Effects of recombinant human FSH in immature hypophysectomized male rats: evidence for Leydig cell-mediated action on spermatogenesis

1994 ◽  
Vol 141 (3) ◽  
pp. 449-457 ◽  
Author(s):  
T Matikainen ◽  
J Toppari ◽  
K K Vihko ◽  
I Huhtaniemi
Keyword(s):  
Leydig Cell ◽  
Leydig Cells ◽  
Cell Function ◽  
Serum Testosterone ◽  
Male Rats ◽  
Seminiferous Tubules ◽  
Spermatogenic Cells ◽  
Hypophysectomized Rats ◽  
First Time ◽  
Recombinant Human Fsh

Abstract The mode of FSH actions within the testis was studied in immature hypophysectomized male rats by treatment with recombinant human FSH (recFSH, Org 32489). To elucidate the involvement of Leydig cells and androgens in the maintenance of spermatogenesis in FSH-treated hypophysectomized rats further, the recFSH treatment was given both alone and after destruction of Leydig cells with ethane-1,2-dimethane sulphonate (EDS). Three days after hypophysectomy (at 31 days of age) the rats were given one i.p. injection of vehicle or EDS and, 4 days later, they were implanted with osmotic minipumps releasing either 0·9% (w/v) NaCl or 1 IU recFSH/day. Recombinant FSH alone increased testicular weights 2·5-fold in 7 days (P<0·01). The effect of FSH was similar in EDS-pretreated rats (P<0·01). Testicular testosterone increased from 6·5 ± 1·6 to 16·9 ± 5·3 (s.e.m.) pmol/g tissue (P<0·05) and serum testosterone from 0·12 ± 0·02 to 0·22 ± 0·03 nmol/l (P<0·05) when the rats were treated with recFSH. EDS alone did not affect testicular testosterone but, when combined with recFSH, it totally abolished the stimulatory effect of FSH on testosterone. Testicular binding of 125I-labelled iodo human chorionic gonadotrophin (hCG) and 125I-labelled iodo recFSH was increased 2·5- and 2·1-fold respectively with recFSH treatment (P<0·01). EDS, either alone or with FSH, abolished specific testicular hCG binding (P<0·01), but had no effect on that of recFSH. However, FSH increased its own receptors only in animals not treated with EDS. Histological analysis of the testes revealed that the diameters of the seminiferous tubules increased from 115 ± 6·1 to 160 ± 7·2 μm (P<0·05) with recFSH, and a comparable increase was observed when EDS treatment preceded that of recFSH (143 ± 1·5 μm, P<0·05 vs. controls). Quantification of the spermatogenic cells indicated that recFSH supported the progression of spermatogenesis, as shown by increased number of meiotic and haploid spermatogenic cells (P<0·05). In all EDS-treated animals, spermatogenesis was severely disturbed and only a few spermatids were seen. In conclusion: (1) these results further support the suggestion that FSH has indirect stimulatory effects on Leydig cell function, (2) the completion of meiosis and spermiogenesis are supported by FSH, the effect of which is enhanced by the presence of Leydig cells, suggesting its dependence on androgens, and (3) we show for the first time that FSH is able to stimulate its own receptors only in the presence of Leydig cell-derived factors, probably androgens. Journal of Endocrinology (1994) 141, 449–457

Inhibition of testicular and somatic development after treatment of the postnatal rat with the Leydig cell cytotoxic ethylene dimethanesulphonate

1988 ◽  
Vol 119 (3) ◽  
pp. 467-NP ◽  
Author(s):  
I. D. Morris ◽  
R. G. Lendon ◽  
A. Zaidi
Keyword(s):  
Leydig Cell ◽  
Leydig Cells ◽  
Serum Testosterone ◽  
Male Rats ◽  
Seminiferous Tubules ◽  
Testicular Development ◽  
Interstitial Tissue ◽  
Somatic Development ◽  
Serum Lh ◽  
Loss Of Weight

ABSTRACT The Leydig cell cytotoxic ethylene dimethanesulphonate (EDS) was administered s.c. daily (50 mg/kg) to male rats aged 5–16 days. Apart from loss of weight and that the eyelids unfused earlier, no gross toxicity was observed during treatment. On day 17 testis weights, serum testosterone concentrations, testicular serum testosterone content and 125I-labelled human chorionic gonadotrophin (hCG) binding to testicular homogenates were reduced. Serum LH and FSH concentrations were elevated. The testes did not recover from EDS treatment and at 63 and 120 days were minute (<2% of control), and the prostate and seminal vesicles were small although not completely atrophied. In addition, body weights were substantially reduced. Serum and testicular testosterone and 125I-labelled hCG binding to testicular homogenates were reduced but not absent. Serum LH and FSH concentrations were increased. Light microscopy of the adult testes showed that EDS treatment inhibited the development of the seminiferous tubules. Most of the tubules were devoid of germ cells and Sertoli cells were rare. Occasionally tubules also contained spermatogonia and spermatocytes but no signs of spermiogenesis. The testes were composed mainly of closely packed interstitial tissue with no lymphatic space. The interstitial cells resembled Leydig cells and stained for 3β-hydroxysteroid dehydrogenase. Histochemically identified Leydig cells were absent during treatment but reappeared when treatment was withdrawn. Testicular Leydig cell numbers were only 7% of control values in the 63-day-old EDS-treated rat. The effect on the testis of EDS treatment administered at a crucial time of testicular development may be explained by withdrawal of androgen; however, the systemic effects indicate non-specific toxicity so any explanation of these changes must be viewed with caution. J. Endocr. (1988) 119, 467–474

scholarly journals Leydig cell apoptosis in the rat testes after administration of the cytotoxin ethane dimethanesulphonate: role of the Bcl-2 family members

1998 ◽  
Vol 157 (2) ◽  
pp. 317-326 ◽  
Author(s):  
MF Taylor ◽  
I Woolveridge ◽  
AD Metcalfe ◽  
CH Streuli ◽  
JA Hickman ◽  
...  
Keyword(s):  
Cell Death ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Family Members ◽  
Tumour Suppressor Gene ◽  
Male Rats ◽  
Seminiferous Tubules ◽  
Gene Products ◽  
Bax Protein ◽  
Ethane Dimethanesulphonate

Ethane dimethanesulphonate (EDS) is cytotoxic to Leydig cells in the adult rat. To investigate the role and regulation of apoptosis in the Leydig cell, EDS (100 mg/kg i.p.) was administered to adult male rats and the testes examined 6, 12, 18, 24, 48 and 72 h later. Numbers of Leydig cells, identified by 3 beta-hydroxysteroid dehydrogenase immuno-histochemistry started to fall by 12 h after EDS injection and were almost undetectable by 72 h. Apoptotic cells in the interstitium, visualised by in situ end labelling of DNA, increased in number to reach a maximum 24 h after injection of EDS, and were undetectable by 72 h. In many tissues the apoptosis-related gene products act in cohort: Bcl-2 and Bcl-xl promoting survival of a cell, whilst Bax promotes cell death often positively regulated by the tumour-suppressor gene p53. Western blot analysis showed that: (1) Bcl-2 and p53 were absent from interstitial Leydig cells but were expressed in the seminiferous tubules. (2) Bax protein although expressed in the interstitium was not present in the Leydig cells. (3) Bcl-xl in Leydig cells was transiently increased after EDS. In conclusion, EDS kills Leydig cells by apoptosis; however the control of Leydig cell death does not involve p53 or the Bcl-2 family members but may require other gene products yet to be identified.

Bisphenol A decreases expression of insulin-like factor 3 and induces histopathological changes in testes of rat

2021 ◽  
pp. 074823372110140
Author(s):  
Leman Sencar ◽  
Gulfidan coskun ◽  
Dilek Şaker ◽  
Tuğçe Sapmaz ◽  
Abdullah Tuli ◽  
...  
Keyword(s):  
Bisphenol A ◽  
Leydig Cell ◽  
Cell Function ◽  
Light And Electron Microscopy ◽  
Serum Testosterone ◽  
Testicular Atrophy ◽  
Male Rats ◽  
Chemical Agent ◽  
High Doses ◽  
Leydig Cell Function

Bisphenol A (BPA) is a chemical agent known to have detrimental reproductive and developmental effects. The tissue-specific impacts of BPA exposures and target tissues sensitiveness to BPA are still unclear. The aim of this study was to determine the short- and long-term dose-dependent toxic effects of BPA on rat testes. Forty-eight Wistar albino male rats were divided into four groups each containing 12 rats. To induce toxicity, BPA was administered orally at three different dosages (50, 100, and 200 mg/kg) for 14 and 28 days, respectively. Testis tissues were examined using light and electron microscopy, immunohistochemistry, and biochemical methods. Serum testosterone (T) and luteinizing hormone (LH) levels were measured. Additionally, insulin-like factor 3 (INSL3) as a marker of Leydig cell function was evaluated immunohistochemically. Groups administered high doses of BPA showed severe degenerations such as testicular atrophy, spermatogenic arrest, and interstitial edema in testis. Also, a significant decrease in INSL3 immunoreactivity and serum LH and T levels was found. The results indicated that both increased exposure time and dosage of BPA caused more serious detrimental effects on testes in the rat. Decreased INSL3 and T levels was evidence of Leydig cell function impairment due to BPA.

Leydig cell resistance to the cytotoxic effect of ethylene dimethanesulphonate in the adult rat testis

1985 ◽  
Vol 105 (3) ◽  
pp. 311-NP ◽  
Author(s):  
I. D. Morris
Keyword(s):  
Seminal Vesicle ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Serum Testosterone ◽  
Male Rats ◽  
Cell Physiology ◽  
Testis Weight ◽  
Endocrine Activity ◽  
Adult Rat ◽  
Seminal Vesicle Weight

ABSTRACT Weekly doses of the Leydig cell cytotoxic ethylene dimethanesulphonate (EDS) were administered to adult male rats in an attempt to study the endocrine activity of the testis in the absence of Leydig cells. One week after the first dose serum testosterone and LH concentrations and seminal vesicle weights were close to levels in castrated rats and testicular human chorionic gonadotrophin (hCG) binding was severely depressed. These changes were maintained for a further week but subsequently began to return to, but did not achieve, control levels. After six weekly doses seminal vesicle weight and serum testosterone concentrations were significantly higher than in the castrated rats. Serum LH concentrations were declining towards control values at 4 weeks but had risen again at 6 weeks. Serum FSH concentrations were raised to about 50% of the value in castrated rats throughout the period studied. Testis weight and hCG binding, which initially fell, were partially restored at 6 weeks and spermatogenesis was recovering. The data show that responses of the testis to multiple doses of EDS are similar to those after a single dose. This apparent resistance indicates that the regenerating Leydig cells are functionally different from the mature Leydig cell. The similarities between the maturing Leydig cell seen after EDS destruction and those in the immature rat suggest that EDS will provide a valuable model for the investigation of Leydig cell physiology. J. Endocr. (1985) 105, 311–316

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.

Effects of hypophysectomy and human chorionic gonadotrophin on Leydig cell function in mature rats

1990 ◽  
Vol 126 (3) ◽  
pp. 367-NP ◽  
Author(s):  
D. M. Stocco ◽  
K. J. Teerds ◽  
M. van Noort ◽  
F. F. G. Rommerts
Keyword(s):  
Leydig Cell ◽  
Leydig Cells ◽  
Cell Function ◽  
Fold Increase ◽  
Specific Protein ◽  
Chorionic Gonadotrophin ◽  
Human Chorionic Gonadotrophin ◽  
Cell Functions ◽  
Complete Restoration ◽  
Hypophysectomized Rats

ABSTRACT The biochemical activities involved in the maintenance of Leydig cell functions, and the effects of hypophysectomy and human chorionic gonadotrophin (hCG) on these functions are largely unknown. In the present study, adult hypophysectomized rats were used as a model to determine the effects of these treatments on a number of biochemical and morphological parameters. After 33 days of hypophysectomy, the morphology of the Leydig cells had been drastically altered. In addition, α-naphthol and β-naphthol esterase activity as well as the steroidogenic capacity of the Leydig cells were greatly reduced at this time. In contrast, the level of sterol carrier protein 2 (SCP2), a Leydig cell-specific protein, was affected by hypophysectomy much less than the other parameters measured. Two daily injections of hCG to rats hypophysectomized for 31 days resulted in no change in the morphology of the Leydig cells, or in their proliferative activity. Non-specific esterase activities were also unaffected by 2 days of treatment with hCG. However, two injections of hCG to rats hypophysectomized for 31 days resulted in nearly complete restoration of steroidogenic capacity, and a 3·5-fold increase in the level of SCP2. These findings indicate that hypophysectomy results in significant morphological and biochemical changes in Leydig cells, and that hCG is capable of restoring some of these capacities within a short time. Journal of Endocrinology (1990) 126, 367–375

A switch in the cellular localization of macrophage migration inhibitory factor in the rat testis after ethane dimethane sulfonate treatment

1999 ◽  
Vol 112 (9) ◽  
pp. 1337-1344
Author(s):  
A. Meinhardt ◽  
M. Bacher ◽  
M.K. O'Bryan ◽  
J.R. McFarlane ◽  
C. Mallidis ◽  
...  
Keyword(s):  
Western Blot ◽  
Leydig Cell ◽  
Migration Inhibitory Factor ◽  
Sertoli Cells ◽  
Leydig Cells ◽  
Macrophage Migration Inhibitory Factor ◽  
Inhibitory Factor ◽  
Male Rats ◽  
Seminiferous Tubules ◽  
Macrophage Migration

Macrophage migration inhibitory factor (MIF), one of the first cytokines to be discovered, has recently been localized to the Leydig cells in adult rat testes. In the following study, the response of MIF to Leydig cell ablation by the Leydig cell-specific toxin ethane dimethane sulfonate (EDS) was examined in adult male rats. Testicular MIF mRNA and protein in testicular interstitial fluid measured by ELISA and western blot were only marginally reduced by EDS treatment, in spite of the fact that the Leydig cells were completely destroyed within 7 days. Immunohistochemistry using an affinity-purified anti-mouse MIF antibody localized MIF exclusively to the Leydig cells in control testes. At 7 days post-EDS treatment, there were no MIF immunopositive Leydig cells in the interstitium, although distinct MIF immunostaining was observed in the seminiferous tubules, principally in Sertoli cells and residual cytoplasm, and some spermatogonia. A few peritubular and perivascular cells were also labelled at this time, which possibly represented mesenchymal Leydig cell precursors. At 14 and 21 days, Sertoli cell MIF immunoreactivity was observed in only a few tubule cross-sections, while some peritubular and perivascular mesenchymal cells and the re-populating immature Leydig cells were intensely labeled. At 28 days after EDS-treatment, the MIF immunostaining pattern was identical to that of untreated and control testes. The switch in the compartmentalization of MIF protein at 7 days after EDS-treatment was confirmed by western blot analysis of interstitial tissue and seminiferous tubules separated by mechanical dissection. These data establish that Leydig cell-depleted testes continue to produce MIF, and suggest the existence of a mechanism of compensatory cytokine production involving the Sertoli cells. This represents the first demonstration of a hitherto unsuspected pattern of cellular interaction between the Leydig cells and the seminiferous tubules which is consistent with an essential role for MIF in male testicular function.

scholarly journals Quantitation of Leydig Cell in Testicular Biopsies of Gossypol Treated rats

2005 ◽  
Vol 29 (1) ◽  
pp. 179-189
Author(s):  
Muhannad A. A. Al Bayaty
Keyword(s):  
Cell Density ◽  
Leydig Cell ◽  
Seminiferous Tubule ◽  
Leydig Cells ◽  
Histological Section ◽  
Treated Group ◽  
Male Rats ◽  
Male Rat ◽  
Seminiferous Tubules ◽  
Cell Clusters

Leydig cell density was evaluated quantitatively in bilateral testicularbiopsies from twenty male rats of two equal groups Gossypol treated andcontrol. The method utilized for this quantitation is based on the determinationof total number of Leydig cells, Leydig cell clusters and seminiferous tubules inthe entire histological section of each biopsy and the calculation of the followingindices: mean Leydig cells per seminiferous tubule, mean Leydig cell clustersper seminiferous tubule and mean Leydig cells per cluster. A significant positivecorrelation between Leydig cells per tubule and Leydig cell clusters per tubulewas demonstrated. The results of indices curve showed shifted all the curves tothe right in Gossypol treated group, a significant reduction in plasmatestosterone levels of Gossypol treatment group as compared to control groupwhich is due to decrease in Leydig cells number, suggesting that determinationof Leydig cell clusters per seminiferous tubule in testicular biopsies is anobjective and clinically applicable method for quantitative evaluation of Leydigcell density and indirectly evaluated the secretary activity of the testicularLeydig cells. The results are attributed to the direct effect of Gossypol onsecretary site of testosterone in Leydig cells or presumably indirect disturbanceof hypothalamic – pituitary gland – Leydig cells axis. An Association ofGossypol treatment with Leydig cell hypo-function and decrease number of cellswas noticed for the male rat testosterone level. To our knowledge this is the firstreport of quantitative analysis of Leydig cell density in rat with Gossypoltreatment and it is suitable for clinical evaluation of testicular dysfunction.التأثر

scholarly journals Effects of Osteocalcin on Synthesis of Testosterone and INSL3 during Adult Leydig Cell Differentiation

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Gulfidan Coskun ◽  
Leman Sencar ◽  
Abdullah Tuli ◽  
Dilek Saker ◽  
Mustafa Muhlis Alparslan ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Postnatal Development ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Development Process ◽  
Gnrh Antagonist ◽  
Serum Testosterone ◽  
Male Rats ◽  
Significant Difference ◽  
Adult Leydig Cells

Proliferation and differentiation of adult Leydig cells are mainly completed in puberty. In many studies, apart from normal postnatal development process, it is widely indicated that, through administrating EDS, Leydig cell population is eliminated and regenerated. It is believed that osteocalcin released from osteoblasts, which is responsible for modulating bone metabolism, induces testosterone production in Leydig cells, independent of the HPG axis. In addition, INSL3 produced by Leydig cells, such as testosterone, plays a critical role in bone metabolism and is known to reflect the development process and functional capacities of Leydig cells. This study is aimed at investigating OC-mediated testosterone regulation and INSL3 synthesis during differentiation of adult Leydig cells that are independent of LH. For this purpose, male rats were divided into 2 groups: prepubertal normal rats and adult EDS-injected rats. Each group was divided into 4 subgroups in which GnRH antagonist or OC was applied. After adult Leydig cells completed their development, testicular tissue samples obtained from the sacrificed rats were examined by light-electron microscopic, immunohistochemical, and biochemical methods. Slight upregulation in 3βHSD, INSL3, and GPRC6A expressions along with the increase in serum testosterone levels was observed in groups treated with osteocalcin against GnRH antagonist. In addition, biochemical and microscopic findings in osteocalcin treated groups were similar to those in control groups. While there was no significant difference in the number of Leydig cells reported, the presence of a significant upregulation in INSL3 and GPRC6A expressions and the increase in serum testosterone and ucOC levels were observed. After evaluation of findings altogether, it is put forward that, for the first time in this study, although osteocalcin treatment made no significant difference in the number of Leydig cells, it increased the level of testosterone through improving the function of existing adult Leydig cells during normal postnatal development process and post-EDS regeneration. This positive correlation between osteocalcin-testosterone and osteocalcin-INSL3 is concluded to be independent of LH at in vivo conditions.

Role of testicular macrophages in the response of Leydig cells to gonadotrophins in young hypophysectomized rats

1995 ◽  
Vol 147 (3) ◽  
pp. 463-471 ◽  
Author(s):  
F Gaytan ◽  
C Bellido ◽  
C Morales ◽  
N van Rooijen ◽  
E Aguilar
Keyword(s):  
Leydig Cells ◽  
Male Rats ◽  
Ventral Prostate ◽  
Seminiferous Tubules ◽  
Left Testis ◽  
Cross Sectional ◽  
Testicular Weight ◽  
Hypophysectomized Rats ◽  
Testicular Macrophages

Abstract The Leydig cells of young hypophysectomized rats are highly sensitive to the stimulatory effects of exogenous pituitary hormones. The aim of this study was to analyse the role of testicular macrophages in the response of Leydig cells to different hormones. Male rats were hypophysectomized at 28 days of age and 10 days later they were injected intratesticularly with dichloromethylene diphosphonate-containing liposomes (right testis) to deplete testicular macrophages, and with 0·9% NaCl (left testis). One week later, the animals were treated daily with 1 IU rat GH (rGH)/rat, 5 IU recombinant human FSH (recFSH)/rat, 10 IU human chorionic gonadotrophin (hCG)/rat, or vehicle for 7 days. The animals were killed on the day after the last injection. The animals treated with rGH showed increased body weight and increased number and size of testicular macrophages in the left testes, but no significant effects on Leydig cells were found. Treatment with recFSH induced a significant increase in testicular weight and tubular diameter in both testes. In the left testes, the number and size of macrophages were increased; the number of Leydig cells was not changed, although they showed a significantly increased cross-sectional area. This effect was abolished in the right (macrophage-depleted) testes. However, the effect of recFSH on the growth of the seminiferous tubules was not modified by the absence of macrophages. Rats treated with hCG showed increased testicular weight and serum testosterone levels, as well as an increased weight of the ventral prostate. In the left testes, the number and size of both macrophages and Leydig cells were increased. Otherwise, the number of Leydig cells was unchanged in the absence of macrophages, whereas the increase in the size of Leydig cells was partially abolished. These data indicate that testicular macrophages are needed for the response of Leydig cells to gonadotrophin treatment. Journal of Endocrinology (1995) 147, 463–471

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