Increased risk of Venous Thrombosis in XXY/KS further exacerbated by testosterone therapy

This study demonstrates poor awareness of the known VTE risks in KS and the potential VTE risks of TT within this cohort. Patients not informed of the inherent risks associated with their condition may be less vigilant to complications, unaware of lifestyle decisions affecting risks, and not able to make informed decisions about medical care. Further studies are needed to understand the mechanisms leading to the increased VTE rate in KS. Moreover, an investigation into the relationship between TT and VTE is warranted to weigh the benefits of TT in VTE-prone patient groups like KS. Educational materials, such as a patient information pamphlet distributed in clinics and via associations like the UK’s KSA, are also needed to enhance awareness amongst KS patients of their VTE risk and potentially increased risk with TT.

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Pulmonary Embolism in a Patient with Klinefelter’s Syndrome

BACKGROUND

Dyspnoea and syncope are common causes of admission to hospitals. Pulmonary embolism is often a differential diagnosis, and by examining the clinical history the clinician searches for known predisposing factors. This case report highlights the importance of Klinefelter’s syndrome as a predisposing factor for venous thromboembolism. The syndrome is caused by an extra X chromosome in men, among whom the prevalence is estimated to be 1:500−1:1000. Probably only 25 % of men with the syndrome are diagnosed.

CASE PRESENTATION

A man in his forties was admitted to hospital due to dyspnoea and syncope. CT showed submassive pulmonary embolism. The course illustrates the challenges of pulmonary embolism and its association with Klinefelter’s syndrome.

INTERPRETATION

Several studies have shown an increased incidence of venous thromboembolism in patients with Klinefelter’s syndrome. Klinefelter’s patients have a higher pre-test likelihood of venous thromboembolism than other patients, similar to patients with hereditary thrombophilia. Klinefelter’s syndrome is a persistent risk factor for recurrent thromboembolism. Thus, Klinefelter’s syndrome impacts both the diagnosis and treatment of thromboembolic disease.

DISCUSSION

No single factor has been identified that can explain why patients with Klinefelter’s syndrome are at increased risk of venous thromboembolism, but the genes for factor VIII and factor IX are located on the X chromosome, and increased levels of coagulation factors have been observed in Klinefelter’s syndrome. Testosterone-replacement therapy could potentially increase the risk of thromboembolism. Thrombosis risk should therefore be considered prior to the initiation of testosterone-replacement therapy in patients with Klinefelter’s syndrome.

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High Dose Fish Oil Does Not Reduce Risk of Cardiac Events

Many people take fish oil supplements to try to improve various aspects of their health, but new work from the Cleveland Clinic has suggested that high doses of an omega-3 fatty acid supplement don’t help people at high risk of cardiovascular events reduce their risk of those events. The conclusions are from the STRENGTH Trial: Cardiovascular Outcomes With Omega-3 Carboxylic Acids (Epanova) In Patients With High Vascular Risk And Atherogenic Dyslipidemia, which were reported in the Journal of the American Medical Association (JAMA) and at the virtual Scientific Sessions of the American Heart Association.

The STRENGTH trial involved 13,078 volunteers that took either high dose omega-3 fatty acids or a corn oil placebo. Compared to people taking corn oil, there was no reduction in major adverse cardiovascular events for people taking the omega-3 drug, and the trial was halted early because no difference between the groups was identified.

These results are contrary to another study done in 2018, which suggested that compared to a mineral oil placebo, a highly pure form of omega-3 fatty acid called icosapent ethyl could significantly reduce adverse cardiovascular events and cardiovascular death among patients at high-risk. The mineral oil placebo was a potential study problem, however, that may have promoted the benefit of mineral oil.

“These results have prompted the question of why the STRENGTH trial was neutral while a previous trial was favorable,” said senior study author Steven Nissen, M.D., Chief Academic Officer of the Heart, Vascular and Thoracic Institute at Cleveland Clinic. “Compared with mineral oil used in the previous trial, corn oil did not raise levels of bad cholesterol or markers of inflammation, suggesting that it was a truly neutral placebo.”

“The question of whether administration of omega-3 fatty acids plays a role in the prevention of cardiovascular disease has been investigated with varying results,” said study co-author Michael Lincoff, M.D., vice chair in the department of cardiovascular medicine and director of C5Research at Cleveland Clinic.

“The STRENGTH trial showed a 67 percent increase in atrial fibrillation in the omega-3 CA treatment group, indicating that there is some uncertainty whether there is net benefit or harm with administration of any omega-3 fatty acid formulation. Given that two large clinical trials have now demonstrated a greater incident rate of atrial fibrillation with high dose omega-3 fatty acid administration, this observation requires further study,” Lincoff said.

“These results suggest that a review of the entire class of fish oil products is warranted to determine what labeling changes might be appropriate for these products, including whether high-dose fish oil supplements truly provide benefits given the risk of atrial fibrillation,” Nissen added. “These results also have implications for over-the-counter fish oil since many patients take large doses to avoid the expense of prescription drugs.”

Continue reading…. 

Evidence For Long Noncoding RNA Up-regulation in Klinefelter Syndrome

Klinefelter syndrome (KS) is the most common sex-chromosome variation among males, with an estimated prevalence of 1:660 newborns. The most common karyotype is the classic 47,XXY, which accounts for the 80–90% of all cases. It is a consequence of a non-disjunction of paired X-chromosomes during the first or second meiotic division, equally due to a paternal or maternal meiotic mal segregation event. The remaining 10% of KS are due to chromosome mosaicisms (e.g. 46,XY/47,XXY) or to more complex karyotypes (X chromosome structural abnormalities such as 47,XX, der(Y), 47,X, der(X),Y, or other numeric sex chromosome abnormalities such as 48, XXXY, 48, XXYY and 49, XXXXY).

The chromosomal abnormality leads to a progressive germ cell degeneration starting from mid-puberty, impaired Sertoli cell function. total tubular atrophy or hyalinizing fibrosis and Leydig cell hyperplasia, clinically causing hypergonadotropic hypogonadism, small testis with increased consistency and infertility. Occasionally, foci of spermatogenesis have been observed in testis of KS patients. Clinically, azoospermia is present in the 90% of non-mosaic KS, whereas severe oligozoospermia in the remaining 10%.

Several clinical manifestations are associated with KS. These include learning and language disability, reduction in intelligence quotient (IQ) scores of 10 to 15 points, but not into the intellectual disability range, increased risk for mitral valve prolapse, lower-extremity varicose veins, venous stasis ulcers, deep vein thrombosis and pulmonary embolism, autoimmune diseases, 20-fold-higher risk of developing breast cancer, type II diabetes mellitus (T2 DM) and metabolic syndrome , osteoporosis, extragonadal germ cell tumors and non-Hodgkin lymphoma.

Molecular mechanisms underlying the variability in KS phenotype have not been clearly understood yet. Epigenetic mechanisms have been suggested to play a role. Growth arrest-specific 5 (GAS5) gene, mapping on the 1q25.1 chromosome, encodes for a long non-coding RNA (lncRNA) which is involved in the modulation of gene expression, targeting many different downstream miRNAs.

LncRNA GAS5 was initially identified as a tumor suppressor gene. However, it has also been shown to support female germline stem cell (FGSC) survival and adipocyte differentiation. In addition, recent evidence pointed to lncRNA GAS5 a role in atherosclerosis and autoimmune diseases, which are widely recognized as KS comorbidities.

Continue reading………

Combating Metabolic Disease

The Centres for Disease Control and Prevention (CDC) estimates that in 2018, obesity impacted about 42 percent of American adults. People with obesity are at higher risk for many diseases, including type 2 diabetes, coronary heart disease, and stroke; they also tend to generally have a lower quality of life and a higher risk of death. As of 2008, obesity was thought to cost the United States about $147 billion a year. All this makes obesity an intense focus of research studies.

Scientists are now learning more about how the different types of fat in the human body are involved in metabolic disease. It’s known that brown fat cells work to burn energy, instead of storing it as white fat cells do. If there was a way to add brown fat or convert white fat into brown fat it could help reduce the prevalence of obesity.

Researchers have now developed a way to genetically modify human white fat cells with CRISPR technology so they are more similar to brown fat cells. These HUMBLE (human brown-like) fat cells that generate heat instead of storing energy could then be transplanted into patients with obesity as a therapeutic, said Yu-Hua Tseng, Ph.D., a senior investigator in Joslin Diabetes Centre’s Section on Integrative Physiology and Metabolism. Tseng is the senior author of the report on this work in Science Translational Medicine.These newly-transplanted brown fat cells would then theoretically be able to reduce the levels of excess glucose and lipids in the blood, which is a characteristic of metabolic diseases like diabetes. People that are overweight or obese often have less beneficial brown fat, and the HUMBLE cells can help them overcome this problem, Tseng said.

The HUMBLE cells were made by using human white fat cells that are not fully differentiated; they are in a progenitor state and not in their final form. With CRISPR-Cas9, the researchers raised the expression of a gene called UCP1 to cause the progenitor white fat cells to become like brown fat cells. The scientists transplanted these cells into a mouse model that lacked an immune system, reducing the likelihood of rejection, and the cells seemed to function like brown fat cells. Mice with the transplanted cells had greater sensitivity to insulin and were better at removing glucose from their blood, and they gained less weight than mice that had received transplanted white cells.

The scientists found that any health benefits were primarily due to transplanted cells to signaling to existing brown fat cells in the mice. “Cells in different tissues communicate with each other,” Tseng said. “In this case, we found that our transplanted HUMBLE cells secrete a molecule called nitric oxide, which is carried by red blood cells to the endogenous brown cells and activates those cells.”

This therapy is not ready for the clinic, but Tseng is hopeful that if it works in pre-clinical studies, it may one day be possible to apply this technique to individual patients. In that process, a small number of cells would be removed from a patient, isolated and modified, then returned to the patient as HUMBLE cells. Tseng’s team is also interested in a more generally applicable and less costly approach. For example, it may be possible to use generic cells that are not removed from the patient, by coating them in a material that would protect them from the immune system.

“Employing cell-based or gene therapies to treat obesity or type 2 diabetes used to be science fiction,” she says. “Now scientific advances, such as CRISPR gene-editing technologies, will help us to improve the metabolism, the body weight, the quality of life, and the overall health of people with obesity and diabetes.”

Continue reading…….

Genetic risk factors for Venous Thromboembolism associated with Klinefelter Syndrome

The tendency towards thromboembolism is a serious complication related to Klinefelter’s Syndrome. Some KS patients may suffer from VTE in the form of deep vein thrombosis or pulmonary embolism, or both while others may complain of recurrent venous ulcers. The primary cause of this increased risk of VTE in KS patients is not clearly understood and so this has encouraged scientists to look for the cause and whether it is an outcome of an underlying genetic susceptibility, hormonal disturbances, or both.

In this study, screening for hereditary thrombophilia was done using a broad panel of six genes known to be established risk factors for thromboembolism and which, to the best of our knowledge, have never been assessed before in infertile men with KS.

Updated May 2021 to include this advice from the Australian Government. If the Astra Zeneca vaccine is the only vaccine been offered to you, then we would encourage you to make your health provider aware of these findings, doing so, just might save your life.
Is it true? Does the AstraZeneca COVID-19 vaccine cause blood clots?

Australian Government, Department of Health

47XXY and Deep Venous Thrombosis – Support

Symptoms and Signs of Deep Vein Thrombosis

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The Promises and Pitfalls of Sex Difference Research

It’s been hypothesised that XXY’s are biological females dressed in male clothing, that being so we ask you keep in mind when reading how an XXY experience might have greater similarity to females than males, of course none of this would be necessary if researches were to include Intersex as a variable. Still comparing the binary sexes is a step in the right direction but should by no means be the final step.

The XXY Project

In 2016 the USA National Institutes of Health (NIH) mandated that all pre-clinical research must include sex as a biological variable (SABV), unless strongly justified otherwise. This has substantially increased attention to sex differences research, with good reason. Studying how biological sex contributes to our health can help understanding of disease etiology, manifestation, progression, and treatment. Indeed, males are more likely to be diagnosed with autism spectrum disorders or develop Parkinson’s disease whereas females are more likely to be diagnosed with major depressive disorder, anxiety disorders, autoimmune disease, and multiple sclerosis.

Sex differences are also noted in specific disease subsets, thus more females than males display the relapsing-remitting type of multiple sclerosis than men. Similarly, whereas the incidence of epilepsy is higher in males than females, only women are susceptible to a catamenial epilepsy, where seizures are tied to the menstrual cycle, and up to 70% of females with epilepsy show a variant of catamenial type. Perhaps less well known, there are also sex differences in the timing or onset of neuropsychiatric disorders. Onset of obsessive compulsive disorder is more likely to occur in early adolescence for males but during the perinatal period for females.

Even when prevalence of disease shows no sex bias, such as in schizophrenia, there can be profound differences in timing onset. Males are more likely to present with schizophrenia as teens, but females are more likely to present a couple of years later than males with a secondary peak in middle-age. Each of these examples gives us important clues on the nature of the disease. Yet, sex differences in onset and prevalence are rarely explored despite that studying these sex differences could yield powerful clinical and pre-clinical models of disease, and clues to disease etiology and pathology.

Continue reading………

Association of Testosterone Therapy With Risk of Venous Thromboembolism Among Men With and Without Hypogonadism

Is clinical prescription of testosterone therapy associated with short-term risk of venous thromboembolism in men with and without hypogonadism?

In this case-crossover study comparing 6-month testosterone use for 39,622 men who had a venous thromboembolism with testosterone use 6 to 12 months before the venous thromboembolism, use of testosterone therapy in the 6-month case period was associated with an increased risk of venous thromboembolism among men with and without hypogonadism.

The findings suggest that testosterone therapy is associated with increased short-term risk of venous thrombo-embolism among all men prescribed the therapy

The clinical indication for testosterone therapy is primarily to treat hypogonadism, a condition in which serum testosterone levels in men decrease below a specific threshold, resulting in sexual dysfunction, altered bone metabolism and body composition, and potential emotional dysregulation. Although testosterone levels may decrease with age, external causes of clinical hypogonadism include genetic diseases or complications from surgery, infection, and medications. Testosterone prescriptions among men increased more than 300% from 2001 to 20135,6; the increase is thought to be caused by testosterone therapy being prescribed for common symptoms, such as low libido and fat redistribution, associated with ageing, obesity, and diabetes and not necessarily with clinical hypogonadism. This increase in prescription rate was more pronounced among men aged 18 to 45 years than among older men. In 2014, the US Food and Drug Administration released a warning about testosterone therapy and the potential risk of heart attack and stroke; since then, testosterone therapy prescriptions have decreased and eventually plateaued. Recent trends estimate that, in the United States, 2.3 million men older than 30 years (3.2%) were prescribed testosterone therapy in 2013 and that this trend decreased to approximately 1.15 million men (1.6%) in 2016. Evidence suggests that testosterone therapy is still being prescribed to men without hypogonadism.

Venous thromboembolism (VTE), consisting of deep vein thrombosis and pulmonary embolism, is a common condition in the United States, with more than 1 million individuals experiencing a VTE annually. Baseline testosterone levels are not associated with increase in VTE risk. However, exogenous testosterone therapy may increase endogenous hematocrit levels, which can increase blood viscosity, platelet accumulation, and thromboxane A2 concentrations for up to 6 months and could subsequently increase risk of blood clot formation and subsequent VTE events. Testosterone therapy is most commonly administered via transdermal gels, patches, or intramuscular routes, each having their own rate of absorption and prescription strengths that potentially affect cardiovascular pathophysiologic factors. Pathophysiologic research suggests that exogenous testosterone therapy could increase VTE risk, but the 2 largest observational studies evaluating this association reached conflicting conclusions. Furthermore, these studies were underpowered to examine testosterone therapy use within important clinical subgroups, such as by clinical hypogonadism status, age, route of testosterone therapy exposure, and duration of testosterone therapy use.

Continue reading…….

47XXY and Deep Venous Thrombosis – Support

Klinefelter’s syndrome: Associations with increased blood clot (thrombosis)
events (deep venous thrombosis, pulmonary embolus, venous
thromboembolism).

Free consultation and evaluation.

The close association of Klinefelter’s syndrome (47XXY) with unexplained thrombosis has been known for at least 33 years. Venous thromboemboli (VTE) are ~20 fold more frequent in Klinefelter’s syndrome than in the general population. Previous single case studies of Klinefelters with VTE have found Protein C deficiency, Lupus anticoagulant and anticardiolipin antibodies, and protein S deficiency, homocysteinemeia, the lupus anticoagulant, Factor V Leiden Heterozygosity, Prothrombin gene 20210A heterozygosity, high Factor VIII and high Factor XI .

In our most recent publications, of 67 patients with VTE after taking testosterone, had Klinefelters treated with testosterone replacement therapy. The uniform normal practice to treat the testosterone deficiency of Klinefelters syndrome is with exogenous testosterone. Since exogenous testosterone can interact with previously undiagnosed thrombophilias to produce VTE, there is a reasonable likelihood that the VTE observed in Klinefelters cases does not represent some unique prothrombotic characteristic of Klinefelters itself, but reflects the thrombotic effects of uniform testosterone supplementation interacting with an inherited or acquired increased tendency to form blood clots (thrombophilia) in a group which may also be enriched with familial thrombophilia.

Take Action:

If you have a well-defined diagnosis of Klinefelters syndrome, and have had VTE while taking testosterone therapy, you may have a high likelihood of having an inherited or acquired thrombophilia. We would be glad to assist as follows:

  1. If you can get to Cincinnati for a FREE 1 hour outpatient consultation, we will obtain the appropriate blood tests for thrombophilia, as well as evaluate your case, and make recommendations for future therapy.
  2. If you cannot get to Cincinnati for the free 1 hour outpatient consultation, we will, FREE OF CHARGE, provide the necessary laboratory orders for the appropriate blood tests for thrombophilia, evaluate your case, and make recommendations for future therapy. However, your health insurance will have to cover the costs of the laboratory testing for thrombophilia, and unless your health policy covers these costs, they would be very very expensive for you to pay by yourself. If you already have laboratory results for thrombophilia, we will be glad, FREE OF CHARGE, to evaluate them and make recommendations.

Charles J. Glueck MD, Jewish Hospital of Cincinnati, 2135 Dana Avenue, Cincinnati OH, 45207. Email cjglueck@mercy.com, Phone 513-924-8250; Fax 513-924-8273.

High Risk of Venous Thromboembolism in Klinefelter Syndrome

How broken sleep promotes cardiovascular disease

Given the high incidence of Sleep Apnoea amongst XXY’s administering exogenous Testosterone, research of this nature would seem to indicate a far greater impact than insomnia alone.

Most people have at some point echoed Macbeth’s complaint about the loss of “sleep that knits up the ravelled sleeve of care”. Sleep disorders, such as obstructive sleep apnoea (when breathing temporarily stops, causing both sleep disruption and lack of oxygen in the blood) and sleep deprivation, have been associated with an increased risk of atherosclerosis and its harmful cardiovascular effects. Atherosclerosis is characterized by the formation of ‘plaques’ in arteries, as white blood cells enter the artery wall, take up cholesterol and other substances from the blood and trigger an inflammatory response. However, the mechanisms linking sleep disruption and atherosclerosis have been largely unknown. Writing in Nature, McAlpine et al. show that persistent sleep disruption causes the brain to signal the bone marrow to increase the production of white blood cells.

Full article available at nature.com