Mild Androgen Insensitivity Syndrome presenting in male with infertility and sexual difficulties

Androgen insensitivity syndrome has a wide spectrum of presentations. It results from a mutation in androgen receptor (AR) gene. It ranges from mild androgen insensitivity syndrome (MAIS) which is the mildest form to complete androgen insensitivity syndrome (CAIS). In case of MAIS, the abnormality that can be observed appears to be male infertility and sexual difficulties including premature ejaculation and erectile dysfunction. In this case report, we discuss a case of MAIS in a 37-year-old male who presented with infertility, premature ejaculation, and secondary erectile dysfunction.Copyright © 2023, Ibn Sina Trust. All rights reserved.

The Racial and Socioeconomic Characteristics of a Cohort of Men Using at-Home Fertility Tests in the United States

INTRODUCTION AND OBJECTIVE: Infertility is a global health concern that affects couples worldwide. Economic, racial, and geographic disparities in reproductive medicine have long affected access to fertility care. These inequalities further worsened during the COVID-19 pandemic as fertility care services were systematically paused and treatments were delayed. At-home fertility tests emerged as a seemingly convenient, affordable and accessible option for all men seeking initial semen analysis testing and screening. We aim to study the racial and socioeconomic characteristics of a cohort of men utilizing at-home sperm testing kits in the United States over 3 years. METHOD(S): We retrospectively reviewed the records of 5,822 men who requested semen analysis at Give Legacy, Inc. (Legacy) facilities from 2019 to 2021. The demographic characteristics of these men were collected including their age, race/ethnicity, and place of residence. Further, the weighted median household income of Legacy customers was calculated using their personal ZIP codes and corresponding median income data from the U.S. census bureau. RESULT(S): The mean age (SD) of this cohort was 34.9+/-7.3 years. Among these 5,822 men, there were 3,936 (67.6%) normozoospermic men and 1,886 (32.3%) oligozoospermic men. The group consisted of predominantly white men (64.9%) with only 5.2% Black, 5.4% Latino, 8.9% Asian, 3.1% Arab, 2% Native Hawaiian, 2.4% Indian American, and 8.2% other groups. The geographic distribution of participants showed a majority of men from the Northeast (31.6%) and Pacific (23.4%) regions. The median household income of a Legacy customer is $108,858;significantly higher than the U.S. median household income of $70,784 (P<.01). CONCLUSION(S): Despite the fact that at-home, mail-in kits provide a better and more affordable access to initial fertility care, ethnic minorities and lower socioeconomic classes are still underrepresented in the population of men seeking fertility testing in this cohort. Further research is needed to understand the racial and socioeconomic drivers of the existing disparities in fertility care.

Microbiology and immune mechanisms associated with male infertility.

Up to 50% of infertility is caused by the male side. Varicocele, orchitis, prostatitis, oligospermia, asthenospermia, and azoospermia are common causes of impaired male reproductive function and male infertility. In recent years, more and more studies have shown that microorganisms play an increasingly important role in the occurrence of these diseases. This review will discuss the microbiological changes associated with male infertility from the perspective of etiology, and how microorganisms affect the normal function of the male reproductive system through immune mechanisms. Linking male infertility with microbiome and immunomics can help us recognize the immune response under different disease states, providing more targeted immune target therapy for these diseases, and even the possibility of combined immunotherapy and microbial therapy for male infertility.

Molecular diversity and phenotypic pleiotropy of ancient genomic regulatory loci derived from human endogenous retrovirus type H (HERVH) promoter LTR7 and HERVK promoter LTR5_Hs and their contemporary impacts on pathophysiology of Modern Humans.

Timelines of population-level effects of viruses on humans varied from the evolutionary scale of million years to contemporary spread of viral infections. Correspondingly, these events are exemplified by: (i) emergence of human endogenous retroviruses (HERVs) from ancient germline infections leading to stable integration of viral genomes into human chromosomes; and (ii) wide-spread viral infections reaching a global pandemic state such as the COVID-19 pandemic. Despite significant efforts, understanding of HERV's roles in governance of genomic regulatory networks, their impacts on primate evolution and development of human-specific physiological and pathological phenotypic traits remains limited. Remarkably, present analyses revealed that expression of a dominant majority of genes (1696 of 1944 genes; 87%) constituting high-confidence down-steam regulatory targets of defined HERV loci was significantly altered in cells infected with the SARS-CoV-2 coronavirus, a pathogen causing the global COVID-19 pandemic. This study focused on defined sub-sets of DNA sequences derived from HERVs that are expressed at specific stages of human preimplantation embryogenesis and exert regulatory actions essential for self-renewal and pluripotency. Evolutionary histories of LTR7/HERVH and LTR5_Hs/HERVK were charted based on evidence of the earliest presence and expansion of highly conserved (HC) LTR sequences. Sequence conservation analyses of most recent releases 17 primate species' genomes revealed that LTR7/HERVH have entered germlines of primates in Africa after the separation of the New World Monkey lineage, while LTR5_Hs/HERVK successfully colonized primates' germlines after the segregation of Gibbons' species. Subsequently, both LTR7 and LTR5_Hs undergo a marked ~ fourfold-fivefold expansion in genomes of Great Apes. Timelines of quantitative expansion of both LTR7 and LTR5_Hs loci during evolution of Great Apes appear to replicate the consensus evolutionary sequence of increasing cognitive and behavioral complexities of non-human primates, which seems particularly striking for LTR7 loci and 11 distinct LTR7 subfamilies. Consistent with previous reports, identified in this study, 351 human-specific (HS) insertions of LTR7 (175 loci) and LTR5_Hs (176 loci) regulatory sequences have been linked to genes implicated in establishment and maintenance of naïve and primed pluripotent states and preimplantation embryogenesis phenotypes. Unexpectedly, HS-LTRs manifest regulatory connectivity to genes encoding markers of 12 distinct cells' populations of fetal gonads, as well as genes implicated in physiology and pathology of human spermatogenesis, including Y-linked spermatogenic failure, oligo- and azoospermia. Granular interrogations of genes linked with 11 distinct LTR7 subfamilies revealed that mammalian offspring survival (MOS) genes seem to remain one of consistent regulatory targets throughout ~ 30 MYA of the divergent evolution of LTR7 loci. Differential GSEA of MOS versus non-MOS genes identified clearly discernable dominant enrichment patterns of phenotypic traits affected by MOS genes linked with LTR7 (562 MOS genes) and LTR5_Hs (126 MOS genes) regulatory loci across the large panel of genomics and proteomics databases reflecting a broad spectrum of human physiological and pathological traits. GSEA of LTR7-linked MOS genes identified more than 2200 significantly enriched records of human common and rare diseases and gene signatures of 466 significantly enriched records of Human Phenotype Ontology traits, including Autosomal Dominant (92 genes) and Autosomal Recessive (93 genes) Inheritance. LTR7 regulatory elements appear linked with genes implicated in functional and morphological features of central nervous system, including synaptic transmission and protein-protein interactions at synapses, as well as gene signatures differentially regulated in cells of distinct neurodevelopmental stages and morphologically diverse cell types residing and functioning in human brain. These include Neural Stem/Precursor cells, Radial Glia cells, Bergman Glia cells, Pyramidal cells, Tanycytes, Immature neurons, Interneurons, Trigeminal neurons, GABAergic neurons, and Glutamatergic neurons. GSEA of LTR7-linked genes identified significantly enriched gene sets encoding markers of more than 80 specialized types of neurons and markers of 521 human brain regions, most prominently, subiculum and dentate gyrus. Identification and characterization of 1944 genes comprising high-confidence down-steam regulatory targets of LTR7 and/or LTR5_Hs loci validated and extended these observations by documenting marked enrichments for genes implicated in neoplasm metastasis, intellectual disability, autism, multiple cancer types, Alzheimer's, schizophrenia, and other brain disorders. Overall, genes representing down-stream regulatory targets of ancient retroviral LTRs exert the apparently cooperative and exceedingly broad phenotypic impacts on human physiology and pathology. This is exemplified by altered expression of 93% high-confidence LTR targets in cells infected by contemporary viruses, revealing a convergence of virus-inflicted aberrations on genomic regulatory circuitry governed by ancient retroviral LTR elements and interference with human cells' differentiation programs.

CRYOPRESERVED SEMINAL SAMPLES FROM PATIENTS WITH ACUTE COVID-19 HAVE THE WORST POST-THAW QUALITY WHEN COMPARED TO OTHER ANDROLOGICAL DISEASES

OBJECTIVE: To evaluate the effect of COVID-19 in sperm cryopreservation processes, including functional parameters evaluated pre-cryopreservation and post-thaw, and to compare post-thaw results from COVID-19 patients to samples from others systemic and andrological Disease MATERIALS AND METHODS: In this cross-sectional study, 37 semen samples of male patients aged 18 to 45 years at Division of Urology, Department of Surgery, Hospital das Clinicas of the University of Sao Paulo or at Androscience- Science and Innovation Center in Andrology, High-Complex Clinical and Research Andrology Laboratory, were initially recruited from April 2020 to April 2021. Patients were categorized as acute COVID-19 (n=15), confirmed by RT-PCR (COVID-19 group), and healthy individuals with normozoospermic semen samples (n=22;Control group). Were evaluated seminal parameters, cryosurvival rates (%), mitochondrial activity (%;3,30 -diaminobenzidine stain), reactive oxygen species levels (ROS;chemiluminescent technique) and DNA fragmentation (%;SCSA method) in precryopreservation and post-thaw samples. Samples were cryopreserved by the slow freezing technique. A complementary retrospective study was performed comparing post-thawed samples from COVID-19 group with data from patients with others male diseases: Male infertility (n=35);Severe infertility (n=62), caused severe oligozoospermia, grade 3 varicocele, gonadal dysgenesis, testicular nodule, testicular hypotrophy;testicular cancer (n=55);and other malignant diseases (leukemia, lymphoma, sarcoma, multiple myeloma;n=30). Was used T-test to statistical analysis (p<0.05). RESULTS: Macroscopy analysis of COVID-group revealed abnormal viscosity in 53.33%, semen volume = 4.50 ± 1.72 ml and pH = 8.13 ± 0.23. COVID-19 fresh samples demonstrated mean of progressive motility = 29.07±16.83%, sperm morphology = 2.07±1.58%, and DNA fragmentation index = 42.91±33.38%. Cryopreservation decreased progressive motility (to 5.39±7.92%;p=0.02), sperm vitality (70.46±8.50 vs. 72.20±23.27;p=0.042) and ROS (0.516±0.978 vs. 4.393±9.956 x 104 cpm;p=0.018). When we compared with cryopreserved normozoospermic samples, there was observed a significant difference in HDS (p=0.002). Cryosurvival rate from COVID-19 samples was 19.93;19.71%, and had significant difference when compared with severe infertility (40.16;31.05%;p=0.003), and other malignant diseases (53.14;28.55%, <0.001). CONCLUSIONS: Seminal samples from patients with COVID-19 showed reduced fertile potential, especially when compared to the reference values. In the comparisons performed with samples from patients with different andrological diagnoses, common in the specialized andrology laboratory routine, we can suggest that samples from patients with the acute form of COVID-19 had the worst quality, with low cryosurvival rates. This information contribute to the conduct of these patients during assisted reproduction routines and preservation of male fertility. IMPACT STATEMENT: It will contribute to conducts in the cryopreservation of sperm in patients with acute COVID-19.

EFFECT OF COVID-19 mRNA VACCINES ON SPERM QUALITY

OBJECTIVE: Fertility related safety data was neither reported in the clinical trials nor evaluated in animal models prior to emergency use authorization (EUA) for two novel mRNA vaccines, BNT162b2 and mRNA-127.1,2 Despite excellent safety profiles for both vaccines, 44% of Americans are hesitant in receiving the vaccine. Although the specific reasons for COVID-19 vaccine hesitancy are unknown, concerns over fertility has previously decreased other vaccine uptake. As COVID-19 vaccination in the United States opens to children and adolescents, evaluating any potential impact of the vaccine on male reproduction is imperative for public reassurance. We hypothesized that since both vaccines only contain mRNA encoding the SARS-CoV-2 spike protein without biologic ability to replicate live virus, the vaccines would not decrease semen parameters. MATERIALS AND METHODS: We conducted a single-center prospective cohort study after IRB approval from the University of Miami (#20201451). Healthy men aged 18-50 scheduled for mRNA COVID-19 vaccination in Miami, Florida were recruited.Participants provided a semen sample after 2-7 days of abstinence, prior to receiving the first dose of either vaccine and about 72 days after the second dose. Specimens were self-collected into a wide-mouth sterile container and semen analysis (SA) performed by HCLD trained andrology clinicians examined semen volume, concentration, motility, and total motile sperm count (TMSC). RESULTS: 45 men provided a semen sample. Neither median sperm concentration nor total motile sperm count (TMSC) declined post vaccination (Figure 1). There was no clinically significant change in TMSC. Only 12 (26.6%) men had a marginal decrease in TMSC. In fact, the remaining 33 (73.3%) men demonstrated normal sperm parameters. Importantly, 8 (17%) men with oligospermia prior to vaccination did not experience a decrease in spermatogenesis. Only one subject had an abnormal TMSC (TMSC ≤ 9) after vaccination. CONCLUSIONS: After receiving the two doses of the vaccines, we did not observe a clinically significant sperm parameter decline within the cohort, suggesting the vaccines do not negatively impact male fertility potential. IMPACT STATEMENT: This is the first male fertility evaluation of the COVID-19 mRNA vaccines, in which we found that the vaccines do not negatively impact semen parameters. (Table Presented).

Impaired spermatogenesis in COVID-19 patients.

BACKGROUND: The current study aimed to determine the impact of SARS-CoV-2 infection on male fertility. METHODS: This is a single-center, hospital-based observational study that included autopsied testicular and epididymal specimens of deceased COVID-19 male patients (n=6) and recruited recovering COVID-19 inpatients (n=23) with an equal number of age-matched controls, respectively. We performed histopathological examinations on testicular and epididymal specimens, and also performed TUNEL assay and immunohistochemistry. Whereas, we investigated the semen specimen for sperm parameters and immune factors. FINDINGS: Autopsied testicular and epididymal specimens of COVID-19 showed the presence of interstitial edema, congestion, red blood cell exudation in testes, and epididymides. Thinning of seminiferous tubules was observed. The number of apoptotic cells within seminiferous tubules was significantly higher in COVID-19 compared to control cases. It also showed an increased concentration of CD3+ and CD68+ in the interstitial cells of testicular tissue and the presence of IgG within seminiferous tubules. Semen from COVID-19 inpatients showed that 39.1% (n=9) of them have oligozoospermia, and 60.9% (n=14) showed a significant increase in leucocytes in semen. Decreased sperm concentration, and increased seminal levels of IL-6, TNF-α, and MCP-1 compared to control males were observed. INTERPRETATION: Impairment of spermatogenesis was observed in COVID-19 patients, which could be partially explained as a result of an elevated immune response in testis. Additionally, autoimmune orchitis occurred in some COVID-19 patients. Further research on the reversibility of impairment and developing treatment are warranted. FUNDING: This study was supported by Ministry of Science and Technology of China Plan, Hubei Science and Technology Plan, National Key Research and Development Program of China, HUST COVID-19 Rapid Response Call, China and National Natural Science Foundation of China; these funding bodies are public institutions, and they had no role in study conception, design, interpretation of results, and manuscript preparation.

Recent advances in clinical diagnosis and treatment of male factor infertility.

Infertility is a significant global health issue affecting around 8-12% of couples worldwide with male factor infertility accounting for a substantial proportion of these cases. Despite significant advances within the past few decades, an etiology for male factor infertility cannot be identified in up to 80% of patients and thus, this continues to be an area of active study. This review aims to provide an update on recent advances in the field of male infertility including semen analysis and at-home semen testing, genetics, DNA fragmentation, surgical approaches, and the rise of telemedicine in the era of COVID19.