Can Insulin-like peptide 3 (INSL3) levels predict future hypogonadism?

From the Guidelines

Insulin-like peptide 3 (INSL3) levels are not currently established as a definitive predictor of future hypogonadism in clinical practice. The most recent and highest quality study, 1, does not provide evidence to support the use of INSL3 as a predictive tool for hypogonadism. Currently, diagnosis of hypogonadism relies primarily on testosterone measurements, clinical symptoms, and other hormonal assessments like luteinizing hormone (LH) and follicle-stimulating hormone (FSH) 1. While INSL3 shows potential as an early marker of testicular dysfunction, more research is needed before it can be recommended as a standard predictive tool for hypogonadism in clinical practice. Some key points to consider include:

• INSL3 is produced by Leydig cells in the testes and maintains relatively stable levels throughout the day, unlike testosterone which fluctuates significantly.
• Research suggests that declining INSL3 levels may precede drops in testosterone and could potentially identify men at risk for developing hypogonadism before clinical symptoms appear.
• However, INSL3 testing is not routinely available in clinical settings, and standardized reference ranges have not been fully established.
• The American College of Physicians recommends that clinicians measure fasting morning concentrations of total testosterone on 2 occasions to diagnose hypogonadism, but varies in recommendations regarding the threshold at which to categorize a total testosterone level as low 1. Therefore, testosterone measurements and clinical symptoms remain the primary tools for diagnosing hypogonadism, and INSL3 levels are not yet a recommended predictive tool in clinical practice.

From the Research

INSL3 Levels and Hypogonadism

• INSL3 levels can be used as a marker of Leydig cell function and testis-bone-skeletal muscle network in adult men 2.
• Low INSL3 levels could cause or contribute to some symptoms and signs of male hypogonadism, such as sarcopenia and osteoporosis 2.
• The measurement of INSL3 levels should be considered in the clinical management of male hypogonadism and in the evaluation of testicular endocrine function 2.

Relationship Between INSL3 and Testicular Function

• INSL3 is produced in human prenatal and neonatal, and in adult Leydig cells to various extents, and is in a developmental context regulated like testosterone 3.
• INSL3 production is entirely dependent on the state of Leydig cell differentiation, and is stimulated by the long-term trophic effects mediated by luteinizing hormone (LH) 3.
• Serum INSL3 levels can be a usable tool to monitor basal Leydig cell function in patients with various disorders affecting Leydig cell function 3.

Clinical Utility of INSL3 Measurement

• INSL3 levels are low in many conditions of undifferentiated or altered Leydig cell status, and the potential clinical utility of INSL3 measurement is not yet well defined 2.
• INSL3 is as sensitive a marker as testosterone for the evaluation of altered Leydig cell function in patients with congenital hypogonadotropic hypogonadism/Kallmann syndrome 4.
• FSH-hCG combination therapy or hCG monotherapy, contrary to T and FSH monotherapies, significantly increased INSL3 levels in patients with congenital hypogonadotropic hypogonadism/Kallmann syndrome 4.

Independence of Testicular Hormones

• The four testicular hormones (testosterone, AMH, INSL3, and InhB) can be independently deficient in older men 5.
• The average hormonal levels were lower in older men, with diverse profiles of the four testicular hormones, and testosterone levels were not indicative of the complete state of the endocrine testes 5.
• The four hormones vary independently of each other, in younger and older men, indicating that they are regulated dynamically rather than influenced by endocrine cell number 5.