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Klinefelter syndrome KS 47, XXY is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. 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 difficult 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.
Despite being the most common sex chromosomal disorder affecting 1 in men, 1 Klinefelter syndrome KS 47, XXY remains highly under-diagnosed because of substantial variation in the clinical presentation.
During the past decades, much new information about the long-term consequences of the syndrome has emerged, describing many of the problems these men suffer from. KS is not just about testicular malfunction and increased height; it has marked effects on brain, behavior and psychiatric morbidity, body composition and insulin sensitivity, bone formation and fracture risk, and it affects general morbidity and mortality in a negative direction.
Epidemiological studies in two cohorts of KS patients from UK and Denmark have shown that KS is associated with a range of long-term consequences not only affecting morbidity 8 and mortality, 9 , 10 but also affects the socioeconomic status in a negative way, 11 as well as increased risk of being convinced for criminality. A substantial number of reviews concerning KS have been published during the past few years. Herein, we will focus on what is known about the consequences of hypogonadism in KS and discuss current knowledge on the effect of testosterone treatment.
KS affects testicular function. This has been known since the first description of the syndrome by Klinefelter et al. Interestingly, a recent study by Samango-Sprouse et al. However, current knowledge does not support systematic treatment with testosterone in infancy except for cases of micropenis.
At the beginning of puberty, which in general occurs at a normal age, 21 testes grow a little but subsequently shrink and in parallel with this, the gonadotrophins rise to the greatly elevated levels seen in adults with KS. Infertility without assisted reproduction is invariable, although a few spontaneous proven fatherhoods among KS men have been reported.
It has been questioned whether testosterone treatment prior to micro-TESE could decrease the chance of retrieving spermatocytes, 27 and some offer presurgery hormonal treatment with aromatase inhibitors, human choriogonadotrophin hCG or clomiphene, but presently, no controlled trials exists on this topic.
Knowledge about the neuropsychological phenotype of KS has expanded during the past decades resulting in a very comprehensive description, although the phenotype is very variable. The majority of boys and men with KS suffer in varying degree from cognitive disabilities, the most consistent finding being verbal deficits, 32 , 33 , 34 but deficits in other cognitive abilities such as memory function 35 , 36 and executive functions 37 , 38 , 39 also seem to be common.
Total brain volume, gray matter volume and white matter volume has been reported to be decreased in several studies. Both a gene dosage effect due to the supernumerary X-chromosome and androgen deficiency or a combination of both have been proposed to cause the neuropsychological phenotype seen in KS. Many of the cognitive disabilities and psychological traits are already present in childhood, 34 before hypergonadotropic hypogonadism develops. If androgen insufficiency were to account for these neuropsychological traits, it should be present prenatally, where testosterone is known to influence brain development.
Before any conclusion regarding the impact of testosterone deficiency in infancy on the cognitive and psychological phenotype can be drawn, more conclusive studies about testosterone levels in infants and follow up studies investigating the correlations between infant testosterone level and neuropsychological phenotype have to be performed.
Regarding the impact of hypogonadism on the changes in brain volumes seen in KS, very little is known. In our current study of structural brain volumes 49 we found the same volumetric changes as a previous study on boys with KS, 43 indicating that the difference in brain volumes seen in KS develop during fetal development either due to a gene-dosage effect or due to prenatal androgen deficiency. In favor of the first, the brain size of girls with congenital adrenal hyperplasia who are known to be exposed to high levels of androgens are not different from normal girls.
The modulating effect of testosterone therapy on the neuropsychological phenotype has also been investigated in adults with KS, however, with inconsistent conclusions. In traits such as behavior, energy level, well-being and learning capacity and verbal fluency testosterone therapy has been shown to have a positive impact. Before we can conclude if there are effects of testosterone therapy, follow-up studies are needed. Consistent conclusions regarding the effect of testosterone therapy on brain volumes in KS males are still lacking.
One study reported smaller left temporal volumes in KS men not receiving testosterone therapy compared to controls, whereas KS males receiving testosterone treatment did not differ from controls.
In conclusion, the effect of prenatal and postnatal androgen deficiency on the neuropsychological phenotype and brain volumes in KS is putative and evidence for an effect of testosterone therapy on the neuropsychological phenotype is lacking, implying that the mechanism behind the neuropsychological phenotype and changes in brain volumes may instead be caused by the gene dosage effect of having a supernumerary X-chromosome.
Regarding the modulating effect of testosterone therapy on the neuropsychological phenotype follow-up studies are needed. KS patients have altered body composition with increased body fat and reduced muscle mass, but to date it is unknown whether these changes are a consequence of the specific KS genotype, the hormonal milieu or a combination of both. In men with normal chromosomes, hypogonadism independently predicts the development of abdominal adiposity, 57 whereas testosterone treatment of middle-aged abdominal obese men reduces the amount of intraabdominal fat.
A number of case reports have described an association between diabetes and KS, but reasons for this association remain unclear. Epidemiological studies on both morbidity 8 , 10 and mortality in patients with KS 9 have confirmed this increased risk of diabetes. We recently described a strikingly high incidence of the insulin resistance and the metabolic syndrome in 70 patients KS patients compared with age-matched controls. Numerous prospective studies have shown that low levels of testosterone can predict the metabolic syndrome 69 and type 2 diabetes, 70 and cross-sectional studies have consistently reported an inverse relationship between plasma testosterone and insulin resistance in normal males.
The effects of testosterone treatment in hypogonadal patients, however, are conflicting, and generally, most studies on this topic only used rough or indirect measures of insulin sensitivity and body composition.
Testosterone treatment in hypogonadal patients with type 2 diabetes, however, primarily improved insulin sensitivity in the obese, 74 , 75 but not in the lean 76 , 77 patients, and comparable results have been obtained with testosterone treatment of obese hypogonadal normo-glycemic men. Only few clinical studies, however, have demonstrated direct effects of testosterone on insulin sensitivity.
Surprisingly, the prevalence increased markedly with testosterone treatment during a median follow up period of 4 years, but unfortunately, testosterone treatment only resulted in low to sub-normal testosterone levels in both groups and only crude measures of body composition changes were provided. Apart from the association between low testosterone, body composition, the metabolic syndrome and insulin sensitivity, hypogonadism has been associated with an adverse cardiovascular risk profile, with increased C-reactive protein CRP , triglycerides and decreased high-density lipoprotein HDL cholesterol.
Likewise, the biological active high molecular weight subform of adiponectin was nonsuppressed. This hypothesis is supported by the finding of decreased mortality risk from ischemic heart disease in KS patients, 10 but findings from recent epidemiological studies in non-KS are contradictory and have demonstrated higher cardiovascular disease risk in men both in untreated hypogonadal men as well as in hypogonadal men after testosterone treatment.
The vicious circle of hypogonadism — abdominal obesity — insulin resistance in Klinefelter syndrome, with secondary consequences. Solid arrows indicates promotion, broken arrows indicates inhibition. VO 2max is a measure of maximal oxygen consumption, a measure of physical fitness. This figure is reproduced from Bojesen et al. Collectively, substantial evidence points toward a dramatically increased risk of diabetes and metabolic syndrome in KS.
Current knowledge, however, does not support hormone replacement therapy of KS patients with the primary aim of improving insulin sensitivity, but such effects may occur indirectly through favorable effects on body composition, resting energy expenditure and physical fitness.
Unfortunately, prospective studies addressing these issues are not at hand in KS patients, but are deemed necessary to prove the postulated efficacy of testosterone therapy in preventing the occurrence of the metabolic syndrome and to guide clinicians in the clinical care of these patients. Hypogonadism in both females and males are well known causes of low bone mineral density BMD and osteoporosis. In males, both testosterone and estrogen play a fundamental role in accretion and maintenance of bone mass.
The androgen receptor AR is expressed in many bone cells, and testosterone is important in both bone growth and bone maintenance, and the effect of testosterone is both direct through AR and indirect through aromatisation to estrogens.
In adulthood, testosterone is important for trabecular bone maintenance. Apart from one study, 92 all studies have shown decreased BMD 93 , 94 , 95 , 96 including recent studies on large cohorts of KS patients using modern DEXA scanning technology to measure bone density. Longitudinal studies on KS patients regarding the effect of testosterone treatment on BMD have reported contradicting results; one study showing a positive effect if testosterone treatment was initiated before the age of 20 years, 99 while another study showed a rather high prevalence of low BMD despite testosterone treatment.
The high or normal to high level of estrogen may protect against excessive bone loss in KS. While the first study by Zitzmann et al. It is important to stress that all results are based on cross-sectional studies, and neither longitudinal studies in KS examining the role of pubertal hormone increments on developing bones, nor RCTs evaluating the effect of early testosterone treatment have been published.
Although no evidence exists, it is plausible that a diminished testosterone production in puberty and longstanding low- or sub-normal testosterone production hereafter may cause the unfavorable low BMD, which ultimately may cause the increased morbidity and mortality from fractures seen in KS.
And although no substantial evidence exists for a positive effect of testosterone treatment in KS, we recommend that hormone replacement therapy with adequate doses of testosterone should be instituted early in puberty, to secure a proper development of bone and muscle bulk, and to prevent the later consequences of low BMD.
Testosterone treatment in KS patients is recommended by most endocrinologists, but clear evidence for an effect of treatment is missing, since no randomized placebo controlled trials on testosterone treatment in KS has ever been published. A few nonrandomized studies have demonstrated some positive effects. Several testosterone preparations for oral, transdermal and intramuscular administration with different costs and pharmacokinetics are available and are listed in Table 1.
The oral route can be administered by undecanoated testosterone, being lipofile and therefore partly absorbed by the lymphatic system and bypassing the initial metabolism in the liver, decreasing the liver toxicity of oral testosterone. Oral administration gives a peak concentration after about 4 hours but there is a considerable variability in the same individual on different days. Patches is also available but is shown inferior to gel in normalizing serum testosterone and may cause skin irritation.
For testosterone gel the first few 4—6 hours after dermal administration, the patient should remain dry and avoid skin contact with especially females and children to avoid incidental transfer of testosterone to others.
It can be administered intramuscular every 2—3 weeks and have serum peak level after 2—3 days and serum trough testosterone levels about 10 days after injection. The pellets may extrude spontaneously. Monitoring of treatment should be based mainly on clinical effects including libido, ejaculate volume, body hair growth, muscle mass and energy level , but should also be aimed at possible adverse effects.
This is complemented with biochemical monitoring of serum testosterone either steady state or trough concentrations depending on the formulation , and or LH values, which should be in the normal range. Monitoring for side effects like increased hemoglobin, sleep apnea, acne and signs of too high or too low testosterone should be part of the routine outpatient program.
Treatment of children and adolescents should be monitored carefully, with slow dose increments in order to mimic normal pubertal development. A recently proposed outpatient program is shown in Table 2. National Center for Biotechnology Information , U. Journal List Asian J Androl v. Published online Jan This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.
This article has been cited by other articles in PMC. Abstract Klinefelter syndrome KS 47, XXY is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men.
Open in a separate window. Table 1 Summary of different testosterone preparations. Table 2 Proposed assessment and follow-up program for at patient with Klinefelter syndrome. Prenatal and postnatal prevalence of Klinefelter syndrome: J Clin Endocrinol Metab. The prevalence and diagnosis rates of Klinefelter syndrome: Am J Hum Genet. Syndrome characterized by gynecomastia, aspermatogenesis without a-leydigsm and increased secretion of follicle-stimulating hormone.
Bojesen A, Gravholt CH. Klinefelter syndrome in clinical practice. Nat Clin Pract Urol.
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