RESUMEN

Objectives: Recurrence and regrowth of non-functioning pituitary macroadenomas (NFPMs) after surgery are common but remain unpredictable. Therefore, the optimal timing and frequency of follow-up imaging remain to be determined. We sought to determine the long-term surgical outcomes of NFPMs following surgery and develop an optimal follow-up strategy. Methods: Patients underwent surgery for NFPMs between 1987 and 2018, with a follow-up of 6 months or more, were identified. Demographics, presentation, management, histology, imaging, and surgical outcomes were retrospectively collected. Results: In total, 383 patients were included; 256 were men (256/383; 67%) with median follow-up of 8 years. Following primary surgery, 229 patients (229/383; 60%) achieved complete resection. Of those, 28 (28/229; 11%) developed recurrence, including six needed secondary surgery (6/229; 3%). The rate of complete resection improved over time; in the last quartile of cases, 77 achieved complete resection (77/95; 81%). Reoperation-free survival at 5, 10 and 15 years was 99%, 94% and 94%, respectively. NFPMs were incompletely resected in 154 patients (154/383; 40%); of those, 106 (106/154; 69%) had regrowth, and 84 (84/154; 55%) required reoperation. Surgical reintervention-free survival at 5, 10 and 15 years was 74%,49% and 35%, respectively. Young age and cavernous sinus invasion were risk factors for undergoing reoperation (P < 0.001 and P < 0.0001, respectively) and radiotherapy (P = 0.003 and P < 0.001, respectively). Patients with residual tumour required reoperation earlier than those underwent complete resection (P = 0.02). Radiotherapy to control tumour regrowth was delivered to 65 patients (65/383; 17%) after median time of 1 year following surgery. Radiotherapy was administered more in patients with regrowth of residual disease (61/106; 58%) than those who had NFPMs recurrence (4/28; 14%) (P ≤ 0.001) Following postoperative radiotherapy, one patient (1/65; 2%) had evidence of regrowth, seven (7/65; 11%) had tumour regression on imaging, and no patients underwent further surgery. Conclusions: NFPMs recurrence and regrowth are common, particularly in patients with residual disease post-operatively. We propose a follow-up strategy based on stratifying patients as "low risk" if there is no residual tumour, with increasing scan intervals, or "high risk" if there is a residual tumour, with annual scans for at least five years and extended lifelong surveillance after that.

RESUMEN

BACKGROUND: Non-functioning pituitary macroadenomas (NFPMs) may present with hypopituitarism. Pituitary surgery and radiotherapy pose an additional risk to pituitary function. OBJECTIVES: To assess the incidence of hypopituitarism at presentation, the impact of treatment, and the likelihood of endocrine recovery during follow-up. METHODS: All patients treated surgically with and without radiotherapy for NFPMs between 1987 and 2018 who had longer than six months follow-up were identified. Demographics, presentation, investigation, treatment, and outcomes were collected. RESULTS: In total, 383 patients were identified. The median age was 57 years, with a median follow-up of 8 years. Preoperatively, 227 patients (227/375; 61%) had evidence of at least one pituitary deficiency. Anterior panhypopituitarism was more common in men (p = 0.001) and older patients (p = 0.005). Multiple hormone deficiencies were associated with large tumours (p = 0.03). Patients treated with surgery and radiotherapy had a higher incidence of all individual pituitary hormone deficiency, anterior panhypopituitarism, and significantly lower GH, ACTH, and TSH deficiencies free survival probability than those treated with surgery alone. Recovery of central hypogonadism, hypothyroidism, and anterior panhypopituitarism was also less likely to be reported in those treated with surgery and radiotherapy. Those with preoperative hypopituitarism had a higher risk of pituitary impairment at latest review than those presented with normal pituitary function (p = 0.001). CONCLUSION: NFPMs are associated with a significant degree of hypopituitarism at time of diagnosis and post-therapy. The combination of surgery and radiotherapy is associated with a higher risk of pituitary dysfunction. Recovery of pituitary hormone deficit may occur after treatment. Patients should have regular ongoing endocrine evaluation post-treatment to assess changes in pituitary function and the need for long-term replacement therapy.

Asunto(s)

Hipopituitarismo , Hipotiroidismo , Neoplasias Hipofisarias , Masculino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Hipopituitarismo/epidemiología , Hipopituitarismo/etiología , Hipopituitarismo/diagnóstico , Hipófisis/patología , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/epidemiología , Neoplasias Hipofisarias/cirugía , Hormonas Hipofisarias , Hipotiroidismo/complicaciones

RESUMEN

The syndrome of inappropriate antidiuresis (SIAD), the commonest cause of hyponatraemia, is associated with significant morbidity and mortality. Tolvaptan, an oral vasopressin V2-receptor antagonist, leads through aquaresis to an increase in serum sodium concentration and is the only medication licenced in Europe for the treatment of euvolaemic hyponatraemia. Randomised controlled trials have shown that tolvaptan is highly efficacious in correcting SIAD-related hyponatraemia. Real-world data have confirmed the marked efficacy of tolvaptan, but they have also reported a high risk of overly rapid sodium increase in patients with a very low baseline serum sodium. The lower the baseline serum sodium, the higher the tolvaptan-induced correction rate occurs. Therefore, a lower starting tolvaptan dose of 7.5 mg has been evaluated in small cohort studies, demonstrating its efficacy, but it still remains unclear as to whether it can reduce the risk of overcorrection. Most international guidelines, except for the European ones, recommend tolvaptan as second-line treatment for SIAD after fluid restriction. However, the risk of unduly rapid sodium correction in combination with its high cost have limited its routine use. Prospective controlled studies are warranted to evaluate whether tolvaptan-related sodium increase can improve patient-related clinical outcomes, such as mortality and length of hospital stay in the acute setting or neurocognitive symptoms and quality of life in the chronic setting. In addition, the potential role of a low tolvaptan starting dose needs to be further explored. Until then, tolvaptan should mainly be used as second-line treatment for SIAD, especially when there is a clinical need for prompt restoration of normonatraemia. Tolvaptan should be used with specialist input according to a structured clinical pathway, including rigorous monitoring of electrolyte and fluid balance and, if needed, implementation of appropriate measures to prevent, or when necessary reverse, overly rapid hyponatraemia correction.

RESUMEN

PURPOSE: Hyponatraemia is a common complication following transsphenoidal surgery. However, there is sparse data on its optimal management and impact on clinical outcomes. The aim of this study was to evaluate the management and outcome of hyponatraemia following transsphenoidal surgery. METHODS: A prospectively maintained database was searched over a 4-year period between January 2016 and December 2019, to identify all patients undergoing transsphenoidal surgery. A retrospective case-note review was performed to extract data on hyponatraemia management and outcome. RESULTS: Hyponatraemia occurred in 162 patients (162/670; 24.2%) with a median age of 56 years. Female gender and younger age were associated with hyponatraemia, with mean nadir sodium being 128.6 mmol/L on postoperative day 7. Hyponatraemic patients had longer hospital stay than normonatraemic group with nadir sodium being inversely associated with length of stay (p < 0.001). In patients with serum sodium ≤ 132 mmol/L, syndrome of inappropriate antidiuretic hormone secretion (SIADH) was the commonest cause (80/111; 72%). Among 76 patients treated with fluid restriction as a monotherapy, 25 patients (25/76; 32.9%) did not achieve a rise in sodium after 3 days of treatment. Readmission with hyponatraemia occurred in 11 cases (11/162; 6.8%) at a median interval of 9 days after operation. CONCLUSION: Hyponatraemia is a relatively common occurrence following transsphenoidal surgery, is associated with longer hospital stay and risk of readmission and the effectiveness of fluid restriction is limited. These findings highlight the need for further studies to better identify and treat high-risk patients, including the use of arginine vasopressin receptor antagonists.

Asunto(s)

Hiponatremia , Síndrome de Secreción Inadecuada de ADH , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Femenino , Humanos , Hiponatremia/epidemiología , Hiponatremia/etiología , Hiponatremia/terapia , Síndrome de Secreción Inadecuada de ADH/complicaciones , Síndrome de Secreción Inadecuada de ADH/tratamiento farmacológico , Persona de Mediana Edad , Estudios Retrospectivos , Sodio/uso terapéutico

RESUMEN

Introduction: Cushing's disease presents major diagnostic and management challenges. Although numerous preoperative and intraoperative imaging modalities have been deployed, it is unclear whether these investigations have improved surgical outcomes. Our objective was to investigate whether advances in imaging improved outcomes for Cushing's disease. Methods: Searches of PubMed and EMBASE were conducted. Studies reporting on imaging modalities and clinical outcomes after surgical management of Cushing's disease were included. Multilevel multivariable meta-regressions identified predictors of outcomes, adjusting for confounders and heterogeneity prior to investigating the effects of imaging. Results: 166 non-controlled single-arm studies were included, comprising 13181 patients over 44 years.The overall remission rate was 77.0% [CI: 74.9%-79.0%]. Cavernous sinus invasion (OR: 0.21 [CI: 0.07-0.66]; p=0.010), radiologically undetectable lesions (OR: 0.50 [CI: 0.37-0.69]; p<0.0001), previous surgery (OR=0.48 [CI: 0.28-0.81]; p=0.008), and lesions ≥10mm (OR: 0.63 [CI: 0.35-1.14]; p=0.12) were associated with lower remission. Less stringent thresholds for remission was associated with higher reported remission (OR: 1.37 [CI: 1.1-1.72]; p=0.007). After adjusting for this heterogeneity, no imaging modality showed significant differences in remission compared to standard preoperative MRI.The overall recurrence rate was 14.5% [CI: 12.1%-17.1%]. Lesion ≥10mm was associated with greater recurrence (OR: 1.83 [CI: 1.13-2.96]; p=0.015), as was greater duration of follow-up (OR: 1.53 (CI: 1.17-2.01); p=0.002). No imaging modality was associated with significant differences in recurrence.Despite significant improvements in detection rates over four decades, there were no significant changes in the reported remission or recurrence rates. Conclusion: A lack of controlled comparative studies makes it difficult to draw definitive conclusions. Within this limitation, the results suggest that despite improvements in radiological detection rates of Cushing's disease over the last four decades, there were no changes in clinical outcomes. Advances in imaging alone may be insufficient to improve surgical outcomes. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42020187751.

Asunto(s)

Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Radiología , Humanos , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico por imagen , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/cirugía , Resultado del Tratamiento , Radiografía , Imagen por Resonancia Magnética

RESUMEN

CONTEXT: Dysnatremia is an independent predictor of mortality in patients with bacterial pneumonia. There is paucity of data about the incidence and prognostic impact of abnormal sodium concentration in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: This work aimed to examine the association of serum sodium during hospitalization with key clinical outcomes, including mortality, need for advanced respiratory support and acute kidney injury (AKI), and to explore the role of serum sodium as a marker of inflammatory response in COVID-19. METHODS: This retrospective longitudinal cohort study, including all adult patients who presented with COVID-19 to 2 hospitals in London over an 8-week period, evaluated the association of dysnatremia (serum sodium < 135 or > 145 mmol/L, hyponatremia, and hypernatremia, respectively) at several time points with inpatient mortality, need for advanced ventilatory support, and AKI. RESULTS: The study included 488 patients (median age, 68 years). At presentation, 24.6% of patients were hyponatremic, mainly due to hypovolemia, and 5.3% hypernatremic. Hypernatremia 2 days after admission and exposure to hypernatremia at any time point during hospitalization were associated with a 2.34-fold (95% CI, 1.08-5.05; P = .0014) and 3.05-fold (95% CI, 1.69-5.49; P < .0001) increased risk of death, respectively, compared to normonatremia. Hyponatremia at admission was linked with a 2.18-fold increase in the likelihood of needing ventilatory support (95% CI, 1.34-3.45, P = .0011). Hyponatremia was not a risk factor for in-hospital mortality, except for the subgroup of patients with hypovolemic hyponatremia. Sodium values were not associated with the risk for AKI and length of hospital stay. CONCLUSION: Abnormal sodium levels during hospitalization are risk factors for poor prognosis, with hypernatremia and hyponatremia being associated with a greater risk of death and respiratory failure, respectively. Serum sodium values could be used for risk stratification in patients with COVID-19.

Asunto(s)

COVID-19/epidemiología , COVID-19/mortalidad , Sodio/sangre , Lesión Pulmonar Aguda/epidemiología , Lesión Pulmonar Aguda/etiología , Anciano , Anciano de 80 o más Años , COVID-19/sangre , Estudios de Cohortes , Femenino , Mortalidad Hospitalaria , Humanos , Hipernatremia/etiología , Hipernatremia/mortalidad , Hiponatremia/etiología , Hiponatremia/mortalidad , Incidencia , Tiempo de Internación , Londres/epidemiología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Respiración Artificial , Factores de Riesgo , Síndrome de Respuesta Inflamatoria Sistémica/sangre , Síndrome de Respuesta Inflamatoria Sistémica/etiología

RESUMEN

BACKGROUND: The optimal management of craniopharyngiomas remains controversial. OBJECTIVES: To examine temporal trends in the management of craniopharyngioma with a focus on endocrine outcomes. METHODS: This was a cross-sectional, multicentre study. Patients treated between 1951 and 2015 were identified and divided into four quartiles. Demographics, presentation, treatment and outcomes were collected. RESULTS: In total, 142 patients with childhood-onset craniopharyngioma (48/142; 34%) and adult-onset disease (94/142; 66%) were included. The median follow-up was 15 years (IQR 5-23 years). Across quartiles, there was a significant trend towards using transsphenoidal surgery (P < .0001). The overall use of radiotherapy was not different among the four quartiles (P = .33). At the latest clinical review, the incidence of GH, ACTH, gonadotrophin deficiencies and anterior panhypopituitarism fell significantly across the duration of the study. Anterior panhypopituitarism was not affected by treatment modality (surgery vs surgery and radiotherapy) (P = .23). There was no difference in the incidence of high BMI (≥25 kg/m2 ) among the four quartiles (P = .14). BMI was higher in patients who treated with surgery and radiotherapy than those treated with surgery only (P = .006). Tumour regrowth occurred in 51 patients (51/142; 36%) with no difference in regrowth among quartiles over the time course of the study (P = .15). CONCLUSION: We demonstrate a significant reduction in panhypopituitarism in craniopharyngioma patients over time, most likely because of a trend towards more transsphenoidal surgery. However, long-term endocrine sequelae remain common and lifelong follow-up is required.

Asunto(s)

Craneofaringioma , Hipopituitarismo , Neoplasias Hipofisarias , Adulto , Niño , Craneofaringioma/radioterapia , Craneofaringioma/cirugía , Estudios Transversales , Estudios de Seguimiento , Humanos , Hipopituitarismo/etiología , Neoplasias Hipofisarias/cirugía , Estudios Retrospectivos

RESUMEN

Olfactory ensheathing cells (OECs) are a specialized class of glia, wrapping around olfactory sensory axons that target the olfactory bulb (OB) and cross the peripheral nervous system/central nervous system boundary during development and continue to do so post-natally. OEC subpopulations perform distinct subtype-specific functions dependent on their maturity status. Disrupted OEC development is thought to be associated with abnormal OB morphogenesis, leading to anosmia, a defining characteristic of Kallmann syndrome. Hence, anosmin-1 encoded by Kallmann syndrome gene (KAL-1) might modulate OEC differentiation/maturation in the OB. We performed in ovo electroporation of shRNA in the olfactory placode to knock-down kal in chick embryos, resulting in abnormal OB morphogenesis and loss of olfactory sensory axonal innervation into OB. BLBP-expressing OECs appeared to form a thinner and poorly organized outmost OB layer where SOX10 expressing OECs were completely absent with emergence of GFAP-expressing OECs. Furthermore, in embryonic day 10 chick OB explant cultures, GFAP expression in OECs accumulating along the OB nerve layers was dramatically reduced by recombinant anosmin-1. We then purified immature OECs from embryonic day 10 chick OB. These cells express GFAP after 7 days in vitro, exhibiting a multipolar morphology. Overexpression of chick anosmin, exogenous anosmin-1 or FGF2 could inhibit GFAP expression with cells presenting elongated morphology, which was blocked by the FGF receptor inhibitor Su5402. These data demonstrate that anosmin-1 functions via FGF signalling in regulating OEC maturation, thereby providing a permissive glial environment for axonal innervation into the OB during development.

Asunto(s)

Neuroglía/citología , Animales , Proliferación Celular/efectos de los fármacos , Embrión de Pollo , Proteína de Unión a los Ácidos Grasos 7/biosíntesis , Factor 2 de Crecimiento de Fibroblastos/biosíntesis , Proteínas del Tejido Nervioso/metabolismo , Neuroglía/metabolismo , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/crecimiento & desarrollo , Pirroles/farmacología , ARN Interferente Pequeño/farmacología

RESUMEN

OBJECTIVE: Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood. DESIGN: We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders. METHODS: Exome sequencing data were used to identify rare variants in known genes in CHH (n = 116), CDGP (n = 72) and control cohorts (n = 36 874 ExAC and n = 405 CoLaus). RESULTS: Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, P = 7.6 × 10-11) or controls (18%, P = 5.5 × 10-12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, P = 0.002) and controls (2%, P = 6.4 × 10-7). CONCLUSIONS: Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.

Asunto(s)

Trastornos del Crecimiento/diagnóstico , Trastornos del Crecimiento/genética , Hipogonadismo/diagnóstico , Hipogonadismo/genética , Pubertad Tardía/diagnóstico , Pubertad Tardía/genética , Adulto , Anciano , Estudios de Cohortes , Femenino , Finlandia/epidemiología , Trastornos del Crecimiento/epidemiología , Humanos , Hipogonadismo/epidemiología , Masculino , Persona de Mediana Edad , Mutación/genética , Pubertad Tardía/epidemiología

RESUMEN

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease characterized by absent puberty and infertility due to GnRH deficiency, and is often associated with anosmia [Kallmann syndrome (KS)]. The genetic etiology of CHH is heterogeneous, and more than 30 genes have been implicated in approximately 50% of patients with CHH. We hypothesized that genes encoding axon-guidance proteins containing fibronectin type-III (FN3) domains (similar to ANOS1, the first gene associated with KS), are mutated in CHH. We performed whole-exome sequencing in a cohort of 133 CHH probands to test this hypothesis, and identified rare sequence variants (RSVs) in genes encoding for the FN3-domain encoding protein deleted in colorectal cancer (DCC) and its ligand Netrin-1 (NTN1). In vitro studies of these RSVs revealed altered intracellular signaling associated with defects in cell morphology, and confirmed five heterozygous DCC mutations in 6 probands-5 of which presented as KS. Two KS probands carry heterozygous mutations in both DCC and NTN1 consistent with oligogenic inheritance. Further, we show that Netrin-1 promotes migration in immortalized GnRH neurons (GN11 cells). This study implicates DCC and NTN1 mutations in the pathophysiology of CHH consistent with the role of these two genes in the ontogeny of GnRH neurons in mice.

Asunto(s)

Receptor DCC/genética , Hipogonadismo/genética , Netrina-1/genética , Adulto , Estudios de Cohortes , Receptor DCC/metabolismo , Femenino , Dominio de Fibronectina del Tipo III , Hormona Liberadora de Gonadotropina/deficiencia , Humanos , Hipogonadismo/metabolismo , Hipogonadismo/patología , Masculino , Mutación , Netrina-1/metabolismo , Neuronas/metabolismo , Neuronas/patología , Linaje , Secuenciación del Exoma

RESUMEN

BACKGROUND: Hypogonadotropic hypogonadism (HH) in men results in insufficient testicular function and deficiencies in testosterone and spermatogenesis. Combinations of human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (recFSH) have been successful in the treatment of HH. Corifollitropin alfa is a long-acting FSH-analog with demonstrated action in women seeking infertility care. The aim of this study was to investigate the efficacy and safety of corifollitropin alfa combined with hCG to increase testicular volume and induce spermatogenesis in men with HH. METHODS: This was a Phase III, multi-center, open-label, single-arm trial of corifollitropin alfa in azoospermic men aged 18 to 50 years with HH. After 16 weeks of pretreatment of 23 subjects with hCG alone, 18 subjects with normalized testosterone (T) levels who remained azoospermic entered the 52-week combined treatment phase with hCG twice-weekly and 150 µg corifollitropin alfa every other week. The increase in testicular volume (primary efficacy endpoint) and induction of spermatogenesis resulting in a sperm count ≥1 × 106/mL (key secondary efficacy endpoint) during 52 weeks of combined treatment were assessed. Safety was evaluated by the presence of anti-corifollitropin alfa antibodies and the occurrence of adverse events (AEs). RESULTS: Mean (±SD) testicular volume increased from 8.6 (±6.09) mL to 17.8 (±8.93) mL (geometric mean fold increase, 2.30 [95% CI: 2.03, 2.62]); 14 (77.8%) subjects reached a sperm count ≥1 × 106/mL. No subject developed confirmed anti-corifollitropin alfa antibodies during the trial. Treatment was generally well tolerated. CONCLUSIONS: Corifollitropin alfa 150 µg administrated every other week combined with twice-weekly hCG for 52 weeks increased testicular volume significantly, and induced spermatogenesis in >75% of men with HH who had remained azoospermic after hCG treatment alone. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01709331 .

Asunto(s)

Azoospermia/tratamiento farmacológico , Gonadotropina Coriónica/uso terapéutico , Hormona Folículo Estimulante Humana/uso terapéutico , Hipogonadismo/tratamiento farmacológico , Adulto , Azoospermia/complicaciones , Esquema de Medicación , Humanos , Hipogonadismo/complicaciones , Masculino , Persona de Mediana Edad , Tamaño de los Órganos/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Testículo/efectos de los fármacos , Testículo/patología , Resultado del Tratamiento , Adulto Joven

RESUMEN

PURPOSE: The syndrome of inappropriate antidiuresis is often undertreated with most patients discharged with persistent hyponatraemia. This study tested the hypothesis that an endocrine input is superior to routine care in correcting hyponatraemia and can improve patient outcomes. METHODS: This single-centre prospective-controlled intervention study included inpatients admitted at a UK teaching hospital, with serum sodium ≤ 127 mmol/l, due to syndrome of inappropriate antidiuresis over a 6-month period. The prospective intervention group (18 subjects with mean serum sodium 120.7 mmol/l) received prompt endocrine input, while the historical control group (23 patients with mean serum sodium 124.1 mmol/l) received routine care. The time needed for serum sodium increase ≥ 5 mmol/l was the primary endpoint. RESULTS: The intervention group achieved serum sodium rise by ≥5 mmol/l in 3.5 vs. 7.1 days in the control group (P = 0.005). In the intervention group, the mean total serum sodium increase was 12 mmol/l with only 5.8 % of patients discharged with serum sodium < 130 vs. 6.3 mmol/l increase (P < 0.001) and 42.1 % of the subjects discharged with serum sodium < 130 mmol/l in the control group (P = 0.012). The mean length of hospital stay in the intervention group (10.9 days) was significantly shorter than in the control group (14.5 days; P = 0.004).The inpatient mortality rate was 5.5 % in intervention arm vs. 17.4 % in control arm, but this difference was not statistically significant. CONCLUSIONS: Since the endocrine input improved time for correction of hyponatraemia and shortened length of hospitalisation, widespread provision of endocrine input should be considered.

Asunto(s)

Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Benzazepinas/uso terapéutico , Demeclociclina/uso terapéutico , Síndrome de Secreción Inadecuada de ADH/terapia , Solución Salina Hipertónica/uso terapéutico , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Síndrome de Secreción Inadecuada de ADH/sangre , Síndrome de Secreción Inadecuada de ADH/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , Sodio/sangre , Tolvaptán , Resultado del Tratamiento

RESUMEN

The hypothalamic GnRH neurons are a small group of cells that regulate the reproductive axis. These neurons are specified within the olfactory placode, delaminate from this structure, and then migrate to enter the forebrain before populating the hypothalamus. We have used microarray technology to analyze the transcriptome of the olfactory placode at a number of key time points for GnRH ontogeny using the chick embryo. This resulted in the identification of a large number of genes whose expression levels change significantly over this period. This repertoire includes those genes that are known to be important for GnRH neuronal development as well as many novel genes, such as the serotonin receptor 1A, HTR1A. We find that HTR1A is expressed in the region of the olfactory placode that generates GnRH neurons. We further show that when this receptor is inactivated using a selective HTR1A antagonist as well as a gene knockdown approach using RNAi, this resulted in delayed migration causing the GnRH neurons to stall just outside the forebrain. These findings implicate HTR1A as being important for GnRH neuronal migration from the olfactory placode to the forebrain. Our study thus extends the repertoire of genes involved in GnRH neuron biology and thus identifies new candidate genes that can be screened for in patients who do not show mutations in any of the previously identified hypogonadotrophic hypogonadism/Kallmann syndrome genes.

Asunto(s)

Movimiento Celular/fisiología , Hormona Liberadora de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Neuronas/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Animales , Movimiento Celular/genética , Embrión de Pollo , Regulación del Desarrollo de la Expresión Génica , Hipotálamo/citología , Neurogénesis/genética , Neurogénesis/fisiología , Neuronas/citología , Interferencia de ARN , Receptor de Serotonina 5-HT1A/genética

Asunto(s)

Andrógenos/administración & dosificación , Hipogonadismo/sangre , Hipogonadismo/tratamiento farmacológico , Testosterona/análogos & derivados , Testosterona/sangre , Adulto , Humanos , Hipogonadismo/congénito , Inyecciones Intramusculares , Masculino , Testosterona/administración & dosificación

RESUMEN

OBJECTIVE: European guidelines do not recommend tolvaptan for treatment of syndrome of inappropriate antidiuretic hormone secretion (SIADH), principally owing to concerns about risk of overly rapid correction of hyponatraemia. This study evaluated the real-life effectiveness and safety of tolvaptan. DESIGN: Consecutive case series. PATIENTS: Inpatients treated with tolvaptan for SIADH in 2 UK hospitals over a 3-year period. MEASUREMENTS: The primary outcome measures were serum sodium (sNa) correction at 24 and 48 h after tolvaptan therapy. RESULTS: This case series included 61 patients aged 74·4 ± 15·3 years with (mean ± SD) sNa 119·9 ± 5·5 mmol/l. The mean sNa increase 24 h after tolvaptan initiation was 9 ± 3·9 mmol/l. Excessive correction of hyponatraemia was observed in 23% of patients with all these patients having baseline sNa <125 mmol/l, but no cases of osmotic demyelination syndrome were recorded. At the end of tolvaptan therapy, sNa increase was 13·5 ± 5·9 mmol/l with 96·7% of patients having sNa increase ≥5 mmol/l in 48 h. There was a negative significant correlation (P = 0·012) between baseline sNa and 24-h change; for every 1 mmol/l reduction in baseline value, sNa increased by an additional 0·23 mmol/l (95% CI 0·05-0·41). CONCLUSIONS: Tolvaptan is effective in correcting hyponatraemia. Without rigorous electrolyte monitoring, tolvaptan carries a significant risk of overly rapid sodium correction, especially in patients with starting sNa <125 mmol/l. Tolvaptan should be used with great caution under close electrolyte monitoring.

Asunto(s)

Benzazepinas/uso terapéutico , Hiponatremia/tratamiento farmacológico , Síndrome de Secreción Inadecuada de ADH/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Humanos , Hiponatremia/patología , Pacientes Internos/estadística & datos numéricos , Tiempo de Internación/estadística & datos numéricos , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Sodio/sangre , Factores de Tiempo , Tolvaptán , Resultado del Tratamiento

RESUMEN

BACKGROUND: Adrenal insufficiency is often present in cirrhosis. We hypothesize that a prolonged adrenocorticotropic hormone (ACTH) stimulus can restore cellular capacity of adrenal glands to secrete cortisol. Aim of our study was to assess adrenal responsiveness to prolonged ACTH stimulation in cirrhotics. METHODS: Prospective observational study in 121 consecutively admitted cirrhotic patients undergoing a low dose short synacthen test and plasma ACTH measurement using a chemiluminescence immunoassay. Long synacthen test was performed if the low dose was abnormal. RESULTS: 46 patients had abnormal low dose short test (38%), and 29 underwent the long test: 41% showed normal response (Group 1), 55% showed delayed response (Group 2) and 1 had abnormal response (4%). Baseline ACTH levels did not significantly differ between the two groups. Median basal cortisol was higher in Group 1 (296 vs. 198 nmol/L; p=0.02). Using ROC curve basal cortisol <254 nmol/L was associated with a delayed long synacthen test response (AUC 0.78, p=0.001) with good accuracy (sensitivity 67%, specificity 81%). CONCLUSION: A delayed cortisol response after a prolonged ACTH stimulation is found in over fifty percent of cirrhotics with abnormal low dose short synacthen test, confirming that the mechanism of hypoadrenalism in these patients could be related both to adrenal cellular dysfunction and hypothalamus-pituitary adrenal axis impairment.

Asunto(s)

Insuficiencia Suprarrenal/sangre , Cosintropina/sangre , Hidrocortisona/sangre , Sistema Hipotálamo-Hipofisario/fisiopatología , Cirrosis Hepática/fisiopatología , Sistema Hipófiso-Suprarrenal/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Curva ROC , Sensibilidad y Especificidad

RESUMEN

KAL1 is implicated in 5% of Kallmann syndrome cases, a disorder which genotypically overlaps with septo-optic dysplasia (SOD). To date, a reporter-based assay to assess the functional consequences of KAL1 mutations is lacking. We aimed to develop a luciferase assay for novel application to functional assessment of rare KAL1 mutations detected in a screen of 422 patients with SOD. Quantitative analysis was performed using L6-myoblasts stably expressing FGFR1, transfected with a luciferase-reporter vector containing elements of the FGF-responsive osteocalcin promoter. The two variants assayed [p.K185N, p.P291T], were detected in three females with SOD (presenting with optic nerve hypoplasia, midline and pituitary defects). Our novel assay revealed significant decreases in transcriptional activity [p.K185N: 21% (p < 0.01); p.P291T: 40% (p < 0.001)]. Our luciferase-reporter assay, developed for assessment of KAL1 mutations, determined that two variants in females with hypopituitarism/SOD are loss-of-function; demonstrating that this assay is suitable for quantitative assessment of mutations in this gene.

Asunto(s)

Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Luciferasas/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Polimorfismo de Nucleótido Simple , Displasia Septo-Óptica/genética , Animales , Células COS , Chlorocebus aethiops , Femenino , Humanos , Técnicas In Vitro , Modelos Moleculares , Linaje , Hipófisis/metabolismo , Displasia Septo-Óptica/metabolismo , Displasia Septo-Óptica/patología

RESUMEN

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ∼50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRH-synthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ∼10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

Asunto(s)

Hipogonadismo/patología , Hipogonadismo/terapia , Consenso , Europa (Continente) , Femenino , Hormona Liberadora de Gonadotropina/genética , Hormona Liberadora de Gonadotropina/metabolismo , Humanos , Hipogonadismo/diagnóstico , Hipogonadismo/genética , Masculino , Maduración Sexual

RESUMEN

BACKGROUND: Hyponatraemia is a very common medical condition that is associated with multiple poor clinical outcomes and is often managed suboptimally because of inadequate assessment and investigation. Previously published guidelines for its management are often complex and impractical to follow in a hospital environment, where patients may present to divergent specialists, as well as to generalists. DESIGN: A group of senior, experienced UK clinicians, met to develop a practical algorithm for the assessment and management of hyponatraemia in a hospital setting. The latest evidence was discussed and reviewed in the light of current clinical practicalities to ensure an up-to-date perspective. An algorithm was largely developed following consensus opinion, followed up with subsequent additions and amendments that were agreed by all authors during several rounds of review. RESULTS: We present a practical algorithm which includes a breakdown of the best methods to evaluate volume status, simple assessments for the diagnosis of the various causes and a straightforward approach to treatment to minimise complexity and maximise patient safety. CONCLUSION: The algorithm we have developed reflects the best available evidence and extensive clinical experience and provides practical, useable guidance to improve patient care.

Asunto(s)

Algoritmos , Antibacterianos/uso terapéutico , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Benzazepinas/uso terapéutico , Demeclociclina/uso terapéutico , Fluidoterapia , Hiponatremia/terapia , Síndrome de Secreción Inadecuada de ADH/terapia , Hospitalización , Humanos , Hiponatremia/diagnóstico , Síndrome de Secreción Inadecuada de ADH/diagnóstico , Guías de Práctica Clínica como Asunto , Tolvaptán , Desequilibrio Hidroelectrolítico/diagnóstico , Desequilibrio Hidroelectrolítico/terapia

RESUMEN

This study assessed the effect of endocrine input on the investigation of hyponatraemia and examined the prevalence of endocrine causes of hyponatraemia. This single-centre, retrospective study included 139 inpatients (median age, 74 years) with serum sodium (Na) levels ≤128 mmol/l during hospitalisation at a UK teaching hospital over a three-month period. In total, 61.9% of patients underwent assessment of volume status and 28.8% had paired serum and urine osmolality, and Na measured. In addition, 14.4% of patients received endocrine input; 80% of these patients underwent full work-up of hyponatraemia compared with 5% of patients not referred to endocrine services (p < 0.001; relative risk, 15.86; 95% confidence interval, 7.17-31.06). The prevalence of adrenal insufficiency was 0.7%, but basal serum cortisol levels were not measured in around two-thirds of patients. Despite 26.7% of patients having abnormal thyroid function tests, no patient was diagnosed with severe hypothyroidism. More widespread provision of expert input should be considered.

Asunto(s)

Hospitalización/estadística & datos numéricos , Hiponatremia , Sodio/sangre , Anciano , Anciano de 80 o más Años , Femenino , Glucocorticoides/sangre , Humanos , Hiponatremia/clasificación , Hiponatremia/diagnóstico , Hiponatremia/epidemiología , Hiponatremia/etiología , Síndrome de Secreción Inadecuada de ADH/complicaciones , Síndrome de Secreción Inadecuada de ADH/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Pruebas de Función de la Tiroides , Tiroxina/sangre