This is a revised version of our application B2311 (2015).

Insulin-like peptide 3 (INSL3) is a relatively new hormone which is made by the steroid-producing Leydig cells of the testes in men. Unlike the male sex steroid testosterone, it is secreted into the bloodstream in a constant way which is independent of daily rhythms and the irregular feedback mechanisms from the brain and pituitary gland. It is therefore an ideal biomarker for the so-called ‘functional capacity’ of the Leydig cells, which is equivalent to their total number and maturity status, and which indicates their total capacity to make steroid hormones (1,2). In adult men we have shown that INSL3 (and hence Leydig cell functional capacity) declines with age, such that in older men it is a good indicator of poor androgen production and associated organ dysfunction (3,4). New data by us now show that within any one individual INSL3 remains consistently low or high over periods of years, reflecting the fact that the Leydig cells are relatively fixed in number throughout adult life, neither growing nor dying (4). Importantly, we have shown that there is a 10-fold variation in INSL3 blood levels in both older and younger men, and that if a young man has a low INSL3 concentration in his blood, we can predict that he will have poor androgen production and hence related debility (bone and muscle weakness, cognitive decline, sexual dysfunction, cardiovascular disease) in old age (4,5). But we have no idea as to what causes this 10-fold spread of INSL3 values in young men.

In this retrospective study, we wish to measure INSL3 in the later blood samples from the ALSPAC cohort of boys collected at 17-18 years of age and most recently at 21-22 years of age (ca. 1500 boys). By applying already collected basic data (birthweight, gestational age at birth, maternal smoking, height and weight through puberty; Tanner staging) for these boys at previous ages, we can calculate pubertal transition, and thus gain insight into possible factors (birthweight; childhood BMI; timing of puberty; height at 8 years; etc) which might be associated with Leydig cell functional capacity in young adulthood, and thus the early factors which might contribute and predict androgen-related debility in old age.

References:

1. Ivell R, Anand-Ivell R (2009) The biology of Insulin-like Factor 3 (INSL3) in human reproduction. Human Reproduction Update 15: 463-476.
2. Ivell R, Wade JD, Anand-Ivell R. (2013) Insulin-like factor 3 (INSL3) as a biomarker of Leydig cell functional capacity. Biol Reprod 88: 147
3. Anand-Ivell RJK, Wohlgemuth J, Haren MT, Hope PJ, Hatzinikolas G, Wittert G, Ivell R. (2006) Peripheral INSL3 concentrations decline with age in a large population of Australian men. Int J Androl 29: 618-626.
4. Ivell R, Heng K, Anand-Ivell R, Wu F, and the EMAS Consortium. (2017) The Leydig cell biomarker Insulin-like peptide 3 (INSL3) in the European Male Aging Study (EMAS). Abstract 87. International Congress of Andrology, Copenhagen, May 2017.
5. Atlantis E, Martin SA, Haren MT, O’Loughlin PD, Taylor AW, Anand-Ivell R, Ivell R, Wittert GA (2009) Demographic, physical and lifestyle factors associated with androgen status, the Florey Adelaide Male Aging Study (FAMAS). Clinical Endocrinology 71: 261-272.
6. Anand-Ivell R, Heng K, Hafen B, Setchell B, Ivell R (2009) Dynamics of INSL3 peptide expression in the rodent testis. Biol Reprod 81: 480-487.
7. Johansen ML, Anand-Ivell R*, Mouritsen A, Hagen CP, Mieritz MG, Søeborg T, Johannsen TH, Main KM, Andersson AM, Ivell R, Juul A. (2014) Serum levels of Insulin-like factor 3, Anti-Müllerian Hormone, Inhibin B and Testosterone during pubertal transition in healthy boys: a longitudinal pilot study. Reproduction 147: 529-535.
8. Monteilh C, Kieszak S, Flanders WD, Maisonet M, Rubin C, Holmes AK, Heron I, Golding J, McGeehin MA, Marcus M. (2011) Timing of maturation and predictors of Tanner stage transitions in boys enrolled in a contemporary British cohort. Paed Perinat Epidem 25: 75-87.
9. Khairullah A, May MT, Tilling K, Howe LD, Leonard G, Perron M, Richer L, Veillette S, Pausova Z, Paus T (2013) Height-based indices of pubertal timing in male adolescents. Int J Dev Sci 7: 105-116.
10. Khairullah A, Klein L, Ingle SM, May MT, Whetzel CA, Susman EJ, Paus T (2014) Testosterone trajectories and reference ranges in a large longitudinal sample of male adolescents. PLOS One 9: e108838.