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Clinical infertility is the inability of a couple to conceive after 12 months of trying. Male factors are estimated to contribute to 30–50% of cases of infertility. Infertility or reduced fertility can result from testicular dysfunction, endocrinopathies, lifestyle factors (such as tobacco and obesity), congenital anatomical factors, gonadotoxic exposures and ageing, among others. The evaluation of male infertility includes detailed history taking, focused physical examination and selective laboratory testing, including semen analysis. Treatments include lifestyle optimization, empirical or targeted medical therapy as well as surgical therapies that lead to measurable improvement in fertility. Although male infertility is recognized as a disease with effects on quality of life for both members of the infertile couple, fewer data exist on specific quantification and impact compared with other health-related conditions.Male infertility is increasing globally and is an under-recognized factor in couples’ infertility. In this Primer, Eisenberg and colleagues provide an overview of the epidemiology, aetiology, diagnosis, prevention and treatment of male infertility, focusing on impairments in spermatogenesis.

Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by premature exhaustion of primordial follicles. POI causes infertility, severe daily life disturbances and long-term health risks. However, the underlying mechanism remains largely unknown. We previously identified a Basonuclin 1 ( BNC1 ) mutation from a large Chinese POI pedigree and found that mice with targeted Bnc1 mutation exhibit symptoms of POI. In this study, we found that BNC1 plays key roles in ovarian reserve and maintaining lipid metabolism and redox homeostasis in oocytes during follicle development. Deficiency of BNC1 results in premature follicular activation and excessive follicular atresia. Mechanistically, BNC1 deficiency triggers oocyte ferroptosis via the NF2-YAP pathway. We demonstrated that pharmacologic inhibition of YAP signaling or ferroptosis significantly rescues Bnc1 mutation-induced POI. These findings uncover a pathologic mechanism of POI based on BNC1 deficiency and suggest YAP and ferroptosis inhibitors as potential therapeutic targets for POI. Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction that results in infertility. Here they show that BCN1 mutation results in premature ovarian follicle activation and atresia through dysregulation of ferroptosis.

Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. We find further support for 21 genes in a 2-stage burden test with 2072 cases and 11,587 fertile controls. The disrupted genes are primarily on the autosomes, enriched for undescribed human “knockouts”, and, for the most part, have yet to be linked to a Mendelian trait. Integration with single-cell RNA sequencing data shows that azoospermia genes can be grouped into molecular subforms with synchronized expression patterns, and analogs of these subforms exist in mice. This analysis framework identifies groups of genes with known roles in spermatogenesis but also reveals unrecognized subforms, such as a set of genes expressed across mitotic divisions of differentiating spermatogonia. Our findings highlight NOA as an understudied Mendelian disorder and provide a conceptual structure for organizing the complex genetics of male infertility, which may provide a rational basis for disease classification. The GEMINI consortium sequenced 1,000 cases of idiopathic male infertility and identified a plausible Mendelian cause in 20% of cases. The infertility genes can be grouped by expression pattern, facilitating their interpretation and follow-up.

The reaction of CO 2 with H 2 O to form bicarbonate (HCO 3 − ) and H + controls sperm motility and fertilization via HCO 3 − -stimulated cAMP synthesis. A complex network of signaling proteins participates in this reaction. Here, we identify key players that regulate intracellular pH (pH i ) and HCO 3 − in human sperm by quantitative mass spectrometry (MS) and kinetic patch-clamp fluorometry. The resting pH i is set by amiloride-sensitive Na + /H + exchange. The sperm-specific putative Na + /H + exchanger SLC9C1, unlike its sea urchin homologue, is not gated by voltage or cAMP. Transporters and channels implied in HCO 3 − transport are not detected, and may be present at copy numbers < 10 molecules/sperm cell. Instead, HCO 3 − is produced by diffusion of CO 2 into cells and readjustment of the CO 2 /HCO 3 − /H + equilibrium. The proton channel H v 1 may serve as a unidirectional valve that blunts the acidification ensuing from HCO 3 − synthesis. This work provides a new framework for the study of male infertility. Bicarbonate (HCO 3 − ) is critical in sperm for stimulation of cAMP synthesis during fertilization, though there is dispute over how  HCO 3 − is transported into sperm. Here the authors use limit-of-detection LC/MS to characterize sperm protein expression and show that HCO 3 −  is produced from CO 2  diffusion into sperm rather than active transport.

Intracytoplasmic sperm injection (ICSI) has become the most commonly used method of fertilization in assisted reproductive technology. The primary reasons for its popularity stem from its effectiveness, the standardization of the procedure, which means that it can easily be incorporated into the routine practice of fertility centres worldwide, and the fact that it can be used to treat virtually all forms of infertility. ICSI is the clear method of choice for overcoming untreatable severe male factor infertility, but its (over)use in other male and non-male factor infertility scenarios is not evidence-based. Despite all efforts to increase ICSI efficacy and safety through the application of advanced sperm retrieval and cryopreservation techniques, as well as methods for selecting sperm with better chromatin integrity, the overall pregnancy rates from infertile men remain suboptimal. Treating the underlying male infertility factor before ICSI seems to be a promising way to improve ICSI outcomes, but data remain limited. Information regarding the health of ICSI offspring has accumulated over the past 25 years, and there are reasons for concern as risks of congenital malformations, epigenetic disorders, chromosomal abnormalities, subfertility, cancer, delayed psychological and neurological development, and impaired cardiometabolic profile have been observed to be greater in infants born as a result of ICSI than in naturally conceived children. However, as subfertility probably influences the risk estimates, it remains to be determined to what extent the observed adverse outcomes are related to parental factors or associated with ICSI.

The mechanisms underlying the homeostatic estrogen negative feedback pathway central to mammalian fertility have remained unresolved. Direct measurement of gonadotropin-releasing hormone (GnRH) pulse generator activity in freely behaving mice with GCaMP photometry demonstrated striking estradiol-dependent plasticity in the frequency, duration, amplitude, and profile of pulse generator synchronization events. Mice with Cre-dependent deletion of ESR1 from all kisspeptin neurons exhibited pulse generator activity identical to that of ovariectomized wild-type mice. An in vivo CRISPR-Cas9 approach was used to knockdown ESR1 expression selectively in arcuate nucleus (ARN) kisspeptin neurons. Mice with >80% deletion of ESR1 in ARN kisspeptin neurons exhibited the ovariectomized pattern of GnRH pulse generator activity and high frequency LH pulses but with very low amplitude due to reduced responsiveness of the pituitary. Together, these studies demonstrate that estrogen utilizes ESR1 in ARN kisspeptin neurons to achieve estrogen negative feedback of the GnRH pulse generator in mice. Estrogen secreted by the ovary controls how the brain drives pulsatile reproductive hormone secretion. The authors show that in mice, estrogen receptor alpha within a specific population of hypothalamic kisspeptin neurons is the principal pathway through which estrogen brings about this classic negative feedback pathway common to all mammals.

Key Points Downward trends in sperm concentrations have been described in several geographical areas during this century In several countries, sperm concentration of a considerable proportion of young men has been described to be on a level that has been associated with prolonged time to pregnancy Longitudinal studies suggest that almost full sperm production capacity is achieved around the age of 20 years, which points to the importance of earlier developmental phases in establishment of spermatogenic capacity Environmental factors are likely to have contributed to the declining trends in sperm concentrations; however, identifying the most important factors causing adverse effects remains a challenge Semen quality in young men has been declining, and shows geographical, as well as temporal, variation. Several aspects of modern life, including lifestyle and environmental factors, stress, and exposure to endocrine disruptors and radiation, could be contributing to these trends. In this Review, the authors describe how semen quality is changing in the 21 st century, and consider how we can best identify and avoid the underlying causes. Although semen quality is an important determinant of fertility, defining clear thresholds for normal ranges has proven difficult. According to 'time to pregnancy' studies, fecundity starts to decline when sperm concentrations fall below 30–55 × 10 6 /ml, whereas the WHO criterion for normal values is currently 15 × 10 6 /ml. Multiple studies over the past 15 years have reported median sperm concentrations of 41–55 × 10 6 /ml in young men (mean age 18–21 years) from the general population, suggesting that many of them have suboptimal semen quality. Sperm numbers remain fairly constant between 19 and 29 years of age, which points to the importance of developmental effects. Discussion on whether population semen quality has declined has continued for decades, as regional differences in trends have been noted. The reasons for poor semen quality and adverse trends are not well established, but some associations suggest a causal relationship, for example, with maternal smoking during pregnancy. The role of chemical exposures leading to endocrine disruption and detrimental reproductive effects has been in the focus of research during the past 20 years. Identification of exposures that affect fertility could provide opportunities for effective prevention of reproductive health problems.

In vitro follicle growth is a potential approach to preserve fertility for young women who are facing a risk of premature ovarian failure (POF) caused by radiation or chemotherapy. Our two-step follicle culture strategy recapitulated the dynamic human follicle growth environment in vitro . Follicles developed from the preantral to antral stage, and, for the first time, produced meiotically competent metaphase II (MII) oocytes after in vitro maturation (IVM).

This study aims to enhance the understanding of how the increasing use of assisted reproductive technologies (ART) has contributed to the increase in the total fertility rate (TFR) and to further delaying childbearing. Moreover, it addresses the gap in the methodology concerning the quantification of the effect of ART on fertility postponement. Czechia is one of few countries that are able to serve for the study of the demographic impacts of ART. ART and non-ART fertility rates were calculated using unique data on all children born in Czechia. Excluding mothers who received cross-border reproductive care, the proportion of ART live births in Czechia has not exceeded 4%. However, without ART the TFR would have stood at just 1.65 instead of 1.71 in 2020. ART significantly contributed to a reduction in childlessness and to the increase in fertility rates at ages over 35. Applying the decomposition method, the contribution of the use of ART to delaying childbearing between 2013 and 2020 was 4%. The findings have important policy implications. ART has the potential to support fertility recovery in the context of delayed childbearing. The findings served to alleviate concerns about the contribution of ART to the further undesired delay of childbearing.

Sperm selection in the female reproductive tract (FRT) is sophisticated. Only about 1,000 sperm out of millions in an ejaculate reach the fallopian tube and thus have a chance of fertilizing an oocyte. In assisted reproduction techniques, sperm are usually selected using their density or motility, characteristics that do not reflect their fertilization competence and, therefore, might result in failure to fertilize the oocyte. Although sperm processing in in vitro fertilization (IVF) and intrauterine insemination (IUI) bypasses many of the selection processes in the FRT, selection by the cumulus mass and the zona pellucida remain intact. By contrast, the direct injection of a sperm into an oocyte in intracytoplasmic sperm injection (ICSI) bypasses all natural selection barriers and, therefore, increases the risk of transferring paternal defects such as fragmented DNA and genomic abnormalities in sperm to the resulting child. Research into surrogate markers of fertilization potential and into simulating the natural sperm selection processes has progressed. However, methods of sperm isolation — such as hyaluronic acid-based selection and microfluidic isolation based on sperm tactic responses — use only one or two parameters and are not comparable with the multistep sperm selection processes naturally occurring within the FRT. Fertilization-competent sperm require a panel of molecules, including zona pellucida-binding proteins and ion channel proteins, that enable them to progress through the FRT to achieve fertilization. The optimal artificial sperm selection method will, therefore, probably need to use a multiparameter tool that incorporates the molecular signature of sperm with high fertilization potential, and their responses to external cues, within a microfluidic system that can replicate the physiological processes of the FRT in vitro.In this Review, the authors describe current sperm selection methods and the advances in selection technologies for assisted reproductive techniques, highlighting their mechanisms of selection, advantages, limitations and clinical outcomes. They also propose a conceptual sperm selection model that uses multiple selection mechanisms.