Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

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children

1st line – multidisciplinary care

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children
1st line – 

multidisciplinary care

Specific treatment interventions for KS vary depending 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 pediatricians, endocrinologists, speech-language therapists, psychologists, and primary care physicians.[1][2][4][23]​​​

Plus – individualized educational and/or psychological support

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children
Plus – 

individualized educational and/or psychological support

Treatment recommended for ALL patients in selected patient group

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

  • It is important to have a full developmental and cognitive pediatric assessment to direct individual therapies for any learning or behavioral challenges.[2][17]​​[18]​ Many boys with KS will require speech-language therapy, special educational support, and psychological counseling, but this must be targeted to their individual needs.[2][18]​​[23]​ 

  • For any boy diagnosed prenatally, ensure ongoing monitoring of speech development, learning and educational progress, and psychosocial problems so that appropriate support can be provided as needed.[3]

  • Parents can be reassured that the majority of boys and men with KS function fairly normally.[2]

Consider – testosterone therapy

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children
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with micropenis
Consider – 

testosterone therapy

Treatment recommended for SOME patients in selected patient group

Evidence is insufficient to support the routine use of testosterone in KS in infancy and prepubertal childhood.

Consider referral to a pediatric endocrinologist if micropenis is present (stretched length ≥2.5 standard deviations [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 luteinizing hormone (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).[38]​ 

  • Formulation and dose regimen of testosterone is individualized by the pediatric endocrinologist.

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

Complications of testosterone deficiency are rare in children with KS. Low bone density is not a typical feature of KS in childhood; a risk of reduced bone mass generally begins in mid-puberty.[2][3]​ Nonetheless, assessment of vitamin D and calcium status is recommended throughout childhood and adolescence, with dual-energy x-ray absorptiometry (DXA) to evaluate bone mineral density every 2 years if vitamin D deficiency is identified.[3]

adolescents

1st line – multidisciplinary care

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adolescents
1st line – 

multidisciplinary care

Specific treatment interventions for KS vary depending on the age and developmental stage at diagnosis and the severity of the phenotype. From adolescence onward, testosterone replacement therapy becomes a mainstay of management.

Multidisciplinary specialist care from a team with specific expertise in KS is the ideal, particularly for patients with a severe phenotype.[1][2][4][23]

Plus – individualized educational and/or psychological support

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adolescents
Plus – 

individualized educational and/or psychological support

Treatment recommended for ALL patients in selected patient group

Depending on the severity of the phenotype, adolescents with KS may have educational, social, and psychological problems. In particular, deficits in expressive language skills are more common in adolescents with KS than among their non-KS peers.[3] Ongoing monitoring of speech, educational, and psychosocial development is recommended, with support provided as needed.[3] In some cases, referral to a neuropsychologist may be indicated.[4]

Plus – testosterone therapy

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adolescents
Plus – 

testosterone therapy

Treatment recommended for ALL patients in selected patient group

​Testosterone therapy is a key element in the management of KS and is a mainstay of treatment for postpubertal adolescents.[2] 

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

  • Promotion of pubertal maturation and reduction of gynecomastia

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

  • Reduced fat mass and increased muscle strength[4]​

  • Improved mood.

Starting testosterone therapy

Testosterone therapy should be supervised by a pediatric 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: slow virilization (i.e., stalled pubertal progress); gynecomastia (note that testosterone therapy can alleviate or resolve gynecomastia 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).[2]

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

  • Gonadotropin 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]

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][39][40]​ Buccal formulations are not available in the US.

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

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

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

Risk of osteopenia/osteoporosis

The increased risk of osteopenia/osteoporosis that is associated with KS is attenuated by testosterone therapy but requires careful monitoring.[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]​ 

  • 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]

Primary options

testosterone transdermal: consult specialist for guidance on dose

Plus – fertility counseling

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adolescents
Plus – 

fertility counseling

Treatment recommended for ALL patients in selected patient group

Fertility counseling is an important aspect of care for individuals with KS.​

  • More than 90% of individuals with KS are azoospermic. However, focal spermatogenesis may be identified, in which case techniques such as testicular sperm extraction (TESE) or microscopic testicular sperm extraction (mTESE) offer some prospect of having biological children.[2][4]

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

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

  • Because testicular fibrosis and hyalinization is progressive in KS, starting when gonadotropin 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 ages <16 years because mTESE has lower retrieval rates for germ cells in this age group compared with those ages 16-30 years.[42]​ 

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

Many young males with KS are emotionally less mature than their peers and the concept of fertility prediction/estimation needs careful counseling. Key points are best presented in a simple structured way, backed up by written text.[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.

adults

1st line – multidisciplinary care ± psychological support

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adults
1st line – 

multidisciplinary care ± psychological support

Specific treatment interventions for KS vary depending on the age at diagnosis and the severity of the phenotype. Adults with KS may have been diagnosed during adolescence or earlier in childhood, but in most cases the diagnosis is made in adulthood during evaluation for male infertility or other symptoms/signs of hypogonadism.[3][4]​​​​ ​

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 endocrinologists, infertility specialists, psychologists, and primary care physicians.[1][2][4][23]​​​​

Social and neurocognitive challenges can persist into adulthood, often necessitating referral to a neuropsychologist.​[4]

Plus – testosterone therapy

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adults
Plus – 

testosterone therapy

Treatment recommended for ALL patients in selected patient group

Testosterone therapy is a mainstay of treatment for adult men with KS.[2] The aim is to normalize testosterone and luteinizing 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]​

Lifelong testosterone therapy is normally recommended to help prevent complications of hypogonadism.[1]​ Benefits of testosterone therapy include:[2][3]

  • Reduction of gynecomastia, although the most effective window for achieving this is when breast tissue enlargement first appears during adolescence.

  • 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.

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]

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][39][40]​​​ Choice of testosterone regimen varies between countries. Buccal formulations are not available in the US. 

  • 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 enanthate or testosterone cypionate is also commonly used in the US. In other parts of the world, intramuscular formulations with mixed testosterone esters may be used.

  • 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, gonadotropins, and hematocrit, initially at 3-6 months (depending on the testosterone formulation), then at 12 months and annually thereafter.[3][32]

Plus – fertility counseling ± assisted reproductive technology

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ONGOING
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adults
Plus – 

fertility counseling ± assisted reproductive technology

Treatment recommended for ALL patients in selected patient group

​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]

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

Testicular sperm extraction

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 follicle-stimulating hormone (FSH) levels, and testicular volume were found to have no significant impact on outcome.[41]​

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

  • Because testicular fibrosis and hyalinization is progressive in KS, starting when gonadotropin 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 ages <16 years because mTESE has lower retrieval rates for germ cells in this age group compared with those ages 16-30 years.[42]​ 

  • On balance, performing TESE/mTESE in young adulthood rather than delaying until an individual is keen to have a biological child maximizes 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]

Plus – lifestyle measures and cardiovascular disease/osteoporosis risk reduction

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adults
Plus – 

lifestyle measures and cardiovascular disease/osteoporosis risk reduction

Treatment recommended for ALL patients in selected patient group

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 fulfill 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 pharmacologic 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]

  • For men diagnosed as adults, a baseline dual-energy x-ray absorptiometry (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]

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Choose a patient group to see our recommendations

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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