LITERATURE for the INFERTILITY CLINIC
In this section, we offer commentaries on a broad survey of recent articles. These articles are chosen for two reasons: their potential translational value for immediate clinical practice or to help determine where clinical practice might evolve. Today’s subject is Male Infertility.
A new potential breakthrough treatment for selected men with oligospermia
A recent Danish paper in Cell Reports Medicine may turn out to be game-changing for at least some males with oligospermia (1), and here is why: Sperm production is dependent on proper Sertoli-germ cell interaction. For several reasons, the Danish investigators hypothesized that receptor activator of nuclear factor κB ligand (RANKL) activity in Sertoli cells may, therefore, influence spermatogenesis.
A RANKL inhibitor called denosumab (brand name Prolia and others) is already an FDA-approved human monoclonal antibody used to treat osteoporosis. The investigators, therefore, explored its use in the context of male infertility. As they had hypothesized, treatment with denosumab increased testicular weight, inhibin B levels, and germ cell proliferation in ex vivo testis cultures and in vivo in a humanized RANKL mouse model. Moreover, germ cell proliferation was positively associated with baseline serum concentrations of anti-Müllerian hormone (AMH). Denosumab also increased germ cell proliferation in ex vivo human testis cultures with low/moderate but not severe impairment of Sertoli cell function.
In a placebo-controlled, randomized clinical trial, denosumab showed no effect on semen quality but did increase sperm concentration in a subgroup of infertile men with baseline serum AMH ≥38 pmol/L. A high serum AMH, therefore, may increase the probability of a beneficial response to denosumab treatment in infertile men.
Reference
1. Andreassen et al., Cell Rep Med 2024:5:101783
Does sperm have a non-reproductive immune function?
This is what Brazilian investigators have apparently come to believe after observing that men with moderate to severe COVID-19 showed that their gametes released extracellular traps (in a process called ETosis) in response to the infection. This immune response is common for macrophages and neutrophils but has never before been observed in mammalian reproductive cells (1).
Reference
1. Moura J. Medscape Medical news. October 14, 2024. https://www.medscape.com/viewarticle/sperm-appear-have-nonrepoductive-function-2024a1000ipl?form=fpf
How sperm sticks to the egg
There is lots of news on this front. An article in Science magazine summarized the work of two different teams, which independently came to a similar conclusion. It has been known for some time that two sperm proteins and the egg receptor must interact for the cells to join. How that happens, however, was unclear. Both groups, therefore, utilized the recently developed Multimer tool of AlphaFold (for which a Nobel Prize was awarded) to determine how different proteins, in this case, may slot together based on their structures. And what the AI predicted was the formation of a three-protein complex (trimer) – instead of just two proteins – not only including Izumol and Spaca6 but also the protein TMem81, which had never before been associated with fertilization. An Austrian research group then demonstrated that deleting Tmem81 in zebrafish and mice caused the same sperm defects as the deletion of Izumol or Spaca6. In other words, all three proteins are needed. To further confirm the importance of this triad of proteins, they added antibodies to these three proteins in zebrafish sperm, confirming that all three proteins together were consistently pulled out. This represented formal experimental evidence (1).
Remarkably, the sperm complex has remained the same across vertebrate evolution, while the egg receptors have changed. Suffice it to say, these discoveries may have significant translational relevance for the development of new male fertility treatments and/or male contraceptives.
Reference
1. Leslie M. Science 2024;386(6720):363-364
RNA binding proteins in mammalian spermatogenesis
The mammalian testis contains one of the most complex transcriptomes of any tissue as well as abundant RNA binding proteins. To provide insight into the biology of male fertility, Chinese investigators now examined mouse male germ cells at different stages of development to generate an atlas of RNA binding proteins and their roles in sperm development. They then identified major evolutionarily conserved RNA binding proteins and regulatory elements and demonstrated their roles in mouse spermatogenesis. Their relevance to clinical practice was then demonstrated by collecting data from hundreds of human males in treatments for male infertility and demonstrating the significance of the mouse findings to human health (1). This paper, thus, represents an important step in decoding the genetic and molecular basis of male fertility.
Reference
1. Li et al., Science 2024;386(6720):397