Testosterone Induced Polycythemia/Erythrocytosis (Elevated Hematocrit/Hemoglobin)

Discussion in 'Men's Health Forum' started by Michael Scally MD, Jul 21, 2010.

  1. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    testosterone regulates erythropoiesis in numerous mammalian species, including humans of both sexes (1). Excessive erythrocytosis is the most common serious adverse event associated with testosterone therapy in older men (2). However, the mechanisms by which testosterone stimulates erythropoiesis remain poorly understood.

    It has been suggested that testosterone stimulates erythropoietin secretion and directly stimulates erythroid progenitor cells (3, 4). We showed previously, however, that testosterone dose-dependently increases hemoglobin and hematocrit, but without an associated increase in erythropoietin (5). In addition, testosterone has minimal proliferative effect on purified (CD34_) erythroid progenitors ex vivo (6).

    We considered the hypothesis that testosterone increases hematocrit by suppressing the master iron regulatory peptide hepcidin, thus resulting in increased bioavailable iron. Hepcidin is a liver-derived peptide that binds to and degrades the iron channel ferroportin (7, 8). Increased hepcidin, in response to infection and inflammation restricts systemic iron bioavailability and results in mild anemia in chronic disease (9). Low hepcidin, conversely, is associated with increased iron absorption, increased systemic iron transport, and erythropoiesis.

    To test the hypothesis that testosterone suppresses serum hepcidin, we measured serum hepcidin levels in a testosterone dose response study, in which healthy younger (19–35 yr old) and older (59–75 yr) men were administered a long-acting GnRH agonist to suppress endogenous testosterone production, along with varying doses of testosterone enanthate for 20 wk (10, 11). This design produced cohorts of subjects with graded, stable levels of testosterone within 4wkthat were maintained for 20 wk. This intervention resulted in dose-dependent increases in hematocrit and hemoglobin that were greater in older than younger men (5).

    We measured serum hepcidin in serum samples from these men, and tested the hypothesis that age-related differences in erythropoietic response are related to the magnitude of hepcidin suppression. We also assessed whether early changes in hepcidin levels predict subsequent changes in hematocrit and hemoglobin.


    Bachman E, Feng R, Travison T, et al. Testosterone Suppresses Hepcidin in Men: A Potential Mechanism for Testosterone-Induced Erythrocytosis. J Clin Endocrinol Metab:jc.2010-0864. Testosterone Suppresses Hepcidin in Men: A Potential Mechanism for Testosterone-Induced Erythrocytosis

    Context: The mechanisms by which testosterone increases hemoglobin and hematocrit are unknown.

    Objective: The aim was to test the hypothesis that testosterone-induced increase in hematocrit is associated with suppression of the iron regulatory peptide hepcidin.

    Participants: Healthy younger men (ages 19-35 yr; n = 53) and older men (ages 59-75 yr; n = 56) were studied.

    Methods: Weekly doses of testosterone enanthate (25, 50, 125, 300, and 600 mg) were administered over 20 wk, whereas endogenous testosterone was suppressed by monthly GnRH agonist administration. Blood and serum parameters from each individual were measured at wk 0, 1, 2, 4, 8, and 20. Longitudinal analyses were performed to examine the relationship between hepcidin, hemoglobin, hematocrit, and testosterone while controlling for potential confounders.

    Results: High levels of testosterone markedly suppressed serum hepcidin within 1 wk. Hepcidin suppression in response to testosterone administration was dose-dependent in older men and more pronounced than in young men, and this corresponded to a greater rise in hemoglobin in older men. Serum hepcidin levels at 4 and 8 wk were predictive of change in hematocrit from baseline to peak levels.

    Conclusion: Testosterone administration is associated with suppression of serum hepcidin. Greater increases in hematocrit in older men during testosterone therapy are related to greater suppression of hepcidin.
     
    Last edited: Aug 8, 2013
  2. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Re: testosterone Induced Polycythemia (Elevated Hematocrit/Hemoglobin)

    For those of you that want some background information on Hepcidin, the following is a review.


    Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003;102(3):783-8. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation

    Human hepcidin, a 25-amino acid peptide made by hepatocytes, may be a new mediator of innate immunity and the long-sought iron-regulatory hormone. The synthesis of hepcidin is greatly stimulated by inflammation or by iron overload. Evidence from transgenic mouse models indicates that hepcidin is the predominant negative regulator of iron absorption in the small intestine, iron transport across the placenta, and iron release from macrophages. The key role of hepcidin is confirmed by the presence of nonsense mutations in the hepcidin gene, homozygous in the affected members, in 2 families with severe juvenile hemochromatosis. Recent evidence shows that deficient hepcidin response to iron loading may contribute to iron overload even in the much milder common form of hemochromatosis, from mutations in the HFE gene. In anemia of inflammation, hepcidin production is increased up to 100-fold and this may account for the defining feature of this condition, sequestration of iron in macrophages. The discovery of hepcidin and its role in iron metabolism could lead to new therapies for hemochromatosis and anemia of inflammation.
     
    Last edited: Jun 14, 2013
    Millard Baker likes this.
  3. Bridger

    Bridger Member

    Re: testosterone Induced Polycythemia (Elevated Hematocrit/Hemoglobin)

    What can be done about decreased levels of Hepcidin? Any way to limit the elevation of Hct and Hgb? Aside from reducing test dose...
     
  4. m_ob

    m_ob Member

    Polycythemia

    Anyone ever had it, and most prominent symptoms were?
     
  5. toolman

    toolman Member

    Re: Polycythemia

    High hematocrit levels due to high RBC count I beleve. Yes I got it when on 200mgs a week of test. I felt nothing other than headaches but my BP was higher. Theraputic phlebotomy is the only way to deal with it whether or not it is TRT induced
     
  6. retpsd

    retpsd Member

    Re: Polycythemia

    I've had high hematocrit levels, the symptoms I had were shortness of breath during cardio, elevated BP, general lethargy. I also had a darker red, flushed look in the neck and upper chest area. I now donate blood every couple of months and it keeps my levels in range now....it was amazing how much better I felt just 36 hrs after my first donation.
     
  7. m_ob

    m_ob Member

    Re: Polycythemia

    I'm all good with injecting things into my body, but when it comes to things being sucked out, I get pretty squeamish. Is it a big deal to have a phlebotomy if you struggle with thinking about giving blood? :p
     
  8. toolman

    toolman Member

    Re: Polycythemia

    Lol, Im exactly the same. I have no problem sticking myself in a muscle. However when it is someone sticking my vein I feel queesy as well, but you get used to it. It is actually easier than a blood draw as you do not feel that vacuum sensation from the test tubes (Although feeling that vacuum sensation may be in my head.) You sit on a recliner and they stick your arm and tape it and walk away. Takes about 10 minutes. Great for your health and helps out others as well. I dont watch either and that really helped. After one time you will not be freaked out at all. That said I still hate going for blood tests.
     
  9. m_ob

    m_ob Member

    Re: Polycythemia

    Wohoo! Who would I contact to set something like this up? Local blood bank or hospital?
     
  10. toolman

    toolman Member

    Re: Polycythemia

    Google local blood bank in your area. You would be amazed how many places there are to give blood. I never knew until I looked.
     
  11. foreveryoung

    foreveryoung Member

    Re: Polycythemia

    if we go for a blood test, what test and levels should we look at to think of ourselves as a candidate to give blood?
     
  12. toolman

    toolman Member

    Re: Polycythemia

    cbc.

    Look at your hematocrit. If it is over 50% then give blood. Youll notice your BP starts to climb, at least mine does. THere are many who argue that there are no cases of people that had problems but I disagree. Viscous blood can lead to strokes and other heart issues involving enlarged left ventricles.
     
  13. cvictorg

    cvictorg Member

    Re: Polycythemia

    I was the same way but when my hematocrit hit 55% I had no choice. So I sucked it up and went and I was surprised how EASY and painless it was.[:eek:)] Now I go every 3 -4 months and on my next visit I'll donate platelets.
     
  14. toolman

    toolman Member

    Re: Polycythemia

    That is not as easy as just blood donation. They pump the fluid back into you after the platelet removal. Never had it done myself but others have told me it fels really wierd when they pump back in.
     
  15. cvictorg

    cvictorg Member

    Re: Polycythemia

    Well then it will be an interesting new experience
     
  16. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Re: Polycythemia

    [NO] Is The Haematopoietic Effect Of testosterone Mediated By Erythropoietin?

    Maggio M, Snyder PJ, Ceda GP, et al. Is the haematopoietic effect of testosterone mediated by erythropoietin? The results of a clinical trial in older men. Andrology 2013;1(1):24-8. Is the haematopoietic effect of testosterone mediated by erythropoietin? The results of a clinical trial in older men - Maggio - 2012 - Andrology - Wiley Online Library

    The stimulatory effects of testosterone on erythropoiesis are very well known, but the mechanisms underlying the erythropoietic action of testosterone are still poorly understood, although erythropoietin has long been considered a potential mediator.

    A total of 108 healthy men >65 years old with serum testosterone concentration <475 ng/dL were recruited by direct mailings to alumni of the University of Pennsylvania and Temple University, and randomized to receive a 60-cm2 testosterone or placebo patch for 36 months. Ninety-six subjects completed the trial.

    We used information and stored serum specimens from this trial to test the hypothesis that increasing testosterone increases haemoglobin by stimulating erythropoietin production. We used information of 67 men, 43 in the testosterone group and 24 in the placebo group who had banked specimens available for assays of testosterone, haemoglobin and erythropoietin at baseline and after 36 months.

    The original randomized clinical study was primarily designed to verify the effects of testosterone on bone mineral density. The primary outcome of this report was to investigate whether or not transdermal testosterone increases haemoglobin by increasing erythropoietin levels.

    The mean age ± SD of the 67 subjects at baseline was 71.8 ± 4.9 years. Testosterone replacement therapy for 36 months, as compared with placebo, induced a significant increase in haemoglobin (0.86 ± 0.31 g/dL, p = 0.01), but no change in erythropoietin levels (?0.24 ± 2.16 mIU/mL, p = 0.91). Included time-varying measure of erythropoietin did not significantly account for the effect of testosterone on haemoglobin (Treatment-by-time: Beta = 0.93, SE = 0.33, p = 0.01). No serious adverse effect was observed.

    Transdermal testosterone treatment of older men for 36 months significantly increased haemoglobin, but not erythropoietin levels. The haematopoietic effect of testosterone does not appear to be mediated by stimulation of erythropoietin production.
     
  17. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Re: testosterone Induced Polycythemia (Elevated Hematocrit/Hemoglobin)

    Yang Q, Jian J, Katz S, Abramson SB, Huang X. 17Beta-Estradiol Inhibits Iron Hormone Hepcidin Through an Estrogen Responsive Element Half-Site. Endocrinology 2012;153(7):3170-8. http://endo.endojournals.org/content/153/7/3170.abstract

    Interaction of estrogen with iron at the systemic level is long suspected, but direct evidence linking the two is limited. In the present study, we examined the effects of 17Beta -estradiol (E2) on hepcidin, a key negative regulator of iron absorption from the liver.

    We found that transcription of hepcidin was suppressed by E2 treatment in human liver HuH7 and HepG2 cells, and this down-regulation was blocked by E2 antagonist ICI 182780. Chromatin immunoprecipitation, deletion, and EMSA detected a functional estrogen responsive element half-site that is located between ?2474 and ?2462 upstream from the start of transcription of the hepcidin gene. After cloning the human hepcidin promoter into the pGL3Luc-Reporter vector, luciferase activity was also down-regulated by E2 treatment in HepG2 cells. E2 reduced hepcidin mRNA in wild-type mice as well as in hemochromatosis Fe gene knockout mice.

    In summary, our data suggest that hepcidin inhibition by E2 is to increase iron uptake, a mechanism to compensate iron loss during menstruation. This mechanism may also contribute to increased iron stores in oral contraceptive users.
     
  18. Dr JIM

    Dr JIM Member

    Re: testosterone Induced Polycythemia (Elevated Hematocrit/Hemoglobin)

    Very enlightening DOC, yet does tolerance developing over time with chronically elevated levels H/H which typically occurs in most cases of erythropoietin mediated erythrocytosis?
    :)
     
  19. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Re: testosterone Induced Polycythemia (Elevated Hematocrit/Hemoglobin)

    What do you mean by tolerance? What conditions are you referring to for "erythropoietin mediated erythrocytosis?" As shown above, AAS medicated erythrocytosis is non-erythropoietin mediated. IIRC, PV is non-erythropoietin mediated as well.
     
  20. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Re: testosterone Induced Polycythemia (Elevated Hematocrit/Hemoglobin)

    Are the studies showing trough testosterone levels to correlate to increased H/H tracking E2 changes?

    Yang Q, Jian J, Katz S, Abramson SB, Huang X. 17Beta-Estradiol Inhibits Iron Hormone Hepcidin Through an Estrogen Responsive Element Half-Site. Endocrinology 2012;153(7):3170-8. 17?-Estradiol Inhibits Iron Hormone Hepcidin Through an Estrogen Responsive Element Half-Site

    Interaction of estrogen with iron at the systemic level is long suspected, but direct evidence linking the two is limited. In the present study, we examined the effects of 17Beta -estradiol (E2) on hepcidin, a key negative regulator of iron absorption from the liver.

    We found that transcription of hepcidin was suppressed by E2 treatment in human liver HuH7 and HepG2 cells, and this down-regulation was blocked by E2 antagonist ICI 182780. Chromatin immunoprecipitation, deletion, and EMSA detected a functional estrogen responsive element half-site that is located between ?2474 and ?2462 upstream from the start of transcription of the hepcidin gene. After cloning the human hepcidin promoter into the pGL3Luc-Reporter vector, luciferase activity was also down-regulated by E2 treatment in HepG2 cells. E2 reduced hepcidin mRNA in wild-type mice as well as in hemochromatosis Fe gene knockout mice.

    In summary, our data suggest that hepcidin inhibition by E2 is to increase iron uptake, a mechanism to compensate iron loss during menstruation. This mechanism may also contribute to increased iron stores in oral contraceptive users.
     
    Last edited: Dec 23, 2012