Testosterone therapy in the hypogonadal man

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Sabine, Kliesch, MD, Department Of Urology, University Of Muenster, Muenster, Germany

I am happy to talk to you about testosterone therapy in the hypogonadal man, although it is a very, very old topic. We have a lot of experience with testosterone treatment in hypogonadal men for several decades, but in recent years new drugs and new developments have come up. In addition to the younger hypogonadal patients we very well know, the aging male was in a way detected as a hypogonadal patient positively too.

Everyone will know the symptoms of testosterone deficiency, there are some somatic parameters, either the patients tell us or we can notice when the patient presents with problems. First, the decrease of muscle strength, changes of body hair, the onset of hot flushes, fatigue, the increase of body fat, of course, problems in sexual life are often very disturbing for the patient, the loss of libido and decrease of potency. Also the well being is really impaired. There are patients with depression or depressed mood at least. And you have some laboratory parameters to determine the testosterone deficiency in the patients. You will find a low testosterone serum level. You may also notice a mild anaemia, with low red blood cells counts that are depending on the decrease of metabolism. The bone metabolism will additionally be impaired, you may have osteoporosis, even up to risk fractures for the patients, and of course, you will see changes in the prostate volume - in younger hypogonadal patients with a low prostate volume, but that may be different in the aging male. They may have benign prostatic hyperplasia although they have low testosterone levels.

For the diagnostic of the testosterone deficiency you have to take a very careful patient’s history and to ask for the possible symptoms. You have to perform a thorough clinical investigation that includes palpation of breast, testes and prostate of course, and finally you have to determine the serum total testosterone. And to determine the free, active part of testosterone, additionally you should determine the sexual hormone binding globulin. Other parameters as LH, FSH, prolactin, oestradiol are up to differential work up and are not basically mandatory.

In the aging man, up to now, it is well known that the occurrence of testosterone deficiency increases with age. So, in a group of patients older than 60 years you will have about 21% of patients with testosterone deficiency. In patients over 80 years of age, even more, up to 35%. The problem is, is it really clinically relevant?

The testosterone decreases physiologically with age, which is known since the Massachusetts Male Aging study was published in 1991. There is one very important message, especially for the aging male to have in mind; the decrease with testosterone is paralleled by the increase in SHBG, so the free part of the active testosterone is further reduced. This effect will be increased even in patients who have additional diseases. So you have here two red lines that show quite parallel the decrease of free testosterone with increasing age. The lower line determines those patients who have additional diseases. There is an effect of disease on testosterone, so the decrease of testosterone with age may be also an effect of, for example, diabetes, coronary heart diseases or something else. The same can be noticed for the SHBG. The lower line of those who are healthy and the upper line there, with even more increase of SHBG, are those patients with concomitant disease. I think that is important for the evaluation of the patient.

Finally, the indication for testosterone therapy or treatment you will have in patients that have definitely decreased testosterone serum levels, and, this is very important, clinical symptoms and signs of androgen deficiency. You will not treat the laboratory parameter only, but you will treat the patient with the symptoms.

There are some absolute and some relative contraindications you have to keep in mind. The absolute contraindication is quite clear, it is prostate cancer. That is something you have to keep in mind when you do your work up. You have to exclude prostate cancer before starting any treatment. If you find the seldom occurring male breast cancer, that is also a contraindication for any testosterone therapy. Sleep apnoea syndrome or obstructive pulmonary diseases may be enhanced by testosterone therapy and are relative contraindication. Polycythemia is something you may also observe under treatment and then you have to stop the therapy until the red blood cell counts are in the normal range again.

What do we want to reach with testosterone therapy? There is the aim, clinically defined by the international consensus published in 1992 by WHO, and I think Professor Behre and Professor Nieschlag will be of the same opinion, it is still true today: “The major goal we have for therapy is to replace testosterone levels as close to the physiologic concentrations as is possible”. This aim has not changed over the decades.

If you have this aim, which testosterone preparation should we finally use for the substitution therapy? It should be the naturally produced testosterone. It can either be chemically modified, but nowadays we use preparations that are esterified in position 17, or we change the different routes of administration.

The most prominent esters with esterification at position 17, are for example, the testosterone enanthate and the testosterone undecanoate. There are some other preparations - testosterone propionate, -cypionate and in development also -buciclate.

The different routes we have nowadays are in fact, more or less, four. There are some others I am skipping for this talk. The oral route of administration with the testosterone undecanoate, you have the intramuscular preparations, you have some subcutaneous implants and you can choose between different transdermal applications.

What are the advantages and the disadvantages of the different preparations and the different routes of administration for treatment? Testosterone only coming as capsules have to be taken several times a day to be resorbed by the lymph system and have a very, very short half life of 1.5 hours. You see here the pharmacokinetic simulations taken from the testosterone book from Nieschlag and Behre and you see that this finally is not an effective testosterone substitution because the patients will not have continuously physiological testosterone serum levels and that was our aim.

What about the intramuscular preparations? Testosterone enanthate is very well known for several years, several decades. You have to apply it every 14 to 21 days. It has a half life, a bit longer, of 4.5 days. You see here again the pharmacokinetic simulation with the different injection intervals. You see that within 2 weeks after injection you have immediately supraphysiological levels and these will decline at the end of two weeks, and after three and four weeks after injection you are in the sub-normal range. However, when you adopt the intervals of injection you will have a very, very effective testosterone substitution of male hypogonadism.

What about the drugs in development? Here you find again the testosterone undecanoate and it is about 8 to 10 years ago that the testosterone undecanoate was first injected intramuscularly that is now ready to take off for clinical practice. The testosterone buciclate was tested in clinical studies. You see that these two experimental drugs have favourable pharmacokinetics because they have a long lasting physiological concentration after application intramuscularly. Nowadays the testosterone undecanoate has shown in the clinical studies published in recent years that it will be a very effective intramuscularly applied drug for testosterone therapy with longer intervals about ten weeks for injection intervals. This is quite favourable for the patient. There are some problems of course for the aging male because you have no chance to stop the treatment immediately if necessary.

The advantages of the intramuscular testosterone therapy are that it’s safe, it is effective. The disadvantages so far are still the variations in serum levels, the regular injection for the patient, and the problems with ending the treatment.

Just a short note on the testosterone implants. They are very long lasting preparations for about six months with a favourable pharmacokinetic, very effective therapy but again, for the aging male, a bit difficult because of the long lasting effectiveness. There are several complications with the implantation, so it’s not accepted in the European area. It will be accepted of course for hypogonadal patients in those countries where you have long distances to the doctors. David Handelsman, coming from Australia, has the most experience of course with testosterone pellets implanted subcutaneously.

Very favourable, very attractive for patients and doctors at the same time, is the transdermal testosterone therapy. There are two forms, the patches or the membranes, and the gels. The patches have to be applied every day and again you see the pharmacokinetic intervals. Here you have, if you apply it every day physiological testosterone serum level. If you skip one membrane, if you don’t renew it, then the testosterone level will be immediately below the lower normal limit. There are possible side effects due to these patches with allergic skin reactions in about 25% to 30% of patients, so you have to try it, and if there are problems you have to change the treatment modality.

What about the gels? They are on the market for several years now and the clinical experiences are very good so far. Here I am presenting some data on the pharmacokinetic testosterone gel from Mrs. Wang and Mr. Swerdloff. Here you see it does not make a difference whether you apply the whole dosage on one part of the skin or if you take several parts of the skin. You will have after application of the testosterone gel within 24 hours, very normal physiological testosterone serum concentrations.

Here you see a comparison between the patches and the testosterone gel in two different concentrations. You see at the starting point before treatment that every patient was hypogonadal, and after treatment all patients have physiological normal serum levels. You get the impression that in the long run the testosterone gel seems to have a favourable pharmacokinetic level with the two preparations. The patients finally will decide because they have to report whether it works fine for them, or not. But for the pharmacokinetic and the data of the pharmacodynamics that are available, both preparations are very convenient.

One point I want to pick up is the free testosterone because of course, when you apply testosterone the metabolism will produce free testosterone. You will have free testosterone in the blood and that’s critical because everybody looks at the prostate. You see here on the middle panel on the left side that all three preparations, the patches, the gel in two different concentrations, the different dosages, will have quite normal serum free testosterone concentrations in all these patients over 90 days treatment.

With transdermal testosterone therapy we have definitely a very modern effective testosterone substitution that is safe, that is effective, and it produces physiological testosterone serum concentrations, and makes the patient, to some extent, independent from his doctor. It can be immediately stopped, and that may be an advantage, especially for the aging male. The disadvantages of course are still the costs of the treatment, the membranes or patches, the possible allergic reactions of the skin, and you have to counsel your patient very carefully, because if they use patches or gel inadequately, there may be contamination of partners or children.

Of course you have to survey your hypogonadal patients under treatment. You have to determine the testosterone levels, the red blood cell count, the PSA, and you have to ask for the well being, otherwise you’re not a good doctor. Very, very important, you have to look at the prostate to detect changes and possible effects on the prostate very early. In the first year you should do it every three months. From the second year on, intervals may become longer if there are no pathologies detected, so you can have intervals of six to 12 months. In addition, you may observe possible effects of sexuality. You will have changes in the somatic parameters, and of course you may, if osteoporosis is one of your topics, have the chance to measure changes in bone density. You will see effects there.

To summarise, what is important for the testosterone therapy in the hypogonadal man: which testosterone will be used, or should be used - the oral preparations so far are not effective. The subcutaneous implants are effective but not generally accepted. I think, for the moment, especially for the aging male, they are not that interesting. But the intramuscular and the transdermal preparations both have their advantages and some disadvantages. But we have here altogether what we consider full working preparations that we can use for the hypogonadal patient to perform a very effective and safe testosterone substitution.

Thank you.