Testosterone Therapy in Men A Big-Picture Approach

Barry Wheeler, ND, ABAAHP

A recent study published in the Journal of the American Medical Association raised concerns about the safety of testosterone replacement therapy in men.¹ In particular, the observational study showed a possible increased risk of cardiovascular events, such as stroke or heart attack. If you decide that your patient needs testosterone replacement therapy (TRT), your goal should be, as always, to reduce potential risks and increase potential benefits.

Low testosterone, believe it or not, is quite prevalent in both men and women. Women produce mostly estrogen, with some of it being converted from testosterone. Men produce mostly testosterone and then convert some of their testosterone to estrogen. It is yin and yang sort of situation. The balance of those hormones will affect disease risk, as well as quality of life. The focus on this article is men, but many women experience the symptoms of low testosterone as well.

According to Osterberg and colleagues,² “Testosterone replacement therapy (TRT) is a widely used treatment for men with symptomatic hypogonadism. The benefits seen with TRT, such as increased libido and energy level, beneficial effects on bone density, strength and muscle as well as cardioprotective effects, have been well-documented.”

Testosterone replacement therapy is not a cure-all; however, for many men, low testosterone (hypogonadism) can be a major problem.³ Low testosterone can be caused by a lack of response in the testicles or by reduced signaling from the brain. Remember, estradiol acts as a negative feedback mechanism in the brain to regulate signals (luteinizing hormone and follicle-stimulating hormone) to the testicles. It is important to detect low testosterone in both old and young patients. Low testosterone will affect a boy’s development, with possible lifelong consequences, such as reduced penis size. Too much testosterone in a young male can lead to short stature by causing early closure of the growth plates.

Evaluating Hypogonadism

Elevated or high-normal levels of luteinizing hormone (LH) along with low levels of testosterone suggests primary hypogonadism, whereas low testosterone with low or low-normal LH levels suggests secondary hypogonadism. Some patients may have a combination of poor testicular function and inadequate signaling from the pituitary. “In the aging male patient, signs and symptoms of hypogonadism can include loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, and loss of muscle mass and strength.”³

Current guidelines suggest testosterone levels should be checked in the morning. As one expert suggests, “For aging men, laboratory testing should include early morning (8:00–10:00 AM) measurement of serum testosterone; levels less than 300 ng/dL clearly indicate hypogonadism, and under most circumstances benefit will be derived from testosterone replacement therapy.”³

Other experts suggest that the importance of morning measurement varies by age. For example, Harvard expert Abraham Morgentaler, MD, writes, “For years, the recommendation has been to get a testosterone value early in the morning because levels start to drop after 10 or 11 a.m. But the data behind that recommendation were drawn from healthy young men. Two recent studies showed little change in blood testosterone levels in men 40 and older over the course of the day. One reported no change in average testosterone until after 2 p.m. Between 2 and 6 p.m., it went down by 13%, a modest amount, and probably not enough to influence diagnosis. Most guidelines still say it’s important to do the test in the morning, but for men 40 and above, it probably doesn’t matter much, as long as they get their blood drawn before 5 or 6 p.m.”⁴

Personally, I have found morning checks to be unnecessary in most cases, since we can usually assume that the levels were likely higher in the morning, and by matching that information with the patient’s symptoms we can often make a diagnosis that leads to an effective treatment. Some guidelines advise repeating the testing 2 more times on separate days. Repeat testing can be helpful, especially when a patient’s symptoms are not matching up with the results, or if he is under 30 years of age.

I often see patients with low-normal testosterone and moderate symptoms. In these cases, we typically hold off on TRT and repeat the testing in 3-6 months. Typically, their levels are lower at this time, indicating that when we first tested their testosterone levels, it was in the beginning stages of a decline that could have been precipitated by age and other factors, such as stress.

Contraindications & Side Effects

According to a review by Osterberg et al,² “TRT has numerous benefits that can greatly enhance a patient’s quality-of-life. Before prescribing TRT, one must be conscientious of its adverse effects. Data on the safety of TRT specific to our aging population is not currently available; however, TRT has been linked to prostate cancer, BPH [benign prostatic hypertrophy], polycythemia and OSA [obstructive sleep apnea]. A full assessment of the morbidity of TRT would require a large-scale, randomized, controlled trial. To date, physicians remain in a quandary about the best approach to care for men with symptoms of hypogonadism. TRT, when given to appropriately selected patients with vigilant monitoring … can bring improvements in quality-of-life, energy level, libido, muscle mass, cognition and bone density.²

TRT is contraindicated in men with untreated prostate and breast cancer. Men on TRT should be monitored for side-effects such as polycythemia, peripheral edema, cardiac and hepatic dysfunction.”²

Besides checking testosterone levels, basic clinical guidelines advise doing a prostate exam, reviewing prostate symptoms, and running lab tests for lipids and hematocrit. Known absolute contraindications to testosterone replacement therapy are prostate cancer, breast cancer, an elevated hematocrit (55% or greater), or a sensitivity to the medication. There are some other relative contraindications, such as severe, untreated sleep apnea, genetic mutations (eg, Factor V Leiden) that increase the risk of clotting, and liver disease that impairs a patient’s ability to process the medication.

I have diagnosed and treated several thousand male patients since graduating from naturopathic medical school 5 years ago. Based on my experience and recent studies, there are 3 main issues that I advise doctors working at my clinics to keep a close eye on:

1. Excessive erythrocytosis
2. Hyper-aromatization
3. Testicular shrinkage

Potential side-effects from TRT include increased risk of blood clotting, fluid retention/swelling, decreased fertility and reduction in testicle size, breast enlargement, hair loss, acne, mood swings, worsening of sleep apnea, prostate enlargement, and changes in liver function.⁵ Most of these side effects are due to too much conversion of testosterone to estradiol (hyper-aromatization) or excessive erythrocytosis (secondary polycythemia).

Secondary Polycythemia

Testosterone replacement therapy stimulates erythropoietin, leading to increased production of hemoglobin and a higher hematocrit.⁶ Iron levels in red blood cells will likely decline, not increase, due to increased iron utilization. Increased red blood cell production increases the blood’s viscosity. Thicker blood will lead to more wear and tear on the plumbing (blood vessels) and increase strain on the heart. Thicker blood can also increase the risk of a stroke or blood clot developing. There are certainly other factors affecting blood viscosity, such as hydration and genetics.

Some clinical guidelines suggest that a patient discontinue TRT if his hematocrit reaches 55%. I like to see the hematocrit around 45%. In patients with a low-normal hematocrit, I am less concerned about polycythemia, but we still monitor them, usually by checking their hematocrit 6 weeks after starting TRT and then again 6 weeks later, and so on, as indicated. In patients with a high-normal hematocrit and low testosterone, it is likely that their hematocrit will increase further. In these patients, it is important to attempt to rule out any potential causes of polycythemia and consider holding off on TRT, or monitoring more closely for increases in hematocrit.

I often advise patients to donate blood regularly to prevent secondary erythrocytosis. Donating blood benefits others, as well as the patient by decreasing blood viscosity. Once the hematocrit is elevated or if the patient has a condition or reason that he cannot donate blood to others, you might write a prescription for therapeutic phlebotomy. Keep in mind that some blood centers will not let patients donate blood again after they receive a therapeutic phlebotomy, so it is important to discuss this with your patients. I have had a few male patients who donated blood regularly at a certain blood bank, but after doing therapeutic phlebotomy there, they were put on a list of unacceptable donors. This was upsetting to a few patients; they were able to get this off this list, but the process wasn’t easy.

According to gerontologist, J. Lisa Tenover,⁷ “The increase in oxygen-carrying capacity that results from the increased hemoglobin levels may contribute to the decrease in fatigue and improved energy levels reported by some men on testosterone therapy. In other instances, however, the increases in hemoglobin and hematocrit have been great enough to necessitate termination of therapy, phlebotomy, or a significant decrease in testosterone dose. Although coexisting sleep apnea or large body mass may contribute to the development of polycythemia, they have not done so in many cases. A greater increase in hemoglobin levels seems to occur with the injectable testosterone esters and implantable pellets, and may correlate with peak serum testosterone level.”⁷

Many patients that come to see me have tried topical testosterone and initially felt better, but reported that the benefits then seemed to decline over time. This may be due to excessive use of the topical testosterone or poor absorption. Topical testosterone tends to travel more through the lymphatic system than the blood, hence monitoring patients on topical testosterone can be difficult. There is also the risk of transfer to others via physical contact. Furthermore, even after discontinuing topical testosterone, the remaining testosterone that has accumulated in their skin may keep their levels increased for weeks after stopping TRT. Testosterone injections are easy to monitor in the blood and are almost completely out of the patient’s system after 2-4 weeks of an injection, depending on the dose.

Testosterone injections may be more likely to increase the hematocrit and hemoglobin because the levels peak for a few days after the injection. Most doctors give a patient 200 mg testosterone cypionate IM every 2 weeks, and some may even give 400 mg once a month! The problem with this approach is that the male body normally produces about 5-10 mg of testosterone daily, but only at around 25 years of age. A bolus dose of 400 mg will lead to ultra-supraphysiologic levels the first week, and possible low levels by the fourth week. The resulting super-high levels following the injection are likely to exacerbate any side effects.

In my clinics, we typically start men on much more conservative doses that are given weekly (about 100 mg per week). This reduces potential side effects from elevated testosterone levels, and if a side effect does develop, the medication will leave their systems more quickly.

Hyper-Aromatization

As mentioned, testosterone converts to estrogen via the aromatase enzyme. Some doctors treat men with low testosterone and never check their estradiol levels. My goal in men on testosterone therapy is to get their blood estradiol level between 20 and 30 pg/mL. Young men typically have a testosterone:estradiol ratio of 50:1, but the ratio in healthy older men may be as low as 20:1.⁸ In my opinion, the ratio of total testosterone to estradiol should ideally be between 20:1 and 50:1.

While increased estrogen and decreased testosterone in a man may please some spouses by making their partners more “sensitive,” there are many health risks associated with elevated estrogen (particularly estradiol) levels. Estradiol is known to increase blood coagulation in both men and women. Increased levels of estradiol may thus increase the risk of a stroke or deep vein thrombosis (DVT).⁹ This is not the case with testosterone. Animal studies suggest that too much estradiol may also impair the ability of the penis to maintain erections.¹⁰ This highlights how increasing a man’s testosterone levels without simultaneously addressing his estrogen levels can lead to unintended outcomes.

After screening a large number of men for levels of testosterone and estradiol, investigators Tan et al¹¹ stated, “Testosterone replacement improves quality of life and is aromatized in men in adipose tissues to estrogen. Hyperestrogenism is believed to be harmful to male sexuality. This is a description of our experience of screening 34,016 men in the Low T Centers, of which approximately 50% were converted to treatment … It was observed that practitioners used aromatase inhibitor and selective estrogen receptor modulator to treat symptoms of hyperestrogenism, irrespective of blood estradiol levels. Gynecomastia was rarely documented as a reason for the prescription. Our finding was that high estradiol levels were not associated with higher rates of low libido but established higher rates of documented low libido with those with normal or lower estradiol levels.”¹¹

On the flip side, low levels of estrogen can lead to problems with erections, bone and cartilage health, and other problems.¹² Keeping estrogen balanced will help keep testosterone levels balanced as well. By reducing the conversion of testosterone to estradiol, levels of testosterone will be better maintained, with less drop-off.¹³ Patients with Factor V Leiden and other blood coagulation disorders may be even more sensitive to increases in estradiol levels and consequently be more prone to DVT and increased clotting.^14,15

Conclusion

Testosterone therapy has potential risks and benefits. While testosterone therapy may reduce the risk of myocardial infarction,¹⁶ it may also increase risk of abnormal blood clotting. A holistic approach to testosterone therapy takes into account the other hormones that are affected by testosterone in the body. While there continues to be new research supporting this approach, it is still a developing field. Physicians should be aware of the potential side effects of testosterone therapy and how best to address them.

 References:

1. Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-1836.
2. Osterberg EC, Bernie AM, Ramasamy R. Risks of testosterone replacement therapy in men. Indian J Urol. 2014; 30(1):2-7.
3. Carnegie C. Diagnosis of hypogonadism: clinical assessments and laboratory tests. Rev Urol. 2004;6 Suppl 6:S3-S8.
4. A Harvard expert shares his thoughts on testosterone-replacement therapy: An interview with Abraham Morgentaler, M.D. Originally published March 2009; last reviewed February 18, 2011. Harvard Medical School & Harvard Health Publications Web site. http://www.harvardprostateknowledge.org/a-harvard-expert-shares-his-thoughts-on-testosterone-replacement-therapy. Accessed August 1, 2014.
5. Myers JB, Meacham RB. Androgen replacement therapy in the aging male. Rev Urol. 2003;5(4):216-226.
6. 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. 2014;69(6):725-735.
7. Tenover JL. The androgen-deficient aging male: current treatment options. Rev Urol. 2003;5 Suppl 1:S22-S28.
8. Giampapa VC., Breaking the Aging Code: Unlock the Tremendous Potential for a Longer, Healthier Life Stored Within Your Genes. Basic Health Publications, Inc, 2003.
9. Holmegard HN, Nordestgaard BG, Schnohr P, et al. Endogenous sex hormones and risk of venous thromboembolism in women and men. J Thromb Haemost. 2014;12(3):297-305.
10. Kataoka T, Hotta Y, Ohno M, et al. Limited effect of testosterone treatment for erectile dysfunction caused by high-estrogen levels in rats. Int J Impot Res. 2013;25(6):201-205.
11. Tan RS, Cook KR, Reilly WG. High Estrogen in Men After Injectable Testosterone Therapy: The Low T Experience. Am J Mens Health. 2014 Jun 13. pii: 1557988314539000. [Epub ahead of print]
12. Funder JW. The multiple actions of testosterone in men: nature knows best. Asian J Androl. 2014;16(2):266-267.
13. Mechlin CW, Frankel J, McCullough A. Coadministration of anastrozole sustains therapeutic testosterone levels in hypogonadal men undergoing testosterone pellet insertion. J Sex Med. 2014;11(1):254-261.
14. Glueck CJ, Richardson-Royer C, Schultz R, et al. Testosterone, thrombophilia, and thrombosis. Clin Appl Thromb Hemost. 2014;20(1):22-30.
15. Glueck CJ, Goldenberg N, Budhani S, et al. Thrombotic events after starting exogenous testosterone in men with previously undiagnosed familial thrombophilia. Transl Res. 2011;158(4):225-234.
16. Baillargeon J, Urban RJ, Kuo YF, et al. Risk of Myocardial Infarction in Older Men Receiving Testosterone Therapy. Ann Pharmacother. 2014;48(9):1138-1144.

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Barry Wheeler, ND, ABAAHP, is a licensed naturopathic doctor in the states of Washington, Oregon, and California, and is certified by the American Board of Anti-Aging Health Practitioners in Anti-Aging and Regenerative Medicine. He attended and graduated from Oregon State University, majoring in biology and International Studies, and the National College of Natural Medicine (NCNM). He currently works at Revive Low-T Clinic in Bellevue, Washington.