Redefining Male Factor Infertility: Toward a Novel Diagnostic and Therapeutic Classification- Preliminary Findings

Background Male factor infertility (MFI) is estimated to contribute to 30-50% of cases of couple infertility. Although MFI impact on couple infertility is relevant, during infertility investigations it is often neglected or considered only through the examination of a single semen analysis. On the contrary, it is important to have a complete andrological assessment, beyond semen analysis, which is just a sign of an underlying disorder, and alone it is not sufficient for a correct diagnosis of MFI. This can only be achieved through a proper diagnostic pathway, aimed at identifying precise patho-physiological etiologies, reducing the idiopathic counterpart. Only following a precise diagnosis, a proper therapeutic pathway for fertility restoration can be initiated. The previous classification into pre-testicular, testicular and post-testicular causes, although serving research purposes, has limited clinical utility and does not specifically guide therapy. A new proposal of classification has been proposed, including the following six categories: I) Infection/inflammation; II) Congenital or acquired seminal pathway obstruction, including retrograde ejaculation; III) Primary testicular disease, further divided into IIIa whit hypergonadotropic testiculopathy and IIIb whit normogonadotropic testiculopathy; IV) Hypogonadotropic hypogonadism; V) Idiopathic infertility with seminal alterations; VI) Idiopathic infertility with normal semen analysis. Aim of the study This study aims to pragmatically analyze preliminary findings of the new diagnostic-therapeutic classification of MFI and evaluate its real-life diagnostic and therapeutic outcome. Materials and Methods We conducted a monocentric retrospective study including 505 male patients from the Unit of Andrology and Reproduction Medicine from 2023-2025. Specifically, only male patients with isolated MFI were included in the study, after the exclusion of patients with known female infertility factors or those with semen alterations but not trying to conceive. We classified patients according to the new diagnostic-therapeutic classification of MFI (category I-VI), adding category VII as well, for significant Varicocele, considering only high-grade varicoceles after the exclusion of other relevant causes of infertility. Furthermore, we conducted an evaluation on FSH treatment on a selected population of 31 subjects of the whole cohort of 505 patients. Results We enrolled 505 patients with a mean age of 35.7 +/- 7.8 years and a mean age of the female partner of 35.1 +/- 5.2. From preliminary data of our evaluation, we found that, as a leading cause of MFI, the categories to be the most populated were category III (IIIa with 33.41% and IIIb with 28.54%) and category I (27.88%). Relevant differences were found considering hormonal profiles (especially FSH), seminal parameters and testicular volumes. Importantly, after our analysis, we found an overall condition of idiopathic infertility (category V and VI) in 2.77% of patients. In addition, varicocele was found to be significant only in 1.39% of patients. Finally, we showed that, when an appropriate selection of subjects (belonging to category IIIb without infections and sub-obstructions) is performed, FSH treatment can lead to meaningful improvement of semen parameters (> 100%) in 90.3% of patients evaluated. Discussion and Conclusions According to our results we understood that a large portion of MFI causes can be reversed or improved with specific treatment, when patients are properly categorized after a meticulous diagnostic pathway. We saw that the Idiopathic share among MFI is actually very low, as well as that of significant varicoceles. Too often the diagnosis of idiopathic infertility is made without a thorough diagnostic process, and it should be reserved as a real exclusion diagnosis and when a varicocele is found, other causes should not be overlooked, but on the contrary, investigations should continue.