280. INSL3 is a measure of human Leydig cell functionality both during fetal and adult life

2008 ◽  
Vol 20 (9) ◽  
pp. 80
Author(s):  
R. Anand-Ivell ◽  
J. Manson ◽  
G. Wittert ◽  
J. Wohlgemuth ◽  
B. Hafen ◽  
...  
Keyword(s):  
Leydig Cell ◽  
Leydig Cells ◽  
Cell Function ◽  
Adult Life ◽  
Physiological Role ◽  
South Australia ◽  
Testicular Descent ◽  
Adult Type ◽  
Hpg Axis ◽  
Age Related

Insulin like factor 3 (INSL3) and testosterone are the two major secretory products of the testis, both produced by the interstitial Leydig cells. The Leydig cells of the testis have two distinct generations, one developing before birth (fetal Leydig cells, FLC) and an adult type (adult Leydig cells, ALC) that become differentiated and functional at puberty. Although these two types of Leydig cells represent distinct populations, rodent studies show that both types produce testosterone and INSL3. Both are presumed to have evolved from a common stem cell pool. We measured INSL3 levels in human amniotic fluids collected at various times of gestation and show for the first time that the human male fetus indeed generates INSL3 at a time appropriate for the first transabdominal phase of testicular descent, which appears to be the primary physiological role for the fetal hormone. INSL3 appears to be independent of androgen production. The adult type Leydig cells (in adult men) secrete INSL3 that can be measured in the peripheral circulation at levels ranging from 0.5 to 2.5 ng/mL. We studied a large randomly recruited cohort of 1183 men from South Australia, comparing serum INSL3 concentrations with age, and a variety of endocrine, cognitive and morphological parameters. INSL3 concentration was observed to decline significantly with age. This however, had no correlation with testosterone or components of the HPG axis. INSL3 is an independent measure of Leydig cell function (quality and number), which appears to be independent of acute control via the HPG axis. Its decline with age reflects a decline in the properties of the Leydig cell population only, and emphasises a gonadal component in the age-related decrease in androgen production. Research supported by ARC Discovery grant DP0773315.

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 Increased Exposure to Estrogens Disturbs Maturation, Steroidogenesis, and Cholesterol Homeostasis via Estrogen Receptor α in Adult Mouse Leydig Cells

Endocrinology ◽  
2009 ◽  
Vol 150 (6) ◽  
pp. 2865-2872 ◽  
Author(s):  
Leena Strauss ◽  
Jenny Kallio ◽  
Nimisha Desai ◽  
Pirjo Pakarinen ◽  
Tatu Miettinen ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Cell Function ◽  
Smooth Endoplasmic Reticulum ◽  
Estrogen Receptor Α ◽  
Cholesterol Homeostasis ◽  
Matrix Composition ◽  
Adult Type ◽  
Estrogen Exposure

Deteriorated male reproductive health has been connected to overexposure to estrogens or to imbalanced androgen-estrogen ratio. Transgenic male mice expressing human aromatase (AROM+ mice) serve as an apt model for the study of the consequences of an altered androgen-estrogen ratio. Our previous studies with AROM+ mice showed that low androgen levels together with high estrogen levels result in cryptorchidism and infertility. In the present study, the AROM+ mice were shown to have severe abnormalities in the structure and function of Leydig cells before the appearance of spermatogenic failure. Decreased expression of adult-type Leydig cell markers (Ptgds, Vcam1, Insl3, Klk21, -24 and -27, Star, Cyp17a1, and Hsd17b3) indicated an immature developmental stage of the Leydig cells, which appears to be the first estrogen-dependent alteration. Genes involved in steroidogenesis (Star, Cyp17a1, and Hsd17b3) were suppressed despite normal LH levels. The low expression level of kallikreins 21, 24, and 27 potentially further inhibited Leydig cell function via remodeling extracellular matrix composition. In connection with disrupted steroidogenesis, Leydig cells showed enlarged mitochondria, a reduced amount of smooth endoplasmic reticulum, and an accumulation of cholesterol and precursors for cholesterol synthesis. The results of studies with AROM+ mice crossed with estrogen receptor α or β (ERα and ERβ, respectively) knockout mice lead to the conclusion that the structural and functional disorders caused by estrogen exposure were mediated via ERα, whereas ERβ was not involved.

Age-related changes in human Leydig cell status

2020 ◽  
Vol 35 (12) ◽  
pp. 2663-2676
Author(s):  
Valentina Mularoni ◽  
Valentina Esposito ◽  
Sara Di Persio ◽  
Elena Vicini ◽  
Gustavo Spadetta ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Sertoli Cell ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Cell Number ◽  
Organ Donors ◽  
Steroidogenic Enzymes ◽  
Age Related ◽  
Age Range

Abstract STUDY QUESTION What are the consequences of ageing on human Leydig cell number and hormonal function? SUMMARY ANSWER Leydig cell number significantly decreases in parallel with INSL3 expression and Sertoli cell number in aged men, yet the in vitro Leydig cell androgenic potential does not appear to be compromised by advancing age. WHAT IS KNOWN ALREADY There is extensive evidence that ageing is accompanied by decline in serum testosterone levels, a general involution of testis morphology and reduced spermatogenic function. A few studies have previously addressed single features of the human aged testis phenotype one at a time, but mostly in tissue from patients with prostate cancer. STUDY DESIGN, SIZE, DURATION This comprehensive study examined testis morphology, Leydig cell and Sertoli cell number, steroidogenic enzyme expression, INSL3 expression and androgen secretion by testicular fragments in vitro. The majority of these endpoints were concomitantly evaluated in the same individuals that all displayed complete spermatogenesis. PARTICIPANTS/MATERIALS, SETTING, METHODS Testis biopsies were obtained from 15 heart beating organ donors (age range: 19–85 years) and 24 patients (age range: 19–45 years) with complete spermatogenesis. Leydig cells and Sertoli cells were counted following identification by immunohistochemical staining of specific cell markers. Gene expression analysis of INSL3 and steroidogenic enzymes was carried out by qRT-PCR. Secretion of 17-OH-progesterone, dehydroepiandrosterone, androstenedione and testosterone by in vitro cultured testis fragments was measured by LC-MS/MS. All endpoints were analysed in relation to age. MAIN RESULTS AND THE ROLE OF CHANCE Increasing age was negatively associated with Leydig cell number (R = −0.49; P < 0.01) and concomitantly with the Sertoli cell population size (R= −0.55; P < 0.001). A positive correlation (R = 0.57; P < 0.001) between Sertoli cell and Leydig cell numbers was detected at all ages, indicating that somatic cell attrition is a relevant cellular manifestation of human testis status during ageing. INSL3 mRNA expression (R= −0.52; P < 0.05) changed in parallel with Leydig cell number and age. Importantly, steroidogenic capacity of Leydig cells in cultured testis tissue fragments from young and old donors did not differ. Consistently, age did not influence the mRNA expression of steroidogenic enzymes. The described changes in Leydig cell phenotype with ageing are strengthened by the fact that the different age-related effects were mostly evaluated in tissue from the same men. LIMITATIONS, REASONS FOR CAUTION In vitro androgen production analysis could not be correlated with in vivo hormone values of the organ donors. In addition, the number of samples was relatively small and there was scarce information about the concomitant presence of potential confounding variables. WIDER IMPLICATIONS OF THE FINDINGS This study provides a novel insight into the effects of ageing on human Leydig cell status. The correlation between Leydig cell number and Sertoli cell number at any age implies a connection between these two cell types, which may be of particular relevance in understanding male reproductive disorders in the elderly. However aged Leydig cells do not lose their in vitro ability to produce androgens. Our data have implications in the understanding of the physiological role and regulation of intratesticular sex steroid levels during the complex process of ageing in humans. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grants from Prin 2010 and 2017. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

248. Oestrogen receptor beta is involved in the regulation of Leydig cell number in the mouse

2005 ◽  
Vol 17 (9) ◽  
pp. 99
Author(s):  
M. Gould ◽  
H. D. Nicholson
Keyword(s):  
Leydig Cell ◽  
Sertoli Cells ◽  
Leydig Cells ◽  
Oestrogen Receptor ◽  
Physiological Role ◽  
Plasma Testosterone ◽  
Testis Weight ◽  
Wild Type ◽  
Significant Difference ◽  
Receptor Beta

Recent evidence suggests that oestrogen plays a physiological role in the testis. Both oestrogen receptor alpha and oestrogen receptor beta (ERb) are present in the testis and administration of oestrogen has been shown to inhibit the development of Sertoli, Leydig and germ cells. This study investigates the effect of ERb on the testis using ERb knockout mice (bERKO). Adult male bERKO mice (n=8) and their wild-type littermates (n=7) were killed at 11 weeks postpartum. One testis from each animal was fixed in Bouin’s fluid and embedded. Each testis was fractionated and thick sections cut and stained with PAS. The optical disector method was used to count the number of Leydig cells, Sertoli cells, spermatogonia, spermatocytes and spermatids in each testis. Trunk blood was collected and plasma testosterone concentrations measured by radioimmunoassay. No significant differences in body or testis weight were seen between the bERKO or wild-type mice. Similar numbers of Sertoli cells, spermatogonia, spermatocytes and spermatids were also observed between the two groups. The number of Leydig cells was significantly increased in bERKO mice compared with their wild-type littermates (P < 0.05). Despite the increased number of Leydig cells in the bERKO mice there was no significant difference in plasma testosterone concentrations in this group compared to the wild-type mice. Oestrogen has been reported to inhibit proliferation of adult-type Leydig cells and to inhibit steroidogenesis. This study suggests that the regulation of Leydig cell proliferation may be mediated by ERb. The presence of normal circulating testosterone concentrations in bERKO mice suggests that the effects of oestrogen on steroidogenesis are not brought about by ERbeta.

scholarly journals Effects of pharmacologically induced Leydig cell testosterone production on intratesticular testosterone and spermatogenesis†

2019 ◽  
Vol 102 (2) ◽  
pp. 489-498 ◽  
Author(s):  
Jin-Yong Chung ◽  
Sean Brown ◽  
Haolin Chen ◽  
June Liu ◽  
Vassilios Papadopoulos ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Leydig Cell ◽  
Mitochondrial Membrane ◽  
Leydig Cells ◽  
Translocator Protein ◽  
Brown Norway ◽  
Inner Mitochondrial Membrane ◽  
Negative Effects ◽  
Rate Determining Step ◽  
Age Related

Abstract The Leydig cells of the mammalian testis produce testosterone (T) in response to luteinizing hormone (LH). In rats and men with reduced serum T levels, T replacement therapy (TRT) will raise T levels, but typically with suppressive effects on sperm formation. The rate-determining step in T formation is the translocation of cholesterol to the inner mitochondrial membrane, mediated by protein–protein interactions of cytosolic and outer mitochondrial membrane proteins. Among the involved proteins is cholesterol-binding translocator protein (TSPO) (18 kDa TSPO). We hypothesized that in contrast to TRT, the administration of the TSPO agonist N,N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide (FGIN-1-27), by stimulating the ability of the Leydig cells to produce T, would result in the elevation of serum T levels while maintaining intratesticular T concentration and therefore without suppression of spermatogenesis. Age-related reductions in both serum and intratesticular T levels were seen in old Brown Norway rats. Both exogenous T and FGIN-1-27 increased serum T levels. With exogenous T, serum LH and Leydig cell T formation were suppressed, and intratesticular T was reduced to below the concentration required to maintain spermatogenesis quantitatively. In contrast, FGIN-1-27 stimulated Leydig cell T formation, resulting in increased serum T without reductions in intratesticular T concentrations or in testicular sperm numbers. FGIN-1-27 also significantly increased serum and intratesticular T levels in rats made LH-deficient by treatment with the gonadotropin-releasing hormone antagonist cetrorelix. These results point to a possible approach to increasing serum T without negative effects on spermatogenesis, based upon stimulating T production by the Leydig cells themselves rather than administering T exogenously.

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 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.

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