype in patient 05 and the nIHH phenotype in patient 07, which need to be confirmed by further evidence. Additionally, long-term testosterone or estradiol replacement treatment effectively improved the development of sexual characteristics in patients with IHH.
Conclusion
Next-generation sequencing is a powerful tool for identifying the molecular etiology and early diagnosis of IHH. Efficient therapeutic outcomes strongly indicate a need for timely treatment.
... The severity of DP observed varies according to the degree of gonadotrophic deficiency (14), with an extensive clinical spectrum ranging from extreme forms with classical features, to milder forms that are difficult to distinguish from and often overlap with SLDP (1). Up to 20% of patients with HH may also have periods of reversal of their phenotype, a little understood phenomenon where patients become eugonadal for a variable length of time (15). ...
Introduction
Delayed puberty (DP) is a frequent concern for adolescents. The most common underlying aetiology is self-limited DP (SLDP). However, this can be difficult to differentiate from the more severe condition congenital hypogonadotrophic hypogonadism (HH), especially on first presentation of an adolescent patient with DP. This study sought to elucidate phenotypic differences between the two diagnoses, in order to optimise patient management and pubertal development.
Methods
This was a study of a UK DP cohort managed 2015-2023, identified through the NIHR clinical research network. Patients were followed longitudinally until adulthood, with a definite diagnosis made: SLDP if they had spontaneously completed puberty by age 18 years; HH if they had not commenced (complete, cHH), or had commenced but not completed puberty (partial, pHH), by this stage. Phenotypic data pertaining to auxology, Tanner staging, biochemistry, bone age and hormonal treatment at presentation and during puberty were retrospectively analysed.
Results
78 patients were included. 52 (66.7%) patients had SLDP and 26 (33.3%) patients had HH, comprising 17 (65.4%) pHH and 9 (34.6%) cHH patients. Probands were predominantly male (90.4%). Male SLDP patients presented with significantly lower height and weight standard deviation scores than HH patients (height p=0.004, weight p=0.021). 15.4% of SLDP compared to 38.5% of HH patients had classical associated features of HH (micropenis, cryptorchidism, anosmia, etc. p=0.023). 73.1% of patients with SLDP and 43.3% with HH had a family history of DP (p=0.007). Mean first recorded luteinizing hormone (LH) and inhibin B were lower in male patients with HH, particularly in cHH patients, but not discriminatory. There were no significant differences identified in blood concentrations of FSH, testosterone or AMH at presentation, or in bone age delay.
Discussion
Key clinical markers of auxology, associated signs including micropenis, and serum inhibin B may help distinguish between SLDP and HH in patients presenting with pubertal delay, and can be incorporated into clinical assessment to improve diagnostic accuracy for adolescents. However, the distinction between HH, particularly partial HH, and SLDP remains problematic. Further research into an integrated framework or scoring system would be useful in aiding clinician decision-making and optimization of treatment.
... 50 During testosterone treatment to induce puberty, the patient's gonadotropin levels increased, yet testis size remained small and serum inhibin B level low, arguing against extreme form of constitutional delay of growth and puberty or reversal of CHH. 51 Interestingly, POGZ is expressed in spermatogonia and developing spermatogenic cells (https://www. proteinatlas.org/), ...
Objective:
Congenital hypogonadotropic hypogonadism (CHH) is a rare, genetically heterogeneous reproductive disorder caused by gonadotropin-releasing hormone (GnRH) deficiency. Approximately half of CHH patients also have decreased or absent sense of smell, i.e. Kallmann syndrome (KS). We describe a patient with White-Sutton syndrome (developmental delay and autism spectrum disorder) and KS due to a heterozygous de novo mutation in POGZ (c.2857C > T, p.(Gln953*)), a gene encoding pogo transposable element derived with zinc finger domain, which acts as a transcriptomic regulator of neuronal networks.
Design & methods:
We modelled the role of POGZ in CHH by generating two clonal human pluripotent stem cell lines with CRISPR/Cas9, carrying either the heterozygous patient mutation (H11 line), or a homozygous mutation (c.2803-2906del; p.E935Kfs*7 encoding a truncated POGZ protein; F6del line).
Results:
During the differentiation to GnRH neurons, neural progenitors derived from F6del line displayed severe proliferation defect, delayed wound-healing capacity, downregulation of intermediate progenitor neuron genes TBR1 and TBR2 and immature neuron markers PAX6 and TUBB3, and gave rise to fewer neurons with shorter neurites and less neurite branch points compared to the WT and H11 lines (P < 0.005). Both lines, however, could be successfully differentiated to GnRH neurons.
Conclusions:
In conclusion, this is the first report on the overlap between White-Sutton syndrome and CHH. POGZ mutations do not hinder GnRH neuron formation, but may cause CHH/KS by affecting the size and motility of the anterior neural progenitor pool, and neurite outgrowth.
... Evidence suggests that rare variants of idiopathic hypogonadotropic hypogonadism can be associated with Axl mutations that impair AXL function (76). Idiopathic hypogonadotropic hypogonadism involves defects in neuronal GnRH release or GnRH action (77,78). Consistent with the documented role of AXL in GnRH neuronal migration from the olfactory placode to the hypothalamus, these mutations result in impaired survival and migration of neurons, including GnRH neurons, from the medial olfactory placode to the hypothalamus. ...
AXL is a receptor tyrosine kinase commonly associated with a variety of human cancers. Along with its ligand Gas6 (growth arrest-specific protein 6), AXL is emerging as an important regulator of neuroendocrine development and function. AXL signaling in response to Gas6 binding impacts neuroendocrine structure and function at the level of the brain, pituitary, and gonads. During development, AXL has been identified as an upstream inhibitor of gonadotropin receptor hormone (GnRH) production and also plays a key role in the migration of GnRH neurons from the olfactory placode to the forebrain. AXL is implicated in reproductive diseases including some forms of idiopathic hypogonadotropic hypogonadism and evidence suggests that AXL is required for normal spermatogenesis. Here, we highlight research describing AXL/Gas6 signaling mechanisms with a focus on the molecular pathways related to neuroendocrine function in health and disease. In doing so, we aim to present a concise account of known AXL/Gas6 signaling mechanisms to identify current knowledge gaps and inspire future research.
... The reason for this transformation from hypo-to hyper-gonadotropic is complex. Studies have shown that 5-16% of IHH patients may have HPG axis function reversal [28][29][30][31] . ...
Purpose
Kallmann syndrome is a rare disease characterized by delayed puberty, infertility and anosmia. We report the clinical and genetic characteristics of four patients with Kallmann syndrome who presented with Klinefelter syndrome or primary testicular disease and defined a new type of hypogonadism as mixed hypogonadism.
Methods
Clinical data and examinations were obtained, including laboratory examination and magnetic resonance imagination (MRI) of the olfactory structures. Idiopathic hypogonadotropic hypogonadism (IHH) related genes were screened by next generation sequencing (NGS).
Results
Four patients with Kallmann syndrome were included. Patient 1–3 had co-existence with Klinefelter syndrome and showed hypogonadotropic hypogonadism. Patient 1 was complicated with germinoma. Patient 4 had a history of hypogonadotropic hypogonadism and cryptorchidism, and then gradually converted to hypergonadotropic hypogonadism during follow-up.
Conclusion
Mixed hypogonadism was defined as hypogonadotropic hypogonadism in Klinefelter syndrome or primary testicular disease. Clinicians should be alert to mixed hypogonadism when spermatogenesis induction failed in patients with IHH or gonadotropin levels decrease in patients with Klinefelter syndrome.
... Kallmann syndrome (KS) is defined as idiopathic hypogonadotropic hypogonadism (IHH) combined with hyposmia or anosmia, whereas IHH with a normal sense of smell has been termed 'normosmic idiopathic hypogonadotropic hypogonadism' (nIHH) (Raivio et al. 2007). The main clinical phenotype of IHH patients is an absent or incomplete sexual maturation. ...
WD40 repeat-containing proteins play a key role in many cellular functions including signal transduction, protein degradation, and apoptosis. The WD40 domain is highly conserved, and its typical structure is a β-propeller consisting of 4-8 blades which probably serves as a scaffold for protein-protein interaction. Some WD40 repeat-containing proteins form part of the corepressor complex of nuclear hormone receptors, a family of ligand-dependent transcription factors that play a central role in the regulation of gene transcription. This explains their involvement in endocrine physiology and pathology. In the present review, we first touch upon the structure of WD40 repeat-containing proteins. Next, we describe our current understanding of the role of WD40 domain containing proteins in nuclear receptor signaling e.g. as corepressor or coactivator. In the final part of this review, we focus on WD40 domain containing proteins that are associated with endocrine pathologies. These pathologies vary from isolated dysfunction of one endocrine axis, e.g., congenital isolated central hypothyroidism, to more complex congenital syndromes comprising endocrine phenotypes, such as the Triple-A syndrome.
... Supporting this possibility, lineage tracing studies showed that the conditional deletion of a transcription factor Vax1 (ventral anterior homeobox 1) in GnRH neurons rendered GnRH neurons unable to produce GnRH without impacting their survival (73). In addition, approximately 10% of CHH patients experienced spontaneous reversal to gain fertility after the termination of hormone replacement therapy (74)(75)(76)(77)(78)(79). These patients included those harboring mutations on genes such as Fgfr1, Chd7, Prokr2 originally thought to irreversibly disrupt GnRH neuronal development and reduce postnatal GnRH neuronal population. ...
Neurons that secrete gonadotropin-releasing hormone (GnRH) drive vertebrate reproduction. Genetic lesions that disrupt these neurons in humans lead to congenital hypogonadotropic hypogonadism (CHH) and reproductive failure. Studies on CHH have largely focused on the disruption of prenatal GnRH neuronal migration and postnatal GnRH secretory activity. However, recent evidence suggests a need to also focus on how GnRH neurons initiate and maintain their identity during prenatal and postnatal periods. This review will provide a brief overview of what is known about these processes and several gaps in our knowledge, with an emphasis on how disruption of GnRH neuronal identity can lead to CHH phenotypes.
