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Thread: Understanding SHBG

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    Exclamation Understanding SHBG

    Understanding SHBG


    Recently, I have felt inclined to say a few words in defense of the misunderstood and often-maligned hormone, SHBG. Yes, SHBG is not merely a binding glycoprotein, but actually a hormone in its own right, with its own receptor. More about that later, let's start by reviewing some basic known facts about SHBG. SHBG is often mischaracterized as a compound that binds to sex hormones, like Testosterone (and estradiol), and “deactivates” them, rendering them useless. Nothing could be farther from the truth. While most systemic sex hormones are in bound form, this does not destroy them. Free-Testosterone has a very short active half-life; it is very quickly, within a matter of minutes, eliminated from the body. SHBG preserves sex hormones, and regulates their access to target tissues in diverse parts of the body, so they can work better. This is the exact opposite of what most people seem to think. As we shall see, SHBG can even enable sex hormone signal transduction at the cellular membrane enabling sex hormones to function without binding to the AR (androgen receptor), and without even entering the target cell.


    The free hormone hypothesis states that only free lipophilic hormones are able to diffuse across the cellular membrane and bind to their intracellular receptors, and that protein-bound hormones are therefore “inactive,” unable to bind their receptors. However, research has shown that this is not the case. Lipophilic hormones (including retinols, thyroid hormones, vitamin D, and steroids) do not merely diffuse passively across the cellular membrane. They are actively transported, in bound form thru an endocytotic process. The transport protein megalin appears to play an important role in this process.


    Few Things in Life are “Free”: Cellular Uptake of Steroid Hormones by an Active Transport Mechanism


    Conventional dogma holds that steroid hormones traverse cell membranes passively, owing to their lipophilic nature. The recently characterized protein megalin, however, functions as a transport protein on cell surfaces to carry steroids across the plasma membrane. Upon hydrolysis of steroid-associated binding globulins in lysosomes, free hormone is liberated and may exert its effects in the cell. Megalin-independent mechanisms of steroid uptake are likely important too, as the phenotypes of megalin-deficient mice do not completely mimic the phenotypes of androgen receptor– or Estrogen receptor–null mice.


    steroid hormones participate in the regulation of normal vertebrate homeostasis, development, and reproduction. The best understood mechanism of steroid action is for these signaling molecules to enter target cells and bind to their cognate intracellular receptors that, subsequently, regulate the transcription of corresponding steroid responsive genes. Defects in these signaling pathways can lead to a variety of endocrine and neoplastic disorders. Most circulating steroids are bound to carrier proteins that deliver these hormones to their target cells. Upon reaching their destination, steroids are released and, by virtue of their small size and lipophilic nature, are believed to traverse the plasma membrane by free diffusion to carry out their regulatory effects inside the cell. Thus, the free hormone hypothesis states that the biological activity of a particular hormone is only affected by its free (protein unbound) concentration, rather than its protein-bound concentration in plasma (1).


    Recent findings refute the long-held notion that lipophilic hormones, such as androgens and estrogens, solely diffuse into cells by a free, non-specific mechanism. Megalin (2, 3), a member of the low density lipoprotein receptor superfamily of endocytic proteins, has been identified as an important facilitator of steroid entry into cells. Previous work by Nykjaer and colleagues (4) has demonstrated the existence of megalin-dependent endocytic pathways for tissue specific uptake of complexed vitamin D [i.e., 25-(OH) vitamin D3 bound to vitamin D binding protein (DBP)], suggesting that megalin may be important in maintaining steroid hormone balance in mammals. Specifically, they demonstrated that megalin knockout (KO) mice were unable to resorb the vitamin into the epithelial cells of the renal proximal tubules, where the receptor is normally expressed. As a result, these megalin-null animals developed bone calcification defects, likely owing to the inability of 25-(OH) vitamin D3 to be converted to the active vitamin D receptor ligand, 1,25-(OH)2 vitamin D3. Physiologically, this megalin-mediated pathway is very appealing, given that the overwhelming majority of plasma 25-(OH) vitamin D3 is found in complex with DBP, with only a very small percentage of the metabolite existing in the free form (5).


    In addition to the renal proximal tubules, megalin is expressed in a variety of other tissues, including ones that are steroid responsive. Notably, this endocytic receptor has been found in both male and female reproductive organs (i.e., epididymis, prostate, ovaries, and uterus) (6). Given the tissue distribution of megalin and its proposed role in cellular uptake of vitamin D, Hammes et al. (7) hypothesized that this endocytic receptor may also be important for the cellular delivery of sex steroids. This group has recently presented convincing evidence that androgens and estrogens in complex with their carrier protein, the sex hormone binding globulin (SHBG), are endocytosed in cultured cells expressing megalin. The presence of accessible megalin appears to be necessary for optimal internalization of these steroid-SHBG complexes, as evidenced by the reduced levels of uptake observed when receptor-associated protein (RAP, an antagonist of ligand binding to megalin) or megalin-specific antiserum was added, or in cells that lack megalin expression. Furthermore, transcriptional activation (the hallmark of intracellular steroid action) of an androgen-sensitive reporter was observed when androgen-SHBG complexes were added to megalin-expressing cells in vitro; this activity was also inhibited by the addition of RAP. Finally, the most striking evidence supporting a role for megalin in proper sex steroid uptake and signaling came from in vivo studies of megalin KO mice. Males lacking megalin showed impaired descent of the testes whereas megalin-deficient females exhibited abnormalities in vaginal development––both defects being consistent with insensitivity to androgens and estrogens, respectively. Hence, as is the case for megalin involvement with vitamin D3, there seems to be significant physiological relevance for megalin in the cellular uptake of sex steroids. Depending on the steroid, the majority of metabolites of certain steroids can be found in complex with their corresponding binding proteins (8). Thus, free diffusion of these molecules may not play as important a role in delivery, especially in tissues that require large amounts of steroid hormones.


    Despite the intriguing findings regarding the proposed role of megalin in the endocytosis of steroid hormones, it is certainly worth noting that megalin-null mice are not phenotypic replicas of mice that lack the androgen or Estrogen receptor (9). These observations suggest that megalin-independent mechanisms must also exist for the sex steroids to carry out their effects. Thyroid hormone (another small, lipophilic molecule) was also traditionally believed to enter target cells by passive diffusion; however, thyroid hormone can be actively transported into target cells via the monocarboxylate transporter MCT8 (10). It is not unreasonable to think that a similar mode of transport may occur for the sex steroid hormones.


    The identification of endocytic pathways for estrogens and androgens could have potentially important therapeutic implications, given the existence of breast and prostate tumors that are dependent on their respective sex steroids for growth and proliferation. If megalin is indeed the primary mediator for the uptake of these steroid hormones in pathological settings, drugs that target this endocytic receptor could help to block the supply of these molecules to cancer cells, and serve as an alternative or cooperative treatment to currently existing therapies (e.g., Estrogen antagonists and biosynthesis inhibitors in the case of breast cancer) (Figure 1). There are many questions, however, that must first be addressed regarding the role of megalin in tumor biology. For example, do tumor cells that are androgen- or Estrogen-dependent overexpress megalin at the plasma membrane, relative to their normal counterparts? What is the precise megalin binding site for the steroid-SHBG complex and is this site distinct for androgens versus estrogens? Given that megalin acts as a promiscuous receptor for a wide variety of ligands (e.g., vitamin and steroid–binding protein complexes, lipoproteins, enzymes, drugs, toxins, etc.), how is specificity of endocytosis achieved? More importantly, from a drug development standpoint, how might antagonism and target tissue specificity be achieved such that uptake of other endogenous megalin ligands (e.g. vitamin D3 in the kidneys) and normal physiological processes are minimally affected? Although megalin may be a promising new target for cancer therapy, much target validation work remains to be done.


    In conclusion, the findings presented by Hammes et al. (7) demonstrate that megalin has a potentially significant role in sexual and reproductive development in mice. This active transport mechanism is particularly interesting, and perhaps important, regarding: 1) the proper function of tissues that require large amounts of steroids or, 2) the pathophysiological processes involved in steroid-dependent tumors. In these two examples, passive diffusion alone would be unlikely to deliver the necessary amounts of steroids to propagate their effects in target cells. Thus, the identification of megalin as an endocytic receptor for the cellular uptake of sex steroids represents a novel paradigm for a physiological role of these carrier bound molecules and should be factored into future steroid hormone biology research. See also:
    Role of endocytosis in cellular uptake of sex steroids.
    "Bound" to work: the free hormone hypothesis revisited.
    Cellular uptake of steroid carrier proteins--mechanisms and implications.


    What are some facts we know about systemic SHBG?
    Systemic (found in serum) SHBG is produced in the liver. Its production was once thought to be reduced by insulin due to the observed inverse relationship between SHBG and insulin levels in obese and other persons with metabolic syndrome. However, we now know that insulin levels have no effect on SHBG. The effect seems to be the other way around; SHBG improves insulin sensitivity, decreasing both glucose and insulin levels. In fact, low serum SHBG level is an independent risk factor for fatty liver disease, insulin resistance, diabetes, cardiovascular disease, as well as other metabolic and degenerative conditions. SHBG is not the enemy. The importance of adequate SHBG levels in maintaining healthful metabolic function throughout the body has been well established. See references, below.
    What can we do to maintain healthful levels of this important hormone?
    Thyroid hormones are known to increase SHBG by increasing expression of the transcription factor, NF4alpha. On the other hand, sugars and high-glycemic foods are known to decrease hepatic SHBG. They do this because sugar consumption promotes hepatic lipogenesis (fat production) which reduces the availability of NF4alpha. Hence, two important steps we can take to maintain healthful systemic SHBG levels are reduce intake of high-glycemic foods, and monitor thyroid function to ensure optimal thyroid hormone levels.
    References:
    Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4?
    Sex hormone-binding globulin gene expres... [Mol Cell Endocrinol. 2010] - PubMed - NCBI
    Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone?binding globulin gene
    Relationships of Circulating Sex Hormone?Binding Globulin With Metabolic Traits in Humans
    Association of Testosterone and Sex Hormone?Binding Globulin With Metabolic Syndrome and Insulin Resistance in Men
    Testosterone Concentrations in Diabetic and Nondiabetic Obese Men
    http://www.revespcardiol.org/sites/d...6166pdf001.pdf
    Sex Hormone?Binding Globulin and Risk of Type 2 Diabetes in Women and Men
    MMS: Error
    http://www.revespcardiol.org/sites/d...6162pdf001.pdf
    Serum sex hormone-binding globulin, a determinant... [Metabolism. 2007] - PubMed - NCBI
    Too Much Sugar Turns Off Gene That Controls Effects Of Sex Steroids -- ScienceDaily

    Is SHBG produced anywhere else in the body?
    Although the liver is the source of systemic SHBG, it is also expressed in other tissues including the prostate, testes, and even the brain.
    SHBG is produced locally in the testes by the Sertoli cells, and is necessary for fertility. By binding to Testosterone and DHT, SHBG makes them less lipophilic (fat-soluble), which increases their concentration within the seminiferous tubules where spermatogenesis takes place. Clearly SHBG serves to amplify the local effects androgens necessary for fertility; it in no way neutralizes their bioactivity.


    The prostate is one area where SHBG dysfunction can lead to problems. First, let me make one thing clear: Systemic SHBG and androgen levels have no relationship to levels in the prostate. So, the next time your physician tells you that you should not use androgen replacement therapy because it causes prostate cancer, show him this study: An Error Occurred Setting Your User Cookie
    Conclusions: Robust supraphysiologic increases in serum DHT do not significantly alter intraprostatic levels of DHT, Testosterone, or prostate epithelial cell androgen–regulated gene expression in healthy men. Changes in circulating androgen concentrations are not necessarily mimicked within the prostate microenvironment, a finding with implications for understanding the impact of androgen therapies in men.
    The same is true for SHBG, see: Sex Hormone-binding Globulin in the Human Prostate Is Locally Synthesized and May Act as an Autocrine/Paracrine Effector
    These hormones are produced locally and have localized paracrine/autocrine effects. Increasing or decreasing systemic levels of these hormones will not necessarily have any effect on their local expression and activity, just as local expression does not affect systemic levels. Prostate cells in addition to androgen receptors, also have SHBG receptors. Not only does this allow SHBG to directly affect prostate tissues, but it allows other sex hormones such as Estrogen and DHT to affect transcriptional changes within the cell, without entering the cell, and without binding to the androgen receptors. Instead they bind to the SHBG-receptor complex on the cell membrane. This can result in activation of adenylyl cyclase, generating cAMP, possibly leading benign hyperplasia, or even cancer. This also explains how Estrogen can have androgenic effects on prostate tissue without activating the androgen receptor.

    There are several observations suggesting that SHBG mediates the signal leading to the activation
    of a second messenger system. Firstly, antiestrogens do not block the response, which would be
    the case if it was mediated through intracellular Estrogen receptor. Secondly, diethylstilbestrol
    (DES), a potent Estrogen that does not bind to SHBG, fails to mimic the effects of estradiol.
    Thirdly, DHT, which has a significantly higher affinity for SHBG than estradiol, blocks the
    response probably by displacing the bound estradiol from SHBG. Thus, BPH tissue requires
    estradiol for the activation of the secondary messenger system, as opposed to LNCaP cells,
    which respond to both estrogens and androgens (Nakhla et al., 1990, 1994).
    More detailed study of the SHBG receptor-mediated signaling system in prostate tissue suggested
    that estradiol could, through SHBG, activate AR via a ligand-independent mechanism.
    DHT stimulates the secretion of prostate specific antigen (PSA) by prostate tissue through
    classical transcriptional activation mediated by AR (Riegman et al., 1991; Lee et al., 1995;
    Henttu et al., 1992). Similar stimulation is achieved by estradiol in the presence of SHBG. As
    with DHT alone, the estradiol-SHBG mediated stimulation is inhibited by antiandrogens, but
    not by antiestrogens, which suggests that Estrogen receptor (ER) does not mediate this response
    (Nakhla et al., 1997). SHBG can also mediate the regulation of cell growth by estrogens and
    androgens. DHT and estradiol stimulate, in the presence of SHBG, the growth of prostate carcinoma
    cells, and this increased cell proliferation is associated with elevated cAMP levels inside the cell
    (Nakhla and Rosner, 1996). By contrast, Estrogen induced growth of MCF-7 breast cancer cells is
    inhibited by SHBG (Fortunati et al., 1996). The reduction in growth rate is accompanied by intracellular
    cAMP accumulation, which is absolutely dependent on both estradiol and SHBG. Therefore, it
    seems unlikely that SHBG simply sequesters estradiol and restricts its availability to cells, but
    may actually transmit the growth inhibitory signal to the cell nucleus.”


    Undoubtedly, future research will expand our understanding of the role of SHBG in prostate enlargement and cancer. SHBG research seems to have been neglected. I was very surprised at what little information I could find. I am certain that SHBG plays a much more important role in the regulation of the effects of sex hormones, including anabolic effects, than is currently known. It has been suggested that Estrogen might have similar androgenic effects in muscle tissue, via the SHBG-receptor. We know that muscle tissues also have SHBG-receptors, so it is clear the SHBG does something to muscle cells by binding to this receptor. Without a doubt, SHBG is much more than a mere binding protein.


    References
    Sex hormone-binding globu... [J Steroid Biochem Mol Biol. 1999 Apr-Jun] - PubMed - NCBI
    http://www.eaumilan2008.org/typo3con.../962-Romas.pdf
    Interactions of sex hormone-binding globulin with target cells


    Does SHBG affect the brain?
    Besides their effects on the pituitary and hypothalamus, sex steroids are well known to have many neuroactive effects. In addition to receptor-mediated changes in transcriptional activity within neurons, they can directly modulate the effects of neurotransmitters. We also now know that SHBG is taken up into neurons in the brain:
    Abstract
    Background: Sex hormone-binding globulin (SHBG) is a 94-kDa homodimer that binds steroids and is made in the hypothalamus. We have demonstrated that infusions of SHBG into the hypothalami of rats increase their female sexual receptivity except when SHBG is coupled to dihydrotestosterone (DHT) suggesting that SHBG has an active function in behavioral neuroendocrinology. Methods: This study examines the possibility that SHBG is internalized by neuronal and/or non-neuronal brain cells as one possible mode of action using in vitro and in vivo techniques. Results: First, analysis of the uptake of radiolabeled SHBG (125I-SHBG) found 125I-SHBG uptake in HT22 hippocampal cells stably transfected with cDNA for ERβ (HT22-ERβ). The addition of DHT to 125I-SHBG significantly inhibited 125I-SHBG uptake in HT22-ERβ cells but not in HT22-ERα or HT22 wild-type cells. SHBG internalization was specific as it did not occur in either the human neuroblastoma cell line SK-N-SH or the glioma cell line C6. Second, SHBG was labeled with a fluor (Alexa-555TM), and infused into the lateral cerebroventricles of ovariectomized rats. Optimal SHBG uptake was seen 10 min after these infusions. SHBG uptake was seen in specific parts of the choroid plexus and periventricular cells as well as into cells in the paraventricular nucleus, the medial forebrain bundle, and the habenula. Conclusions: These studies suggest that SHBG is internalized by brain cells, which may be affected by the presence of ERβ. The gonadal steroids have numerous effects in brain and the discovery that the steroid-binding protein SHBG is taken up into neurons and brain cells may demand a change in thinking about how steroids are delivered to brain cells to affect neurophysiology. PayPerView: Internalization of Sex Hormone-Binding Globulin into Neurons and Brain Cells in vitro and in vivo - Karger Publishers


    See also:
    Neuroactive steroid regulation of neurotransmitter release in the CNS: Neuroactive steroid regulation of neurotransm... [Prog Neurobiol. 2009] - PubMed - NCBI
    Neuroactive effects of DHEA: Neurobiological and Neuropsychiatric Effects of Dehydroepiandrosterone (DHEA) and DHEA Sulfate (DHEAS)
    3D Structure of SHBG: Crystal structure of human sex hormone-binding globulin: steroid transport by a laminin G-like domain
    SHBG Gene Expression: Human sex hormone-binding globulin gene expression- multiple promoters and complex alternative splicing

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    By VX1

  2. #2
    VET warmouth's Avatar
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    Thank you! Great thread and very informative.

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    Steroidal.com Writer/Mod Dan C's Avatar
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    Excellent information. I hope to integrate this information into my future writings some time.
    Chief writer for Steroidal.com
    Formerly known as Atomini
    Steroidal.com: the world's largest informational resource on anabolic steroids and all things performance enhancing drug related!
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    Originally written by VX1.

    Its a very good article with references.

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    very nice info about steroids.

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