Klinefelter Syndrome. the Effects of Early Androgen Therapy on Competence and Behavioral Phenotype

REVIEW

Klinefelter Syndrome. The Effects of Early Androgen Therapy on Competence and Behavioral Phenotype

Ryan Flannigan, MD,1 Premal Patel, MD,2 and Darius A. Paduch, MD, PhD1,3

ABSTRACT

Introduction: Klinefelter syndrome (KS) is the result of sex chromosome aneuploidy most often characterized as 47,XXY. The typical features of KS include tall stature, gynecomastia, small firm testicles, hypergonadotropic hypogonadism, and infertility. However, abnormalities in neurodevelopment, cognition, and social and behavioral functioning also can be present. The abnormalities in neurodevelopment are believed to be due in part to androgen deficiency during early development and puberty. Aim: To discuss the role of androgens in normal adolescent development; discuss the cognitive, behavioral, and social functioning of children with KS; evaluate the evidence for early androgen therapy in men with KS; and discuss management strategies in the development of boys with KS. Methods: A systematic review of early androgen therapy and KS was performed using PubMed-Medline and Scopus databases. Relevant articles commenting on social, behavioral, cognitive, and physical outcomes among infants, children, and adolescents were included for reporting and discussion. Main Outcome Measures: Social and behavior functioning; cognitive outcomes; adverse effects associated with androgen therapy. Results: 3 retrospective articles and 2 randomized controlled trials addressing early androgen therapy in boys with KS were reviewed. These studies showed an improvement in several aspects of social and cognitive functioning based on validated questionnaires. Treatment strategies, potential negative effects, and limitations of the literature on early androgen therapy in boys with KS are discussed. Conclusion: Our findings indicate that early androgen supplementation in children with KS combined with specific educational, family, and social support improves behavioral functioning. The optimal timing of hormonal therapy might require prospective studies, but based on our data and review of the literature, the benefit of early hormonal and therapeutic intervention in KS is very encouraging. Flannigan R, Patel P, Paduch DA. Klinefelter Syndrome. The Effects of Early Androgen Therapy on Competence and Behavioral Phenotype. Sex Med Rev 2018;6:595e606. Copyright 2018, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. Key Words: Klinefelter Syndrome; 47,XXY; Testosterone; Neurodevelopment; Behavioral Phenotype; Androgen

INTRODUCTION testicles, androgen deﬁciency, infertility, and gynecomastia. The 1 Klinefelter syndrome (KS) refers to the genetic diagnosis of an syndrome was 1st described by Klinefelter et al, when they re- X chromosome polyploidy with at least 1 additional X chro- ported on a series of 9 men in 1942; these men were found to mosome present and a clinical phenotype of tall stature, small have azoospermia, small hard testicles, limited hair growth to the face and body, and gynecomastia. However, it wasn’t until 1959 when patients presented with this phenotype and were found to Received October 17, 2017. Accepted February 2, 2018. have an additional X chromosome.2 KS has since become the 1Department of Urology, Weill Cornell Medicine, New York, NY, USA; 2 most common genetic X chromosome abnormality. KS is iden- Division of Urology, Department of Surgery, University of Manitoba, ﬁ Winnipeg, MB, Canada; ti ed in 0.1% to 0.2% of newborn boys and is the most com- 3Consulting Research Services, Inc, North Bergen, NJ, USA mon genetic cause of male infertility, with an incidence of 3% to ª 4% in infertile men, attributed to oligozoospermia in 0.6% and Copyright 2018, International Society for Sexual Medicine. Published by 3e6 Elsevier Inc. All rights reserved. azoospermia in 10% to 12%. Most diagnoses of KS are made https://doi.org/10.1016/j.sxmr.2018.02.008 through prenatal diagnosis in mothers older than 35 years.

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extraction. Boys with KS also might have abnormal physical features including a small or micropenis, truncal hypotonia (68%), joint laxity (50%), hand tremors in children after 5 years of age (20e50%), clinodactyly or curved 5th digit (26%), pectus excavatum, delayed puberty (50%), gynecomastia (30%), mirror movements (40%), infantile cherubic faces, and disproportion- ately long limbs. Other clinical features include developmental abnormalities in speech with decreased phoneme repertoire (50e75%), age-appropriate language comprehension (80%), delayed auditory memory (50e80%), enhanced visual memory (50e80%), normal IQ within 10 to 15 points of siblings (80%), reading deficiencies or dyslexia (50%), delayed balance skill acquisition (50e80%), sensory differences, pseudo-torticollis Figure 1. Gynecomastia in a man with Klinefelter syndrome. (20%), developmental dyspraxia (50e80%), and psychosocial Figure 1 is available in color online at www.smr.jsexmed.org. e functioning.11 13 The behavioral profile of boys with KS consists Genetics of KS of poor self-esteem, shyness, increased anxiety, depression, and e In KS, non-dysjunction of the sex chromosomes results in at social difficulties.12 14 Because of androgen deficiency in infants least 1 additional X chromosome. 80% to 90% of men with KS and boys with KS, they can exhibit, albeit less commonly, fea- have a 47,XXY karyotype. Several variant karyotypes also have tures of under-virilization such as micropenis, bifid scrotum, been described such as 47,iXq,Y, 48,XXYY, and 48,XXXY or cryptorchidism, and hypospadias.15 During adolescence 62% of mosaicisms 47,XXY and 46,XY. In these cases, non-dysjunction boys can maintain serum testosterone (T) levels higher than 10 occurs most frequently during meiosis I in oogenesis (50%) and nmol/L through hypergonadotropic compensation, and most 7 spermatogenesis (40%) or in meiosis II during oogenesis (10%). will enter puberty.16 However, relative androgen deficiency is 2 Rarely, non-disjunction occurs in early embryogenesis (3%). It progressive in most men in later stages of life; men with KS are at is important to discuss with the patient and parents that it is the risk of sequelae of androgen deficiency such as osteoporosis, low Y chromosome that determines the sex of an individual; hence, libido, and erectile dysfunction (ED). It appears that ED is likely regardless of the number of X chromosomes, boys and men with the result of androgen deficiency and not linked to the syndrome KS are phenotypically male. Genes derived from the X chro- itself, because 1 study reported a comparable rate of ED in 40 mosome are predominantly expressed in the brain, testes, and men with KS compared with age- and T-matched controls17; ovaries. Most of the genetic material on 1 X chromosome in similarly, a study of 53 men with KS had a comparable rate of women undergoes inactivation; hence, in 46,XX female and ED as 75 age-matched controls with a rate of 18.9% but 46,XY male individuals, there is only 1 functional X chromo- significantly lower sexual desire.18 The severity of ED in young some. Inactivation of additional X chromosomes occurs by epigenetic regulation through non-coding RNAs called XIST, which is expressed on the X chromosome to be inactivated.8 Unfortunately, the process of X chromosome inactivation is promiscuous and not complete; hence, the entire additional X chromosome is not always inactivated.9 It is believed that the variability in X chromosome inactivation, and approximately 15% of X chromosome genes escaping silencing, could be responsible for the phenotypic variability observed in KS.

Clinical Phenotype and Endocrinology of KS The clinical manifestation has been further characterized since its initial inception. The clinical phenotype classically includes tall stature, gynecomastia (Figure 1), gynoid hips, sparsity of body hair, firm hypotrophic testes (<4 mL; Figure 2), hypergonadotropic hypogonadism, infertility, and a propensity toward obesity.2 Infertility is typically associated with progressive hyali- Figure 2. Tanner stage vs mean right testis length (millimeters). Gray line represents testicular growth during puberty in a normal nization, fibrosis, Leydig cell hyperplasia, and depletion of germ boy. Red line represents decreased trajectory of testicular growth cells among the seminiferous tubules. This typically results in during puberty in a boy with Klinefelter syndrome and decreased Sertoli cell only syndrome and is believed to worsen immediately final testis length by the end of puberty compared with boys 10 after puberty. This most often results in azoospermia and re- without Klinefelter syndrome. Figure 2 is available in color online at quires surgical sperm retrieval by microdissection testicular sperm www.smr.jsexmed.org.

Sex Med Rev 2018;6:595e606 Early Androgen Therapy in Klinefelter Syndrome 597 men with KS varies by report, but 2.5% (mean age ¼ 23.3 cytogenetics in evaluation of children with developmental delay. years)17 to 22.7% (mean age ¼ 40 years)19 of men with KS were These can present as language-based difficulties, executive found to have severe ED. It also is important to acknowledge dysfunction, learning disabilities, and speech delays. It is the that these individuals most often do not have normal levels of myriad of these dysfunctions that is believed to contribute to the androgen (65e85% of men with KS have total T levels < 12 complex social and behavioral phenotypes commonly seen in nmol/L15) and therefore typically have normal libido and sexual children with KS.26,31 Children with KS also are at an increased function even at minimally low serum levels. In fact, significant risk for attention-deficit/hyperactivity disorder (ADHD) and heterogeneity exists in the clinical phenotype of men with other psychological conditions.31 Awareness about the associa- KS, and many of the features progressively worsen as the tion of these symptoms with KS among pediatricians and individual ages.15,20,21 This can be due to varying levels of educators should lead to more common implementation of androgens, T/estradiol ratios, androgen receptor sensitivity dif- cytogenetic testing. Early identification allows implementation of ferences associated with variable CAG repeat lengths, or variation treatment strategies for learning and/or emotional disorders, in X chromosome inactivation.22 access to appropriate resources, and alleviation of parental Examination of the testes during the 2nd trimester in fetuses distress. Implementing language therapy can help children with KS has demonstrated variable findings, with half reporting a develop more advanced language comprehension and expression 28 smaller number of germ cells and the others finding normal skills, which can prevent social isolation. Medically, KS is histology.23 Androgen levels in infants and young children have associated with hypergonadotropic hypogonadism, which tends 31 been variable, with some studies finding a lower level of circu- to manifest clinically by midpuberty. Early diagnosis can allow e lating androgens and a decreased postnatal surge.24 26 Others the initiation of androgen replacement therapy before signs and 28 have reported diminished muscle tone and a smaller penis, which symptoms of hypogonadism develop. Early diagnosis also has serves as a reflection of androgen deficiency.27 Based on our the advantage of considering fertility preservation. Because KS is experience, it is rather clear that most, if not all, male individuals associated with a decline in spermatogenic capacity likely at birth with KS exhibit a certain level of androgen resistance; hence, and more convincingly during puberty, a study looking at pe- rather than focusing on absolute T levels, we use markers of diatric and parental attitude toward neonatal screening and androgenization such as muscle and penile development, sperm preservation found a positive attitude and appreciation for 32 strength, bone age, presence of acne, and hair distribution. these strategies.

Early Diagnosis of KS Neuroendocrinology of KS Diagnostic delay is a common feature of KS because of the With respect to the complex neurobehavioral deficits often wide variability in clinical presentation and often delayed onset of seen in patients with KS, they could be a result of abnormal symptoms at or beyond puberty. Furthermore, the more mild neurodevelopment. Findings of structural imaging studies have forms tend to lack any obvious clinical signs other than small and been varied, with most reporting a decrease in gray and white firm testes.28 A study from the United Kingdom estimated that matter volume. The most pronounced effects have been on the 64% of cases of KS might never be diagnosed, 10% are diag- frontal and temporal lobes.27,33 The neuroanatomic phenotype is nosed prenatally, and the remaining 26% are diagnosed before just as variable as the clinical phenotype. What are paramount for puberty and at adulthood.29 A similar study from Denmark appropriate neurodevelopment are androgens, specifically T, found comparable results with approximately 75% of cases which plays an important role in mammalian brain development undiagnosed and fewer than 10% identified before puberty when and exerts a wide array of influence on cognitive functioning and comparing postnatal prevalence with prenatal incidence in those social behaviors in boys and men. Specifically, cognitive flexi- undergoing prenatal cytogenetic studies.6 With increasing bility improves, decreases in perseverative behavior occur, and maternal ages, more diagnoses are being made in utero. task switching, working memory, social cognition, and concept Conventionally, KS is diagnosed by cytogenetic studies from formation improve during the adolescent period corresponding peripheral blood lymphocytes evaluating the karyotype in GTG to pubertal changes as we enter adulthood.34 Sex hormone in- and RHG banding. However, fluorescence in situ hybridization fluence begins in utero and continues through adulthood.26,35 can be performed on peripheral blood lymphocytes by using These early androgens are believed to influence gray matter probes targeting DXZ1 and DYZ3 and aid in diagnosing volume and cortical maturation leading to an organizational individuals with mosaicism.30 There has been growing interest in effect of social and cognitive behaviors. 2 surges were found to the rationale for postnatal screening of KS to allow early influence neurodevelopment before puberty, which include an identification to potentially implement beneficial interventions intrauterine surge that happens at 8 to 24 weeks’ gestation and a because many sequelae are related to a time-dependent exposure neonatal surge, also known as “mini-puberty,” that occurs at 2 of low T. Because children with KS often possess weeks after birth and continues until at least 24 weeks. Studies neurodevelopmental delays and variable extents of cognitive have identified thinning of the prefrontal cortex associated with deficits, neurologists and developmental pediatricians use progression of Tanner stages during puberty.36 However,

Sex Med Rev 2018;6:595e606 598 Flannigan et al increased size of the subcortical white matter and corpus consequences and bone mineral density loss.40 However, only callosum has been correlated with T levels.37,38 Furthermore, in recently published reports are emerging concerning androgen non-human primate studies, androgen receptors have been supplementation in infants and young children. localized to numerous regions in the brain including several A retrospective study of children with 49,XXXXY, a rare hypothalamic nuclei, lateral septum, stria terminalis, cortex, variant of KS, found a positive treatment effect in speech and 39 medial preoptic area, and amygdala. Thus, neurodevelopment language domains, gestural communication, and vocabulary fl and functioning could be largely in uenced by the presence of development for those treated with early androgen replacement. adequate ligands for the naturally occurring androgen receptors Initiation of androgen replacement was based on phallus size, among these areas. A multitude of studies have reported on those with 10 children receiving T enanthate 25 mg/month for 3 fi with androgen de ciency and the positive impact of T replace- months and 1 child receiving 40 mg/month for 3 months. The 2 ment in adolescents and adults with KS. However, little is known groups consisted of 11 children, with the mean age of T about T levels in children and whether early androgen replace- administration in the intervention group being 12 months. The 26 ment could lead to improvements in neurodevelopment. 1st evaluation was conducted at 74 months in the treatment arm Different formulations of T replacement have been used, pre- and 84 months in the control group. Limitations of the study as dominately T enanthate and oxandrolone. Aromatase inhibitors outlined by the investigators include that T administration was also are sometimes used in response to excessive estradiol levels. based on phallus size and androgen levels were not measured before initiation of therapy. Discrepancy in timing of evaluation METHODS after treatment was not discussed. Timing of androgen supplementation also varied substantially from newborn to 30 months A systemic literature search of the PubMed-Medline and of age.41 Scopus databases was performed on October 2017, including literature from 1999 through 2017. We included English- A follow-up study was performed that included 101 boys with languages articles only. The search strategy included broad 47,XXY referred for a comprehensive neurodevelopmental terms in isolation or in combination: testosterone therapy, testos- assessment at the Neurodevelopmental Diagnostic Centre for terone replacement, androgen therapy, androgen replacement, Young Children (Davidsonville, MD, USA). 34 of these children Klinefelter, Klinefelter syndrome, neurodevelopment, cognitive received T injections as a treatment course for small phallus at a development, and cognitive development. Relevant articles on the dose of 25 mg/month for 3 months as per their pediatric effects of early androgen therapy on cognition, behavior, and endocrinologist, with treatment age ranging from 4 to 15 social functioning of children with KS were sought. Review ar- months. At 36 and 72 months, standardized questionnaires were fi ticles, editorials, case reports, comments, and meeting abstracts given to all participants. Their ndings showed improved func- were excluded. Additional relevant articles were selected from tion in several aspects of neuromotor, speech and language, authors’ bibliographies. All studies of interest were obtained as intellectual, and reading function. In accord with their prior full-text articles. Study eligibility was determined by 2 authors retrospective study, limitations include that T was administered (R.K.F. and P.P.). based on phallus size, which serves as a clinical surrogate of androgen deficiency.42 However, this could signify that androgen replacement has a positive impact on cognitive and behavioral RESULTS outcomes in those with presumed androgen deficiency based on 7 studies specific to androgen replacement therapy in young phallus size. A follow-up study of patients from the same cohort male patients with KS were retrieved for our review. 3 of the was published in 2015. 29 boys were administered T enanthate, studies were by the same author (Samango-Sprouse) with 1 of as described previously, at a dose of 25 mg/month for 3 months the studies evaluating children with 49,XXXXY and the impact when the boys were 4 to 15 months old. 57 children served as of T therapy. The 2 randomized trials in the literature were controls. Children were 9 to 11 years old. They found fewer published in 2017 by Ross et al and Davis et al and were derived behavioral problems and improved social behavioral skills of the from the same patient cohort. Ross et al reported improved so- boys who received T. Children who received early T also had cial, behavior, and visuomotor performance in children receiving fewer somatic complaints such as headaches and stomach aches, androgen supplementation. The studies and their findings are which have been reported to be higher in children with anxiety, fi presented in Table 1. language-based disabilities, and social communication dif - culties. The most significant behavioral differences observed in this study were within social domains, including social cognition, DISCUSSION communication, and overall social problems. The investigators Early Androgen Replacement did not identify any adverse outcomes in those receiving 26 Androgen supplementation has been most commonly studied androgen supplementation. in postpubescent and adult men with KS and is commonly A retrospective study reported on 151 boys with a mean adopted to improve quality of life and prevent metabolic age 11.6 years at presentation and serum T level lower than

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Table 1. Summary of articles relevant to early androgen therapy in KS included in this review Study Inclusion Cohort Treatment Follow-up Outcome

Kubler et al,40 1992 KS 21 men with KS without T, Intramuscular injection Men with KS <20 y BMD decrease those with no T treatment 10 men with KS with T of T 250 mg old received T for and those with KS treated beyond 20 before 20 y of age, 11 (Testoviron) every mean 5.7 ± 7.1 y; y of age (P < 0.001 and P ¼ 0.04); men with KS with T 4e6wk men with KS >20 BMD maintained in men with KS after 20 y of age y old at T initiation treated before 20 y of age (105% of received T for mean normal controls) 5.4 ± 5.3 y Samango-Sprouse 49,XXXXY 22 children: 11 in treatment 10 boys received T Treatment arm 74 mo, Positive treatment effect in speech and et al,41 2011 group (age range ¼ 8 enanthate 25 mg control 84 mo language domains, gestural mo to 14 y), 11 in for 3 mo, 1 boy communication, and vocabulary untreated group received T enanthate development (age range ¼ 27 40 mg for 3 mo mo to 9 y) Samango-Sprouse 47,XXY 101 children: 34 in 34 boys received T Analyzed at 36 and Improved function in several aspects of et al,42 2013 treatment group enanthate 25 mg 72 mo neuromotor, speech, and language (age range ¼ 4e15 mo), for 3 mo 67 in untreated group (age range ¼ 3mo to 11 y) Mehta et al,43 2014 KS 151 boys; mean age at T Topical T therapy in all 3.4 ofﬁce visits within Obesity rate trended down (17% to 11%; initiation ¼ 11.6 y 110 boys titrated to 5-y period P ¼ 0.25); serum T increased 240 (range ¼ 10e21 y); high normal serum e650 ng/dL; 104 of 110 boys achieved starting serum T levels, aromatase serum T within normal range using T T < 350 ng/dL inhibitors added in gel; serum LH and FSH increased 75 boys during puberty (2.6e16.6 and 7e42 (anastrazole 1 mg/d) mIU/mL, respectively) Samango-Sprouse 47,XXY 86 children: 29 in 29 boys received T Age range at Fewer behavioral problems, improved et al,26 2015 treatment group enanthate 25 mg evaluation: ¼ 9e11 y social behavioral skills (age range ¼ 4e15 mo), for 3 mo 57 in untreated group (age range ¼ 3mo to 11 y) Ross et al,44 2017 47,XXY 84 children: 43 in Ox dose 0.06 mg/kg/d Evaluated at baseline Improved visual-motor performance, (NCT00348946) treatment group rounded to nearest and then at 12 positive effects on several aspects of (age ¼ 6.9 ± 2.2 y), 2.5 mg, or placebo, (n ¼ 84) and 24 anxiety and depression and social 41 in untreated group for 24 mo (n ¼ 72) mo functioning, not signiﬁcant on most (age ¼ 8.2 ± 2.7 y) aspects of cognition Davis et al,45 2017 47,XXY; 93 children: 39 in Ox dose 0.06 mg/kg/d Evaluated at baseline decreased body fat, decreased (NCT00348946) 47,XXY/46,XY; treatment group rounded to nearest and then at 12 triglycerides, decreased HDL 48,XXYY; (age ¼ 8.2 ± 2.7 y), 2.5 mg, or placebo, (n ¼ 84) and 24 cholesterol 48,XXXY 41 in placebo group for 24 mo (n ¼ 72) mo (age ¼ 6.9 ± 2.2 y) BMD ¼ bone mineral density; FSH ¼ follicle-stimulating hormone; HDL ¼ high-density lipoprotein; KS ¼ Klinefelter syndrome; LH ¼ luteinizing hormone; Ox ¼ oxandrolone; T ¼ testosterone.

350 ng/dL. Topical formulations of T (AndroGel, AbbVie, Most recently, a study evaluated 84 boys 4 to 12 years North Chicago, IL, USA; and Axiron, Eli Lilly, Indianapolis, IN, old with KS for a 24-month period.44 In double-blinded, ran- USA) were used in 110 boys and an aromatase inhibitor (anas- domized controlled fashion, these boys received oxandrolone trozole 1 mg/day) was used in 75. 104 of the 110 boys receiving (0.06 mg/kg) or placebo. Doses were lowered if the following topical T therapy achieved serum T levels within the normal events were noted: high low-density lipoprotein cholesterol, low range, with an increase from 240 to 650 ng/dL. The rate of high-density lipoprotein cholesterol, abnormal liver enzymes, obesity trended downward from 17% to 11% but was not Tanner stage 2 in boys younger than 8 years, systolic or diastolic statistically significant. They reported no adverse events with use blood pressure increasing beyond the age-specific 95th percentile, of topical T or aromatase inhibitors.43 or bone age advancement greater than 12 months in a 6-month Because of the high prevalence of gynecomastia in untreated interval and where the bone age was older than the chronologic KS in the past and documented hyperestrogenism in KS, many age. Results demonstrated that early androgen therapy using physicians including our group use aromatase inhibitors.43 oxandrolone improved visuomotor function compared with Specifically, reversible aromatase inhibitors such as anastrozole placebo and psychosocial functions such as anxiety, depression, have been studied in other pediatric conditions such as consti- and social interactions. However, no changes were noted for tutional short stature. Treatment with anastrazole seems to cognitive function and language, working memory, executive 44 decrease the prevalence of gynecomastia. function, attention, and aggressive or hyperactive behaviors.

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Oxandrolone also decreased body fat during the study period, factors, therapeutic considerations, and goals of therapy in boys increased bone age, and lowered total cholesterol, high-density with KS. Psychological and medical management are the lipoprotein cholesterol, and triglycerides.45 mainstay components of management of boys with KS. Psychologically, behavioral and learning aids and direction are of fi Timing of Androgen Therapy bene t for these boys. Medically, early androgen therapy has 3 flares in physiologic T production occur naturally been reported, with favorable results to date; however, despite throughout life: during the 1st trimester for male genital tract the recently published randomized controlled trial of early development; during 2 to 6 months of age; and during adoles- androgen therapy with 24 months of follow-up and 5 retro- cent puberty into adulthood.10 These physiologic T flares have spective series, no long-term randomized controlled trials are been demonstrated in boys with KS, with some reports available to guide treatment approaches of KS. Surgical measuring lower T production than controls during these time management is limited to sperm retrieval as part of fertility e points, although results are heterogeneous.24,46 48 This has preservation or at the time of desired fertility when sperm is not developed the rationale for androgen supplementation during the available in the ejaculate. neonatal and pubertal time points. No guidelines are available for The goal of management should be to allow each patient to the dose and timing of androgen supplementation. Based on the reach his full potential and to function independently in society. available literature published, the following time points have As such, the approach to treatment should be holistic, individ- been reported. ualized, multidisciplinary, and uniquely age dependent. Academic progress, social interactions, emotional maturity, physical development, sexual and pubertal progress, and preser- 3 to 15 Months of Age vation and management of infertility are key elements of Intramuscular injection of T enanthate 25 to 50 mg/month management. For an additional review of KS management, see for 3 months has been described, corresponding to the natural Wosnitzer and Paduch10 and Verri et al.49 postnatal T surge. AndroGel 1% (1 pump, 1.25 g of gel/day) also has been described in older children with close monitoring for Academic Progress skin reaction and minimizing risk of transference to siblings or fi other children. Penile length is monitored as a proxy for response Most boys with KS have expressive language de cits e 51,52 to T therapy.10 (50 75%), expressive language dyspraxia, auditory delayed processing issues, and executive skills deficits, and many have problems with attention (ADHD). Speaking clearly, in a linear fi Adolescents Before Puberty and focused manner, and nishing tasks are key elements of Multiple groups have provided T therapy up to a 24-month learning. Early introduction of speech therapy to overcome duration during this period using topical T (ie, AndroGel 1%; expressive language dyspraxia is a critical step for academic fi 1 pump, 1.25 g/day), injectable T enanthate 25 to 50 mg/in- progress and success. Often the de cits in speech are not severe fi jection, and oxandrolone 0.06 mg/kg per day. enough or the resources are dif cult to obtain for in-school services, although 60% to 86% of boys with KS require special education services51,52; therefore, as a leading physician, one has Puberty to be proactive with directing parents to help the child with One group reported on initiating at onset of puberty (w11 years language and speech development. This can be done through of age). Before initiation of therapy, it was recommended to obtain online resources and paying close attention to appropriate serum T levels, gonadotropins, estradiol, prolactin, inhibin-B, articulation when the child communicates with his parents and insulin-like growth factor-1, and cortisol. These levels can be peers. Other strategies include home exercises such as reading monitored starting before onset of puberty and then every aloud with a concerted effort for crisp pronunciation. 6 months throughout puberty. The clinician also should monitor Boys with KS have deficits in language and communica- secondary sexual characteristics relative to puberty including penile tion.51,52 Although the delay is often minimal, it can be signif- length and girth, testicular growth, and pubic and axillary hair icant to the point that parents and older siblings tend to answer 10 every 6 months throughout puberty. T formulations reported questions for the patient; this approach is highly counterpro- during this period include AndroGel 1%, 2 pumps (2.5 g of gel/ ductive because it prevents the boy from focusing on spoken day) with titration up to 3 pumps (3.75 g of gel/day); and Axiron language and auditory cues, thus impairing further normal 43 2%, 1 pump (30 mg/day). Anastrazole 1 mg/day also has been development of communication skills in the child. It is 43 reported for use in boys with high estradiol/T ratios. important to emphasize to the educators that the child should be given time to answer the question when asked because boys with Principles of Management of KS KS do not have global cognitive impairment but they do have A multidisciplinary approach is essential in optimal manage- selective deficits in language and communication.51,52 These ment of patients with KS. Table 2 presents developmental limitations in language and communication have significant

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Table 2. Developmental abnormalities, therapeutic considerations, and goals of therapy* Developmental abnormalities Therapeutic considerations Goals of therapy

Delayed expressive language and Early speech therapy and language Improve impaired speech, language, speech milestones evaluation voice, fluency Encouragement for patient to speak Improve communication and avoid for himself and answer questions social consequences of speech disability Acquisition of strategies to enhance effectiveness of communication Attention deficit, without hyperactivity Classroom accommodations, Increase likelihood of academic during school communication to teacher, avoid success for boys with KS through distractions at home when doing behavioral interventions and homework, stimulant medications environmental optimization Deterioration in school performance in Retest to identify disciplines requiring Prompt identification and intervention transition from elementary to additional attention, consider at or for deficits middle school before middle school entrance Math difficulties Retest, identify deficits, and remediate Improve mathematical knowledge, skillset, and concepts in numeracy Identification of left-handedness Consideration and accommodation Enhance gross and fine motor skills with writing and sporting activities Deficient complex language production Assess written and verbal language Improve written and verbal and comprehension comprehension and communication; comprehension and communication discuss performance with teachers; identify areas requiring additional attention Decreased athleticism: running, agility, Physical therapy, occupational therapy Improved positive body self-perception strength, and gross and fine motor through exercise, practice, and coordination strategies for gross and fine motor skills, balance and coordination, strength and endurance, and cognitive and sensory processing and integration Choose sports that emphasize strengths Consider testosterone therapy Delayed puberty Ensure timely progress through pubertal milestones, with adequate testosterone levels Body image disorder Group psychotherapy Address sense of isolation and experience support from peers, improved body self-perception Communication of KS diagnosis Emotional support; address Improve comprehension, acceptance of psychological, behavioral, and social diagnosis, and positive self- factors that might influence the perception adaptive process to the KS condition Anxiety, depression, psychoses Psychotherapy, cognitive-behavioral Alleviate dysfunctional emotions, therapy ± medication when behaviors, and cognitions through a medically indicated goal-oriented, systematic procedure Pharmacologic compliance Teach strategies to improve Decrease patient non-compliance by compliance with medication understanding the reasons for maintaining the behavior Infertility Referral to infertility specialist for Help patient achieve fertility evaluation and consideration of preservation or pregnancy sperm retrieval if necessary, assessment of gonadotropin levels, semen analysis KS ¼ Klinefelter syndrome. *Adapted from Verri et al49 and Ross et al,50 with modifications.

Sex Med Rev 2018;6:595e606 602 Flannigan et al impact on development of personality, behavior, and social Boys with KS also can have phenotypic abnormalities such as adaptation.53 long arms and legs or gynecomastia, differentiating them from Most boys with KS do not have difficulties with arithmetic but their peers, potentially leading to teasing, and further under- fi 49 do have problems with writing, comprehension, and languages.54 mining their self-con dence. Poor physical performance and In the opinion of the senior author, the expressive language stamina can further alienate boys from their peer group. Simi- fi 51 deficits are part of more global fine motor dysfunction and larly, clumsiness from poor development of ne motor skills hypotonia. Because androgens stimulate growth of muscles, we lead to suboptimal performance in sports and daily activities. believe that positive effects of early hormonal manipulation can Considering our societal values of sport and physical prowess, it be due to a direct effect of androgens on neuromotor function. is conceivable that many boys with KS who were not treated This leads to not only increased muscle mass but also motor early with androgens feel as outsiders, or alienated, and avoid e function49 and subsequently improved self-esteem.55 57 How- social activities with peers. Hence, it is critical that in planning ever, androgens are complementary treatment in addition to the treatment we as clinicians pay attention to keeping our pa- ongoing educational accommodation, speech, occupational, and tients at the front of the developmental curve when possible with physical therapy. Execution of tasks requires planning, gathering respect to physical and pubertal development. There is no tools, finishing the product, and sharing the product. Executive question in the view of the senior author that our patients do fi skills deficits are extremely common in boys with KS.51 signi cantly better socially because they feel like they are on par or slightly ahead of other boys in their class with respect to their Executive skills often coincide with ADHD, one of the most pubertal development. Helping boys with KS socially integrate common psychiatric diagnoses in men with KS, particularly the with their peers is believed to be the most important factor in inattentive subtype of ADHD.58 Most, but not all, boys with KS helping these boys graduate from high school.63 respond to stimulants positively. Here, it is important to recognize that initiation of stimulants should be the last resort and not 1st- line therapy. In the senior author’s practice, androgen supple- Potential Negative Effects of Androgen mentation is initiated with educational and family support to help Supplementation in KS with concentration, stamina, and focus. Brain maturation occurs The available evidence addressing early androgen supple- during adolescence, improving cognitive control and focus. A mentation in boys with KS is predominately limited to retro- significant degree of brain maturity is related to the action of sex spective series and is subject to biases inherent to these types of 59 hormones. However, if despite hormonal supplementation, the studies. As such, clinicians must consider the evidence for boys continue to have issues with ADHD, then initiation of potential benefit and the potential negative effects and harm in stimulants can be considered if meeting criteria for ADHD, using this therapeutic strategy. Furthermore, the results are not initially at the lowest dose and titrate as required. Use of stimulants easily quantifiable, and thus it is difficult to determine the has shown positive effects in 79% of patients with sex chromosome number needed to treat to improve physiologic or psychological 58 aneuploidies including KS. Using a combination of educational outcomes. Negative effects from androgen supplementation interventions, androgen therapy, and family support, all our pa- include penile pain from prolonged erections, development of tients have graduated from high school and most patients enter pubic hair without progression of puberty, which could be college. An individualized multimodal therapeutic approach con- embarrassing to the child and the parents, and excessive 60 tributes to successful outcomes for boys with KS. masturbation and penile length. During puberty, adverse events can include premature closure of epiphyses, possible down- Social Interactions and Emotional Maturity regulation of androgen receptors, and exacerbation of acne. In Neurobiologically, sex hormones contribute to emotional our experience, the use of topical T applications with aromatase stability and maturity, which are attained during and beyond inhibitors seems to have minimal impact on lowering follicle- puberty.61 Because boys with KS have a significant deficit in T stimulating hormone and luteinizing hormone levels in 64 production or partial resistance to androgens, there is no surprise adolescents with KS ; however, topical use must be prescribed that their emotional maturity lags significantly behind that of in an appropriately selected population of reliable patients their peers. There are several aspects of KS that impair social because of the potential risk of transference to others. Deep vein fi interactions: language barriers described earlier, especially poor thrombosis and pulmonary embolism were reported at signi - clarity of speech, shyness, lack of assertiveness, anxiety, and social cantly higher rates in men with KS and should be considered and 65 immaturity.62 The barriers to being well understood often lead to discussed when initiating therapy. frustration, marginalization, and avoidance of verbal contacts Furthermore, oxandrolone (oral), T enanthate (injection), and with peers. Here, there is no replacement for good parenting, topical T have been predominately reported in the literature for providing explanation and guidance of appropriateness of verbal patients with KS. Oxandrolone is an anabolic steroid related to and non-verbal communications with peers. Often, involving a T. It is consumed orally, and relevant contraindications for men psychologist is helpful in overcoming the emotional immaturity with KS as issued by the Food and Drug Administration (FDA) and social anxiety faced by boys with KS. include nephrosis, hypercalcemia, and carcinoma of the breast or

Sex Med Rev 2018;6:595e606 Early Androgen Therapy in Klinefelter Syndrome 603 prostate. Other side effects can include insomnia, depression, or appropriate progression of Tanner stages over 3 to 5 years during libido changes, bleeding in patients with concomitant anti- puberty. An objective measurement for age-specific strength coagulation therapy, gynecomastia, body hair growth, acne, parameters that can be used includes a digital hand dynamometer premature closure of epiphyses, edema through retention of grip strength measuring device; age- and sex-stratified normative sodium chloride, potassium, phosphate, and calcium, decreased data in a population-based study have been published and can be glucose tolerance, increased renal creatinine excretion, inhibition used as a practical guide.69 Clinicians also can follow normative of gonadotropin secretion, impaired spermatogenesis, and liver height and weight growth curves and penile growth curves toxicity.66 during puberty.70 Some groups also have used weight-based As discussed earlier, the use of topical T therapy in children dosing for oxandrolone and have rules to lower the dose if and adolescents must be appropriately selected because of the risk bone age advancement greater than 12 months occurs in a of transference and potential harm to other children. T enanthate 6-month duration and bone age is older than chronologic age; is one of the most common forms of T replacement. It is injected progression of Tanner stage higher than 2 if younger than 8 intramuscularly, and relevant contraindications for men with KS years; systolic or diastolic blood pressure above the 95th as issued by the FDA include men with prostate cancer and those percentile for age, height, and sex; low-density lipoprotein with a history of insensitivity to any of the drug components. increasing above 159 mg/dL; high-density lipoprotein decreasing Warnings of use have been issued for individuals with breast below 20 mg/dL; or alanine aminotransferase liver enzyme 44 cancer, immobilization, and hypercalcemia from increased increasing beyond twice the upper limit of normal. Although resorption of calcium among other electrolytes such as sodium, other groups report T enanthate dosage to be individualistic and ’ chloride, phosphate, and potassium; prolonged use has been based on the pediatric endocrinologist s clinical judgement, reported in cases of cholestatic and peliosis hepatitis and hepatic serum T levels are not typically measured before or after in- 42 neoplasms; edema; gynecomastia; accelerated bone maturation jections. Furthermore, response to androgen replacement is and premature closure of epiphyses; impaired spermatogenesis individualistic. Based on our clinical experience, boys with KS from decreased gonadotropin release; and venous thromboem- demonstrate a weaker response to T replacement therapy bolic events and potential cardiovascular events in general in compared with boys without KS. Biologically, it has been shown fi older men.67 that men with KS have impaired traf cking of androgen receptor from the cytoplasm to the nucleus, and thus boys with KS might In cases of excessively increased estradiol levels, some clinicians require greater T replacement than those without KS.71 will consider off-label use of aromatase inhibitors such as anastrozole to bring the levels within normal limits. Anastrazole It is also important to note that the FDA has not approved T is taken orally. Relevant warnings and precautions as issued by administration to those younger than 18 years. In early adult- the FDA include decreased bone mineral density, increased hood, it is important to discuss and counsel these men regarding cholesterol, and hypersensitivity reactions. Serious adverse fertility potential and the possible role for fertility preservation reactions are rare, occurring in less than 1 in 10,000 patients, and through microdissection testicular sperm extraction. Reports include skin reactions, allergic reactions, and changes in serum have been shown that topical gel-based therapies have less effect liver function tests.68 of decreasing gonadotropin levels (luteinizing hormone and follicle-stimulating hormone) and thus likely have less of a negative effect on spermatogenesis compared with injectable T, Disclosure and Initiation of Treatment which typically has a higher peak level.10 In our practice, the In our practice, managing androgen supplementation in in- senior author sees children, adolescents, and adults with KS. dividuals with KS requires an individualized and tailored However, among institutions that have separate designations of approach to each boy according to his natural curve of pubertal pediatric or adult clinicians, it is essential to establish open development. Typically, we wait with initiation of androgens communication of past, present, and future care needs for each until 13 to 14 years of age, which corresponds to the time of patient at the transition from child to adult. A multidisciplinary pubertal onset among most boys in the United States.43 Other transition program, when possible, can optimize clinical care and centers also prescribe androgen therapy in the infantile period an effective transition to adulthood as their therapeutic goals (3e6 months). Adolescent interventions before puberty would evolve. be justified in cases of severe muscle loss and hypotonia and in boys with significant developmental concerns. The androgen doses are adjusted to mimic normal pubertal progression over 3 CONCLUSION to 5 years. The best indicators of the appropriate titration of KS is commonly known for the classic constellation of features androgen supplementation are biological determinants such as such as tall stature, gynecomastia, gynoid hips, small firm testes, development of armpit hair, pubic hair, increase in penile length hypergonadotropic hypogonadism, and infertility. However, and thickness, upper body muscle development, and increase in many of these individuals have abnormal neurocognitive devel- semen volume. In addition to using total T, we rely on signs and opment and subsequently altered psychosocial functioning. Some physical development during adolescence and titrate to of these abnormalities might be due in part to abnormal androgen

Sex Med Rev 2018;6:595e606 604 Flannigan et al exposure in utero, infancy, and adolescence to promote normal 5. Forti G, Corona G, Vignozzi L, et al. Klinefelter’s syndrome: a neural development. Few studies have reported their experience clinical and therapeutical update. Sex Dev 2010;4:249-258. using early androgen supplementation. Results suggest improved 6. Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prev- speech, language, reading, intellectual functioning, behavior, and alence of Klinefelter syndrome: a national registry study. J Clin social functioning in children treated with androgens. However, Endocrinol Metab 2003;88:622-626. the evidence is currently limited to retrospective results and 1 7. Hansmann I. Clustering of chromosomal aneuploidy and prospective trial; further prospectively designed studies are tracing of nondisjunction in man. Environ Health Perspect necessary to make firm conclusions on the timing and intricacies 1979;31:23-25. of androgen supplementation in children with KS. 8. Sarkar MK, Gayen S, Kumar S, et al. An Xist-activating anti- sense RNA required for X-chromosome inactivation. Nat Corresponding Author: Darius A. Paduch, MD, PhD Commun 2015;6:8564. Department of Urology, Weill Cornell Medicine, 525 East 68th 9. Loda A, Brandsma JH, Vassilev I, et al. Genetic and epigenetic Street, Starr Pavilion, 9th Floor, Room 900, New York, NY features direct differential efficiency of Xist-mediated silencing 10065, USA. Tel: 212-746-5309; Fax: 212-746-7287; E-mail: at X-chromosomal and autosomal locations. Nat Commun [email protected] 2017;8:690. Conflicts of Interest: The authors report no conflicts of interest. 10. Wosnitzer MS, Paduch DA. Endocrinological issues and hormonal manipulation in children and men with Klinefelter Funding: Frederick J. and Theresa Dow Wallace Fund of the syndrome. Am J Med Genet C Semin Med Genet 2013; New York Community Trust; American Urology Association 163C:16-26. New York Section E; Darracott Vaughan, MD, Research Scholar 11. Linden MG, Bender BG, Robinson A. Sex chromosome tet- Award; and Irena and Howard Laks. rasomy and pentasomy. Pediatrics 1995;96:672-682. 12. Ross JL, Roeltgen DP, Kushner H, et al. Behavioral and social STATEMENT OF AUTHORSHIP phenotypes in boys with 47,XYY syndrome or 47,XXY Kline- felter syndrome. Pediatrics 2012;129:769-778. Category 1 13. Lepri F, De Luca A, Stella L, et al. SOS1 mutations in Noonan (a) Conception and Design syndrome: molecular spectrum, structural insights on patho- Ryan Flannigan; Premal Patel; Darius A. Paduch genic effects, and genotype-phenotype correlations. Hum (b) Acquisition of Data Mutat 2011;32:760-772. Ryan Flannigan; Premal Patel (c) Analysis and Interpretation of Data 14. Bishop DV, Scerif G. Klinefelter syndrome as a window on the Ryan Flannigan; Premal Patel; Darius A. 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