Morbidity in Klinefelter syndrome and the effect of testosterone treatment.
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ABSTRACT:
SUBMITTER: Chang S
PROVIDER: S-EPMC7413637 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesKlinefelter syndrome (KS), 47,XXY, can be viewed as a disease model for investigating the risk of thrombosis in male hypogonadism and the subsequent risk related to testosterone treatment. We describe rates of thrombotic risk factors, thrombosis and thrombosis mortality in KS and the association with testosterone treatment.MethodsNational registry-based matched cohort study with follow-up from 1995 to 2016 set in Denmark. For the study, 1155 men with KS were each matched by year and month of birth to 100 men from the background population. First thrombotic events and thrombosis mortality was evaluated by event rates and hazard ratios (HRs) and by applying testosterone treatment as a time-dependent covariate.ResultsThe KS cohort had higher incidence of venous thromboembolism relative to the comparison cohort (HR, 3.95; 95% CI, 2.83-5.52). Total thrombotic deaths were increased in KS (HR, 1.76; 95% CI, 1.18-2.62), and all-cause mortality was increased in KS following arterial thrombosis (HR 1.73; 95% CI 1.22-2.47). Only 48.7% of men with KS redeemed prescriptions for testosterone. Untreated men with KS were on average born 12 years before those treated, and the majority of untreated men with KS with available biochemistry were hypogonadal. Testosterone treatment in KS was associated with a non-significant decrease in venous thromboembolism and thrombotic deaths.ConclusionThrombosis and thrombotic deaths are increased in KS. Only half of the men with KS ever received testosterone treatment, despite overt hypogonadism in the non-treated. Testosterone treatment in Klinefelter syndrome was insignificantly associated with lower incidence rates of venous thrombosis and thrombotic deaths.
| S-EPMC6993257 | biostudies-literature
Project description:ContextKlinefelter Syndrome (KS) is the most frequent sex chromosome disorder in males. Due to hypergonadotropic hypogonadism, treatment with testosterone replacement therapy (TRT) is commonly indicated. There are no international guidelines for the most appropriate TRT in KS.ObjectiveWe aimed to evaluate how different routes of testosterone administration impact testosterone-responsive variables, as well as the development of later metabolic diseases and other complications.MethodsWe conducted a retrospective study covering 5 years from 2015 to 2020. Data on TRT, biochemical parameters, bone mineral density (BMD), medications, comorbidity, and karyotyping were derived from electronic patient records and The Danish Cytogenetic Register.ResultsA total of 147 KS males were included: 81 received injection TRT, 61 received transdermal TRT, and 5 did not receive TRT. Testosterone levels were similar in the 2 TRT groups (P = 0.9), while luteinizing hormone and follicle-stimulating hormone levels were higher in the group receiving transdermal TRT (P = 0.002). Levels of cholesterol, blood glucose, hemoglobin A1c, hemoglobin, hematocrit, liver parameters, prostate-specific antigen, and spine and hip BMD were similar in the 2 treatment groups (Ps > 0.05).ConclusionTRT, irrespective of route of administration, affects androgen-responsive variables similarly in males with KS. Neither long-acting injection nor transdermal gel seem to reduce the risk of metabolic diseases significantly. These results should encourage clinicians in seeking the route of administration resulting in the highest degree of adhesion to treatment based on individual patient preferences. Implementation of shared decision-making with patients may be important when choosing TRT.
| S-EPMC8143670 | biostudies-literature
Project description:Adult patients with Klinefelter syndrome (KS) are characterized by a highly variable phenotype, including tall stature, obesity, and hypergonadotropic hypogonadism, as well as an increased risk of developing insulin resistance, metabolic syndrome, and osteoporosis. Most adults need testosterone replacement therapy (TRT), whereas the use of TRT during puberty has been debated. In this retrospective, observational study, reproductive hormones and whole-body dual-energy x-ray absorptiometry-derived body composition and bone mineral content were standardized to age-related standard deviation scores in 62 patients with KS aged 5.9-20.6 years. Serum concentrations of total testosterone and inhibin B were low, whereas luteinizing hormone and follicle-stimulating hormone were high in patients before TRT. Despite normal body mass index, body fat percentage and the ratio between android fat percentage and gynoid fat percentage were significantly higher in the entire group irrespective of treatment status. In patients evaluated before and during TRT, a tendency toward a more beneficial body composition with a significant reduction in the ratio between android fat percentage and gynoid fat percentage during TRT was found. Bone mineral content (BMC) did not differ from the reference, but BMC corrected for bone area was significantly lower when compared to the reference. This study confirms that patients with KS have an unfavorable body composition and an impaired bone mineral status already during childhood and adolescence. Systematic studies are needed to evaluate whether TRT during puberty will improve these parameters.
| S-EPMC10305500 | biostudies-literature
Project description:Klinefelter syndrome (KS, 47,XXY) is the most common sex chromosome aneuploidy in males. A variety of complex clinical needs is associated with KS, including physical, cognitive and psychosocial impairments. Standard treatment for KS consists of androgen replacement therapy in adolescence to offset testosterone deficiency. Such treatment has a beneficial effect on the physical and behavioral manifestations of this syndrome. Whether androgen supplementation has a significant influence on the brain, however, is unknown. In the current study, we examined regional gray matter volume in boys with KS to assess whether treatment with oxandrolone, a synthetic hormone analog of testosterone, was associated with structural changes in the brain. Specifically, we focused our investigation on the hippocampus, given (1) its involvement in KS, and (2) the high concentration of androgen receptors found in this region. Structural magnetic resonance imaging data was acquired from a subsample of boys who completed a 2-year double-blind clinical trial in which patients were randomized to treatment with oxandrolone or to placebo, as well as from a sample of typically developing (TD) boys. Group differences in hippocampal volume were examined. A significant main effect of group was observed. Pairwise comparisons indicated smaller hippocampal volume in the placebo group relative to the oxandrolone group, as well as smaller volume in the placebo group relative to the TD control group. No difference in volume was observed between the treatment and TD groups. Moreover, across KS subgroups, a significant positive association was observed between hippocampus volume and performance on a spatial memory task, indicating treatment-based changes in brain structure may underlie cognitive change. These findings confirm prior reports implicating a role of the hippocampus in KS and are important in extending previous research by demonstrating a significant effect of androgens on brain structure.
| S-EPMC6644684 | biostudies-literature
Project description:The widelyvariable phenotypic spectrum and the different severity of symptoms in men with Klinefelter syndrome (KS) suggest a role for epigenetic mediators. Therefore, the aim of this study is to evaluate the possible involvement of miRNAs in the clinical manifestations of KS. To accomplish this, we performed a transcriptome analysis in peripheral blood mononuclear cells (PBMCs) of 10 non-mosaic KS patients, 10 aged-matched healthy men and 10 aged-matched healthy female controls with normal karyotype. After RNA extraction from PBMC and the preparation of RNA libraries, the samples were sequenced using next generation high-throughput sequencing technology. Expression profiling analysis revealed a significant differential expression of 2 miRNAs in KS compared to male controls. In particular, MIR3648 resulted significantly (q-value?<?0.0001) down-regulated by -19.084- fold, while MIR3687was strongly down-regulated (q-value?<?0.0001) considering KS patients. These results were confirmed by qRT-PCR. The functional analysis of the two transcripts showed that they seem to play a role in breast cancer, hemopoietic abnormalities, immune defects and adipocyte differentiation and fat cell maturation. Therefore, we speculate that both miRNAs may play a role in the immune and metabolic disorders and in the risk of breast cancer development in men with KS.
| S-EPMC5709391 | biostudies-literature
Project description:Klinefelter syndrome (KS) (47, XXY) is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as only 25% are diagnosed and only a few of these before puberty. Apart from hypogonadism and azoospermia, most men with KS suffer from some degree of learning disability and may have various kinds of psychiatric problems. The effects of long-term hypogonadism may be diffi cult to discern from the gene dose effect of the extra X-chromosome. Whatever the cause, alterations in body composition, with more fat and less muscle mass and diminished bone mineral mass, as well as increased risk of metabolic consequences, such as type 2 diabetes and the metabolic syndrome are all common in KS. These findings should be a concern as they are not simply laboratory findings; epidemiological studies in KS populations show an increased risk of both hospitalization and death from various diseases. Testosterone treatment should be offered to KS patients from early puberty, to secure a proper masculine development, nonetheless the evidence is weak or nonexisting, since no randomized controlled trials have ever been published. Here, we will review the current knowledge of hypogonadism in KS and the rationale for testosterone treatment and try to give our best recommendations for surveillance of this rather common, but often ignored, syndrome.
| S-EPMC3955327 | biostudies-other
Project description:ContextKlinefelter 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.ObjectiveTo compare onset of puberty and testicular function in prepubertal boys treated with 2 years of oxandrolone (Ox) vs placebo (Pl).DesignDouble-blind, randomized, controlled trial.SettingSingle tertiary care referral center.ParticipantsEighty prepubertal boys with KS; mean age: 8.0 ± 2.2 years (range: 4 to 12).InterventionsOx 0.05 mg/kg vs identical-appearing Pl capsule given for 2 years.Outcome measuresOnset of gonadarche (testicular volume ≥4 mL) and onset of pubarche (Tanner 2 pubic hair); change in testicular hormone concentrations.ResultsOx-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.ConclusionsTwo 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.
| S-EPMC6126887 | biostudies-literature
Project description:The widely variable phenotypic spectrum and the different symptom severity in men with Klinefelter syndrome (KS) suggest a role for epigenetic mediators. Therefore, the aim of this study was to evaluate the possible involvement of miRNAs in the clinical manifestations of KS. To accomplish this, we performed a transcriptome analysis in peripheral blood mononuclear cells (PBMCs) of 10 non-mosaic KS patients , 10 aged-matched healthy male and 10 aged-matched healthy female controls with normal karyotype. After RNA extraction from PBMC and the preparation of small RNA libraries, the samples were sequenced using next generation high-throughput sequencing technology. Expression profiling analysis revealed a significant differential expression of 2 miRNAs in KS compared to male controls. In particular, MIR3648 resulted significantly (p<0.0001) down-regulated by -19.084- fold, while MIR3687was non-expressed at all (p<0.0001) in KS patients. These results were confirmed by qRT-PCR. The functional analysis of the two transcripts showed that they seem to play a role in breast cancer, hemopoietic abnormalities, immune defects and adipocyte differentiation and fat cell maturation. Therefore, we speculate that both miRNAs may play a role in the immune and metabolic disorders and in the risk of breast cancer development in men with KS.
2017-12-02 | E-MTAB-6107 | biostudies-arrayexpress
Project description:Klinefelter syndrome (KS) results from an extra chromosome X, which is due to the failure of normal chromosomal segregation during meiosis. Patients with KS have gynecomastia, small testes, and azoospermia. Apoptosis is a mechanism responsible for the normal regulation of spermatogenesis. LDOC1 gene is a known regulator of nuclear factor mediated pathway to apoptosis through inhibition of nuclear factor kappa B (NF-kappaB). Furthermore, the transcription factor myeloid zinc finger gene 1 (MZF-1) has been shown to interact with LDOC1 and to enhance LDOC1 activity favoring apoptosis. We investigated the expression of LDOC1 gene mRNA, by quantitative reverse transcription polymerase chain reaction (qRT-PCR), in peripheral blood leukocytes of 13 patients with KS compared to 13 healthy men chosen as controls. LDOC1 expression was higher in 9 of the 13 KS patient compared to normal controls. These finding led us to hypothesize that LDOC1 gene upregulation may play a role in the spermatogenesis derangement observed in patients with KS.
| S-EPMC6807188 | biostudies-literature
Project description:With increasing modernization and urbanization of Asia, much of the future focus of the obesity epidemic will be in the Asian region. Low testosterone levels are frequently encountered in obese men who do not otherwise have a recognizable hypothalamic-pituitary-testicular (HPT) axis pathology. Moderate obesity predominantly decreases total testosterone due to insulin resistance-associated reductions in sex hormone binding globulin. More severe obesity is additionally associated with reductions in free testosterone levels due to suppression of the HPT axis. Low testosterone by itself leads to increasing adiposity, creating a self-perpetuating cycle of metabolic complications. Obesity-associated hypotestosteronemia is a functional, non-permanent state, which can be reversible, but this requires substantial weight loss. While testosterone treatment can lead to moderate reductions in fat mass, obesity by itself, in the absence of symptomatic androgen defi ciency, is not an established indication for testosterone therapy. Testosterone therapy may lead to a worsening of untreated sleep apnea and compromise fertility. Whether testosterone therapy augments diet- and exercise-induced weight loss requires evaluation in adequately designed randomized controlled clinical trials.
| S-EPMC3955331 | biostudies-literature