title: Klinefelter Syndrome and medical treatment: hypogonadism and beyond.
abstract: Klinefelter syndrome (KS), though described more than 70 years ago, still imposes significant diagnostic challenges. Based on data from epidemiological studies, KS is associated with increased morbidity and mortality. Although the pathophysiology and etiology behind these observations are as yet not well understood, a significant contribution of hypogonadism, central to the syndrome, is traditionally suspected. However, other unknown effects inherent to the syndrome also seem to modify the disease pattern. Herein we show that KS is under-diagnosed since only roughly 25% of patients are diagnosed and the mean age of diagnosis is during adult life. KS is associated with increased morbidity resulting in loss of 2-5 years in lifespan with increased mortality from different diseases and a poor socioeconomic profile. Small testes, hypergonadothrophic hypogonadism and cognitive impairment are usually found. The accompanying hypogonadism can lead to altered body composition and a risk of developing metabolic syndrome, type 2 diabetes and cardiovascular disease. Cancer risk is generally not different from that observed in the background population, although specific cancers like breast cancer and extragonadal germ cell tumors are seen more frequently in KS. The mainstay of medical treatment is testosterone replacement therapy to both attenuate acute and long-term consequences of hypogonadism and possibly prevent the frequent comorbidity. We believe that the diagnostic challenges should be tackled more efficiently, while there is also a pressing need to generate better evidence for timing and the proper dose of testosterone replacement. We advocate for a multidisciplinary setup with the inclusion of pediatricians, speech therapists, general practitioners, psychologists, infertility specialists, urologists and endocrinologists.
authors.affiliation: Department of Clinical Biochemistry, Hospital of South West Denmark, and Unit for Thrombosis Research, Institute of Public Health, University of Southern Denmark, Esbjerg, Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Chang
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Skakkebæk
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Department of Molecular Medicine (MOMA), Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Claus Højbjerg
authors.initials: CH
authors.lastname: Gravholt
mesh_terms: D000728:Androgens / Q000627:therapeutic use*; D041321:Chromosomes, Human, X; D041322:Chromosomes, Human, Y; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D020249:Hormone Replacement Therapy / Q000379:methods*; D006801:Humans; D007006:Hypogonadism / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D007713:Klinefelter Syndrome / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D008297:Male; D010641:Phenotype; D011237:Predictive Value of Tests; D012307:Risk Factors; D013739:Testosterone / Q000172:deficiency / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000728:Androgens; D013739:Testosterone