Klinefelter Syndrome

[Michael Scally MD]

Calogero AE, Giagulli VA, Mongioi LM, et al. Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders. J Endocrinol Invest. https://link.springer.com/article/10.1007%2Fs40618-017-0619-9

Klinefelter syndrome (KS) is one of the most common genetic causes of male infertility. This condition is associated with much comorbidity and with a lower life expectancy. The aim of this review is to explore more in depth cardiovascular and metabolic disorders associated to KS.

KS patients have an increased risk of cerebrovascular disease (standardized mortality ratio, SMR, 2.2; 95% confidence interval, CI, 1.6-3.0), but it is not clear whether the cause of the death is of thrombotic or hemorrhagic nature.

Cardiovascular congenital anomalies (SMR, 7.3; 95% CI, 2.4-17.1) and the development of thrombosis or leg ulcers (SMR, 7.9; 95% CI, 2.9-17.2) are also more frequent in these subjects.

Moreover, cardiovascular abnormalities may be at least partially reversed by testosterone replacement therapy (TRT).

KS patients have also an increased probability of endocrine and/or metabolic disease, especially obesity, metabolic syndrome and type 2 diabetes mellitus. The effects of TRT on these abnormalities are not entirely clear.

 

[Michael Scally MD]

[OA] Portal Vein Thrombosis Due to an Increase in Dose of Testosterone in a Young Man with Klinefelter Syndrome

Klinefelter syndrome (KS) is associated with increased incidence of thrombotic events. Hypofibrinolysis is associated with increased risk of thromboembolism. Although testosterone replacement therapy (TRT) inhibits the hypofibrinolysis, it can still cause thrombosis paradoxically due to increased dose and duration of use.

Herein, we present a case of a young male diagnosed with KS who was taking testosterone. The dose was increased to boost the energy levels, and the patient presented with abdominal pain. Computed tomography (CT) of the abdomen showed extensive portal vein thrombosis. He was started on enoxaparin followed by apixaban. Studies need to be done regarding the need for thromboembolism prophylaxis in patients on TRT.

Amjad W, Khatoon S, Tarasaria T, Sharifova G. Portal Vein Thrombosis Due to an Increase in Dose of Testosterone in a Young Man with Klinefelter Syndrome. Cureus 2017;9:e1823. Portal Vein Thrombosis Due to an Increase in Dose of Testosterone in a Young Man with Klinefelter Syndrome

 

[Michael Scally MD]

[OA] Klinefelter Syndrome: More Than Hypogonadism

Klinefelter syndrome (KS) is the most frequent chromosome disorder in males (1:650 newborn males), defined by 47,XXY karyotype. The classical phenotype is that of a tall male with relatively long legs, small, firm testes and gynecomastia. Azoospermia and infertility are almost inevitably present, but may be overcome by TESE and ICSI. Nevertheless, a broad spectrum of phenotypes has been described and >70% of the actually existing KS men may remain undiagnosed throughout their lifespan.

Accordingly, hypogonadism is usually not evident until early adulthood and progresses with ageing. KS patients present a series of comorbidities that increase morbidity and mortality by 40%. Such disturbances are the impaired metabolic profile (obesity, dyslipidemia, insulin resistance) and a tendency to thrombosis, which all favor cardiovascular disease.

They also present susceptibility for specific neoplasias (breast cancer, extragonadal germ cell tumors), autoimmune diseases as well as osteoporosis and bone fractures. Moreover, KS has been associated with verbal processing and attention deficits as well as social skill impairments, leading KS individuals to academic and professional achievements inferior to those of their peers of comparable socio-economic status. Nevertheless, the majority fall within the average range regarding their intellectual abilities and adaptive functioning.

Testosterone replacement therapy (TRT) is the mainstay of treatment in hypogonadal KS patients; however, randomized trials are needed to determine optimal therapeutic regimens and follow-up schedules.

Kanakis GA, Nieschlag E. Klinefelter syndrome: more than hypogonadism. Metabolism: clinical and experimental 2018. Klinefelter syndrome: more than hypogonadism. - PubMed - NCBI

 

[Michael Scally MD]

Management of Cardiovascular Complications in Klinefelter Syndrome Patients

INTRODUCTION: Klinefelter syndrome (KS), also known as 47, XXY, shows increased mortality when compared with mortality rates among the general population. Cardiovascular, hemostatic, metabolic diseases are implicated. Moreover, cardiac congenital anomalies in KS can contribute to the increase in mortality.

AREAS COVERED: In this study, we have systematically reviewed the relationships between KS and the cardiovascular system and the management of cardiovascular complication. In summary, patients with KS display increased cardiovascular risk profile, characterized by increased prevalence of metabolic alterations including dyslipidemia, diabetes mellitus (DM), and abnormalities in biomarkers of cardiovascular disease.

KS subjects are characterized by subclinical abnormalities in endothelial function and in left ventricular (LV) systolic and diastolic function, which - when associated with chronotropic incompetence - may negatively influence cardiopulmonary performance.

Moreover, KS patients appear to be at a higher risk for cardiovascular disease, due to thromboembolic events with high prevalence of recurrent venous ulcers, venous insufficiency, recurrent venous and arterial thromboembolism leading to deep venous thrombosis or pulmonary embolism.

EXPERT OPINION: Considering the unequivocal finding of increased mortality of KS patients, we suggest a periodic cardiovascular follow up in specialized centers with multidisciplinary care teams that comprise endocrinologists and cardiologists dedicated to KS syndrome.

Accardo G, Amoresano Paglionico V, Di Fraia R, et al. Management of cardiovascular complications in Klinefelter syndrome patients. Expert review of endocrinology & metabolism 2019:1-8. https://www.tandfonline.com/doi/abs/10.1080/17446651.2019.1584036?journalCode=iere20

 

[Michael Scally MD]

Klinefelter Syndrome and Diabetes

Purpose of Review - Klinefelter syndrome (KS) is associated with increased insulin resistance and high rates of type 2 diabetes (T2DM). Our aim was to review what is known about the prevalence of diabetes in men with KS, potential mechanisms underlying the observed metabolic phenotype, and the data that are available to guide treatment decisions.

Recent Findings - The increased prevalence of T2DM seen in men with KS appears to be the result of multiple mechanisms including increased truncal adiposity and socioeconomic disadvantages, but it is likely not a direct consequence of hypogonadism alone.

No randomized trials have been conducted to evaluate the impact of testosterone replacement therapy on T2DM in men with KS, but observational data suggest that testosterone replacement is not associated with lower rates of diabetes or improved glycemic control.

Summary - Metabolic derangements are common in KS, but treatment strategies specific to this population are lacking. Early lifestyle and dietary interventions are likely important. Additional research is needed to dissect the complex interaction between genotype and metabolic phenotype.

Collaboration between academic centers caring for men with KS is needed to facilitate the development of evidence-based clinical practice guidelines, which would inform optimal screening and treatment strategies for this patient population.

O’Connor MJ, Snyder EA, Hayes FJ. Klinefelter Syndrome and Diabetes. Current Diabetes Reports 2019;19:71. Klinefelter Syndrome and Diabetes

 

[Michael Scally MD]

Testosterone Treatment and Association with Thrombin Generation and Coagulation Inhibition in Klinefelter Syndrome

Highlights
· Men with Klinefelter syndrome do not demonstrate a severe pro-coagulant state.
· Thrombin generation was lowest in testosterone treated patients.
· Increased androgen action was associated with a milder coagulation profile.
· Coagulation inhibitor levels were increased in Klinefelter syndrome.

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/L × 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 18 U-KS and 27 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.

Chang S, Biltoft D, Skakkebæk A, et al. Testosterone treatment and association with thrombin generation and coagulation inhibition in Klinefelter syndrome: A cross-sectional study. Thrombosis research 2019. https://www.sciencedirect.com/science/article/pii/S004938481930341X

 

[Michael Scally MD]

Testosterone Treatment and Association with Thrombin Generation and Coagulation Inhibition in Klinefelter Syndrome

Highlights
· Men with Klinefelter syndrome do not demonstrate a severe pro-coagulant state.
· Thrombin generation was lowest in testosterone treated patients.
· Increased androgen action was associated with a milder coagulation profile.
· Coagulation inhibitor levels were increased in Klinefelter syndrome.

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/Lxmin, 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: 18U-KS and 27T-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.

Chang S, Biltoft D, Skakkebaek A, et al. Testosterone treatment and association with thrombin generation and coagulation inhibition in Klinefelter syndrome: A cross-sectional study. Thrombosis research 2019;182:175-81. https://www.thrombosisresearch.com/article/S0049-3848(19)30341-X/abstract

 

[Michael Scally MD]

[OA] A Case Report of Exacerbation of Leg Ulcers Associated with Acute High-dose Acetylsalicylic Acid in a Patient with Klinefelter Syndrome

Klinefelter syndrome (KS) is the most frequent type of congenital sex-chromosomal disorder caused by at least one extra X chromosome and commonly treated with lifetime testosterone therapy. Ulcerative lesions on lower extremities may occur as a complication of KS. The pathogenesis of ulcers in KS patients has not been clarified on a molecular level.

Here we present a case of leg ulcers exacerbation associated with the administration of a high dose of acetylsalicylic acid in a 63-year-old KS patient with karyotype 47,XXY undergoing testosterone replacement therapy for the last 20 years. The appearance of the ulcer on the patient's leg occurred during one week of high oral acetylsalicylic acid intake (1.2 g daily). The patient was advised to return to his standard daily dose of 0.1 g of acetylsalicylic acid and significant improvement of his leg ulcer was observed after two weeks.

We hypothesize that testosterone-mediated nitric oxide balance in KS patient is perturbed under the condition of acute high-dose acetylsalicylic acid administration. We propose that small standard doses of approximately 0.1 g/day of acetylsalicylic acid have no apparent effect on nitric oxide status, whereas higher doses may cause dysregulation of nitric oxide production and/or utilization, creating conditions which may cause the appearance of leg ulcers in the KS patients.

Arizanovic L, Spasic S, Miljevic C, Spasic MB, Nikolic M. A Case Report of Exacerbation of Leg Ulcers Associated with Acute High-dose Acetylsalicylic Acid in a Patient with Klinefelter Syndrome. Cureus. 2019;11(12):e6449. Published 2019 Dec 23. https://www.cureus.com/articles/19478-a-case-report-of-exacerbation-of-leg-ulcers-associated-with-acute-high-dose-acetylsalicylic-acid-in-a-patient-with-klinefelter-syndrome

 

[Michael Scally MD]

Testosterone Treatment in Male Patients with Klinefelter Syndrome

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.

Pizzocaro A, Vena W, Condorelli R, et al. Testosterone treatment in male patients with Klinefelter syndrome: a systematic review and meta-analysis [published online ahead of print, 2020 Jun 21]. J Endocrinol Invest. 2020;10.1007/s40618-020-01299-1. doi:10.1007/s40618-020-01299-1 Testosterone treatment in male patients with Klinefelter syndrome: a systematic review and meta-analysis