Serum Insulin-like Factor 3 Levels Are Reduced in Former Androgen Users, Suggesting Impaired Leydig Cell Capacity

Abstract

Background Illicit use of anabolic androgenic steroids (AAS) is frequently observed in men and is associated with subsequent testosterone deficiency although the long-term effect on gonadal function is still unclear. Serum insulin-like factor 3 (INSL3) has been suggested to be a superior biomarker of Leydig cell secretory capacity compared to testosterone. The objective of this study was to investigate serum INSL3 concentrations in AAS users. Methods This community-based cross-sectional study included men aged 18 – 50 years, involved in recreational strength training and allocated to one of three groups: never-AAS users as controls (n=44), current (n=46) or former AAS users (n=42) with an average duration since AAS cessation of 32 (23;45) months. Results Serum INSL3 was lower in current AAS users and former AAS users than in controls, median (IQR), 0.04 (ND – 0.07) and 0.39 (0.24 – 0.62) versus 0.59 (0.45 – 0.72) µg/L, P<0.001. Former AAS users exhibited lower serum INSL3 levels than controls in a multivariate linear regression even after adjusting for serum total testosterone and other relevant confounders, (B) (95%CI), -0.16 (-0.29;-0.04) µg/L, P=0.011. INSL3 and total testosterone were not associated in the model, P=0.821. Longer accumulated AAS duration (log2) was associated with lower serum INSL3 in former AAS users, (B) (95%CI), -0.08 (-0.14;-0.01), P=0.022. Serum INSL3, but not inhibin B or testosterone, was associated with testicular size in a multivariate linear regression, (B) (95%CI); 4.7 (0.5 ; 8.9), P=0.030. Conclusions Serum INSL3 is reduced years following AAS cessation in men, independently of testosterone, suggesting persistently impaired Leydig cell capacity.

Association of age, hormonal, and lifestyle factors with the Leydig cell biomarker INSL3 in aging men from the European Male Aging Study cohort

“…Such interventions indeed lead to increased circulating INSL3. INSL3 was recently assessed in body builders using anabolic steroids to promote muscle development 36 . Not only did INSL3 become reduced in these subjects because of loss of Leydig cell functional capacity, but some of this reduction persisted even after several months of stopping the anabolic steroids and consequent recovery of the HPG axis.…”

Addiction and human male fertility: A systematic review and a critical appraisal

“…Overall, 15 articles were recruited that had reported impaired semen parameters &/or hormonal changes in response to AAS. [79][80][81][82][83][84][85][86][87][88][89][90][91][92][93] This is presented in Table 1.…”

“…94 Such changes may be persistent many years after cessation of AAS administration under the effect of reduced INSL3 that may cause persistent Leydig cell dysfunction. 93 It is worth-mentioning here that caution should be taken while addressing relevant studies, because of the generally low level of evidence and the considerable inconsistency in methodology, particularly in terms of the multiple forms of AAS, variations in doses and duration of exposure to AAS investigated. All these factors may alter the results and hence; solid conclusions could be difficult to obtain.…”

“…The effect of AAS on male fertility has attracted reasonable attention as many studies tried to address this point many decades before. Overall, 15 articles were recruited that had reported impaired semen parameters &/or hormonal changes in response to AAS 79–93 . This is presented in Table 1.…”

Society for Endocrinology guidelines for testosterone replacement therapy in male hypogonadism

“…However, as androgens are typically abused in very high doses and as some products have an extended half‐life, recovery of HPG axis function can take from several months to a year or longer, 33,34 with fertility taking up to 3 years to fully recover 34 . Significantly, levels of Insulin‐like factor 3 (INSL3) remain low for at least 3 years following cessation of androgen abuse, independently of testosterone, suggesting a persistent impairment of Leydig cell function 35 …”