Mesenchymal stem cells (MSCs) are a source of a wide range of soluble factors, including different proteins, growth factors, cytokines, chemokines, and DNA and RNA molecules, in addition to numerous secondary metabolites and byproducts of their metabolism. MSC secretome can be formally divided into secretory and vesicular parts, both of which are very important for intercellular communication and are involved in processes such as angiogenesis, proliferation, and immunomodulation. Exosomes are thought to have the same content and function as the MSCs from which they are derived, but they also have a number of advantages over stem cells, including low immunogenicity, unaltered functional activity during freezing and thawing, and a lack of tumor formation. In addition, MSC pre-treatment with various inflammatory factors or hypoxia can alter their secretomes so that it can be modified into a more effective treatment. Paracrine factors secreted by MSCs improve the survival of other cell populations by several mechanisms, including immunomodulatory (mostly anti-inflammatory) activity and anti-apoptotic activity partly based on Hsp27 upregulation. Reproductive medicine is one of the fields in which this cell-free approach has been extensively researched. This review presents the possible applications and challenges of using MSC secretome in the treatment of infertility. MSCs and their secretions have been shown to have beneficial effects in various models of female and male infertility resulting from toxic damage, endocrine disorders, trauma, infectious agents, and autoimmune origin.

A major factor affecting male fertility is excessive death of germ cells, both immature germ cells and mature spermatozoa. It can be due to various factors causing testicular and/or post-testicular damage, such as infections, obstructive conditions, toxins, oxidative stress, hormonal imbalance, hyperthermia, and anti-sperm antibodies. Massive death of spermatozoa leads to a high proportion of dead sperm cells in the ejaculate (necrozoospermia or necrospermia) while death of immature germ cells can lead to low sperm count (oligozoospermia or oligospermia). Cell death can occur both by necrosis and by apoptosis; in recent decades, it has been found that apoptosis of mature spermatozoa is not only possible but quite common, and can contribute to infertility. Treatment approaches are primarily directed to the underlying condition, i.e. removing the cause(s) of sperm cell death whenever possible, but include also attempts to bypass the cell death event by intracytoplasmic sperm injection with testicular spermatozoa.

Serum antibodies against the small heat shock protein Hsp27 (HspB1) have been associated with certain diseases but have not been studied in infertility. Sera from 73 infertile patients were tested for antisperm antibodies using agglutination and immobilization tests and ELISA, and for anti-Hsp27 antibodies using ELISA. Of these sera, 31 (42.5%) were positive for anti-Hsp27 antibodies, and 46 (63%) were positive for antisperm antibodies through analysis with at least one method. A total of 17 sera (23.3%) were positive for both anti-Hsp27 and antisperm antibodies. When sera containing both anti-Hsp27 and antisperm antibodies were used for immunofluorescence, the neck and tail of spermatozoa were stained, where the related sperm-specific protein HspB10 (ODF1) is localized. These data suggest that anti-Hsp27 antibodies are elevated in a certain proportion of infertile patients, which, in some of them, could be due to cross-reactivity between Hsp27 and the related sperm cytoskeletal component ODF1.