A multidisciplinary research team led by the University of Coimbra (UC) has conducted a study to deepen knowledge about male infertility of unknown origin. The scientists were able to clarify molecular and metabolic details linked to this type of infertility, which are not routinely assessed and which could be decisive for better diagnosis and the effectiveness of treatments.
Infertility "is a disease with a major impact on the lives, health and well-being of affected couples, who often suffer from psychosocial and financial problems," explains Sandra Amaral, a researcher at the Reproductive Biology and Stem Cells Research Group at the UC Center for Neuroscience and Cell Biology (CNC-UC). "In Portugal, it is estimated that infertility affects around 300,000 couples, with the male factor contributing to around 50% of infertility cases. However, identifying the cause of male infertility is not possible in approximately 30% of cases - so-called male infertility of unknown origin," she adds.
The scientific article New Insights on Sperm Function in Male Infertility of Unknown Origin: A Multimodal Approach, published in the journal Biomolecules, involved more than 1,400 patients, analyzing sperm from healthy individuals without fertility problems and also from men diagnosed with infertility of unknown origin. The scientists were able to identify some functional aspects of the male gamete that are affected: the integrity of its DNA (genetic material to be passed on to future generations), the process of capacitation (which gives the gamete the ability to fertilize) and also mitochondrial function (related to mitochondria, a cell organelle involved in numerous functions such as energy production). In addition, the research team also identified six proteins differentially expressed in individuals diagnosed with infertility. The researchers believe that all these aspects are affecting the fertilization potential of sperm.
"These new functional aspects that we present in this study provide new information that may make it possible, in the future, to identify the factors that cause infertility in these men, opening the door to improved diagnostic methods and future treatments," says Sandra Amaral.
In men, the diagnosis of this pathology involves an integrated assessment, which includes a clinical history, a physical examination, an ultrasound scan, and hormonal and seminal analysis. Currently, "it is in the seminal analysis that some questions arise, since this analysis, which is carried out routinely, has some limitations," explains Sandra Amaral.
"Although seminal analysis (analysis of semen, which is essentially made up of seminal fluid and sperm) is the mainstay of infertility diagnosis, it doesn't always allow us to predict the exact cause of infertility and the likelihood of getting pregnant, since sperm has many other characteristics and functions that are not routinely analyzed," explains the UC researcher. "This highlights the need to study other cellular and molecular details of these cells, as we have done in this study, in an attempt to gain a more in-depth understanding of their functioning and, consequently, to better understand and treat male infertility," stresses the study leader.
In this context, this study "allows us to increase our knowledge of this disease so that, in the future, we can overcome it and avoid the immense suffering associated with it", Sandra Amaral points out. "An integrated approach to male infertility of unknown origin - involving the various functional aspects of the male gamete, as well as other external factors that can impact it - has the potential to contribute to better diagnosis and effectiveness of treatments, contributing to a more sustainable health system, promoting reproductive health, well-being and improved fertilization rates," the researcher explains.
Following the lines of research pointed out in this study, "the next step will be to better understand the function of the proteins that we identified as being differentially expressed in individuals with infertility, to understand how their expression may be related to the state of infertility and eventually find a biomarker for this type of infertility," says Sandra Amaral.

The research, funded by the Foundation for Science and Technology, involved scientists, doctors, embryologists, psychologists and biostatisticians, and involved three UC faculties (Faculty of Science and Technology, Faculty of Medicine and Faculty of Psychology and Educational Sciences). It was conducted in close collaboration with the Reproductive Medicine Service of the Coimbra Hospital and University Center.
The first authors of the scientific article are Rita Ivo Pacheco and Maria Inês Cristo, the latter also a doctoral student at the UC, and it is available here.