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Serum Insulin-Like Factor 3 Levels during Puberty in Healthy Boys and Boys with Klinefelter Syndrome

Hospital for Children and Adolescents (A.M.W., M.H., L.D.), Helsinki University Central Hospital, University of Helsinki, FI-00029 Helsinki, Finland; University Department of Growth and Reproduction (K.B., A.-M.A.), Rigshospitalet, DK-2100 Copenhagen, Denmark; and Department of Pediatrics (L.D.), Kuopio University Hospital, University of Kuopio, FI-70211 Kuopio, Finland

Address all correspondence and requests for reprints to: Anne Wikström, M.D., Helsinki University Central Hospital, Hospital for Children and Adolescents, P.O. Box 281, FI-00029 Helsinki, Finland. E-mail: anne.wikstrom{at}fimnet.fi.

Context: Levels of the Leydig cell-specific hormone insulin-like factor 3 (INSL3) are incompletely characterized in boys during pubertal development.

Objective: The objective of the study was to characterize changes in INSL3 levels during spontaneous puberty in healthy boys, boys with aromatase inhibitor-induced hypergonadotropic hyperandrogenism, and boys with Leydig cell dysfunction.

Design: This was a prospective clinical study.

Setting: The study was conducted at a university hospital pediatric endocrinology outpatient clinic.

Patients: Patients included 30 healthy boys with idiopathic short stature (ISS) aged 9.0–14.5 yr and 14 boys with Klinefelter syndrome (KS) aged 10–13.9 yr.

Intervention: In ISS boys, intervention included aromatase inhibitor letrozole or placebo for 24 months.

Main Outcome Measures: Serum INSL3 levels in relation to bone age, Tanner pubertal stages, and LH and testosterone levels were measured.

Results: Onset of puberty was associated with a significant increase in INSL3 levels from 0.06 ± 0.01 ng/ml at Tanner G1 to 0.32 ± 0.16 ng/ml at G2 (P < 0.0001). Adult INSL3 levels (0.55 ng/ml) were attained at bone age 13–14 yr. ISS boys with letrozole-induced hypergonadotropic hyperandrogenism had, after 12 months of therapy, higher INSL3 levels than did placebo treated (0.85 ± 0.54 vs. 0.26 ± 0.17 ng/ml, P < 0.01). In KS boys during spontaneous puberty, after an initial increase similar to that in healthy boys, INSL3 concentrations leveled off despite hyperstimulation by LH. Positive correlations occurred between serum INSL3 and LH and between INSL3 and testosterone levels in all three groups (P < 0.0001).

Conclusions: In boys, the Leydig cell-specific hormone INSL3 may serve as a new marker for onset and progression of puberty. Pubertal increase in INSL3 levels seems to depend on LH. In KS subjects, INSL3 concentrations indicate Leydig cell dysfunction from midpuberty onward.

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