Guideline for unexplained couple infertility: misunderstandings on the approach to the male factor

Sir, We read with interest the guideline about unexplained infertility developed by the Guideline Group (GDG) on Unexplained Infertility of ESHRE (Romualdi et al., 2023). We appreciated the efforts to have clear, evidence-based recommendations on this important topic but would like to point out fundamental problems and misunderstandings on the approach to the male factor. Although we can agree on the definition of unexplained infertility made by the GDG as ‘infertility in couples with apparently normal ovarian function, fallopian tubes, uterus, cervix and pelvis, age ≤40 years and with adequate coital frequency; and apparently normal testicular function, genito-urinary anatomy, and a normal ejaculate’, substantial differences in the diagnostic approach for the female and male partner are then proposed to assess these features. In fact, a comprehensive evaluation of the female partner is recommended considering ovulation, ovarian reserve, tubal factor, uterine factor, and even vaginal microbiota, whereas the approach to the male partner is limited only to semen analysis. The entire following line of reasoning assumes that a normal semen analysis is sufficient to rule out male factor infertility and no further examination is needed. There are several problems with this approach. First of all, it is quite clear that a normal testicular function and genito-urinary anatomy cannot be determined by semen analysis only, but instead require a combination of, at least, history, physical examination, endocrine assessment, and ultrasound examination of the testes and seminal tract. For semen analysis, the GDG correctly refers to the World Health Organization (WHO) manual for semen analysis (6th edition) (World Health Organization, 2021) but misinterpreted it because the GDG does not recommend any other diagnostic procedure when ‘semen analysis according to WHO criteria is normal’. Not only did the GDG neglect to consider a broad approach to understand whether the testicular function and genito-urinary anatomy are normal, but also it made substantial misunderstandings on the role and significance of semen analysis and its relation with fertility. A main point is that the WHO manual does not define normal semen analysis (World Health Organization, 2021), simply because the so-called ‘reference values’, and in particular the fifth percentile reference, do not represent cut-off limits for fertility and infertility. These values represent the distribution of results from around 3500 presumed fertile men and they are ‘not sufficient to establish clinically useful decision limits’ (World Health Organization, 2021). WHO is very clear when stating that ‘reference values cannot be used to distinct limits between fertile and subfertile men’, ‘the lower fifth percentile of data from men in the reference population does not represent a limit between fertile and infertile men’, and ‘for an individual patient, a semen analysis is never prognostic of infertility’. Since, it is well known that natural fertility is possible with semen parameters below the fifth percentile and infertility with semen parameters above the fifth percentile, a ‘normal ejaculate’ cannot be defined. Therefore, there is a ‘problem in applying a dichotomous categorization to fertility that must be considered a continuum. It is also well known that there is a substantial overlap of semen examination results between fertile and infertile men’ (World Health Organization, 2021). Hence, the reference limits cannot be used as a specific limit between infertile and fertile men (Björndahl et al., 2023). Results of semen examination below the WHO reference values do not automatically mean that the problem of the couple resides in the male, and results above the limits do not always mean that the male partner of an infertile couple is undoubtedly fertile (Björndahl et al., 2023). Semen analysis is fundamental in the initial investigation of the male partner of an infertile couple, but its results should be interpreted together with other clinical and diagnostic procedures to assess the fertility potential and the health of the genital tract. Therefore, semen analysis is not an absolute indicator of the (in)fertility of the couple. Of particular note, semen analysis does not represent the final diagnosis, but rather the starting point in the diagnostic process of the male partner of an infertile couple, as an alteration of semen parameters is a sign of an underlying disorder (Ferlin et al., 2022). Information on genito-urinary anatomy, testicular function, and the causes and risk factors for infertility can be obtained only combining different clinical and diagnostic procedures, as hormonal assessment, testicular and transrectal imaging, microbiology testing, genetic analysis, and second-level sperm analyses, and this approach is particularly important in the context of unexplained infertility (Ferlin et al., 2022). To this regard, it seems quite curious for example that even body mass index measurement is recommended by the GDG for the female but not for the male partner (Romualdi et al., 2023). In conclusion, bearing in mind that unexplained infertility is an exclusion diagnosis, we agree with its definition made the GDG (Romualdi et al., 2023) but not with the methodology to diagnose it for the male component. The criteria for diagnosis of unexplained infertility mean that an extensive andrological approach is performed to exclude problems in the testicular function and genito-urinary anatomy, and semen analysis cannot be used to define for sure the fertility status of the male partner. Indeed, in our experience, such a comprehensive approach for the identification of factors associated with male factor infertility will leave very few cases with a real diagnosis of unexplained infertility. All authors declare no conflict of interest in relation to this manuscript.