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.

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.

scholarly journals Autoradiographical Localization of Luteinizing Hormone Releasing Hormone (LHRH) Receptors on Rat Testicular Intertubular Cells Fractionated on Percoll Density Gradients

1985 ◽  
Vol 38 (4) ◽  
pp. 435 ◽  
Author(s):  
MP Hedger ◽  
OP Risbridger ◽  
DM de Kretser
Keyword(s):  
Leydig Cell ◽  
Leydig Cells ◽  
Cell Function ◽  
Specific Binding ◽  
Density Gradients ◽  
Direct Stimulation ◽  
Density Region ◽  
Luteinizing Hormone Releasing Hormone ◽  
Testicular Cells ◽  
Leydig Cell Function

The specific binding of 125I-1abelled [D-Ser(tBu)6,des-GlyNH21OJ LHRH ethylamide (LHRH-A) to testicular intertubular cells fractionated on Percoll density gradients was investigated. The greatest binding per cell occurred in the density region which contained the largest proportion of Leydig cells (sp. gr. 1�0820-1�0585). Autoradiographs of the cells from this region confirmed that silver stains were predominantly located over the Leydig cell, significantly (P < 0�01) more grains were observed over this cell type in the total binding fractions than in the non-specific binding fractions. However, 5�9% of cells other than Leydig cells (testicular macrophages and indeterminate connective tissue cells) from this region also displayed significant disp1aceable binding (P < 0�01). The location of HRH-A binding to cells in other density regions, which did not contain identifiable Leydig cells, could not be established by autoradiography. These results confirm that the Leydig cell possesses LHRH receptors, but also indicate that other testicular cells have specific, highaffinity binding sites for LHRH-A, and may either be responsive to direct stimulation by LHRH, or may partially mediate the effects of LHRH and its agonists on Leydig cell function.

scholarly journals Insulin-Like Factor 3 Levels in Cord Blood and Serum from Children: Effects of Age, Postnatal Hypothalamic-Pituitary-Gonadal Axis Activation, and Cryptorchidism

2007 ◽  
Vol 92 (10) ◽  
pp. 4020-4027 ◽  
Author(s):  
Katrine Bay ◽  
Helena E. Virtanen ◽  
Stefan Hartung ◽  
Richard Ivell ◽  
Katharina M. Main ◽  
...  
Keyword(s):  
Cord Blood ◽  
Leydig Cell ◽  
Outcome Measure ◽  
Cell Function ◽  
Perinatal Period ◽  
Testicular Descent ◽  
Cell Hormone ◽  
Prepubertal Boys ◽  
A Prospective Study ◽  
Leydig Cell Function

Abstract Context: The Leydig cell hormone insulin-like factor 3 (INSL3) is important for testicular descent. Currently INSL3 levels in cord blood, in serum throughout childhood, and in relation to congenital cryptorchidism are unknown. Objective: The objective of the study was to characterize INSL3 levels in cord blood during the postnatal activation of the hypothalamic-pituitary-gonadal axis and in later childhood in normal boys and girls and cryptorchid boys. Design and Participants: Serum from 267 3-month-old boys of a prospective study with standardized cryptorchidism classification was analyzed for INSL3 (of these, 99 also had cord blood samples). Testicular position was known in 151 controls and 54 transiently cryptorchid and 62 persistently cryptorchid subjects. Eight infant girls, 26 boys (4.1–10.1 yr), and 13 girls (3.7–8.7 yr) were also included. Outcome Measure: INSL3, age, testicular position, LH, and testosterone were measured. Results: INSL3 levels were significantly higher (P &lt; 0.001) in cord blood and 3-month-old boys as compared with older prepubertal boys. At 3 months of age, INSL3 correlated significantly with LH in healthy boys. Cord blood INSL3 was significantly reduced in persistently cryptorchid boys (P = 0.001), and 3-month-old persistently cryptorchid boys had a significantly increased LH to INSL3 ratio (P = 0.014). INSL3 was unmeasurable in girls at all ages. Conclusions: In boys, early postnatal INSL3 is markedly higher as compared with later childhood, presumably because it is stimulated by the transient postnatal LH peak. INSL3 was unmeasurable in girls at all ages. Reduced cord blood INSL3 and an increased LH to INSL3 ratio at 3 months of age in persistently cryptorchid boys suggest impaired Leydig cell function in cryptorchid boys already in the perinatal period.

Expression of the glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase 2 in pig testes cells along fetal development

2007 ◽  
Vol 19 (5) ◽  
pp. 664 ◽  
Author(s):  
S. Haeussler ◽  
R. Claus
Keyword(s):  
Germ Cells ◽  
Leydig Cell ◽  
Fetal Development ◽  
Leydig Cells ◽  
Cell Function ◽  
Hydroxysteroid Dehydrogenase ◽  
Immunocytochemical Staining ◽  
Tunel Staining ◽  
Steroid Synthesis ◽  
Leydig Cell Function

The glucocorticoid (GC)–cortisol receptor (GCR)–11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) system is involved in the regulation of Leydig cell function and spermatogenesis in mature animals. Herein, we describe the expression of the GCR and 11β-HSD2 and the occurrence of apoptosis during fetal development. Male fetuses were collected from Weeks 6, 10, 13, and 15 of pregnancy and from neonates. The testes were used for the immunocytochemical staining of GCR, 11β-HSD2 and for terminal deoxyribonucleotidyl transferase-mediated dUTP–digoxigenin nick end-labelling (TUNEL) staining of apoptosis. Apoptosis did not occur in any Leydig cells, but approximately 30% expressed GCR and 11β-HSD2. The number of GCR-positive cells was similar at all stages, but the number of 11β-HSD2-positive cells tended to be higher at Weeks 6 and 15. Steroid synthesis was also higher compared with Weeks 10 and 13. Apoptosis occurred in only a few germ cells. Nearly all germ cells were GCR positive at Weeks 10 and 13, when 11β-HSD2 was also increased. The total number of 11β-HSD2-positive germ cells was approximately 30%. Thus, elevated GCR expression coincided with the differentiation of gonocytes to spermatogonia and their migration to the basal lamina.

CHANGES IN LEYDIG CELL HYDROXYSTEROID DEHYDROGENASES INDUCED BY ADMINISTRATION OF TESTOSTERONE PROPIONATE TO NORMAL MEN

1974 ◽  
Vol 60 (1) ◽  
pp. 175-NP ◽  
Author(s):  
H. C. MORSE ◽  
C. G. HELLER
Keyword(s):  
Leydig Cell ◽  
Leydig Cells ◽  
Cell Function ◽  
Testosterone Propionate ◽  
Testicular Biopsy ◽  
Frozen Sections ◽  
Histochemical Technique ◽  
Biopsy Specimens ◽  
Normal Men ◽  
Leydig Cell Function

SUMMARY By the employment of an improved histochemical technique, frozen sections from human testicular biopsy specimens were examined for 3β-and 17β-hydroxysteroid dehydrogenase (HSD) activity, before, during, and after administration of 25 or 50 mg testosterone propionate per day to normal men. This administration strongly suppressed Leydig cell HSD activity and caused these cells to be transformed into fibroblast-like cells. After cessation of administration, the Leydig cells recovered morphologically and so did, simultaneously their 3β- and 17β-HSD activity. It is concluded that histochemically detectable 3β- and 17β-HSD are under gonadotrophin control and change with alterations in Leydig cell function. The morphology or 3β- and 17β-HSD are therefore probably acceptable as indicators of Leydig cell function in reproductively normal men.

scholarly journals Impaired Leydig Cell Function in Infertile Men: A Study of 357 Idiopathic Infertile Men and 318 Proven Fertile Controls

2004 ◽  
Vol 89 (7) ◽  
pp. 3161-3167 ◽  
Author(s):  
A.-M. Andersson ◽  
N. Jørgensen ◽  
L. Frydelund-Larsen ◽  
E. Rajpert-De Meyts ◽  
N. E. Skakkebæk
Keyword(s):  
Leydig Cell ◽  
Leydig Cells ◽  
Infant Development ◽  
Cell Function ◽  
Serum Testosterone ◽  
Seminiferous Epithelium ◽  
Lower Serum ◽  
Infertile Men ◽  
Serum Lh ◽  
Leydig Cell Function

Abstract To investigate whether an impaired Leydig cell function is present in severely oligospermic men, serum testosterone (T), LH, estradiol (E2), and SHBG levels in 357 idiopathic infertile men were compared with levels in 318 proven fertile men. In addition, the T/LH ratio, E2/T ratio, and calculated free T index (cFT) were compared between the two groups. A shift toward lower serum T levels, cFT, and T/LH ratio and higher serum LH, E2, and E2/T levels was observed in the group of infertile men. On average, the infertile men had 18, 26, and 34% lower serum T, cFT, and T/LH levels, respectively, and 19, 18, and 33% higher serum LH, E2, and E2/T levels, respectively, than the fertile men. Twelve percent of the infertile men had a serum T level that fell below the 2.5 percentile of the fertile levels, and 15% of the infertile men had a LH level that was above the 97.5 percentile of the fertile levels. Thus, the group of infertile men showed significant signs of impaired Leydig cell function in parallel to their impaired spermatogenesis. The association of decreased spermatogenesis and impaired Leydig cell function might reflect a disturbed paracrine communication between the seminiferous epithelium and the Leydig cells, triggered by distorted function of the seminiferous epithelium. On the other hand, the parallel impairment of spermatogenesis and Leydig cells may reflect a congenital dysfunction of both compartments caused by a testicular dysgenesis during fetal/infant development.

THE MECHANISMS INVOLVED IN TESTICULAR DEGENERATION IN MAN

1967 ◽  
Vol 56 (4_Suppl) ◽  
pp. S17-S40 ◽  
Author(s):  
Svend G. Johnsen
Keyword(s):  
Leydig Cell ◽  
Leydig Cells ◽  
Cell Function ◽  
Frequent Occurrence ◽  
Human Testis ◽  
Cell Hyperplasia ◽  
Number Of Factors ◽  
Leydig Cell Hyperplasia ◽  
Leydig Cell Function ◽  
Testicular Degeneration

ABSTRACT The study presents a correlation between the regulatory mechanisms of the human testis and a number of factors involved in the degenerative processes in idiopathic hypospermatogenesis. As a working hypothesis, it is assumed that temporary damage cannot result in permanent hypospermatogenesis unless this is maintained by a special mechanism, and the object of the study is to find such a mechanism. It is shown 1) that in man the full spermatogenetic cycle can take place in the absence of Leydig cells; 2) that decreased spermatogenesis leads to increased release of gonadotrophins and further to Leydig cell hyperplasia; 3) that spermatogenetic lesions do not per se induce deposition of hyaline material in the tubular wall, but that hyalinization damages the epithelium; 4) that a special feature of the structure of the testis in Klinefelter's syndrome strongly suggests that the hyalinization process is not a direct gonadotrophin effect but is related to Leydig cell function. The nature of Leydig cell function has been shown to depend upon the qualitative nature of gonadotrophin stimulation, and findings indicating a qualitative change in the secretion of hyperplastic Leydig cells in hypospermatogenesis are presented. From these relationships a theory of the pathogenesis of "idiopathic" hypospermatogenesis is advanced. Temporary damage to the germinal epithelium induces increased gonadotrophin release and changes in the FSH/LH ratio. These result in Leydig cell hyperplasia and in qualitative changes in Leydig cell function. This may start a hyalinization process which damages the epithelium, this damage in turn maintains the gonadotrophin rise, etc., etc., The existence of a pathogenetic vicious circle in the human testis affords an explanation for the frequent occurrence of testicular degeneration and permanent cryptogenetic, hypospermatogenesis in man. The aim of this presentation is to correlate the mechanisms involved in the regulation of testicular function in man with the processes of non-specific testicular degeneration. By a total consideration of a large number of factors an attempt will be made to arrive at an explanation of the frequent occurrence of testicular degeneration in man. Although testicular degeneration has frequently been dealt with in the literature (cf. below), no such attempt has apparently been published.

scholarly journals Androgen and Luteinizing Hormone Stimulate the Function of Rat Immature Leydig Cells Through Different Transcription Signals

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoheng Li ◽  
Qiqi Zhu ◽  
Zina Wen ◽  
Kaimin Yuan ◽  
Zhijian Su ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Luteinizing Hormone ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Cell Function ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Transcription Signals ◽  
Leydig Cell Function

The function of immature Leydig cells is regulated by hormones, such as androgen and luteinizing hormone (LH). However, the regulation of this process is still unclear. The objective of this study was to determine whether luteinizing hormone (LH) or androgens contribute to this process. Immature Leydig cells were purified from 35-day-old male Sprague Dawley rats and cultured with LH (1 ng/ml) or androgen (7α-methyl-19- nortestosterone, MENT, 100 nM) for 2 days. LH or MENT treatment significantly increased the androgens produced by immature Leydig cells in rats. Microarray and qPCR and enzymatic tests showed that LH up-regulated the expression of Scarb1, Cyp11a1, Cyp17a1, and Srd5a1 while down-regulated the expression of Sult2a1 and Akr1c14. On the contrary, the expression of Cyp17a1 was up-regulated by MENT. LH and MENT regulate Leydig cell function through different sets of transcription factors. We conclude that LH and androgens participate in the regulation of rat immature Leydig cell function through different transcriptional pathways.

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