Disease relevance of SHBG

• RESULTS: No clear associations were found between the unadjusted levels of individual hormones or SHBG and the risk of prostate cancer [1].
• Furthermore, SHBG alleles within the general population contain at least 6-10 TAAAA repeats, and the transcriptional activity of a human SHBG promoter-luciferase reporter construct containing 6 TAAAA repeats was significantly lower than for similar reporter constructs containing 7-10 TAAAA repeats when tested in human HepG2 hepatoblastoma cells [2].
• Low SHBG levels may contribute to the menstrual disturbance seen in acromegaly in addition to any gonadotropin deficiency or hyperprolactinemia and may account for hirsutism in the presence of normal testosterone levels [3].
• However, the independent negative correlation between GH and SHBG levels suggests that GH may, directly or indirectly, lead to a fall in SHBG, possibly determined by the hyperinsulinemia known to occur in acromegaly [3].
• We investigated the prevalence of hypogonadism in type 2 diabetes by measuring serum total T, free T (FT), SHBG, LH, FSH, and prolactin (PRL) in 103 type 2 diabetes patients [4].
• Dietary isoflavones are thought to reduce breast cancer risk by stimulating circulating sex hormone-binding globulin (SHBG) levels [5].

Psychiatry related information on SHBG

• CONCLUSIONS: The high SHBG concentration observed in anorexia nervosa and kwashiorkor seems to be of multifactorial origin [6].
• After adjustment for age, body mass index (BMI), physical activity, alcohol consumption, and smoking, the bioavailable testosterone level (p = 0.03) was positively and the SHBG level (p < 0.001) was negatively associated with the logCRP level [7].
• After smoking cessation, statistically significant decreases of 25-hydroxyvitamin D and SHBG plasma levels were observed in men and women, respectively [8].
• Partial correlation coefficients (controlled for level of education) revealed significant associations of total T (r = -.52, p = -.009), SHBG (r - .59, p = .002) and IGF-1 (r = .54, p = .007) with the composite measure of fluid intelligence test performance, but not with crystallized intelligence, nor verbal long-term memory [9].
• Prolactin, sex hormone-binding globulin, testosterone, estradiol, progesterone, follicle-stimulating hormone, and luteinizing hormone levels; psychopathology; and side effects were measured [10].

High impact information on SHBG

• Furthermore, the Cnr phenotype results from a spontaneous epigenetic change in the SBP-box promoter [11].
• Using positional cloning and virus-induced gene silencing, here we demonstrate that an SBP-box (SQUAMOSA promoter binding protein-like) gene resides at the Cnr locus [11].
• We measured serum steroid hormones, insulin-like growth factor I, lipids, and sex hormone-binding globulin, and we evaluated well-being and sexuality with the use of validated psychological questionnaires and visual-analogue scales, respectively [12].
• RESULTS: Treatment with dehydroepiandrosterone raised the initially low serum concentrations of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and testosterone into the normal range; serum concentrations of sex hormone-binding globulin, total cholesterol, and high-density lipoprotein cholesterol decreased significantly [12].
• The pulse rate and serum sex hormone-binding globulin concentrations were slightly higher after treatment with thyroxine plus triiodothyronine, but blood pressure, serum lipid concentrations, and the results of neurophysiologic tests were similar after the two treatments [13].

Chemical compound and disease context of SHBG

• CONCLUSIONS: High levels of circulating testosterone and low levels of SHBG-both within normal endogenous ranges-are associated with increased risks of prostate cancer [1].
• Since hyperinsulinemia and hyperprolactinemia both occur in disease states in which low serum SHBG levels are found, the effects of insulin and PRL were compared to and/or studied in combination with estradiol (E2), T4, and testosterone (T) in a human hepatoma cell line (Hep G2) [14].
• Hyperinsulinemia, increased early insulin responses to glucose, increased glucose uptake rate in peripheral tissues, elevated free androgen indexes, and decreased SHBG and IGFBP-1 levels are present in most girls with PP from childhood [15].
• In the cross-sectional study plasma IGF-I, free and total testosterone, and SHBG levels were significantly lower in relation to the severity of sleep apnea, whereas plasma LH, FSH, PRL, T4, T4-binding globulin, and cortisol were not [16].
• Low SHBG indicated increased cardiovascular and coronary disease mortality; the association remained after adjustment for abnormal glucose tolerance, but not after adjustment for prevalent cardiovascular disease [17].

Biological context of SHBG

• This apparent size difference is due in part to differences in glycosylation of plasma and acrosomal SHBG isoforms [18].
• Little is known about SHBG gene expression in the human testis, but human SHBG transcripts accumulate in a spermatogenic stage-dependent manner in the testes of mice containing an 11-kb human SHBG transgene [18].
• Remarkably, these mice express the modified human SHBG transgene in the testis as well as the liver [19].
• This could influence the binding kinetics of 2-MeOE2 and/or facilitate ligand-dependent interactions between SHBG and other proteins [20].
• These two disparate functions of SHBG, regulation of the concentration of free steroids in plasma and signal transduction in selected tissues, raise the question of how its synthesis and secretion might be regulated so as to best perform these two disparate functions [21].

Anatomical context of SHBG

• In this paper we demonstrate that SHBG is produced in human prostate cancer cell lines (LNCaP, DU 145, and PC 3) as well as in cultured human prostate epithelial and stromal cells [21].
• These observations are consistent with the hypothesis that SHBG, destined to participate in signaling at the cell membrane, is locally regulated and produced [21].
• It is known that unliganded sex hormone-binding globulin (SHBG) binds to a receptor (RSHBG) on prostate membranes [22].
• In rodents, the SHBG gene is also expressed in Sertoli cells giving rise to the testicular androgen-binding protein, which is secreted into the seminiferous tubule where it presumably controls testosterone action [19].
• Plasma SHBG is produced by hepatocytes, but the human SHBG gene is also expressed in the testis [18].

Associations of SHBG with chemical compounds

• However, a strong correlation was observed between the levels of testosterone and SHBG (r = .55), and weaker correlations were detected between the levels of testosterone and the levels of both estradiol (r = .28) and DHT (r = .32) (all P < .001) [1].
• Immunoassays were used to measure the levels of total testosterone, dihydrotestosterone (DHT), 3 alpha-androstanediol glucuronide (AAG), estradiol, SHBG, and prolactin in the stored (at -82 degrees C) plasma samples [1].
• Plasma SHBG levels were highly correlated with plasma high-density lipoprotein cholesterol levels, which were also higher in vegetarians than in nonvegetarians [23].
• SHBG levels were 12% higher in parous women, but there was no difference in percentage of free E2 [24].
• In comparison with matched nonvegetarian women, postmenopausal vegetarian women were found to have lower urinary levels of estriol and total estrogens, lower plasma prolactin levels, and higher plasma sex hormone-binding globulin (SHBG) levels [23].
• First pass metabolism of orally administered oxandrolone may decrease hepatic synthesis of SHBG, allowing exogenously supplied testosterone to be excreted [25].

Physical interactions of SHBG

• A cDNA (912 nucleotides) coding for human plasma sex steroid-binding protein (SBP) was characterized from a phage clone previously isolated by screening a Charon 21A human liver cDNA library with rat androgen binding protein (ABP) cDNA [26].
• In the prostate, it has been suggested that the estradiol-activated SHBG/SHBG-R complex cross-talks with the androgen receptor, and is able to activate AR even in the absence of DHT [27].
• Addition of the 2-F diminishes ER and AFP-binding affinities while augmenting the affinity for the SHBG [28].
• Also, the DHEA, androstenedione, non-SHBG-bound testosterone and DHT levels were correlated with CD4 cell counts, showing that hypogonadism occurs as the CD4 lymphocytes decrease.(ABSTRACT TRUNCATED AT 250 WORDS)[29]
• OBJECTIVE: We studied the effects of ovarian electrocauterization on the serum levels of luteinizing hormone (LH), testosterone, insulin, sex hormone-binding globulin (SHBG) and insulin-like growth factor binding globulin-1 (IGFBP-1) in women with polycystic ovarian disease (PCOD) [30].

Regulatory relationships of SHBG

• We conclude that insulin and PRL inhibit SHBG production and confirm that T4, T, and E2 stimulate SHBG production in vitro [14].
• SHBG was less influenced by body mass index than IGFBP-1 [17].
• Higher tissue SHBG may activate the androgen receptor through cyclic adenosine monophosphate dependent pathways [31].
• We speculate that SHBG is regulated by adiponectin and that there is an inhibitory effect of testosterone on the adiponectin gene [32].
• It was postulated that IGF-1 and free testosterone may regulate SHBG synthesis [33].

Other interactions of SHBG

• Clinical response was assessed monthly together with serum sex hormone binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogens (E1, E2, and E1S), lipids, insulin-like growth factor-1 (IGF-1), and bone metabolites (CrossLaps CTx) [34].
• CONCLUSION: This study is the first to demonstrate that targeting the TNF pathway can significantly decrease Lp(a) and homocysteine levels and elevate Apo A-I and SHBG concentrations [35].
• Whether the action of the IGF/IGFBP system on bone metabolism is mediated partly through its effects on muscle mass or SHBG deserves further study [36].
• We conclude that high levels of some biochemical markers of bone turnover, low serum estradiol, low DHEA sulfate, high SHBG, and high PTH are associated with increased risk of osteoporotic fracture in postmenopausal women, independently of each other and of BMD [37].
• IGFBP-2 remained an independent negative predictor of BMD in men, postmenopausal women, and all women combined after additional adjustment for bioavailable sex steroids, but not at all sites after adjustment for SHBG and muscle mass [36].

Analytical, diagnostic and therapeutic context of SHBG

• Western blots of germ cell extracts from these transgenic mice and from human sperm indicate that the immunoreactive human SHBG in the acrosome composes electrophoretic variants, which are 3-5 kDa smaller than the major electrophoretic isoforms of human SHBG in the blood [18].
• In addition, in tissue sections of human prostate, we demonstrate the presence of SHBG (immunocytochemistry) and SHBG mRNA (in situ hybridization) [21].
• The calcium supplemented (n = 15; age 60.9 +/- 9.4 years, body mass index [BMI] 33.2 +/- 4.6 kg/m2) and placebo (n = 16; age 55.8 +/- 8.3 years, BMI 32.9 +/- 4.5 kg/m2) groups lost similar amounts of weight over the study interval (10.2 +/- 5.3% vs. 10.0 +/- 5.2%) and both groups increased SHBG (p < 0.001) [38].
• Although the relative abundance of the various SHBG-related mRNAs in the testis has not been established, Northern blot analysis indicates that they are similar in size (1.6 kb) to that of hepatic SHBG mRNA [39].
• Sequence analysis of the gene indicates that the complete coding region for the SHBG precursor is comprised of 8 exons, which are distributed over 3.2 kilobase (kb) of genomic DNA, and the unique 5' regions associated with the two SHBG-related testicular cDNAs were identified 1.9 kb upstream from the initiating codon for SHBG [39].

References