Hormone Therapy During Infancy or Early Childhood for Patients with Hypogonadotropic Hypogonadism, Klinefelter or Turner Syndrome: Has the Time Come?

Managing patients unable to produce sex steroids using gonadotropins to mimic minipuberty in hypogonadotropic hypogonadism, or sex steroids in patients with Klinefelter or Turner syndrome, is promising. There is a need to pursue research in this area, with large prospective cohorts and long-term data before these treatments can be routinely considered.

Testosterone Replacement Therapy in Klinefelter Syndrome-Follow-up Study Associating Hemostasis and RNA Expression.

BACKGROUND: Men with Klinefelter syndrome (KS) develop hypergonadotropic hypogonadism, are in need of testosterone replacement therapy (TRT), and present with a more than 4-fold increased risk of thrombosis. TRT in KS has the potential to modify thrombotic risk, but data are scarce. AIM: To assess effects of 18 months of TRT on hemostasis in KS and identify genes associated with the prothrombotic phenotype. METHODS: Untreated and TRT-treated men with KS were included at baseline and matched to healthy controls. TRT was initiated in untreated KS and all groups were reassessed after 18 months of follow-up. Thrombin generation was evaluated with or without thrombomodulin, and fibrin clot lysis was evaluated by turbidity measurements. RNA expression was assessed in blood, fat, and muscle tissue of patients with TRT-treated KS and controls. RESULTS: Thrombin generation with thrombomodulin was slightly increased in untreated KS, but overall KS was not associated with a hypercoagulable state. KS presented with fibrinolytic impairment associated with higher body fat and higher levels of fibrinogen. Eighteen months of TRT in KS was associated with a reduction in body fat and fibrinogen, attenuating the prothrombotic profile. The expression of ENPP4 was higher in men with KS and served as a key player among a group of genes associated with impaired fibrinolysis. CONCLUSION: KS is associated with a specific expression profile contributing to fibrinolytic impairment and increased thrombotic risk in the patients. TRT in patients with KS has the potential for alleviating the prothrombotic phenotype, in particular by reducing body fat and fibrinogen.

Leydig cell metabolic disorder act as a new mechanism affecting for focal spermatogenesis in Klinefelter syndrome patients: a real world cross-sectional study base on the age.

Background: Klinefelter's syndrome (KS) was once considered infertile due to congenital chromosomal abnormalities, but the presence of focal spermatozoa changed this. The key to predict and promote spermatogenesis is to find targets that regulate focal spermatogenesis. Objective: To explore the trend of fertility changes in KS patients at different ages and identify potential therapeutic targets. Methods: Bibliometric analysis was used to collect clinical research data on KS from the Web of Science Core Collection (WoSCC) from 1992 to 2022. A cross-sectional study was conducted on 75 KS patients who underwent microscopic testicular sperm extraction (mTESE) from 2017 to 2022 in the real world. The reproductive hormones, testicular histopathology, androgen receptors, insulin-like factor 3 (INSL3) receptors and sperm recovery rate (SRR) were analyzed. Results: Male infertility, dysplasia, Sertoli cells, Leydig cells, testosterone and spermatogenesis were the research focuses related to KS. Luteinizing hormone (LH), testosterone, and INSL3 were evaluation indicators of Leydig cell function that fluctuate with age. Testosterone and LH peaked at ages 13-19 and 30-45, while INSL3 only peaked at ages 13-19. 27 patients (27/75) recovered sperm through mTESE and experienced SRR peaks at the ages of 20, 28, 34, and 37. The SRR of fibrosis patients was 46.15%, fatty degeneration was 7.14%, and melanosis was 40.00%. The INSL3 and androgen receptors were highly expressed and roughly balanced in focal spermatogenesis. Conclusion: Abnormal metabolism of Leydig cells led to imbalanced expression of INSL3 and androgen receptors, which might be a potential target for spermatogenesis in KS.

The Effect of Hormonal Therapy on the Behavioral Outcomes in 47,XXY (Klinefelter Syndrome) between 7 and 12 Years of Age.

47,XXY, also known as Klinefelter syndrome, is the most commonly occurring sex chromosomal aneuploidy (SCA). Hormonal replacement therapy (HRT) has been associated with improved neurodevelopmental capabilities in boys with 47,XXY, although studies investigating HRT's possible positive effect on behavioral outcomes are scarce. This study explores the association between behavioral outcomes and HRT in boys ages 7-12. Patients were divided into 4 groups based on HRT status: untreated, early hormonal treatment (EHT), hormonal booster therapy (HBT), and both EHT and HBT. Analysis of Variance (ANOVA) and Kruskal-Wallis tests were conducted to determine group differences on the Child Behavior Checklist (CBCL) and the Behavior Rating Inventory of Executive Function (BRIEF). The treated groups were found to have better scores in emotional control, initiative, organization of materials, behavioral rating index, metacognition index, and global executive composite than the untreated group on the BRIEF. On the CBCL, the treated groups presented better scores for somatic complaints, social problems, thought problems, attention problems, aggressive behavior, internalizing problems, total problems, affective problems, somatic problems, ADHD problems, oppositional defiant problems, and sluggish problems in comparison to the untreated group. These results offer evidence that HRT, specifically the combination of both EHT and HBT, may be successful in mitigating some undesirable behavioral outcomes. Further research is necessary to determine the efficacy of the combination of EHT and HBT regarding dosage, specific ages, and long-term benefits.

Testicular Dysfunction in 47,XXY Boys: When It All Begins. A Semilongitudinal Study.

OBJECTIVE: Klinefelter syndrome is the most common chromosomal disorder in males and the most common cause of hypergonadotropic hypogonadism. We describe the natural history of testicular dysfunction in patients with Klinefelter syndrome through the integration of clinical, hormonal, and quantitative ultrasound data in a life-course perspective. DESIGN: Prospective semilongitudinal study. METHODS: We included 155 subjects with 47,XXY karyotype (age range: 7 months-55 years) naïve to testosterone replacement therapy. Subjects were divided according to pubertal stage and age group (transition age and adults). Serial clinical, hormonal, and testicular ultrasound (US) assessments were performed. RESULTS: Testicular development progresses until Tanner stage 4, with subsequent regression, whereas Sertoli and germ cell impairment is not hormonally detected before Tanner stages 3-4, as reflected by normal inhibin B values until stage 4 and the fall in the inhibin B/follicle-stimulating hormone ratio thereafter. The testosterone/luteinizing hormone ratio peaks during Tanner stages 2-3 and declines from Tanner stage 4 onward, preceding the development of overt hypogonadism. US echotexture progressively worsens until transition age, reflecting ongoing gonadal compromise, whereas quantitative US echotexture measures and the presence of both hypoechoic lesions and microlithiasis independently and significantly predict a lower circulating testosterone level. CONCLUSIONS: The findings from this large prospective study contribute to our understanding of the natural history of testicular dysfunction in Klinefelter syndrome, underlining the importance of quantitative testicular US in infancy and childhood, as well as during pubertal development and transition age, for the optimal care of Klinefelter syndrome patients.

The effect of testosterone treatment on bone mineral density in Klinefelter syndrome: A retrospective cohort study.

BACKGROUND: Although Klinefelter syndrome (KS) is the most frequent sex-hormone disorder, there is ongoing uncertainty about the often associated sex-hormone deficiency, its impact on common comorbidities, and therefore about prevention and treatment. In this study, we focus on bone loss, reported to occur in over 40% of KS patients, and the impact of testosterone replacement therapy (TRT) on this comorbidity. OBJECTIVES: This single-center retrospective cohort study in a tertiary hospital compared the effect of treatment with TRT to no TRT on evolution of bone mineral density (BMD) in KS patients. METHODS: After a medical chart review, a total of 52 KS subjects were included in this study. BMD was measured by dual-energy X-ray absorptiometry (DXA) and expressed as T-scores. RESULTS: The subjects were divided into three groups, according to TRT. In the subgroup that only started TRT after baseline measurements (mean age 31 years), we observed significant gain in BMD T-score at the lumbar spine (0.58 ± 0.60, p = 0.003; mean gain of 0.62% areal BMD per year) and total femur T-score (0.24 ± 0.39, p = 0.041; mean gain of 0.25% areal BMD per year) after a mean follow-up period of 7.5 years. Compared to untreated subjects, a significant difference in evolution was demonstrated at the lumbar level (+0.58 ± 0.60 vs. -0.14 ± 0.42, p = 0.007). In untreated subjects with normal testosterone levels, a loss of BMD (-0.27 ± 0.37, p = 0.029; mean loss of 0.49% areal BMD per year) at the femoral neck was measured. This decline was equal to the predicted loss seen in the general male population. CONCLUSION: TRT results in BMD gain in patients with KS with testosterone deficiency, mainly at the lumbar spine. However, this effect is limited (0.62% per year). Patients who were not treated with TRT because of sufficient endogenous testosterone levels, showed only the predicted age-related bone loss during follow-up. The need for TRT in maintaining bone health in KS should be evaluated on an individual basis according to the degree of sex steroid deficiency.

Platelet aggregation in Klinefelter syndrome is not aggravated by testosterone replacement therapy: A longitudinal follow-up study.

BACKGROUND: Men with Klinefelter syndrome (KS) are routinely offered testosterone replacement therapy (TRT) suggested to potentially promote platelet aggregation and increase cardiovascular risk. OBJECTIVE: We investigated platelet aggregation in men with KS before and during TRT. MATERIALS AND METHODS: Forty-one adult men with KS participated, of which 20 had no history of TRT at baseline, with 15 completing follow-up after 18 months TRT. Further, we included 21 adult men with KS on long-term TRT (>10 years) and a male reference population. We assessed platelet impedance aggregometry using adenosine diphosphate (6.5 µM), thrombin-receptor-activating-peptide-6 (TRAP 32 µM), and arachidonic acid (ASPI 0.5 mM) as agonists in KS compared to a male reference population and stratified by route of TRT administration. RESULTS: Platelet aggregation among men with KS at baseline or during TRT was not increased compared with the male reference population. For all three agonist, no change was seen in platelet aggregation in KS at follow-up compared with baseline (p ≥ 0.2). Platelet aggregation was not associated with total testosterone and furthermore, platelet count was not affected by treatment with testosterone. Men with KS treated with testosterone gel showed slightly increased TRAP- and ASPI-induced platelet aggregation compared with those treated with testosterone injection (p = 0.02 and p = 0.04, respectively). DISCUSSION AND CONCLUSIONS: We observed normal platelet aggregation in men with KS before TRT and following both short and long term treatment. Our findings do not support an independent role of platelets in driving the cardiovascular risk in KS.

Klinefelter syndrome: going beyond the diagnosis.

Although Klinefelter syndrome (KS) is common, it is rarely recognised in childhood, sometimes being identified with speech or developmental delay or incidental antenatal diagnosis. The only regular feature is testicular dysfunction. Postnatal gonadotropin surge (mini-puberty) may be lower, but treatment with testosterone needs prospective studies. The onset of puberty is at the normal age and biochemical hypogonadism does not typically occur until late puberty. Testosterone supplementation can be considered then or earlier for clinical hypogonadism. The size at birth is normal, but growth acceleration is more rapid in early and mid-childhood, with adult height greater than mid-parental height. Extreme tall stature is unusual. The incidence of adolescent gynaecomastia (35.6%) is not increased compared with typically developing boys and can be reduced or resolved by testosterone supplementation, potentially preventing the need for surgery. Around two-thirds require speech and language therapy or developmental support and early institution of therapy is important. Provision of psychological support may be helpful in ameliorating these experiences and provide opportunities to develop strategies to recognise, process and express feelings and thoughts. Boys with KS are at increased risk of impairment in social cognition and less accurate perceptions of social emotional cues. The concept of likely fertility problems needs introduction alongside regular reviews of puberty and sexual function in adolescents. Although there is now greater success in harvesting sperm through techniques such as testicular sperm extraction, it is more successful in later than in early adolescence. In vitro maturation of germ cells is still experimental.

Fertility Preservation in Adolescents with Klinefelter Syndrome is Experimental but May Increase Therapeutic Options for Biological Paternity.

While approximately half of adult Klinefelter syndrome (KS) patients have retrievable sperm on micro testicular sperm extraction, success is limited by testicular hyalinization beginning at puberty. Recent surgical and laboratory advances lend themselves to experimental fertility preservation in appropriately selected adolescent KS patients.

A longitudinal perspective of hormone replacement therapies (HRTs) on neuromotor capabilities in males with 47,XXY (Klinefelter syndrome).

PURPOSE: The purpose of this study was to delineate the effects of variable hormone replacement therapies on neuromotor function in a large cohort of males with 47,XXY from birth to adulthood. METHODS: A total of 270 participants aged 16 days to 17 years 11 months prenatally diagnosed with 47,XXY were assessed by their pediatric endocrinologist and were administered hormone replacement therapies accordingly. Infants and school-aged children with 47,XXY were administered neuromotor assessments during routine neurodevelopmental evaluations. For statistical analysis, participants were segregated on the basis of treatment status. Two-tailed t tests, 1-way analysis of variance, and post hoc analysis determined significant group differences on each assessment. RESULTS: In infants, the early hormonal treatment (EHT) group performed significantly better than the untreated group on fine motor and motor composite domains. In school-aged children, we observed significantly improved scores on fine motor control, coordination, agility, and strength domains among males treated with EHT (or any combination thereof) compared with those who did not receive early treatment. CONCLUSION: The highest treated combination group was associated with the highest neuromotor function, although the EHT group also often performed better than the other groups. This suggests EHT may be essential in promoting long-term optimal neuromotor outcome in males with an additional X.

Visual loss and optic neuropathy in a patient with Klinefelter's syndrome, open-angle glaucoma, vitamin B12 (cobalamin) and folate deficiency.

A 54-year-old man with Klinefelter's syndrome presented to the neuro-ophthalmology clinic with progressive painless visual blurring in the right eye over 2 years. He was receiving intramuscular testosterone therapy for hypogonadism and hypromellose for dry eye. Acuity was reduced bilaterally, and the right optic nerve head appeared pale and asymmetrically cupped. Optical coherence tomography revealed loss of retinal nerve fibre layer thickness in the right eye and visual field testing showed a developing right-ring scotoma. Blood tests showed vitamin B12 and folate deficiencies and polycythaemia. The patient was managed with intramuscular hydroxocobalamin, oral folate administration and re-initiation of his glaucoma medication. In Klinefelter's syndrome, signs of comorbid deficiency can be masked by the polycythaemic effect of testosterone therapy. For patients on long-term testosterone therapy, such as those with Klinefelter's syndrome, we recommend baseline ophthalmic examination and assessment, including intraocular pressure measurement, pachymetry, gonioscopy and screening 24-2 visual field testing.

Onset and progression of puberty in Klinefelter syndrome.

OBJECTIVE: Klinefelter syndrome (KS) (47,XXY and variants, KS) is the most common sex chromosome disorder in humans. However, little is known about the onset and progression of puberty in patients with KS. In this study, we describe the onset and progression of puberty in a large series of boys with KS in a single tertiary centre. DESIGN AND PATIENTS: Retrospective data (Tanner stages, testicular length, testosterone supplementation, levels of luteinizing hormone [LH] and testosterone) before possible testosterone treatment on 72 KS patients with 47,XXY karyotype were reviewed, and G (n = 59 patients) and P (n = 56 patients) stages were plotted on puberty nomograms. MEASUREMENTS AND RESULTS: One boy had a delayed onset of puberty, as he was at the G1 stage at the age of 13.8 years (-2.2 SDs). No observations of delay were made of boys at Stage G2. The progression of G stages was within normal limits in the majority of patients; only few boys were late at G3 (4.1%; 1 out of 24) and G4 (7.4%; 2 out of 27). Testosterone supplementation was started at the average age of 15.5 years to 35 boys (47%), 2 of whom were over 18 years old. LH level was on average 18.2 IU/L (SD: 6.3 IU/L) and testosterone 9.1 nmol/L (SD: 3.1 nmol/L) when testosterone supplementation was started. CONCLUSIONS: Our results suggest that puberty starts within the normal age limits in boys with KS, and testosterone supplementation is not needed for the initial pubertal progression in the majority of patients.

Incidence of gynaecomastia in Klinefelter syndrome adolescents and outcome of testosterone treatment.

The aim was to define the true incidence of gynaecomastia in adolescent boys with Klinefelter syndrome (KS) and to observe testosterone treatment effects on its duration by examination of the prospectively collected data from a specialist referral clinic for boys with KS, with comparison being made with KS boys identified by a historical newborn chromosome screening programme, together with chromosomally normal controls. Fifty-nine boys over age 13 years were referred to a specialist KS clinic; 21 developed gynaecomastia. The comparator was 14 KS boys identified at birth and 94 chromosomally normal control boys. Testosterone was routinely started at the onset of puberty if gynaecomastia, a manifestation of clinical hypogonadism, was present. Oral or transdermal testosterone was administered in the morning, in a reverse physiological rhythm, and doses were increased according to standard pubertal regimens. The incidence of gynaecomastia was not increased in both the KS cohorts compared with controls. The incidence and age of onset of gynaecomastia was 35.6%, at 12.3 (1.8) years in the KS clinic group; 36.0%, at 13.7 (0.6) years in the newborn survey group; and 34.0%, at 13.6 (0.8) years in the controls. Full resolution of the gynaecomastia occurred in the 12/14 KS clinic boys on testosterone treatment who had completed puberty and as long as adherence was maintained.Conclusion: The incidence of gynaecomastia in KS boys (overall 35.6%) is not increased over typically developing boys. Commencing testosterone when gynaecomastia develops with physiological dose escalation and full adherence can result in the resolution of the gynaecomastia. What is Known: • Gynaecomastia is a common feature in Klinefelter syndrome men. • Hypogonadism occurs from mid-puberty onwards with the absence of the usual rise in testosterone levels. What is New: • The incidence of pubertal gynaecomastia in Klinefelter syndrome is not different from typically developing boys. • Early and prompt starting of testosterone gel treatment and increasing the dose physiologically may help to resolve the gynaecomastia without the need for surgery.

Successful thrombolysis of normotensive pulmonary embolism with life-threatening hypoxia in a young man with Klinefelter syndrome.

Klinefelter syndrome (KS) affects males born with an additional X chromosome giving the genotype 47XXY classically. This syndrome has primary features of infertility and hypogonadism along with other features including a genetically hypercoagulable state. When associated with other risk factors, KS further increases the risk of venous thromboembolism and could result in life-threatening pulmonary embolism (PE). There should be a lower threshold in suspecting PE as a cause of acute respiratory failure in this patient group and thrombolysis should be considered early in normotensive PE with severe hypoxia for best patient outcomes. Furthermore, clinicians should be cautious in managing testosterone therapy in patients with KS and additional thromboembolic risk factors.

The effect of early hormonal treatment (EHT) on expressive and receptive language capabilities in boys with 47,XXY (Klinefelter syndrome) during infancy and early childhood.

PURPOSE: 47,XXY is associated with variable neurodevelopmental outcomes including deficits in expressive and receptive language development. Early hormonal treatment (EHT) has been associated with mitigating some deficiencies in boys with 47,XXY. This study investigates these language capabilities of 47,XXY boys in the first five years of life and the associated effects of EHT on these capabilities. METHODS: One hundred and seventy-five boys with 47,XXY between the ages of 0 and 5 years, 11 months completed neurodevelopmental assessments specific to age examining their expressive and receptive language capabilities. Subjects were grouped by treatment (EHT and No-T) and differences were analyzed. RESULTS: In the age groups of under 12 months, 24-35 months, 36-47 months, and 60-71 months, the EHT group scored significantly higher on expressive language assessments than the No-T group (p = 0.09, p = 0.0002, p = 0.009, and p = 0.02, respectively). In the age groups of under 12 months and 24-35 months, the EHT group scored significantly better on the auditory comprehension domain of the PLS-4/5 (p = 0.02 and p = 0.05, respectively) than the No-T group. CONCLUSION: Study data suggest EHT may be essential in optimizing receptive and expressive language development in 47,XXY boys during early childhood, which is critical in fostering reading skills and later academic success.

Serum insulin-like factor 3 quantification by LC-MS/MS in male patients with hypogonadotropic hypogonadism and Klinefelter syndrome.

PURPOSE: Insulin-like factor 3 (INSL3) is an emerging testicular marker, yet larger studies elucidating the clinical role of INSL3 in patients with hypogonadism are lacking. The aim was to describe serum INSL3 concentrations analyzed by LC-MS/MS methodology in males with hypogonadotropic hypogonadism (HH) and Klinefelter syndrome (KS). METHODS: This was a combined study from two tertiary centers in Denmark and France analyzing INSL3 concentrations by LC-MS/MS. In total, 103 patients with HH and 82 patients with KS were grouped into treated (HH: n = 96; KS: n = 71) or untreated (HH: n = 7; KS: n = 11). Treatment modalities included testosterone and hCG. Serum concentrations and standard deviation (SD) scores of INSL3, total testosterone, and LH according to age and treatment were evaluated. RESULTS: In both HH and KS, INSL3 concentrations were low. In HH, INSL3 was low regardless of treatment, except for some hCG-treated patients with normal concentrations. In untreated HH, testosterone was low, while normal to high in most testosterone- and hCG-treated patients. In untreated KS, INSL3 and testosterone concentrations were low to normal, while in testosterone-treated KS, serum INSL3 was low in most patients. INSL3 SD scores were significantly lower in untreated HH than in untreated KS (p = 0.01). CONCLUSIONS: The dichotomy between lower INSL3 and higher testosterone concentrations, particularly observed in hCG-treated patients with HH, confirms that INSL3 is a different marker of Leydig cell function than testosterone. However, the clinical application of INSL3 in males with hypogonadism remains unclear.

Neurocognitive development and capabilities in boys with 49,XXXXY syndrome.

49,XXXXY was previously associated with profound to severe intellectual deficits. However, prior research papers on the cognitive profiles of this population were confounded by small samples sizes, wide age spreads, and incomplete histories of testosterone replacement therapy. This study is the first comprehensive, international investigation of the neurocognitive aspects of 49,XXXXY, and the potential effects of biological treatment on this profile. Sixty-seven boys from infancy to 11 years of age were enrolled in this longitudinal study, with the majority of boys postnatally diagnosed though chromosomal analysis. These boys received a comprehensive neurocognitive evaluation tailored to specific language-based deficits and cognitive challenges. Results revealed higher neurocognitive capacities, both verbally and nonverbally, than previously reported in this disorder. Infant boys with 49,XXXXY who received early hormonal therapy (EHT) had significantly higher scores on the cognitive domain of the Bayley Scales of Infant Development than untreated infants (p = .013). In addition, treated school-aged participants had significantly better scaled scores than untreated boys in form completion (p = .042), a task that requires deductive reasoning, on nonverbal testing on the Leiter International Performance Scales. This study indicates greater cognitive capacities with a wide range of abilities in the child with 49,XXXXY, thus warranting further investigation to identify and understand the critical influences on the etiology and the variability of those capacities.

Morbidity in Klinefelter syndrome and the effect of testosterone treatment.

Klinefelter syndrome (KS; 47,XXY) is the most common sex chromosome abnormality in males (150 per 100,000 males). The condition leads to hypergonadotropic hypogonadism and ever since the condition was described approximately 80 years ago, testosterone treatment has been the cornerstone in care for individuals with KS. However, KS is associated with an array of health-related and socioeconomic challenges and it is becoming progressively clear that proper care for boys and men with KS reaches far beyond simply supplementing with testosterone. There are no widely implemented guidelines for KS care, and studies investigating crucial aspects of testosterone treatment in individuals with KS, including both beneficial and potentially adverse effects, have only begun to emerge during the last decades. For this descriptive review, we present an overview of literature describing health-related outcomes of testosterone treatment in KS and outline the clinical applications of testosterone treatment in KS. Collectively, beneficial effects of testosterone treatment on overall health in KS are described with few apparent adverse effects. However, larger randomized studies in adult and pediatric patients are warranted to elucidate key aspects of treatment. We stress the implementation of centralized multidisciplinary clinics and the need for a dedicated international guideline to ensure optimal care of boys and men with KS.

Testosterone treatment in male patients with Klinefelter syndrome: a systematic review and meta-analysis.

PURPOSE: Low testosterone (T) in Klinefelter's syndrome (KS) can contribute to typical features of the syndrome such as reduced bone mineral density, obesity, metabolic disturbances and increased cardiovascular risk. The aim of the present study is to review and meta-analyze all available information regarding possible differences in metabolic and bone homeostasis profile between T treated (TRT) or untreated KS and age-matched controls. METHODS: We conducted a random effect meta-analysis considering all the available data from observational or randomized controlled studies comparing TRT-treated and untreated KS and age-matched controls. Data were derived from an extensive MEDLINE, Embase, and Cochrane search. RESULTS: Out of 799 retrieved articles, 21 observational and 22 interventional studies were included in the study. Retrieved trials included 1144 KS subjects and 1284 healthy controls. Not-treated KS patients showed worse metabolic profiles (including higher fasting glycemia and HOMA index as well as reduced HDL-cholesterol and higher LDL-cholesterol) and body composition (higher body mass index and waist circumference) and reduced bone mineral density (BMD) when compared to age-matched controls. TRT in hypogonadal KS subjects was able to improve body composition and BMD at spinal levels but it was ineffective in ameliorating lipid and glycemic profile. Accordingly, TRT-treated KS subjects still present worse metabolic parameters when compared to age-matched controls. CONCLUSION: TRT outcomes observed in KS regarding BMD, body composition and glyco-metabolic control, are similar to those observed in male with hypogonadism not related to KS. Moreover, body composition and BMD are better in treated than untreated hypogonadal KS. Larger and longer randomized placebo-controlled trials are advisable to better confirm the present data, mainly derived from observational studies.

Androgen Treatment in Adolescent Males With Hypogonadism.

During adolescence, androgens are responsible for the development of secondary sexual characteristics, pubertal growth, and the anabolic effects on bone and muscle mass. Testosterone is the most abundant testicular androgen, but some effects are mediated by its conversion to the more potent androgen dihydrotestosterone (DHT) or to estradiol. Androgen deficiency, requiring replacement therapy, may occur due to a primary testicular failure or secondary to a hypothalamic-pituitary disorder. A very frequent condition characterized by a late activation of the gonadal axis that may also need androgen treatment is constitutional delay of puberty. Of the several testosterone or DHT formulations commercially available, very few are employed, and none is marketed for its use in adolescents. The most frequently used androgen therapy is based on the intramuscular administration of testosterone enanthate or cypionate every 3 to 4 weeks, with initially low doses. These are progressively increased during several months or years, in order to mimic the physiology of puberty, until adult doses are attained. Scarce experience exists with oral or transdermal formulations. Preparations containing DHT, which are not widely available, are preferred in specific conditions. Oxandrolone, a non-aromatizable drug with higher anabolic than androgenic effects, has been used in adolescents with preserved testosterone production, like Klinefelter syndrome, with positive effects on cardiometabolic health and visual, motor, and psychosocial functions. The usual protocols applied for androgen therapy in boys and adolescents are discussed.