What is the mechanism that Metformin would reduce free test levels?

  1. Registered User
    willis3's Avatar
    Join Date
    Feb 2007
    Posts
    50
    Answers
    0

    What is the mechanism that Metformin would reduce free test levels?


    Wonedering if someone could give me some insigt into how metformin xr 500 mg daily would affect my free test levels? I have read that metformin lowers free test levels or could potentially. I take HGH 1.5 IU per day before bedtime with the metformin (which I take at dinner).

    Also does anyone have any experience with metformin xr and facial water retention? Ever since I have started taking it I have actually managed to finally lose some weight which is nice and my appetite is down but my face has swelled up big time.

  2. Registered User
    Speedbacker's Avatar
    Join Date
    Mar 2005
    Posts
    191
    Answers
    0


    Good question. I have wondered why metformin would lower test levels as well? I don't know, but if i'm not mistaken (which I very well could be) all of those studies were done on obese men, so I don't know if it would have the same result (lowered test) if metformin were used on healthy individuals. I know stupid pondering, but I would also like to know the mechanism to which glucophage lowers testosterone levels.
  3. Registered User
    willis3's Avatar
    Join Date
    Feb 2007
    Posts
    50
    Answers
    0


    From everything I've read it looks as though it does so through it's "significant" increase in SHBG. This is because of it's ability to lower the amont of insulin in the blood and insulin is known to decrease SHBG. But you're right these studies were done in obese individuals and not healthy people so it's tough.
    •   
       

  4. Registered User
    Cosmonaut's Avatar
    Stats
    6'3"  200 lbs.
    Join Date
    Oct 2008
    Posts
    28
    Answers
    0


    Metformin increases insulin sensitivity which would result in a smaller insulin spike/secretion. SHBG levels are inversely related to insulin levels so when you spike insulin levels you decrease SHBG secretion and increase Free testosterone amount and visa versa.
  5. Registered User
    Bobaslaw's Avatar
    Join Date
    Jun 2007
    Posts
    495
    Answers
    0


    Yes, Insulin levels are inversely proportional to SHBG levels as depicted in the study below. Metformin is responsible for reducing both insulin resistance and stabalizing insulin secretion, and plasma insulin levels.

    This study below documents the relationship of increased Insulin levels (GH mediated) and SHBG:

    Title: Comparative effects of GH, IGF-I and insulin on serum sex hormone binding globulin.
    Author: Gafny, M : Silbergeld, A : Klinger, B : Wasserman, M : Laron, Z
    Citation: Clin-Endocrinol-(Oxf). 1994 Aug; 41(2): 169-75

    Abstract:
    The serum level of sex hormone binding globulin (SHBG) changes inversely with that of both insulin and insulin-like growth factor (IGF-I), during several nutritional conditions, as well as in response to GH treatment. However, with exogenous IGF-I administration, endogenous IGF-I increases, while insulin decreases. In order to study the separate roles of these hormones in controlling SHBG metabolism, we compared SHBG levels in patients treated with IGF-I and GH. DESIGN AND PATIENTS: Serum levels of IGF-I, insulin and SHBG were measured before and during the treatment of patients with IGF-I or GH. Blood samples were drawn in the fasting state, prior to and during therapy, 24 hours after drug administration. Sixteen children and adults with Laron syndrome (LS) received daily s.c. injections of IGF-I (120-150 micrograms/kg) for up to 5 months. Three adults with isolated GH deficiency (IGHD) received daily s.c. injections of GH (0.03-0.06 U/kg) for 16 months. Two groups of nine prepubertal children with constitutional short stature (CSS) received GH (0.1 U/kg/day) for 3 months. MEASUREMENTS: Serum levels of insulin and acid extractable IGF-I were determined by RIA, and that of SHBG by IRMA. RESULTS: Basal insulin and SHBG levels were within normal range in the LS, IGHD and CSS patients. IGF-I levels were low in LS and IGHD patients, and normal in the CSS children. The mean peak response to chronic therapy was as follows: in LS patients, IGF-I administration decreased insulin levels to 62%, and increased SHBG levels by 64% above basal values. Chronic GH therapy in IGHD caused a marked rise in both IGF-I levels (473%), and insulin levels (96%), and a gradual decline of SHBG to 75% of the basal concentration. In GH treated CSS patients, serum IGF-I peaked at 80% and insulin levels at 102% above the respective basal levels, while SHBG decreased to 83% after 5 days of treatment. CONCLUSION: The results obtained in Laron syndrome, isolated GH deficiency and constitutional short stature patients treated with IGF-I or GH, indicate that serum insulin had consistently an inverse relation with the levels of circulating SHBG. No relation was found between IGF-I and SHBG levels.
    Additionally, Dat posted a wonderful writeup on why Metformin is not ideal (substitute for Insulin) while on a protocol to increase GH/IGF. Metformin is responsible for reducing insulin secretion and resulting hepatic IGF-1 synthesis, as well as increase in IGFBP3. Also, downstream IGF-1 mediated signaling pathways that lead to the events we hope for, are blunted.
    Definitely the opposite of the preferred synergy that is attained when using insulin along with GH.

    Here is a relevent snippet taken from Dat's post on PM:

    Quote Originally Posted by datBtrue
    ....Instead I'm going to explain to you why your use of Metformin with CJC-1295/GHRP-6 produced less than stellar results. From this explanation hopefully you'll understand that the proper answer to the types of questions you raise are far deeper then the gaggle of penises you survey would ever believe possible. Knowledge resides deeper then surface level...so lets take a look.

    By now everyone should understand how we end up with more IGF-1 as a result of administering GHRH (CJC-1295, modified GRF(1-29) & Sermorelin) and a Ghrelin mimetic (GHRP-6, GHRP-2, Hexarelin, Ipamorelin & the nonmpeptide molecules) but I'll quickly recap.

    Growth hormone (GH) is produced in the anterior pituitary, and is modulated by two hypothalamic hormones, growth hormone-releasing hormone (GHRH), which stimulates both the synthesis and secretion of GH; and somatostatin (SS), which inhibits GH release in response to GHRH.

    GHRPs further modulate GH release by acting at both the hypothalamus and the anterior pituitary to enhance both the release and effect of GHRH and inhibit both the release and effect of somatostatin.

    Administering GHRH (in the form of CJC-1295, modified GRF(1-29) or Sermorelin) together with a Ghrelin-mimetic (GHRP-6, GHRP-2, Hexarelin, Ipamorelin & the nonmpeptide molecules) both creates and amplifies a GH pulse in synergistic fashion.

    GH is naturally secreted in pulsatile bursts from the anterior pituitary gland, a pattern that is necessary to achieve full biological activity. Basal concentrations (between pulses) of GH in blood are very low. GH also feeds back to inhibit GHRH secretion and probably has a direct inhibitory effect on secretion from the somatotroph (GH-producing cells).

    GH binds with high affinity to its receptor, found in tissues throughout the body, and activation of this receptor stimulates the synthesis and secretion of insulin-like growth factor 1 (IGF-1). Although 90% of circulating IGF-1 is synthesized and secreted by the liver, many types of cells, including some found in the brain, muscle and vasculature, are capable of IGF-1 production.

    Binding of the hormone IGF-1 to the IGF-1 receptor (IGFR) causes potent mitogenic effects, including increases in DNA, RNA and protein synthesis.

    IGF-1 binding activates the IGF-1 receptor (IGFR), a receptor tyrosine kinase (which in essence means subsequent pathway activation will be by phosphorylation symbolized below by red p). The IGFR subsequently recruits the insulin receptor substrate (IRS-1), which results in the activation of two signaling pathways: the Ras–Raf– MEK–ERK pathway and the PI3K–Akt pathway. The Ras–Raf–MEK–ERK pathway is crucial in mitosis-competent cells for cell proliferation and cell survival. However, in adult skeletal muscle, the function of the Ras–Raf–MEK–ERK pathway is less clear.

    The PI3K–Akt pathway has been shown to be both necessary and sufficient to induce skeletal muscle hypertrophy.

    Moving down that pathway it has been demonstrated that Akt1 activity is required for IGF-1- mediated hypertrophy, and expression of activated Akt1 is sufficient to induce muscle hypertrophy.

    Moving further down the pathway we find mTOR has been shown to have an important and central function in integrating a variety of growth signals, from simple nutritional stimulation to activation by protein growth factors, resulting in protein synthesis. Akt phosphorylates (or activates) mTOR and both Akt phosphorylation and mTOR phosphorylation are increased during muscle hypertrophy.

    Name:  IGFPathway.gif
Views: 993
Size:  26.0 KB

    Metformin

    Metformin chronically activates AMP-activated kinase (AMPK). AMPK slows liver glucose output by down-regulating expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase; in skeletal muscle, it boosts the efficiency of insulin-stimulated glucose uptake by increasing expression of GLUT-4. These effects mandate a down-regulation of insulin secretion.

    The resulting reduction of liver insulin activity will suppress liver production of IGF-I while boosting that of IGFBP-1, thereby decreasing plasma free IGF-I.

    Stimulation of AMPK with Metformin also interferes with the Ras–Raf–MEK–ERK pathway of IGF-I signaling by inhibiting the ability of IGF-I to activate ras and its downstream targets.

    Stimulation of AMPK with Metformin also blocks the ability of the PI3K-Akt pathway to activate mTOR.

    Since the Ras–Raf–MEK–ERK cascade, as well as mTOR and its downstream targets, are key mediators of IGF-I’s ability to increase hypertrophy a systemic increase in AMPK activity as brought about by Metformin will hinder the potential for hypertrophy not only by diminishing plasma levels of insulin and free IGF-I, but also by intervening in the post-receptor intracellular pathways mediated events which bring about these bodybuilding effects.
  6. Registered User
    Cosmonaut's Avatar
    Stats
    6'3"  200 lbs.
    Join Date
    Oct 2008
    Posts
    28
    Answers
    0


    Quote Originally Posted by Bobaslaw View Post
    Yes, Insulin levels are inversely proportional to SHBG levels as depicted in the study below. Metformin is responsible for reducing both insulin resistance and stabalizing insulin secretion, and plasma insulin levels.

    This study below documents the relationship of increased Insulin levels (GH mediated) and SHBG:



    Additionally, Dat posted a wonderful writeup on why Metformin is not ideal (substitute for Insulin) while on a protocol to increase GH/IGF. Metformin is responsible for reducing insulin secretion and resulting hepatic IGF-1 synthesis, as well as increase in IGFBP3. Also, downstream IGF-1 mediated signaling pathways that lead to the events we hope for, are blunted.
    Definitely the opposite of the preferred synergy that is attained when using insulin along with GH.

    Here is a relevent snippet taken from Dat's post on PM:
    Is there any information on how long the effects of Metformin last? Would it be a good drug to use when carbing up once every few days? I think it could be useful during cutting cycles most people are not gaining muscle in that span of time anyway.
  •   

      
     

Similar Forum Threads

  1. Replies: 18
    Last Post: 01-18-2012, 07:59 PM
  2. what is the earliest age you would consider....
    By utvol in forum 35 and Older
    Replies: 4
    Last Post: 07-16-2009, 03:56 PM
  3. Replies: 13
    Last Post: 09-18-2007, 02:23 PM
  4. What is the best portable protein that's real food?
    By baham99 in forum Weight Loss
    Replies: 52
    Last Post: 12-02-2004, 03:38 PM
  5. Replies: 8
    Last Post: 06-24-2004, 09:53 PM

Posting Permissions

  • You may not post new threads
  • You may not post replies
  • You may not post attachments
  • You may not edit your posts
  •  

Log in

Log in