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Receptors for insulin, IGF1 and IGF2. INSR and IGF1R are composed of two αβ dimers which associate to form heterotetrameric complexes. The αβ dimers are linked together by disulfide bonds and two dimers are also linked by disulfide bonds to form the tetramer. The α subunit is the extracellular portion of the receptor while the β subunit spans the membrane and its cytoplasmic portion interacts with IRS proteins which are key intracellular mediators of insulin/IGF signaling. Single αβ dimers are derived from separate genes and the INSR has two splice variants, INSR-B and INSR-A. Each variant shares the same membrane-spanning β subunit (dark blue) but differs in the extracellular α subunit (light pink or dark pink, respectively). The IGF1R has different α and β subunits compared to the INSR (dark green). These combinations of αβ dimers allow for hybrid receptors, which bind insulin, IGF1, and IGF2 with differing affinities. The schematic shows the αβ dimers, α2β2 hybrid receptors, and the known ligands that bind each receptor. Relative binding affinities are represented by arrows, where a solid arrow signifies a higher binding affinity than a broken arrow.
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The insulin-like family of growth factors (IGFs) – composed of insulin, and insulin-like growth factors I (IGF1) and II (IGF2) – provides essential signals for the control of testis development and function. In the testis, IGFs act in an autocrine-paracrine manner but the extent of their actions has been underestimated due to redundancies at both t...
Citations
... Indeed, loss of vasa function in the mouse affects differentiation of the male germ cells, resulting in male sterility [35]. Studies in vertebrates have shown that insulin-like growth factor plays an important role in gonadal development, sex determination, and gender differentiation [36]. Knockdown of insulin-like growth factor and its receptor in mice leads to reduced testis size, spermatogenic cell numbers, and sperm production [37]. ...
Insulin-like androgenic gland hormone (IAG) is a key regulator of male sexual differentiation in crustaceans that plays important roles in secondary sexual characteristics and testicular development. As a hormone, IAG interacts with its membrane receptor to initiate downstream signal pathways to exert its biological functions. In this study, we isolated a full-length cDNA of an insulin-like receptor (Sp-IR) from the mud crab Scylla paramamosain. Sequence analysis revealed that this receptor consists of a Fu domain, two L domains, three FN-III domains, a transmembrane domain, and a tyrosine kinase domain, classifying it as a member of the tyrosine kinase insulin-like receptors family. Our results also suggested that Sp-IR was highly expressed in the testis and AG in males. Its expression in the testis peaked in stage I but significantly decreased in stages II and III (p < 0.01). Next, both short- and long-term RNA interference (RNAi) experiments were performed on males in stage I to explore Sp-IR function in mud crabs. The results showed that Sp-vasa and Sp-Dsx expression levels in the testis were significantly down-regulated after the specific knockdown of Sp-IR by RNAi. Additionally, the long-term knockdown of Sp-IR led to a considerable decrease in the volume of seminiferous tubules, accompanied by large vacuoles and a reduced production of secondary spermatocytes and spermatids. In conclusion, our results indicated that Sp-IR is involved in testicular development and plays a crucial role in transitioning from primary to secondary spermatocytes. This study provided a molecular basis for the subsequent analysis of the mechanism on male sexual differentiation in Brachyuran crabs.
... Insulin and IGF1 actions are mediated through the activation of two related tyrosine kinase receptors, insulin receptor (INSR) and IGF1 receptor (IGF1R). These receptors are composed of two extracellular α subunits and two transmembrane β subunits, which come together to form heterotetrameric glycoproteins (reviewed in [119]). Interestingly, both insulin and IGF1 can bind to both receptors, albeit with different affinities. ...
... Insulin exhibits a high affinity for INSR but can also bind to IGF1R, albeit with a lower affinity. Similarly, IGF1 exhibits preferential binding to IGF1R while also displaying a lower affinity for INSR (reviewed in [119]). ...
... Insulin-like Growth Factor 1 (IGF1) is a small peptide hormone produced primarily by the liver in response to GH stimulation, but almost all tissues, including the testes, can synthesize IGF1 ( [134,135], reviewed in [78]). In the testes, IGF1 and its receptor (IGFR) are present in Sertoli, Leydig, germ, and peritubular cells [119,130,135,136]. In rodent Leydig cells, IGF1 secretion and upregulation of IGFR can be stimulated by LH, hCG, and GH [137][138][139][140]. ...
Leydig cells, located in the testis interstitial space, are the primary source of testosterone in males. Testosterone plays critical roles in both reproductive and metabolic functions and therefore is essential for male health. Steroidogenesis must be properly regulated since dysregulated hormone production can lead to infertility and metabolic disorders. Leydig cell steroidogenesis relies on the coordinated interaction of various factors, such as hormones and signaling molecules. While luteinizing hormone (LH) is the main regulator of Leydig cell steroidogenesis, other molecules, including growth hormones (GH), prolactin, growth factors (insulin, IGF, FGF, EGF), and osteocalcin, have also been implicated in the stimulation of steroidogenesis. This review provides a comprehensive summary of the mechanisms and signaling pathways employed by LH and other molecules in the stimulation of Leydig cell steroidogenesis, providing valuable insights into the complex regulation of male reproductive and metabolic health.
... Other Cys-rich proteins like G-proteincoupled receptors-targeting proteins (interleukin-8, somatostatin, oxytocin), enzymecoupled receptor-targeting proteins (insulin-like growth factors, epidermal growth factor), extracellular enzyme inhibitors and antimicrobial peptides could also be targets for Hg [53]. For instance, the insulin growth factor family (insulin, insulinlike growth factors -IGF1 and IGF2, and their insulin receptors/IGF1R), provide essential signals for the control of growth, metabolism, and reproductive functions (during embryogenesis, SC proliferation, germ cell proliferation/differentiation and steroidogenesis) [14,30]. In the testis, IGFs act in an autocrine-paracrine manner [30], and IGF1R mediates the effects of follicle-stimulating hormone (FSH) via the PI3K/AKT pathway [14]. ...
... For instance, the insulin growth factor family (insulin, insulinlike growth factors -IGF1 and IGF2, and their insulin receptors/IGF1R), provide essential signals for the control of growth, metabolism, and reproductive functions (during embryogenesis, SC proliferation, germ cell proliferation/differentiation and steroidogenesis) [14,30]. In the testis, IGFs act in an autocrine-paracrine manner [30], and IGF1R mediates the effects of follicle-stimulating hormone (FSH) via the PI3K/AKT pathway [14]. ...
There is the main agreement that proteins are key targets for heavy metals. Apart from the oxidative stress (OS) pathway, the harmful effects of heavy metal ions are also represented by different modes of interaction with protein molecules. For example, by changing the functions of proteins (such as displacement of the main metal ions in enzymes and metalloproteins/MT, or oxidation of amino acids in side residues of peptide molecules), including their attachment to free functional groups (thiol, carboxyl or other groups). In addition, heavy metals can interfere with the synthesis and spatial structuring of forming proteins (by inhibiting the processes of protein folding or refolding upon transfer through cell membranes, or denaturation), causing aggregation of nascent proteins in living cells. The current review aims to discuss some of the possible biochemical and physiological mechanisms related to the protein/enzyme structure and functional activity through which metals influence or contribute to the disruption of male reproductive processes.
... Insulin growth factor-1 (IGF-1) also has an improving effect on spermatogenesis and steroidogenesis. It also plays a role in the biosynthesis of antioxidant enzymes [49]. Epidermal growth factor (EGF) has a beneficial effect on spermatogenesis. ...
Oxymetholone is one of the anabolic steroids that has widely been used among teenagers and athletes to increase their muscle bulk. It has undesirable effects on male health and fertility. In this study, the therapeutic effects of platelet-rich plasma (PRP) on oxymetholone-induced testicular toxicity were investigated in adult albino rats. During the experiments, 49 adult male albino rats were divided into 4 main groups: Group 0 (donor group) included 10 rats for the donation of PRP, Group I (control group) included 15 rats, Group II included 8 rats that received 10 mg/kg of oxymetholone orally, once daily, for 30 days, and Group III included 16 rats and was subdivided into 2 subgroups (IIIa and IIIb) that received oxymetholone the same as group II and then received PRP once and twice, respectively. Testicular tissues of all examined rats were obtained for processing and histological examination and sperm smears were stained and examined for sperm morphology. Oxymetholone-treated rats revealed wide spaces in between the tubules, vacuolated cytoplasm, and dark pyknotic nuclei of most cells, as well as deposition of homogenous acidophilic material between the tubules. Electron microscopic examination showed vacuolated cytoplasm of most cells, swollen mitochondria, and perinuclear dilatation. Concerning subgroup IIIa (PRP once), there was a partial improvement in the form of decreased vacuolations and regeneration of spermatogenic cells, as well as a reasonable improvement in sperm morphology. Regarding subgroup IIIb (PRP twice), histological sections revealed restoration of the normal testicular structure to a great extent, regeneration of the spermatogenic cells, and most sperms had normal morphology. Thus, it is recommended to use PRP to minimize structural changes in the testis of adult albino rats caused by oxymetholone.
... Many growth factors have an essential role in spermatogenesis process such as Bone Morphogenic Protein 4 which plays a vital function in germ cell proliferation and differentiation. Essentially, growth factor has a positive influence in spermatogenesis [9]. Platelet derived growth factor which stimulates the germinal cell and regulates paracrine and autocrine functions [10]. ...
Cisplatin is considered the first-line chemotherapy, reducing its cytotoxicity is still unmet need. Platelet-rich plasma (PRP) has a potential effect on tissue repair through regeneration and differentiation of tissue progenitor cells. Here, we used PRP as a biomaterial to protect and regenerate testicular tissue against cisplatin toxicity. PRP was applied locally using intra-testicular injection as a single dose per week for three following the cisplatin treatment (intra-peritoneum injection). Cisplatin treatment alone and PRP intra-testicular injection alone were used as control groups. The results show that PRP treatment was able to restore sperm counts and sperm morphology following cisplatin exposure. PRP treatment significantly reintited reproductive hormonal balance in affected rats with cisplatin. The results also showed that PRP treatment minimized histological damaged in testicular tissue resulting by the cisplatin, however, also increasing the number of spermatocytes in all stages of spermatogenesis. As well as elevation in the number of leydig cells and thickness of interstitial tissue was restored. This indicates the potential role of PRP in tissue regeneration in addition to tissue repair which may provide a promising use of PRP in different aspects related to chemotherapy.
... Leydig cells, Sertoli cells, spermatogonia and spermatocytes express IGF1 and INS1R. Sertoli cells' energy metabolism is regulated by the utilization of nucleotides (GTP, ATP, UTP), by the secretion of pyruvate, transferrin and lactate, it is concluded that insulin is highly participating in the commencement and sustenance of spermatogenesis Griffeth et al., 2014;Kaur et al., 2018;Kim and Moley, 2008;MacLean et al., 2013;Sakkas et al., 1993). ...
Diabetes is a considerate metabolic disorder that can lead to a series of complications, involving the malfunctioning of the reproductive system of males. It has been observed that there is a gradual rise in male diabetic patients and almost half of the diabetic males have low semen quality and decrease reproductive function. In diabetic conditions, prolonged hyperglycemia leads to oxidative stress, diabetic neuropathy, and insulin resistance. Insulin resistance and its deficiency can impair the hypothalamus, pituitary gland, gonads, and perigonads. This causes a decrease in the secretion of gonadal steroids such as GnRH (gonadotropin-releasing hormone), FSH (follicle-stimulating hormone), LH (luteinizing hormone), and Testosterone. Moreover, it also causes damage to the testicles, spermatogenic and stromal cells, seminiferous tubules, and various structural injuries to male reproductive organs. During spermatogenesis, glucose metabolism plays an important role, because the fundamental activities of cells and their specific features, such as motility and mature sperm fertilization activity, are maintained by glucose metabolism. All these activities can influence the fertility and reproductive health of males. But the glucose metabolism is primarily disrupted in diabetic conditions. Until now, there has been no medicine focusing on the reproductive health of diabetic people. In this chapter, we review the consequences of diabetes on the reproductive system of males and all the pathways involved in the dysfunction of the reproductive system. This will help interpret the effects of DM on male reproductive health.
... The IGF system plays an important role in the proliferation and differentiation of Sertoli cells and germ cells in testicular development during embryogenesis [52]. Since FSH is associated with IGF pathways by way of common downstream signaling pathways or FSH-dependent secretion of IGFs, it has been suggested that the IGF system may regulate FSH activity in the gonads [53]. It can be thought that the deterioration may be caused by the decrease in IGF1 levels, due to the decreased FSH levels in the EMF-42 group. ...
Background and objectives: It has been shown that electromagnetic fields (EMFs) have negative effects on the reproductive system. The biological effects of EMF on the male reproductive system are controversial and vary depending on the frequency and exposure time. Although a limited number of studies have focused on the structural and functional effects of EMF, the effects of prenatal and postnatal EMF exposure on testes are not clear. We aimed to investigate the effects of 50-Hz, 3-mT EMF exposure (5 days/wk, 4 h/day) during pre- and postnatal periods on testis development. Materials and Methods: Pups from three groups of Sprague-Dawley pregnant rats were used: Sham, EMF-28 (EMF-exposure applied during pregnancy and until postnatal day 28), EMF-42 (EMF-exposure applied during pregnancy and until postnatal day 42). The testis tissues and blood samples of male offspring were collected on the postnatal day 42. Results: Morphometric analyses showed a decrease in seminiferous tubule diameter as a result of testicular degeneration in the EMF-42 group. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were decreased in the EMF-42 group. Lipid peroxidation levels were increased in both EMF groups, while antioxidant levels were decreased only in the EMF-28 group. We found decreased levels of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF1) in the EMF-42 group, and decreased levels of the SRC homology 3 (SH3) and multiple ankyrin repeat domain (SHANK3) in the EMF-28 group in the testis tissue. Conclusions: EMF exposure during pre- and postnatal periods may cause deterioration in the structure and function of testis and decrease in growing factors that would affect testicular functions in male rat pups. In addition to the oxidative stress observed in testis, decreased SHANK3, VEGF, and IGF1 protein levels suggests that these proteins may be mediators in testis affected by EMF exposure. This study shows that EMF exposure during embryonic development and adolescence can cause apoptosis and structural changes in the testis.
... IGF-I is one of the important factors for germ cell development and maturation and the motility of the spermatozoa (Hoe ich et al. 1999). Interestingly, PUFA is known to be associated with IGF-I in the regulation of testicular development (Lejeune et al.1996;Fair et al. 2014;Griffeth et al. 2014). In the present study, the testosterone concentration was high in the bulls fed a high-energy diet and housed with improved management. ...
This study was conducted to assess the effect of management practices along with different feed supplementation in the age of puberty of Murrah buffalo male calves. Thirty calves were divided into 5 groups, having 6 in each Group. Groups 1 to 3 were reared under routine management, while 4 to 5 were under better management practices. A basal diet was provided in Group 1. Group 2 had access to a 10% higher energy supplement (molasses) along with basal diet, Group 3 had access to a basal diet plus 10% higher energy till 12 months of age and thereafter roasted flax seed till the age of first semen ejaculation; Group 4 fed similar to Group 2, and Group 5 fed similar to Group 3. Growth performance, scrotal circumference, semen quality and quantity, testosterone concentration, and fatty acid profile of blood serum were measured fortnightly. In One-way Analysis of Variance, it was found that the provision of better management practices and a high-energy diet reduced the age of puberty (P < 0.05). The concentration of serum testosterone increased linearly with the increase in body weight. The semen quality and quantity (volume, concentration, motility, live %) were higher in Group 5 than that in Groups 1 to 4 (P < 0.01). This study concluded that the Murrah buffalo male calves have the potential to attain the age of puberty earlier with the provision of better management practices and an energy-rich diet than that of conventional.
... Moreover, FSH signaling also cross-talks with insulin growth factor signaling to promote mouse SC proliferation. It is reported that FSH amplifies insulin growth factor signaling mediated Akt phosphorylation [134]. Interestingly, in female mice, FSH can stimulate granulosa cells proliferation via inducing Octamer-binding transcription factor 4 (OCT4) expression [135]. ...
Follicle-stimulating hormone signaling is essential for the initiation and early stages of spermatogenesis. Follicle-stimulating hormone receptor is exclusively expressed in Sertoli cells. As the only type of somatic cell in the seminiferous tubule, Sertoli cells regulate spermatogenesis not only by controlling their own number and function but also through paracrine actions to nourish germ cells surrounded by Sertoli cells. After follicle-stimulating hormone binds to its receptor and activates the follicle-stimulating hormone signaling pathway, follicle-stimulating hormone signaling will establish a normal Sertoli cell number and promote their differentiation. Spermatogonia pool maintenance, spermatogonia differentiation and their entry into meiosis are also positively regulated by follicle-stimulating hormone signaling. In addition, follicle-stimulating hormone signaling regulates germ cell survival and limits their apoptosis. Our review summarizes the aforementioned functions of follicle-stimulating hormone signaling in Sertoli cells. We also describe the clinical potential of follicle-stimulating hormone treatment in male patients with infertility. Furthermore, our review may be helpful for developing better therapies for treating patients with dysfunctional follicle-stimulating hormone signaling in Sertoli cells.
... Insulin-like growth factor-1 (IGF-1) plays an essential role in testicular development [7,8]. In the testis, IGF-1 is produced by Sertoli cells and Leydig cells, and it can modulate reproductive performance by stimulating cell proliferation, cell differentiation and steroidogenesis [9][10][11][12][13]. IGF-1 receptors have been identified in the spermatogonia [14], early spermatids [12], spermatocytes [15], spermatozoa [16,17] and cells of epididymis [18,19], indicating that IGF-1 may be involved in steroidogenesis and signals regulating spermatogenesis possibly via the paracrine-autocrine system. ...
... IGF-1 [15,51] and testosterone [52] are produced in the testis and appear to regulate sperm head formation during spermatogenesis via endocrine, paracrine and autocrine systems [53,54]. In Leydig cells, testosterone stimulates IGF-1 production and IGF-1 binding proteins (IGFBPs) [55], which in turn regulates the normal function of Sertoli cells [13,56]. Mice with an Igf1 null mutation gene are observed to have smaller testis and epididymis sizes, and lower levels of testosterone and sperm concentration compared to the controls [57]. ...
The objective of this study was to find relationships among serum IGF−1, serum testosterone, seminal plasma IGF−1 concentrations and semen parameters in Asian elephants (Elephas maximus). A total of 17 ejaculates (one to three ejaculates/bull) were collected from seven captive elephant bulls by performing rectal massage. Before each ejaculation, blood samples were obtained for serum IGF−1 and testosterone assays. Subsequently, the semen characteristics of each ejaculate were evaluated. Mean serum IGF−1 concentration of elephant bulls was estimated as 326.3 ± 114.6 ng/mL (median, 286.2 ng/mL; range, 167.4–542.7 ng/mL). An increase in serum IGF−1 concentration was found to correlate with the percentage of spermatozoa with intact acrosomes. In addition, IGF−1 concentration was positively correlated with testosterone level. However, seminal IGF−1 concentrations could not be detected. In conclusion, our findings suggest that serum IGF−1 concentration is likely a biomarker of normal testicular functions, particularly spermatogenesis in elephants. Moreover, this commercial IGF−1 ELISA is eligible for analyzing serum IGF−1 concentration in Asian elephants.
