Male Reproductive Abnormalities Research Articles

The Relationship Between Chromosomal Polymorphism and Male Reproductive Abnormalities.

This study aims to investigate the association between chromosomal polymorphisms and abnormalities in male reproductive health. Within the period from January 2018 to December 2022, a cohort of 10,827 males seeking fertility services at our reproductive center was selected for inclusion in this study. Peripheral blood chromosomal karyotype analysis was conducted for each participant to identify carriers of chromosomal polymorphisms, who were subsequently categorized into a polymorphism group. Additionally, a control group was constituted by randomly selecting 1,630 patients exhibiting normal chromosomal karyotypes. The study conducted statistical analyses to compare clinical outcomes between the two groups, focusing on infertility, history of spontaneous miscarriage in partners, anomalies in reproductive development, fetal abnormalities, and sperm quality metrics. (1) Among the cohort of 10,827 males, chromosomal polymorphisms were identified in 1,622 participants, yielding a detection rate of 14.98%. This rate is significantly elevated in comparison to the baseline prevalence of 1.77% observed in the general population. (2) The predominant variant among these polymorphisms was related to the Y chromosome, accounting for 1,082 cases (66.71% of the polymorphic findings), corresponding to a detection rate of 9.99%. This is markedly higher than the approximate 0.09% prevalence noted within a normative demographic. (3) Statistical analysis revealed significant disparities between the chromosomal polymorphism group and the control group in several clinical outcomes. Notably, the rates of spontaneous abortion (18.06% vs. 1.35%), fetal anomalies (1.97% vs. 0.25%), and poor sperm quality (41.74% vs. 7.18%) were markedly higher in the polymorphism group. Additionally, incidences of testicular dysgenesis (2.28% vs. 0.92%) and hypogonadism in partners (0.62% vs. 0.37%) also demonstrated significant differences, underscoring the potential reproductive implications of chromosomal polymorphisms. The study establishes a significant link between chromosomal polymorphisms and critical reproductive outcomes, including male infertility, spontaneous miscarriages in partners, fetal anomalies, and reduced sperm quality. These findings highlight the clinical relevance of chromosomal polymorphisms in reproductive health assessments and suggest the necessity for their consideration in the diagnostic and therapeutic strategies for male reproductive disorders.

The use of L-arginine in male reproductive abnormalities: An educational article and expert opinion

Dietary health supplements have been increasingly used in the treatment of a variety of conditions. During the previous decades, L-arginine has been reported to have beneficial effects on male reproductive functions. Arginine is an amino acid that is important for being a precursor for the synthesis of nitric oxide, and playing a role in the regulation of blood pressure. The aim of this paper is to review L-arginine research findings relevant to its use in male reproductive abnormalities. Conclusion and expert opinion: A variety of agents have been used in the treatment of poor semen quality of unknown etiology (Idiopathic) with a beneficial effect including mesterolone, zinc sulphate, coenzyme Q10, vitamin E, folic acid, pentoxifylline, and L-carnitine. A beneficial effect of arginine on oligospermia has been suggested as early as 1947. There is convincing research evidence suggesting that L-arginine can improve male reproductive abnormalities and can be useful in the treatment of some form’s male infertility and erectile dysfunction. The addition of a safe therapeutic supplement to the already known therapeutic armamentarium is desirable. The current evidence-based opinion suggests that because L-arginine is safe and can be beneficial when used in patients with male reproductive abnormalities, to be aware of such potentially important therapy.

The use of L-carnitine in male reproductive abnormalities: The available evidence

Dietary health supplements have been increasingly used in the prevention and treatment of chronic disorders. During the previous decades, l-carnitine has been reported to have beneficial effects on male reproductive functions. L-carnitine, a non-protein amino acid produced endogenously in the human body from the essential amino acids lysine and methionine or obtained from exogenous dietary sources. The main natural forms of L-carnitine are Acetyl-L-carnitine and propionyl-L-carnitine. The aim of this paper is to review l-carnitine research findings relevant to its use in male reproductive abnormalities. Treatment of reproductive male abnormalities caused by abnormalities of idiopathic semen quality including oligozoospermia, asthenospermia, and azoospermia include hormonal therapies (Clomiphene citrate, tamoxifen, recombinant FSH, and testosterone undecanoate). Non-hormonal therapies include pentoxifylline, and dietary health supplements including carnitine. Carnitine has the additional advantage of improving associated erectile dysfunction. Conclusion: There is convincing research evidence suggesting that l-carnitine can improve male reproductive and can be useful in the treatment of some form’s male infertility and erectile dysfunction.

The use of L-Carnitine in Male Reproductive Abnormalities: The Available Evidence

Dietary health supplements have been increasingly used in the prevention and treatment of chronic disorders. During the previous decades, L-carnitine has been reported to have beneficial effects on male reproductive functions. L-carnitine, a non-protein amino acid produced endogenously in the human body from the essential amino acids lysine and methionine or obtained from exogenous dietary sources. The main natural forms of L-carnitine are Acetyl-L-carnitine and propionyl-L-carnitine. The aim of this paper is to review l-carnitine research findings relevant to its use in male reproductive abnormalities. Treatment of reproductive male abnormalities caused by abnormalities of idiopathic semen quality including oligozoospermia, asthenospermia, and azoospermia include hormonal therapies (Clomiphene citrate, tamoxifen, recombinant FSH, and testosterone undecanoate).Non-hormonal therapies include pentoxifylline, and dietary health supplements including carnitine. Carnitine has the additional advantage of improving associated erectile dysfunction. Conclusion: There is convincing research evidence suggesting that l-carnitine can improve male reproductive and can be useful in the treatment of some forms male infertility and erectile dysfunction.

The use of L-Carnitine in Male Reproductive Abnormalities: The Available Evidence

The use of L-Carnitine in Male Reproductive Abnormalities: The Available Evidence

P-105 Genetic variants in the spermatogenic transcription regulators RFX2 and TAF7 enhance the incidence of azoospermia

Abstract Study question What are the genetic variants of meiotic regulator genes that are implicated in male infertility among men from West Bengal, India? Summary answer TAF7 C16T (MW827584 G > A) and RFX2 562delT (MZ560629delA) new variations may have a major impact on optimal fertility in men from West Bengal. What is known already According to published research, roughly 50% of reported infertility cases in India are due to male reproductive abnormalities. Because of the involvement of several gene regulatory networks in the spermatogenesis process, the genetic etiology of idiopathic male infertility remains a mystery. The AZF region of the Y chromosome microdeletion has been discovered as a prevalent cause of male infertility across all ethnicities. Infertility in men has also been linked to sex chromosomal copy number variation and autosomal gene polymorphisms. Study design, size, duration This is a case-control study to infer whether the genetic variants are significantly associated in favor of cases or in favor of controls. The study included 160 healthy male controls and 150 azoospermic cases submitted to the Institute of Reproductive Medicine in Kolkata (IRM). All of the subjects agreed to participate in the study and provided blood and sperm samples. The duration of the study is three years. Seminograms were made to filter azoospermic individuals. Participants/materials, setting, methods 2 ml of venous blood samples were taken from azoospermic men using the venipuncture procedure and stored in EDTA coated vacutainer tubes at -20°C for DNA isolation.QIAamp Blood Mini Kit was used to isolate genomic DNA. For PCR analysis, unique primers for TAF7 and RFX2 functional domains were created. Taq Dye Deoxy Terminator sequencing kit (Applied Biosystems, Foster City, USA) and ABI Prism 377 DNA sequencer were used to analyze PCR results. Main results and the role of chance We have found two significant genetic alterations in the coding region of TAF7 and RFX2 which are MW827584 G > A(C16T) and MZ560629delA(562delT) respectively. Both were found to have a strong association to the occurrence of azoospermia. For MW827584 G > A, minor allele ‘A’ has shown elevated risk of azoospermic against the odd 4.684 (95% C.I = 2.900-7.564, Relative risk =2.110, p value = <0.001). Fisher’s exact test was performed to calculate Odds ratios with respective 95% confidence interval (CI). After Bonferroni's correction, a two-tailed P-value of less than 0.02 was considered statistically significant throughout. Only the case sample cohort had the RFX2 deletion MZ560629 delA. Only 9 cases with this unique deletion in heterozygous form were found out of 150 azoospermic patients. This frameshift mutation results in the production of an early termination signal at exon 6, resulting in the creation of a truncated protein. The wild-type RFX2 protein has 729 amino acids but this frameshift mutation results in a 212-amino-acid RFX2 protein that lacks several secondary motifs and domains, rendering the wild-type function useless. In silico analysis of SIFT, PROVEAN, MUTATION TASTER and REGULATION SPOTTER predicted that these genetic variants are disease-causing. Limitations, reasons for caution There are some potential limitations to our research. A larger sample size investigation is needed to reconfirm the genetic association study. Moreover, confounding effects of allelic variation of those genetic modifiers may cause differences in the manifestation of fertility state along with the allelic variants of TAF7 and RFX2 genes. Wider implications of the findings This diagnostic technique will not only reduce the hazards connected with assisted reproductive technologies (ART), but it will also provide insight into previously unknown areas of infertility and enable clinicians in conducting a more thorough investigation of the patients. Trial registration number not applicable

In Utero Exposure to a Mixture of the Perfluoroalkyl-Isopropyl Pesticide Pyrifluquinazon With Dibutyl Phthalate Cumulatively Disrupts Male Rat Reproductive Development via Different Mechanisms of Action.

Administration of individual chemicals and mixtures during sexual differentiation that disrupt the androgen signaling pathway can induce reproductive abnormalities in male rats. In this study, we coadministered the heptafluoroisopropyl pesticide pyrifluquinazon (PFQ), and dibutyl phthalate (DBP) to pregnant rats during sexual differentiation of the reproductive tract. Both chemicals have been shown to disrupt reproductive tract differentiation in a dose-related manner reducing male anogenital distance, permanently reducing androgen-dependent tissue weights and sperm counts, and inducing reproductive malformations in male offspring, albeit by different mechanisms of action that converge downstream in the androgen signaling pathway on a common key event. Rats were orally dosed from gestation days 14-18 with dilutions of PFQ and DBP at 0%, 12.5%, 25%, 50%, 75%, and 100% of the top dose (100 mg/kg PFQ and 750 mg/kg DBP). The mixture ratio was selected such that each chemical would contribute equally to multiple effects on the male offspring reproductive tract and the dose range was designed to determine if the mixture produced additive effects predicted by dose addition (DA) or response addition (RA) models, or whether significant interactions occurred. Observed data were compared with DA and RA model predictions. As hypothesized, the mixture reduced F1 male anogenital distance, reproductive organ weights and sperm counts and induced hypospadias with DA consistently providing a better prediction of the observed effects than RA. These results support our hypothesis that chemicals that disrupt the androgen signaling pathway induce dose-additive male reproductive abnormalities regardless of the specific mechanism of action.

Potential dual protective effects of melatonin on spermatogonia against hexavalent chromium

Hexavalent chromium (Cr (VI)) is a widely used metal and has been shown to cause male reproductive abnormalities. However, the underlying mechanisms for the Cr (VI)-induced reproductive toxicity remain incompletely understood. In this study, we investigated the spermatogonial damage caused by Cr (VI) as well as the protective effect of melatonin against Cr (VI)-triggered toxicity. We observed that Cr (VI) caused spermatogonial damage in a time- and dose-dependent manner. Results further showed that melatonin could protect spermatogonia from Cr (VI)-triggered damage via elimination of reactive oxygen species (ROS) as well as via suppression of ATM-p53 phosphorylation and the mitogen-activated protein kinase (MAPK) pathway. Prior administration of melatonin also prevented the Cr (VI)-caused enrichment of H3K9me3 in the Mad1, Mad2 and Bcl2 gene promoter regions, precluding the G2/M arrest and apoptosis in spermatogonia. Taken together, this study demonstrates that melatonin can effectively protect spermatogonia against the damage and against the histone modification changes induced by Cr (VI). This, along with the uncovered molecular mechanism, provide important implications for male infertility induced by environmental pollution.

Perspectives on Potential Fatty Acid Modulations of Motility Associated Human Sperm Ion Channels.

Human spermatozoan ion channels are specifically distributed in the spermatozoan membrane, contribute to sperm motility, and are associated with male reproductive abnormalities. Calcium, potassium, protons, sodium, and chloride are the main ions that are regulated across this membrane, and their intracellular concentrations are crucial for sperm motility. Fatty acids (FAs) affect sperm quality parameters, reproductive pathologies, male fertility, and regulate ion channel functions in other cells. However, to date the literature is insufficient to draw any conclusions regarding the effects of FAs on human spermatozoan ion channels. Here, we aimed to discern the possible effects of FAs on spermatozoan ion channels and direct guidance for future research. After investigating the effects of FAs on characteristics related to human spermatozoan motility, reproductive pathologies, and the modulation of similar ion channels in other cells by FAs, we extrapolated polyunsaturated FAs (PUFAs) to have the highest potency in modulating sperm ion channels to increase sperm motility. Of the PUFAs, the ω-3 unsaturated fatty acids have the greatest effect. We speculate that saturated and monounsaturated FAs will have little to no effect on sperm ion channel activity, though the possible effects could be opposite to those of the PUFAs, considering the differences between FA structure and behavior.

Oxidant-Sensitive Inflammatory Pathways and Male Reproductive Functions.

Male component is the major contributing factor in over half of all cases of infertility, with over 25% of infertile males having no recognised underlying causeof infertility. In around 40-50% of male infertility cases, oxidative stress (OS)-related processes have been found to be responsible for fertility impairment. Inflammation is a major stress signal leading to OS. Redox imbalance occurs when endogenous antioxidant network fails to curb the excess generation of reactive oxygen species (ROS), leading to activation of stress-sensitive intracellular signalling pathways directed to cellular damage. Oxidant-sensitive-inflammatory pathways are intricate vicious intracellular networking loops that initiate and exaggerate cellular damage, including chronic impact on male reproductive tissues. These mechanisms, however, are poorly known in connection to male reproductive abnormalities. Thus, the goal of this chapter is to explain the oxidant-sensitive-inflammatory pathways in male reproductive organs in a succinct manner, as well as their potential influence on male fertility.

Stem cells technology as a platform for generating reproductive system organoids and treatment of infertility-related diseases.

In recent years, stem cells have known as a helpful biological tool for the accurate diagnosis, treatment and recognition of diseases. Using stem cells as biomarkers have presented high potential in the early detection of many diseases. Another advancement in stem cell technology includes stem cell derived organoids model that could be a promising platform for diagnosis and modeling different diseases. Furthermore, therapeutic capabilities of stem cell therapy have increased hope in the face of different disability managements. All of these technologies are also widely used in reproductive related diseases especially in today's world that many couples encounter infertility problems. However, with the aid of numerous improvements in the treatment of infertility, over 80% of couples who dreamed of having children could now have children. Due to the fact that infertility has many negative effects on personal and social lives of young couples, many researchers have focused on the treatment of male and female reproductive system abnormalities with different types of stem cells, including embryonic stem cells, bone marrow mesenchymal stem cells (MSCs), and umbilical cord-derived MSCs. Also, design and formation of reproductive system organoids provide a fascinating window into disease modeling, drug screening, personalized therapy, and regeneration medicine. Utilizing these techniques to study, model and treat the infertility-related diseases has drawn attention of many scientists. This review explains different applications of stem cells in generating reproductive system organoids and stem cell-based therapies for male and female infertility related diseases treatment.

A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene-disease relationships.

BACKGROUNDHuman male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a majority (60–70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next-generation sequencing (NGS) technologies, and the absence of clear statements from field leaders as to what constitutes a validated cause of human male infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of male infertility NGS studies. These have revealed a considerable number of novel gene–disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype–phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known male infertility genes and an assessment of the evidence for reported GDRs.OBJECTIVE AND RATIONALEIn 2019, the first standardised clinical validity assessment of monogenic causes of male infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of 1 July 2020) for monogenic causes of isolated or syndromic male infertility, endocrine disorders or reproductive system abnormalities affecting the male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of male infertility, using a framework designed for a more appropriate clinical interpretation of disease genes.SEARCH METHODSWe performed a literature search according to the PRISMA guidelines up until 1 July 2020 for publications in English, using search terms related to ‘male infertility’ in combination with the word ‘genetics’ in PubMed. Next, the quality and the extent of all evidence supporting selected genes were assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment and functional evidence based on gene expression, mutant in-vitro cell and in-vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, across the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines and were recorded in spreadsheets for each GDR, which are available at imigc.org.OUTCOMESThe primary outcome of this review was an overview of all known GDRs for monogenic causes of human male infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 infertility phenotypes.WIDER IMPLICATIONSOur systematic review curates all currently available evidence to reveal the strength of GDRs in male infertility. The existing guidelines for genetic testing in male infertility cases are based on studies published 25 years ago, and an update is far overdue. The identification of 104 high-probability ‘human male infertility genes’ is a 33% increase from the number identified in 2019. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of male infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility. Based on our findings, the IMIGC consortium recommend several updates to the genetic testing standards currently employed in the field of human male infertility, most important being the adoption of exome sequencing, or at least sequencing of the genes validated in this study, and expanding the patient groups for which genetic testing is recommended.

Gut microbiota may contribute to the postnatal male reproductive abnormalities induced by prenatal dibutyl phthalate exposure

Phthalate is an environmental endocrine disruptor that causes direct and intergenerational male reproductive damage. However, its mechanisms require further investigation. The role of gut microbiota in male reproductive function has been gradually revealed in the past. To explore the intergenerational testicular injury and the influence on offspring gut microbiota of the widely used phthalate dibutyl phthalate (DBP), we conducted a prenatal DBP exposure experiment with microbiota sequencing. We finally explained the gestational DBP exposure-induced gut dysbacteriosis, which is one of the mechanisms of testicular injury in the offspring. The occurrence of seminiferous atrophy and spermatogenic cells apoptosis showed a slight increase. Our study partially supported the results of previous research works on the characteristics of gut dysbacteriosis, which featured the increased relative abundance of Bacteroidetes, Prevotella and P. copri. Focusing on the role of gut microbiota in reproductive function is important. Future studies need to investigate the relationship between environmental pollution and human health.

Genetics of Male Infertility - Present and Future: A Narrative Review.

Infertility affects 8%–12% of couples worldwide with a male factor contributing to nearly 50% of couples either as a primary or contributing cause. Several genetic factors that include single-gene and multiple-gene defects associated with male infertility were reported in the past two decades. However, the etiology remains ambiguous in a majority of infertile men (~40%). The objective of this narrative review is to provide an update on the genetic factors associated with idiopathic male infertility and male reproductive system abnormalities identified in the last two decades. We performed a thorough literature search in online databases from January 2000 to July 2021. We observed a total of 13 genes associated with nonobstructive azoospermia due to maturation/meiotic arrest. Several studies that reported novel genes associated with multiple morphological abnormalities of the sperm flagella are also discussed in this review. ADGRG2, PANK2, SCNN1B, and CA12 genes are observed in non-CFTR-related vas aplasia. The genomic analysis should be quickly implemented in clinical practice as the detection of gene abnormalities in different male infertility phenotypes will facilitate genetic counseling.

Identification of abnormal protein expressions associated with mouse spermatogenesis induced by cyclophosphamide.

Cyclophosphamide (CP) is a clinical anticancer drug that can cause male reproductive abnormalities, but the underlying mechanisms for this remain unknown. The present study aimed to explore the potential toxicity induced by CP in spermatogenesis events of germ cell proliferation, meiosis, and blood‐testis barrier integrity at the molecular level. CP‐treated mice showed significantly reduced serum testosterone levels, sperm motility and concentration. The results of immunohistochemistry and Western blot showed that CP reduced the proliferation of germ cells (PCNA, PLZF) and increased germ cell apoptosis (Bax and TUNEL‐positive cells) in CP‐treated mice testes. The expression of meiotic related proteins (SYCP3, REC8, MLH1) decreased significantly in the fourth week after administration, and the expression of blood‐testis barrier related proteins (β‐catenin, ZO‐1) and sperm quality‐associated proteins (PGK2, HSPA4) decreased significantly in the first week after administration. CP leads to the apoptosis of male germ cells, inhibits the proliferation of germ cells, and affects meiosis and the blood‐testis barrier, resulting in the decline of sperm quality. This study provides information to further the study of molecular mechanism and protective strategy of CP influence.

Pyridaben induces mitochondrial dysfunction and leads to latent male reproductive abnormalities

As an organochloride pesticide, pyridaben (PDB) has been used on various plants, including fruiting plants and other crops. Because of emerging concerns regarding exposure to pesticides, the deleterious effects of PDB, including neuronal disease and reproductive abnormalities, have been determined. However, the intracellular mechanisms that contribute to the effects of PDB on the male reproductive system are still unknown. Therefore, we investigated the effects of PDB on the male reproductive organ, focusing on the testes using mouse testicular cells. We demonstrated that PDB suppressed cellular proliferation of mouse Leydig (TM3) and Sertoli (TM4) cells. Additionally, PDB disturbed calcium homeostasis via mitochondrial dysfunction and activation of endoplasmic reticulum stress. Furthermore, PDB inhibited transcriptional gene expression regarding the cell cycle, as well as steroidogenesis and spermatogenesis, which are the primary functions of TM3 and TM4 cells. Moreover, we verified via western blot analysis that PDB dysregulated the intracellular cell signaling pathways in mitochondrial-associated membranes and the Mapk/Pi3k pathway. Lastly, we confirmed that PDB efficiently suppressed the spheroid formation of TM3 and TM4 cells mimicking an in vivo environment. Collectively, the current results indicate that PDB induces testicular toxicity and male reproductive abnormalities by inducing mitochondrial dysfunction, endoplasmic reticulum stress and calcium imbalance.

β-Endorphin Induction by Psychological Stress Promotes Leydig Cell Apoptosis through p38 MAPK Pathway in Male Rats.

Psychological stress (PS) disturbs the reproductive endocrine system and promotes male infertility, but the underlying pathogenic mechanisms have not been extensively studied. This study aimed to uncover the mechanisms of PS-induced male reproductive related abnormalities subjected to a ‘terrified sound’ exposure. Male rats subjected to PS displayed slow growth, decreased sperm quality, abnormal levels of the reproductive endocrine hormones, decreased expression of the reproductive-related proteins androgen-binding protein (ABP) and bromodomain-containing protein (BRDT), increased apoptosis in the testis, and accompanied by elevated levels of β-endorphin (β-EP). These effects were reversed by naloxone. Furthermore, PS-induced β-EP could promote mu opioid receptor (MOR) activation and ensure intracellular p38 MAPK phosphorylation and then lead to Leydig cells (LCs) apoptosis. The current result showed that β-EP was a key factor to PS-induced male infertility.

Understanding the molecular mechanisms of bisphenol A action in spermatozoa.

Bisphenol A (BPA) is an endocrine-disrupting chemical that is capable of interfering with the normal function of the endocrine system in the body. Exposure to this chemical from BPA-containing materials and the environment is associated with deleterious health effects, including male reproductive abnormalities. A search of the literature demonstrated that BPA, as a toxicant, directly affects the cellular oxidative stress response machinery. Because of its hormone-like properties, it can also bind with specific receptors in target cells. Therefore, the tissue-specific effects of BPA mostly depend on its endocrine-disrupting capabilities and the expression of those particular receptors in target cells. Although studies have shown the possible mechanisms of BPA action in various cell types, a clear consensus has yet to be established. In this review, we summarize the mechanisms of BPA action in spermatozoa by compiling existing information in the literature.

The present crisis in male reproductive health: an urgent need for a political, social, and research roadmap.

There is a global crisis in male reproductive health. Evidence comes from globally declining sperm counts and increasing male reproductive system abnormalities, such as cryptorchidism, germ cell tumors, and onset of puberty. Male factor infertility occurs in ~40% of couples experiencing infertility. Data demonstrate an association between male infertility and overall health. Associated significant health conditions include diabetes mellitus, metabolic disorders, and cardiovascular disease. Adding to the complexity is that men typically do not seek health care unless there is acute medical need or, as in the case of the infertile couple, the male goes for a reproductive examination and semen analysis. However, 25% of the time a reproductive health examination does not occur. Couples are increasingly utilizing IVF at more advanced ages, and advanced paternal age is associated with increased risk for (i) adverse perinatal outcomes for both offspring and mother; (ii) early child mortality, cancer, and mental health issues. In addition to age, paternal lifestyle factors, such as obesity and smoking, impact not only the male fertility but also the offspring wellness. The purpose of this paper was (i) to spotlight emerging and concerning data on male reproductive health, the relationship(s) between male reproductive and somatic health, and the heritable conditions father can pass to offspring, and (ii) to present a strategic roadmap with the goals of increasing (a) the awareness of men and society on the aforementioned, (b) the participation of men in healthcare seeking, and (c) advocacy to invigorate policy and funding agencies to support increased research into male reproductive biology. The Male Reproductive Health Initiative (MRHI) is a newly established and rapidly growing global consortium of key opinion leaders in research, medicine, funding and policy agencies, and patient support groups that are moving forward the significant task of accomplishing the goals of the strategic roadmap.

Estrogen in the male: a historical perspective.

Estrogens have traditionally been considered female hormones. Nevertheless, the presence of estrogen in males has been known for over 90 years. Initial studies suggested that estrogen was deleterious to male reproduction because exogenous treatments induced developmental abnormalities. However, demonstrations of estrogen synthesis in the testis and high concentrations of 17β-estradiol in rete testis fluid suggested that the female hormone might have a function in normal male reproduction. Identification of estrogen receptors and development of biological radioisotope methods to assess estradiol binding revealed that the male reproductive tract expresses estrogen receptor extensively from the neonatal period to adulthood. This indicated a role for estrogens in normal development, especially in efferent ductules, whose epithelium is the first in the male reproductive tract to express estrogen receptor during development and a site of exceedingly high expression. In the 1990s, a paradigm shift occurred in our understanding of estrogen function in the male, ushered in by knockout mouse models where estrogen production or expression of its receptors was not present. These knockout animals revealed that estrogen's main receptor (estrogen receptor 1 [ESR1]) is essential for male fertility and development of efferent ductules, epididymis, and prostate, and that loss of only the membrane fraction of ESR1 was sufficient to induce extensive male reproductive abnormalities and infertility. This review provides perspectives on the major discoveries and developments that led to our current knowledge of estrogen's importance in the male reproductive tract and shaped our evolving concept of estrogen's physiological role in the male.