به نام پروردگاری که هنوز ذهن بشر در برابر آفریده هایش درمانده است.
Origin, Development and Regulation of Human Leydig Cells
Azam Naderi Farjam
Hamedan Islamic Azad University
Advisor: Dr.M.mahmoodi
2o10
1-Stem Leydig Cell : 2-Progenitor Leydig Cell : 3-Immature Leydig Cell :
4-Mature (Adult) Leydig Cell:
The development and maturation of Leydig cells are dynamic processes involving interaction between hormones and numerous additional factors. In humans, fetal and adult populations of Leydig cells with distinct lineages have been described. During the embryonic and fetal period, these cells secrete testosterone and other androgens, which regulate not only the masculinization of internal and external genitalia,
The development of fetal Leydig cells in humans is a complex process involving cascades of cellular events leading to proliferation, differentiation and involution and associated specific changes in morphology and function. The close functional similarity between fetal Leydig cells and adrenocortical cells found recently suggests a common origin during embryogenesis.. These cells possess well-developed steroidogenic machinery expressing both the luteinizing hormone receptor (LHR) (fig. 1a) and the key steroidogenic enzymes (e.g. 3βHSD, P450scc, P450c17) required for androgen biosynthesis
Immunohistochemical analysis of the expression of receptors and steroidogenic enzymes by Leydig cells and their putative precursors isolated from the rat testis. a Expression of LH receptor by fetal Leydig cells isolated from 7-day-old rats. b Expression of PDGF receptor-α by putative Leydig stem cells isolated from rats 7 days postnatally. c Expression of the steroidogenic acute regulatory (StAR) protein by immature Leydig cells. d Expression of cytochrome P450scc by adult-type Leydig cells. e Expression of α-actin by peritubular cells isolated from 20-day-old rats.
The neonatal androgen surge (‘baby puberty’) may play a role in imprinting various cell types in the prostate, kidney and brain in such a manner they respond appropriately to androgen stimulation during adulthood. the Leydig cells are stimulated by the pituitary gonadotropin LH to grow in number and cellular size, and, the pubertal surge of testosterone required for start and maintenance of full spermatogenesis, development of the accessorysex glands and the appearance of the secondary sexual characteristics.
The development of fetal Leydig cells can be separated into three stages, i.e. differentiation, fetal maturation and involution In the embryonic and fetal human testis, differentiation occurs at a gestational age of 7–14 weeks; maturation during the weeks 14–18 of gestation; and the involution thereafter until the time of full-term birth. The maximal number of Leydig cells per pair of human testes (48 × 106) is observed ig Cells during weeks 13–16 of gestation The Leydig cells appear embryonic gonad shortly after testis determination and probably arise from multiple embryonic tissues including the coelomic epithelium, gonadal ridge mesenchyme, and migrating mesonephric cells .
Moreover, it has been proposed that fetal Leydig cells may have initially evolved through slight modifications of the fetal adrenal cells. This suggestion is based on the observation that patients suffering from congenital adrenal hyperplasia, which in inadequately controlled cases may be associated with chronically elevated levels of ACTH, develop testicular masses known as adrenal rest tissue [8]. This tissue is generally thought to arise from ectopic adrenal tissue which has failed to separate from the gonad during fetal differentiation .However, it is also possible that in some cases these masses arise from ACTH-sensitive fetal Leydig cells that are probably still present in the testis. Of interest in this context is the observation that chronically elevated secretion of ACTH in a boy to stimulate androgen production and cause precocious puberty .
The precursors of fetal human Leydig cells become functionally active as early as after 6–7 weeks of gestation, at which time testosterone can be detected in the human embryonic testis. The differentiation of these cells must be independent of LH, since the onset of testicular androgen production precedes the secretion of LH by the fetal pituitary. Recently, Lambrot et al. have added more support to this conclusion demonstrating that the capacity of the embryonic testis to produce ., retinoic acid can stimulate the expression of the key steroidogenic enzymes and, thereby, steroidogenesis by human embryonic Leydig cells . These observations provide strong support for the idea that neither hCG secreted by the placenta nor LH are involved in regulating the initial phase of human Leydig cell differentiation. However, LH does stimulate testicular testosterone production after more than 7 weeks of gestation, indicating that hCG/LH is absolutely required for the maintenance of this production at later
Moreover, gonadotropin insufficiency is often associated with undermasculinization including micropenis, which is an indication of insufficient testosterone production by fetal Leydig cells . Similarly, males carrying an inactivating mutation of the LHR exhibit reduced numbers of Leydig cells and show poor development of the external genitalia . However, a certain development of androgen-sensitive organs (e.g. the ductus deferens and epididymis) may occur in these individuals indicating some LH/hCG-independent production of androgen,., mutation of the LHβ gene that eliminates the ability of this hormone to bind to its receptor eliminated Leydig cell development in a patient with male hypogonadism.
The Leydig cells proliferate and differentiate gradually and continuously until they attain peak development and maturation before week 19 of gestation, followed by regression .To date, there is no information available concerning the testicular and/or circulating factor(s) that triggers the degeneration of fetal human Leydig cells. Interestingly, in rodents this regression occurs when plasma levels of LH are still high , indicating that this gonadotropin is unable to protect the cells from involution. Several signal molecules, including transforming growth factor (TGF)-β, anti-Müllerian hormone (AMH) and gonadotropin-releasing hormone (GnRH), have been proposed to play a role in the degeneration of fetal Leydig cells in rodents .
Regulatory Factors Controlling the Functions of Fetal HumaHuman Leydig Cells
Desert Hedgehog Although most data concerning the role of Desert hedgehog (Dhh) in the regulation of fetal Leydig cells have been obtained in rodents, there are also reports on the significant role of Dhh signaling in the development normal testicular phenotype in humans . In rodents, Dhh is known to be required for the differentiation and expansion of fetal Leydig cells during the embryonic phase. Secreted by the Sertoli cell, Dhh acts in a paracrine fashion to induce the differentiation of both the fetal Leydig cells and of the peritubular myoid cells, surrounding the testicular cords . Mutant mouse male gonads that lack functional Dhh contain no Leydig cells and the consequent absence of androgens results in feminization of the external genitalia of these animals. Recently compound Sf1+/– ; Dhh –/– mutant male mice were shown not to masculinize and to appear externally female as a result of their lack of differentiated fetal Leydig cells. These findings led to the proposal that the Sf1 and Dhh pathways may be necessary for the differentiation and survival of fetal and adult Leydig cells in rodent Dhh in humans still remains to be demonstrated.
Human fetal Leydig cells have been found to express significant levels of growth factor of both isoforms, PDGF-A and PDGF-B, as well as their corresponding receptors, PDGFRα and PDGFRβ . Therefore, it is reasonable to suggest that the PDGF system is involved in the control of Leydig cell development and function also in humans, similarly to what has been observed in rodents. Deletion of the gene encoding PDGF-A was found to attenuate the expression of cytochrome P450 side-chain cleavage (P450scc) , which converts cholesterol into pregnenolone, and thereby disrupts early Leydig cell I differentiation in mice.
The expression of this regulatory molecule in human fetal Leydig cells has recently been shown to peak week 15 postconception, in parallel with the highest testosterone levels of the fetus , suggesting a role for GATA-4 in the regulation of steroidogenesis in human fetal Leydig cell. Experiments on rodents have shown that GATA-4 plays a role in the differentiation of and/or steroidogenesis by somatic gonadal cells, including fetal and adult Leydig cells,
Furthermore, some evidence suggests that ligands of the IGF system affect the differentiation and steroidogenic capacity of fetal Leydig cells, both in rodents and humans . In the human testis, IGFs and the type I IGF receptor are differentially expressed at different maturational stages and seem to be involved in the regulation of Leydig cell proliferation and survival, and steroidogenic maturation . In line with this hypothesis, boys with a genetic deficiency in production of this growth factor are undermasculinized,
Postnatal Differentiation of Human Leydig Cells
Division of the development of human Leydig cells into the three stages is based on the triphasic development of plasma testosterone levels, with the initial testosterone peak appearing at the end of the first trimester of fetal life, when mature fetal Leydig cells are functional, the second after 2–3 months of postnatal life, and the third peak being established in connection with established puberty and lasting thereafter throughout adulthood, until a decline at old age. Morphometric analysis reflects this fluctuation in testosterone levels, revealing a decline in the number of fetal Leydig cells following their peak development during 14–18 weeks of gestation and the appearance of a new wave of Leydig cells designated as neonatal 2–3 months after birth. In humans, the development and function of neonatal Leydig cells are thought to be controlled by the elevated level of LH, which originates from reactivation of the hypothalamic-pituitary-gonadal (HPG) axis during the neonatal period , and is associated with an increased plasma testosterone level. Thus, blockage of the neonatal activation of the HPG axis by an antagonist of GnRH suppresses the maturation of Leydig cells in primates and abolishes the neonatal rise in testosterone secretion .
The enhancement in the numbers of mature Leydig cells that occurs during puberty indicates that precursor cells (e.g. peritubular-like Leydig stem cells and perivascular cells) are being recruited for this purpose . The peritubular-like Leydig stem cells express PDGFRα (fig. 1b) but not the LHR or steroidogenic enzymes . After experimental ablation of Leydig cells with ethane dimethane sulfonate (EDS), peritubular spindle-shaped cells have been shown to be precursors of regenerating Leydig cells in rats . Interestingly, certain investigations on both humans and experimental animals have demonstrated that fully mature Leydig cells can dedifferentiate back to their previous stage of development. This event is associated with several morphological changes, including reductions in the volume of the smooth endoplasmic reticulum and number of mitochondria, as well as with impairment of testosterone secretion
Fig. 2. A putative scheme for the differentiation of human Leydig cells. Peritubular (PTC) and Sertoli cells (SC) secrete a number of critical factors including LIF, PDGF-α and Dhh which trigger Leydig stem cells (LSC) to proliferate and migrate into the interstitial compartment of the testis, where they differentiate into progenitor Leydig cells (PLC). Subsequently, a combination of growth factors and hormones (e.g. LH, T3, IGF-1 and PDGF-α) activate their signaling pathways that promote transition of the PLC into immature Leydig cells (ILC) and, finally, into the adult Leydig cell (ALC) population.
Regulation of the Function of Human Adult Leydig Cell Lineage
Insulin-Like Factor 3 Insulin-like factor 3 (INSL3), a peptide that controls the early phase of testicular descent during embryonic development, is expressed and secreted not only by fetal but also by adult-type human Leydig cells. Importantly. Recently, the INSL3 concentration in the peripheral blood of men has been shown to decline continuously in a linear fashion between the ages of 35 and 80, a phenomenon that probably reflects a reduction in Leydig cell functionality with age All these reports agree well with recent findings showing that testosterone upregulates the expression of INSL3 in primary rat Leydig cell cultures suggesting a positive correlation between testosterone production and INSL3 expression by Leydig cells.
Ghrelin The peptide ghrelin, an endogenous ligand for growth hormone, detected in the human stomach, hypothalamus and testis, is also an important regulator of human Leydig cell function. In the case of the testis, ghrelin has been localized immunohistochemically to Leydig cells and Sertoli cells.
This peptide inhibits both hCG- and cAMP-activated testosterone production by Leydig cells in vitro, an effect which is associated with significant attenuation of hCG-stimulated expression of mRNAs coding for several key steroidogenic proteins, e.g. StAR, P450scc, 3β-HSD, and 17β-HSD type III . Recently, the level of ghrelin expression by Leydig cells was found to be inversely correlated to serum levels of testosterone in patients ,in seminiferous tubules of the rat testis ghrelin regulates the expression of the stem cell factor (SCF), a major paracrine stimulator of germ cell development which promotes the survival of spermatogonia, spermatocytes, and spermatids in the adult rat seminiferous epithelium.
Leptin Leptin, a 16-kDa protein produced primarily by adipose tissue [68] and exerting a significant influence on reproduction and fertility in mammals. Experiments on rodents have shown that leptin is a potent suppressor of steroidogenesis in Leydig cells. The rapid and dose-dependent inhibition of hCG-stimulated testosterone production by primary cultures of rat Leydig cells exerted by leptin is associated with attenuation of androstenedione levels and a concomitant elevation of the levels of the precursor molecules 17-OH progesterone, progesterone and pregnenolone, Moreover, leptin reduces the expression of mRNAs encoding SF-1, StAR and P450scc, which are key elements of the steroidogenic machinery in this same system . These effects in rodent models are consistent with those observed in humans. Obese individuals demonstrate elevated levels of leptin and reduced concentrations of androgens in their blood [72]. Furthermore, circulating concentrations of leptin have been suggested to be the most reliable predictor of obesity-related attenuation of the androgen response to hCG in vitro. Recently, leptin was demonstrated to be expressed in germ cells, while the expression of the leptin receptor was found exclusively in the Leydig cells of fertile men ,leptin receptor expression in Leydig cells is inversely correlated with the serum levels of testosterone. Thus, overexpression of the leptin receptor by Leydig cells appears to inhibit testosterone production in infertile men.
At present, our knowledge concerning the intracellular signaling cascades that control the development of different populations of human Leydig cells is still incomplete.
In addition, possible reduction of the capacity of fetal human Leydig cells to produce androgens induced by xenobiotics (see, for example ), which may lead to incomplete masculinization of male fetuses and various malformations in the reproductive tract, should be explored.
The signaling molecules that trigger the dedifferentiation of fully mature Leydig cells to their previous stage of development are completely unknown and a better understanding of this phenomenon may provide insight into the mechanisms underlying aging and tumorigenesis.
Figure 1 is a scanning electron micrograph of a cross-section of the rat testis . The micrograph shows the beautiful architecture of the testis. The seminiferous tubules are quite prominent and reveals tubules at different stages of spermatogenesis. The web like interstitium that surrounds the tubules is where Leydig cells, testicular macrophages, endothelial cells and other interstitial cells reside.
Figure 3: testosterone biosynthetic pathway in Leydig cells.
the end
Origin, Development and Regulation of Human Leydig Cells
Azam Naderi Farjam
Hamedan Islamic Azad University
Advisor: Dr.M.mahmoodi
2o10
1-Stem Leydig Cell : 2-Progenitor Leydig Cell : 3-Immature Leydig Cell :
4-Mature (Adult) Leydig Cell:
The development and maturation of Leydig cells are dynamic processes involving interaction between hormones and numerous additional factors. In humans, fetal and adult populations of Leydig cells with distinct lineages have been described. During the embryonic and fetal period, these cells secrete testosterone and other androgens, which regulate not only the masculinization of internal and external genitalia,
The development of fetal Leydig cells in humans is a complex process involving cascades of cellular events leading to proliferation, differentiation and involution and associated specific changes in morphology and function. The close functional similarity between fetal Leydig cells and adrenocortical cells found recently suggests a common origin during embryogenesis.. These cells possess well-developed steroidogenic machinery expressing both the luteinizing hormone receptor (LHR) (fig. 1a) and the key steroidogenic enzymes (e.g. 3βHSD, P450scc, P450c17) required for androgen biosynthesis
Immunohistochemical analysis of the expression of receptors and steroidogenic enzymes by Leydig cells and their putative precursors isolated from the rat testis. a Expression of LH receptor by fetal Leydig cells isolated from 7-day-old rats. b Expression of PDGF receptor-α by putative Leydig stem cells isolated from rats 7 days postnatally. c Expression of the steroidogenic acute regulatory (StAR) protein by immature Leydig cells. d Expression of cytochrome P450scc by adult-type Leydig cells. e Expression of α-actin by peritubular cells isolated from 20-day-old rats.
The neonatal androgen surge (‘baby puberty’) may play a role in imprinting various cell types in the prostate, kidney and brain in such a manner they respond appropriately to androgen stimulation during adulthood. the Leydig cells are stimulated by the pituitary gonadotropin LH to grow in number and cellular size, and, the pubertal surge of testosterone required for start and maintenance of full spermatogenesis, development of the accessorysex glands and the appearance of the secondary sexual characteristics.
The development of fetal Leydig cells can be separated into three stages, i.e. differentiation, fetal maturation and involution In the embryonic and fetal human testis, differentiation occurs at a gestational age of 7–14 weeks; maturation during the weeks 14–18 of gestation; and the involution thereafter until the time of full-term birth. The maximal number of Leydig cells per pair of human testes (48 × 106) is observed ig Cells during weeks 13–16 of gestation The Leydig cells appear embryonic gonad shortly after testis determination and probably arise from multiple embryonic tissues including the coelomic epithelium, gonadal ridge mesenchyme, and migrating mesonephric cells .
Moreover, it has been proposed that fetal Leydig cells may have initially evolved through slight modifications of the fetal adrenal cells. This suggestion is based on the observation that patients suffering from congenital adrenal hyperplasia, which in inadequately controlled cases may be associated with chronically elevated levels of ACTH, develop testicular masses known as adrenal rest tissue [8]. This tissue is generally thought to arise from ectopic adrenal tissue which has failed to separate from the gonad during fetal differentiation .However, it is also possible that in some cases these masses arise from ACTH-sensitive fetal Leydig cells that are probably still present in the testis. Of interest in this context is the observation that chronically elevated secretion of ACTH in a boy to stimulate androgen production and cause precocious puberty .
The precursors of fetal human Leydig cells become functionally active as early as after 6–7 weeks of gestation, at which time testosterone can be detected in the human embryonic testis. The differentiation of these cells must be independent of LH, since the onset of testicular androgen production precedes the secretion of LH by the fetal pituitary. Recently, Lambrot et al. have added more support to this conclusion demonstrating that the capacity of the embryonic testis to produce ., retinoic acid can stimulate the expression of the key steroidogenic enzymes and, thereby, steroidogenesis by human embryonic Leydig cells . These observations provide strong support for the idea that neither hCG secreted by the placenta nor LH are involved in regulating the initial phase of human Leydig cell differentiation. However, LH does stimulate testicular testosterone production after more than 7 weeks of gestation, indicating that hCG/LH is absolutely required for the maintenance of this production at later
Moreover, gonadotropin insufficiency is often associated with undermasculinization including micropenis, which is an indication of insufficient testosterone production by fetal Leydig cells . Similarly, males carrying an inactivating mutation of the LHR exhibit reduced numbers of Leydig cells and show poor development of the external genitalia . However, a certain development of androgen-sensitive organs (e.g. the ductus deferens and epididymis) may occur in these individuals indicating some LH/hCG-independent production of androgen,., mutation of the LHβ gene that eliminates the ability of this hormone to bind to its receptor eliminated Leydig cell development in a patient with male hypogonadism.
The Leydig cells proliferate and differentiate gradually and continuously until they attain peak development and maturation before week 19 of gestation, followed by regression .To date, there is no information available concerning the testicular and/or circulating factor(s) that triggers the degeneration of fetal human Leydig cells. Interestingly, in rodents this regression occurs when plasma levels of LH are still high , indicating that this gonadotropin is unable to protect the cells from involution. Several signal molecules, including transforming growth factor (TGF)-β, anti-Müllerian hormone (AMH) and gonadotropin-releasing hormone (GnRH), have been proposed to play a role in the degeneration of fetal Leydig cells in rodents .
Regulatory Factors Controlling the Functions of Fetal HumaHuman Leydig Cells
Desert Hedgehog Although most data concerning the role of Desert hedgehog (Dhh) in the regulation of fetal Leydig cells have been obtained in rodents, there are also reports on the significant role of Dhh signaling in the development normal testicular phenotype in humans . In rodents, Dhh is known to be required for the differentiation and expansion of fetal Leydig cells during the embryonic phase. Secreted by the Sertoli cell, Dhh acts in a paracrine fashion to induce the differentiation of both the fetal Leydig cells and of the peritubular myoid cells, surrounding the testicular cords . Mutant mouse male gonads that lack functional Dhh contain no Leydig cells and the consequent absence of androgens results in feminization of the external genitalia of these animals. Recently compound Sf1+/– ; Dhh –/– mutant male mice were shown not to masculinize and to appear externally female as a result of their lack of differentiated fetal Leydig cells. These findings led to the proposal that the Sf1 and Dhh pathways may be necessary for the differentiation and survival of fetal and adult Leydig cells in rodent Dhh in humans still remains to be demonstrated.
Human fetal Leydig cells have been found to express significant levels of growth factor of both isoforms, PDGF-A and PDGF-B, as well as their corresponding receptors, PDGFRα and PDGFRβ . Therefore, it is reasonable to suggest that the PDGF system is involved in the control of Leydig cell development and function also in humans, similarly to what has been observed in rodents. Deletion of the gene encoding PDGF-A was found to attenuate the expression of cytochrome P450 side-chain cleavage (P450scc) , which converts cholesterol into pregnenolone, and thereby disrupts early Leydig cell I differentiation in mice.
The expression of this regulatory molecule in human fetal Leydig cells has recently been shown to peak week 15 postconception, in parallel with the highest testosterone levels of the fetus , suggesting a role for GATA-4 in the regulation of steroidogenesis in human fetal Leydig cell. Experiments on rodents have shown that GATA-4 plays a role in the differentiation of and/or steroidogenesis by somatic gonadal cells, including fetal and adult Leydig cells,
Furthermore, some evidence suggests that ligands of the IGF system affect the differentiation and steroidogenic capacity of fetal Leydig cells, both in rodents and humans . In the human testis, IGFs and the type I IGF receptor are differentially expressed at different maturational stages and seem to be involved in the regulation of Leydig cell proliferation and survival, and steroidogenic maturation . In line with this hypothesis, boys with a genetic deficiency in production of this growth factor are undermasculinized,
Postnatal Differentiation of Human Leydig Cells
Division of the development of human Leydig cells into the three stages is based on the triphasic development of plasma testosterone levels, with the initial testosterone peak appearing at the end of the first trimester of fetal life, when mature fetal Leydig cells are functional, the second after 2–3 months of postnatal life, and the third peak being established in connection with established puberty and lasting thereafter throughout adulthood, until a decline at old age. Morphometric analysis reflects this fluctuation in testosterone levels, revealing a decline in the number of fetal Leydig cells following their peak development during 14–18 weeks of gestation and the appearance of a new wave of Leydig cells designated as neonatal 2–3 months after birth. In humans, the development and function of neonatal Leydig cells are thought to be controlled by the elevated level of LH, which originates from reactivation of the hypothalamic-pituitary-gonadal (HPG) axis during the neonatal period , and is associated with an increased plasma testosterone level. Thus, blockage of the neonatal activation of the HPG axis by an antagonist of GnRH suppresses the maturation of Leydig cells in primates and abolishes the neonatal rise in testosterone secretion .
The enhancement in the numbers of mature Leydig cells that occurs during puberty indicates that precursor cells (e.g. peritubular-like Leydig stem cells and perivascular cells) are being recruited for this purpose . The peritubular-like Leydig stem cells express PDGFRα (fig. 1b) but not the LHR or steroidogenic enzymes . After experimental ablation of Leydig cells with ethane dimethane sulfonate (EDS), peritubular spindle-shaped cells have been shown to be precursors of regenerating Leydig cells in rats . Interestingly, certain investigations on both humans and experimental animals have demonstrated that fully mature Leydig cells can dedifferentiate back to their previous stage of development. This event is associated with several morphological changes, including reductions in the volume of the smooth endoplasmic reticulum and number of mitochondria, as well as with impairment of testosterone secretion
Fig. 2. A putative scheme for the differentiation of human Leydig cells. Peritubular (PTC) and Sertoli cells (SC) secrete a number of critical factors including LIF, PDGF-α and Dhh which trigger Leydig stem cells (LSC) to proliferate and migrate into the interstitial compartment of the testis, where they differentiate into progenitor Leydig cells (PLC). Subsequently, a combination of growth factors and hormones (e.g. LH, T3, IGF-1 and PDGF-α) activate their signaling pathways that promote transition of the PLC into immature Leydig cells (ILC) and, finally, into the adult Leydig cell (ALC) population.
Regulation of the Function of Human Adult Leydig Cell Lineage
Insulin-Like Factor 3 Insulin-like factor 3 (INSL3), a peptide that controls the early phase of testicular descent during embryonic development, is expressed and secreted not only by fetal but also by adult-type human Leydig cells. Importantly. Recently, the INSL3 concentration in the peripheral blood of men has been shown to decline continuously in a linear fashion between the ages of 35 and 80, a phenomenon that probably reflects a reduction in Leydig cell functionality with age All these reports agree well with recent findings showing that testosterone upregulates the expression of INSL3 in primary rat Leydig cell cultures suggesting a positive correlation between testosterone production and INSL3 expression by Leydig cells.
Ghrelin The peptide ghrelin, an endogenous ligand for growth hormone, detected in the human stomach, hypothalamus and testis, is also an important regulator of human Leydig cell function. In the case of the testis, ghrelin has been localized immunohistochemically to Leydig cells and Sertoli cells.
This peptide inhibits both hCG- and cAMP-activated testosterone production by Leydig cells in vitro, an effect which is associated with significant attenuation of hCG-stimulated expression of mRNAs coding for several key steroidogenic proteins, e.g. StAR, P450scc, 3β-HSD, and 17β-HSD type III . Recently, the level of ghrelin expression by Leydig cells was found to be inversely correlated to serum levels of testosterone in patients ,in seminiferous tubules of the rat testis ghrelin regulates the expression of the stem cell factor (SCF), a major paracrine stimulator of germ cell development which promotes the survival of spermatogonia, spermatocytes, and spermatids in the adult rat seminiferous epithelium.
Leptin Leptin, a 16-kDa protein produced primarily by adipose tissue [68] and exerting a significant influence on reproduction and fertility in mammals. Experiments on rodents have shown that leptin is a potent suppressor of steroidogenesis in Leydig cells. The rapid and dose-dependent inhibition of hCG-stimulated testosterone production by primary cultures of rat Leydig cells exerted by leptin is associated with attenuation of androstenedione levels and a concomitant elevation of the levels of the precursor molecules 17-OH progesterone, progesterone and pregnenolone, Moreover, leptin reduces the expression of mRNAs encoding SF-1, StAR and P450scc, which are key elements of the steroidogenic machinery in this same system . These effects in rodent models are consistent with those observed in humans. Obese individuals demonstrate elevated levels of leptin and reduced concentrations of androgens in their blood [72]. Furthermore, circulating concentrations of leptin have been suggested to be the most reliable predictor of obesity-related attenuation of the androgen response to hCG in vitro. Recently, leptin was demonstrated to be expressed in germ cells, while the expression of the leptin receptor was found exclusively in the Leydig cells of fertile men ,leptin receptor expression in Leydig cells is inversely correlated with the serum levels of testosterone. Thus, overexpression of the leptin receptor by Leydig cells appears to inhibit testosterone production in infertile men.
At present, our knowledge concerning the intracellular signaling cascades that control the development of different populations of human Leydig cells is still incomplete.
In addition, possible reduction of the capacity of fetal human Leydig cells to produce androgens induced by xenobiotics (see, for example ), which may lead to incomplete masculinization of male fetuses and various malformations in the reproductive tract, should be explored.
The signaling molecules that trigger the dedifferentiation of fully mature Leydig cells to their previous stage of development are completely unknown and a better understanding of this phenomenon may provide insight into the mechanisms underlying aging and tumorigenesis.
Figure 1 is a scanning electron micrograph of a cross-section of the rat testis . The micrograph shows the beautiful architecture of the testis. The seminiferous tubules are quite prominent and reveals tubules at different stages of spermatogenesis. The web like interstitium that surrounds the tubules is where Leydig cells, testicular macrophages, endothelial cells and other interstitial cells reside.
Figure 3: testosterone biosynthetic pathway in Leydig cells.
the end
هیچ نظری موجود نیست:
ارسال یک نظر