Side Effects of Testosterone Therapy

Share on FacebookTweet about this on TwitterShare on StumbleUponShare on RedditPin on Pinterest

Testosterone replacement therapy (TRT) is usually well tolerated as long as testosterone is kept within normal, physiologic levels. Side effects of testosterone therapy are generally mild. However, it is important for you and your physician to be aware of the following potential side effects. Many of the side effects may be mitigated by avoiding the most common testosterone replacement mistakes and by following-up regularly with your physician.

Also, it should be noted that the FDA has recently decided to require manufacturers to include labeling that informs patients about the possible increased risk of heart attacks and stroke in patient taking testosterone.



Side Effects of Testosterone Therapy

1. Increased Levels of Red Blood Cells

Side Effects of Testosterone Therapy

One of the potential side effects of testosterone therapy is an increase in red blood cell count beyond what is healthy for the body. Testosterone promotes the synthesis of red blood cells. Thus, taking exogenous testosterone increases red blood cell count.

Red blood cells contribute to the viscosity of blood. More red blood cells lead to thicker, more viscous blood. In certain cases, red blood cell count may become too high, leading to overly viscous blood. Overly viscous blood increases your risk of forming blood clots, which can subsequently lead to a heart attack and/or stroke.

A measure of your red blood cell count can alert your physician of this problem. Your doctor can then correct the problem by temporarily interrupting the dose, changing the method of administration, or performing a simple withdrawal of blood, if necessary. It is important to note that injectable testosterone is more likely to cause an increased red blood cell count than any of the other forms of testosterone.1-4 Men using injectable testosterone should be vigilant in monitoring for this particular problem. Lowering the injectable dosage and shortening the time between injections may potentially reduce the possibility of this side effect.

2. Worsening of Sleep Apnea.

Testosterone therapy may increase your odds of getting sleep apnea, or it may worsen sleep apnea if you already suffer from the disease.5-7 Sleep apnea is a serious condition that causes you to lose oxygen supply intermittently while you sleep. It is important to know the signs of sleep apnea and report them to your doctor both before starting therapy and after beginning therapy.

3. Infertility

HCG and Testosterone

Testosterone therapy suppresses the natural production of testosterone by the testes. Since sperm production requires high levels of testosterone within the testes and TRT suppresses testosterone production by the testes, TRT reduces sperm production. In most men, it reduces sperm production to levels below what is necessary for fertility. As a result, most men on testosterone therapy are infertile. Diminished testicular size also may occur because of the down-regulation of the gonadotropins.

While this side effect may not concern certain men, men looking to conceive a child or remain fertile must be aware of this potential side effect of TRT. While infertility is usually reversible, the testosterone dosage must either be decreased or TRT must be stopped all together.4

Men looking to maintain fertility may discuss adding human chorionic gonadotropin (HCG) to their TRT regimen with their physician. In men, HCG stimulates testosterone production by the testes, leading to sperm production.

4. Gynecomastia

One of the more unappealing potential side effects of testosterone therapy is gynecomastia. Gynecomastia is male breast enlargement due to benign (non-cancerous) breast tissue growth. While it is benign, it is aesthetically unappealing. It is related to aromatization of testosterone into estradiol in peripheral fat and muscle tissue. This aromatization causes the breast tissue to swell. Unfortunately, medical treatment of gynecomastia that has persisted beyond a year is often ineffective.

Gynecomastia Final

5. Small Decrease in HDL Cholesterol

Testosterone therapy may adversely affect cholesterol levels, slightly lowering HDL cholesterol and slightly raising LDL cholesterol. Most cases of adverse affects to cholesterol deal with supraphysiological doses of testosterone, not replacement doses. Therefore, the risk of cholesterol related side effects of testosterone therapy is modest.

6. Fluid Retention in the Extremities

Fluid retention may occur in the arms and legs at the beginning of therapy. It generally resolves after the first few months of treatment.


FDA Statements on Side Effects of Testosterone Therapy

In 2014 and 2015, the FDA released statements on testosterone replacement therapy. The first statement released on January 31st, 2014 said that it is investigating the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products. This statement was in response to two observational studies that observed an increased risk of stroke and heart attack in men on testosterone therapy.8,9

On March 3rd, 2015, the FDA released a follow-up statement to its initial 2014 statement. This statements states the that testosterone replacement therapy is only for men with low testosterone levels due to certain medical conditions. It also requires manufacturers to add labeling to inform patients about the possible increased risk of heart attacks and stroke in patient taking testosterone. The FDA statement includes the following summary:

“The U.S. Food and Drug Administration (FDA) cautions that prescription testosterone products are approved only for men who have low testosterone levels caused by certain medical conditions. The benefit and safety of these medications have not been established for the treatment of low testosterone levels due to aging, even if a man’s symptoms seem related to low testosterone. We are requiring that the manufacturers of all approved prescription testosterone products change their labeling to clarify the approved uses of these medications. We are also requiring these manufacturers to add information to the labeling about a possible increased risk of heart attacks and strokes in patients taking testosterone. Health care professionals should prescribe testosterone therapy only for men with low testosterone levels caused by certain medical conditions and confirmed by laboratory tests.”

Interestingly, a new meta-analysis (Testosterone Therapy and Cardiovascular Risk: Advances and Controversies) in the Mayo Clinic Proceedings published during this FDA review says there is no evidence of increased cardiovascular risks. This meta-analysis is the largest to date, and it revealed no increase in cardiovascular risks in men who received testosterone. It also revealed reduced cardiovascular risk among those men with metabolic disease. This analysis contradicts the findings of the two studies that led the FDA to begin a review of the risk of cardiovascular disease side effects of testosterone therapy.10

Currently, there is no clear consensus on the whether or not testosterone therapy increase the risk of heart attack or stroke.



Contraindications of Testosterone Therapy

In certain situations, testosterone therapy should not be initiated or continued. The Endocrine Society Clinical Practical Guidelines detail the conditions in which testosterone administration is associated with a high risk of adverse outcome and in which testosterone should not be administered:11

Very high risk of serious adverse outcomes
Metastatic prostate cancer
Breast cancer
Moderate to high risk of adverse outcomes
Unevaluated prostate nodule or induration
PSA >4 ng/ml (>3 ng/ml in individuals at high risk for prostate cancer, such as African-Americans or men with first-degree relatives who have prostate cancer)
Hematocrit >50%
Severe lower urinary tract symptoms associated with benign prostatic hypertrophy as indicated by AUA/IPSS >19
Uncontrolled or poorly controlled congestive heart failure


Other Potential Concerns Regarding Testosterone Therapy

1. TRT does not appear to cause or worsen prostate cancer.

For years, physicians have worried that one of the potential side effects of testosterone therapy would be the causing or worsening of prostate cancer. Fortunately, most studies agree that testosterone does not induce a development of malignant prostate cells.12-15 Furthermore, most studies have found no relation between testosterone levels and the likelihood of developing prostate carcinomas.5,6,16,17

Current available information suggests that even men with prostate cancer can safely be treated with TRT, although the Endocrine Society’s Guidelines do not recommend administering therapy to men with metastatic prostate cancer.4 Nevertheless, more long-term studies are necessary to fully understand side effects of testosterone therapy on the prostate.

2. TRT does not cause benign prostatic hyperplasia (BPH).

Testosterone therapy may increase the prostate’s size, but the evidence shows that it does not cause or worsen symptoms of benign prostatic hyperplasia (BPH). The increase in the prostate typically occurs in the first six months and is relative to the amount of testosterone taken. The increase in size of the prostate usually is equivalent to that of men with normal testosterone levels. Fortunately, the increase in size does not typically increase urinating problems.18,19 Urine flow rates, post-urinating residual urine volumes, and prostate voiding symptoms, however, do not change significantly.18,19

Final Notes

As can be seen, it is important to understand that like any prescription-based therapy potential side effects of testosterone therapy exist. Nevertheless, side effects are generally mild as long as testosterone is kept within normal, physiologic levels. Keeping testosterone levels comes down to your physician and you. Your physician is responsible for designing a regimen and continually following-up on your progress. You are responsible for following the regimen and following up with and providing feedback to your physician. Ultimately, treatment comes down to the individual’s personal problems with low testosterone.


EMG’s TRT Homepage: Testosterone Replacement Therapy

External Resources:

Updated: April 22nd, 2015

1. Claustres M, Sultan C. Androgen and erythropoiesis: evidence for an androgen receptor in erythroblasts from human bone marrow cultures. Horm Res. 1988; 29 (1): 17-22.

2. Drinka PJ, Jochen AL, Cuisinier M, Bloom R, Rudman I, Rudman D. Polycythemia as a complication of testosterone replacement therapy in nursing home men with low testosterone levels. J Am Geriatr Soc. Aug 1995; 43 (8): 899-901.

3. Jockenhövel F, Vogel E, Reinhardt W, Reinwein D. Effects of various modes of androgen substitution therapy on erythropoiesis. Eur J Med Res. Jul 1997; 2 (7): 293-298.

4. Miner MM. Low Testosterone Medscape CME Expert Column Series. Issue 3: Delivering Safe and Effective Testosterone Replacement Therapy. Medscape Education. 2011.

5. Sandblom RE, Matsumoto AM, Schoene RB, et al. Obstructive sleep apnea syndrome induced by testosterone administration. N Engl J Med. Mar 1983; 308 (9): 508-510.

6. Schneider BK, Pickett CK, Zwillich CW, et al. Influence of testosterone on breathing during sleep. J Appl Physiol. Aug 1986; 61 (2): 618-623.

7. Liu PY, Yee B, Wishart SM, et al. The short-term effects of high-dose testosterone on sleep, breathing, and function in older men. J Clin Endocrinol Metab. Aug 2003; 88 (8): 3605-3613.

8. 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.

9. Finkle, WD, Hoover, RN, et al. Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men. PONE. January 29, 2014.

10. Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clinic Proceedings. 2015; 90 (2): 224-251.

11. Bhasin S, Cunnigham GR, Hayes FJ, Matsumoto AM, Synder PJ, Swerdloff RS, Montori, VM. Testosterone Therapy in Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2010, 95 (6): 2536 –2559.

12. Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of serum androgen levels in men with and without prostate cancer. Prostate. Jul 1995; 27 (1): 25-31.

13. Slater S, Oliver RT. Testosterone: its role in development of prostate cancer and potential risk from use as hormone replacement therapy. Drugs Aging. Dec 2000; 17 (6): 431-439.

14. Heikkilä R, Aho K, Heliövaara M, et al. Serum testosterone and sex hormone-binding globulin concentrations and the risk of prostate carcinoma: a longitudinal study. Cancer. Jul 1999; 86 (2): 312-315.

15. Hsing AW. Hormones and prostate cancer: what’s next? Epidemiol Rev. 2001; 23 (1): 42-58.

16. Shaneyfelt T, Husein R, Bubley G, Mantzoros CS. Hormonal predictors of prostate cancer: a meta-analysis. J Clin Oncol. Feb 2000; 18 (4): 847-853.

17. Stattin P, Lumme S, Tenkanen L, et al. High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study. Int J Cancer. Jan 2004; 108 (3): 418-424.

18. Behre HM, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol (Oxf). Mar 1994; 40 (3): 341-349.

19. Jin B, Conway AJ, Handelsman DJ. Effects of androgen deficiency and replacement on prostate zonal volumes. Clin Endocrinol (Oxf). Apr 2001; 54 (4): 437-445.