RESUMO
Objective: This study aimed to investigate the triglyceride-glucose (TyG) index, which is a simple surrogate marker of insulin resistance that is associated with various cardiometabolic diseases, in patients with Klinefelter syndrome (KS). Subjects and methods: A total of 30 patients with KS (mean age: 21.53 ± 1.66 years) and 32 healthy controls (mean age: 22.07 ± 1.01 years) were included in the study. The clinical and laboratory parameters, TyG index, asymmetric dimethylarginine (ADMA) level, homeostatic model assessment of insulin resistance (HOMA-IR) score, and high-sensitivity C-reactive protein level were measured in patients with KS and healthy subjects. Results: Patients with KS had higher HOMA-IR score (p = 0.043), ADMA levels (p < 0.001), and TyG index (p = 0.031) and lower high-density lipoprotein cholesterol levels (p < 0.001) than healthy subjects. TyG index was positively correlated with plasma ADMA (r = 0.48, p < 0.001) and HOMA-IR (r = 0.36, p = 0.011). Multivariate analyses showed that total testosterone level (ß = -0.44, p = 0.001) and TyG index (ß = 0.29, p = 0.045) were independent determinants of plasma ADMA levels. Conclusion: Patients with KS had higher TyG indices than healthy subjects. Moreover, TyG index was independently associated with endothelial dysfunction in patients. TyG index may be a practical and useful measure to show the increased endothelial dysfunction in patients with KS.
Assuntos
Resistência à Insulina , Síndrome de Klinefelter , Estudos Transversais , Humanos , Masculino , Adulto Jovem , Adulto , Síndrome de Klinefelter/sangue , Síndrome de Klinefelter/complicações , Glicemia/análise , Triglicerídeos/sangue , Células Endoteliais/patologia , Testosterona/sangueRESUMO
The prokineticin-2 (PROK2) is a small peptide belonging to the prokineticin family. In humans and rodents this chemokine is primarily involved in the control of central and peripheral reproductive processes. Klinefelter's syndrome (KS) is the first cause of male genetic infertility, due to an extra X chromosome, which may occur with a classical karyotype (47, XXY) or mosaic forms (46, XY/47, XXY). In affected subjects, pubertal maturation usually begins at an adequate chronological age, but when development is almost complete, they display a primary gonadal failure, with early spermatogenesis damage, and later onset of testosterone insufficiency. Thus, the main aim of the present study was to investigate the serum levels of PROK2 in prepubertal and adult KS patients, comparing them with healthy subjects. We showed for the first time the presence of PROK2 in the children serum but with significant changes in KS individuals. Indeed, compared with healthy subjects characterized by PROK2 serum elevation during the growth, KS individuals showed constant serum levels during the sexual maturation phase (higher during the prepubertal phase but lower during the adult age). In conclusion, these data indicate that in KS individuals PROK2 may be considered a biomarker for investigating the SK infertility process.
Assuntos
Hormônios Gastrointestinais/sangue , Infertilidade Masculina/diagnóstico , Síndrome de Klinefelter/sangue , Neuropeptídeos/sangue , Adolescente , Adulto , Biomarcadores/sangue , Criança , Humanos , Infertilidade Masculina/etiologia , Cariótipo , Síndrome de Klinefelter/complicações , Masculino , Pessoa de Meia-Idade , Maturidade Sexual , Espermatogênese , Testosterona/deficiência , Adulto JovemRESUMO
Current literature regarding systemic autoimmune diseases in X-chromosome aneuploidies is scarce and limited to case reports. Our aim was to evaluate the frequency of anti-nuclear (ANAs), extractable nuclear (ENA), anti-double-stranded DNA (dsDNAs), anti-smooth muscle (ASMAs) and anti-mitochondrial (AMAs) antibodies in a large cohort of adults with Klinefelter's syndrome (KS, 47,XXY) and rare higher-grade sex chromosome aneuploidies (HGAs) for the first time. Sera from 138 X-chromosome aneuploid patients [124 adult patients with 47,XXY KS and 14 patients with HGA (six children, eight adults)] and 50 age-matched 46,XY controls were recruited from the Sapienza University of Rome (2007-17) and tested for ANAs, ENAs, anti-dsDNAs, ASMAs and AMAs. Non-organ-specific immunoreactivity was found to be significantly higher in patients with 47,XXY KS (14%) than in the controls (2%, p = 0.002). Among all the antibodies investigated, only ANAs were observed significantly more frequently in patients with 47,XXY KS (12.1%) than in the controls (2%, p = 0.004). No anti-dsDNA immunoreactivity was found. Stratifying by testosterone replacement therapy (TRT), non-organ-specific autoantibody frequencies were higher in TRT-naive (p = 0.01) and TRT-treated groups than in controls. No patients with HGA were found positive for the various autoantibodies. Non-organ-specific autoantibodies were significantly present in 47,XXY adult patients. Conversely, HGAs did not appear to be target of non-organ-specific immunoreactivity, suggesting that KS and HGAs should be considered as two distinct conditions. The classification and diagnosis of systemic autoimmune diseases is frequently difficult. To support a correct clinical evaluation of KS disease and to prevent eventual secondary irreversible immune-mediated damages, we highlight the importance of screening for non-organ-specific autoimmunity in Klinefelter's syndrome.
Assuntos
Anticorpos Antinucleares/sangue , Autoanticorpos/sangue , Doenças Autoimunes/genética , Síndrome de Klinefelter/sangue , Mitocôndrias/imunologia , Músculo Liso/imunologia , Adolescente , Adulto , Aneuploidia , Anticorpos Antinucleares/imunologia , Antígenos Nucleares/sangue , Antígenos Nucleares/imunologia , Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Criança , Pré-Escolar , Humanos , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/imunologia , Masculino , Pessoa de Meia-Idade , Aberrações dos Cromossomos Sexuais , Adulto JovemRESUMO
CONTEXT: Klinefelter syndrome (KS) is a condition at increased risk of thrombosis compared to 46,XY men. OBJECTIVE: This work aimed to investigate the coagulation balance of KS patients by thrombin generation assay (TGA) and thromboelastometry. METHODS: An observational, cross-sectional study was conducted at 3 tertiary endocrinological centers in Milan, Italy. Fifty-eight KS patients and 58 age-matched healthy controls were included. Anticoagulant or antiplatelet therapy and known coagulation disorders were exclusion criteria. TGA was performed in platelet-poor plasma (PPP) and platelet-rich plasma (PRP). Whole-blood thromboelastometry and activities of coagulation factors were assessed. Endogenous thrombin potential (ETP), the area under the thrombin generation curve, assessed with and without thrombomodulin (ETP-TM+ and ETP-TM-), and their ratio (ETP ratio), were considered as indexes of procoagulant imbalance. RESULTS: Patients with KS displayed higher PPP-ETP-TM+ (mean 1528 vs 0.1315 nMâ ×â min; Pâ <â .001), PPP-ETP ratio (0.78 vs 0.0.70; Pâ <â .001), factor (F)VIII (135% vs 0.107%; Pâ =â .001), fibrinogen (283 vs 0.241 mg/dL; Pâ <â .001), and FVIII/protein C ratio (1.21 vs 0.1.06; Pâ <â .05) compared to controls. Protein C was comparable in the 2 groups. Similar results were observed in PRP. The ETP ratio was positively associated with FVIII (ρâ =â 0.538, Pâ <â .001) in KS. Thromboelastometry parameters confirmed evidence of hypercoagulability in KS. CONCLUSION: Patients with KS display a procoagulant imbalance expressed by increased thrombin generation both in PPP and PRP, which is at least in part explained by increased FVIII levels. The procoagulant imbalance, which was confirmed by thromboelastometry, may be responsible for the thrombotic events observed in these patients. Further investigation on the benefit/risk ratio of antithrombotic prophylaxis is warranted.
Assuntos
Fatores de Coagulação Sanguínea/metabolismo , Síndrome de Klinefelter/sangue , Trombina/metabolismo , Adolescente , Adulto , Idoso , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Tromboelastografia , Adulto JovemRESUMO
OBJECTIVE: To investigate whether preoperative human chorionic gonadotropin (hCG) treatment can help predict the outcomes of microdissection testicular sperm extraction (micro-TESE) and affect fertility outcomes in non-mosaic Klinefelter syndrome (KS) patients. DESIGN: Retrospective cohort study. SETTING: University-affiliated fertility center. PATIENT(S): A total of 184 non-mosaic KS patients who underwent micro-TESE with or without preoperative hCG treatment from January 2016 to July 2019. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Sperm retrieval rate (SRR) with and without hCG treatment, logistic models analysis. RESULT(S): Eighty KS patients (43.5%) had successful sperm retrievals after micro-TESE. There was no statistically significant difference in the SRR between the group who received hCG treatment and the group that did not (44.0% vs. 43.3%). Logistic regression analyses demonstrated that the hCG treatment had no statistically significant effect on successful sperm retrieval. However, higher preoperative testosterone (T) levels seemed to be associated with a higher probability of successful sperm retrieval (multivariate adjusted odds ratio 1.09; 95% confidence interval [CI], 1.04-1.16). The prediction model for SRR on KS patients had an area under the curve of 67.3% (95% CI, 59.3-75.3%). In the hCG treatment group, the data indicated that the three parameters of testicular volume, pretreatment T level, and alterations of T were associated with the probability of successful sperm retrieval. Moreover, hCG therapy did not affect intracytoplasmic sperm injection (ICSI) outcomes. No differences in the pregnancy rate or live-birth rate were observed between the two groups. CONCLUSION(S): Therapy with hCG does not affect SRR or ICSI outcomes of non-mosaic KS patients. However, preoperative T levels, whether treated with hCG or not, can predict the chance of sperm retrieval with micro-TESE.
Assuntos
Gonadotropina Coriônica/administração & dosagem , Síndrome de Klinefelter/terapia , Microdissecção/métodos , Injeções de Esperma Intracitoplásmicas/métodos , Recuperação Espermática , Testículo/cirurgia , Adulto , Gonadotropina Coriônica/sangue , Estudos de Coortes , Feminino , Humanos , Síndrome de Klinefelter/sangue , Masculino , Indução da Ovulação/métodos , Estudos Retrospectivos , Testículo/citologia , Resultado do TratamentoRESUMO
Hypergonadotropic hypogonadism is a major feature of Klinefelter syndrome (KS), assumed to be caused by testicular hormone resistance. It was previously shown that intratesticular testosterone levels in vivo and Leydig cell function in vitro seem to be normal indicating other functional constraints. We hypothesized that impaired testicular vascularization/blood flow could be a co-factor to the observed hypergonadotropic hypogonadism. We evaluated the testicular vascular system by measuring blood vessel sizes during postnatal development and testis blood flow in adult 41,XXY* mice. Proportional distribution and size of blood vessels were analyzed during testicular development (1, 3, 5, 7, 10, 21 dpp, 15 wpp). While ratios of the vessel/testis area were different at 15 wpp only, a lower number of smaller and mid-sized blood vessels were detected in adult KS mice. For testicular blood flow determination we applied contrast enhanced ultrasound. Floating and reperfusion time for testicular blood flow was increased in 41,XXY* mice (floating: XY* 28.8 ± 1.69 s vs XXY* 44.6 ± 5.6 s, p = 0.0192; reperfusion XY* 19.7 ± 2.8 s vs XXY*: 29.9 ± 6.2 s, p = 0.0134), indicating a diminished blood supply. Our data strengthen the concept that an impaired vascularization either in conjunction or as a result of altered KS testicular architecture contributes to hormone resistance.
Assuntos
Síndrome de Klinefelter/fisiopatologia , Testículo/irrigação sanguínea , Testículo/crescimento & desenvolvimento , Animais , Circulação Sanguínea , Vasos Sanguíneos/diagnóstico por imagem , Modelos Animais de Doenças , Hipogonadismo/fisiopatologia , Síndrome de Klinefelter/sangue , Células Intersticiais do Testículo , Masculino , Camundongos , Camundongos Transgênicos , Espermatogênese/genética , Testosterona/sangue , Ultrassonografia/métodosRESUMO
PURPOSE: Low testosterone (T) in Klinefelter's syndrome (KS) can contribute to typical features of the syndrome such as reduced bone mineral density, obesity, metabolic disturbances and increased cardiovascular risk. The aim of the present study is to review and meta-analyze all available information regarding possible differences in metabolic and bone homeostasis profile between T treated (TRT) or untreated KS and age-matched controls. METHODS: We conducted a random effect meta-analysis considering all the available data from observational or randomized controlled studies comparing TRT-treated and untreated KS and age-matched controls. Data were derived from an extensive MEDLINE, Embase, and Cochrane search. RESULTS: Out of 799 retrieved articles, 21 observational and 22 interventional studies were included in the study. Retrieved trials included 1144 KS subjects and 1284 healthy controls. Not-treated KS patients showed worse metabolic profiles (including higher fasting glycemia and HOMA index as well as reduced HDL-cholesterol and higher LDL-cholesterol) and body composition (higher body mass index and waist circumference) and reduced bone mineral density (BMD) when compared to age-matched controls. TRT in hypogonadal KS subjects was able to improve body composition and BMD at spinal levels but it was ineffective in ameliorating lipid and glycemic profile. Accordingly, TRT-treated KS subjects still present worse metabolic parameters when compared to age-matched controls. CONCLUSION: TRT outcomes observed in KS regarding BMD, body composition and glyco-metabolic control, are similar to those observed in male with hypogonadism not related to KS. Moreover, body composition and BMD are better in treated than untreated hypogonadal KS. Larger and longer randomized placebo-controlled trials are advisable to better confirm the present data, mainly derived from observational studies.
Assuntos
Síndrome de Klinefelter/tratamento farmacológico , Testosterona/uso terapêutico , Adulto , Composição Corporal/efeitos dos fármacos , Índice de Massa Corporal , Densidade Óssea/efeitos dos fármacos , Humanos , Hipogonadismo/sangue , Hipogonadismo/tratamento farmacológico , Hipogonadismo/epidemiologia , Hipogonadismo/etiologia , Síndrome de Klinefelter/sangue , Síndrome de Klinefelter/complicações , Síndrome de Klinefelter/epidemiologia , Masculino , Pessoa de Meia-Idade , Testosterona/sangueRESUMO
Klinefelter syndrome (KS) occurs in 1:600 males and is associated with high morbidity and mortality due to diabetes and cardiovascular disease. Up to 50% of men with KS have metabolic syndrome, a cluster of features conferring increased risk for diabetes and cardiovascular disease. These cardiometabolic (CM) risk features have not been studied in adolescents with KS. The objective of this cohort study was to compare CM risk features in adolescents with KS to controls matched for sex, age, and BMI z score. Fifty males with KS (age 10-17 years) were well-matched to male controls (n = 50) for age (14.0 ± 1.7 vs. 14.0 ± 1.5 years) and BMI z score (0.3 ± 1.3 vs. 0.4 ± 1.2). Three CM risk features were present in 30% of adolescents with KS compared to 12% of controls (RR 2.5, 95% CI 1.1-5.9, p = .048). The KS group had significantly lower HDL cholesterol (p = .006), higher triglycerides (p < .001), and greater waist circumference percentile (p < .001). Despite a normal BMI, the prevalence of CM risk features was very high in adolescents with KS, particularly for central adiposity and dyslipidemia. The pathophysiology of this metabolic profile independent of obesity needs further investigation to facilitate prevention of the high morbidity of cardiovascular disease and diabetes in this population. ClinicalTrials.gov identifiers: NCT01585831 and NCT02723305.
Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus/epidemiologia , Síndrome de Klinefelter/epidemiologia , Obesidade/epidemiologia , Adolescente , Índice de Massa Corporal , Fatores de Risco Cardiometabólico , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/patologia , Estudos de Casos e Controles , Criança , Estudos de Coortes , Diabetes Mellitus/sangue , Diabetes Mellitus/patologia , Feminino , Humanos , Síndrome de Klinefelter/sangue , Síndrome de Klinefelter/patologia , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/patologia , Obesidade/sangue , Obesidade/patologia , Testosterona/sangue , Triglicerídeos/sangue , Circunferência da CinturaRESUMO
BACKGROUND: It has recently been suggested that the hypergonadotropic hypogonadism characterizing Klinefelter syndrome (KS) might not be due to a steroidogenic dysfunction per se, but mainly to an altered testosterone (T) secretion into the bloodstream. However, the Leydig cell functionality remains incompletely studied in KS, and new markers should be considered. Previous data indicated that chronic hCG stimulation influences the production of both insulin-like peptide 3 (INSL3) and 25-hydroxy-vitamin D (25-VD) in eugonadal men. AIM OF THE STUDY: To evaluate INSL3 and 25-VD serum levels, as markers of Leydig cell functionality, in association with sex steroids, after an acute hCG test in a group of KS patients and healthy volunteers. METHODS: A retrospective analysis of a prospective case-control clinical trial was carried out. KS patients (n = 11) and age-matched healthy controls (n = 11) provided a basal blood sample (V0) immediately followed by a single intramuscular injection of hCG 5000 IU. Blood samples were taken in the following five days (V1-V5). RESULTS: At baseline, INSL3 was lower in KS patients compared with controls (P = .007). When adjusted for INSL3 levels, the production of steroids was similar between KS patients and controls. 25-VD was in the insufficient range both in KS patients and in controls and was not different (P = .064). Acute hCG stimulation increased neither INSL3 nor 25-VD in both KS patients and controls. In controls, an inverse correlation was detected between INSL3 levels and body mass index (P = .020) and waist circumference (P = .020). CONCLUSIONS: INSL3 secretion is independent from steroidogenesis, and its production is mostly not influenced by acute hCG stimulation both in KS men and in controls. INSL3 serum levels should be considered as a marker of Leydig cell differentiation and numbers rather than steroidogenesis. 25-VD serum levels are also not increased by a single acute hCG administration, which was not able to restore the normal concentrations of 25-VD.
Assuntos
Calcifediol/sangue , Gonadotropina Coriônica/metabolismo , Insulina/sangue , Síndrome de Klinefelter/sangue , Células Intersticiais do Testículo/metabolismo , Gonadotropina Coriônica/sangue , Humanos , Células Intersticiais do Testículo/citologia , Masculino , Proteínas , Estudos Retrospectivos , Testosterona/sangueRESUMO
Klinefelter syndrome (KS; 47,XXY) is the most common sex chromosomal anomaly and causes a multitude of symptoms. Often the most noticeable symptom is infertility caused by azoospermia with testicular histology showing hyalinization of tubules, germ cells loss, and Leydig cell hyperplasia. The germ cell loss begins early in life leading to partial hyalinization of the testis at puberty, but the mechanistic drivers behind this remain poorly understood. In this systematic review, we summarize the current knowledge on developmental changes in the cellularity of KS gonads supplemented by a comparative analysis of the fetal and adult gonadal transcriptome, and blood transcriptome and methylome of men with KS. We identified a high fraction of upregulated genes that escape X-chromosome inactivation, thus supporting previous hypotheses that these are the main drivers of the testicular phenotype in KS. Enrichment analysis showed overrepresentation of genes from the X- and Y-chromosome and testicular transcription factors. Furthermore, by re-evaluation of recent single cell RNA-sequencing data originating from adult KS testis, we found novel evidence that the Sertoli cell is the most affected cell type. Our results are consistent with disturbed cross-talk between somatic and germ cells in the KS testis, and with X-escapee genes acting as mediators.
Assuntos
Metilação de DNA/genética , Infertilidade Masculina/genética , Síndrome de Klinefelter/sangue , Transcriptoma/genética , Adulto , Cromossomos Humanos X/genética , Cromossomos Humanos Y/genética , Gônadas/crescimento & desenvolvimento , Gônadas/metabolismo , Humanos , Infertilidade Masculina/patologia , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/patologia , Masculino , Células de Sertoli/metabolismo , Células de Sertoli/patologia , Testículo/metabolismo , Testículo/patologiaRESUMO
An induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells of a 3-day-old boy with 47,XXY and ornithine transcarbamylase deficiency carrying hemizygote mutation (c.663+2T>G (sliping)) in OTC. The iPSCs had original 47,XXY, and mutation in OTC, expressing pluripotency markers and bearing differentiation potential in vitro.
Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/patologia , Doença da Deficiência de Ornitina Carbomoiltransferase/genética , Doença da Deficiência de Ornitina Carbomoiltransferase/patologia , Hemizigoto , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Lactente , Síndrome de Klinefelter/sangue , Leucócitos Mononucleares/patologia , Masculino , Mutação , Doença da Deficiência de Ornitina Carbomoiltransferase/sangueRESUMO
Klinefelter syndrome (KS) is frequently complicated by diabetes. However, it is severely underdiagnosed due to a lack of reliable screening methods. We diagnosed two patients with KS at the Center for Diabetes and Endocrinology, Tazuke Kofukai Medical Research Institute Kitano Hospital, Osaka, Japan. By comparing the patients with 39 non-KS patients with diabetes, we propose a screening tool for KS in patients with diabetes.
Assuntos
Complicações do Diabetes , Síndrome de Klinefelter/complicações , Síndrome de Klinefelter/diagnóstico , Programas de Rastreamento/métodos , Adulto , Estatura , Complicações do Diabetes/sangue , Hormônio Foliculoestimulante/sangue , Humanos , Síndrome de Klinefelter/sangue , Hormônio Luteinizante/sangue , Masculino , Testosterona/sangueRESUMO
BACKGROUND: The background for the increased occurrence of thrombosis seen in Klinefelter syndrome (KS) is unknown. The aim was to compare thrombin generation and coagulation inhibition between men with KS and controls, and to investigate whether coagulation in KS was associated with testosterone treatment (TT), and as such, measures of androgen action. METHODS: Untreated men with KS (U-KS) or testosterone treated men with KS (T-KS) were included. KS groups were matched by age and education to groups of control males with no history of TT. Blood samples were collected after overnight fasting. Low tissue factor (1pM) thrombin generation was expressed as lag time (min), time to peak (min), peak (nmol/L), and endogenous thrombin potential (nmol/Lâ¯×â¯min, ETP). Coagulation inhibitors, sex hormones, and haematocrit were measured. Matched groups were compared by Student's t-test or Wilcoxon rank sum test. Among KS, TT status as an outcome predictor was evaluated by linear regression. RESULTS: 18â¯U-KS and 27â¯T-KS with corresponding controls participated. Thrombin generation was not different comparing U-KS and T-KS with respective control groups. Among KS, ETP was lower in T-KS compared with U-KS and inversely associated with testosterone, LH-testosterone ratio and haematocrit. CONCLUSION: Neither U-KS nor T-KS expressed a pro-coagulant state compared with controls. Thrombin generation among KS was inversely associated with androgen action and lower in T-KS compared with U-KS. Whether TT is capable of lowering thrombotic risk among men with KS needs to be assessed prospectively.
Assuntos
Androgênios/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Síndrome de Klinefelter/tratamento farmacológico , Testosterona/uso terapêutico , Trombina/metabolismo , Adolescente , Adulto , Idoso , Androgênios/farmacologia , Estudos Transversais , Humanos , Síndrome de Klinefelter/sangue , Síndrome de Klinefelter/metabolismo , Masculino , Pessoa de Meia-Idade , Testosterona/farmacologia , Trombose/sangue , Trombose/etiologia , Trombose/metabolismo , Adulto JovemRESUMO
PURPOSE: The prevalence and the etiopathogenesis of thyroid dysfunctions in Klinefelter syndrome (KS) are still unclear. The primary aim of this study was to evaluate the pathogenetic role of hypogonadism in the thyroid disorders described in KS, with the scope to distinguish between patients with KS and hypogonadism due to other causes (Kallmann syndrome, idiopathic hypogonadotropic hypogonadism, iatrogenic hypogonadism and acquired hypogonadotropic hypogonadism after surgical removal of pituitary adenomas) called non-KS. Therefore, we evaluated thyroid function in KS and in non-KS hypogonadal patients. METHODS: This is a case-control multicentre study from KING group: Endocrinology clinics in university-affiliated medical centres. One hundred and seventy four KS, and sixty-two non-KS hypogonadal men were enrolled. The primary outcome was the prevalence of thyroid diseases in KS and in non-KS. Changes in hormonal parameters were evaluated. Exclusion criterion was secondary hypothyroidism. Analyses were performed using Student's t test. Mann-Whitney test and Chi-square test. RESULTS: FT4 was significantly lower in KS vs non-KS. KS and non-KS presented similar TSH and testosterone levels. Hashimoto's thyroiditis (HT) was diagnosed in 7% of KS. Five KS developed hypothyroidism. The ratio FT3/FT4 was similar in both groups. TSH index was 1.9 in KS and 2.3 in non-KS. Adjustment for differences in age, sample size and concomitant disease in multivariate models did not alter the results. CONCLUSIONS: We demonstrated in KS no etiopathogenic link to hypogonadism or change in the set point of thyrotrophic control in the altered FT4 production. The prevalence of HT in KS was similar to normal male population, showing absence of increased risk of HT associated with the XXY karyotype.
Assuntos
Síndrome de Klinefelter/fisiopatologia , Glândula Tireoide/fisiologia , Centros Médicos Acadêmicos , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Doença de Hashimoto/sangue , Doença de Hashimoto/fisiopatologia , Humanos , Hipogonadismo/sangue , Hipogonadismo/fisiopatologia , Itália , Síndrome de Klinefelter/sangue , Masculino , Pessoa de Meia-Idade , Doenças da Glândula Tireoide/sangue , Doenças da Glândula Tireoide/fisiopatologia , Testes de Função Tireóidea , Hormônios Tireóideos/sangue , Tireotropina/sangue , Adulto JovemRESUMO
OBJECTIVE: Klinefelter Syndrome (KS) is classically described as characterized by hyperestrogenism, although solid evidence is lacking. This study aims to test the hypothesis that men with KS have higher serum estradiol than normal controls. DESIGN: Meta-analysis of all studies extracted by MEDLINE from 1942 to 31 January 2018. All studies reporting serum estradiol measurement were considered, among them only case-control studies were included in the meta-analysis. METHODS: Meta-analysis was conducted according to the PRISMA statement using RevMan. RESULTS: Out of 4120 articles, 23 case-control studies, 14 case series, and 19 case reports reported data on serum estradiol. A total of 707 KS and 1019 controls were included in the meta-analysis. Serum estradiol was slightly, but significantly higher in KS than controls (mean difference 4.25 pg/mL; CI: 0.41, 8.10 pg/mL; p = 0.030). This difference was lost considering only studies using estradiol assays with good accuracy (5.48 pg/mL, CI: -2.11, 13.07 pg/mL; p = 0.160). Serum testosterone and estradiol/testosterone ratio were significantly lower and higher in KS than controls, respectively. Data from KS case series and case reports confirmed that serum estradiol is within the normal ranges. CONCLUSIONS: Serum estradiol is not increased in KS although slightly higher than controls. However, the meta-analysis that included only studies using a serum estradiol assay with good accuracy showed no difference in serum estradiol between KS and controls. The traditional belief that KS is associated with elevated serum estradiol should be reconsidered. This meta-analysis shows that men with KS have relative hyperestrogenism (increased estradiol/testosterone ratio) compared to controls.
Assuntos
Estradiol/sangue , Síndrome de Klinefelter/sangue , Humanos , Masculino , Testosterona/sangueRESUMO
PURPOSE OF REVIEW: Klinefelter syndrome is the most common sex chromosome abnormality in men. Hypogonadism and testicular degeneration are almost universal. Truncal adiposity, metabolic syndrome and low bone mass occur frequently. This review summarizes the most recent advances in the pathogenesis and management of the endocrine abnormalities in Klinefelter syndrome. It is expected that optimal endocrine management will improve outcomes and quality of life in Klinefelter syndrome. RECENT FINDINGS: In Klinefelter syndrome, testosterone replacement is routinely prescribed despite lack of evidence on the optimal dose and time for initiation of therapy. Cross-sectional studies have linked hypogonadism to the development of metabolic abnormalities and low bone mass. Testosterone therapy, however, is not consistently associated with improved metabolic and bone outcomes. Increased truncal adiposity and high rates of metabolic syndrome are present in prepubertal children. A randomized trial of oxandrolone in prepubertal boys showed improvement in visual-motor function, socialization and cardiometabolic health. Testicular sperm extraction (TESE) has success rates similar to other causes of nonobstructive azoospermia when performed between 16 and 35 years of age. SUMMARY: Endocrine care in Klinefelter syndrome should start in childhood and include evaluation of metabolic risk factors and bone health. Further research to guide evidence-based endocrine care is very much needed.
Assuntos
Sistema Endócrino/fisiologia , Hormônios/sangue , Síndrome de Klinefelter/sangue , Síndrome de Klinefelter/fisiopatologia , Adolescente , Adulto , Criança , Estudos Transversais , Hormônios/análise , Humanos , Hipogonadismo/sangue , Hipogonadismo/diagnóstico , Hipogonadismo/etiologia , Hipogonadismo/terapia , Síndrome de Klinefelter/diagnóstico , Síndrome de Klinefelter/terapia , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/etiologia , Síndrome Metabólica/terapia , Qualidade de Vida , Fatores de Risco , Adulto JovemRESUMO
OBJECTIVE: In literature, the importance of X-linked gene dosage as a contributing factor for autoimmune diseases is generally assumed. However, little information is available on the frequency of humoral endocrine organ-specific autoimmunity in X-chromosome aneuploidies. In our preliminary study, we investigated the endocrine organ-specific humoral autoimmunity relative to four different organ-specific autoimmune diseases in a group of adult 47,XXY KS patients and in adults 46,XY control males (type 1 diabetes, T1DM; Addison's disease, AD; Hashimoto thyroiditis, HT; autoimmune chronic atrophic gastritis, AG). The aim of the present study is to evaluate the frequency of autoantibodies (Abs) specific for T1DM, AD, HT, and AG in rarer higher grade X-chromosome aneuploidies (HGA) and in 47,XXY children. DESIGN AND METHODS: Samples from 192 Caucasian patients with an X-chromosome aneuploidy (176 patients (55 children, 121 adults) with 47,XXY karyotype (KS patients) and 16 HGA patients (eight children, eight adults)) recruited from Sapienza, University of Rome (2007-2017) were tested for Abs specific for T1DM (insulin-Abs, GAD-Abs, IA-2-Abs, Znt8-Abs), HT (TPO-Abs), AD (21-OH-Abs), and AG (APC-Abs). The results were compared to those found in 213 46,XY control subjects (96 children, 117 adults). RESULTS: Altogether humoral organ-specific immunoreactivity was found in 13% of KS and HGA patients, with a significantly higher frequency than in the controls (p=.008). Almost 19% of HGA patients were positive for at least one of the organ-specific Abs investigated compared to 12.5% of KS patients. The frequency of the overall immunoreactivity was higher in KS children than in KS adults. The frequency of diabetes-specific Abs was significantly higher in the patient cohort than in controls (p=.005). Thyroid- and gastric-specific autoimmunity was also found in KS and HGA patients, while adrenal-specific immunoreactivity was rare. CONCLUSIONS: These results suggest for the first time that the risk of endocrine organ-specific humoral autoimmunity progressively increases with the severity of X-chromosome polisomy. The screening for diabetes-, thyroid-, and gastric-specific autoimmunity should be considered in clinical practice for identifying rare and classic X-chromosome aneuploid patients at risk of developing organ-specific autoimmune diseases.
Assuntos
Doença de Addison/imunologia , Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Gastrite Atrófica/imunologia , Doença de Hashimoto/imunologia , Síndrome de Klinefelter/imunologia , Doença de Addison/sangue , Doença de Addison/genética , Doença de Addison/patologia , Adolescente , Adulto , Idoso , Especificidade de Anticorpos , Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Gastrite Atrófica/sangue , Gastrite Atrófica/genética , Gastrite Atrófica/patologia , Doença de Hashimoto/sangue , Doença de Hashimoto/genética , Doença de Hashimoto/patologia , Humanos , Síndrome de Klinefelter/sangue , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/patologia , Masculino , Pessoa de Meia-Idade , Trissomia/imunologiaRESUMO
Context: Klinefelter syndrome (KS) is a common genetic condition in which males have an extra X chromosome. KS is associated with testosterone deficiency, neurodevelopmental delays, and cardiometabolic disorders. There has been recent interest in prepubertal androgen treatment; however, the effects on puberty and gonadal function are unknown. Objective: To compare onset of puberty and testicular function in prepubertal boys treated with 2 years of oxandrolone (Ox) vs placebo (Pl). Design: Double-blind, randomized, controlled trial. Setting: Single tertiary care referral center. Participants: Eighty prepubertal boys with KS; mean age: 8.0 ± 2.2 years (range: 4 to 12). Interventions: Ox 0.05 mg/kg vs identical-appearing Pl capsule given for 2 years. Outcome Measures: Onset of gonadarche (testicular volume ≥4 mL) and onset of pubarche (Tanner 2 pubic hair); change in testicular hormone concentrations. Results: Ox-treated group had 20.5 times higher odds of reaching gonadarche (OR 95% CI: 6.5, 77.8) and 28.1 times higher odds of reaching pubarche (OR 95% CI: 8.8, 110.4) during the 2-year study period after adjusting for baseline age. Gonadarche and pubarche both occurred at a younger age in the Ox group (gonadarche: 9.8 ± 1.5 vs 12.1 ± 1.0 years, P < 0.001; pubarche: 10.2 ± 1.1 vs 11.6 ± 1.3 years, P = 0.02). Serum concentrations of testicular hormones and gonadotropins were not different between groups. Conclusions: Two years of Ox treatment in prepubertal boys with KS results in an increased risk of early gonadarche, on average 2 years earlier than in Pl-treated boys. Ox did not affect serum concentrations of testicular hormones.
Assuntos
Androgênios/administração & dosagem , Síndrome de Klinefelter/tratamento farmacológico , Oxandrolona/administração & dosagem , Puberdade/efeitos dos fármacos , Criança , Pré-Escolar , Método Duplo-Cego , Humanos , Síndrome de Klinefelter/sangue , Síndrome de Klinefelter/fisiopatologia , Masculino , Hormônios Testiculares/sangue , Testículo/efeitos dos fármacos , Testículo/crescimento & desenvolvimento , Resultado do TratamentoRESUMO
Context: The early activation of the hypothalamic-pituitary-gonadal axis during infancy can be used in the evaluation of infants suspected of disorders of sex development (DSD). However, few data exist on sex-specific reference ranges for these hormones during early life. Objective: To evaluate sex differences in reproductive hormone concentrations in serum from healthy infants to define sex-specific cutoff values and to apply these in infants with DSD. Design: A cross-sectional study. Setting: A tertiary center for pediatric endocrinology at the University Hospital of Copenhagen. Patients or Other Participants: Healthy infants (1840) and patients with DSD (27), aged 2 to 5 months. Main Outcome Measures: Serum concentrations of LH, FSH, testosterone (T), estradiol, sex hormone-binding globulin (SHBG), inhibin B, anti-Müllerian hormone (AMH), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), 17-hydroxyprogesterone (17-OHP), androstenedione, and LH/FSH ratio. Results: LH and FSH concentrations showed overlap between sexes, with LH being highest in boys and FSH being highest in girls. The LH/FSH ratio separated infant boys from girls with minimal overlap at a cutoff value of 0.32. Inhibin B and AMH concentrations were markedly higher in boys compared with girls, with minimal or no overlap. In infants with Klinefelter syndrome, 45,X/46,XY mosaicism and male phenotype, and Turner syndrome, the LH/FSH ratio matched the gender of rearing. However, infants with complete androgen insensitivity syndrome had LH/FSH ratios within the male range. Conclusions: Reference ranges for reproductive hormones and LH/FSH ratio during mini-puberty were established in this study. The classifiers that best separated sex in mini-puberty were AMH, LH/FSH ratio, and T. Use of the LH/FSH ratio may add valuable information in the workup of infants suspected of DSD.
Assuntos
Transtornos do Desenvolvimento Sexual/sangue , Hormônios Esteroides Gonadais/sangue , Maturidade Sexual/fisiologia , Androstenodiona/sangue , Hormônio Antimülleriano/sangue , Estudos Transversais , Desidroepiandrosterona/sangue , Sulfato de Desidroepiandrosterona/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Lactente , Síndrome de Klinefelter/sangue , Hormônio Luteinizante/sangue , Masculino , Caracteres Sexuais , Globulina de Ligação a Hormônio Sexual/metabolismo , Síndrome de Turner/sangueRESUMO
BACKGROUND: Testicular sperm extraction (TESE) is a surgical procedure to retrieve spermatozoa from the testes of men with azoospermia to help them achieve biological parenthood. Although effective, the surgical procedure is not without complications and haematoma, devascularization, inflammation and a decrease in testosterone levels have been described as such. The prevalence and duration of hypogonadism and associated symptoms after TESE have not been studied systematically. OBJECTIVE AND RATIONALE: In this systematic review we addressed the following research questions: Are serum testosterone levels decreased after TESE and, if so, do these levels recover over time? What is the prevalence of symptoms and signs related to hypogonadism after TESE and are they related to testosterone levels? SEARCH METHODS: We searched the databases Pubmed and Embase from 1 January 1993 to 26 June 2017. We combined subject headings with terms in title and/or abstract for participants, intervention and outcomes. We included all studies that reported on TESE, regardless of the specific technique used, that measured testosterone and/or LH, and/or had information on signs or symptoms related to hypogonadism as defined by hypogonadism guidelines. An additional inclusion criterion was that studies described these measurements both before and after TESE. The quality of the included studies was assessed using the Risk Of Bias In Non-randomized Studies-of Interventions tool. OUTCOMES: We identified 15 studies reporting on total testosterone levels of which five studies also reported on testicular volume and one study on erectile dysfunction. Men with Klinefelter syndrome and men with non-obstructive azoospermia had the strongest decrease in total testosterone levels 6 months after TESE, with a mean decrease of 4.1 and 2.7 nmol/l, respectively, which recovered again to baseline levels 26 and 18 months after TESE, respectively. At 6 months after TESE, some studies reported serum total testosterone concentrations below a cut-off value of 12 nmol/l, where symptoms and signs related to hypogonadism may appear. Furthermore, an increased prevalence of erectile dysfunction related to decreased total testosterone levels 6 months after TESE was reported. Also, in some men a decrease in testicular volume was reported. However, it is not clear if this is related to low testosterone levels. WIDER IMPLICATIONS: The transient, but statistically significant, decrease in total testosterone levels indicates that men are at risk of developing a temporary hypogonadism after TESE, but there is insufficient evidence for whether patients actually experience clinical symptoms in case of decreased serum testosterone levels. To be able to properly counsel TESE patients, more large-scale monitoring on signs and symptoms of hypogonadism, in combination with testosterone measurements, needs to be performed in men undergoing TESE.