Golden Days of Yore Edition

JDcuth

Does anyone else tolerate most alcoholic drinks but get a headache in the hours after drinking red wine? My Dad said it runs in the family and I’ve looked into whether there may be a compound unique to red wine that causes it and opinion seems to vary (it seems quercetin is the latest suspect). I’m ok with all beers including dark beer like Guinness and white wine also doesn’t cause the same problem. Thanks for any suggestions

Mark Rippetoe

Usually, a headache indicates dehydration. I can’t imagine why red wine would preferentially cause this more than anything else. Try drinking an equal amount of water along with the wine and see what happens.

BareSteel

Keyword “tannin” might be worth researching in respect to red wine.

Jason Donaldson

My wife has had similar issues with red, but not white wines. Her sensitivity varies in intensity. I’ve heard theories about sulfites, tannins, and histamines, though nothing is certain. Avoidance is her general approach.

CbYoung

Hey Mark, I’m about to start TRT and I have a concern and wondered what your thoughts are on this. To start I have two close friends already on TRT. One is 35 and the other is 60. Both have been on TRT for a while and one of the things I have discussed with them is they have noticed a side effect of elevated red blood cell count to the point their physician was a little concerned. What causes this and what ways can it be managed if it even needs to be addressed? Also do you think the standard script of 1 CC of 100mg/ml Test C given every 2 to 3 weeks is adequate?

Mark Rippetoe

We talked about this with Dr. Keith Nichols on the podcast. Look it up, and learn other things as well. And 100mg test cyp every 2-3 weeks is not a therapeutic dose. Women are prescribed more than that. You need a better doctor, immediately.

VNV

My experience with Nichols is excellent.

J. Keith Nichols MD

Testosterone Therapy as a cause of Secondary Erythrocytosis

The most common side effect of testosterone therapy, and the one that causes the most concern for the patient and their family physician, is a secondary erythrocytosis which is an increase in red blood cells. It is often described by the patient and their physician as “thick blood” requiring a blood donation because they fear it could possibly lead to a heart attack, stroke, or blood clot.

Where does this fear originate? When the family physician or internist sees an increase in red blood cells along with hemoglobin and hematocrit, it is frequently misinterpreted as the patient having Polycythemia Vera which is a myeloproliferative neoplasm of the bone marrow (bone marrow cancer). Thrombosis (blood clots) are a leading cause of morbidity and mortality in this disorder. Polycythemia vera is known as a primary erythrocytosis where there is an unregulated proliferation of hematopoietic clonal stem cells which leads to overproduction of red blood cells, white blood cells, and platelets. In Polycythemia Vera, in contrast to the secondary erythrocytosis from testosterone therapy, not only is there a quantitative change in the number of circulating blood cells, but there is also a qualitative change that leads to the expression of procoagulant characteristics. In addition there are abnormalities involving the vascular endothelial cells which become procoagulant in response to inflammatory stimuli. These abnormalities result in a hypercoagulable state leading to an increase in arterial thrombosis and venous thrombosis. Therefore part of the recommended treatment is blood donation to reduce the risk of thrombosis. The risk of elevated hematocrit seen in patients with polycythemia vera cannot be extrapolated to hematocrit elevation seen during testosterone therapy. They are not the same and should not be treated as such.

The secondary erythrocytosis from testosterone therapy is an increase in red blood cells only leading to an increase in hemoglobin and hematocrit. The mechanisms behind testosterone stimulating red blood cell production is not completely understood but is thought to occur through stimulation of erythropoietin, stimulation of hematopoietic progenitor cells, and reduced hepcidin. A secondary erythrocytosis is also seen in other conditions such as smoking, obstructive sleep apnea, chronic obstructive pulmonary disease, and living at high altitude. While a primary erythrocytosis has been well established as a risk factor for thromboembolic events the secondary erythrocytosis from testosterone therapy has not been shown to cause an increase in thromboembolic events in any randomized control trial or prospective study to date. Most guidelines recommend following hematocrit after initiating testosterone therapy and if the Hct exceeds 54% clinicians should either adjust testosterone dosage, stop therapy, order phlebotomy, or recommend a combination of these. These recommendations are based on assumptions and the Hct cut off of 54% was arbitrarily chosen and not based on any study showing harm when this value is exceeded with testosterone therapy. The upper limit of normal for hematocrit in most laboratory reference ranges for healthy adult males is 54% which is where this value is likely derived.

This normal Hct range for men is for those without a secondary erythrocytosis and not for men on testosterone or living at high altitude for instance. There are over 80 million people that live higher than 2,500 meters and they develop a secondary erythrocytosis. Men in parts of Bolivia for instance have a normal range of Hct from 45-61%. These men are not at an increased risk of thrombotic events nor do they have to undergo phlebotomies to manage their hematocrit. One also cannot ignore the observation that literally tens of thousands of men presently use and abuse testosterone in this country and have done so for decades. A large percentage of these men are not under the supervision of a physician or getting lab work and yet we have not seen an epidemic of heart attacks, strokes, or blood clots in these men. Almost all previously reported cases of testosterone therapy-related venous thromboembolism were seen in patients with a previously undiagnosed thrombophilia like factor five Leiden deficiency.

The other concern with increasing hematocrit is that it will increase viscosity and decrease blood flow resulting in thrombotic events. In experimental studies using rigid glass viscometers or cone-plate viscometers there is a logarithmic increase in viscosity with increasing hematocrit. It is inappropriate to correlate these in vitro viscosity readings to what occurs to flowing blood through tiny distensible vessels in vivo. In other words, viscometer measures in these experiments do not translate to human blood vessels. Firstly, the flow through these narrow blood vessels is rapid (high shear rate), which in a non-Newtonian fluid such as blood causes a marked decrease in viscosity. Second, blood flowing through these narrow channels is axial with a central core of packed red blood cells sliding over a peripheral layer of lubricating low viscosity plasma. With a secondary erythrocytosis there is an increase in blood volume which enlarges the vascular bed, decreases peripheral resistance and increases cardiac output. Therefore, in a secondary erythrocytosis optimal oxygen transport with increased blood volume occurs at a higher hematocrit value than with a normal blood volume. A moderate increase in hematocrit may be beneficial despite the increased viscosity.

Testosterone also exerts multiple beneficial effects on the vasculature and its components which may protect against thrombosis. In other words testosterone has positive effects on vascular reactivity.

• Testosterone is a vasodilator and increases nitric oxide
• T decreases plasma concentrations of pro-coagulatory substances
• T improves erythrocyte membrane lipid composition and fluidity
• T increases red blood cell deformability
• T reduces levels of lipoprotein-a

Donating blood to reduce hematocrit may also provide men with a false sense of security. In a study done over a two-year period of time they looked at men who donated blood that were on testosterone therapy at least 25% of them had a hematocrit above 54% and when they came back for repeat donations 44% of them had a persistent elevation of hematocrit above 54%. So it essentially showed that repeat donations were insufficient to maintain a hematocrit below 54%.

Testosterone therapy was first used clinically 1937 and it has been used in thousands of randomized control trials. There is not a single randomized control trial to date that shows an increased risk of major adverse cardiac events with testosterone therapy.

Normal Hb/Hct

• Men 14-18/ 40-54
• Women 12-16 /36-48