Approach

Key Points

  • Treatment interventions for Klinefelter syndrome (KS) depend on the age at diagnosis and the severity of the symptoms/signs. Multidisciplinary care is the ideal, especially for any individual with a severe phenotype.[1][2][4]

  • If KS is diagnosed antenatally or in childhood, early intervention is recommended and must be tailored to the boy’s individual developmental, learning, or behavioural challenges.[2][3]

  • Testosterone therapy is the mainstay of treatment for post-pubertal adolescents and adult men, with the goal of reversing clinical and biochemical hypogonadism.[3] 

  • Fertility counselling is important, as >90% of men with KS are azoospermic.[2][4] Assisted reproductive technologies such as testicular sperm extraction (TESE) or microscopic TESE (mTESE) have improved the prospects for men with KS to have biological children, although use of donor sperm or adoption remains a common alternative option. Performing TESE/mTESE in young adulthood appears to offer the best chance of extracting viable sperm for cryopreservation.[2][3] 

  • Adults with KS have a significantly increased risk of developing diabetes, cardiovascular disease, osteoporosis, and breast cancer. This can be minimised with testosterone therapy, lifestyle advice, and regular surveillance of risk factors.[3][4]​​[23]​​

Treatment of KS focuses on testosterone replacement therapy (from adolescence onwards), together with neuropsychological and adaptive therapies tailored to the individual’s age and symptoms. Specific interventions vary based on the age and developmental stage at diagnosis and the severity of the phenotype.

  • Multidisciplinary specialist care from a team with specific expertise in KS is the ideal, particularly for patients with a severe phenotype who will benefit from input from paediatricians, endocrinologists, infertility specialists, speech-language therapists, psychologists, and primary care physicians.[1][2][4][23]

Individuals diagnosed antenatally or in childhood

When KS is diagnosed antenatally or in childhood, there is an opportunity to ensure early intervention, although evidence is lacking that this improves long-term adult outcomes.[3] Parents can be reassured that the majority of boys and men with KS function fairly normally.[2] 

  • The goals of treatment differ based on the age of the boy and the specific developmental delays. It is important to have a full developmental and cognitive paediatric assessment to direct individual therapies for any learning or behavioural challenges.[2][17][18]​ Many boys with KS will require speech-language therapy, special educational support, and psychological counselling, but this must be targeted to their individual needs.[2][18][23]​ 

  • For any boy diagnosed antenatally, ensure  ongoing monitoring of speech development, learning and educational progress, and psychosocial problems. This should start from the point of diagnosis and continue into adolescence so that appropriate support can be provided as needed.[3]

Testosterone therapy

Testosterone therapy is a key element in the management of KS and is a mainstay of treatment for post-pubertal adolescents and adult men.[2] The aim is to normalise testosterone and luteinising hormone (LH) levels to the mid-normal range, although treatment can also be guided by symptom response with the goal of reversing clinical hypogonadism.[1]​ 

Benefits of testosterone therapy include:[2][3]

  • Promotion of pubertal maturation and reduction of gynaecomastia.

  • Improved bone mineral density and hence a reduced risk of developing osteoporosis in adulthood.

  • Reduced fat mass and improved muscle strength. This attenuates the increased prevalence of diabetes and cardiovascular disease among men with KS.[4]​

  • Improved libido and mood.

Starting testosterone therapy in adolescents

Testosterone therapy should be supervised by a paediatric endocrinologist and can be considered in adolescents when it becomes clear that spontaneously secreted testosterone has become insufficient to support continued normal pubertal maturation.

A decision to start testosterone therapy can be based on the diagnosis of either biochemical or clinical hypogonadism.[2][23]​

  • Low testosterone levels on early-morning testing confirm the onset of biochemical hypogonadism, which usually begins in late puberty (Tanner stage 5).[2]

  • Symptoms/signs of clinical hypogonadism may occur earlier than the onset of biochemical hypogonadism. They include:[2]

    • Slow virilisation (i.e., stalled pubertal progress).

    • Gynaecomastia. Note that testosterone therapy can alleviate or resolve gynaecomastia but is most effective if started at the first appearance of breast tissue enlargement.

    • Micropenis (stretched length ≥2.5 standard deviations [SD] below the mean for age).

    • High body mass index/obesity. The typical male pattern is to slim down and become more muscular as puberty progresses. Failure of this change to occur may be an indication for treatment to start.

    • Lethargy (a weak indication on its own).

Do not base a decision to initiate testosterone therapy solely on rising gonadotrophin (LH/follicle-stimulating hormone [FSH]) levels.[3][14][15]​ 

  • Gonadotrophin levels will begin to rise from the start of puberty but, in isolation, this is not a sign to begin treatment if the individual has not yet developed testosterone deficiency or clinical signs of hypogonadism.

  • However, in the authors’ experience, all patients with rising levels of LH/FSH will have some clinical features of hypogonadism that are a sufficient indication to start testosterone therapy, albeit these may be subtle signs: for example, high fat mass/low muscle mass detected on dual-energy x-ray absorptiometry (DXA) scanning.

An informed discussion about fertility is recommended prior to initiation of testosterone therapy in adolescence.[3]

Testosterone therapy in adults

In adult men with KS, the principles of testosterone therapy are the same as for any other man with primary hypogonadism. For more detail, see Hypogonadism in men.

  • If testosterone therapy has been started during adolescence, it should be continued into adulthood.

  • If KS is diagnosed in an adult man, postpone initiation of testosterone therapy if there is a plan in the near term to attempt sperm retrieval for fertility treatment.[1][3]​​​[23][32]

Lifelong treatment is normally recommended to help prevent complications of hypogonadism such as osteoporosis and obesity.[1]

Rare indications for testosterone therapy in children

Evidence is insufficient to support the routine use of testosterone in KS in infancy and pre-pubertal childhood, but consider referral to a paediatric endocrinologist if  micropenis is present (stretched length ≥2.5 SD below the mean for age).[2] In this rare scenario: 

  • The European KS guideline recommends that short-term, low-dose testosterone therapy may be justified if serum levels of testosterone are found to be abnormally low and LH levels are elevated.[3]

  • The British Society for Paediatric Endocrinology and Diabetes guideline recommends short-term, low-dose testosterone therapy (either via monthly injections for 3 months or topical application).[37]​ 

  • Formulation and dose regimen of testosterone is individualised by the paediatric endocrinologist.

If cryptorchidism is noted, refer to paediatric urology.[2] For more detail, see Cryptorchidism.

Choice of testosterone regimen

There are many formulations of testosterone available for administration. Options include oral, transdermal, intramuscular, intranasal, and buccal formulations, although the availability of these formulations varies between countries.[3][38][39]​ 

  • Transdermal testosterone gel is the preferred mode for managing pubertal replacement and allows for easy dose escalation.[1][2]

  • For longer-term replacement for adults, either the transdermal gel or the long-acting intramuscular injection (testosterone undecanoate) tends to be best for adherence purposes.[2]

  • Intramuscular or subcutaneous injection with testosterone enantate or testosterone cipionate is also commonly used in the US. In other parts of the world, intramuscular formulations with mixed testosterone esters may be used (e.g., testosterone propionate, phenylpropionate, isocaproate, and decanoate esters).

For more detail on the options for adults, see Hypogonadism in men.

Regular monitoring is needed to ensure adherence, assess effectiveness, adjust dosing, and monitor any adverse effects.

  • Monitoring should include regular checks of serum testosterone, gonadotrophins, and haematocrit, initially at 3-6 months (depending on the testosterone formulation), then at 12 months and annually thereafter.[3][32]​ 

Fertility treatment

More than 90% of individuals with KS are azoospermic.[2][4]​​

  • In the other 10%, mobile spermatozoa may be found in the semen and can be cryopreserved for use in assisted reproduction.[3]

Among those who are azoospermic, techniques such as testicular sperm extraction (TESE) or microscopic testicular sperm extraction (mTESE) have improved the prospects of having biological children.[2][3]

  • Focal spermatogenesis may be identified, with the possibility of attempting TESE/mTESE to harvest viable sperm for use in intracytoplasmic sperm injection (ICSI).[3]

  • A meta-analysis suggested a success rate for sperm retrieval of 44% in men with KS. Age, testosterone and FSH levels, and testicular volume were found to have no significant impact on outcome.[40]​

The optimal timing for attempting sperm extraction with TESE/mTESE is unclear.[2]

  • Because testicular fibrosis and hyalinisation is progressive in KS, starting when gonadotrophin levels begin to rise in early puberty, there is debate about whether to harvest and cryopreserve sperm as early as possible after diagnosis in adolescents and young men with KS.[3] However, there is increasing evidence that this option should not be offered to individuals aged <16 years because mTESE has lower retrieval rates for germ cells in this age group compared with those aged 16-30 years.[41]​ 

  • On balance, performing TESE/mTESE in young adulthood rather than delaying until an individual is keen to have a biological child maximises the potential for obtaining viable sperm.[2][3] 

  • When KS is diagnosed in an adult man who has a current or potential wish for biological children, initiation of testosterone therapy should be delayed until after TESE/mTESE.[3]

In spite of these advances in reproductive technology, use of donor sperm or adoption remains the best chance of having a child for many men with KS, although cultural factors may influence the decision for some men.​[23][32]

Counselling for possible infertility

Many young adult males with KS are emotionally less mature than their peers and the concept of fertility prediction/estimation needs careful counselling.[2]

  • In particular, the emotional consequences of knowing they are going to be infertile needs careful consideration prior to discussion of the results of any semen analysis procedures.

  • The benefit of carrying out a surgical sperm retrieval at the optimal time must be balanced against the potential psychological distress if no sperm is found.

  • Some men with KS may have a reduced capacity to understand complex explanations so key points are best presented in a simple structured way, backed up by written text.

Other aspects of care

Adults with KS have a significantly increased risk of insulin resistance, obesity, metabolic syndrome, and cardiovascular disease.[3][23]​​

  • Almost half of men with KS fulfil the criteria for metabolic syndrome compared with 10% of controls, and the reported prevalence of type 2 diabetes is 10% to 39%.[1]

  • Increased insulin resistance associated with hypogonadism does not fully explain this increased risk. Poorly understood epigenetic mechanisms are also thought to be a contributory factor, hence the increased risk is only partially attenuated by testosterone therapy.[3]

  • Along with testosterone therapy, lifestyle advice, regular surveillance of cardiovascular risk, and standard pharmacological interventions to manage risk factors are all important.[2] Annual checks of weight, waist circumference, blood pressure, fasting glucose, HbA1c, and lipid profile are recommended in all adult men with KS.[3] 

  • See Type 2 diabetes mellitus in adults and Metabolic syndrome.

The increased risk of osteopenia/osteoporosis requires careful monitoring, although it is attenuated by testosterone therapy.[4]​

  • The risk of lower bone mass begins around mid-puberty, preventing the achievement of peak bone mass.[3] Osteopenia and osteoporosis have a reported prevalence of 5% to 40% and 10%, respectively, among men with KS.[1]

  • Low bone density is not a typical feature of KS in childhood or adolescence.[2] Nonetheless, assessment of vitamin D and calcium status is recommended throughout childhood and adolescence, with DXA to evaluate bone mineral density every 2 years if vitamin D deficiency is identified.[3]

  • For men diagnosed as adults, a baseline DXA and fracture risk assessment is recommended, with subsequent monitoring dependent on the individual’s risk level.[3] If osteoporosis develops, it can be treated as per standard guidelines for the condition. See Osteoporosis.

Men with KS are also at increased risk of breast cancer (approximately fourfold risk compared with non-KS males, although the lifetime risk is still low).[4]​

  • Breast examination to check for cancer risk is recommended in any adult with KS, initially at the point of diagnosis and thereafter on an individual basis according to risk.[3]

Neurocognitive challenges can persist into adulthood, often necessitating referral to a neuropsychologist.[4]

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