Are Adolescent Boys with Klinefelter Syndrome Androgen Deficient? A Longitudinal Study of Finnish 47,XXY Boys

Abstract

Testosterone (T)-substitution therapy is widely used in adult patients with Klinefelter syndrome (KS) to prevent symptoms and sequels of androgen deficiency, but it is currently unknown if adolescent boys with KS benefit from early T therapy. To evaluate the optimal age to start T substitution, we searched for signs of androgen deficiency in pubertal boys with KS. 14 nonmosaic 47,XXY boys, aged 10 -13.9 y, were followed up for 4 -37 mo with staging of puberty and frequent reproductive hormone measurements. Furthermore, indices reflecting androgen action (serum SHBG, leptin, and prostate-specific antigen (PSA) levels) were studied. Both onset and progression of puberty according to Tanner stages were normal in boys with KS. Consistently, serum T concentrations increased as expected and remained normal throughout follow-up. Changes in the indices of androgen action (decreases in serum SHBG and leptin, and increase in serum PSA concentrations) occurred normally, except that average leptin levels were higher in the boys with KS (KS boys 11.8 Ϯ 7.0 g/L; controls 7.6 Ϯ 4.7 g/L; p ϭ 0.033). Despite normal T concentrations, the KS boys displayed from the age of 13 y elevated serum FSH and LH levels, and exaggerated gonadotropin responses to gonadotropin-releasing hormone. These data do not demonstrate an unequivocal androgen deficiency in adolescent boys with KS that would necessitate androgen supplementation therapy during early puberty.

High normal testosterone levels in infants with non-mosaic Klinefelter’s syndrome

“…These Klinefelter boys entered puberty at the expected age with increasing T secretion and showed normal changes in indices of androgen action (i.e. serum SHBG, leptin and prostate-specific antigen) (30). In that study, T secretion remained normal throughout puberty, whereas gonadotrophins increased to supranormal levels around mid-puberty.…”

“…In a recent longitudinal study during puberty in KS, no signs of hypogonadism were evident until mid-puberty (30). These Klinefelter boys entered puberty at the expected age with increasing T secretion and showed normal changes in indices of androgen action (i.e.…”

Therapy of endocrine disease: Testicular function and fertility in men with Klinefelter syndrome: a review

“…3) and appropriate rise in serum concentrations of testosterone, INSL3, and inhibin B. However, from around midpuberty the testicular deterioration occurs, as evidenced by a regression of testicular volume (5,41) (Fig. 3) and levelling off in the serum concentrations of testosterone and INSL3, both of which remain in the low-normal range through puberty (17,36,37,39).…”

“…In childhood, KS boys are characterized by normal concentrations of testosterone, FSH, LH, anti-Mü llerian hormone (AMH), inhibin B, and insulin-like factor 3 (INSL3) until the onset of puberty (17,18,36,37,38,39,40,41,42,43). KS boys usually enter puberty at the expected age with an initial normal increase in testicular volume (Fig.…”

“…At midpuberty, a relative hypogonadism is usually evident by increasing LH and FSH concentrations to hypergonadotropic levels. FSH increases earlier and more markedly than LH (5,36,37,41). Adults with KS are characterized by hypergonadotropic hypogonadism with highly elevated serum concentrations of FSH and LH.…”