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Review
. 2023 Feb 22:14:1145533.
doi: 10.3389/fendo.2023.1145533. eCollection 2023.

New horizons in human sperm selection for assisted reproduction

Brett Nixon  1   2 , John E Schjenken  1   2 , Nathan D Burke  1   2 , David A Skerrett-Byrne  1   2 , Hanah M Hart  1   2 , Geoffry N De Iuliis  1   2 , Jacinta H Martin  1   2 , Tessa Lord  1   2 , Elizabeth G Bromfield  1   2
Affiliations
Review

New horizons in human sperm selection for assisted reproduction

Brett Nixon et al. Front Endocrinol (Lausanne). .

Abstract

Male infertility is a commonly encountered pathology that is estimated to be a contributory factor in approximately 50% of couples seeking recourse to assisted reproductive technologies. Upon clinical presentation, such males are commonly subjected to conventional diagnostic andrological practices that rely on descriptive criteria to define their fertility based on the number of morphologically normal, motile spermatozoa encountered within their ejaculate. Despite the virtual ubiquitous adoption of such diagnostic practices, they are not without their limitations and accordingly, there is now increasing awareness of the importance of assessing sperm quality in order to more accurately predict a male's fertility status. This realization raises the important question of which characteristics signify a high-quality, fertilization competent sperm cell. In this review, we reflect on recent advances in our mechanistic understanding of sperm biology and function, which are contributing to a growing armory of innovative approaches to diagnose and treat male infertility. In particular we review progress toward the implementation of precision medicine; the robust clinical adoption of which in the setting of fertility, currently lags well behind that of other fields of medicine. Despite this, research shows that the application of advanced technology platforms such as whole exome sequencing and proteomic analyses hold considerable promise in optimizing outcomes for the management of male infertility by uncovering and expanding our inventory of candidate infertility biomarkers, as well as those associated with recurrent pregnancy loss. Similarly, the development of advanced imaging technologies in tandem with machine learning artificial intelligence are poised to disrupt the fertility care paradigm by advancing our understanding of the molecular and biological causes of infertility to provide novel avenues for future diagnostics and treatments.

Keywords: andrology diagnosis; assisted reproductive technologies (ART); biomarker; male infertility; sperm; sperm function assay.

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Conflict of interest statement

The authors declare that this review article has been prepared in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Summary of current and prospective tools for sperm selection and the clinical diagnosis of male infertility. Conventional protocols for the diagnosis of male infertility include assessment of sperm morphology, motility and concentration [including World Health Organisation (WHO) assessment criteria (35), computer assisted sperm analysis (CASA) (17), and motile sperm organelle morphology assessment (MSOME)] (16). These protocols are facilitated by the purification of sperm cells from seminal plasma with swim-up techniques or, more commonly, with density gradient centrifugation based on the use of colloidal silica suspensions. More innovative sperm selection strategies including microfluidics (36) and electrophoresis (Felix™; (37)) are also showing promise for use in clinical settings. Recent additions to the armoury of sperm selection tools include assays with the ability to determine DNA integrity and fertilization capacity [including the Cap-Score test (38), hyaluronan-based sperm immobilization methods (39), and high-throughput flow cytometry assays to detect DNA integrity [e.g., probes for the oxidized base 8-hydroxyl-2-deoxyguanosine (8-OHdG) (40)]. Further, smart phone technology is making semen analyses more accessible with at home YO sperm tests (41), and artificial intelligence (AI) advances have enabled new holographic 3D sperm imaging (28) and sperm quality assessment. Finally, technological advancements in omics platforms (34, 42) are permitting the identification of molecular biomarkers with which to stratify infertile patients, allowing enhanced evaluation of subfertility phenotypes, aiding our understanding of the genetic and epigenetic causes of male infertility, and potentially revolutionising fertility treatment with personalized therapeutic regimens.
Figure 2
Figure 2
The biological processes and biomarkers of sperm production and functional maturation; an untapped resource for diagnostic tools of male infertility and sperm selection techniques. (A) In the male reproductive tract sperm nuclear compaction transitions from histone packaging to one characterized by predominantly protamines (43). Developing spermatozoa are simultaneously loaded with regulatory RNA cargo (42, 44) while also shedding excess cytoplasm and spermatogenic legacy proteins (34). Mature spermatozoa are identifiable upon completion of epididymal transit by an enrichment glycosylated surface proteins (34) and dynamic changes in their small non-coding RNAs (sncRNA) profile (45, 46). (B) Seminal plasma conveys not only spermatozoa to the female reproductive tract, but also several non-cellular components including antioxidants, lipids, and cell-free nucleic acids and proteins (47). Many of these non-cellular features offer high potential as biomarkers of a healthy, fertile human ejaculate. (C) After spermatozoa are deposited in the female reproductive tract they must successively negotiate the uterus and uterotubal junction before progressing through the oviduct isthmus and ampulla to contact the ovulated oocyte. Thereafter, spermatozoa must undergo a process termed capacitation, which is accompanied by dynamic protein phosphorylation events giving rise to altered patterns of motility (hyperactivated motility) and substantial membrane remodeling to facilitate the presentation/unmasking of the sperm surface receptors that orchestrate cumulus matrix (hyaluronan) and sperm-zona pellucida adhesion and penetration (30, 48). Finally, spermatozoa undergo an acrosome reaction leading to release of their acrosomal contents and remodeling of the sperm head architecture compatible with downstream gamete membrane fusion and fertilization (49). Beyond the delivery of the paternal genome, there is now compelling evidence that sperm convey epigenetic factors including sncRNAs to influence the trajectory of pre-implantation embryogenesis (50, 51).
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Grants and funding

BN is supported by a National Health and Medical Research Council of Australia (NHMRC) Senior Researcher Fellowship (Grant number: APP1154837). EB is supported by an Australian Research Council (ARC) Discovery Early Career Researcher Award (Grant number: DE210100103). TL is supported by an Australian Research Council Discovery Early Career Research Award (DE220100032).