Testosterone Induced Polycythemia/Erythrocytosis (Elevated Hematocrit/Hemoglobin)

[Dr JIM]

DOC
Tolerance to chronically elevated erythropoietin levels occurs in patients with Renal Failure such that blood donation is rarely required, is one example.
Thx
Jim

 

[Millard]

Therapeutic phlebotomy is not only way to keep AAS - induced polycythemia in check. Cycling 100 to 200 miles per week will do the trick too

 

[demon]

HRT and controling RBC/Hemog/Crit

Just curious how many guys on HRT have trouble keeping these in acceptable ranges? I've been on HRT (125mg a week)for several years and until recently I have been unable to get these numbers to drop. For the lat 2 years I've donated blood every 8 weeks. My latest bloods are RBC 6.3, Hemoglobin 17, Hemocrit 51.

 

[Demondosage]

Re: HRT and controling RBC/Hemog/Crit

yes, I'm right there with you. I've been on 200mg/wk for the past year, but before that I was doing my own TRT, so probably about past 3-4 yrs straight on test. I just started donating blood myself, my numbers are almost identical to what your are at. Recently my A1C starting coming in higher and higher, I was at 6.4 last time it was checked so Dr. put me on metformin to try and get it lower. The issue with me is I've been adding shit to the mix now for awhile, every 12 wks i just change compounds and only discontinue about 3-4 wks before my boodwork. I'm dropping everything besides my test and increasing my cardio to 5x/wk and see if I cant get the #'s down. The fucked up part is my cholesterol and liver values are actually good!!

 

[Demondosage]

Re: HRT and controling RBC/Hemog/Crit

I also should add that although I think HRT gives you a better quality of life, when it gets to be a very prolonged period of time you've been on (several years) more and more precautions need to be taken to keep #'s in check. If its monitored and adjusted accordingly its a good thing, but let something sip out of whack and your walking around like a ticking time bomb

 

[demon]

Re: HRT and controling RBC/Hemog/Crit

I agree about the quality of life. My hrt dr. just gives me the run around. Wants me to try gel instead of injections. Ive thought about giving it a break but im worried about my T levels bottoming out and how that would affect me healthwise.


QUOTE=Demondosage;855475]I also should add that although I think HRT gives you a better quality of life, when it gets to be a very prolonged period of time you've been on (several years) more and more precautions need to be taken to keep #'s in check. If its monitored and adjusted accordingly its a good thing, but let something sip out of whack and your walking around like a ticking time bomb[/QUOTE]

 

[demon]

Re: HRT and controling RBC/Hemog/Crit

Here's a response I received from another board I belong too...Just thought I would pass it along for everyone to read.............................


It's the nature of the beast, rather sucks. Essentially what is happening under normal circumstances is, we have a part of our liver that controls our Iron levels, it's referred to as Hepcidin.
Testosterone is known to suppress Hepcidin therefore increasing Iron uptake in blood, hence the elevation of Hemoglobin. It seems that as we age the use of Exogenous Testosterone further suppress Hepcidin more so than in younger aged males, unless they (younger males) are predisposed to hereditary Hemochromatosis, in which this is believed to be a congenital defect with Hepcidin regulation.

Another possibility that those on TRT tend to ignore is OSA, sleep apnea is common place for increased Testosterone levels. In the presence of sleep apnea, Hypoxic hypoxia is a result of insufficient oxygen available to the lungs during sleep hours, when this happens our body sends a signal to our bone marrow to increase Red Blood Cell production.

So with all that said, there's possibly a few other causes that's raising your HH, ie; Iron intake or some other underlying cause such as heart and lung diseases, smoking, dehydration ect, ect.

Some feel that cardio helps lower HH, for me, not so much, as I've run anywhere from 3-4 miles every morning. What helped me from having monthly phlebotomies was being diagnosed with OSA and wearing my CPAP religiously every night.

 

[vantage108]

Re: HRT and controling RBC/Hemog/Crit

My hematocrit was up to 53 when tested last June -- not "red alert" territory, but top of the range. I upped my cardio and in December it was 49. My doc says no cause for concern right now, but we're watching it.

 

[demon]

Re: HRT and controling RBC/Hemog/Crit

do you thing cardio helped in dropping it? Were you doing anything else different? Ive stopped cardio once summer was over so I think I may start cardio back up.

My hematocrit was up to 53 when tested last June -- not "red alert" territory, but top of the range. I upped my cardio and in December it was 49. My doc says no cause for concern right now, but we're watching it.

 

[vantage108]

Re: HRT and controling RBC/Hemog/Crit

do you thing cardio helped in dropping it? Were you doing anything else different? Ive stopped cardio once summer was over so I think I may start cardio back up.

I don't know for sure. It's not a huge drop and some or all of it could be attributed to day-to-day variability. But cardio is the one significant thing I changed over that period, and it did come down, so I figured it was worth mentioning in this thread.

 

[Michael Scally MD]

Guo W, Bachman E, Li M, et al. Testosterone Administration Inhibits Hepcidin Transcription and is Associated with Increased Iron Incorporation into Red Blood Cells. Aging Cell. Testosterone Administration Inhibits Hepcidin Transcription and is Associated with Increased Iron Incorporation into Red Blood Cells - Guo - Aging Cell - Wiley Online Library

Testosterone administration increases hemoglobin levels and has been used to treat anemia of chronic disease. Erythrocytosis is the most frequent adverse event associated with testosterone therapy of hypogonadal men, especially older men. However, the mechanisms by which testosterone increases hemoglobin remain unknown.

Testosterone administration in male and female mice was associated with a greater increase in hemoglobin and hematocrit, reticulocyte count, reticulocyte hemoglobin concentration, and serum iron and transferring saturation than placebo.

Testosterone downregulated hepatic hepcidin mRNA expression, upregulated renal erythropoietin mRNA expression, and increased erythropoietin levels. Testosterone-induced suppression of hepcidin expression was independent of its effects on erythropoietin or hypoxia-sensing mechanisms. Transgenic mice with liver-specific constitutive hepcidin over-expression failed to exhibit the expected increase in hemoglobin in response to testosterone administration.

Testosterone upregulated splenic ferroportin expression and reduced iron retention in spleen. After intravenous administration of transferrin-bound 58Fe, the amount of 58Fe incorporated into red blood cells was significantly greater in testosterone-treated mice than in placebo-treated mice. Serum from testosterone-treated mice stimulated hemoglobin synthesis in K562 erythroleukemia cells more than that from vehicle-treated mice.

Testosterone administration promoted the association of androgen receptor (AR) with Smad1 and Smad4 to reduce their binding to BMP-response elements in hepcidin promoter in the liver. Ectopic expression of AR in hepatocytes suppressed hepcidin transcription; this effect was blocked dose-dependently by AR antagonist flutamide.

Testosterone did not affect hepcidin mRNA stability.

Conclusion: Testosterone inhibits hepcidin transcription through its interaction with BMP-Smad signaling. Testosterone administration is associated with increased iron incorporation into red blood cells.

 

[Dr JIM]

Interesting stuff DOC!

However I'm curious, because in the majority of patients on TRT the H/H either normalizes or "stabilizes" over time.

Could the return or maintenance of baseline hepcidin levels be used as marker for erythrocytosis tolerance to supplemental testosterone therapy?

I've looked quite extensively yet can't locate any studies which cofirm or refute this possibility?

Jim

 

[Michael Scally MD]

Preza GC, Pinon R, Ganz T, Nemeth E. Cellular Catabolism of the Iron-Regulatory Peptide Hormone Hepcidin. PLoS One 2013;8(3):e58934. PLOS ONE: Cellular Catabolism of the Iron-Regulatory Peptide Hormone Hepcidin

Hepcidin, a 25-amino acid peptide hormone, is the principal regulator of plasma iron concentrations. Hepcidin binding to its receptor, the iron exporter ferroportin, induces ferroportin internalization and degradation, thus blocking iron efflux from cells into plasma. The aim of this study was to characterize the fate of hepcidin after binding to ferroportin. We show that hepcidin is taken up by ferroportin-expressing cells in a temperature- and pH-dependent manner, and degraded together with its receptor. When Texas red-labeled hepcidin (TR-Hep) was added to ferroportin-GFP (Fpn-GFP) expressing cells, confocal microscopy showed co-localization of TR-Hep with Fpn-GFP. Using flow cytometry, we showed that the peptide was almost completely degraded by 24 h after its addition, but that lysosomal inhibitors completely prevented degradation of both ferroportin and hepcidin. In addition, using radio-labeled hepcidin and HPLC analysis we show that hepcidin is not recycled, and that only degradation products are released from the cells. Together these results show that the hormone hepcidin and its receptor ferroportin are internalized together and trafficked to lysosomes where both are degraded.

 

[Michael Scally MD]

Transcriptional Regulation Of Hepcidin Expression In Mice By Testosterone
Transcriptional regulation of hepcidin expression in mice by testosterone -- Guo et al. 34 (3): SAT-345 -- Endocrine Reviews

Background. Hepcidin is a hepatocyte-secreted hormone transcriptionally regulated by the BMP/Smad1 signaling pathway. Hepcidin functions by inhibiting iron release from tissue store into bloodstream, hence indirectly limiting iron availability for erythropoiesis. Testosterone is known to increase hemoglobin and hematocrit in human and animal models. This pro-erythropoietic effect is associated with a reduction of serum hepcidin in men after testosterone supplementation.

Hypothesis. Testosterone, via its nuclear receptor, may directly down-regulate hepcidin expression; this effect may contribute to increase iron bioavailability to enhance erythropoiesis and increase red cell mass.

Methods. Testosterone was administered to female and castrated male mice. The effect of testosterone on liver expression of hepcidin and its upstream regulatory pathway was examined by real-time PCR, Western analysis, and ChIP. The effect of testosterone on hepcidin promoter activity was measured by luciferase reporter assays in HepG2 cells. The model of signal interference between androgen receptor (AR) and BMP/Smad1 was further tested in vivo by co-treatment of testosterone with dorsomorphin, a Smad1 inhibitor and in vitro by co-treatment of testosterone with BMP2, a Smad1 activator, for their collective effect on hepcidin expression. Functional readouts were measured as the effect of testosterone on splenic ferroportin expression, splenic iron store, serum iron, and iron incorporation into red cells in vivo as well as serum-induced hemoglobin accumulation in K562 erythroleukemia cells.

Results. Testosterone down-regulated hepatic hepcidin mRNA expression in mice, in association with increased splenic ferroportin protein level, reduced splenic iron store, and increased serum iron. Testosterone-treated mice showed increased red cell mass and greater red cell iron incorporation after i.v. administration of transferrin-bound 58Fe. Serum from testosterone-treated mice stimulated hemoglobin synthesis in K562 cells more than serum from vehicle-treated mice. The pro-erythropoietic effect of testosterone was abolished in mice with liver-specific transgenic expression of hepcidin. Administration of Smad1 inhibitor alone inhibited hepcidin expression similar to testosterone but the effect was not enhanced further by co-treatment with both. Testosterone promoted the association of AR with Smad1 and Smad4 and reduced their binding to the BMP-response elements in hepcidin promoter in the liver. Ectopic expression of AR in hepatocytes suppressed hepcidin transcription; this effect was blocked dose-dependently by AR antagonist flutamide and by Smad1 activator BMP2.

Conclusion. Testosterone inhibits hepcidin transcription through its interaction with BMP-Smad signaling, which may contribute to the increased serum iron and enhanced erythropoietic activity.

 

[Michael Scally MD]

Bachman E, Travison TG, Basaria S, et al. Testosterone Induces Erythrocytosis via Increased Erythropoietin and Suppressed Hepcidin: Evidence for a New Erythropoietin/Hemoglobin Set Point. J Gerontol A Biol Sci Med Sci. Testosterone Induces Erythrocytosis via Increased Erythropoietin and Suppressed Hepcidin: Evidence for a New Erythropoietin/Hemoglobin Set Point

BACKGROUND: The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear.

METHODS: We assessed the hormonal and hematologic responses to testosterone administration in a clinical trial in which older men with mobility limitation were randomized to either placebo or testosterone gel daily for 6 months.

RESULTS: The 7%-10% increase in hemoglobin and hematocrit, respectively, with testosterone administration was associated with significantly increased erythropoietin (EPO) levels and decreased ferritin and hepcidin levels at 1 and 3 months. At 6 months, EPO and hepcidin levels returned toward baseline in spite of continued testosterone administration, but EPO levels remained nonsuppressed even though elevated hemoglobin and hematocrit higher than at baseline, suggesting a new set point. Consistent with increased iron utilization, soluble transferrin receptor (sTR) levels and ratio of sTR/log ferritin increased significantly in testosterone-treated men. Hormonal and hematologic responses were similar in anemic participants. The majority of testosterone-treated anemic participants increased their hemoglobin into normal range.

CONCLUSIONS: Testosterone-induced increase in hemoglobin and hematocrit is associated with stimulation of EPO and reduced ferritin and hepcidin concentrations. We propose that testosterone stimulates erythropoiesis by stimulating EPO and recalibrating the set point of EPO in relation to hemoglobin and by increasing iron utilization for erythropoiesis.

 

[Michael Scally MD]

Fung E, Nemeth E. Manipulation of the hepcidin pathway for therapeutic purposes. Haematologica 201;98(11):1667-76. Manipulation of the hepcidin pathway for therapeutic purposes

Hepcidin, the liver-produced peptide hormone, is a principal regulator of iron homeostasis. Abnormal hepcidin production has emerged as a causative factor in several common iron disorders. Hepcidin insufficiency results in iron overload in hereditary hemochromatosis and iron-loading anemias, whereas hepcidin excess causes or contributes to the development of iron-restricted anemias in inflammatory diseases, infections, some cancers and chronic kidney disease. Not surprisingly, hepcidin and related pathways have become the target for the development of novel therapeutics for iron disorders. In this review, we will summarize the strategies and development programs that have been devised for agonizing or antagonizing hepcidin and its receptor ferroportin.

 

[Dr JIM]

Nice overview, thx DOC

 

[foreveryoung]

at what hemocrit level are doctors recommending phlebotomy?

my last test came up rbc 5.7 ter/L range (4.20-5.40)

being just over high range, is that just something that would be watched in the future with no action taken in the present?

 

[Michael Scally MD]

Polycythemia/Erythrocytosis & Estradiol

During pregnancy, females require increased blood volume and cells to maintain adequate circulation. Hematopoietic stem cells (HSCs) are a population of self-renewing precursor cells that reside in the bone marrow and spleen and respond to extracellular cues by undergoing proliferation and differentiation to produce blood cells.

Nakada et al. found that, compared with male mice, female mice exhibited increased proliferation of HSCs without depletion of the stem cell pool, indicative of self-renewal. Ovariectomy, but not castration, eliminated the difference in HSC proliferation between males and females.

Estrogen E2 administration to castrated or intact male mice or ovariectomized female mice stimulated incorporation of BrdU (a marker of cell division) into HSCs, increased the frequency of cells positive for an HSC marker, and reduced the number of cells positive for a fluorescently tagged histone, indicative of increased cell division.

Whereas E2 stimulated HSC self-renewal, administration of an inhibitor of estrogen synthesis to female mice reduced HSC proliferation. Conditional knockout of the estrogen receptor alpha (ER?) from hematopoietic cells resulted in reduced incorporation of BrdU in HSCs of female, but not male, mice.

Pregnant female mice with the conditional ER? knockout failed to show the increase in HSC frequency in the spleen observed in wild-type pregnant female mice. However, the increase in HSC frequency in the bone marrow was not affected, suggesting that the bone marrow responds to other systemic regulators of HSC proliferation.

This study identifies a gender-specific difference in stem cell regulation and may explain some of the physiological changes associated with human pregnancy, such as enlarged spleen.


Nakada D, Oguro H, Levi BP, et al. Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy. Nature 2014;505(7484):555-8. http://www.nature.com/nature/journal/v505/n7484/full/nature12932.html

Sexually dimorphic mammalian tissues, including sexual organs and the brain, contain stem cells that are directly or indirectly regulated by sex hormones. An important question is whether stem cells also exhibit sex differences in physiological function and hormonal regulation in tissues that do not show sex-specific morphological differences.

The terminal differentiation and function of some haematopoietic cells are regulated by sex hormones, but haematopoietic stem-cell function is thought to be similar in both sexes. Here we show that mouse haematopoietic stem cells exhibit sex differences in cell-cycle regulation by oestrogen.

Haematopoietic stem cells in female mice divide significantly more frequently than in male mice. This difference depends on the ovaries but not the testes. Administration of oestradiol, a hormone produced mainly in the ovaries, increased haematopoietic stem-cell division in males and females.

Oestrogen levels increased during pregnancy, increasing haematopoietic stem-cell division, haematopoietic stem-cell frequency, cellularity, and erythropoiesis in the spleen. Haematopoietic stem cells expressed high levels of oestrogen receptor-alpha (ERalpha). Conditional deletion of ERalpha from haematopoietic stem cells reduced haematopoietic stem-cell division in female, but not male, mice and attenuated the increases in haematopoietic stem-cell division, haematopoietic stem-cell frequency, and erythropoiesis during pregnancy.

Oestrogen/ERalpha signalling promotes haematopoietic stem-cell self-renewal, expanding splenic haematopoietic stem cells and erythropoiesis during pregnancy.

 

[toolman]

at what hemocrit level are doctors recommending phlebotomy?

my last test came up rbc 5.7 ter/L range (4.20-5.40)

being just over high range, is that just something that would be watched in the future with no action taken in the present?

How much test are you on? Mine is just north of normal as well and the endo said not to worry about it. I donate blood now which brings it down.