Testosterone Induced Polycythemia/Erythrocytosis (Elevated Hematocrit/Hemoglobin)

[Michael Scally MD]

Aghazadeh M, Pastuszak AW, Johnson WG, McIntyre MG, Hsieh TM, Lipshultz LI. Elevated Dihydrotestosterone is Associated with Testosterone-Induced Erythrocytosis. J Urol. http://www.jurology.com/article/S0022-5347(15)00059-2/abstract

INTRODUCTION: Erythrocytosis is the most common dose-limiting adverse effect of testosterone therapy (TTh), but the mechanisms of T-mediated erythropoiesis remain unclear. In this study, we examine risk factors for erythrocytosis associated with TTh.

METHODS: Retrospective review of 179 hypogonadal men on TTh in a single andrology clinic was performed. Demographic data, TTh formulation and duration of treatment, and 5alpha reductase inhibitor (5ARI) use were assessed. Serum dihydrotestosterone (DHT), total T (TT), free T (FT), follicle stimulating hormone (FSH), luteinizing hormone (LH), Hematocrit (Hct), and lipid levels were extracted and changes during treatment determined. Spearman's rank correlation was used to identify relationships between change in Hct (DeltaHct) and study variables.

RESULTS: Of 179 patients, 49 (27%) developed a >/=10% DeltaHct and 36 (20.1%) developed erythrocytosis (Hct >/=50%) at a median follow-up of 7 months.

Topical gels were used by 41.3% of patients, injectable T by 52.5%, and subcutaneous pellets by 6.1%. More men who developed DeltaHct >/=10% used injectable T than men with DeltaHct <10% (65% vs. 48%, p=0.035), and were less likely to be on 5ARI (2% vs. 15%, p=0.017).

Men with DeltaHct >/=10% had higher post-treatment DHT levels (605.0 vs. 436.0 ng/dL, p=0.017) and lower LH and FSH levels than men with DeltaHct <10%. Spearman's rank correlations yielded relationships between DeltaHct and post-treatment DHT (rho=0.258, p=0.001) and TT (rho=0.171, p=0.023).

CONCLUSION: DHT may play a role in TTh-related erythrocytosis, and monitoring of DHT levels during TTh should be considered. In men who develop erythrocytosis, 5ARIs may be therapeutic.

 

[Michael Scally MD]

Saito H. Metabolism of Iron Stores. Nagoya J Med Sci. 2014;76(3-4):235-54. http://www.med.nagoya-u.ac.jp/medlib/nagoya_j_med_sci/7634/02_Saito.pdf

Remarkable progress was recently achieved in the studies on molecular regulators of iron metabolism. Among the main regulators, storage iron, iron absorption, erythropoiesis and hepcidin interact in keeping iron homeostasis.

Diseases with gene-mutations resulting in iron overload, iron deficiency, and local iron deposition have been introduced in relation to the regulators of storage iron metabolism. On the other hand, the research on storage iron metabolism has not advanced since the pioneering research by Shoden in 1953.

However, we recently developed a new method for determining ferritin iron and hemosiderin iron by computer-assisted serum ferritin kinetics. Serum ferritin increase or decrease curves were measured in patients with normal storage iron levels (chronic hepatitis C and iron deficiency anemia treated by intravenous iron injection), and iron overload (hereditary hemochromatosis and transfusion dependent anemia).

We thereby confirmed the existence of two iron pathways where iron flows followed the numbered order
(1) labile iron,
(2) ferritin and
(3) hemosiderin in iron deposition and mobilization among many previously proposed but mostly unproven routes.

We also demonstrated the increasing and decreasing phases of ferritin iron and hemosiderin iron in iron deposition and mobilization. The author first demonstrated here the change in proportion between pre-existing ferritin iron and new ferritin iron synthesized by removing iron from hemosiderin in the course of iron removal.

In addition, the author disclosed the cause of underestimation of storage iron turnover rate which had been reported by previous investigators in estimating storage iron turnover rate of normal subjects.



Interactions Among The Major Factors Regulating Iron Homeostasis

These factors; iron absorption, erythropoiesis, storage iron and hepcidin, are regulated by erythropoietin, transferrin saturation, interleukins, divalent metal transporter 1, iron regulatory proteins, iron responsive element, hemojuvelin, hypoxia-inducible factor, growth differentiation factor 15, and others.

 

[Burrr]

subbed to this thread for future reading.

 

[Michael Scally MD]

Hepcidin: Regulation of the Master Iron Regulator

In addition to growth factors, hormones like oestrogen and testosteron have been known to affect HAMP (HAMP, hepcidin anti-microbial peptide; type 2B) synthesis.

Treatment of cells with 17β-oestradiol (E2) decreased HAMP levels, this was shown to be mediated through direct binding to the oestrogen-response elements on the HAMP promoter. In another study, it was shown that treatment of HuH7 and HepG2 cells with E2 increases HAMP.

Unlike the effects of oestrogen, testosterone has been shown to reduce the levels of HAMP. Until recently, it was unclear whether this down-regulation is a direct or indirect effect (due to increased erythropoiesis), when it was shown that even in the presence of an EPO neutralizing antibody, testosterone treatment reduced Hamp levels in micE.

Rishi G, Wallace DF, Subramaniam VN. Hepcidin: regulation of the master iron regulator. Biosci Rep. 2015;35(3). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438303/

Iron, an essential nutrient, is required for many diverse biological processes.

The absence of a defined pathway to excrete excess iron makes it essential for the body to regulate the amount of iron absorbed; a deficiency could lead to iron deficiency and an excess to iron overload and associated disorders such as anaemia and haemochromatosis respectively.

This regulation is mediated by the iron-regulatory hormone hepcidin. Hepcidin binds to the only known iron export protein, ferroportin (FPN), inducing its internalization and degradation, thus limiting the amount of iron released into the blood.

The major factors that are implicated in hepcidin regulation include iron stores, hypoxia, inflammation and erythropoiesis.

The present review summarizes our present knowledge about the molecular mechanisms and signalling pathways contributing to hepcidin regulation by these factors.

 

[Avies48]

Sooo my question:

Other than stopping trt, is there any way to turn the hepcidin back on thru another means???

 

[blazinshotguns]

Is it an issue of red blood cell count is high, but hemoglobin is normal ?

 

[Bodo III]

When RBC is high and HGB/HCT is normal, often MCV and MCH will be low and RWD will be high.
I believe this is caused by the counteracting forces of T driving erythropoiesis and diminished iron stores (low ferritin) limiting the amount of hemoglobin in individual blood cells. Essentially a somewhat distorted blood profile.

 

[Michael Scally MD]

Jones SD, Dukovac T, Sangkum P, Yafi FA, Hellstrom WJG. Erythrocytosis and Polycythemia Secondary to Testosterone Replacement Therapy in the Aging Male. Sexual Medicine Reviews 2015;3(2):101-12. http://onlinelibrary.wiley.com/doi/10.1002/smrj.43/abstract

Introduction Testosterone replacement therapy (TRT) is a common treatment for hypogonadism in aging males. Men with low to low-normal levels of testosterone have documented benefit from hormone replacement.

Recent meta-analyses have revealed that increases in hemoglobin (Hb) and hematocrit (Hct) are the variants most commonly encountered. Clinically, this response is described as erythrocytosis or polycythemia secondary to TRT. However, the recent Food and Drug Administration warning regarding the risk for venothromboembolism (VTE) has made the increases in Hb and Hct of more pertinent concern. The risks associated with androgen replacement need further examination.

Aim To review the available literature on erythrocytosis and polycythemia secondary to TRT. To discuss potential etiologies for this response, the role it plays in risk for VTE, and recommendations for considering treatment in at-risk populations.

Methods A literature review was performed through PubMed regarding TRT and erythrocytosis and polycythemia.

Main Outcome Measures To assess the mechanisms of TRT-induced erythrocytosis and polycythemia with regard to basic science, pharmacologic preparation, and route of delivery. To review Hct and risk for thrombotic events. To offer clinical suggestions for therapy in patients at risk for veno-thrombotic events.

Results Men undergoing TRT have a 315% greater risk for developing erythrocytosis (defined as Hct > 0.52) when compared with control. Mechanisms involving iron bioavailability, erythropoietin production, and bone marrow stimulation have been postulated to explain the erythrogenic effect of TRT. The association between TRT-induced erythrocytosis and subsequent risk for VTE remains inconclusive.

Conclusions All TRT formulations cause increases in Hb and Hct, but injectables tend to produce the greatest effect. The evidence regarding the risk for VTE with increased Hct is inconclusive. For patients with risk factors for veno-thrombotic events, formulations that provide the smallest effect on blood parameters hypothetically provide the safest option. Further trials are needed to fully evaluate the hematological side effects associated with TRT.

 

[GarageLifter]

Phytates, Oxalates, Phosphates and Polyphenols

• Phytates are found in legumes, grains and rice as well as many other plant foods and can reduce iron absorption by as much as 50 percent. However, consuming vitamin C with phytates can negate this effect. Another compound that can reduce bodily uptake of iron are oxalates, which are found in chocolate and spinach, as will the phosphates found in sodas. Polyphenols are an antioxidant found in red wine and grape juice, as well as coffee, tea and some fruits and vegetables. Polyphenols will, unfortunately, also interfere with the bodily absorption of iron.
  

Tannins

• Tannins are a chemical in certain plants that discourage the consumption of those plants by herbivores. Tannins are found in coffee and tea and are another compound that decreases iron absorption.
  

Fiber

• Foods high in fiber, such as wheat bran, may interfere in iron absorption.
  

Minerals

• Foods high in other minerals such as calcium, zinc, magnesium and copper will decrease iron absorption. Milk products are included in this category, as they are high in calcium.
  

Proteins

• The protein found in legumes such as lentils, mung beans, split peas and black beans will reduce iron absorption, as will soy proteins and the proteins found in the yolk and the white of eggs.
  

Medications and Herbs

• Certain medications, such as antacids, histamine blockers or proton-pump inhibitors can also reduce the absorption of iron. Also, certain herbs, such as peppermint and chamomile, if taken in large quantities, will decrease iron absorption.
  

Increasing Iron Absorption

• Eating foods high in vitamin C can improve iron uptake enough to outweigh the iron-blocking effects of certain foods. It is a good idea to only eat iron-blocking foods several hours before or after iron-rich foods or supplements to maximize the uptake of this mineral.
  

Read more : http://www.ehow.com/list_7165582_foods-block-iron.html

 

[GarageLifter]

http://healthyeating.sfgate.com/lower-iron-levels-food-7736.html

Eggs and milk help block iron absorption.
You can affect the levels of iron absorbed into your bloodstream by adjusting the foods you eat, but before you make any changes, be sure you're getting the amount needed to maintain optimal health. Iron is crucial to many life-sustaining processes, and you shouldn't purposefully lower your levels without first consulting your health care provider.
Basics
If you’re not sure how much iron you consume, track the foods you eat for a few days. Men should get 8 milligrams daily, while pre-menopausal women need 18 milligrams. To lower iron, you need to do more than simply eat low-iron foods. You’ll have to target the foods that impact the amount of iron that enters your bloodstream, eating more of those that inhibit absorption and less of the foods that enhance it. The combination of foods eaten together, the amount of each one you eat and your body’s current iron needs determine how much iron is actually absorbed. Those various factors make it difficult to calculate the exact impact of your diet on iron levels.
Heme vs. Non-Heme Iron
There are two forms of iron found in food: heme and non-heme. Heme iron, which is in meat, fish and poultry, is absorbed two to three times more efficiently than non-heme iron. Whole grains, legumes, fruits and vegetables all contain non-heme iron. To lower levels of iron, limit the heme-containing foods you eat. Legumes and beans make good choices for alternative sources of protein because they're high in protein and the iron they contain is not easily absorbed. Your body may only absorb as little as 2 percent of the iron in legumes, such as lentils, black beans and split peas.
Non-Heme Inhibitors
The amount of non-heme iron your body absorbs is highly sensitive to foods that enhance or block it during digestion. Two plant-based substances, phytates and polyphenols, bind with non-heme iron and block its absorption during digestion. Phytates are found in whole grains, nuts, seeds, beans, soy products and tubers such as potatoes. Eating just a small amount of phytate may reduce non-heme iron absorption by 50 percent, according to the Linus Pauling Institute. You’ll get polyphenols from tea, coffee, cocoa and green leafy vegetables.
Heme Inhibitor
Calcium is the one substance that’s able to interfere with the absorption of heme iron. It won’t have an impact in small amounts, but consuming 300 to 600 milligrams is enough to stop some heme iron from entering your system. If you drink 1 cup of low-fat milk with your meal, its 314 milligrams of calcium are just enough to have an influence.
Absorption Enhancers
Don’t eat foods that are high in vitamin C at the same time you eat foods with iron because its one of the best enhancers of iron absorption. Foods that are rich in vitamin C may double or triple the bio-availability of iron, according to the Food and Agricultural Organization of the United Nations. Eating heme sources of iron at the same time as non-heme sources also increases the amount of iron absorbed from non-heme foods.

 

[Michael Scally MD]

The Role of Testosterone in the Utilization of Iron in Erythropoiesis
https://endo.confex.com/endo/2016endo/webprogram/Paper27007.html

Since the syndrome of hypogonadotropic hypogonadism (HH) is associated with anemia and the administration of testosterone restores hematocrit to normal, we investigated the potential mechanisms which may contribute to it.

We measured serum concentrations of erythropoietin, iron, iron binding capacity, transferrin (saturated and unsaturated), ferritin and hepcidin and the expression of ferroportin in peripheral blood mononuclear cells (MNC) of 94 men with type 2 diabetes. 44 men had HH (defined as free testosterone <5ng/dl along with low or normal LH concentrations) while 50 were eugonadal.

Hematocrit concentrations were lower in hypogonadal men (41.2±3.8% vs. 43.8±3.2%, p=0.001). There were no differences in plasma concentrations of hepcidin, ferritin, erythropoietin, transferrin, iron or transferrin saturation or in ferroportin expression in MNC among hypogonadal and eugonadal men.

Men with HH were randomized to testosterone treatment (200 mg i.m., every two weeks) or placebo (saline 1ml every 2 weeks) for 24 weeks. 20 men in testosterone group and 14 men in placebo group completed the study.

Free testosterone concentrations increased from 4.5±1.3 to 13.8±4.1ng/dl (p<0.001) after testosterone therapy but did not change in placebo group.
The hematocrit increased from 42.0±2.7% to 45.4±4.6% (p<0.001) but did not change after placebo (40.7±2.9% to 41.6±3.1%, p=0.22).

There was a 30±7% decrease in plasma hepcidin (p<0.01) and 29±8% increase in erythropoietin concentrations (p<0.05) after testosterone therapy.

There was no significant change in iron or ferritin concentrations but transferrin concentration increased by 21±7% and transferrin saturation decreased by 30±10% (p<0.01). Ferroportin mRNA expression in MNC increased by 70±13% (p<0.01) at 4 weeks and 15 weeks but came back to baseline at 24 weeks after testosterone therapy when the hematocrit normalized. There was no change in any of these parameters after placebo.

We conclude that the administration of testosterone to restore normal testosterone concentration led to a significant increase in plasma erythropoietin concentrations, reduction in plasma hepcidin concentration, marked increase in ferroportin expression which was transient, a smaller but significant increase in transferrin and a small reduction in plasma iron concentrations.

Clearly, therefore, the increase in hematocrit is supported by an increase in erythropoietin and an increase in iron transport through an increase in ferroportin. This increase is probably through the known suppression of hepcidin which suppresses ferroportin expression.

 

[Dr JIM]

^^^
Nice summation of the physiologic mechanisms believed responsible for "TRT" erythropoiesis.

 

[Michael Scally MD]

Sangkhae V, Nemeth E. Regulation of the Iron Homeostatic Hormone Hepcidin. Adv Nutr 2017;8(1):126-36. Regulation of the Iron Homeostatic Hormone Hepcidin

Iron is required for many biological processes but is also toxic in excess; thus, body iron balance is maintained through sophisticated regulatory mechanisms. The lack of a regulated iron excretory mechanism means that body iron balance is controlled at the level of absorption from the diet.

Iron absorption is regulated by the hepatic peptide hormone hepcidin. Hepcidin also controls iron release from cells that recycle or store iron, thus regulating plasma iron concentrations. Hepcidin exerts its effects through its receptor, the cellular iron exporter ferroportin.

Important regulators of hepcidin, and therefore of systemic iron homeostasis, include plasma iron concentrations, body iron stores, infection and inflammation, and erythropoiesis.

Disturbances in the regulation of hepcidin contribute to the pathogenesis of many iron disorders: hepcidin deficiency causes iron overload in hereditary hemochromatosis and nontransfused beta-thalassemia, whereas overproduction of hepcidin is associated with iron-restricted anemias seen in patients with chronic kidney disease, chronic inflammatory diseases, some cancers, and inherited iron-refractory iron deficiency anemia.

This review summarizes our current understanding of the molecular mechanisms and signaling pathways involved in the control of hepcidin synthesis in the liver, a principal determinant of plasma hepcidin concentrations.

 

[ddp7]

Sangkhae V, Nemeth E. Regulation of the Iron Homeostatic Hormone Hepcidin. Adv Nutr 2017;8(1):126-36. Regulation of the Iron Homeostatic Hormone Hepcidin

Iron is required for many biological processes but is also toxic in excess; thus, body iron balance is maintained through sophisticated regulatory mechanisms. The lack of a regulated iron excretory mechanism means that body iron balance is controlled at the level of absorption from the diet.

Iron absorption is regulated by the hepatic peptide hormone hepcidin. Hepcidin also controls iron release from cells that recycle or store iron, thus regulating plasma iron concentrations. Hepcidin exerts its effects through its receptor, the cellular iron exporter ferroportin.

Important regulators of hepcidin, and therefore of systemic iron homeostasis, include plasma iron concentrations, body iron stores, infection and inflammation, and erythropoiesis.

Disturbances in the regulation of hepcidin contribute to the pathogenesis of many iron disorders: hepcidin deficiency causes iron overload in hereditary hemochromatosis and nontransfused beta-thalassemia, whereas overproduction of hepcidin is associated with iron-restricted anemias seen in patients with chronic kidney disease, chronic inflammatory diseases, some cancers, and inherited iron-refractory iron deficiency anemia.

This review summarizes our current understanding of the molecular mechanisms and signaling pathways involved in the control of hepcidin synthesis in the liver, a principal determinant of plasma hepcidin concentrations.

Thanks

 

[BBC3]

Keep SUCKING COCK AND SWALLOWING CUM.. Yea that will get you there DDP...

Thanks

 

[Michael Scally MD]

Hepcidin Is Not Essential for Mediating Testosterone's Effects on Erythropoiesis

Background We have shown that testosterone administration suppresses hepcidin, stimulates iron-dependent erythropoiesis, and increases hemoglobin and hematocrit.

Objective We investigated whether testosterone-mediated suppression of hepcidin plays an essential role in mediating testosterone's stimulatory effects on erythropoiesis.

Methods We utilized two mouse models to elucidate the role of hepcidin as a mediator of testosterone's effects on erythropoiesis:

First, we used a whole-body hepcidin knockout (HepKO) mouse. Because testosterone's effects on hepcidin expression are mediated through androgen receptor, we also utilized a liver-specific androgen receptor knockout mouse (L-ArKO).

Effects of 6 weeks of testosterone (50 mg/kg weekly) administration relative to vehicle on hemoglobin and hematocrit, red blood cell indices, and markers of iron stores and availability were compared between wild-type (WT) and the two genetically modified mouse models.

Results HepKO mice had significantly higher baseline levels of hemoglobin, hematocrit, serum and liver iron, and ferritin than WT mice. Compared to vehicle group, testosterone administration was associated with significant increases in hematocrit, hemoglobin, red cell counts, reticulocyte count, reticulocyte hemoglobin, and serum iron levels in both HepKO and WT mice.

Baseline hematocrit levels did not differ between WT and L-ArKO mice.

Compared to vehicle, testosterone treatment was associated with significantly greater increase in hematocrit, hemoglobin, red cell count, reticulocyte count, reticulocyte hemoglobin, and serum iron in WT and L-ArKO mice.

Conclusion Although hepcidin suppression by testosterone increases iron availability and erythropoiesis, hepcidin suppression is not essential for mediating testosterone's effects on erythropoiesis in healthy mice.

Guo W, Schmidt PJ, Fleming MD, Bhasin S. Hepcidin is not essential for mediating testosterone's effects on erythropoiesis. Andrology 2019;0. https://doi.org/10.1111/andr.12622