Leydig Cells in Patients with Non-Obstructive Azoospermia: Do They Really Proliferate?

Background: Non-obstructive azoospermia (NOA) is a form of male infertility caused by disorders of the testicular parenchyma and impaired spermatogenesis. This study aimed to investigate the nature of Leydig cell changes in patients with NOA, especially whether their actual proliferation occurred. Methods: 48 testicular biopsies from infertile patients with NOA and 24 testicular biopsies originating from azoospermic patients suffering from obstructive azoospermia (OA) were included in the study. Leydig cells and their possible proliferative activity were analysed by immunohistochemistry and morphometry (stereology). Results: Unlike in the OA group, Leydig cells in NOA patients were sometimes organised into larger clusters and displayed an abundant cytoplasm/hypertrophy. Moreover, significant fibrosis of the interstitial compartment was demonstrated in some NOA samples, often accompanied by inflammatory cells. Stereological analysis showed no increase/proliferation of Leydig cells; on the contrary, these cells decreased in number in the NOA group. Conclusions: The decrease in the number of Leydig cells can be explained by previous inflammatory changes within the testicular interstitium and consequent interstitial fibrosis. The interstitial fibrosis might have a deteriorating effect on Leydig cells.

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Detection Y Chromosome Microdeletions Among Iraq Population in Infertile Patients with Azoospermia and Severe Oligospermia

International Journal of Drug Delivery Technology ◽

10.25258/ijddt.9.2.23 ◽

2019 ◽

Vol 9 (02) ◽

Author(s):

Samah A Hammood ◽

Alaauldeen S M AL-Sallami ◽

Saleh M Al-Khafaji

Keyword(s):

Y Chromosome ◽

Karyotype Analysis ◽

Semen Analysis ◽

Obstructive Azoospermia ◽

Severe Oligozoospermia ◽

Infertile Men ◽

Y Chromosome Microdeletions ◽

Detailed Evaluation ◽

Health Organization ◽

Infertile Patients

Objective: To detection of microdeletions of Y chromosome and study the frequency of microdeletions in infertile men with non-obstructive azoospermia or severe oligozoospermia(Middle Euphrates center)in Iraq population. Material and methods: 153 males were included in the study, the casesweredivided into groups according to the infertility etiology and semen analysis according to Word health organization, the frequencies and the characteristicsof Y chromosome microdeletions were investigated in groups. Multiplex PCR was applied to detect the microdeletions. Results:Y chromosome microdeletion was detected in 42 (40.7%) of 153 cases ,Microdeletions in azoospermia showed more frequently detected 28 (52.8%), followed by severe oligospermia 14 (28 %),Microdeletions in the AZFc region were the most common 12 (22.64%), followed by AZFb 11(20.75%) and AZFa 5(9.43%) in azoospermia compared to severe oligospermisAZFc 6 (12%) AZFb 4 (8 %) and AZFa 4 (8%). Conclusion: Y chromosome microdeletions were detected quite frequently in certain infertility subgroups. Therefore, detailed evaluation of an infertile man by physical examination, semen analysis, hormonal evaluationsand when required, karyotype analysis may predict the patients for whom Y chromosome microdeletionanalysis is necessary and also prevent cost increases. Recommendation: This study emphasizes that analysis of microdeletions should be carried out for all patients with idiopathic azoospermia and severe oligospermia who are candidates for intracytoplasmic sperm injection

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Cellular Therapy via Spermatogonial Stem Cells for Treating Impaired Spermatogenesis, Non-Obstructive Azoospermia

Cells ◽

10.3390/cells10071779 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1779

Author(s):

Nesma E. Abdelaal ◽

Bereket Molla Tanga ◽

Mai Abdelgawad ◽

Sahar Allam ◽

Mostafa Fathi ◽

...

Keyword(s):

Stem Cells ◽

Male Infertility ◽

Cellular Therapy ◽

Antihypertensive Drugs ◽

Testicular Biopsy ◽

Testicular Tissue ◽

Spermatogonial Stem Cells ◽

Obstructive Azoospermia ◽

Promising Alternative ◽

Major Health Problem

Male infertility is a major health problem affecting about 8–12% of couples worldwide. Spermatogenesis starts in the early fetus and completes after puberty, passing through different stages. Male infertility can result from primary or congenital, acquired, or idiopathic causes. The absence of sperm in semen, or azoospermia, results from non-obstructive causes (pretesticular and testicular), and post-testicular obstructive causes. Several medications such as antihypertensive drugs, antidepressants, chemotherapy, and radiotherapy could lead to impaired spermatogenesis and lead to a non-obstructive azoospermia. Spermatogonial stem cells (SSCs) are the basis for spermatogenesis and fertility in men. SSCs are characterized by their capacity to maintain the self-renewal process and differentiation into spermatozoa throughout the male reproductive life and transmit genetic information to the next generation. SSCs originate from gonocytes in the postnatal testis, which originate from long-lived primordial germ cells during embryonic development. The treatment of infertility in males has a poor prognosis. However, SSCs are viewed as a promising alternative for the regeneration of the impaired or damaged spermatogenesis. SSC transplantation is a promising technique for male infertility treatment and restoration of spermatogenesis in the case of degenerative diseases such as cancer, radiotherapy, and chemotherapy. The process involves isolation of SSCs and cryopreservation from a testicular biopsy before starting cancer treatment, followed by intra-testicular stem cell transplantation. In general, treatment for male infertility, even with SSC transplantation, still has several obstacles. The efficiency of cryopreservation, exclusion of malignant cells contamination in cancer patients, and socio-cultural attitudes remain major challenges to the wider application of SSCs as alternatives. Furthermore, there are limitations in experience and knowledge regarding cryopreservation of SSCs. However, the level of infrastructure or availability of regulatory approval to process and preserve testicular tissue makes them tangible and accurate therapy options for male infertility caused by non-obstructive azoospermia, though in their infancy, at least to date.

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Decreased expression of DNA methyltransferases in the testes of patients with non-obstructive azoospermia leads to changes in global DNA methylation levels

Reproduction Fertility and Development ◽

10.1071/rd18246 ◽

2019 ◽

Vol 31 (8) ◽

pp. 1386 ◽

Cited By ~ 1

Author(s):

Fatma Uysal ◽

Gokhan Akkoyunlu ◽

Saffet Ozturk

Keyword(s):

Dna Methylation ◽

Male Infertility ◽

De Novo ◽

Biological Effects ◽

Testicular Biopsy ◽

Round Spermatid ◽

Dna Methyltransferases ◽

Global Dna Methylation ◽

Obstructive Azoospermia ◽

Spermatogenic Cells

DNA methylation plays key roles in epigenetic regulation during mammalian spermatogenesis. DNA methyltransferases (DNMTs) function in de novo and maintenance methylation processes by adding a methyl group to the fifth carbon atom of the cytosine residues within cytosine–phosphate–guanine (CpG) and non-CpG dinucleotide sites. Azoospermia is one of the main causes of male infertility, and is classified as obstructive (OA) or non-obstructive (NOA) azoospermia based on histopathological characteristics. The molecular background of NOA is still largely unknown. DNA methylation performed by DNMTs is implicated in the transcriptional regulation of spermatogenesis-related genes. The aim of the present study was to evaluate the cellular localisation and expression levels of the DNMT1, DNMT3A and DNMT3B proteins, as well as global DNA methylation profiles in testicular biopsy samples obtained from men with various types of NOA, including hypospermatogenesis (hyposperm), round spermatid (RS) arrest, spermatocyte (SC) arrest and Sertoli cell-only (SCO) syndrome. In the testicular biopsy samples, DNMT1 expression and global DNA methylation levels decreased gradually from the hyposperm to SCO groups (P<0.05). DNMT3A expression was significantly decreased in the RS arrest, SC arrest and SCO groups compared with the hyposperm group (P<0.05). DNMT3B expression was significantly lower in the RS arrest and SCO groups than in the hyposperm group (P<0.05). Although both DNMT1 and DNMT3A were localised in the cytoplasm and nucleus of the spermatogenic cells, staining for DNMT3B was more intensive in the nucleus of spermatogenic cells. In conclusion, the findings suggest that significant changes in DNMT expression and global DNA methylation levels in spermatogenic cells may contribute to development of male infertility in the NOA groups. Further studies are needed to determine the molecular biological effects of the altered DNMT expression and DNA methylation levels on development of male infertility.

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Ultrastructural Changes in the Pancreata of Selenium-Vitamin E-Deficient Chicks

Veterinary Pathology ◽

10.1177/030098587701400609 ◽

1977 ◽

Vol 14 (6) ◽

pp. 629-642 ◽

Cited By ~ 7

Author(s):

A. H. Rebar ◽

J. F. Van Vleet

Keyword(s):

Endoplasmic Reticulum ◽

Vitamin E ◽

Acinar Cell ◽

Interstitial Fibrosis ◽

Ultrastructural Changes ◽

Zymogen Granules ◽

Cell Cytoplasm ◽

Torula Yeast ◽

Cell Changes ◽

Ductular Proliferation

Three hundred and seventy 1-day-old male, white Leghorn chicks were divided into seven groups and fed a series of semipurified torula yeast diets either deficient in or supplemented with selenium and vitamin E. Chicks in each group were necropsied sequentially and the pancreata examined by light microscopy. Selected pancreata of selenium deficient chicks in various stages of the deficiency disease were examined by electron microscopy. Supplements of either selenium (0.2 mg/kg) or vitamin E (100 IU/kg diet) resulted in protection against pancreatic lesions. Changes in pancreata of selenium deficient chicks progressed from cytoplasmic vacuolation of acinar cell cytoplasm to focal disseminated acinar necrosis. There was ductular proliferation and interstitial fibrosis in advanced lesions. Acini around islets were less frequently affected than acini further away. Ultrastructurally, the mildest lesions were focal dilation of the endoplasmic reticulum and autophagic vacuoles in acinar cell cytoplasm. Necrotic areas contained both membranous and granular debris and fragments of intact endoplasmic reticulum. In fibrotic pancreata the main acinar cell changes were uniform dilation of endoplasmic reticulum and reduction in number of zymogen granules.

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Metalloproteinase and growth factor interactions: do they play a role in pulmonary fibrosis?

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00489.2001 ◽

2002 ◽

Vol 283 (1) ◽

pp. L1-L11 ◽

Cited By ~ 26

Author(s):

Margaret K. Winkler ◽

John L. Fowlkes

Keyword(s):

Acute Lung Injury ◽

Growth Factors ◽

Growth Factor ◽

Pulmonary Fibrosis ◽

Lung Injury ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Inflammatory Cells ◽

Transforming Growth Factor Β ◽

Target Cells

Chronic lung disease due to interstitial fibrosis can be a consequence of acute lung injury and inflammation. The inflammatory response is mediated through the migration of inflammatory cells, actions of proinflammatory cytokines, and the secretion of matrix-degrading proteinases. After the initial inflammatory insult, successful healing of the lung may occur, or alternatively, dysregulated tissue repair can result in scarring and fibrosis. On the basis of recent insights into the mechanisms underlying acute lung injury and its long-term consequences, data suggest that proteinases, such as the matrix metalloproteinases (MMPs), may not only be involved in the breakdown and remodeling that occurs during the injury but may also cause the release of growth factors and cytokines known to influence growth and differentiation of target cells within the lung. Through the release of and activation of fibrosis-promoting cytokines and growth factors such as transforming growth factor-β1, tumor necrosis factor-α, and insulin-like growth factors by MMPs, we propose that these metalloproteinases may be integral to the initiation and progression of pulmonary fibrosis.

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Protective Effects of HBSP on Ischemia Reperfusion and Cyclosporine A Induced Renal Injury

Clinical and Developmental Immunology ◽

10.1155/2013/758159 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 7

Author(s):

Yuanyuan Wu ◽

Junlin Zhang ◽

Feng Liu ◽

Cheng Yang ◽

Yufang Zhang ◽

...

Keyword(s):

Cyclosporine A ◽

Caspase 3 ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Inflammatory Cells ◽

Protective Effects ◽

Tubulointerstitial Damage ◽

Apoptosis And Inflammation ◽

The Right ◽

Active Caspase

Ischemia reperfusion (IR) and cyclosporine A (CsA) injuries are unavoidable in kidney transplantation and are associated with allograft dysfunction. Herein, the effect and mechanism of a novel tissue protective peptide, helix B surface peptide (HBSP) derived from erythropoietin, were investigated in a rat model. The right kidney was subjected to 45 min ischemia, followed by left nephrectomy and 2-week reperfusion, with or without daily treatment of CsA 25 mg/kg and/or HBSP 8 nmol/kg. Blood urea nitrogen was increased by CsA but decreased by HBSP at 1 week and 2 weeks, while the same changes were revealed in urinary protein/creatinine only at 2 weeks. HBSP also significantly ameliorated tubulointerstitial damage and interstitial fibrosis, which were gradually increased by IR and CsA. In addition, apoptotic cells, infiltrated inflammatory cells, and active caspase-3+ cells were greatly reduced by HBSP in the both IR and IR + CsA groups. The 17 kD active caspase-3 protein was decreased by HBSP in the IR and IR + CsA kidneys, with decreased mRNA only in the IR + CsA kidneys. Taken together, it has been demonstrated, for the first time, that HBSP effectively improved renal function and tissue damage caused by IR and/or CsA, which might be through reducing caspase-3 activation and synthesis, apoptosis, and inflammation.

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Study on clinical and genetic characteristics of male patients with non-obstructive azoospermia

Tạp chí Nghiên cứu Y học ◽

10.52852/tcncyh.v141i5.211 ◽

2021 ◽

Vol 141 (5) ◽

pp. 39-45

Author(s):

Nguyen Hoai Bac ◽

Hoang Long

Keyword(s):

Sex Chromosome ◽

Chromosomal Abnormalities ◽

Klinefelter Syndrome ◽

Obstructive Azoospermia ◽

Genetic Characteristics ◽

Azfc Deletion ◽

Genetic Abnormalities ◽

History Of ◽

Male Patients ◽

Infertile Patients

We examined 501 patients with non - obstructive azoospermia to evaluate clinical, subclinical, and genetic characteristics. The results show that the average age of patients in the study was 29.8 ± 5.5 years. Primary infertility accounts for the majority, with a rate of 90.3%. There was 38.6% of patients had a history of mumps orchitis. The average levels of FSH, LH, testosterone were 31.6 ± 16.5 mIU/mL, 15.5 ± 10 mIU/mL and 12.8 ± 7.13 nmol/L, respectively. The prevalence of chromosomal abnormalities was 30.7%. Of these, the sex chromosome aneuploidy with 47,XXY karyotype (Klinefelter syndrome) accounted for 27.3%. The incidence of AZF microdeletion was 13.8%. Of these, AZFc deletion was the most common at the rate of 42.1%, AZFa deletion, which accounted for 2.6%, were the least prevalent, and the frequency of AZFd deletion was 5.3%. However, there was no solitary AZFb deletion, which combined with other AZF deletions with 34.2%. Our research shows that mumps orchitis and chromosomal abnormalities are the leading causes of azoospermia. Screening for genetic abnormalities plays an important role in infertile patients with non - obstructive azoospermia.

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P–074 Chromatin Maturity Index (CMI) in unfixed and live spermatozoa and Aniline Blue (AB) stained as an additional evaluation parameter in idiopathic male infertility

Human Reproduction ◽

10.1093/humrep/deab130.073 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

T Notari ◽

M Piscopo ◽

L Bosco ◽

S Pecoraro ◽

N Serra ◽

...

Keyword(s):

Observational Study ◽

Male Infertility ◽

Aniline Blue ◽

Semen Parameters ◽

Sperm Chromatin ◽

Idiopathic Male Infertility ◽

Seminal Parameters ◽

Starting Point ◽

Dark Blue ◽

Infertile Patients

Abstract Study question To investigate whether idiopathic male infertility may be due to the presence of histones in motile spermatozoa using a modified AB staining protocol. Summary answer No correlation between CMI in live motile spermatozoa, DNA Fragmentation Index (DFI) and other conventional seminal parameters were found in male infertile patients. What is known already The AB stain discriminates between lysine-rich histones and arginine/cysteine-rich protamines. Transition from histones to protamines during spermatogenesis remodels chromatin packaging and abnormalities in the substitution of those proteins maybe interfere with seminal parameters and affect male infertility. The correlation between CMI and seminal parameters is known, but little is knowledge about live and motile spermatozoa associated to CMI because literature report only spermatozoa fixation before staining. Sperm chromatin carries half of the genomic material to offspring. Spermatozoa nuclear status is crucial for balanced transmission to future generations, and histones modifications are directly involved in epigenetic mutations. Study design, size, duration Retrospective observational study of 77 men underwent to standard semen analysis, including the evaluation of CMI and DFI, enrolled from January to December 2020. Mean age of the men was 36.63±8.26 years old, sperm concentration 46.69±37.23 mill/mL, linear progressive motility 39.35±15.31%, normal morphology 6.42±3.40%, DFI 25.91±10.29%. 200 spermatozoa for evaluation of CMI and 300 for DFI were analyzed respectively. Participants/materials, setting, methods Semen samples of 77 patients were collected and analyzed according to 5th edition of WHO guidelines (2010) for examination of human semen. For the evaluation of CMI we performed a new modified protocol for AB stain directly in live spermatozoa. Dilution 1:1 fresh semen and Aniline Blue colorant were mixed and placed on a slide and examined in bright field microscopy x1000 magnification. DFI was evaluated using Sperm Chromatin Dispersion (SCD) test. Main results and the role of chance Of all spermatozoa analyzed, 82.58±29.98% were white, 17.17±17.21% were pale blue, and 28.53±21.09% were dark blue. By our modified protocol, directly in live spermatozoa, we correlated AB staining with motility and , surprisingly, all motile spermatozoa observed were not stained (white), while pale or dark blue spermatozoa resulted always immotile. For this reason, we have considered pale blue spermatozoa as AB positive, in disagreement with some authors. So, maybe, we should reconsider pale blue stained spermatozoa as abnormal. We also observed AB negative spermatozoa with morphological head, neck and tail defects, underlining the independence of these two parameters: nuclear status and morphology. We have observed no statistically significant differences between conventional semen parameters, DFI and CMI, so nuclear analysis seems to be independent parameters. The statistical analysis was performed by Matlab statistical toolbox version 2008 (MathWorks, Natick, MA, USA) for Windows at 32 bit; finally all tests with p-value (p) < 0.05 were considered significant. Attention should be paid to the evaluation of CMI not only in astenozoospermic patients, where a lower CMI is known, but also in normozoospermic infertile patients. Limitations, reasons for caution This is a preliminary observational study on a small number of normozoospermic or mild asthenozoospermic patients. The study should be considered as a pilot study. Future studies with higher number of samples are necessary in order to confirm the results obtained. Wider implications of the findings: This is the first study that reports AB staining on unfixed live spermatozoa with a modified protocol. Our study underlines the necessity of classify pale blue spermatozoa as AB positive. Further investigations are necessary. This is a starting point for future analysis to be carried out under the project EcoFoodFertility. Trial registration number Not applicable

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Abstract 13869: Inflammatory Changes in the Lungs of Rats Exposed to E-cigarettes Without Marijuana, Vitamin E Oil, or Nicotine

Circulation ◽

10.1161/circ.142.suppl_3.13869 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Jianru Shi ◽

Michael T Kleinman ◽

Rebecca J Arechavala ◽

Dave Herman ◽

Irene Hasen ◽

...

Keyword(s):

Vitamin E ◽

High Power ◽

Inflammatory Cells ◽

Lung Parenchyma ◽

Heating Element ◽

Chromium Alloy ◽

Sprague Dawley ◽

High Power Field ◽

Quantitative Manner ◽

Inflammatory Changes

Background: Recently, the clinical entity of EVALI (E-cigarette or vaping product use associated lung injury) was described and has similarities to COVID -19 pneumonia. We determined in a quantitative manner the inflammatory changes in the lungs associated with EVALI in a rodent model that does not include use of marijuana, vitamin E oil, or nicotine, which had been implicated as a cause. Methods: Adult Sprague Dawley rats were exposed to either pure air (n=5) or electronic cigarette (eC) vapor (propylene glycol/vegetable glycerin, tobacco flavoring) using a device with a nickel-chromium alloy (NC) heating element at 70 Watts (n=6) for 2 hours. The e-liquid did not contain nicotine, marijuana, or Vitamin E oil. Rats were euthanized within a few days of exposure and H&E-stained lung sections were assessed. Inflammatory cells were counted from 10 random areas per section at 20х magnification. Results: Alveolar structure appeared normal in the air group (Figure, panel C); the eC group using the NC heating element showed alveolar inflammation (D). The numbers of inflammatory cells per high power field in the lung parenchyma were significantly greater in the rats exposed to eC using NC heating element (67.5 ± 44.5) compared to the air group (6.7 ± 0.3; P < 0.001, Kruskal-Wallis test). The predominant cell type was mononuclear and secondary were neutrophils. Other features included accumulation of fibrin and inflammatory cells in the lumen of the trachea (A); thickened alveolar walls; and red blood cell congestion (D). Inflammation of the nasal passages was also observed (B). Exposure of rats to e cigarettes using a stainless steel heating element did not result in EVALI, and the amount of inflammatory cells was closer to air exposed rats (7.2± 0.4). Conclusion: Vaping using a nichrome heating element at high power leads to respiratory tract pathology and a significant increase in the number of inflammatory cells in the alveoli. EVALI occurred without marijuana, vitamin E oil or nicotine.

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Abstract 88: Small Molecule Inhibition of Mixed Lineage Kinase 3 Attenuates Cardiac Fibroblast Activation and Pathologic Cardiac Remodeling

Circulation Research ◽

10.1161/res.111.suppl_1.a88 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Melissa L Martin ◽

Stephen Dewhurst ◽

Harris A Gelbard ◽

Val Goodfellow ◽

Burns C Blaxall

Keyword(s):

Small Molecule ◽

Intercellular Communication ◽

Cardiac Remodeling ◽

Interstitial Fibrosis ◽

Smooth Muscle Actin ◽

Cardiac Injury ◽

Inflammatory Cells ◽

Cardiac Fibroblast ◽

Neonatal Rat ◽

Cardiac Phenotype

Heart failure (HF) is a manifestation of most cardiovascular diseases whose increasing prevalence highlights the need for novel therapeutics. The extent of pathologic cardiac remodeling is correlated with clinical outcome. Importantly, cardiac injury enhances cardiac fibroblast (CF) activation, producing myofibroblasts that release pro-fibrotic/inflammatory mediators which target cardiomyocytes (CM), CFs, and local inflammatory cells to exacerbate remodeling. Mixed Lineage Kinases (MLKs) are a family of stress-activated MAPKKKs whose functional role(s) in the heart remain largely unknown. MLK3 has been implicated in HIV-associated neurocognitive disorder (HAND), where it mediates deleterious cross-talk between microglia and neurons, suggesting an analogous mechanism of pathologic intercellular CF-CM communication in HF. We hypothesize that MLK3 exacerbates cardiac remodeling through enhanced CF activation that contributes to pathologic cardiac intercellular communication. We have synthesized a series of MLK3-specific small molecule inhibitors, one of which (URMC-099) was found to attenuate microglial-mediated neurotoxicity in murine models of HAND. To investigate the role of MLK3 in CF activation, neonatal rat ventricular CFs were stimulated with isoproterenol (Iso) or angiotensin II (AngII). Concurrent treatment with URMC-099 attenuated both α-smooth muscle actin expression, indicative of myofibroblast transition, and proinflammatory cytokine production. Further, therapeutic efficacy and specificity of URMC-099 were tested in iso-infused and myocardial infarction (MI) models of HF using wild-type (WT) and MLK3-/- mice (shown to have no overt cardiac phenotype). URMC-099 significantly attenuated cardiac hypertrophy (HW:BW) and reduced interstitial fibrosis (assessed by Masson's Trichrome staining) in an acute iso-pump model of HF in WT mice. Current echocardiographic data post-MI suggest cardioprotection in the MLK3-/- and URMC-099 treated mice. In conclusion, our collaborative data not only suggest a role for MLK3 in cardiac remodeling through pathologic CF activation but indicate a possibly novel paradigm of pathologic intercellular communication in multiple disease states.

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