We note the researchers are not highly critical of these findings even in the face of androgens failing to induce any functionality of the testes beyond enlargement, leaving one to surmise the child will be life dependent on exogenous testosterone even though dysfunction of this nature would not usually be evident at such a young age. But, the child (it seems) will have a longer penis and will have begun puberty several years before its peers, which one can only imagine would expose them to all sorts of situations they would not normally have to deal with until later years. When you combine this with a socially awkward child mentally trailing its peers by as many as five years, you have in our humble opinion created a recipe for disaster and one where parents are usually left to fend for themselves.
The lead researcher Shanlee Davis, MD, MS, is a member of The eXtraordinarY Kids Clinic in Colorado, America where she works under the direction of Nicole Tartaglia MD, MS (Dr T as she likes to be known) hence the findings were never going to be over critical of its own department, a department which prides itself on its connection with AXYS US (otherwise known as the testosterone factory). In place of calling to a halt these unnecessary interventions, the doctor’s preference is to proceed with caution!
Klinefelter syndrome (KS) is a common genetic condition affecting phenotypic boys who are born with an additional X chromosome, typically with a karyotype 47,XXY. It affects ;1 in every 650 boys but is widely under diagnosed, and interventions aimed at improving the manifestations in KS are understudied . Recently there has been increased interest within the scientific and lay communities to give pre-pubertal boys with KS androgen treatment, with benefits cited in cognitive, behavioural, psychosocial, and cardio metabolic profiles. These reports have not addressed the effect of exogenous androgens on endogenous gonadal function, a critical safety outcome.
Testicular function in KS has been studied from infancy through adulthood, although studies with longitudinal components have historically had low sample sizes limiting generalizability. There is general consensus that testicular function is compromised in KS from midpuberty through adulthood. Whether testicular function is impaired in younger prepubertal boys is not resolved. We have previously reported hormone concentrations in a cohort of 93 prepubertal boys with KS. This cohort participated in a 2-year, randomised, controlled trial of the low-dose, orally available androgen, oxandrolone (Ox), with improvements in body composition, fasting triglycerides, measures of anxiety, and visual-motor integration compared with placebo (Pl), but no significant changes in cognition or motor function. Ox was well tolerated with no serious adverse events; however, growth acceleration and bone age advancement was noted despite Ox being a nonaromatisable androgen and not expected to have an effect on the growth plate. We hypothesised Ox may have an impact on testicular function. Therefore, the objective of this work was to compare onset of puberty and testicular function in prepubertal boys treated with Ox compared with Pl.
In this analysis of a 2-year, randomised, Pl-controlled trial in boys with KS, we observed that treatment with Ox led to earlier gonadarche and pubarche. Nearly a quarter of boys treated prior to age 9 experienced gonadarche during the 2-year study period. However, Ox did not affect testicular function during puberty as assessed by testicular volumes and serum testosterone, LH, FSH, INHB, and AMH concentrations. Predicted adult height and psychosocial measures were not compromised in the Ox group, including in five boys who experienced early gonadarche.
Ox is an anabolic steroid with a much less virilising effect compared with testosterone. It is a weak agonist of the androgen receptor, so pubic hair development could be a direct effect of Ox binding to the androgen receptor on epithelial hair follicles. An alternative hypothesis is that pubic hair development is secondary to endogenous androgen production, as supported by the observation of increasing testicular volume, serum LH, serum testosterone, and bone age advancement in the Ox-treated boys. As Ox is not aromatised to estrogen, bone age advancement would not be an expected effect of Ox directly. Serum hormone concentrations did not differ in the treated vs untreated groups as would be expected based on the higher likelihood of gonadarche and pubarche in the treated group; however, our study did not follow many participants beyond the initial signs of puberty and may be under-powered to detect differences in hormone concentrations.
Studies of Ox in children have been primarily focused on three populations: girls with Turner syndrome (.8 years of age), boys with constitutional delay of growth and puberty (.12 years of age), and children with substantial burn injuries (all ages). In girls with Turner syndrome, a meta-analysis concluded there is a dose dependent relationship between Ox .0.06 mg/kg/d and virilisation (hirsutism, voice deepening, clitoromegaly). Importantly, the large majority of these girls have gonadal dysgenesis. Therefore, it is not possible to evaluate the effect of Ox on central puberty in this cohort.
For adolescent boys with constitutional delay, Ox 2.5 mg daily resulted in increased testicular volume, serum testosterone concentrations, and pubic hair development compared with untreated controls, in addition to greater bone age advancement . A small study of boys .13 years with constitutional delay of puberty suggested that Ox (n = 5) may result in temporary suppression of the pituitary-gonadal axis followed by an increase in serum LH and testosterone with corresponding increase in testicular volume. In another study that included younger boys with growth delay (9 to 14 years), 40 of the 46 participants entered puberty within the follow-up period (mean of 9 months). These data are consistent with our study results, although notably endogenous puberty is typically desired in boys with constitutional delay of puberty
In contrast, use of Ox in burn victims does not seem to effect virilisation or testicular function despite the use of higher doses. In one study of 70 burn victims treated for 1 year with 0.1 mg/kg/d of Ox starting at a mean age of 8, virilisation was not observed in any subjects. In addition, TT concentrations were not different between Ox and control groups. Testicular volumes and pubertal status were not reported in this study, and pre and post-pubertal subjects of both sexes were analysed together, potentially masking effects unique to pre-pubertal boys. In addition, given that our cohort experienced gonadarche at a median of 18 months into Ox treatment, it is possible the effects on the gonadal axis would not yet be apparent with only 1 year of treatment.
The recognition that chronic pre-pubertal sex steroid exposure may result in early activation of the hypothalamicpituitary-gonadal axis is not unique. Poorly controlled congenital adrenal hyperplasia and McCune Albright syndrome, resulting in chronically elevated testosterone and estrogen concentrations, respectively, are well known to lead to earlier central puberty. However, both of these conditions are associated with significant bone age advancement, and central puberty often commences when the bone age reaches a pubertal age. In contrast, the boys treated with Ox in our study reached gonadarche at a significantly younger bone age than would be expected. Prolonged prepubertal exposure to Ox and other sex steroids may interrupt the normal suppression of the hypo thalamic pituitary-gonadal axis in at least a subset of children, and this may be a useful model in studying disorders of pubertal development and/or treatment of delayed puberty.
Does early gonadarche or pubarche matter? Our participants were not followed beyond these very early signs of puberty, so we cannot determine if puberty progresses or if earlier gonadarche or pubarche have sequelae. Although there are ample data pointing toward increased depression in girls with precocious puberty, there are very few data on mental health in boys with precocious puberty. Our data do not suggest any ill effects on psychosocial functioning or predicted final height in this small cohort. Although we cannot discern if early gonadarche is problematic, this risk should be discussed with parents if pre-pubertal androgen treatment is being considered. In addition, given our findings, all studies using Ox in pre-pubertal children should rigorously evaluate signs of puberty, hormone concentrations, and potential sequelae of precocious puberty.
An inherent weakness in this study is that assessing pubertal status and gonadal function in pre-pubertal boys with KS is not straightforward. For this analysis, we defined gonadarche at >4 mL; however, as boys with KS have smaller testes throughout the lifespan, this may not reflect the commencement of central puberty in KS. In addition, relying on morning LH levels to define puberty may under classify central puberty, and in some boys with KS, LH may be elevated into the pubertal range even at a very young age secondary to primary hypogonadism rather than true puberty. Another limitation is, due to the young age of our cohort and defined follow-up period of 2 years, we were unable to assess the effects of Ox on fertility. Importantly, serum measures of Sertoli cell function were not different between groups. In addition, the natural history of testicular function in KS demonstrates markedly reduced spermatozoa starting in infancy and progressing throughout childhood and adolescence, even without androgen treatment. Strengths of this study include that it is the largest pre-pubertal cohort of boys with KS, as well as the randomised design, the 2-year follow-up period, and the multi model safety assessments.
In conclusion, 2 years of Ox treatment in pre-pubertal boys with KS results in increased risk of early gonadarche, on average 2 years earlier than in Pl-treated boys. The underlying mechanism of this finding warrants further investigation, as it potentially has implications for other populations with pubertal disorders. Ox increases penile length and does not seem to impair the natural history of testicular function in boys with KS. For now, caution should be used in treating pre-pubertal boys with KS due to a possible risk of precocious puberty. As studies have suggested potential benefits of pre-pubertal androgens on neurodevelopment and cardio metabolism in KS, further studies are needed to fully evaluate the effects of exogenous androgens on testicular function in boys with KS, including optimisation of formulation, dose, and duration.
Clinical Trial Information:
Androgen Effect on Klinefelter Syndrome Motor Outcome
Footnote: The Image used herein does not have a biblical reference, it relates to pathology and how children are gifted to it