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  1. #21
    Senior Member eclypz's Avatar
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    <div class='quotetop'>QUOTE (oswaldosalcedo @ Nov 8 2008, 09:45 AM) <{POST_SNAPBACK}></div><div class='quotemain'>Saudi Med J. 2002 Aug;23(8):934-7.

    Effects of short term metformin administration on androgens in normal men.


    Shegem NS, Nasir AM, Jbour AK, Batieha AM, El-Khateeb MS, Ajlouni KM.

    National Center for Diabetes Endocrinology and Genetics, Jordan University Hospital, Amman, Jordan.

    OBJECTIVE: To study the effect of metformin on androgens in normal men. METHODS: A total of 12 healthy males volunteered to participate in the study. A blood sample was obtained from each of them and analyzed for the following: Testosterone (total and free), sex hormone binding globulin dehydroepiandrosterone sulphate, 17-hydroxyprogesterone, luteinizing hormone, and follicle stimulating hormone. In addition, each participant was subjected to a glucose tolerance test and his insulin level was measured. Metformin 850 mg twice daily for 2-weeks was given to each subject after which the above tests were repeated. A paired t-test was used to assess the statistical significance of any observed differences before and after metformin. RESULTS: After metformin administration, there was a significant reduction in serum level of total testosterone (p=0.0001), free testosterone (P=0.002), and 17 hydroxyprogesterone (p=0.0001). There was also a significant increase in serum level of sex hormone binding globulin (p=0.009) and dehydroepiandrosterone sulphate (P=0.0008). Serum levels of luteinizing hormone and follicle stimulating hormone showed no significant changes. Similarly, there were no changes in fasting plasma glucose, fasting serum insulin, weight, or blood pressure. CONCLUSION: Metformin administration was associated with a reduction in total testosterone, free testosterone, and 17-hydroxyprogesterone and an increase in sex hormone binding globulin and dehydroepiandrosterone sulphate in normal males.





    <span style="color:#C0C0C0">.</span></div>


    Right, I've read this one a couple times and could never find anything in there where it said HOW specifically it lowers testosterone. It does increase SHBG, yes, but it also decreases Total Testosterone as well.

    AND

    DHEA is elevated. This leads me to believe that an enzyme responsible for converting dhea to test is being inhibited. There are quite a few things that help inhibit shbg, but I don't think this alone would solve the problem we see here.


  2. #22
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    <div class='quotetop'>QUOTE (eclypz @ Nov 8 2008, 11:07 AM) <{POST_SNAPBACK}></div><div class='quotemain'>Right, I've read this one a couple times and could never find anything in there where it said HOW specifically it lowers testosterone.

    AND

    DHEA is elevated. This leads me to believe that an enzyme responsible for converting dhea to test is being inhibited.</div>

    .......of course, "HOW"

    DHEA first have to be converted to Androstenodione, later androstenodione to testosterone, metformin decreases 3beta-hsd the enzyme responsible for the conversion.



    <span style="color:#C0C0C0">.</span>

  3. #23
    Senior Member eclypz's Avatar
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    ok so it may lower testosterone but it seems to help in other, ehem, areas...

    http://www.andrologyjournal.org/cgi/.../full/28/4/555

    NOS expression in fat rats.

  4. #24
    Senior Member eclypz's Avatar
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    so ampk activators in general are going to inhibit steroidogenesis? I think I remember reading about this in crash dieting and how it affects testosterone.




    http://www.ncbi.nlm.nih.gov/pubmed/1712394...ogdbfrom=pubmed

    In mammals, IGFs are important for the proliferation and steroidogenesis of ovarian cells. Metformin is an insulin sensitizer molecule used for the treatment of the infertility of women with polycystic ovary syndrome. It is, however, unclear whether metformin acts on ovarian cells. Adenosine 5' monophosphate-activated protein kinase (AMPK) is involved in metformin action in various cell types. We investigated the effects of metformin on bovine granulosa cell steroidogenesis in response to IGF1 and FSH, and studied AMPK in bovine ovaries. In granulosa cells from small follicles, metformin (10 mM) reduced production of both progesterone and estradiol and decreased the abundance of HSD3B, CYP11A1, and STAR proteins in presence or absence of FSH (10(-8) M) and IGF1 (10(-8) M). In cows, the different subunits of AMPK are expressed in various ovarian cells including granulosa and theca cells, corpus luteum, and oocytes. In bovine granulosa cells from small follicles, metformin, like AICAR (1 mM) a pharmaceutical activator of AMPK, increased phosphorylation of both Thr172 of AMPK alpha and Ser 79 of ACACA (Acetyl-CoA Carboxylase). Both metformin and AICAR treatment reduced progesterone and estradiol secretion in presence or absence of FSH and IGF1. Metformin decreased phosphorylation levels of MAPK3/MAPK1 and MAPK14 in a dose- and time-dependent manner. The adenovirus-mediated production of dominant negative AMPK abolished the effects of metformin on secretion of progesterone and estradiol and on MAPK3/MAPK1 phosphorylation but not on MAPK14 phosphorylation.<span style="font-size:14pt;line-height:100%"><u> Thus, in bovine granulosa cells, metformin decreases steroidogenesis and MAPK3/MAPK1 phosphorylation through AMPK activation.</u></span>

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    AMPK is muscles sparing. So degredation wouldn't be an issue.

    I wonder is clomid's effects on FSH would help offset the loss of 3beta-HSD.

    I would suggest adding GPA to this and stop doign cardio.

  6. #26
    Senior Member eclypz's Avatar
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    <div class='quotetop'>QUOTE (Jakeshorts @ Nov 21 2008, 07:53 AM) <{POST_SNAPBACK}></div><div class='quotemain'>AMPK is muscles sparing. So degredation wouldn't be an issue.

    I wonder is clomid's effects on FSH would help offset the loss of 3beta-HSD.

    I would suggest adding GPA to this and stop doign cardio.</div>


    what i think is interesting is the similarity in names of gpa and metformin.


    metformin = aminoguanidine
    gpa = guanidinopropionic acid


    i don't think clomid will help. All the signalling in the world won't matter if your liver is being prohibited from making the enzymes necessary for conversion.

  7. #27
    Senior Member eclypz's Avatar
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    heres someone trying to get a patent on gpa for exercise capacity increases and mentions that gpa is derived from the same family as metformin

    http://www.patentstorm.us/patents/6008253/fulltext.html


  8. #28
    Senior Member eclypz's Avatar
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  9. #29
    Senior Member eclypz's Avatar
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    WOAH WOAH,,, stop the press!!!

    Thiazolidinediones but Not Metformin Directly Inhibit the Steroidogenic Enzymes P450c17 and 3beta -Hydroxysteroid Dehydrogenase*
    Wiebke ArltDagger , Richard J. Auchus§, and Walter L. MillerDagger ¶

    From the Dagger Department of Pediatrics and the Metabolic Research Unit, University of California, San Francisco, California 94143-0978 and the § Department of Medicine, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-8857

    Androgen biosynthesis requires 3beta -hydroxysteroid dehydrogenase type II (3beta HSDII) and the 17alpha -hydroxylase and 17,20-lyase activities of cytochrome P450c17. Thiazolidinedione and biguanide drugs, which are used to increase insulin sensitivity in type 2 diabetes, lower serum androgen concentrations in women with polycystic ovary syndrome. However, it is unclear whether this is secondary to increased insulin sensitivity or to direct effects on steroidogenesis. To investigate potential actions of these drugs on P450c17 and 3beta HSDII, we used "humanized yeast" that express these steroidogenic enzymes in microsomal environments. The biguanide metformin had no effect on either enzyme, whereas the thiazolidinedione troglitazone inhibited 3beta HSDII (KI = 25.4 ± 5.1 µM) and both activities of P450c17 (KI for 17alpha -hydroxylase, 8.4 ± 0.6 µM; KI for 17,20-lyase, 5.3 ± 0.7 µM). The action of troglitazone on P450c17 was competitive, but it was mainly a noncompetitive inhibitor of 3beta HSDII. The thiazolidinediones rosiglitazone and pioglitazone exerted direct but weaker inhibitory effects on both P450c17 and 3beta HSDII. These differential effects of the thiazolidinediones do not correlate with their effects on insulin sensitivity, suggesting that distinct regions of the thiazolidinedione molecule mediate these two actions. <span style="font-size:10pt;line-height:100%">Thus, thiazolidinediones inhibit two key enzymes in human androgen synthesis contributing to their androgen-lowering effects, whereas metformin affects androgen synthesis indirectly, probably by lowering circulating insulin concentrations. </span>


    so it looks like they think it's just lowered insulin. How does low insulin lead to lowered testosterone?

  10. #30
    Senior Member eclypz's Avatar
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    I have found that 250mg once daily still works very well to balance blood sugar without interupting my testosterone production.

  11. #31
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    <div class='quotetop'>QUOTE (oswaldosalcedo @ Nov 8 2008, 02:41 PM) <{POST_SNAPBACK}></div><div class='quotemain'>.......of course, "HOW"

    DHEA first have to be converted to Androstenodione, later androstenodione to testosterone, metformin decreases 3beta-hsd the enzyme responsible for the conversion.



    <span style="color:#C0C0C0">.</span></div>

    I'd say Oswaldo was pretty right on with the above statement. The trick then becomes - how do we replace the 3Beta-HSD that your metaformin is killing?

    I believe the answer lies in another thread that just hadn't been stumbled upon yet. Glucocorticoids. Since 3B-HSD isn't a P450 enzyme, all the little P450 tricks do not apply. Administration of loss corticosteroid levels could replace the loss.

    <div class='quotetop'>QUOTE </div><div class='quotemain'>J Steroid Biochem Mol Biol. 2002 Sep;82(1):55-63. Links
    Glucocorticoids enhance activation of the human type II 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase gene.Feltus FA, Cote S, Simard J, Gingras S, Kovacs WJ, Nicholson WE, Clark BJ, Melner MH.
    Department of OB/GYN, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. [email protected]

    Glucocorticoids indirectly alter adrenocortical steroid output through the inhibition of ACTH secretion by the anterior pituitary. However, previous studies suggest that glucocorticoids can directly affect adrenocortical steroid production. Therefore, we have investigated the ability of glucocorticoids to affect transcription of adrenocortical steroid biosynthetic enzymes. One potential target of glucocorticoid action in the adrenal is an enzyme critical for adrenocortical steroid production: 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase (3beta-HSD). Treatment of the adrenocortical cell line (H295R) with the glucocorticoid agonist dexamethasone (DEX) increased cortisol production and 3beta-HSD mRNA levels alone or in conjunction with phorbol ester. This increase in 3beta-HSD mRNA was paralleled by increases in Steroidogenic Acute Regulatory Protein (StAR) mRNA levels. The human type II 3beta-HSD promoter lacks a consensus palindromic glucocorticoid response element (GRE) but does contain a Stat5 response element (Stat5RE) suggesting that glucocorticoids could affect type II 3beta-HSD transcription via interaction with Stat5. Transfection experiments show enhancement of human type II 3beta-HSD promoter activity by coexpression of the glucocorticoid receptor (GR) and Stat5A and treatment with 100nM dexamethasone. Furthermore, removal of the Stat5RE either by truncation of the 5' flanking sequence in the promoter or introduction of point mutations to the Stat5RE abolished the ability of DEX to enhance 3beta-HSD promoter activity. These studies demonstrate the ability of glucocorticoids to directly enhance the expression of an adrenal steroidogenic enzyme gene albeit independent of a consensus palindromic glucocorticoid response element.

    PMID: 12429139 [PubMed - indexed for MEDLINE]</div>


    Obviously, DEX looks like it's a bit harsh for something like this, however, progesterone might be a more viable option.

    Any way to get your glucocorticoid levels measured while high dosing?

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    <div class='quotetop'>QUOTE (eclypz @ Dec 10 2008, 10:31 AM) <{POST_SNAPBACK}></div><div class='quotemain'>I have found that 250mg once daily still works very well to balance blood sugar without interupting my testosterone production.</div>
    Any labs? Or does it just "feel" like it?

  13. #33
    Senior Member eclypz's Avatar
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    No, no labs.

    This might sound lame but I have a testicle that ascends like a mofo anytime I go on a cycle. Same thing started happening along with a lack of erective abilities about two weeks into higher dosing.


  14. #34
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    E, how do you gauge your test production?

  15. #35
    Senior Member eclypz's Avatar
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    I'm not. I just know when I'm shutting down.

  16. #36
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    <div class='quotetop'>QUOTE (Jakeshorts @ Dec 10 2008, 10:12 AM) <{POST_SNAPBACK}></div><div class='quotemain'>I'd say Oswaldo was pretty right on with the above statement. The trick then becomes - how do we replace the 3Beta-HSD that your metaformin is killing?

    I believe the answer lies in another thread that just hadn't been stumbled upon yet. Glucocorticoids. Since 3B-HSD isn't a P450 enzyme, all the little P450 tricks do not apply. Administration of loss corticosteroid levels could replace the loss.




    Obviously, DEX looks like it's a bit harsh for something like this, however, progesterone might be a more viable option.

    Any way to get your glucocorticoid levels measured while high dosing?</div>


    bright !

    i was thinking, "IMPOSSIBLE".

    BRIGHT !

    have to be considered.


    edit:

    related

    ..........Glucocorticoid treatment inhibited AMPK activity in rat adipose tissue and heart, while stimulating it in the liver and hypothalamus. Similar data were observed in vitro in the primary adipose and hypothalamic cells and in the liver cell line. Metformin, a known AMPK regulator, prevented the corticosteroid-induced effects on AMPK in human adipocytes and rat hypothalamic neurons......................



    <span style="color:#C0C0C0">.</span>

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    <div class='quotetop'>QUOTE (eclypz @ Nov 21 2008, 03:49 PM) <{POST_SNAPBACK}></div><div class='quotemain'>WOAH WOAH,,, stop the press!!!

    J Biol Chem. 2001 May 18;276(20):16767-71.


    Thiazolidinediones but Not Metformin Directly Inhibit the Steroidogenic Enzymes P450c17 and 3beta -Hydroxysteroid Dehydrogenase*
    Wiebke ArltDagger , Richard J. Auchus§, and Walter L. MillerDagger ¶

    From the Dagger Department of Pediatrics and the Metabolic Research Unit, University of California, San Francisco, California 94143-0978 and the § Department of Medicine, University of Texas, Southwestern Medical Center, Dallas, Texas 75390-8857

    Androgen biosynthesis requires 3beta -hydroxysteroid dehydrogenase type II (3beta HSDII) and the 17alpha -hydroxylase and 17,20-lyase activities of cytochrome P450c17. Thiazolidinedione and biguanide drugs, which are used to increase insulin sensitivity in type 2 diabetes, lower serum androgen concentrations in women with polycystic ovary syndrome. However, it is unclear whether this is secondary to increased insulin sensitivity or to direct effects on steroidogenesis. To investigate potential actions of these drugs on P450c17 and 3beta HSDII, we used "humanized yeast" that express these steroidogenic enzymes in microsomal environments. The biguanide metformin had no effect on either enzyme, whereas the thiazolidinedione troglitazone inhibited 3beta HSDII (KI = 25.4 ± 5.1 µM) and both activities of P450c17 (KI for 17alpha -hydroxylase, 8.4 ± 0.6 µM; KI for 17,20-lyase, 5.3 ± 0.7 µM). The action of troglitazone on P450c17 was competitive, but it was mainly a noncompetitive inhibitor of 3beta HSDII. The thiazolidinediones rosiglitazone and pioglitazone exerted direct but weaker inhibitory effects on both P450c17 and 3beta HSDII. These differential effects of the thiazolidinediones do not correlate with their effects on insulin sensitivity, suggesting that distinct regions of the thiazolidinedione molecule mediate these two actions. <span style="font-size:10pt;line-height:100%">Thus, thiazolidinediones inhibit two key enzymes in human androgen synthesis contributing to their androgen-lowering effects, whereas metformin affects androgen synthesis indirectly, probably by lowering circulating insulin concentrations. </span>


    so it looks like they think it's just lowered insulin. How does low insulin lead to lowered testosterone?</div>

    stop the run............

    .............metformin significantly inhibited the expression of steroidogenic acute regulatory (StAR) protein and 17 alpha-hydroxylase (CYP17)..............................


    and:

    Biol Reprod. 2007 Mar;76(3):368-78.


    .....................decreased the abundance of HSD3B, CYP11A1, and STAR proteins................



    <span style="color:#C0C0C0">.</span>

  18. #38
    Senior Member eclypz's Avatar
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    <div class='quotetop'>QUOTE (oswaldosalcedo @ Dec 11 2008, 11:16 AM) <{POST_SNAPBACK}></div><div class='quotemain'>stop the run............

    .............metformin significantly inhibited the expression of steroidogenic acute regulatory (StAR) protein and 17 alpha-hydroxylase (CYP17)..............................


    and:

    Biol Reprod. 2007 Mar;76(3):368-78.


    .....................decreased the abundance of HSD3B, CYP11A1, and STAR proteins................



    <span style="color:#C0C0C0">.</span></div>

    so the study was wrong?

  19. #39
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    No, I think he's saying that replacing the 3bHSD will solve all of the above. I could be wrong though.

  20. #40
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    this line is very important:



    ..................glucocorticoid agonist dexamethasone (DEX) increased cortisol production and 3beta-HSD mRNA levels alone...................

    of

    J Steroid Biochem Mol Biol. 2002 Sep;82(1):55-63.

    Glucocorticoids enhance activation of the human type II 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase gene





    ------------------------
    J Biol Chem. 2001 May 18;276(20):16767-71.

    Thiazolidinediones but Not Metformin Directly Inhibit the Steroidogenic Enzymes P450c17 and 3beta -Hydroxysteroid Dehydrogenase


    its not conclusive.




    <span style="color:#C0C0C0">. </span>

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