Insulin-like Factor 3 (INSL3) and Leydig Cell Function

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Insulin-like factor 3 (INSL3) is a hormone produced by the Leydig cells. Its secretion in adults has been found to be dependent on the state of the differentiation of these cells, which in turn is dependent on LH. The secretion and regulation of INSL3 during puberty is unknown. Ferlin et al evaluated the concentrations of INSL3 in 75 healthy male subjects (ages 9.5 to 17.5 years, distributed into 5 pubertal groups of 15 subjects) during normal puberty and assessed the relation of INSL3 to LH, FSH, and testosterone. Concentrations of INSL3 and LH increased from Tanner stage 2 to 4, FSH increased from stage 2 to 3, and testosterone levels increased from stage 3 to 4. Secretion of INSL3 seemed to anticipate the increase in testosterone. However, while FSH, LH, and testosterone levels reached adult levels by Tanner stage 4, INSL3 plasma concentrations at pubertal stages 4 and 5 were only about one-fourth of adult levels. This study is the first to provide information on the physiological secretion of INSL3 during puberty, demonstrating that the concentrations of this hormone increase progressively throughout puberty under the differentiating action of LH on Leydig cells; however, prolonged LH exposure seems to be needed to reach adult INSL3 concentrations. INSL3 seems to be a good marker of Leydig cell differentiation and function and may be useful in the evaluation of pubertal disorders.

Ferlin A, Garolla A, Rigon F, Rasi Caldogno LR, Lenzi A, Foresta C. Changes in serum insulin-like factor 3 during normal male puberty. J Clin Endocrinol Metab. 2006;91:3426-31.

Editor’s Comment

Insulin-like factor 3, a member of the relaxin-insulin hormone family, is produced almost exclusively by the Leydig cells of the testis and affects testicular descent during fetal development by acting on the gobernaculum. Its production is dependent on the state of differentiation of Leydig cells, which in turn depends on LH.¹ Thus, reduced concentrations of this hormone can be seen in cases of undifferentiated or altered Leydig cell function. Recent studies in adults have demonstrated that the production and secretion of INSL3 is dependent on human chorionic gonadotropin (hCG) and that patients with hypogonadotropic hypogonadism have very low concentrations of this hormone, which increase following hCG administration.² Some authors have suggested that INSL3 may turn out to be an even more sensitive marker of impaired Leydig cell function than testosterone.

This study by Ferlin et al demonstrated that INSL3 concentrations increased progressively throughout puberty, seemed to be dependent on the differentiating action of LH on the Leydig cells, and were not affected by testosterone. It also showed that INSL3 levels, in contrast with those of LH, FSH, and testosterone, did not reach adult levels by the end of puberty, suggesting that prolonged exposure to LH is necessary to fully differentiate Leydig cells. From this data one can conclude that testosterone better reflects the steroidogenic activity which is acutely sensitive to LH, while INSL3 may better reflect the differentiation status of Leydig cells. INSL3 may prove to be a good marker for conditions associated with decreased testicular function such as those of infertility or hypogonadism of testicular origin in the adult and of premature or delayed puberty in the adolescent. Further studies are needed to corroborate these findings.

Roberto Lanes, MD

References - (linked to )

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Last Updated: 04/30/2008