Michael Kleerekoper, MD, MACE, has joined the faculty at the University of Toledo Medical School where he is Professor in the Department of Internal Medicine and section chief of the Endocrinology Division. The author of numerous journal studies, Dr. Kleerekoper serves on the editorial boards for Endocrine Today, Endocrine Practice, Journal of Clinical Densitometry, Journal of Women's Health, Osteoporosis International and Calcified Tissue International. Dr. Kleerekoper is also a founding board member of the newly formed Academy of Women’s Health.

Testosterone replacement for male hypogonadism

I noted in an earlier blog that I have prescribed clomiphene citrate for men with hypogonadotropic hypogonadism — low testosterone without a compensatory increase in gonadotropins or an elevated prolactin — with good clinical success. However, I have experienced some hassle getting this “female fertility drug” approved by insurance carriers, and I am prescribing it for off-label use. When it is effective, it has the singular advantage of being a once-daily or every-other-day oral medication.

Testosterone itself is available as either a transdermal preparation or an intramuscular injection. There is also a buccal preparation, but I have only prescribed it a few times since the patients were not fully satisfied with this unusual means of taking a medication. It is effective but patient preference plays a big role in our prescribing habits. Recently, I have received flyers about a long-lasting (three months) testosterone pellet, but I have no experience with it.

There are several preparations of both transdermal and injectable testosterone. I find that most insurance carriers only cover one of the transdermals but cover each of the injectables. To a great extent, the choice between transdermal and injectable is governed by patient preference with most initially opting for transdermal.

What’s the difference?

In the long term, I do not think there is any difference in outcome. Patients feel better, have more energy and tend to lose weight.

In the short term, patients prefer the idea of being able to apply the therapy themselves rather than have to go to their doctor’s office for an intramuscular injection every two weeks. That said, they seem to do better with the injectable. The levels of testosterone achieved within 24 to 72 hours of the injection are supraphysiologic and the patient can quickly detect the effectiveness of therapy. Over time, anywhere from 10 to 21 days, they can detect the effects are wearing off, and I use this as a guide to spacing the doses. With the transdermals, the levels attained are in the middle of the physiologic range, and there is a considerable delay in recognizing the benefits, sometimes a matter of months.

Most often, I recommend that patients started on intramuscular testosterone switch to the transdermal after a few months, and many, probably most, adjust to this quite comfortably. Conversely, patients started on transdermals who are not satisfied because they are not noting any clinical benefit can be switched to an intramuscular regimen for a short time. I am somewhat surprised that many such patients do not want to go back to the transdermal.

The FDA has recently released a warning notice that transdermal testosterone can be absorbed by others who come in direct contact with the area of the skin to which the gel has been applied. That makes common sense, but we need to make sure our patients know about it and that they wash their hands thoroughly with soap and water after they have applied the gel. That seems obvious, but please take the time to tell the patient.

Transdermal testosterone patches are available, and this obviates the issue. However, the patches have some tendency to come off during the day, and some may cause skin irritation. This latter is usually easily overcome by putting a small amount of over-the-counter cortisone cream on the skin before applying the patch over it. This does not seem to dampen the effectiveness of the patch. The clinical response is very similar to that achieved with the gel, but the patch is often quickly discarded if this is the patient’s first choice.

What about monitoring therapy?

Prevalence of prostate cancer is lower in hypogonadal men compared with eugonadal men and prostate-specific antigen levels in untreated patients are usually quite low. The level will increase with hormone therapy but infrequently exceeds the upper limit of the reference interval. There is no clear evidence that testosterone replacement is associated with an increased incidence of prostate cancer, but PSA should be measured every three to four months. A marked increase, say a jump from 1.2 to 2.8, catches the patient’s attention but this too has not been associated with development of prostate cancer. Nonetheless, if the patient is overly concerned, don’t persist with therapy. If the PSA exceeds the upper limit, therapy should be interrupted and a urologist consulted.

In my practice, this is very uncommon. I am currently caring for a 64-year-old whose father died from prostate cancer and whose brother was recently diagnosed with it. Caution is the operative word, and he is being evaluated by a urologist every six months.

The hematocrit should be monitored as regularly as the PSA, and an elevated hematocrit is the most common reason I encounter for temporarily interrupting therapy.

The marker that gives me most grief is the HDL. I have a few patients who surprisingly have a baseline HDL in the low 20s despite longstanding hypogonadism. They are at increased baseline risk for coronary artery disease, although low HDL as a marker of heart disease risk has recently been questioned. I have discussed this with colleagues with more expertise in the management of male hypogonadism, and most do not see this as a contraindication to therapy. Sometimes experience, common sense and judgment trump knowledge.