StanleyG
Active member
1- Love to see it
2- Are you going to take 10mg of melatonin /day? Thats a lot of melatonin. I dont think I would take that much.
The Official OL UK Ghar1ne Q&A
- Thread starter Olympus UK
- Start date
1- Love to see it
2- Are you going to take 10mg of melatonin /day? Thats a lot of melatonin. I dont think I would take that much.
crowbar46
Active member
I think you better re-read the second paragraph. The whole point is that there has been a reevaluation of the role of SHBG. The second paragraph does NOT say that SHBG renders less of the hormone active.
crowbar46
Active member
The great google machine is fired up I hear most of the time!
StanleyG
Active member
Yeah, your wrong. It is not even up for debate. The higher SHBG- the lower free test. That is an established fact.
Thats half the problem around here people like you have no idea how to interpret things they read. Thats the issue when people do not possess true knowledge. What you end up with is a parrot that spouts off thing he reads yet has no true understanding of how things actually work. Due to that ignorance they have no ability to correctly interpret things they read and they spread misinformation just like you are doing here. Your are worng- period, end of story.
Obviously it is as you, in all of your ignorance, are using it. Sadly you dont have the background knowledge to correctly interpret it. As so far everything you have said is wrong and everything you have tried to interpret is incorrect you will have to excuse me if I choose not to believe your contention re: melatonin lowering GHIH in humans at a dose of 10mg/day. Even if you have actually read it if you used the same level of interpretation skill that you have when it comes to your understanding of SHBG then it is worthless. Now if you would actually post the study you are basing your melatonin claims on here, perhaps others could interpret it as well and maybe you might end up being correct. Until you do so, based on the ignorant statements you are making re SHBG and such there is no way that anyone with any level of intelligence or even common sense would take you at your word. Also I will re iterate what I said above, even if you are correct I would not take melatonin at a dosage of 10mg/day for any length of time at all.
hamdysayed
Well-known member
I was thinking that 10 mg might be a bit much, I probably will ease into it, now that I'm reading more about melatonin.
StanleyG
Active member
If I was going to try it I would def work up to a dose like that. Also I would ensure that there is sound documentation a data to support he contention being made here. Based on how things are shaking out it may be best not take this on someones word and just do it. Id do some research and see what you can find as far as data and dosage in humans before I just jump in. At some point yu are going to have to stop taking melatonin and you dont want your sleep patterns all shot to hell because you took mega doses of it. Especially if it turns out there isnt merit to this entire thing.
tballz
New member
You don't really believe this do you? Is that really what you are reading? Bro your beating a dead horse when it comes to shbg. Very well known and established that it is responsible for the amount of free and available testosterone. I am not reading what you are at all here man. At all.
NewAgeMayan
Well-known member
Stan, fwiw, you are offering some great input here but the ad homs are not doing anything to further your claims.
StanleyG
Active member
I asked the guy nicely, if he is going to be a prick then so be it. The good thing is they aren't my claims, they are the facts so its not an issue. They aren't going to change. The only claims being made are the ones he is incorrectly making.
Im not going to sit by and let him pass off BS misinformation. Then when I offer him an opportunity to reevaluate or even substantiate things and he comes back being a prick well then as far as im concerned he gets what he gets.
NoAddedHmones
Well-known member
You are obviously switched on with a lot of stuff relevant to the AM community, being humble in your posts rather than attacking still has the same outcome (providing correct information)
hamdysayed
Well-known member
Cruel but on point lol, just for my reference u seem knowledgeable, r u in scientific field etc?
chedapalooza
Legend
Truly invaluable feedback
crowbar46
Active member
Stanley, my apologies I certainly accept the age old fact that testosterone binds tightly to SHBG and is thus unable to exert effects on cells.
The wording of the article was confusing, and it sure reads as if he was saying there was a new understanding of the role of SHBG. I don't get what he means then when he says that SHBG is a transporter protein that carries testosterone to the receptor sites where it can then perform its actions. How can it "then perform it's actions" if it's bound to SHBG.
I guess I also don't understand what he means when he says, "for decades most people thought, even the medical community, that free testosterone was all that mattered, as bound testosterone was believed to be unusable by the body; held hostage by SHBG. We now know we were wrong..."
The wording of the article was confusing, and it sure reads as if he was saying there was a new understanding of the role of SHBG. I don't get what he means then when he says that SHBG is a transporter protein that carries testosterone to the receptor sites where it can then perform its actions. How can it "then perform it's actions" if it's bound to SHBG.
I guess I also don't understand what he means when he says, "for decades most people thought, even the medical community, that free testosterone was all that mattered, as bound testosterone was believed to be unusable by the body; held hostage by SHBG. We now know we were wrong..."
crowbar46
Active member
This is what I was talking about. It's along read from steroidal.com but well worth the time.
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
Invalid Link Removed
Sex Hormone?Binding Globulin and Risk of Type 2 Diabetes in Women and Men
MMS: Error
Invalid Link Removed
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
Invalid Link Removed
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
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
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Sex Hormone?Binding Globulin and Risk of Type 2 Diabetes in Women and Men
MMS: Error
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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
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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
StanleyG
Active member
I would simply get back to basics before trying to grasp all of what you have just posted. SHBG binds to test (and estrogen, and other hormones btw). While the hormones are bound they are unable to be utilized by the body or to attach to their respective receptor and exert their primary role if you will. In the case of test it is the androgen receptor. The thing to understand is that just because hormone is bound by SHBG doesnt mean it is forever inactive, it isnt. This is because free test has a short active life whereby test bound to shbg does not (compare to free test). This bound test actually becomes a source for free test in the future if you will.
All that being said it really doesnt matter as the level of free test and total test, while they do fluctuate, remain somewhat static. Well lets say static in the sense they are directly dependent upon the levels of SHBG.
The first paragraph refereed to by you was merely stating that in addition to binding to test, (it is a binding protein) it also acts to transport hormone to the receptor site. It is a "dual role" if you will however this does not change the effect on free and total test that SHBG exerts. Is it often misunderstood how this works? Yes because people think that once test is bound it will/can never be utilized which is not the case. That being said it doesnt change the fact the SHBG DOES control the level of free and available test.
All that being said it really doesnt matter as the level of free test and total test, while they do fluctuate, remain somewhat static. Well lets say static in the sense they are directly dependent upon the levels of SHBG.
The first paragraph refereed to by you was merely stating that in addition to binding to test, (it is a binding protein) it also acts to transport hormone to the receptor site. It is a "dual role" if you will however this does not change the effect on free and total test that SHBG exerts. Is it often misunderstood how this works? Yes because people think that once test is bound it will/can never be utilized which is not the case. That being said it doesnt change the fact the SHBG DOES control the level of free and available test.
crowbar46
Active member
All I can say--all I care to say on the subject--is that you clearly did not read, or understand, the article/summary. The article clearly lays out a line of evidence that SHBG has it's own receptor on numerous cell types, including muscle. Further, Megalin has been identified as an active transport system (an endocytic receptor for the uptake of sex hormones) likely involved in the active transport of steroid hormones in tissue requiring large amounts of sex hormones (e.g., muscle). To quote the article "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". Finally, "There are several observations suggesting that SHBG mediates the signal leading to the activation of a second messenger system." That is to say, testosterone bound to SHBG may transcribe its effects through a mechanism independent of the AR.
OK, I'm done with this. This is getting this thread way off course!
ericool007
Active member
I've been using 3mg melatonin with 10 mg ghar1ne for now pre bed, i will likely bump both up in the future but for now what i've noticed is waking up seems a bit harder in the morning but once i do manage to get up im wide awake and feeling great after only a few minutes.
i do have huperzine-a on hand but i havent started it and im debating whether i want too as im very prone to anxiety and high BP, i may experiemnt but for now im probably just going to stick with melatonin.
i do have huperzine-a on hand but i havent started it and im debating whether i want too as im very prone to anxiety and high BP, i may experiemnt but for now im probably just going to stick with melatonin.
crowbar46
Active member
That would be my suggestion. I'm also a little prone to anxiety and definitely high blood pressure; huperzine was simply a no go for me--too many side effects. It is interesting to see how powerful it is though!
StanleyG
Active member
Yes it is best to move on as clearly there is quite a disconnect when it come to a basic understanding here. You see all that fancy stuff yet it still holds 100% true the higher the SHBG the lower the free test and the lower the SHBG the higher the free test. Which is all I said that you disagreed with. It was correct then and even after posting a lot of information you yourself clearly do not understand it still 100% is true. Any questions feel free to pm me.
NewAgeMayan
Well-known member
So a cheap source of melatonin would be drinking ones early morning urine...
Contaygious
Active member
Hey I'm running this with rad for two months at 10m should I keep going after the rad through pct?
kboxer7
Well-known member
Ghar1ne is great during pct and can be taken for many months on end with increasing benefits.
Regards,
edje007
Well-known member
MidwestBeast
Legend
I'm about a week in so far. Nothing huge to report, but I'm keeping an eye on a couple things and will report when I can confirm one way or another.
Nothing else as a new variable at this point and planning on a full month before making any changes (e.g. adding in huperzine, EGCg, melatonin, etc.).
Nothing else as a new variable at this point and planning on a full month before making any changes (e.g. adding in huperzine, EGCg, melatonin, etc.).
nump
New member
Is this something that I have to feel in order to be effective? I've been dosing it for a week at 20mg before bed and haven't felt the side effects of numb hands, etc. Sleep is decent, nothing out of the ordinary. I just came off a rad-140 cycle and I'm extremely tolerant from supplements. I can take high doses of preworkouts and clen, but never feel anything. My skin is clearing up, though I discontinued some other supps that gave me a rash/hives.
CJNator
Well-known member
Bloating, clear skin, and lethargy is all I can think of. What's your diet like?
BamBam0319
Well-known member
So much good info and discussion on this thread. It's hard to find time to read everything!
I have a bottle of ghar1ne ordered - finally able to afford thanks to the Labor Day sale - and had a couple inquiries.
In the past when taking supplements that "increase growth hormone" my experience has always been phenomenal the first dose and then hardly any noticeable effects for the rest of the run. However, being that this isn't a "natural" GH boosting supplement I think I'm going to run it at 10 mg/ED for the first week to see how my body responds to this product. If it seems to be affecting me well then I may run it that way for a whole 4 weeks and that will give me enough product to bump it up to 20mg for a whole 4.5 more weeks. Does this sound like a good or bad idea to you all?
I already take melatonin before bed every night and plan to continue that/up the dose on that once the gharine comes in.
Another thought I had was increased prolactin; has anyone had any issues with this in regards to MK 677 supplementation? I already have pramipexole on hand from back in the day (last year...) when trenavar was still on the market. Lol. So I may run that at a low dose during this MK cycle.
I am already using letrozole to combat some gyno issues I'm currently having and once that clears up I also have aromasin and nolvadex on hand.
Also, just my 2 cents after reading a small portion of this thread: I have never taken a BLR product (and I have taken a few) and thought, "Wow! That worked really well!" But I have never taken their letrone product so I don't have an opinion on how well that works.
I look forward to hearing some feedback! Thanks guys.
I have a bottle of ghar1ne ordered - finally able to afford thanks to the Labor Day sale - and had a couple inquiries.
In the past when taking supplements that "increase growth hormone" my experience has always been phenomenal the first dose and then hardly any noticeable effects for the rest of the run. However, being that this isn't a "natural" GH boosting supplement I think I'm going to run it at 10 mg/ED for the first week to see how my body responds to this product. If it seems to be affecting me well then I may run it that way for a whole 4 weeks and that will give me enough product to bump it up to 20mg for a whole 4.5 more weeks. Does this sound like a good or bad idea to you all?
I already take melatonin before bed every night and plan to continue that/up the dose on that once the gharine comes in.
Another thought I had was increased prolactin; has anyone had any issues with this in regards to MK 677 supplementation? I already have pramipexole on hand from back in the day (last year...) when trenavar was still on the market. Lol. So I may run that at a low dose during this MK cycle.
I am already using letrozole to combat some gyno issues I'm currently having and once that clears up I also have aromasin and nolvadex on hand.
Also, just my 2 cents after reading a small portion of this thread: I have never taken a BLR product (and I have taken a few) and thought, "Wow! That worked really well!" But I have never taken their letrone product so I don't have an opinion on how well that works.
I look forward to hearing some feedback! Thanks guys.
nump
New member
its pretty clean, high protein/fat, low carbs. I eat once a day at night which is where the carbs come from. The rest of my nutrition is protein shakes with MCT oil, fiber, and wheat grass mixed in. I also have my morning preworkout with 60g lecithin granules. Been on this diet for a month and I'm leaning out nicely.
hamdysayed
Well-known member
About 3 weeks here on gharine , lethargy is goneeee bloat is still here tho.
kboxer7
Well-known member
Happy to hear the lethargy subsided for you.
CJNator
Well-known member
Sounds great man, damn I wish you logged it lol! I read that the longer you are on mk677 the higher your GH levels go.
hamdysayed
Well-known member
Yeah man shiat was no bueno but the sleep convince u to continue .
crowbar46
Active member
I think your plan of starting out at 10 Mg. is fine; you do want to see how it affects you. Some people seem to experience more water retention than others, for example, or more lethargy.
A couple of points:
1) As far as the lethargy, it subsides, just stick it out.
2) the increase in estrogen and prolactin with MK is transient and within normal limits, they will return to baseline after about a week. There is no need for any extra precautions.
3) take your Gharine on as empty of a stomach as possible; I give myself 5 hours between my last meal and my pre-bed casein/whey shake, taking my Gharine/melatonin at 4 hours, 15 Min. (That is, 45min. before my pre-bed shake).
4) Avoid having elevated blood sugar levels at the time you take the Gharine. Elevated blood sugar inhibits GH release (thus, one of the reasons for taking it on an empty stomach).
5) If I can remember it I'm going to add a low dose aspirin with my pre-bed shake, per Stanley's advice, to see if it helps with the water retention (the claim being that aspirin inhibits vasopressin, the purported mechanism behind the water retention from MK--although I have not verified either claim).
GNO
Well-known member
i will have to put some thought into my dosing protocol when I start this in a couple months. Due to my schedule I have my largest meal at night and go to bed within an hour.
Depending on the day that meal may include some dessert lol. Any suggestions based on users experience?
GNO
Well-known member
That would work, but worried about the spike to hunger. Is it acute (from first dose) or gradual?
crowbar46
Active member
crowbar46
Active member
I wish I had something for you, but honestly I just stuck it out. I does suck at first, but for me it took a good 4 weeks for lethargy to subside. However, everyone's going to be different and it may take longer for you.
Also, you seem very responsive to MK, so some of the sides may simply be worse for you. For example, I'm on 30 Mg. a night. This actually makes sense, as the studies using younger subjects showed that MK was even more effective at raising GH levels than the studies with older subjects. That seems completely logical, as older subjects probably have more sluggish hypothalamus and pituitary glands, less sensitive to the stimulation from MK.
Actually, come to think of it, one of the reasons that older people are less responsive to MK than younger subjects, is that your somatostatin levels increase with age.
crowbar46
Active member
Just as a general comment, I think some people may be getting a little impatient to see results from Gharine. This is a supplement that is going to produce results over an extended period of time. Hell, when you use pharmaceutical grade GH you either plan to use it for extended periods, or you don't use it. I knew guys who ran Pharma grade for a year straight!
So, I've got a 6 month supply (@30 mg./night) stocked up.
So, I've got a 6 month supply (@30 mg./night) stocked up.
muay thai
Member
good perspective - i am 27 . I have experience with cjc1295, ghrp 6,9, lr3igf1, hgh frag, pt141, pgcl, hcg .... as far as ghrp the ghar1ne give me same symptoms as a ghrp
thanks for feedback brother
crowbar46
Active member
good perspective - i am 27 . I have experience with cjc1295, ghrp 6,9, lr3igf1, hgh frag, pt141, pgcl, hcg .... as far as ghrp the ghar1ne give me same symptoms as a ghrp
thanks for feedback brother
Anytime. Yeah, I think Gharine, over the long run, will be one of the more effective of the new batch of OL products. I really like some of the effects of Cardarine, for example, others not so much. All the new SARMs seem to have drawbacks--either just not strong enough, liver stress, negative changes in lipids, suppression, etc., not to mention some of my lingering doubts about their safety.
MidwestBeast
Legend
I was wondering if we could get someone on the formulation side to comment. I've been going on label instructions which are listed here:
Invalid Link Removed
and that is to dose with a meal -- not an empty stomach.
Now my initial thought would have been empty stomach, pre-bed, but I've followed the label.
Should I be dosing empty stomach?
crowbar46
Active member
I'll just add quickly that with Pharma grade it's standard procedure to inject at least a couple hours post meal, and wait a least a half-hour to eat.
ericool007
Active member
let me know how it goes with the aspirin and when you say a low dose are you talking like 81mgs?
Contaygious
Active member
I'm starting to see a lot of talk on Internet about lethargy and crappy workouts with 677. How long until it passes? Thinking of starting ghari1ne first before the rad
kboxer7
Well-known member
I've seen reports ranging from 2 weeks - a month. Some don't experience it at all, whilst others it seems to hit hard.