Gonadal function is associated with cardiometabolic health in pre‐pubertal boys with Klinefelter syndrome

Abstract

The most common sex chromosome aneuploidy, Klinefelter syndrome (KS), is associated with primary gonadal failure and increased morbidity and mortality from cardiometabolic disorders in adulthood. Children with KS also have a high prevalence of metabolic syndrome (MetS). To assess the relationship of gonadal and cardiometabolic function in children with KS, we evaluated serum hormones (gonadotropins, inhibin B (INHB), anti-mullerian hormone (AMH), total testosterone (TT)), and features of MetS (waist circumference, fasting lipid panel, fasting blood glucose (FBG), and blood pressure) in 93 prepubertal boys with KS age 4–12 years (mean 7.7 ± 2.5 years). The cohort was grouped by age and tanner stage, and biomarkers were compared to normal ranges. 80% of this prepubertal cohort had ≥1 feature of metabolic syndrome (MetS) and 11% had ≥3 features of MetS. Risk of MetS was independent of age and body mass index. Sertoli cell dysfunction was common with 18% having an INHB below the normal range. A low INHB was associated with higher FBG, triglycerides, and LDL and lower HDL (p<0.05). An INHB <50 ng/dl yielded a sensitivity of 83% and a specificity of 79% for having ≥3 features of MetS. INHB and AMH positively correlated with each other (p<0.001), and high AMH was protective of MetS. TT was below the lower limit of normal in 49% of subjects, with mean values significantly lower than expected (3.3 ng/dl versus 4.9 ng/dl, p<0.0001), however no convincing relationship between TT and MetS was seen. In conclusion, gonadal and cardiometabolic dysfunction are prevalent in prepubertal boys with KS. Although the relationship of testosterone deficiency and MetS is well known, this study is the first to report an association between impaired sertoli cell function and cardiometabolic risk.

Testis Development and Fertility Potential in Boys with Klinefelter Syndrome

“…79,85,88 We have found a small but potentially significant number of boys with elevated gonadotropins for age (LH elevated in 7%, FSH elevated in 10%) in a large sample of 86 boys with KS, 4–11 years of age. 40 Serum testosterone concentrations in prepubertal boys with KS within the normal range for age, however the majority are in the bottom quartile. 72,85 It is also imperative to note that normal prepubertal hormone concentrations can be below the detection limit for many assays and testosterone radioimmunoassays in particular will overestimate the testosterone concentrations in children.…”

“…18,36–39 Randomized controlled trials investigating androgen replacement in adults with KS have not been done, although several randomized controlled trials in children with KS are underway or recently completed. 40–42 In the KS mouse model, replacement of testosterone improves psychosocial dysfunction but not osteopenia or metabolic dysfunction. 43,44 More research is needed to understand the pathophysiology of the multiple phenotypic features of males with KS.…”

“…85,88,90 In a much larger sample of nearly 90 boys with KS, we have found a subset who have very low concentrations of AMH (13%) and/or low inhibin B (31%), while a quarter of subjects had rather elevated levels of AMH. 40 This raises the suspicion for sertoli cell dysfunction and in addition to germ cell depletion starting prior to external signs of puberty in boys with KS. However, it is difficult to conclude whether leydig cell dysfunction, in particular defective testosterone production, is present in childhood.…”

“…Despite very little published data of prepubertal androgen treatment in infants with KS, we have found up to 1 in 5 boys with KS receive androgen treatment in infancy or early childhood. 40 Some of these infants will receive a short course of either intramuscular or topical testosterone for the indication of micropenis or small phallus. Other clinicians have suggested testosterone treatment should be considered standard of care in infancy, 100 although no therapeutic benefits have been clearly delineated aside from penile growth.…”

Advances in the Interdisciplinary Care of Children with Klinefelter Syndrome

“…However, 10–20% of boys with KS may have prepubertal elevation of FSH, low inhibin B, and/or elevated AMH reflecting abnormal Sertoli cell function. 118 Whether prepubertal Sertoli cell function is related to overall gonadal function in puberty and adulthood is yet to be determined. Results from a recently completed randomized controlled trial of oxandrolone (a non-aromatizable androgen) are expected soon.…”