Male factor infertility (MFI) is frequently labelled idiopathic when evaluation relies primarily on semen analysis, potentially overlooking endocrine and pathophysiological mechanisms relevant for targeted management.
To phenotypically define MFI and develop a pathophysiology-based classification aimed at reducing idiopathic infertility following comprehensive evaluation.
Prospective monocentric cohort study conducted at a tertiary referral academic centre.
Eight hundred male partners of infertile couples evaluated between October 2024 and January 2026 after exclusion of isolated female factor infertility.
Prevalence of MFI categories, hormonal patterns across phenotypes, and proportion of idiopathic infertility after comprehensive work-up.
All patients underwent standardized clinical evaluation, hormonal assessment (total testosterone, FSH, LH), testicular ultrasound, and complete semen analysis. Microbiological testing, transrectal ultrasound, and genetic analyses were performed according to guidelines.
Primary spermatogenic failure was the most prevalent category (56.0%), followed by infection/inflammation (22.4%) and hypogonadotropic hypogonadism (8.5%). Idiopathic infertility was identified in only 5.3% of cases. Distinct endocrine profiles were observed, with high-FSH spermatogenic failure representing the dominant phenotype.
Comprehensive phenotyping markedly reduces the proportion of patients classified as having idiopathic infertility and identifies clinically relevant subgroups. This prospective study provides validation of a pathophysiology-based classification and supports a shift toward endocrine-integrated diagnostic strategies in male infertility, with potential implications for targeted management.
The Journal of clinical endocrinology and metabolism. 2026 Jul 04 [Epub ahead of print]
Giuseppe Grande, Andrea Graziani, Nicola Caretta, Antonella Di Mambro, Andrea Garolla, Luis Lopez-Fando Lavalle, Maurizio Merico, Giulia Masi, Pierfrancesco Palego, Maria Santa Rocca, Alberto Scala, Riccardo Selice, Cinzia Vinanzi, Luca De Toni, Alberto Ferlin
Unit of Andrology and Reproductive Medicine, Department of Systems Medicine, University Hospital of Padova, Padova, Italy., Unit of Urology, University Hospital de la Princesa, Madrid, Spain., Department of Medicine, University of Padova, Padova, Italy.