Male hypogonadism: an extended classification based on a developmental, endocrine physiology-based approach

Area of Science:

• Reproductive Endocrinology
• Male Reproductive Physiology
• Pediatric Endocrinology

Background:

• Normal testicular function relies on integrated tubular and interstitial compartments.
• Current male hypogonadism definitions are limited, particularly in childhood, and don't fully capture germ and Sertoli cell deficiencies.
• A comprehensive approach considering the hypothalamic-pituitary-testicular axis across development is needed for accurate hypogonadism diagnosis.

Purpose of the Study:

• To propose an extended classification of male hypogonadism.
• To integrate pathophysiology, affected testicular cell populations, and onset timing into a new classification system.
• To provide a framework for diagnosing male hypogonadism across different life periods.

Main Methods:

• Review and synthesis of current understanding of testicular physiology and hypogonadism.
• Development of a novel classification based on the hypothalamic-pituitary-testicular axis.
• Consideration of diagnostic markers (e.g., testosterone, INSL3, AMH, inhibin B) and their interpretation across developmental stages.

Main Results:

• Male hypogonadism classification is extended based on: 1) affected axis level (central, primary, combined), 2) impaired cell population (whole testis vs. dissociated dysfunction), and 3) onset period (foetal vs. postnatal).
• Evaluation in infancy/childhood primarily uses Sertoli cell markers like anti-Müllerian hormone (AMH) and inhibin B.
• Hypergonadotropism is not essential for diagnosing primary hypogonadism in childhood; its absence in primary gonadal failure in adolescents/adults suggests combined hypogonadism.

Conclusions:

• The proposed extended classification offers a more comprehensive approach to diagnosing male hypogonadism.
• Accurate diagnosis requires considering the specific level of hypothalamic-pituitary-testicular axis impairment, the affected testicular cells, and the timing of onset.
• This framework aids in understanding and managing male hypogonadism throughout life, especially in pediatric and adolescent populations.