scholarly journals Male 41, XXY* Mice as a Model for Klinefelter Syndrome: Hyperactivation of Leydig Cells

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2898-2910 ◽  
Author(s):  
Joachim Wistuba ◽  
C. Marc Luetjens ◽  
Jan-Bernd Stukenborg ◽  
Andreas Poplinski ◽  
Steffi Werler ◽  
...  
Keyword(s):  
Germ Cell ◽  
X Chromosome ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Cell Function ◽  
Klinefelter Syndrome ◽  
Cell Loss ◽  
Endocrine Function ◽  
Maximal Response ◽  
Different Ages

Sex chromosome imbalance in males is linked to a supernumerary X chromosome, a condition resulting in Klinefelter syndrome (KS; 47, XXY). KS patients suffer from infertility, hypergonadotropic hypogonadism, and cognitive impairments. Mechanisms of KS pathophysiology are poorly understood and require further exploration using animal models. Therefore, we phenotypically characterized 41, XXY* mice of different ages, evaluated observed germ cell loss, studied X-inactivation, and focused on the previously postulated impaired Leydig cell maturation and function as a possible cause of the underandrogenization seen in KS. Xist methylation analysis revealed normal X-chromosome inactivation similar to that seen in females. Germ cell loss was found to be complete and to occur during the peripubertal phase. Significantly elevated FSH and LH levels were persistent in 41, XXY* mice of different ages. Although Leydig cell hyperplasia was prominent, isolated XXY* Leydig cells showed a mature mRNA expression profile and a significantly higher transcriptional activity compared with controls. Stimulation of XXY* Leydig cells in vitro by human chorionic gonadotropin indicated a mature LH receptor whose maximal response exceeded that of control Leydig cells. The hyperactivity of Leydig cells seen in XXY* mice suggests that the changes in the endocrine milieu observed in KS is not due to impaired Leydig cell function. We suggest that the embedding of Leydig cells into the changed testicular environment in 41 XXY* males as such influences their endocrine function.

INSL3: A Marker of Leydig Cell Function and Testis-Bone-Skeletal Muscle Network

2020 ◽  
Vol 27 (12) ◽  
pp. 1246-1252
Author(s):  
Paolo Facondo ◽  
Andrea Delbarba ◽  
Filippo Maffezzoni ◽  
Carlo Cappelli ◽  
Alberto Ferlin
Keyword(s):  
Skeletal Muscle ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Cell Function ◽  
Cell Damage ◽  
Endocrine Function ◽  
Testicular Descent ◽  
Male Hypogonadism ◽  
Adult Men ◽  
Leydig Cell Function

This article reviews the role of INSL3 as biomarker of Leydig cell function and its systemic action in testis-bone-skeletal muscle crosstalk in adult men. Insulin-like factor 3 (INSL3) is a peptide hormone secreted constitutively in a differentiation-dependent mode by testicular Leydig cells. Besides the role for the testicular descent, this hormone has endocrine anabolic functions on the bone-skeletal muscle unit. INSL3 levels are low in many conditions of undifferentiated or altered Leydig cell status, however the potential clinical utility of INSL3 measurement is not yet well defined. INSL3 levels are modulated by the long-term cytotropic effect of the hypothalamicpituitary- gonadal axis, unlike testosterone that is acutely sensitive to the stimulus by luteinizing hormone (LH). INSL3 directly depends on the number and differentiation state of Leydig cells and therefore it represents the ideal marker of Leydig cell function. This hormone is more sensitive than testosterone to Leydig cell impairment, and the reduction of INSL3 in adult men can precociously detect an endocrine testicular dysfunction. Low INSL3 levels could cause or contribute to some symptoms and signs of male hypogonadism, above all sarcopenia and osteoporosis. The measurement provided suggested that the measurement of INSL3 levels should be considered in the clinical management of male hypogonadism and in the evaluation of testicular endocrine function. The monitoring of INSL3 levels could allow an early detection of Leydig cell damage, even when testosterone levels are still in the normal range.

scholarly journals Leydig cell genes change their expression and association with polysomes in a stage-specific manner in the adult mouse testis†,‡

2018 ◽  
Vol 98 (5) ◽  
pp. 722-738 ◽  
Author(s):  
Estela J Jauregui ◽  
Debra Mitchell ◽  
Savanna M Garza ◽  
Traci Topping ◽  
Cathryn A Hogarth ◽  
...  
Keyword(s):  
Germ Cell ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Adult Mouse ◽  
Cell Function ◽  
Cell Development ◽  
Seminiferous Epithelium ◽  
Mouse Testis ◽  
Germ Cell Development ◽  
Specific Manner

Abstract Spermatogenesis in mammals occurs in a very highly organized manner within the seminiferous epithelium regulated by different cell types in the testis. Testosterone produced by Leydig cells regulates blood–testis barrier formation, meiosis, spermiogenesis, and spermiation. However, it is unknown whether Leydig cell function changes with the different stages of the seminiferous epithelium. This study utilized the WIN 18,446 and retinoic acid (RA) treatment regime combined with the RiboTag mouse methodology to synchronize male germ cell development and allow for the in vivo mapping of the Leydig cell translatome across the different stages of one cycle of the seminiferous epithelium. Using microarrays analysis, we identified 11 Leydig cell-enriched genes that were expressed in stage-specific manner such as the glucocorticoid synthesis and transport genes, Cyp21a1 and Serpina6. In addition, there were nine Leydig cell transcripts that change their association with polysomes in correlation with the different stages of the spermatogenic cycle including Egr1. Interestingly, the signal intensity of EGR1 and CYP21 varied among Leydig cells in the adult asynchronous testis. However, testosterone levels across the different stages of germ cell development did not cycle. These data show, for the first time, that Leydig cell gene expression changes in a stage-specific manner during the cycle of the seminiferous epithelium and indicate that a heterogeneous Leydig cell population exists in the adult mouse testis.

Impaired Testicular Function in Patients With Carcinoma-In-Situ of the Testis

1999 ◽  
Vol 17 (1) ◽  
pp. 173-173 ◽  
Author(s):  
Peter Meidahl Petersen ◽  
Aleksander Giwercman ◽  
Steen W. Hansen ◽  
Jørgen G. Berthelsen ◽  
Gedske Daugaard ◽  
...  
Keyword(s):  
Testicular Cancer ◽  
Germ Cell ◽  
Leydig Cell ◽  
Carcinoma In Situ ◽  
Cell Function ◽  
Semen Quality ◽  
Sperm Concentration ◽  
Testicular Dysfunction ◽  
Leydig Cell Function

PURPOSE: To elucidate the biologic association between germ cell neoplasia and testicular dysfunction, through investigation of Leydig cell function and semen quality in men with carcinoma-in-situ (CIS) of the testis. PATIENTS AND METHODS: We examined two groups of men, unilaterally orchidectomized for testicular cancer. Biopsy of the contralateral testis had showed CIS in a group of 24 patients and no evidence of CIS in the other group of 30 patients. Semen quality and serum levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were compared in these two groups of men after orchidectomy but before further treatment for testicular cancer. RESULTS: Significantly higher LH levels (median, 8.1 IU/L v 4.8 IU/L; P < .001) and generally lower testosterone levels (median, 12.5 nmol/L v 15.5 nmol/L; P = .13) were found in the CIS group. The proportion of patients with Leydig cell dysfunction was higher in the group of patients with CIS (11 of 24) than in the group of patients without (two of 30) (P = .01). Sperm concentration and total sperm count were significantly lower (P < .001) in patients with CIS (median, 0.03 × 106/mL and 0.10 × 106, respectively) than in patients without (median, 9.1 × 106/mL and 32 × 106, respectively), whereas the levels of FSH were significantly higher (P < .001) in the former group of men (median, 19.6 IU/L v 9.0 IU/L). CONCLUSION: Not only spermatogenesis but also Leydig cell function is impaired in testes with CIS. This impairment could be due to common factors in the pathogenesis of germ cell neoplasm and testicular dysfunction. Alternatively, CIS cells may have a negative impact on Leydig cell function.

Adult rat Sertoli cells secrete a factor or factors which modulate Leydig cell function

1987 ◽  
Vol 114 (3) ◽  
pp. 459-467 ◽  
Author(s):  
V. Papadopoulos ◽  
P. Kamtchouing ◽  
M. A. Drosdowsky ◽  
M. T. Hochereau de Reviers ◽  
S. Carreau
Keyword(s):  
Cyclic Amp ◽  
Sertoli Cell ◽  
Leydig Cell ◽  
Sertoli Cells ◽  
Leydig Cells ◽  
Cell Function ◽  
Cell Interaction ◽  
Adult Rats ◽  
Adult Rat ◽  
Stimulating Factor

ABSTRACT Production of testosterone and oestradiol-17β by Leydig cells from adult rats was stimulated by LH or dibutyryl cyclic AMP (10 and 2·5-fold respectively). The addition of spent medium from normal, hemicastrated or γ-irradiated rat seminiferous tubule cultures, as well as from Sertoli cell cultures, to purified Leydig cells further enhanced both basal (44 and 53% for testosterone and oestradiol-17β respectively) and LH-stimulated (56 and 18%) steroid output. Simultaneously, a decrease (20–30%) in intracellular cyclic AMP levels was observed. This stimulating factor (or factors) secreted by the Sertoli cells is different from LHRH, is of proteinic nature and has a molecular weight ranging between 10 000 and 50 000; its synthesis is not controlled by FSH nor by testosterone. This factor(s) involved in rat Leydig cell steroidogenesis, at a step beyond the adenylate cyclase, does not require protein synthesis for testosterone formation whereas it does for oestradiol-17β production. It should be noted that a germ cell–Sertoli cell interaction modulates the synthesis of this factor(s). J. Endocr. (1987) 114, 459–467

scholarly journals Effects of environmental Bisphenol A exposures on germ cell development and Leydig cell function in the human fetal testis

PLoS ONE ◽  
2018 ◽  
Vol 13 (1) ◽  
pp. e0191934 ◽  
Author(s):  
Soria Eladak ◽  
Delphine Moison ◽  
Marie-Justine Guerquin ◽  
Gabriele Matilionyte ◽  
Karen Kilcoyne ◽  
...  
Keyword(s):  
Bisphenol A ◽  
Germ Cell ◽  
Leydig Cell ◽  
Cell Function ◽  
Cell Development ◽  
Germ Cell Development ◽  
Fetal Testis ◽  
Leydig Cell Function

scholarly journals Probing GATA factor function in mouse Leydig cells via testicular injection of adenoviral vectors

Reproduction ◽  
2017 ◽  
Vol 154 (4) ◽  
pp. 455-467 ◽  
Author(s):  
Gervette M Penny ◽  
Rebecca B Cochran ◽  
Marjut Pihlajoki ◽  
Antti Kyrönlahti ◽  
Anja Schrade ◽  
...  
Keyword(s):  
Leydig Cell ◽  
Leydig Cells ◽  
Cell Function ◽  
Chromatin Condensation ◽  
Adenoviral Vectors ◽  
Lymphoid Cells ◽  
Testicular Atrophy ◽  
Ultrastructural Changes ◽  
Gata Factor

Testicular Leydig cells produce androgens essential for proper male reproductive development and fertility. Here, we describe a new Leydig cell ablation model based on Cre/Lox recombination of mouse Gata4 and Gata6, two genes implicated in the transcriptional regulation of steroidogenesis. The testicular interstitium of adult Gata4flox/flox; Gata6flox/flox mice was injected with adenoviral vectors encoding Cre + GFP (Ad-Cre-IRES-GFP) or GFP alone (Ad-GFP). The vectors efficiently and selectively transduced Leydig cells, as evidenced by GFP reporter expression. Three days after Ad-Cre-IRES-GFP injection, expression of androgen biosynthetic genes (Hsd3b1, Cyp17a1 and Hsd17b3) was reduced, whereas expression of another Leydig cell marker, Insl3, was unchanged. Six days after Ad-Cre-IRES-GFP treatment, the testicular interstitium was devoid of Leydig cells, and there was a concomitant loss of all Leydig cell markers. Chromatin condensation, nuclear fragmentation, mitochondrial swelling, and other ultrastructural changes were evident in the degenerating Leydig cells. Liquid chromatography-tandem mass spectrometry demonstrated reduced levels of androstenedione and testosterone in testes from mice injected with Ad-Cre-IRES-GFP. Late effects of treatment included testicular atrophy, infertility and the accumulation of lymphoid cells in the testicular interstitium. We conclude that adenoviral-mediated gene delivery is an expeditious way to probe Leydig cell function in vivo. Our findings reinforce the notion that GATA factors are key regulators of steroidogenesis and testicular somatic cell survival. Free Finnish abstract: A Finnish translation of this abstract is freely available at http://www.reproduction-online.org/content/154/4/455/suppl/DC2.

Germ cell loss in the XXY male mouse: Altered X-chromosome dosage affects prenatal development

1998 ◽  
Vol 49 (2) ◽  
pp. 101-111 ◽  
Author(s):  
Patricia A. Hunt ◽  
Carol Worthman ◽  
Holland Levinson ◽  
Joy Stallings ◽  
Renée LeMaire ◽  
...  
Keyword(s):  
Germ Cell ◽  
X Chromosome ◽  
Male Mouse ◽  
Cell Loss ◽  
Prenatal Development

scholarly journals Growing Up Under Constant Light: A Challenge to the Endocrine Function of the Leydig Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Dijana Z. Marinkovic ◽  
Marija L. J. Medar ◽  
Alisa P. Becin ◽  
Silvana A. Andric ◽  
Tatjana S. Kostic
Keyword(s):  
Leydig Cell ◽  
Leydig Cells ◽  
Mitochondrial Dynamics ◽  
Positive Element ◽  
Endocrine Function ◽  
Constant Light ◽  
Mtdna Copy Number ◽  
Voluntary Activity ◽  
Genes Encoding ◽  
Negative Effect

The factors influencing Leydig cell maturity and the acquisition of functional capacity are incompletely defined. Here we analyzed the constant light (LL) influence on Leydig cells’ endocrine function during reproductive maturation. Rats were exposed to LL from P21 to P90. Data were collected at juvenile (P35), peri/pubertal (P42, P49), and adult (P90) stages of life. The results proved the effect of LL on rats’ physiology by changing of bimodal voluntary activity pattern into free-running. Additionally, the peripheral clock in Leydig cells changed in LL condition, indicating disturbed rhythm: the positive element (Bmal1) increased in pre-/pubertal but decreased in the adult period, while negative elements (Per2 and Reverba) were increased. The effects of LL were most prominent in puberty: pituitary genes encoding gonadotropic hormones (Cga, Lhb, Fshb) decreased; serum corticosterone increased, while serum androgens and mass of testicular and sex accessory organs reduced; markers of Leydig cells maturity/differentiation (Insl3, Lhcgr) and steroidogenesis-related genes (Scarb1, Star, Cyp11a1, Cyp17a1) decreased; the steroidogenic and energetic capacity of the Leydig cell mitochondria decreased; the mtDNA copy number reduced, and mitochondrial dynamics markers changed: fusion decreased (Opa1 and Mfn2), and mitophagy increased (Pink1). In adults, the negative effect of LL on mitochondrial function and steroidogenic capacity persists in adult Leydig cells while other parameters reached control values. Altogether, the results indicate that LL slows down Leydig cells’ maturation by reducing the endocrine and energy capacity of cells leading to the delay of reproductive development.

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