Male factor infertility contributes to roughly 50% of the causes of infertility among couples. Advancements in the diagnostic field of reproduction allowed for the recognition of various etiologies for male factor infertility. Various pretesticular, testicular, and posttesticular etiologies have been identified and are believed to arise from genetic causes in 15–30% of cases. While a number of laboratory tests are available, the indication of genetic testing relies primarily on the findings in the history, physical examination, and semen analysis. Men with suspicion of nonobstructive azoospermia and those with idiopathic severe oligozoospermia are investigated with karyotype and Y-chromosome microdeletion assays. Analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is reserved for patients with obstructive azoospermia secondary to a unilateral or bilateral complete absence of the vas deference. In addition to the more commonly adopted tests, the genetic evaluation may have a role in patients with congenital hypogonadotropic hypogonadism and androgen insensitivity syndrome. Genetic testing of male infertility is a rapidly evolving field in andrology. Epigenetics, next-generation DNA sequencing, and microarray-based technologies represent some of the promising development in the area and may further expand the clinical utilization of genetic evaluation.

Human spermatogonial stem cells (hSSCs), the only type of germline stem cells in adult men, are responsible to ensure lifetime-long sperm production in men after sex maturation. As the starting point of spermatogenesis, this cell type delicately balances its self-renewal and differentiation, which is essential for spermatogenesis to proceed continuously. A deep and systematic understanding of hSSCs is critical for treating testis-related pathology such as male infertility and testicular germ cell tumor. In this chapter, we provide a systematic review of our previous and current understanding of hSSCs, as well as the advancement of ex vivo systems to culture human germline. Ultimately, the successful establishment of an hSSC-based human germline culture system will not only greatly benefit the study of human germ cell biology by serving as a useful platform, but also provide potential therapeutic options to treat male infertility and preserve fertility for childhood cancer patients.

In nature varying strategies are used to ensure that the best sperm arrives at the egg. Strategies to select the best sperm are far less rigorous in the setting of in vitro fertilization. In this chapter we discuss how in vitro sperm selection strategies utilize different components of the spermatozoon including their motility characteristics, size, membrane properties, and nuclear structure. Sperm selection strategies have included microfluidics, spectroscopy, label-free imaging, hyaluronan binding, and separation of sperm by charge. Although some studies have shown that sperm selection can improve embryo euploidy rates and pregnancy outcomes, in particular by reducing miscarriages, large clinical trials, focused on the male population who would benefit most from sperm selection, are still needed.

Exogenous testosterone functions as a male contraceptive. As a result, men treated with testosterone who desire fertility will need help when trying to restore or preserve fertility. In this chapter, we provide a framework for counseling and managing hypogonadal men who desire fertility. We explore strategies ranging from cessation of exogenous testosterone to using human chorionic gonadotropin, selective estrogen receptor modulators, aromatase inhibitors, or recombinant follicle-stimulating hormone with or without testosterone to preserve Sertoli and Leydig cell function. Furthermore, we provide strategies to maintain fertility while starting testosterone and clinical pathways for a hypogonadal man to recover fertility based on his desired timeline for a pregnancy.

Spermatogenesis is a complex process that ensures daily production of mature male gametes. The differentiation of spermatogonia stem cells into spermatozoa requires the unfolding of several events that are highly regulated in time and space. During spermatogenesis, which takes place inside the seminiferous tubules, germ cells undergo profound morphological rearrangement as can be observed by classical histological analysis of human testis specimens. Spermatogenesis also brings about the dramatic rearrangement of genetic makeover of developing germ cells including homologous recombination and changes in the epigenetic landscape. In this chapter the different phases of human spermatogenesis and cell types involved are described with an emphasis on their morphological arrangements. In parallel, an update on novel findings concerning the cycle of the seminiferous epithelium, the kinetic of spermatogonial compartment, and the implications of single-cell transcriptome analysis of testicular cells will be provided.

This chapter briefly introduces microfluidics as an enabling technology for medicine, focusing on microfluidic-enabled treatments for male infertility. The first section provides a brief overview of microfluidics-based applications in biomedical research and assisted reproductive technology (ART). In the following sections, we review notable demonstrations of microfluidic technology applied to sperm sample preparation and sperm identification. Finally, we conclude the chapter by providing our perspective on the application of microfluidics technology for male infertility treatment, and the challenges/opportunities for further growth of microfluidics-enabled ART for male infertility.

Male-factor infertility contributes significantly to the burden of infertility. Fortunately, many causes of male-factor infertility are amenable to surgical intervention. These interventions can be grouped broadly into three categories: 1) those that improve sperm delivery, including vasovasostomy, vasoepididymostomy, and transurethral resection of the ejaculatory ducts, for obstruction of the vas deferens, epididymitis, and ejaculatory ducts, respectively; 2) those that improve testicular function and optimize spermatogenesis, namely varicocelectomy; and 3) those that enable direct retrieval of sperm from either the epididymis (microsurgical epididymal sperm aspiration and percutaneous epididymal sperm aspiration) or testicle (testicular sperm aspiration and testicular sperm extraction). When used in conjunction with other assisted reproductive techniques, including IVF/ICSI, these surgical procedures have vastly improved the reproductive outlook for many subgroups of infertile men who had previous been considered completely infertile.

In this review we reflect on the many attempts highlighting key achievements in the field of in vitro spermatogenesis made so far. The research in this field is at a crucial juncture. The evolving technologies (like biofabricated 3D organoids, 3D bioprinting, microfluidics, or organ-on-a-chip) may offer excellent tools and in vitro testicular model systems to advance our understanding and bridge the existing knowledge gaps. Each of these culture systems offers unique advantages and may complement each other to address the common goal of achieving primate spermatogenesis in vitro. There are various possibilities and future scenarios for applying in vitro spermatogenesis as a tool for research and clinical applications in the future.

Male factors significantly contribute to the issues faced by couples who are experiencing difficulties with conception. Management of the infertile male is complicated and based on a multitude of factors. Each couple is unique and has diverse issues, necessitating unique interventional approaches. Management can range from the optimization of lifestyle factors to treatment with surgery and medications. Several options exist in the medical optimization of the infertile, or subfertile male including treatment with gonadotropins (HCg, FSH), selective estrogen receptor modulators (i.e., clomiphene citrate), aromatase inhibitors (i.e., arimidex, letrozole), and prolactin altering agents (i.e., dostinex, bromocriptine). The use of the agents, both alone and in combination, is detailed in the current chapter.

The male experience of infertility has been widely misunderstood, largely because cultural socialization and methodologic limitations restrict men’s expression. While many have believed that men are not emotionally impacted by infertility, recent studies show that men actually experience a variety of complex emotional reactions to an infertility diagnosis, including depression, helplessness, and threats to their masculine identity. In addition, men commonly report feeling they have little to contribute to medical treatments – even in cases of male-factor infertility. Qualitative research has provided insight into the complex inner landscape men experience when navigating infertility. Healthcare and mental health professionals are in a unique position to increase men’s involvement in the treatment process. Fertility counselors now have the skills and training to help men navigate the infertility journey by giving them the tools and strategies they need to cope with this unexpected life stressor, increase social support, and enhance their overall quality of life and well-being.

Why are men infertile?Oxidative stress is one of the major causes of male infertility can be induced by a wide range of biological (age), clinical (varicocele), lifestyle (diet) and environmental (electromagnetic radiation and chemical pollutants) factors. Oxidative stress may impact all aspects of spermatogenesis but is particularly damaging when it is experienced late in the spermatogenic process when male germ cells are differentiating into spermatozoa and are rapidly losing their capacity for DNA repair. An immediate consequence of oxidative stress is that spermatozoa lose their capacity for fertilization, thereby generating a state of infertility/subfertility. However lower levels of oxidative stress can result in spermatozoa that are still competent to fertilize ova but are carrying significant quantities of oxidative DNA damage. If this damage occurs early in spermatogenesis, it can result in a mutation that will be carried to the ovum at the moment of fertilization. Alternatively, if the oxidative DNA damage occurs late in spermatogenesis, it can become fixed as a mutation following fertilization as a result of defective DNA repair in the oocyte. Such DNA damage may be responsible for a range of congenital disorders seen in children, particularly neuropsychiatric conditions such as autism and, critically, infertility.

Since its inception, ICSI has become the most widely used ART technique, and the ultimate treatment for severe male factor infertility. In this chapter, we provide fertilization and clinical pregnancy outcomes with ICSI utilizing oligo-, crypto- and astheno- zoospermic samples. We also describe the negative impact of ooplasmic dysmaturity on fertilization and propose methods to correct it. We also report the selection of spermatozoa with higher genomic integrity using a microfluidic chip in couples with high chromatin fragmentation and complete embryo aneuploidy. This will be followed by a discussion on the safety of ICSI in which we enlist various follow-up studies on the development and health of ICSI offspring through adulthood. To provide an overview on the widespread utilization of this procedure, we comment on the ICSI results reported worldwide.