Sertoli Cells Of Patients Research Articles

Single-cell analysis of developing and azoospermia human testicles reveals central role of Sertoli cells

Clinical efficacy of treatments against non-obstructive azoospermia (NOA), which affects 1% of men, are currently limited by the incomplete understanding of NOA pathogenesis and normal spermatogenic microenvironment. Here, we profile >80,000 human testicular single-cell transcriptomes from 10 healthy donors spanning the range from infant to adult and 7 NOA patients. We show that Sertoli cells, which form the scaffold in the testicular microenvironment, are severely damaged in NOA patients and identify the roadmap of Sertoli cell maturation. Notably, Sertoli cells of patients with congenital causes (Klinefelter syndrome and Y chromosome microdeletions) are mature, but exhibit abnormal immune responses, while the cells in idiopathic NOA (iNOA) are physiologically immature. Furthermore, we find that inhibition of Wnt signaling promotes the maturation of Sertoli cells from iNOA patients, allowing these cells to regain their ability to support germ cell survival. We provide a novel perspective on the development of diagnostic methods and therapeutic targets for NOA.

Molecular mechanisms underlying AMH elevation in hyperoestrogenic states in males

Anti-Müllerian hormone (AMH) is secreted by Sertoli cells of the testes from early fetal life until puberty, when it is downregulated by androgens. In conditions like complete androgen insensitivity syndrome (CAIS), AMH downregulation does not occur and AMH increases at puberty, due in part to follicle-stimulating hormone (FSH) effect. However, other conditions like Peutz-Jeghers syndrome (PJS), characterised by low FSH, also have increased AMH. Because both CAIS and PJS may present as hyperoestrogenic states, we tested the hypothesis that oestradiol (E2) upregulates AMH expression in peripubertal Sertoli cells and explored the molecular mechanisms potentially involved. The results showed that E2 is capable of inducing an upregulation of endogenous AMH and of the AMH promoter activity in the prepubertal Sertoli cell line SMAT1, signalling through ERα binding to a specific ERE sequence present on the hAMH promoter. A modest action was also mediated through the membrane oestrogen receptor GPER. Additionally, the existence of ERα expression in Sertoli cells in patients with CAIS was confirmed by immunohistochemistry. The evidence presented here provides biological plausibility to the hypothesis that testicular AMH production increases in clinical conditions in response to elevated oestrogen levels.

Sertoli cell only syndrome: Status of sertoli cell maturation and function

Background of the study:Mature and functional Sertoli cells are essential for the survival of germ cells in testes. In Sertoli cell only syndrome (SCOS), there is no germ cells. Then, question arises whether absence of germ cells in SCOS secondary to Sertoli cells immaturity or mal function. Sertoli cells maturational and functional status is unclear in SCOS. This study investigated status of maturation and function of Sertoli cells in patients with SCOS.Materials and Methods:The present study was comprised of 37 cases of SCOS and 50 normal control males. Detailed clinical examination and investigation were carried out as per pre-determined proforma. Semen analysis, hormonal analysis (FSH, LH, testosterone, etc.), and fine needle aspiration cytology (FNAC) of testes (bilateral) were performed. Fluorescence in situ hybridization (FISH) with XY probes was carried out in addition to conventional chromosome analysis to find out chromosomal abnormalities, in particular sex chromosome aneuploidy, including mosaicism. Yq microdeletion status was also investigated. The anti-mullerian hormone (AMH), inhibin B, and seminal lactate were estimated by ELISA methods.Results:The study did not find any case of high AMH. About 78% cases had low inhibin B, and 60% had low AMH. FSH was high in about 78% cases. Low level of lactate was found in 49% cases. There was one case of high level of inhibin B. There were 6 (16.2%) cases of chromosomal abnormality (2 mosaic Klinefelter and 4 Klinefelter syndrome) and 4 (10.8%) cases of Yq microdeletion.Conclusion:We conclude that Sertoli cell immaturity does not play any role in SCOS (no case of high AMH). It seems, in majority cases, Sertoli cells are functionally- and/or numerically-deficient (low inhibin B, AMH and lactate). However, in about 22% cases, Sertoli cell function and/or number remains normal (normal inhibin B, AMH). Inhibin B and FSH seems best predictor/marker of Sertoli cell function.

2011 ROLE OF TRANSCRIPTION FACTOR DAX-1 AS A NEW FUNCTIONAL MARKER OF UNDIFFERENTIATED SERTOLI CELLS IN AZOOSPERMIA PATIENTS

You have accessJournal of UrologyInfertility: Physiology, Pathophysiology, Basic Research1 Apr 20112011 ROLE OF TRANSCRIPTION FACTOR DAX-1 AS A NEW FUNCTIONAL MARKER OF UNDIFFERENTIATED SERTOLI CELLS IN AZOOSPERMIA PATIENTS Yoshiyuki Kojima, Yutaro Hayashi, Kentaro Mizuno, Yukihiro Umemoto, Shoichi Sasaki, and Kenjiro Kohri Yoshiyuki KojimaYoshiyuki Kojima Nagoya, Japan More articles by this author , Yutaro HayashiYutaro Hayashi Nagoya, Japan More articles by this author , Kentaro MizunoKentaro Mizuno Nagoya, Japan More articles by this author , Yukihiro UmemotoYukihiro Umemoto Nagoya, Japan More articles by this author , Shoichi SasakiShoichi Sasaki Nagoya, Japan More articles by this author , and Kenjiro KohriKenjiro Kohri Nagoya, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.2239AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES DAX-1 is an orphan member of the nuclear hormone receptor superfamily and acts as a transcriptional repressor. It plays a critical role in gonadal function and steroidogenesis. The characterization of Dax-1-deficient male mice suggested that Dax1 plays an important role in the maintenance of spermatogenesis. In our study, we examined the expression levels of DAX-1 in several azoospermiac patients with Sertoli cell-only testes and discuss the possibility of DAX-1 as a functional marker of undifferentiated Sertoli cells in azoospermia patients. METHODS All patients were diagnosed as Sertoli cell-only by histological observation. Ten idiopathic azoospermia patients with Sertoli cell-only syndrome, five azoospermia patients with cryptorchidism, and four azoospermia patients with hypogonadropic hypogonadism were enrolled. Five obstructive azoospermia patients with normal spermatogenesis were included as additional testicular samples. We performed immunohistochemical study and quantitiative RT-PCR using testicular biopsy samples to examine the DAX-1 expression, and analyzed the role of DAX-1 in Sertoli cells. In addition, transcriptional activities of DAX-1 by FSH stimulation were examined with TM4 derived from mouse testicular Sertoli cells. RESULTS Immunohistochemical study showed that DAX-1 was strongly expressed in the nuclei of Sertoli cells in patients with cryptorchidism, hypogonadropic hypogonadism or normal spermatogenesis. On the other hand, it was faintly expressed in the nuclei of Sertoli cell in patients with idiopathic azoospermia. The average expression levels of DAX-1 mRNA in idiopathic azoospermia patients with Sertoli cell-only syndrome (0.13±0.08) were lower than those with cryptorchidism (1.38±0.37), hypogonadropic hypogonadism (0.98±0.34) or normal spermatogenesis (1.30±1.41). Identical amounts of DAX1 were detected regardless of FSH stimulation in TM4 cells, and DAX1 was not activated significantly by FSH with TM4. CONCLUSIONS These results suggest that the function of DAX-1 in Sertoli cells may be required for normal spermatogenesis and fertility. Idiopathic azoospermia may result in abnormal Sertoli cell function, which disrupts the normal progression of spermatogenesis. Transcription of the DAX-1 gene may be negatively regulated by factors other than FSH, especially in Sertoli cells in Sertoli cell-only syndrome. Given the essential role of DAX-1 in Sertoli cells with normal spermatogenesis, its defect could reflect a new functional marker of undifferentiated Sertoli cells. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e804-e805 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yoshiyuki Kojima Nagoya, Japan More articles by this author Yutaro Hayashi Nagoya, Japan More articles by this author Kentaro Mizuno Nagoya, Japan More articles by this author Yukihiro Umemoto Nagoya, Japan More articles by this author Shoichi Sasaki Nagoya, Japan More articles by this author Kenjiro Kohri Nagoya, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Developmental Evaluation of Aldo-keto Reductase 1C3 Expression in the Cryptorchid Testis

To characterize aldo-keto reductase 1C3 (AKR1C3) expression in surgically-removed cryptorchid testes. Human AKR1C3 is a monomeric, cytoplasmic, multifunctional enzyme that reduces ketosteroids, ketoprostaglandins, and lipid aldehydes. AKR1C3 expression has been demonstrated in normal adult Leydig cells and peritubular fibromyocytes. No prior studies have evaluated AKR1C3 expression patterns across different age groups. Surgically excised cryptorchid testes were subjected to hematoxylin-eosin evaluation to review overall testicular pathology. These samples were then evaluated for AKR1C3 distribution via immunohistochemical staining with a monospecific AKR1C3 monoclonal antibody. Single-pathologist grading of AKR1C3 expression was correlated with clinical presentations. A total of 16 cryptorchid testes were identified from the 2000 to present. Median age at the time of surgery was 9 years (range, 1-17). The testes were excised due to atrophy, poor tissue consistency, and short spermatic cord length. AKR1C3 expression was identified at all ages in fibromyocytes surrounding the testicular tubules. Leydig cell expression was absent at Tanner stages 1 and 2, while strong expression was found at Tanner stage 3 and beyond. No AKR1C3 expression was seen in germ cells at any stage. AKR1C3 expression was identified in 18%-26% of Sertoli cells in patients at Tanner stages 2 and beyond. AKR1C3 expression occurs in a Tanner stage dependent-fashion. Pre- and peri-pubertal changes appear to promote expression of the enzyme in Leydig cells. In contrast to the normal adult testis, the pediatric cryptorchid testis reveals AKR1C3 expression in Sertoli cells. Additional studies are warranted to determine the involvement of AKR1C3 in testicular descent and development.

Impaired Gap Junction Connexin43 in Sertoli Cells of Patients with Secretory Azoospermia: A Marker of Undifferentiated Sertoli Cells

Gap junctions are intercellular channels formed of connexins (Cx) at appositional plasma membranes between adjacent cells that have been involved in the control of cell proliferation and differentiation. Altered Cx expression is implicated consistently in several human diseases and in tumorigenesis. Although Cx43 plays a critical role in Sertoli cell control of spermatogenesis, there is no evidence of its altered expression in human testicular pathologies. We show here that Cx43 mRNA expression was significantly reduced in testes of infertile patients with secretory azoospermia (p < 0.05) compared with testes displaying normal spermatogenesis (excretory azoospermic patients). In Sertoli cell-only syndrome, in situ hybridization and immunohistochemistry analyses indicated that Cx43 mRNA and protein were undetectable in Sertoli cells but were still present in the interstitial compartment. In a rat model of Sertoli cell-only syndrome, the lack of Cx43 in Sertoli cells was associated with an impairment of gap junction intercellular communication between adjacent Sertoli cells. These results reveal that Cx43 mRNA and protein expression are markedly impaired in Sertoli cells of infertile patients. This defect could be a new functional marker of undifferentiated Sertoli cells and could be related to the increased risk of testicular cancer recently described in the population of infertile men.

Molecular biology of human male infertility: links with aging, mitochondrial genetics, and oxidative stress?

Molecular biology of human male infertility: links with aging, mitochondrial genetics, and oxidative stress?

Giant nuclear bodies (sphaeridia) in sertoli cells of patients with testicular tumors

Sertoli cells in the immediate vicinity of testicular tumors (seminoma and teratoma) display a conspicuously high number of nuclear bodies. These organelles show a great structural variability and may reach an unusually large size. Apart from the well-known types, there are variants with a granular, a fibrillar and an amorphous component which thus resemble complete nucleoli. This finding, as well as the close contact between nuclear bodies and nucleoli and the inverse relationship in the size of both organelles, supports the concept that nuclear bodies may originate from nucleoli.

Leydig and Sertoli Cell Function in Normal and Oligospermic Males: A Preliminary Report

Sertoli and Leydig cell function was evaluated in patients with oligospermia. Testicular biopsy specimens were incubated in vitro with follicle-stimulating hormone (FSH) or luteinizing hormone (LH), and the amount of cyclic adenosine 3':5'-monophosphate (cyclic AMP) generated was measured. Cyclic AMP has been shown to be intracellular mediator for the pituitary gonadotropins FSH and LH. The amount generated by the Sertoli cells response to FSH, and by the Leydig cells in response to LH, was contrasted with that in age-matched, normal control subjects. The Leydig cell response was similar in both groups. However, the amount of cyclic AMP generated by the Sertoli cells from oligospermic males was much less when compared with normal control subjects. This finding suggests a possible metabolic abnormality in the Sertoli cells of patients with oligospermia which might, in turn, alter spermatogenesis.

Patho-physiological observations of Sertoli cells in patients with germinal aplasia or severe germ cell depletion. Ultrastructural findings and hormone levels.

The purpose of this study was to examine the fine structure of Sertoli cells in patients with a severe or complete depletion of germ cells. In normal seminiferous tubules Sertoli cells are characterized by a cytoplasm rich in the common cellular organelles, particularly smooth endoplasmic reticulum and mitochondria. Lipid droplets, Golgi, rough endoplasmic reticulum, dense granules, annulate lamellae and crystals of Charcot-Böttcher are also present, although the latter two structures are not constantly observed. Occluding junctional complexes join adjacent Sertoli cells near the base of the seminiferous epithelium. In patients exhibiting germinal aplasia or severe germ cell depletion there are three morphological features of the Sertoli cells which stand out: 1) A marked increase in the number of fine filaments in the basal portion of the Sertoli cell cytoplasm. In some of these regions few other organelles are present; 2) Extensive junctional complexes between neighboring Sertoli cells extending from the base of the tubule to the lumen; and 3) Elaborate interdigitations between the plasma membrane of adjacent Sertoli cells. In addition to these special features, many areas of Sertoli cells in germinal aplasia show the common organelles found in normal humans. It has previously been assumed that Sertoli cells are normal in patients with germinal aplasia, but the present ultrastructural study demonstrates that they possess certain morphological abnormalities. These observations are consistent with the conjecture that in patients with severe germ cell depletion the increase in plasma FSH may be due to impaired Sertoli cell function resulting in diminished feedback inhibition of gonadotropin release.