Testosterone Replacement Therapy and Polycythemia in HIV-Infected Patients
A research letter recently published in the journal AIDS by Vorkas et al determined that testosterone use was associated with polycythemia, and intramuscular administration demonstrated a stronger association than topical (testosterone patch) use. No adverse cardiovascular or thrombotic events were observed. HIV-infected patients taking testosterone should undergo routine hematologic monitoring with adjustment of therapy when appropriate.
Polycythemia is an excessive production of red blood cells. With polycythemia the blood becomes very viscous or "sticky," making it harder for the heart to pump. High blood pressure, strokes and heart attacks can occur.
The association between testosterone replacement therapy and polycythemia has been reported for the past few years as this therapy has become more mainstream. In addition to increasing muscle and sex drive, testosterone can increase the body's production of red blood cells. This hematopoietic (blood-building) effect could be a good thing for those with mild anemia.
Although all testosterone replacement products can increase the amount of red blood cells, the study showed a higher incidence of polycythemia in those using intramuscular testosterone than topical administration (testosterone patch was the main option used -- no gels). Smoking has also been associated with polycythemia and may contribute to the effects of other risk factors.
Twenty-five patients met the criteria for polycythemia (21 male; four female). Using the number of unique patients with five clinic visits during the time frame of the study as the denominator, the estimated prevalence of polycythemia was 0.42% (95% CI 0.27-0.61). Mean hemoglobin at the time of diagnosis of polycythemia was 18.9+/-0.42 g/dl in men and 17.0+/-0.83 g/dl in women. Among the four female cases, one was diagnosed with chronic obstructive pulmonary disease (COPD) and severe pulmonary hypertension, while the other three did not have a documented explanation for elevated hemoglobin. Because of the relatively small number of female cases and the fact that the primary hypothesis is related to testosterone use, this case-control study focused on the 21 male patients.
Five of the 21 cases (24%) did not use testosterone, but had other explanations for their polycythemia: pulmonary hypertension, COPD and plasma volume contraction. In two of the 21 cases (10%) there was no documented reason for elevated hemoglobin. No cases met the criteria for polycythemia vera, and no adverse cardiovascular or thrombotic events were noted among the cases or controls.
The letter recommends that all HIV-infected patients taking testosterone should undergo routine hematologic monitoring and adjustment of testosterone dose or cessation of testosterone therapy as appropriate based on hemoglobin values. Unfortunately, no mention is made of therapeutic phlebotomy as a management strategy for this problem. Considering that stopping testosterone replacement would affect patients' quality of life and leave their hypothalamic-pituitary-gonadal axis in a dysfunctional state for weeks, months or permanently, other ways to manage polycythemia besides treatment cessation need to be discussed.
Below is an excerpt from my book, Testosterone: A Man's Guide, further detailing the prevention and management of polycythemia.
Preventing and Managing Polycythemia
It's important to check patients' hemoglobin and hematocrit blood levels while on testosterone replacement therapy. As we all know, hemoglobin is the substance that makes blood red and helps transport oxygen in the blood. Hematocrit reflects the proportion of red cells to total blood volume. A hematocrit of over 52 percent should be evaluated. Decreasing testosterone dose or stopping it are options that may not be the best for assuring patients' best quality of life, however. Switching from injectable to transdermal testosterone may decrease hematocrit, but in many cases not to the degree needed.
The following table shows the different guideline groups that recommend monitoring for testosterone replacement therapy. They all agree about measuring hematocrit at month 3, and then annually, with some also recommending measurements at month 6 after starting testosterone (it is good to remember that there is a ban on gay blood donors in the United States).
Many patients on testosterone replacement who experience polycythemia do not want to stop the therapy due to fears of re-experiencing the depression, fatigue and low sex-drive they had before starting treatment. For those patients, therapeutic phlebotomy may be the answer. Therapeutic phlebotomy is very similar to what happens when donating blood, but this procedure is prescribed by physicians as a way to bring down blood hematocrit and viscosity.
A phlebotomy of one pint of blood will generally lower hematocrit by about 3 percent. I have seen phlebotomy given weekly for several weeks bring hematocrit from 56 percent to a healthy 46 percent. I know physicians who prescribe phlebotomy once every 8-12 weeks because of an unusual response to testosterone replacement therapy. This simple procedure is done in a hospital blood draw or a blood bank facility and can reduce hematocrit, hemoglobin, and blood iron easily and in less than one hour. Unfortunately, therapeutic phlebotomy can be a difficult option to get reimbursed or covered by insurance companies. The reimbursement codes for therapeutic phlebotomy are CPT 39107, icd9 code 289.0.
Unless a local blood bank is willing to help, some physicians may need to write a letter of medical necessity for phlebotomy if requested by insurance companies. If the patient is healthy and without HIV, hepatitis B, C, or other infections, they could donate blood at a blood bank.
The approximate amount of blood volume that needs to be withdrawn to restore normal values can be calculated by the following formula, courtesy of Dr. Michael Scally, an expert on testosterone side effect management. The use of the formula includes the assumption that whole blood is withdrawn. The duration over which the blood volume is withdrawn is affected by whether concurrent fluid replacement occurs.
Volume of Withdrawn Blood (cc)=
Weight (kg) × ABV×[Hgbi - Hgbf]/[(Hgbi +Hgbf)/2]
ABV = Average Blood Volume (default = 70)
Hgbi (Hcti) = Hemoglobin initial
Hgbf (Hctf) = Hemoglobin final (desired);
So, for a 70 kg (154 lbs) man (multiply lbs x 0.45359237 to get kilogram) with an initial high hemoglobin of 20 mg/mL who needs to have it brought down to a normal hemoglobin of 14 mg/mL, the calculation would be:
CC of blood volume to be withdrawn = 75 x 70 x [20 - l4]/[(20 + l4)/2] = 75 x 70 x (6/17) = approximately 1850 cc;
One unit of whole blood is around 350 to 450 cc; approximately 4 units of blood need to be withdrawn to decrease this man's hemoglobin from 20 mg/mL to 14 mg/mL.
The frequency of the phlebotomy depends on individual factors, but most men can do one every two to three months to manage their hemoglobin this way. Sometimes red blood cell production normalizes without any specific reason. It is impossible to predict exactly who is more prone to developing polycythemia, but men who use higher doses, men with higher fat percentage, and older men may have a higher incidence.
Some doctors recommend the use of a baby aspirin (81 mg) a day and 2,000 to 4,000 mg a day of omega-3 fatty acids (fish oil capsules) to help lower blood viscosity and prevent heart attacks. These can be an important part of most people's health regimen but they are not alternatives for therapeutic phlebotomy if the patient has polycythemia and does not want to stop testosterone therapy. It is concerning that many people assume that they are completely free of stroke/heart attack risks by taking aspirin and omega-3 supplements when they have a high hematocrit.
Although some people may have more headaches induced by high blood pressure or get extremely red when they exercise, most do not feel any different when they have polycythemia. This does not make it any less dangerous.