Sex Hormone-Binding Globulin Gene - Essay Example

Sex Hormone-Binding Globulin (SHBG) Gene. Sex hormone-binding globulin gene is a homodimeric protein coding gene mainly synthesized by liver cells. It functions as the main transporter of biologically active estrogens and androgens within the blood of all vertebrate species excluding the birds. The similar transcription unit which encodes plasma SHBG is also expressed in the testes of most mammalian organisms. In these species, the SHBG homologue widely referred to as the androgen binding protein (ABP) is produced and secreted by sertoli cells. This production and synthesis of ABP is usually under the influence of follicle stimulating hormone. Although the single human SHBG gene is expressed in the testis, human transcripts of this gene are confined to testicular germ cells. This gene encodes an amino-terminally truncated SHBG isoform which accumulates in the acrosome of sperm and subsequently binds to steroids in the same way as plasma SHBG. As a result of its high affinity and selective nature towards sex steroids, the concentration of SHBG in human blood is major determining factor of the quantity of free androgens and estrogens in target cells. Additionally, it is possible that SHBG in plasma within extracellular matrix of particular tissues may affect the biological activities of sex steroids at the target cell level. SHBG can also bind to a number of pharmaceutically manufactured steroids, xenobiotics and flavonoids. However, such interactions may have far-implicating effects in medicine an environmental toxicology. In clinical medicine, these associations are exemplified in areas of hormone-replacement therapy, diagnostic imaging of cancer and oral contraceptives (Xita & Tsatsoulis, 2010). In human beings, sex hormone-binding globulin (SHBG) is produced mainly in the liver under the influence of metabolic and hormonal factors. In the circulation, SHBG binds to androgens with high affinity and estrogens with a lower affinity and hence controls their access and action in target tissues. Sex hormone-binding globulin is also produced in other tissues such as the brain, placenta, endometrium and testis. The proper expression of SHBG by the placenta and fetal liver during growth may be significant in maintaining normal fetal exposures to androgens emanating from both the mother and the fetus itself. Consequently, differences in the levels of SHBG may influence sex steroid bioavailability and cellular effects with resultant clinical ramifications (Hammond & Bocchinfuso, 1995). Currently, it is known that synthesis of SHBG is under multifactorial control mechanisms including metabolic, hormonal and nutritional impacting on SHBG levels. Moreover, genetic predisposition may also contribute in the variation of the levels of SHBG. Not only therefore are environmental factors critical in SHBG level variation but also genetic factors come into play. Given the clinical importance of the SHBG gene, numerous studies have evaluated the potential link between polymorphisms of the SHBG gene and serum SHBG levels that can be relate to pathogenesis of several clinical conditions. As such, polymorphisms within the coding sequence and potentially within the regulatory sequence of SHBG gene which modulate production and metabolism of the protein is useful in genetic underpinning of its activity in humans (Xita, Tsatsoulis, Chatzikyriakidou & Georgiou, 2003). Structure of the SHBG gene The human SHBG is encoded by a 4-kb gene found within the short arm (p12-p13) of chromosome number 17. This vital gene possesses a total of eight exons. Exon number 1 contains the coding sequence for the SHBG secretion signal polypeptide. In addition, Exon 1 contains the first few amino-terminal residues of the mature secreted protein. Exons 2 to 8 code two flanking laminin-G domains. The N-terminal G sphere of the SHBG is responsible for the transport of steroids. However, the functional importance of C-terminal G domain of SHBG is not well elucidated. This domain usually contains two sites for N-glycosylation. There are two main SHBG transcripts that have been recognized, each emanating from different promoters. The first chief transcript codes a precursor for the secreted (plasma) form of SHBG and was initially reported in the liver tissue. The second principal transcript encodes a protein of unknown functionality which was originally described in the testis. The two transcripts show differences in their 5’ sequences and in the absence of exon 7 in the second transcript (Hammond & Bocchinfuso, 1995). SHBGL is the first transcript encoded in the liver and has eight exons ranging in size between 90 and 208 base pairs. Exceptional in this transcript is the 733 bp that separates exons 6 and 7, which probably contains alternative splicing regulatory elements. However, the remaining introns are relatively small in size ranging between 133 and 331 bp. This transcript is under the modulation of a TATA- less promoter that has multiple protein binding sites. These sites also include those for hepatocyte nuclear factor 4 and SP-1. The nascent SHBGL transcript codes a precursor protein containing a 29 amino acid, rich in lysine. The mature secreted form of SHBG in human plasma however lacks the lysine peptide and circulates as a glycosylated 92.5 kd homodimer possessing two steroid binding sites (Avvakumov, Cherkasov, Muller & Hammond, 2010). The other transcript, SHBGT is modulated by an uncharacterized promoter which lies upstream of the SHBGL promoter. The two transcripts show differences at the 5’ sequences and the absence of exon 7. The complete 5’ end sequence of SHBGT has not been reported, the incomplete sequence contains an initial, long open reading frame wherein the first ATG start coon does not appear until the shared exon 2. On the basis of current information, SHBGT would encode a truncated version of the secreted SHBG precursor with a different carboxyl terminus. This protein would probably be unstable as similar to 5’ en truncations of SHBGL code for unstable proteins. If stable, the SHBGT protein would most likely not bind steroids, although it would possess the domain known to contain the site of SHBG that binds to its receptor, (RSHBG) (Avvakumov, Cherkasov, Muller & Hammond, 2010). Cytogenic location: 17p 13-p12 Molecular location: chromosome 17; base pairs 7517382 to 7536700. The gene is located at the short arm of the chromosome 17. Official full name: sex hormone-binding globulin. Type of gene: protein coding gene. Occurrence organism: Homo sapiens. Other names: ABP, SBP, TEBG. (ncbi.nlm.nih.gov 2013). Fig. 1. Description of SHBG gene and location of polymorphisms. The SHBG receptor An active function for SHBG in steroid signaling was suggested initially by the discovery of specific, high-affinity binding sites for SHBG on human placenta, uterine endometrial cell membranes and isolated prostatic cell membranes. Consequently, SHBG binding was demonstrated in MCF-7 breast cancer cells normal breast and epididymis. The binding capabilities of SHBG are consistent with the presence of a definite RSHBG on the cell membrane. Primarily, RSHBG only binds steroid-free SHBG. All the steroids that attach to SHBG inhibit the interaction of SHBG to RSHBG. The extent of this inhibition is directly proportional to the magnitude of the interaction constant for the steroid SHBG association. Once attached, to RSHBG, SHBG bins steroids with affinities equal SHBG that is in solution. Despite the enormous knowledge about the receptor, RSHBG, its structural conformation remains an elusive case. A member of the low density lipoprotein (LDL) receptor gene family called Megalin has also been proposed as the SHBG receptor. Megalin enhances the endocytosis of SHBG-bound sex steroids into the target cell. A particular series of activities initiate signaling via the steroid receptor, RSHBG. These are exemplified by binding of unoccupied SHBG to RSHBG within the cell membrane, followed by steroid binding to the SHBG-RSHBG complex. This arrangement leads to activation of the complex which stimulates the synthesis of cyclic AMP (cAMP). Production of cyclic AMP at the cell membrane triggers downstream signaling and initiates genomic effects. It is able to achieve this through the activation of promoters possessing responsive elements. These occurrences happen at a rapid rate such that they cannot be affected either by dissociation of the SHBG-RSHBG complex through agonist binding. Additionally, transcriptional activation of classical steroid hormone receptors cannot reverse the sequence of events. Moreover, inhibitors of the transcriptional activation of the androgen and estrogen receptor do not affect the cyclic AMP response, hence depicting the independence of the pathway. RSHBG appears to be connected to a G-protein. There is a dose related reduction in the binding of SHBG to RSHBG following incubation with the non-hydrolyzable GTP, guanylyl-5’ imidodiphosphate. This phenomenon is characteristic behavior of receptors coupled to G-proteins (Rosner, Hryb, Khan, Nakhla & Romas, 1999). Steroids which bind to SHBG can either act as agonists or antagonist to the RSHBG mediate signaling. However, this particular attribute is also dependent on the cell type which acts as the target site. In the prostate, two steroids namely 5α-androstan-3α, 17β diol (3α-diol) and estradiol are potent steroids. Precise chromosomal abnormalities have not been linked with diseases characterized by low SHBG levels. However, the p12 segment of chromosome 17 is considered to be prone within the human genome containing numerous Alu sequences in the introns. These sequences have been associated as the mediators of chromosomal recombination events. Additionally, these sequences have been linked to alternative exon splicing. Genetic alterations manifested by mutations and single nucleotide polymorphisms (SNPs) of SHBG have been rarely established. Nonetheless, only a small number of nucleotide differences have been reported and established (Xita, Tsatsoulis, Chatzikyriakidou & Georgiou, 2003). The (TAAAA) n repeat polymorphism in SHBG promoter. The pentanucleotide (TAAAA) n repeat polymorphism has been recognize within the upstream region of human SHBG promoter within an Alu sequence. The numerical quantity of TAAAA repeats is highly variable and six alleles containing 6-11 TAAAA repeats have been reported. The distribution of the polymorphism is widely dispersed across populations. In employing short-lived transaction experiments in human hapatoblastoma (HepG2) cells, it was observed that transcriptional activity of the SHBG promoter was directly connected to the number of TAAAA repeats. However, this finding was not linear with respect to TAAAA duplicate number. A decrease in transcription level was observed to be linked particularly with the six TAAAA sequence. This finding was attributed to the preferential binding of a 46kDa liver enriched nuclear protein to six TAAAA duplicates. Accordingly, the allele containing six TAAAA repeats was found to possess a silencing effect on SHBG transcription (Xita, Tsatsoulis, Chatzikyriakidou & Georgiou, 2003). Single nucleotide polymorphisms of SHBG gene The earliest documented variation of SHBG was the 327N polymorphism. It is a missense single nucleotide polymorphism (SNP) (G>A) at nucleotide 5790, in exon 8 of SHBG and results in an amino-acid substitution of asparagines for aspatarte at residue 327 (rs6259). This polymorphism is dispersed widely throughout the world and at varied frequencies across ethnic groups. The D327N polymorphism is a functional polymorphism. This variance introduces an additional site for N-linked glycosylation within the carboxy-terminal globular laminin G-like chain. Studies of expression assays have indicated that this polymorphism does not influence the steroid binding properties. Functions of the SHBG gene Sex hormone-binding globulin is a protein produced mainly by the liver that binds to the sex steroids, testosterone, dihydrotestosterone and estradiol. It transports these steroids in circulation and influences their action in target tissues by controlling their bioavailability. SHBG consequently influences the expression of sex hormone susceptible phenotypes. Such phenotypic traits are exemplified by sexual characteristics and reproductive function in both women and men. In blood, human SHBG binds biologically active androgens and estrogens with high affinity. The plasma concentrations of SHBG play a critical role in modulating the bioavailability of these steroids between the protein-bound and non protein-bound fractions. The steroid which has the greatest binding affinity for plasma SHBG is dihydrotestosterone (DHT). This is followed by testosterone and finally by estradiol in that order in terms of affinity. For the most appropriate binding to occur, there has to be an electronegative group at the C-3 terminal in the planar C-19. Additionally, there is the need for a 17β-hyroxyl group. The existing bond between testosterone and SHBG as well as that of dihydrotestosterone and SHBG is similar to that of androgen receptor-ligand. The SHBG has no affinity for numerous antiestrogens exemplified by cyproterone and antiandrogens such as tamoxifen. The presence of SHBG in blood plasma in human has been described as that with a high androgen affinity and a low estradiol capacity. As a result, the gene is presumed to play a significant role in the control and metabolic clearance of the two steroids. According to Burke an Anderson (2002), the higher affinity of SHBG to testosterone compared to estradiol makes it a possible gene target in elevating estrogen in women. Sex hormone-binding globulin has also been reported to play a role in the movement of sex steroids to target tissues. This is manifested with the affinity between estradiol and SHBG which occurs within the cell membranes o the endometrium. Numerous SHBG receptors are also found on a number of tissues which rely on sex steroids. These tissues are exemplified by those of prostate and testis. Signaling Pathways affected by SHBG SHBG affects numerous cellular processes by activating and inactivating signaling pathways. These are exemplified by epidermal growth factor-R (EGF-R), MAPK, PDGF and PI3K. Insulin plays a significant role as a growth factor in addition to being primarily involved in the modulation of lipid, carbohydrate and protein metabolism. As a growth factor it stimulates migration and cell mitosis as well as inhibiting apoptosis, effects which can be elevated. Conditions of insulin resistance and consequent defects of insulin regulated metabolic pathways. Generally, the metabolic effects of insulin such as transport of glucose are mediated through the phosphatidylinositol-3-kinase (PI3K). The mitogenic effects of insulin involve the activation of Ras and the mitogen-activated protein kinase (MAPK). When insulin resistance exemplified by hyperinsulinemia is present, the capacity for induction of the P13K pathway is lost. Conversely, there is enhance activation of MAPK and elevation in insulin induced prenylation of Ras protein. Specific insulin receptors (IR) are present on the surface of most cells. Amplification of insulin receptors tyrosine kinase leads to rapid phosphorylation of several proteins including Shc adaptor protein 1 an members of the insulin receptor substrate (IRS) (Rosner, Hryb, Khan, Nakhla & Romas, 1999). EGF-R-derived signalling pathway By inhibiting estradiol induction of EGF-R, a member of the epidermal growth factor family of trans-membrane receptors, SHBG affects this important pathway. Overexpression of the epidermal growth factor- R in breast cancer, is probably induced by estradiol, a negative prognostic factor. Through this cascade, the estradiol molecules promote the activation of the EGF-R signalling pathway. This effect in consequence has the effect of amplifying breast cancer. Health conditions related to SHBG The sex hormone binding globulin has been implicated in a number of chronic, metabolic and hormone dependent illnesses. These include obesity, diabetes, hirsutism, polycystic ovary syndrome, breast and prostate cancer Polycystic Ovary Syndrome. Polycystic ovary syndrome is a familiar disorder of the endocrine system affecting women in reproductive age, and is exemplified by hyperandrogenism and anovulation. PCOS is also linked with metabolic abnormalities manifested by central adiposity, hyperinsulinism an insulin resistance. Polycystic ovary syndrome is a sophisticated disorder, with whose etiology remains elusive. However, more significant evidence is emanating linking its origin to genetic contribution. There are two prepositions which have been put forward to explain the pathogenesis of PCOS. The first hypothesis relates to the dysregulation of steroidogenic enzymes involved in adrenal or ovarian synthesis of androgen. The second proposition involves deficiencies responsible for insulin resistance and hyperinsulinemia which in essence increases hyperandrogenism. Recently, a merging linear representation base on developmental etiology proposition has been suggested. In this hypothesis, the phenotype of PCOS can arise due to genetically determined exposure to androgen excess at fetal stage (Rosner, Hryb, Khan, Nakhla & Romas, 1999). Consequently, this exposure programs the hypothalamic pituitary unit in favor of luteinizing hormone (LH) secretion. This has the effect of contributing towards the development of abnormal obesity that predisposes the individual to insulin resistance. At the promoter of the SHBG gene is the (TAAAA) n pentanucleotide repeat which has been shown to affect transcription of the gene. There has been a proposition that the polymorphism in functionality has a probable involvement to individuals’ diversities in the level of plasma SHBG. Therefore, overall, this has the effect of influencing the access to target sites. Another characteristic of PCOS is the general increase in the plasma concentrations luteinizing hormone both at increased pulse frequency and amplitude. The observed upsurge in the level of serum LH probably leads to a promotion of ovarian theca interstitial cell steroidogenesis. Evidence based on genetic analyses of PCOS is very broad. However, it still remains inadequate in terms of the understanding the pathogenesis of the syndrome. Molecular defects in gonadotrophins and the receptors in enzymes involved in steroidogenesis have been examined tremendously. Additionally, their basic secretion pathways as well insulin action have investigated but with inconsistent results (Xita, Tsatsoulis, Chatzikyriakidou & Georgiou, 2003). Hyperandrogenism The main source of hyperandrogenism in PCOS is the ovary. An excess of the androgens interferes with the process of selection of the primary ovarian follicle. The biosynthesis of androgen within the human ovary takes place in the thecal interstitial cells, TIC; and their activity in PCOS is excessive. The elevated activity in the steroid manufacturing pathway of thecal cells results in hyperandrogenism. The increases activity is inherent to the thecal cells because it carries on manifold relay passages of thecal cell cultures in vitro. Patients with PCOS have ovarian thecal cells that convert steroid precursors into testosterone in a more efficient manner compared to thecal cells in normal patients. A number of findings point out that the elevated production of testosterone in PCOS thecal cells is not necessarily due to dysregulation of androgenic 17 HSD activity, but by an increase in precursors synthesis. As it has been reported, PCOS patients have clinical and biological hyperandrogenism, with androgen circulating levels considerably high compared to non-PCOS individuals. PCOS, a reproductive and metabolic disease has been identified as a complex mutagenic nature with environmental features (Rosner, Hryb, Khan, Nakhla & Romas, 1999). Type 2 Diabetes Both cross-sectional studies and prospective analyses have reported a link between low serum SHBG quantities and increased risk of type 2 diabetes development. Of these, 23 cross-sectional analysis as well as 10 prospective studies were included in a 2006 systematic review and meta-analysis. These studies reported higher levels of SHBG was connected to lower risk of type 2 diabetes development. This relationship was stronger among postmenopausal women compare to men. Furthermore, genetic studies using Mendelian randomization principle have supported the observation. Such studies indicate that the development of type 2 diabetes is dependent on the SHBG genotype. Sufficient epidemiological proof shows that there is a correlation between development of type 2 diabetes and low serum SHBG levels. Genetic studies show that there is a link between three single nucleotide polymorphisms (SNPs), incidence of type 2 diabetes and SHBG concentration. The three single nucleotide polymorphisms are rs6257, rs6259 and rs1799941. However, the defects in insulin synthesis and insulin resistance are involved in type 2 diabetes pathogenesis. Therefore, the link between SHBG with this metabolic disease suggests a correlation with insulin resistance. SHBG levels are inversely related with glycated hemoglobin in both women and men without diabetes. Hence this suggests a relationship between SHBG and glucose homeostasis before the development of diabetes. SHBG levels are reduced among women with polycystic ovary syndrome, an insulin resistant disorder with an elevated risk of diabetes development. However, this relation is partly attributed to the characteristic hyperandrogenism exhibited in PCOS. Low testosterone levels are associated with a higher incidence of developing type 2 diabetes in men. Conversely, low concentrations of estrogen lead to increase risk of developing type 2 diabetes in women. Elevated levels of estradiol in both genders increase the risk of developing type 2 diabetes (Wallace, McKinley, Bell & Hunter, 2013). Breast cancer The human serum sex hormone-binding globulin (SHBG) plays a vital role in the pathogenesis of breast cancer. Additionally, SHBG plays a crucial role in risk definition because it modulates the bioavailable fraction of circulating estradiol. Various studies have showed the connection of sex hormone and sex hormone-binding globulin levels in women in relation to breast cancer risk. SHBG is one of the factors able to regulate estrogen balance. It has been observed that there is a correlation between serum SHBG levels and estrogen receptor (ER) in postmenopausal breast cancer patients. It has been documented that Megalin, an endocytic receptor in the reproductive tissues advance the cellular uptake of biologically active androgens and estrogens. Within the endometrium, SHBG binds the carboxyl-terminal chains of fibulin-1D and fibulin-2 in a steroid dependent fashion. In this association, estradiol becomes the most effective ligand. Additionally, SHBG co-immunoprecipitates with these fibulins within the uterine tract. This indicates that these matrix connected proteins sequester plasma SHBG and regulate sex steroid access to target cells (Fortunati, Catalano, Boccuzzi & Frairia, 2010). The laminin-G domain of SHBG is the most conserved portion of this molecule. The structural stability of the O-glycosylation site in the Thr7 of the SHBG laminin-G chain is vital for significant biological effects observed in breast cancer cells. Numerous reports show that the association of SHBG and breast cancer cell membranes is closely related to cell sensitivity to estrogens. The binding sites for SHBG have been elaborated in MCF-7 breast cancer cells, which are positive for the estrogen receptor-α (ER- α). The interaction of SHBG to MCF-7 cell membranes generates a cascade of signals; the first event being reported is the elevation in concentration of cyclic AMP. Estradiol has been shown to inhibit estrogen-dependent cell growth. Estradiol stimulates and maintains the proliferation of breast cancer cells. Via its nuclear receptor ER-α, estradiol modulate the transcription and expression of many genes that take part in cell growth, including positive regulators of cell proliferation. Conversely, it inhibits the negative regulators. Furthermore, by binding to the membrane receptor, it activates ERK and inhibits Jun kinase. Consequently, this leads to initiation of the bcl-2 and hence the inhibition of apoptosis in MCF-7 breast cancer cells (Fortunati, Catalano, Boccuzzi & Frairia, 2010). The antiproliferative impact of SHBG is detectable when the appropriate sequence of binding is followed. Thus SHBG first binds to its membrane receptor on MCF-7 cells an then estradiol attaches at the steroid binding site of SHBG. SHBG is effective on a small number of genes most of which are involve in apoptosis control, cell growth and cell estrogen dependence. Specifically, SHBG inhibits estradiol up-regulation of c-myc, PR, EGF-R and bcl-2 and its down regulation of the ER-α receptors. The effect of SHBG on expression of genes is highly selective but dependent on its association with the cells. This effect is also only restricted to genes linked to estrogen sensitivity and cell growth. Some nucleotide variations in the human SHBG gene have been documented in both regulatory and coding sequences. The Asp327Asn polymorphism has been widely assessed in relationship to breast cancer (Fortunati, Catalano, Boccuzzi & Frairia, 2010). Prostate cancer A downstream occurrence of potential biologic importance is the intersection of the SHBG signaling pathway with an androgen receptor (AR)-mediated event. Such an event leads to triggering of the prostate specific antigen gene and secretion of its translational product. The human prostate specific gene possesses an androgen response element in its promoter. It undergoes transcription upon stimulation of the androgen receptor within the prostate cells. When treated with DHT, prostate explants secrete PSA . Conversely, when treated with estradiol which does not bind to androgen receptor, the prostate explants do not secrete PSA. Additionally, inhibitors of estrogen receptor stimulation do not block estradiol-SHBG-RSHBG mediated PSA secretion. In contrast, inhibitors of androgen receptors mediate PSA induction. These results suggest that estradiol-SHBG-RSHBG initiates independently ligand stimulation of PSA secretion (Fortunati, Catalano, Boccuzzi & Frairia, 2010). Obesity Obesity can be defined as a medical in which there is excessive accumulation of fats within the body that can eventually have adverse effects leading to conditions of heart and other metabolic syndromes. There is substantial heterogeneity in the outcome of studies investigating the link between SHBG variants with serum SHBG levels and their possible role in development of common diseases. Recently, four genetic variants have been identified and all have been indicated to be having single nucleotide polymorphisms. Despite the SHBG SNPs variables being associated with type 2 diabetes, they do not seem to be linked to PCOS. Genotypes rs727428 and rs799941 have been connected with SHBG levels free of the influence caused by obesity and insulin resistance (Goto, Morita, Goto, Sasaki, Miyachi, Aiba, et al. 2012). Hirsutism Idiopathic hirsutism is another immunological condition related to polymorphisms in the SHBG gene. An mspI restriction fragment polymorphism has been described having an allele frequency of 0.04 in French-Canadian population. This polymorphism codes for a missense mutation, the P156L located at exon number 4/ introns number 4 boundary. This mutation allows normal steroid ligand binding although it causes defective glycosylation and deficient secretion of SHBG. The combination of this polymorphism with a single nucleotide deletion in exon 8 leads to production of an open reading frame shift within codon E326 (Coviello, et al. 2012). Infertility Genes involved in estrogenic activities are expressed in different tissues of male reproductive organs. Estrogen receptor α, aromatase, as well as estrogen receptor β are expressed within the testicular cells of both humans and animal models. The knockout of estrogen receptor since puberty and the phenotype of testicular tissue have indicated an atrophy of the testes and seminiferous tubule dysfunction. As a result of this dysmorphogenesis, there is reduction in sperm motility and spermatogenesis. Additionally, estrogen may also play a role in balancing luminal fluid in epididymis. In serum, majority of the estradiol reversibly binds to sex hormone binding globulin (SHBG). Polymorphisms of SHBG have been widely reported and associated with elevated SHBG and free e2 among postmenopausal women. However, the relationship between SHBG level and sex hormone quantities in men has been controversial. in a specific study, higher SHBG level were linked to lower levels of non-SHBG bound estradiol but slightly elevated levels of non-SHBG bound testosterone in eugonadal men. In another assessment, SHBG levels were depicted to barely affect level of non-SHBG bound testosterone both in adults and male newborns (Damassa, & Cates, 1995). Therefore, the association of SHBG genotypes among males has not been clear. Probably, SHBG genotypes are linked to changes in SHBG level. Essentially, this has the effect of increasing o decreasing the accessibility of estrogens and androgens to the testis. Nonetheless, the testicular effect of SHBG can be complicated by taking into account the potential intracrine effect of SHBG. This is because within the sperm, there are various SHBG isofoms. Intratesticular testosterone has been postulated to play a vital role in modulating spermatogenesis. Two single nucleotide polymorphisms within the SHBG gene have been linked with spermatogenic effects. These are exemplified by rs1799941 and rs6259 and confer susceptibility at the prereceptor, receptor an post receptor levels. Hypothyroidism Thyroid hormone promotes the synthesis of plasma sex hormone binding globulin indirectly bu increasing HNF-4 α levels in the liver. Consequently, in hypothyroid patients, the SHBG levels are general low compared to patients with hyperthyroidism. SHBG becomes a useful biomarker in assessing the thyroid status of patients (Coviello, et al. 2012). Consequently, during diagnosis, the failure of thyroid hormone treatment in eliciting a rapid and robust amplification of SHBG levels is enough to identify such patients with peripheral resistance to thyroid hormone. Hypogonadism SHBG is able to bind to testosterone with high affinity and is concerned with the modulation of free testosterone’s active fraction. This can be attributed to two major factors which slow down the hepatic synthesis of the protein. First, is that the hyperinsulinemia with SHBG is an indication of insulin resistance. Secondly, is the effect of hyperandrogenism (Coviello, et al. 2012). References Avvakumov, G., Cherkasov, A., Muller, Y., & Hammond, G. (2010). Structural analyses of sex hormone- binding globulin reveal novel ligands and function. Molecular and Cellular Endocrinology , 13-23. Coviello, A. D. et al. (2012). A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone– Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation. PLoS Genetics , 1-12. Damassa, D., & Cates, J. (1995). Sex Hormone-Binding Globulin and Male Sexual Development. Neuroscience and Biobehavioral Reviews , 165-175. Fortunati, N., Catalano, M., Boccuzzi, G., & Frairia, R. (2010). Sex Hormone-Binding Globulin (SHBG), estradiol and breast cancer. Molecular and Cellular Endocrinology , 86-92. Goto, A., Morita, A., Goto, M., Sasaki, S., Miyachi, M., Aiba, N., et al. (2012). Associations of sex hormone-binding globulin and testosterone with diabetes among men and women (the Saku Diabetes study): a case control study. Cardiovascular Diabetology , 1-9. Hammond, G., & Bocchinfuso, W. (1995). Sex Hormone-binding Globulin/Androgen-binding Protein: Steroid-binding and Dimerization Domains. Journal of Steroid Biochemistry and Molecular Biology , 543-552. Kahn, S., Hryb, D., Nakhla, A., Romas, N., & Rosner, W. (2002). Sex hormone-binding globulin is synthesized in target cells. Journal of Endocrinology , 113-120. Rosner, W., Hryb, D., Khan, S., Nakhla, A., & Romas, N. (1999). Sex hormone-binding globulin mediates steroid hormone signal transduction at the plasma membrane. Journal of Steroid Biochemistry and Molecular Biology , 481-485. Wallace, I., McKinley, M., Bell, P., & Hunter, S. (2013). Sex hormone binding globulin and insulin resistance. Clinical Endocrinology , 321-329. Xita, N., & Tsatsoulis, A. (2010). Genetic variants of sex hormone-binding globulin and their biological consequences. Molecular and Cellular Endocrinology , 60-65. (Rosner, Hryb, Khan, Nakhla & Romas, 1999). Xita, N., Tsatsoulis, A., Chatzikyriakidou, A., & Georgiou, I. (2003). Association of the (TAAAA)n Repeat Polymorphism in the Sex Hormone-Binding Globulin (SHBG) Gene with Polycystic Ovary Syndrome and Relation to SHBG Serum Levels. 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