The following was sent to me by Dr. Keith Nichols:
J. Keith Nichols, MD
John Keith Nichols is the Medical Director and CEO of Tier 1 Health and Wellness.
Dr. Nichols is an author and a speaker who has become recognized as one of America’s foremost experts in testosterone replacement therapy and hormone optimization. Dr. Nichols is also a notable physician in the emerging field of endocrine disrupting chemicals. He is board certified in physical medicine and rehabilitation and is well known for his skill and expertise in the areas of interventional spinal procedures. Dr. Nichols is a graduate of the Medical College of Georgia in Augusta, Ga. He completed his residency training at the University of Louisville in Louisville, Ky.
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 over production 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.
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.
Currently, numerous testosterone formulations are
available, including short and long-acting injections, topical
gels, topical creams, implantable pellets, transdermal and
buccal patches, oral testosterone , and nasal sprays. All
types of testosterone therapies result in a statistically
significant increase in hematocrit when compared to placebo
and this increase is more pronounced in older than younger
men. These increases in hematocrit are both dose
dependent and serum level dependent. Short acting
testosterone injections have been associated with a greater
incidence of increased hematocrit compared with other
methods of delivery in multiple studies. These studies did not
include any compounded products such as the compounded
testosterone cream that is available in concentrations up to
200 mg/ gram in various delivery bases. This 20%
concentration is much higher than the commercially available
topical testosterone creams or gels. The serum levels of
testosterone obtained with these compounded products are
similar to that obtained with the short acting injectable
testosterone preparations , therefore, the incidence of
increased hematocrit may not differ significantly between
these two methods of delivery.
Guidelines vary depending on the country and the medical
society with regard to the upper limit of normal for
hematocrit in men on testosterone therapy. The Canadian
guidelines cite a hematocrit of 55% as the safe upper limit,
while the European Association of urology, the American
Urology Association, and the Endocrine society state that
the hematocrit should not exceed 54%. 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. In fact, when Dr. Glenn Cunningham
one of the authors of the Endocrine Society's guidelines for
testosterone therapy was asked by Dr. Abraham
Morgentaler where the upper limit of 54% came from he
replied that “the number was not based on any actual
medical data ,but we had to pick a number and it seemed like
a reasonable number.”
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. Also creating
confusion is the fact that different labs have different
upper limits of normal for hematocrit. Some may use an
upper limit of normal of 50% and others 54%. If you are a
midshipmen on the USS Eisenhower, one of our nuclear
aircraft carriers, the upper limit of normal for hematocrit in
their lab is 60% (see image 1 on next page).
These normal ranges of hematocrit are for men 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.
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. Testosterone decreases plasma
concentrations of pro coagulatory substances and reduces
levels of lipoprotein a. Testosterone increases red blood cell
deformability and improves erythrocyte membrane lipid
composition and fluidity.
The donation of blood for altruistic reasons is both
necessary and commendable. It is imperative that we maintain
our blood supply as every two seconds someone in the
United States needs blood or platelets. Every day, whole
blood donations help save the lives of children and adults
fighting to survive cancer, blood disorders, traumatic injuries
and more. The American red cross allows whole blood
donation as often as every 56 days up to six times a year.
Several positive effects of blood donation have been
described in the medical literature including feelings of
satisfaction, greater alertness, and increased well-being etc.
Minor adverse effects such as fatigue, vasovagal symptoms,
fainting and bruising can occur in some individuals. The main
concern is the development of Iron deficiency anemia which
can occur in up to 35% of repeat donors. Moderately trained
athletes may also see a decrement in performance after
whole blood donation. Maximal power output, VO2 max, and
hemoglobin mass were decreased up to four weeks after a
single whole blood donation in moderately trained people.
Beneficial training adaptations were also lowered by
repeated whole blood donations. Some athletes may want to
consider plasma donation as an alternative as it will not have
an effect on their hemoglobin levels.
Many asymptomatic men on testosterone donate blood
out of fear and not altruism. This fear is propagated by
clinics even though no randomized or prospective studies
have observed a direct relation between the testosterone
induced secondary erythrocytosis and thromboembolic
events. Some men will report that they feel better after a
blood donation and that can be secondary to several factors
in addition to what has been previously discussed. Firstly,
blood donation elicits an adrenal response. Secondly, blood
donation will decrease the anxiety and fear associated with
the increase in hematocrit . Because of repeated, and at
times unnecessary donations, men unknowingly develop an
Iron deficiency anemia and the associated symptoms of
fatigue, weakness, shortness of breath, exercise intolerance,
and rapid heart rate etc. In many instances these symptoms
will be wrongly blamed on testosterone or one of its active
metabolites such as DHT or estradiol leading to unnecessary
adjustments in dosages and levels. 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 and 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% in many men.
In contrast to asymptomatic otherwise healthy men on
testosterone, men on testosterone therapy with unknown or
known comorbid conditions such a sleep apnea, obesity,
type II diabetes etc..that develop symptoms they attribute to
increased hematocrit such as headache, dizziness, shortness
of breath, or fatigue etc...can donate blood and either stop
therapy or adjust dosage to control symptoms. Men who
develop an excessive erythrocytosis during testosterone
therapy should also be evaluated for sleep apnea, and if
diagnosed should undergo appropriate treatment so as to
better tolerate a therapeutic dose of testosterone.
Testosterone therapy should be based on clinical effect and
therapeutic response while avoiding unwanted side effects.
Testosterone therapy was first used clinically in the mid
1930’s 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.
Keith Nichols MD
