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Patients with non-obstructive azoospermia （NOA） were once considered to be infertile with few treatment options due to the absence of sperm in the ejaculate. In the last two decades, the advent of intracytoplasmic sperm injection （ICSI）, and the application of various testicular sperm retrieval techniques, including fine needle aspiration （FNA）, conventional testicular sperm extraction （TESE） and microdissection testicular sperm extraction （micro-TESE） have revolutionized treatment in this group of men. Because most men with NOA will have isolated regions of spermatogenesis within the testis, studies have illustrated that sperm can be retrieved in most men with NOA, including Klinefelter＇s syndrome （KS）, prior history of chemotherapy and cryptorchidism. Micro-TESE, when compared with conventional TESE has a higher sperm retrieval rate （SRR） with fewer postoperative complications and negative effects on testicular function. In this article, we will compare the efficacy of the different procedures of sperm extraction, discuss the medical treatment and the role of testosterone optimization in men with NOA and describe the micro-TESE surgical technique. Furthermore, we will update our overall experience to allow counseling on the prognosis of sperm retrieval for the specific subsets of NOA.

The rise in sea level that is occurring from the melting of Antarctica is only going to accelerate as climate warms. However, Larour et al. report that crustal uplift in the Amundsen Sea sector is helping to reduce grounding line retreat, thereby stabilizing the ice sheet and slowing its rate of mass loss (see the Perspective by Steig). This effect will not stop or reverse ice sheet loss, but it could delay the progress of dynamic mass loss of Thwaites Glacier by approximately 20 years. Science , this issue p. eaav7908 ; see also p. 936 Crustal uplift will slow the decay of the Thwaites Glacier in Antarctica. Geodetic investigations of crustal motions in the Amundsen Sea sector of West Antarctica and models of ice-sheet evolution in the past 10,000 years have recently highlighted the stabilizing role of solid-Earth uplift on polar ice sheets. One critical aspect, however, that has not been assessed is the impact of short-wavelength uplift generated by the solid-Earth response to unloading over short time scales close to ice-sheet grounding lines (areas where the ice becomes afloat). Here, we present a new global simulation of Antarctic evolution at high spatiotemporal resolution that captures all solid Earth processes that affect ice sheets and show a projected negative feedback in grounding line migration of 38% for Thwaites Glacier 350 years in the future, or 26.8% reduction in corresponding sea-level contribution.

Previous studies, including our own, have reported that spermatozoa isolated from the testis have remarkably higher occurrence of aneuploidy once isolated from azoospermic men. This notion, however, did not translate into a lower pregnancy rate nor a greater proportion of miscarriages. Indeed, ICSI offspring generated from surgically retrieved gametes did not suffer from increased karyotypic aneuploidy than children generated from ejaculated specimens. In recent years, aneuploidy assessments on a larger number of cells and utilizing more chromosome probes have reported a progressive decrease in chromosomal aberrations in spermatozoa directly retrieved from the seminiferous tubules. In light of the availability of more accurate molecular genetic techniques, we have decided to challenge the notion that sampling epididymal and testicular tissues yields spermatozoa with higher incidence of aneuploidy than those retrieved in the ejaculate. In a retrospective manner, we have carried out an analysis by FISH with 9 chromosome probes on at least 1000 cells from the ejaculates of 87 consenting men and the specimens of 6 azoospermic men, while spermatozoa of fertile donors were used as control. Aneuploidy by FISH yielded 0.9% for the donor control but rose in the study group to 3.6% in the ejaculated, 1.2% for the epididymal, and 1.1% for testicular spermatozoa. There were no differences in autosomal or gonosomal disomies, nor nullisomies. In this group, once the specimens of these men were used for ICSI, ejaculated spermatozoa yielded a 22% clinical pregnancy rate that resulted in 62.5% pregnancy loss. The surgically retrieved specimens yielded a 50% clinical pregnancy rate that progressed to term. To confirm our findings, in a prospective analysis, DNA sequencing was carried out on the ejaculates and surgical samples of 22 men with various spermatogenic characteristics. In this comparison, the findings were similar with actually a higher incidence of aneuploidy in the ejaculated spermatozoa (n = 16) compared to those surgically retrieved (n = 6) (P<0.0001). For this group, the clinical pregnancy rate for the ejaculated specimens was 47.2% with 29.4% pregnancy loss, while the surgically retrieved yielded a 50% clinical pregnancy rate, all progressing to term. A subsequent prospective combined assessment on ejaculated and surgically retrieved spermatozoa by FISH and NGS was performed on non-azoospermic men with high DNA fragmentation in their ejaculate. The assessment by FISH evidenced 2.8% chromosomal defects in the ejaculated and 1.2% in testicular biopsies while by NGS became 8.4% and 1.3% (P = 0.02), respectively. Interestingly, we evidenced a pregnancy rate of 0% with ejaculated while 100% with the testicular spermatozoa in this latter group. This indicates that improved techniques for assessing sperm aneuploidy on a wider number of cells disproves earlier reports and corroborates the safe utilization of testicular spermatozoa with a positive impact on chances of pregnancy.

In a recent report [4], we have found that for unselected men with NOA, 9% or more of men with prior documented azoospermia can be found to have rare sperm in the ejaculate – obviating the need for planned surgery – if semen analysis is repeated on the day of sperm retrieval. Comparison of microdissection testicular sperm extraction, conventional testicular sperm extraction, and testicular sperm aspiration for nonobstructive azoospermia: a systematic review and meta-analysis. Successful Cryptozoospermia management with multiple semen specimen collection.

A particular class of small noncoding RNAs are transcribed from DNA and then processed by enzymes to generate short oligonucleotides that then control gene expression. This study underscores their relevance to human health and fitness.

Severely compromised spermatogenesis typical of men with virtual azoospermia or non-obstructive azoospermia requires an extreme search for spermatozoa. Our goal was to evaluate the usefulness of a meticulous search carried out in ejaculated or surgically retrieved specimens in achieving pre- and post-implantation embryo development. In a retrospective cohort study carried out in an academic institution, intracytoplasmic sperm injection (ICSI) outcomes were reviewed as a function of length of microscopic sperm search in ejaculated and surgically retrieved specimens. Couples whose male partner presented with either virtual or non-obstructive azoospermia were treated by ICSI and categorized according to the time spent in identifying and retrieving enough spermatozoa to inject all the oocyte cohort. Semen parameter, fertilization, pregnancies, deliveries, and child welfare in relation to increasing search time were analyzed and compared. The maternal and paternal ages were comparable in both ejaculated and testicular sperm extraction (TESE) groups along with the oocytes retrieved. The fertilization rates for both ejaculated and TESE progressively decreased with increasing time (P<0.0001). Clinical pregnancies in the ejaculated cohort remained satifactory. In the TESE cohort, there was a decrease in pregnancy rate with increasing time, from 44% to 23%. In a limited number of cases, offspring health was evaluated in both semen sources and appeared reassuring. An extensive and at time exhaustive sperm quest yields kinetically and morphologically impaired spermatozoa without apparent impact on embryo developmental competence. Retrieval of spermatozoa from the seminiferous tubules provided more consistent fertilization and pregnancy outcomes than those retrieved from the ejaculate. A trend indicated that pregnancy rate decreased as search time increased in the TESE group. The utilization of the scarce and unselected spermatozoa did not obviously impair embryo development or cause post-implantation errors.

Estradiol (E2) modulates testicular functions including steroidogenesis, but the mechanisms of E2 signaling in human testis are poorly understood. GPER-1 (GPR30), a G protein-coupled membrane receptor, mediates rapid genomic and non-genomic response to estrogens. The aim of this study was to evaluate GPER-1 expression in the testis, and its role in estradiol dependent regulation of steroidogenesis in isolated rat Leydig cells and human testis. Isolated Leydig cells (LC) from adult rats and human testicular tissue were used in this study. Expression and localization studies of GPER-1 were performed with qRT-PCR, immunofluorescence, immunohistochemistry and Western Blot. Luteinizing Hormone (LH) -stimulated, isolated LC were incubated with estradiol, G-1 (GPER-1-selective agonist), and estrogen receptor antagonist ICI 182,780. Testosterone production was measured with radioimmunoassay. LC viability after incubation with G-1 was measured using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. GPER-1 mRNA is abundantly expressed in rat LC and human testis. Co-localization experiments showed high expression levels of GPER-1 protein in LC. E2-dependent activation of GPER-1 lowers testosterone production in isolated rats LCs and in human testis, with statistically and clinically significant drops in testosterone production by 20-30% as compared to estradiol-naïve LC. The exposure to G-1 does not affect viability of isolated LCs. Our results indicate that activation of GPER-1 lowers testosterone levels in the rat and human testis. The expression of GPER-1 in human testis, which lack ERα, makes it an exciting target for developing new agents affecting testosterone production in men.

Sertoli cell-only (SCO) syndrome is a severe form of human male infertility seemingly characterized by the lack all spermatogenic cells. However, tubules of some SCO testes contain small patches of active spermatogenesis and thus spermatogonial stem cells. We hypothesized that these stem cells cannot replicate and seed spermatogenesis in barren areas of tubule because as-of-yet unrecognized deficits in Sertoli cell gene expression disable most stem cell niches. Performing the first thorough comparison of the transcriptomes of human testes exhibiting complete spermatogenesis with the transcriptomes of testes with SCO syndrome, we defined transcripts that are both predominantly expressed by Sertoli cells and expressed at aberrant levels in SCO testes. Some of these transcripts encode proteins required for the proper assembly of adherent and gap junctions at sites of contact with other cells, including spermatogonial stem cells (SSCs). Other transcripts encode GDNF, FGF8 and BMP4, known regulators of mouse SSCs. Thus, most SCO Sertoli cells can neither organize junctions at normal sites of cell-cell contact nor stimulate SSCs with adequate levels of growth factors. We propose that the critical deficits in Sertoli cell gene expression we have identified contribute to the inability of spermatogonial stem cells within small patches of spermatogenesis in some SCO testes to seed spermatogenesis to adjacent areas of tubule that are barren of spermatogenesis. Furthermore, we predict that one or more of these deficits in gene expression are primary causes of human SCO syndrome.

New York City was the international epicenter of the COVID-19 pandemic. Health care providers responded by rapidly transitioning from in-person to video consultations. Telemedicine (ie, video visits) is a potentially disruptive innovation; however, little is known about patient satisfaction with this emerging alternative to the traditional clinical encounter. This study aimed to determine if patient satisfaction differs between video and in-person visits. In this retrospective observational cohort study, we analyzed 38,609 Press Ganey patient satisfaction survey outcomes from clinic encounters (620 video visits vs 37,989 in-person visits) at a single-institution, urban, quaternary academic medical center in New York City for patients aged 18 years, from April 1, 2019, to March 31, 2020. Time was categorized as pre-COVID-19 and COVID-19 (before vs after March 4, 2020). Wilcoxon-Mann-Whitney tests and multivariable linear regression were used for hypothesis testing and statistical modeling, respectively. We experienced an 8729% increase in video visit utilization during the COVID-19 pandemic compared to the same period last year. Video visit Press Ganey scores were significantly higher than in-person visits (94.9% vs 92.5%; P<.001). In adjusted analyses, video visits (parameter estimate [PE] 2.18; 95% CI 1.20-3.16) and the COVID-19 period (PE 0.55; 95% CI 0.04-1.06) were associated with higher patient satisfaction. Younger age (PE -2.05; 95% CI -2.66 to -1.22), female gender (PE -0.73; 95% CI -0.96 to -0.50), and new visit type (PE -0.75; 95% CI -1.00 to -0.49) were associated with lower patient satisfaction. Patient satisfaction with video visits is high and is not a barrier toward a paradigm shift away from traditional in-person clinic visits. Future research comparing other clinic visit quality indicators is needed to guide and implement the widespread adoption of telemedicine.