Patients with congenital hypogonadism will encounter many health care professionals during their ... more Patients with congenital hypogonadism will encounter many health care professionals during their lives managing their health needs; from antenatal and infantile periods, through childhood and adolescence, into adult life and then old age. The pubertal transition from childhood to adult life raises particular challenges for diagnosis, therapy and psychological support, and patients encounter many pitfalls. Many patients with congenital hypogonadism and delayed or absent puberty are only diagnosed and treated after long diagnostic journeys, and their management across different centres and countries is not well standardised. Here we reconsider the management of pubertal delay, whilst addressing problematic diagnostic issues and highlighting the limitations of historic pubertal induction protocols – from the perspective of both an adult and a paediatric endocrinologist, dealing in our everyday work with the long-term adverse consequences to our hypogonadal patients of an incorrect and/...
Expert Review of Endocrinology & Metabolism, Jan 2, 2022
ABSTRACT Introduction Congenital hypogonadotropic hypogonadism (CHH) is a genetic disorder of rep... more ABSTRACT Introduction Congenital hypogonadotropic hypogonadism (CHH) is a genetic disorder of reproduction and development, characterized by deficient gonadotropin-releasing hormone (GnRH) secretion or action, affecting 1-in-4,000–15,000 males. Micropenis and undescended testes are cardinal features of antenatal GnRH deficiency and could indicate absent minipuberty in the first postnatal months. In this review, we outline the pathophysiology and clinical consequences of absent minipuberty and its implications for optimal approaches to the endocrine management of affected boys. Areas covered Deficient GnRH activity during fetal development and neonatal-infancy phase of minipuberty accounts for the diminished mass of Sertoli cells and seminiferous tubules among CHH males, enduring impairment of reproductive function even during gonadotropin replacement in adult life. In overcoming this obstacle, several clinical studies of neonatal gonadotropin replacement have consistently shown positive results in inducing testicular development and correcting cryptorchidism. Expert opinion A high index of clinical suspicion, combined with hormonal testing undertaken in the postnatal period of 1–4 months, can reliably confirm or refute the diagnosis of CHH. Timely identification of CHH in affected male infants (having characteristic “red flag’ developmental anomalies) opens up the possibility for gonadotropin replacement as a targeted therapy to restore the normal hormonal milieu of minipuberty. Further work is necessary in formulating optimal gonadotropin treatment regimens to be more widely adopted in clinical practice.
We defined inpatients with severe COVID-19 as those requiring admission to the Intensive Therapy ... more We defined inpatients with severe COVID-19 as those requiring admission to the Intensive Therapy Unit (ITU). It was rightly highlighted that this group did not include patients who were deemed inappropriate for escalation of care, so it is indeed possible that they had a higher prevalence of vitamin D deficiency (VDD), due to older age or multiple comorbidities, and therefore a wider difference between ITU vs. non-ITU groups might have been shown; it may even have brought out a difference in mortality between the groups. However, this was beyond our primary aim to audit the local clinical care pathway with regards to diagnosing and treating VDD in patients with COVID-19.
Lay summary Anabolic steroids (also known as ‘steroids’) are banned drugs like testosterone, whic... more Lay summary Anabolic steroids (also known as ‘steroids’) are banned drugs like testosterone, which make muscles bigger in men. These drugs are dangerous because they stop the testes from making natural testosterone and can cause heart attacks. Men stopping steroids have very low testosterone, which makes them feel weak, depressed, suicidal, infertile, and unable to have erections. We surveyed over 100 doctors to find out how they treat men giving up steroids. We report that doctors differ widely in the way they treat these men. Most doctors simply advise men to wait for the natural recovery of testosterone levels to happen. But 20% of doctors give men drugs to boost testosterone and make men feel better. Unfortunately, many patients had not recovered by the time of our survey. In summary, our survey highlights differences and limitations in the treatment of men giving up steroids. The use of steroids is increasing rapidly among young men, so we recommend further work to improve the ...
Introduction Functional hypothalamic amenorrhea (HA) is commonly associated with increased exerci... more Introduction Functional hypothalamic amenorrhea (HA) is commonly associated with increased exercise or decreased caloric intake and often with stress. We have previously demonstrated an increased burden of rare sequence variants (RSVs) in genes involved in GnRH ontogeny and upstream regulation in women with HA, but the role of metabolic and stress signaling to the GnRH neuronal system is poorly defined in this population. Methods The study included 100 women with a confirmed diagnosis of HA. The control cohort consisted of 468 women (aged 45-65 years) drawn from the NIH ClinSeq® Project. Exome sequencing was performed on peripheral blood genomic DNA. A subset of 72 genes was analyzed that have been shown to: 1) link metabolic or stress with reproductive phenotypes or 2) integrate metabolic and stress pathways with control of GnRH secretion. Joint genotyping of case and control samples was performed using the GATK GenotypeGVCFs function, locus-filtering using the VariantRecalibrato...
Les hypogonadismes hypogonadotropes congenitaux (HHC) sont caracterises par une absence du develo... more Les hypogonadismes hypogonadotropes congenitaux (HHC) sont caracterises par une absence du developpement pubertaire et d’une infertilite causes par une deficience de la secretion hypothalamique de GnRH. La prevalence de cette pathologie est d’environ 1/10 000. Les HHC sont habituellement divises en deux entites cliniques : le syndrome de Kallmann associant l’HH a une anosmie, et l’HHC sans anosmie. Cette pathologie est une maladie genetique heterogene possedant plusieurs modes de transmission. Depuis une vingtaine d’annees, plus de 30 genes ont ete decouvert dans la pathogenese de l’HHC, cependant plus de 45 % des cas n’ont toujours pas d’etiologies genetiques. Le sequencage par « whole-exome » dans une cohorte de 134 patients, incluant les familles, a permis de souligner l’implication de nouveaux genes candidats : le recepteur DCC et son ligand Netrin-1, qui sont associes a la migration des neurones a GnRH. Cinq variations heterozygotes du gene DCC, extremement bien conservees au s...
Male hypogonadism (MH) is a common endocrine disorder. However, uncertainties and variations in i... more Male hypogonadism (MH) is a common endocrine disorder. However, uncertainties and variations in its diagnosis and management exist. There are several current guidelines on testosterone replacement therapy that have been driven predominantly by single disciplines. The Society for Endocrinology commissioned this new guideline to provide all care providers with a multidisciplinary approach to treating patients with MH. This guideline has been compiled using expertise from endocrine (medical and nursing), primary care, clinical biochemistry, urology and reproductive medicine practices. These guidelines also provide a patient perspective to help clinicians best manage MH.
Background: Hypogonadotropic hypogonadism (HH) is hypogonadism due to either hypothalamic or pitu... more Background: Hypogonadotropic hypogonadism (HH) is hypogonadism due to either hypothalamic or pituitary dysfunction. While gonadotropin-releasing hormone (GnRH) can directly test pituitary function, no specific test of hypothalamic function exists. Kisspeptin-54 (KP54) is a neuropeptide that directly stimulates hypothalamic GnRH release and thus could be used to specifically interrogate hypothalamic function. Congenital HH (CHH) is typically due to variants in genes that control hypothalamic GnRH neuronal migration or function. Thus, we investigated whether KP54 could accurately identify hypothalamic dysfunction in men with CHH. Methods: Men with CHH (n = 21) and healthy eugonadal men (n = 21) received an intravenous bolus of either GnRH (100 μg) or KP54 (6.4 nmol/kg), on 2 occasions, and were monitored for 6 h after administration of each neuropeptide. Results: Maximal luteinizing hormone (LH) rise after KP54 was significantly greater in healthy men (12.5 iU/L) than in men with CHH ...
Purpose: SOX10 mutations previously implicated in Waardenburg syndrome (WS), have now been linked... more Purpose: SOX10 mutations previously implicated in Waardenburg syndrome (WS), have now been linked to Kallmann Syndrome [KS], the anosmic form of idiopathic hypogonadotropic hypogonadism (IHH). We investigated whether SOX10-associated WS and IHH represent elements of a phenotypic continuum within a unifying disorder or if they represent phenotypically distinct allelic disorders. Methods: Exome sequencing from 1309 IHH subjects (KS: 632; normosmic idiopathic hypogonadotropic hypogonadism [nIIHH:677) were reviewed for SOX10 rare sequence variants (RSVs). The genotypic and phenotypic spectrum of SOX10-related IHH (this study & literature) and SOX10-related WS cases (literature) were reviewed and compared with SOX10-RSV spectrum in gnomAD population. Results: Thirty-seven SOX10-associated IHH cases were identified: Current study:16 KS; 4 nIHH; literature:16 KS; 1 nIHH. Twenty-three IHH cases (62%; all KS), had ≥1 known WS-associated feature(s). Moreover, five previously reported SOX10-associated WS cases showed IHH-related features. Four SOX10 missense RSVs showed allelic overlap between IHH-ascertained and WS-ascertained cases. The SOX10-HMG domain showed an enrichment of RSVs in disease-states vs. gnomAD. Conclusions: SOX10 mutations contribute to both anosmic (KS) and normosmic (nIHH) forms of IHH. IHH and WS represent SOX10-associated developmental defects that lie along a unifying phenotypic continuum. The SOX10-HMG domain is critical for the pathogenesis of SOX10-related human disorders.
Patients with congenital hypogonadism will encounter many health care professionals during their ... more Patients with congenital hypogonadism will encounter many health care professionals during their lives managing their health needs; from antenatal and infantile periods, through childhood and adolescence, into adult life and then old age. The pubertal transition from childhood to adult life raises particular challenges for diagnosis, therapy and psychological support, and patients encounter many pitfalls. Many patients with congenital hypogonadism and delayed or absent puberty are only diagnosed and treated after long diagnostic journeys, and their management across different centres and countries is not well standardised. Here we reconsider the management of pubertal delay, whilst addressing problematic diagnostic issues and highlighting the limitations of historic pubertal induction protocols – from the perspective of both an adult and a paediatric endocrinologist, dealing in our everyday work with the long-term adverse consequences to our hypogonadal patients of an incorrect and/...
Expert Review of Endocrinology & Metabolism, Jan 2, 2022
ABSTRACT Introduction Congenital hypogonadotropic hypogonadism (CHH) is a genetic disorder of rep... more ABSTRACT Introduction Congenital hypogonadotropic hypogonadism (CHH) is a genetic disorder of reproduction and development, characterized by deficient gonadotropin-releasing hormone (GnRH) secretion or action, affecting 1-in-4,000–15,000 males. Micropenis and undescended testes are cardinal features of antenatal GnRH deficiency and could indicate absent minipuberty in the first postnatal months. In this review, we outline the pathophysiology and clinical consequences of absent minipuberty and its implications for optimal approaches to the endocrine management of affected boys. Areas covered Deficient GnRH activity during fetal development and neonatal-infancy phase of minipuberty accounts for the diminished mass of Sertoli cells and seminiferous tubules among CHH males, enduring impairment of reproductive function even during gonadotropin replacement in adult life. In overcoming this obstacle, several clinical studies of neonatal gonadotropin replacement have consistently shown positive results in inducing testicular development and correcting cryptorchidism. Expert opinion A high index of clinical suspicion, combined with hormonal testing undertaken in the postnatal period of 1–4 months, can reliably confirm or refute the diagnosis of CHH. Timely identification of CHH in affected male infants (having characteristic “red flag’ developmental anomalies) opens up the possibility for gonadotropin replacement as a targeted therapy to restore the normal hormonal milieu of minipuberty. Further work is necessary in formulating optimal gonadotropin treatment regimens to be more widely adopted in clinical practice.
We defined inpatients with severe COVID-19 as those requiring admission to the Intensive Therapy ... more We defined inpatients with severe COVID-19 as those requiring admission to the Intensive Therapy Unit (ITU). It was rightly highlighted that this group did not include patients who were deemed inappropriate for escalation of care, so it is indeed possible that they had a higher prevalence of vitamin D deficiency (VDD), due to older age or multiple comorbidities, and therefore a wider difference between ITU vs. non-ITU groups might have been shown; it may even have brought out a difference in mortality between the groups. However, this was beyond our primary aim to audit the local clinical care pathway with regards to diagnosing and treating VDD in patients with COVID-19.
Lay summary Anabolic steroids (also known as ‘steroids’) are banned drugs like testosterone, whic... more Lay summary Anabolic steroids (also known as ‘steroids’) are banned drugs like testosterone, which make muscles bigger in men. These drugs are dangerous because they stop the testes from making natural testosterone and can cause heart attacks. Men stopping steroids have very low testosterone, which makes them feel weak, depressed, suicidal, infertile, and unable to have erections. We surveyed over 100 doctors to find out how they treat men giving up steroids. We report that doctors differ widely in the way they treat these men. Most doctors simply advise men to wait for the natural recovery of testosterone levels to happen. But 20% of doctors give men drugs to boost testosterone and make men feel better. Unfortunately, many patients had not recovered by the time of our survey. In summary, our survey highlights differences and limitations in the treatment of men giving up steroids. The use of steroids is increasing rapidly among young men, so we recommend further work to improve the ...
Introduction Functional hypothalamic amenorrhea (HA) is commonly associated with increased exerci... more Introduction Functional hypothalamic amenorrhea (HA) is commonly associated with increased exercise or decreased caloric intake and often with stress. We have previously demonstrated an increased burden of rare sequence variants (RSVs) in genes involved in GnRH ontogeny and upstream regulation in women with HA, but the role of metabolic and stress signaling to the GnRH neuronal system is poorly defined in this population. Methods The study included 100 women with a confirmed diagnosis of HA. The control cohort consisted of 468 women (aged 45-65 years) drawn from the NIH ClinSeq® Project. Exome sequencing was performed on peripheral blood genomic DNA. A subset of 72 genes was analyzed that have been shown to: 1) link metabolic or stress with reproductive phenotypes or 2) integrate metabolic and stress pathways with control of GnRH secretion. Joint genotyping of case and control samples was performed using the GATK GenotypeGVCFs function, locus-filtering using the VariantRecalibrato...
Les hypogonadismes hypogonadotropes congenitaux (HHC) sont caracterises par une absence du develo... more Les hypogonadismes hypogonadotropes congenitaux (HHC) sont caracterises par une absence du developpement pubertaire et d’une infertilite causes par une deficience de la secretion hypothalamique de GnRH. La prevalence de cette pathologie est d’environ 1/10 000. Les HHC sont habituellement divises en deux entites cliniques : le syndrome de Kallmann associant l’HH a une anosmie, et l’HHC sans anosmie. Cette pathologie est une maladie genetique heterogene possedant plusieurs modes de transmission. Depuis une vingtaine d’annees, plus de 30 genes ont ete decouvert dans la pathogenese de l’HHC, cependant plus de 45 % des cas n’ont toujours pas d’etiologies genetiques. Le sequencage par « whole-exome » dans une cohorte de 134 patients, incluant les familles, a permis de souligner l’implication de nouveaux genes candidats : le recepteur DCC et son ligand Netrin-1, qui sont associes a la migration des neurones a GnRH. Cinq variations heterozygotes du gene DCC, extremement bien conservees au s...
Male hypogonadism (MH) is a common endocrine disorder. However, uncertainties and variations in i... more Male hypogonadism (MH) is a common endocrine disorder. However, uncertainties and variations in its diagnosis and management exist. There are several current guidelines on testosterone replacement therapy that have been driven predominantly by single disciplines. The Society for Endocrinology commissioned this new guideline to provide all care providers with a multidisciplinary approach to treating patients with MH. This guideline has been compiled using expertise from endocrine (medical and nursing), primary care, clinical biochemistry, urology and reproductive medicine practices. These guidelines also provide a patient perspective to help clinicians best manage MH.
Background: Hypogonadotropic hypogonadism (HH) is hypogonadism due to either hypothalamic or pitu... more Background: Hypogonadotropic hypogonadism (HH) is hypogonadism due to either hypothalamic or pituitary dysfunction. While gonadotropin-releasing hormone (GnRH) can directly test pituitary function, no specific test of hypothalamic function exists. Kisspeptin-54 (KP54) is a neuropeptide that directly stimulates hypothalamic GnRH release and thus could be used to specifically interrogate hypothalamic function. Congenital HH (CHH) is typically due to variants in genes that control hypothalamic GnRH neuronal migration or function. Thus, we investigated whether KP54 could accurately identify hypothalamic dysfunction in men with CHH. Methods: Men with CHH (n = 21) and healthy eugonadal men (n = 21) received an intravenous bolus of either GnRH (100 μg) or KP54 (6.4 nmol/kg), on 2 occasions, and were monitored for 6 h after administration of each neuropeptide. Results: Maximal luteinizing hormone (LH) rise after KP54 was significantly greater in healthy men (12.5 iU/L) than in men with CHH ...
Purpose: SOX10 mutations previously implicated in Waardenburg syndrome (WS), have now been linked... more Purpose: SOX10 mutations previously implicated in Waardenburg syndrome (WS), have now been linked to Kallmann Syndrome [KS], the anosmic form of idiopathic hypogonadotropic hypogonadism (IHH). We investigated whether SOX10-associated WS and IHH represent elements of a phenotypic continuum within a unifying disorder or if they represent phenotypically distinct allelic disorders. Methods: Exome sequencing from 1309 IHH subjects (KS: 632; normosmic idiopathic hypogonadotropic hypogonadism [nIIHH:677) were reviewed for SOX10 rare sequence variants (RSVs). The genotypic and phenotypic spectrum of SOX10-related IHH (this study & literature) and SOX10-related WS cases (literature) were reviewed and compared with SOX10-RSV spectrum in gnomAD population. Results: Thirty-seven SOX10-associated IHH cases were identified: Current study:16 KS; 4 nIHH; literature:16 KS; 1 nIHH. Twenty-three IHH cases (62%; all KS), had ≥1 known WS-associated feature(s). Moreover, five previously reported SOX10-associated WS cases showed IHH-related features. Four SOX10 missense RSVs showed allelic overlap between IHH-ascertained and WS-ascertained cases. The SOX10-HMG domain showed an enrichment of RSVs in disease-states vs. gnomAD. Conclusions: SOX10 mutations contribute to both anosmic (KS) and normosmic (nIHH) forms of IHH. IHH and WS represent SOX10-associated developmental defects that lie along a unifying phenotypic continuum. The SOX10-HMG domain is critical for the pathogenesis of SOX10-related human disorders.
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