Q&A: Best Practices for Managing Low Testosterone in Men With Erectile Dysfunction

Course Director

Richard Sadovsky, MD

Richard Sadovsky, MD
State University of New York
Downstate Medical Center
Brooklyn, New York


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Overview

Male hypogonadism is an endocrine disorder characterized by testosterone deficiency due to testicular dysfunction, pituitaryÔÇÉhypothalamic dysfunction, or aging. Despite a significant burden on patients, male hypogonadism is often under-recognized. Symptoms are often nonspecific, challenging physicians to identify patients at risk of male hypogonadism. Erectile dysfunction that is refractory to standard treatment is often a hallmark symptom.


Disclosures

This activity is supported by an educational grant from AbbVie. Additional support provided by Penn State College of Medicine and Answers in CME.

Course Director
Richard Sadovsky, MD, has a financial interest/relationship or affiliation in the form of:
Consultant for Eli Lilly and Company.
Medical Director
Annette Wiggins
Answers in CME, Inc.
Annette Wiggins currently has no financial interests/relationships or affiliations in relation to this activity.

Answers in CME staff who may potentially review content for this activity have disclosed no relevant financial relationships.

Penn State College of Medicine staff and faculty involved in the development and review of this activity have disclosed no relevant financial relationships.

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How often is erectile dysfunction (ED) associated with low testosterone?

Dr. Sadovsky: Normal erectile function is mainly a neurovascular event; there are neurologic impulses that help to cause vasodilation and there's an increase in vascular flow. However, this is occurring in a milieu of both a psychologic as well as a hormone environment—and that hormone environment involves the amount of testosterone that's circulating in the male patient.

So, if you find that you have a man whose complaint is truly erectile dysfunction and you’ve tried treating him with one of the medications that are used—most commonly PDE5 inhibitors that help to promote vasodilation and increase vascular flow—and that medication doesn’t give a satisfactory response, the first step would probably be to educate the patient about how to use the medication properly, how to have better sexual activity, and perhaps even change the PDE5 inhibitor. However, if all these don't work, then certainly looking at the hormonal environment by quantitating the testosterone may be very useful. The testing that's generally used to help to identify men with low testosterone [who] have erectile dysfunction would be doing a total testosterone; doing a free testosterone and/or a sex hormone-binding globulin level may be useful if the total testosterone is borderline.1 However, if a person falls in the ranges that have been established by The Endocrine Society, notably normal testosterone being 350 ng/dL or above, and a low testosterone being 250 ng/dL or below, then additional testing is not needed. I know many urologists do [measure] the testosterone [levels] when the patient with erectile dysfunction comes into their office for the first time; many primary care doctors are waiting and not testing testosterone [levels] unless the patient already has low libido or if they fail one of the classical treatments.

Narrator: Other typical signs and symptoms of hypogonadism, such as hot flushes, loss of body hair, sleep disturbances, or reduced muscle bulk or strength should also prompt clinicians to test patients’ testosterone levels.1

Dr. Sadovsky: Of course, various situations can cause transient elevations or declines in testosterone: Malnutrition, a viral infection, stress. So, we do recheck the total testosterone twice before we make a conclusion about the testosterone level. Other indications for testing the man with erectile dysfunction for testosterone would be some of the other classical signs or symptoms of low testosterone. Those would include fatigue, depression or mood swings, but also some of the more common medical problems—we're starting to see that [the] metabolic syndrome; increasing weight; cardiovascular risk factors, such as hypertension, dyslipidemia or increased abdominal girth, all seem to be associated with low testosterone.

If your patient with erectile dysfunction fails to improve in terms of his erections with classical treatment and has low testosterone, there are several studies that have been published in the Journal of Sexual Medicine that point out that these resistant-to-treatment ED patients may improve if you normalize their testosterone level.2-4 Some of our patients who are true treatment failures, who also have low testosterone, will clearly benefit from testosterone replacement.

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I have a patient with multiple comorbid conditions, including coronary artery disease, hypertension, dyslipidemia, and elevated PSA. He is experiencing reported erectile dysfunction but has not responded to therapy with PDE5 inhibition. He was subsequently found to have low testosterone levels. How should this patient be managed?

The rationale for testosterone replacement therapy would be that if you improve the hormonal milieu for this patient who you're treating for erectile dysfunction with PDE5 inhibitors, the PDE5 inhibitors may work more effectively.4 The current recommendations for testosterone replacement therapy are that you try and reach a normal level—so you have to retest the patient so that you are certain that you're not overshooting and making him supraphysiologic, with markedly elevated testosterone levels. This causes a higher risk of side effects or complications.

Now the question specifically asks about patients with multiple comorbid conditions. Let's look first at the cardiovascular-risk conditions of coronary artery disease, hypertension, and dyslipidemia. [For patients] with those conditions, most of them are stable; most of them have not had recent coronary events and most of them are able to ambulate and don't show signs of stage 3 or stage 4 congestive heart failure. So, these men can be treated to a normal level of testosterone.1 We generally aim at a normal range, so 500-800 ng/dL.1 And once we achieve that level, hopefully the man will have better erections.

Now, when do we have to be cautious in these patients with multiple comorbid conditions? Well, certainly with respect to erectile dysfunction, we know that [for] men who have severe congestive heart failure, men who have an unstable arrhythmia, [and] men who have documented coronary artery disease with a recent coronary event, we have to be very careful about the PDE5 inhibitors.5-7 And equally, we may want to be careful about giving testosterone supplementation to these particular men.1

Treating the man with an elevated PSA is a little bit different. The evaluation of an elevated PSA is a controversial topic—an elevated PSA above 2.5 [ng/mL] may require further evaluation [depending on the clinical situation]: A digital rectal exam, perhaps a referral to a urologist to consider doing a biopsy or some type of ultrasound exam or even an MRI.1 It's very important before you give testosterone to try and rule out even a subclinical bit of prostate cancer tissue because, if you give testosterone when there is prostate cancer present, you run the risk of enlarging that prostate cancer. However, there's data that shows that testosterone does not cause prostate cancer de novo.8,9 So, we have to be careful with men who have elevated PSAs: Do routine screening that you would for prostate cancer and, if you have any question, send the patient to a urologist for further evaluation.

The potential risks associated with testosterone replacement therapy in combination with ED treatment include polycythemia, worsening of COPD, worsening of [the patient’s] lipid profile, and a decrease in sperm production.

Narrator: In a systematic review of 19 randomized trials to determine the risks of adverse events associated with testosterone therapy in older men, rates of prostate cancer, PSA >4 ng/mL, and prostate biopsies were higher in the testosterone group than in the placebo group, although differences between groups were not statistically significant. Testosterone-treated men were nearly four times more likely than placebo-treated men to experience hematocrit above 50%. The frequency of cardiovascular events, sleep apnea, or death did not differ significantly between groups. In addition, a separate meta-analysis has found insignificant changes in major lipid fractions.1

Dr. Sadovsky: There was one article published in the New England Journal of Medicine that reported that in [a study of] men who were pretty frail, if you gave them testosterone, they turned out to have a more frequent development of coronary artery disease risk factors and even symptomatic coronary artery disease than a similar control group.10 This particular study is the only study that's shown that testosterone in a patient population with comorbid conditions, such as coronary artery disease or hypertension or dyslipidemia, might be harmed by testosterone. We're waiting for the results of longer-term studies, but the current opinion is that if you have a man who you're treating with PDE5 inhibitors for erectile dysfunction and he is rather frail and has multiple comorbid conditions for coronary artery disease, or he has full-blown metabolic syndrome, then testosterone replacement therapy can still be used if he's hypogonadal—but you would shoot for a low-normal testosterone level on retest. So, instead of shooting for a testosterone level of 500-800 ng/dL, you may want to shoot for a testosterone level between 350-500 ng/dL.

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What is the best way to manage low-to-normal testosterone levels in a 47-year-old man who has decreased libido and ED? He is concerned about the risk of future prostate cancer related to testosterone replacement therapy.

Dr. Sadovsky: It's very important to talk with all of your male patients about what their goals are and find out whether their goals are realistic, and try and help them arrive at realistic goals before you start treatment. If they expect to have an interest in sex eight times a day and they want to have eight erections a day, that's unlikely to happen. So, it's helpful to try and tease out which of these problems may have come first. It's possible that the primary problem is decreased libido and the erectile dysfunction is coming as a result. Then, of course, erectile dysfunction continuously can decrease the libido of a particular man.

So, let's say you have found out that the decreased libido has been going on for a long time and the ED is relatively new. Then you may want to try replacing testosterone first for this particular man, trying to reach a normal physiologic testosterone level of 500-800 ng/dL on retest. There are several different modalities for augmenting testosterone, and they include creams, gels, and lotions; there are patches; there are injections; there are pellets that go under the skin and that go between the buccal mucosa and the cheek, twice a day.

These are all thought to be [largely] interchangeable in terms of their side effects, risks, and benefits [when used correctly]. The main issue is to watch the testosterone level after treatment, and you have to check that at an appropriate time.

Narrator: When monitoring patients receiving testosterone replacement therapy, please refer to the recommendations set forth by the The Endocrine Society. When testosterone is measured, it is suggested to be measured in the morning.1

Dr. Sadovsky: So, it's really the testosterone level that you've achieved that's really going to determine whether the patient's a little bit more at risk for developing an adverse event from the administration of testosterone. One might be a little more careful with injections because injections are a little more likely to develop a supraphysiologic level of testosterone immediately following the injection. Then, if the man continues to have erectile dysfunction after you’ve normalized the testosterone—and we generally do that for about three months as a trial period to see if we can replete or improve the erectile function—then adding a PDE5 inhibitor may be useful. If it's vice versa, and you think the erectile dysfunction is the more prominent problem, then you start out with a PDE5 inhibitor and then you can add testosterone if you feel that the erectile function isn't improving adequately.

Now, our question involves a middle-aged man who's concerned about the risk of future prostate cancer. And we certainly can understand that—if you look at the history [of this concern], thoughts about testosterone initiating prostate cancer are really based on a very small number of patients. And also, men can develop prostate cancer who have low testosterone, normal testosterone, and high testosterone; there's no direct correlation between the level of testosterone and the initiation of prostate cancer in any individual man.11

So, experts believe that testosterone levels are not related to the initiation of prostate cancer. Certainly it does run in families, so you need to speak to your patients—and this particular patient—about whether there's a family history of prostate cancer.1

If the man is concerned about prostate cancer, then you may want to also check the PSA and do a digital rectal exam. The exam would look for nodules and PSA would give you some idea about the size of the prostate and also give you an idea about whether the patient should be referred to a urologist for further evaluation. If you have a male patient with a normal PSA but has a strong family history of prostate cancer, especially if he's African American, you may want to send him to a urologist for further evaluation and confirmation that there's no occult nidus of prostate cancer.1

It does turn out that testosterone replacement therapy does increase the PSA slightly in all men, up about 0.5 to 0.7 [ng/dL] in the level of PSA. However, it shouldn’t increase it more than that and, if you see the rate of PSA going up rapidly, then you need to get the patient to a urologist and you need to stop the testosterone therapy.1

Now, all this being said, should patients taking testosterone replacement therapy undergo more frequent monitoring for prostate cancer? Because what if you’ve missed a small nidus of prostate cancer and then you go ahead and give the man testosterone? Well, it is possible that that nidus of prostate cancer may grow a little bit faster with the testosterone supplementation. So, we generally recommend that you do a digital rectal exam and that you do another PSA three and six months after the initiation of testosterone, and then annually, the way you would with any other patient.1 Please discuss this all with your patient. Your patient needs to be informed and prepared to monitor for potential side effects. Most of us have been giving testosterone to these men for many years. The development of prostate cancer has not increased in this population and careful monitoring really does the job.

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References

  1. Bhasin S et al. J Clin Endocrinol Metab. 2010;95:2536-2559.
  2. Yassin AA, Saad F. J Sex Med. 2007;4:497-501.
  3. Reyes-Vallejo L et al. J Sex Med. 2007;4:1757-1762.
  4. Khera M et al. J Sex Med. 2011;8:3204-3213.
  5. Viagra (sildenafil) Prescribing Information. http://www.pfizer.com/files/products/uspi_viagra.pdf. Accessed August 9, 2013.
  6. Levitra (vardenafil) Prescribing Information. http://www.bayerresources.com.au/resources/uploads/PI/file9359.pdf. Accessed August 9, 2013.
  7. Adcirca (tadalafil) Prescribing Information. http://pi.lilly.com/us/adcirca-pi.pdf. Accessed August 9, 2013.
  8. Isbarn H et al. Eur Urol. 2009;56:48-56.
  9. Traish AM et al. Am J Med. 2011;124:578-587.
  10. Basaria S et al. N Engl J Med. 2010;363:109-122.
  11. Kaplan AL, Hu JC. Urology. 2013;82:321-326.

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